MX2008004749A - Inhibitors of viral replication - Google Patents

Abstract

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

Description

VIRAL REPLICATION INHIBITORS Field of the Invention The present invention is concerned with compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV).

BACKGROUND OF THE INVENTION Hepatitis C virus (HCV) infection is the most common chronic blood-borne infection in the United States of America. Although the numbers of new infections have declined, the burden of chronic infection is substantial, the centers for disease control give estimated values of 3.9 million (1.8%) of personnel infected in the United States of America. Chronic liver disease is the tenth leading cause of death among adults in the United States of America and accounts for approximately 25,000 deaths annually or approximately 1% of all deaths. Studies indicate that 40% of chronic liver disease is related to HCV, resulting in 8,000-10,000 estimated deaths each year. End-stage liver disease associated with HCV is the most common indication for liver transplantation among adults. Chronic hepatitis C antiviral therapy has evolved rapidly in the last decade, with improvements significant differences in the efficacy of the treatment. However, even with combination therapy using IFN-a coated with PEG plus ribavirin, 40% to 50% of patients fail therapy, that is, they do not respond or relapse. These patients currently have no effective therapeutic alternative. In particular, patients who have fibrosis or advanced cirrhosis in liver biopsy are at significant risk of developing advanced liver complications, which include ascites, jaundice, varicial bleeding, encephalopathy, and progressive liver failure, as well as a markedly increased risk of hepatocellular carcinoma. The high prevalence of chronic HCV infection has important public health implications for the future burden of chronic disease in the United States of America. Data derived from the National Health and Nutrition Examination (NHANES III) study indicate that a large increase in the proportion of new HCV infections occurred in the last decade of the 60s in the early 1980s, particularly among people between 20 to 40 years old. age. It is estimated that the number of people with long-term HCV of 20 years or longer could be more than quadruple from 1990 to 2015, from 750,000 to more than 3 million. The proportional increase of people infected for 30 or 40 years would be even greater. Since the risk of HCV-related chronic liver disease is related to the duration of infection, when the risk of cirrhosis increases relatively for people infected for more than 20 years, this will result in a substantial increase in morbidity and mortality related to cirrhosis among infected patients between the years 1965-1985. HCV is an enveloped positive-strand RNA virus of the Flaviviridae family. The single-strand HCV RNA genome is approximately 9500 nucleotides in length and has an individual open reading frame (ORF) that encodes a single large polyprotein of approximately 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins of the virus. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A and NS5B) is carried out by means of two viral proteases. The first viral protease is cleaved at the NS2-NS3 junction of the polyprotein. The second viral protease is serine protease contained within the N-terminal region of NS3 (hereinafter referred to as "NS3 protease"). The NS3 protease moderates all subsequent cleavage events at sites downstream relative to the position of NS3 in the polyprotein (i.e., sites located between the NS3 terminus and the C terminus of the polyprotein). The NS3 protease exhibits activity both in cis, at the NS3-NS4 cleavage site and in trans, for the remaining NS4A-NS4B, NS4B-NS5A and NS5A-NS5B sites. It is believed that the NS4A protein serves multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. Apparently, complex formation between NS3 and NS4A is necessary for processing events modulated by NS3 and improves proteolytic efficiency in all sites recognized by NS3. The NS3 protease also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is an RNA-dependent polymerase involved in the replication of HCV RNA.

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BRIEF DESCRIPTION OF THE INVENTION Preferred embodiments provide a compound of formula (I): wherein: R1 is an optionally substituted aryl, an optionally substituted heterocyclyl comprising at least one of N, 0 or S, optionally substituted arylalkyl or an optionally substituted heterocyclylalkyl comprising at least one of N, 0 or S in the system of heterocyclyl; R2, R3 and R4 are each individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2o optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C20 partially or fully saturated optionally substituted cycloalkyl, C3 to C20 optionally substituted partial or fully saturated heterocyclic, C5 to C2o optionally substituted aryl, C2 to C20 optionally substituted heteroaryl, C2 to C2 or optionally substituted arylalkyl, C3 to C20 optionally substituted cycloalkylalkyl, C5 to C20 optionally substituted heteroarylalkyl, C3 to C2 or heterocyclylalkyl optionally substituted, Ci to C2o optionally substituted alkoxy, C5 to C2o optionally substituted aryloxy, Ci to C2o optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C20) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof or At least two of R2, R3 and R4 are joined to form a ring, wherein the ring is an unsubstituted or substituted ring of 3 to 20 members, wherein the ring members are selected from the group consisting of carbon, nitrogen , oxygen and sulfur; Where the formula (I) does not include the following structure: Preferred embodiments provide a compound of formula (II): gave : wherein: R12, R13, R14 and R17 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C2 or partially or fully saturated cycloalkyl optionally substituted C3 to C2o partially or fully saturated heterocyclic, optionally substituted C5 to C2o aryl, optionally substituted C2 to C20 heteroaryl, optionally substituted X to C2o alkoxy, optionally substituted C5 to C2o aryloxy, optionally substituted Ci to C2o optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl , thiocarbonyl, thiocarboxy and combinations thereof, wherein not all of R12, R13, R14 and R17 are H; R15 and R16 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to partially or fully saturated cycloalkyl optionally substituted, C3 to C2 or partial heterocyclic or fully saturated optionally substituted, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, Ci to C2o heterocyclyl optionally substituted C5 to C2o heteroarylalkyl, optionally substituted Ci to C20 alkoxy, optionally substituted C5 to C2o aryloxy, optionally substituted Ci to C20 alkylthio, optionally substituted Ci to C2o arylthio optionally substituted, mono- and di - (Ci to C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl and combinations thereof or R15 and R16 together form a ring, wherein the ring is a ring of three to seven members without substituted or substituted, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur; wherein formula (II) does not include the following structures: Preferred embodiments provide a compound of formula (IV): :? v) wherein: R12, R13, R14 and R17 are individually selected from the group consisting of H, Cx to C2o or optionally substituted alkyl, Ci to C2 or optionally substituted alkenyl, Ci to C20 alkynyl optionally substituted, C3 to C20 partial cycloalkyl or fully saturated, optionally substituted C3 to C2o partially or fully saturated heterocyclic, optionally substituted C to C2o aryl, optionally substituted C2 to C2o heteroaryl optionally substituted Ci to C2o alkoxy, optionally substituted C5 to C20 aryloxy, optionally substituted Ci to C2o alkylthio optionally substituted, Ci to C2o optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C20) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 is selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2o optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C2o partially or fully saturated cycloalkyl optionally substituted, C3 to C2o partially or fully saturated heterocyclic optionally substituted C5 to C2o aryl, optionally substituted C2 to C2o heteroaryl optionally substituted Ci to C2o heterocyclyl optionally substituted C5 to C20 heteroarylalkyl, optionally substituted Ci to C2o alkoxy, optionally substituted C5 to C2o aryloxy, optionally substituted Cx to C2o optionally alkylthio substituted, Ci to C2o optionally substituted arylthio, mono- and di- (Ci to C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl and combinations thereof; R18 is selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Cx to C2o optionally substituted alkoxy, mono- and di- (Ci to C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl and combinations thereof. Preferred embodiments provide a method for modulating the activity of NS3 comprising contacting a NS3 protein with a compound disclosed herein. Preferred embodiments provide a method for the treatment of hepatitis by modulating the NS3 helicase comprising contacting an NS3 helicase with the compound disclosed herein. Preferred embodiments provide a compound that can bind to an NS3 helicase site and inhibit the unwinding of a nucleic acid substrate, thereby modulating the helicase activity of NS3.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions As used herein, the term "hepatic fibrosis" is used herein with "liver fibrosis" refers to the growth of healing tissue in the liver that may occur in the context of a infection of chronic hepatitis. The terms "individual", "host", "subject" and "patient" are used interchangeably herein if they refer to a mammal, which includes, but is not limited to, primates, which include apes and humans . As used herein, the term "liver function" refers to a normal function of the liver, in which, but not limited to, a synthetic function, including, but not limited to, protein synthesis such as as whey proteins (e.g., albumin, coagulation factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5 '-nucleosidase and β-glutaminyltranspeptidases, etc.), bilirubin synthesis, cholesterol synthesis and synthesis of bile acids; a metabolic function of the liver, which includes but is not limited to carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, in which visceral and portal hemodynamics and the like are included. The term "sustained viral response" (SVR, also referred to as a "sustained response" or a "sustained response"), as used herein, refers to the response of an individual to a treatment regimen for HCV infection, in terms of HCV title in the serum. In general, a "sustained viral response" refers to an undetectable HCV RNA (eg, less than about 500, less than about 200 or less than about 100 copies of genome per mi of serum) found in the patient's serum for a period of at least about one month, at least about two months, at least about three months, at least about four months, at least about five months or at least about six months following the cessation of treatment. "patient failure to treatment" as used herein, refers generally to patients infected with HCV who failed to respond to prior therapy for HCV (referred to as "non-responders") or who initially responded to prior therapy, but in which the therapeutic response was not maintained (referred to as "recaptors"). Prior therapy in general may include treatment with IFN-a monotherapy or IFN-a combination therapy, wherein the combination therapy may include the administration of IFN-a and an antiviral agent such as ribavirin. As used herein, the terms "treatment", "treating" and the like, refer to obtaining a desired pharmacological and / or physiological effect. The effect may be prophylactic in terms of completely or partially inhibiting a disease or symptoms thereof and / or it may be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease. "Treatment", as used herein, covers any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but still he has not been diagnosed as having it; (b) inhibit the disease, that is, stop its development and (c) alleviate the disease, that is, cause regression of the disease.

The terms "individual", "student", "subject" and "patient" are used interchangeably herein and refer to a mammal, which includes but is not limited to murine, simian, human, mammal fringe animals, mammal sporting animals, and mammalian pets. The term "dosage event" as used herein, refers to the administration of an antiviral agent to a patient in need thereof, such an event may encompass one or more releases of an antiviral agent from a drug delivery device. Thus, the term "dosing event" as used herein, includes but is not limited to installation of a continuous delivery device (e.g., a pump or other injectable controlled release system) and a single subcutaneous injection followed by the installation of a continuous administration system. or "continuous administration" as used herein (eg, in the context of "continuous administration of a substance to a tissue") is intended to refer to the movement of the drug to a site of administration, for example, to a tissue of a way that provides for the administration of a desired amount of substance to the tissue in a selected period of time, wherein approximately the same amount of drug is received by the patient each minute during the selected period of time. "controlled release" as used in this (e.g., in the context of "controlled drug release") it is proposed to encompass the release of a substance (e.g., a type I or type III interferon receptor agonist, e.g. IFN-a) at a controllable rate selected or a speed otherwise controllable, range and / or quantity, which is not substantially influenced by the environment of use. "controlled release" encompasses such but is not necessarily limited to subsequent continuous administration and feeding in a pattern (eg, intermittent administration over a period of time that is interrupted by regular or irregular time intervals.) with "pattern" -or " "temporary" as used in the context of drug administration means administration of drug in a pattern, in general, a substantially regular pattern, in a preselected period of time (eg, different from a period associated with for example, an injection of bolus.) Administration of "patterned" or "temporary" drug is intended to encompass drug administration at a rate or range of increased, decreasing, substantially constant or pulsatile rates (eg, amount of drug per unit time or volume of drug). formulation of drug per unit time) and also covers administration that is continuous or substantial Continuous or chronic The term "controlled drug delivery device" is intended to cover any device where the release (eg, velocity, release timing) of a drug or other desired substance contained therein is controlled by or determined by the device itself and is not substantially influenced by the environment of use or release at a rate that is reproducible within the environment of use. "substantially continuous" as used for example in the context of "substantially continuous infusion" or "substantially continuous administration" is intended to refer to the administration of the drug in a manner that is substantially uninterrupted for a preselected drug administration period, wherein the amount of drug received by the patient during any interval of 8 hours in the preselected period never falls to zero. In addition, administration of the drug "substantially continuous" may also encompass administration of the drug at a rate or range of substantially constant, preselected rates (e.g., amount of drug per unit time or volume of drug formulation per unit time) which is substantially uninterrupted for a period of preselected drug administration. "Substantially stable state" as used in the context of a biological parameter that can vary as a function of time means that the biological parameter exhibits a substantially constant value in a time course of such that the area under the curve defined by the value of the biological parameter as it functions in time for any period of 8 hours during the time course (AUC 8 hours) is not more than about 20% above or about 20% below and preferably not more than about 15% above or about 15% below and more preferably not more than about 10% above or about 10% below, the average area under the curve of the biological parameter over a period of 8 days. hours during the time course (average AUC 8 hours). The average AUC 8 hours is defined as the quotient (q) of the area under the curve of the biological parameter throughout the time course (total AUC) inhibited by the number of intervals of 8 hours in the course of time (total / 3 days ), that is, q = (total AUC) / (total / 3 days). For example, in the context of a concentration in the serum of a drug, the concentration in the serum of the drug is maintained at a substantially stable state for a time course, when the area under the curve of the concentration in the serum of the drug in time for any 8-hour period during the time course (AUC 8 hours) is not more than about 20% above or approximately 20% below the average area under the curve of the serum concentration of the drug during a period of 8 hours in the course of time (average AUC 8 hours), that is, the AUC 8 hours is not more than 20% above or 20% below the AUC 8 hours average to the concentration in the serum of the drug in the course of time. The term "homologous" and "variants" as used herein in reference to proteins refers to a similarity or identity of sequences, identity is preferred. As is known in the art, a number of different programs are used to identify a protein (or nucleic acid as discussed hereinafter) having sequence identity or similarity with a known sequence. Thus, in a preferred embodiment, the homologous proteins or variants have an amino acid sequence that can differ from a free or wild-type sequence by up to substantially 40% of the residues, thus having approximately 60% homology.

In other preferred embodiments, the homologous proteins may have about 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% homology. The term "alkyl" used refers to a monovalent straight or branched chain radical of 1 to 20 carbon atoms, which include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like. The term "halo" used herein refers to fluoro, chloro, bromo or iodo. The term "alkoxy" used herein refers to a straight or branched chain alkyl radical covalently bonded to the parent molecule via a bond - O- Examples of alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like. The term "alkenyl" used herein refers to a straight or branched monovalent chain radical of 2 to 20 carbon atoms that contains a carbon double bond in which but not limited to 1-propenyl, 2-propenyl is included , 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. The term "alkynyl" • used herein refers to a straight or branched monovalent chain radical of 2 to 20 carbon atoms containing a triple carbon bond in which but not limited to 1-propynyl, 1- Butynyl, 2-butynyl and the like. The term "aryl" used herein refers to a homocyclic aromatic radical whether fused or non-fused. Examples of aryl groups include but are not limited to phenyl, naphthyl, diphenyl, phenanthrenyl, naphthacenyl and the like. The term "cycloalkyl" used herein refers to a radical of the saturated aliphatic ring system having 3 to 20 carbon atoms including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The term "cycloalkenyl" used herein is refers to an aliphatic ring system radical having 3 to 20 carbon atoms having at least one carbon-carbon double bond in the ring. Examples of cycloalkenyl groups include but are not limited to cyclopropenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl and the like. The term "polycycloalkyl" • used herein refers to a saturated aliphatic ring system radical having at least two rings that are fused with or without bridgehead carbons. Examples of polycycloalkyl groups include but are not limited to bicyclo [4.4.0] decannyl, bicyclo [2.2.1] heptanyl, adamantyl, norbornyl and the like. The term "polycycloalkenyl" used herein refers to a radical of the aliphatic ring system having at least two rings that are fused with or without bridgehead carbons in which at least one of the rings has a double bond carbon-carbon. Examples of polycycloalkynyl groups include but are not limited to norbornylnyl, 1,1'-bicyclopentenyl and the like. The term "polycyclic hydrocarbon" used herein refers to a ring system radical in which all ring members are carbon atoms. The polycyclic hydrocarbons may be aromatic or may contain less than the maximum number of non-cumulative double bonds. Examples of polycyclic hydrocarbons include but they are not limited to naphthyl, duhudronaphthyl, indenyl, fluorenyl and the like. The term "heterocyclic" or "heterocyclyl" used herein refers to a cyclic ring system radical having at least one ring system in which at least one or more ring atoms are not carbon, is say, heteroatoms. The heterocycles may be non-aromatic or aromatic. Examples of heterocyclic groups include but are not limited to morpholinyl, tetrahydrofuranyl, dioxolanyl, pyrolidinyl, oxacolyl, pyranyl, pyridyl, pyrimidinyl, pyrrolyl and the like. The term "heteroaryl" used herein refers to a heterocyclic group formally derivatized in an arene by replacement of one or more methine and / or vinylene groups by trivalent or divalent heteroatoms respectively, in such a manner as to maintain the aromatic system. Examples of heteroaryl groups include but are not limited to pyridyl, pyrrolyl, oxazolyl, indolyl and the like. The term "arylalkyl" used herein refers to one or more aryl groups attached to an alkyl radical. Examples of arylalkyl groups are included but are not limited to benzyl, phenethyl, phenpropyl and the like. The term "cycloalkylalkyl" used herein refers to one or more cycloalkyl groups attached to a alkyl radical. Examples of cycloalkylalkyl include but are not limited to cyclohexylmethyl, cyclohexylethyl, cyclopentylmethyl, cyclopentylethyl and the like. The term "heteroarylalkyl" as used herein refers to one or more heteroaryl groups attached to an alkyl radical. Examples of heteroarylalkyl include but are not limited to pyridylmethyl, furanylmethyl, thiophenylmethyl and the like. The term "heterocyclylalkyl" used herein refers to one or more heterocyclyl groups attached to an alkyl radical. Examples of heterocyclylalkyl include but are not limited to morpholinylmethyl, morpholinylethyl, morpholinylpropyl, tetrahydrofuranylmethyl, pyrrolidinylpropyl and the like. The term "aryloxy" used herein refers to an aryl radical covalently bonded to the parent molecule via an -0- bond. The term "alkylthio" used herein refers to a straight or branched chain alkyl radical covalently bonded to the parent molecule via an -S- linkage. The term "arylthio" used herein, refers to an aryl radical covalently bonded to the original molecule via an -S- bond. The term "alkylamino" used herein is refers to a nitrogen radical with one or more alkyl groups appended thereto. Thus, monoalkylamino refers to a nitrogen radical with an alkyl group appended thereto and dialkylamino refers to the nitrogen radical with two alkyl groups attached thereto. The term "cyanoamino" used herein refers to the nitrogen radical with a nitrile group appended thereto. The term "carbamyl" used herein, refers to RNHCOO-. The term "keto" and "carbonyl" used herein, refer to C = 0. The term "carboxy" used herein refers to -COOH. The term "sulfamyl" used herein refers to -S02NH2. The term "sulfonyl" used herein refers to -S02-. The term "sulfinyl" used herein refers to -SO-. The term "thiocarbonyl" as used herein refers to C = S. The term "thiocarboxy" used herein refers to CSOH As used herein, a radical indicates a species with a single unpaired electron in such a way that the species containing the radical can be covalently linked to another species. Hence, in this context, a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule. The term "radical" can be used interchangeably with the term "group". As used herein, a substituted group is derived from the original unsubstituted structure, in which there has been an exchange of one or more hydrogen atoms for another atom or group. When (s) is (are) substituted, the substituent group (s) is (are) one or more group (s) selected individually or independently from C? -C20 alkyl, Ci-Cd alkenyl, C C20 alkynyl, C3-C20 cycloalkyl, C3-C20 heterocycloalkyl (e.g., tetrahydrofuryl), aryl, heteroaryl, halo (e.g., chloro, bromo, iodo and fluoro), cyano, hydroxy, C1-C20 alkoxy, aryloxy, sulfhydryl (mercapto), C1-C20 alkylthio, arylthio, mono- and di- (C? -C20 alkylamino), quaternary ammonium salts, amino (C? -C2o) alkoxy, hydroxy (C? ~ Co) alkylamino, amino ( C? -C20) alkylthio, cyanoamino, nitro, carbamyl, keto (oxy), carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof. The protective groups that can form the protective derivatives of the above substituents are known to those of skill in the art and can be found in references such as Greene and Wuts Protective Groups in Organi c Syn thesi s; John Wiley and Sons: New York, 1999. Whenever a substituent is described as "optionally substituted" that substituent can be substituted with the above substituents. Asymmetric carbon atoms may be present in the described compounds. All such isomers, in which diastereomers and enantiomers are included, also as mixtures thereof are intended to be included in the scope of the aforementioned compound. In certain cases, the compounds may exist in tautomeric forms. It is intended that all tautomeric forms be included in the scope of the aforementioned compound. Also, when the compounds contain an alkenyl or alkenylene group, there is a possibility of cis- and trans-isomeric forms of the compounds. Both cis- and trans- isomers are also contemplated as mixtures of cis- and trans-isomers. Thus, the reference herein to a compound includes all isomeric forms mentioned above unless the context clearly determines otherwise. Several forms are included in the modalities in which polymorphs, solvates, hydrates, conformers, salts and prodrug derivatives are included. A polymorph is a composition that has the same chemical formula but different structure. A solvate is a composition formed by solvation (the combination of solvent molecules with molecules or ions of the solute). A hydrate is a compound formed by incorporation of water. A conformer is a structure that is a conformational isomer. The conformational isomerism is the phenomenon of molecules with the same structural formula but different conformations (shapers) of atoms around a rotating link. Salts of compounds can be prepared by methods known to those skilled in the art. For example, salts of compounds can be prepared to react the appropriate base or acid with a stoichiometric equivalent of the compound. A prodrug is a compound that undergoes biotransformation (chemical conversion) before exhibiting its pharmacological effects. For example, a prodrug can thus be viewed as a drug containing specialized protecting groups used transiently to alter or illuminate undesirable properties in the original molecule. Thus, the reference herein to a compound includes all the forms mentioned above unless the context clearly determines otherwise. Where a range of values is provided, it is understood that each intermediate value, to the tenth of the unit of the lower limit unless the context clearly determines otherwise, between the upper and lower limits of that interval and any other value intermediate affirmed or intermediate in that affirmed interval is encompassed within the modalities. The upper and lower limits of these smaller ranges can be included independently in the smaller ranges also covered in the invention, subject to any limits specifically excluded in the stated range. Where the stated interval includes one or both of the limits, intervals that exclude both of those limits included are also included in the modalities. Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art with which the modalities belong. Although any methods and materials similar or different to those described herein may also be used in the practice or testing of modalities, 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 relation to which the publications are cited. It should be noted that as used herein and in the appended claims, the singular forms "a", "and" and "the" include plural references unless the context clearly dictates otherwise. So, for example, the reference to "a method" includes a plurality of such methods and the reference to "a dose" includes reference to one or more doses and equivalents thereof known to those skilled in the art and so forth. The present embodiments provide compounds of formulas I-IV, also as pharmaceutical compositions and formulations comprising any compound of formulas I-IV. A subject compound is useful for treating HCV infection and other disorders, as discussed hereinafter.

Compositions The present embodiments provide compounds having the general Formula I: (i: wherein: R1 is an optionally substituted aryl, an optionally substituted heterocyclyl comprising at least one of N, O or S, optionally substituted arylalkyl or an optionally substituted heterocyclylalkyl comprising at least one of N, O or S in the heterocyclyl system; R2, R3 and R4 are each individually selected from the group consisting of H, Cx to C2o or optionally substituted alkyl, Ci to C20 optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C2 or partially or previously optionally substituted cycloalkyl, C3 to C2o optionally substituted partial or previously saturated heterocyclic, C5 to C2o optionally substituted aryl, optionally substituted C2 to C20 heteroaryl, optionally substituted arylalkyl, optionally substituted C3 to C2 or cycloalkylalkyl, optionally substituted C5 to C2o or optionally substituted heteroarylalkyl, C3 to C2o or optionally substituted heterocyclylalkyl Ci to C2o optionally substituted alkoxy, C5 to C2o optionally substituted aryloxy, Ci to C20 optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C20) alkylamino, cyanoamino , nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, gu anidyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof or at least two of R2, R3 and R4 join to form a ring wherein the ring is a ring of 3 to 20 members unsubstituted or substituted, wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen and sulfur; where formula (I) does not include the following structure: The present embodiments provide compounds having the general Formula (II) wherein: R12, R13, R14 and R17 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl, Ci to C20 alkynyl optionally substituted, C3 to C2 or partial cycloalkyl or previously saturated optionally substituted, C3 to C20 partially heterocyclic or previously optionally saturated substituted, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, Ci to C20 optionally substituted alkoxy, C5 to C2o optionally substituted aryloxy, Ci to C20 optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, guanidyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 and R16 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C2C partially or previously saturated cycloalkyl optionally substituted, C3 to C2 or partial heterocyclic or previously optionally substituted saturated, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, C3 to C2o optionally substituted heterocyclylalkyl, C5 to C20 optionally substituted heteroarylalkyl, Ci to C20 optionally substituted alkoxy, optionally substituted C5 to C20 aryloxy, Ci a C2o optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, mono- and di- (Ci to C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanidyl, and combinations thereof or R15 and R16 together form a ring, wherein the ring is a ring of 3 to 7 unsubstituted or substituted members, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur; Where formula II) does not include the following structures: The present embodiments provide compounds having the general Formula III: wherein: R 11 is H, halo, Ci to C 20 optionally substituted alkyl, Ci to C 2 or optionally substituted alkenyl, Ci to C 2 or optionally substituted alkynyl or Ci to C 2 or optionally substituted alkoxy; R12, R13 and R14 are individually selected from the group consisting of H, Ci to C2o optionally substituted alkyl, Ci to C20 alkenyl optionally substituted, Ci to C0 alkynyl optionally substituted, C3 to C2c cycloalkyl partial or previously saturated optionally substituted, C3 to C20 optionally substituted partial or pre-saturated heterocyclic, C5 to C2o optionally substituted aryl, C2 to C20 optionally substituted heteroaryl, Ci to C2o optionally substituted alkoxy, C5 to C2o optionally substituted aryloxy, Ci to C20 optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanidyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 and R16 are individually selected from the group consisting of H, Ci to C2o or optionally substituted alkyl, Ci to C20 alkenyl optionally substituted, Ci to C2 or alkynyl optionally substituted, C3 to C2 or partially saturated or optionally substituted cycloalkyl, optionally substituted C3 to C2o or partially saturated optionally substituted heterocyclic, C5 to C2o optionally substituted aryl, C2 to C20 optionally substituted heteroaryl, C3 to C2o optionally substituted heterocyclylalkyl, C5 to C2 or heteroarylalkyl optionally substituted, Ci to C2o optionally substituted alkoxy, C5 to C20 optionally substituted aryloxy, Ci to C20 optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, mono- and di- (C? a C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanidyl, and combinations thereof or R15 and R16 together form a ring, wherein the ring is a ring of 3 to 7 unsubstituted or substituted members, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur; The present embodiments provide compounds having the general Formula IV: IV) wherein: R12, R13, R14 and R17 are individually selected from the group consisting of H, C to C2o or optionally substituted alkyl, Ci to C20 optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C2 or partially cycloalkyl or previously optionally saturated substituted, C3 to C2o optionally substituted partial or pre-saturated heterocyclic, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, Ci to C2o optionally substituted alkoxy, C5 to C2o optionally substituted aryloxy, Ci to C20 optionally substituted alkylthio, Ci a C2o optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanidyl, sulfamyl, sulfonyl, sulfinyl , thiocarbonyl, thiocarboxy and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 is selected from the group consisting of H, Ci to C2o optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl, Ci to C20 allynyl optionally substituted, C3 to C20 cycloalkyl partial or previously saturated optionally substituted, C3 to C20 heterocyclic partial or previously saturated optionally substituted, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, C3 to C2o heterocyclylalkyl optionally substituted, C5 to C2o optionally substituted heteroarylalkyl, Ci to C2o optionally substituted alkoxy, optionally substituted C5 to C20 aryloxy, Ci to C2o optionally substituted alkylthio, Cx to C20 optionally substituted arylthio, mono- and di- (Ci to C2o) alkylamino, carbamyl , keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanidyl, and combinations thereof; R18 is selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C20 optionally substituted alkoxy, mono- and di- (Ci to C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanidil, and combinations thereof. Examples of compounds of Formula I are summarized in Table 1 below.

TABLE 1 Examples of compounds of formulas II-IV are summarized in table 2 below Table 2 twenty 15 25 twenty 25 twenty 25 25 twenty twenty twenty In a preferred embodiment, a compound of formula (I) is provided: where : R1 is an optionally substituted aryl, an optionally substituted heterocyclyl comprising at least one of N. 0 or S, optionally substituted arylalkyl or an optionally substituted heterocyclylalkyl comprising at least one of N, 0 or S in the heterocyclyl system; R2, R3 and R4 are each individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C20 optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C20 partially or fully saturated optionally substituted cycloalkyl, C3 to C2o optionally substituted partially or fully saturated heterocyclic, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, optionally substituted arylalkyl, C3 to C20 optionally substituted cycloalkylalkyl, C5 to C2o optionally substituted heteroarylalkyl, C3 to C20 heterocyclylalkyl optionally substituted, Ci to C2o optionally substituted alkoxy, C5 to C2o optionally substituted aryloxy, Ci to Co optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (C? a C20) alkylamino , cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guan Iyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof or at least two of R2, R3 and R4 are joined to form a ring, wherein the ring is a ring of 3 to 20 unsubstituted or substituted members, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen and sulfur; wherein formula (I) does not include the following structure: In a preferred embodiment, a compound of formula I is provided, wherein R1 is an optionally substituted aryl or an optionally substituted heterocyclyl which comprises at least one of N, O or S. In a preferred embodiment, a compound of formula is provided I wherein R1 is optionally substituted aryl or an optionally substituted heterocyclyl comprising at least one of N, O or S. In a preferred embodiment, a compound of formula I is provided, wherein R2, R3 and R4 are each individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, C3 to C2 or optionally substituted partial or fully saturated cycloalkyl, C5 to C20 optionally substituted aryl, C6 to C2 or arylalkyl optionally substituted, C3 to C20 cycloalkylalkyl optionally substituted, C5 to C20 heteroarylalkyl optionally substituted, C3 to C20 heterocyclylalkyl optionally substituted, Ci to C2o optionally substituted alkoxy, carbamyl, keto, carboxy and combinations thereof. In a preferred embodiment, a compound of formula (I) is provided, wherein at least two of R2, R3 and R4 are joined to form a ring, wherein the ring is a 3 to 7 member unsubstituted or substituted , wherein the members of the ring are selected from the group consisting of carbon, nitrogen, oxygen or sulfur. In a preferred embodiment, a compound of formula (I) is provided, wherein R 1 is thiophene. In a preferred embodiment, a compound of the formula I is provided, wherein R1 is optionally substituted phenyl. In a preferred embodiment, a compound of formula I is provided, wherein R 1 is thiophene or optionally substituted phenyl and wherein each of R 2, R 3 and R 4 are individually selected from the group consisting of H, Ci to C 2 or optionally substituted alkyl , C3 to C2o optionally substituted partial or fully saturated cycloalkyl, C5 to C20 optionally substituted aryl, ea C20 arylalkyl optionally substituted, C3 to C2o optionally substituted cycloalkylalkyl, C5 to Co optionally substituted heteroarylalkyl, C3 to C2o optionally substituted heterocyclylalkyl, Ci to C20 optionally substituted alkoxy, carbamyl, keto, carbonyl, carboxy and combinations thereof. In a preferred embodiment, a compound of formula I is provided, wherein R1 is thiophene or optionally substituted phenyl and wherein at least two of R2, R3 and R4 are joined to form a ring, wherein the ring is a ring of 3 to 7 unsubstituted or substituted members, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur. One embodiment provides compounds of Formulas (la), (Ib) and (le): (Ib) of) In the Formulas (la), (Ib) and (le), Ar represents aryl (for example, phenyl, thiophenyl, etc.) and n is one or two, represents the number of carbon atoms in the ring in the position indicated. For example, for n = 1, the ring contains four carbon atoms and one nitrogen atom; for n = 2, the ring contains five carbon atoms and one nitrogen atom. The compounds of Formulas (la), (Ib) and (le) are examples of compounds of Formula (I). In a preferred embodiment, a compound of formula is provided where R12, R13, R14 and R17 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C20 optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C20 partially or fully saturated optionally substituted cycloalkyl, C3 to C2o partially or fully-saturated optionally substituted heterocyclicC5 to C2o optionally substituted aryl, C2 to C20 optionally substituted heteroaryl, Ci to C2o optionally substituted alkoxy, C5 to C20 optionally substituted aryloxy, Ci to C2 optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, halo, cyano, mercapto, hydroxy , mono- and di- (C? a C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 and R16 are individually selected from the group consng of H, Ci to C2o or optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl, Ci to Co optionally substituted alkynyl, C3 to C2 or optionally substituted partial or fully saturated cycloalkyl, C3 to partial heterocyclic Co or fully saturated optionally substituted, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, C3 to C2o or optionally substituted heterocyclylalkyl, C5 to C2o optionally substituted heteroarylalkyl, Ci to C2o optionally substituted alkoxy, optionally substituted C5 to C20 aryloxy, Ci to C20 optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, mono- and di (Ci to C2o) alkylamino, carbamyl, keto, carbonyl, carboxy , glycolyl, glycyl, hydrazino, guanylyl, and combinations thereof; or R15 and R16 together form a ring, wherein the ring is a ring of 3 to 7 unsubstituted or substituted mes, wherein the ring mes are selected from the group consisting of carbon, nitrogen, oxygen or sulfur; wherein formula (II) does not include the following structures: In a preferred embodiment, a compound of formula II is provided, wherein R12, R13, R14 and R17 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2 or optionally substituted alkenyl, Ci to C2 or alkynyl optionally substituted, Ci to C2o optionally substituted alkoxy, C5 to C2o optionally substituted aryloxy, Ci to C2o optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C20) alkylamino , cyanoate, nitro, carbamyl, keto,. carbonyl and carboxy. In a preferred embodiment, a compound of formula II is provided, wherein R15 and R16 are individually selected from the group consisting of H, Ci to C2o or optionally substituted alkyl, Ci to C20 optionally substituted alkenyl, Ci to C2 or optionally substituted alkynyl, mono and di- (Ci to C2o) alkylamino, C5 to C2o or optionally substituted aryl, C3 to C2o or optionally substituted heterocyclylalkyl, C5 to C2 or optionally substituted heteroarylalkyl, carbamyl, keto, carbonyl, carboxy and combinations thereof. In a preferred embodiment, a compound of formulas (II) is provided, wherein R15 and R16 together form a ring, wherein the ring is an unsubstituted or substituted 4- to 6-meed ring, wherein the mes of the ring are selected from the group consisting of carbon, nitrogen, oxygen and sulfur. In a preferred embodiment, a compound of formula (II) having the formula is provided: The present embodiments provide compounds having the general Formula III: n: wherein: R11 is H, halo, Ci to C20 optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl, Ci to C2o or optionally substituted alkynyl or Ci to C20 alkoxy optionally substituted; R12, R13 and R14 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2o optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl or C3 to C20 partially or fully saturated optionally substituted cycloalkyl, C3 to C2o partially or fully saturated heterocyclic optionally substituted, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, Ci to C2o optionally substituted alkoxy, C5 to C2C optionally substituted aryloxy, Ci to C2o optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C20) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxyl and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 and R16 are selected individually from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl, Ci to C2o or optionally substituted alkynyl or C3 to C2 or partially or fully saturated cycloalkyl optionally substituted, C3 to C2 or partial heterocyclic or fully saturated optionally substituted, C5 to C2o optionally substituted aryl, C2 to C20 optionally substituted heteroaryl, C3 to C20 optionally substituted heterocyclylalkyl, C5 to C2o or optionally substituted heteroarylalkyl, Ci to C2o optionally substituted alkoxy, C5 to optionally substituted aryloxy, Ci to C2 or optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, mono- and di- (Ci to C2o) alkylamino , carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl and combinations thereof; or R15 and R15 together form a ring, wherein the ring is an unsubstituted or substituted 3 to 7 membered ring, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur. In a preferred embodiment, a compound of formula II is provided, wherein R 11 is H, halo, Ci to C 2 or optionally substituted alkyl or Ci to C 2 or optionally substituted alkoxy. In a preferred embodiment, a compound of formula III is provided, wherein R12, R13 and R14 are individually selected from the group consisting of H, Ci to C2o or optionally substituted alkyl, Ci to C20 optionally substituted alkoxy, Ci to C2 or optionally substituted alkylthio halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxyl and combinations thereof; where not all of R12, R13, and R14 they are H In a preferred embodiment, a compound of formula III is provided, wherein R12, R13, and R14 are individually selected from the group consisting of H, Ci to C2o, optionally substituted alkyl, Ci to C2o, optionally substituted alkoxy, Ci to C2 or alkylthio optionally substituted, halo, hydroxy, mono- and di- (Ci to C2o) alkylamino and combinations thereof; where not all of R12, R13, and R14 are H. In a preferred embodiment, a compound of formula III is provided, wherein R15 and R16 are individually selected from the group consisting of H, Ci to C2o, optionally substituted alkyl, C3 to C2 or optionally substituted partial or fully saturated cycloalkyl, C2 to C20 heterocyclic partially or fully saturated optionally substituted, C5 to C2o optionally substituted aryl, C2 to C20 optionally substituted heteroaryl, C3 to C20 optionally substituted heterocyclylalkyl, C5 to C20 optionally substituted heteroarylalkyl, Ci to C2o optionally substituted alkoxy, mono- and di- (C? to C20) alkylamino, carbamyl, keto, carbonyl, carboxy and combinations thereof. In a preferred embodiment, a compound of formula III is provided, wherein R15 and R16 together form a ring, wherein the ring is a ring of 4 to 6 unsubstituted or substituted members, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur. In a preferred embodiment, there is provided a compound of formula III, wherein R11 is fluoro and R12, R13 and R14 are individually selected from the group consisting of H, alkyl and halo. The present embodiments provide compounds having the general Formula IV: wherein: R12, R13, R14 and R17 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C20 optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C20 partially or fully saturated cycloalkyl optionally substituted, C3 to C20 partially or fully saturated optionally substituted heterocyclic, C5 to C2o or optionally substituted aryl, C2 to C20 optionally substituted heteroaryl, Ci to C2o optionally substituted alkoxy, C5 to C2o optionally substituted aryloxy, Ci to C20 optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazyl, guanidyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 is selected from the group consisting of H, Ci to C2o optionally substituted alkyl, Ci to C20 optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C2o optionally substituted partially or fully saturated cycloalkyl, C3 to C2o optionally substituted partially or fully saturated heterocycle, C5 to C20 aryl optionally substituted, C2 to C2o optionally substituted heteroaryl, C3 to C2o optionally substituted heterocyclylalkyl, C5 to C2o or optionally substituted heteroarylalkyl, Ci to C2o optionally substituted alkoxy, C5 to C2 or optionally substituted aryloxy, Ci to C2o optionally substituted alkylthio, Ci to C20 optionally substituted arylthio , mono- and di- (Ci to C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazyl, guanidyl and combinations thereof; R18 is selected from the group consisting of H, Ci a C2o optionally substituted alkyl, Ci to C20 optionally substituted alkoxy, mono- and di- (C? A C20) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazyl, guanidyl and combinations thereof. Preferred embodiments provide a method for treatment by infection of hepatitis C virus in an individual, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound. Preferred embodiments provide a method for the treatment of liver fibrosis in an individual, the method comprises administering to the individual an effective amount of a composition comprising a preferred compound. Preferred embodiments provide a method for increasing liver function in an individual having hepatitis C virus infection, the method comprising administering to the individual an effective amount of a composition comprising a preferred compound. The present embodiments further provide compositions that include pharmaceutical compositions, comprising compounds of general Formulas I-IV, salts, esters or other derivatives thereof. A subject pharmaceutical composition comprises a compound and a pharmaceutically acceptable excipient. A wide variety of pharmaceutically acceptable excipients are known in the art and are not They need to be discussed in detail in the present. Pharmaceutically acceptable excipients have been extensively described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, and Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., Eds., 7th ed., Lippincott, Williams, and Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., Eds., 3rd ed. Amer. Pharmaceutical Assoc. The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. In addition, pharmaceutically acceptable auxiliary substances, such as pH adjusting agents and pH regulating agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public. In many embodiments, a subject compound inhibits the enzymatic ability of HCV NS3 helicase with an IC50 of less than about 50 μM, eg, a subject compound inhibits an HCV NS3 protease with an IC50 of less than about 40 μM, less than about 25 μM, less than about 10 μM, less than about 1 μM, less than about 100 nM, less than about 80 nM, less than about 60 nM, less than about 50 nM, less than about 25 nM, less than about 10 nM or less than approximately 1 nM or less. In many embodiments, a subject compound inhibits viral replication of HCV. For example, a subject compound inhibits viral replication of HCV by at least about 10%, by at least about 15%, by at least about 20%, by at least about 25%, by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% or more, compared to the viral replication of HCV in the absence of the compound. If a subject compound inhibits viral replication HCV can be determined using methods known in the art, including an analysis of viral replication in Vi tro.

NS3 helicase HCV is a positive strand RNA virus. After infection, its genomic RNA produces a large polyprotein that is processed by viral and cellular proteins to at least 10 different viral proteins. Like other positive-strand RNA ingredients, replication of the positive strand involves the initial synthesis of a negative strand RNA. This negative strand RNA, which is an intermediary of replication, serves as a template for the production of progenie genomic RNA. It is believed that this process is carried out by two or more viral encoded enzymes, in which RNA-dependent RNA polymerase and RNA-helicase are included. The RNA polymerase copies the RNA template for the production of progeny RNA. This enzyme does not synthesize RNA molecules from the DNA template. RNA helicase unwinds the secondary structure present in the single-stranded RNA molecule. The helicase also unwinds the duplex RNA in single-stranded forms. Genomic HCV RNA molecules contain extensive secondary structure. It is believed that the HCV RNA replication intermediates are present as duplex RNA consisting of positive and negative strand RNA molecules. It is believed that RNA helicase activity facilitates the activity of RNA-dependent RNA polymerase that is believed to unwind single-stranded RNA molecules as a template. Accordingly, it is believed that the biological activity of the helicase is important for the replication of HCV.

Modulation of NS3 helicase activity The NS3 helicase comprises approximately 631 amino acids (SEQ ID NO: 1) which include three domains: Domain 1, Domain 2 and Domain 3. Homologous structures of NS3 helicase are contemplated as part of the modalities. Domain 1 comprises a region of residues or variants of residues that extend from Residue 190 to Residue 324 as indicated in SEQ.

ID NO: 1. Domain 2 comprises a region of residues or variants thereof extending from Residue 328 to Residue 483 as indicated in SEQ ID NO: 1. Domains 1 and 2 form parallel ß-sheets surrounded by a -lices. It is believed that the compounds described herein (e.g., Formulas I-IV) bind to NS3 helicase in Domain 1 and / or Domain 2. It is believed that the binding of the compounds to NS3 helicase in Domain 1 comprises interactions with one or more of the 209 Residues a 221; Residues 286 to 288; Residues 317 to 319 and / or Residues 214 to 218 as set forth in SEQ ID NO: 1. It is believed that the links of the compounds to NS3 helicase in Domain 2 comprises interactions with one or more of Residues 412 to 423; Residue 363; Residue 365; Residue 406; Residue 408; Residue 408; Residue 391; Residue 397; Residue 400 and Residues 400 to 404 as indicated in SEQ ID NO: 1. The binding of a compound to NS3 helicase in Domain 1 and / or Domain 2 as described above may cause the movement of one or more Residues 412 to 423 Additional NS3 helicase movements may also occur. The movement or movements resulting from the binding of the compound can cause an allosteric movement of NS3 helicase such as the binding of a nucleic acid substrate in a remote portion of the NS3 helicase can be inhibited. In modalities preferred, the nucleic acid substrate is DNA or RNA. By inhibiting the binding of the nucleic acid substrate, the activity of NS3 helicase can be modulated. In preferred embodiments, the modulation of NS3 helicase activity is the inhibition of NS3 helicase activity. In preferred embodiments, the activity of NS3 helicase that is modulated is the replication of NS3. The modulation of NS3 helicase activity can occur in vivo or ex vivo. One embodiment provides a compound comprising at least one functional group configured to facilitate the binding of the compound to NS3 helicase, the linkage being effective to modulate (eg, inhibit) the activity of NS3 helicase. The compounds of formulas I-IV are examples of compounds comprising such configured functional groups. For example, the compound can be any one or more of I-I to 1-183 or II-1 to 11-82 described in Tables 1 and 2 above. In one embodiment, the binding is effective to inhibit the unwinding of a nucleic acid substrate (eg, DNA and / or RNA) by the NS3 helicase. The link can facilitate the allosteric movement of the NS3 helicase, modulating by this the activity of NS3 helicase. The functional group can be configured to facilitate the binding of the compound to the NS3 helicase domain, for example, to one or more residues in Domain 1 of NS3 helicase. For example, the waste can be any of Residues 209 to 221, Residues 286 to 288, Residues 317 to 319 or Residues 214 to 218. In another embodiment, the functional group may be configured to facilitate the binding of the compound to Domain 2 of NS3 helicase, for example, to one or more residues in Domain 2 of NS3 helicase. For example, the waste can be any of Residues 412 to 423, Residue 363, Waste 365, Waste 406, Waste 408, Waste 391, Waste 397, Waste 400 or Waste 400 to 404. Another embodiment provides a pharmaceutical composition comprising a compound and a pharmaceutically acceptable carrier, wherein the compound comprises at least one functional group configured to facilitate the binding of the compound to NS3 helicase, the linkage is effective to modulate the activity of NS3 helicase, as described above. For example, the compound in the composition can be a compound of Formulas I-IV and thus can be any one or more of the compounds 1-1, 1-183 or 00-1 to 11-82 described in Tables 1 ay 2 previous. Another embodiment provides a method for modulating the activity of NS3 helicase comprising contacting an NS3 protein with a compound or a composition comprising the compound, wherein the compound comprises at least one functional group configured to facilitate the binding of the compound At NS3 helicase, the binding is effective to modulate the activity of NS3 helicase as described above. The contact can occur ex vivo or in vivo. Yes is in vivo, contact can occur in a human body. In one embodiment, the method comprises identifying a person having a medical condition or disease as disclosed herein, for example, a liver disease or condition such as HCV.

Hepatitis virus treatment-infection The methods and compositions described herein are generally useful in the treatment of an HCV infection. If a subject method is effective in the treatment of an HCV infection it can be determined by a reduction in viral load, a reduction in the time for seroconversion (undetectable virus in the patient's serum), an increase in the rate of sustained viral response to therapy, a reduction in morbidity or mortality in clinical outcomes or another indicator of disease response. In general, an effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents is an amount that is effective in reducing viral load or obtaining a sustained viral response to therapy. Whether a subject method is effective in the treatment of an HCV infection can be determined by measuring a viral load or by measuring a parameter associated with HCV infection, in those that are included but not limited to fibrosis of the liver, elevations in transaminase levels in the serum and necroinflammatory activity in the liver. Indicators of liver fibrosis are discussed in detail later in this. The method involves administering an effective amount of a compound of Formulas I-IV, optionally in combination with an effective amount of one or more additional antiviral agents. In some embodiments, an effective amount of a compound of Formulas I-IV or optionally one or more additional antiviral agents, is an amount that is effective to reduce viral titers to undetectable levels, for example, to about 1000 to about 5000, approximately 500 to about 1000 or about 100 to about 500 copies of genome / ml in the serum. In some embodiments, an effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents is an amount that is effective to reduce the viral load to less than 100 copies of genome / ml of serum. In some embodiments, an effective amount of the compound of Formulas I-IV and optionally one or more additional antiviral agents is an amount that is effective to obtain a 1.5-logarithmic reduction, a 2-logarithmic reduction, a 2.5-logarithmic reduction, a 3-logarithmic reduction, a 3.5-logarithmic reduction, a 4-logarithmic reduction, a 5-logarithmic reduction, or a 5- reduction logarithmic in the viral titre in the individual's serum. In many embodiments, an effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents, is an amount that is effective to obtain a viral response obtained, for example, undetectable or substantially undetectable HCV RNA ( for example, less than about 500, less than about 400, less than about 200 or less than about 100 copies of genome per milliliter of serum) is found in the patient's serum for a period of at least about one month, so less about two months, at least about three months, at least about four months, at least about five months or at least about six months after the cessation of therapy. As indicated above, if a subject method is effective in the treatment of an HCV infection it can be determined by measuring a parameter associated with HCV infection, such as liver fibrosis. Methods for determining the extent of liver fibrosis are discussed in detail later herein. In some embodiments, the level of a liver fibrosis serum marker indicates the degree of liver fibrosis. As a non-limiting example, serum alanine aminotransferase (ALT) levels are measured using standard analyzes. In general, an ALT level of Less than approximately 45 international units is considered normal. In some embodiments, an effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents is an amount effective to reduce ALT levels to less than about 45 IU / ml of serum. A therapeutically effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents, is an amount that is effective to reduce a serum level of a liver fibrosis marker by at least about 10%, so that less 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 50X at least about 55 %, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more, compared to the level of the marker in an individual without treat or with an individual treated with placebo. Methods of measuring serum markers include methods based on immunology, for example, enzyme-linked immunosorbent assays (ELISA), radioimmunoassays and the like, using a specific antibody for a given serum marker.

In many embodiments, an effective amount of a compound of Formulas I-IV and an additional antiviral agent is a synergistic amount. As used herein, a "synergistic combination" or "synergistic amount" of a compound of Formulas I-IV and an additional antiviral agent is a combined dosage that is most effective in the therapeutic or prophylactic treatment of an HCV infection. that the improved improvement in the treatment result that could be preceded or expected from an additive combination only of (i) the therapeutic or prophylactic benefit of the compound of Formulas I-IV when administered at the same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the additional antiviral agent when administered at the minimum dosage as monotherapy In some embodiments, a selected amount of a compound of Formulas I-IV and a selected amount of an additional antiviral agent are effective when used in a combination therapy for a disease, but the selected amount of the compound of Formulas I-IV and / or the selected amount of the additional antiviral agent are not effective when used in monotherapy for the disease. Thus, the modalities encompass (1) regimens in which a selected amount of an additional antiviral agent improves the therapeutic benefit of a selected amount of the Composite of Formulas I-IV when used in combination therapy for a disease, wherein the selected amount of an additional antiviral agent does not provide any therapeutic benefit when used in immunotherapy for the disease, (2) regimens in which a The selected amount of the compound of Formulas I-IV improves the therapeutic benefit of a selected amount of the additional antiviral agent when used in combination therapy for a disease, wherein the selected amount of the compound of Formulas I-IV does not provide any therapeutic benefit. when used in immunotherapy for the disease and (3) regimens in which a selected amount of the compound of Formulas I-IV and a selected amount of an additional antiviral agent provides a therapeutic benefit when used in combination therapy for a disease, where each of the selected diseases of the For compound Mules I-IV and the additional antiviral agent, respectively, provide no therapeutic benefit when used in monotherapy for the disease. As used herein, a "synergistically effective amount" of a compound of Formulas I-IV and an additional antiviral agent and its grammatical equivalents, will be understood to include any regimen encompassed by any of (l) - (3) above.

Fibrosis The embodiments provide methods for the treatment of liver fibrosis (in which forms of liver fibrosis resulting from or associated with HCV infection are included), which generally involve administering a therapeutic amount of the compound of Formulas I-IV and optionally one or. more additional antiviral agents. Effective amounts of the compound of Formulas I-IV, with and without one or more additional antiviral agents, also as dosage regimens, are as discussed hereinafter. If treatment with a compound of Formulas I-IV and optionally one or more additional antiviral agents, it is effective in reducing liver fibrosis is determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. The reduction of liver fibrosis is determined when analyzing a liver biopsy sample. An analysis of a liver biopsy comprises determinations of two major components: necroinflammation determined by "grade" as a measure of the severity and activity of disease in progress and lesions of fibrosis and parenchymal and vascular remodeling as determined by "stages" being reflective of long-term disease progression. See, for example, Brunt (2000) Hepatol. 31: 241-246 and METAVIR (1994) Hepatology 20: 15-20. Based on the analysis of the liver biopsy, a punctuation. A number of standardized scoring systems exist that provide a quantitative determination of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Lud ig and Ishak scoring systems. The METAVIR scoring system is based on an analysis of several elements of a liver biopsy, which includes fibrosis (portal fibrosis, centrilobular fibrosis and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction and degeneration of balloon formation); inflammation (inflammation of the portal system; portal lymphoid aggregates and distribution of portal inflammation); Bile duct changes and the Knodell Index (periportal necrosis scores, lobular necrosis, portal inflammation, fibrosis and floral disease activity). The definitions of each stage in the METAVIR system are as follows: score 0, no fibrosis; score 1, stellar expansion of the portal system but without septa formation; score 2, expansion of the portal system with rare septa formation; score 3, numerous septas without fibrosis and score 4, cirrhosis. The Knodell scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histological elements: I. Periportal and / or portage necrosis; II. Intralobular degeneration and focal necrosis; III. Inflammation portal and IV. Fibrosis. In the classification system by Knodell stages, scores are as follows: score 0: no fibrosis; score 1: soft fibrosis (fibrous portal expansion); score 2, moderate fibrosis; score 3, severe fibrosis (porta fibrosis) and score 4, cirrhosis. The higher the score, the more severe damage to the liver tissue. Knodell (1981) Hepatol. 1: 431 In Scheuer's scoring system the scores are as follows: score 0, no fibrosis; score 1, expanded fibrotic portal systems; score 2, periportal septas or portal-portal, but intact architecture; score 3, fibrosis with architectural distortion, but no obvious cirrhosis, score 4, probable or definite cirrhosis. Scheuer (1991) J. Hepatol. 13: 372. The Ishak scoring system is described in Ishak (1995) J. Hepatol. 22: 696-699. Stage 0, no fibrosis; Stage 1, fibrous expansion of some portal areas, with or without short fibrous septa; - Stage 2, fibrous expansion of most portal areas, with or without short fibrous septa; Stage 3, fibrous expansion of most portal areas with occasional portal to portal (P-P) counting; Stage 4, fibrous expansion of portal areas with marked counting (P-P), as well as portal-central (P-C); Stage 5, marked count (P-P and / or P-C) with occasional nodules (incomplete cirrhosis); Stage 6, cirrhosis, probable or definite.

The benefit of anti-fibrotic therapy can be measured and determined by using the Child-Plug scoring system comprising a multicomponent point system based on abnormalities in serum bilirubin level, serum albumin level, prothrombin, the presence and severity of ascites and the presence and severity of encephalopathy. Based on the presence and severity of abnormality of these parameters, patients can be placed in one of three categories of increased severity of clinical disease A, B or C. In some embodiments, a therapeutically effective amount of a compound of Formulas I- IV and optionally one or more additional antiviral agents, is an amount that effects a change of one or more units in the stage of fibrosis based on liver biopsy pre- and post-therapy. In particular embodiments, a therapeutically effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents, reduces liver fibrosis by at least one unit in the METAVIR scoring system, Knodell, Scheuer, Lud ig or Ishak Secondary or indirect indices of liver function can also be used to evaluate the efficacy of treatment with a compound of Formulas I-IV. The computerized semiautomatized morphometric determination of the quantitative degree of liver fibrosis based on specific dyeing of collagen and / or liver fibrosis serum markers can also be measured as an indication of the efficacy of the subject treatment method. Secondary liver function indices include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and determination of Child-Plug score. An effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents is an amount that is effective to increase a liver function index by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more, compared to the index of liver function in an individual without treating with an individual treated with placebo. Those skilled in the art can easily measure such liver function indices, using standard analysis methods, many of which are commercially available and are used systematically in clinical settings.

Liver fibrosis serum markers can also be measured as an indication of the efficacy of a subject treatment medium. Liver fibrosis serum markers include but are not limited to hyaluronate, peptide III of N-terminal procollagen, 7S domain of type IV collagen, C-terminal procollagen peptide and laminite. Additional biochemical markers of liver fibrosis include a-2-macroglobulin, haptoglobin, gamma globulin, apoliprotein A and gamma glutamyl transpeptidase. A therapeutically effective amount of a compound of Formula I-IV and optionally one or more additional antiviral agents is an amount that is effective to reduce a level in the serum of a fibrosis marker in the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more, compared to the marker level of an untreated individual or with an individual treated with placebo. Those skilled in the art can easily measure such liver fibrosis serum markers using standard analysis methods, many of which are commercially available and are used systematically in clinical facilities. Methods of measuring serum markers include immunology-based methods, for example, enzyme-linked immunosorbent assays (ELISA), radioimmunoassays and the like, using the antibody specific for a given serum marker. Quantitative functional liver reserve tests can also be used to determine the efficacy of treatment with an interferon receptor agonist and pirfenidone (or a pirfenidone analog). These include: indocyanine green clearance (ICG), galactose clearance (GEC), aminopyrin breathing test (ABT), antipitin clearance, monoethylglycine-xylidide clearance (MEG-X), and caffeine clearance. As used herein, a "complication associated with cirrhosis of the liver" refers to an alteration that is a sequela of decompensated liver disease, that is, or presents subsequently to and as a result of the development of liver fibrosis and includes but it is not limited to development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver failure, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation and liver-related mortality.

A therapeutically effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents is an amount that is effective to reduce the incidence (eg, the likelihood that an individual will develop) of an alteration associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% or more compared to an individual without treatment or with an individual treated with placebo. If treatment with a compound of Formulas I-IV and optionally one or more additional antiviral agents is effective in reducing the incidence of an alteration associated with cirrhosis of the liver it can be readily determined by those skilled in the art. The reduction in fibrosis of the liver increases liver function. Thus, the modalities provide methods for increasing liver function, it generally involves administering a therapeutically effective amount of a compound of Formulas I-IV and optionally one or more agents additional antivirals. Liver functions include but are not limited to protein synthesis such as whey proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferase (e.g., alanine transaminase, aspartate transaminase), 5 '-nucleosidase,? glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol and synthesis of bile acids; a metabolic function of the liver in which are included but not limited to carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function in which visceral hemodynamics and portal hemodynamics and the like are included. If a liver function is increased it can be easily determined by those skilled in the art, using well-established tests of liver function. Thus, the synthesis of liver function markers such as albumin, alkaline phosphagase, alanine transaminase, aspartate transaminase, bilirubin and the like can be determined by measuring these markers in serum, using standard immunological and enzymatic analysis. The portal splanchnic and hemodynamic circulation can be measured by portal wedge pressure and / or resistance using standard methods. The metabolic functions can be measured by measuring the level of ammonia in the serum.

If the serum proteins normally secreted by the hyphae are in the normal range, it can be determined by measuring the levels of such proteins using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples. The normal level of alanine transaminase is approximately 45 IU per milliliter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard analysis. Normal bilirubin levels are usually less than about 1.2 mg / dL. The albumin levels in the serum are measured using standard analysis. Normal levels of albumin in the serum are in the range of about 35 to about 55 g / l. The prolongation of prothrombin time is measured using standard analysis. The normal prothrombin time is less than about 4 seconds longer than the control. A therapeutically effective amount of a compound of Formula I-IV and optionally one or more additional antiviral agents, is one that is effective to increase liver function by at least about 10%, at least about 20%, at least about 25%, at least approximately 30%, so less 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. For example, a therapeutically effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents, is an amount effective to reduce a high level of a liver function serum marker by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, by at least about 50%, by less, about 55%, by at least about 60%, by at least about 65%, by at least about 70%, by at least about 75% or by at least about 80% or more or to reduce the level of the liver function serum within a normal range. A therapeutically effective amount of a compound of Formulas I-IV and optionally one or more additional antiviral agents, is also an amount effective to increase a reduced level of a serum marker of liver function by at least about 10%, by at least about 20%, by at least approximately 25%, by at least about 30%, by at least about 35%, by at least about 40%, by at least about 45%, by at least about 50%, by at least about 55%, by at least about 60%, by at least about 65%, by at least about 70%, by at least about 75% or by at least about 80% or more or to increase the level of serum liver function marker within a normal range.

Dosages, formulations and routes of administration In the present methods, in the active agent (s) (eg, compound of Formulas I-IV and optionally one or more additional antiviral agents) can be administered ( s) to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agent can be incorporated into a variety of formulations for therapeutic administration. More particularly, the agents of the embodiments can be formulated into pharmaceutical compositions by combination with acceptable pharmaceutically acceptable carriers or diluents and can be formulated into solid, semisolid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

Formulations The active agent (s) discussed above can be formulated using well-known reagents and methods. Compositions are provided in formulation with pharmaceutically acceptable excipient (s). A wide variety of pharmaceutically acceptable excipients are known in the art and do not need to be discussed in detail herein. Pharmaceutically acceptable excipients have been extensively described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams and Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., Eds., 7th ed., Lippincott, Williams and Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., Eds., 3rd ed. Amer. Pharmaceutical Assoc. The pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents are readily available to the public. In addition, pharmaceutically acceptable auxiliary substances, such as pH adjusting agents and pH regulating agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public. In some embodiments, an agent is formulated in a buffer solution of the aqueous pH. Regulatory solutions of Suitable aqueous pHs include, but are not limited to, pH regulating solutions of acetate, succinate, citrate, and phosphate ranging in intensities from about 5 mM to about 100 m. In some embodiments, the aqueous pH buffer includes reagents that provide an isotonic solution. Such reagents include but are not limited to, sodium chloride and sugars, for example, mannitol, dextrose, sucrose and the like. In some embodiments, the aqueous pH buffer also includes a non-ionic surfactant such as polysorbate 20 or 80. Optionally, the solutions may also include a preservative. Suitable preservatives include but are not limited to benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride and the like. In many cases, the formulation is stored at approximately 4 ° C. The formulations may also be lyophilized, in which cases they generally include cryoprotectants such as sucrose, trihalosa, lactose, maltose, mannitol and the like. The lyophilized formulations can be stored over extended periods of time even at ambient temperatures. As such, the administration of the agents can be obtained in various ways, which include oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc. administration. In many modalities, the administration is by bolus injection, for example, subcutaneous bolus injection, intramuscular bolus injection and the like. The pharmaceutical compositions of the embodiments can be administered orally, parenterally or via an implanted reservoir. Oral administration or administration by injection is preferred. Subcutaneous administration of a pharmaceutical composition of the modalities is carried out using standard methods and devices, for example, needle and syringe, a subcutaneous injection orifice administration system and the like. See, for example, U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137 and 6,017,328. A combination of a subcutaneous injection port and a device for administration of a pharmaceutical composition of the modalities to a patient by means of an orifice is referred to herein as "subcutaneous injection orifice delivery systems". In many embodiments, subcutaneous administration is obtained by administration of boluses by needle and syringes. In pharmaceutical dosage forms, the agents can be administered in the form of their pharmaceutically acceptable salts or can also be used alone or in appropriate selection, also as in combination with other pharmaceutically active compounds. The following methods and excipients are only exemplary and in no way limiting. For oral preparations, the agents may be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives such as lactose, mannitol, corn starch or parara starch; with binders, salts such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatin; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants such as talc or magnesium stearate and if desired with diluents, pH regulating agents, wetting agents, preservatives and flavoring agents. The agents can be formulated into injection preparations upon dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as vegetable oils or other similar oils, glycerides of synthetic aliphatic acids, esters of higher aliphatic acids or propylene glycol and, if desired, with conventional additives such as solubilizers, isotonic agents, dispersing agents, emulsifying agents, stabilizers and preservatives. In addition, the agents can be manufactured in suppositories by mixtures with a variety of bases such as emulsifying bases or water soluble bases. The compounds of the modalities can be administered rectally via a suppository. The suppository may include carriers such as cocoa butter, charcoal and polyethylene glycols, which melt at body temperature, and are still solidified at room temperature. Unit dosage forms for oral or rectal administration such as syrups, elixirs and suspensions may be provided wherein each dosage unit, eg, teaspoon, tablespoon, tablet or suppository, contains a predetermined amount of the composition containing one or more inhibitors. Similarly, the unit dosage forms by injection or intravenous administration may comprise the inhibitor (s) in a composition as a solution in sterile water, normal saline or other pharmaceutically acceptable carrier. The term "unit dosage form", as described herein, refers to physically discrete units suitable as unit dosages for human and animal supplies, each unit containing a predetermined quantity of compounds of the modalities calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for the new unit dosage forms of the modalities depend on the particular compound used and the effect to be obtained and the pharmacodynamics associated with each compound in the host. The pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents, are readily available to the public. In addition, pharmaceutically acceptable auxiliary substances, such as pH adjustment and pH regulating agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

Co-administration with other antiviral or antifibrotic agents A method present in some embodiments will be carried out by administering an NS3 inhibitor which is a compound of Formulas I-IV and optionally one or more additional antiviral agent (s). In some embodiments, the method further includes administering one or more interferon receptor agonist (s). In other embodiments, the method further includes the administration of pirfenidone or a pirfenidone analog. Additional antiviral agents that are suitable for use in combination therapy include, but are not limited to, nucleotide and nucleoside analogs. Non-limiting examples include azidothymidine (AZT) (zidovudine) and analogues and derivatives thereof; 2 ', 3' -dideoxyinosine (DDI) (didanosine) and analogs and derivatives thereof; 2X3'- dideoxycytidine (DDC) (dideoxycytidine) and analogues and derivatives thereof; 2X 3 '-dideshydro-2 3? Dideoxythymidine (D4T) (stavudine) and analogs and derivatives thereof; live together; abacavir; adefovir dopoxil; cidofovir; robavirin; ribavirin analogues and the like. In some embodiments, the method also includes the administration of ribavirin. Ribavirin, 1-β-riboduranosyl-lH-1,2,4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Cpsta Mesa, California, is described in the Merck Index, Compound No. 8199, 11th edition. Its manufacture and formulation is described in U.S. Patent No. 4,211,771. Some embodiments also involve the use of ribavirin derivatives (see, for example, U.S. Patent No. 6,277,830). Ribavirin can be administered orally in the form of a capsule or tablet or in the same or different administration form and in the same or different route as an interferon receptor antagonist. Of course, other types of administration of both drugs, as they become available, are contemplated, such as by nasal spray, transdermally, intravenously, by suppository, by sustained release dosage form, etc. Any form of administration will work so long as the appropriate dosages are administered without destroying the active ingredient. In some modalities, an additional antiviral agent it is administered throughout the course of the treatment of the NS3 inhibitor compound. In other embodiments, an additional antiviral agent is administered for a period of time that is overlapping with that of the treatment of the NS3 inhibitor compound, for example, the treatment of the additional antiviral agent may begin before treatment with the inhibitory compound of NS3 and finish before the end of the treatment of the NS3 inhibitor compound; the treatment of the additional antiviral agent may begin after the beginning of the treatment with the NS3 inhibitor compound and terminate after the treatment with the NS3 inhibitor compound ends; treatment with the additional antiviral agent may begin after treatment with the NS3 inhibitor compound begins and ends before the treatment with the NS3 inhibitor compound is terminated or treatment with the additional antiviral agent may begin before the start of the treatment. treatment with the NS3 inhibitor compound and terminates after the treatment with the NS3 inhibitor compound ends.

Methods of treatment Mono erapias The NS3 inhibitor compounds described herein can be used in acute or chronic therapy for HCV disease. In many modalities, the compound NS3 inhibitor is administered for a period from about one day to about seven days or about one week to about two weeks or about two weeks to about three weeks or about three weeks to about four weeks, or about one month to about two months, or approximately two months to approximately four months, or approximately four months to approximately six months, or approximately six months to approximately eight months, or approximately eight months to approximately twelve months, or for at least one year and may be administered in periods of time longer. The NS3 inhibitor compound can be administered five times a day, four times a day, tid, bid, qd, qod, biw, tiw, qw, 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, an NS3 inhibitor compound is administered orally. In relation to the methods described above for the treatment of HCV disease in a patient, an NS3 inhibitor compound as described herein may be administered to the patient at a dosage of about 0.01 mg to about 100 mg / kg of body weight of the patient per day, in one to five divided doses per day. In some embodiments, the NS3 inhibitor compound is administered at a dosage of about 0.5 mg to about 75 mg / kg of the patient's body weight per day in one to five divided doses per day. The amount of the active ingredient can be combined with carrier materials to produce a dosage form that can vary depending on the host to be treated and the particular mode of administration. A typical pharmaceutical formulation may contain from about 5% to about 25% of active ingredient (weight / weight). In other embodiments, the pharmaceutical preparation may contain from about 20% to about 80% active ingredient. Those of skill will readily appreciate that the dosage levels may vary as a function of the specific NS3 inhibitor compound, the severity of the symptoms and the subject's susceptibility to side effects. Preferred dosages for a given NS3 inhibitor compound can be readily determined for those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given interferon receptor agonist. In many embodiments, multiple doses of the NS3 inhibitor compound are administered. For example, an inhibitor compound of NS3 is administered once a month, twice a month, three times a month, a week yes and another no (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, a day yes and another no (qid), duarnually (qd), twice a day (qid) or three times a day (tid), in a period of time ranging from about one day to about a week, from about two weeks to about four weeks, about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about one year, from about one year to about two years or from about two years to about four years or more.

Patient identification In certain embodiments, the specific drug therapy regimen used in the treatment of the HCV patient is selected according to certain disease parameters exhibited by the patient, such as the initial viral load, HCV genotype in the patient, histology. of liver and / or stage of liver fibrosis in the patient. Thus, some embodiments provide any of the methods described above for the treatment of HCV infection in which the present method is modified. to treat a patient with treatment failure for a duration of 48 weeks. Other embodiments provide any of the methods described above for HCV in which the present method is modified to treat an unresponsive patient, wherein the patient receives a course of therapy for 48 weeks. Other embodiments provide any of the methods described above for the treatment of HCV infection in which the present method is modified to treat a relapsing patient, wherein the patient receives a course of therapy for 48 weeks. Other embodiments provide any of the methods described above for the treatment of HCV infection in which the present method is modified to treat a natural patient infected with HCV genotype 1, wherein the patient receives a course of therapy for 48 weeks. Other embodiments provide any of the methods described above for the treatment of HCV infection in which the present method is modified to treat a natural patient infected with HCV phenotype 4, wherein the patient receives a course of therapy for 48 weeks. Other modalities provide any of the methods described above for the treatment of HCV infection in which the present method is modified to treat a natural patient infected with HCV genotype 1, wherein the patient has a high viral load (HVL), where "HVL" refers to an HCV load greater than 2 x 106 copies of the HCV genome per my serum and where the patient receives a course of therapy 48 weeks One embodiment provides any of the methods described above for the treatment of HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient the drug therapy of the present method for a period of time from about 24 weeks to about 60 weeks or about 30 weeks to about one year or about 36 weeks to about 50 weeks or about 40 weeks to about 48 weeks or at least about 24 weeks or at least about 30 weeks or at least about 36 weeks or at least about 40 weeks or at least about 48 weeks or at least about 60 weeks Another embodiment provides any of the methods described above for the treatment of an infection of HCV, wherein the present method is modified to include the steps of (1) identifying a patient who has advanced or severe stage liver fibrosis as measured by a Knodell score of 3 or 4 and then (2) administering to the patient. The method drug therapy patient is present for a period of time from about 40 weeks to about 50 weeks or about 48 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV treatment, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and a viral load. initial greater than 2 million copies of viral genome per my patient's serum and then (2) administer to the patient the drug therapy of the present method for a period of time from 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 approximately 48 weeks, or at least approximately 60 weeks. Another modality provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load greater than 2 million copies of genome viral per my serum of the patient and then (2) administer to the patient the drug therapy of the present method for a period of time greater than about 40 weeks to about 50 weeks, or about 48 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load. more than 2 million viral genome copies per my patient's serum and none or premature stage liver fibrosis as measured by a Knodell score of 0, 1 or 2 and then (2) administer the patient's therapy drug of the present method for a period of time from about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least about 60 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load. greater than 2 million viral genome copies per my patient serum and none or premature stage liver fibrosis as measured by a Knodell score of 0, 1 or 2 and then (2) administer to the patient the therapy of drugs of the present method for a period of time from about 40 weeks to about 50 weeks, or about 48 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load. less than or equal to 2 million viral genome copies per my patient serum and then (2) administer to the patient the drug therapy of the present method for a period of time from about 20 weeks to about 50 weeks, or about 24 weeks at about 48 weeks, or about 30 weeks at about 40 weeks, or up to about 20 weeks, or up to about 24 weeks. weeks, or up to approximately 30 weeks, or up to approximately 36 weeks, or up to approximately 48 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load. less than or equal to 2 million copies of the viral genome per my patient's serum and then (2) administer to the patient the drug therapy of the present method for a period of time from about 20 weeks to about 24 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 infection and an initial viral load. less than or equal to 2 million copies of the viral genome per my patient serum and then (2) administering the drug therapy of the present method to the patient for a period of time from about 24 weeks to about 48 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then ( 2) administer to the patient the drug therapy of the present method for a period of time from about 24 weeks to about 60 weeks, or about 30 weeks to about a year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks, or so less about 24 weeks to about at least 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 methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then ( 2) administer to the patient the drug therapy of the present method for a period of time from 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. weeks or up to approximately 30 weeks or up to approximately 36 weeks or up to approximately 48 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then (2) administering the present method drug therapy to the patient for a period of time from about 20 weeks to about 24 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 2 or 3 infection and then ( 2) administer to the patient the drug therapy of the present method for a period of time of at least about 24 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV genotype 1 or 4 infection and then ( 2) administer to the patient the drug therapy of the present method for a period of time from about 24 weeks to about 60 weeks, or about 30 weeks to about one year, or about 36 weeks to about 50 weeks, or about 40 weeks to about 48 weeks or at least about 24 weeks, or at least about 30 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 48 weeks, or at least approximately 60 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of the genotypes. , 6, 7, 8 and 9 of HCV and then (2) administer to the patient the drug therapy of the present method for a period of time from about 20 weeks to about 50 weeks. Another embodiment provides any of the methods described above for the treatment of an HCV infection, wherein the present method is modified to include the steps of (1) identifying a patient having an HCV infection characterized by any of the genotypes 5, 6, 7, 8 and 9 of HCV and then (2) administer to the patient the drug therapy of the present method for a period of time of at least about 24 weeks and up to about 48 weeks.

Subjects suitable for treatment Any of the above treatment regimens may be administered to individuals who have already been diagnosed with HCV infection. Any of the above treatment regimens can be administered to individuals who have failed prior treatment for HCV infection ("treatment failure patients" in which those who do not respond and those who relapse are included). Individuals who have been clinically diagnosed as being infected with HCV are of particular interest in many modalities. Individuals who are infected with HCV are identified as having HCV RNA in their blood and / or having anti-HCV antibody in their serum. Such individuals include ELISA-positive anti-HCV individuals and individuals with a positive recombinant immunoabsorbent assay (RIBA). Such individuals may also, but do not need, elevated ALT levels in the serum. Individuals who are clinically diagnosed as being infected with HCV include natural individuals (eg, individuals not previously treated with HCV, particularly those who have not previously received therapy based on IFN-a and / or ribavirin) and individuals who have failed treatment previous by HCV (patients with "treatment failure"). Patients who fail treatment include those who do not respond (ie, individuals in whom the HCV titer was not significant or sufficiently reduced by previous treatment with HCV, for example, prior IFN-a monotherapy, combination of IFN-a and previous ribavirin or a combination therapy of IFN-a coated with PEF and previous ribavirin) and relapse (ie, individuals who were previously treated with HCV, for example, who received prior IFN-a monotherapy, a combination therapy of IFN-a and previous ribavirin, or a combination therapy of IFN-a coated with PEG and previous ribavirin, whose title of HCV decreased and then increased subsequently). In particular embodiments of interest, individuals have an HCV titre of at least about 105, at least about 5 x 105 or at least about 10d, or at least about 2 x 106, copies of HCV genome per milliliter of serum. The patient may be infected with any genotype of HCV (genotype 1, in which are included and Ib, 2, 3, 4, 6, etc. and subtypes (eg, 2a, 2b, 3a, etc.)); particularly a difficulty in treating genotype such as HCV genotype 1 in particular subtypes and quasispecies of HCV. Also of interest are HCV positive individuals (as described above) who exhibit severe fibrosis or premature cirrhosis (Child-Plug Class A non-decompensated or lower) or more advanced cirrhosis (Class B or C of decompensated Child-Plug) due to infection of Chronic HCV and that are viraemic despite previous antiviral treatment with therapies based on IFN-a or that can not tolerate therapies based on IFN-a or that have a contraindication to such therapies. In modalities of particular interest, HCV-positive individuals with stage 3 or 4 of Liver fibrosis according to the METAVIR scoring system are appropriate for treatment with the methods described herein. In other modalities, appropriate individuals for treatment with the methods of the modalities are patients with decompensated cirrhosis with clinical manifestations, which include patients with very advanced liver cirrhosis, in which those who wait for a liver transplant are included. In yet other embodiments, appropriate individuals for treatment with the methods described herein include patients with milder degrees of fibrosis in which those with premature fibrosis are included (stages 1 and 2 in the METAVIR, Ludwig and Scheuer scoring systems; stages 1, 2 or 3 in the Ishak scoring system).

Preparation of NS3 inhibitors The NS3 inhibitors in the following sections can be prepared according to the procedures and schemes shown in each section, the numbering in each NS3 Inhibitor Preparation Section are proposed for those specific sections only and should not be interpreted as or confused with the same numerations in other sections.

Methodology Preparation of NS3 inhibitors HCV helicase inhibitors can be prepared according to the procedures and schemes shown hereinafter. The synthesis of NS3 helicase inhibitors having Formula I is summarized in Reaction Scheme I. The general procedure below describes the reaction conditions for the synthesis of these compounds. R3 can be an alkyl group, for example, a methyl or ethyl group.

REACTION SCHEME 1 1 2 General procedure for the synthesis of Compounds of Formula I A solution of 2-isocyanatothiophene 1 (0.125 mmol / L in THF) is added to a solution of amino ester 2 (1.2 equivalents) and DIEA (ml / mmol of 2) in a appropriate amount of chloroform. The reaction is stirred at room temperature until all the isocyanate has been consumed (commonly 2-24 hours). Isocyanate is added on silica (5 equivalents) and the reaction is stirred at room temperature until the excess amino ester has been trapped (commonly 6-24 hours). The reaction is filtered and the filtrate concentrated in vacuo. The residue obtained is taken in an appropriate amount of 2-methoxyethanol and DIEA (1 ml / mmol of 1) is added. The reaction is stirred at room temperature for 24-36 hours. At this point the reaction is verified by LC-MS by the remaining 3-cyclized product. If significant amounts of 3 are found, the reaction mixture is heated to 60 ° C until the cyclization is complete. Once no intermediate 3 is detected, the reaction is concentrated in va cuo to obtain the crude product. If the crude product is not sufficiently pure, it can be modified using normal or reverse phase chromatography. The NS3 helicase inhibitors having Formula I shown in Table 3 were prepared as described above.

TABLE 3 General procedure for the synthesis of Compounds of Formula II REACTION SCHEME 2 equivalent acetate The substituted aryl cinnamide analogue 5 can be prepared according to the method illustrated in the Scheme of Reaction 1 using protocols published in the literature (O / 00139081, Marty Winn et al., J. Med. Chem. 2001 44 (25), 4393-4403). The diarylsulfide 3 intermediate can be prepared by the reaction of several halo benzaldehydes substituted (such as 2 or 4-fluorobenzaldehyde, 2 or 4-chlorobenzaldehyde) with various substituted thiophenols (for example: 4-fluorothiophenol, 2-methoxythiophenols or the like) in the presence of an appropriate base such as a potassium carbonate base, sodium carbonate, triethylamine or the like in a polar solvent (eg, DMF, DMA, acetone, methanol and the like). The resulting diarylsulfide aldehyde 3 can be reacted with an acetate equivalent such as malonic acid or triethoxyphosphonoacetate or other similar reagents to provide cinnamic acid 4 or the corresponding ester. In the case of the ester, it can be hydrolyzed with an organic base (such as LiOH, NaOH, KOH or the like) in a mixture of alcohol (for example ethanol, methanol) and water to provide the acid 4. Coupling of cinnamic acid 4 with a primary or secondary amine under bonding conditions of standard amine (which includes activation of the acid using thionyl chloride or dicyclohexylcarbodiimide and N-hydroxysuccinimide or the like) can provide the final cinnamide analogue 5. Alternatively, compound 8 can be prepared from the sequence shown in the Scheme of Reaction 3.

REACTION MODEL 3 equivalent acetate 6 Rß = alkyl ~~ | hydrolysis 7. R6 = H - A substituted para-nitro halo benzene analogue 1 can be reacted with a substituted arylthiol .2 (such as 4-fluorobenzothiol, 2-methoxybenzothiol and the like) in the presence of an appropriate base such as potassium carbonate, sodium carbonate, triethylamine or the like in a polar solvent (eg, DMF, DMA, acetone, methanol and the like) to provide the intermediate 3. Intermediate 3 can be converted to the corresponding aniline 4 by hydrogenation using a catalyst such as Pd / C , Pt / C, Pd (OH) 2, Pd (OAc) 2 and the like or with the use of Zn / EtOH, SnCl2 or the like. The aniline 5 can be converted to the corresponding diode or bromo analogue by standard Sandmeyer reaction conditions published in the literature. The cinnamide analog 6 can be prepared from the reaction of 5 with one equivalent of acetate such as triethoxyphosphonoacetate or other similar reagents. The resulting ester 6 can be hydrolyzed to the corresponding acid 7 using an inorganic base (such as LiOH, NaOH, KOH or the like) in a mixture of an alcohol (e.g., ethanol, methanol) and water. The final diarylsulfide compound 8 can be prepared from the reaction of acid 7 in a primary or secondary amine under conditions of standard amide bond formation (which includes activation of the acid using thionyl chloride or dicyclohexylcarbodiimide and N-hydroxysuccinimide or the like).

REACTION SCHEME 4 Reaction Scheme 3 illustrates the preparation of amino substituted cinnamides 4. The substituted halo benzaldehyde 1 (such as 2 or 4-fluorobenzaldehyde, 2 or 4-chlorobenzaldehyde) can be reacted with a primary or secondary amine (eg, methylamine, dimethylamine, morpholine, piperidine, substituted piperazines and the like) in the presence of a suitable base (such as potassium carbonate, sodium carbonate, triethylamine or the like) in a polar solvent ( example, DMF, DMA, acetone, methanol and the like). The resulting aldehyde 2 can be reacted with an equivalent acetate such as malonic acid or triethoxyphosphonoacetate or other similar reagents to provide cinnamic acid 3 or the corresponding ester. In the case of the ester, it can be hydrolyzed with an inorganic base (such as LiOH, NaOH, KOH or the like) in a mixture of an alcohol (for example, ethanol, methanol) and water to provide the acid 3. The coupling of the cinnamic acid 3 with a primary or secondary amine under conditions of standard amide bond formation (which includes activation of the acid using thionyl chloride or diclohexylcarbodiimide and N-hydroxysuccinimide or the like) can provide the final cinnamide analog 4.

REACTION SCHEME 5 The 2,3-dichloro substituted diarylsulfide 8 can be prepared from the Reaction Sequence described in the literature (O / 00139081). Bromide 2 can be prepared from the sprouting of phenol 1 with Br 2 in a non-polar solvent such as CH 2 C 12 or CHC 13 at a lower temperature (0 ° C at room temperature). Then, Heck coupling of this intermediate with alkyl acrylate would provide intermediate 3. Phenol 3 can be converted to triflate 4 by using triflicanhydride in CH2C12 or CHCI3 at a lower temperature (0 ° C to -20 ° C) in the presence from a base such as Hunig's base, triethylamine, lutidine or the like. The coupling of triflate 4 with a thiophenyl 5 can be carried out in the presence of a base (LiOcBu, KOfcBu or the like) in a polar solvent (DMF, NMP or the like) to provide the diarylsulfide analogue 6. The hydrolysis of the ester 6 can be obtained using a base such as LiOH, NaOH, KOH or the like in a mixture of solvents (eg, EtOH / water, MeOH / water, THF: MeOH / water or a similar solvent system). The coupling of cinnamic acid 7 with a primary or secondary amine under conditions of standard amine bond formation (which includes activation of the acid using thionyl chloride or dicyclohexylcarbodiimide and N-hydroxysuccinimide or the like) can provide the final cinnamide analog. .

Example 1 (E) -3- (2-Chloro-4- (4-fluorophenylthio) phenyl) -1- (4- (furan-3-carbonyl) piperazin-1-yl) prop-2-en-1-one Example IA (E) -3- (2-Chloro-4- (4-fluorophenylthio) -phenyl) acrylic acid Example A was prepared from the reaction of 4-fluorobenthiol with 2-chloro-4-fluorobenzaldehyde followed by condensation. with malonic acid according to the procedure described by Marty Winn et al., J. Med. Chem. 2001, 44 (25), 4393-4403.

Example IB (E) -3- (2-Chloro- (4-fluorophenylthio) phenyl) -1- (4- (furan-3-carbonyl) piperazin-1-yl) prop-2-en-l-one One solution of Example IA (60 mg, 0.194 mmol), HOBt. H20 (44.64 mg, 0.2915 mmol), N-methylmorpholine (64 μM, 0.583 mmol) and furan-3-yl (piperazin-1-yl) methanone (42 mg, 0.233 mmol) in DMF (1 mL) was treated with EDCI (56 mg, 0.292 mmol) and stirred at room temperature. After 18 hours, the mixture was diluted with CH2C12 (2 mL) and washed with water (2 mL). The CH2C12 layer was separated and purified directly by flash chromatography on silica gel (5 g of Alltech SEP packs) eluting with a step gradient of 30% EtOAc / hexane to provide the title compound (38 mg, 42% yield ) as white solid. LCMS (APCI) at m / z 469 (M-H). " Example 2 (E) -3- (2-Chloro-4- (4-fluorophenylthio) phenyl) -1- (piperidin-1-yl) prop-2-en-l-one Example 2 was prepared as described for Example IA (60 mg, 0.194 mmol), except substituting furan-3-yl (piperazin-1-yl) methanone with piperidine. The product was isolated in 68% yield (49 mg) after flash chromatography on silica gel. LCMS (APCI) "at m / z 374 (M-H)", Rt = .32 min.

Example 3 (E) -3- (2-Chloro-4- (4-fluorophenylthio) phenyl) -1-morpholinoprop-2-en-1-one Example 3 was prepared from Example IA (60 mg, 0.194 mmol ), according to the method described for Example IB, except substituting furan-3-yl (piperazin-1-yl) methanone with morpholine. LCMS (APCI) "at m / z 378 (M-H)", Rt = 3.82 min.

Example 4 (E) -3- (2-chloro-4- (4-fluorophenylthio) phenyl) -N, N-diethylacrylamide Example 4 (37 mg) was prepared from Example IA (60 mg, 0.194 mmol) according to the method described for the Example IB, except substituting furan-3-yl (piperazin-1-yl) methanone with diethylamine. LCMS (APCI) "at m / z 362 (M-H)", R = Example 5 (E) -methyl- (3- (2-chloro-4- (4-fluorophenylthio) phenyl) acryloyl) piperidine-4-carboxylate Example 5 (46 mg) was prepared from Example IA (60 mg , 0.194 mmol) according to the method described for the Example IB, except substituting furan-3-yl (piperazin-1-yl) methanone with methyl isonipecotate. LCMS (APCI) "at m / z 432 (M-H)", Rt = 4.08 min.

Example 6 Acid: E) -l- (3- (2-chloro-4- (4-fluorophenylthio) phenyl) acryloyl) piperidin-4-carboxylic acid The hydrolysis of Example 5 (40 mg, 0.095 mmol) with LiOH.H20 was carried out according to the procedure described in J. Med. Chem. 2001, 44 (25), 4393-4403 by Marty inn et al. , to provide the title compound as a white powder. LCMS (APCI) "at m / z 426 (M-H)", Rt = 2.99 min.

Example 7 3- (3- (2-Chloro-4- (4-fluorophenylthio) phenyl) acrylamido) benzoate (E) -methyl The title compound was prepared from Example 1A as described in Example IB except substituting furan-3-yl (piperazin-1-yl) methanone with methyl 3-aminobenzoate. Example 7 was isolated as a white powder. LCMS (APCI) "to m / z 441 (M-H) Example 8 (E) -3- (3- (2-Chloro-4- (4-fluorophenylthio) phenyl) acrylamido) benzoic acid Example 8 was prepared from Example 7 according to the method described for Example 6. The title compound was obtained as a white powder. LCMS (APCI) "at m / z 418 (M-H)". , Rt = 2.79 min.

Example 9 (E) -1- (4-acetylpiperazin-1-yl) -3- (2-chloro- (dimethylamino) phenyl) prop-2-en-1-one Example 9a (E) -3- (2-Chloro-4- (dimethylamino) phenyl) acrylic acid Example 9A was prepared from the reaction of 2-chloro-4-fluorobenzaldehyde with dimethylamine followed by Subsequent condensation with malonic acid as described for Example IA.

Example 9B (E) -1- (4-acetylpiperazin-1-yl) -3- (2-chloro-4- (dimethylamino) phenyl) prop-2-en-1-one The title compound (115 mg) was prepared from Example 9A as described for Example IB except substituting furan-3-yl (piperazin-1-yl) methanone with 1- (piperazin-1-yl) ethanone. LCMS (APCI) + at m / z 336 (M + H) +, Rt = 2. 73 min.

Example 10 (E) -3- (2-chloro-4- (dimethylamino) phenyl) -N- (2-morpholinoethyl) acrylamide Example 9A was processed as in Example IB except substituting furan-3-yl (piperazin-1) -yl) methanone with 2-morpholinoethenamine to provide the title compound (27.4 g). LCMS (APCI) + at m / z 338 (M + H) +, R t = 2.64 min.

Example 11 (E) -N- (3- (1H-imidazol-1-yl) propyl) -3- (2-chloro-4- (dimethylamino) phenyl) acrylamide Example 11 (15 mg) was prepared from Example 9A as described for Example IB except substituting furan-3-yl (piperazin-1-yl) methanone with 3- (1H-imidazol-1-yl) propan-1-amine. LCMS (APCI) + at m / z 333 (M + H) +, R t = 2.62 min.

Example 12 (E) -3- (2-Chloro-4- (dimethylamino) phenyl) -1- (4- (furan-3-carbonyl) piperazin-1-yl) prop-2-en-l-one Example 12 (69 mg) was prepared from Example 9A according to the method described for Example IB. LCMS (APCI) + at m / z 388 (M + H) + Rt = 3.81 min.

Example 13 (E) -3- (2-Chloro-4- (dimethylamino) phenyl) -1-morpholinoprop-2-en-l-one Example 13 (51.9 mg) was prepared according to the method described for Example IB except substituting furan-3-yl (piperazin-1-yl) methanone with morpholine. LCMS (APCI) + to m / z 295 (M + H) +, Rt = 3.01 min.

Example 14 1- (3- (2-Chloro-4- (dimethylamino) phenyl) acryloyl) piperidine-4-carboxylate of (E) -methyl The title compound (73 mg) was prepared from Example 9A as described for Example 5. LCMS (APCI) + at m / z 351 (M + H) +, Rt = 3.32 min.

Example 15 Acid: E) -l- (3- (2-chloro-4- (dimethylamino) phenyl) acryloyl) piperidinecarboxylic Example 15 (24 mg) was prepared from Example 14 as described for Example 6. LCMS (APCI) + at m / z 335 (MH) ", Rt = 2.19 min.

Example 16 (E) -3- (2-Chloro-4- (4-fluorophenylthio) -5-methylphenyl) -1- (piperidin-1-yl) prop-2-en-1-one Example 16A 1-Chloro-5-iodo-methyl-2-nitrobenzene Example 16A was prepared from 5-chloro-2-methyl-4-nitroaniline according to the method described in Tetrahedron Letters, 2005, 46 ( 18), 3197. XH NMR (400 MHz, DMSO d6) d 8.267 (s, 1H), 8.062 (s, 1H), 2.434 (s, 3H).

Example 16B (5-Chloro-2-methyl-4-nitrophenyl) (4-fluorophenyl) sulfane Example 16A was treated with 4-fluorobenzothiol as described in Organic Letters, 2002, 9 (20), 3517 to provide the compound of 87% performance title. 1 H NMR (400 MHz, DMSO d6) d 8.073 (s, 1H), 7.687-7.647 (m, 2H), 7.45-7.40 (m, 2H), 6.79 (s, 1H), 2.38 (s, 3H).

Example 16C 2-chloro-4- (4-fluorophenylthio) -5-methylaniline Example 16B was reduced according to the method described in Bioorganic & Medicinal Chemistry Letters, 2005, 15 (8), 2033-2039 to provide the title compound as a colorless oil (99% yield). * H NMR (400 MHz, DMSO d6) d 7.32 (s, 1H), 7.15-7.11 (m, 2H), 7.05-7.02 (m, 2H), 6.77 (s, 1H), 5.71 (br s, 2H) , 2.15 (s, 3H).

Example 16D (5-chloro-4-iodo-2-methylphenyl) (4-fluorophenyl) sulfane Example 16D was prepared from Example 16C (1.8 g, 6.723 mmol) according to the method described for Example 16A. 1 H NMR (400 MHz, DMSO d6) d 7.85 (s, 1H), 7.4-7.41 (m, 2H), 7.29-7.24 (m, 2H), 6.99 (s, 1H), 2.22 (s, 3H).

Example 16E 3- (2-Chloro-4- (4-fluorophenylthio) -5-methylphenyl) (E) -methyl acrylate Example 16E was prepared from the reaction of Example 16D with methyl acrylate according to the procedure described in WO / 00139081. NMR * H (400 MHz, DMSO d6) d 7.89 (s, 1H), 7.77 (d, J = 16.01 Hz, 1H), 7.54-7.51 (m, 2H), 7.35-7.31 (m, 2H), 6.79 ( s, 1H), 6.69 (d, J = 16.01 Hz, 1H), 3.71 (s, 3H), 2.29 (s, 3H).

Example 16F (E) -3- (2-Chloro- (4-fluorophenylthio) -5-methylphenyl) acrylic acid Example 16E (400 mg, 1188 mmol) was treated with LiOH.H20 as described for Example 6 to provide the yield title compound of 93% (300 mg). X H NMR (400 MHz, DMSO d6) d 12.61 (s, 1H), 7.89 (s, 1H), 7.75 (d, J = 16.01 Hz, 1H), 7.56-7.53 (m, 2H), 7.37-7.33 (m 2H), 6.83 (s, 1H), 6.61 (d, J = 16.01 Hz, 1H), 2.32 (s, 3H).

Example 16G (E) -3- (2-Chloro-4- (4-fluorophenylthio) -5-methylphenyl) -1- (piperidin-1-yl) prop-2-en-l-one Example 16G (53 mg ) was prepared from the Example 16F according to the method described for Example IB except substituting piperidine for 3-yl (piperazin-1-yl) methanone. LCMS (APCI) + at m / z 390 (M + H) +, R t = 4.56 min.

Example 17 (E) -3- (2-Chloro-4- (4-fluorophenylthio) -5-methylphenyl) -1- (4- (furan-3-carbonyl) piperazin-1-yl) prop-2-en- l -one The title compound (34 mg) was prepared from Example 16F as described for Example IB. LCMS (APCI) + at m / z 485 (M + H) +, R t = 4.02 min.

Example 18 (E) -3- (2-Chloro-4- (4-fluorophenylthio) -5-methylphenyl) -N, N-diethylacrylamide Example 16 was processed as in Example 4 to provide the title compound (49 mg ). LCMS (APCI) + to m / z 378 (M + H! Rt = 4.44 min.

EXAMPLE 19 3- (3- (2-chloro-4- (4-fluorophenylthio) -5-methylphenyl) acrylamido) propanoate of (E) -ethyl Example 19 was prepared from Example 16F according to the method for Example IB, except substituting furan-3-yl (piperazin-1-yl) methanone with ethyl 3-aminopropanoate. LCMS (APCI) + at m / z 421 (M + H) "1, R t = 4.21 min.

Example 20 (E) -3- (3- (2-Chloro-4- (4-fluorophenylthio) -5-methylphenyl) acrylamido) propanoic acid Example 20 was processed as in Example 6 to provide the title compound (39 mg). LCMS (APCI) "at m / z 392 [(M-H)", R t = 2.74 min.

Example 21 Acid -3- (3- (2-chloro-4- (4-fluorophenylthio) -5-methylphenyl) acrylamido) benzoic Example 21 (12 mg) was prepared from Example 16F and methyl 3-aminobenzoate followed by treatment by LiOH.H20 according to the method described for the preparation of Example 8. LCMS (APCI) "a / z 440 (MH)", Rt = 3.12 min.

Example 22 Acid?) -l- (3- (2-chloro-4- (4-fluorophenylthio) -5-methylphenyl) acryloyl) piperidine-4-carboxylic Example 22 (47 mg) was prepared from Example 16F as is described for Example 6. LCMS (APCI) "am / z 432 (MH)", Rt = 2.88 min.

Example 23 (E) -3- (2-Chloro-4- (4-fluorophenylthio) -5-methylphenyl) -1-morpholinoprop-2-en-l-one Example 23 (52 mg) was prepared from Example 16F according to the procedure described for Example 3.

LCMS (APCI) + at m / z 392 (M + H) +, Rt = 4. 05 min.

Example 24 (E) -3- (2-chloro-4- (2-methoxyphenylthio) phenyl) -N- (3- (dimethylamino) propyl) acrylamide Example 24A (E) -3- (2-Chloro-4- (2-methoxyphenylthio) phenyl) acrylic acid Example 24 was prepared from the reaction of 2-methoxybenzothiol and 2-chloro-4-fluorobenzaldehyde followed by condensation with malonic acid according to the procedure described by Marty Winn et al., J. Med. Chem. 2001, 44 (25), 4393-4403.

Example 24B (E) -3- (2-chloro-4- (2-methoxyphenylthio) phenyl) -N- (3- (dimethylamino) propyl) acrylamide Example 24B was prepared from Example 24A as described for Example IB, except replacing furan-3- il (piperazin-1-yl) methanone with N 11, N717I-dimethylpropan-1,3-diamine. LCMS (APCI) + at m / z 405 (M + H) +, Rt = 2,456 min Example 25 (E) -3- (2-Chloro-4- (2-methoxyphenylthio) phenyl) -? - (2- (1-methylpyrrolidin-3-yl) ethyl) acrylamide The title compound was prepared from Example 24A as is described for the preparation of Example IB, except substituting furan-3-yl (piperazin-1-yl) methanone with 2- (l-methylpyrrolidin-3-yl) ethanamine. LCMS (APCI) + at m / z 431 (M + H) +, Rt = 2.515 min.

Example 26 (E) -l- (3- (2-Chloro-4- (2-methoxyphenylthio) phenyl) acryloyl) piperidine-carboxylic acid Example 26 (49 mg) was prepared from Example 24A as described for Example 6. LCMS (APCI) "am / z 430 (MH)", Rt = 2.84 min.

Example 27 (E) -3- (2-Chloro-4- (2-methoxyphenylthio) phenyl) -1- (4- (furan-3-carbonyl) piperazin-1-yl) prop-2-en-l- One Example 24A was processed as in Example IB to provide the title compound. LCMS (APCI) "at m / z 483 (M-H)", Rt = 3.65 min.

Example 28 (E) -3- (2-Chloro-4- (2-methoxyphenylthio) phenyl) -N, N-diethylacrylamide Example 28 is prepared according to the method described for Example 18. LCMS (APCI) "am / z 376 (MH) ", Rt = 4.08 min.

Example 29 (E) -3- (3- (2-Chloro-4- (2-methoxyphenylthio) phenyl) acrylamido) propanoic acid Example 29 is prepared from Example 24A according to the procedure described in Example 20. LCMS (APCI) "at m / z 390 (M-H; Rt = 2. 54 min.

Example 30 (E) -3- (2-chloro-4- (2-methoxyphenylthio) phenyl) -1- (4- (pyrrolidin-1-yl) piperidin-1-yl) prop-2-en-l- ona Example 30 was prepared from Example 24A described for Example IB except substituting furan-3-yl (piperazin-1-yl) methanone with 4- (pyrrolidin-1-yl) piperidine. LCMS (APCI) + at m / z 457, 459 (M + H) +, Rt = 2.94 min Example 31 Acid E) -1- (3- (4- (4-fluorophenylthio) -2- [trifluorornethyl) phenyl) acryloyl) piperidine-4-carboxylic Example 31A (E) -3- (4- (4-fluorophenylthio) -2- (trifluoromethyl) phenyl) acrylaldehyde Example 31A is prepared from the reaction of 4-fluorobenzothiol with 4-fñuoro-2- (trifluoromethyl) benzaldehyde followed by condensation with malonic acid according to the procedure described for Example IA.

Example 31B [E) -1- (3- (4- (4-fluorophenylthio) -2- (trifluoromethyl) phenyl) acryloyl) piperidine-4-carboxylic acid The title compound (47 mg) was prepared from Example 31 according to the procedure described for Example 6. LCMS (APCI) "am / z 452 (MH)", Rt = 2.88 min.

Example 32 Acid (E) -l- (3- (2,3-dichloro-4- (2-methoxyphenylthio) phenyl) acryloyl) piperidine-4-carboxylic acid Example 32A 4-bromo-2,3-dichlorophenol ^ 2, 3-dichlorophenol was treated with Br2 in CH2C12 according to the method described in WO / 00139081. LCMS (APCI-) at m / e 241 (M + H) +.

Example 32B 3- (2, 3-dichloro-4-hydroxyphenyl) acrylate of (E) -methyl Example 32A was treated with methylacrylate in the presence of Pd2 (dba) 3, (Tol) 3P, triethylamine and anhydrous DMF (300 ml. ) as described in WO / 00139081. X H NMR (400 MHz, DMS0-d6). d 11.27 (s, 1H), 7.83 (d, J = 16.01 Hz, 1H), 7.77 (d, J = 8.98 Hz, 1H), 6.97 (d, J = 8.98 Hz, 1H), 6.53 (d, J = 16.01 Hz, 1H), 3.69 (s, 3H).

Example 32C (E) -3- (2,3-Dichloro-4- (2-methoxyphenylthio) phenyl) acrylic acid Example 32B was treated with 2,2,2-trifluoroacetic anhydride according to the literature protocol (O / 00139081) to obtain the corresponding triflate. Then the isolated product was treated with 2-methoxybenzothiol as described in WO / 00139081. Then, the isolated product was processed as in Example 16F to provide the title compound. X-NMR (400 MHz, DMSO-d6) d 12.65 (br s, 1H), 7.83 (d, J = 16.01 Hz, 1H), 7.74 (d, J = 8.59 hz, 1H), 7.61-7.56 (m, 1H) ), 7.53-7.51 (m, 1H), 7.25 (d, J = 8.20 Hz, 1H), 7.11-7.07 (m, 1H), 6.53-6.50 (m, 1H), 6.51 (d, J = 167.01 Hz, 1 HOUR) Example 32D (E) -l- (3- (2,3-Dichloro-4- (2-methoxyphenylthio) phenyl) acryloyl) piperidin-4-carboxylic acid Example 32C was treated with isonipecotic acid according to the procedure described for Example 5. Then the isolated product was treated with LiOH.H20 as described in Example 6 to provide the title compound. (400 MHz, DMSO-d6) .d 12.26 (br s, 1H), 7.79 (d, J = 8.59 Hz, 1H), 7.69 (d, J = 16.01 Hz, 1H), 7.56-7.51 (m, 1H) , 7.45-7.43 (m, 1H), 7.23-7.20 (m, 2H), 7.06-7.03 (m, 1H), 6.51 (d, J = 8.98 Hz, 1H), 4.27-4.21 (m, 1H), 4.10 -4.04 (m, 1H), 3.76 (m, 3H), 3.27 (m, 1H), 3.18-3.08 (m, 1H), 2.85-2.78 (m, 1H), 1.83-1.77 (m, 2H), 1.45 -1.35 (m, 2H).

REACTION SCHEME 6 General procedure: A solution of substituted phenylacryloyl chloride (2.50 mmol) in CH2C12 (2 mL) was added amine (2.75 mmol) followed by PS-DMAP (2.50 mmol) and stirred at room temperature for a weekend. The reaction mixture was filtered and concentrated to give title compounds in yields of 70-90% at high pyrex.

Example 33 (E) -3- (2-chlorophenyl) -N- (2-hydroxyethyl) acrylamide LC-MS: m / z 226.959 (M + l).

Example 34 (E) -3- (2-chlorophenyl) -1- (isoindolin-2-yl) prop-2-en-l-one LC-MS: m / z 285.197 (M + 1).

Example 35 (E) -3- (2-chlorophenyl) -N-phenylacrylamide LC-MS: m / z 259.133 (M + i; Table 4 TRI-FRET de-binding assay of HCV helicase The potency of the compound was determined by determining the compound's ability to inhibit DNA detachment in a time-resolved fluorescence quench analysis in Vi tro. The helicase substrate (Perkin Elmer, TruPoint Helicase Substrate) consisted of partially double-stranded DNA, with one strand of oligonucleotide labeled with a fluorescent europium chelate and the other strand marked with the QSY ™ 7 hutch. In the presence of helicase and ATP, this DNA is uncoiled and a large increase in fluorescence is observed. An excess of an unlabeled oligonucleotide (also from Perkin Elmer, TruePoint Helical Capture Strand) that is complementary to the quencher strand was also included in the analysis to prevent annealing of the europium and the QSY threads that are marked. The pH buffer of the analysis consisted of mM MOPS (pH 7.0), 500 μM MgCl2 and Triton X-100 at 0.005% (v / v) with DMSO that is present at a final concentration of 2% (v / v). The purified, recombinant full-length NS3 protein (1-631) was included in these analyzes at a final concentration of 2.5 nM. The compound was incubated with NS3 protein for 5 minutes in a 384 cavity Proxiplate ™ (Perkin Elmer) blank before the addition of the TruPoint Helicase Substrate (final concentration 4 nM), TruPoint Helicase Capture Strand (final concentration 15 nM) and ATP (final concentration 100 μM). The final reaction volume was 20 μl. Immediately after the addition of the substrates and capture strand, the initial velocities of the detangling reactions were determined at room temperature via an Envisiion plate reader (Perkin Elmer). The rates of reactions containing test compound were compared with those lacking the reprobate compound in order to evaluate the potency of the compound. The IC50 values were determined using the XLfit curve fitting programming elements (IDBS).

Analysis of BS3-NS4 protease Formation of NS3 complex with NS4A-2 E. Recombinant coli or Baculovirus full length NS3 was diluted to 3.33 μM with pH buffer and the material was transferred to an Eppendorf tube and placed in a water bath in a refrigerator at 4 ° C. The appropriate amount of NS4A-2 at 8.3 mM in the pH buffer of the analysis was added to an equal volume of NS3 in step 2.1.1 (conversion factor - 3.8 mg / 272 μl of pH buffer). The material was transferred to an Eppendorf tube and placed in a water bath in a refrigerator at 4 ° C. After equilibration at 4 ° C, equal volumes of NS3 and NS4A-2 solutions were combined in one tube Eppendorf, mixed gently with a manual pipettor and the mixture was piped for 15 minutes in the water bath to 4 ° C. The final concentrations in the mixture were 1.67 μm of NS3, 4.15 mM of NS4A-2 (molar excess of 2485 times NS4A-2). After 15 minutes at 4 ° C, the Eppendorf tube of NS3 / NS4A-2 was removed and placed in a water bath at room temperature for 10 minutes. NS3 / NS4A-2 was taken as an aliquot at appropriate volumes and stored at -80 ° C (NS3 from E. coli ran at 2 nM in the analysis, aliquoted at 25 μL, BV NS3 ran at 3 nM in the analysis, aliquot at 30 μl).

Analysis of NS3 inhibition Stage 2.2.5. The sample compounds were dissolved in 10 mM in DMSO and then diluted to 2.5 mM (1: 4) in DMSO. Commonly, the compounds were added to a test plate at a concentration of 2.5 mM, yielding after the dilution a starting concentration of 50 mM in the analysis inhibition curve. The compounds were serially diluted in the analytical pH buffer to provide test solutions at lower concentrations.

Stage 2.2.6. The NS3 / NS4A-2 of E. coli can be diluted to 4 nM of NS3 (1: 417.5 of concentrated solution of 1.67 μM -18 μl of concentrated solution of 1.67 μm + 7497 μl solution regulator of the pH of analysis). NS3 / NS4A-2 was diluted to 6 nM of NS3 (1: 278.3 of concentrated solution 1.67 μM-24 μL of 1.67 μM concentrated solution + 6655 μL of pH buffer for analysis). Stage 2.2.7. Using the manual multi-channel cleaner and taking care not to introduce bubbles into the plates, 50 μl of the pH buffer of the analysis was added to AO1 H01 cavities of a black Costar 96-well polypropylene storage plate. Stage 2.2.8. Using the manual channel multipipette and taking care not to introduce bubbles to the plate, 50 μ of diluted NS3 / NS4A-2, from stage 2.2.6 dueron added to cavities A02 H12 of the plate in step 2.2.7. Stage 2.2.9. Using the manual channel multipipetter and taking care not to introduce bubbles to the plate, 25 μl of the cavities in the drug dilution plate in step 2.2.5 were transferred to corresponding cavities in the analysis plate in step 2.2. 8 the tips in the multichannel pipettor were changed for each row of the transferred compounds. Stage 2.2.10. Using the manual channel multipleyer and taking care not to introduce bubbles to the plate, the cavities of the analysis plate in stage 2.2.9 were mixed when aspirating and supplying 35 rμl of the 75 μl in each cavity five times. The tips in the multichannel pipettor were changed for each row of mixed cavities. Stage 2.2.11. The plate was covered with a polystyrene plate cap and the plate from step 2.2.10 containing NS3 protease and sample compounds was pre-incubated 10 minutes at room temperature. While the plate in step 2.2.11 was pre-incubated, the RETS1 substrate was diluted in a 15 ml polypropylene entrifuge tube. The substrate of REST1 was diluted to 8 μM (1: 80.75 of concentrated solution 646 μM - 65 μL of concentrated solution 646 μM + 5184 μL solution regulating the pH of analysis). After the plate in stage 2.2.11 the pre-incubation was performed using the manual multichannel, 25 μl of the substrate were added to all the cavities in the plate. The content of the cavities was mixed rapidly, as in step 2.2.10, but mixing 65 μl of the 100 μl in the cavities. The plate was read in kinetic mode on the Gemini XS plate reader from Molecular Devices SpectraMax. Reader settings: Reading time: 30 minutes; Interval: 36seconds, Readings: 51,? of Excitation: 335 nm,? of Emission: 495 nm, cut 475 nm, Automix: off, Calibrated: once, PMT: high, Readings / cavity: 6, Vmax pts: 21 or 28/51 depending on the linearity of reaction. The IC50 were determined using a four-parameter curve fitting equation and converted to Ki using the following Km: NS3 of E. full length coli - 2.03 μM full length BV NS3 - 1.74 μM where Ki = IC50 / (1+ [S] / Km)) Quantification by ELISA of the selectable marker protein, neomycin phosphotransferase II (NPTII) in the dub-genomic replicon of HCV, GS4.3 The sub-genomic replicon of HCV (1377 / NS3-3X Accession No. AJ242652), stably maintained in HuH-7 hematoma cells was created by Lohmann et al. Science 285: 110-113 (1999). Cell culture containing replicon, designated GS4.3, was obtained from Dr. Christoph Seeger of the Cancer Research Institute, Fox Chase Cancer Center, Philadelphia, Pennsylvania. GS4.3 cells were maintained at 37 ° C, 5% C02, in DMEM (Gibco 11965-092) supplemented with 200mM L-glutamine (100X) (Gibco25030-081), non-essential amino acids (NEAA) (Biowhittaker 13-114E ), thermal inactivated fetal bovine serum (FBS) (Hl) (Hyclone SH3007.03) and 750 μg / ml geneticin (G418) (Gibco 10131-035). The cells were subdivided 1: 3 or 4 each 2-3 days 24 hours before the analysis, the GS4.3 cells were collected, counted and deposited in 96-well plates (Costar 3585) at 7500 cells / well in a standard maintenance medium of 100 μl (above) and incubated under the above conditions. To start the analysis, the culture medium was removed, the cells were lacquered once with PBS (Gibco 10010-023) and 90 μl of Analysis Medium (DMEM, L-glutamine, NEAA, 10% Hl GBS without G418) was aggregate. The inhibitors were made as a 10X concentrated solution in Analysis Medium (3-fold dilutions from 10 μM to 56 pM final concentration, concentration of 1% FINAL DMSO), 10 μL were added to cavities in duplicate, the plates were shaken for mixing and incubated as above for 72 hours. An NPTII ELISA kit was obtained from AGDIA, Inc. (Compound direct ELISA test system for Neomycin Phosphotransferase II, PSP 73000/4800). The manufacturer's instructions were followed with some modifications. 10X PEB-1 lysis buffer was composed to include 500 μM PMSF (50 mM concentrated solution in isopropanol, Sigma P7626). After incubation for 72 hours, the cells were washed once with PBS and 150 μl of PEB-1 with PMSF were added per well. The plates were vigorously stirred for 15 minutes, at room temperature, then frozen at -70 ° C. The plates were thawed, the lysates were thoroughly mixed and 100 μl were applied to an Elisa NPTII plate. A standard curve was made. The lysate of control cells treated with DMSO was accumulated, serially diluted with PEB-1 with PMSF and applied to duplicate cavities of ELISA plate, in an initial lysate cavity range of 150μl-2.5ul. In addition, 100 μl of pH buffer solution alone was applied in duplicate as a blank. The plates were sealed and gently shaken at room temperature for two hours. Following the capture incubation, the plates were washed 5X with 300 μl with PBS-T (0.5% Tween-20, PBS-T was supplied in the ELISA kit). For detection, a dilution IX di conjugate of MRS-2 diluent enzyme (5X) was made in PBS-T, to which 1: 100 dilutions of enzyme conjugates A and B were added, according to the instructions. The plates were resealed and incubated with shaking, covered at room temperature for two hours. Then the wash was repeated and 100 μl of TMB substrate at room temperature were added. After approximately 30 minutes of incubation (room temperature, shaking covered), the reaction was stopped with 50 μl of 3M sulfuric acid. Plates were read at 450 nm in a Molecular Devices plate reader Versamax The effect of the inhibitor was expressed as a percentage of the control signal expressed with DMSO and the inhibition curves were calculated using an equation of four parameters: y = A + ((BA) / (1+ ((C / x) D) ))), where C is the maximum average activity or EC50. where: A indicates an IC50 or EC50, as indicated below 50 μM B indicates an IC50 or EC50, as indicated below 10 μM C indicates an IC50 or EC50, as indicated below 1 μiM YD indicates an IC50 or EC50, as indicated below 0.1 μM Conclusion Inhibitors of potent HC3 NS3 helicase molecules have been developed. While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in the art that various changes and equivalents may be made may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt to a situation, material, composition of matter, process, stage of process or particular stages, to the objective, spirit and scope of the present invention. It is intended that all such modifications be within the scope of the claims appended hereto.

Claims (1)

1. CLAIMS 1. A compound of the formula (I): characterized in that: R1 is an optionally substituted aryl, an optionally substituted heterocyclyl comprising at least one of N, O or S, optionally substituted arylalkyl or an optionally substituted heterocyclylalkyl comprising at least one of N, O or S in the system of heterocyclyl; R2, R3 and R4 are each individually selected from the group consisting of H, Ci to C2o or optionally substituted alkyl, Ci to C2 or optionally substituted alkenyl, Ci to C2 or optionally substituted alkynyl, C3 to C2 or optionally substituted partially or fully saturated cycloalkyl, C3 to C2o optionally substituted partial or fully saturated heterocyclic, C5 to C2o optionally substituted aryl, C to C2o optionally substituted heteroaryl, C6 to C20 optionally substituted arylalkyl, optionally substituted C3 to C2 or cycloalkylalkyl, C5 to C20 optionally substituted heteroarylalkyl, C3 to C20 heterocyclylalkyl optionally substituted, Ci to C20 alkoxy optionally substituted, C5 to C2o optionally substituted aryloxy, Ci to C20 optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C20) alkylamino, cyanoamino, nitro, carbamyl, keto , carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof or at least two of R2, R3 and R4 are joined to form a ring, wherein the ring is a ring of 3 to 20 members unsubstituted or substituted, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen and sulfur; Where the formula (I) does not include the following structure: 2. The compound according to claim 1, characterized in that R1 is an optionally substituted aryl or an optionally substituted heterocyclyl which comprises at least one of N, O or S. 3. The compound according to claim 1, characterized in that R2, R3 and R4 are each individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, C3 to C2 or optionally substituted partially or fully saturated cycloalkyl, C5 to C20 optionally substituted aryl, C2 or arylalkyl optionally substituted, C to C20 optionally substituted cycloalkylalkyl, C5 to C2o or optionally substituted heteroarylalkyl, C3 to C2 or optionally substituted heterocyclylalkyl, carbamyl, keto, carbonyl, carboxy, and combinations thereof. 4. The compound according to claim 1, characterized in that at least two of R2, R3 and R4 are joined to form a ring, wherein the ring is a ring of 3 to 7 members unsubstituted or substituted, wherein Ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur. 5. The compound according to claim 2, characterized in that R1 is thiophene. 6. The compound according to claim 5, characterized in that R2, R3 and R4 are each individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, C3 to C2 or optionally substituted partial or fully saturated cycloalkyl, C5 to C2o optionally substituted aryl, C20 optionally substituted arylalkyl, C3 to C2 or cycloalkylalkyl optionally substituted, C5 to C2o optionally substituted heteroarylalkyl, C3 to C2o optionally substituted heterocyclylalkyl, Ci to C2o optionally substituted alkoxy, carbamyl, keto, carbonyl, carboxy, and combinations thereof. 7. The compound according to claim 5, characterized in that at least two of R2, R3 and R4 are joined to form a ring, wherein the ring is a ring of 3 to 7 members unsubstituted or substituted, wherein Ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur. 8. The compound according to claim 2, characterized in that R1 is substituted phenyl. 9. The compound according to claim 8, characterized in that R2, R3 and R4 are each individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, C3 to C2 or optionally substituted partial or fully saturated cycloalkyl, C5 to C20 optionally substituted aryl, β to C2 or optionally substituted arylalkyl, C3 to C20 optionally substituted cycloalkylalkyl, C5 to C20 optionally substituted heteroarylalkyl, C3 to C0 optionally substituted heterocyclylalkyl, Ci to C2o optionally substituted alkoxy, carbamyl, keto, carbonyl, carboxy, and combinations thereof. 10. The compound according to claim 8, characterized in that at least two of R2, R3 and R4 are joined to form a ring, wherein the ring is an unsubstituted or substituted 3 to 7 membered ring, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur. 11. The compound according to claim 1, characterized in that it has a formula selected from 1-1 to I- 183 12. A compound of the formula (I wherein: R 12, R 13, R 14, and R 17 are selected individually from the group consisting of H, Ci to C 2 or optionally substituted alkyl, Ci to C 2 or optionally substituted alkenyl, Ci to C 20 allyl optionally substituted, C 3 to C 2 or cycloalkyl partially or fully saturated optionally substituted, C3 to C2n optionally substituted partial or fully saturated heterocycle, C5 to C20 optionally substituted aryl, or C2 to C20 optionally substituted heteroaryl, Ci to C2n optionally substituted alkoxy, C5 to C20 aryloxy optionally substituted, Ci to C20 optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C20) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 and R16 are individually selected from the group consisting of H, Ci to C2o optionally substituted alkyl, Ci to C20 alkenyl optionally. Ci substituted C20 alkynyl optionally substituted C3 to C2o optionally substituted partially or fully saturated cycloalkyl, C3 to C20 optionally substituted partial or fully saturated heterocyclic, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, C3 to C20 optionally substituted heterocylalkyl, C5 to C20 optionally substituted heteroarylalkyl, Ci to C2o optionally substituted alkoxy, Ci to C2o optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, mono- and di- (C? A C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl , glycyl, hydrazino, guanylyl and combinations thereof, or R15 and R16 together form a ring wherein the ring is a ring of 3 to 7 membered or unsubstituted members, wherein the ring members are selected from the group consisting of carbon, nitrogen, oxygen or sulfur; wherein formula (II) does not include the following structures: 13. The compound according to claim 12, wherein R12, R13, R14, and R17 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C2 or optionally substituted alkenyl, Ci to C20 alkynyl optionally substituted, Ci to C20 optionally substituted alkoxy, Ci to C20 optionally substituted alkylthio, halo, cyano, mercapto, hydroxy, mono- and di- (C? A C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl and carboxy. The compound according to claim 12, wherein R15 and Rld are individually selected from the group consisting of H, Ci to C2o or optionally substituted alkyl, Ci to C2o or optionally substituted alkenyl Ci to C2o or optionally substituted alkynyl, mono- and di- - (C ?a C2o) C5 to C2 alkylamino optionally substituted aryl, C3 to C2o optionally substituted heterocyclylalkyl, C5 to C2o or optionally substituted heteroarylalkyl, carbamyl, keto, carbonyl, carboxy and combinations thereof. 15. The compound according to claim 12, characterized in that R15 and R16 together form a ring wherein the ring is a ring of 4 ad-substituted or unsubstituted members, wherein the ring members are selected from the group consisting of of carbon, nitrogen, oxygen and sulfur. 16. The compound according to claim 12, characterized in that it has the formula (III): wherein: R 11 is H, halo, C x to C 20 optionally substituted alkyl, Ci to C 2 or optionally substituted alkenyl Ci to C 20 allyl optionally substituted or Ci to C 20 alkoxy optionally substituted; R12, R13, and R14 are individually selected from the group consisting of H, Ci to C2o, optionally substituted alkyl, Ci to C2o, optionally substituted alkenyl, Ci to C2o, optionally substituted alkynyl, C3 to C20, partially or fully saturated cycloalkyl optionally substituted, C3 to C2o partially or fully saturated heterocyclic optionally substituted C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, C3 to C2o optionally substituted alkoxy, C5 to C20 optionally substituted aryloxy, Ci to C2o optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxyl and combinations thereof, wherein none of R12, R13, R14, and R17 are H. R15 and R16 are individually selected from the which consists of H, Ci to C2o, optionally substituted alkyl, Ci to C2o, or optionally substituted alkenyl Ci to C2o or optionally substituted alkynyl C3 to C2 or partial cycloalkyl or fully saturated optionally substituted, C3 to C20 partially or fully saturated heterocyclic optionally substituted, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, C2 to C20 optionally substituted heteroaryl, C3 to C2 or optionally substituted heterocylalkyl, C5 to C2 or optionally substituted heteroarylalkyl Ci to C20 optionally substituted alkoxy, C5 to C20 optionally substituted aryloxy, Ci to C2o optionally substituted alkylthio, Ci to C20 optionally substituted arylthio, mono- and di- (Ci to C20) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl , glycyl, hydrazino, guanylyl and combinations thereof, or R15 and R16 together form a ring wherein the ring is a ring of 3 to 7 substituted or unsubstituted members, wherein the ring members are selected from the group consisting of of carbon, nitrogen, oxygen or sulfur. 17. The compound according to claim 16, characterized in that R11 is H, halo, Ci to C20 optionally substituted alkyl or Ci to C20 optionally substituted alkoxy. 18. The compound according to claim 16, characterized in that R12, R13, and R14 are individually selected from the group consisting of H, Ci to C2o or optionally substituted alkyl, Ci to C20 optionally substituted alkoxy, Ci to C2 or optionally substituted alkylthio, halo, cyano, mercapto, hydroxy, mono- and di- (C? a C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof; wherein none of R12, R13, R14, and R17 are H. 19. The compound according to claim 16, characterized in that R12, R13, and R14 are individually selected from the group consisting of H, Ci to C2o or optionally substituted alkyl C3 to C2o optionally substituted cycloalkyl, C3 to C20 optionally substituted heterocyclic, C5 to C2o optionally substituted aryl, C2 to C2o optionally substituted heteroaryl, C3 to C2o optionally substituted heterocyclylalkyl, C5 to C2 or optionally substituted heteroarylalkyl, Ci to C2o or optionally substituted alkoxy, mono- and di- (Ci to C2o) alkylamino,, nitro, carbamyl, keto, carbonyl, carboxy and combinations thereof. 21. The compound according to claim 16, characterized in that R15 and Rld together form a ring wherein the ring is a ring of 4 to 6 substituted or unsubstituted members, wherein the ring members are selected from the group that consists of carbon, nitrogen, oxygen or sulfur. 22. The compound according to claim 16, characterized in that R is fluoro and R, R and R are selected individually from the group consisting of H, alkyl and halo. 23. The compound according to claim 16, characterized in that it has the formula selected from II-1 to 11-82. 24. A compound according to claim 12, characterized in that it has the formula: 25. The compound according to claim 24, characterized in that it has a formula selected from II-1 to 11-82. 26. A compound of the formula (IV): wherein: R12, R13, R14, and R17 are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C20 optionally substituted alkenyl, Ci to C2o optionally substituted alkynyl, C3 to C20 partially or fully saturated cycloalkyl optionally substituted, C3 to C2o optionally substituted partially or fully saturated heterocyclic, C5 to C20 optionally substituted aryl, or C2 to C2o optionally substituted heteroaryl, C2 to C2o optionally substituted heteroaryl, Ci to C2o optionally substituted alkoxy, C5 to C2 or optionally substituted aryloxy, C to C2o optionally substituted alkylthio, Ci to C2 or optionally substituted arylthio, halo, cyano, mercapto, hydroxy, mono- and di- (Ci to C2o) alkylamino, cyanoamino, nitro, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl, sulfamyl, sulfonyl, sulfinyl, thiocarbonyl, thiocarboxy and combinations thereof; wherein not all of R12, R13, R14 and R17 are H; R15 and Rld are individually selected from the group consisting of H, Ci to C20 optionally substituted alkyl, Ci to C20 alkenyl optionally substituted Ci to C2o or optionally substituted C3 to C2 alkynyl or partially or fully saturated cycloalkyl optionally substituted, C3 to C2o partially or fully saturated heterocyclic optionally substituted, C5 to C2o optionally substituted aryl, C2 to C20 optionally substituted heteroaryl, C3 to C2 or optionally substituted heterocylalkyl, C5 to C2 or optionally substituted heteroarylalkyl, Ci to C2o optionally substituted alkoxy, Ci to C2 or optionally substituted alkylthio, Ci to C2o optionally substituted arylthio, mono- and di- (C? A C20) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl and combinations thereof R18 is selected from the group consisting of H, Ci to C2o optionally substituted alkyl, Ci to C2o optionally substituted alkoxy, Ci to C2o optionally substituted alkoxy, mono- and di- (C? A C2o) alkylamino, carbamyl, keto, carbonyl, carboxy, glycolyl, glycyl, hydrazino, guanylyl and combinations thereof. 27. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable excipient and a compound according to any of the preceding claims. 28. A method for modulating NS3 activity, characterized in that it comprises contacting an NS3 protein with an effective amount of a compound or composition according to any of the preceding claims. 29. The method according to claim 28, characterized because the contact occurs ex vivo. 30. The method according to claim 28, characterized in that the contact occurs in vivo. 31. The method according to claim 30, characterized in that the contact occurs in a human body. 32. The method according to claim 31, characterized in that it comprises identifying a person having hepatitis C. 33. The method according to claim 28, characterized in that the NS3 protein comprises an NS3 helicase domain. 34. The method according to claim 28, characterized in that it comprises inhibiting the NS3 helicase activity. 35. A compound comprising at least one functional group configured to facilitate the binding of the compound to the NS3 helicase, characterized in that the linkage is effective to modulate NS3 helicase activity. 36. The compound according to claim 35, characterized in that the binding is effective to inhibit the coiling of a nucleic acid substrate by the NS3 helicase. 37. The compound according to claim 35, characterized in that the link facilitates the allosteric movement of the NS3 helicase. 38. The compound according to claim 35, characterized in that the nucleic acid substrate is DNA or RNA. 39. The compound according to claim 35, characterized in that the functional group is configured to facilitate the binding of the compound to Domain 1 of helicase NS3. 40. The compound according to claim 39, characterized in that the functional group is configured to facilitate the link of the. compound to at least one residue in Domain 1 of NS3 helicase. 41. The compound according to claim 40, characterized in that the waste is one of any of the Residues 209 to 221, Residues 286 to 288, Wastes 317 to 319 or Residues 214 to 218. 42. The compound according to the claim 35, characterized in that the functional group is configured to facilitate the binding of the compound to Domain 2 of helicase NS3. 43. The compound according to claim 42, characterized in that the functional group is configured to facilitate the binding of the compound to at least one residue of Domain 2 of helicase NS3. 44. The compound according to claim 43, characterized in that the residue is any one of Residuals 412 to 423, Residue 363, Residue 365, Residue 406, Residue 408, Residue 391, Residue 397, Residue 400 or Residues 400 to 404. 45. The compound according to claim 35, characterized in that the modulating activity is inhibition. 46. The compound according to claim 35, characterized in that the compound is any of 1-1 to 1-183 and II-1 to 11-82 as described in the specification. 47. A pharmaccal composition characterized in that it comprises a compound according to claim 35 and a pharmaccally acceptable carrier. 48. The pharmaccal composition according to claim 47, characterized in that the compound is any of 1-1 to 1-183 and II-1 to 11-82 as described in the specification. 49. A modulation method of NS3 helicase characterized in that it comprises contacting an NS3 protein with a compound according to claim 35. 50. The method according to claim 49, characterized in that the contact occurs ex vivo. 51. The method according to claim 49, characterized in that the contact occurs in vivo. 52. The method according to claim 51, characterized in that the contact occurs in a human body. 53. The method according to claim 51, characterized in that it also comprises a step of identifying a person having hepatitis C. 54. A compound or composition according to any of claims 1-27 for use in modulating the activity of an NS3 protein. 55. The compound or composition according to claim 54, characterized in that the protein is ex vivo. 56. The compound or composition according to claim 54, characterized in that the protein is in vi vo. 57. The compound or composition according to claim 56, characterized in that the protein is in a human body. 58. The compound or composition according to claim 54, for use in the treatment against hepatitis C. 59. The compound or composition according to claim 54, characterized in that the NS3 protein comprises an NS3 helicase domain. 60. The compound or composition according to claim 54, for use in inhibiting NS3 helicase activity. 61. The compound or composition according to claim 54, for use in the modulation of NS3 helicase activity from an NS3 protein. 62. The compound or composition according to claim 61, characterized in that the protein is ex vivo. 63. The compound or composition according to claim 61, characterized in that the protein is in vivo. 64. The compound or composition according to claim 63, characterized in that the protein is in a human body. 65. The compound or composition according to claim 61, for use in the treatment against hepatitis C.