MX2008009479A - Viral polymerase inhibitors - Google Patents

Abstract

Compounds of formula (I):wherein X, R2, R3, R5and R6are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.

Description

VIRAL POLYMERASE INHIBITORS FIELD OF THE INVENTION The present invention relates to compounds, compositions and methods for the treatment of an infection with the hepatitis C virus (HCV). In particular, the present invention provides new inhibitors of the NS5B polymerase of hepatitis C virus, pharmaceutical compositions containing these compounds and methods for using these compounds in the treatment of HCV infection. BACKGROUND OF THE INVENTION It is estimated that at least 130 million people worldwide are infected with the hepatitis C virus (HCV). Acute HCV infection progresses to chronic infection in a large number of cases and, in some infected individuals, chronic infection leads to serious liver diseases, such as cirrhosis and hepatocellular carcinoma. Currently, the standard treatment of a chronic hepatitis C infection involves the administration of pegylated interferon-alpha in combination with ribavirin. However, this therapy is not effective in reducing HCV RNA to undetectable levels in many infected patients and is associated with often intolerable side effects such as fever and other flu-like symptoms, depression, thrombocytopenia and hemolytic anemia. . In addition, some patients infected with HCV have co-existing conditions, which contraindicates this treatment. Therefore, there is a need for alternative treatments for viral infection of hepatitis C. A possible strategy to meet this need is the development of effective antiviral agents that inactivate viral or host cells that are essential for the replication of the virus. HCV is a positive strand-coated RNA virus of the Hepacivirus genus of the Flaviviridae family. The single chain HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF), flanked by 5 'and 3' untranslated regions. The 5 'untranslated region of HCV is 341 nucleotides in length and functions as an entry site to the internal ribosome for the initiation of the independent translation cap structure. The open reading frame encodes a single large polyprotein of approximately 3000 amino acids that is cleaved at multiple sites by cellular and viral proteases to produce the mature, structural and non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B). The viral protease NS2 / 3 cleaves at the NS2-NS3 junction; whereas the NS3 viral protease mediates the cleavages located downstream of NS3, at the cleavage sites of NS3-NS4A, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. The NS4A protein acts as a co-factor for the NS3 protease and may also aid in membrane localization of NS3 and other viral replicase components. Although the phosphoproteins NS4B and NS5A are also possible components of the replicase, their specific functions are unknown. The NS5B protein is the elongation subunit of the HCV replicase that possesses RNA-dependent RNA polymerase (RdRp) activity. The development of new and specific anti-HCV treatments is a high priority, and the specific functions of the virus, essential for replication, are the most attractive objectives for the development of drugs. The absence of RNA-dependent RNA polymerases in mammals, and the fact that it is enzyme seems to be essential for the replication of the virus, suggests that the NS5B polymerase is an ideal target for anti-HCV therapeutics. Recently, mutations that destroy NS5B activity have been shown to suppress RNA infectivity in a chimpanzee model (Kolykhalov, AA; Mihalik, K .; Feinstone, SM; Rice, CM; 2000 J. Virol. 74: 2046 -2051). THE INVENTION The present invention provides a new series of compounds having inhibitory activity against HCV polymerase. In particular, the compounds according to this invention inhibit the synthesis of RNA by the RNA-directed RNA polymerase of HCV, especially the NS5B enzyme encoded by HCV. An additional advantage of the compounds provided by this invention is their low to very low, or even nonsignificant activity, against other polymerases. Additional objectives of the invention arise for the person skilled in the art from the following description and examples. One aspect of the invention provides compounds of formula (I): where: X is selected from O and S; R2 is aryl, optionally substituted with R20, wherein R20 is 1 to 5 substituents, each independently selected from: a) halo, (C-6) alkyl, haloalkyl (Ci-β), (C 3-7) cycloalkyl or (C3-7) cycloalkyl- (Ci-6) alkyl, b) -N (R7) R8 or -YN (R7) R8, wherein Y is selected from -C (= 0) -, -S02- and -alkylene (C1-6), R7 is independently selected from H and (C1-6) alkyl, and R8 is selected, in each case independently, from H, alkyl (Ci-6), haloalkyl (Ci-6) ), (C3-7) cycloalkyl, (C3-7) cycloalkyl- (C1-6) alkyl. aryl, Het, -C (= 0) -R9, -C (= 0) OR9 and -C (= 0) NHR9, wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl ( Ci-6), cyano, -NH2, -NHalkyl (Ci-4) or -N ((Ci-4) alkyl) 2, and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (C1-6), -SO2alkyl (C1.6), -NHalkyl (Ci-4), -N ((1-4C) alkyl) 2 or ii) (C 1-6) alkyl, optionally substituted with -OH or -O-alkyl (Ci-β); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-β); and wherein R9 is selected from: i) alkyl (Cie), optionally substituted with -COOH, -NH2) -NHalkyl (C1-4) or -N (C1-4alkyl)) 2, and ii) Het, optionally substituted with alkyl (?? - ??), or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S, or a heteropolycycle of 7 to 14 members, which optionally contains 1 to 3 additional heteroatoms, each independently selected from N, O and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, halo (C1-6) alkyl, -SO2alkyl (C1-6), -NH (C 1-4) alkyl, -N (C 1-4 alkyl) 2 or -NH-C (= O) (C -4) alkyl) (C 1-6) alkyl, optionally substituted with -OH or - O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-β), c) aryl, aryl-alkyl (Ci-6), Het or Het-alkyloyl ), wherein each of the aryl, aryl-alkyl (Ci-6), Het and Het-alkyl (Ci-6) is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (C1-6), -SO ^ Ikyloid-e), -C (= O) -NH2, -C (= O) -NHalkyl (C1-4) , -C (= O) -N ((1-4C) alkyl) 2, -NH 2 1 -NHalkyl (Ci-4), -N ((C 1-4) alkyl) 2 or -NH-C (= O) alkyl (C -4), ii) alkyl (Ci-β), optionally substituted with -OH or -O-alkyl (Ci-β); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or (C1-6) alkyl, and d) -C (= O) -R10, -O-R10, -C (= O) ) -O-R10, -alkylene (Ci.6) -O-R10, -S-R10, -SO-R10, -SO2-R10, -alkylene (C1-6) -S-R10, -alkylene ( C1-6) -SO-R10 or -alkylene (Ci-6) -SO2-R10, wherein R10 is selected, in each case independently, from H, (C1-6) alkyl, haloalkyl (Ci-6), cycloalkyl (C3-7). (C3-7) cycloalkyl-alkyl (Ci-6), aryl and Het; wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6), cyano, -NH2, or -N ((Ci-4) alkyl) 2; and where each of the aril and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C-6), -C (= O) -alkyl (C-6), -SO 2 (C 1-6) alkyl , -C (= O) -NH2, -C (= O) -N ((1-4C) alkyl) 2, -NH2, -NHalkyl (Ci-), -N ((C -4) alkyl) 2 or ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6); with the proviso that when X is O, R2 is not a group of the formula R3 is selected from H, halo, alkyl (Ci-4), -O-alkyl (Ci-4), -S-alkyl (d-4), -NH2l -NHalkyl (C1-4) and -N (alkyl ( C -4)) 2; R5 is selected from H, alkyl (Ci-6), cycloalkyl (C3-7), cycloalkyl (C3-7) -alkyl (Ci-3) and Het; the alkyl (Ci-6) and Het each being optionally substituted with 1 to 4 substituents each independently selected from (C1-6) alkyl, -OH, -COOH, -C (= O) -alkyl (Ci-6) , -C (= O) -O- (C1-6) alkyl, -C (= O) -NH- (C1-6) alkyl, -C (= O) -N (alkyl (Ci.6)) 2 and -SO2alkyl (C1-6), and R6 is selected from cycloalkyl (C5-7), cycloalkyl (C5-7) -alkyl (Ci-3), aryl and aryl-alkyl (Ci-3), each of the (C5-7) cycloalkyl, (C5-7) cycloalkyl (Ci-3) alkyl, aryl, and aryl-alkyl (Ci-3) optionally substituted with 1 to 5 substituents, each independently selected from halo, (C1-6) alkyl 6), haloalkyl (Ci-6), -OH, -SH, -O-alkyl (Ci-4) and -S-alkyl (Ci-4), where Het is a saturated, unsaturated or aromatic 4 to 7 membered heterocycle having from 1 to 4 heteroatoms, each independently selected from O, N and S, or a 7 to 14 membered heteropolycycle, saturated, unsaturated or aromatic which has, whenever possible, from 1 to 5 heteroatoms, each independently selected from O, N and S, or one of its salts or esters. Another aspect of this invention provides a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as a medicament. Yet another aspect of this invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof; and one or more pharmaceutically acceptable vehicles. According to an embodiment of this aspect, the pharmaceutical composition according to this invention additionally comprises at least one other antiviral agent. The invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of a viral hepatitis C infection in a mammal suffering from or at risk of infection. A further aspect of the invention involves a method of treating a hepatitis C viral infection in a mammal suffering from or at risk of infection, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), a salt or ester pharmaceutically acceptable thereof, or a composition thereof as described hereinabove. Yet another aspect of the invention involves a method of treating a viral infection of hepatitis C in a mammal suffering from or at risk of infection, the method comprising administering to the mammal a therapeutically effective amount of a combination of a compound of formula I), or a pharmaceutically acceptable salt or ester thereof, and at least one other antiviral agent; or a composition thereof. Also within the scope of this invention is the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or ester thereof, for the treatment of a viral hepatitis C infection in a mammal that suffers or that has the risk of suffering from the infection. Another aspect of this invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of a viral hepatitis C infection. in a mammal that suffers or that has the risk of suffering the infection. A further aspect of this invention relates to a processing article comprising a composition effective to treat an infection with the hepatitis C virus; and packaging material comprising a label indicating that the composition can be used to treat infection with the hepatitis C virus; wherein the composition comprises a compound of formula (I) according to this invention or a pharmaceutically acceptable salt or ester thereof.

Yet another aspect of this invention relates to a method for inhibiting the replication of hepatitis C virus, which comprises exposing the virus to an effective amount of the compound of formula (I), or a salt or ester thereof, under conditions of those which inhibit the replication of the hepatitis C virus. It is further included within the scope of the invention the use of a compound of formula (I), or a salt or ester thereof, to inhibit the replication of the hepatitis B virus. hepatitis C. DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the following definitions apply unless otherwise indicated: The term "substituent", as used herein and unless otherwise specified mode, is intended to indicate an atom, radical or group that can be attached to a carbon atom, a heteroatom or any other atom that can be part of a molecule or fragment thereof that would otherwise be attached to at least one atom of hydrogen. The substituents contemplated in the context of a specific molecule or fragment thereof are those that give rise to chemically stable compounds, as recognized by those skilled in the art. The term "(Ci-n) alkyl", as used herein, wherein n is an integer, either alone or in combination with another radical, is meant to mean acyclic, straight or branched chain alkyl radicals containing 1 an atoms of carbon. "Alkyl (Ci-6)" includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (/ so-propyl), 1-methylpropyl (sec-butyl) , 2-methylpropyl (/ so-butyl), 1,1-dimethylethyl (tere-butyl), pentyl and hexyl. The abbreviation Me means a methyl group; Et means an ethyl group, Pr means a propyl group, Pr means a 1-methylethyl group, Bu means a butyl group and tBu means a 1, 1-dimethylethyl group. The term "alkylene (Ci-n)", as used herein, wherein n is an integer, either alone or in combination with another radical, is meant to mean acyclic, straight-chain or divalent alkyl radicals. branched, containing 1 an atoms of carbon. "(C1-6) alkylene" includes, but is not limited to -CH2-, -CH2CH2-, The term "(C3-m) cycloalkyl", as used herein, wherein m is an integer, either alone or in combination with another radical, is intended to indicate a cycloalkyl substituent that contains 3 a. Carbon atoms. and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "(C3-m) cycloalkyl-alkyl (Ci-n) -", as used herein, in which n and m are both integers, either alone or in combination with another radical, is intended to indicate an alkyl radical with 1 carbon atoms as defined above, which is itself substituted with a cycloalkyl radical containing 3 am carbon atoms as defined above. Examples of (C3.7) cycloalkyl-alkyl (Ci-β) include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl and 2- cyclohexylethyl. When a (C3-m) -alkyl (Ci-n) cycloalkyl group is substituted, it is understood that the substituents may be attached to the cycloalkyl part or the alkyl part thereof or both, unless otherwise specified. The term "aryl", as used herein, either alone or in combination with another radical, is intended to mean a carbocyclic, aromatic monocyclic group containing 6 carbon atoms which may also be fused to a second carbocyclic group of 5 carbon atoms. or 6 members, which can be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and dihydronaphthyl. The term "aryl-alkyl (Ci-n)", as used herein, wherein n is an integer, either alone or in combination with another radical, is intended to indicate an alkyl radical having 1 an atoms carbon, as defined above, which is substituted with an aryl radical as defined above. Examples of aryl (C1-n) alkyl include, but are not limited to, phenylmethyl (benzyl), 1-phenylethyl, 2-phenylethyl and phenylpropyl. When an aryl-alkyl group (Ci-n) is substituted, it is understood that the substituents may be attached to either the aryl part or the alkyl part thereof or both, unless otherwise specified. The term "Het", as used herein, either alone or in combination with another radical, is intended to mean a 4- to 7-membered, saturated, unsaturated or aromatic heterocycle, having 1 to 4 heteroatoms, each one independently selected from O, N and S, or a 7 to 14 membered heteropolycycle, saturated, unsaturated or aromatic having, whenever possible, from 1 to 5 heteroatoms, each independently selected from O, N and S, unless otherwise specified.

When a Het group is substituted, it is understood that the substituents may be attached to any carbon atom or heteroatom thereof which would otherwise carry a hydrogen atom, unless otherwise specified.

The term "Het-alkyl (Ci-n)", as used herein and unless otherwise specified, wherein n is an integer, either alone or in combination with another radical, is intended to indicate an alkyl radical having 1 to carbon atoms, as defined above, which is substituted with a Het substituent as defined above. Examples of Het-alkyl (Ci-n) include, but are not limited to, thienylmethyl, furylmethyl, piperidinylethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, quinolinylpropyl, and the like. When a Het-alkyl (Ci-n) group is substituted, it is understood that the substituents may be attached to either the Het portion or the alkyl portion thereof, unless otherwise specified. The term "heteroatom", as used herein, is meant to mean O, S or N. The term "heterocycle", as used herein and unless otherwise specified, is either alone or combined with another radical, it is intended to indicate a 4 to 7 membered, saturated, unsaturated or aromatic heterocycle containing from 1 to 4 heteroatoms, each independently selected from O, N and S; or a monovalent radical obtained by separating it from a hydrogen atom. Examples of heterocycles of this type include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, oxazolidine, pyrrole, thiophene, furan, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, tetrazole, piperidine, piperazine, azepine, diazepine, pyran, 1,4-dioxane, 4-morpholine, 4-thiomorpholine, pyridine, pyridine-N-oxide, pyridazine, pyrazine and pyrimidine, and saturated, unsaturated and aromatic derivatives thereof. The term "heteropolycycle", as used herein and unless otherwise specified, either alone or in combination with another radical, is intended to indicate a heterocycle as defined above condensed to one or more other cycles, which include a carbocycle, a heterocycle or any other cycle; or a monovalent radical obtained by separating it from a hydrogen atom. Examples of heteropolyclics of this type include, but are not limited to, indole, isoindole, benzimidazole, benzothiophene, benzofuran, benzodioxole, benzothiazole, quinoline, isoquinoline and naphthyridine. The term "halogen", as used herein, is intended to indicate a halogen substituent selected from fluorine, chlorine, bromine or iodine. The expression "(C1-n) halogenoalkyl". as used herein, wherein n is an integer, either alone or in combination with another radical, is meant to indicate an alkyl radical having 1 to carbon atoms as defined above, wherein one or more atoms of hydrogen are each replaced by a halogen substituent. Examples of haloalkyl (Ci-n) include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl. The terms "-O-alkyl (Ci-n)" or "(C1-n) alkoxy", as used interchangeably herein, in which n is an integer, either alone or in combination with another radical , they are intended to indicate an oxygen atom additionally attached to an alkyl radical having 1 to carbon atoms as defined above. Examples of -O-alkyl (Ci-n) include, but without limitation, methoxy (CH3O-), ethoxy (CH3CH2O-), propoxy (CH3CH2CH2O-), 1-methylethoxy (/ 'so-propoxy; (CH3) 2CH-O-) and 1,1-dimethylethoxy (ert-butoxy); (CH3) 3C-O-). When a radical -O-alkyl (Ci-n) is substituted, it is understood that it is substituted on the alkyl part (Ci-n) thereof. The terms "-S-alkyl (Ci-n)" or "alkylthio (Ci-n)", as used interchangeably herein, in which n is an integer, either alone or in combination with another radical, they are intended to mean a sulfur atom additionally attached to an alkyl radical with 1 to carbon atoms as defined above. Examples of -S-alkyl (Ci.n) include, but are not limited to, methylthio (CH3S-), ethylthio (CH3CH2S-), propylthio (CH3CH2CH2S-), 1-methylethylthio (/ sopropylthio; (CH3) 2CH-S- ) and 1, 1-dimethylethylthio (fer-butylthio; (CH3) 3C-S-). When a radical -S-alkyl (Ci-n), or an oxidized derivative thereof, such as a radical -SO-alkyl (C1-n) or a radical -SO2-alkyl (Ci-n), is substituted, understands that each is substituted in the alkyl part (Ci-n) thereof. The term "oxo", as used herein, is intended to indicate an oxygen atom attached to a carbon atom as a substituent by a double bond (= O). The term "thioxo", as used herein, is intended to mean a sulfur atom attached to a carbon atom as a substituent by a double bond (= S). The term "COOH", as used herein, is intended to indicate a carboxyl group (-C (= O) -OH). The person skilled in the art knows well that the carboxyl groups can be replaced by equivalents of the functional group. Examples of functional group equivalents of this type, referred to in this invention, include, but are not limited to, esters, amides, imides, boric acids, phosphonic acids, phosphoric acids, tetrazoles, triazoles, N-acylsulfamides (RCONHSO2NR2) and N-acylsulfonamides (RCONHS02R). The term "functional group equivalent", as used herein, is intended to indicate an atom or group that can replace another atom or group having similar electronic, hybridizing or binding properties.

The term "protecting group", as used herein, is intended to mean protecting groups that can be used during the transformation of synthesis, including but not limited to examples listed in Greene, "Protective Groups in Organic Chemistry." , John Wiley & Sons, New York (1981), and more recent editions of it. The following designation 'is used in sub-formulas to indicate the link that is connected to the rest of the molecule as defined. The term "salt thereof", as used herein, is meant to mean any addition salt of an acid and / or a base of a compound according to the invention, including, but not limited to, a salt pharmaceutically acceptable thereof. The term "pharmaceutically acceptable salt", as used herein, is meant to mean a salt of a compound according to the invention which, within the medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, which corresponds to a reasonable risk / benefit ratio, generally soluble or dispersible in water or oil, and effective for their intended use. The term includes pharmaceutically acceptable acid addition salts and base addition salts pharmaceutically acceptable Suitable salt lists are found, for example, in S.M. Birge et al., J. Pharm. Sci., 1977, 66, pgs. 1-19. The term "pharmaceutically acceptable acid addition salt", as used herein, is meant to mean those salts which retain their biological efficacy and the properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids, including, but not limited to, acetic acid, trifluoroacetic acid, adipic acid , ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulphic acid, hexanoic acid, acid formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (acid) or isethionic), lactic acid, hydroxymelic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, phenylpropionic, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulphanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid and the like. The term "pharmaceutically acceptable base addition salt", as used herein, is meant to mean those salts which retain their biological efficacy and the properties of free acids and which are not biologically undesirable or otherwise formed with bases inorganic, including, but not limited to, ammonia or hydroxide, carbonate, or ammonium bicarbonate or a metal cation, such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from non-toxic, pharmaceutically acceptable organic bases include, but are not limited to, primary, secondary and tertiary amine salts, quaternary amine compounds, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N -ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine,?,? -dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine,?,? -dibenzymphenethylamine, 1-efenamine, N, N'-dibenzylethylenediamine, polyamine resins and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. The term "ester thereof", as used herein, is meant to mean any ester of a compound according to the invention in which any of the -COOH substituents on the molecule is replaced by a -COOR substituent, wherein the R moiety of the ester is any carbon containing group that forms a stable ester moiety, including, but not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, each of which optionally being further substituted. The term "ester thereof" includes, but is not limited to, pharmaceutically acceptable esters thereof.

The term "pharmaceutically acceptable ester", as used herein, is meant to mean esters of the compound according to the invention in which any of the COOH substituents in the molecule is replaced by a -COOR substituent, in which the R moiety of the ester is selected from alkyl (including, but not limited to, methyl, ethyl, propyl, 1-methylethyl, 1,1-dimethylethyl, butyl); alkoxyalkyl (including, but not limited to, methoxymethyl); acyloxyalkyl (including, but not limited to, acetoxymethyl); arylalkyl (including, but not limited to, benzyl); aryloxyalkyl (including, but not limited to, phenoxymethyl); and aryl (including, but not limited to, phenyl), optionally substituted with halogen, (1-4C) alkyl or (C-4) alkoxy. Other suitable esters can be found in Design of prodrugs, Bundgaard, H. Ed. Elsevier (1985). Said pharmaceutically acceptable esters are usually hydrolysed in vivo when they are injected into a mammal and transformed into the acid form of the compound according to the invention. With respect to the esters described above, unless otherwise specified, any alkyl moiety present preferably contains 1 to 16 carbon atoms, more preferably 1 to 6 carbon atoms. Any aryl moiety present in said esters preferably comprises a phenyl group. In particular, the esters can be an alkyl ester (Ci-?), An unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, (Ci-6) alkyl, (C 1-6) alkoxy, nitro or trifluoromethyl . The term "mammal", as used herein, is intended to encompass humans, as well as non-human mammals that are susceptible to infection by the hepatitis C virus. Non-human mammals include, but are not limited to, domestic animals, such as cows, pigs, horses, dogs, cats, rabbits, rats and mice, and non-domestic animals. The term "treatment", as used herein, is meant to mean administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of hepatitis C disease and / or to reduce viral load in a patient. The term "treatment" also encompasses the administration of a compound or composition according to the present invention after exposure of the individual to the virus, but before the onset of disease symptoms, and / or prior to detection of the virus in the blood, to prevent the onset of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood. The term "antiviral agent," as used herein, is intended to mean an agent that is effective to inhibit the formation and / or replication of a virus in a mammal, including, but not limited to, agents that interfere with any of the the mechanisms of the host or virus necessary for the formation and / or replication of a virus in a mammal. Preferred embodiments In the following preferred embodiments, groups and substituents of the compounds according to this invention are described in detail. X: X-A: in one embodiment, X is O. X-B: in another embodiment, X is S. Each and every one of the individual definitions of X as set forth in this memory can be combined with each and every one of the individual definitions of R2, R3, R5 and R6 as set forth herein.

R2-A: in one embodiment, R2 is naphthyl or phenyl, the phenyl being optionally substituted with R20, wherein R20 is defined as embodiment R20-A; with the proviso that when X is O, R2 is not a group of the formula R -A in this embodiment, R is 1 to 5 substituents, each independently selected from: a) halo, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3-7) or cycloalkyl (C3-7) ) -alkyl (Ci-6); b) -N (R7) R8 or -YN (R7) R8, wherein Y is selected from -C (= 0) -, -SO2- and -alkylene (C1-6), R7 is selected, in each case independently , of H and alkyl (Ci-6), and R8 is selected, in each case independently, from H, alkyl (Ci-6), haloalkyl (C1-6), cycloalkyl (C3-7), cycloalkyl (C3.7) ) -alkyl (Ci-6), aryl, Het, -C (= 0) -R9, -C (= O) OR9 and -C (= 0) NHR9, wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6), cyano, -NH2, -NHalkyl (Ci-4) or -N (alkyl (Ci.4)) 2, and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (Ci-6), -SO2alkyl (Ci-6), -NHalkyl (C1-4), -N (C1-4alkyl) 2 or -NH-C ^ OJalkyloylCi ^), ü) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-β); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6); and wherein R9 is selected from: i) alkyl (C-i-e), optionally substituted with -COOH, -NH2, -NHalkyl (C1-4) or -N (alkyl (Ci-4)) 2; and ii) Het, optionally substituted with alkyl (Ci-6); or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S, or a heteropolycycle of 7 to 14 members, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (C -6), -SO2alkyl (C1-6), -NHalkyl (C -4), -N ((1-4C) alkyl) 2 or -NH-C (= O) (1-4C) alkyl, ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (d-6), and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci_6), c) aryl, Het or Het-alkyl (Ci-6), wherein each of the aryl, aryl-alkyl (Ci.6), Het and Het-alkyl (d-6) is optionally substituted with 1 to 3 substituents, each independently selected of i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (C1-6), -SO2alkyl (Ci.6), -C (= O) -NH2, -C (= O) -NHalkyl (C1-4), -C ^ OJ-NKalkylotC ^, -NH2, -NHalkyl (C1-4), ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (? -? -?), and d) -C (= O) -R10, -O-R10, -C ( = O) -O-R10, -alkylenenoid ^ -O-R10, -S-R10, -SO-R10, -SO2-R10, -alkylene (C -6) -S-R10, -alkylene (C1-6) -SO-R10 or -alkylene (Ci-6) -SO2-R10, wherein R10 is selects, in each case independently, from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C 3-7), cycloalkyl (C 3-7) -alkyl (Ci-6), aryl and Het; wherein (C 1-6) alkyl is optionally substituted with -OH, -O-(C-6) alkyl, cyano, -NH 2) -NH (C 1-4) alkyl or -N (C 1-4) alkyl); and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (C -6) , -SO2alkyl (C1-6), -C (= O) -NH2, -C (= 0) -NHalkyl (CM), -C (= O) -N (C1-4alkyl)) 2, -NH2, -NHalkyl (C1-4), -N ((Ci-4) alkyl) 2 or -NH-C (= O) alkyl (d ^), ii) (Ci-6) alkyl, optionally substituted with -OH or - O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or alkyl (Ci-6). R2-B: in another embodiment, R2 is naphthyl or phenyl, the phenyl being optionally substituted with R20, wherein R20 is defined as embodiment R20-B; with the proviso that when X is O, R2 is not a group of the formula R ° -B: in this embodiment, R is 1 to 5 substituents, each independently selected from: a) halo, alkyl (Ci-6) or haloalkyl (Ci-6); b) -N (R7) R8 or -Y-N (R7) R8, wherein Y is selected from -C (= 0) -, -SO2- and -alkylene (Ci-6); R7 is selected, in each case independently, from H and alkyl (Ci-6), and R8 is selected, in each case independently, from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3-) 7), (C3-7) cycloalkyl- (Ci-6) alkyl, aryl, Het, -C (= 0) -R9, -C (= 0) OR9 and -C (= 0) NHR9; wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6), cyano, -NH2, -NHalkyl (Ci-4) or -N (alkyl (Ci-4)) 2; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (C1-6) , -SO2alkyl (Ci.6), -NHalkyl (C1-4), -N (C1-4alkyl)) 2 or ii) alkyl (Ci-β), optionally substituted with -OH or -O-alkyl (Ci-β), and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (? -β), and wherein R9 is selected from: i) alkyl (C ^), optionally substituted with -COOH, -NH2, -NHalkyl (C1-4) or -N (C1-4alkyl)) 2, and ii) Het, optionally substituted with alkyl (Ci-6), or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O, and S, or a 7 to 14 membered heteropolycycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O, and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkylid-e), -SO2alkyl (C1-6), -C (= O) -NH2, -C (= O) -NHalkyl (C1-4), -C (= O) -N (C1-4alkyl)) 2, - NH 2, -NHalkyl (C 1-4), -N (C 1-4 alkyl) 2 or -NH-C (= O) (C 1-4) alkyl, ii) C 1-6 alkyl, optionally substituted with - OH or -O- (C1-6) alkyl, and i) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6); c) aryl, Het or Het-alkyl (C ^) -, wherein each of the aryl, Het and Het-alkyl (?? -?) - is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (C1-6), -SO2alkyl (C -6), -C (= O) -NH2, -C (= O) -NHalkyl (C1-4), -C (= O) -N ((C1-4) alkyl) 2 > -NH 2, -NHalkyl (Ci-4), -N ((Ci-4) alkyl) 2 or -NH-C (= O) (C 1-4) alkyl; ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci.6), and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci) -6); and d) -C (= O) -R10, -O-R10, -C (= O) -O-R10 or -alkylene (Ci-6) -O-R10, wherein R10 is selected, in each case independently, of H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C 3-7), cycloalkyl (C37) -alkyl (Ci-6), aryl and Het; wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6), cyano, -NH2, or -N ((Ci-4) alkyl) 2; and where each of the aril and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (C1-6), -SO2alkyl (C1-6) , -C (= O) -NH2, -C (= O) -NHalkyl (C1-4), -C (= O) -N (alkyl (Ci-4)) 2, -NH2, -NHalkyl (C1-4), -N ((Ci-4) alkyl) 2 or -NH-C (= O) (C1-4) alkyl, i) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (Ci-6), and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or alkyl (Ci-6). R2-C: still in another embodiment, R2 is phenyl, optionally substituted with R20, wherein R20 is defined as embodiment R20-A earlier herein; with the proviso that when X is O, R2 is not a group of the formula R2-D: still in another embodiment, R2 is phenyl, optionally substituted with R, wherein R is defined as embodiment R-B before memory; with the proviso that when X is O, R2 is not a group of the formula In an alternative embodiment, R2 is a group of formula: wherein R21 and R22 are as defined below. R21-A: In this embodiment, R21 is selected from H, halo, (C1-6) alkyl, haloalkyl (Ci-6) and -O-haloalkyl (Ci-6). R21-B: in this embodiment, R21 is selected from H, Cl, Br, CH3, CF3 and -OCF3. R21-C: in this embodiment, R2 is H or CF3. R21-D: in this embodiment, R21 is CF3. R ^ -A: in this embodiment, R22 is selected from H, halo, alkyl (Ci.3), haloalkyl (Ci-3), -alkylene (C1-3) -OH, -C (= 0) -alkyl ( Ci-3) and -COOH. R22-B: in this embodiment, R22 is selected from H, halo, alkyl (Ci-3), -alkylene R22-C: in this embodiment, R22 is selected from H, F, I, -CH2OH, CF3, -C (= O) CH3 and -COOH. R22-D: in this embodiment, R22 is selected from: b) -N (R7) R8 or -YN (R7) R8, wherein Y is selected from -C (= O) -, -SO2- and -alkylene ( Ci-6), R7 is selected from H and alkyl (ß-ß), and R8 is selected from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3-7), cycloalkyl (C3 -7) -alkyl (C1-6), aryl, Het, -C (= O) -R9, -C (= O) OR9 and -C (= O) NHR9, wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6), cyano, -NH2, -NHalkyl (Ci-4) or -N (alkyl (Ci-4)) 2, and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (d-e), -C (= O) -alkyl (C1-6), -SO2alkyl (Ci-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N ((C1-4) alkyl) 2, -NH2, -NH-alkyl the (C1-4), -N ((C1-4) alkyl) 2 or -NH-C (= O) alkyl (C), i) alkyl (Ci-6), optionally substituted with -OH or -O- alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6), and wherein R 9 is selected from: i) alkyl (β-β), optionally substituted with -COOH, -NH2, -NHalkyl (C1-4) or -N (alkyl (C ^)) 2, and ii) Het, optionally substituted with alkyl (Ci-6), or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S, or a 7- to 14-membered heteropolycycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (Ci-6), -SO2alkyl (Ci-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N ((Ci-4) alkyl) 2 , -NH2, -NH- (C1-4) alkyl, -N (C1-4) alkyl) 2 or -NH-C (= O) (C1-4) alkyl, ii) C1.6 alkyl, optionally substituted with -OH or -O-alkyl (? -? -?), and iii) aryl or Het, where each of the aryl and Het groups is optionally substituted with halo or alkyl (? -? -?), and ) aryl, Het or Het-alkyl (Ci-6) -, wherein each of the aryl, Het and Het-alkyl (Ci-6) - is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (Ci-6), -SO2alkyl (d-6), -C (= O) - NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N (alkyl (CM)) 2, -NH2l-NH-alkyl (CM), -N (alkyl (C1 -4)) 2 or -NH-C (= O) (C 1-4) alkyl, ii) C 1-6 alkyl, optionally substituted with -OH or -O-alkyl (? -β), and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or alkyl (Ci-6). R22-E: in this embodiment, R22 is selected from: b) -N (R7) R8, wherein R7 is selected from H and alkyl (Ci-6); and R8 is selected from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3-7), cycloalkyl (C3-7) -alkyl (C1-6), aryl, Het, -C (= O) -R9, -C (= O) OR9 and -C (= O) NHR9; wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6), cyano, -NH2, -NHalkyl (Ci-4) or -N ((C1-4) alkyl) 2l and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (C1-6) , -SO2alkyl (C1-6), -C (= O) -NH2, -C (= O) -NH-alkyl (C ^), -C (= O) -N (alkyl (C ^)) 2, -NH2, -NH- (C1-4) alkyl, -N ((Ci-4) alkyl) 2 or -NH-C (= O) alkyl (CM), ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (C- | .6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6), and wherein R9 is selected from: i) (Ci-6) alkyl, optionally substituted with - COOH, -NH2, -NHalkyl (C1-4) or -N (C1-4alkyl)) 2, and ii) Het, optionally substituted with alkyl (Ci-6), or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each one independently selected from N, O and S, or a 7 to 14 membered heteropolycycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkyl (d-6), -C (= O) -alkyl (C1-6), -SO2alkyl (Ci-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N ((C4-4) alkyl) 2 , -NH2, -NH-alkyl (C1-4), -N (alkyl (C ^^ or -NH-C (= O) (C1-4) alkyl, ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl ( Ci-6), and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (ß-ß), and c) Het, optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (Ci-6), -SO2alkyl (Ci-6), -C (= O) -NH2, -C (= O) -NH-alkyl (C ^), -C (= O) -N ((C1-4) alkyl) 2, -NH2, -NH-alkyl (C1-4), -N ((Ci-4) alkyl) 2 or -NH-C (= O) alkyl (CM), i) alkyl (Ci-6), optionally substituted with -OH or -O- alkyl (Ci-β), and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or alkyl (Ci ^). R22-F: in this embodiment, R22 is selected from: b) -N (R7) R8, wherein R7 is selected from H, methyl and ethyl; Y R8 is selected H, (C1-3) alkyl, -C (= 0) -R9, -C (= 0) OR9 and -C (= O) NHR9; the alkyl (Ci-3) being optionally substituted with -OCH 3; wherein R9 is selected from: i) alkyl (Ci-), optionally substituted with -COOH or -N (CH3) 2; and ii) a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms, each independently selected from N, O and S, wherein the heterocycle is optionally substituted with (1-3C) alkyl, or R7 and R8 are linked, together with the N to which they are attached, to form a 5, 6 or 7 membered heterocycle, optionally containing 1 or 2 additional heteroatoms, each independently selected from N, O and S, or a 9 or 10 membered heteropolycycle, which optionally it contains 1 or 2 additional heteroatoms, each independently selected from N, O and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) -OH, -CF3, -C (= O) -alkyl (C1-3), -SO2alkyl (C1-3) ), -C (= O) -NH2, -C (= O) -NHalkyl (C1-3), -C (= O) -N ((C1-3) alkyl) 2, -NH2, -NHalkyl (C1-3), -N ((1-3C) alkyl) 2 or ii) alkyl (Ci-3), optionally substituted with -OH or -O-alkyl (Ci-3); and ii) a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms, each independently selected from N, O and S or phenyl, the phenyl being optionally substituted with fluoro, and c) Het, wherein the Het is a heterocycle of 5, 6 or 7 members, optionally containing 1 or 2 additional heteroatoms, each independently selected from N, O and S, or a 9 or 10 member heteropolycycle, optionally containing 1 or 2 additional heteroatoms, each independently selected from N, O and S; and wherein the Het is optionally substituted with 1 to 3 substituents, each independently selected from i) -OH, -CF3, -SO2alkyl (Ci-3), -C (= O) -NH2, -C (= O) -NHalkyl (C1-3), -C (= O) -N ((Ci-3) alkyl) 2, - NH2, -NHalkyl (Ci-3), -N (alkyl (Ci.3)) 2 or -NH-C (= O) alkyl (Ci-3), ii) alkyl (Ci-3), optionally substituted with - OH or -O-alkyl (Ci-3); and ii) a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms, each independently selected from N, O and S or phenyl, the phenyl being optionally substituted with fluoro. R22-G: in this embodiment, R22 is selected from: b) -N (R7) R8, wherein R7 is selected from H, methyl and ethyl, and R8 is selected from H, methyl, ethyl, -CH2CH2-OCH3, -C (= O) -CH3, -C (= O) -CH2CH2COOH, -C (= O) OC (CH3) 3, -C (= 0) NHCH2CH2N (CH3) 2 and ; or R7 and R8 are linked, together with the N to which they are fixed, to form a heterocycle selected from: or a heteropolycycle selected from: the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: CH3, CH2CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -OH, -CF3, -C (= O) -CH3l- SO2CH3, -C (= O) -NH2, -C (= O) -N (CH2CH3) 2, -NH2, -N (CH3) 2) -NH-C (= O) CH3, c) Het, where the Het is selected from: and wherein the Het is optionally substituted with 1 to 3 substituents, each independently selected from: CH3, CH2CH3 > -CH2OH, -CH2CH2OH, -CH2OCH3, -OH, -CF3, -C (= O) -CH3, -SO2CH3, -C (= O) -NH2, -C (= O) -N (CH2CH3) 2, - NH2, -N (CH3) 2, -NH-C (= O) CH3, R -H: in this embodiment, R is selected from b) -Y-N (R7) R8, wherein Y is selected from -C (= 0) -, -S02- and -CH2-; R7 is selected from H and alkyl (Ci-6); and R8 is selected from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3-7). (C3-7) cycloalkyl-C1-6alkyl, aryl, Het, -C (= 0) -R9, -C (= O) OR9 and -C (= O) NHR9; wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6), cyano, -NH2, -NHalkyl (Ci-4) or -N (alkyl (Ci-4)) 2; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (C1-6) , -SO2alkyl (C1-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N (C1-4alkyl)) 2, -NH 2, -NH-C 1-4 alkyl, -N (C 1-4 alkyl) 2 or -NH-C (= O) alkyl (Ci-), i) alkyl (Ci-6) , optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or (C -6) alkyl, and wherein R9 is selected from: i) alkyl (? -? -?), optionally substituted with -COOH, -NH2, -NHalkyl (C1-4) or -N (alkyl (C ^)) 2, yi) Het, optionally substituted with alkyl (C ^). or | R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O, and S, or a 7 to 14 membered heteropolycycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O, and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (C1-6), -SO2alkyl (Ci-e), -C (= O) -NH2, -C (= 0) -NH- (C1-4) alkyl, -C (= 0) -N (C1-4alkyl)) 2 , -NH2, -NH- (C1-4) alkyl, -N (C1-4 alkyl) 2 or -NH-C (= O) (C1-4) alkyl, ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (Ci-6), and ni) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6), and c) Het-alkyl (Ci-β), optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (Ci-6), -SO2alkyl ( C1-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N ((C1-4) alkyl) 2, -NH2 , -NH- (1-4C) alkyl, -N ((Ci-*) alkyl) 2 or -NH-C (= O) (1-4C) alkyl, ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (Cie), and iii) aryl or He t, wherein each of the aryl and Het is optionally substituted with halo or alkyl (Ci-6). R22- !: In this embodiment, R22 is -YN (R7) R8, wherein Y is selected from -C (= 0) - and -SO2-, R7 is selected from H and methyl, and R8 is selected from H, alkyl (Ci-6), haloalkyl (C 1-6), cycloalkyl (C 3-7), cycloalkyl (C 3-7) -alkyl (Ci-6) and a 5- or 6-membered heterocycle containing 1 to 3 heteroatoms, each independently selected from N, O and S; wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-3), cyano or -NalkyloylC ^ Jk, or R7 and R8 are linked together with the N to which they are attached , to form a 5- or 6-membered heterocycle optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S; the heterocycle being optionally substituted with 1 to 3 substituents, each independently selected from -OH and N ((Ci-3) alkyl) 2. R22-J: in this embodiment, R22 is -Y-N (R7) R8, wherein Y is selected from -C (= O) - and -SO2-; R is selected from H and methyl; and R8 is selected from H, alkyl (Ci-4), -CH2CF3, cycloalkyl (C3-5), cyclopropylmethyl, wherein the alkyl (Ci-4) is optionally substituted with -OH, -OCH3, -OCH2CH3, cyano or -N (CH3) 2, or R7 and R8 are linked, together with the N to which they are attached, to form selected heterocycle of and the heterocycle being optionally substituted with 1 to 3 substituents, each independently selected from -OH and N (CH3) 2. R22-K: in this embodiment, R22 is selected from b) -CH2-N (R7) R8, wherein R7 is H; and R8 is H or -C (= 0) -R9; wherein R9 is alkyl (Ci.6), or R7 and R8 are linked, together with the N to which they are attached, to form a 5- or 6-membered heterocycle optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S, and c) Het-CH2-, where Het is a 5- or 6-membered heterocycle optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S. R22-L: in this embodiment, R22 is selected from b) -CH2-N (R7) R8, wherein R7 is H; and R8 is H or -C (= 0) -CH3; or R7 and R8 are linked together with the N to which they are fixed to form a c) Therefore, examples of additional embodiments of R2 are listed in the following table, wherein each substituent group is defined according to the definitions set forth above: R2-S: in yet another embodiment, R2 is selected from: R2-T: in yet another embodiment, R2 is selected from: ?? Each and every one of the individual definitions of R2 as set forth in this specification may be combined with each and every one of the individual definitions of X, R3, R5 and R6 as set forth herein.

R3-A: in one embodiment, R3 is selected from H, halogen, alkyl (Ci-4), -0-alkyl (C1-4) and -N ((C1-4) alkyl) 2. R3-B: in another embodiment, R3 is selected from H, F, Br, CH3 | OCH3 and -N (CH3) CH2CH3. R3-C: in an alternative embodiment, R3 is H, F, Cl or Br. R3-D: still in another embodiment, R3 is H or F. R3-E: still in another embodiment, R3 is H. Each and every one of the individual definitions of R3 as set forth herein may be combined with each and every one of the individual definitions of X, R2, R5 and R6 as set forth herein. R5: R5-A: In one embodiment, R5 is H or alkyl (C1"6), where the alkyl (Ci-β) is optionally substituted with 1 to 4 substituents each independently selected from -OH, -COOH, -C (= O) -alkyl (Ci-6), -C (= O) -O-alkyl (C1 -6), -C (= O) -NH-alkyl (Ci-6), -C (= O) -N ((C 1-6) alkyl) 2 and -SO 2 (C 1-6) alkyl. R5-B: in another embodiment, R5 is selected from H or (C1-4) alkyl, wherein the alkyl (Ci-4) is optionally substituted with 1 or 2 substituents each independently selected from -OH and -COOH. R5-C: still in another embodiment, R5 is selected from H, methyl, ethyl, propyl, 1- methylethyl, COOH and . R5-D: in yet another embodiment, R5 is methyl, ethyl, propyl or 1-methylethyl. R5-E: in a further embodiment, R5 is 1-methylethyl. R5-F: in an alternative embodiment, R5 is Het, optionally substituted with 1 to 4 substituents each independently selected from (C1-6) alkyl, -OH, -COOH, -C (= O) -alkyl (C1-6) ), -C (= O) -O-alkyl (C -6), -C (= O) -NH- (C1-6) alkyl, -C (= O) -N (C1-6alkyl)) 2 and -SO2alkyl (Ci-6). R5-G: in another alternative embodiment, R5 is a saturated heterocycle, of 5 or 6 members, containing from 1 to 3 heteroatoms, each independently selected from O, N and S, the heterocycle being optionally substituted with 1 to 4 substituents, each independently selected from alkyl (Ci-4), -C (= O) -alkyl (C 1-4), -C (= O) -O- (C 1-4) alkyl, -C ( = O) -NH- (1-4C) alkyl, -C (= O) -N ((1-4C) alkyl) 2 and -SO2alkyl (Ci-4). R5-H: in yet another alternative embodiment, R5 is a saturated, 6-membered heterocycle, containing 1 or 2 heteroatoms, each of them independently selected from O and N, the heterocycle being optionally substituted with 1 or 2 substituents, each independently selected from CH3, -C (= 0) -CH3, -C (= 0) -0-CH3I-C (= 0) -0-C (CH3) 3, -C (= 0) -NH-CH2CH3 and -SO2CH3. R-1: In yet another alternative embodiment, R 5 is selected from: Each and every one of the individual definitions of R5 as set forth herein may be combined with each and every one of the individual definitions of X, R3 and R6 as set forth herein. R6: R6-A: in one embodiment, R6 is selected from cycloalkyl (C5-7) and cycloalkyl (C5-7) -alkyl (Ci-3) -, each of the cycloalkyl (C5-7) and cycloalkyl (C5 -7) -alkyl (Ci-3) optionally substituted with 1 to 5 substituents, each independently selected from halo, alkyl (Ci-6), haloalkyl (Ci.sub.6), -OH, -SH, -O-alkyl ( C1-4) and -S- (C1-4) alkyl. R6-B: in another embodiment, R6 is cyclopentyl, cyclohexyl or cycloheptyl, each of cyclopentyl, cyclohexyl and cycloheptyl being optionally substituted with 1 to 3 substituents, each selected independently between halo, -OH, alkyl and haloalkyl (C-). R6-C: still in another embodiment, R6 is cyclohexyl, optionally substituted with 1 to 3 substituents, each independently selected from fluoro, -OH, alkyl (C ^) and CF3. R6-D: In yet another embodiment, R6 is selected from: R6-F: In an alternative embodiment, R6 is aryl, optionally substituted with 1 to 5 substituents, each independently selected from halo, (C1-6) alkyl, haloalkyl (Ci-6), -OH, -SH, -O-alkyl (Ci-4) and -S-(C 1-4) alkyl. R6-G: in another alternative embodiment, R6 is phenyl, optionally substituted with 1 to 5 substituents, each independently selected from halo, alkyl (Ci-4), haloalkyl (Ci-4) and -S-alkyl (C-) . R6-H: still in another alternative embodiment, R6 is phenyl, optionally substituted with 1 to 3 substituents, each independently selected from F, Cl, Br, methyl, ethyl, CF3 and -S-CH3.

In yet another embodiment, R is selected from: Each and every one of the individual definitions of R6 as set forth herein may be combined with each and every one of the individual definitions of X, R2, R3 and R5 as set forth herein. The following table presents Examples of preferred subgeneric embodiments of the present invention, wherein each substituent group of each embodiment is defined according to the definitions set forth above: Examples of the most preferred compounds according to this invention are each of the individual compounds listed in the following Tables 1 and 2. In general, all tautomeric and isomeric forms and mixtures thereof are included, for example, individual geometric isomers, stereoisomers, enantiomers, diastereomers, racemates, racemic or non-racemic mixtures of stereoisomers, mixtures of diastereomers, or mixtures of any of the foregoing forms of a chemical structure or compound, unless the stereochemistry is specifically indicated in the name or structure of the compound or the specific isomeric form.

It is well known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit significantly different biological activity, including differences in pharmacokinetic properties, including metabolism, protein binding and the like, and pharmacological properties, which include the type of activity presented, the degree of activity, toxicity and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may have beneficial effects when it is á in greater quantity than the other enantiomer or when it is separated from the other enantiomer. In addition, one skilled in the art would know how to selectively separate, enrich or prepare the enantiomers of the compounds of the present invention from this description and from the knowledge in the art. The preparation of pure stereoisomers, for example enantiomers and diastereomers, or mixtures with a desired enantiomeric excess (ee) or enantiomeric purity, is achieved by one or more of the many methods of (a) separation or resolution of enantiomers, or ( b) enantioselective synthesis known to those skilled in the art, or a combination of the two methods. These resolution methods are generally based on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-host complex formation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or crystallization. spontaneous enantioselectiva. These methods are described, in general, in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T. E. Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc, 2000. In addition, there are equally well known methods for the quantification of enantiomeric excess or purity, for example CG, HPLC, CE or NMR, and the assignment of absolute configuration and conformation, for example CD ORD, X-ray crystallography or NMR. The compounds according to the present invention are inhibitors of the NS5B RNA-dependent RNA polymerase of hepatitis C virus and, thus, can be used to inhibit the replication of hepatitis C viral RNA. A compound according to the present invention. invention can also be used as a laboratory reagent or a research reagent. For example, a compound of the present invention can be used as a positive control to validate assays, including but not limited to, cell-based substitution assays and viral replication assays in vitro or in vivo. The compounds according to the present invention can also be used as probes to study the NS5B polymerase of hepatitis C virus, including, but not limited to, the mechanism of action of the polymerase, conformational changes to which it is subject. polymerase under different conditions and interactions with entities to which they bind or otherwise interact with the polymerase. Compounds of the invention used as probes can be marked with a marker that allows the recognition either directly or indirectly of the compound, so that it can be detected, measured and quantified. Markers contemplated for use with the compounds of the invention include, but are not limited to, fluorescent labels, labels chemiluminescents, colorimetric markers, enzymatic markers, radioactive isotopes, affinity labels and photoreactive groups. The compounds of the invention used as probes can also be labeled with an affinity tag, whose strong activity for a receptor can be used to extract the entity to which the ligand is bound from a solution. Affinity tags include, but are not limited to, biotin or a derivative thereof, a histidine polypeptide, a polyarginine, a sugar amylose moiety, or a defined epitope, recognizable by a specific antibody. In addition, the compounds of the invention used as probes can be labeled with a photoreactive group which, after activation by light, is transformed from an inert group into a reactive species, such as a free radical. Photoreactive groups include, but are not limited to, photoaffinity markers such as benzophenone and azide groups. In addition, a compound according to the present invention can be used to treat or prevent viral contamination of materials and, therefore, reduce the risk of a viral infection of laboratory or medical personnel or of patients coming into contact with materials. of this type (eg, blood, tissue, surgical instruments and garments, laboratory instruments and garments and equipment and materials for collecting blood). Pharmaceutical Composition The compounds of the present invention can be administered to a mammal in need of a treatment for viral infection of hepatitis C as a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the invention or a pharmaceutically acceptable salt or ester. acceptable thereof; and one or more excipients, adjuvants or conventional non-toxic and pharmaceutically acceptable vehicles. The specific formulation of the composition is determined by the solubility and chemical nature of the compound, the chosen route of administration and standard pharmaceutical practice. The pharmaceutical composition according to the present invention can be administered orally or systemically. For oral administration, the compound, or a pharmaceutically acceptable salt or ester thereof, can be formulated into any orally acceptable dosage form, including but not limited to, suspensions and aqueous solutions, capsules or tablets. For systemic administration, which includes, but is not limited to administration by subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques, it is preferred to use a solution of the compound, or a pharmaceutically acceptable salt or ester thereof, in a sterile, pharmaceutically acceptable aqueous vehicle. The pharmaceutically acceptable carriers, adjuvants, carriers, excipients and additives, as well as the methods of formulating pharmaceutical compositions for various modes of administration are well known to those skilled in the art and are described in pharmaceutical texts such as Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, 2005; and L.V. Alien, N.G. Popovish and H.C. Ansel, Pharmaceutical Dosage Forms and Drug Delivery Systems, 8th ed., Lippincott Williams & Wilkins, 2004. The dosage administered will vary depending on known factors including, but not limited to, activity and pharmacodynamic characteristics. of the specific compound employed and its mode, time and route of administration; the age, diet, sex, body weight and general health of the recipient; the nature and degree of the symptoms; the severity and course of the infection; the type of simultaneous treatment; the frequency of treatment; the desired effect; and the criteria of the doctor who is treating you. In general, the compound is administered, in the most desirable manner, with a dosage level that, in general, will provide effective antiviral results without causing harmful or harmful side effects. It can be expected that a daily dose of the active ingredient is from about 0.01 to about 200 milligrams per kilogram of body weight, with the preferred dose being from about 0.1 to about 50 mg / kg. Typically, the pharmaceutical composition of this invention will be administered from about 1 to about 5 times per day or, alternatively, in the form of a continuous infusion. Said administration can be used as chronic or acute therapy. The amount of active ingredient that can be combined with the support materials to produce a single dosage form, will vary depending on the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (weight / weight). Preferably, said preparations contain from about 20% to about 80% of the active compound. Combination therapy A combination therapy is contemplated in which a compound according to the invention, or a pharmaceutically acceptable salt or ester thereof, is co-administered with at least one additional antiviral agent. The agents Additional compounds can be combined with compounds of this invention to create an individual dosage form. Alternatively, these additional agents can be administered separately, at the same time or sequentially, as part of a multiple dosage form. When the pharmaceutical composition of this invention comprises a combination of a compound according to the invention, or a pharmaceutically acceptable salt or ester thereof, and one or more additional antiviral agents, both the compound and the additional agent should be present at levels of dosage of between about 10 and 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. In the case of a synergistic interaction between the compound of the invention and the additional antiviral agent or agents, the dosage of any or all of the active agents in the combination can be reduced compared to the dosage normally administered in a monotherapy regimen . Antiviral agents contemplated for use in such combination therapy include agents (compounds or biological products) that are effective to inhibit the formation and / or replication of a virus in a mammal, including, but not limited to, agents that interfere with any of the host or virus mechanisms necessary for the formation and / or replication of a virus in a mammal. Agents of this type may be selected from another anti-HCV agent; an HIV inhibitor; a HAV inhibitor; and a HBV inhibitor. Other anti-HCV agents include those agents that are effective in decreasing or preventing the progression of symptoms related to hepatitis C or the illness. Such agents include, but are not limited to, immunomodulatory agents, HCV NS3 protease inhibitors, other HCV polymerase inhibitors, other HCV life cycle inhibitors, and other anti-HCV agents, including but not limited to. , ribavirin, amantadine, levovirin and viramidine. Immunomodulatory agents include those agents (compounds or biological products) that are effective to strengthen or enhance the immune system response in a mammal. Immunomodulatory agents include, but are not limited to, inosine monophosphate dehydrogenase inhibitors such as VX-497 (merimepodib, Vertex Pharmaceuticals), class I interferons, class II interferons, consensus interferons, asialo-interferons, pegylated interferons and conjugated interferons that include, but are not limited to, interferons conjugated with other proteins, including, but not limited to, human albumin. Class I interferons are a group of interferons that bind to the type I receptor, including class I interferons produced both naturally and synthetically, while class II interferons all bind to the type II receptor. Examples of class I interferons include, but are not limited to, interferons, β, d,? and t, while examples of class II interferons include, but are not limited to, interferons? Inhibitors of the HCV NS3 protease include agents (compounds or biological products) that are effective to inhibit the function of the HCV NS3 protease in a mammal. Inhibitors of the HCV NS3 protease include, but are not limited to, the compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO 2006/000085 (all from Boehringer Ingelheim), WO 02/060926, WO 03/053349, WO 03/099274, WO 03/099316, WO 2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO 2005/051410, WO 2005/054430 (all of BMS), WO 2004/072243, WO 2004/093798, WO 2004/113365, WO 2005/010029 (all of Enanta), WO 2005/037214 (Intermune), WO 01/77113, WO 01/81325, WO 02/08187, WO 02/08198, WO 02. / 08244, WO 02/08256, WO 02/48172, WO 03/062228, WO 03/062265, WO 2005/021584, WO 2005/030796, WO 2005/058821, WO 2005/051980, WO 2005/085197, WO 2005 / 085242, WO 2005/085275, WO 2005/087721, WO 2005/087725, WO 2005/087730, WO 2005/087731, WO 2005/107745 and WO 2005/113581 (all from Schering); and candidates VX-950 and SCH-503034. HCV polymerase inhibitors include agents (compounds or biological products) that are effective in inhibiting the function of an HCV polymerase. Such inhibitors include, but are not limited to, non-nucleoside inhibitors and nucleoside inhibitors of HCV NS5B polymerase. Examples of HCV polymerase inhibitors include, but are not limited to, the compounds described in the documents: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO 2004/064925, WO 2004 / 065367, WO 2005/080388 (all from Boehringer Ingelheim), WO 01/47883 (Japan Tobacco), WO 03/000254 (Japan Tobacco), WO 03/026587 (BMS), WO 03/101993 (Neogenesis), WO 2004 / 087714 (IRBM), WO 2005/012288 (Genelabs), WO 2005/014543 (Japan Tobacco), WO 2005/049622 (Japan Tobacco), and WO 2005/121132 (Shionogi), and the HCV 796 candidates (ViroPharma / Wyeth), R-1626 and R-1656 (Roche), XTL-2125 (XTL), VCH-759 (Virochem) and NM 283 (Idenix / Novartis). Inhibitors of another target in the HCV life cycle include agents (compounds or biological products) that are effective in inhibiting the formation and / or replication of HCV other than by inhibiting the function of the HCV NS3 protease or HCV polymerase. . Such agents may interfere with the host or viral mechanisms of HCV, necessary for the formation and / or replication of HCV. Inhibitors * of another target in the HCV life cycle include, but are not limited to, entry inhibitors, agents that inhibit a target selected from a helicase, an NS2 / 3 protease and an internal ribosome entry site (IRES) and agents which interfere with the function of other viral targets including, but not limited to, an NS5A protein and an NS4B protein. It may happen that a patient may be coinfected with the hepatitis C virus and one or more other viruses, including, but not limited to, the human immunodeficiency virus (HIV), hepatitis A virus (HAV) and HIV virus. Hepatitis B (HBV). Thus, a combination therapy for treating said co-infections by co-administration of a compound according to the present invention with at least one of an HIV inhibitor, a HAV inhibitor and a HBV inhibitor is also contemplated. HIV inhibitors include agents (compounds or biological products) that are effective in inhibiting the formation and / or replication of HIV. These include, but are not limited to, agents that interfere with host or virus mechanisms necessary for the formation and / or replication of HIV in a mammal. HIV inhibitors include, but are not limited to: • NRTI (nucleoside or nucleotide reverse transcriptase inhibitors; including, but not limited to, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, emtricitabine, abacavir and tenofovir), • NNRTI (non-nucleoside inhibitors of reverse transcriptase, including, but not limited to, nevirapine, delavirdine, efavirenz, capravirin, etravirine, rilpivirine and BILR 355); • protease inhibitors (including, but not limited to, ritonavir, tipranavir, saquinavir, nelfinavir, indinavir, amprenavir, fosamprenavir, atazanavir, lopinavir, VX-385 and TMC-114); • input inhibitors, including, but not limited to, CCR5 antagonists (including, but not limited to, maraviroc (UK-427,857) and TAK-652), CXCR4 antagonists (including, but not limited to, AMD-11070) , fusion inhibitors (including, but not limited to, enfuvirtide (T-20)) and others (including, but not limited to, BMS-488043); • integrase inhibitors (including, but not limited to, MK-0518, c-1605, BMS-538158 and GS 9137), • TAT inhibitors, • maturation inhibitors (including, but not limited to, PA-457) , Y • immunomodulatory agents (including, but not limited to, levamisole). HAV inhibitors include agents (compounds or biological products) that are effective in inhibiting the formation and / or replication of HAV. These include, but are not limited to, agents that interfere with host or virus mechanisms necessary for the formation and / or replication of HAV in a mammal. HAV inhibitors include, but are not limited to, vaccines for hepatitis A. HBV inhibitors include agents (compounds or products) biological) that are effective to inhibit the formation and / or replication of HBV in a mammal. These include, but are not limited to, agents that interfere with host or virus mechanisms necessary for the formation and / or replication of HBV in a mammal. HBV inhibitors include, but are not limited to, agents that inhibit viral HBV DNA polymerase and vaccines for HBV. Therefore, according to one embodiment, the pharmaceutical composition of this invention additionally comprises a therapeutically effective amount of one or more antiviral agents. A further embodiment provides the pharmaceutical composition of this invention, wherein said one or more antiviral agents comprise at least one other anti-HCV agent. According to a more specific embodiment of the pharmaceutical composition of this invention, said at least one other anti-HCV agent comprises at least one immunomodulatory agent. According to another more specific embodiment of the pharmaceutical composition of this invention, said at least one other anti-HCV agent comprises at least one other HCV polymerase inhibitor. According to another still more specific embodiment of the pharmaceutical composition of this invention, said at least one other anti-HCV agent comprises at least one inhibitor of the HCV NS3 protease. According to another yet more specific embodiment of the pharmaceutical composition of this invention, said at least one other anti-HCV agent comprises at least one inhibitor of another target in the life cycle of HCV. METHODOLOGY AND SYNTHESIS The synthesis of compounds of formula (I) according to this invention is conveniently achieved by following the general process outlined in Figure 1 below, wherein R2, X, R3, R5 and R6 are as defined herein. memory. Additional instruction is provided to a person skilled in the art by the specific examples collected hereinafter. The intermediates of formula (II), wherein R3a is R3 as defined herein or is a precursor group transformable into R3 as defined herein, R is an ester protecting group, such as methyl or ethyl, and LG is a leaving group such as F or Cl, are commercially available or can be prepared by methods well known in the art as set forth in the examples set forth below. It will be apparent to one skilled in the art that when the R3a group is a precursor group, it can be transformed into R3 as defined herein in any chemically convenient intermediate step in the figure, prior to the formation of the compounds of formula ( I), by methods well known in the art or as set forth in the examples set forth below. The reaction of the intermediates (II) with reactants of the formula R2X-H, wherein R2 and X are as defined herein, under SwAr reaction conditions well known to those skilled in the art, provides intermediates of formula (III). One skilled in the art will appreciate that the R2 groups of the compounds according to the invention differ in their substitution patterns and that it is contemplated that one R2 group can be transformed into another R2 group by procedures well known in the art or as it is collected. in the examples listed below, in any Chemically convenient intermediate stage in the figure. The nitro group of the intermediates (III) is reduced in an amino group under well-known conditions to provide the intermediates of formula (IV), or their salts with acids such as hydrochloric acid. The group R5 can be added to the amino group of intermediates of formula (IV) by a reductive amination reaction with an appropriately substituted aldehyde or ketone or a suitable derivative thereof, followed by treatment with sodium triacetoxyborohydride, according to Abdel- Magid, AF; Carson, K. G .; Harris, B. D .; Maryanoff, C. A .; Shah, R. D. J. Org. Chem. 1996, 61, 3849, to provide intermediates of formula (V). Suitable aldehyde and ketone derivatives are well known in the art and include, but are not limited to, enol ethers and the like. Suitable aldehydes, ketones or derivatives thereof are commercially available or obtainable by methods well known in the art or as set forth in the examples set forth below. The intermediates (V) are acylated with suitable acylating agents, which are commercially available or obtainable by methods well known in the art or as set forth in the examples set forth below. The ester R protecting group is then hydrolyzed by methods well known in the art or as set forth in the examples set forth below, to provide compounds of formula (I). Alternatively, the amino group of the intermediates of formula (IV) can be acylated as previously described to provide intermediates of formula (VI). The alkylation of the nitrogen atom of the amide of the intermediates of formula (VI), by means of well processes known in the art or as set forth in the examples below, followed by hydrolysis of the ester protecting group, as previously described, provides compounds of formula (I). One skilled in the art will appreciate that the groups R5 and R6 of the compounds according to the invention differ in their substitution models and that it is contemplated that one group R5 can be transformed into another group R5, or that a R6 group can be transformed into another R6 group, by procedures well known in the art or as set forth in the examples set forth below, at any chemically convenient intermediate stage in the figure. Alternatively, the preparation of the compounds of formula (I) can be achieved by the process outlined in Figure 2 below, wherein R2, X, R3, R5 and R6 are as defined herein, R is a ester protecting group such as methyl or ethyl and PG is a protective group suitable for the functional group XH, well known to one skilled in the art, including but not limited to a benzyl group. The intermediates of formula VII are commercially available or can be prepared by methods well known in the art or as set forth in the examples set forth below. The reduction of the nitro group to the amino group and the introduction of the groups R5 and -C (= 0) R6 is achieved as described above to give the intermediates of formula (XI). The intermediates of formula (XI) are transformed into compounds of formula (I), deprotecting the XH group by methods well known in the art or as set forth in the examples set forth below, coupling the resulting free phenol or thiol to a reactant of formula R2-LG, wherein LG is a leaving group such as F or Cl, using procedures well known in the art or as set forth in the examples set forth below, and deprotecting the ester by hydrolysis as previously described. EXAMPLES Other features of the present invention will become apparent from the following non-limiting examples which illustrate, by way of example, the principles of the invention. As is well known to a person skilled in the art, the reactions are carried out in an inert atmosphere (including, but not limited to, nitrogen or argon), if necessary to protect the reaction components from air or moisture. Temperatures are given in degrees Celsius (° C). The percentages and relationships in solution express a volume-to-volume relationship, unless otherwise stated. The flash chromatography is carried out on silica gel (S1O2) according to the procedure of W.C. Still et al., J. Org. Chem., (1978), 43, 2923. Mass spectral analyzes are recorded using electrospray mass spectrometry. Analytical HPLC is carried out under standard conditions using a Combiscreen ODS-AQ C18, YMC reverse phase column, 50 x 4.6 mm di, 5 μ ?, 120 A at 220 nM, elution with a linear gradient as described in next table (solvent A is 0.06% TFA in H2O, solvent B is 0.06% TFA in CH3CN): Abbreviations or symbols used herein include: Ac: acetyl, AcCI: acetyl chloride, AcOH: acetic acid, AC2O: acetic anhydride, BINAP: 2,2-bis (diphenylphosphino) -l, 1'-biphenyl, Bn: benzyl (phenylmethyl), BnBr: benzyl bromide, BOC or Boc: tert-butyloxycarbonyl, Bu: butyl, DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene, DCM: dichloromethane, DMAP : 4-dimethylaminopyridine, DME: dimethoxyethane, DMF: A /, / V-dimethylformamide, DMSO: dimethylsulfoxide EC50: 50% effective concentration, EEDQ: 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, Et: ethyl, ???: triethylamine, Et ^ O: diethyl ether, EtOAc: ethyl acetate, EtOH: ethanol, HPLC: high performance liquid chromatography, IC50: 50% inhibitory concentration, 'Pr or i-Pr: 1-methylethyl (so-propyl), Me: methyl, MeCN: acetonitrile, Mel: iodomethane, MeOH: methanol, MS: mass spectrometry (MALDI-TOF: Matrix Assisted Laser Desorption lonization-Time of Flight - desorption / ionization by matrix-assisted laser-time of flight, FAB: Fast Atom Bombardment), NIS: N-yodosuccinamide, NMR: nuclear magnetic resonance spectroscopy, Ph: phenyl, PG: protective group, Pr: propyl, TA: room temperature (approximately 18 ° C to 25 ° C), TBTU: O-benzotriazole-1-yl-A / tetrafluoroborate, A /, A / ', A /' - tetramethyluron, tert-butyl or t -butyl: 1, 1-dimethylethyl, TFA: trifluoroacetic acid, THF: tetrahydrofuran, TLC: thin layer chromatography. EXAMPLE 1 A mixture of methyl 5-chloro-2-nitrobenzoate 1a (2.27 g, 10.5 mmol), K2C03 (2.19 g, 15.8 mmol) and 2-bromophenol 1 b (1.83 mL_, 15.8 mmol) in dry DMSO (30 mL_) is heated to 80 ° C. After stirring overnight at 80 ° C, the mixture is diluted in EtOAc and washed with water and brine. The organic phase is dried with MgSO 4, filtered and concentrated under reduced pressure. Purification by flash chromatography (EtOAc / Hex) gives the diaryl ether 1c. Other intermediates of formula (III), wherein X is O and R3a is H, are prepared using the process of Example 1 by replacing 2-bromophenol with other appropriately substituted phenols.

To 2-trifluoromethylphenol 2a (5.04 g, 31.1 mmol) in DMF (50 mL) is added NIS (7.0 g, 31.1 mmol). The reaction mixture is stirred overnight at room temperature and then poured into 700 mL of water. The mixture is extracted three times with EtOAc and the combined organic extracts are washed successively with 10% aqueous Na 2 S 2 O 3, water (3 times) and brine. The organic phase is dried with MgSO, filtered and concentrated under reduced pressure. Purification by flash chromatography (EtOAc / Hex) provides the iodide 2b. A mixture of methyl 5-chloro-2-nitrobenzoate 1a (Example 1) (750 mg, 3.5 mmol), K2CO3 (720 mg, 5.2 mmol) and phenol 2b (1.0 g, 3.5 mmol) in dry DMSO (8 mL) is heated to 95 ° C. The mixture is allowed to stir for 7.5 hours at 95 ° C, then at room temperature overnight and is then added to Saturated aqueous NH4CI. The mixture is extracted three times with EtOAc and the combined organic extracts are washed with water and brine. The organic phase is dried with MgSO 4, filtered and concentrated under reduced pressure. Purification by flash chromatography (8% EtOAc / Hex) gives the diaryl ether 2c. EXAMPLE 3 1a 3b A mixture of methyl 5-chloro-2-nitrobenzoate 1a (Example 1) (1.08 g, 5.0 mmol), K2CO3 (0.90 g, 6.5 mmol) and 2-trifluoromethylthiophenol 3a (1.07 g, 6.0 mmol) in dry DMSO (10 mL) is stirred at room temperature for 1 hour. The mixture is diluted with EtOAc and washed with 1 N HCl, water, 1 N NaOH and brine. The organic phase is dried with MgSO 4, filtered and concentrated under reduced pressure. Purification by flash chromatography (EtOAc / Hex) provides the diarylthioether 3b. Other intermediate compounds of formula (III), wherein X is S and R3a is H, are prepared using the process of Example 3 by replacing 2-trifluoromethylphenol with other appropriately substituted thiophenols. 4a 4 4c Excess of a solution of CH2N2 in E220 (100 ml_) is added to a mixture of acid 4a (2.0 g, 10 mmol), MeOH (15 ml_) and EtOAc (50 ml_) at 0 ° C. The mixture is allowed to stir for 10 minutes and then concentrated under reduced pressure to provide ester 4b. 2-trifluoromethylphenol 2a (Example 2) (973 mg, 6.0 mmol) is added to a mixture of K2CO3 (967 mg, 7.0 mmol) and anhydrous DMSO (10 mL) and the mixture is heated at 65 ° C for 30 minutes. To this mixture is added a mixture of ester 4b (1.1 g, 5.0 mmol) and DMSO (4 mL) and heating continues at 65 ° C for 1 hour. The mixture is cooled to room temperature, diluted with EtOAc (60 mL) and Et2O (30 mL), and washed with 1 N HCl, water, 1 N NaOH and brine. The organic extract is dried (MgSO_i) and concentrated under reduced pressure. The residue is purified by flash chromatography (10% EtOAc / hexane) to provide compound 4c. EXAMPLE 5 To a solution of fluoroarene 4c (Example 4) (0.36 g, 1.0 mmol) in DMSO (5 mL) in a sealed tube with a screw cap is added NaOCH3 (1 M solution in MeOH, 1.5 mL, 1.5 mmol). The mixture is heated to 65 ° C and stirred overnight, and then allowed to cool to room temperature. The mixture is diluted with EtOAc and washed with 1 N aqueous HCl, water and brine. The organic phase is dried with MgSO 4, filtered and concentrated under reduced pressure. Purification by flash chromatography (EtOAc / Hex) gives compound 5a.

EXAMPLE 6 To a solution of fluoroarene 4c (Example 4) (0.27 g, 0.8 mmol) in DMSO (5 mL) in a sealed tube with a screw cap is added CH3CH2NHCH3 (0.11 mL, 1.1 mmol). The mixture is stirred overnight at room temperature, then diluted with EtOAc and washed with saturated aqueous NaHCO3, water and brine. The organic phase is dried with MgSO 4, filtered and concentrated under reduced pressure. Purification by flash chromatography (EtOAc / Hex) provides 6a.

To 3-fluoro-4-methylbenzoic acid 7a (0.55 g, 3.6 mmol) in concentrated H 2 SO 4 (3 mL) at 0 ° C is added KNO 3 (0.36 g, 3.6 mmol). The mixture is stirred at 0 ° C for 30 minutes and then poured into MeOH (15 mL). The mixture is refluxed for 24 h, then allowed to cool to room temperature and concentrated under reduced pressure. The residue is dissolved in EtOAc and washed successively with water (2 times), saturated aqueous NaHCO3, water (2 times) and brine. The organic phase is dried (MgSOzj), filtered and concentrated under reduced pressure to provide the nitroarene 7b.

Compound 7b is allowed to react with 2-trifluoromethylphenol 2a (Example 2) using the method described in Example 1, to give compound 7c. Intermediates of formula (III), wherein R3a is Br, are prepared using the method of Example 7, but replacing 3-fluoro-4-methylbenzoic acid 7a with 4-bromo-3-fluorobenzoic acid. EXAMPLE 8 Nitroarene 8a (prepared from phenol and compound 1a using the method of Example 1) (1.26 g, 4.6 mmol) is combined with 10% palladium on carbon (0.1 g) in methanol (20 mL). The mixture is shaken under a hydrogen atmosphere for 1 hour and then filtered through a pad of Celite ™. The solution is concentrated under reduced pressure and then dissolved in Et20 (35 mL). Hydrogen chloride is slowly added in EIO2 (1 N, 15 mL, 15 mmol). Filtration of the resulting solid provides intermediate compound 8b. EXAMPLE 9 To a mixture of nitroarene 2c (Example 2) (0.88 g, 1.9 mmol) in methanol (140 mL) is added SnCl2-2H20 (4.25 g, 18.8 mmol) and the mixture is refluxed for 2 hours. After concentration, the residue is taken up in EtOAc and poured onto saturated aqueous NH 4 Cl. The aqueous layer is extracted two EtOAc and the combined organic extracts are filtered through a short pad of silica gel. After concentration, the residue is purified by flash chromatography (15% EtOAc-hexane) to provide the desired aniline 9a. EXAMPLE 10 To a mixture of nitroarene 1c (Example 1) (1.26 g, 3.6 mmol) and ethanol (15 mL) is added saturated aqueous NH 4 Cl (2 mL), water (2 mL) and Fe powder (0.60 g, 10.8 mmol) and The mixture is stirred for 4 hours at 80 ° C. The mixture is diluted in EtOAc and washed with saturated aqueous NaHCO3 and brine and the combined organic phase is dried with MgSO4I filtered and concentrated under reduced pressure. The residue is dissolved in Et2O and treated with 1 N HCl in Et, 2O (5.4 mL, 5.39 mmol) to give the hydrochloride salt 10a which is recovered by filtration. Other intermediate compounds of formula (IV) are prepared from the appropriate intermediates of formula (III) using the processes of Examples 8, 9 and / or 10.

Compound 8b (Example 8) (663 mg, 2.4 mmol) is suspended in CH2Cl2 (15 mL) and 2-methoxypropene (908 pL, 9.5 mmol) is added, followed by NaBH (OAc) 3 (1.0 g, 4.7 mmol) . The reaction mixture is allowed to stir to the Room temperature overnight, then diluted with EtOAc and washed with NaHCO 3 and brine. The organic phase is dried over MgSO 4, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (5% EtOAc / hexane) to give compound 11a. EXAMPLE 12 12a 12b Compound 12a (prepared from 2-trifluoromethylphenol 2a using the methods of Examples 1 and 8) (278 mg, 0.80 mmol) is suspended in anhydrous CH 2 Cl 2 (6 mL) under a nitrogen atmosphere, and 1 is added. -erc-butyloxycarbonyl-4-piperidone (319 mg, 1.60 mmol), followed by Ti (OMe) 4 (275 mg, 4.60 mmol). The mixture is heated at 80 ° C for 5 h, NaBH (OAc) 3 (339 mg, 1.60 mmol) is added and the mixture is heated at 80 ° C overnight. The mixture is cooled to room temperature, diluted with EtOAc and washed with saturated NaHCO3, water and brine. The organic extract is dried over MgSO4 and concentrated under reduced pressure. The residue is purified by flash chromatography (25% EtOAc / hexane) to provide compound 12b. Other intermediate compounds of formula (V) are prepared from the appropriate intermediates of formula (IV) using the processes of Examples 11 and / or 12 and appropriate aldehydes, ketones or suitable derivatives thereof. EXAMPLE 13 To a solution of compound 12a (Example 12) (300 mg, 0.86 mmol) in EtOAc (50 mL) is added saturated aqueous NaHCO 3 (6.0 mL). The layers are separated and the organic layer is washed with water and brine, then dried (MgSO4) and concentrated under reduced pressure to give compound 13a. The process used in the second stage is adapted from: Chandrasekhar, S .; RamaChandar, T .; Jaya Prakash, S Synthesis 2000, 1817. Compound 13a (0.052 g, 0.17 mmol) is combined with anhydrous CH 2 Cl 2 (6 mL), propylene oxide (0.058 mL, 0.84 mmol), silica gel (0.01 g) and TaCl 5 ( 0.063 g, 0.18 mmol). The mixture is stirred at room temperature for 60 hours, then filtered through Celite ™, diluted with EtOAc and washed with 1 N HCl, water, saturated NaHCO 3 and brine. The organic extract is dried over MgSO 4 and concentrated under reduced pressure to provide compound 13b. EXAMPLE 14 Preparation of Compound 1008 (Table 1): To a mixture of carboxylic acid 14a (1.00 g, 6.4 mmol) and CH2Cl2 (10 mL) under an atmosphere of N2 is added oxalyl chloride (2 M in CH2Cl2) 6.4 mL, 12.87 mmol), followed by one drop of DMF. The solution is stirred for 3 hours at room temperature, and then concentrated under reduced pressure. The residue is diluted in pentanes (~2 mL) and filtered. The solution is concentrated and the residue is diluted in pentanes and concentrated to provide 14b acid chloride. Acid chloride 14b (87 mg, 0.5 mmol) is added to an aniline 11a solution (Example 11) (0.03 g, 0.1 mmol) in pyridine (0.5 mL). The mixture is heated to 60 ° C and stirred overnight. Aqueous sodium hydroxide (10 N, 0.15 mL, 1.5 mmol) and water (0.15 mL) are added and stirring is continued overnight at 50 ° C. The mixture is diluted in EtOAc and washed with 1 N aqueous HCl and brine and the organic phase is dried with MgSO, filtered and concentrated under reduced pressure. The residue is dissolved in DMSO and purified by preparative HPLC to provide compound 1008 (Table 1). EXAMPLE 15 Preparation of Compound 1039 (Table 1): To a solution of compound 12b (Example 12) (100 mg, 0.20 mmol) in anhydrous pyridine (6 mL) is added 3,4-dimethylbenzoyl chloride (50.6 mg, 0.30 mmol) and DMAP (35 mg, 0.29 mmol). The reaction mixture is stirred overnight at 60 ° C, then cooled to room temperature and diluted with EtOAc (50 mL). The mixture is washed sequentially with 1 N HCl, water, 1 N NaOH, water and brine, then dried (MgSO 4), filtered and concentrated under reduced pressure. The residue is purified by flash chromatography to provide compound 15a. Trifluoroacetic acid (0.5 mL) is added to a mixture of compound 15a (64 mg, 0.1 mmol) and CH2Cl2 (0.5 mL) and the mixture is stirred at room temperature for 1 hour. Concentration under reduced pressure affords compound 15b in the form of the trifluoroacetate salt. To a solution of compound 15b (21.6 mg, 0.03 mmol) in THF (0.70 mL) and MeOH (0.30 mL) is added 10 N NaOH (30 uL, 0.30 mmol) and the mixture is allowed to stir at room temperature for 2 days . The mixture is acidified with TFA (28 pL, 0.36 mmol) and concentrated under reduced pressure. The residue is dissolved in DMSO and purified by preparative HPLC to provide compound 1039 (Table 1) in the form of the trifluoroacetate salt. Other compounds of formula (I) are prepared from the appropriate intermediates of formula (V) using the processes of Examples 13 and / or 14 and / or the first and last steps of Example 15 and appropriate acylating agents. EXAMPLE 16 A mixture of thionyl chloride (7.7 mL, 105 mmol) and acid 16a (5.0 g, 35 mmol) is heated at 80 ° C for 1 hour. Concentration of the mixture under reduced pressure provides 16b acid chloride. Acid Chloride 16b (361 mg, 2.25 mmol) is added slowly to a solution of Compound 12a (Example 12) (521 mg, 1.50 mmol) in anhydrous pyridine (10 mL) at 60 ° C and the mixture is stirred at 60 ° C. C for 15 minutes. The mixture is cooled to room temperature, diluted with EtOAc (75 mL) and EtOAc (75 mL), and washed with 1 N HCl, water, 1 N NaOH, water and brine. The organic phase is dried over MgSO 4, filtered and concentrated under reduced pressure to provide compound 16c. Other intermediate compounds of formula (VI) are prepared from the appropriate intermediates of formula (IV) using the procedures of Example 16 and appropriate acylating agents. EXAMPLE 17 Preparation of Compound 2063 (Table 2): To a mixture of compound 16c (Example 16) (50 mg, 0.12 mmol) and anhydrous DMF (2.0 mL) is added NaH (4.2 mg, 0.17 mmol) and the mixture is allowed to stir at room temperature for 5 minutes. Mel (38 pL, 0.58 mmol) is added and the stirring continues for 1.5 hours. H2O (0.5 mL), MeOH (1.0 mL) and 5 N LiOH (400 pL) were added to the mixture and stirring was continued at room temperature for 1 hour. The mixture is acidified with TFA, concentrate and purify by preparative HPLC to provide compound 2063 (Table 2). Other intermediates of formula (I) are prepared from the appropriate intermediates of formula (VI) using the procedures of Example 17 and appropriate alkylating agents. When the alkylating agent is tere 2-bromoacetate. -butyl, the intermediate ester can be deprotected by treatment with an acid, such as trifluoroacetic acid, under well-known conditions. EXAMPLE 18 Preparation of Compound 1040 (Table 1): To a solution of compound 15b (Example 15) (27 mg, 0.04 mmol) in THF (0.7 mL) is added Ac2O (0.02 mL, 0.20 mmol), Et3N (0.017 mL, 0.12 mmol) and DMAP (1 mg, cat. ), and the mixture is stirred at room temperature for 1 hour. Aqueous NaOH (10 N, 0.06 mL, 0.6 mmol) is added and the mixture is stirred during one night. The mixture is acidified with TFA (0.062 mL, 0.8 mmol) and concentrated under reduced pressure. The residue is dissolved in DMSO (1 mL) and purified by preparative HPLC to provide compound 1040 (Table 1 ). EXAMPLE 19 Preparation of Compound 1041 (Table 1): To a solution of compound 15b (0.036 g, 0.6 mmol) in EtOH (0.7 mL) is added HCHO (37% aqueous solution, 0.024 mL, 0.3 mmol), NaBH3CN (0.023 g, 0.36 mmol) and AcOH (0.055 mL, 0.1 mmol). The mixture is stirred overnight at room temperature, then diluted in EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase is dried with MgSO 4, filtered and concentrated under reduced pressure. The residue is dissolved in THF / MeOH (4: 1, 1 mL), aqueous NaOH (10 N, 0.06 mL, 0.6 mmol) is added and the solution is stirred for 60 hours at room temperature. The reaction is acidified with TFA (0.055 mL, 0.7 mmol) and concentrated under reduced pressure. The residue is dissolved in DMSO and purified by preparative HPLC to provide compound 1041 (Table 1). EXAMPLE 20 Preparation of Compound 2059 (Table 2): To a solution of compound 20a (prepared from compound 12b (Example 12) using the method of Example 15, but replacing 3,4-dimethylbenzoyl chloride with compound 16b (Example 16)) (30 mg, 0.05 mmol) in DMSO (2 mL) is added CH3SO2CI (0.006 mL, 0.07 mmol) and Et3N (0.067 mL, 0.46 mmol), and the mixture is stirred at room temperature for 30 minutes. Aqueous LiOH (5 N, 0.45 mL, 2.3 mmol) and MeOH (1 mL) are added and the mixture is warmed to 50 ° C and stirred for 1 hour. The MeOH is removed under reduced pressure and the mixture is acidified with TFA (0.23 mL, 3 mmol), filtered and purified by preparative HPLC to provide compound 2059 (Table 2). EXAMPLE 21 Preparation of Compound 2060 (Table 2): To a solution of compound 20a (Example 20) (30 mg, 0.05 mmol) in DMSO (2 mL) is added Et-N = C = O (0.067 mL, 0.09 mmol and Et3N (0.067 mL, 0.46 mmol), and the The mixture is stirred at room temperature for 1 hour, aqueous LiOH (5 N, 0.45 mL, 2.3 mmol) and MeOH (1 mL) are added and the mixture is heated. up to 50 ° C and stirred for 1 hour. The MeOH is removed under reduced pressure and the mixture is acidified with TFA (0.23 mL, 3 mmol), filtered and purified by preparative HPLC to provide compound 2060 (Table 2). EXAMPLE 22 Preparation of Compound 2061 (Table 2): To a solution of compound 20a (Example 20) (30 mg, 0.05 mmol) in DMSO (2 mL) is added methyl chloroformate (0.013 mL, 0.16 mmol) and Et3N (0.066 mL, 0.46 mmol), and the mixture is stirred at room temperature for 30 minutes. Aqueous LiOH (5 N, 0.45 mL, 2.3 mmol) and MeOH (1 mL) are added and the mixture is heated to 55 ° C and stirred for 2 hours. The MeOH is removed under reduced pressure and the mixture is acidified with TFA (0.23 mL, 3 mmol), filtered and purified by preparative HPLC to provide compound 2061 (Table 2). EXAMPLE 23 Preparation of Compound 2022 (Table 2): Compound 23a is prepared using the method of Example 1, but replacing 2-bromophen with 4-aminophenol; protecting the amino group of the corresponding compound of formula (III) in the form of a tert-butyloxycarbamate, by treatment with Boc2O and NaHCO3 using processes well known in the art; and transforming the protected compound of formula (III) into compound 23a using the processes of Examples 8, 11 and 14, but replacing compound 14b with compound 16b. To a solution of compound 23a (0.51 g, 0.97 mmol) in CH 2 Cl 2 (2 mL) is added TFA (2 mL). The mixture is stirred for 1 hour at room temperature, and then concentrated at reduced pressure. The residue is triturated in Et.sub.20 and the solid is isolated by filtration to provide compound 23b in the form of the trifluoroacetate salt. To a solution of compound 23b (0.045 mg, 0.08 mmol) in pyridine (3 mL) is added AcCl (0.036 mL, 0.50 mmol). The mixture is stirred at 55 ° C for 15 minutes and allowed to cool to room temperature, then diluted with EtOAc and washed with 1 N HCl, water, 1 N NaOH and brine. The organic phase Dry with MgSO_t, filter and concentrate under reduced pressure. The residue is dissolved in DMSO / MeOH (2: 1, 3.0 ml_), followed by the addition of aqueous LiOH (5 N, 0.4 ml_, 2.0 mmol). The mixture is stirred at 55 ° C for 1 hour and allowed to cool to room temperature. TFA (0.030 ml_, 0.4 mmol) is added and the mixture is concentrated. Purification of the residue by preparative HPLC gives compound 2022 (Table 2). It will be apparent to one skilled in the art that compound 23a is transformed to compound 2018 of Table 2 by hydrolysis using the method of the last step of Example 15. Similarly, compound 23b is converted to compound 2019 of Table 2, using the hydrolysis method of the last step of Example 15. Compound 23b is also used to synthesize urea derivatives, such as compounds 2025 and 2026 of Table 2 using processes described in Thavonekham, B. Synthesis 1997, 1189. EXAMPLE 24 Preparation of Compound 2015 (Table 2): Compound 24a is prepared from compound 9a (Example 9) using the methods of Examples 11 and 14, but replacing compound 14b with compound 16b (Example 16). A mixture of racemic BINAP (0.011 g, 2 pmol) and Pd (OAc) 2 (4 mg, 2 pmol) is treated with ultrasound for 10 minutes in dry toluene (1.5 mL). This mixture is combined with a mixture of compound 24a (0.10 g, 0.17 mmol), morpholine (0.020 mL, 0.22 mmol) and Cs2CO3 (0.28 g, 0.85 mmol) in dry toluene (6.5 mL) and the resulting mixture is stirred at 110 ° C for 16 h. The mixture is allowed to cool to room temperature and is filtered through Celite ™. The filtrate is concentrated under reduced pressure and the residue is dissolved in DMSO (1.50 mL). NaOH (10 N, 0.17 mL, 1.7 mmol) is added and the mixture is heated to 50 ° C and allowed to stir for 1 hour. The mixture is acidified with TFA (0.16 mL, 2.0 mmol) and purified by preparative HPLC to provide the compound 2015 (Table 2). Other compounds of formula (I), wherein R 2 is a phenyl group bearing a cyclic or acyclic amine group at the 4-position are prepared using the method of Example 24, but replacing morpholine with an appropriate amine. EXAMPLE 25 Preparation of Compound 2074 (Table 2): To a solution of compound 24a (Example 24) (0.025 g, 0.04 mmol) in DMF (0.5 mL) are added successively 4-pyridyl-boric acid (0.007 g, 0.06 mmol), 2 M aqueous Na 2 CO 3 (0.082 mL, 0.16 mmol). ) and bis- (tri-ferc.-butylphosphino) palladium (0.002 mg, 10% by mole). The mixture is heated at 125 ° C for 8 min in a microwave (Biotage Initiator ™ Sixty). DMSO (0.3 mL) and 5 N aqueous NaOH (0.82 mL, 0.41 mmol) are added and the mixture is stirred at 50 ° C for 30 min. The mixture is acidified with AcOH and then purified by preparative HPLC to provide compound 2074 (Table 2).

Compounds 2075, 2076 and 2077 of Table 2 are also prepared using the method of Example 25, but replacing 4-pyridyl-boric acid with an appropriate boric acid. EXAMPLE 26 Preparation of Compound 2087 (Table 2): The process is adapted from: Antilla, J. C; Baskin, J. M .; Barder, T. E .; Buchwald, S. W. J. Org. Chem. 2004, 69, 5578. A mixture of compound 24a (Example 24) (21.7 mg, 0.036 mmol), imidazole (2.5 mg, 0.037 mmol), cesium carbonate (24.0 mg, 0.074 mmol), copper iodide (I ) (1.8 mg, 0.009 mmol), DMF (1.0 mL) and frans- / V, A / -dimethyl-1,2-cyclohexanediamine (3.0 mg, 0.021 mmol) under an N 2 atmosphere is heated overnight at 100 ° C. C. Aqueous NaOH (5 N, 0.072 mL, 0.36 mmol) is added and the mixture is heated at 55 ° C for 30 min and then quenched with AcOH. The mixture is purified using a semi-preparative LC-MS system to provide compound 2087 (Table 2). Compounds 2089 to 2102 of Table 2 are also prepared using the method of Example 26, but replacing imidazole with an appropriate heterocycle. EXAMPLE 27 Preparation of Compound 2064 (Table 2): Step 1: A mixture of carboxylic acid 27a (5.0 g, 27 mmol) and concentrated H2SO4 (4 mL) in MeOH (80 mL) is stirred at reflux for 12 hours. The mixture is concentrated under reduced pressure and poured onto a mixture of ice and saturated aqueous NaHCO3 solution. The aqueous mixture is acidified with citric acid and extracted twice with EtOAc. The combined organic extracts are washed with water and brine, dried over MgSO 4, filtered and concentrated under reduced pressure. Purification by flash chromatography (3: 7 EtOAc / hexane) provides ester 27b. Step 2: To a solution of phenol 27b (4.30 g, 22 mmol) in acetone (50 mL) is added K2CO3 (12.1 g, 87 mmol), followed by BnBr (3.1 mL, 26 mmol). The mixture is stirred for 72 hours at room temperature, then diluted with EtOAc and washed with water and brine. The organic phase is dried with MgSO 4, filtered and concentrated under reduced pressure to provide benzyl ether 27c.

Step 3: Compound 27c is converted to amide 27d, using the methods of Examples 10, 11 and 14, but replacing compound 14b with compound 16b (Example 16). Step 4: Pd / C (10%, 0.035 g) is added to a solution of benzyl ether 27d (0.35 g, 0.83 mmol) in MeOH / EtOAc (2: 5, 14 mL). The mixture is stirred at room temperature for 5 h under 1 atm of H2, and then filtered through Celite ™. The filtrate is concentrated under reduced pressure and the resulting residue is triturated with Et.sub.2 O / hexanes. Filtration of the solid provides the desired phenol 27e. Step 5: A mixture of carboxylic acid 27f (1.00 g, 4.8 mmol), DBU (0.86 mL, 5.8 mmol) and BnBr (0.63 mmol, 5.3 mmol) in MeCN (10 mL) is stirred at room temperature for 16 hours. The mixture is diluted with EtOAc and washed with 1 N HCl, 1 N NaOH and brine. The organic phase is dried with MgSO 4, filtered and concentrated in vacuo to give the benzyl ester 27g. Step 6: A mixture of phenol 27e (step 4) (1.17 g, 3.5 mmol), fluoroarene 27 g (step 5) (1.15 g, 3.9 mmol) and K2CO3 (1.21 g, 8.8 mmol) in DMSO (11 mL) is stirred at 100 ° C for 2 hours. The mixture is diluted with aqueous citric acid and the resulting solid is collected by filtration, washed with water and dried. Purification by flash chromatography affords compound 27h. Step 7: A mixture of benzyl ester 27h (3.5 mmol) and 10% Pd / C (0.11 g) in EtOAc is stirred under 1 atm of H2 for 16 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure to provide the carboxylic acid 27. Step 8: A mixture of carboxylic acid 27i (0.025 g, 0.05 mmol), NH 4 HCO 3 (0.015 g, 0.19 mmol) and EEDQ (0.018 g, 0.07 mmol) in CHCl 3 (1 mL) is stirred for 16 hours at room temperature. CHCl3 is removed under reduced pressure and DMSO (1 mL) is added to the residue, followed by aqueous NaOH (10 N, 0.050 mL, 0.50 mmol). The mixture is stirred at 55 ° C for 60 hours, and then purified by preparative HPLC to provide compound 2064 (Table 2). EXAMPLE 28 Preparation of Compound 2065 (Table 2): A mixture of carboxylic acid 27i (Example 27) (0.025 g, 0.05 mmol), (CH 3) 2 NH-HCl (0.005 g, 0.06 mmol) and TBTU (0.019 g, 0.06 mmol) in DMSO (1 mL) is stirred for 2 hours. hours at room temperature and aqueous NaOH (10 N, 0.050 mL, 0.50 mmol) and water (0.2 mL) are added. The mixture is heated to 55 ° C and stirred for 60 hours, and then purified by preparative HPLC to provide compound 2065 (Table 2). EXAMPLE 29 Preparation of Compound 2081 (Table 2): A mixture of carboxylic acid 27i (Example 27) (101 mg, 0.194 mmol), SOCI2 (1.0 ml_, 13.7 mmol) and DMF (10 μ? _) Is allowed to stir at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, CH2Cl2 was added to the residue and the mixture was again concentrated to give the acid chloride 29a. A mixture of 29a-acid chloride (26 mg, 0.048 mmol), 3-aminopyridine (5.5 mg, 0.058 mmol) and Et3N (9.0 pL), 0.065 mmol) in CH2Cl2 (1.0 mL) is allowed to react at 70 ° C overnight. The mixture is concentrated under reduced pressure and to the residue is added NaOH (10 N, 50 pL, 0.50 mmol), DMSO (0.5 mL) and water (50 pL). The mixture is heated at 55 ° C for 1 h, acidified with AcOH and purified by preparative HPLC to give compound 2081 (Table 2). Other compounds of formula (I), wherein R 2 is a phenyl group carrying an amide group at the 4-position are prepared using the methods of Example 28 or 29, but replacing (CH 3) 2 NH-HCl or 3-aminopyridine with an amine or appropriate amine salt. EXAMPLE 30 Preparation of Compound 2071 (Table 2): A mixture of phenol 27e (Example 27) (0.50 g, 1.5 mmol), fluoroarene 30a (0.35 g, 1.8 mmol) and K2C03 (0.52 g, 3.8 mmol) in DMSO (10 mL) is stirred at 100 ° C for 45 minutes. . The mixture is diluted with saturated aqueous citric acid, and the resulting solid is collected by filtration, washed with water and then dried to provide compound 30b. A mixture of aldehyde 30b (0.30 g, 0.6 mmol) and NaBH 4 (0.5 M in Et 20, 1.4 mL, 0.71 mmol) in MeOH (10 mL) is stirred for 1 hour and then concentrated under reduced pressure. The residue is diluted with concentrated aqueous citric acid and extracted twice with EtOAc. The combined organic extracts are washed with brine, dried with MgSO 4, filtered and concentrated under reduced pressure to provide alcohol 30c. To a mixture of alcohol 30c (0.31 g, 0.6 mmol) in CH2Cl2 (3 mL) are added DMF (0.03 mL) and SOCI2 (0.059 mL, 0.8 mmol). The mixture is stirred for 15 minutes and concentrated under reduced pressure. The residue is diluted with water and extracted twice with EtOAc. The combined organic extracts are washed with water and brine, dried over MgSO 4, filtered and concentrated reduced pressure to provide compound 30d. A mixture of compound 30d (0.025 g, 0.05 mmol), morpholine (0.005 mL, 0.06 mmol) and Et3N (0.01 mL, 0.07 mmol) in THF (1 mL) is stirred at 65 ° C for 1 day. Morpholine (0.005 mL, 0.06 mmol) and Kl (0.03 g, 0.02 mmol) are added and stirring is continued at 65 ° C for an additional day. The solution is concentrated under reduced pressure and to the residue is added DMSO (0.5 mL), aqueous NaOH (10 N, 0.1 mL, 1.0 mmol) and water (0.1 mL). The mixture is stirred for 1 hour at 55 ° C, then acidified with AcOH and purified by preparative HPLC to provide compound 2071 (Table 2). Compound 30c is transformed into compound 2135 (Table 2) by hydrolysis with 10 N NaOH as described in the last step of Example 30. EXAMPLE 31 Preparation of Compound 2085 (Table 2): A mixture of compound 30d (Example 30) (25 mg, 0.048 mmol), imidazole (3.9 mg, 0.058 mmol), Cs2CO3 (19 mg, 0.058 mmol) and Kl (0.80 mg, 0.005 mmol) in DMF (0.50 mL) were let react at 70 ° C overnight. The mixture is concentrated under reduced pressure and to the residue is added NaOH (10 N, 50 pL, 0.50 mmol), DMSO (0.5 mL) and water (50 pL). The mixture is heated at 55 ° C for 1 h, acidified with AcOH and purified by preparative HPLC to give compound 2085 (Table 2). Compound 2086 (Table 2) is prepared by the method of Example 31, but replacing imidazole with pyrazole. EXAMPLE 32 Preparation of Compound 2073 (Table 2): A mixture of compound 30d (Example 30) (0.050 g, 0.10 mmol) and NaN3 (0.008 g, 0.06 mmol) in DMSO (1 mL) is allowed to stir at 65 ° C for 40 minutes. The residue is diluted with water and extracted twice with EtOAc. The combined organic extracts are washed with water and brine, dried with MgSO 4, filtered and concentrated under reduced pressure to provide azide 32a. A mixture of azide 32a (0.052 g, 0.1 mmol) and 10% Pd / C (9 mg) in MeOH (1 mL) is stirred under 1 atm of H2 at room temperature for 2 hours. The mixture is filtered and concentrated under reduced pressure to provide the amine 32b. A mixture of amine 32b (0.023 g, 0.04 mmol), Ac 2 O (0.042 mL, 0.44 mmol) and Et 3 N (0.061 mL, 0.44 mmol) in THF (1 mL) is stirred at room temperature for 16 hours. The mixture is concentrated under reduced pressure and to the residue are added DMSO (0.50 mL), aqueous NaOH (10 N, 0.1 mL, 1.0 mmol) and water (0.1 mL). The mixture is stirred for 1 hour at 55 ° C, then acidified with AcOH and purified by preparative HPLC to provide compound 2073 (Table 2). Compound 32b is transformed into compound 2072 (Table 2) by hydrolysis with 10 N NaOH as described in the last step of Example 32. EXAMPLE 33 Inhibition of RNA-directed RNA polymerase activity NS5B Inhibitory activity is tested against the RNA-directed polymerase (NS5B) of hepatitis C virus in the representative compounds of the invention, according to the protocol described below. His-NS5BA21 polymerase of HCV [SEQ ID. No. 1] lacks the 21 C-terminal amino acids and is expressed with an N-terminal hexa-histidine marker from a pET-based vector in strain JM109 (DE3) of E. coli and purified as described by McKercher et al. al., (2004) Nucleic Acids Res. 32: 422-431. The homogenous enzyme preparation is stored at -20 ° C in storage buffer (25 mM Tris / HCl pH 7.5, 300 mM NaCl, 5 mM DTT, 1 M EDTA and 30% glycerol (v / v)). The purified His-NS5BA21 polymerase is reconstituted in an assay that measures the incorporation of 3H-UTP during the lengthening of an annealed biotin-oligo- (U) i2 RNA primer to a poly (A) homopolymer template. First the test compound is added, followed by the substrate and then the enzyme. At the end of the reaction, streptavidin beads are added for proximity scintillation analysis (SPA) and the radioactivity of the captured double-stranded RNA product is quantified in a TopCount instrument (Packard).

The components of the assay reaction are: 20 mM Tris-HCl pH 7.5, 1 mM TCEP, 1 mM EDTA, 5 mM MgCl 2, 0.01% w / v BSA, 5% v / v DMSO, 10 pg / ml poly (A), 1 pg / ml biotin-oligo- (U) i2, 333 nM UTP, 0.01 mCi / ml, 3 H-UTP (300 nM), 80 units / ml Rnasin, His-NS5BA21 polymerase 12.5 nM and test inhibitor compound that is diluted serially over a wide range of concentrations. The assay is carried out in 384-well plates with an incubation of 1.5 hours at 22 ° C, and then it is stopped with a 0.5 M EDTA solution and the products captured with streptavidin-coated beads. After the addition of CsCl 6 M to the bottom of each well, the plate is left at room temperature for 90 minutes before counting for 60 seconds in a TopCount. The calculated% inhibition values are then used to determine the IC 50, the slope factor (n) and the maximum inhibition (lmax) by the routine NLIN SAS non-linear regression procedure. EXAMPLE 34 Specificity for the inhibition of the RNA-directed RNA polymerase NS5B The inhibitory activity of the RNA-directed RNA polymerase of the polio virus and the RNA polymerase II directed by calf thymus DNA of the representative compounds of the invention is tested as described by McKercher et al., (2004) Nucleic Acids Res. 32: 422-431. EXAMPLE 35 HCV RNA replication assay with cell-based luciferase indicator Activity is assayed as inhibitors of virus RNA replication of hepatitis C in cells expressing a stable subgenomic HCV replicon of the representative compounds of the invention, using the assay described in WO 2005/028501. COMPOUND TABLES The following tables list representative compounds of the invention. Representative compounds listed in Tables 1 and 2 below are tested in the NS5B polymerase activity inhibition assay of Example 33, and are found to have IC 50 values below 30 μ ?. The retention times (R) for each compound are measured using the standard analytical HPLC conditions described in the Examples. As is well known to a person skilled in the art, the values of the retention time are sensitive to the specific measurement conditions. Therefore, even if identical conditions of solvent, flow rate, linear gradient and the like are used, the values of the retention time may vary when measured, for example, in different HPLC instruments. Even when measured on the same instrument, the values may vary, for example, using different individual HPLC columns, or when measured on the same instrument and with the same individual column, values may vary, for example, between individual measurements taken on different occasions.

?? Table 2 ??

Claims (28)

1. CLAIMS 1.- Compound of formula I: wherein: X is selected from O and S, R2 is aryl, optionally substituted with R20, wherein R20 is 1 to 5 substituents, each independently selected from: a) halo, alkyl (Ci.6), haloalkyl (Ci) 6), (C3-7) cycloalkyl or (C3-7) cycloalkyl- (C1-6) alkyl, b) -N (R7) R8 or -YN (R7) R8, wherein Y is selected from -C (= 0) -, -SO2- and -alkylene (Ci-6), R7 is selected, in each case independently, from H and alkyl (Ci-6); and R8 is selected, in each case independently, from H, alkyl (Ci-6), haloalkyl (C1-6), cycloalkyl (C3-7), cycloalkyl (C3-7) -alkyl (C1-6), aryl, Het, -C (= 0) -R9, -C (= 0) OR9 and -C (= 0) NHR9, wherein the alkyl (Ci.6) is optionally substituted with -OH, -O-alkyl (Ci-) 6), cyano, -NH2, -NHalkyl (Ci-4) or -N (alkyl (Ci.4)) 2; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci_6), -C (= O) -alkyl (01-6), - SO 2 (C 1-6) alkyl, -C (= O) -NH 2, -C (= O) -NH-alkyl (C 1), -C (= O) -N ((C 1-4) alkyl) 2, - NH2, -NH-alkyl (C ^), -N ((C -4) alkyl) 2 or -NH-C (= O) alkyl (C-), ii) (Ci-6) alkyl, optionally substituted with - OH or -O-alkyl ^ -e); and ii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (C-i-e); and wherein R9 is selected from: i) (Ci-6) alkyl, optionally substituted with -COOH, -NH2, -NHalkyl (Ci.4) or -N (alkyl (Ci.)) 2; and ii) Het, optionally substituted with alkyl (Ci-6); or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S, or a heteropolycycle of 7 to 14 members, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (C1-6), -SO2alkyl (Ci-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N (C1-4alkyl)) 2 , -NH2, -NH- (C1-4) alkyl, -N (C1-4alkyl)) 2 or -NH-C (= O) alkyl (Ci-4), ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci_6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (? -? -?), c) aryl, aryl-alkyl (Ci-6), Het or Het-alkyl ( Ci-6), wherein each of the aryl, aryl-alkyl (Ci-6), Het and Het-alkyl (Ci-β) is optionally substituted with 1 to 3 substituents, each independently selected from ) halo, -OH, haloalkyl (C -6), -C (= O) -alkyl (C -6), -SO2alkyl (Ci-6), -C (= O) -NH2, -C (= O) -NH- (1-4C) alkyl, -C (= O) -N ((1-4C) alkyl) 2, -NH2, -NH- (C1-) alkyl, -N ((Ci-4) alkyl) 2 or -NH-C (= O) alkyl (Ci ^), ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6); and d) -C (= O) -R10, -O-R10, -C (= O) -O-R10, -alkylene (C1-6) -O-R10, -S-R10, -SO-R10, - SO2-R10, -alkylene (Ci.6) -S-R10, -alkylene (C1-6) -SO-R10 or -alkylene (Ci-6) -SO2-R10, wherein R10 is independently selected from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3-7), cycloalkyl (C3) .7) -alkyl (Ci.6), aryl and Het, wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-(C1-6) alkyl, cyano, -NH2, -NHalkyl (Ci-4) or and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (C-6) , -SO2 (C1-6) alkyl, -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N ((Ci-4) alkyl) 2, -NH2, -NH- (C1-4) alkyl, -N ((Ci-4) alkyl) 2 or -NH-C (= O) alkyl (Ci ^), ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-β), with the proviso that when X is O, R2 is not a group of the formula R3 is selected from H, halo, alkyl (Ci-4), -O-alkyl (Ci-4), -S-alkyl (C -4), -NH2, -NHalkyl (Ci-4) and -N (alkyl) (Ci-4)) 2, R5 is selected from H, alkyl (Ci-6), cycloalkyl (C3-7), cycloalkyl (C3-7) -alkyl (Ci-3) and Het; the alkyl (Ci-6) and Het each being optionally substituted with 1 to 4 substituents each independently selected from alkyl (???), -OH, -COOH, -C (= O) -alkyl (Cm), -C (= O) -O- (C1-6) alkyl, -C (= O) -NH- (C1-6) alkyl, -C (= O) -N ((Ci-6) alkyl) 2 and -SO2alkyl (Ci-6); and R6 is selected from cycloalkyl (C5-7), cycloalkyl (C5.7) -alkyl (Ci-3), aryl and aryl-alkyl (Ci.3), each of the cycloalkyl (C5.7), cycloalkyl ( C5-7) -alkyl (Ci.3), aryl and aryl-alkyl (Ci-3) optionally substituted with 1 to 5 substituents, each independently selected from halo, alkyl (Ci.6), haloalkyl (Ci-6) , -OH, -SH, -O-alkyl (Ci-4) and -S-alkyl (Ci-4), where Het is a saturated, unsaturated or aromatic 4 to 7 membered heterocycle having from 1 to 4 heteroatoms, each one independently selected from O, N and S, or a 7 to 14 membered heteropolycycle, saturated, unsaturated or aromatic having, whenever possible, from 1 to 5 heteroatoms, each independently selected from O, N and S, or one of its salts or esters. 2. - Compound according to claim 1, wherein X is O. 3. - Compound according to claim 1, wherein X is S. 4. Compound according to one or more of claims 1 to 3, wherein R2 is naphthyl or phenyl, the phenyl being optionally substituted with R20, wherein R20 is as defined in claim 1, with the proviso that when X is O, R2 is not a group of the formula 5. - Compound according to claim 4, wherein R2 is phenyl optionally substituted with R20, wherein R20 is as defined in claim 4, with the proviso that when X is O, R2 is not a group of the formula 6. - Compound according to claim 5, wherein R2 group of formula: wherein R21 is selected from H, halo, alkyl (Ci-6), haloalkyl (Ci -0-haloalkyl (Ci-6); and R22 is selected from H, halo, alkyl (C- | .3), haloalkyl (Ci-alkylene (1-3C) -OH, -C (-0) -alkyl (C -3) and -COOH. - Compound according to claim 5, wherein R2 is a group of the formula: wherein R21 is selected from H, halo, alkyl (Ci-6), haloalkyl (Ci-6) and -0-haloalkyl (Ci-6); and R22 is selected from: b) -N (R7) R8 or -YN (R7) R8, wherein Y is selected from -C (= 0) -, -SO2- and -alkylen (Ci-6), R7 is selected from H and alkyl (Ci-6); and R8 is selected from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3-7), cycloalkyl (C3-7) -alkyl (Ci-6), aryl, Het, -C (= 0) -R9, -C (= 0) OR9 and -C (= 0) NHR9, wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6) , cyano, -NH2, -NHalkyl (Ci-4) or -N ((C1-4) alkyl) 2; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (Ci-6) , -SO2 (C1-6) alkyl, -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N (alkyl (d.4)) 2l -NH2 > -NH-alkyl (? 1-4), -N ((1-4C) alkyl) 2 or -NH-C (= O) alkyl (C), ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (C-i-6); and wherein R9 is selected from: i) (Ci-6) alkyl, optionally substituted with -COOH, -NH2, -NHalkyl (Ci-4) or -N ((Ci-4) alkyl) 2; and ii) Het, optionally substituted with alkyl (Ci-6); or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O, and S, or a 7- to 14-membered heteropolycycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O, and S; the heterocycle and the heteropolycycle being each optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (C -6), -SO2 (C1-6) alkyl, -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N (C1-4 alkyl)) 2 , -NH2, -NH- (C1-4) alkyl, -N ((Ci-4) alkyl) 2 or -NH-C (= O) alkyl (Ci-4), ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6); and c) aryl, Het or Het-C 1-6 alkyl-, wherein each of the aryl, Het and Het-alkyl (Ci-6) -is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (C1-6), -SO2alkyl (C1-6), -C (= O) -NH2, -C (= O) - NH-C 1-4 alkyl, -C (= O) -N (C 1-4 alkyl) 2, -NH 2, -NH-alkyl (C 1), -N (alkyl (1-4)) 2 or -NH-C (= O) alkyl (Ci-), ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or alkyl (Ci-6). 8. Compound according to claim 7, wherein R2 is a group of formula: wherein R21 is CF3; and R22 is selected from: b) -N (R7) R8, wherein R7 is selected from H and alkyl (Ci-6); and R8 is selected from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3.7), cycloalkyl Ca ^ -alkyloylC-ie), aryl, Het, -C (= 0) -R9, -C (= O) OR9 and -C (= 0) NHR9, wherein the (C1-6) alkyl is optionally substituted with -OH, -O-alkyl (Ci-6), cyano, -NH2, -NHalkyl (Ci-4) or -N (alkyl (Ci-6) 4)) 2; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (C ^ e), -C (= O) -alkyl (C1-6) , -SO2alkyl (Ci.6), -C (= O) -NH2, -C (= O) -NH-alkyl (C1.4), -C (= O) -N (C1-4alkyl)) 2, -NH2, -NH-alkyl (Ci-4), -N ((Ci-4) alkyl) 2 or -NH-C (= O) alkyl (Ci-4), ii) alkyl (Ci-6) , optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-β); and wherein R9 is selected from: i) (Ci-6) alkyl, optionally substituted with -COOH, -NH2, -NHalkyl (Ci-4) or -N ((Ci-4) alkyl) 2; and ii) Het, optionally substituted with alkyl (Ci-6); or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S, or a heteropolycycle of 7 to 14 members, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (de), -SO2alkyl (C1-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N ((C -4) alkyl) 2, - NH2, -NH-alkyl (C ^), -N ((C ^ 4) alkyl) 2 or -NH-C (= O) alkyl (Ci-4); ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-β), and c) Het, optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci-β), -C (= O) -alkyl (C1-6), -SO2alkyl (C1-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N ((C1-) alkyl) 2, -NH2, -NH- (C1-4) alkyl, -N (alkyl (Ci -4)) 2 or -NH-C (= O) alkyl (Ci-4), ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-6), and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or alkyl (Ci-6). 9. Compound according to claim 7, wherein R2 is a group of the formula: wherein R21 is CF3; and R22 is selected from: b) -Y-N (R7) R8, wherein Y is selected from -C (= O) -, -SO2- and -CH2, R7 is selected from H and alkyl (Ci-6); and R8 is selected from H, alkyl (Ci-6), haloalkyl (Ci-6), cycloalkyl (C3-7), cycloalkyl (C3-7) -alkyl (C1-6), aryl, Het, -C (= O) -R9, -C (= O) OR9 and -C (= O) NHR9, wherein the alkyl (Ci-6) is optionally substituted with -OH, -O-alkyl (Ci-6), cyano , -NH2l -NHalkyl (Ci-4) or -N ((Ci-4) alkyl) 2; and wherein each of the aryl and Het is optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (Ci-6), -C (= O) -alkyl (C1-6) , -SO2alkyl (Ci-6), -C (= O) -NH2, -C (= O) -NH-alkyl (Ci-4), -C (= O) -N (C1-4alkyl)) 2, -NH2, -NH- (C1-4) alkyl, -N (C1-) alkyl) 2 or -NH-C (= O) alkyl (Ci-4), ii) (Ci-6) alkyl, optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6); and wherein R9 is selected from: i) alkyl (Ci-6), optionally substituted with -COOH, -NH2, or -N (alkyl (Ci-4)) 2. and ü) Het, optionally substituted with alkyl (Ci-6), or R7 and R8 are linked, together with the N to which they are attached, to form a 4- to 7-membered heterocycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S, or a 7 to 14 membered heteropolycycle, optionally containing 1 to 3 additional heteroatoms, each independently selected from N, O and S; the heterocycle and the heteropolycycle each being optionally substituted with 1 to 3 substituents, each independently selected from: i) halo, -OH, haloalkyl (C1-6), -C (= O) -alkyl (Ci-6), -SO2 (C1-6) alkyl, -C (= O) -NH2, -C (= O) -NH- (C1-) alkyl, -C (= O) -N ((Ci-4) alkyl) 2, -NH2, -NH-alkyl (C ^), -N ((C1-4) alkyl) 2 or -NH-C (= O) alkyl (C-), ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-6), and iii) aryl or Het, wherein each of the aryl and Het groups is optionally substituted with halo or alkyl (Ci-6); and c) Het-alkyl (Ci-6), optionally substituted with 1 to 3 substituents, each independently selected from i) halo, -OH, haloalkyl (ß-ß), -C (= O) -alkyl (Ci) 6), -SO2alkyl (Ci-6), -C (= O) -NH2, -C (= O) -NH- (C1-4) alkyl, -C (= O) -N (alkyl (C ^) ) 2, -NH2, -NH-alkyl (C ^), -N ((Ci-4) alkyl) 2 or -NH-C (= O) alkyl (Ci ^), ii) alkyl (Ci-6), optionally substituted with -OH or -O-alkyl (Ci-6); and iii) aryl or Het, wherein each of the aryl and Het is optionally substituted with halo or alkyl (Ci-6). 10. Compound according to one or more of claims 1 to 9, wherein R3 is H or F. 11. Compound according to claim 10, wherein R3 is H. 12. Compound according to one or more of claims 1 to 11, wherein R5 is H or (C1"6) alkyl, wherein the alkyl (Ci-6) is optionally substituted with 1 to 4 substituents each independently selected from -OH, -COOH, -C (= O) -alkyl (C1-6), -C ^ OJ-O-alkyloid-e), -C (= O) -NH-alkyl (Ci-6), -C (= O) -N ((C1-6) alkyl) 2 and -SO2alkyl (C -6). 13. - Compound according to claim 12, wherein R5 is 1-methylethyl. 14. Compound according to one or more of claims 1 to 11, wherein R5 is Het optionally substituted with 1 to 4 substituents each independently selected from (C1-6) alkyl, -OH, -COOH, -C ( = O) -alkyl (C1-6), -C (= O) -O- (C1-6) alkyl, -C (= O) -NH- (C1-6) alkyl, -C (= O) - N ((C-6) alkyl) 2 and -SO2alkyl (Ci-6). 15. Compound according to one or more of claims 1 to 14, wherein R6 is selected from cycloalkyl (C5-7) and cycloalkyl Cs ^ -alkyloylCi-a) -, each of the cycloalkyl being (C5-7) and cycloalkyl Cs-rJ-alkyloxyCi. 3) optionally substituted with 1 to 5 substituents, each independently selected from halo, alkyl (Ci-6), haloalkyl (Ci-6), -OH, -SH, -O-alkyl (Ci-4) and -S- alkyl (Ci-4). 16. - Compound according to claim 15, wherein R6 17. - Compound according to one or more of claims 1 to 14, wherein R6 is aryl optionally substituted with 1 to 5 substituents, each independently selected from halo, alkyl (Ci-6), haloalkyl (Ci-6), - OH, -SH, -O-alkyl (Ci.4) and -S-alkyl (Ci-4). 18. Compound according to one or more of claims 1 to 17, or a pharmaceutically acceptable salt or ester thereof; as a medicine. 19. - Pharmaceutical composition comprising a therapeutically effective amount of a compound according to one or more of claims 1 to 17, or a pharmaceutically acceptable salt or ester thereof; and one or more pharmaceutically acceptable vehicles. 20. - Pharmaceutical composition according to claim 19 further comprising at least one other antiviral agent. 21. Use of a composition according to one or more of claims 19 or 20, for the treatment of a viral infection of hepatitis C in a mammal suffering from or at risk of suffering from the infection. 22. - Method of treating a hepatitis C viral infection in a mammal suffering from or at risk of infection, the method comprising administering to the mammal a therapeutically effective amount of a compound according to one or more of claims 1 to 17, a pharmaceutically acceptable salt or ester thereof, or a composition thereof. 23. - Method of treating a hepatitis C viral infection in a mammal suffering from or at risk of infection, the method comprising administering to the mammal a therapeutically effective amount of a combination of a compound according to one or more of the claims 1 to 17, or a pharmaceutically acceptable salt or ester thereof, and at least one other antiviral agent; or a composition thereof. 24. Use of a compound according to one or more of claims 1 to 17, or a pharmaceutically acceptable salt or ester thereof, for the treatment of a hepatitis C viral infection in a mammal suffering from or at risk of suffer the infection 25. - Use of a compound according to one or more of the claims 1 to 17, or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of a hepatitis C viral infection in a mammal suffering from or at risk of infection. 26.- Production article comprising an effective composition for treating a hepatitis C viral infection; and packaging material comprising a label indicating that the composition can be used to treat infection with the hepatitis C virus; wherein the composition comprises a compound according to one or more of claims 1 to 17, or a pharmaceutically acceptable salt or ester thereof. 27. Method for inhibiting the replication of the hepatitis C virus, which comprises exposing the virus to an effective amount of the compound according to one or more of claims 1 to 17, or a salt or ester thereof, under conditions in which inhibits the replication of the hepatitis C virus. 28.- Use of a compound according to one or more of claims 1 to 17, or a salt or ester thereof, to inhibit the replication of hepatitis virus. C.