MXPA06007729A - Azabenzofuran substituted thioureas as inhibitors of viral replication - Google Patents

Abstract

The present invention provides compounds of Formula:(1), wherein the variables Ar, A1, A2, A3, A4, R5, R6, R7, V, W, X, and Y are defined herein. Certain compounds of Formula (1) described herein possess potent antiviral activity. The invention also provides compounds of Formula (1) that are potent and/ or selective inhibitors of Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing oneor more compounds of Formula (1), or a salt, solvate, or acylated prodrug of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The invention further comprises methods of treating patients suffering from certain infectious diseases by administering to such patients an amount of a compound of Formula (1) effective to reduce signs or symptoms of the disease. These infectious diseases include viral infections, particularly HCV infections. The invention is particularly includes methods of treating human patients suffering from an infectious disease, but also encompasses methods of treating other animals, including livestock and domesticated companion animals, suffering from an infectious disease. Methods of treatment include administering a compound of Formula (1) as a single active agent or administering a compound of Formula (1) in combination with on or more other therapeutic agent.

Description

TIOU EAS SUBSTITUTED WITH AZABENZOFURAN: VIRAL REPLICATION INHIBITORS REFERENCE TO RELATED REQUEST The present invention claims the priority of the US provisional patent application number 60 / 534,839, filed on January 6, 2003, which is incorporated herein in its entirety.

FIELD OF THE INVENTION The present invention provides thiourea compounds substituted with azabenzofuran, particularly thurane derivatives substituted with furanylpyridinyl and related compounds, useful as antiviral agents. Certain thiourea compounds substituted with azabenzofuran, including furanylpyridinyl-substituted thiourea compounds described herein, are potent and / or selective inhibitors of viral replication, particularly replication of the hepatitis C virus. The invention also provides pharmaceutical compositions containing one or more compounds of thiourea substituted with azabenzofuran, and one or more carriers, excipients or diluents acceptable for pharmaceutical use. These pharmaceutical compositions may contain a thiourea compound substituted with azabenzofuran as the sole active agent, or may contain a combination of a thiourea compound substituted with azabenzofuran and one or more pharmaceutically active agents. The invention also provides methods for treating hepatitis C viral infections in mammals.

BACKGROUND OF THE INVENTION In the 1940s, the disease originally called viral hepatitis was distinguished into two separate disorders called infectious hepatitis (hepatitis A, HAV) and homologous serum hepatitis (hepatitis B, HBV). The transfusion of blood products had proved to be a common route for the transmission of viral hepatitis. It was originally assumed that HBV was the causative agent of post-transfusion hepatitis, given that the clinical and epidemiological characteristics of the disorder did not match those of OAB. Soon after a radioimmunological assay for hepatitis B surface antigen (HBsAg) became available as a tool to identify patients infected with HBV, it became clear that most of the patients who had post-transfusion hepatitis were negative for the HBsAg. Thus, hepatitis after blood transfusion was not caused by hepatitis A or by hepatitis B, and was subsequently referred to as non-A, non-B hepatitis. The causative agent of non-A hepatitis, non-B (hepatitis C virus, HCV), was discovered in 1989 by screening cDNA expression libraries made of RNA and chimpanzee DNA infected with serum from a patient with hepatitis. no-A, no-B after a transfusion. To identify parts of the genome that encoded the viral proteins, the libraries were screened with antibodies from patients who did not have non-A, non-B hepatitis. These researchers showed that the virus they identified was responsible for the vast majority of cases of non-A, non-B hepatitis. Hepatitis C virus is one of the most widespread causes of chronic liver disease in the United States. The virus produces approximately 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Nearly 4 million Americans, or 1.8 percent of the US population, have antibodies to HCV (anti-HCV), indicating a developing infection or previous infection with the virus. Hepatitis C causes an estimated 8,000 to 10,000 deaths annually in the United States. Infection with the hepatitis C virus (HCV) occurs throughout the world, and before its identification, it was the main cause of transfusion-associated hepatitis. It has been shown that the occurrence in serum of anti-HCV in blood donors around the world varies between 0.02% 1.23%. HCV is also a common cause of hepatitis in individuals exposed to blood products. There has been an estimated 150, 000 new cases of HCV infection each year in the United States only during the past decade. The acute phase of HCV infection is usually associated with mild symptoms. However, evidence suggests that only 15% to 20% of infected people will eliminate HCV. Among the group of chronically infected people, 10% to 20% will progress to life-threatening conditions, known as cirrhosis, and another 1% to 5% will develop a liver cancer called hepatocellular carcinoma. Unfortunately, the entire infected population is at risk of suffering from these life-threatening conditions, because no one can predict which individual will eventually progress to any of them. HCV is a small, enveloped virus with single-stranded positive RNA in the Flaviviridae family. The genome is approximately 10,000 nucleotides and encodes a single polyprotein of approximately 3,000 amino acids. The polyprotein is processed by the host cell and the viral proteases in three major structural proteins and several non-structural proteins necessary for viral replication. It has been identified since then that several different genotypes of HCV with slightly different genomic sequences correlate with differences in response to treatment with alpha interferon. HCV reproduces in infected cells in the cytoplasm, in close association with the endoplasmic reticulum. Positive direct RNA is released and translation is initiated by means of an internal initiation mechanism. Internal initiation is directed by an RNA element with cis-acting at the 5 'end of the genome; some reports have suggested that the total activity of this internal ribosome entry site, or IRES, is seen with the first 700 nucleotides, which extend the 5 'untranslated region (UTR) and the first 123 amino acids of the open reading frame (ORF). All HCV protein products are produced by proteolytic cleavage of a large polyprotein (approximately 3000 amino acids), transported by one of three proteases: the host signal peptidase, the viral self-cleavable metalloproteinase, NS2, or the viral serine protease NS3. / 4A. The combined action of these enzymes produces the structural proteins (C, E1 and E2) and non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B), proteins that are required for the replication and packaging of viral genomic RNA. NS5B is the viral RNA-dependent RNA polymerase (RDRP) which is responsible for the conversion of the genomic RNA input into a negative chain copy (complementary RNA or cRNA), the cRNA then serves as a template for transcription by NS5B of the most positive sense genomic / messenger RNA An effective vaccine is greatly needed, however, its development is unlikely in the near future, due to: i) absence of an efficient cell culture system and models in small animals; ii) a weak humoral neutralization and protective cellular immune response; Ii) marked genetic variability of the virus, and iv) the absence of a viral reading test mechanism. Several institutions and laboratories are trying to identify and develop anti-HCV drugs. Currently, the only effective therapy against HCV is alpha-interferon, which reduces the amount of virus in the liver and blood (viral load) in only a small proportion of infected patients. Alpha interferon was first approved for use in the treatment of HCV more than ten years ago. Alpha interferon is a host protein that is made in response to viral infections and has natural antiviral activity. These standard forms of interferon, however, have now been replaced by pegylated interferons (peginterferons). Peginterferon is an alpha-interferon that has been chemically modified by the addition of a large inert molecule of polyethylene glycol. At present, the optimal regimen appears to be a 24- or 48-week course of the combination of pegylated interferon alpha and the nucleoside Ribavarin, an oral antiviral agent that has activity against a wide range of viruses. By itself, Ribavarin has little effect on HCV, but adding it to interferon increases the rate of sustained response by two to three times. However, the response rates to interferon / Ribavarin combination therapy are moderate, in the range of 50 to 60%, from the fact that the response rates for selected HCV genotypes (notably genotypes 2 and 3) are typically higher Among patients who became negative for HCV RNA during treatment, a significant proportion relapsed when therapy ceased. In addition, there are frequently significant adverse side effects associated with each of these agents. Patients who received interferon often have symptoms similar to those of the flu. Pegylated interferon has been associated with bone marrow suppressive effects. Importantly, alpha-interferon has multiple neuropsychiatric effects. Prolonged therapy can cause marked irritability, anxiety, personality changes, depression, and even suicide or acute psychosis. Interferon therapy has also been associated with relapse in people with a previous history of drug or alcohol abuse. Side effects of treatment with Ribavarin include side effects similar to those produced by histamine (itching and nasal congestion) and anemia due to dose-related red cell hemolysis and side effects similar to those produced by histamine. Taken together, the described facts indicate a significant need for small molecule inhibitors for the replication of the hepatitis C virus, which do not suffer from the aforementioned disadvantages.

BRIEF DESCRIPTION OF THE INVENTION The invention provides compounds of formula 1 (shown below), and includes certain thioureas substituted with azabenzofuran and related compounds, which possess antiviral activity. The invention provides compounds of formula 1 which are potent and / or selective inhibitors of the replication of hepatitis C virus. The invention also provides pharmaceutical compositions containing one or more compounds of formula 1, or a salt, solvate, or acylated prodrug of these compounds, and one or more carriers, excipients or diluents acceptable for pharmaceutical use. The invention further comprises methods for the treatment of patients suffering from certain infectious diseases, by administering to such patients an amount of a compound of formula 1 effective to reduce the signs or symptoms of the disease. These infectious diseases include viral infections, particularly HCV infections. The invention includes in particular methods for the treatment of human patients suffering from an infectious disease, but also comprises methods for the treatment of human patients suffering from an infectious disease, but also comprises methods for treating other animals, including livestock and animals. domestic companions, who suffer from an infectious disease. Treatment methods include administering a compound of formula 1 as an active agent alone or administering a compound of formula 1 in combination with one or more other therapeutic agents. Also disclosed herein is a method for inhibiting HCV replication in vivo by administering to a patient infected with HCV a concentration of a compound or salt of formula 1 that is sufficient to inhibit replication of the HCV replicon in vitro. Thus, in a first aspect the invention includes compounds of the formula 1: and its salts acceptable for pharmaceutical use. The variables Ar, A, A2, A3, A4, R5, R6, R, V, W, X and Y carry the definitions established below. X and W are independently O, S, NR or absent, when R is hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, or (aryl) alkyl of 0 to 4 carbon atoms optionally substituted. V is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkenyl of 2 to 6 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms, or Y he is absent; where when V is absent, W is absent. Ai is nitrogen or CRÍ; A2 is nitrogen or CR2; A3 is nitrogen or CR3; and A is nitrogen or CR4; where 1 or 2 of A ,, A2, A30 A4 is nitrogen. Ri to R4, when present, are independently chosen from: hydrogen, halogen, hydroxy, cyano, nitro, amino, acetyl, -NHCO2-, -NHSO2, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 atoms of carbon, and alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, mono- and di- (alkyl of 1 to 6 carbon atoms) amino, alkanoyl of 2 to 6 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, alkykaneboxamide of 1 to 4 carbon atoms carbon, mono- and di (to Iq ui I of 1 to 6 carbon atoms) carboxamide, (cycloalkyl of 3 to 8 carbon atoms) alkyl of 0 to 2 carbon atoms, monocyclic heterocycloalkyl of 2 to 7 carbon atoms, phenyl , pyridyl and pyrimidinyl; each of which is substituted with 0 to 5 substituents independently selected from halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) carbon) amino, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms. R5 is hydrogen, halogen, hydroxy, amino, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 2 carbon atoms, or haloalkoxy of 1 to 2 carbon atoms. R6 and R are independently hydrogen, or R6 and R7 are independently alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms, or R6 and R7 join to form a heterocyclic ring saturated from 5 to 7 members or mono-unsaturated, optionally containing an additional heteroatom selected from N, S and O, whose 5- to 7-membered or mono-unsaturated saturated heterocyclic ring is substituted with 0 to 3 substituents, independently selected from halogen , hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms. Ar is optionally substituted aryl or optionally substituted heteroaryl. Certain compounds of formula 1 described herein show good activity in a HCV replication assay, such as the HCV replicon assay that is explained in Example 5, below. Preferred compounds of formula 1 show an EC50 of about 10 micromolar or less, or more preferably an EC50 of about 1 micromolar or less; or even more preferably an EC50 of about 500 nanomolar or less in a replicon assay with HCV.

DETAILED DESCRIPTION OF THE INVENTION CHEMICAL DESCRIPTION AND TERMINOLOGY Before explaining the invention in detail, it may be useful to provide definitions of certain terms that will be used here. The compounds of the present invention are described using standard nomenclature. Unless otherwise defined, all the technical and scientific terms used herein have the same meaning as a connoisseur of the material to which this invention belongs, commonly understood. Formula 1 includes all the sub-formulas of it. For example, the formula 1 includes the compounds of the formulas 2 to 12. In certain instances, the compounds of the formula 1 are referred to herein as thioureas substituted with azabenzofuran. The term "azabenzofuran" is used to indicate a benzo analogue, a six-membered aromatic ring containing one to more nitrogen atoms, fused to a furanyl ring. In certain situations, the compounds of formula 1 may contain one or more asymmetric elements, such as stereogenic centers, stereogenic axes and the like, for example asymmetric carbon atoms, such that the compounds may exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds that have asymmetric centers, it should be understood that all optical isomers and their mixtures are included. In addition, compounds with carbon-carbon double bonds can appear in Z- and E- forms, with all isomeric forms of the compounds included in the present invention. In these situations, the single enantiomers, that is, optically active forms, can be obtained by asymmetric synthesis, synthesis from pure optical precursors, or by resolution of the racemates. The resolution of the racemates can also be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent, or by chromatography, using, for example, a chiral HPLC column. Where there is a compound in various tautomeric forms, the invention is not limited to any of the specific tautomers, but instead includes all tautomeric forms. The invention includes compounds of formula 1 which have all possible isotopes of atoms appearing in the compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, hydrogen isotopes include tritium and deuterium, and carbon isotopes include 11C, 13C and 14C. Certain compounds are described herein using a general formula that includes variables, for example, Ar, V, W, X, Y, A1-A4, and R5-R7. Unless otherwise specified, each variable within this formula 1 is defined independently of other variables. Thus, if a group is said to be substituted, for example with 0-2 R * ,. then said group can be substituted with up to two groups R * and R * in each occurrence is selected independently of the definition of R *. Also, combinations of substituents and / or variables are permissible only if these combinations result in stable compounds. The term "substituted", as used herein, means that any or more hydrogens of the designated atom or group is replaced with a selection of the indicated group, provided that the normal valence of the designated atom is not exceeded. When the substituent is oxo (ie, = O), then 2 hydrogens on the atom are replaced. When the aromatic portions are replaced by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example, a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure means to imply a compound that is sufficiently robust to survive the isolation of a reaction mixture, and to the subsequent formulation into an effective therapeutic agent. The phrase "optionally substituted" indicates that these groups can be unsubstituted or substituted in one or more of any of the available positions, typically 1, 2, 3 or 4 positions, by one or more appropriate groups such as those described herein. Suitable groups that may be present in a "substituted" position include, without limitation, halogen, cyano, hydroxyl, nitro, azido, alkanoyl (such as alkanoyl group of 2 to 6 carbon atoms such as acyl or the like); carboxamido; alkyl groups (including cycloalkyl groups, having from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms); alkenyl and alkynyl groups (including groups having one or more unsaturated bonds and from 2 to about 8, or from 2 to about 6 carbon atoms); alkoxy groups having one or more oxygen bonds and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy, naphthyloxy and 5,6,7,8-tetrahydronaphthyloxy; alkylthio groups including those having one or more thioether bonds and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those having one or more sulfinyl bonds and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those having one or more sulfonyl bonds and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; aminoalkyl groups, which may have a single nitrogen atom or more than one nitrogen atom, and from 1 to approximately 8, or from 1 to approximately 6 carbon atoms; aryl having 6 or more carbons and one or more rings, (for example, phenyl, biphenyl, naphthyl or the like, each ring substituted or unsubstituted); arylalkyl having from 1 to 3 separate or fused rings, and from 6 to about 18 carbon atoms, with benzyl being an example of an alkylaryl group; arylalkoxy having from 1 to 3 separate or fused rings and from 6 to about 18 carbon atoms, with benzyloxy being an example of an arylalkoxy group; or a saturated, unsaturated or aromatic heterocyclic group, having from 1 to 3 separate or fused rings with from 3 to about 8 members per ring and at least one ring with one or more N, O or S atoms. A dash ("- ") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, - (CH2) cycloalkyl of 3 to 8 carbon atoms is bonded via the carbon to the methylene group (CH2). As used herein, "acetyl" is a group of the formula - (C = O) CH3. As used herein, "alkyl" includes saturated straight-chain aliphatic hydrocarbon groups, having the specified amount of carbon atoms, generally from 1 to about 12 carbon atoms. As used herein, the term alkyl of 1 to 8 carbon atoms denotes an alkyl group having from 1 to about 8 carbon atoms. When the alkyl of 0 to carbon atoms is used here in conjunction with another group, for example, (aryl) alkyl of 0 to 4 carbon atoms, the indicated group, in this case aryl, is directly linked by a single covalent bond (C0), or linked by an alkyl chain having the specified amount of carbon atoms, in this case from 1 to 4 carbon atoms. Examples of alkyl include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl and sec-pentyl. The alkyl groups described herein typically have from 1 to about 12 carbon atoms. Preferred alkyl groups are lower alkyl groups, those alkyl groups having from 1 to about 8 carbon atoms, from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms, for example, alkyl groups of 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1 to 4 carbon atoms. As used herein, "alkenyl" denotes a straight or branched hydrocarbon chain, containing one or more carbon-carbon bonds, which may occur at any stable point along the chain. The alkenyl groups described herein typically have from 2 to about 12 carbon atoms. Preferred alkenyl groups are lower alkenyl groups, those alkenyl groups having from 2 to 8 carbon atoms, for example alkenyl groups of 2 to 8 carbon atoms of 2 to 6 carbon atoms and 2 to 4 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl and butenyl groups. As used herein, "alkynyl" denotes a straight or branched hydrocarbon chain, comprising one or more triple carbon-carbon bonds, which may occur at any stable point along the chain, such as ethynyl and propynyl. The alkynyl groups described herein typically have from 2 to about 12 carbon atoms. Preferred alkynyl groups are lower alkynyl groups, those alkynyl groups having from 2 to about 8 carbon atoms, for example alkynyl groups of 2 to 8 carbon atoms, 2 to 6 carbon atoms and 2 to 4 carbon atoms . "Alkoxy" means an alkyl group as defined above, with the indicated amount of carbon atoms attached via an oxygen bridge (-O). Examples of alkoxy include, without limitation, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. "Alkenyloxy" denotes an alkenyl group as defined above with the amount of carbon atoms indicated linked by an oxygen bridge (-O-). Examples of alkenyloxy groups include, without limitation, prop-1-en -loxy and but-1-enyloxy. "Alkanoyl" denotes an alkyl group as defined above, linked by a keto bridge (- (C = O) -). The alkanoyl groups have the indicated amount of carbon atoms, with the carbon of the keto group included in the amount of carbon atoms. For example, an alkanoyl group of 2 carbon atoms is an acetyl group having the formula CH 3 (C = O) -. As used herein, the term "alkanoyloxy" denotes an alkanoyl group as defined above, having the indicated amount of carbon atoms, linked by an oxygen bridge (-O-). Examples of alkanoyloxy groups include groups of the formula CH 3 (CH 2) (C = O) -O- and the like. As used herein, the term "mono- and / or di-alkylcarboxamide" refers to groups of the formula (alkyl ^ -NH- (C = O) - and (alkyl-?) (Alky2) -N- (C = O) - in which the alkyl1 and alkyl2 groups are independently chosen alkyl groups, as defined above, with the amount of carbon atoms indicated Mono and / or di-alkylcarboxamide also refers to groups of the formula -NH (C = O) (alkyl1) and -N (alkyl2) (C = O) (alkyl), carboxamide groups in which the point of attachment is the nitrogen atom, in which the alkyl and alkyl2 groups are groups alkyl independently chosen, as defined above, with the indicated amount of carbon atoms As used herein, the term "mono- and / or di-alkylsulfonamide" refers to groups of the formula -NHSO2 (alkyl1) and -N (alkyl2) SO2 (alkyl?), in which the alkyl-i and alkyl2 groups are independently chosen alkyl groups as defined above, with the indicated amount of alkyl carbon atoms As used herein, "alkylsulfinyl" means alkyl- (SO) -, wherein the alkyl group is an alkyl group as defined above, with the defined amount of carbon atoms. An example of an alkylsulfinyl group is ethylsulfinyl. As used herein, "alkylsulfonyl" means alkyl- (SO 2) -, wherein the alkyl group is an alkyl group as defined above, with the defined amount of carbon atoms. An example of an alkylsulfonyl group is methylsulfonyl. As used herein, "alkylthio" means alkyl-S-, wherein the alkyl group is an alkyl group as defined above, having the defined amount of carbon atoms. An example of the alkylthio group is methylthio. As used herein, the term "alkoxycarbonyl" denotes an alkoxy group, as defined above, having the indicated amount of carbon atoms, joined by a keto bridge (- (C = O) -). The alkoxy portion of the alkoxycarbonyl group has the indicated amount of carbon atoms; the carbon of the keto bridge is not included in this amount. An alkoxycarbonyl group having 3 carbon atoms indicates, for example, groups of the formula CH 3 (CH 2) 2 -O- (C = O) - or (CH 3) 2 (CH) -O- (C = O) -. As used herein, "aminoalkyl" is an alkyl group as defined herein, having the indicated amount of carbon atoms, and substituted with at least one amino substituent (-NH2). When indicated, aminoalkyl groups, like other groups described herein, may be further substituted. As used herein, the term "mono- and / or di-alkylamino" denotes secondary or tertiary alkylamino groups, wherein the alkyl groups are as defined above, and have the indicated amount of carbon atoms. The point of attachment of the alkylamino group is in the nitrogen. The alkyl groups are independently chosen. Examples of mono- and dialkylamino groups include ethylamino, dimethylamino, and methyl-propylamino. The "mono- and / or di-aminoalkyl" groups are mono- and / or dialkylamino groups linked by an alkyl linker having the specified amount of carbon atoms, for example a di-methylaminoethyl group. Tertiary amino substituents can be referred to as a nomenclature of the form? / - R- / V-R ', indicating that the R and R' groups are both linked to a single nitrogen atom. As used herein, the term "aryl" denotes aromatic groups that contain only carbon in the aromatic ring or rings. These aromatic groups can be further substituted with carbon or non-carbon atoms or groups. Typical aryl groups contain from 1 to 2 separate, fused or pendent rings, and from 6 to about 12 ring atoms, without heteroatoms as ring members. Where indicated, the aryl groups may be substituted. This substitution may include fusion to a 5- to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently chosen from N, O and S, to form, for example, a 3,4-methylenedioxy-phenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and bi-phenyl. In the term "(aryl) alkyl", aryl and alkyl are as defined above, and the point of attachment is in the alkyl group. "(Aryl) alkyl of 0 to 4 carbon atoms" denotes an aryl group that is directly attached by means of a simple covalent bond (aryl) alkyl of 0 carbon atoms, or linked by an alkyl group having from 1 to 4 carbon atoms. The term (aryl) alkyl comprises, without limitation, benzyl, phenylethyl and piperonyl. As used herein, "cycloalkyl" denotes a saturated monocyclic or multicyclic hydrocarbon ring group, having the specified amount of carbon atoms, usually from 3 to about 10 carbon atoms in the ring. Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon atoms in the ring, or from 3 to 7 carbon atoms in the ring. The multicyclic cycloalkyl groups may have 2 or 3 cycloalkyl rings fused or contain bridged or enclosed cycloalkyl groups. The cycloalkyl substituents may be pendent for a nitrogen or substituted carbon atom, or when they are attached to a substituted carbon atom which may have two substituents, a cycloalkyl group may be attached as a spiro group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, as well as bridged or nested saturated ring groups, such as norbornane or adamantane. In the term "(C i c I o a I q u i I) a I q u i i o", cycloalkyl and alkyl are as defined above, and the point of attachment is in the alkyl group. This term includes, without limitation, cyclopropylmethyl, cyclohexylmethyl, and cyclohexylmethyl. "(cycloalkyl) alkyl of 0 to 2 carbon atoms" denotes a cycloalkyl group which is directly attached by means of a simple covalent bond (ie, (cycloalkyl) alkyl of 0 carbon atoms) or linked by an alkyl group having from 1 to about 2 carbon atoms. As used herein, the term "cycloalkylcarboxamide" refers to a cycloalkyl group as defined above, linked via a linker -NH- (C = O) - wherein the cycloalkyl group is covalently linked to the nitrogen atom. "Bicyclic carbocyclic groups of 9 to 10 members" refers to saturated, partially unsaturated and aromatic ring groups having 2 ring, a total of 9 to 10 ring atoms, with all ring members being carbon. Examples include naphthyl, indanyl and tetrahydronaphthyl. In certain embodiments described herein, the 9- to 10-membered bicyclic carbocyclic group is a group in which no more than one of the two rings is aromatic. As used herein, "haloalkyl" denotes both straight and branched chain alkyl groups, having the specified amount of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable amount of carbon atoms. Examples of haloalkyl include, without limitation, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl. "Haloalkoxy" denotes a haloalkyl group as defined above, linked by an oxygen bridge. As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo or iodo. As used herein, "heteroaryl" denotes a 5- to 7-membered monocyclic aromatic ring containing from 1 to 3, or preferably from 1 to 2, selected heteroatoms of N, O, and S, with the remaining atoms in the ring being carbon or a stable bicyclic or tricyclic system containing at least one 5 to 7 membered aromatic ring containing from 1 to 3, or preferably from 1 to 2, selected heteroatoms of N, O and S, with the remaining ring atoms being carbon. When the total amount of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total amount of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total amount of S and O atoms in the aromatic heterocycle is not more than 1. The examples of heteroaryl groups include, without limitation, oxazolyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrasolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo [d] oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl , benzoxadiazolyl, dihydrobenzodioxililo, furanyl, imidazolyl, indolyl and isoxazolyl. The term "heterocycloalkyl" denotes a saturated monocyclic group containing from 1 to about 3 selected heteroatoms of N, O and S, with the remaining atoms in the ring being carbon, or a saturated bicyclic ring system having at least one N atom. , O or S in the ring with the remaining atoms being carbon. Monocyclic heterocycloalkyl groups have from 4 to about 8 ring atoms, and more typically have from 5 to 7 carbon atoms in the ring. Bicyclic heterocycloalkyl groups typically have from about five to about 12 ring atoms, in certain cases, the size of a heterocycloalkyl group is indicated by the amount of carbon atoms in the ring containing the group. For example, a heterocycloalkyl group of 2 to 7 carbon atoms contains from 2 to about 7 carbon atoms in the ring with the remaining atoms in the ring, up to about 3 per ring, chosen from N, O and S. The heterocycloalkyl groups Preferred include monocyclic heterocycloalkyl groups of 2 to 7 carbon atoms and bicyclic heterocycloalkyl groups of 5 to 10 carbon atoms. Examples of heterocycloalkyl groups include morpholinyl groups, piperazinyl, piperidinyl and pyrrolidinyl. The term "5- or 7-membered saturated or mono-unsaturated heterocyclic ring" denotes a cyclic group having from 5 to 7 ring atoms, containing an unsaturated bond, such as an alkenyl or alkynyl linkage. The 5-7 membered saturated or mono-unsaturated heterocyclic ring contains from 1 to 3 heteroatoms independently selected from N, O and S. Examples of these rings, which are saturated, include piperazine, piperidine, morpholine, and pyrrolidine. Examples of these groups which are monounsaturated include 1, 2, 3,6-tetrahydropyridine and 2,3-dihydrooxazole. The term "9 to 10 membered bicyclic heterocyclic groups" refers to partially or unsaturated saturated aromatic ring groups having 2 rings, a total of 9 to 10 ring atoms, having from 1 to about 4 ring atoms chosen independently of N, S and O, with the remaining atoms of the ring being carbon. Examples include quinolinyl, dihydroquinolinyl and indolyl. In certain embodiments described herein, the 9- to 10-membered bicyclic heterocyclic group contains a nitrogen atom in the ring, with the rest of the ring atoms being carbon. As used herein, an "imino" group is a group of the formula C = N, wherein the carbon atom additionally contains two single bonds. "Acceptable salts for pharmaceutical use" include derivatives of the disclosed compounds, wherein the parent compound is modified by making non-toxic acidic or basic salts thereof, and further refers to pharmaceutically acceptable solvates of such compounds and such salts. Examples of acceptable salts for pharmaceutical use include, without limitation, mineral or organic acid salts or basic residues, such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and similar. Salts acceptable for pharmaceutical use include conventional non-toxic salts and quaternary ammonium salts of the parent compound formed, for example, of non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, mesylic, silyl, besylic, sulphanilic , 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC- (CH2) n -COOH wherein n is from 0 to 4, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from an originating compound, a basic or acid portion, by conventional chemical methods. Generally, these salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as or hydroxide, carbonate, bicarbonate, or the like of Na, Ca, Mg or K), or by reacting forms of free base of these compounds with a stoichiometric amount of the appropriate acid. These reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, when practical. Additional appropriate salt lists can be found, for example, in Remington's Pharmaceutical Sciences, 17a. Edition, Mack Publishing Company, Easton, Pa., p. 1418 (1985). The term "prodrugs" includes any compounds that are converted to compounds of formula 1 when administered to a mammalian subject, for example, with the metabolic processing of the prodrug. Examples of prodrugs include, without limitation, acetate, formate and benzoate, and similar derivatives of functional groups (such as alcohol or amine groups) in the compounds of formula 1. The term "therapeutically effective amount" of a compound of this invention means an effective amount, when administered to a human or a non-human patient, to provide a therapeutic benefit such as an improvement in symptoms, for example an amount effective to decrease the symptoms of a viral infection, and preferably a enough to reduce the symptoms of an HCV infection. In certain circumstances, a patient suffering from a viral infection may not have symptoms of being infected. Thus, a therapeutically effective amount of a compound is also an amount sufficient to prevent a significant increase or to significantly reduce the detectable level of virus or viral antibodies in the blood, serum or tissues of the patient. A significant increase or decrease in the detectable level of virus or viral antibodies is any detectable change that is statistically significant in a standard parametric test of statistical significance, such as a Student's T test, where p < 0.05. As used herein, a "replicon" includes any genetic element, eg, a plasmid, cosmid, bacmid, phage or virus, that is capable of replication extensively under its own control. A replicon can be RNA or DNA, and can be single-stranded or double-stranded. As used herein, "nucleic acid" or a "nucleic acid molecule" refers to any DNA or RNA molecule, either single-stranded or double-stranded, and if it is single-stranded, the molecule of its complementary sequence, whether in linear or circular shape. In the description of the nucleic acid molecules, a sequence or structure of a particular nucleic acid molecule can be described herein in accordance with the normal convention of providing the sequence in the 5 'to 3' direction.

VIRAL INHIBITORS The invention provides compounds and salts of formula 1 but where the variable Ar is defined as follows: Ar is aryl or heteroaryl substituted with 0 to 5 substituents independently chosen from: (iii) halogen, hydroxy, cyano, nitro, oxo, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms, and (iv) alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyloxy of 2 to 8 carbon atoms, mono- and di- (alkenyl of 1 to 8 carbon atoms) amino, mono- and di- (alkyl of 1 to 4 carbon atoms) aminoalkyl from 1 to 4 carbon atoms, alkanoyl of 2 to 8 carbon atoms, alkanoyloxy of 2 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, mono- and di- (alkyl of 1 to 8 carbon atoms) carboxamide, (cycloalkyl of 3 to 7 carbon atoms) carboxamide, and alkylthio of 1 to 8 carbon atoms, and (v) -GRa. G is chosen from - (CH2) n-, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, -O (C = O) - and - (CH2) nO (CH2) m, - ( CH2) nN (CH2) m-, where n and m are independently 0, 1, 2, 3 or 4; and Ra is chosen from cycloalkyl of 3 to 8 carbon atoms, monocyclic heterocycloalkyl of 2 to 7 carbon atoms, mono- unsaturated heterocyclic rings of 5 to 7 members, bicyclic carbocyclic groups of 9 to 10 members, bicyclic heterocyclic groups of 9 to 10 members containing 1 nitrogen atom, aryl and heteroaryl; Each of (iv) and (v) is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkoxy) I of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl.

VARIABLES V. W. X AND Y The invention includes compounds and salts of formula 1 in which X is oxygen and Y is -CH2-. The invention includes compounds and salts of formula 1 in which X is oxygen and Y is -CH2CH2-. The invention also includes compounds and salts of formula 1 in which X and Y are absent. The invention includes compounds and salts of formula 1 in which V and W are absent. The invention includes compounds and salts of formula 1 in which V is alkyl of 1 to 2 carbon atoms and W is absent.

THE VARIABLES A? -A? The invention includes compounds and salts of formula 1, in which A ^ is nitrogen; A2 is CR2; A3 is CR3; and A4 is CR4, for example, compounds and salts of the formula 1-A: The invention also includes compounds of formula 1, in which A ^ is CR-i, A2 is nitrogen, A3 is CR3 and A4 is CR4, for example, compounds and salts of formula 1-B: Formula 1-B The invention includes compounds of formula 1, in which A-! is CR ^, A2 is CR2; A3 is nitrogen, and A4 is CR 4, for example, compounds and salts of the formula 1-C: Formula 1-C The invention includes compounds of formula 1, in which A-1 is CR ^ A2 is CR2, A2 is CR3 and A4 is nitrogen, for example, compounds and salts of formula 1-D: The invention includes compounds of formula 1, in which A-i is nitrogen, A2 is CR2, A3 is nitrogen, and A4 is CR4; for example, compounds and salts of the formula 1-E The invention includes compounds of formula 1, in which Ai is CRi, Ar2 is nitrogen, A3 is CR3 and A4 is nitrogen, for example, compounds and salts of formula 1-F.

The invention includes compounds of formula 1, in which Ai is nitrogen, A2 is CR3, A3 is CR3 and A4 is nitrogen, for example, compounds and salts of the formula 1-G.

The invention includes compounds and salts of formula 1, wherein R -? - R4, when present, are independently chosen from (i) hydrogen, halogen, hydroxy, cyano, nitro, amino, acetyl, haloalkyl of 1 to 2 atoms of carbon, and haloalkoxy of 1 to 2 carbon atoms, and (ii) alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, alkanoyl of 2 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyridyl and pyrimidinyl; each of which is substituted with 0 to 5 substituents independently selected from halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) carbon) amino, trifluoromethyl, and trifluoromethoxy.

The invention also includes compounds and salts of formula 1, wherein R? -R4, when present, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, alkyl from 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, alkanoyl of 2 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyridyl, and pyrimidinium. The invention also includes compounds and salts of formula 1, wherein R? -R4, when present, are independently selected from hydrogen, halogen, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, alkyl of 1 to 2 carbon atoms, carbon, alkoxy of 1 to 2 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, pyrrolidinyl, phenyl and pyridyl.

THE VARIABLE Rfi The invention includes compounds and salts of formula 1, wherein R5 is hydrogen or methyl.

THE RB AND R7 VARIABLES The invention includes compounds and salts of formula 1, wherein R6 and R7 are independently hydrogen, or alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, or alkynyl of 2 to 4 carbon atoms, each one of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxy, amino, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms. The invention also includes compounds and salts of formula 1, wherein R6 and R are independently hydrogen, methyl or ethyl.

THE VARIABLE Ar The invention includes compounds and salts of formula 1, wherein Ar is phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, benzo. [d] oxazolyl, dihydrobenzodioxinyl, indolyl, pyrazolopyrimidinyl, thienylpyrazolyl, or benzopyranyl, each of which is substituted with 0 to 5 substituents independently chosen from (iii), (iv) and (v). The invention also includes compounds and salts of formula 1, wherein Ar is phenyl or pyridyl, each of which is substituted with 0 to 5 substituents independently chosen from (iii), (iv) and (v). Wherein: (ii) represents halogen, hydroxy, cyano, nitro, oxo, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms, and (iv) represents alkyl of 1 to 8 carbon atoms , alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyloxy of 2 to 8 carbon atoms, mono- and di- (alkyl of 1 to 8 carbon atoms) carbon) amino, mono- and di (alkyl of 1 to 4 carbon atoms) aminoalkyl of 1 to 4 carbon atoms, alkanoyl of 2 to 8 carbon atoms, alkanoyloxy of 2 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, mono- and di- (to I qui I of 1 to 8 carbon atoms) carboxamide, (cycloalkyl of 3 to 7 carbon atoms) carboxamide, and alkylthio of 1 to 8 carbon atoms, and (v) represents -Ga, wherein G is chosen from - (CH2) n-, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, -O (C = O) -, - (CH2) nO (CH2 ) m-, and - (CH2) nN (CH2) m-, where n and m are ind ependently 0, 1, 2, 3 or 4; and Ra is chosen from cycloalkyl of 3 to 8 carbon atoms, monocyclic heterocycloalkyl of 2 to 7 carbon atoms, mono- unsaturated heterocyclic rings of 5 to 7 members, bicyclic carbocyclic groups of 9 to 10 members, bicyclic heterocyclic groups of 9 to 10 members containing 1 nitrogen atom, aryl and heteroaryl. Each of (iv) and (v) is substituted with 0 to 5 substituents independently chosen from halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl) 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl. In certain embodiments, the invention relates to compounds and salts of formulas 2 to 12, below.

Formula 2 the 3 Formula 6 Formula 7 Formula 9 Formula 10 Formula 1 1 Formula 12 where: Ai-A4 imply the definitions set forth above. A8, A8 \ A9, A9 ', are independently nitrogen or CH, wherein 0, 1 or 2 of A8, A8', Ag and A9 'are nitrogen. R5 is hydrogen or methyl. R6 and R7 are hydrogen or methyl. R 0 is alkyl of 1 to 6 carbon atoms. Rn represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms. These substituents can replace any hydrogen atom in the rings to which they are attached. For example, when A8 is CH, R1t can replace the hydrogen atom, such that A8 is R12 represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; or in the compounds of formula 4 to 7 and 9 to 10, they can also represent a 5- to 7-membered oxygen containing ring with 1 to 2 oxygen atoms, and fused to the phenyl to which it is attached. In certain embodiments, the oxygen-containing ring, of 5 to 7 members, is a heterocycloalkyl ring. R13 and 14 are independently hydrogen or methyl, and m is 0, 1 or 2. Ris represents alkoxy of 3 to 6 carbon atoms, or alkyl of 3 to 6 carbon atoms, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, alkoxy of 1 to 3 carbon atoms, and mono- and di- (1 to 5 carbon alkylamino). R16 is hydrogen or alkyl of 1 to 4 carbon atoms. In formula 8, J is nitrogen or CH; and Q is O, NR16, or CH2 In formulas 11 and 12, Q is absent, O, -CR13R14-, or R? E > and Ra is a 9 to 10 membered bicyclic carbocyclic group, or a 9 to 10 membered bicyclic heterocyclic group containing 1 nitrogen atom, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxy, cyano , alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, trifluoromethyl and trifluoromethoxy. In certain embodiments, Ra is indanyl or quinolinyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 2 carbon atoms, alkoxy, trifluoromethyl and trifluoromethoxy. Examples of compounds of formulas 4 to 7 and 9 to 10 in which R12 is a 5- to 7-membered ring containing 1 or 2 oxygen atoms and fused to the phenyl to which it is attached, include the following: (A compound of formula 4, in which R12 is a 5-membered ring containing 1 oxygen, fused with the phenyl to which it is attached) (A compound of formula 5, in which R12 represents a methyl and a 5-membered ring containing 2 oxygen atoms, fused to the phenyl to which it is attached) (A compound of the formula 6, in which R12 represents a methoxy and a 6-membered ring, which contains 2 oxygen atoms, fused with the phenyl to which it is attached).

(A compound of formula 7, in which R-? 2 represents a 6-membered ring containing 1 oxygen atom, fused with the phenyl to which it is attached). The invention includes compounds and salts of formulas 2 to 12 above, wherein cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (at I qui of 1 to 4 carbon atoms) amino, alkanoyl of 2 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyridyl and pyrimidinyl. The invention further includes compounds and salts of formulas 2 to 12, above, wherein R-to R4, when present, are independently selected from hydrogen, halogen, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, pyrrolidinyl, phenyl and pyridyl. The invention includes compounds and salts of formulas 2 to 12, above, in which X and Y are both absent. The invention also includes compounds and salts of formulas 2 to 12, in which R5, R6 and R7 are all hydrogen. The compounds of formula 1 have any combination of definitions for the variables, for example A1-A4, 5, Re, R7, V, W, Y and Ar discussed herein, are included within the scope of the invention. For example, a compound of formula 1 in which A1 is nitrogen; A2 is CR2; A3 is CR3; and A4 is CR, wherein R2-R4 is independently selected from hydrogen, halogen, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, ridinyl, pyrrolidinyl, phenyl and pyridyl. And Ar is phenyl or pyridyl; each of which is substituted with 0 to 5 substituents chosen independently of (iii), (iv) and (v). Without wishing to be bound by any particular theory, it is believed that the anti-HCV activity of the compounds of formula 1 is due to their ability to inhibit the replication of the HCV replicon. Preferred compounds of formula 1 show an ECso of about 10 micromolar or less, or more preferably an EC50 of about 1 micromolar or less; or an EC5o of about 500 nanomolar or less in a HCV replication-based HCV replication assay, such as the assay provided in example 5. Preferred compounds of formula 1 will have certain pharmacological properties. These properties include, without limitation, oral bioavailability, low toxicity, low serum protein binding, and desirable half-lives in vitro and in vivo. The invention includes packaged pharmaceutical formulations. These packaged formulations include a pharmaceutical composition containing one or more compounds or salts of formula 1 in a container and instructions for using the composition for treating a patient suffering from hepatitis C infection (HCV infection).

PHARMACEUTICAL PREPARATIONS The compounds and salts of formula 1 can be administered as the pure chemical substance, but preferably they are administered as a pharmaceutical composition or formulation. Accordingly, the invention provides pharmaceutical formulations comprising a compound or salt of formula 1, acceptable for pharmaceutical use, together with one or more carriers, excipients, adjuvants, diluents or other ingredients acceptable for pharmaceutical use. The compounds of the general formula 1 can be administered orally, topically, parenterally, by inhalation or atomization, sublingually, transdermally, by buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing carriers. non-toxic acceptable for pharmaceutical use, excipients, adjuvants, and vehicles. In addition to the compound in question, the compositions of the invention may contain a carrier acceptable for pharmaceutical use, one or more solid or liquid diluents, fillers or encapsulants, which are suitable for administration to an animal. The carriers must be of sufficiently high purity and toxicity low enough to make them suitable for administration to the animal being treated. The carrier may be inert or may possess pharmaceutical benefits by itself. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Examples of carriers or components thereof acceptable for pharmaceutical use are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth, malt, gelatin, talcum, solid lubricants, such as stearic acid and magnesium stearate, calcium sulfate, vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and oil of corn; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as TWEENS; wetting agents, such as sodium lauryl sulfate; coloring agents; flavoring agents; agents for tablet formation, stabilizers, antioxidants; conservatives; pyrogen-free water, isotonic saline, and phosphate buffer solutions. In particular, carriers acceptable for pharmaceutical use for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, saline isotonic, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. Optional active agents may be included, which do not substantially interfere with the activity of the compound of the present invention. Effective concentrations of one or more of the compounds of the invention including pharmaceutically acceptable salts, esters or other derivatives thereof are mixed with a carrier, excipient, adjuvant or vehicle acceptable for pharmaceutical use, in cases where the compounds show Insufficient solubility, methods can be used to solubilize compounds. Such methods are familiar to those skilled in the art, and include, without limitation, using cosolvents, such as dimethyl sulfoxide (DMSO), using surfactants, such as Tween, or aqueous sodium bicarbonate solution. Derivatives of the compounds, such as salts of the compounds or prodrugs of the compounds can be used to formulate effective pharmaceutical compositions. With the mixture or addition of the compound or compounds of formula 1, the resulting mixture can be a solution, suspension, emulsion or the like. The form of the resulting mixture depends on a number of factors, including the expected mode of administration and the solubility of the compound in the carrier or vehicle chosen. Effective enough concentration to improve the symptoms of the disease, disorder or condition treated, can be determined empirically. Pharmaceutical compositions containing compounds of the general formula 1 may be in a form suitable for oral use, for example, as tablets, soluble tablets, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweetening agents, flavoring agents, coloring agents and preservatives, with in order to provide pharmaceutically acceptable and palatable preparations.

Oral formulations contain between 0.1 and 99% of a compound of the invention between 0.1 and 99% of a compound of the invention, and usually at least about 5% (% by weight) of a compound of the present invention. Some embodiments contain from about 25% to about 50% or from 5% to 75% of a compound of the invention.

LIQUID FORMULATIONS The compounds of the invention can be incorporated into oral liquid preparations, such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives, such as suspending agents (eg, sorbitol syrup, methyl cellulose, glucose / sugar, syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, and hydrogenated edible fats, emulsifying agents (e.g., lecithin, sorbitan monooleate, or acacia), non-aqueous vehicles, which may include edible oils (e.g., almond oil, fractionated coconut oil, silyl esters, propylene glycol, and ethyl alcohol), and preservatives ( for example, methyl or propyl p-hydroxybenzoate and sorbic acid).

Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, dyes, syrups and the like. Acceptable carriers for pharmaceutical use, for the preparation of such compositions, are well known in the art. Oral formulations may contain preservatives, flavoring agents, sweetening agents, such as sucrose or saccharin, taste masking agents, and coloring agents. Typical carrier components for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. The syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent.

SUSPENSIONS For a suspension, typical suspending agents include methylcellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Aqueous suspensions contain the material or active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; the dispersing or wetting agents may be a phosphate of natural origin, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic chain alcohols long, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitoi such as a polyoxyethylene sorbitol substitute, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan substitute. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate. The oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those described above, and flavoring agents, can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant, such as ascorbic acid.

EMULSIONS The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents can be gums of natural origin, for example gum acacia or gum tragacanth, phosphatides of natural origin, for example soybean, lecithin, and partial esters or esters derived from fatty acids and hexitol, anhydrides, for example monooleate sorbitan, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.

DISPERSIBLE POWDERS . The powders and dispersible granules suitable for the preparation of an aqueous suspension by the addition of water, provide the active ingredient in admixture with a dispersing or wetting agent, suspending agents and one or more preservatives. Suitable dispersing or wetting agents are exemplified by those already mentioned above.

TABLETS AND CAPSULES The tablets typically contain pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Coloring agents, such as colorants from the US FDC, can be added to improve appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint and fruit flavors, are useful adjuvants for chewable tablets. Capsules (including programmed release and prolonged release formulations) typically contain one or more solid diluents described above. The selection of carrier components often depends on secondary considerations, such as flavor, cost and storage stability. These compositions can also be coated by conventional methods, typically with pH or time dependent coatings, such that the compound in question is released into the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. These dosage forms typically include, without limitation, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and Shellac. Formulations for oral use can also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the Active ingredient is mixed with water or an oily medium, for example peanut oil, liquid paraffin or olive oil.

INJECTABLE AND PARENTERAL FORMULATIONS The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using these suitable dispersing agents or humectants and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic diluent or solvent acceptable for parenteral use, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used, as a solvent or as a suspending medium. For this purpose any soft fixed oil can be used, including mono- or di-glycerides. In addition, fatty acids such as oleic acid are useful in the preparation of injectables. The compounds of formula 1 can be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous, intravenous, intramuscular injections, injection techniques or intrathecal infusion. The drug, depending on the vehicle and concentration used, can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and regulating agents can be dissolved in the vehicle. In compositions for parenteral administration the carrier comprises at least about 90% by weight of the total composition.

SUPPOSITORIES The compounds of formula 1 can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at the rectal temperature, and which therefore melts in the rectum to release the drug.

These materials are cocoa butter and polyethylene glycols.

TOPICAL FORMULATIONS The compounds of the invention can be formulated for local or topical application, such as topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams and lotions, and for application to the eye or for intracisternal or intraspinal application. The topical compositions of the present invention can be in any form, including, for example, solutions, creams, ointments, celes, lotions, milks, cleansers, humectants, sprays, skin patches and the like. These solutions can be formulated as isotonic solutions at 0.01% up to 10%, with a pH of about 5 to 7, with appropriate salts. The compounds of the invention can also be formulated for transdermal administration as a transdermal patch. Topical compositions containing the active compound can be mixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil , propylene glycol, PPG-2 myristyl propionate, and the like. Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which may be used alone or as mixtures of one or more materials, are as follows: Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, 1,2-propane -diol, butane-1, 3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palimtate, isocetyl stearate, oleic alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan -2-ol, acetyl alcohol, cetyl palmitate, dimethyl polysiloxane, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil , coconut oil, peanut oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, lactate of myristyl, decyl oleate, and myristyl myristate; propellants, such as propane, butane, isobutane, dimethyl ether, carbon dioxide, and nitric oxide; solvents, such as ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium 2-pyrroidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as calcium carbonate, talc, smectic earths, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkylammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminum silicate, montmorillonite clay organically modified, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, and ethylene glycol monoesterarate. The compounds of the invention can also be administered topically in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

OTHER FORMULATIONS Other compositions useful for achieving systemic delivery of the compounds in question include sublingual, buccal and nasal dosage forms. These compositions typically contain one or more soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. Sliding agents, lubricants, sweeteners, colorants, antioxidants and flavorings may also be included.

Compositions for inhalation can typically be supplied in the form of a solution, suspension or emulsion which can be administered as a dry powder or in the form of an aerosol using a conventional propellant (for example, dichlorodifluoromethane or trichlorofluoromethane).

ADDITIONAL COMPONENTS The compositions of the present invention may also optionally contain an activity enhancer. The activity enhancer can be chosen from a wide variety of molecules that function in different ways to improve the antimicrobial effects of the compounds of the present invention. Particular classes of activity enhancers include skin penetration enhancers and absorption enhancers. The pharmaceutical compositions of the invention may also contain additional active agents of a wide variety of molecules, which may function in different ways to amplify the therapeutic effects of a compound of the present invention. These other optional active agents, when present, are typically employed in the compositions of the invention at a level ranging from about 0.01% to about 15%. Some embodiments contain from about 0.1% to about 10% by weight of the composition. Other embodiments contain from about 0.5% to about 5% by weight of the composition.

PACKAGED FORMULATIONS The invention includes packaged pharmaceutical formulations. These packaged formulations include a pharmaceutical composition containing one or more compounds or salts of formula 1 in a container, and instructions for using the composition for treating an animal (typically a human patient) suffering from infection by a microorganism), or prevent an infection by a microorganism in an animal. In all of the foregoing, the compounds of the invention may be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.

METHODS OF TREATMENT The invention includes methods for treating viral infections, particularly HCV infections, by administering an effective amount of one or more compounds of the formula 1 to a patient suffering from a viral infection. An effective amount of a compound of formula 1 can be an amount sufficient to reduce the symptoms of viral infection. Alternatively, an effective amount of a compound of formula 1 may be an amount sufficient to significantly reduce the amount of virus or detectable viral antibodies in the tissues or body fluids of a patient. Treatment methods include administering an amount of a compound of formula 1 sufficient to reduce or alleviate jaundice, fatigue, dark urine, abdominal pain, loss of appetite and nausea, associated with HCV infection. The compounds of formula 1 are thought to improve the disease process by HCV by virtue of their inhibition of replication of the hepatitis C virus. The compounds provided herein can be virucidal, because they actually kill the active virus, as well as inhibit the viral replication independently. The compounds provided can also function by mechanisms that involve a combination of virucidal activity and inhibition of replication. Treatment methods encompassed by the invention include administering a compound of formula 1 as the sole active agent, and administering a compound of formula 1 together with one or more other active agents, such as another antiviral agent, particularly an antiviral agent effective against HCV infection. The invention includes administering one or more compounds of formula 1 together with pegylated interferon, pegylated interferon alpha-2b, ribavarin (REBETOL), natural interferon, Albuferon, recombinant interferon alpha-2b (INTRON), interferon beta-1a, IL-10 , interferon gamma-1b, AMANTADINE or ZADAXIM. Methods of treating hepatitis C infection particularly include administering a compound of formula 1 as the sole active agent and combination methods in which a compound of formula 1 is administered in combination with ribavarin and / or an interferon, such as pegylated interferon or recombinant interferon alfa-2b. Treatment methods also include inhibiting HCV replication in vivo, in a patient infected with HCV, by administering a sufficient concentration of a compound of formula 1 to inhibit replication of the HCV replicon in vitro. By "sufficient concentration" of a compound administered to the patient, it is meant the concentration of the compound available in the patient's system to fight the infection. This concentration can be determined experimentally, for example by testing the blood concentration of the compound, or theoretically, by calculating the bioavailability. The dose levels of the order from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated above (approximately 0.5 mg to approximately 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Dosage unit forms will generally contain from about 1 mg to about 500 mg of active agent. The frequency of the dose may also vary depending on the compound used and the particular disease treated. However, for the treatment of most infectious diseases, a dose regimen of 4 times daily or less is preferred, and a dose regimen of 1 or 2 times daily or even less frequently is particularly preferred. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration , route of administration, and elimination rate, combination of drugs and the severity of the particular disease that is under therapy.

SYNTHESIS OF COMPOUNDS Below, in Example 1, an illustration of the preparation of the compounds of the present invention is presented. Those skilled in the art will recognize that the materials and additional steps employed to produce the compound encompassed by the present invention can be changed. EXAMPLES SYNTHESIS SCHEME SCHEME 1 A general method for preparing the compounds of the present invention is shown in Scheme 1 and is further illustrated by the following synthesis examples. As shown, a chloride (or bromide) acid 1 is reacted with a metal or ammonium thiocyanate in an appropriate solvent to provide the corresponding acylthiocyanate 2. Reaction of 2 with a primary (R6 = H) or secondary amine 3 Appropriate, gives the acylthiourea 4. Additional alkylation, when desirable, can be carried out at 4 to provide compounds of the general formula 1. Alternatively, the compounds of the general formula 1 can be prepared by treatment of a primary amide (R6) = H) or secondary 5 with base followed by reaction of the resulting anion with an isothiocyanate 6 appropriately substituted to provide the acylthiourea 7. Further alkylation, when desirable, may be carried out at 7 to provide compounds of the general formula 1. reaction to form the acid chloride is generally carried out in a solvent. The appropriate solvents in this case are inert organic solvents that do not change under the reaction conditions. These preferably include ethers, such as diethyl ether or tetrahydrofuranyl, or tertiary methylbutyl ether; halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, hydrocarbons such as benzene, xylene, toluene, hexane, heptane, cyclohexane or mineral oil fractions, nitromethane, or acetonitrile. It is also possible to use mixtures of these solvents.

The reaction of the acid chloride with ammonium or potassium thiocyanate is typically carried out in a solvent in which the inorganic thiocyanate is moderately soluble. In some cases, water may be added to increase solubility. The percentage of water added can vary from one percent to 90 percent, with 50% (v / v) typically as the most preferred. Other alkaline thiocyanates, such as lithium thiocyanates, can be used. Lithium thiocyanate has increased solubility in tetrahydrofuran and therefore may allow the use of smaller amounts of aqueous components. Cesium, rubidium, strontium, and barium can all be used as counter-ions for thiocyanate, as a connoisseur of the subject well knows.

EXAMPLE 1. PREPARATION OF ACID ESTER BUTILICO 4-T3- (FU RO, 3.2-C1PIRlDIN-2-IL-CARBONIL) -TIOUR The DO, -BENZOIC (COMPOUND 1) Furo [3,2-c] pyridino-2-carbonyl chloride (161 mg, 1 mmol) is added to a solution of ammonium thiocyanate (200 mg, approximately 3 mmol) in acetone (5 mL) and stirred at room temperature for 1 hour. Butyl 4-aminobenzoate (180 mg, 0.93 mmol) is added to the reaction mixture. Stirring is continued overnight at room temperature. The solvent is evaporated to dryness, and the residue is diluted with 10% aqueous NaHCO3. The product is filtered, washed with water and methanol, and dried.

EXAMPLE 2. PREPARATION OF 3-FLUORO-4- (PENTILOXI) BENCENAMINE (COMPOUND 2) EXAMPLE 3. PREPARATION OF 1 - ((2-METHYLPHIDE, 3,2-C1 PYRIDINE.

IL-CARBONIL) -3- (3-FLUORO-4-PENTILOXI) -FENIL) TIOUREA (COMPOUND 3) 8 COgCl? L ~ cs 9 10 11 The compound 3.1 - ((2-methylfuro [3,2-c] pyridin-yl-carbonyl) -3- (3-fluoro-4-petyloxy) -phenyl) thiourea is prepared by the synthetic route graphically outlined above . The chemicals are purchased from Aldrich Chemical Company and the solvents are purchased from Fisher Scientific. All reactions are carried out in a nitrogen or argon atmosphere at the indicated temperatures. As shown above, furilacrylic acid is treated with ethyl chloroformate (4.83 mL, 50.72 mmol) in dry acetone (50 mL) in the presence of triethylamine (6.05 mL, 43.5 mmol). After stirring at room temperature for 1 hour, sodium azide (3.53 g, 53035 mmol) in water (10 mL) is added at 0 ° C and the suspension is stirred for 1 hour. The reaction mixture is diluted with ice water (150 mL) and extracted with benzene (70 mL x 3). Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate to a small volume (~60 mL). The resulting azide compound (5) in benzene is added in a solution of diphenylmethane (40 mL) and tributylamine (7 mL) pre-heated to 180 ° C. The addition has to be controlled in such a way that the temperature does not fall below 170 ° C. After the addition is complete (~ 2.5 h), the reaction mixture is cooled to room temperature, and allowed to stand overnight. The resulting yellow precipitate is collected by filtration and washed with hexanes to give furopyridone (6). The furopyridone (6, 3.26 g, 24.15 mmol) is treated with phosphorus oxychloride (10 mL) at reflux temperature for 3 hours. After cooling, the dark solution is emptied on ice and basified with aqueous sodium hydroxide to pH ~ 9. The mixture is extracted with chloroform. After evaporation of the chloroform, the brown oil is applied to flash column chromatography on silica gel to give chlorofuropyridine as a crystalline yellow solid (7). The chlorofuropyridine (7, 1.27 g, 8.27 mmol) is treated with zinc (3.23 g, 49.6 mmol) in acetic acid (20 mL) at reflux temperature until the initial material disappears (~ 4 hours). The reaction is filtered to remove the solid. The filtrate is concentrated and the residue is dissolved in water. After basification with 1N sodium hydroxide, the mixture is extracted with methylene chloride. Evaporation leaves a yellow oil, which is purified by flash column chromatography on silica gel, to give furopyridine as a yellow oil (8). Furopyridine (8, 0.71 g, 5.96 mmol) is treated with n-butyl lithium (2.5 M in hexane, 2.86 mL, 7.15 mmol) in anhydrous THF (30 mL) at -79 ° C. After 30 minutes, carbon dioxide is passed through the reaction mixture and the temperature is allowed to rise gradually to room temperature in 3 hours. The mixture is concentrated until it is dried. The residue is dissolved in water (-10 mL) and extracted with ethyl acetate. The aqueous layer is acidified to pH ~ 3 with 1N HCl and kept in the refrigerator overnight. The resulting precipitates are filtered and dried to give carboxylic acid azabenzofuran as a white powder (9). The carboxylic acid azabenzofuran (8, 0.054 g, 0.33 mmol) is suspended in DCM (2 mL) and treated with oxalyl chloride (0.058 mL, 0.66 mmol) in the presence of DMF (1 drop). The reaction is stirred at 0 ° C for 2 hours until no more bubbles are produced. The reaction mixture is concentrated to dry to yield acid chloride, which is treated with ammonium thiocyanate (0.05 g, 0.66 mmol) in anhydrous acetone (3 mL) at room temperature for 1 hour. To this reaction mixture is added acyl isothiocyanate, 3-fluoro-4-pentoxy aniline (0.0591 g, 0.30 mmol), which is synthesized separately as shown in scheme 2, and the mixture is stirred at room temperature during 2 hours. The acetone is evaporated in a retroevaporator and the residue is diluted with 10% sodium bicarbonate (1 mL). The solid is filtered, washed with water, methanol and dried to give compound 12 as a yellow powder (0.0958 g). Compound 12 (0.0863 g, 0.215 mmol) is dissolved in methylene chloride (5 mL) and HCl / ether (2.0 M, 0.215 mL, 0.43 mmol) is added at 0 ° C. After stirring for 30 minutes, the solvent is evaporated to give the final product, 1 - ((2-methylfuro [3,2-c] pyridin-1-carbonyl) -3- (3-fluoro-4-pentyloxy) - phenyl) thiourea, as a yellow powder (3). The product is characterized by NMR (Brucker, 300 MHz) and MS. NMR (1H, CDCl 3): 0.99 (3H), 1.40-1.31 (m, 4H), 1.79-1.74 (m, 2H), 3.98 (t, 2H), 6.91 (t, 1H), 7.22 (m, 1H) , 7.57-7.50 (m, 2H), 7.74 (s, 1H), 8.64 (1H), 9.06 (s, 1H), 9.33 (s, 1H, NH); 12.03 (s, 1H, NH); MS: APCI (Finnigan MSQ single quadrupole): 402 (M + 1) 443 (M + + 1 + ACN).

EXAMPLE 4. PREPARATION OF ADDITIONAL COMPOUNDS OF FORMULA 1 The compounds shown in Table 1 are prepared by the methods described in scheme 1 and examples 1 to 3. Certain compounds shown in the table 1 were analyzed by LC-MS. The times and retention masses of the M + 1 ion are given for those compounds. The retention time (tR) is measured in a gradient that increases from 30 to 100% B in 3.00 minutes, wherein regulator A is trifluoroacetic acid at 0. 1% in water and regulator B is 0.1% trifluoroacetic acid in acetonitrile. A Phenomenex Luna C8 column with a flow rate of 2.5 mL / min was used. All HPLC / MS analytical data were observed at a wavelength of 220 nm using a Gilson 151 UV / VIS detector followed by a ThermoFinnigan Surveyor MSQ.

STRUCTURE Name RT M + 1 14- (Furo [2,3- c] pyridin-2-yl-carbonyl) -3 - ((4-pentyl) phenyl) -thiourea 1- (7-Chloro-furo [2,3 - 1.02 438 c] pyridin-2-yl-carbonyl) -3 - ((3-benzyloxy) phenyl) -thiourea 1-Q Hydrochloride (Furo [3,2-cjpyridn-2-yl-carbonyl) -3 - ((3-phenoxy) phenyl) -thiourea Hydrochloride 1- (Furo [3,2-c] ] pyridin-2-yl-carbonyl) -3 - ((3-fluoro-4-pentyloxy) phenyl) -thiourea EXAMPLE 5. TEST TO IDENTIFY COMPOUNDS THAT INHIBIT THE VHC REPLICATION The compounds claimed herein are tested for the ability to inhibit viral replication of the hepatitis C replicon in cultured cells in which the HCV replicon construct has been incorporated. The HCV replicon system was described by Bartenschlager and co-authors (Science, 285, pp. 110-113 (1999)). The replicon system is a predictor of anti-HCV activity in vivo; Compounds that are active in humans uniformly show activity in the replicon assay. In this assay, the HCV replicon contains cells that are treated with different concentrations of the test compound to determine the ability of the test compound to suppress the replication of the HCV replicon. As a positive control, cells containing the HCV replicon are treated with different concentrations of interferon alpha, a known inhibitor of HCV replication. The replicon assay system includes neomycin phosphotransferase (NPT) as a component of the replicon itself in order to detect the transcription of replicon gene products in the host cell. Cells in which the HCV replicon actively reproduces have high levels of TPN; the level of TPN is proportional to the replication of HCV. Cells in which the HCV replicon is not reproducing also have low levels of TPN and therefore do not survive when treated with Neomycin. The NPT level of each sample is measured using a captured ELISA. A method for testing compounds to determine their ability to inhibit viral replication of cells cultured with hepatitis C replicon, in which the replicon construct has been incorporated, follows. 5A. REVOLUTION OF HCV AND REPLICATION EXPRESSION The HCV genome consists of a single ORF that encodes a polyprotein of 3000 amino acids. The ORF is flanked on the 5 'side by a non-translated region that serves as an internal ribosome entry site (IRES) and on the 3' side by a highly conserved sequence necessary for viral replication (3 'NTR) . The structural proteins necessary for viral infection are located near the 5 'end of the ORF. The non-structural proteins, called NS2 up to NS5B, contain the rest of the ORF. The HCV replicon contains, 5'-3 \ IRES of HCV, the (neo) neomycin phosphotransferase gene, the IRES of the encephalomyocarditis virus, which directs the translation of the HCV NS3 sequences up to NS5B, and the 3 'NTR. The sequence of the replicon of VHC has been deposited in GenBank (registration number AJ242652). The replicon is transfected into Huh-7 cells using standard methods such as electrophoresis. 5B. CELL MAINTENANCE Equipment and materials include, but are not limited to, cells containing HCV Huh-7 replicon, maintenance media (DMEM (Dulbecco's Modified Eagle's Medium) supplemented with 10% FBS, L-glutamine, non-essential amino acids, penicillin (100 units / mL), streptomycin (100 micrograms / mL), and 500 micrograms / mL of Geneticin (G418), screening medium (DMEM supplemented with 10% FBS, L-glutamine, non-essential amino acids, penicillin (100 units / mL) and streptomycin (100 micrograms / mL)), 96-well culture plates (flat bottom), 96-well plates (U-bottom for drug dilution), Interferon alpha for positive control, fixation reagent (such such as methanol: acetone), primary antibody (anti-rabbit NPTIl), secondary antibody: Eu-N1 1, and enhancer solution.Cells containing the HCV replicon support high levels of replication of the viral RNA replicon when its density is appropriate. e-confluence results in decreased viral RNA replication. Therefore, the cells have to be kept growing in the log phase in the presence of 500 micrograms / mL of G418. Generally, cells should be passed twice a week at a dilution of 1: 4 to 1: 6. Cell maintenance is done as follows: Cells containing the HCV replicon are examined under a microscope to make sure the cells grow well. The cells are rinsed once with PBS and 2 mL of trypsin is added. The cell / trypsin mixture is incubated at 37 ° C in a CO2 incubator for 3 to 5 minutes. After incubation, 10 mL of complete medium is added to stop the trypsinization reaction. The cells are gently blown, placed in a 15 mL tube and rotated at 1200 rpm for 4 minutes. The trypsin / medium solution is removed. Medium (5 mL) is added and the cells are mixed carefully. The cells are counted. The cells are then seeded in 96 well plates with a density of 6000 to 7500 cells / 100 microliters / well (6 to 7.5 x 10 5 cells / 10 mL / dish). The plates are then incubated at 37 ° C in an incubator with 5% CO2. The cells are examined under a microscope approximately 24 hours after sowing and before adding drugs. If counting and dilution were performed correctly, the cells are confluent at 60-70% and almost all cells should be joined and spread evenly in the receptacle. 5C. TREATMENT OF CELLS CONTAINING HCV REPLICON WITH THE TEST COMPOUND The cells containing the HCV replicon are rinsed once with PBS, then 2 mL of trypsin is added. The cells are incubated at 37 ° C in an incubator with 5% CO2 for 3 to 5 minutes. 10 mL of complete medium is added to stop the reaction. The cells are gently blown, placed in a 15 mL tube, and rotated at 1200 rpm for four minutes. The trypsin / medium solution is removed and 5 mL of medium (500 mL of DMEM (high glucose)) is added from the BRL catalog number 12430-054; 50 mL of 10% FBS, 5% Geneticin G418 (50 mg / mL, catalog BRL number 10131-035), 5 mL of non-essential amino acids MEM (100x BRL number 11140-050) and 5 mL of pen-strep (BRL 15140-148). Cells and media are mixed carefully. Cells are plated with screening medium (500 mL of DMEM (BRL number 21063-029), 50 mL of FBS (BRL number 10082-147) and 5 mL of non-essential amino acid MEM (BRL number 11140-050) a 6000-7500 cells / 100 μL / 96-well plate receptacle (6-7.5 cells / 10 mL / plate) Plates are placed in incubator with 5% CO2 at 37 ° C overnight.

D. TEST The next morning, the drugs (test compounds or interferon alfa) are diluted in 96-well plates with U-bottom, medium or DMSO / medium, depending on the final concentration chosen for the examination. Usually, 6 concentrations of each test compound are applied, ranging from 10 micromolar to 0.03 micromolar. 100 μL of the dilution of the test compound is placed in receptacles of the 96-well plate containing the HCV replicon cells. Medium without drug is added to some receptacles as negative controls. It is known that DMSO affects cell growth. Therefore, if drugs diluted in DMSO are used, all receptacles, including receptacles with negative control (only medium) and with positive control) interferon alpha, must contain the same concentration of DMSO, for simple dose screening . The plates are incubated at 37 ° C in a humidified environment with 5% CO2 at 37 ° C for 3 days. On day four, the NTPII assay is quantified. The medium is emptied from the plates and the plates are washed once in 200 μL / methane-acetone receptacle (1: 1) previously cooled (-20 ° C) and then the plates are placed at -20 ° C for 30 minutes. The fixing solution is emptied from the plates, and the plates are allowed to air dry completely (approximately 1 hour). The appearance of the dried cells layer is recorded and the density of the cells in the toxic receptacles is evaluated to the eye. Alternatively, cell viability can be evaluated using the MTS assay described below. The receptacles are blocked with 200 μL of blocking solution (10% FBS); 3% NGS in PBS) for 30 minutes at room temperature. The blocking solution is removed and 100 μL of rabbit anti-NPTIl 1: 1000 in blocking solution is added to each well. The plates are then incubated for 45 to 60 minutes at room temperature. After incubation, the wells are washed six times with PBS-0.05% Tween solution. 100 μL of Europium conjugate (EU) -anti-rabbit botenido in goat diluted 1: 15,000 in blocker regulator is added to each receptacle, and incubated at room temperature for 30 to 45 minutes. The plates are again washed and 100 μL of enhancing solution (Perkin Elmer number 40001-0010) is added to each receptacle. Each plate is stirred (approximately 30 rpm) on a plate shaker for three minutes. Transfer 95 μL of each receptacle to a black plate; the EU signal is quantified in a plate reader VICTOR Perkin-Elmer (EU Lance).

TEST RESULTS The compounds shown in Table 1 have been tested in the above assay and found to inhibit replication of the HCV replicon with EC50 values of less than 10 micromolar.

EXAMPLE 6. CYTOTOXICITY TESTS To ensure that the decrease in replicon replication is due to the activity of the compound against the HCV replicon rather than non-specific toxicity, assays are used to quantitate the cytotoxicity of the compound.

EXAMPLE 6A. ASSAY WITH CELL PROTEIN ALBUMIN TO DETERMINE CITOTOXICITY Measurements of cellular protein albumin provide a marker of cytotoxicity. Protein levels obtained from cell albumin assays can also be used to provide a standardization reference for the antiviral activity of the compounds. In the protein albumin assay, cells containing the HCV replicon are treated for three days with different concentrations of helioxanthin; a compound that is known to be cytotoxic in high concentrations. The cells are used and the cell lysate is used to bind goat anti-albumin antibody bound to the plate, at room temperature (25 ° C to 28 ° C) for 3 hours. The plate is then washed 6 times with 1X PBS. After unbound proteins are washed out, mouse monoclonal anti-human serum albumin is applied to bind the albumin in the plate. The complex is then detected using phosphatase-labeled anti-mouse IgG as a second antibody.

EXAMPLE 6B. ESSAY WITH MTS TO DETERMINE THE CYTOTOXICITY Cell viability can also be determined by cell proliferation assay with CELLTITER 96 AQUEOUS ONE solution (Promega, Madison Wl), a colorimetric assay to determine the amount of viable cells. In this method, before fixing the cells, 10 to 20 μL of MTS reagent is added to each receptacle according to the manufacturer's instructions, the plates are incubated at 37 ° C and read at OD 490 nm. During the incubation period, the living cells convert the MTS reagent into a formazan product that is absorbed at 490 nm. Thus, the absorbance at 490 nm is directly proportional to the amount of living cells in the culture. A direct comparison of the cellular albumin and MTS methods, to determine cytotoxicity, can be obtained as follows: The cells are treated with different concentrations of test compound or Helioxanthin over a period of three days. Prior to lysis for the detection of albumin as described above, MTS reagent is added according to the manufacturer's instruction to each receptacle, and incubated at 37 ° C and read at OD 490 nm. The quantification of the cellular albumin is then carried out as described above.

EXAMPLE 7. PHARMACEUTICAL FORMULATIONS Examples 7A to 7G are examples of pharmaceutical compositions containing the compounds of formula 1. The abbreviation "V.l" means the viral inhibitory compounds of Formula 1 of the present invention.

EXAMPLE 7A. ORAL DROPS Dissolve 5 grams of V.l. in 5 mL of 2-hydroxypropanoic acid and 15 mL of polyethylene glycol at about 60 ° C to about 80 ° C. After cooling to about 30 ° C - 40 ° C, 350 mL of polyethylene glycol is added and the mixture is stirred well. Then a solution of 17.5 g of sodium saccharin in 25 mL of purified water is added. Flavor and polyethylene glycol are added in a sufficient amount to a volume of 500 mL, while stirring to provide a solution in oral drops containing 10 mg / mL of V.l.

EXAMPLE 7B. CAPSULES grams of the V.I., 6 grams of sodium lauryl sulfate, 56 grams of starch, 56 grams of lactose, 0.8 grams of colloidal silicon dioxide, and 1.2 grams of magnesium stearate are stirred together. The resulting mixture is then used to fill 1000 suitable hardened gelatin capsules, each of which contains 20 mg of the active ingredient. EXAMPLE 7C. COATED TABLETS WITH FILM Preparation of tablet core: A mixture of 10 grams of VI, 57 grams of lactose and 20 grams of starch, mixes well and then moistened with a solution of .5 grams of sodium dodecyl sulfate, and 1.0 grams of Polyvinylpyrrolidone (KOLLIDON-K 90) in approximately 20 mL of water. The wet powder mixture is screened, dried and sieved again. Then add 100 grams of microcrystalline cellulose (AVICEL) and 15 grams of hydrogenated vegetable oil (STEROTEX). Everything is mixed well and compressed into tablets, producing 1000 tablets, each of which contains 10 mg of the active ingredient. Coating: Ethyl cellulose (0.5 grams, ETHOCEL 22 CPS) is added in 15 mL of dichloromethane to a solution of 1.0 grams of methyl cellulose (Methocel 60 HG.RTM) in 7.5 mL of denatured ethanol. Then 7.5 mL of dichloromethane and 0.25 mL of 1,2,3-propanetriol are added. Polyethylene glycol (1.0 grams) is melted and dissolved in 7.5 mL of dichloromethane and added to the solution containing cellulose. Magnesium octadecanoate (.25 grams), 0.5 grams of polyvinylpyrrolidone, and 3.0 mL of concentrated color suspension (OPASPRAY K-1-2109) are added and the entire mixture is homogenized. The tablet cores are coated with this mixture in a coating apparatus.

EXAMPLE 7. INJECTABLE SOLUTIONS (i) Dissolve 1.8 grams of methyl 4-hydroxybenzoate and 0.2 grams of propyl 4-hydroxybenzoate in approximately 0.5 L of boiling water. After cooling to about 50 ° C, 4 grams of lactic acid, O.o05 grams of propylene glycol, and 4 grams of viral inhibitor are added while stirring. The solution is cooled to room temperature and supplemented with water for injection in sufficient quantity to give a solution containing 4 mg / mL of V. The solution is sterilized by filtration and filled with sterile containers. (ii) 100.0 g of an acid salt of a V.l. of the invention, in boiling water. After cooling to about 50 ° C, 37.5 grams of lactic acid (90% by weight) is added while stirring. The solution is cooled to room temperature and water is added to 1 L. The solution is sterilized by filtration and filled with sterile containers. (Ii) 5.00 g of an acid salt of a V.l. of the invention in boiling water. After cooling to about 50 ° C, 2.20 grams of lactic acid (90% by weight) is added while stirring. Then the solution is cooled to room temperature and water is added to 100 mL: EXAMPLE 7E. GEL A compound or salt of the invention can be formed as a gel for topical application. A gel is prepared by suspending V.l. (0.2 g - 5.0 g) in benzyl alcohol at room temperature. A mixture of hydroxypropyl cellulose (2.5 grams) and demineralized water (sufficient quantity for 100 g) is added to the suspension with stirring.

EXAMPLE 7F. CREAM Phase I contains sorbitan monostearate (2.0 g), polyoxyethylene (20) sobutane monostearate (1.5 g), synthetic spermaceti (3.0 g), cetyl stearyl alcohol (10.0 g) and 2-octyldodecanol (13.5 g). The mixture of phase I is heated to 75 ° C, stirred and mixed. Phase II contains V. i. (1.0 g). Stage II is added to phase I, stirred and suspended. Phase III contains benzyl alcohol (1.0 g) and demineralized water (sufficient quantity for 100 g). Phase III is heated to 75 ° C and added to phase II. The cream is thoroughly mixed and cooled slowly to room temperature, with additional stirring. After cooling to room temperature, the cream is homogenized.

EXAMPLE 7. ATOMIZERS Solutions or suspensions of the active compound prepared according to example 7D can also be processed in atomizers. For this purpose, for example, 60 to 90% of active compound solution is mixed with 20 to 40% of the usual propellants, for example, N2, N2O, CO2, propane, butane, halogenated hydrocarbons and the like.

Claims (50)

1. A compound of formula 1 or a salt thereof acceptable for pharmaceutical use, characterized in that: X and W are independently O, S, NR or absent, when R is hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, or (aryl) alkyl of 0 at 4 carbon atoms optionally substituted. V is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkenyl of 2 to 6 carbon atoms, or is absent; Y is alkyl of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms substituted with cycloalkyl of 3 to 7 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, or Y he is absent; where when V is absent, W is absent. A- is nitrogen or CR-i; A2 is nitrogen or CR2; A3 is nitrogen or CR3; A is nitrogen or CR4; where 1 or 2 of A ^ A2, A3 or A4 is nitrogen. Ri to R4, when present, are independently chosen from: (i) hydrogen, halogen, hydroxy, cyano, nitro, amino, acetyl, -NHCO2-, -NHSO2, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms, and (ii) alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, mono- and di- - (C 1-6 alkyl) amino, alkanoyl of 2 to 6 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, alkycarboxamide from 1 to 4 carbon atoms, mono- ydi (at I qui of 1 to 6 carbon atoms) carboxamide, (cycloalkyl of 3 to 8 carbon atoms) alkyl of 0 to 2 carbon atoms, monocyclic heterocycle of 2 to 7 carbon atoms, phenyl, pyridyl and pyrimidinyl; each of which is substituted with 0 to 5 substituents independently selected from halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms. R5 is hydrogen, halogen, hydroxy, amino, nitro, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 2 carbon atoms, or haloalkoxy of 1 to 2 carbon atoms. R6 and R7 are independently hydrogen, or R6 and R are independently alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, alkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms, or R6 and R7 are bonded to form a heterocyclic ring saturated or mono-unsaturated 5-7 membered, optionally containing an additional heteroatom chosen from N, S and O, whose saturated or mono-unsaturated 5- or 7-membered heterocyclic ring is substituted with 0 to 3 substituents, independently selected from halogen , hydroxy, amino, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; and Ar is optionally substituted aryl or optionally substituted heteroaryl.

2. A compound or salt of claim 1, further characterized in that Ar is aryl or heteroaryl, each of which is substituted with 0 to 5 substituents independently chosen from: (iii) halogen, hydroxy, cyano, nitro, oxo, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms, and (iv) alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, alkoxy from 1 to 8 carbon atoms, alkenyloxy of 2 to 8 carbon atoms, mono- and d i- (a Iq ui I of 1 to 8 carbon atoms) amino, mono- and di- (alkyl of 1 to 4 carbon atoms) aminoalkyl of 1 to 4 carbon atoms, alkanoyl of 2 to 8 carbon atoms, alkanoyloxy of 2 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms carbon, mono- and di- (alkyl of 1 to 8 carbon atoms) carboxamide, (cycloalkyl of 3 to 7 carbon atoms) carboxamide, and alkylthio of 1 to 8 carbon atoms, and (v) -GRa, wherein G is chosen from - (CH2) n-, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, -O (C = O) - and - (CH2) nO (CH2) m, - ( CH2) nN (CH2) m-, where n and m are independently 0, 1, 2, 3 or 4; and Ra is chosen from cycloalkyl of 3 to 8 carbon atoms, monocyclic heterocycloalkyl of 2 to 7 carbon atoms, mono- unsaturated heterocyclic rings of 5 to 7 members, bicyclic carbocyclic groups of 9 to 10 members, bicyclic heterocyclic groups of 9 to 10 members containing 1 nitrogen atom, aryl and heteroaryl; each of which (iv) and (v) is substituted with 0 to 5 substituents independently selected from halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl.

3. A compound or salt according to any of claims 1 or 2, further characterized in that X is oxygen and And it's -CH2-.

4. A compound or salt of claim 1 or 2, further characterized in that X is oxygen and Y is -CH2CH2-.

5. A compound or salt of claim 1 or 2, further characterized in that X and Y are absent.

6. A compound or salt of any of claims 1 to 5, further characterized in that V and W are absent.

7. A compound or salt of any of claims 1 to 5, further characterized in that V is alkyl of 1 to 2 carbon atoms and W is absent.

8. A compound or salt according to any of claims 1 to 7, further characterized in that R6 and R7 independently are hydrogen, or alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, or alkynyl of 2 to 4 carbon atoms, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, amino, alkoxy of 1 to 4 carbon atoms, haloalkoxy of 1 to 4 carbon atoms, haloalkyl of 1 to 2 carbon atoms and haloalkoxy of 1 to 2 carbon atoms.

9. A compound or salt of claim 8, further characterized in that R6 and R7 are independently hydrogen, methyl or ethyl.

10. A compound or salt of any of claims 1 to 9, further characterized in that A-i is nitrogen, A2 is CR2, A3 is CR3 and A4 is CR4.

11. A compound or salt of any of claims 1 to 9, further characterized in that A1 is CR-i, A2 is CR2, A2 is nitrogen and A is CR4.

12. A compound or salt of any of claims 1 to 9, further characterized in that A-i is CR1f A2 is CR2, A3 is nitrogen and A4 is CR4.

13. A compound or salt of any of claims 1 to 9, further characterized in that A is CR-i, A2 is CR2, A3 is CR3 and A4 is nitrogen.

14. A compound or salt of any one of claims 1 to 9, further characterized in that A-i is nitrogen, A2 is CR2, A3 is nitrogen and A4 is CR4.

15. A compound or salt of any of claims 1 to 9, further characterized in that Ai is CR-i, A2 is nitrogen, A3 is CR3 and A is nitrogen.

16. A compound or salt of any of claims 1 to 9, further characterized in that AT is nitrogen, A2 is CR2, A3 is CR3 and A4 is nitrogen.

17. A compound or salt of any of claims 1 to 16, further characterized in that R1 through R4, when present, are independently chosen from (i) hydrogen, halogen, hydroxy, cyano, nitro, amino, acetyl, haloalkyl of to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms, and (ii) alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alky 1 to 4) carbon atoms) amino, alkanoyl of 2 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyridyl and pyrimidinyl; each of which is substituted with 0 to 5 substituents independently selected from halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) carbon) amino, trifluoromethyl, and trifluoromethoxy.

18. A compound or salt of claim 17, further characterized in that R1 through R4, when present, are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, alkyl of 1 to 4 atoms carbon, alkoxy of 1 to 4 carbon atoms mono- and di- (alkyl of 1 to 4 carbon atoms) amino, alkanoyl of 2 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyridyl and pyrimidinyl.

19. A compound or salt of claim 18, further characterized in that R1 through R4, when present, are independently chosen from hydrogen, halogen, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, pyrrolidinyl, phenyl, and pyridyl.

20. A compound or salt of any of claims 1 to 19, further characterized in that R5 is hydrogen or methyl.

21. A compound or salt of any of claims 1 to 20, further characterized in that Ar is phenyl, pyridyl, pyrimidinyl, thienyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, benzo [d] oxazolyl, dihydrobenzodioxinyl, indolyl, pyrazolopyrimidinyl, thienylpyrazolyl or benzopyranyl, each of which is substituted with 0 to 5 substituents independently selected from (iii) halogen, hydroxy, cyano, nitro, oxo, haloalkyl, 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms, and (iv) alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, alkynyl of 2 to 8 carbon atoms, alkoxy of 1 to 8 carbon atoms, alkenyloxy of 2 to 8 carbon atoms, mono- and di- (alkyl of 1 to 8 carbon atoms) amino, mono - and di- (C 1-4 alkyl) aminoalkyl of 1 to 4 carbon atoms, alkanoyl of 2 to 8 carbon atoms, alkanoyloxy of 2 to 8 carbon atoms, alkoxycarbonyl of 1 to 8 carbon atoms, mono- and di- (alkyl of 1 to 8 carbon atoms) carboxamide, (cycloalkyl of 3 to 7 carbon atoms) carboxamide, and alkylthio of 1 to 8 carbon atoms, and (v) -GRa, wherein G is choose from - (CH2) n-, alkenyl of 2 to 4 carbon atoms, alkynyl of 2 to 4 carbon atoms, -O (C = O) - and - (CH2) nO (CH2) ra, - (CH2) nN (CH2) m-, where n and are independently 0, 1, 2, 3 or 4; and Ra is chosen from cycloalkyl of 3 to 8 carbon atoms, monocyclic heterocycloalkyl of 2 to 7 carbon atoms, mono- unsaturated heterocyclic rings of 5 to 7 members, bicyclic carbocyclic groups of 9 to 10 members, bicyclic heterocyclic groups of 9 to 10 members containing 1 nitrogen atom, aryl and heteroaryl; each of which (iv) and (v) is substituted with 0 to 5 substituents independently selected from halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and d i- ( to Iq ui I of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl.

22. A compound or salt of claim 21, further characterized in that Ar is phenyl or pyridyl; each of which is substituted with 0 to 5 substituents independently selected from (iii), (iv) and (v).

23. A compound or salt of claim 1 or 2, of formula 2, Formula 2 wherein: A8, A8 ', A9 and A9' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', Ag and Ag' are nitrogen; R5 is hydrogen or methyl; R6 and R independently are hydrogen or methyl; R10 is alkyl of 1 to 8 carbon atoms; and Rn represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms.

24. A compound or salt of claim 1 or 2, of formula 3, characterized in that: Formula 3 A8, A8 ', Ag and Ag' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', A9 and A9' are nitrogen; R5 is hydrogen or methyl; R6 and R7 independently are hydrogen or methyl; Rp represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; and R15 represents alkoxy of 3 to carbon atoms or alkyl of 3 to 8 carbon atoms, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxy, alkoxy of 1 to 3 carbon atoms and mono- and di- (1 to 5 carbon atoms) amino, or R 15 represents (3 to 8 carbon atoms) cycloalkyl, 0 to 2 carbon atoms or (3 to 8 carbon atoms) cycloalkyl 0 to 2 carbon atoms.

25. A compound or salt of claim 1 or 2, of formula 4, wherein A8, A8 ', A9 and A9' independently are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', A9 and Ag' are nitrogen; R5 is hydrogen or methyl; R6 and R7 independently are hydrogen or methyl; R p represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; and R12 represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl; or R12 represents a 5- to 7-membered ring containing 1 or 2 hydrogen atoms and is fused to the phenyl to which it is attached.

26. A compound or salt according to claim 1 or 2 of formula 5, characterized in that: A8, A8 ', A9 and A9' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', Ag and Ag' are nitrogen; R5 is hydrogen or methyl; R6 and R independently are hydrogen or methyl; R-11 represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino), haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; and R 2 represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms). carbon) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl; or R12 represents a 5- to 7-membered ring containing 1 or 2 oxygen atoms and is fused to the phenyl to which it is attached; and R13 and R14 are independently chosen from hydrogen and methyl, and m is 1 or 2.

27. A compound or salt of any of claims 1 or 2, of formula 6, characterized in that Formula 6 A8, A8 ', A9 and A9' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', Ag and Ag' are nitrogen; R5 is hydrogen or methyl; R6 and R7 independently are hydrogen or methyl; Rn represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; and R12 represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl; or R12 represents a 5- to 7-membered ring containing 1 or 2 oxygen atoms and is fused to the phenyl to which it is attached.

28. A compound or salt of claim 1 or 2, of formula 7: Formula 7 characterized in that A8, A8 ', A9 and A9' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', A9 and A9' are nitrogen; R5 is hydrogen or methyl; R6 and R independently are hydrogen or methyl; Rn represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; and R12 represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl; or R12 represents a 5- to 7-membered ring containing 1 or 2 oxygen atoms and is fused to the phenyl to which it is attached; Y R13 and? they are independently chosen from hydrogen and methyl, and m is 1 or 2.

29. A compound or salt of claim 1 or 2, of formula 8 characterized in that A8, A8 ', A9 and A9' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', A9 and A9' are nitrogen; J is nitrogen or CH; Q is O, NR16, or CH2; R5 is hydrogen or methyl; R6 and R7 independently are hydrogen or methyl; R11 and 22 each represent from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4) carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; Y R-I6 is hydrogen or alkyl of 1 to 4 carbon atoms.

30. A compound or salt according to claim 1 or 2, of formula 9, characterized in that: Formula 9 A8, A8 ', A9 and A9' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 \ A9 and A9 'are nitrogen; R5 is hydrogen or methyl; R6 and R7 independently are hydrogen or methyl; Rn represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; and R 2 represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl; or R12 represents a 5- to 7-membered ring containing 1 or 2 oxygen atoms and is fused to the phenyl to which it is attached; and R13 and R4 are independently chosen from hydrogen and methyl, and m is 1 or 2.

31. A compound or salt of any of claims 1 or 2, of formula 10, characterized in that A8, A8 ', Ag and A9' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 \ A9 and A9 'are nitrogen; R5 is hydrogen or methyl; R6 and R7 independently are hydrogen or methyl; Rn represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; and R12 represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino, haloalkyl of 1 to 2 carbon atoms, haloalkoxy of 1 to 2 carbon atoms, and phenyl; R12 represents a 5- to 7-membered ring containing 1 or 2 oxygen atoms and is fused to the phenyl to which it is attached; and 13 and 4 4 are independently chosen from hydrogen and methyl, and m is 1 or 2.

32. A compound or salt of any of claims 1 or 2, of formula 11, characterized in that Formula 11 A8, A8 ', A9 and Ag' independently, are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', Ag and A9' are nitrogen; R is hydrogen or methyl; R6 and R7 independently are hydrogen or methyl; R p represents from 0 to 3 substituents independently chosen from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms; Q is absent, is O, -CR13R1 -, or NR16. R13 and R14 are independently chosen from hydrogen or methyl, Ra is a bicyclic carbocyclic group of 9 to 10 members, or a bicyclic heterocyclic group of 9 to 10 members, which contains 1 nitrogen atom, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, trifluoromethyl and trifluoromethoxy.

33. A compound or salt of claim 32, further characterized in that Ra is indanyl or quinolinyl, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 2 carbon atoms, alkoxy of 1 to 2 carbon atoms, trifluoromethyl and trifluoromethoxy.

34. A compound or salt according to claim 1 or 2, of formula 12, characterized in that Formula 12 A8, A8 ', A9, A9', independently are nitrogen or CH; wherein 0, 1 or 2 of A8, A8 ', A9 and A9' are nitrogen. R5 is hydrogen or methyl. R6 and R7 independently are hydrogen or methyl. Rn represents from 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, mono- and di- (alkyl of 1 to 4 carbon atoms) amino , haloalkyl of 1 to 2 carbon atoms, and haloalkoxy of 1 to 2 carbon atoms. Q is absent, is -CR13R14-, or NR16; R-I3 and i4 are independently hydrogen or methyl; R16 is hydrogen or alkyl of 1 to 4 carbon atoms; and Ra is a bicyclic carbocyclic group of 9 to 10 members or a bicyclic heterocyclic group containing 1 nitrogen atom, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxy, cyano, alkyl of 1 to 2. carbon atoms, alkoxy of 1 to 2 carbon atoms, trifluoromethyl and trifluoromethoxy.

35. A compound or salt of any of claims 23 to 34, further characterized in that X and Y are both absent.

36. A compound or salt of any of claims 23 to 34, further characterized in that R5, R6 and R are all hydrogen.

37. A compound or salt of any of claims 23 to 34, further characterized in that Rlhasta R4 are present, independently chosen from hydrogen, halogen, hydroxy, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, alkyl from 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, di (aiqil of 1 to 4 carbon atoms) amino, alkanoyl of 2 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, phenyl, pyridyl and pyrimidinyl.

38. A compound or salt of claim 37, further characterized in that R1 through R4, when present, are independently chosen from hydrogen, halogen, cyano, nitro, amino, acetyl, trifluoromethyl, trifluoromethoxy, alkyl of 1 to 2 carbon atoms , alkoxy of 1 to 2 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, piperidinyl, pyrrolidinyl, phenyl and pyridyl.

39. A compound or salt of claim 1, further characterized in that the compound is 4- [3- (Furo [3,2-c] pyridin-2-yl-carbonyl) -thioureido] -benzoic acid butyl ester; 1 - ((3-Methoxyfuro [3,2-b] pyridin-2-yl-carbonyl) -3- (4-pentyl) -phenyl) thiourea; ((furo [2,3-b] pyridin-2-yl-carbonyl) -3- (3-benzyloxy) phenyl) -thiourea; ((Furo [2,3-b] pyridin-2-yl-carbonyl) -3- (3-phenyloxy) phenyl) -thiourea; ((Furo [2,3-b] pyridin-2-yl-carbonyl) -3- (4- (pentyloxy) phenyl) -thiourea; ((Furo [2,3-b] pyridin-2-yl-carbonyl) -3 - ((4-pentyl) phenyl) -thiourea; (Furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-phenyloxy) phenyl] -thiourea; (Furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((4-pentyloxy) phenyl) -thiourea; (Furo [3,2-c] pyridin-2-yl-carbon I) -3 - ((3-Fluro-4-piperidin-1-yl) pheniI) = thiourea; 1- (Furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3 -benzyloxy) phenyl) -thiourea; 1-Furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((4-pentii) phenyl) -thiourea; 1- (Furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-fluoro-4-pentyloxy) pheny!) -thiourea; 1 - (Furo [2,3-c] pyridin-2-yl-carbonyl) -3 - ((4-pentyloxy) phenyl) -thiourea; 1- (Furo [2,3-c] pyridin-2-yl-carbonyl) -3 - ((4-pentyl) phenyl) -thiourea; 1- (7-Chloro-furo [2,3-c] pyridin-2-yl-carbonyl) -3 - ((3-benzyloxy) phenyl) -thiourea; 1- (Furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-phenoxy) phenyl) -thiourea hydrochloride; 1- (Furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-fluoro-4-pentyloxy) phenyl) -thiourea hydrochloride; hydrochloride 1- (Furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((4-pentyloxy) phenyl) -thiourea; 1- (4-Chloro-furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-phenoxy) -phenyl) -thiourea; 1- (3- (benzyloxy) phenyl) -3- (4-chlorofuro [3,2-c] pyri in-2-carbonyl) thiourea; 1- (4-Chloro-furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((4-pentyloxy) phenyl) -thiourea; 1- (4-Chloro-furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-fluoro-4-pentyloxy) phenyl) -thiourea; 1- (4-Chloro-furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((4-pentyl) phenyl) -thiourea; 1- (4-Methoxy-furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-phenoxy) -phenyl) -thiourea; 1- (4-Methoxy-furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-benzoxy) -phenyl) -thiourea; 1- (4-methoxyfuro [3,2-c] pyridine-2-carbonyl) -3- (4- (pentyloxy) phenyl) thiourea; 1- (4-methoxyfuro [3,2-c] pyridm-2-carbonyl) -3- (4-pentylphenyl) thiourea; 1- (4-Methoxy-furo [3,2-c] pyridin-2-yl-carbonyl) -3 - ((3-fluoro-4-pentyloxy) phenyl) -thiourea; 1- (4-hydroxy-furo [3,2-c] pyridine-2-carbonyl) -3- (4- (pentyloxy) phenyl) thiourea; 1- (3- (benzyloxy) phenyl) -3- (4- (dimethylamino) furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (4- (dimethylamino) furo [3,2-c] pyridin-2-carbonyl) -3- (4- (pentyloxy) phenyl) thiourea; 1- (4- (dimethylamino) furo [3,2-cjpyridine-2-carbonyl) -3- (4-pentylphenyl) thiourea; 1- (4- (dimethylamino) furo [3,2-c] pyridine-2-carbonyl) -3- (3-fluoro-4- (pentyloxy) phenyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (4- (octyloxy) phenyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (4-octylphenyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (4- (hexyloxy) phenyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (4-hexylphenyl) thiourea; 1- (4-cyclohexylphenyl) -3- (furo [3,2-c] pipdin-2-carbonyl) thiourea; 1- (3-benzylphenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (3-phenoxyphenethyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (4-phenyl-benzyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (3-phenyl-phenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (4-benzylphenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (4-phenyl-phenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (4-phenoxyphenyl) thiourea; 1- (3- (4-phenyl-benzyloxy) phenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (3- (3,4-difluorobenzyloxy) phenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (4- (3,4-dihydroisoquinolin-2 (1 H) -yl) phenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (3- (2,3-dihydro-1 H -inden-2-yloxy) phenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (3-phenetoxyphenyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (4- (pentyloxy) -3- (trifluoromethyl) phenyl) thiourea; 1- (4-butoxyphenyl) -3- (furo [3,2-c] pyridine-2-carbonyl) thiourea; 1 - (furo [3, 2-c] pyridine-2-carbonyl) -3- (4- (heptyloxy) -3- (trifluoromethyl) phenyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (3- (isoquinolin-3-ylmethoxy) phenyl) -thiourea; 1 - (4- (cyclohexyl) methoxy) -3-f luorof in i 1) -3- (furo [3, 2-c] p indi n-2-carbonyl) thiourea; 1- (7-chlorofuro [2,3-c] pyridin-2-carbonyl) -3- (3-phenoxyphenyl) thiourea; 1- (furo [3,2-c] pyridine-2-carbonyl) -3- (3-methoxy-4-phenyl-phenyl) thiourea; or 1- (3-tert-butoxyphenyl) -3- (furo [3,2-c] pyridin-2-carbonyl) thiourea.

40. A pharmaceutical composition containing a compound or salt of any of claims 1 to 39, together with a carrier, diluent or excipient acceptable for pharmaceutical use.

41. A pharmaceutical composition of claim 40, further characterized in that the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a pill, a capsule, a syrup, an ophthalmic solution, or a transdermal patch.

42. A package containing a pharmaceutical composition of claim 40 or 41 in a container, and which further contains instructions for using the composition to treat a patient suffering from hepatitis C infection.

43. A compound or salt of any one of claims 1 to 39, which shows an EC50 of less than 10 micromolar in an assay with HCV replication replicon.

44. A compound or salt of any of claims 1 to 39, which shows an EC50 of less than 1 micromolar in an HCV replication replicon assay.

45. A method for treating hepatitis C infection, comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound or salt of any of claims 1 to 39.

46. The method of claim 45, which comprises administering the compound or salt of any of claims 1 to 39 in combination with one or both of ribavarin and interferon.

47. The method of claim 45 or 46, further characterized in that the patient is a human patient.

48. A method of any of claims 45 to 47, wherein the therapeutically effective amount is an amount sufficient to significantly decrease the amount of HCV antibodies in the blood or serum of the patient.

49. A method for inhibiting HCV replication in vivo, comprising administering to a patient infected with HCV a concentration of a compound or salt of any one of claims 1 to 39, sufficient to inhibit replication of the HCV replicon in vitro.

50. The use of a compound or salt of any of claims 1 to 39, for the manufacture of a medicament for the treatment of a Hepatitis C infection.