KR20010099623A - Compounds, compositions and methods for treating or preventing viral infections and associated diseases - Google Patents

Abstract

The present invention relates to compounds, compositions, and methods for treating and preventing infections and related diseases caused by the virus with Flaviviridae by administering certain rhodanine analogs and analogs. Tricyclic and tetracyclic rhodanine alkanoic acid and rhodanine benzoic acid are particularly effective.

Description

COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATING OR PREVENTING VIRAL INFECTIONS AND ASSOCIATED DISEASES}

The Flaviviridae family consists of three genus viruses and some viruses that do not currently have a specific genus. The hepacivirus genus includes hepatitis C virus (HCV). Viruses such as GB virus-A and GB virus-A-like agents, GB-virus B and GBV-C or hepatitis G virus, are currently not normally classified as hepaciviruses, but are closely related to HCV. , An unspecified member of the Flaviviridae family. Flaviviridae also includes viruses such as the genus pestivirus, including bovine viral diarrhea virus (BVDV), border disease viruses, and the classical swine fever virus, and dengue fever, yellow fever, Japanese encephalitis, and tick-borne encephalitis virus. It includes a flavivirus genus including.

Viruses in this family cause important diseases in humans and animals. HCV is the leading cause of human hepatitis worldwide. The World Health Organization estimates that 1.7 billion people worldwide are currently infected with the virus. Most infections persist, with 60% of cases developing chronic hepatitis disease. Chronic HCV infection can lead to cirrhosis, liver cancer and liver failure.

For hepatitis caused by HCV, interferon in combination with interferon and ribavirin is used in the United States. These treatments show an improved serum enzyme response in some patients. However, the remaining patients do not respond to treatment. In the case of responding patients, only a small proportion of patients were observed to show continuous clinical improvement. Most patients relapse on discontinuation of treatment. Thus, the efficacy of treatment for chronic hepatitis C is variable and the treatment rate is low. Moreover, treatment often involves significant side effects.

Pestivirus infection in livestock raises significant economic losses worldwide. Pestiviruses cause clinical symptoms, including miscarriage, malformations, respiratory problems, chronic wasting diseases, immune system dysfunction and predisposition to secondary viral and bacterial infections. Some BVDV strains cause acute fatal disease. BVDV can also cause persistent infections in the fetus. At birth, these persistently infected (PI) animals maintain viremia while alive and act as continuous viral carriers. PI animals often die from fatal mucosal diseases.

Flaviviruses are an important pathogen of humans and are widespread worldwide. There are more than 38 flaviviruses associated with human diseases, including dengue virus, yellow fever virus, and Japanese encephalitis virus. Flaviviruses cause acute recessive disease and encephalitis and hemorrhagic disease.

At present, there are no antiviral agents to prevent or treat pestivirus and flavivirus infections.

There is a clear need for new therapies and prophylaxis for infections and diseases caused by the Flaviviridae virus.

In considering an approach to the diagnosis, control, prevention and treatment of virus-induced infections and related diseases, it is often desirable to identify virus specific functions that can be developed in such an approach. In particular, the enzymatic activity of the polypeptides encoded by the virus is very useful. These virus specific components are often essential for viral replication and may be suitable targets for antiviral drug discovery strategies.

A pivotal target in the life cycle of many RNA viruses is the RNA dependent RNA polymerase (RdRp) protein that the virus encodes. In Flaviviridae viruses, this protein is called NS5B for hepaciviruses and pestiviruses and NS5 for flaviviruses (collectively NS5). RdRp protein is a major component of the viral replicaase complex, which allows the virus to replicate its RNA genome to produce progeny virus. RdRp of RNA viruses is of interest in antiviral drug development.

The present invention is filed on U.S. Provisional Application No. 60 / 097,476, filed Aug. 21, 1998, U.S. Provisional Application No. 60 / 113,212, filed Dec. 22, 1998, Claims benefit of US Provisional Application No. 60 / 119,328, US Provisional Application No. 60 / 135,585, filed May 24, 1999, US Provisional Application No. 60 / 135,586, filed May 24, 1999 . The entire disclosure of each pseudonym application is incorporated herein by reference, as described.

Field of invention

The present invention relates to a novel rhodamine analogue and analogue as well as a composition containing the same and a viral infection and related diseases, in particular in the treatment or prevention of viral infections and related diseases caused by a virus belonging to the family Flaviviridae. It relates to the use of the same.

Summary of the Invention

A first aspect of the invention provides a method for treating or preventing said infection and diseases associated with such infection in a live host having or susceptible to infection caused by one or more viruses of the Flaviviridae. The method comprises administering to a infected or susceptible host a therapeutically or prophylactically effective amount of a compound represented by formula (I) or a precursor thereof and an isomer and a pharmaceutically acceptable salt thereof.

Where

R is hydrogen or alkyl;

m is an integer of 0 to 4;

R ₁ is hydrogen, or —R ₃ COOH radical, where R ₃ is unsubstituted or substituted, branched or straight chain, saturated or unsaturated C ₁ -C ₁₀ hydrocarbon moiety, unsubstituted or substituted phenyl (C ₆ H ₅ ) a radical selected from the group consisting of radicals or unsubstituted or substituted phenylalkyl radicals, wherein the R ₃ substituent is a straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, unsubstituted or substituted heterocyclic radical Or one or more selected from the group consisting of unsubstituted or substituted phenyl (C ₆ H ₅ ) radicals, wherein the heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole, tria Sol, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine;

X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or C _1-5 alkyl;

R ₂ is an unsubstituted or substituted phenylalkyl radical, an unsubstituted or substituted phenylalkenyl radical, an unsubstituted or substituted phenylalkynyl radical, an unsubstituted or substituted biphenylalkyl radical, an unsubstituted or substituted polycyclic radical, Unsubstituted or substituted C _5-8 alicyclic radical or formula (R _2a- ) _n (L-) _p R _2b -wherein R _2a and R _2b can be the same or different and an unsubstituted or substituted heterocyclic radical Or an unsubstituted or substituted phenyl radical, R _2a represents an unsubstituted or substituted polycyclic radical, L is a valence bond,-(CH ₂ ) _q- , -HC = CH-, -C≡C-,- ₂ selected from the group consisting of C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ — or NR _2c , where R _2c is hydrogen or alkyl Is a linking moiety, n and p are each 0 or 1 and q is an integer of 1 to 3;

The heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, isoxazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, isothiazole, thiadia Sol, imidazole, pyrrole, tetrazole and triazine;

The polycyclic radicals are benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, indole, 2-isoindole, benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3 With benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene Selected from the group consisting of;

Heterocyclic radical substituents, polycyclic radical substituents and alicyclic radical substituents are linear or branched, saturated or unsaturated C_1-6 Alicyclic group, halogen, perhaloalkyl, monohaloalkyl, dihaloalkyl, alkoxy, acyl, acyloxy, acyloxyalkyl, phenylalkoxy, hydroxy, hydroxyalkyl, thio, alkylthio, nitro, carboxy, carb At least one selected from the group consisting of alkoxy;

Phenyl radical substituents, phenylalkyl radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents and biphenylalkyl radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitros, carboxys, hydrides Hydroxy, hydroxyalkyl, perhaloalkyl, monohaloalkyl, dihaloalkyl, alkoxy, phenylalkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkyl At least one member selected from the group consisting of sulfonyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, carboxamido, alkanoylamino;

Y represents O or S;

Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; R ₁ and R _b may be joined to form an imidazole or benzimidazole moiety.

Infections and related diseases caused by the Flaviviridae virus can be effectively treated or prevented by administering a compound represented by the following formula (I-1), and an isomer and a pharmaceutically acceptable salt thereof.

Where

R ₁ is hydrogen or a radical selected from the group consisting of —R ₃ COOH wherein R ₃ is a branched or straight chain C _1-10 aliphatic moiety or an unsubstituted or substituted phenyl (C ₆ H ₅ ) group;

X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or C _1-5 alkyl;

R ₂ is an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted bicyclic ring moiety, an unsubstituted or substituted phenyl group, an unsubstituted or substituted biphenyl (C ₆ H ₅ -C ₆ H _4- ) group or non- A radical selected from the group consisting of a ring or a substituted cinnamenyl (C ₆ H ₅ CH = CH-) group, the heterocyclic group being furan, thiophene, oxadiazole, pyridine, pyrimidine, pyrazole, thiazole, pyri Selected from the group consisting of chopped, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, pyrrole and triazine, wherein the bicyclic ring moiety is benzofuran, isobenzofuran, benzothiophene, isobenzoti Offen, benzoxazole, benzopyrrole, indolenin, 2-isobenzazole, benzpyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, 1,2,3-benzotria Selected from the group consisting of sol, benzothiazole, benzimidazole, 1,2,3-benzotriazine and 1,2,4-benzotriazine, which are heterocyclic and bicyclic The li moiety is one or more selected from the group consisting of C _1-5 alkyl, halogen, alkoxy, hydroxy, nitro or unsubstituted or substituted phenyl groups;

Phenyl group substituents, biphenyl group substituents and cinnamenyl group substituents are halogen, nitro, carboxy, hydroxy, C _1-5 alkyl, trifluoromethyl, alkoxy, acyloxy, cyano, carvalkoxy, alkylthio, alkylsulfinyl At least one member selected from the group consisting of alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido or carboxamido;

Y represents O or S;

Z is O, S or N (R _b ), where R _b is hydrogen or C _1-5 alkyl;

Or R ₁ and R _b may be joined to form a benzimidazole moiety.

In a second aspect of the invention, there is provided a pharmaceutical composition for the treatment or prophylaxis of a viral infection, comprising an effective amount of an antiviral agent and a pharmaceutically acceptable carrier medium to direct viral infection. In one embodiment, the composition of the present invention comprises a compound of formula II.

Where

R is hydrogen or alkyl;

m is an integer of 0 to 4;

R ₃ represents an unsubstituted or substituted, branched or straight, saturated or unsaturated C _1-10 hydrocarbon moiety in the main chain, and the hydrocarbon moiety substituent is a branched or straight, saturated or unsaturated C _1-6 aliphatic group, unsubstituted or At least one member selected from the group consisting of substituted heterocyclic radicals or unsubstituted or substituted phenyl (C ₆ H ₅ ) radicals, wherein the heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine , Pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine; Substituents for R ₂ , X, Y, Z and heterocyclic radicals, polycyclic radicals, cycloaliphatic radicals, phenyl radicals, phenylalkyl radicals, phenylalkenyl radicals, phenylalkynyl radicals and biphenylalkyl radicals are as defined in Formula I above same. According to this embodiment, the antiviral agent includes a compound of formula II-1, an isomer of this compound and a pharmaceutically acceptable salt.

Where

R ₃ represents an unsubstituted or substituted, branched or straight chain, saturated or unsaturated C _1-10 aliphatic moiety in the main chain, wherein the aliphatic partial substituent is one or more branched or straight chain, saturated or unsaturated C _1-6 aliphatic group, unsubstituted It is selected from the group consisting of a ring or substituted mono- heterocyclic group or an unsubstituted or substituted phenyl (C ₆ H ₅ ) group, the heterocyclic group is furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole , Triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine,

X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl;

R ₂ is an unsubstituted or substituted mono-heterocyclic group or a bi-heterocyclic group, an unsubstituted or substituted polycyclic ring moiety, an unsubstituted or substituted C _5-8 alicyclic group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted Biphenyl (C ₆ H ₅ -C ₆ H _4- ) groups, unsubstituted or substituted phenyl ether groups (C ₆ H ₅ -OC ₆ H _4- ) or unsubstituted or substituted cinnamenyl (C ₆ H ₅ A radical selected from the group consisting of CH = CH-) groups, said mono-heterocyclic group being furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3- Two heterocycles selected from the group consisting of oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine, wherein the bi-heterocyclic group is selected from a mono-heterocyclic group member and can be the same or different Ventilation, wherein the polycyclic ring portion is benzofuran, isobenzofuran, benzothiophene, isoben Thiophene, benzoxazole, benzopyrrole, indolenin, 2-isobenzazole, benzpyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, 1,2,3-benzo Triazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine and 1,2,4-benzotriazine, naphthalene, anthracene and fluorene;

Mono- or bi-cyclic substituents, alicyclic substituents and polycyclic ring substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, trifluoromethyl, alkoxy, hydroxy, thio, nitro At least one member selected from the group consisting of an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenylalkenyl group, or an unsubstituted or substituted phenylalkynyl group;

Phenyl group substituents, biphenyl group substituents, phenyl ether group substituents, phenylalkenyl group substituents, phenylalkynyl group substituents and cinnamenyl group substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitro, carboxy, hydroxy , Trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonami At least one selected from the group consisting of carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl;

Y represents O or S;

Z is O, S or N (R _b ), where R _b is hydrogen or alkyl;

Or R ₁ and R _b may be joined to form an amidazole or benzimidazole moiety.

In another embodiment, the composition of the present invention comprises a compound of formula III

Where

R is hydrogen or alkyl;

m is an integer of 0 to 4;

R ₁ is hydrogen or -OH, -COOR ₄ , -CONR ₅ R ₆ , -SO ₂ NR ₇ R ₈ [R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each selected from hydrogen or an alkyl group] Or a substituent selected from the group consisting of or R ₁ represents furan, thiophene, pyridine, pyrimidine, pyridazine, 1,3-oxathiolane, tetrazole, oxadiazole, oxazole, triazole, imidazoline , Mono-heterocyclic radicals selected from the group consisting of imidazole, thiazole, thiadiazole, pyrrole, piperidine, morpholine, triazine and pyrazole;

W and W 'may be the same or different and are hydrogen or straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, halogen, nitro, hydroxy, perfluoroalkyl, difluoromethyl, alkoxy, phenoxy Phenyl, alkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxami And substituents selected from the group consisting of alkanoylamino;

t is an integer from 0 to 8; Substituents for R ₂ , X, Y, Z and heterocyclic radicals, polycyclic radicals, cycloaliphatic radicals, phenyl radicals, phenylalkyl radicals, phenylalkenyl radicals, phenylalkynyl radicals and biphenylalkyl radicals have already been defined in formula (I) As shown. According to this embodiment, the antiviral agent includes a compound of formula III-1, and an isomer and a pharmaceutically acceptable salt thereof.

Where

R ₁ is hydrogen or -OH, -COOR ₃ , -CONR ₄ R ₅ , -SO ₂ NR ₆ R ₇ [R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are each selected from the group of hydrogen or alkyl Or a substituent selected from the group consisting of] or R ₁ represents tetrazole, oxadiazole, oxazole, triazole, imidazoline, imidazole, thiazole, thiadiazole, pyrrole, piperidine, morpholine And a heterocyclic ring selected from the group consisting of pyrazoles;

W and W 'may be the same or different and are hydrogen or straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, halogen, nitro, hydroxy, perfluoroalkyl, difluoromethyl, alkoxy, phenoxy Substituents selected from the group consisting of c, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamide, carboxamide and alkanoylamino Represents;

t is an integer from 0 to 8;

X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl;

R ₂ is an unsubstituted or substituted mono-heterocyclic group or a bi-heterocyclic group, an unsubstituted or substituted polycyclic ring moiety, an unsubstituted or substituted C _5-8 alicyclic group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted Biphenyl (C ₆ H ₅ -C ₆ H _4- ) groups, unsubstituted or substituted phenyl ether groups (C ₆ H ₅ -OC ₆ H _4- ), unsubstituted or substituted cinnamenyl (C ₆ H ₅ CH = CH-) group, or a radical selected from the group consisting of an unsubstituted or substituted stilbenyl group, wherein the mono-heterocyclic group is furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole, Triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine, the bi-heterocyclic group is selected from a mono-heterocyclic group, Comprising two heterocyclic groups, which may be the same or different, wherein the polycyclic ring moiety is benzofuran, isobenzofu Column, benzothiophene, isobenzothiophene, benzoxazole, benzopyrrole, indolenin, 2-isobenzazole, benzpyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine , 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene Become;

Mono-heterocyclic substituents, bi-heterocyclic substituents, cycloaliphatic substituents and polycyclic ring substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, trifluoromethyl, alkoxy, hydroxy, thio, At least one selected from the group consisting of nitro, carboxy, carbalkoxy, unsubstituted or substituted phenyl groups, unsubstituted or substituted phenylalkyl groups, unsubstituted or substituted phenylalkenyl groups, or unsubstituted or substituted phenylalkynyl groups ;

Phenyl group substituents, biphenyl group substituents, phenyl ether group substituents, phenylalkyl group substituents, phenylalkenyl group substituents, phenylalkynyl group substituents, cinnamenyl group substituents and stilbenyl group substituents may be linear or branched, saturated or unsaturated C _1-6 aliphatic groups. Groups, halogen, nitro, carboxy, hydroxy, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino At least one selected from alkylamino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl;

Y is O or S;

Z is O, S or N (R _b ), where R _b is hydrogen or alkyl;

Or R ₁ and R _b may be joined to form an imidazole or benzimidazole moiety.

R ₂ radicals in formulas II and III are of formula (R _2a- ) _n (L-) _p R _2b- [p is 0] and m is O.

In a third aspect of the present invention, there is provided a compound represented by the following formula (II-1), an isomer thereof and a pharmaceutically acceptable salt thereof.

Formula II-1

Where

R ₃ represents an unsubstituted or substituted, branched or straight, saturated or unsaturated C _1-10 hydrocarbon moiety in the main chain, and the hydrocarbon moiety substituents are branched or straight, saturated or unsaturated C _1-6 aliphatic groups, unsubstituted or At least one selected from the group consisting of a substituted mono-heterocyclic group or an unsubstituted or substituted phenyl (C ₆ H ₅ ) group, the mono-heterocyclic group being furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, Pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine;

X represents a moiety selected from -S-, -O- or -N (R _a )-, wherein R _a is hydrogen or alkyl;

R ₂ is an unsubstituted or substituted mono-heterocyclic group or a bi-heterocyclic radical, an unsubstituted or substituted polycyclic radical, an unsubstituted or substituted polycyclic-heterocyclic radical, an unsubstituted or substituted C _5-8 alicyclic radical , Unsubstituted or substituted phenyl radical, unsubstituted or substituted biphenyl (C ₆ H ₅ -C ₆ H _4- ) radical, unsubstituted or substituted phenyl ether (C ₆ H ₅ -OC ₆ H _4- ) radical Or a radical selected from the group consisting of unsubstituted or substituted 2-phenylethenyl (C ₆ H ₅ CH═CH—) radicals, wherein the mono-heterocyclic group is furan, thiophene, oxazole, oxadiazole, pyridine , Pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine, and the bi-heterocyclic group is mono Two heterocyclic groups, selected from heterocyclic radical members, which may be the same or different Wherein the polycyclic ring moiety is benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, indole, 2-isoindole, benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine , 1,3-benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine and 1,2,4-benzotriazine, naphthalene, anthracene And fluorene, wherein the polycyclic heterocyclic radical comprises a heterocyclic moiety selected from a mono-heterocyclic radical group member and a polycyclic moiety selected from a member of the polycyclic radical group;

Mono-heterocyclic radical substituents, bi-heterocyclic radical substituents, alicyclic radical substituents, polycyclic radical substituents and polycyclic-heterocyclic radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, trifluoro At least one selected from the group consisting of methyl, alkoxy, hydroxy, thio, nitro, carbalkoxy, unsubstituted or substituted phenyl radicals, unsubstituted or substituted phenylalkenyl radicals or unsubstituted or substituted phenylalkynyl radicals Is;

Phenyl radical substituents, biphenyl radical substituents, phenyl ether radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents and 2-phenylethenyl radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens , Nitro, carboxy, hydroxy, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino , Dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl;

Y represents O or S;

Z is O, S or N (R _b ), where R _b is hydrogen or alkyl;

Or R ₁ and R _b may be joined to form an amidazole or benzimidazole moiety.

According to the 4th aspect of this invention, the compound represented by following formula (III-1), an isomer of this compound, and a pharmaceutically acceptable salt are provided.

Formula III-1

Where

R ₁ is hydrogen or -OH, -COOH, -CONR ₄ R ₅ , -SO ₂ NR ₆ R ₇ [R ₄ , R ₅ , R ₆ and R ₇ are each selected from the group of hydrogen or alkyl] Or R ₁ represents furan, thiophene, pyridine, pyrimidine, pyridazine, 1,3-oxathiolane, tetrazole, oxadiazole, oxazole, triazole, imidazoline, imidazole , A heterocyclic ring selected from the group consisting of thiazole, thiadiazole, pyrrole, piperidine, morpholine, triazine and pyrazole;

W and W 'may be the same or different and are hydrogen or straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, halogen, nitro, hydroxy, perfluoroalkyl, difluoromethyl, alkoxy, phenoxy C, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxamido and alkanoylamino Represents a selected substituent;

t is an integer from 0 to 8;

X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl;

R ₂ is unsubstituted or substituted mono-heterocyclic radical or bi-heterocyclic radical, unsubstituted or substituted polycyclic radical, unsubstituted or substituted polycyclic-heterocyclic radical, unsubstituted or substituted C _5-8 alicyclic Radical, unsubstituted or substituted phenyl radical, unsubstituted or substituted biphenyl (C ₆ H ₅ -C ₆ H _4- ) radical, unsubstituted or substituted phenyl ether (C ₆ H ₅ -OC ₆ H _4- ) As a radical, unsubstituted or substituted 2-phenylethenyl (C ₆ H ₅ CH = CH-) radical, or as an unsubstituted or substituted stilbenyl (C ₆ H ₅ -CH = CH-C ₆ H _4- ) radical A radical selected from the group consisting of, wherein said mono-heterocyclic radical is furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole , Thiadiazole, imidazole, tetrazole, pyrrole and triazine, the bi-heterocyclic group of the mono-heterocyclic radical group Two heterocyclic groups selected from members, which may be the same or different, wherein the polycyclic radicals are benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, benzopyrrole, 2-isoindole, Benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzo Selected from the group consisting of triazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene, the polycyclic-heterocyclic radical is a member of the polycyclic moiety and the mono-heterocyclic radical group selected from the members of the polycyclic radical group A heterocyclic moiety selected from;

Mono-heterocyclic radical substituents, bi-heterocyclic radical substituents, alicyclic radical substituents, polycyclic radical substituents and polycyclic-heterocyclic radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, trifluoro Methyl, alkoxy, hydroxy, thio, nitro, acyl, carboxy, carbalkoxy, unsubstituted or substituted phenyl radicals, unsubstituted or substituted phenylalkyl radicals, unsubstituted or substituted phenylalkenyl radicals or unsubstituted or substituted At least one selected from the group consisting of phenylalkynyl radicals;

Phenyl radical substituents, biphenyl radical substituents, phenyl ether radical substituents, phenylalkyl radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents, 2-phenylethenyl radical substituents and stilbenyl radical substituents are linear or branched, saturated Or unsaturated C _1-6 aliphatic groups, halogen, nitro, carboxy, hydroxy, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, phenylalkoxy, acyl, acyloxy, cyano, carvalkoxy, thio , Alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, furan, thiophene, pyridine, pyrimidine, pyridazine, 1,3 One selected from oxadiolane, tetrazole, oxadiazole, oxazole, triazole, imidazoline, imidazole, thiazole, thiadiazole, pyrrole, piperidine, morpholine and pyrazole Above;

Y is O or S;

Z is O, S or N (R _b ), where R _b is hydrogen or alkyl;

Or R ₁ and R _b may be joined to form an imidazole or benzimidazole moiety.

Detailed description of the invention

Rhodamine derivatives or analogs of the present invention can be conveniently prepared from known starting materials by the general synthesis shown in Scheme 1 below.

Wherein R, R ₁ , R ₂ , X, Y, Z and m are as described above.

In carrying out the general synthesis as exemplified above, a reaction mixture is prepared which comprises the appropriate aldehyde in ethanol and the appropriate rhodamine derivative or analog and the reaction mixture is heated to reflux in the presence of a catalytic amount of piperidine. Suitable aldehyde starting materials or precursors thereof are obtained from commercially available products. In addition, various 5-substituted puraldehydes can be prepared by treating the corresponding dimethylacetals as shown below. Specifically, 5-bromofuran-2-carboxaldehyde dimethylacetal is treated with n-butyl lithium and n-tributyltin chloride in tetrahydrofuran at -78 ° C to produce tri-n-butylfuran analogs, This yields a 5-substituted furan intermediate upon treatment with the appropriate substituted bromobenzene. The conversion of the intermediate produced with pyridine using a catalytic amount of pyridinium p-toluene sulfonate (PPTS) gives 5- (substituted phenyl) furan-2-carboxaldehyde.

Aldehydes can be prepared by the method disclosed in Pong et al., Arzneim, Forsch, 33: 1411 (1983).

All possible isomers of formulas (I) to (III) are within the scope of the present invention. Representative examples of such isomers include, but are not limited to, E and Z isomers and various isomers of heterocyclic substituents that may be present in the compounds of the present invention.

In vitro studies were conducted demonstrating the rheology of the compounds as antiviral agents herein. Antiviral activity was determined by the inhibitory activity of the compound against viral RdRp in enzymatic analysis of RNA synthesis.

Preferred compounds for practicing the present invention are those wherein R ₃ is C _1-5 straight alkylene, Y is oxygen, X and Z are sulfur, and R ₂ is unsubstituted from the group consisting of furan, thiophene and oxazole Or a substituted mono-heterocyclic radical or an unsubstituted or substituted bi-heterocyclic radical selected from the group consisting of bithienyl and 1H-pyrazolylthienyl, wherein the heterocyclic radical substituent is halogen, trifluoromethyl or non- At least one member selected from the group consisting of a ring or a substituted phenyl radical, wherein the phenyl radical substituent is halogen, nitro, carboxy, hydroxy, methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyl Oxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidinyl, 1-piperi A compound of the carbonyl or 4-morpholinyl one kinds yisangim] of the formula II, selected from the group consisting of.

Further preferred compounds are those in which R ₃ is C _1-5 straight alkylene, Y is oxygen, X and Z are sulfur, R ₂ is an unsubstituted or substituted phenyl radical [phenyl radical substituent is halogen, nitro, carboxy , Hydroxy, methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino , Dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidinyl, 1-piperidinyl, or 4-morpholinyl; and at least one selected from the group consisting of to be.

R ₃ is C _1-5 straight chain alkylene, Y is oxygen, X and Z are sulfur, and R ₂ is an unsubstituted or substituted polycyclic radical selected from the group consisting of 9-phenanthryl and 2-fluorenyl [The polycyclic radical substituent is at least one member selected from the group consisting of methyl, ethyl, halogen, alkoxy, hydroxy, thio, nitro or unsubstituted or substituted phenyl radical, the phenyl radical substituent is halogen, nitro, carboxy, hydroxy , Methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carbalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkyl Preferably at least one member selected from the group consisting of amino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl]. .

In the compound of Formula III, R ₁ is a carboxyl group, W and W 'represent hydrogen, halogen, hydroxy, alkyl or trifluoromethyl substituent, Y is oxygen, X and Z are sulfur, and R ₂ is Unsubstituted or substituted furan group or unsubstituted or substituted thiophene group [furan substituent (s) and thiophene substituent (s) are alkyl, monohalophenyl, dihalophenyl, monohalocarboxyphenyl, carboxyphenyl , At least one selected from the group consisting of trifluoromethylphenyl, monohalotrifluoromethylphenyl, phenylethynyl, monoalkylphenyl, dialkylphenyl, furanyl and thienyl], and m = 0 and t = 0 desirable.

R ₂ in the compounds of formulas (II) and (III) is preferably an unsubstituted or substituted thiazole, and the thiazole substituents are identical to the furan and thiophene substituents in the following paragraphs.

Other preferred compounds in practicing the present invention are those in which R ₁ is a carboxyl group, W and W 'are hydrogen, halogen, hydroxy or trifluoromethyl substituents, Y is oxygen, X and Z are sulfur, R ₂ Is an unsubstituted or substituted phenyl group [phenyl substituent (s) consists of a halogen, alkoxy, carboxy, unsubstituted or substituted 2-phenylethenyl group, unsubstituted or substituted furan group, or unsubstituted or substituted thiophene group At least one selected from the group, 2-phenylethenyl substituent (s), furan substituent (s) and thiophene substituent (s) may be linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitros, Carboxy, hydroxy, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, phenylalkoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino , Dialkylamino, sulfonamide, carbox 'S amide, or represents an alkanoylamino one kinds yisangim], selected from the group consisting of the compound of m = 0 and t = 0 in the formula (III) are preferred. In the compounds of formula III, W and W 'preferably represent a methyl (CH ₃ ) group.

As used herein, "alkyl" refers to a C _1-6 aliphatic hydrocarbon radical of length. Similarly, "alkyl" and any variant thereof used in combination to refer to a substituent, such as alkoxy, alkylthio, alkylamino, alkylsulfinyl or alkylsulfonyl, is a C _1-6 aliphatic hydrocarbon radical of length. it means.

"Acyl" as used herein in the general sense means a free radical derived from a carboxylic acid by removing hydroxyl groups such as acetyl, benzoyl and the like.

As used herein, "carboxamido" refers to a radical or substituent of the formula -C (= 0) -NR "R" 'wherein R "and R"' represent hydrogen or alkyl.

As used herein, "sulfonamido" refers to a radical or substituent of the formula -SO ₂ -NR "R"'or -NR "-SO ₂ R"' wherein R "and R"'are as described above. it means.

As used herein, "alkanoylamino" refers to a radical or substituent of the formula -NH-C (= 0) -R ", wherein R is as described above.

As used herein, "carvalkoxy" means a radical or substituent of -C (= 0) -OR "where R" is as described above.

A "bi-heterocyclic group" is a radical having two heterocyclic moieties which may be the same or different, which are chemically linked to each other by a valent bond or a divalent linking moiety such as oxygen or sulfur. Used to describe this. See eg V9 and V33 in Table V below. See also V41 and V43.

In most cases, rhodamine derivatives or analogs and isomers and pharmaceutically acceptable salts of the above-described types exhibit antiviral activity. The compounds of the present invention are particularly effective against Flaviviridae viruses and are useful for treating and / or preventing infections and diseases associated with these viruses in the live host.

The compounds of the present invention or their precursors, and their isomers and pharmaceutically acceptable salts, include, but are not limited to, other active agents, including but not limited to interferons, ribavirin, protease inhibitors, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antiviral agents, When used in combination with an inhibitor, it is useful for treating and preventing viral infections and diseases in the live host.

The compounds disclosed herein are useful for preventing or eliminating viral infections in cell, tissue or organ cultures, and for other in vitro applications. For example, the inclusion of a compound of the present invention as a supplement in a cell or tissue culture growth medium or as a cell or tissue culture component can prevent viral infection or contamination of cultures not previously infected with the virus. The compounds described above can be used to remove virus from cultures or other biological materials (eg, blood) infected or contaminated with virus after a suitable treatment period under various treatment conditions as determined by one of ordinary skill in the art.

The compounds of the present invention can form useful salts with inorganic acids and organic acids such as hydrochloric acid, sulfuric acid, acetic acid, lactic acid, and the like, and salts useful with inorganic bases and organic bases such as sodium hydroxide or potassium, piperidine, morpholine, ammonium hydroxide and the like. Can be formed. Pharmaceutically acceptable salts of compounds of formula I are prepared according to the following procedures familiar to those skilled in the art.

The antiviral pharmaceutical composition of the present invention comprises, as an active ingredient, a compound represented by one or more of the aforementioned formulas as the active ingredient, and optionally one or more supplementary active agents described above, together with a pharmaceutically acceptable carrier medium or adjuvant.

The compositions can be prepared in various dosage forms such as tablets, caplets, pills or dragees. Alternatively, it can be filled into a suitable container, such as a capsule, or in the case of a suspension, bottled. As used herein, a “pharmaceutically acceptable carrier medium” is any solvent, diluent or other liquid excipient, dispersion or suspension aid, surface active agent, isotonic agent, thickener or emulsifier suitable for the specific dosage form desired. , Preservatives, solid binders, lubricants and the like. Remington's Pharmaceutical Sciences, 15th edition, E.W. Martin (Mack Publishing Co., 1975, Easton, Pa.) Describes various carriers used to formulate pharmaceutical compositions and known manufacturing techniques thereof. Except where any conventional carrier medium is incompatible with the antiviral compound of the invention, such as causing any undesirable biological effect or interacting in a deleterious manner with any other component (s) of the pharmaceutical composition However, the use of the same is within the scope of the present invention.

In the pharmaceutical compositions of the present invention, the active agent, if present, may be present in an amount of at least 0.5% by weight and generally at most 90% by weight, based on the total weight of the composition comprising the carrier medium and / or adjuvant (s). . The proportion of active agent varies from 5 to 50% by weight of the composition.

The compositions can be prepared using pharmaceutically organic or inorganic solid or liquid carrier media suitable for enteral or parenteral administration. Gelatin, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gums, polyalkylene glycols, or other known pharmaceutical ingredients are all suitable as carrier media or excipients.

The compounds of the present invention can be administered using any amount and any route of administration effective for monitoring the infectivity of the virus. Thus, as used herein, "an effective amount that directs the infectivity of a virus" refers to an amount of antiviral agent that is nontoxic but sufficient to provide the desired treatment of viral infection. The exact amount required will vary from sample to sample, depending on the type of sample, age and general condition, the severity of the infection, the specific antiviral agent and the route of administration.

The antiviral compound is preferably formulated in dosage unit form, taking into account ease of administration and uniformity of dosage. As used herein, “dose unit form” relates to an antiviral agent of a physical discrete unit suitable for the patient to be treated. Each dose should include the amount of active substance that is calculated by itself or in combination with the selected pharmaceutical carrier medium and / or supplemental active agent (s), if present, to produce the desired therapeutic effect. Typically, the antiviral compound of the invention is administered in a dosage unit comprising about 0.1 to about 500 mg, preferably about 1 to about 100 mg of the antiviral agent.

The compounds of the present invention can be administered by themselves or in the form of precursors such as prodrugs from which the active ingredient can be derived. Prodrugs are derivatives of the aforementioned compounds, the pharmacological action of which results from the conversion of the active ingredient to chemical or metabolic processes in vivo. Non-limiting examples of prodrugs include esters of the foregoing compounds with carboxyl or hydroxyl functional groups. Pivaloyloxymethyl esters are useful for this purpose, and esters derived from simple or functionalized C _1-6 alcohols or carboxylic acids are also useful. Such prodrugs can be prepared according to procedures known in the medical chemistry and pharmaceutical formulation sciences.

The compounds of the present invention may be administered orally, rectally, parenterally, such as intramuscular injection, subcutaneous injection, intravenous infusion, etc., depending on the nature and the severity of the infection to be treated, such as intranasal administration, vaginal administration, intraperitoneal administration, It may be administered topically by powder, ointment, droplets or the like or by inhalation by aerosol. Depending on the route of administration, the compounds of the present invention may be administered at a dosage level of about 10 ⁻³ to about 120 mg, preferably about 10 ⁻² to about 30 mg per kg of body weight per day, at least once a day for The therapeutic effect can be obtained. As an example, a suitable dose for oral administration is 30 mg per kg body weight per day, while a typical intravenous dose is 10 mg per kg body weight per day.

Compounds of the invention are typically administered 1 to 4 times per day to deliver the daily doses described above. However, the exact method of administration of the compounds and compositions disclosed herein depends on the needs of each host or patient to be treated, the type of treatment administered and the judgment of the participating physician.

In view of the inhibitory effect on the viral RNA synthesis produced by the compounds of the present invention, these compounds are expected to be useful not only for the treatment of viral infections but also for the prevention of viral infections. The dose may be substantially the same for the treatment or prevention of a viral infection.

The following examples are provided to further illustrate the present invention. These embodiments, which illustrate the preferred manners presently contemplated in carrying out the invention, are for illustration and are not intended to limit the invention.

Examples 1-8 illustrate suitable methods of synthesizing representative compounds of the present invention. However, the synthesis method is not limited to those illustrated below.

Example 1

Preparation of 5- [5- (2-chlorophenyl) -furan-2-yl-methylene] -4-oxo-2-thiothiothiazolidine

a) 5-tributyltin-2-furancarboxaldehyde dimethylacetal

To a solution of 6.03 g (0.0273 mol) of 5-bromo-2-furancarboxaldehyde dimethylacetal (Aldrich) in 75 ml of dry THF at -78 ° C and argon was added 12 ml (1.1 equiv) of 2.5 M n-butyl lithium. . After 10 minutes, the resulting yellow solution was quenched with 8.88 g (1 equiv) of tributyl tin chloride, and then the reaction temperature was gradually warmed to room temperature. After extraction with t-butyl-methyl ether, the organic phase is washed with water. The organic layer was dried over anhydrous sodium sulfate to remove 11.3 g (96%) of solvent in the product and recovered as an orange oil.

b) 5- (2-chlorophenyl) -2-furancarboxaldehyde dimethylacetal

2.11 g (4.8 mmol) of tributyltin compound and 0.22 mL (1.92 mmol) of 1-bromo-2-chlorobenzene and dichlorobis (triphenylphosphine) palladium (II) in 8 mL of re-distilled THF ) 67 mg (5 mol%) of solution was heated under reflux for 12 hours. After cooling the solution, it was diluted with 100 ml of diethyl ether and the mixture was filtered through celite. The organic solution was then washed with two parts of water (80 ml each) and dried over anhydrous potassium carbonate. As a result of removing the solvent, 264 mg of brown oil was obtained.

c) 5- (2-chlorophenyl) -2-furancarboxaldehyde

To a solution of 260 mg (1.03 mmol) of dimethylacetal obtained from step b) in 5 ml of acetone was added 388 mg (1.54 mmol) of pyridinium p-toluenesulfonate, and the solution was stirred at room temperature for 12 hours. The reaction mixture was then diluted with 40 ml of ethyl acetate, and the solution was washed with two parts of water (30 ml each) and dried over magnesium sulfate. As a result of removing the solvent, yellow oil 123 mg was obtained.

d) 5- [5- (2-chlorophenyl) furan-2-yl-methylene] -4-oxo-2-thiothiothiazolidine

0.1 mL of piperidine was added to 94 mg (0.455 mmol) of 5- (2-chlorophenyl) -2-furancarboxaldehyde and 64 mg (0.478 mmol) of rhodanine solution thus prepared in 10 mL of ethanol, The solution was heated to reflux. After 20 minutes, the solution was cooled, diluted with 80 ml of diethyl ether, and the mixture was passed through a fine filter, the reddish orange solid was washed with water and dried under vacuum to give 116 mg of solid product. .

Example 2

5- [5- (2-chloro-5-nitrophenyl) thien-2-yl-methylene] -4-oxo-2-thiothiothiazolidine

a) 5-bromo-2-thiophenecarboxaldehyde dimethylacetal

A solution of 5.9 g (26.2 mmol) of 5-bromothiophene-2-carboxaldehyde, 3 g (28.3 mmol) of methylorthoformate, and a catalytic amount of pyridinium p-toluene sulfonate (10 mg) in 10 ml of methanol was subjected to 48 hours. Heated to 40 ° C. The solution was then concentrated to dryness, eluted with 4: 1 hexanes: ethyl acetate and subjected to flash chromatography on basic alumina to yield 5.69 g of a clear cryptographic oil.

b) 5-tributyltin-2-thiophenecarboxaldehyde dimethylacetal

10.4 mL (1.1 equiv) of 2.5 M n-butyllithium was added to a solution of 5.6 g (23.6 mmol) of 5-bromo-2-thiophenecarboxaldehyde dimethylacetal in 80 mL of anhydrous tetrahydrofuran at -78 ° C under argon. . After 15 minutes, the dark orange solution was quenched with 7.69 g (1 equiv) of tributyltin chloride. After warming the orange red solution to room temperature, t-butylmethylether (200 mL) was added. The organic phase was then washed with 2 parts of water (each 100 ml each) and then dried over sodium sulfate. The solvent was removed to give 10.15 g of the product as an orange oil.

c) 5- (2-chloro-5-nitrophenyl) -2-thiophenecarboxaldehyde dimethylacetal

4.16 g (1.1 equiv) of tributyltin compound obtained in step b) described above in 20 mL of dry THF, 2 g (8.4 mmol) of 1-bromo-2-chloro-5-nitrobenzene and dichlorobis (triphenylphosphine) A suspension of 297 mg (5 mol%) of palladium (II) was heated under reflux for 20 hours under argon. The reaction was then concentrated in vacuo and the dark red oil was passed through a basic alumina column. The resulting oil was then purified by preparative HPLC over silica gel eluted with 4: 1 hexanes: ethyl acetate solution to give 1.93 g of the product as a viscous oil.

d) 5- (2-chloro-5-nitrophenyl) -2-thiophenecarboxaldehyde

A solution of 1.93 g of dimethylacetal and pyridinium p-toluene sulfonate catalyst amount (10 mg) obtained in step c) in 100 ml of acetone was stirred at room temperature under argon for 20 hours. The resulting yellow solution was concentrated to dryness and then the residual yellow solid was dissolved in 100 ml of ethyl acetate. The organic phase was then washed with 2 parts of water (100 ml each) and dried over sodium sulfate. The solvent was removed to give 1.46 g of a yellow powder product.

e) 5- [5- (2-chloro-5-nitrophenyl) thien-2-yl-methylene] -4-oxo-2-thiothiothiazolidine

A solution of 200 mg (0.747 mmol) of aldehyde, 104 mg (0.787 mmol) of 2-thioxo-4-thiazolidinone and 0.02 ml of piperidine prepared in step d) in 3 ml of ethanol was heated under reflux for 30 minutes. During this time, the solution turned dark orange and separation of solids started. After cooling the solution to room temperature, the mixture was diluted with water, the solid was collected by filtration and washed with water. The solid was then heated with ethyl acetate. After cooling to room temperature, the mixture was collected by filtration and dried to give 137 mg of product.

Example 3

(5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid

Piperi in a solution of 191 mg (1 mmol) of rodanine-3-acetic acid, 274 mg (1 mmol) of 5- [2-chloro-5- (trifluoromethyl) phenyl] -2-furaldehyde in 6 ml of ethanol After dropping 1 drop of Dean, the solution was heated at reflux for 10 minutes. From this a yellow solid was separated and after cooling the mixture, the material was collected by filtration and washed with ethanol and hexane to give 234 mg of the desired product.

Example 4

3- (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid

a) A solution of 5.0 g (28.6 mmol) of 5-bromo-2-furaldehyde, 4 ml of trimethylorthoformate and 10 mg of pyridinium p-toluenesulfonate in 20 ml of anhydrous methanol was heated under reflux for 18 hours under argon. It was. The solution was then concentrated to dryness, and the crude yellow oil was passed through basic alumina and diluted with 4: 1 hexanes / ethyl acetate to give 6.03 g of 5-bromo-2-furaldehyde dimethylacetal.

b) 12 ml (1.1 equivalents) of 25 M n-butyl lithium in a solution of 6.03 g (0.0273 mol) of 5-bromo-2-furaldehyde dimethylacetal prepared as described above in 75 ml of dry THF under -78 ° C, argon. ) Was added. After 10 minutes, the yellow solution was quenched with 8.88 g (1 equiv) of tributyltin chloride and the reaction temperature was slowly warmed to room temperature. After the solution was extracted with water, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed to obtain 11.3 g of tri-n-butylstannyl-furaldehyde dimethylacetal as a red oil.

c) Palladium (II) chloride bis (triphenylphosph) in a solution of 8 g (18 mmol) of the aforementioned tributyltin compound and 3.5 g (15 mmol) of 1-bromo-3,4-dichlorobenzene in 25 ml of distilled THF. Pin) 530 mg was added. The solution was then heated at reflux for 12 hours. The reaction mixture was diluted with 100 mL of water and then extracted with 2 parts of ethyl acetate. The organic layer was washed with 2 parts of water, washed with 1 part of saturated sodium chloride and dried over magnesium sulfate. After filtration, the solution was concentrated and passed through a silica column and eluted with 9: 1 hexanes / ethyl acetate to give 760 mg of 5- (3,4-dichlorophenyl) -2-furaldehyde.

d) 2 drops of piperidine in a solution of 150 mg (0.62 mmol) of aldehyde and 130 mg (0.62 mmol) of 2-thioxo-4-thiazolidinone-2-propionic acid obtained in the previous experiment in 5 ml of ethanol. After addition, the solution was heated at reflux for 20 minutes. The solution was then diluted with 20 mL of water and 3N HCl was added until the mixture became slightly acidic. From this, a dark orange solid was collected, which was washed with hexane and dried to give 198 mg of the desired product.

Example 5

6- (5- [5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) hexanoic acid

a) To a mixture of 1 g (4.4 mmol) of trithiocarbonate and 520 mg of 6-aminohexanoic acid, 5 ml of water and 280 mg of potassium carbonate were added. The mixture was then heated at reflux for 2 hours, then cooled to room temperature and acidified with 3 N hydrochloric acid. The mixture was then extracted with ethyl acetate and the organic layer was washed with water and dried over magnesium sulfate. After filtration, the solvent was removed to suspend the remaining solid in methylene chloride and the suspended solid was filtered off. The solution was concentrated to dryness and the remaining solid 2-thioxo-4-thiazolidinone-2-hexanoic acid was recrystallized from a mixture of ethyl acetate and hexanes.

b) Droplet 1 of piperidine was added dropwise to 75 mg (0.32 mmol) of furalaldehyde and rhodanine hexanoic acid derivatives prepared by the method described above in 10 ml of ethanol, and the solution was heated to reflux. After 90 minutes, the mixture was cooled to room temperature and diluted with water to separate the solids. The material was then collected and dried to give 10 mg of the desired product in solid form.

Example 6

3- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid

2.48 g (9.8 mmol), 5-([2-chloro-5-trifluoromethylphenyl) -2- (4-oxo-2-thioxothiazolidin-3-yl) -benzoic acid in 150 mL ethanol A solution of 2.69 g (9.8 mmol) of furaldehyde, 0.854 mL of piperidine was heated under reflux for 4 hours. After cooling to room temperature, the solution was acidified with 1 M hydrochloric acid and the precipitated solid was collected by filtration, washed with ethanol and dried to give 3.7 g of product.

Example 7

4- (5- [5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) methylbenzoic acid

a) 4- (4-oxo-2-thioxothiazolidin-3-yl) methylbenzoic acid

A mixture of 3 g (19.8 mmol) of 4- (aminomethyl) benzoic acid, 1.05 g (9.98 mmol) of anhydrous sodium carbonate, and 4.49 g (19.8 mmol) of bis (carboxymethyl) trithiocarbonate in 50 ml of water was added for 100 hours. Heated to ° C. The yellow solid collected by filtration was then washed with water and then dried to give 4.67 g of product.

b) 4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) methylbenzoic acid

100 mg (0.374 mmol) of methylbenzoic acid derivative prepared in step a), 10 mg of ethanol, 103 mg (0.374 mmol) of 5- [2-chloro-5-trifluoromethyl] phenyl) furfural and piperidine 31 The mg solution was heated at reflux for 20 minutes. The mixture was then poured into 10 ml of water, and the orange precipitate formed thereon was collected by filtration, washed with water and dried to give 116 mg of a yellow solid.

Example 8 describes another synthetic method for preparing the compounds of the present invention.

Example 8

4- (5-phenylmethylene-4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid

a) 4- (4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid

A mixture of 6.86 g (0.05 mol) of 4-aminobenzoic acid, 11.31 g (0.025 mol) of bis (carboxymethyl) trithiocarbonate and 2.65 g (0.025 mol) of anhydrous sodium carbonate in 50 mL of water was heated under reflux for 12 hours. . After cooling to room temperature, the separated solids were collected and washed with water. This was then recrystallized to give 7.028 g of product.

b) 4- (5-phenylmethylene-4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid

A solution of 225 mg (0.89 mmol) of 4- (4-oxo-2-thioxothiazolidin-3-yl) benzoic acid, 0.108 ml (1.07 mmol) of benzaldehyde, 280 mg of ammonium hydride and 309 mg of ammonium chloride in 5 ml of ethanol. Was heated at reflux for 12 h. The resulting precipitate was then collected by filtration, washed with ethanol to give 72 mg of a yellow solid which was melted at 298-301 ° C.

By appropriately selecting the appropriate aldehyde or precursor thereof and the specific reactant to provide the N-substituent or analog thereof of the desired rhodanine, the other compounds of the invention described in the foregoing examples can be prepared. Representative examples of additional rhodanine derivatives thus prepared are shown in the table below.

Rhodanine Alkanoic Acid Derivatives Ⅳ-1 3- (5-[(5- {2-chloro-5-trifluoromethylphenyl) -furan-2-yl) methylene] -4-oxo-2-thioothiazolidin-3-yl) propionic acid Ⅳ-2 3- (5-[(5- {3-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-3 (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid IV-4 4- (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) butyric acid IV-5 3-([5- (4-diethylaminophenyl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid Ⅳ-6 3-([5- (3-phenoxy-4-methoxyphenyl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-7 3-([5- (3,4-dichlorophenyl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid Ⅳ-8 3-([5- (9-phenanthryl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-9 3-([5- (2-fluorenyl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid Ⅳ-10 (5-[(5- {phenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid IV-11 3- (5-[(5- {phenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid

IV-12 (5-[(5- {3,4-dichlorophenyl} thien-2-yl) methylene-4-oxo-2-thioothiazolidin-3-yl) acetic acid IV-13 3- (5-[(5- {phenylethynyl} thien-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-14 3- (5-[(5- {thien-2-yl} thien-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-15 (5-[(5- {3,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid IV-16 ([5-{(3-para-t-butyl-phenoxy) -phenyl} methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid IV-17 ([5- {3- (4-Netrylphenoxy) -phenyl} -methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid IV-18 (5-[((2,5-dimethyl-1- {3-trifluoromethylphenyl})-1H-pyrrol-3-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl Acetic acid IV-19 (5-[(5- {3-trifluoromethyl-1-methyl-1H-pyrazol-5-yl} thien-2-yl) methylene] -4-oxo-2-thiothiothiazolidine-3 -Yl) -3-acetic acid IV-20 (5-[((2,5-dimethyl-1 {(phenyl}) 1H-pyrrol-3-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid IV-21 5-[(5- {4-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid IV-22 3- (5-[(5- {3,4-dichlorophenyl} -2-thienyl) methylene] -4-oxo-2-thioxothiazolidin-3-yl) propionic acid IV-23 (5-[(5- {4-carboxylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid

IV-24 (5-[((5-trifluoromethyl-1-methyl-1H-pyrazol-3-yl) thien-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl Acetic acid IV-25 (5- [3- (3-trifluoromethylphenoxy) -phenylmethylene] -4-oxo-2-thiothiazolidin-3-yl) acetic acid IV-26 3-([5- {4-Isopropenyl-cyclohex-1-enyl} methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-27 3-([5- (2,4-dichlorophenyl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-28 3- (5-[(5- (benzofuran-2-yl) furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-29 3- (5-[(5- {3,5-bistrifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-30 3- (5-[(5- {phenylethynyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-31 3- (5-[(5- {5-methylpyrid-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-32 3- (5-[(5- {thiazol-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid IV-33 5- (4-Chlorophenyl) -2- (5- (4-oxo-2-thiothiothiazolidinyl) -3-carboxyethyl) -methylenefuran-3-yl-carboxylic acid ethyl ester IV-34 5- (4-Chlorophenyl) -2- (5- (4-oxo-2-thioxo-4-thiazolidinyl) -3-carboxymethyl) -methylenefuran-3-yl-carboxylic acid ethyl ester IV-35 3- (5-[(5- (benzothiophen-2-yl) furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidinone-3-yl) propionic acid

4- (5-R ₂ -methylene) -4-oxo-2-thioxo-thiazolidin-3-yl) benzoic acid R ₂ Ⅴ-1 5- [2-chloro-5-trifluoromethylphenyl] furan-2-yl Ⅴ-2 5-phenylethynylfuran-2-yl Ⅴ-3 5- [3,4-dichlorophenyl] furan-2-yl Ⅴ-4 5- [4-bromophenyl] furan-2-yl Ⅴ-5 5- [3,5-dichlorophenyl] furan-2-yl Ⅴ-6 5- [2,5-dichlorophenyl] furan-2-yl Ⅴ-7 5- [4-n-butylphenyl] furan-2-yl Ⅴ-8 5- [4-n-propylphenyl] furan-2-yl Ⅴ-9 5- [thien-2-yl] furan-2-yl Ⅴ-10 5- [2-chlorophenyl] furan-2-yl Ⅴ-11 5- [3-carboxyphenyl] furan-2-yl Ⅴ-12 5- [2,3-dichlorophenyl] furan-2-yl Ⅴ-13 5- [3-trifluoromethylphenyl] furan-2-yl Ⅴ-14 5- [2-trifluoromethylphenyl] furan-2-yl Ⅴ-15 5- [2,6-dichlorophenyl] furan-2-yl Ⅴ-16 (3- (5-carboxy-2-furanyl) phenyl) Ⅴ-17 4-trans-steelbenyl Ⅴ-18 3-styryl

Ⅴ-19 2,4-dichlorophenyl Ⅴ-20 3,4-dichlorophenyl Ⅴ-21 4-bromophenyl Ⅴ-22 4-methoxyphenyl Ⅴ-23 4-carboxyphenyl Ⅴ-24 2-furanyl Ⅴ-25 5-methylfuran-2-yl Ⅴ-26 5-ethylfuran-2-yl Ⅴ-27 4,5-dimethylfuran-2-yl Ⅴ-28 5- [3,5-dimethylphenyl] furan-2-yl Ⅴ-29 5- [3,4-dimethylphenyl] furan-2-yl Ⅴ-30 4- (benzyloxyl) phenyl Ⅴ-31 2-naphthyl Ⅴ-32 5- [3,4-dichlorophenyl] thiophen-2-yl Ⅴ-33 5- [1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl] thiophen-2-yl Ⅴ-34 5- [4-chlorophenyl] furan-2-yl Ⅴ-35 5- [benzofuran-2-yl] furan-2-yl Ⅴ-36 5- [benzothiophen-2-yl] furan-2-yl Ⅴ-37 5- [5-chlorothiophen-2-yl] furan-2-yl Ⅴ-38 5- [3-chloro-5-trifluoromethylpyrid-2-yl] furan-2-yl Ⅴ-39 5- [2,3,5,6-tetrafluoropyrid-4-yl] furan-2-yl Ⅴ-40 5- [6-methoxypyridaz-3-yl] furan-2-yl Ⅴ-41 5- [5-thiazol-2-yl] furan-2-yl Ⅴ-42 5- [2-methyltetrazol-5-yl] furan-2-yl Ⅴ-43 5- (5-trifluoromethyl- [1,2,4] oxadiazol-3-yl) furan-2-yl

Ⅶ-1 3- [5- (3-phenylpropenylideneyl) -4-oxo-2-thiothiothiazolidin-3-yl] benzoic acid Ⅶ-2 3- [5- (5- {1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl} thien-2-yl) methylene-4-oxo-2-thiothiothiazolidine-3 -Yl] benzoic acid Ⅶ-3 3- [5- (5- {1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl} thien-2-ylmethylene) -4-oxo-2-thiothiothiazolidine-3 -Yl] benzoic acid Ⅶ-4 5- (4-Chlorophenyl) -2- (3- (4-carboxyphenyl) -4-oxo-2-thiothiothiazolidin-5-yl) ydenfuran-3-yl carboxylic acid ethyl ester

Example 9

Inhibition of Viral RNA Replication

In general, the discovery of inhibitors for viral polymerases and related proteins requires evaluation of many chemical compounds or mixtures of these chemical compounds. Therefore, assays for polymerase activity that can perform large amounts of screening, ie high throughput assays, are preferred. There are a number of assay methods well known to those skilled in the art that can efficiently screen large quantities of samples. See, eg, Cole, JL, Meth Enzymology , 275: 310-328 (1996). Any of these assays may be suitable for viral RdRp activity.

In the case of Flaviviridae virus, one method of measuring viral RdRp activity utilizes recombinant NS5 protein purified in an in vitro RdRp assay. For example, Behrens et al. (EMBO J., 15: 12-22 (1996)) and Lohmann et al. J. Virol, 71: 8416-8428 (1997) describe the baculovirus expression of HCV NS5B RdRp. , Purification and enzymatic activity are described. In bacterial expression, purification and enzymatic activity of the HCV NS5B RdRp protein are described in PCT / US96 / 15571 [WO 97/12033] and Yuan et al., Boichem Biophys Res Comm, 232: 231-235 (1997). have. As a further example, Collett's PCT / US99 / 07404, commonly owned herein, describes compositions comprising functional HCV NS5B sequences and their use in identifying compounds useful for the treatment of hepacivirus infection. . As an example as described above for HCV RdRp, the dengue flavivirus NS5 protein expressed by bacteria was purified, from which the NS5B protein of BVDV had a protein which was purified from recombinant baculovirus infected cells. It can be confirmed that the RdRp activity (Tan et al., Virology, 216: 317-325 (1996)), such as (Zhong et al., J. Virol., 72: 9365-9369 (1998)). .

Through this example, the inhibitory activity of the compounds of the present invention can be demonstrated by an in vitro RdRp assay using NS5 protein, which is essentially prepared according to Collett's PCT / US99 / 07404. Purified NS5 protein was incubated in a standard RdRp reaction mixture. Such reaction mixtures generally include nucleoside triphosphate and RNA template-primers in buffers, salts, cations, reducing agents and the like. Modification of the individual components of this reaction mixture is necessary to adjust the specific reaction preferences of each NS5 protein. Such modifications are well known to those skilled in the art.

As can be seen from Examples 1 to 8 and the foregoing tables, representative compounds within the scope of the present invention were evaluated for antiviral activity in this assay. The measured value of the inhibitory activity of the compound of the present invention can be expressed as an IC ₅₀ value. IC ₅₀ values represent the concentration of the compound when RdRp activity is 50% inhibited. Assay of inhibition of RdRp activity of hepacivirus, pestivirus and flavivirus NS5 proteins for the majority of compounds tested revealed an IC ₅₀ value of 0.02 to about 30 μM for each of the three genera.

IC ₅₀ values of many tested compounds were ≦ 1 μM. These compounds include the following.

A. R _One Is a hydrogen rhodanine derivative of formula (I):

5-[(5- (3,4-dichlorophenyl) furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine;

5-[(5- (2-chloro-5-trifluoromethylphenyl) furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine;

5- (5- [2-chloro-5-nitrophenyl] furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine;

5-[(5- (3,4-dichlorophenyl) thien-2-yl) methylene] -4-oxo-2-thiothiothiazolidine;

5-[(5- (thien-2-yl) thien-2-yl) methylene] -4-oxo-2-thiothiothiazolidine;

5-[(5- (4-n-propylphenyl) thien-2-yl) methylene] -4-oxo-2-thioothiazolidine;

5-[(5- (4-methylphenyl) thien-2-yl) methylene] -4-oxo-2-thiothiothiazolidine; And

5- [5- (4,5-dimethylfuran-2-yl) furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine

B. Rhodanine acetic acid derivative of Formula II:

(5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiono-thiazolidin-3-yl) acetic acid;

(5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid;

(5-[(5- {3-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid;

(5-[(5- {3,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid;

(5-[(5- {4-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid;

(5-[(5- {4-chlorophenyl-3-ethoxycarbonyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid;

(5-[(5- {3,4-dichlorophenyl} thiophen-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid; And

(5-[(5- {3-t-butylphenoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid.

C. Rhodinine propionic acid derivative of Formula II:

2- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

2- (5-[(5- {5-chlorothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {benzofuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {benzothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {3,5-ditrifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {furan-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {thiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thioxothiazolidin-3-yl) propionic acid;

3- (5-[(5- {chlorothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(-{4-bromophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {isoquinolin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {2-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {3,4-methylenedioxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {3,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {3,5-dimethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {methylthiophen-2-yl} furan-2-yl) methylene] -4-oxo-thioothiazolidin-3-yl) propionic acid;

3- (5-[(5- {5-methyl-2-pyridyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(6-benzyloxybenzofuran-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {phenanthren-9-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {thiophen-2-yl} thiophen-2-yl) methylene] -4-oxo-2-thioothiazolidin-3-yl) propionic acid;

3- (5-[(5- {fluoren-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {phenylethynyl} thiophen-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {3-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(4- {phenylethynyl} thiophen-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid;

3- (5-[(5- {5-n-propylthiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; And

3- (5-[(5- {4-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid.

D. Rhodamine benzoic acid derivatives of Formula III:

4- (5-[(5- {benzofuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {benzothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3,5-Ditrifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3,4-dimethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {5-chlorothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-furanyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {5-methylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {5-methylthiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3,4-difluorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4-methoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {5-acetothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3-chloro-5-trifluoromethylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl ) Benzoic acid;

4- (5-[(5- {3,4-dimethoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3,4-methylenedioxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {5-trifluoromethylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {6-methoxypyridazin-3-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4,6-dimethylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3-bromo-6-methoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5-phenylethynylfuran-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-yl) benzoic acid;

4- (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4-bromophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) -6-chloro Benzoic acid;

4- (5-[(5- {3-carboxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2,3,5,6-tetrafluoropyridin-4-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine-3- Benzoic acid;

4- (5-[(5- {3-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-thienyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4-n-butylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) methylenebenzoic acid;

4- (5-[(5- {3,5-difluorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3,5-dimethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4-acetophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4-n-propylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2,3-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {indol-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {3-methoxy-2- (N, N-diethylaminocarbonylphenyl) furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine- 3-yl) benzoic acid;

4- (5-[(5- {phenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {5-methylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {5-chloro-3-methylbenzothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) Benzoic acid;

4- (5-[(5- {5-n-propylthiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4,5-dimethylfuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {5-thiazol-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {formyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {4-methylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-acetophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid;

4- (5-[(5- {2-nitrophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; And

4- (5-[(5- {4,5-dichloroimidazol-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid.

The fact that low concentrations of test compounds are required to inhibit 50% RdRp activity suggests that the compounds of the present invention are effective in inhibiting RNA synthesis by RdRp enzymes of viruses.

While the present invention has been described and illustrated through any preferred embodiment, other embodiments will be apparent to those skilled in the art. Thus, the present invention is not limited to the specific embodiments described and illustrated, but may be modified and changed without departing from the spirit of the invention, that is, the full scope of the invention as defined by the appended claims.

Claims (59)

At least one virus-induced infection of Flaviviridae, comprising administering to the host a therapeutically or prophylactically effective amount of a compound of formula (I) or a precursor thereof and an isomer and a pharmaceutically acceptable salt of the compound: And a method for treating or preventing a disease associated with an infection in a live host that possesses or is susceptible to such an infection. Formula I Where R is hydrogen or alkyl; m is an integer of 0 to 4; R ₁ is hydrogen, or —R ₃ COOH radical, where R ₃ is unsubstituted or substituted, branched or straight chain, saturated or unsaturated C ₁ -C ₁₀ hydrocarbon moiety, unsubstituted or substituted phenyl (C ₆ H ₅ ) a radical selected from those consisting of a radical or an unsubstituted or substituted phenylalkyl radical, wherein the R ₃ substituent is a straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, unsubstituted or substituted heterocyclic radical Or at least one selected from those consisting of unsubstituted or substituted phenyl (C ₆ H ₅ ) radicals, wherein the heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole, tria Sol, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine; X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or C _1-5 alkyl; R ₂ is an unsubstituted or substituted phenylalkyl radical, an unsubstituted or substituted phenylalkenyl radical, an unsubstituted or substituted phenylalkynyl radical, an unsubstituted or substituted biphenylalkyl radical, an unsubstituted or substituted polycyclic radical, Unsubstituted or substituted C _5-8 alicyclic radical or formula (R _2a- ) _n (L-) _p R _2b -wherein R _2a and R _2b can be the same or different and an unsubstituted or substituted heterocyclic radical Or an unsubstituted or substituted phenyl radical, R _2a represents an unsubstituted or substituted polycyclic radical, L is a valence bond,-(CH ₂ ) _q- , -HC = CH-, -C≡C-,- ₂ selected from the group consisting of C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ — or NR _2c , where R _2c is hydrogen or alkyl Is a linking moiety, n and p are each 0 or 1 and q is an integer of 1 to 3; The heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, isoxazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, isothiazole, thiadia Sol, imidazole, pyrrole, tetrazole and triazine; The polycyclic radicals are benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, indole, 2-isoindole, benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3 With benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene Selected from the group consisting of; Heterocyclic radical substituents, polycyclic radical substituents and alicyclic radical substituents are linear or branched, saturated or unsaturated C_1-6 Alicyclic group, halogen, perhaloalkyl, monoalkyl, dihaloalkyl, alkoxy, acyl, acyloxy, acyloxyalkyl, phenylalkoxy, hydroxy, hydroxyalkyl, thio, alkylthio, nitro, carboxy, carvaloxy At least one selected from the group consisting of; Phenyl radical substituents, phenylalkyl radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents and biphenylalkyl radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitros, carboxy, hydrides. Hydroxy, hydroxyalkyl, perhaloalkyl, monohaloalkyl, dihaloalkyl, alkoxy, phenylalkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkyl At least one member selected from the group consisting of sulfonyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, carboxamido, alkanoylamino; Y represents O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; R ₁ and R _b may be joined to form an imidazole or benzimidazole moiety. The raw host of claim 1, wherein the compound or precursor of the compound contains about 10 ⁻³ to about 120 mg of compound per kilogram of body weight per day and may be in unit dosage form, which may comprise a pharmaceutically acceptable carrier medium. A method for treating or preventing an infection by one or more viruses of Flaviviridae characterized by being administered to and diseases associated with the infection. The method of claim 1, wherein the precursor of the compound is administered in the form of a prodrug, wherein the infection is caused by one or more viruses of Flaviviridae and a disease associated with the infection. The method of claim 1, wherein the compound or a precursor of the compound is administered or concurrently or sequentially administered with one or more other therapeutic agents, to treat or prevent infection by one or more viruses of Flaviviridae and diseases associated with the infection. How to. 5. The Flaviviridae of claim 4, wherein the other therapeutic agent is selected from the group consisting of interferon, ribavirin, protease inhibitors, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antiviral agents, and infection inhibitors. Infections by more than one virus and methods of treating or preventing diseases associated with the infection. The method of claim 1, wherein the compound or a precursor of the compound is administered orally, and is treated or prevented by an infection with one or more viruses of the Flaviviridae. The method of claim 1, wherein the compound or a precursor of the compound is administered rectally, and the treatment or prevention of infection with one or more viruses of the Flaviviridae. The method of claim 1, wherein the compound or a precursor of the compound is parenterally administered, and is treated or prevented by infection with one or more viruses of Flaviviridae. 2. The method of claim 1, wherein the compound or a precursor of the compound is administered in a tank, wherein the infection is caused by one or more viruses of Flaviviridae and a disease associated with the infection. The method of claim 1, wherein the compound or a precursor of the compound is administered intravaginally, wherein the infection is caused by one or more viruses of Flaviviridae and a disease associated with the infection. 2. The method of claim 1, wherein the compound or a precursor of the compound is administered intraperitoneally. The method of claim 1, wherein the compound or a precursor of the compound is topically administered and treated or prevented by infection with one or more viruses of the Flaviviridae. The method of claim 1, wherein the compound or a precursor of the compound is administered by inhalation, wherein the infection is caused by one or more viruses of Flaviviridae and a disease associated with the infection. The method of claim 1, wherein the Flaviviridae virus belongs to the virus of the genus Hepacivirus, the virus of the pestivirus, the virus of the flavivirus and the Flaviviridae, but is designated as a specific genus. A method for treating or preventing a disease caused by one or more viruses of Flaviviridae, characterized by being selected from the group consisting of non-viruses. 15. The species of Flaviviridae according to claim 14, wherein the compound or a precursor of the compound is administered to the raw host in a unit dose form containing about 10 ^-3 to about 120 mg of the compound per kilogram of body weight per day. A method for treating or preventing an infection caused by an abnormal virus and a disease associated with the infection. 15. The method of claim 14, wherein the precursor of the compound is administered in the form of a prodrug, wherein the infection is caused by one or more viruses of Flaviviridae and a disease associated with the infection. The method according to claim 1, wherein the compound is a compound represented by the following formula (II), an isomer thereof, and a pharmaceutically acceptable salt thereof. Way. Formula II Where R is hydrogen or alkyl; m is an integer of 0 to 4; R ₃ represents an unsubstituted or substituted, branched or straight, saturated or unsaturated C _1-10 hydrocarbon moiety in the main chain, and the hydrocarbon moiety substituent is a branched or straight, saturated or unsaturated C _1-6 aliphatic group, unsubstituted or At least one member selected from the group consisting of substituted mono-heterocyclic radicals or unsubstituted or substituted phenyl (C ₆ H ₅ ) radicals, wherein the mono-heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, Isoxazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine; X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl; R ₂ is an unsubstituted or substituted phenylalkyl radical, an unsubstituted or substituted phenylalkenyl radical, an unsubstituted or substituted phenylalkynyl radical, an unsubstituted or substituted biphenylalkyl radical, an unsubstituted or substituted polycyclic radical, Unsubstituted or substituted C _5-8 alicyclic radical or formula (R _2a- ) _n (L-) _p R _2b -wherein R _2a and R _2b can be the same or different and an unsubstituted or substituted heterocyclic radical Or an unsubstituted or substituted phenyl radical, R _2a represents an unsubstituted or substituted polycyclic radical, L is a valence bond,-(CH ₂ ) _q- , -HC = CH-, -C≡C-,- ₂ selected from the group consisting of C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ — or NR _2c , where R _2c is hydrogen or alkyl Is a linking moiety, n and p are each 0 or 1 and q is an integer of 1 to 3]; a radical selected from the group consisting of radicals; The heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, isoxazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, isothiazole, thiadia Sol, imidazole, pyrrole, tetrazole and triazine; The polycyclic radicals are benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, indole, 2-isoindole, benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3 With benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene Selected from the group consisting of; Heterocyclic radical substituents, polycyclic radical substituents and alicyclic radical substituents are linear or branched, saturated or unsaturated C_1-6 Alicyclic group, halogen, perhaloalkyl, monoalkyl, dihaloalkyl, alkoxy, acyl, acyloxy, acyloxyalkyl, phenylalkoxy, hydroxy, hydroxyalkyl, thio, alkylthio, nitro, carboxy, carvaloxy At least one selected from the group consisting of; Phenyl radical substituents, phenylalkyl radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents and biphenylalkyl radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitros, carboxy, hydrides. Hydroxy, hydroxyalkyl, perhaloalkyl, monohaloalkyl, dihaloalkyl, alkoxy, phenylalkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkyl At least one member selected from the group consisting of sulfonyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, carboxamido, alkanoylamino; Y represents O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; R ₃ and R _b may combine to form an imidazole or benzimidazole moiety. 18. The compound of claim 17, wherein the compound is 3- (5-[(5- {benzofuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl -Propionic acid; 3- (5-[(5- {benzothiophen-2-yl} -furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl-propionic acid; 3 -(5-[(5- (2-chloro-5-trifluoromethylphenyl) -2-furanyl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl-propionic acid; 3- ( Selected from the group consisting of 5-[(5- (5-chlorothiophen-2-yl) furan-2-yl) -methylene-4-oxo-2-thiothiothiazolidin-3-yl) propionic acid Characterized by one or more viruses of the Flaviviridae, and methods of treating or preventing diseases associated with the infection. The method of claim 1, wherein the compound is a compound represented by the following formula (III), an isomer thereof, and a pharmaceutically acceptable salt thereof. Way. Formula III Where R is hydrogen or alkyl; m is an integer of 0 to 4; R ₁ is -OH, -COOR ₄ , -CONR ₅ R ₆ , -SO ₂ NR ₇ R ₈ [R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each selected from hydrogen or alkyl group] Or R ₁ is furan, thiophene, pyridine, pyrimidine, pyridazine, 1,3-oxathiolane, tetrazole, oxadiazole, oxazole, triazole, imidazoline, imidazole, thiazole , Mono-heterocyclic radicals selected from the group consisting of thiadiazole, pyrrole, piperidine, morpholine, triazine and pyrazole; W and W 'may be the same or different and are hydrogen or straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, halogen, nitro, hydroxy, perfluoroalkyl, difluoromethyl, alkoxy, phenoxy Phenyl, alkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, phenylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido , A substituent selected from the group consisting of carboxamido and alkanoylamino; t is an integer from 0 to 8; X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl; R ₂ is an unsubstituted or substituted phenylalkyl radical, an unsubstituted or substituted phenylalkenyl radical, an unsubstituted or substituted phenylalkynyl radical, an unsubstituted or substituted biphenylalkyl radical, an unsubstituted or substituted polycyclic radical, Unsubstituted or substituted C _5-8 alicyclic radical or formula (R _2a- ) _n (L-) _p R _2b -wherein R _2a and R _2b can be the same or different and an unsubstituted or substituted heterocyclic radical Or an unsubstituted or substituted phenyl radical, R _2a represents an unsubstituted or substituted polycyclic radical, L is a valence bond,-(CH ₂ ) _q- , -HC = CH-, -C≡C-,- ₂ selected from the group consisting of C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ — or NR _2c , where R _2c is hydrogen or alkyl Is a linking moiety, n and p are each 0 or 1 and q is an integer of 1 to 3; The heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, isoxazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, isothiazole, thiadia Sol, imidazole, pyrrole, tetrazole and triazine; The polycyclic radicals are benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, indole, 2-isoindole, benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3 With benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene Selected from the group consisting of; Heterocyclic radical substituents, polycyclic radical substituents and alicyclic radical substituents are linear or branched, saturated or unsaturated C_1-6 Alicyclic group, halogen, perhaloalkyl, monoalkyl, dihaloalkyl, alkoxy, acyl, acyloxy, acyloxyalkyl, phenylalkoxy, hydroxy, hydroxyalkyl, thio, alkylthio, nitro, carboxy, carvaloxy At least one selected from the group consisting of; Phenyl radical substituents, phenylalkyl radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents and biphenylalkyl radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitros, carboxy, hydrides. Hydroxy, hydroxyalkyl, perhaloalkyl, monohaloalkyl, dihaloalkyl, alkoxy, phenylalkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkyl At least one member selected from the group consisting of sulfonyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, carboxamido, alkanoylamino; Y represents O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; R ₁ and R _b may be joined to form an imidazole or benzimidazole moiety. The compound of claim 19, wherein the compound is 4- (5- (5- [2-chloro-5-trifluoromethylphenyl] furan-2-yl-methylene) 4-oxo-2-thiothiothiazolidine-3 -Yl) benzoic acid; 4- (5- (5- [3,4-dichlorophenyl] furan-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- (5- [benzothiophen-2-yl] furan-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- (5- [benzofuran-2-yl] furan-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- {5- [3-bromo-6-methoxyphenyl] furan-2-yl-methylene} -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- (4- [5-chlorothiophen-2-yl] thiazol-2-yl-methylene) -4-oxo-2-thioothiazolidin-3-yl) benzoic acid; Selected from the group consisting of 4- (5- (5- [3,5-ditrifluoromethylphenyl] furan-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid A method of treating or preventing infection by one or more viruses of the Flaviviridae, characterized in that the disease is associated with the infection. A method of treating genus Flaviviridae in a patient in need thereof, comprising administering to a patient a therapeutically effective amount of a compound represented by formula (I-1) or a precursor thereof and isomers and pharmaceutically acceptable salts of the compound: Infections caused by one or more viruses and methods of treating diseases associated with the infection. Formula I-1 Where R ₁ is hydrogen or a radical selected from the group consisting of —R ₃ COOH wherein R ₃ is a branched or straight chain C _1-10 aliphatic moiety or an unsubstituted or substituted phenyl (C ₆ H ₅ ) group; X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or C _1-5 alkyl; R ₂ is an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted bicyclic ring moiety, an unsubstituted or substituted phenyl group, an unsubstituted or substituted biphenyl (C ₆ H ₅ -C ₆ H _4- ) group or non- A radical selected from the group consisting of a ring or a substituted cinnamenyl (C ₆ H ₅ CH = CH-) group, the heterocyclic group being furan, thiophene, oxadiazole, pyridine, pyrimidine, pyrazole, thiazole, pyri Selected from the group consisting of chopped, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, pyrrole and triazine, wherein the bicyclic ring moiety is benzofuran, isobenzofuran, benzothiophene, isobenzoti Offen, benzoxazole, benzopyrrole, indolenin, 2-isobenzazole, benzpyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, 1,2,3-benzotria Selected from the group consisting of sol, benzothiazole, benzimidazole, 1,2,3-benzotriazine and 1,2,4-benzotriazine, which are heterocyclic and bicyclic The li moiety is one or more selected from the group consisting of C _1-5 alkyl, halogen, alkoxy, hydroxy, nitro or unsubstituted or substituted phenyl groups; Phenyl group substituents, biphenyl group substituents and cinnamenyl group substituents are halogen, nitro, carboxy, hydroxy, C _1-5 alkyl, trifluoromethyl, alkoxy, acyloxy, cyano, carvalkoxy, alkylthio, alkylsulfinyl At least one member selected from the group consisting of alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido or carboxamido; Y represents O or S; Z is O, S or N (R _b ), where R _b is hydrogen or C _1-5 alkyl; Or R ₁ and R _b may be joined to form a benzimidazole moiety. A pharmaceutical composition for the treatment or prophylaxis of a viral infection comprising an effective amount of a compound of formula (II), an isomer thereof and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier medium, which supervise the degree of viral infection. Formula II Where R is hydrogen or alkyl; m is an integer of 0 to 4; R ₃ represents an unsubstituted or substituted, branched or straight, saturated or unsaturated C _1-10 hydrocarbon moiety in the main chain, and the hydrocarbon moiety substituent is a branched or straight, saturated or unsaturated C _1-6 aliphatic group, unsubstituted or At least one member selected from the group consisting of substituted heterocyclic radicals or unsubstituted or substituted phenyl (C ₆ H ₅ ) radicals, wherein the heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine , Pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine; X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl; R ₂ is an unsubstituted or substituted phenylalkyl radical, an unsubstituted or substituted phenylalkenyl radical, an unsubstituted or substituted phenylalkynyl radical, an unsubstituted or substituted biphenylalkyl radical, an unsubstituted or substituted polycyclic radical, Unsubstituted or substituted C _5-8 alicyclic radical or formula (R _2a- ) _n (L-) _p R _2b -wherein R _2a and R _2b can be the same or different and an unsubstituted or substituted heterocyclic radical Or an unsubstituted or substituted phenyl radical, R _2a represents an unsubstituted or substituted polycyclic radical, L is a valence bond,-(CH ₂ ) _q- , -HC = CH-, -C≡C-,- ₂ selected from the group consisting of C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ — or NR _2c , where R _2c is hydrogen or alkyl Is a linking moiety, n and p are each 0 or 1 and q is an integer of 1 to 3]; a radical selected from the group consisting of radicals; The heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, isoxazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, isothiazole, thiadia Sol, imidazole, pyrrole, tetrazole and triazine; The polycyclic radicals are benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, indole, 2-isoindole, benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3 With benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene Selected from the group consisting of; Heterocyclic radical substituents, polycyclic radical substituents and alicyclic radical substituents are linear or branched, saturated or unsaturated C_1-6 Alicyclic group, halogen, perhaloalkyl, monoalkyl, dihaloalkyl, alkoxy, acyl, acyloxy, acyloxyalkyl, phenylalkoxy, hydroxy, hydroxyalkyl, thio, alkylthio, nitro, carboxy, carvaloxy At least one selected from the group consisting of; Phenyl radical substituents, phenylalkyl radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents and biphenylalkyl radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitros, carboxys, hydrides Hydroxy, hydroxyalkyl, perhaloalkyl, monohaloalkyl, dihaloalkyl, alkoxy, phenylalkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkyl At least one member selected from the group consisting of sulfonyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, carboxamido, alkanoylamino; Y represents O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; R ₃ and R _b may combine to form an imidazole or benzimidazole moiety. The pharmaceutical composition for treating or preventing a viral infection according to claim 22, wherein the R ₂ radical is a formula (R _2a- ) _n (L-) _p R _2b -wherein p is 0 and m is 0. . 23. The unsubstituted or substituted mono selected according to claim 22, wherein R ₃ is C _1-5 straight alkylene, Y is oxygen, X and Z are sulfur, and R ₂ is selected from the group consisting of furan, thiophene and oxazole -A heterocyclic radical or an unsubstituted or substituted bi-heterocyclic radical selected from the group consisting of bithienyl and 1H-pyrazolylthienyl [heterocyclic radical substituents are halogen, trifluoromethyl or unsubstituted or substituted phenyl At least one member selected from the group consisting of radicals, and the phenyl radical substituent is halogen, nitro, carboxy, hydroxy, methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, Carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidinyl, 1-piperidinyl Or consisting of 4-morpholinyl In one kinds selected yisangim] The pharmaceutical composition for the treatment or prevention of viral infection is characterized by comprising a compound of formula II. The compound of claim 22, wherein R ₃ is C _1-5 straight alkylene, Y is oxygen, X and Z are sulfur, R ₂ is an unsubstituted or substituted phenyl radical [where the phenyl radical substituent is halogen, nitro, Carboxy, hydroxy, methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkyl At least one selected from the group consisting of amino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl; A pharmaceutical composition for the treatment or prevention of viral infection, characterized in that it comprises a compound. The unsubstituted compound of claim 22, wherein R ₃ is C _1-5 linear alkylene, Y is oxygen, X and Z are sulfur, and R ₂ is unsubstituted from the group consisting of 9-phenanthryl and 2-fluorenyl Or a substituted polycyclic radical [The polycyclic radical substituent is at least one selected from the group consisting of methyl, ethyl, halogen, alkoxy, hydroxy, thio, nitro or unsubstituted or substituted phenyl radicals, the phenyl radical substituent is halogen, nitro , Carboxy, hydroxy, methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, At least one selected from the group consisting of alkylamino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl] Viruses characterized by comprising a compound of A pharmaceutical composition for the treatment or prevention of infection. The compound of claim 22, further comprising 3- (5-[(5- {benzofuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl-propionic acid; 3- (5-[(5- {benzothiophen-2-yl} -furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl-propionic acid; 3- (5 -[(5- (2-Chloro-5-trifluoromethylphenyl) -2-furanyl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl-propionic acid; 3- (5- [ A compound of formula II selected from the group consisting of (5- (5-chlorothiophen-2-yl) furan-2-yl) -methylene-4-oxo-2-thiothiothiazolidin-3-yl) propionic acid Pharmaceutical composition for the treatment or prevention of viral infection, characterized in that it comprises. The virus of claim 22, further comprising at least one therapeutic agent selected from the group consisting of interferon, ribavirin, protease inhibitors, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antiviral agents, and inhibitors. Pharmaceutical compositions for the treatment or prevention of infections. A pharmaceutical composition for the treatment or prophylaxis of a viral infection comprising an effective amount of a compound of formula (II-1), an isomer thereof, and a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier medium to direct the viral infectivity. Formula II-1 Where R ₃ represents an unsubstituted or substituted, branched or straight chain, saturated or unsaturated C _1-10 aliphatic moiety in the main chain, wherein the aliphatic partial substituent is one or more branched or straight chain, saturated or unsaturated C _1-6 aliphatic group, unsubstituted It is selected from the group consisting of a ring or substituted mono- heterocyclic group or an unsubstituted or substituted phenyl (C ₆ H ₅ ) group, the heterocyclic group is furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole , Triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine, X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl; R ₂ is an unsubstituted or substituted mono-heterocyclic group or a bi-heterocyclic group, an unsubstituted or substituted polycyclic ring moiety, an unsubstituted or substituted C _5-8 alicyclic group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted Biphenyl (C ₆ H ₅ -C ₆ H _4- ) groups, unsubstituted or substituted phenyl ether groups (C ₆ H ₅ -OC ₆ H _4- ) or unsubstituted or substituted cinnamil (C ₆ H ₅ A radical selected from the group consisting of CH = CH-) groups, said mono-heterocyclic group being furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3- Two heterocycles selected from the group consisting of oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine, wherein the bi-heterocyclic group is selected from a mono-heterocyclic group member and can be the same or different Ventilation, wherein the polycyclic ring portion is benzofuran, isobenzofuran, benzothiophene, isobenzo Offen, benzoxazole, benzopyrrole, indolenin, 2-isobenzazole, benzpyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, 1,2,3-benzotria Sol, benzothiazole, benzimidazole, 1,2,3-benzotriazine and 1,2,4-benzotriazine, naphthalene, anthracene and fluorene; Mono- or bi-cyclic substituents, alicyclic substituents and polycyclic ring substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, trifluoromethyl, alkoxy, hydroxy, thio, nitro , An unsubstituted or substituted phenyl group, an unsubstituted or substituted phenylalkenyl group or an unsubstituted or substituted phenylalkynyl group; Phenyl group substituents, biphenyl group substituents, phenyl ether group substituents, phenylalkenyl group substituents, phenylalkynyl group substituents and cinnamenyl group substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitro, carboxy, hydroxy , Trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonami At least one selected from the group consisting of carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl; Y represents O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; Or R ₁ and R _b may be joined to form an amidazole or benzimidazole moiety. A pharmaceutical composition for the treatment or prophylaxis of a viral infection comprising an antiviral agent comprising an effective amount of a compound of formula III, an isomer thereof and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier medium to direct viral infection. Formula III Where R is hydrogen or alkyl; m is an integer of 0 to 4; R ₁ is hydrogen or -OH, -COOR ₄ , -CONR ₅ R ₆ , -SO ₂ NR ₇ R ₈ [R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each selected from hydrogen or an alkyl group] Or a substituent selected from the group consisting of R ₁ is furan, thiophene, pyridine, pyrimidine, pyridazine, 1,3-oxathiolane, tetrazole, oxadiazole, oxazole, isoxazole, triazole, A mono-heterocyclic radical selected from the group consisting of imidazoline, imidazole, thiazole, thiadiazole, pyrrole, piperidine, morpholine, triazine and pyrazole; W and W 'may be the same or different and are hydrogen or straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, halogen, nitro, hydroxy, perfluoroalkyl, difluoromethyl, alkoxy, phenoxy Phenyl, alkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxami And substituents selected from the group consisting of alkanoylamino; t is an integer from 0 to 8; X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl; R ₂ is unsubstituted or substituted phenylalkyl radical, unsubstituted or substituted phenylalkenyl radical, unsubstituted or substituted phenylalkynyl radical, unsubstituted or substituted biphenylalkyl radical, unsubstituted or substituted polycyclic radical, Unsubstituted or substituted C _5-8 alicyclic radical or formula (R _2a- ) _n (L-) _p R _2b -wherein R _2a and R _2b can be the same or different and an unsubstituted or substituted heterocyclic radical Or an unsubstituted or substituted phenyl radical, R _2a represents an unsubstituted or substituted polycyclic radical, L is a valence bond,-(CH ₂ ) _q- , -HC = CH-, -C≡C-,- ₂ selected from the group consisting of C (═O) —, —O—, —S—, —S (═O) —, —S (═O) ₂ — or NR _2c , where R _2c is hydrogen or alkyl Is a linking moiety, n and p are each 0 or 1 and q is an integer of 1 to 3]; a radical selected from the group consisting of radicals; The heterocyclic radicals are furan, thiophene, oxazole, oxadiazole, isoxazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, isothiazole, thiadia Sol, imidazole, pyrrole, tetrazole and triazine; The polycyclic radicals are benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, indole, 2-isoindole, benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3 With benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene Selected from the group consisting of; Heterocyclic radical substituents, polycyclic radical substituents and alicyclic radical substituents are linear or branched, saturated or unsaturated C_1-6 Alicyclic group, halogen, perhaloalkyl, monoalkyl, dihaloalkyl, alkoxy, acyl, acyloxy, acyloxyalkyl, phenylalkoxy, hydroxy, hydroxyalkyl, thio, alkylthio, nitro, carboxy, carvaloxy At least one selected from the group consisting of; Phenyl radical substituents, phenylalkyl radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents and biphenylalkyl radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, nitros, carboxy, hydrides. Hydroxy, hydroxyalkyl, perhaloalkyl, monohaloalkyl, dihaloalkyl, alkoxy, phenylalkoxy, acyl, acyloxy, acyloxyalkyl, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkyl At least one member selected from the group consisting of sulfonyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonamido, carboxamido, alkanoylamino; Y represents O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; R ₁ and R _b may be joined to form an imidazole or benzimidazole moiety. The pharmaceutical composition of claim 30, wherein the R ₂ radical is of formula (R _2a- ) _n (L-) _p R _2b -wherein p is 0 and m is 0. . 31. The compound of claim 30, wherein R ₁ is a carboxyl group, W and W 'represent hydrogen, halogen, hydroxy, alkyl or trifluoromethyl substituents, Y is oxygen, X and Z are sulfur, and R ₂ is non- Ring or substituted furan group or unsubstituted or substituted thiophene group [furan substituent (s) and thiophene substituent (s) are alkyl, monohalophenyl, dihalophenyl, monohalocarboxyphenyl, carboxyphenyl, At least one selected from the group consisting of trifluoromethylphenyl, monohalotrifluoromethylphenyl, phenylethynyl, monoalkylphenyl, dialkylphenyl, furanyl and thienyl], m = 0 and t = 0 A pharmaceutical composition for the treatment or prevention of viral infection, characterized in that it comprises a compound. 31. The compound of claim 30, wherein R ₁ is a carboxyl group and W and W 'are hydrogen, halogen, hydroxy or trifluoromethyl substituents, Y is oxygen, X and Z are sulfur, and R ₂ is unsubstituted or substituted Phenyl group [phenyl substituent (s) is one or more selected from the group consisting of halogen, alkoxy, carboxy, unsubstituted or substituted 2-phenylethenyl group, unsubstituted or substituted furan group, or unsubstituted or substituted thiophene group 2-phenylethenyl substituent (s), furan substituent (s) and thiophene substituent (s) may be linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogen, nitro, carboxy, hydroxy, tri Fluoromethyl, difluoromethyl, alkoxy, phenoxy, phenylalkoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfone Consists of amides, carboxamides or alkanoylamino At least one member selected from the group consisting of: m = 0 and t = 0, wherein the pharmaceutical composition for the treatment or prevention of a viral infection, characterized in that it comprises a compound of formula III. 32. The compound of claim 30, wherein 4- (5- (5- [2-chloro-5-trifluoromethylphenyl] furan-2-yl-methylene) 4-oxo-2-thiothiothiazolidin-3-yl) Benzoic acid; 4- (5- (5- [3,4-dichlorophenyl] furan-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- (5- [benzothiophen-2-yl] furan-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- (5- [benzofuran-2-yl] furan-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- {5- [3-bromo-6-methoxyphenyl] furan-2-yl-methylene} -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- (5- [5-chlorothiophen-2-yl] thiazol-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5- (5- [3,5-Ditrifluoromethylphenyl] furan-2-yl-methylene) -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid selected from the group consisting of A pharmaceutical composition for the treatment or prevention of viral infections, characterized by comprising a compound of formula III. 31. The virus of claim 30, further comprising at least one therapeutic agent selected from the group consisting of interferon, ribavirin, protease inhibitors, immunoglobulins, immunomodulators, hepatoprotectants, anti-inflammatory agents, antibiotics, antiviral agents, and inhibitors. Pharmaceutical compositions for the treatment or prevention of infections. A pharmaceutical composition for the treatment or prophylaxis of a viral infection comprising an antiviral agent comprising an effective amount of a compound of formula III-1, an isomer thereof, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier medium to direct the viral infection. Formula III-1 Where R ₁ is hydrogen or -OH, -COOR ₃ , -CONR ₄ R ₅ , -SO ₂ NR ₆ R ₇ [R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are each selected from the group of hydrogen or alkyl Or a substituent selected from the group consisting of] or R ₁ represents tetrazole, oxadiazole, oxazole, triazole, imidazoline, imidazole, thiazole, thiadiazole, pyrrole, piperidine, morpholine And a heterocyclic ring selected from the group consisting of pyrazoles; W and W 'may be the same or different and are hydrogen or straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, halogen, nitro, hydroxy, perfluoroalkyl, difluoromethyl, alkoxy, phenoxy Substituents selected from the group consisting of c, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamide, carboxamide and alkanoylamino Represents; t is an integer from 0 to 8; X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl; R ₂ is an unsubstituted or substituted mono-heterocyclic group or a bi-heterocyclic group, an unsubstituted or substituted polycyclic ring moiety, an unsubstituted or substituted C _5-8 alicyclic group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted Biphenyl (C ₆ H ₅ -C ₆ H _4- ) groups, unsubstituted or substituted phenyl ether groups (C ₆ H ₅ -OC ₆ H _4- ), unsubstituted or substituted cinnamil (C ₆ H ₅ CH = CH-) group, or a radical selected from the group consisting of an unsubstituted or substituted cinnamilphenyl group, wherein the mono-heterocyclic group is furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole , Triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine, the bi-heterocyclic group is selected from a mono-heterocyclic group and , Two heterocyclic groups which may be the same or different, wherein the polycyclic ring moiety is benzofuran, isobenzofu Column, benzothiophene, isobenzothiophene, benzoxazole, benzopyrrole, indolenin, 2-isobenzazole, benzpyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine , 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene Become; Mono-heterocyclic substituents, bi-heterocyclic substituents, cycloaliphatic substituents and polycyclic ring substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, trifluoromethyl, alkoxy, hydroxy, thio, At least one selected from the group consisting of nitro, carboxy, carbalkoxy, unsubstituted or substituted phenyl groups, unsubstituted or substituted phenylalkyl groups, unsubstituted or substituted phenylalkenyl groups, or unsubstituted or substituted phenylalkynyl groups ; Phenyl group substituents, biphenyl group substituents, phenyl ether group substituents, phenylalkyl group substituents, phenylalkenyl group substituents, phenylalkynyl group substituents, cinnamil group substituents and cinnamilphenyl group substituents may be linear or branched, saturated or unsaturated C _1-6 aliphatic groups. Halogen, nitro, carboxy, hydroxy, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, At least one selected from alkylamino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl; Y is O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; Or R ₁ and R _b may be joined to form an imidazole or benzimidazole moiety. A compound of formula II-1, isomers and pharmaceutically acceptable salts thereof. Formula II-1 Where R ₃ represents an unsubstituted or substituted, branched or straight, saturated or unsaturated C _1-10 hydrocarbon moiety in the main chain, and the hydrocarbon moiety substituents are branched or straight, saturated or unsaturated C _1-6 aliphatic groups, unsubstituted or At least one selected from the group consisting of a substituted mono-heterocyclic group or an unsubstituted or substituted phenyl (C ₆ H ₅ ) group, the mono-heterocyclic group being furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, Pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine; X represents a moiety selected from -S-, -O- or -N (R _a )-, wherein R _a is hydrogen or alkyl; R ₂ is an unsubstituted or substituted mono-heterocyclic or bi-heterocyclic radical, an unsubstituted or substituted polycyclic radical, an unsubstituted or substituted polycyclic-heterocyclic radical, an unsubstituted or substituted C _5-8 alicyclic radical , Unsubstituted or substituted phenyl radical, unsubstituted or substituted biphenyl (C ₆ H ₅ -C ₆ H _4- ) radical, unsubstituted or substituted phenyl ether (C ₆ H ₅ -OC ₆ H _4- ) radical Or a radical selected from the group consisting of unsubstituted or substituted 2-phenylethenyl (C ₆ H ₅ CH═CH—) radicals, wherein the mono-heterocyclic group is furan, thiophene, oxazole, oxadiazole, pyridine , Pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, tetrazole, pyrrole and triazine, and the bi-heterocyclic group is mono Contain two heterocyclic groups, selected from heterocyclic radical members, which may be the same or different Wherein the polycyclic ring portion is benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, indole, 2-isoindole, benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine and 1,2,4-benzotriazine, naphthalene, anthracene and Selected from the group consisting of fluorene, the polycyclic-heterocyclic radical comprises a heterocyclic moiety selected from the members of the mono-heterocyclic radical group and a polycyclic moiety selected from the members of the polycyclic radical group; Mono-heterocyclic radical substituents, bi-heterocyclic radical substituents, alicyclic radical substituents, polycyclic radical substituents and polycyclic-heterocyclic radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, trifluoro At least one selected from the group consisting of methyl, alkoxy, hydroxy, thio, nitro, carbalkoxy, unsubstituted or substituted phenyl radicals, unsubstituted or substituted phenylalkenyl radicals or unsubstituted or substituted phenylalkynyl radicals Is; Phenyl radical substituents, biphenyl radical substituents, phenyl ether radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents and 2-phenylethenyl radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens , Nitro, carboxy, hydroxy, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino , Dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl; Y represents O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; Or R ₁ and R _b may be joined to form an amidazole or benzimidazole moiety. 38. The unsubstituted or substituted mono selected according to claim 37, wherein R ₁ is C _1-5 straight chain alkylene, Y is oxygen, X and Z are sulfur, and R ₂ is selected from the group consisting of furan, thiophene and oxazole -A heterocyclic group or an unsubstituted or substituted bi-heterocyclic group selected from the group consisting of bithienyl and 1H-pyrazolylthienyl [the heterocyclic substituent is one or more halogen, trifluoromethyl or unsubstituted or substituted phenyl groups The phenyl group substituent is selected from the group consisting of halogen, nitro, carboxy, hydroxy, methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thio Alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidyl, 1-piperidinyl or 4-morpholinyl At least one member selected from the group consisting of This characteristic of the compounds, isomers thereof and pharmaceutically acceptable salts of the formula II-1. 38. The compound of claim 37, wherein R ₁ is C _1-5 straight alkylene, Y is oxygen, X and Z are sulfur, and R ₂ is an unsubstituted or substituted phenyl group, wherein the phenyl group substituent is halogen, nitro, carboxy, Hydroxy, methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thioalkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, di At least one member selected from the group consisting of alkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidinyl, 1-piperidyl or 4-morpholinyl] Of compounds, isomers thereof and pharmaceutically acceptable salts thereof. 38. The compound of claim 37, wherein R ₁ is C _1-5 straight chain alkylene, Y is oxygen, X and Z are sulfur, and R ₂ is unsubstituted from the group consisting of 9-phenanthryl and 2-fluorenyl Or a substituted polycyclic ring moiety, wherein the polycyclic ring moiety is one or more selected from the group consisting of methyl, ethyl, halogen, alkoxy, hydroxy, thio, nitro or unsubstituted or substituted phenyl groups, and the phenyl group substituents are halogen, nitro, Carboxy, hydroxy, methyl, ethyl, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, acyloxy, cyano, carvalkoxy, thioalkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino , Dialkylamino, sulfonamido, carboxamido, alkanoylamino, 1-pyrrolidyl, piperidinyl or 4-morpholinyl; and at least one selected from the group consisting of Isomers and pharmaceutically acceptable salts thereof. The method of claim 37, (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiono-thiazolidin-3-yl) acetic acid; (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid; (5-[(5- {3-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid; (5-[(5- {3,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid; (5-[(5- {4-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid; (5-[(5- {4-chlorophenyl-3-ethoxycarbonyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid; (5-[(5- {3,4-dichlorophenyl} thiophen-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid; One selected from the group consisting of (5-[(5- {3-t-butylphenoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) acetic acid Characterized by compounds of formula II-1, isomers thereof and pharmaceutically acceptable salts. The method of claim 37, 2- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 2- (5-[(5- {5-chlorothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {benzofuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {benzothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {3,5-ditrifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {furan-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {thiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thioxothiazolidin-3-yl) propionic acid; 3- (5-[(5- {5-chlorothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {4-bromophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {isoquinolin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {2-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {3,4-methylenedioxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {3,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {3,5-dimethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {5-methylthiophen-2-yl} furan-2-yl) methylene] -4-oxo-thioothiazolidin-3-yl) propionic acid; 3- (5-[(5- {5-methyl-2-pyridyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(6-benzyloxybenzofuran-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {phenanthren-9-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {thiophen-2-yl} thiophen-2-yl) methylene] -4-oxo-2-thioothiazolidin-3-yl) propionic acid; 3- (5-[(5- {fluoren-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {phenylethynyl} thiophen-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {3-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(4- {phenylethynyl} thiophen-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; 3- (5-[(5- {5-n-propylthiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid; And It is characterized in that it is selected from the group consisting of 3- (5-[(5- {4-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid Compounds of formula II-1, isomers thereof and pharmaceutically acceptable salts. 38. The compound of claim 37 which is 3- (5-[(5- {benzofuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid A compound of formula (II-1), isomers and pharmaceutically acceptable salts thereof characterized by the above-mentioned. 38. The compound of claim 37, wherein the 3- (5-[(5- {benzothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) propionic acid A compound of formula (II-1), isomers and pharmaceutically acceptable salts thereof characterized by: 38. The compound of claim 37, wherein 3- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine-3- 1) A compound of formula (II-1), isomers and pharmaceutically acceptable salts thereof, characterized in that it is propionic acid. 38. The compound of claim 37, wherein 3- (5-[(5- {5-chlorothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl A compound of formula (II-1), isomers and pharmaceutically acceptable salts thereof, characterized in that it is propionic acid. A compound of formula III-1 and isomers and pharmaceutically acceptable salts thereof. Formula III-1 Where R ₁ is hydrogen or -OH, -COOH, -CONR ₄ R ₅ , -SO ₂ NR ₆ R ₇ [R ₄ , R ₅ , R ₆ and R ₇ are each selected from the group of hydrogen or alkyl] Or R ₁ is furan, thiophene, pyridine, pyrimidine, pyridazine, 1,3-oxathiolane, tetrazole, oxadiazole, oxazole, triazole, imidazoline, imidazole , A heterocyclic ring selected from the group consisting of thiazole, thiadiazole, pyrrole, piperidine, morpholine, triazine and pyrazole; W and W 'may be the same or different and are hydrogen or straight or branched chain, saturated or unsaturated C _1-6 aliphatic group, halogen, nitro, hydroxy, perfluoroalkyl, difluoromethyl, alkoxy, phenoxy C, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxamido and alkanoylamino Represents a selected substituent; t is an integer from 0 to 8; X represents a moiety selected from the group consisting of -S-, -O- or N (R _a )-, wherein R _a is hydrogen or alkyl; R ₂ is unsubstituted or substituted mono-heterocyclic radical or bi-heterocyclic radical, unsubstituted or substituted polycyclic radical, unsubstituted or substituted polycyclic-heterocyclic radical, unsubstituted or substituted C _5-8 alicyclic Radical, unsubstituted or substituted phenyl radical, unsubstituted or substituted biphenyl (C ₆ H ₅ -C ₆ H _4- ) radical, unsubstituted or substituted phenyl ether (C ₆ H ₅ -OC ₆ H _4- ) As a radical, unsubstituted or substituted 2-phenylethenyl (C ₆ H ₅ CH = CH-) radical, or as an unsubstituted or substituted stilbenyl (C ₆ H ₅ -CH = CH-C ₆ H _4- ) radical A radical selected from the group consisting of, wherein said mono-heterocyclic radical is furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole , Thiadiazole, imidazole, tetrazole, pyrrole and triazine, the bi-heterocyclic group of the mono-heterocyclic radical group Two heterocyclic groups selected from members, which may be the same or different, wherein the polycyclic radicals are benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, benzopyrrole, 2-isoindole, Benzopyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzo Selected from the group consisting of triazine, 1,2,4-benzotriazine, naphthalene, anthracene and fluorene, the polycyclic-heterocyclic radical is a member of the polycyclic moiety and the mono-heterocyclic radical group selected from the members of the polycyclic radical group A heterocyclic moiety selected from; Mono-heterocyclic radical substituents, bi-heterocyclic radical substituents, alicyclic radical substituents, polycyclic radical substituents and polycyclic-heterocyclic radical substituents are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogens, trifluoro Methyl, alkoxy, hydroxy, thio, nitro, acyl, carboxy, carbalkoxy, unsubstituted or substituted phenyl radicals, unsubstituted or substituted phenylalkyl radicals, unsubstituted or substituted phenylalkenyl radicals or unsubstituted or substituted At least one selected from the group consisting of phenylalkynyl radicals; Phenyl radical substituents, biphenyl radical substituents, phenyl ether radical substituents, phenylalkyl radical substituents, phenylalkenyl radical substituents, phenylalkynyl radical substituents, 2-phenylethenyl radical substituents and stilbenyl radical substituents are linear or branched, saturated Or unsaturated C _1-6 aliphatic groups, halogen, nitro, carboxy, hydroxy, trifluoromethyl, difluoromethyl, alkoxy, phenoxy, phenylalkoxy, acyl, acyloxy, cyano, carvalkoxy, thio , Alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, sulfonamido, carboxamido, alkanoylamino, furan, thiophene, pyridine, pyrimidine, pyridazine, 1,3 One selected from oxadiolane, tetrazole, oxadiazole, oxazole, triazole, imidazoline, imidazole, thiazole, thiadiazole, pyrrole, piperidine, morpholine and pyrazole Above; Y is O or S; Z is O, S or N (R _b ), where R _b is hydrogen or alkyl; Or R ₁ and R _b may be joined to form an imidazole or benzimidazole moiety. 48. The compound of claim 47, wherein R ₁ is a carboxyl group, W and W 'represent hydrogen, halogen, hydroxy, alkoxy or trifluoromethyl substituents, Y is oxygen, X and Z are sulfur, and R ₂ is non- Ring or substituted furan group or unsubstituted or substituted thiophene group [furan substituent (s) and thiophene substituent (s) are alkyl, monohalophenyl, dihalophenyl, monohalocarboxyphenyl, carboxyphenyl, At least one member selected from the group consisting of trifluoromethylphenyl, monohalotrifluoromethylphenyl, phenylethynyl, monoalkylphenyl, dialkylphenyl, furanyl, and thienyl], and formula III-1 And compounds thereof, and isomers and pharmaceutically acceptable salts thereof. 48. The compound of claim 47, wherein R ₁ is a carboxyl group, W and W 'are hydrogen, halogen, hydroxy or trifluoromethyl substituents, Y is oxygen, X and Z are sulfur, and R ₂ is unsubstituted or substituted Phenyl group [phenyl substituent (s) is one selected from the group consisting of halogen, alkoxy, carboxy, unsubstituted or substituted 2-phenylethenyl group, unsubstituted or substituted furan group, or unsubstituted or substituted thiophene group Or 2-phenylethenyl substituent (s), furan substituent (s) and thiophene substituent (s) are linear or branched, saturated or unsaturated C _1-6 aliphatic groups, halogen, nitro, carboxy, hydroxy, Trifluoromethyl, difluoromethyl, alkoxy, phenoxy, phenylalkoxy, acyloxy, cyano, carvalkoxy, thio, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, Sulphonamide, carboxamide or alkanoylamino A represents one kind yisangim] selected from the group, t = 0 which is characterized by the compound, isomers thereof and pharmaceutically acceptable salts of the formula III-1. The method of claim 47, 4- (5-[(5- {benzofuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {benzothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3,5-Ditrifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3,4-dimethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-chlorothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-furanyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-methylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-methylthiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3,4-difluorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4-methoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-acetothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3-chloro-5-trifluoromethylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl ) Benzoic acid; 4- (5-[(5- {3,4-dimethoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3,4-methylenedioxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-trifluoromethylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {6-methoxypyridazin-3-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4,6-dimethylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3-bromo-6-methoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5-phenylethynylfuran-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-yl) benzoic acid 4- (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4-chlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4-bromophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3,5-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) -6-chloro Benzoic acid; 4- (5-[(5- {3-carboxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2,3,5,6-tetrafluoropyridin-4-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine-3- Benzoic acid; 4- (5-[(5- {3-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-thienyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4-n-butylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) methylenebenzoic acid; 4- (5-[(5- {3,5-difluorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3,5-dimethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4-acetophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4-n-propylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2,3-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {indol-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {3-methoxy-2- (N, N-diethylaminocarbonylphenyl) furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine- 3-yl) benzoic acid; 4- (5-[(5- {phenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-methylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-chloro-3-methylbenzothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) Benzoic acid; 4- (5-[(5- {5-n-propylthiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4,5-dimethylfuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-thiazol-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {formyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {4-methylpyridin-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-acetophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {2-nitrophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; 4- (5-[(5- {5-chlorothiophen-2-yl} thiazol-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid; And Group consisting of 4- (5-[(5- {4,5-dichloroimidazol-2-yl} furan-2-yl) methylene-4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid A compound of formula III-1 characterized in that is selected from, isomers and pharmaceutically acceptable salts thereof. The method of claim 47, 3- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furanyl-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) -4- Chlorobenzoic acid; 3- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furanyl-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) -benzoic acid; 2- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furanyl-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) -benzoic acid; 3- (5-[(5- {2-methyl-5-trifluoromethylpyrazol-3-yl} thiophen-2-yl) methylene] -4-oxo-2-thiothiothiazolidine-3 -Yl) benzoic acid; 3- (5-[(5- {2-trifluoromethylphenyl} furanyl-2-yl) methylene] -4-oxo-2-.thiothiothiazolidin-3-yl) benzoic acid selected from the group consisting of Characterized in that the compound of formula III-1 and its isomers and pharmaceutically acceptable salts. 48. The compound of claim 47 wherein 4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furan-2-yl) methylene] 4-oxo-2-thiothiothiazolidin-3-yl A compound of formula III-1 characterized in that it is benzoic acid, and isomers and pharmaceutically acceptable salts thereof. 48. The compound of claim 47 which is 4- (5-[(5- {3,4-dichlorophenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid Characterized in that the compound of formula III-1 and its isomers and pharmaceutically acceptable salts. 48. The compound of claim 47, wherein the 4- (5-[(5- {benzothiophen-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid A compound of formula III-1 characterized in that isomers and pharmaceutically acceptable salts thereof. 48. The compound of claim 47, which is 4- (5-[(5- {benzofuran-2-yl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl) benzoic acid Characterized in that the compound of formula III-1 and its isomers and pharmaceutically acceptable salts. 48. The compound of claim 47 wherein 4- (5-[(5- {3-bromo-6-methoxyphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidine-3- 1) A compound of formula III-1 characterized in that it is benzoic acid, isomers and pharmaceutically acceptable salts thereof. 48. The compound of claim 47 wherein 4- (5-[(5- {5-chlorothiophen-2-yl} thiazol-2-yl) methylene] -4-oxo-2-thioothiazolidine-3- 1) A compound of formula III-1 characterized in that it is benzoic acid, isomers and pharmaceutically acceptable salts thereof. 48. The compound of claim 47 wherein 4- (5-[(5- {3,5-ditrifluoromethylphenyl} furan-2-yl) methylene] -4-oxo-2-thiothiothiazolidin-3-yl A compound of formula III-1 characterized in that it is benzoic acid, and isomers and pharmaceutically acceptable salts thereof. 48. The compound of claim 47 wherein 4- (5-[(5- {2-chloro-5-trifluoromethylphenyl} furanyl-2-yl) methylene] -4-oxo-2-thiothiothiazolidine-3 -Yl) -2,6-difluorophenol, a compound of formula III-1, and isomers and pharmaceutically acceptable salts thereof.