WO2007088148A1

WO2007088148A1 - Derivatives of thiophene carboxilic acid as antiviral agent

Info

Publication number: WO2007088148A1
Application number: PCT/EP2007/050823
Authority: WO
Inventors: Charles David Hartley; Jacqueline Elizabeth Mordaunt; Pritom Shah; Martin John Slater
Original assignee: Smithkline Beecham Corporation
Priority date: 2006-02-01
Filing date: 2007-01-29
Publication date: 2007-08-09
Also published as: GB0602046D0

Abstract

Anti-viral agents of compounds of Formuta (I) : wherein A, R1, R2 and R3 are as defined in the specification, processes for their preparation and their use in HCV treatment are provided.

Description

DERIVATIVES OF THIOPHENE CARBOXILIC ACID AS ANTIVIRAL AGENT

FIELD OF THE INVENTION

The present invention relates to novel 3-carboxy thiophene derivatives useful as anti-viral agents. Specifically, the present invention involves novel inhibitors of Hepatitis C Virus (HCV) replication.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughout the world In the US, an estimated 4.5 million Americans are chronically infected with HCV. Although only 30% of acute infections are symptomatic, greater than 85% of infected individuals develop chronic, persistent infection. Treatment costs for HCV infection have been estimated at $5 46 billion for the US in 1997. Worldwide over 200 million people are estimated to be infected chronically. HCV infection is responsible for 40-60% of all chronic liver disease and 30% of all liver transplants Chronic HCV infection accounts for 30% of all cirrhosis, end-stage liver disease, and liver cancer in the U S. The CDC estimates that the number of deaths due to

HCV will minimally increase to 38,000/year by the year 2010

Due to the high degree of variability in the viral surface antigens, existence of multiple viral genotypes, and demonstrated specificity of immunity, the development of a successful vaccine in the near future is unlikely. Alpha-interferon (alone or in combination with ribavirin) has been widely used since its approval for treatment of chronic HCV infection However, adverse side effects are commonly associated with this treatment: flu-like symptoms, leukopenia, thrombocytopenia, depression from interferon, as well as anemia induced by ribavirin (Lindsay, K.L (1997) Hepatology 26 (suppl 1 ): 71S-77S). This therapy remains less effective against infections caused by HCV genotype 1 (which constitutes -75% of all HCV infections in the developed markets) compared to infections caused by the other 5 major HCV genotypes. Unfortunately, only -50-80% of the patients respond to this treatment (measured by a reduction in serum HCV RNA levels and normalization of liver enzymes) and, of responders, 50-70% relapse within 6 months of cessation of treatment Recently, with the introduction of pegylated interferon (Peg-IFN), both initial and sustained response rates have improved substantially, and combination treatment of Peg-IFN with ribavirin constitutes the gold standard for therapy However, the side effects associated with combination therapy and the impaired response in patients with genotype 1 present opportunities for improvement in the management of this disease.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989) Science 244 359-362), HCV is now widely accepted as the most common causative agent of post-transfusion non A, non-B hepatitis (NANBH) (Kuo, G et al (1989) Science 244'362-364). Due to its genome structure and sequence homology, this virus was assigned as a new genus in the Flavivindae family. Like the other members of the Flaviviridae, such as flaviviruses (e.g yellow fever virus and Dengue virus types 1-4) and pestiviruses (e.g. bovine viral diarrhea virus, border disease virus, and classic swine fever virus) (Choo, Q-L et al (1989) Science 244:359-362; Miller, R.H. and R.H. Purcell (1990) Proc. Natl. Acad. Sci. USA 87:2057-2061 ), HCV is an enveloped virus containing a single strand RNA molecule of positive polarity. The HCV genome is approximately 9.6 kilobases (kb) with a long, highly conserved, noncapped 5' nontranslated region (NTR) of approximately 340 bases which functions as an internal ribosome entry site (IRES) (Wang CY et al 'An RNA pseudoknot is an essential structural element of the internal ribosome entry site located within the hepatitis C virus 5¹ noncoding region' RNA- A Publication of the RNA Society. 1 (5): 526-537, 1995 JuL). This element is followed by a region which encodes a single long open reading frame (ORF) encoding a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins.

Upon entry into the cytoplasm of the cell, this RNA is directly translated into a polypeptide of -3000 amino acids comprising both the structural and nonstructural viral proteins. This large polypeptide is subsequently processed into the individual structural and nonstructural proteins by a combination of host and virally-encoded proteinases (Rice, CM. (1996) in B.N. Fields, D.M.Knipe and P.M. Howley (eds) Virology 2^nd Edition, p931-960; Raven Press, N. Y.). Following the termination codon at the end of the long ORF, there is a 3' NTR which roughly consists of three regions: an ~ 40 base region which is poorly conserved among various genotypes, a variable length poly(U)/polypyrimidine tract, and a highly conserved 98 base element also called the "3' X-tail" (Kolykhalov, A. et al (1996) J. Virology 70:3363-3371 ; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun. 215:744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N. et al (1996) Virology 223:255-261 ). The 3' NTR is predicted to form a stable secondary structure which is essential for HCV growth in chimps and is believed to function in the initiation and regulation of viral RNA replication.

The NS5B protein (591 amino acids, 65 kDa) of HCV (Behrens, S.E. et al (1996) EMBO J. 15:12-22), encodes an RNA-dependent RNA polymerase (RdRp) activity and contains canonical motifs present in other RNA viral polymerases. The NS5B protein is fairly well conserved both intra-typically (-95-98% amino acid (aa) identity across 1 b isolates) and inter-typically (-85% aa identity between genotype 1a and 1 b isolates). The essentiality of the HCV NS5B RdRp activity for the generation of infectious progeny virions has been formally proven in chimpanzees (A. A. Kolykhalov et al.. (2000) Journal of Virology, 74(4): 2046-2051 ). Thus, inhibition of NS5B RdRp activity (inhibition of RNA replication) is predicted to be useful to treat HCV infection.

Based on the foregoing, there exists a significant need to identify synthetic or biological compounds for their ability to inhibit replication of the NS5B polymerase of HCV.

PCT publication number WO2005/009539 generically discloses certain compounds, including certain carboxy thiophene compounds. These compounds are said to be useful as immunosuppressive agents and for treating and preventing inflammatory conditions and immune disorders.

SUMMARY OF THE INVENTION The present invention involves novel 3-carboxy thiophene compounds represented hereinbelow, pharmaceutical compositions comprising such compounds, use of the compounds in treating viral infection, especially HCV infection, and processes for their preparation.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of Formula (I)

R³ ₂

COA wherein

A represents hydroxy;

R¹ represents -R^x-R^γ,

R^x represents phenyl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethy!) or 5- or 6-membered heteroaryl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) bonded through a ring carbon atom to the carbon atom of the thiophene;

R^γ represents (8-, 9- or 10-membered bicyclic heteroaryl), -CH₂CH₂-(5- or 6-membered heteroaryl), -CONH-(5- or 6-membered heteroaryl), -NHC0-(5- or 6-membered heteroaryl), - O-CH₂-(5- or 6-membered heteroaryl), or -CH₂-O-(5- or 6-membered heteroaryl), bonded such that when R^x is phenyl or a 6-membered heteroaryl, R^γ is in the para-position,

R² represents C_{5 7}cycloa]kyl optionally substituted by one or more substituents selected from -C₁ salkyl, =CH(CH₂)_tH, -OR^A, -SR^A, -C(O)NR^BR^C, -C(O)R^D, -CO₂H, -CO₂R⁰, -NR^BR^C, - NR^EC(0)R^D, -NR^EC0₂R^D, -NR^EC(O)NR^FR^G, -S0₂NR^FR^G, -SO₂R⁰, fluoro, -CF₃, nitro, cyano, oxo, and heterocyclyl, or wherein two alkyl substituents may together form a C_{1 2}alkylene bridge substituent, or wherein two alkyl substituents on the same carbon atom may together form a C₃-₄spiro substituent, or phenyl substituted by 1 to 3 halogen atoms.

R³ represents heterocyclyl; or phenyl optionally substituted by one or more substituents selected from -Ci_-6alkyl, halo, -OR^E, -SR^E, -C(O)NR^BR^C, -C(O)R⁰, -CO₂H, -CO₂R^D, -NR^BR^C, -NR^AC(0)R^D, -NR^ACO₂R^D, -NR^AC(O)NR^FR^G, -S0₂NR^FR^G, -SO₂R⁰, nitro, cyano, and heterocyclyl; or R³ represents -C_halky! optionally substituted by one or more substituents selected from -OR^E, -SR^E, -C(O)NR⁸R⁰, -C(O)R⁰, -CO₂H, -CO₂R⁰, -NR^BR^C, -NR^AC(0)R^D, -NR^ACO₂R^D, -NR^AC(0)NR^FR^G, -SO₂NR^FR^G, -SO₂R^D, fluoro, nitro, cyano, oxo, phenyl, heteroaryl and heterocyclyl,

R^A represents hydrogen or -Ci_-6alkyl;

R^B and R^c independently represent hydrogen, -Ci._βalkyl, aryl, heterocyclyl or heteroaryl; or R^B and R^c together with the nitrogen atom to which they are attached form a 5- or 6- membered saturated cyclic group,

R^D is selected from the group consisting of -C_{1 ©}alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, and heteroarylalkyl;

R^E represents hydrogen, -C_1-6alkyl, arylalkyl, heteroarylalkyl, aryl, heterocyclyl or heteroaryl;

R^F and R^G are independently selected from the group consisting of hydrogen, -C_1-Θalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R^F and R^G together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated cyclic group;

or a salt, solvate or ester thereof.

There is provided as a further aspect of the present invention a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or ester thereof for use in human or veterinary medical therapy, particularly in the treatment or prophylaxis of viral infection, particularly flavivirus infection, for example HCV infection

It will be appreciated that reference herein to therapy and/or treatment includes, but is not limited to prevention, retardation, prophylaxis, therapy and cure of the disease It will further be appreciated that references herein to treatment or prophylaxis of HCV infection includes treatment or prophylaxis of HCV-associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.

In a further or alternative aspect there is provided a method for the treatment of a human or animal subject with viral infection, particularly HCV infection, which method comprises administering to said human or animal subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or ester thereof.

According to another aspect of the invention, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or ester thereof in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection. It will be appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. All of these racemic compounds, enantiomers and diastereoisomers are contemplated to be within the scope of the present invention.

In one aspect, R^x represents phenyl optionally substituted by halo, methyl, methoxy or trifluoromethyl or 5-membered heteroaryl optionally substituted by halo, methyl, methoxy or trifluoromethyl In a further aspect, R^x represents phenyl optionally substituted by halo, methyl, methoxy or trifluoromethyl, or furanyl optionally substituted by halo, methyl, methoxy or trifluoromethyl. In a further aspect, R^x represents unsubstituted phenyl or uπsubstituted furanyl. In a further aspect, R^x represents phenyl optionally substituted by halo, methyl, methoxy or trifluoromethyl. In a further aspect R^x represents unsubstituted phenyl.

In one aspect, R^γ represents 9-membered bicyclic heteroaryl or -CH₂CH₂-(5-membered heteroaryl) In a further aspect, R^γ represents furo[3,2-b]pyridin-2-yl, pyrazolo[1 ,5- a]pyrimidin-2-yl, 1 ,3-benzoxazol-2-yl, imιdazo[1 ,2-a]pyrιdin-2-yl or 1 ,3-thiazol-4-ylethyl. In a further aspect, R^γ represents 9-membered bicyclic heteroaryl. In a further aspect, R¹ represents furo[3,2-ib]pyridin-2-yl, pyrazolo[1 ,5-alpyrimιdin-2-yl, 1 ,3-beπzoxazol-2-yl or ιmιdazo[1 ,2-a]pyπdιn-2-yl.

In one aspect, R² represents C_{5 7}cycloalkyl optionally substituted by one or more substituents selected from -C_1-6alkyl, -CF₃ or -OR^A, or R² represents phenyl substituted by one or more halo substituents, for example 2,4-dichloro or 2-fluoro. In a further aspect, R² represents C₆cycloalkyl optionally substituted by one or more C^alkyl substituents In another aspect, R² represents fra/is-4-methylcyclohexyl

In one aspect, R³ represents linear or branched -Ci_-6alkyl (unsubstituted); in a further aspect, R³ represents 1-methylethyl.

In one aspect, R* represents unsubstituted phenyl or unsubstituted furanyl, R^y represents furo[3,2-b]pyrιdιn-2-yl, pyrazolo[1 ,5-a]pyrimιdin-2-yl, 1 ,3-benzoxazol-2-yl, imidazo[1 ,2- a]pyridin-2-yl or 1 ,3-thiazol-4-ylethyl, R² represents frans-4-methylcyclohexyl; and R³ represents 1-methylethyl. In a further aspect, R* represents unsubstituted phenyl; R^y represents furo[3,2-to]pyrιdιn-2-yl, pyrazolo[1 ,5-a]pyrιmιdιn-2-yl, 1 ,3-benzoxazol-2-yl or ιmιdazo[1 ,2-a]pyπdin-2-yl; R² represents fra/7S-4-methylcyclohexyl; and R³ represents 1- methylethyl

It is to be understood that the present invention covers all combinations of aspects and further aspects described herein.

As used herein, "acetyl" refers to -C(O)CH₃. As used herein, unless otherwise specified, "alkyl" or "alkylene" refer to an optionally substituted hydrocarbon group. The alkyl hydrocarbon group may be linear, branched or cyclic, saturated or unsaturated. Where the alkyl group is linear or branched, examples of such groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like. Where the alkyl hydrocarbon group is unsaturated, it will be understood that there will be a minimum of 2 carbon atoms in the group, for example an alkenyl or alkynyl group. Where the alkyl hydrocarbon group is cyclic, it will be understood that there will be a minimum of 3 carbon atoms in the group. In one aspect, alkyl moieties are saturated. In one aspect, alkyl moieties are -C_1-4alkyl. Unless otherwise stated, optional substituents include -C_1-ealkyl (unsubstituted), =CH(CH₂)_tH, fluoro, -CF₃, -OR^E, -SR^E, -C(O)NR^BR^C, -C(O)R^D, -CO₂H, - CO₂R⁰, -NR^BR^C, -NR^AC(O)R^D,

-NR^ACO₂R^D, -NR^AC(O)NR^FR^G, -SO₂NR^FR^G, -SO₂R⁰, nitro, cyano, oxo, aryl, heteroaryl and heterocyclyl.

As used herein, "alkenyl" refers to a linear or branched hydrocarbon group containing one or more carbon-carbon double bonds In one aspect the alkenyl group has from 2 to 6 carbon atoms Examples of such groups include ethenyl, propenyl, butenyl, pentenyl or hexenyl and the like.

As used herein, alkynyl" refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds. In one aspect the alkynyl group has from 2 to 6 carbon atoms. Examples of such groups include ethynyl, propynyl, butynyl, pentynyl or hexynyl and the like.

As used herein unless otherwise specified, "cycloalkyl" refers to an optionally substituted, cyclic hydrocarbon group. The hydrocarbon group may be saturated or unsaturated, monocyclic or bridged bicyclic. Where the cycloalkyl group is saturated, examples of such groups include cyclopropyl, cyclobutyl, cydopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like. Where the cycloalkyl group is unsaturated, examples of such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl and the like. In one aspect, the cycloalkyl group has from 5 to 7 carbon atoms. In one aspect, cycloalkyl moieties are cyclohexenyl, cyclopentenyl and cyclohexyl. Unless otherwise stated, the cycloalkyl group may be substituted by one or more optional substituents including -C_{1 6}alkyl (unsubstituted), =CH(CH₂)₍H, fluoro, -CF₃, -OR^E, -SR^E, -C(O)NR^BR^C, -C(O)R⁰, -CO₂H, -CO₂R⁰, -NR^BR^C, -NR^AC(O)R^D, -NR^ACO₂R^D, -NR^AC(O)NR^FR^G, -SO₂NR^FR^G, -SO₂R⁰, nitro, cyano, oxo, phenyl and heterocyclyl

As used herein, "alkoxy" refers to an -O-alkyl group wherein alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like. As used herein, "aryl" refers to an optionally substituted aromatic group with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems. "Aryl" includes carbocyclic aryl and biaryl groups, all of which may be optionally substituted. In one aspect, "aryl" moieties contain 6-10 carbon atoms In one aspect, "aryl" moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted phenyl. In one aspect, unless otherwise stated, "aryl" substituents are selected from the group consisting of -C_1-βalkyl, halo, -OR^E, -SR^E, -C(O)NR^BR^C, -C(O)R^D, -CO₂H, -CO₂R⁰, -NR^BR^C, -NR^AC(O)R^D, -NR^ACO₂R^D, -NR^AC(O)NR^FR^G, -SO₂NR^FR^G, -SO₂R⁰, nitro, cyaπo, heterocyclyl, -CF₃, -OCF₃ and phenyl.

As used herein, unless otherwise specified, 'arylalkyl' refers to an aryl group attached to the parent molecular moiety through an alkyl group, wherein the terms 'aryl' and 'alkyl' are as defined herein.

As used herein, "carbonyl" refers to -C(O)-.

As used herein, "cyano" refers to -CN.

As used herein, "halogen" or "halo" refer to a fluorine, chlorine, bromine or iodine atom References to "fluoro", "chloro", "bromo" or "iodo" should be construed accordingly.

As used herein, unless otherwise specified, "heteroaryl" refers to an optionally substituted, 5, 6, 8, 9 or 10 membered, aromatic group comprising one to four heteroatoms selected from N, O and S, with at least one ring having a conjugated pi-electron system, containing up to two conjugated or fused ring systems. A heteroaryl group containing two rings fused together is described herein as bicyclic In one aspect, "heteroaryl" moieties are unsubstituted, monosubstituted, disubstituted or trisubstituted (where applicable) pyridine, pyrazine, thiazole, thiophene, furan, oxadiazole, oxazole, pyπmidine, pyndazine, benzodioxole, benzofuran, benzodioxiπ, indole, benzimidazole, benzofuran, indole, indazole, isoindole, benzothiophene, benzothiazole, benzoxazole, benzisoxazole, benzisothiazole, benzotriazole, furopyπdine, furopyπmidine, furopyridazine, furopyrazine, furotπazine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine, pyrrolopyrazine, pyrrolotπazine, thienopyridine, thienopyrimidine, thienopyridazine, thienopyrazine, thienotriazine, thiazolopyridine, thiazolopyπmidine, thiazolopyridazine, thiazolopyrazine, thiazolotπazine, oxazolopyndine, oxazolopyrimidine, oxazolopyπdazine, oxazolopyrazme, oxazolotπazine, imidazopyridine, imidazopyπmidine, imidazopyridazine, imidazopyrazine, imidazotriazine, pyrazolopyridine, pyrazolopyπmidine, pyrazolopyπdazine, pyrazolopyrazine, pyrazolotriazine, triazolopyridine, triazolopyrimidine, tπazolopyridazine, triazolopyrazine, quinoline, naphthyndine, quinoxaline, quinazoline, isoquinoline, cinnoline, pyridopyπdazine, pyπdopyrimidine, pyndopyrazine, pyrazinopyrazine, ptendine, pyrazinopyridazine, pyπmidopyridazine, pyrimidopyπmidine, imidazothiazole, thiazolooxazole All isomers of the above heteroaryls are within the scope of this invention. Each heteroaryl group may be attached at any ring carbon or may be attached through nitrogen when the nitrogen is part of a 5-membered ring. In one aspect, unless otherwise stated, "heteroaryl" substituents are selected from the group consisting of

-C^alkyl, halo, -OR^E, -SR^E, -C(O)NR^BR^C, -C(O)R^D, -CO₂R⁰, -NR^BR^C, -NR^AC(O)R^D, -NR^ACO₂R^D, -NR^AC(O)NR^FR^G, -SO₂NR^FR^G, -SO₂R⁰, oxo, nitro, cyano, heterocyclyl, -CF₃ and phenyl.

As used herein, unless otherwise specified, 'heteroarylalkyl' refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group, wherein the terms 'heteroaryl' and 'alkyl' are as defined herein.

As used herein, unless otherwise specified, "heterocyclic" and "heterocyclyl" refer to an optionally substituted, 5 or 6 membered, saturated or partially saturated, cyclic group containing 1 or 2 heteroatoms selected from N, optionally substituted by hydrogen, -C₁^aIKyI, -C(O)R⁰, -C(O)NR^BR^C, -C(O)OH, -SO₂R⁰, aryl or heteroaryl; O; and S, optionally substituted by one or two oxygen atoms. Ring carbon atoms may be optionally substituted by -C_1-6alkyl, -0R^A, -C(O)R⁰, or -SO₂R⁰. In one aspect, unless otherwise stated, "heterocyclic" moieties are unsubstituted or monosubstituted tetrahydro-2H-pyran-4-yl, piperidinyl and tetrahyd rof u ran-3-yl .

As used herein, "nitro" refers to -NO₂.

As used herein, "oxo" refers to =0.

As used herein, unless otherwise specified, "saturated cyclic group " refers to a cyclic hydrocarbon group wherein one of the carbon atoms may optionally be replaced by a heteroatom selected from N, O and S. Examples of such groups include piperidine, piperazine and morpholine.

As used herein, "Et" refers to "ethyl", "iPr" refers to "1 -methylethyl", "Me" refers to "methyl", "OBn" refers to "benzyloxy", and "Ph" refers to "phenyl".

In one aspect, compounds useful in the present invention may be chosen from compounds of Formula (I) selected from the group consisting of: 5-(4-Furo[3,2-b]pyridiπ-2-ylphenyl)-2-[[(^rans-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-3-thiophenecarboxylic acid;

2-[[(frans-4-Methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-(4-pyrazolo[1 ,5-a]pyrimidin-2- ylphenyl)-3-thiophenecarboxylic acid;

S-K^I .S-Benzoxazol^-yOphenyll^-tl^rans^-methylcyclohexyOcarbonylKI- methylethyl)amino]-3-thiophenecarboxylic acid;

5-(4-lmidazo[1 ,2-a]pyridin-2-ylphenyl)-2-[[(frans-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-3-thiophenecarboxylic acid; 5-[5-(1 ,3-Benzoxazol-2-yl)-3-furany|]-2-[[(frans-4-methylcyclohexyl)carbony|](1- methylethyl)amino]-3-thiophenecarboxylic acid;

2-[[(^ans-4-Methylcyclohexyl)carbonyl](1 -methylethyl)amino]-5-{4-[2-(1 ,3-thiazol-4- yl)ethyl]phenyl}-3-thiophenecarboxylic acid; and salts, solvates and esters, and individual enantiomers thereof where appropriate.

Also included in the present invention are pharmaceutically acceptable salt complexes. The present invention also covers the pharmaceutically acceptable salts of the compounds of Formula (I). Suitable pharmaceutically acceptable salts of the compounds of Formula (I) include add salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono- or di- basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.

The present invention also relates to solvates of the compounds of Formula (I), for example hydrates.

The present invention also relates to pharmaceutically acceptable esters of the compounds of Formula (I), for example carboxylic acid esters -COOR, in which R is selected from straight or branched chain alkyl, for example n-propyl, n-butyl, alkoxyalkyl (e.g. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, -C^alkyl or -Ci_-ltalkoxy or amino); or for example - CH₂OC(O)R' or -CH₂OCO₂R' in which R' is alkyl (e.g. R' is f-butyl). Unless otherwise specified, any alkyl moiety present in such esters may contain 1 to 18 carbon atoms, for example 1 to 4 carbon atoms. Any aryl moiety present in such esters may comprise a phenyl group.

As used herein, the term "pharmaceutically acceptable" used in relation to an ingredient (active ingredient such as an active ingredient, a salt thereof or an excipient) which may be included in a pharmaceutical formulation for administration to a patient, refers to that ingredient being acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and not being deleterious to the recipient thereof.

Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps. It will further be appreciated that certain compounds of the present invention may exist in different tautomeric forms All tautomers are contemplated to be within the scope of the present invention.

PROCESSES

Compounds of Formula (I) in which A is hydroxy may be prepared from a compound of

Formula (II)

in which A is a protected hydroxy group, for example an alkoxy, benzyloxy or silyloxy group and R¹, R², and R³ are as defined above for Formula (I). For example when A is methoxy or ethoxy, and R¹, R² and R³ are as defined above for Formula (I), by treatment with an appropriate base, for example aqueous sodium hydroxide or lithium hydroxide, optionally in a suitable solvent such as methanol or ethanol, tetrahydrofuran or combinations thereof. Suitably, the temperature is in the range 25 to 100⁰C, for example 25 to 50⁰C. Alternatively, when A is methoxy or ethoxy and R¹, R² and R³ are as defined above for Formula (I), by treatment with lithium iodide in a suitable solvent such as pyridine, lutidine or collidine, suitably in the temperature range 100-170⁰C.

For example when A is te/t-butoxy, and R¹, R² and R³ are as defined above for Formula (I), by treatment with an appropriate acid, for example trifluoroacetic acid. Suitably, the reaction is carried out in a solvent, for example dichloromethane. Suitably, the temperature is in the range 0 to 50⁰C, for example 15 to 3O⁰C.

For example when A is silyloxy, and R¹, R² and R³ are as defined above for Formula (I), by treatment with a suitable fluoride source for example tetrabutylammonium fluoride. The reaction is carried out in a suitable solvent, for example tetrahydrofuran. Suitably, the temperature is in the range 0 to 5O⁰C, for example 15 to 30⁰C

Compounds of Formula (I) in which A is hydroxy, or Formula (II) in which A is an alkoxy, benzyloxy or silyloxy group and R¹ and R³ are as defined above for Formula (I), may be prepared by reaction of a compound of Formula (III)

in which A is hydroxy or an alkoxy, benzyloxy or silyloxy group, and R² and R³ are as defined above for Formula (I) and X is a halo atom such as bromo or iodo, with a suitable boronic acid R¹-B(OH)₂ or boronate ester R¹-B(OR')(OR"), in which R' and R" are independently alkyl or R' and R" together with the carbon atoms to which they are attached form a ring optionally substituted by alkyl, such as a pinacol ester, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine) palladium or bis-[(diphenylphosphino)- ferrocene]palladium(ll) chloride, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as DMF, methanol or toluene, or combinations thereof, at a temperature in the range 50-100⁰C, optionally under an inert atmosphere.

Compounds of Formula (I) or Formula (II) in which R^y is -CH₂CH₂-(5- or 6-membered heteroaryl) may be prepared from compounds of Formula (I) or Formula (II) respectively in which R^y is -CH=CH-(S- or 6-membered heteroaryl) by treatment with hydrogen in the presence of a suitable catalyst such as palladium on carbon in a suitable solvent such as ethanol.

Compounds of Formula (I) or Formula (II) in which R^y is -CH=CH-(5- or 6-membered heteroaryl) may be prepared from compounds of Formula (II)'

in which Z is -CHO, by treatment with a suitable (5- or 6-membered heteroa ryl J-CH₂- PPh₃ ⁺X^" in which X is a halo such as bromo or chloro, together with a suitable base such as potassium tert-butoxide in a suitable solvent such as THF, optionally under an inert atmosphere.

Compounds of Formula (III) in which A is an alkoxy, benzyloxy or silyloxy group and X is a halogen may be prepared from compounds of Formula (IV)

in which A is an alkoxy, benzyloxy or silyloxy, and R² and R³ are as defined above for Formula (I), by treatment with a suitable base such as lithium diisopropylamide and a halogen source such as bromine, iodine, N-bromosuccinide or N-iodosuccinimide in a suitable solvent such as tetrahydrofuran, and at a temperature in the range -78 to -20⁰C. Alternatively, they may be prepared by treatment with a suitable halogen source such as N- bromosuccinide in a suitable solvent such as chloroform or carbon tetrachloride, or suitable combinations thereof, at a temperature in the range 50-80^αC. Compounds of Formula (III) in which A is hydroxy may be prepared from compounds of Formula (III) in which A is an alkoxy, benzyloxy or silyloxy group, for example by treatment with an appropriate base, acid or fluoride source as described in relation to the preparation of compounds of Formula (I) from compounds of Formula (II).

Compounds of Formula (IV) may be prepared by reaction of a compound of Formula (V)

in which A is an alkoxy, benzyloxy or silyloxy group, and R³ is as defined above for Formula (I); with a suitable acylating agent, for example R²-C(O)-Y, wherein Y is a halo atom, for example chloro or bromo, and R² is as defined above for Formula (I). The reaction may be carried out in diisopropylethylamine at a temperature in the range 70-1 1O⁰C.

Compounds of Formula (V) may be prepared by reaction of a compound of Formula (Vl)

in which A an alkoxy, benzyloxy or silyloxy group, by treatment with a suitable vinyl ether, or a suitable aldehyde or a suitable ketone, in the presence of a suitable acid, such as acetic acid, and a suitable reducing agent such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane. Alternatively, compounds of Formula (V) may be prepared from compounds of Formula (Vl) in which A is an alkoxy, benzyloxy or silyloxy group, by treatment with a suitable alkylating agent R³-X' where X' is a halo atom such as chloro, bromo or iodo, or X' is a sulphonate ester such as methanesulfonate, in a suitable solvent, such as dimethylformamide, in the presence of a suitable base, such as triethylamine.

Compounds of Formula (IV) may also be prepared by reaction of a compound of Formula

in which A is an alkoxy, benzyloxy or silyloxy group, and R² is as defined above for Formula (I); with a suitable alkylating agent R³-X' in which X¹ is a halo atom such as chloro, bromo or iodo, or X' is a sulphonate ester such as methanesulfonate, and R³ is as defined above for Formula (I). The reaction may be carried out in a suitable solvent such as dimethylformamide or THF, in the presence of a suitable base, such as triethylamine, potassium tert-butoxide or sodium hydride. Compounds of Formula (VIII) may be prepared by reaction of a compound of Formula (Vl) in which A is an alkoxy, benzyloxy or silyloxy group, with a suitable acylating agent, for example R²-C(O)-Y, wherein Y is a halo atom, such as chloro or bromo, and R² is as defined above for Formula (I). The reaction may be carried out in diisopropylethylamine at a temperature in the range 70-1 10⁰C.

Compounds of Formula (II) may also be prepared by reaction of a compound of Formula (IX)

in which A is an alkoxy, benzyloxy or silyloxy group, and R¹ and R³ are as defined above for Formula (I), with a suitable acylating agent, for example R²-C(O)-Y, wherein Y is a halo atom, such as chloro or bromo, and R² is as defined above for Formula (I). The reaction may be carried out in diisopropylethylamine at a temperature in the range 70-110⁰C.

Compounds of Formula (IX) may be prepared by reaction of a compound of Formula (X)

in which A is an alkoxy, benzyloxy or silyloxy group, and R¹ is as defined above for Formula (I), with a suitable ketone in the presence of titanium tetrachloride and sodium triacetoxyborohydride in the presence of a suitable solvent such as dichloromethane at a temperature in the range -80 to -50⁰C, or by treatment with a suitable vinyl ether, or a suitable aldehyde or a suitable ketone, in the presence of a suitable acid, such as acetic acid, and a suitable reducing agent such as sodium triacetoxyborohydride, in a suitable solvent such as dichloromethane. Alternatively, compounds of Formula (V) may be prepared from compounds of Formula (Vl) in which A is an alkoxy, benzyloxy or silyloxy group, by treatment with a suitable alkylating agent R³-X' where X' is a halo atom such as chloro, bromo or iodo, or X' is a sulphonate ester such as methanesulfonate, and R³ is as defined above for Formula (I). The reaction may be carried out in a suitable solvent, such as dimethylformamide, in the presence of a suitable base, such as triethylamine.

Compounds of Formula (X) may be prepared by reaction of a compound of Formula (Xl)

in which A is an alkoxy, benzyloxy or silyloxy group, and R¹ is as defined above for Formula (I), with a suitable acid such as HCI in a suitable solvent such as dioxane. Compounds of Formula (Xl) may be prepared by reaction of a compound of Formula (XII)

in which A is an alkoxy, benzyloxy or silyloxy group, and X is a halo atom such as bromo or iodo, with a suitable boronic acid R¹-B(OH)₂ or boronate ester R¹-B(OR')(OR"), in which R¹ is as defined above for Formula (I) and R' and R" are independently alkyl or R' and R" together with the carbon atoms to which they are attached form a ring optionally substituted by alkyl, such as a pinacol ester, in the presence of a palladium catalyst such as tetrakis(trιphenylphosphιne) palladium or bis-[(dιphenylphosphino)-ferrocene]palladιum(ll) chloride, in the presence of a suitable base such as sodium carbonate, in a suitable solvent such as DMF, methanol or toluene, or combinations thereof, at a temperature in the range

50-100⁰C₁ optionally under an inert atmosphere.

Compounds of Formula (XII) may be prepared by reaction of a compound of Formula

in which A is an alkoxy, benzyloxy or silyloxy group, with a suitable halogen source such as N-bromosuccinide in a suitable solvent such as chloroform or carbon tetrachloride, or suitable combinations thereof, at a temperature in the range 50-80⁰C

Compounds of Formula (XIII) may be prepared by reaction of a compound of Formula (Vl) in which A is an alkoxy, benzyloxy or silyloxy group and R¹ is as defined in Formula (I), with terf-butyloxycarbonyl anhydride (di-terf-butyl dicarbonate) and a catalyst such as N₁N- dimethylaminopyridine in a suitable solvent such as dichloromethane.

Compounds of Formula (III) in which A is an alkoxy, benzyloxy or silyloxy group may also be prepared from compounds of Formula (XIV)

in which A is an alkoxy, benzyloxy or silyloxy group, X is a halo atom, such as bromo or iodo, and R² is as defined above for Formula (I), by treatment with a suitable alkylating agent R³-X' where X' is a halo atom such as chloro, bromo or iodo, or X' is a sulphonate ester such as methanesulfonate, and R³ is as defined in Formula (I), in a suitable solvent, such as dimethylformamide or THF₁ in the presence of a suitable base, such as tπethylamine, potassium fert-butoxide or sodium hydride Compounds of Formula (XIV) may be prepared from compounds of Formula (XV)

in which A is an alkoxy, benzyloxy or silyloxy group, and X is a halo atom, such as bromo or iodo, by reaction with a suitable acylating agent, for example R²-C(O)-Y, wherein Y is a halo atom, such as chloro or bromo, and R² is as defined above for Formula (I). The reaction may be carried out in diisopropylethylamine at a temperature in the range 70-1 1O⁰C.

Compounds of Formula (XV) may be prepared from compounds of Formula (XII) in which A is an alkoxy, benzyloxy or silyloxy group, and X is a halo atom such as bromo or iodo, by reaction with a suitable acid such as HCI in a suitable solvent such as dioxane

Compounds of Formula (II) may also be prepared by reaction of a compound of Formula

in which A is an alkoxy, benzyloxy or silyloxy group, and R¹ and R² are as defined above for Formula (I); with a suitable alkylating agent R³-X' in which X' is a halo atom such as chloro, bromo or iodo, or X' is a sulphonate ester such as methanesulfonate, and R³ is as defined in Formula (I), in a suitable solvent such as dimethylformamide or THF, in the presence of a suitable base, such as triethylamme, potassium terf-butoxide or sodium hydride

Compounds of Formula (XVI) may be prepared by reaction of a compound of Formula (X) in which A is an alkoxy, benzyloxy or silyloxy group, and R¹ is as defined above for Formula (I), with a suitable acylating agent, for example R²-C(O)-Y, wherein Y is a halo atom, such as chloro or bromo, and R² is as defined above for Formula (I). The reaction may be carried out in diisopropylethylamine at a temperature in the range 70-1 10⁰C.

Compounds of Formula (Vl) are commercially available or well known in the art.

Compounds of Formula (I) in which A is hydroxy, or Formula (II) in which A is an alkoxy, benzyloxy or silyloxy group, may be prepared by reaction of a compound of Formula (M)'

in which Z represents a halo atom, such as chloro, bromo or iodo, and R^x, R², R³ are as defined above for Formula (I), and A is hydroxy or an alkoxy, benzyloxy or silyloxy group, by reaction with a suitable heteroaryl boronic acid, R^γ-boronic acid, in which R^γ is as defined above for Formula (I), in the presence of a palladium catalyst such as palladium (II) acetate, a reagent such as 2-dicyclohexylphosphino-2'(N,N-dimethylamino)-biphenyl, and an additional reagent such as caesium fluoride, in a suitable solvent, such as dioxane. Alternatively the R^γ boronic acid or boronic ester may be reacted in the presence of a palladium catalyst such as tetrakis(triphenylphosphonium) palladium, a reagent such as sodium carbonate, in a suitable solvent such as dimethoxymethane or ethanol, optionally at a temperature in the range 50-85⁰C. Alternatively, for coupling the boronic acids or esters methods well known in the art may be employed, see, for example, Chemical Communications (2005) 38, 4759-4763, Angew Chemie lnt Ed (2005) 44, 4442^489, Tetrahedron (2002) 58, 9633-9695, Synthesis (2004) 2419-2440.

Compounds of Formula (I) in which A is hydroxy, or Formula (II) in which A is an alkoxy, benzyloxy or silyloxy group, may also be prepared by reaction of a compound of Formula (II)'

in which Z represents B(OH)₂, and R^x, R², R³ are as defined above for Formula (I), and A is hydroxy or an alkoxy, benzyloxy or silyloxy group, by reaction with a suitable heteroaryl halide, R^γ-hal, in which R^γ is as defined above for Formula (I) and suitably hal is bromo or iodo, in the presence of a palladium catalyst such as palladium (II) acetate, a reagent such as 2-dicyclohexylphosphino-2'(N,N-dimethylamino)-biphenyl, and an additional reagent such as caesium fluoride, in a suitable solvent such as dioxane. Alternatively the R^γ boronic acid or boronic ester may be reacted in the presence of a palladium catalyst such as tetrakis(triphenylphosphonium) palladium, a reagent such as sodium carbonate, in a suitable solvent such as dimethoxymethane or ethanol, optionally at a temperature in the range 50- 85°C. Alternatively, for coupling the boronic acids or esters methods well known in the art may be employed, see, for example, Chemical Communications (2005) 38, 4759-4763, Angew Chemie lnt Ed (2005) 44, 4442-4489, Tetrahedron (2002) 58, 9633-9695, Synthesis (2004) 2419-2440.

Compounds of Formula (H)' in which Z is either halo or -CHO may be prepared by reaction of a compound of Formula (III) with a boronic acid of Formula Z-R^x-boronic acid under the conditions described above for the preparation of compounds of Formula (I) and (II) from (III) and R¹-boronic acid.

Boronic acids Z-R^x-boronic acid, R¹-boronic acid and R^γ-boronic acid are commercially available or may be prepared by analogy to methods provided in Organometallics (1983) 2, 1316, Chem Revs. (1995) 95, 2457, Journal of Org Chem (2004) 69, 1999, SynLett (2004) (5), 892, Bioorg Med Chem (2005) 13, 2305, Tetrahedron Letters (2004) 44, 9359 and Tetrahedron Letters (2005) 45, 6657.

Boronate esters R¹-B(OR')(OR") are commercially available or may be prepared by analogy to methods provided in J. Med Chem (2006) 49, 6848-6857, J. Org. Chem (2006) 71 , 3059- 3962 and J. Org. Chem (2005) 70, 7324-7330.

Compounds of Formula (I) or (II) in which R¹ represents a 4-(furopyridine)phenyl, may be prepared by treatment of a com

in which R¹ represents a 4-ethynylphenyl derivative, and R², R³, R⁴ and A are as defined above for Formula (II), with a suitable pyridine (the pyridine being substituted with adjacent hydroxy and iodo groups), with a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide, in the presence of a suitable base, such as triethylamine, optionally in an additional suitable solvent, such as DMF. Suitably the temperature is in the range 50-80°C. For examples of furopyridine synthesis see Bioorganic and Medicinal Chemistry Letters (2002) 12, 1399, Synthesis (1986) 749.

Compounds of Formula (I) or (II) in which R¹ represents a 4-(pyrrolopyridine)phenyl, may be prepared by treatment of a compound of Formula (II)" in which R¹ represents A- ethynylphenyl with an appropriate pyridine (the pyridine being substituted by adjacent amino and iodo groups), in the presence of a suitable catalyst such as bis(triphenylphosphine)palladιum (II) chloride and copper (I) iodide, in a suitable solvent such as triethylamine. Suitably the temperature is in the range 50-80°C For examples of pyrrolopyridine synthesis see Heterocycles (1986) 24, 31 , Tetrahedron (2003) 59, 1571 , Synlett (1992) 515

Compounds of Formula (I) or (II) in which R¹ represents phenyl substituted by a A- imidazo[1 ,2-alpyridine, may be prepared by analogy to methods described in Tetrahedron Letters (2001 ) 42, 3077

Compounds of Formula (I) or (II) in which R¹ represents a 4-(1 H-benzimidazol-2-yl)phenyl derivative may be prepared by analogy to methods described in J Heterocyclic Chem. (1994) 31 , 957.

Compounds of Formula (I) or (II) in which R¹ represents a 4-(1 ,3-benzoxazol-2-yl)phenyl derivative may be prepared by analogy to methods described in Tetrahedron Letters (2003) 44, 175.

Compounds of Formula (I) or (II) in which R¹ represents a 4-(1 ,3-benzothiazol-2-yl)phenyl derivative may be prepared by analogy to methods described in Tetrahedron Letters (2003) 44, 175 or Synth Commun. (1990) 20, 3379.

Compounds of Formula (I) or (II) in which R¹ represents a 4-(oxazolopyπdιne)phenyl may be prepared by reacting a compound of Formula (II)" in which R¹ represents 4-carboxyphenyl with an appropriate pyridine derivative (the pyridine being substituted with adjacent amino and hydroxyl groups), in the presence of an acid such as polyphosphoric acid at temperatures in the range 180-200⁰C (see for example J. Med Chem (1978) 21 , 1158). Alternatively, the acid chloride of the 4-carboxyphenyl may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent ammo and hydroxyl groups) in a microwave reactor in a suitable solvent such as dioxan (see for example Tetrahedron Letters (2003) 44, 175). Compounds of Formula (II) in which R¹ represents a A- (oxazolopyridine)phenyl may also be prepared by reacting the 4-carboxyphenyl derivative with an appropriate pyridine (the pyridine being substituted with adjacent amino and hydroxyl groups) using a suitable coupling agent such as O-(7-azabenzotrιazol-1-yl)-Λ/,Λ/,Λ/' Λ/- tetramethyluronium hexafluorophosphate (HATU), and then in a second step cyclised using an appropriate reagent such as phosphorous oxychloride

Compounds of Formula (I) or (II) in which R¹ represents a 4-(thiazolopyridιne)phenyl, may be prepared by reacting a compound of Formula (II)" in which R¹ represents 4-phenyl-COCI with an appropriate pyridine (the pyridine being substituted with adjacent amino and chloro groups), in the presence of a suitable base such as pyridine, and then in a second step cyclised using a reagent such as Lawesson's reagent in a suitable solvent such as 1 ,3- dιmethyl-3,4,5,6-tetrahydro-2(1 H)-pyrιmιdinone (DMPU), at a suitable temperature such as 90-110°C

Compounds of Formula (I) or (II) in which R¹ represents a 4-(thiazolopyridιne)phenyl, may also be prepared by reacting a compound of Formula (II)" in which R¹ represents 4- carboxyphenyl with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), in the presence of an acid such as polyphosphoric acid at temperatures in the range 180-200⁰C (see for example J. Med Chem. (1978) 21 , 1158). Alternatively, the acid chloride of the 4-carboxyphenyl may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), in a microwave reactor in a suitable solvent such as dioxan (see for example Tetrahedron Letters (2003) 44, 175) In another alternative the 4-carboxyphenyl compound may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), using a suitable coupling agent such as HATU, and then in a second step cyclised using an appropriate reagent such as phosphorous oxychloride.

Compounds of Formula (I) or (II) in which R¹ represents a 4-(2,3-dihydro-1 ,1 -dιoxo-1 ,2- benzιsothιazol-2(3H)-yl)phenyl derivative, may be prepared by treatment of a compound of Formula (H)' in which Z represents 4-halo with a 2,3-dihydro-1 ,2-benzιsothiazole 1 ,1-dιoxιde derivative in the presence of copper (I) iodide with a suitable base such as potassium carbonate, and in the presence of a reagent such as fraπs-1 ,2-dιaminocyclohexane or trans- N,N'-dimethyl-1 ,2-cyclohexanedιamine, or a combination thereof in a suitable solvent such as dioxan, DMF or pyridine or a combination thereof, and at a temperature in the range 90- 160⁰C.

Compounds of Formula (I) or (II) in which R¹ represents a 4-(1-oxo-1 ,3-dιhydro-2H-ιsoιndol- 2-yl)phenyl derivative, may be prepared by treatment of a compound of Formula (II)" in which R¹ represents a 4-amιnophenyl derivative with a phenyl-1 ,2-di-aldehyde derivative in acetic acid optionally with a suitable solvent such as dichloromethane. Alternatively, compounds of Formula (I) or (II) in which R¹ represents a 4-(1-oxo-1 ,3-dιhydro-2H-isoιndol-2- yl)phenyl derivative may also be prepared by treatment of a compound of Formula (II)" in which R¹ represents 4-aminophenyl with a suitable phenyl derivative (this being substituted with adjacent methyl ester and bromomethyl groups), in the presence of a suitable base such as dnsopropylethylamine, in a suitable solvent such as acetonitπle.

Compounds of Formula (I) or (II) in which R¹ represents a 4-((1-oxo-1 ,3-dιhydro-2H- azaisoιndol-2-yl)phenyl derivative, may be prepared by treatment of a compound of Formula (II)" in which R¹ represents 4-amιnophenyl with an appropriate pyridine derivative (the pyridine being substituted with adjacent methyl ester and bromomethyl groups), in the presence of a suitable base such as diisopropylethylamine in a suitable solvent such as acetonitrile. Compounds of Formula (I) or (II) in which R¹ represents a 4-(pyrazolopyrimidine)phenyl, may be prepared by treating a compound of Formula (II)" in which R¹ represents 4-(phenyl)-1 H- pyrazole-5-amine with 1 ,1 ,3,3-tetramethoxypropane in a suitable solvent, such as acetic acid, suitably the temperature is in the range 90-110⁰C.

Suitable methods for the preparation of compounds with the above discussed R^γ derivatives may be found in the chemical literature, for example those described in Comprehensive Heterocyclic Chemistry, Edited by A.R. Katritzky and CW. Rees, Pergamon 1984, and Heterocyclic Chemistry, Edited by J. A. Joules and K. Mills, 4^th Ed, Blackwell Science.

Compounds of Formula R^Y-R^X-B(OR')₂, R^Y-B(OR')₂ or R^yR^x-B(OR')(OR") for use in the preparation of compounds of Formula (II) are available commercially or may be prepared from compounds of Formula R^γ-R^x-hal or R^γ-hal by methods well known in the art.

Compounds of Formula R^γ-R^x-hal or R^γ-hal for use in the preparation of compounds of Formula (II) are available commercially or may be prepared by methods well known in the art. Representative examples of heteroaryl halide preparation are given below (but are not exhaustive).

A 2-(4-bromophenyl)-2H indazole derivative may be prepared by analogy to methods described in Farmaco Ed Sci (1981 ) 36, 1037 or J. Chem Soc. Perkin Trans 2 (1975), 1185, for example by treating 2-nitrobenzaldehyde with 4-bromoanιline in a suitable solvent such as methanol, and in a separate step reacting the imine with a phosphite such as triethylphosphite, in a microwave reactor at 210°C for 20 mins.

A 2-(4-bromophenyl)imidazo[1 ,2-a]pyridine derivative may be prepared by analogy to methods described in Tetrahedron Letters (2001 ) 42, 3077.

A 2-(4-bromophenyl)-1 H-benzimidazole derivative may be prepared by analogy to methods described in J. Heterocyclic Chem. (1994) 31 , 957.

A 2-(4-bromophenyl)-1 H-benzoxazole derivative may be prepared by analogy to methods described in Tetrahedron Letters (2003) 44, 175.

A 2-(4-bromophenyl)-1 H-benzothiazole derivatives may be prepared by analogy to methods described in Tetrahedron Letters (2003) 44, 175 or Synth. Commun. (1990) 20, 3379.

A 4-(furopyridine)phenyl bromide, may be prepared by treatment of a 4-ethynylphenyl bromide with a suitable pyridine (the pyridine being substituted with adjacent hydroxy and iodo groups), with a suitable catalyst such as bis(triphenylphosphine)palladium (II) chloride and copper (I) iodide, in a suitable solvent such as triethylamine or DMF. Suitably the temperature is in the range 50-80⁰C For examples of furopyridine synthesis see Bioorganic and Medicinal Chemistry Letters (2002) 12, 1399, Synthesis (1986) 749

A 4-(oxazolopyrιdιne)pheπyl bromide may be prepared by reacting a 4-carboxyphenyl bromide with an appropriate pyridine derivative (the pyridine being substituted with adjacent ammo and hydroxyl groups), in the presence of an acid such as polyphosphoric acid at temperatures in the range 180-200⁰C (see for example J Med Chem. (1978) 21 , 1 158) Alternatively, the acid chloride of the 4-carboxyphenyl bromide may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and hydroxyl groups) in a microwave reactor in a suitable solvent such as dioxane (see for example Tetrahedron Letters (2003) 44, 175) A 4-(oxazolopyrιdιne)phenyl bromide may also be prepared by reacting a 4-carboxyphenyl bromide derivative with an appropriate pyridine (the pyridine being substituted with adjacent amino and hydroxyl groups) using a suitable coupling agent such as HATU, and then in a second step cyclised using an appropriate reagent such as phosphorous oxychlonde

A 4-(thιazolopyrιdιne)phenyl bromide may be prepared by reacting an appropriate A- carboxyphenyl bromide with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), in the presence of an acid such as polyphosphoric acid at temperatures in the range 180-200⁰C (see for example J Med Chem (1978) 21 , 1158) Alternatively, the acid chloride of the 4-carboxyphenyl may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), in a microwave reactor in a suitable solvent such as dioxan (see for example Tetrahedron Letters (2003) 44, 175) In another alternative the 4-carboxyphenyl bromide may be reacted with an appropriate pyridine (the pyridine being substituted with adjacent amino and thiol groups), using a suitable coupling agent such as HATLJ, and then in a second step cyclised using an appropriate reagent such as phosphorous oxychlonde

A 4-(thιazolopyrιdιne)-phenyl bromide may be prepared by reacting an appropriate A- bromophenyl-COCI with an appropriate pyridine (the pyridine being substituted with adjacent amino and chloro groups), in the presence of a suitable base such as pyridine, and then in a second step is cyclised using a reagent such as Lawesson's reagent in a suitable solvent such as DMPU, at a suitable temperature such as 90-1 10⁰C

A 4-(1-oxo-1 ,3-dιhydro-2H-ιsoιndol-2-yl)phenyl bromide derivative may be prepared by treatment of an appropriate 4-amιnophenyl bromide derivative with a phenyl-1 ,2-dι-aldehyde derivative in acetic acid optionally with a suitable solvent such as dichloromethane A 4-(1- oxo-1 ,3-dιhydro-2H-ιsoindol-2-yl)phenyl bromide derivative may also be prepared by treatment of an appropriate 4-amιnophenyl bromide with a suitable phenyl derivative (this being substituted with adjacent methyl ester and bromomethyl groups), in the presence of a suitable base such as dnsopropylethylamine, in a suitable solvent such as acetonitrile A 4-(1-oxo-1 ,3-dihydro-2H-azaisoindol-2-yl)phenyl bromide may be prepared by treatment of an appropriate 4-aminophenyl bromide with an appropriate pyridine derivative (the pyridine being substituted with adjacent methyl ester and bromomethyl groups), in the presence of a suitable base such as diisopropylethylamine in a suitable solvent such as acetonitrile.

A 4-(pyrazolopyrimidine)phenyl bromide may be prepared by treating a 3-(4-bromophenyl)- 1 H-pyrazole-5-amine with 1 ,1 ,3,3-tetramethoxypropane in a suitable solvent such as acetic acid, suitably the temperature is in the range 90-110⁰C.

A 5-(1 ,3-benzoxazol-2-yl)-3-furanyl] derivative may be prepared by treatment of a 4-bromo-2- furancarboxylic acid with diethylformamide and oxalyl chloride in a suitable solvent such as dichloromethane followed heating with 2-aminophenol in a suitable solvent such as 1 ,4- dioxane.

Esters of compounds of Formula (I), in which A is -OR where R is selected from straight or branched chain alkyl, aralkyl, aryloxyalkyl, or aryl, may also be prepared by esterification of a compound of Formula (I) in which A is hydroxy by standard literature procedures for esterification.

The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multistage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product.

It will be appreciated that compounds of Formula (I)₁ (II), (II)¹, (II)", (III), (IV), (V), (VIII), (IX), (X) and (XIV) which exist as diastereoisomers may optionally be separated by techniques well known in the art, for example by column chromatography or recrystallisation. For example, the formation of an ester using a chiral alcohol, separation of the resulting diastereoisomers, and subsequent hydrolysis of the ester to yield the individual enantiomeric acid of Formula (I), (II), (II)', (II)", (III), (IV), (V), (VIII), (IX), (X) and (XIV).

It will be appreciated that racemic compounds of Formula (I), (II), (II)', (H)", (III), (IV), (V), (VIII), (IX), (X) and (XIV) may be optionally resolved into their individual enantiomers. Such resolutions may conveniently be accomplished by standard methods known in the art. For example, a racemic compound of Formula (I), (II), (II)', (M)", (III), (IV), (V), (VIII), (IX), (X) and

(XIV) may be resolved by chiral preparative HPLC. Alternatively, racemic compounds of

Formula (I), (II), (II)', (II)", (III), (IV), (V), (VIII), (IX), (X) and (XIV) which contain an appropriate acidic or basic group, such as a carboxylic acid group or amine group may be resolved by standard diastereoisomeric salt formation with a chiral base or acid reagent respectively as appropriate. Such techniques are well established in the art. For example, a racemic basic compound may be resolved by treatment with a chiral acid such as (R)-(-)- 1 1 '-bιnaphthyl-2,2'-dιyl-hydrogen phosphate or (-)-dι-O,O'-p-tolyl-L-tartarιc acid, in a suitable solvent, for example isopropanol The free enantiomer may then be obtained by treating the salt with a suitable base, for example triethylamine, in a suitable solvent, for example methyl terf-butyl ether Alternatively, racemic acid compounds may be resolved using a chiral base, for example (S)-alpha methylbenzylamine, (S)-alpha phenylethylamine, (1 S, 2S)-(+)-2- amιno-1-phenyl-1 ,3-propane-dιol, (-) ephidπne, quinine, brucine. Individual enantiomers of Formula (II), (II)', (II)", (III), (IV), (V), (VIM), (IX), (X) and (XIV) may then be progressed to an enantiomeric compound of Formula (I) by the chemistry described above in respect of racemic compounds

With appropriate manipulation and protection of any chemical functionality, synthesis of compounds of Formula (I) is accomplished by methods analogous to those above and to those described in the Experimental section. Suitable protecting groups can be found, but are not restricted to, those found in T W Greene and P G M Wuts 'Protective Groups in Organic Synthesis', 3^rd Ed (1999), J Wiley and Sons.

Various of the synthetic procedures described above in general terms (and below in specific terms) may involve heating the reactants. It will be appreciated that heating may be carried out by various conventional methods but also with use of a microwave oven

EXAMPLES ABBREVIATIONS DCM dichloromethane

DEF Λ/,Λ/-dιethylformamιde

CCI₄ tetrachloromethane

CHCI₃ chloroform

DMF N,N-dιmethylformamιde EtOAc ethyl acetate h hours

HCI hydrochloric acid

HPLC high pressure liquid chromatography

ISCO Companion Automated flash chromatography equipment with fraction analysis by UV absorption available from Presearch

MDAP HPLC reverse phase HPLC on a C₁₈ column using a two-solvent gradient elution with (A) water containing formic acid (0 1 %) and (B) acetonitrile-water (95-5 v/v) containing formic acid (0.05%) as the eluents, and analysis of the fractions by electrospray mass spectroscopy

MeCN acetonitrile

Na₂CO₃ sodium carbonate NBS N-Bromosuccinimide

Pd CI₂(Cl p pf) [1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloro-palladium(ll)

Pd(PPh₃)₄ tetrakis(triphenylphosphine) palladium

SPE solid phase extraction column THF tetrahydrofuran

All mass spectroscopy was performed using electrospray as the method of ionisation.

Intermediate 1 Methyl 2-[(1 -methylethyl)amino]-3-thiophenecarboxylate

To 2-amino-3-carboxythiophene methyl ester (4.0 g) in DCM (75 ml.) under nitrogen was added 2-methoxypropene (7.2 g), glacial acetic acid (5.7 mL) and sodium triacetoxyborohydride (12.7 g). The reaction mixture was stirred at room temperature for 2 h. Water (75 mL) was added to the reaction mixture which was neutralised using solid sodium bicarbonate. The DCM was separated and the aqueous re-extracted with DCM. The combined organic extract was washed with brine, dried using a hydrophobic frit and evaporated to dryness to give the title compound. MS calcd for (C₉H₁₃NO₂S + H)⁺ : 200 MS found (electrospray) : (M+H)⁺ = 200

Intermediate 2

Methyl 2-[[(frans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-3- thiophenecarboxylate

A solution of Intermediate 1 (3.18 g) in anhydrous Λ/,Λ/-diisopropylethylamine (5.6 mL) was treated with fraπs^-methylcyclohexanecarbonyl chloride¹ (5.2 g) and heated at 8O⁰C overnight. The reaction mixture was cooled to room temperature, diluted with DCM (20 mL) and sodium carbonate solution (20 mL) and stirred for 30 min. The organic was separated, dried using a hydrophobic frit and evaporated to dryness. This was purified by ISCO Companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound. MS calcd for (C₁₇H₂₅NO₃S + H)⁺ : 324 MS found (electrospray) : (M+H)⁺ = 324

Ref 1 : WO 2004/052885

Intermediate 3

Methyl S-bromo^-^fraπs^-methylcyclohexylJcarbonylHI-methylethylJaminol-S- thiophenecarboxylate

A solution of Intermediate 2 (2.8 g) in CHCI₃ (28 mL) and CCI₄ (28 mL) was treated with NBS (2.6 g) and heated at 8O⁰C for 4 h. The reaction mixture was evaporated to dryness, dissolved in DCM (-10 mL) and filtered. The filtrate was purified by ISCO Companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound. MS calcd for (C₁₇H₂₄BrNO₃S + H)⁺ : 402/404 MS found (electrospray) : (M+H)⁺ = 402/404

Intermediate 4 2-(4-Bromophenyl)furo[3,2-ϋ]pyridine

To 4-bromophenylactetylene (1.65 g) was added 2-iodo-3-hydroxypyridine (2.02 g), bis(triphenylphosphine)palladium dichloride (575 mg), copper (I) iodide (225 mg) and triethylamine (35 mL). The reaction was stirred at 5O⁰C, under nitrogen, for 3 h. The reaction was cooled, diluted with DCM (250 mL) and washed with saturated ammonium chloride solution, brine and then concentrated. The crude product was purified by ISCO

Companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound.

MS calcd for (C₁₃H₈BrNO + H)⁺: 274/276 MS found (electrospray): (M+H)⁺ = 274/276

Intermediate 5 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]furo[3,2-b]pyridine

Intermediate 4 (250 mg), potassium acetate (265 mg), bis(pinacolato)diboron (345 mg) and PdCI₂(dppf) (48 mg) were dissolved in anhydrous dioxane (5 mL) and were heated at 100⁰C for 7 h. The reaction mixture was evaporated to dryness and the residue partitioned between water (10 mL) and DCM (20 mL). The aqueous phase was separated and extracted with more DCM (10 mL). The combined organic phases were evaporated to dryness. This was purified by SPE chromatography eluting with cyclohexane: EtOAc (2:1 followed by 1 :1 ). The appropriate fractions were combined and evaporated to dryness. The residue was further purified by SPE chromatography using a stepped gradient, eluting with cyclohexane, cyclohexane: EtOAc, (3:1 , then 1 :1 , then 1 :2), EtOAc, 1 :1 EtOAc:MeCN followed by MeCN. The appropriate fractions were combined and evaporated to dryness to give the title compound. MS calcd for (C₁₉H₂₀BNO₃ + H)⁺ : 322 MS found (electrospray) : (M+H)⁺ = 322

Intermediate 6 2-(4-Bromopheπyl)pyrazolo[1,5-a]pyrimidine

A solution of 3-(4-bromophenyl)-1 H-pyrazol-5-amine (1.19 g) in acetic acid (20 mL) was treated with 1 ,1 ,3,3-tetramethoxypropane (615 mg) and the mixture heated at 11 O⁰C for 1.5 h. On cooling to room temperature the precipitated solid was isolated by filtration, washed with water and allowed to dry in air to give the title compound. MS calcd for (C₁₂H₈BrN₃+ H)⁺: 274/276 MS found (electrospray): (M+H)⁺ = 274/276

Intermediate 7

2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pheπyl]pyrazolo[1,5-a]pyrimidine

Intermediate 6 (200 mg), potassium acetate (214 mg), bis(pinacolato)diboron (276 mg) and PdCI₂(dppf) (40 mg) were dissolved in anhydrous dioxane (4 mL) and were heated at 100⁰C overnight. The reaction mixture was evaporated to dryness and the residue partitioned between water and DCM. The aqueous phase was separated and extracted twice more with DCM. The combined organic phases were dried using a hydrophobic frit and evaporated to dryness. This was purified by ISCO Companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound. MS calcd for (C₁₈H₂₀BN₃O₂ + H)⁺ : 322 MS found (electrospray) : (M+H)⁺ = 322

Intermediate 8 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]imidazo[1,2-a]pyridine

2-(4-Bromophenyl)imidazo[1 ,2-a]pyιϊdine² (300 mg), potassium acetate (393 mg), bis(pinacolato)di boron (508 mg) and PdCI₂(dppf) (58 mg) were dissolved in anhydrous dioxane (6 ml.) and were heated at 100⁰C for 24 h. The reaction mixture was evaporated to dryness and the residue partitioned between water (10 ml_) and DCM (20 imL). The aqueous phase was separated and extracted with more DCM (10 ml_). The combined organic phases were evaporated to dryness. This was purified by SPE chromatography eluting with 3:1 cyclohexane: EtOAc. The appropriate fractions were combined and evaporated to dryness. The residue was purified further by SPE chromatography using a stepped gradient, eluting with cyclohexane, 3:1 cyclohexane:EtOAc, 1 :1 cyclohexane: EtOAc. The appropriate fractions were combined and evaporated to dryness to give the title compound. MS calcd for (C₁₉H₂₁BN₂O₂ + H)⁺ : 321 MS found (electrospray) : (M+H)⁺ = 321

Ref 2: Burkholder, Conrad; Dolbier, William R.; Medebielle, Maurice; Ait-Mohand, Samia, Tetrahedron Lett., 42, 17, 2001 , 3077 - 3080.

Intermediate 9 2-(4-Bromophenyl)-1,3-benzoxazole

A mixture of 2-aminophenol (196 mg) and 4-bromobenzoyl chloride (438 mg) in dioxane (2.5 ml.) was heated in a microwave at 21 O⁰C for 15 mins. The cooled reaction mixture was added to 1 M sodium hydroxide solution (40 mL). The solid was filtered, washed with water and dried in vacuo to give the title compound. MS calcd for (C₁₃H₈BrNO + H)⁺: 274/276 MS found (electrospray): (M+H)⁺ = 274/276

Intermediate 10 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole

Intermediate 9 (0.8 g), potassium acetate (0.86 g), bis(pinacolato)diboron (1.1 g) and PdCI₂(dppf) (160 mg) were dissolved in anhydrous dioxane (16 ml_) and were heated at 100⁰C overnight. The reaction mixture was evaporated to dryness and the residue partitioned between water and DCM. The aqueous phase was separated and extracted twice with DCM. The combined organic phases were dried using a hydrophobic frit and evaporated to dryness. This was purified by ISCO Companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound. MS calcd for (C₁₉H₂₀BNO₃ + H)⁺ : 322 MS found (electrospray) : (M+H)⁺ = 322

Intermediate 11

Methyl 5-(4-furo[3,2-fo]pyridin-2-ylphenyl)-2-[[(fraπs-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-3-thiophenecarboxylate

Intermediate 3 (100 mg), Intermediate 5 (112 mg), Pd(PPh₃)₄ (40 mg) and Na₂CO₃ (106 mg in approximately 15 mL water) were dissolved in DMF (9 ml.) and were heated at 100⁰C for 5 h. The reaction mixture was evaporated to dryness and the residue partitioned between water and DCM. The aqueous phase was separated and extracted twice with DCM. The combined organic phases were dried using a hydrophobic frit and evaporated to dryness.

This was purified by ISCO companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound.

MS calcd for (C₃₀H₃₂N₂O₄S + H)⁺ : 517

MS found (electrospray) : (M+H)⁺ = 517

Intermediate 12 Methyl 2-[[(fraπs-4-methylcyclohexyl)carbonyl](1 -methylethyl)amino]-5-(4- pyrazolo[1 ,5-a]pyrimidin-2-ylphenyl)-3-thiophenecarboxylate

Intermediate 3 (125 mg), Intermediate 7 (140 mg), Pd(PPh₃J₄ (48 mg) and Na₂CO₃ (132 mg in aqueous solution) were dissolved in DMF (12 ml.) and were heated at 100⁰C for 5 h. The reaction mixture was passed through a hydrophobic frit, evaporated to dryness and the residue partitioned between water and DCM. The aqueous phase was separated and extracted twice more with DCM. The combined organic phases were dried using a hydrophobic frit and evaporated to dryness. This was purified by ISCO Companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound, MS calcd for (C_2SH₃₂N₄O₃S + H)⁺ : 517 MS found (electrospray) : (M+H)⁺ = 517

Intermediate 13

Methyl 5-[4-(1 ,3-benzoxazol-2-yl)phenyl]-2-[[(frans-4-methylcyclohexyl)carbonyl](1 - methylethyl)amino]-3-thiophenecarboxylate

Intermediate 3 (150 mg), Intermediate 10 (167 mg), Pd(PPh₃)₄ (58 mg) and Na₂CO₃ (158 mg in aqueous solution) were dissolved in DMF (14 mL) and were heated at 100⁰C for 5 h.

The reaction mixture was evaporated to dryness and the residue partitioned between water and DCM. The aqueous phase was separated and extracted twice more with DCM. The combined organic phases were dried using a hydrophobic frit and evaporated to dryness.

MS calcd for (C₃₀H₃₂N₂O₄S + H)⁺ : 517 MS found (electrospray) : (M+H)⁺ = 517

Intermediate 14

Methyl 5-(4-imidazo[1 ,2-a]pyridin-2-ylphenyl)-2-[[(fraπs-4- methylcyclohexyl)carbonyl](1-methylethyl)amino]-3-thiophenecarboxylate

Intermediate 3 (150 mg), Intermediate 8 (167 mg), Pd(PPh₃)₄ (58 mg) and Na₂CO₃ (158 mg in aqueous solution) were dissolved in DMF (14 mL) and were heated at 100⁰C for 5 h. The reaction mixture was evaporated to dryness and the residue partitioned between water and DCM. The aqueous phase was separated and extracted twice more with DCM. The combined organic phases were dried using a hydrophobic frit and evaporated to dryness. This was purified by ISCO Companion silica chromatography eluting with a gradient of ethyl acetate in cyclohexane to give the title compound. MS calcd for (C₃₀H₃₃N₃O₃S + H)⁺ : 516 MS found (electrospray) : (M+H)⁺ = 516

Intermediate 15 4-Bromo-2-furancarboxylic acid

To a solution of 4-bromo-2-furancarbaldehyde (5 g) in terf-butanol (350 mL) was added 2- methyl-2-butene (100 mL) followed by dropwise addition (over 30 mins) of a solution of sodium dihydrogenphosphate (23.9 g) and sodium chlorite (23 g) in water (165 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated in vacuo and the residue was dissolved in water. The aqueous was extracted with cyclohexane (x 2) and was then acidified to pH3 using 2N HCI. The aqueous was extracted with DCM (x 3) and the combined DCM fractions were dried using a hydrophobic frit and evaporated in vacuo to give the title compound.

MS calcd for (C₅H₃BrO₃ - H)^": 189/191

MS found (electrospray): (M-H) = 189/191

Intermediate 16

2-(4-Bromo-2-furanyl)-1,3-benzoxazole

4-Bromo-2-furancarboxylic acid (1.5 g, a synthesis of which is described above as Intermediate 15) was dissolved in DCM (20 mL). DEF (1 drop) was added followed by oxalyl chloride (1.04 ml_). The reaction mixture was stirred at room temperature overnight and was evaporated in vacuo to give 4-bromo-2-furancarbonyl chloride.

4-Bromo-2-furancarbonyl chloride (300 mg, prepared above) and 2-aminophenol (156 mg) were dissolved in 1 ,4-dioxane (3 mL). The reaction mixture was heated in a microwave at 21O⁰C for 45 mins. This was repeated 4 more times with fresh reagents. The five reaction mixtures were combined and poured into 1 N sodium hydroxide solution and this was extracted with DCM (x 3). The organics were dried by passing through a hydrophobic frit and were evaporated in vacuo. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 5-100% EtOAc in cyclohexane to give the trtle compound.

MS calcd for (C₁₁H₆NO₂Br+ H)⁺: 264/266 MS found (electrospray): (M+H)⁺ = 264/266

Intermediate 17 [5-(1 ,3-Benzoxazol-2-yl)-3-furanyl]boronic acid

Intermediate 16 (422 mg) was dissolved in 1 ,4-dioxane (12 mL) and potassium acetate (459 mg), PdCI₂(dppf) (90 mg) and bis(pinacolato)diboron (568 mg) were added. The reaction was heated at 100⁰C overnight. The reaction was cooled, evaporated in vacuo and partitioned between DCM and water. The organics were dried by passing through a hydrophobic frit and were evaporated in vacuo. The crude material was purified by silica SPE cartridge, eluting with EtOAc (200 mL), 1% MeOH in EtOAc (200 mL) and 5% MeOH in EtOAc (200 mL) to give the title compound as a 2:1 ratio with 2-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2-furanyl]-1 ,3-benzoxazole. Boronic acid:

MS calcd for (C₁₁H₃BNO₄+ H)⁺: 230 MS found (electrospray): (IvRH)⁺ = 230 Boronate ester: MS calcd for (C₁₇H₁₈BNO₄+ H)⁺: 312 MS found (electrospray): (M+H)⁺ = 312

Intermediate 18

Methyl 5-[5-(1,3-benzoxazol-2-yl)-3-furanyl]-2-[[(frans-4-methylcyclohexyl)carbonyl](1- rnethylethyl)amiπo]-3-thiophenecarboxylate

Intermediate 3 (298 mg) was dissolved in DMF (16 ml_). Intermediate 17 (170 mg), sodium carbonate (314 mg) in water (5 mL) and tetrakis(triphenylphosphine)palladium (0) (115 mg) were added and the reaction mixture was heated at 100⁰C for 1.5 h. The reaction was evaporated in vacuo and the residue was partitioned between water and DCM. The organics were dried by passing through a hydrophobic frit and were evaporated in vacuo. The crude material was purified by ISCO Companion silica chromataography, eluting with a gradient 5- 50% EtOAc in cyclohexane to give the title compound. MS calcd for (C₂₈H₃₀N₂O₅S+ H)⁺: 507 MS found (electrospray): (M+H)⁺ = 507

Intermediate 19

Methyl S-^-formylphenylJ^-IKfrans^-methylcyclohexyOcarbonylKI- methylethyl)amino]-3-thiophenecarboxylate

To a solution of methyl δ-bromo^-^fΛans-ΦmethylcyclohexylJcarbonylKI- rnethylethyl)amino]-3-thiophenecarboxylate (3 g, a synthesis of which is described above as Intermediate 3) in DMF (250 mL) was added (4-formylphenyl)boronic acid (1.56 g), sodium carbonate (3.1 g) in water (25 mL) and tetrakis(triphenylphosphine)palladium (0) (0.85 g). The reaction was heated at 10O⁰C for 3 h and was then cooled and evaporated in vacuo. The residue was partitioned between water and DCM and the organics were separated by hydrophobic frit and evaporated in vacuo. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 5-100% EtOAc in cyclohexane to give the title compound. MS calcd for (C₂₄H₂₈NO₄S+ H)⁺: 428 MS found (electrospray): (M+H)⁺ = 428

Intermediate 20

Methyl 2-[[(fra/7S-4-methylcyclohexyl)carbonyl](1 -methylethyl)amiπo]-5-{4-[(E)-2-(1 ,3- thiazol-4-yl)ethenyl]phenyl}-3-thiophenecarboxylate

4-(Chloromethyl)thiazole hydrochloride (5 g) was partitioned between DCM and saturated sodium bicarbonate solution. The organics were separated using a hydrophobic frit and were evaporated in vacuo. The residue was dissolved in toluene (40 mL) and was treated with triphenylphosphine (8.86 g). The reaction was heated at 5O⁰C overnight. The mixture was then allowed to cool and solid was filtered off to give tπphenyl(1 ,3-thiazol-4- ylmethyl)phosphonium chloride

A suspension of triphenyl(1 ,3-thιazol-4-ylmethyl)phosphonιum chloride (1.5 g, prepared above) in dry THF (16 mL) under nitrogen was treated with potassium tert-butoxide (1 M solution in THF, 3.5 mL). The mixture was stirred at room temperature for 10 mins. A solution of Intermediate 19 (0.8 g) in THF (16 mL) was added and the mixture was stirred for 2 h. The reaction was then quenched with saturated ammonium chloride solution and was extracted with EtOAc. The organics were separated, washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude material was purified by ISCO Companion silica chromatography, eluting with a gradient 5-100% EtOAc in cyclohexane to give the title compound.

MS calcd for (C₂₈H₃₂N₂O₃S₂+ H)⁺- 509 MS found (electrospray): (M+H)⁺ = 509

Intermediate 21

Methyl 2-[[(ϊraπs-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-{4-[2-(1,3- thiazol-4-yl)ethyl]phenyl}-3-thiophenecarboxylate

A solution of Intermediate 20 (0 6 g) in ethanol (50 mL) was added to 10% palladium on carbon catalyst (0.1 g) under vacuum The flask was purged with nitrogen, followed by hydrogen and the mixture was stirred for 2 days. The mixture was filtered through a sinter and the filtrate was evaporated in vacuo to give the title compound.

MS calcd for (C₂₈H₃₄N₂O₃S₂+ H)⁺: 511

MS found (electrospray): (M+H)⁺ = 511 Example 1

S^-FuroP^-JbJpyridin^-ylphenylJ^-IKfrans-^methylcyclohexylJcarbonyllti- methylethyl)amino]-3-thiophenecarboxylic acid

Intermediate 11 (69 mg) was dissolved in tetrahydrofuran (0.75 ml.) and ethanol (0.75 tnL) and treated with sodium hydroxide solution (2N, 0.5 ml_). The reaction mixture was stirred at room temperature overnight The reaction mixture was evaporated to dryness, the residue diluted with water and acidified with aqueous 2N HCI solution. The mixture was extracted with DCM, the organic extract separated using a hydrophobic frit and evaporated to dryness. The residue was purified by MDAP HPLC to give the title compound. MS calcd for (C₂₉H₃₀N₂O₄S + H)⁺: 503 MS found (electrospray): (M+H)⁺ = 503

¹H NMR (CDCI₃) δ 8.64 (1 H, d), 8.38 (1 H, d), 8.20 (1 H, s), 8.18 (2H₁ d), 7.94 (1 H, s), 7.86 (2H, d), 7.69 (1 H, dd), 5.03 (1 H, br), 2.23 (1 H, br), 1.82-1.20 (10H, m), 1.03 (3H, d), 0.78 (3H, d), 0.80-0.62 (2H, br) carboxylic acid proton not seen.

Example 2

2-[[(fraπs-4-Methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-(4-pyrazolo[1,5- a]pyrimidin-2-ylphenyl)-3-thiophenecarboxylic acid

Intermediate 12 (82 mg) was dissolved in tetrahydrofuran (1.5 mL) and ethanol (1.5 mL) and treated with sodium hydroxide solution (2N, 1.0 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, the residue diluted with water and acidified with aqueous 2N HCI solution. The mixture was extracted with DCM, the organic extract separated using a hydrophobic frit and evaporated to dryness. The residue was purified by MDAP HPLC to give the title compound. MS calcd for (C₂₈H₃₀N₄O₃S + H)⁺: 503 MS found (electrospray): (M+H)⁺ = 503 ¹H NMR (DMSO, temperature of 378.2 K) 5 9.03 (1 H, m), 8.53 (1 H₁ dd), 8.10 (2H, br d), 7.81 (2H, br d), 7.77 (1 H, s), 7.18 (1 H, br d), 7.02 (1 H, dd), 4.77 (1 H, septet), 2.25 (1 H, m), 1.80- 1.01 (13H, m), 0.79 (3H₁ d), 0.71 (2H, m) carboxylic acid proton not seen. Example 3

S-^^i_jS-Benzoxazol^-yOphenyll-Σ-I^frans^-methylcyclohexylJcarbonyllfi- methylethyl)amino]-3-thiophenecarboxylic acid

Intermediate 13 (150 mg) was dissolved in tetrahydrofuran (1.5 ml_) and ethanol (1.5 mL) and treated with sodium hydroxide solution (2N, 1.0 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, the residue diluted with water and acidified with aqueous 2N HCI solution. The mixture was extracted with DCM, the organic extract separated using a hydrophobic frit and evaporated to dryness. The residue was purified by MDAP HPLC to give the title compound. MS calcd for (C₂₉H₃₀N₂O₄S + H)⁺: 503 MS found (electrospray): (M+H)⁺ = 503 ¹H NMR (MeOD) δ 8.25 (2H, d), 7.88 (1 H, s), 7.85 (2H, d), 7.72 (1 H, m), 7.66 (1 H, m), 7.40 (2H, m), 4.89 (1 H, septet), 3.30 (1 H, m), 1.84-1.72 (2H, br), 170-1.25 (5H, m), 1.25 (3H, d), 1.01 (3H, d), 0.78 (3H, d), 0.78-0.59 (2H, br) carboxylic acid proton not seen.

Example 4

5-(4-lmidazo[1 ,2-a]pyridin-2-ylphenyl)-2-[[(frans-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-3-thiophenecarboxylic acid

Intermediate 14 (95 mg) was dissolved in tetrahydrofuran (1.5 mL) and ethanol (1.5 mL) and treated with sodium hydroxide solution (2N, 1.0 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, the residue diluted with water and acidified with aqueous 2N HCI solution. The mixture was extracted with DCM₁ the organic extract separated using a hydrophobic frit and evaporated to dryness. The residue was purified by MDAP HPLC to give the title compound. MS calcd for (C₂₉H₃₁N₃O₃S + H)⁺: 502 MS found (electrospray): (M+H)⁺ = 502

¹H NMR (MeOD) δ 8.46 (1 H, d), 8.28 (1 H, s), 8.01 (2H, d), 7.79 (1 H, s), 7.77 (2H, d), 7.58 (1 H, d), 7.36 (1 H, td), 6.95 (1 H₁ td), 4.91 (1 H, br), 2.30 (1 H, m), 1.79 (2H, m), 1.72-1.24 (5H, m), 1 26 (3H, d), 1 02 (3H, d), 0 80 (3H, d), 0 80-0.62 (2H, m) carboxylic acid proton not seen

Example 5

5-[5-(1,3-Benzoxazol-2-yl)-3-furanyl]-2-[[(frans-4-methylcyclohexyl)carbonyl]{1- methylethyl)amino]-3-thiophenecarboxylic acid

Intermediate 18 (155 mg) was dissolved in THF (1 5 mL) and EtOH (1.5 ml.) 2N sodium hydroxide solution (1 mL) was added and the reaction was stirred at room temperature overnight DCM (12 mL) was added followed by 2N HCI (5 mL) The mixture was stirred vigorously for 10 mins The organics were dried by passing through a hydrophobic frit and were evaporated in vacuo The crude material was purified by MDAP HPLC to give the title compound MS calcd for (C₂₇H₂₆N₂O₅S + H)⁺ 493 MS found (electrospray) (M+H)⁺ = 493

¹H NMR (CD₃OD) δ 8.31 (1 H, s), 7 77-7 73 (2H, m), 7 72-7.67 (2H, m), 7 49-7 42 (2H, m), 2 32-2 22 (1 H, m), 1 84-1 26 (8H, m), 1.24 (3H, d), 1 01 (3H, d), 0 80 (3H, d), 0 77-0 60 (2H, m), carboxylic acid proton not seen

Example 6

2-[[(rrans-4-Methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-{4-[2-(1,3-thiazol-4- yl)ethyl]phenyl}-3-thiophenecarboxylic acid

Intermediate 21 (508 mg) was dissolved in THF (1 5 mL) and ethanol (1 5 mL) 2N sodium hydroxide (1 mL) was added and the reaction was stirred at room temperature overnight DCM (12 mL) was added followed by 2N HCI (5 mL) and the mixture was stirred vigorously for 10 mins The DCM layer was separated using a hydrophobic frit and was evaporated in vacuo The crude material was purified by MDAP HPLC. The material was purified further using an ABZ + plus 100 x 21 2 mm ID 5μm column, eluting with 0 1% TFA/ water and 0.05% TFA/ MeCN, with a gradient 50-90% in 15 mins at 20 mL/ mm, with 20 mins cycle time, multiple injections, to give the title compound MS calcd for (C₂₇H₃₂N₂O₃S₂ + H)⁺: 497 MS found (electrospray): (M+H)⁺ = 497

¹H NMR (d_B-DMS0) δ 9.04 (1 H, d), 7.72 (1 H, s), 7.63 (2H, d), 7.32 (1 H, d), 7.28 (2H, d), 4.79 (1 H, quintet), 3.11-2.98 (4H, m), 2.19-2.08 (1 H, m), 1.69-1.41 (5H, m), 1.34-1.17 (2H, m), 1.14 (3H, d), 0.90 (3H, d), 0.75 (3H, d), 0.73-0.53 (2H, m), carboxylic acid proton not seen.

The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in therapy, comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.

The compounds of the present invention can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical, transdermal, or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.

Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compounds of the invention are formulated in liquid solutions, preferably, in pharmaceutically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.

For topical administration, the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.

The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound (IC₅₀) potency, (EC₅₀) efficacy, and the biological half-life (of the compound), the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art. Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Oral administration is a preferred method of administration of the present compounds.

Preferably the composition is in unit dosage form. For oral application, for example, a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.

Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula (I). A topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I). The active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.

Compounds of Formula (I) which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.

Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.

Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional non- CFC propellant such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. A typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs

Typical dermal and transdermal formulations comprise a conventional aqueous or nonaqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane

ASSAYS

The potential for chemical entities of the invention to inhibit NS5B wildtype HCV polymerase activity, genotype 1 b, may be demonstrated, for example, using the following in vitro assay:

In Vitro Detection of inhibitors of HCV RNA-dependent RNA Polymerase Activity

Incorporation of [³³P]-GMP into RNA was followed by absorption of the biotin labelled RNA polymer by streptavidin containing SPA beads. A synthetic template consisting of biotinylated 13mer-oligoG hybridised to polyrC was used as a homopolymer substrate.

Genotype 1b Full-Length Enzyme

Reaction Conditions were 0.5 μM [³³P]-GTP (20 Ci/mMol), 1 mM Dithiothreitol, 20 mM MgCI₂, 5mM MnCI₂ 20 mM Tris-HCI, pH7.5, 1.6 μg/mL polyC/0.256 μM biotinylated oligoG13, 10% glycerol, 0 01 % NP-40, 0.2 u/μL RNasin and 50 mM NaCI.

HCV RNA Polymerase (Recombinant full-length NS5B (Lohmann et al, J. Virol. 71 (11 ), 1997, 8416. 'Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity') expressed in baculovirus and purified to homogeneity) was added to 4 nM final concentration.

5x concentrated assay buffer mix was prepared using 1 M MnCI₂ (0.25 mL), glycerol (2.5ml_), 10% NP-40 (0.025 mL) and Water (7.225 mL), Total 10 mL.

2x concentrated enzyme buffer contained 1 M-Tris-HCI, pH7 5 (0.4 mL), 5M NaCI (0 2 mL), 1 M-MgCI₂ (0.4 mL), glycerol (1 mL), 10% NP-40 (10 μL), 1 M DTT (20 μL) and water (7 97 mL), Total 1O mL

Substrate Mix was prepared using 5x Concentrated assay Buffer mix (4μL), [³³P]-GTP (10 μCι/μL, 0.02μL), 25 μM GTP (0 4 μL), 40 u/μL RNasin (0.1 μL), 20 μg/mL polyrC/biotinylated- ohgorG (1.6 μL), and Water (3.94 μL), Total 10 μL. Enzyme Mix was prepared by adding 1 mg/ml full-length NS5B polymerase (1.5 μl_) to 2 81 mL 2x-concentrated enzyme buffer.

The Assay was set up using compound (1μL), Substrate Mix (10 μl_), and Enzyme Mix (added last to start reaction) (10 μl_), Total 21 μL.

The reaction was performed in a U-bottomed, white, 96-well plate The reaction was mixed on a plate-shaker, after addition of the Enzyme, and incubated for 1 h at 22⁰C. After this time, the reaction was stopped by addition of 40 μL 1.875 mg/ml streptavidin SPA beads in 0 1 M EDTA The beads were incubated with the reaction mixture for 1h at 22°C after which 120 μL 0.1 M EDTA in PBS was added. The plate was sealed, mixed centrifuged and incorporated radioactivity determined by counting in a Trilux (Wallac) or Topcount (Packard) Scintillation Counter.

After subtraction of background levels without enzyme, any reduction in the amount of radioactivity incorporated in the presence of a compound, compared to that in the absence, was taken as a measure of the level of inhibition. Ten concentrations of compounds were tested in three- or fivefold dilutions. From the counts, percentage of inhibition at highest concentration tested or IC₅₀S for the compounds were calculated using GraFit 3, GraFit 4 or GraFit 5 software packages or a data evaluation macro for Excel based on XLFit Software (IDBS).

The exemplified compounds had an IC₅₀ of <20μM in the above described assay. In one aspect, compounds have an IC₅₀ of <1 μM Accordingly, the compounds of the invention are of potential therapeutic benefit in the treatment and prophylaxis of HCV.

The pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example immune therapies (eg. Interferon, such as Interferon alfa-2a (Roferon-A; Hoffmann-La Roche), inteferon alpha-2b (Intron-A; Schering-Plough), interferon alfacon-1 (Infergen; Intermune), peginterferon alpha-2b (Peg- Intron; Schering-Plough) or peginterferon alpha-2a (Pegasys, Hoffmann-La Roche)), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial, anti-viral agents (eg ribavirin and amantidine), and anti-HCV agents (eg HCV NS3 protease inhibitors or HCV NS5b polymerase inhibitors). The compositions according to the invention may also be used in combination with gene replacement therapy. The invention thus provides, in a further aspect, a combination comprising a compound of Formula (I) together with at least one other therapeutically active agent, especially Interferon, ribavirin and/or an additional anti-HCV agent.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof represent a further aspect of the invention.

The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.

All publications, including but not limited to patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference as though fully set forth.

Claims

1. A compound of Formula (I) :

wherein: A represents hydroxy;

R¹ represents -R^x-R^γ;

R^x represents phenyl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) or 5- or 6-membered heteroaryl (optionally substituted by halo, methyl, ethyl, methoxy or trifluoromethyl) bonded through a ring carbon atom to the carbon atom of the thiophene;

R^γ represents (8-, 9- or 10-membered bicyclic heteroaryl), -CH₂CI-I₂-(S- or 6-membered heteroaryl), -CONH-(5- or 6-membered heteroaryl), -NHCO-(5- or 6-membered heteroaryl), - O-CH₂-(5- or 6-membered heteroaryl), or -CH₂-O-(S- or 6-membered heteroaryl), bonded such that when R^x is phenyl or a 6-membered heteroaryl, R^γ is in the para-position;

R² represents C₅-₇cycloalkyl optionally substituted by one or more substituents selected from -C_1Jβalkyl, =CH(CH₂)_tH, -OR^A, -SR^A, -C(O)NR^BR^C, -C(O)R⁰, -CO₂H, -CO₂R⁰, -NR^BR^C, - NR^EC(O)R^D, -NR^ECO₂R^D, -NR^EC(O)NR^FR^G, -SO₂NR^FR^G, -SO₂R^D, fluoro, -CF₃, nitro, cyano, oxo, and heterocyclyl, or wherein two alkyl substituents may together form a C^alkylene bridge substituent, or wherein two alkyl substituents on the same carbon atom may together form a C_3J(spiro substituent, or phenyl substituted by 1 to 3 halogen atoms.

R³ represents heterocyclyl; or phenyl optionally substituted by one or more substituents selected from -C_1-aalkyl, halo, -0R^E, -SR^E, -C(O)NR^BR^C, -C(O)R⁰, -CO₂H, -CO₂R⁰, -NR^BR^C, -NR^AC(O)R^D, -NR^ACO₂R^D, -NR^AC{O)NR^FR^G, -S0₂NR^FR^G, -SO₂R⁰, nitro, cyano, and heterocyclyl; or R³ represents -C_1-Balkyl optionally substituted by one or more substituents selected from -OR^E, -SR^E, -C(O)NR^BR^C, -C(O)R⁰, -CO₂H, -CO₂R⁰, -NR^BR^C, -NR^AC(O)R^D, -NR^ACO₂R^D, -NR^AC(O)NR^FR^G, -SO₂NR^FR^G, -SO₂R⁰, fluoro, nitro, cyano, oxo, phenyl, heteroaryl and heterocyclyl;

R^A represents hydrogen or -d._Balkyl;

R⁸ and R^c independently represent hydrogen, -C^alkyl, aryl, heterocyclyl or heteroaryl; or R^B and R^c together with the nitrogen atom to which they are attached form a 5- or 6- membered saturated cyclic group; R^D is selected from the group consisting of -C_1-6alkyl, aryl, heterocyclyl, heteroaryl, arylalkyl, and heteroarylalkyl;

R^F and R^G are independently selected from the group consisting of hydrogen, -Ci_-6alkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; or R^F and R^G together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated cyclic group;

or a salt, solvate or ester thereof.

2. A compound of Formula (I) which is: 5-(4-Furo[3,2-ύ]pyridin-2-ylphenyl)-2-[[(fra/7s-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-3-thiophenecarboxylic acid;

2-[[{fra^s-4-Methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-(4-pyrazolo[1 ,5-a]pyrimidin-2- ylphenyl)-3-thiophenecarboxylic acid;

5-[4-(1 ,3-Benzoxazol-2-yl)phenyl]-2-[[(^rans-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-3-thiophenecarboxylic acid; 5-(4-lmidazo[1 ,2-a]pyridin-2-ylphenyl)-2-[[(fra/7s-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-3-thiophenecarboxylic acid;

5-[5-(1 ,3-Benzoxazol-2-yl)-3-furanyl]-2-[[(fra/is-4-methylcyclohexyl)carbonyl](1- methylethyl)amino]-3-thiophenecarboxylic acid;

2-[[(fraAJS-4-Methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-{4-[2-(1 ,3-thiazol-4- yl)ethyl]phenyl}-3-thiophenecarboxylic acid; or salts, solvates or esters, or individual enantiomers thereof where appropriate.

3. A method of treating or preventing viral infection which comprises administering to a subject in need thereof, an effective amount of a compound of Formula (I) as defined in claim 1 or salts, solvates or esters thereof.

4. A method as claimed in claim 3 which involves inhibiting HCV replication.

5. A compound of Formula (I) as defined in claim 1 or salts, solvates or esters thereof, for use in medical therapy.

6. A compound as claimed in claim 5 wherein the medical therapy is the treatment of viral infection.

7. A pharmaceutical formulation comprising at a compound of Formula (I) as defined in claim 1 or pharmaceutically acceptable salts, solvates or esters thereof in conjunction with at least one pharmaceutically acceptable diluent or carrier.

8. Use of a compound of Formula (I) as defined in claim 1 or pharmaceutically acceptable salts, solvates or esters thereof, in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection.

9. A combination comprising a compound of Formula (I) as defined in Claim 1 , or pharmaceutically acceptable salts, solvates or esters thereof, together with at least one other therapeutically active agent.

10. A combination as claimed in Claim 9, wherein the other therapeutically active agent is selected from Interferon, ribavirin and/or an additional anti-HCV agent.