CHEMICAL COMPOUNDS

Abstract: This invention relates to compounds of formula (1), wherein substituents are defined in the description, that inhibit farnesylation of mutant ras gene products through inhibition of the enzyme farnesyl-protein transferase (FPTase). The invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through farnesylation of ras.

Description: CHEMICA COMPOUNDS This invention relates to compounds that inhibit famesylation of mutant ras gene products through inhibition of the enzyme farnesyl-protein transferase (FPTase). The invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through famesylation of ras. Cancer is believed to involve alteration in expression or function of genes controlling cell growth and differentiation. Whilst not wishing to be bound by theoretical considerations the following text sets out the scientific background to ras in cancer. Ras genes are frequently mutated in tumours. Ras genes encode guanosine triphosphate (GTP) binding proteins which are believed to be involved in signal transduction, proliferation and malignant transformation. H-, K- and N-ras genes have been identified as mutant forms of ras (Barbacid M, Ann. Rev. Biochem. 1987, 56: 779-827). Post translational modification of ras protein is required for biological activity. Famesylation of ras catalysed by FPTase is believed to be an essential step in ras processing. It occurs by transfer of the farnesyl group of famesyl pyrophosphate (FPP) to a cysteine at the C-terminal tetrapeptide of ras in a structural motif called the CAAX box. After further post-translational modifications, including proteolytic cleavage at the cysteine residue of the CAAX box and methylation of the cysteine carboxyl, ras is able to attach to the cell membrane for relay of growth signals to the cell interior. In normal cells activated ras is believed to act in conjunction with growth factors to stimulate cell growth. In tumour cells it is believed that mutations in ras cause it to stimulate cell division even in the absence of growth factors (Travis J, Science 1993, 260: 1877-1878), possibly through being permanently in GTP activated form rather than cycled back to GDP inactivated form. Inhibition of famesylation of mutant ras gene products will stop or reduce activation. One class of known inhibitors of famesyl transferase is based on famesyl pyrophosphate analogues; see for example European patent application EP 534546 from Merck. Inhibitors of famesyl transferase based on mimicry of the CAAX box have been reported. Reiss (1990) in Cell 62, 81-8 disclosed tetrapeptides such as CVIM (Cys-Val-Ile- Met). James (1993) in Science 260, 1937-1942 disclosed benzodiazepine based peptidomimetic compounds. Lerner (1995) in J. Biol. Chem. 270, 26802 and Eisai in International Patent Application WO 95/25086 disclosed further peptidomimetic compounds based on Cys as the first residue. Bristol-Myers Squibb in European Patent Application EP 696593 disclosed famesyl transferase inhibitors having a 4-sulfanylpyrrolidine residue in the first position. International Patent Application WO 97/17070 discloses a broad range of compounds which can contain an imidazole group and a methionine substituent. We have now discovered a narrow class of imidazole compounds which have improved properties. According to one aspect of the present invention there is provided a compound of Formula (1): Formula (1) wherein Ar 1 represents: R "1 is hydrogen, C ]-4 alkyl, phenylC ] -4 alkyl; R is hydrogen, C 1-4 alkyl, hydroxyCι -4 alkyl, haloC, 4 alkyl, dihaloC, „alkyl, C, 4 alkoxy, C, 4 alkoxyC, 4 alkyl, sulfanylC ) - alkyl, aminoC, -4 alkyl, N-(C|_ 4 alkyl)aminoC 1 -4 alkyl, N,N-di(C 1 -4 alkyl)aminoC 1 -4 alkyl or phenylC M alkyl; m is 0,1 or 2; R' 2 and R" are independently hydrogen or C, alkyl; Ar 2 is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, thiazolyl, furyl or oxazolyl, the ring being substituted on ring carbon atoms by R 2 and -(CH 2 ) n R 3 , wherein Ar 2 is attached to Ar'C(R ,2 )R ,3 CH=CH- by a ring carbon atom; or Ar 2 is pyrrolyl, pyrazolyl or imidazolyl, substituted by R 2 and -(CH 2 ) n R 3 (the pyrrolyl, pyrazolyl or imidazolyl rings can bear a substituent on the sp 1 hybridised ring nitrogen or Ar 2 can be attached to Ar'C(R l2 )R l, CH=CH- by the sp' hybridised ring nitrogen); R is a group of the Formula (2): Formula (2) wherein R is hydrogen or C^^alkyl, R* is -(CH 2 ) q -R' 0 wherein q is 0-4 and R 10 is Cι -4 alkylsulfanyl, Cι -4 alkylsulfinyl, C 1 -4 alkylsulfonyl, hydroxy, Cι_ 4 alkoxy, carbamoyl, N-C ] -4 alkyl carbamoyl, N,N-(diCι_ 4 alkyl)carbamoyl, C 1 -4 alkyl, phenyl, thienyl, or Cι_ 4 alkanoylamino, R 9 is hydroxy, C| -6 alkoxy, C, 9 cycloalkyloxy, heterocyclyloxy, heterocyclylC, 4 alkoxy or -NH-SO 2 -R" wherein R" represents, trifluoromethyl, Cι -4 alkyl, phenyl, heteroaryl, arylC, 4 alkyl or heteroarylC, 4 alkyl; or R represents a lactone of Formula (3) Formula (3) O the group of Formula (2) or (3) having L or D configuration at the chiral alpha carbon in the corresponding free amino acid; n is 0, 1 or 2; R " is phenyl or heteroaryl; 2 or R is a group of the Formula (4): -CONHCH(R' « )R' > Formula (4) wherein R 4 is -(CH^ q -R" wherein q is 0-4 and R 1 ' is C alkylsulfanyl, C 1 -4 alkylsulfmyl, C alkylsulfonyl, hydroxy, Cι -4 alkoxy, carbamoyl, N-C 1 -4 alkyl carbamoyl, N,N-(diC alkyl)carbamoyl, C alkyl, phenyl, thienyl, or C alkanoylamino; R 14 is of the formula -CH, OR' 7 (wherein R 17 is hydrogen, C, .4 alkyl, phenyl, heteroaryl, C, ,alkanoyl, C M alkoxymethyl, phenoxymethyl or heteroaryloxymethyl), of the formula -COR 18 or of the formula -CH.COR' 8 (wherein R' 8 is C, alkyl (optionally substituted by halo, cyano, C 2 5 alkanoyloxy, hydroxy, C^alkoxy or Cι_4alkanoyl), phenyl, phenylC, ,alkyl, heteroaryl, heteroarylC, .alkyl, C, 7 cycloalkyl, C, 7 cycloalkylC, ,alkyl, 2-(phenyl)ethenyl, 2-(heteroaryl)ethenyl or N-methoxy-N-methylammo); or R" is morpholinoC l 4 alkyl, pyrrolidιn-l-ylC l 4 alkyl or pιpeπdιn-l-ylC l alkyl wherein the mo holine, pyrrolidine and piperidine rings are optionally substituted by C, 4 alkyl or C 5 7 cycloalkyl; or R 13 is phenyl- 1 -hydroxy C M alkyl or heteroaryl- 1-hydroxyC, 4 alkyl; phenyl and heteroaryl rings in R 3 , R% R 6 , R" and R" (including R 17 and R 18 ) are independently optionally substituted on ring carbon atoms by up to three substituents selected from C]_4alkyl, halogen, hydroxy, Cι _4alkoxy, Cι _4alkoxycarbonyl, Cι _4alkanoyl, Cι_4alkanoyloxy, amino, Cι _4alkylamιno, dι(C galley l)ammo, Cι_4alkanoylammo, nitro, cyano, carboxy, thiol, Cι _4alkylsulfanyl, Cι_4alkylsulfinyl, Cι_4alkylsulfonyl, C, 4 alkanesulphonamido, N-(C, 4 alkylsulphonyl)-N-C, 4 alkylammo, ammosulfonyl, N-(C, 4 alkyl)ammosulfonyl, N,N-di(C, alkyl)amιnosulfonyl, carbamoyl, N-(C 1 -4 alkyl)carbamoyl, N,N-(dιC]- alkyl)carbamoyl, carbamoylC 1-4 alkyl, N-(Cι -4 alkyl)carbamoylCι. 4 alkyl, N,N-(dιCι. 4 alkyl)carbamoylCι_ 4 alkyl, hydroxyC ] -4 alkyl and C )-4 alkoxyCi -4 alkyl and on ring NH groups (replacing hydrogen) by C, 4 alkyl, C, 4 alkanoyl, C M alkylsulfonyl, haloC, 4 alkyl, difluoromethyl or trifluoromethyl; or a pharmaceutically-acceptable salt, prodrug or solvate thereof. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-cham version only. An analogous convention applies to other generic terms. It is to be understood that, insofar as certain of the compounds of Formula (1) defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of inhibiting FTPase. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, inhibitory properties against FTPase may be evaluated using the standard laboratory techniques referred to hereinafter. The term "heterocyclyl" refers to a 5- or 6-membered monocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. The term "heteroaryl" refers to a 5-10 membered monocyclic heteroaryl ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulphur. The ring sp 3 hybridised ring nitrogen in the pyrrolyl, pyrazolyl or imidazolyl rings is the ring nitrogen which can be substituted without becoming quaternised i.e. the ring >NH nitrogen. The term " halogen " refers to fluorine, chlorine, bromine and iodine. The term "carbamoyl" refers to -C(O)NH 2 . The term " BOC " refers to tert-butoxycarbonyl. Examples of C ] -4 alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl and tert- butyl; examples of Cι- alkoxy include methoxy, ethoxy and propoxy; examples of Ci _4alkanoyl include formyl, acetyl and propionyl; examples of Ci _4alkanoyloxy include acetyloxy and propionyloxy; examples of C ) -4 alkylamino include methylamino, ethylamino, propylamino, isopropylamino, sec-butylamino and tert-butylamino; examples of di-(C]. 4 alkyl)amino include di-methylamino, di-ethylamino and N-ethyl-N-methylamino; examples of Cι ^ 4alkanoylamino include acetamido and propionylamino; examples of C| -4 alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of C^^alkylsulfanyl include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, sec-butylsulfanyl and tert-butylsulfanyl; examples of Cj^alkylsulfinyl include methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfmyl, seobutylsulfinyl and tert-butylsulfmyl; examples of Cj^alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl; examples of N- (C l -4 alkyl)carbamoyl include N-methylcarbamoyl and N-ethylcarbamoyl; examples of N,N- (diC 1 -4 alkyl)carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N-ethylcarbamoyl; examples of Cι_4alkanesulfonamido include methanesulfonamido, ethanesulphonamido and propanesulfonamido; examples of C^alkylsulfonyl-N-C^alkylamino include methylsulfonyl-N-methylamino, ethylsulfonyl-N-methylamino and propylsulfonyl-N- methylamino; examples of fluoroC alkyl include fiuoromethyl, 2-fluoroethyl and 3- fluoropropyl; examples of difluoroC alkyl include difluoromethyl, 2,2-difluoroethyl and 3,3- difluoropropyl; examples of carbamoylC alkyl include carbamoylmethyl, carbamoylethyl and carbamoylpropyl; examples of N-(C|. 4 alkyl)carbamoylC 1 - alkyl include N-methyl- carbamoylmethyl and N-ethyl-carbamoylethyl; examples of N,N-(diC| -4 alkyl)carbamoyl-Cι. 4 alkyl include N,N-dimethylcarbamoylethyl and N-methyl-N-ethylcarbamoylethyl; examples of hydroxyCj -4 alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-hydroxypropyl, 2-(hydroxymethyl)propyl and hydroxybutyl; examples of C 1 -4 alkoxyC] -4 alkyl include methoxyethyl, ethoxyethyl and methoxybutyl; examples of sulfanylC| -4 alkyl include sulfanylmethyl, sulfanylethyl, sulfanylpropyl; and examples of N-(C 1 -4 alkyl)aminoCι- alkyl include N-methyl-aminomethyl and N-ethyl-aminoethyl. Examples of 5- or 6-membered heteroaryl ring systems include imidazole, triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene. Preferably the NH group in imidazole is unsubstituted or substituted by C,. 4 alkyl. Examples of heterocyclyl rings include pyrrolidinyl, morpholinyl, piperidinyl, dihydropyridinyl and dihydropyrimidinyl. Preferred heteroatoms are N and S, especially N. In general, attachment of heterocyclic rings to other groups is via carbon atoms. Examples of values for R 8 in Foπnula (2) are side chains of lipophilic amino acids including such as for example methionine, phenylglycine, phenylalanine, serine, leucine, isoleucine or valine. The L configuration in the corresponding free amino acid is preferred. Examples of amino acid side chains are set out below. Amino Acid Side Chain methionine -CH 2 -CH 2 -S-CH 3 phenylglycine Ph phenylalanine -CH 2 -Ph thienylalanine -CH 2 -thien-2-yl serine -CH 2 OH or a C ] -4 alkyl (preferably methyl) ether thereof. Leucine -CH 2 -CHMe 2 homoserine -CH 2 -CH 2 -OH or a C 1 -4 alkyl (preferably methyl) ether thereof N-acetyl-lysine -CH 2 -CH 2 -CH 2 -CH 2 -NH-CO-CH 3 The lactone in Fom ula (3) can be formed from a group of Formula (2) when R'is OH to give a carboxyl and R s is -CH 2 -CH 2 -OH where R 8 and R" together lose a water molecule to form part of a dihydrofuran-2-one heterocyclic ring. Preferably, phenyl and heteroaryl rings in R R R\R" and R" (including R l7 and R' 8 ) are independently optionally substituted on ring carbon atoms by up to two substituents selected from C l 4 alkyl, halogen, hydroxy, C 1 4 alkoxy, C, 4 alkoxycarbonyl, C, 4 alkanoyl, C l 4 alkanoyloxy, amino, C, 4 alkylamino, di(C, 4 alkyl)amino, C l 4 alkanoylamino, cyano, carboxy, C, 4 alkylsufanyl, C, 4 alkylsulfinyl, C ] alkylsulfonyl, C, 4 alkanesulphonamido, carbamoyl, N-(C, 4 alkyl)carbomoyl, N,N-(diC alkyl)carbamoyl and on ring NH groups (replacing hydrogen) by C, 4 alkyl or C, 4 alkanoyl. Preferably R' 2 and R 11 are independently hydrogen or methyl. Most preferably R 12 and R 13 are hydrogen. Preferably R' is hydrogen, C M alkyl, hydroxyC|. alkyl, aminoC|- alkyl, fluoroC, 4 alkyl, difluoroC, 4 alkyl, C, 4 alkoxy or C, 4 alkoxyC, 4 alkyl. More preferably R 6 is hydrogen, methyl, fluoromethyl, difluoromethyl, methoxy or methoxymethy 1. Most preferably R" is hydrogen or methyl. Preferably m is 0 or 1. Preferably R 5 is hydrogen or methyl. More preferably R' is hydrogen. In a particular aspect Ar 1 is l-methylimidazol-5-yl. Preferably Ar 2 is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, thiazolyl, or oxazolyl, the ring being substituted on ring carbon atoms by R 2 and -(CH 2 )„R 3 . Most preferred is where Ar 2 is phenyl, pyridinyl or thienyl, the ring being substituted on ring carbon atoms by R 2 and -(H 2 )„R\ More preferably Ar 2 is phenyl, pyridinyl or thienyl, the ring being substituted on ring carbon atoms by R 2 and -(CH 2 )„R 3 . Yet more preferably Ar 2 is phenyl or pyridyl, the ring being substituted on ring carbon atoms by R 2 and -(CH 2 )„R 3 . Most preferably Ar 2 is phenyl, the ring being substituted on ring carbon atoms by R 2 and -(CH 2 )„R\ Preferably, when n is 0, Ar 2 is substituted by R in the 4-position and -(CH 2 )„R 3 in the 3- or 5-position and when n is 1 or 2, Ar 2 is substituted by R 2 in the 3- or 5-position and — (CH 2 )„R 2 in the 4-position. The positions indicated are relative to the point of attachment of Ar 2 to Ar'C(R l2 )R l3 CH=CH-. Preferably n is 0 or 2. In a particular aspect n is 0. R 2 is preferably a group of formula: R 7 is preferably hydrogen or methyl, especially hydrogen. In R s , q is preferably 1-4, more preferably 1 or 2, especially 2. Within R 8 , R'° is preferably C, alkylsulfanyl, C, 4 alkylsulfinyl, C M alkylsulfonyl, hydroxy or C, 4 alkoxy. More preferably R 10 is methylsulfanyl or methylsulfonyl. R c ' is preferably hydroxy, C, 4 alkoxy, C, cycloalkyloxy, heterocyclyloxy or heterocyclylC,. 4 alkoxy. More preferably R" is hydroxy, methoxy, propoxy, butoxy, tert- butoxy, cyclopentyloxy, piperidin-4-yloxy or morpholinoC, 4 alkyl. Most preferably, R 9 is methoxy, prop-2-oxy, n-butoxy, tert-butoxy or cyclopentyloxy. Preferably R" in R" is phenyl. Preferred substituents for NH groups in heterocyclic groups in R" include methyl, ethyl, acetyl, propionyl, fluorome hyl, difluoromethyl and trifluoromethyl. More preferred substituents for NH groups in heterocyclic groups in R' include methyl and acetyl. Preferred substituents for ring carbon atoms in phenyl or heteroaryl groups in R" include methyl, halo, C l 4 alkanoyl, nitro, cyano, C, 4 alkylsulfinyl, C l 4 alkylsulfonyl, carbamoyl, C, 4 alkylcarbamoyl and diC, 4 alkylcarbamoyl. Formula (4) is preferably a group of formula: In R 14 , q is preferably 1-4, more preferably 1 or 2, especially 2. Within R 14 , R' 4 is preferably C, 4 alkylsulfanyl, C, 4 alkylsulfmyl, C, 4 alkylsulfonyl, hydroxy or C, 4 alkoxy. More preferably R 16 in R' 4 is methylsulfanyl or methylsulfonyl. Preferably R 17 in R 15 is hydrogen or phenyl. Most preferably R 17 in R 15 is hydrogen. Preferably R 18 in R 15 is C,. 4 alkyl, phenyl, phenylC,. 3 alkyl, heteroaryl, heteroarylC, .3 alkyl or C^cycloalkylC, , alkyl. More preferably R 18 in R 1:, is C, 4 alkyl, phenyl, phenylC, ,alkyl or heteroaryl. Most preferably R 18 in R 15 is C, 4 alkyl, phenyl or benzyl. Preferably when R' 8 is C M alkyl, it is optionally substituted by halo, cyano or C 2 6 alkanoyloxy. Preferably morpholinoC, 4 alkyl is moφholinomethyl, pyrrolidin-1-ylC, 4 alkyl is pyπO li din- 1-ylm ethyl and piperidin-l-ylC l 4 alkyl is piperidin-1-ylmethyl. In one aspect R 15 is morpholinomethyl. More preferably R 15 is hydroxymethyl, benzylcarbonyl, 3-(pyridyl)propionyl or moφholinomethyl. Most preferably R' 5 is hydroxymethyl or benzylcarbonyl. R 14 is -(CH 2 ) q R 16 wherein q is 0-4 and R 16 is C, 4 alkylsulfanyl, C, 4 alkylsulfmyl, C, 4 alkylsulfonyl, hydroxy or C, 4 alkoxy; or R' 5 is moφholinomethyl, pyrrolidin-1-ylmethyl or piperi din- 1-ylm ethyl; or R 13 is of the formula -CH,OR 17 wherein R 17 is hydrogen or phenyl; or R 13 is of the formula -COR 18 or -CH 2 COR 18 wherein R 18 is C, alkyl, phenyl, phenylC, ,alkyl, heteroaryl, heteroarylC, 3 alkyl or C 57 cycloalkylC, ,alkyl; Preferably R 3 is phenyl, pyridyl or thiazolyl. Most preferably R 3 is phenyl. Preferred substituents for ring carbon atoms in R 1 include C, 4 alkyl, halo, trifluoromethyl, C,. 4 alkoxy, nitro, cyano and C, 4 alkoxy C 1 4 alkyl. More preferred substituents for ring carbon atoms in R 3 include methyl, fluoro, chloro, trifluoromethyl, methoxy, nitro, cyano and methoxym ethyl. When R' is phenyl it is preferably mono-substituted by fluoro, chloro or cyano or di- substituted by fluoro and triflouromethyl, chloro and trifluoromethyl, fluoro and fluoro or chloro and chloro. A preferred substituent for a ring NH group in a heteroaryl group in R 3 is C, 4 alkyl, particularly methyl. When R 3 is phenyl it is preferably substituted in the 4-position, and when di- substituted it is preferably substituted in the 2- and 4-positions. Preferably n is 0 or 2. Preferably R 7 is hydrogen. Preferably R 8 is -(CH 2 ) - R 10 is C alkylsulfonyl or C, 4 alkylsulfonyl. Preferably R" is hydroxy, C, 6 alkoxy, C, „cycloalkyloxy, heterocyclyloxy or heterocyclylC, 4 alkoxy. A preferred compound of the invention is a compound of the Formula (I) wherein : Ar' is of the formula (A), (B) or (C); R 1 is hydrogen or methyl; R" is hydrogen, C, 4 alkyl, fluoroC, 4 alkyl, difluoroC, 4 alkyl, C, 4 alkoxy or C, 4 alkoxyC, 4 alkyl; m is O or l; R 12 and R" are independently hydrogen or methyl; Ar 2 is phenyl or pyridyl, the ring being substituted on ring carbon atoms by R 2 and -(CH,)„R 3 and wherein Ar 2 is attached to Ar l C(R 12 )R l1 CH=CH- by a ring carbon atom; and n is 0,1 or 2; R 2 is of the formula (2) wherein R 7 is hydrogen or methyl; R s is -(CH,)^ 10 wherein q is 0-4 and R'° is C, 4 alkylsulfanyl, C, 4 alkylsulfmyl, C, 4 alkylsulfonyl, hydroxy or C M alkoxy; R" is hydroxy, C, 4 alkoxy, C 3 „cycloalkyloxy, heterocycloxy or heterocyclylC, 4 alkoxy; or R 2 is of the formula (3); R' is phenyl, pyridyl or thiazolyl; and phenyl, heteroaryl and heterocyclyl rings in R 3 and R" are independently optionally substituted on ring carbon atoms by one or two substituents selected from C, 4 alkyl, halo, C, 4 alkoxy, C, alkanoyl, nitro, cyano, C, 4 alkylsulfmyl, C, 4 alkylsulfonyl, carbamoyl, C, alkylcarbamoyl and diC, 4 alkylcarbamoyl; and optionally substituted on ring NH groups by C, alkyl, C, 4 alkanoyl, fluoromethyl, difluoromethyl or trifluoromethyl; or a pharmaceutically-acceptable salt, prodrug or solvate thereof. A more preferred compound of the invention is a compound of the formula (I) wherein: Ar 1 is ofthe formula (A), (B) or (C); R 3 is hydrogen or methyl; R 6 is hydrogen, methyl, fluoromethyl, difluoromethyl, methoxy or methoxymethyl; m is 0 or 1 ; R 12 and R 13 are independently hydrogen or methyl; Ar 2 is phenyl or pyridyl; the ring being substituted on ring carbon atoms by R 2 and -(CH 2 )„R 3 and wherein Ar 2 is attached to Ar'C(R 12 )R l1 CH=CH- by a ring carbon atom; and n is 0, 1 or 2; R 2 is of formula (2) wherein R 7 is hydrogen or methyl; R s is -(CH 2 ) q R 10 wherein q is 1 or 2, and R'° is methylsulfanyl or methylsulfonyl; R 9 is hydroxy, methoxy, prop-2-oxy, butoxy, tert-butoxy, cyclopentyloxy, piperidin-4-yloxy, or moφholinoC, 4 alkyl; or R 2 is ofthe formula (3); R 3 is phenyl optionally substituted by one or two substituents selected from C, 4 alkyl, halo, C, 4 alkoxy, nitro, cyano, C, 4 alkoxyC M alkyl and trifluoromethyl; or a pharmaceutically-acceptable salt, prodrug or solvate thereof. An even more preferred compound ofthe invention is a compound ofthe formula (I) wherein: Ar 1 is ofthe formula (A), (B) or (C); R 1 is hydrogen or methyl; R° is hydrogen or methyl; m is 0 or 1 ; R" and R 12 are hydrogen; Ar 2 is phenyl; the ring being substituted on ring carbon atoms by R 2 and -(CH 2 )„R 3 and wherein Ar 2 is attached to Ar'(R l2 )R ,3 CH=CH- by a ring carbon atom; and n is 0, 1 or 2; R 2 is ofthe Formula (2) wherein R 7 is hydrogen; R 8 is -(CH 2 ) q R 10 wherein q is 2 and within Formula(2) R 10 is methylsulfanyl or methylsulfonyl; R" is hydroxy, methoxy, prop-2-oxy, butoxy, tert-butoxy, cyclopentyloxy, piperidin-4-yloxy, or 2-moφholinoprop-2-yl; or within Formula(4) R is ofthe fomula -CH 2 OR 17 wherein R 17 is hydrogen; or R 13 is ofthe formula -COR 18 or - CH,COR ls wherein R 18 is C, 4 alkyl, phenyl, phenylC, ,alkyl or heteroaryl; or R 15 is moφholinomethyl, pyrrolidin-1-ylmethyl or piperidin-1-ylmethyl; R 3 is phenyl optionally substituted by fluoro, chloro, cyano or trifluoromethyl; or a pharmaceutically-acceptable salt, prodrug or solvate thereof. Preferably Ar'C(R 12 )R 13 - and Ar 2 are on opposite sides ofthe double bond (this gives the E isomeric configuration). Particular compounds ofthe present invention include those compounds specifically described in the Examples; or a pharmaceutically-acceptable salt, prodrug or solvate thereof. Compounds of Formula (1) may form salts which are within the ambit ofthe invention. Pharmaceutically acceptable salts are prefeπ-ed although other salts may be useful in, for example, isolating or purifying compounds. When the compound contains a basic moiety it may form pharmaceutically-acceptable salts with a variety of inorganic or organic acids, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. A suitable pharmaceutically-acceptable salt ofthe invention when the compound contains an acidic moiety is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, moφholine or tris-(2-hydroxyethyl)amine. Solvates, for example hydrates, are also within the ambit ofthe invention and may be prepared by generally known methods. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al, Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984). Examples of pro-drugs include in vivo hydrolysable esters of a compound ofthe Formula I. Suitable pharmaceutically-acceptable esters for carboxy include C, 8 alkyl esters, C. s cycloalkyl esters, cyclic amine esters, Cι -6 alkoxymethyl esters for example methoxymethyl, C ] -6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 . 8 cycloalkoxycarbonyloxyC]. 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3- dioxolen-2-onylmethyl; and C 1 -6 alkoxycarbonyloxyethyl esters for example 1 -methoxycarbonyloxyethyl wherein alkyl, cycloalkyl and cyclicamino groups are optionally substituted by, for example, phenyl, heterocyclcyl, alkyl, amino, alkylamino, dialkylamino, hydroxy, alkoxy, aryloxy or benzyloxy, and may be formed at any carboxy group in the compounds of this invention. According to another aspect ofthe invention there is provided a pharmaceutical composition comprising a compound as defined in Formula (1) or an individual compound listed above together with a pharmaceutically-acceptable diluent or carrier. A preferred pharmaceutical composition is in the form of a tablet. The compositions ofthe invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions ofthe invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as com starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absoφtion ofthe active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymefhylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti- oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions ofthe invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products ofthe said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more ofthe appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Suppository formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols. Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, may generally be obtained by formulating an active ingredient with a conventional, topically acceptable, vehicle or diluent using conventional procedure well known in the art. Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of average diameter of, for example, 30μ or much less, the powder itself comprising either active ingredient alone or diluted with one or more physiologically acceptable carriers such as lactose. The powder for insufflation is then conveniently retained in a capsule containing, for example, 1 to 50mg of active ingredient for use with a turbo-inhaler device, such as is used for insufflation ofthe known agent sodium cromoglycate. Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. For further information on Formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The size ofthe dose for therapeutic or prophylactic puφoses of a compound ofthe Formula (1) will naturally vary according to the nature and severity of the conditions, the age and sex ofthe animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds ofthe Formula (1) are useful in treating diseases or medical conditions which are due alone or in part to the effects of famesylation of ras. In using a compound ofthe Formula (1) for therapeutic or prophylactic puφoses it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however preferred. Compounds of this invention may be useful in combination with known anti-cancer and cytotoxic agents. If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate. According to another aspect ofthe invention there is provided a compound of Formula (1) or a pharmaceutically-acceptable salt thereof, for use as a medicament. According to another aspect of the invention there is provided a compound of Formula (1) or a pharmaceutically-acceptable salt thereof, for use in preparation of a medicament for treatment of a disease mediated through famesylation of ras. According to another aspect of the present invention there is provided a method of treating ras mediated diseases, especially cancer, by administering an effective amount of a compound of Formula (1) or a pharmaceutically-acceptable salt thereof, to a mammal in need of such treatment. Diseases or medical conditions may be mediated alone or in part by famesylated ras. A particular disease of interest is cancer. Specific cancers of interest include: -carcinoma, including that ofthe bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; -hematopoietic tumors of lymphoid lineage, including acute lymphocytic leukemia, B-cell lymphoma and Burketts lymphoma; - hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias and promyelocytic leukemia; - tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; and - other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma. The compounds of Formula (1) are especially useful in treatment of tumors having a high incidence of ras mutation, such as colon, lung, and pancreatic tumors. By the administration of a composition having one (or a combination) ofthe compounds of this invention, development of tumors in a mammalian host is reduced. Compounds of Formula (1) may also be useful in the treatment of diseases other than cancer that may be associated with signal transduction pathways operating through Ras, e.g., neuro-fibromatosis. Compounds of Formula (1) may also be useful in the treatment of diseases associated with CAAX-containing proteins other than Ras (e.g., nuclear lamins and transducin) that are also post-translationally modified by the enzyme famesyl protein transferase. Although the compounds ofthe Formula (1) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of activation of ras by famesylation. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. In another aspect the present invention provides a process for preparing a compound ofthe Formula (1) or a pharmaceutically-acceptable salt prodrug or solvate thereof which process comprises: deprotecting a compound ofthe formula (5) wherein Ar 1 is Ar 1 or protected Ar 1 and Ar : is Ar 2 or protected Ar 2 and R' 2 and R 13 are as hereinabove defined; wherein at least one protecting group is present; and thereafter if necessary: (i) forming a pharmaceutically-acceptable salt, (ii) forming a prodmg, (iii) forming a solvate. Protecting groups may in general be chosen from any ofthe groups described in the literature or known to the skilled chemist as appropriate for the protection ofthe group in question, and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal ofthe protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which "lower" signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention. A carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester- forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain C 2 alkyl groups (for example isopropyl, t-butyl); lower alkoxy lower alkyl groups (for example methoxymethyl, ethoxymethyl, isobutoxymethyl); lower aliphatic acyloxy lower alkyl groups, (for example acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (for example 1 -methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); phenyl lower alkyl groups (for example benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (for example trimethylsilyl ethyl); and C,„alkenyl groups (for example allyl and vinylethyl). Methods particularly appropriate for the removal of carboxy protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis. Examples of hydroxy protecting groups include lower alkyl groups (for example t-butyl), lower alkenyl groups (for example allyl); lower alkanoyl groups (for example acetyl); lower alkoxycarbonyl groups (for example t-butoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for example benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkylsilyl (for example trimethylsilyl, t-butyldimethylsilyl) and phenyl lower alkyl (for example benzyl) groups. Examples of amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, p-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example t-butoxycarbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for example benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (for example trimethylsilyl and t-butyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or enzymically-catalysed hydrolysis, for groups such as p-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photolytically. The reader is referred to Advanced Organic Chemistry, 4th Edition, by Jerry March, published by John Wiley & Sons 1992, for general guidance on reaction conditions and reagents. The reader is referred to Protective Groups in Organic Synthesis, 2nd Edition, by Green et al, published by John Wiley & Sons for general guidance on protecting groups. Compounds ofthe formula (1) and (5) can be formed by : (i) reacting a compound ofthe formula (6) with a compound ofthe formula (7) : or (ii) converting one value of R" in R 2 into another value of R 9 - or (iii), where the compound of formula (I) includes alternatives of formula (2) and (3), reacting a compound in which R 2 in Ar 2 is carboxy with a compound ofthe formula (8): or (iv), where the compound of formula (I) includes alternative of formula (4), reacting a compound in which R 2 in Ar 2 is carboxy with a compound of formula (8a). or (v) when Ar' is ofthe formula (B) or (C) (optionally protected), reacting a compound ofthe formula (9) or (9a) with a compound ofthe formula (10): /\ P' \ — / ArcH=CHC(R 2 )(R 13 )L 2 (9) (10) (9a) wherein p, Ar 1' , Ar 2 ', Ar 3' R 7 and R 8 are as hereinabove defined, R 21 is R 9 or protected R", L' and L 2 are leaving groups and P' is an amino-protecting group or R 5 providing it is not hydrogen; and thereafter if necessary: (i) removing any protecting groups; (ii) forming a pharmaceutically-acceptable salt, prodrug or solvate thereof. The reaction between compounds ofthe formula (6) and (7) is conveniently carried out under conditions know for the Wittig reaction. Suitable Wittig reaction conditions include using a polar aprotic organic solvent such as THF or methyl ene chloride in the presence of a crown ether and an alkali metal carbonate, such as potassium carbonate, preferably at -10°C to ambient temperature. C18 HPLC may be used to separate E and Z isomers if desired. The Wittig reaction can be used to prepare a compound wherein R 2 in Ar 2 ' is an alkoxycarbonyl group which may be hydrolysed to a carboxy group. If Ar 1' is ofthe formula (A), and the latter route is chosen and basic conditions are used, the E and Z isomers produced by the Wittig reaction are generally not separated if the E isomer is wanted, because the base- hydrolysis step causes isomerisation ofthe Z isomer to the E isomer. A compound ofthe formula (6) is generally prepared by reducing the corresponding ester to the aldehyde. A suitable reducing agent is for example DIBAL which is used in an inert non-polar solvent such as diethyl ether at low temperature, for example in the range -78°C to 0°C. Other suitable reducing agents are known in the art. Alternatively, the ester could be reduced to the corresponding alcohol with a reducing agent such as lithium aluminium hydride or sodium borohydride and the alcohol oxidised to the aldehyde with an oxidising agent such as pyridinium chlorochromate. The ester used to form a compound of the formula (6) can be prepared by introducing Ar 1 into a compound of the formula O COOR, wherein L* is leaving group such as bromo, in the presence of a base such as sodium hydride, sodium hydroxide or potassium carbonate. A compound ofthe formula (7) may be known in the art (for example see International Patent Application publication no. WO 98/32741) or may be prepared by reacting a compound of the formula Ar 2' CH 2 Br with triphenylphosphine. A compound ofthe formula Ar 2 CH 2 Br may be formed by brominating a compound of the formula Ar 2 CH 3 with a suitable brominating agent such as N-bromosuccinimide. A compound ofthe formula Ar 2 CH, wherein the Ar 2 group is substituted by R 2 and -(CH JR 3 group may be prepared from a compound ofthe formula Ar CH, wherein the Ar 2 group is substituted by -(CH 2 ) n R 3 and -COOH' using methods described above for the conversion of -COOH to R 2 . This latter Ar 2 CH, compound could be prepared from a compound ofthe formula Ar 2' CH, wherein the Ar 2 group is substituted by a protected carboxy group (-COOP 2 ) and a leaving group (L 3 ). When n is 0, the CH 3 Ar 2 '(-COOP 2 )-L 3 compound is conveniently reacted with aryl (or heteroaryl) boronic acid in the presence of a palladium catalyst such as palladium tetrakis (triphenylphosphine) palladium (0) under conditions known for the Suzuki reaction (Synfh.Commun. 11, 513 (1981)). An aprotic organic solvent such as dimethyl ether (DME), toluene, dimethylsulphoxide (DMSO) or THF is generally used and a base such as sodium bicarbonate, sodium carbonate and sometimes sodium hydroxide. A fluoride such as caesium fluoride could be used instead ofthe base (J. Org. Chem. 1994, 59, 6095-6097). Preferably L 3 is bromo or triflate. When n is 1, the CH,Ar 2' (-COOP 2 )-L 3 compound wherein L 3 is bromo or chloro, is conveniently reacted with a benzyl (or heteroarylmethyl) zinc chloride or a benzyl (or heteroarylmethyl) -magnesium bromide in the presence of a nickel or palladium catalyst, such as bis(triphenylphosphine)palladium (II) chloride or Pd,(dba)„ in an inert organic solvent such as tetrahydrofuran (THF). For example see the conditions used for the 'Negishi' reaction (J. Org. Chem. 42 (10), 1821-1822, 1977). When n is 2, the CH,Ar (-COOP 2 )-L 3 compound is conveniently reacted with a styrene under conditions known for the Heck reaction. Briefly this involves an inorganic or organic base such as triethylamine, a palladium catalyst such as bis (o-tolylphosphine)palladium (II) chloride in water. (Ace. Chem. Res. 12, 146-151 (1979), J. Organometallic Chem. 486, 259- 262 (1995)). The resulting alkene can then be reduced using standard methods known in the art, for example, catalytic hydrogenation. Alternatively the alkyne could be formed by reacting a CH 3 Ar 2 (-COOP 2 )-L 3 compound, wherein L 3 is triflate or bromo, with a phenyl acetylene in the presence of an organic base such as triethylamine and a palladium catalyst such as palladium tetrakis (triphenylphosphine). For example see the conditions used for the Sonogashira reaction (J. Org. Chem. 1993,58, 6614-6619). The resultant alkyne can be reduced using standard methods known in the art, for example, catalytic hydrogenation. The carboxy-protecting group may then be removed. A compound ofthe formula (1) in which R" in R 2 is alkoxy can conveniently be hydrolysed to another compound ofthe formula (1) in which R 9 is hydroxy using standard methods known in the art. For example, the alkoxy group could be subjected to acid or base hydrolysis with, for example, in the case of base hydrolysis, aqueous sodium hydroxide solution in an organic solvent such as an alcohol in a temperature range of ambient temperature to 60°C. When R" is a hydroxy group the carboxy group in a compound ofthe formula (1) can be converted to an acylsulphonamide by reacting the carboxy group with the appropriate sulphonamido group in the presence of an organic base such as triethylamine or dimethylaminopyridine, in an inert organic solvent such as dimethylformamide (DMF), in temperature range of -20°C to ambient temperature. The reaction between a compound in which R 2 in Ar 2' is carboxy and a compound of the formula (8) and (8a) is generally carried out in the presence of a reagent that converts the carboxy group into a reactive ester, for example a carbodiimide such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDC) or pentafluorophenyl, and in the presence of an organic base such as N-methylmoφholine. The reaction is usually carried out in the temperature range of -20°C to ambient temperature. The reagents, 1-hydroxybenzotriazole and dimethylaminopyridine (DMAP), are often added to assist the reaction (see Chem. Ber. 103, 788, 2024 (1970), J. Am. Chem. Soc. 93, 6318 (1971), Helv. Chim. Acta. 56, 717, (1973)). Suitable solvents include DMF and dichloromethane. For examples of suitable conditions for amide bond forming reactions see International Patent Application No. WO 98/07692. A compound ofthe formula (1) in which R 2 in Ar 2 is carboxy can be prepared by reacting a compound ofthe formula (6) with a compound ofthe formula (7), or a compound of the formula (9) or (9a) with a compound ofthe formula (10) wherein R 2 in Ar 2' is protected carboxy and subsequently removing the carboxy-protecting group. A compound ofthe formula (8a) wherein R 22 is ofthe formula -COR 18 can be formed via the intermediate NH 2 CH(R 21 )CON(OMe)Me which itself is formed by reacting together NH 2 CH(R 2, )COOH with N,O-dimethylhydroxylamine under standard amide bond forming conditions. A compound ofthe formula NH,CH(R 21 )CON(OMe)Me is then conveniently reacted with a Gringard reagent (such as PhCH,MgCl) to form a compound ofthe formula (8). Alternatively, when R 18 contains an alkyl chain linked to the carbonyl group, a compound ofthe formula NH 2 CH(R 2 ')CON(OMe)Me can be converted to the corresponding dimethylphosphono compound (NH,CH(R 2 ')COP(O)(OMe) 2 ) by reacting the former compound with dimethylmethylphosphonate in the presence of a strong base such as n-butyl lithium. A compound ofthe formula (8) can be formed by reacting the dimethylphosphono compound with the appropriate aldehyde or ketone under conditions known for the Wittig or Emmons-Homer reactions. A compound ofthe formula (8) wherein R 22 is moφholinomethyl, pyrrolidin-1- ylmethyl or piperidin-1-ylmethyl is conveniently prepared by reacting NH 2 CH(R 2 ')COOH with the appropriate heterocyclic ring under standard amide bond forming conditions to form a compound ofthe formula (8), wherein R 13 is heterocyclylcarbonyl, and subsequently reducing the carbonyl group to a methyl group with a reducing agent such as lithium aluminium hydride. A compound ofthe formula NH,CH(R 2l )COOH can be extended by one carbon length to produce a compound ofthe formula NH 2 CH(R 2l )CH,COOH using the Arndt-Eistert homologation method. For example by converting the carboxy group to an acid chloride, converting the latter to the diazoketone and hydrolysing this to the carboxylic acid. This homologation method could be used to produce subsequent homologues. A compound ofthe formula NH 2 CH(R 21 )CH 2 COOH and homologues may be used to prepare a compound ofthe formula NH,CH(R 21 )R 22 wherein R 22 is ofthe formula -CH,COR'\ moφholino C, 4 alkyl, pyrrolidin-1-ylC, 4 alkyl or piperidin-1-ylC, alkyl. An anion ofthe formula (9) is conveniently formed with a strong base, such as n-butyl lithium. This generally forms an anion at the 2-position ofthe imidazole compound. The anion fomiation is generally carried out at low temperature e.g. -78°C, in an inert or organic solvent such as diethyl ether. The anion (usually the lithium anion) of a compound ofthe formula (9) is normally converted to an organozinc reagent in the presence of lithium chloride, zinc iodide and copper (I) cyanide and this complex is reacted with a compound ofthe formula (10) in an inert organic solvent such as tetrahydrofuran in a temperature range of -78°C to ambient temperature (see the review of organozinc reagents by Paul Knochel and Robert D Singer in Chem. Rev. 1993, 93, 2117-2188). The anion of a compound ofthe formula (9a) is conveniently formed as a Grignard reagent by reacting the latter compound with an alkyl magnesium bromide in an ether at low temperature. The resulting Grignard reagent is typically reacted with a compound ofthe formula (10) in the presence of copper (I) cyanide and lithium chloride, allowing the temperature to rise from -78°C to ambient temperature. Preferably L 1 in the compound ofthe formula (9a) is halo, for example iodo or bromo. Preferably L 2 in the compound ofthe formula (10) is halo, for example bromo. A compound ofthe formula (10) may be prepared by brominating the corresponding hydroxy compound with a brominating agent such as tetrabromomethane/triphenylphosphine in a suitable solvent such as dichloromethane. The hydroxy compound is typically prepared by reacting a compound ofthe formula (7) and glycoaldehyde under conditions known for the Wittig reaction such as those described above for the reaction between compounds ofthe formulae (6) and (7). The order in which the various groups are introduced can be varied depending upon the nature ofthe desired final product. In general, the preferred last step is the formation or modification of R 2 in Ar 2' . For example, when R l) is hydroxy, the hydrolysis ofthe compound wherein R" is alkoxy, or when R 9 is other than hydroxy, the conversion of a carboxy group to R 2 using the amide bond-forming conditions described above. When Ar' of the formula (A), it is preferable to form the alkene which contains a protected carboxy group later to be converted to R 2 , by reacting together compounds ofthe formulae (6) and (7). When Ar 2 is ofthe formula (B) or (C) the alkene which contains a protected carboxy group later to be converted to R 2 , is preferably formed by reacting together a compound ofthe formula Ar 2 'CH 2 P + Ph,Br (wherein Ar 2 is substituted by -COOP 2 in place of R 2 ) and glycoaldehyde, converting the resultant hydroxy compound to a compound ofthe formula (9) (wherein Ar 2 ' is substituted by -COOP 2 in place of R 2 ) and reacting the latter compound with a compound ofthe formula (8) or (8a). Optionally substituents in a compound ofthe formula (1) and (5) or intermediates in their preparation may be converted into other optional substituents. For example an alkylthio group may be oxidised to an alkylsulphinyl or alkysulphonyl group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, or a bromo group converted to an alkylthio group. Various substituents may be introduced into compounds ofthe formulae (1) and (5) and intermediates in this preparation, when appropriate, using standard methods known in the art. For example, an acyl group or alkyl group may be introduced into an activated benzene ring using Friedel-Crafts reactions, a formyl group by formylation with titanium tetrachloride and dichloromethyl ethyl ester, a nitro group by nitration with concentrated nitric acid concentrated sulphuric acid and bromination with bromine or tetra(n-butyl)ammonium tribromide. It will be appreciated that, in certain steps in the reaction sequence to compounds of the formula (1), it will be necessary to protect certain functional groups in intermediates in order to prevent side reactions. Deprotection may be carried out at a convenient stage in the reaction sequence once protection is no longer required. Biological activity was tested as follows: (i) In-vitro assay The following stock solutions were used and the assays were conducted in 96 well plates: TRIS Buffer (500mM TRIS, 50mM MgCl,.6H 2 0, pH=8.0); Famesyl pyrophosphate (6.4mg/ml); Aprotinin ( 1.9 mg/ml); Ki-ras (0.5mg/ml, stored at -80°C); Acid ethanol (850ml absolute ethanol + 150ml concentrated HC1). Farnesyl protein transferase (FPT) was partially purified from human placenta by ammonium sulphate fractionation followed by a single Q-Sepharose (Pharmacia, Inc) anion exchange chromatography essentially as described by Ray and Lopez-Belmonte (Ray K P and Lopez-Belmonte J (1992) Biochemical Society Transactions 20 494-497). The substrate for FPT was Kras (CVIM C-terminal sequence). The cDNA for oncogenic val 12 variant of human c-Ki-ras-2 4B was obtained from the plasmid pSWl 1-1 (ATCC). This was then subcloned into the polylinker of a suitable expression vector e.g. pIC147. The Kras was obtained after expression in the E. coli strain, BL21. The expression and purification of c-KI-ras-2 4B and the val 12 variant in E. coli has also been reported by Lowe et al (Lowe P N et al. J. Biol. Chem. (1991) 266 1672-1678). The famesyl protein transferase enzyme preparation was stored at -80°C. The famesyl transferase solution for the assay contained the following: dithiothreitol (DTT)(0.6ml of 7.7mg/ml), TRIS buffer (0.6ml), aprotinin (0.48ml), distilled water (1.2ml), famesyl transferase (0.6ml ofthe crude enzyme preparation prepared as described above), zinc chloride (12μl of 5mM). This was left at ambienttemperature for 30 minutes. After this incubation 60μl Ki-ras solution was added and the whole left to incubate for a further 60 minutes prior to use in the assay. Assays were performed in 96 well plates as follows: lOμl of test compound solution was added to each well. Then 30μl famesyl transferase solution (above) was added and the reaction started by addition of lOμl radiolabelled famesyl pyrophosphate solution. After 20 minutes at 37°C the reaction was stopped with lOOμl acid ethanol (as described in Pompliano D L et al (1992) 31 3800-3807). The plate was then kept for 1 hour at 4°C. Precipitated protein was then collected onto glass fibre filter mats (B) using a Tomtec™ cell harvester and tritiated label was measured in a Wallac™1204 Betaplate scintillation counter. Test compounds were added at appropriate concentrations in DMSO (3% final concentration in test and vehicle control), (ii) Intracellular famesylation assay HER313A cells (Grand et al, 1987 Oncogene 3, 305-314) were routinely cultured in Dulbecos Modified Essential Medium (DMEM) plus 10% foetal calf serum (FCS). For the assay HER313A cells were seeded at 200,000 cells/well in a volume of 2.5ml in a 6 well tissue culture plate. After an overnight incubation at 37°C in 10% CO, the medium was removed and replaced with methionine-free minimal essential medium (MEM) and the cells incubated as above for 2 hours. After this time the medium was removed and replaced by methionine-free MEM (1ml) and test compound (l-3μl). The plates were then incubated for a further 2 hours as described above and then 30μCi of 5 S -methionine added to each well. The plate was then incubated overnight as described above. The medium was then removed and the cells were lysed with lysis buffer (lml) (composed of 1000ml phosphate buffered saline, 10ml trition X-100, 5g sodium deoxycholate, lg sodium dodecylsulphate) containing aprotinin (lOμl/ml), the plate scrapped and then left for 10 minutes at 4°C. The lysate was then clarified by centrifugation. To 0.8ml ofthe clarified lysate 80μl of Y13-259 pan-Ras antibody (isolated from the hybridoma - American Tissue Culture Collection Accession Number CRL-1742) (final concentration approximately lμg/ml, the exact working concentration was optimised for each batch of antibody isolated) and protein G beads (30μl of 0.5μg/ml) were added and the mixture incubated overnight with constant agitation. The pellet was then collected by centrifugation, washed and separated by SDS PAGE using a 15% gel. Radioactive bands were detected using a phosphorimager system, (iii) Moφhology and proliferation assay MIA PaCa 2 cells (American Tissue Culture Collection Accession Number: CRL-1420) were routinely cultured in Dulbecos Modified Essential Medium (DMEM) plus 10%) FCS in a 162 cm 2 tissue culture flask . For the assay the cells were seeded at 16,000 cells/well, in 12 well plates, in DMEM containing 5% charcoal dextran treated stripped FCS (lml)(obtained from Pierce and Warriner). The cells were then incubated overnight at 37°C in 10%) CO,. Test compound was then added (lOμl) and the cells incubated for 6 days as described above. On days 1, 2, 3 and 6 the cells were monitored for signs of moφhological change and toxicity. On day 6 the cells were removed from the plate using trypsin/EDTA and counted to determine the proliferation rate. Although the pharmacological properties ofthe compounds ofthe Formula (1) vary with structural change as expected, in general compounds ofthe Formula (1) possess an IC50 in test (i) above in the range, for example, 0.00005 to 50μM in test (i). Thus by way of example the compound of Example 29 herein has an IC 50 of approximately 0.0004μM in test (i). Example 29 has an IC 50 of approximately 0.3 to 1.0 μM in test (iii). No physiologically unacceptable toxicity was observed at the effective dose for compounds tested ofthe present invention. The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated:- (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (ii) operations were carried out at ambient temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as nitrogen or argon; (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were perfomied on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt, Germany or high pressure liquid chromatography (HPLC) C18 reverse phase silica separation; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the end-products ofthe Formula (1) have satisfactory microanalyses and their structures were confirmed by nuclear magnetic resonance (NMR) and mass spectral techniques; chemical shift values were measured on the delta scale; the following abbreviations have been used: s, singlet; d, doublet; t or tr, triplet; m, multiplet; br, broad; (vi) intermediates were not generally fully characterised and purity was assessed by thin layer chromatographic, HPLC, infra-red (IR) or NMR analysis; (vii) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products ofthe Formula (1) were determined after crystallisation from a conventional organic solvent such as ethanol, methanol, acetone, ether or hexane, alone or in admixture; and (viii) the following abbreviations have been used:- DMAP 4-dimethylaminopyridine DMF dimethylformamide EDC 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide HOBT 1-hydroxybenzotriazole MCPBA m-chloroperoxybenzoic acid TFA trifluoroacetic acid THF tetrahydrofuran Example 1 (2SV2-{4-[(EV3-(ImidazoI-l-ynprop-l-en-l-yl]-2-f4-fluorophenvnbenzamido}-4- methylsulfanylbutyric acid A solution of tert-butyl (2S)-2-{4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzamido}-4-methylsulfanylbutyrate (0.2 g ; 0.4 mmol) in dichloromethane (2 ml) was treated at 0°C with TFA (2 ml). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. After evaporation ofthe solvent, the residue was taken up with distilled water (5 ml) ; the pH was adjusted to 6 with NH 4 OH and the solution was purified on reverse phase silica eluting with methanol/ammonium carbonate buffer (2 g / 1 ; pH 7) (40/60) to give the title compound after freeze-drying. Yield : 40% 'H NMR (DMSO + CF 3 COOD, 400 MHz) δ : 1.8-2 (2H, m) ; 2 (3H, s) ; 2.15-2.4 (2H, m) ; 4.32 (IH, m) ; 5.05 (2H, m) ; 6.6-6.85 (2H, m) ; 7.20 (2H, m) ; 7.4-7.6 (5H, m) ; 7.7-7.85 (2H, m) ; 9.21 (IH, s). Anal. Calculated for C 24 H 24 N 3 O 3 SF 1.11 H 2 O C 60.90 H 5.58 N 8.88 S 6.77 Found C 60.80 H 5.32 N 8.83 S 6.37 MS (ESI) m/z : 454 (MH + ) Example 2 tert-ButyI (2S 2-{4-[(EV3-fimidazol-l-ynprop-l-en-l-yl]-2-(4-πuorophenynbenzamido}- 4-methylsulfanyIbutyrate A solution of 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoic acid (0.322 g ; 1 mmol), EDC (0.230 g ; 1.2 mmol), DMAP (0.134 mg ; 1.1 mmol), HOBT (162 mg ; 1.2 mmol) and tert-butyl (2S)-2-amino-4-methylsulfanylbutanoate (L-methionine t-butyl ester) (0.3 g ; 1.5 mmol) in dichloromethane (20 ml) was stirred at ambient temperature for 5 hours. The organic phase was washed with 5% sodium hydrogen carbonate solution and evaporated to dryness ; the residue was purified by flash chromatography eluting with dichloromethane/ethanol (98/2) to give the title compound as a foam. Yield : 60% > 'H NMR (CDC1 3 , 400 MHz) δ : 1.41 (9H, m) ; 1.7-2 (2H, m) ; 2 (3H, s) ; 2.18 (2H, m) ; 4.54 (IH, m) ; 4.75 (2H, m) ; 6 (IH, d) ; 6.3-6.55 (2H, m) ; 6.96 (IH, s) ; 7.05-7.70 (9H, m). Anal. Calculated for C 28 H 32 FN 3 O 3 S C 65.99 H 6.33 N 8.24 S 6.29 Found C 65.81 H 6.78 N 8.21 S 6.07 MS (ESI) m/z : 510 (MH + ) The starting material was prepared as follows: A solution of DIBAL in hexane (440 ml) was added dropwise at -70°C under argon atmosphere to a suspension of ethyl 2-(imidazol-l-yl)acetate (27.13 g ; 0.176 mole) in ether (1.2 1). The mixture was stirred at -70°C for 2 hours 30 minutes. Methanol (100 ml) and distilled water (8 ml) were then added at -70°C and the mixture was allowed to warm to ambient temperature and stirred for 2 hours. The resulting precipitate was filtered, washed with dichloromefhane/methanol (2 x 400 ml) and the filtrate was evaporated and purified by flash chromatography eluting with a gradient 10-25% methanol/dichloromethane to give 2- (imidazol-l-yl)acetaldehyde which was isolated as the hemiacetal 2-(imidazol-l-yl)-l- methoxyethanol. Yield : 68% 'H NMR (CDC1 3 , 400 MHz) δ : 3.48 (3H, s) ; 4.02 (2H, d) ; 6.9-7.5 (3H, m). A solution of 2-(imidazol-l-yl)acetaldehyde (2.6 g ; 0.018 mmol), 3-(4-fluorophenyl)-4- methoxycarbonylbenzyl triphenylphosphonium bromide (5.4 g ; 0.09 mmol), potassium carbonate (1.38 g ; 0.01 mmol) and 18 crown-6 (0.1 g ; 0.37 mmol) in THF (150 ml) was stirred under argon atmosphere at ambient temperature overnight. After filtration ofthe insoluble material and evaporation to dryness, the residue was purified by flash chromatography eluting with a mixture of dichloromethane/ethanol (98/2) to give methyl 4- [3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate as a mixture of E and Z isomers. Yield : 93% A solution of methyl 4-[3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate (E and Z isomers) (1.9 g ; 5.6 mmol) and 2N aqueous sodium hydroxide solution (8.5 ml ; 17 mmol) in methanol (100 ml) was refluxed for 9 hours. After evaporation and acidification with 12N HC1 (1.5 ml), the resulting solid was washed with distilled water and ether, taken up in dichloromethane/methanol (99/1) to give 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid (E isomer) after evaporation as a foam. Yield : 89% 'H NMR (DMSO + CF 3 COOD, 400 MHz) δ : 5.06 (2H, d) ; 6.7-7.85 (2H, m) ; 7.1-7.9 (9H, m) ; 9.22 (IH, s). Example 3 Methyl (2SV2-{4-[(EV3-πmidazol-l-yπprop-l-en-l-yl]-2-(4-fluorophenyI)benzamido}-4- methylsulfanylbutyrate The title compound was prepared using the same method as described for Example 2, but using the L-methionine methyl ester in place ofthe L-methionine tert-butyl ester. Yield : 83% 'H NMR (CDC1 3 , 400 MHz) δ : 1.75-2.05 (2H, m) ; 2.03 (3H, s) ; 2.15-2.25 (2H, m) ; 3.68 (3H, s) ; 4.65-4.72 (IH, m) ; 4.74 (2H, m) ; 6 (IH, d) ; 6.35-6.43 (IH, m) ; 6.52 (IH, d) ; 6.96 (IH, s) ; 7.1-7.7 (9H, m). Anal. Calculated for C 25 H 26 FN 3 O 3 S C 64.22 H 5.61 N 8.99 S 6.86 Found C 63.87 H 5.73 N 8.80 S 6.58 MS (ESI) m/z : 468 (MH + ) Example 4 tert-Butyl (2SV2-{4-[(EV3-(imidazoI-l-yπprop-l-en-l-yl]-2-(4-fluorophenyπbenzamido}- 4-methylsulfonylbutyrate MCPBA (0.89 g ; 3.1 mmol) was added to a solution of tert-butyl (2S)-2-{4-[(E)-3-(imidazol- l-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate (0.64 g ; 1.25 mmol) in methylene chloride (15ml) at 0°C. After stirring at ambient temperature for 2 hours, the solution was washed with 1M Na 2 S,O 3 and 5%o sodium hydrogen carbonate solution. The organic layer was evaporated and the residue was purified by flash chromatography using a gradient of ethanol in dichloromethane (2% - 4%) to give after evaporation ofthe appropriate fractions and trituration in ether, the expected compound as a solid. Yield : 51% M.P. : 100-104°C 'H NMR (CDCl,, 400 MHz) δ : 1.42 (9H, s) ; 1.9-2.4 (2H, m) ; 2.65-2.95 (2H, m) ; 2.84 (3H, s) ; 4.5 (IH, m) ; 4.74 (2H, d) ; 6.08 (IH, d) ; 6.3-6.45 (2H, m) ; 6.96 (IH, s) ; 7.1-7.7 (9H, m). Anal. Calc. for C 28 H 32 FN 3 O 5 S, 0.16 Et 2 O, 0.25 H 2 O C 61.65 H 6.16 N 7.53 S 6.97 Found C 61.27 H 6.13 N 7.59 S 6.13 MS (ESI) m/z : 542 (MH + ) Example 5 (2SV2-{4-[(EV3-αmidazoI-l-yl)prop-l-en-l-yI]-2-(4-fluorophenyl)benzamido}-4- methylsulfonylbutyric acid The title compound was prepared from Example 4 using similar methodology to that of Example 1. Yield : 45% 'H NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ : 1.9-2.25 (2H, m) ; 2.8-3.15 (2H, m) ; 2.96 (3H, s) ; 4.35 (IH, m) ; 5.06 (2H, d) ; 6.6-6.8 (2H, m) ; 7.2 (2H, m) ; 7.4-7.6 (5H, m) ; 7.74 (IH, d) ; 7.80 (IH, d); 9.21 (IH, s). Anal. Calculated for C 24 H 24 FN 3 O 5 S, 1.6 H 2 O C 56.04 H 5.33 N 8.17 S 6.25 Found C 55.76 H 4.88 N 8.16 S 6.34 MS (ESI) m/z : 486 (MH + ) Example 6 2-MethvI-l-(morpholino^prop-2-yl (2SV2-{4-[(EV3-(imidazol-l-yDprop-l-en-l-yl]-2-f4- fluorophenyl)benzamido}-4-methylsuIfanylbutyrate The title compound was prepared from 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid and the appropriate amine using a similar method to that of Example 2. Yield : 50 % Η NMR (CDC1 3 , 400 MHz) δ : 1.42 (6H, m) ; 1.5-2.3 (4H, m) ; 2.04 (3H, s) ; 2.4-2.6 (6H, m) ; 3.65 (4H, m) ; 4.54 (IH, m) ; 4.74 (2H, m) ; 5.98 (IH, d) ; 6.3-6.6 (2H, m) ; 6.9-7.7 (10H, m). Anal. Calculated for C 32 H 39 FN 4 O 4 S C 64.62 H 6.61 N 9.42 S 5.39 Found C 64.39 H 6.86 N 9.55 S 6.09 MS (ESI) m/z : 595 (MH + ) Example 7 Cvciopentyπ2SV2-{4-f(EV3-(imidazol-l-yn P rop-l-en-l-yl]-2-(4- fluorophenyπbenzamido}-4-methylsulfanylbutyrate The title compound was prepared from 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid and the appropriate amine using a similar method to that of Example 2. Yield : 50 % 'H NMR (CDC1 3 , 400 MHz) δ : 1.5-2.2 (12H, m) ; 2.03 (3H, s) ; 4.60 (IH, m) ; 4.74 (2H, m) ; 5.12 (IH, m) ; 6.01 (IH, d) ; 6.3-6.6 (2H, m) ; 6.9-7.7 (10H, m). Anal. Calculated for C 20 H 32 FN 3 O 3 S C 66.77 H 6.18 N 8.06 S 6.15 Found C 67.13 H 6.57 N 8.22 S 6.53 MS (ESI) m/z : 522 (MH + ) Example 8 n-ButvI (2SV2-{4-[(EV3-fimidazoI-l-yr)prop-1 -en-1 -y]l-2-r4-fluorophenvnbenzamido}-4- methylsulfanylbutyrate The title compound was prepared from 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid and the appropriate amine using a similar method to that of Example 2. Yield : 42 % 'H NMR (CDCl,, 400 MHz) δ : 0.93 (3H, t) ; 1.30-1.41 (2H, m) ; 1.54-1.64 (2H, m) ; 1.75- 1.87 (IH, m) ; 1.92-2.02 (IH, m) ; 2.03 (3H, s) ; 2.19 (2H, m) ; 4.02-4.15 (2H, m) ; 4.63-4.70 (IH, m) ; 4.75 (2H, d) ; 6.01 (IH, d) ; 6.34-6.44 (IH, m) ; 6.52 (IH, d) ; 6.97 (IH, s) ; 7.07- 7.16 (3H, m) ; 7.30 (IH, s) ; 7.35-7.44 (3H, m) ; 7.55 (IH, s) ; 7.64 (IH, d). Anal. Calculated for C 28 H 32 FN 3 O 3 S C 65.99 H 6.33 N 8.24 S 6.29 Found C 65.59 H 6.43 N 8.25 S 6.64 MS (ESI) m/z : 510 (MH + ) Example 9 Prop-2-yl ('2S)-2-{4-[(EV3-(imidazol-l-yπprop-l-en-l-yl]-2-(4-fluorophenyl)benzamido}- 4-methylsulfanylbutyrate The title compound was prepared from 4-[(E)-3-(iniidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid and the appropriate amine using a similar method to that of Example 2. Yield : 52 % Η NMR (CDC1 3 , 400 MHz) δ : 1.24 (6H, m) ; 1.76-2.06 (2H, m) ; 2.05 (3H, s) ; 2.16-2.25 (2H, m) ; 4.59-4.66 (IH, m) ; 4.77 (2H, d) ; 4.99 (IH, m) ; 6.05 (IH, d) ; 6.36-6.46 (IH, m) ; 6.53 (IH, d) ; 6.99 (IH, s) ; 7.09-7.66 (9H, m). Anal. Calculated for C 27 H 30 FN 3 O,S, 0.16 H 2 O C 65.13 H 6.13 N 8.44 S 6.44 Found C 65.28 H 6.26 N 8.50 S 6.05 MS (ESI) m/z : 496 (MH + ) Example 10 (2SV2-{5-[(EV3- midazol-l-vnprop-l-en-1-yll-2-r4-fluorophenethvnbenzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 11 using a similar method to that described in Example 1. Yield : 35 % ■ H NMR (DMSO d 6 + CF,COOD, 400 MHz) δ : 1.91-2.15 (2H, m) ; 2.04 (3H, s) ; 2.5-2.66 (2H, m) ; 2.71-2.89 (2H, m) ; 2.89-3.11 (2H, m) ; 4.47-4.59 (IH, m) ; 5.03 (2H, d) ; 6.45-6.56 (IH, m) ; 6.75 (IH, d) ; 7.0-7.52 (7H, m) ; 6.74 (IH, s) ; 7.80 (IH, s) ; 9.20 (IH, s) Anal. Calculated for C 20 H 2S FN 3 O 3 S, 2.4 HO C 64.85 H 5.86 N 8.73 S 6.66 Found C 59.50 H 6.30 N 8.01 S 6.11 MS (ESI) m/z : 482 (MH + ) Example 11 tert-ButvU2SV2-{5-[(EV3-(imidazol-l-vnprop-l-en-l-yl]-2-(4- fluorophenethyl)benzamido}-4-methylsulfanyIbutyrate A solution of pentafluorophenyl 5-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenethyl)benzoate (0.36 g, 0.7 mmol), L-methionine-tert-butyl ester (0.173 g, 0.84 mmol) and l-hydroxy-7-azabenzotriazole (0.1 g, 0.73mmol) in DMF (2 ml) was stirred at ambient temperature overnight. After evaporation ofthe solvent, the residue was taken up in ethyl acetate, washed with 5 % sodium hydrogen carbonate solution and saturated brine and evaporated to dryness. The residue was then purified by flash chromatography eluting with dichloromethane / ethanol (97/3) to give the title compound. Yield : 50 %> 'H NMR (CDCl . ,, 400 MHz) δ : 1.49 (9H, s) ; 1.9-2.3 (2H, m) ; 2.09 (3H, s) ; 2.5-2.7 (2H, m) ; 2.8-3.2 (4H, m) ; 4.75 (3H, m) ; 6.2-6.6 (2H, m) ; 6.9-7.6 (10H, m). MS (ESI) m/z : 538 (MH + ). The starting material was prepared as follows. Methyl 5-[3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenethyl)benzoate was prepared in a similar way to that described for methyl 4-[3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoate in Example 2 but using 4-(4-fluorophenethyl)-3- methoxycarbonylbenzyl triphenylphosphonium bromide instead of 3-(4-fluorophenyl)-4- methoxycarbonylbenzyl triphenylphosphonium bromide. Yield : 70 %. 'H NMR (CDC1 3 , 400 MHz) δ : 2.8-2.95 (2H, m) ; 3.15-3.30 (2H, m) ; 3.89 and 3.91 (3H, s) ; 4.7-4.85 (2H, m) ; 5.8-6.8 (2H, m) ; 6.9-7.85 (10H, m). Sodium hydroxide (0.8 g, 20 mmol) in distilled water (3 ml) was added to a solution of methyl 5-[3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenethyl)benzoate (E and Z isomers) (2.4 g ; 6.6 mmol) in methanol (30 ml). The mixture was refluxed for 6 hours. After evaporation and acidification with 12N HC1 to pH 6, the residue was extracted with dichloromethane and evaporated to dryness to give 5-[3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenethyl)benzoic acid (mixture of E and Z isomers). 'H NMR (DMSOd 6 + CF 3 COOD) 400 MHz) δ : 2.75-2.90 (2H, m) ; 3.1-3.3 (2H, m) ; 4.95- 5.30 (2H, m) ; 5.90 and 6.5-6.85 (2H, m) ; 7-7.95 (10H, m) ; 9.2 (IH, m). Pentafluorophenyl trifluoroacetate (1.47 ml ; 8.6 mmol) was added to a solution of 5-[3- (imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenethyl)benzoic acid (2.5 g, 7.14 mmol) and pyridine (0.7 ml ; 8.6 mmol) in DMF (7 ml). After stirring at ambient temperature overnight, the mixture was evaporated to dryness and the residue extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and saturated brine. After evaporation the reaction mixture was purified by flash chromatography, eluting with dichloromethane/ethanol (99/1) to give E isomer pentafluorophenyl 5-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenefhyl)benzoate and Z isomer pentafluorophenyl 5-[(Z)-3-(imidazol-l-yl)prop-l-en- l-yl]-2-(4-fluorophenethyl)benzoate. Yield : 68 % E isomer : 'H NMR (CDC1 3 , 400 MHz) δ : 2.88 (2H, m) ; 3.26 (2H, m) ; 4.76 (2H, m) ; 6.3-6.6 (2H, m) ; 6.9-7.8 (9H, m) ; 8.17 (lH, d). Z isomer : 'H NMR (CDC1 3 , 400 MHz) δ : 2.90 (2H, m) ; 3.27 (2H, m) ; 4.82 (2H, m) ; 5.89 (IH, m) ; 6.78 (IH, m) ; 6.9-7.6 (9H, m) ; 8.07 (IH, s). Example 12 (2SV2-{5-[(E -3-fImidazol-l-y prop-l-en-l-yl]-2-(4-fluorophenethyπbenzamido}-4- methylsulfonylbutyric acid The title compound was prepared from Example 13 using a similar method to that described in Example 1. Yield : 60 % 'H NMR (DMSO + CF 3 COOD, 400 MHz) δ : 2.1-2.35 (2H, m) ; 2.7-3.1 (4H, m) ; 3.0 (3H, s) ; 3.15-3.4 (2H, m) ; 4.55 (IH, m) ; 5.04 (2H, m) ; 6.4-6.8 (2H, m) ; 7-7.5 (7H, m) ; 7.7-7.85 (2H, m) ; 8.8 (IH, m) ; 9.20 (IH, s). Anal. Calculated for C 26 H 2S FN 3 O 5 S, 1.9 H 2 O C 57.01 H 5.85 N 7.67 S 5.85 Found C 56.88 H 5.80 N 7.79 S 6.04 MS (ESI) m/z : 514 (MH + ). Example 13 tert-Butyl (2SV2-(5-[(EV3-πmidazol-l-vnprop-l-en-l-yl1-2-(4- fluorophenethyπbenzamido}-4-methylsulfonylbutyrate The title compound was prepared from pentafluorophenyl 5-[(E)-3-(imidazol-l-yι)prop-l-en- l-yl]-2-(4-fluorophenefhyl)benzoate using a similar method to that described in Example 11. Yield : 44 % 'H NMR (CDCl,, 400 MHz) δ 1.47 (9H, s) ; 2.2-2.6 (2H, m) ; 2.8-3.3 (6H, m) ; 2.92 (3H, s) ; 4.73 (3H, m) ; 6.2-6.6 (2H, m) ; 6.85-7.6 (10H, m). Anal. Calculated for C, 0 H, 6 FN ,O,S, 0.70 H 2 O C 61.88 H 6.47 N 7.22 S 5.51 Found C 61.66 H 6.42 N 7.22 S 6.18 MS (ESI) m/z : 570 (MH + ) Example 14 r2SV2-i5-[(ZV3-(Tmidazol-l-vnprop-l-en-l-yl]-2-(4-fluorophenethynbenzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 15 using a similar method to that described in Example 1. Yield : 50 % 'HNMR (DMSO d 6 + CF,COOD, 400 MHz) δ : 1.88-2.16 (2H, m) ; 2.04 (3H, s) ; 2.50-2.71 (2H, m) ; 2.72-3.11 (4H, m) ; 4.47-4.62 (2H, m) ; 5.21 (2H, d) ; 5.83-5.96 (IH, m) ; 6.80 (IH, d) ; 7.00-7.39 (7H, m) ; 7.32 (IH, s) ; 7.78 (IH, s) ; 9.19 (IH, s) Anal. Calculated for C 26 H 28 FN 3 O,S, 2.5 H 2 O C 59.30 H 6.32 N 7.98 S 6.00 Found C 59.28 H 5.85 N 7.82 S 5.87 MS (ESI) m/z : 482 (MH + ) Example 15 tert-ButyH2SV2-{5-[(ZV3-πmidazol-l-ynprop-l-eιι-l-yl]-2-f4- fluorophenethyDbenzamido}-4-methylsulfanylbutyrate The title compound was prepared from pentafluorophenyl 5-[(Z)-3-(imidazol-l-yl)prop-l-en- l-yl]-2-(4-fluorophenethyl)benzoate and the appropriate amine using a similar method to that described in Example 11. Yield : 67 % 'H NMR (CDC1 3 , 400 MHz) δ : 1.5 (9H, s) ; 2-2.4 (2H, m) ; 2.08 (3H, s) ; 2.4-2.7 (2H, m) ; 2.8-3.2 (4H, m) ; 4.75 (3H, m) ; 5.85 (IH, m) ; 6.48 (IH, m) ; 6.6-7.6 (10H, m). MS (ESI) m/z : 538 (MH + ) Example 16 (2SV2-{5-[(Z)-3-dmidazol-l-yl)prop-l-en-l-yl1-2-(4-fluorophenethyllbenzamido}-4- methylsulfonylbutyric acid The title compound was prepared from Example 17 using a similar method to that described in Example 1. 'H NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ : 2.1-2.4 (2H, m) ; 2.7-3.45 (6H, m) ; 3.0 (3H, s) ; 4.55 (IH, m) ; 5.22 (2H, m) ; 5.92 (IH, m) ; 6.80 (IH, m) ; 7-7.5 (7H, m) ; 7.75 (2H, d) ; 8.8 (IH, d) ; 9.18 (lH, s). Anal. Calculated for C 26 H 2 ,FN,O 5 S, H O C 58.74 H 5.69 N 7.90 S 6.03 Found C 58.74 H 5.65 N 8.03 S 6.08 MS (ESI) m/z : 514 (MH + ) Example 17 tert-Butyl (2SV2-{5-[rZV3-πmidazol-l-ynprop-l-en-l-yll-2-r4- fluorophenethyPbenzamido}-4-methylsulfonylbutyrate The title compound was prepared from pentafluorophenyl 5-[(Z)-3-(imidazol-l-yl)prop-l-en- l-yl]-2-(4-fluorophenethyl)benzoate and the appropriate amine using a similar method to that described in Example 11. Yield : 65 % 'H NMR (CDC1 3 , 400 MHz) δ : 1.52 (9H, s) ; 2.2-2.6 (2H, m) ; 2.8-3.30 (6H, m) ; 3.05 (3H, s) ; 4.7-4.9 (3H, m) ; 5.85 (IH, m) ; 6.6-7.35 (11H, m) ; 7.49 (IH, s). Anal. Calculated for C 30 H 36 FN 3 O 5 S, 0.2 H 2 O C 62.85 H 6.40 N 7.33 S 5.60 Found C 62.87 H 6.58 N 7.33 S 6.06 MS (ESI) m/z : 570 (MH + ) Example 18 (2SV2-(4-[(EV3-(l-MethyIimidazol-2-ynprop-l-en-l-yl1-2-r4-fluorophenynbenzamido}- 4-methylsuIfanylbutyric acid The title compound was prepared from Example 19 using a similar method to that described in Example 1. 'H NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ : 1.74-2.0 (2H, m) ; 2.01 (3H, s) ; 2.16-2.37 (2H, m) ; 3.83 (3H, s) ; 3.98 (2H, d) ; 4.32 (IH, dd) ; 6.48-6.60 (IH, m) ; 6.69 (IH, d) ; 7.13- 7.26 (2H, m) ; 7.40 -7.57 (5H, m) ; 7.63 (IH, d) ; 7.67 (IH, d). Anal. Calculated for C 25 H 26 FN,O 3 S, 1.15 H 2 O C 61.50 H 5.84 N 8.61 S 6.57 Found C 61.53 H 6.08 N 8.54 S 6.57 MS (ESI) m/z : 468 (MH + ) Example 19 tert-Butyπ2S 2-{4-[(E 3-(l-methylimidazol-2-vnprop-l-en-l-yl1-2-(4- fluorophenyIlbenzamido}-4-methylsulfanylbutyrate The title compound was prepared from 4-[3-(l-methylimidazol-2-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid using a similar method to that described in Example 2. Yield : 30 % 'H NMR (CDC1 3 + CF 3 COOD, 400 MHz) δ : 1.46 (9H, s) ; 1.75-1.99 (2H, m) ; 2.05 (3H, s) ; 2.07-2.33 (2H, m) ; 3.86 (3H, s) ; 3.97 (2H, d) ; 4.59 (IH, dd) ; 6.24-6.33 (IH, m) ; 6.63 (IH, d) ; 7.09-7.17 (3H, m) ; 7.29-7.44 (5H, m). Anal. Calculated for C 2 , ; H 34 FN 3 O 3 S, 0.3 H 2 O C 64.95 H 6.65 N 7.84 S 5.98 Found C 64.85 H 6.52 N 7.81 S 5.94 MS (ESI) m/z : 524 (MH + ) The starting material was prepared as follows : A mixture of 4-(4-fluorophenethyl)-3-methoxycarbonylbenzyl triphenylphosphonium bromide (27 g, 46 mmol), glycolaldehyde (7.2 g ; 92 mmol), potassium carbonate (13 g ; 92 mmol) and 18-crown-6 (0.2 g) in dichloromethane (300 ml) was stirred for 2 days at ambient temperature under argon atmosphere. After addition of distilled water and extraction, the solution was evaporated to dryness to give methyl 2-(4-fluorophenyl)-4-(3-hydroxyprop- 1 -en- 1 -yl)benzoate which was used in the next step without further purification. A solution of methyl 2-(4-fluorophenyl)-4-(3-hydroxyprop-l-en-l-yl)benzoate (17 g), triphenylphosphine (22.8 g ; 87 mmol) and tetrabromomethane (28.8 g ; 87 mmol) in dichloromethane (200 ml) was stirred at 0°C for 1 hour. After filtration ofthe insoluble material and evaporation to dryness, the residue was purified by flash chromatography eluting with dichloromethane/petroleum ether (30/70) to give methyl 2-(4-fluorophenyl)-4-(3- bromoprop-l-en-l-yl)benzoate as a mixture of E and Z isomers. 'H NMR (CDC1 3 , 400 MHz) δ : 3.65 (3H, m) ; 4.15 (2H, m) ; 6.1-6.2 and 6.4-6.7 (2H, m) ; 7- 7.95 (7H, m). n-Butyl lithium (1.6 M solution in ether, 30 ml) was added at -78°C and under argon atmosphere to a solution of N-methylimidazole (3.2 ml ; 40 mmol). After stirring at -78°C for 45 minutes, zinc iodide (14 g ; 44 mmol) in solution in THF (100 ml) was added. The mixture was allowed to warm to ambient temperature for 1 hour, cooled down to -78°C, and a solution of copper (I) cyanide (0.72 g ; 8 mmol) and lithium chloride (0.68 g ; 1.6 mmol) in THF (10 ml) was then added at -78°C followed by a solution of methyl 2-(4-fluorophenyl)-4-(3- bromoprop-l-en-l-yl)benzoate (7 g ; 20 mmol) in THF (50 ml). The mixture was stirred at - 78°C, for 30 minutes and for 1 hour 30 minutes at room temperature. After evaporation ofthe solvent, the residue was treated with EDTA (17 g ; 44 mmol) in distilled water (50 ml) and extracted with dichloromethane. The organic layer was evaporated and purified by flash chromatography eluting with dichloromethane/ ethanol (98/2) to give methyl 4-[3-(l- methylimidazol-2-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate as a mixture of E and Z isomers. Yield : 71 % ■ H NMR (CDCl,, 400 MHz) δ : 3.5-3.8 (8H, m) ; 6.05 and 6.7 (IH, m) ; 6.8-7.9 (9H, m). Methyl 4-[3-(l-methylimidazol-2-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate (5 g ; 14.3 mmol) in solution in methanol (100 ml) was treated at reflux for 4 hours with sodium hydroxide (1.2 g ; 30 mmol) in solution in distilled water (10 ml). After evaporation to dryness, the residue was acidified at pH 6 with 6 N HC1 to give a solid which was triturated in water and subsequently in ether to give 4-[3-(l-methylimidazol-2-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid as a solid (mixture of E and Z isomers). 'H NMR (DMSOd 6 + CF,COOD, 400 MHz) δ : 3.82 and 3.84 (3H, s) ; 4.0 (2H, m) ; 6.5-7.9 (HH, m). MS (ESI) m/z : 336 (MH + ) Example 20 (2S 2-{4-[(EV3-(Tmidazol-2-yl prop-l-en-l-yI1-2-(4-fluorophenvnbenzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 21 using a similar method to that described in Example 1. Yield : 34 % Η NMR (DMSOd 6 + CF,COOD, 400 MHz) δ : 1.73-2.08 (2H, m) ; 2.0 (3H, s) ; 2.14-2.37 (2H, m) ; 3.93 (2H, d) ; 4.31 (IH, dd) ; 6.52-6.63 (IH, m) ; 6.71 (IH, d) ; 7.14-7.24 (2H, m) ; 7.40-7.55 (5H, m) ; 7.63 (2H, s). Anal. Calculated for C 24 H 24 FN,O 3 S, 1.2 H 2 O C 59.99 H 5.66 N 8.74 S 6.67 Found C 59.99 H 5.65 N 8.62 S 6.42 MS (ESI) m/z : 454 (MH + ) Example 21 tert-Butyl (2SV2-{4-[fEV3-πmidazol-2-yllprop-l-en-l-yl1-2-(4-fluorophenynbenzamido}- 4-methylsulfanyIbutyrate The title compound was prepared from 4-[(E)-3-(imidazol-2-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid and the appropriate amine using a similar method to that described in Example 2. Yield : 75 % ■ H NMR (CDCl,, 400 MHz) δ : 1.42 (9H, s) ; 1.76-2.03 (2H, m) ; 2.05 (3H, s) ; 2.17-2.26 (2H, m) ; 3.70 (2H, d) ; 4.50-4.59 (IH, m) ; 6.04 (IH, d) ; 6.39-6.49 (IH, m) ; 6.53 (IH, d) ; 7.0 (2H, s) ; 7.04-7.43 (6H, m) ; 7.59 (IH, d). Anal. Calculated for C 28 H 32 FN 3 O 3 S C 65.99 H 6.33 N 8.24 S 6.29 Found C 65.64 H 6.50 N 8.16 S 5.33 MS (ESI) m/z : 510 (MH + ) The starting material was prepared as follows : Methyl 4-[(E)-3-(l-tritylimidazol-2-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate was prepared from methyl 2-(4-fluorophenyl)-4-(3-bromoprop-l-en-l-yl)benzoate using a similar method to that described for methyl 4-[3-(l-methylimidazol-2-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoate in Example 21 , but using N-tritylimidazole in replacement of N- methylimidazole. Η NMR (CDC1 3 + CF 3 COOD, 400 MHz) δ : 3.66 (2H, m) ; 3.68 (3H, s) ; 6.14 (IH, d) ; 7-7.9 (25H, m). MS (ESI) m/z : 579 (MH + ) A solution of methyl 4-[(E)-3-(l-tritylimidazol-2-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoate (5.78 g ; 6.5 mmol), acetic acid (5 ml) and 12N HC1 (5 ml) in methanol (100 ml) was refluxed for 1 hour 30 minutes. After evaporation to dryness, the residue was neutralised with aqueous NH 4 OH, extracted with dichloromethane, evaporated and purified by flash chromatography, eluting with dichloromethane/ethanol (98/2) to give methyl 4-[(E)-3-(imidazol-2-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate. Yield : 63 % 'H NMR (CDCl,, 400 MHz) δ : 3.72 (3H, s) ; 3.91 (2H, m) ; 6.28 (IH, m) ; 6.67 (IH, d) ; 7- 7.45 (8H, m) ; 7.75 (IH, d). A solution of methyl 4-[(E)-3-(imidazol-2-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate (1.37 g ; 4 mmol) in methanol (20 ml) was treated at reflux for 4 hours with a solution of sodium hydroxide (0.32 g ; 8 mmol) in water (24 ml). After evaporation to dryness the residue was acidified at pH 6 with 12N HC1. The resulting solid was triturated with water and subsequently with ether to give 4-[(E)-3-(imidazol-2-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid. Yield : 46 % 'H NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ : 3.94 (2H, m) ; 6.4-6.8 (IH, m) ; 7-7.9 (10H, m). Example 22 (2S)-2-{4-[(E)-3-(Imidazol-l-yl)prop-l-en-l-yl]-2-(2.4-difluorophenyl)benzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 23 using a similar method to that described in Example 1. Yield : 64 %> 'H NMR (DMSOd 6 + CF,COOD, 400 MHz) δ : 1.73-2.03 (2H, m) ; 2.02 (3H, s) ; 2.23-2.43 (2H, m) ; 4.32 (IH, dd) ; 5.06 (2H, d) ; 6.62-6.73 (IH, m) ; 6.78 (IH, d) ; 7.03-7.14 (IH, m) ; 7.16-7.28 (IH, m) ; 7.35-7.44 (IH, m) ; 7.49 (IH, s) ; 7.55-7.65 (2H, m) ; 7.74 (IH, s) ; 7.81 (IH, s) ; 9.21 (IH, s). Anal. Calculated for C 24 H 23 F 2 N 3 O,S, 0.5 H 2 O C 59.99 H 5.03 N 8.74 S 6.67 Found C 60.19 H 5.11 N 8.65 S 6.28 MS (ESI) m z : 472 (MH + ) Example 23 tert-Butvπ2SV2-{4-r(E 3-πmidazol-l-ynprop-l-en-l-yl]-2-(2.4- difluoropheny .benzamido}-4-methylsulfanylbutyrate The title compound was prepared from 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(2,4- difluorophenyl)benzoic acid and the appropriate amine using a similar method to that described in Example 2. Yield : 74 %> ■ H NMR (CDC1 3 , 400 MHz) δ : 1.44 (9H, s) ; 1.79-2.12 (2H, m) ; 2.07 (3H, s) ; 2.25-2.42 (2H, m) ; 4.53-4.62 (IH, m) ; 4.75 (2H, d) ; 6.27 (IH, d) ; 6.33-6.44 (IH, m) ; 6.51 (IH, d) ; 6.82- 7.04 (3H, m) ; 7.11 (IH, s) ; 7.27-7.38 (2H, m) ; 7.40 -7.48 (IH, dd) ; 7.55 (IH, s) ; 7.67 (IH, d). Anal. Calculated for C 2S H„F 2 N,O 3 S C 63.74 H 5.92 N 7.96 S 6.08 Found C 63.38 H 5.90 N 7.85 S 5.72 MS (ESI) m/z : 528 (MH + ) The starting material was prepared as follows : A mixture of 2-(imidazol-l-yl)acetaldehyde (2.32 g ; 76 mmol), 4-mefhoxycarbonyl-3-(4- trifluoromethylsulphonyloxy)benzyl triphenylphosphonium bromide (5.27 g ; 37 mmol), potassium tert-butoxide (1.2 g ; 10 mmol) in dichloromethane (30 ml) was stirred under argon atmosphere at ambient temperature for 7 hours. After filtration ofthe insoluble, and evaporation, the residue was purified by flash chromatography eluting with isopropanol/dichloromethane (4/96) to give methyl 4-[3-(imidazol-l-yl)prop-l-en-l-yl]-2- (trifluoromethylsulphonyloxy)benzoate as a mixture of E and Z isomers. 'H NMR (CDC1 3 , 400 MHz) δ : 3.98 (3H, s) ; 4.80 (2H, m) ; 6-8.2 (8H, m). A mixture of methyl 4-[3-(imidazol-l-yl)prop-l-en-l-yl]-2- (trifluoromethylsulphonyloxy)benzoate (1.17 g ; 3 mmol), 2,4-difluorophenylboronic acid (0.52 g ; 3.3 mmol), tetrakis(triphenylphosphine) palladium (0.14 g ; 0.12 mmol), 2M aqueous sodium carbonate solution (4.5 ml), lithium chloride (0.25 g ; 6 mmol) and ethanol (13 ml) in toluene (120 ml) was refluxed, under an argon atmosphere, for 8 hours. The mixture was extracted with ethyl acetate and purified by flash chromatography eluting with isopropanol/dichloromethane (3/97) to give methyl 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2- (2,4-difluorophenyl)benzoate as a mixture of E and Z isomers. 'HNMR (CDCl,, 400 MHz) δ : 3.71 (3H, s) ; 4.7-4.9 (2H, m) ; 5.9-6 (IH, m) ; 6.4-8.1 (10H, m). A solution of methyl 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(2,4-difluorophenyl)benzoate (0.9 g ; 2.54 mmol) and 2N sodium hydroxide solution (3.8 ml) in methanol was heated at reflux for 7 hours. After evaporation ofthe solvent and neutralisation to pH 6.5 with 6N HC1, the residue was purified on reverse phase silica eluting with methanol/ammonium carbonate buffer (2 g/1, pH 7) (50/50) to give 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(2,4- difluorophenyl)benzoic acid after freeze-drying. Yield : 49 % 'H NMR (DMSO + CF 3 COOD, 400 MHz) δ : 5.06 (2H, m) ; 6.75 (2H, m) ; 7-8 (8H, m) ; 9.20 (IH, s). Example Ar R Rl 22 2,4-difluorophenyl H SCH 3 23 2,4-difluorophenyl t-Bu SCH 3 24 2 -thienyl t-Bu SCH 3 25 4-chlorophenyl H SCH 3 26 4-chlorophenyl t-Bu SCH, 27 3-chloro-4-fluorophenyl H SCH, 28 3 -chloro-4-fluorophenyl t-Bu SCH, 29 2,4-dichlorophenyl H SCH, 30 2,4-dichlorophenyl t-Bu SCH, 31 2 ,4-dichloropheny 1 t-Bu SO 2 CH, 32 3 -thienyl H SCH, 33 3-thienyl t-Bu SCH, Example Ar R Rl 34 3-chlorophenyl H SCH 3 35 3-chlorophenyl t-Bu SCH, Example 24 tert-Butvl (2SV 2-{4-[(EV3-fimidazol-l-vnprop-l-en-l-vll-2-rthien -2-vHbenzamido}-4- methylsulfanylbutyrate The title compound was prepared using a similar method to that described in Example 23, except using the appropriate boronic acid in place of 2,4-difiuorophenylboronic acid. Yield : 53 % ■ H NMR (CDCl,, 400 MHz) δ : 1.43 (9H, s) ; 1.78-2.08 (2H, m) ; 2.05 (3H, s) ; 2.19-2.32 (2H, m) ; 4.58-4.66 (IH, m) ; 4.75 (2H, d) ; 6.18 (IH, d) ; 6.33-6.44 (IH, m) ; 6.51 (IH, d) ; 6.97 (IH, s) ; 6.04-6.18 (3H, m) ; 6.35-6.45 (3H, m) ; 7.55 (IH, s) ; 7.61 (IH, d). Anal. Calculated for C 26 H„N,O 3 S 2 C 62.75 H 6.28 N 8.44 S 12.89 Found C 62.01 H 6.91 N 8.62 S 12.65 MS (ESI) m/z : 498 (MH + ) Example 25 (2SV2-{4-[(EV3-(Imidazol-l-yπprop-l-en-l-yl]-2-(4-chlorophenynbenzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 26 as described for Example 1. Yield : 54 % Η NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ : 1.75-2.05 (2H, m) ; 2.02 (3H, s) ; 2.15-2.40 (2H, s) ; 4.26-4.37 (IH, s) ; 5.06 (2H, s) ; 6.62-6.74 (IH, m) ; 6.79 (IH, d) ; 7.38-7.62 (7H, m) ; 7.75 (IH, s) ; 7.81 (IH, s) ; 9.22 (IH, s). Anal. Calculated for C 24 H 24 C1N 3 O 3 S,0.8 H 2 O C 59.51 H 5.15 N 8.67 S 6.62 Found C 59.14 H 5.17 N 9.41 S 5.96 MS (ESI) m/z : 469 (MH + ) Example 26 tert-Butyl (2SV2-{4-[(EV3-(imidazol-l-yπprop-l-en-l-yl]-2-(4-chlorophenyπbenzamido}- 4-methylsulfanylbutyrate The title compound was prepared using a similar method to that described in Example 23, except using the appropriate boronic acid in place of 2,4-difluorophenylboronic acid. Yield : 78 % ■ H NMR (CDCl,, 400 MHz) δ : 1.43 (9H, s) ; 1.76 (2H, m) ; 2.06 (3H, s) ; 2.22 (2H, m) ; 4.52-4.59 (IH, m) ; 4.76 (2H, d) ; 6.03 (IH, d) ; 6.34-6.45 (IH, m) ; 6.97 (IH, s) ; 7.12 (IH, s) ; 7.25-7.46 (6H, m) ; 7.55 (IH, s) ; 7.64 (IH, d). Anal. Calculated for C 28 H, 2 ClN,O,S C 63.93 H 6.13 N 7.99 S 6.09 Found C 63.93 H 6.27 N 8.16 S 5.89 MS (ESI) m/z : .527 (MH + ). Example 27 (2SV2-{4-ffEV3-rimidazol-l-vDprop-l-en-l-yl]-2-(3-chloro-4-fluorophenynbenzamido}- 4-methylsulfanyIbutyric acid The title compound was prepared from Example 28 as described for Example 1. Yield : 71 % 'H NMR (DMSOd 6 + CF,COOD, 400 MHz) δ : 1.74-2.05 (2H, m) ; 2.00 (3H, s) ; 2.15-2.37 (2H, m) ; 4.28-4.37 (IH, m) ; 5.06 (2H, d) ; 6.64-6.74 (IH, m) ; 6.78 (IH, d) ; 7.35-7.63 (6H, m) ; 7.75 (IH, s) ; 7.81 (IH, s) ; 9.21 (IH, s). Anal. Calculated for C 24 H 2 ,ClFN,O,S, 2 H 2 O C 55.01 H 5.19 N 8.02 S 6.12 Found C 52.64 H 4.46 N 7.80 S 5.76 MS (ESI) m/z : 480 (MH + ) Example 28 tert-Butyl (2SV2-{4-[rEV3-(imidazoI-l-vnprop-l-en-l-yI]-2-r3-chloro-4- fluorophenyDbenzamido}-4-methylsulfanylbutyrate The title compound was prepared using a similar method to that described in Example 23, except using the appropriate boronic acid in place of 2,4-difluorophenylboronic acid. Yield : 83 % 'H NMR (CDCl,, 400 MHz) δ : 1.43 (9H, s) ; 1.77-2.15 (4H, m) ; 2.06 (3H, s) ; 2.21-2.37 (2H, m) ; 4.51-4.63 (IH, m) ; 4.75 (2H, d) ; 6.13 (IH, d) ; 6.34-6.44 (IH, m) ; 6.50 (IH, d) ; 6.97 (IH, s) ; 7.12 (IH, s) ; 7.14-7.33 (3H, m) ; 7.38-7.49 (2H, m) ; 7.55 (IH, s) ; 7.61 (IH, d). Anal. Calculated for C 28 H„ClFN,O,S C 61.81 H 5.74 N 7.72 S 5.89 Found C 61.45 H 5.91 N 7.67 S 5.81 MS (ESI) m/z : 544 (MH + ) Example 29 (2SV2-{4-[(EV3- midazol-l-vnprop-l-en-l-yl1-2-(2.4-dichlorophenynbenzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 30 as described for Example 1. Yield : 63 % 'H NMR (DMSOd 6 + CF,COOD, 400 MHz) δ : 1.77-2.08 (2H, m) ; 2.02 (3H, s) ; 2.27-2.55 (2H, m) ; 4.27-4.36 (IH, m) ; 5.05 (2H, d) ; 6.59-6.69 (IH, m) ; 6.78 (IH, d) ; 7.29-7.82 (8H, m) ; 9.17 (1H, s). Anal. Calculated for C 24 H 23 Cl 2 N,O 3 S 0.7 H 2 O C 57.15 H 4.60 N 8.33 S 6.33 Found C 55.42 H 4.78 N 8.40 S 6.20 MS (ESI) m/z : 505 (MH + ) Example 30 tert-Butyπ2S 2-{4-[(EV3-(imidazol-l-ynprop-1-en-l-yll-2-(2.4- dichlorophenyllbenzamido}-4-methylsulfanylbutyrate The title compound was prepared using a similar method to that described in Example 23, except using the appropriate boronic acid in place of 2,4-difluorophenylboronic acid. Yield : 85 % Η NMR (CDCl,, 400 MHz) δ : 1.43 (9H, s) ; 1.70-2.43 (4H, m) ; 2.44 (3H, s) ; 4.45-4.59 (IH, s) ; 4.73 (2H, d) ; 6.08-6.28 (IH, m) ; 6.31-6.42 (IH, m) ; 6.51 (IH, d) ; 6.95 (IH, s) ; 7.10 (IH, s) ; 7.19-7.50 (3H, m) ; 7.41-7.50 (2H, m) ; 7.52 (IH, s) ; 7.62-7.77 (IH, m). Anal. Calculated for C 28 H„Cl,N,O,S C 60.00 H 5.57 N 7.50 S 5.72 Found C 59.97 H 5.74 N 7.58 S 5.64 MS (ESI) m/z : 560 (MH + ) Example 31 tert-Butyπ2SV2-{4-[(E -3-(imidazol-l-vnprop-l-en-l-yll-2-(2.4- dichlorophenyl)benzamido}-4-methylsulfonylbutyrate The title compound was prepared from Example 30 as described for Example 4. Yield : 71 % 'H NMR (CDCl,, 400 MHz) δ : 1.45 (9H, s) ; 1.90-2.10 (IH, m) ; 2.24-2.45 (IH, m) ; 2.65- 3.12 (7H, m) ; 4.41-4.59 (IH, m) ; 4.73 (2H, d) ; 6.18-6.54 (3H, m) ; 6.95 (IH, s) ; 7.10 (IH, s) ; 7.15-7.80 (7H, m). Anal. Calculated for C 28 H„Cl 2 N,O . ,S C 56.76 H 5.27 N 7.09 S 5.41 Found C 56.83 H 5.52 N 7.00 S 5.79 MS (ESI) m/z : 592 (MH + ) Example 32 f2SV2-{4-[rEV3-(Imidazol-l-ynprop-l-en-l-yl]-2-(thien-3-ynbenzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 33 as described for Example 1. Yield : 53 % 'H NMR (CDC1 3 , 400 MHz) δ : 1.43 (9H, s) ; 1.75-2.04 (2H, m) ; 2.06 (3H, s) ; 2.18-2.28 (2H, m) ; 4.55-4.62 (IH, m) ; 4.75 (2H, d) ; 6.08 (IH, d) ; 6.33-6.43 (IH, m) ; 6.51 (IH, d) ; 6.97 (IH, s) ; 7.11 (IH, s) ; 7.14-7.19 (IH, m) ; 7.33-7.41 (4H, m) ; 7.55 (IH, s) ; 7.63 (IH, d). Anal. Calculated for C 22 H 23 N 3 O 3 S 2 C 59.84 H 5.25 N 9.52 S 14.52 Found C 57.81 H 5.49 N 9.15 S 14.06 MS (ESI) m/z : 442 (MH + ) Example 33 tert-Butyl (2SV2-{4-[(EV3-(imidazoI-l-vnprop-l-en-1-yl1-2-(thien-3-ynbenzamido}-4- methylsulfanylbutyrate The title compound was prepared using a similar method to that described in Example 23, except using the appropriate boronic acid in place of 2,4-difluorophenylboronic acid. Yield : 72 % 'H NMR (DMSOd„ + CF,COOD, 400 MHz) δ : 1.80-2.10 (2H, m) ; 2.03 (3H, s) ; 2.28-2.51 (2H, m) ; 4.33-4.45 (IH, m) ; 5.06 (2H, d) ; 6.62-6.72 (IH, m) ; 6.78 (IH, d) ; 7.30 (IH, d) ; 7.99 (IH, d) ; 7.46-7.57 (2H, m) ; 7.60-7.66 (2H, m) ; 7.75 (IH, s) ; 7.28 (IH, s) ; 8.65 (IH, d) ; 9.22 (IH, s). Anal. Calculated for C 26 H 3 ,N 3 O 3 S 2 C 62.75 H 6.28 N 8.44 S 12.89 Found C 62.31 H 6.45 N 8.38 S 12.72 MS (ESI) m/z : 498 (MH + ) Example 34 f2SV2-{4-[rE 3-(Imidazol-l-vnprop-l-en-l-yl]-2-r3-chlorophenynbenzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 35 as described for Example 1. Yield : 56 % Η NMR (DMSOd 6 + CF,COOD, 400 MHz) δ : 1.75-2.04 (2H, m) ; 2.10 (3H, s) ; 2.15-2.40 (2H, m) ; 4.25-4.40 (IH, dd) ; 5.06 (2H, d) ; 6.6-6.9 (2H, m) ; 7.28-7.70 (7H, m) ; 7.75 (IH, s) ; 7.81 (IH, s) ; 9.22 (IH, s). MS (ESI) m/z : 470 (MH + ) Example 35 tert-Butyl (2S 2-{4-rfEV3-rimidazol-l-ynprop-l-en-l-yl]-2-(3-chlorophenvnbenzamido}- 4-methylsulfanylbutyrate The title compound was prepared using a similar method to that described in Example 23, except using the appropriate boronic acid in place of 2,4-difluorophenylboronic acid. Yield : 74 % 'H NMR (CDC1 3 , 400 MHz) δ : 1.4 (9H, s) ; 1.74-1.88 (IH, m) ; 1.89-2.05 (IH, m) ; 2.04 (3H, s) ; 2.13-2.28 (2H, m) ; 4.5-4.6 (IH, m) ; 4.78 (2H, d) ; 6.04 (IH, d) ; 6.3-6.6 (2H, m) ; 6.90 (IH, s) ; 7.12 (IH, s) ; 7.2-7.5 (6H, m) ; 7.55 (IH, s) ; 7.64 (IH, d). Anal. Calculated for C 28 H, 2 ClN,O,S C 63.93 H 6.13 N 7.99 Found C 63.75 H 6.16 N 8.08 MS (ESI) m/z : 526 (MH + ) Example 36 (2S)-2-{4-[(EV3-(Imidazol-5-yπprop-l-en-l-yl]-2-(4-fluorophenyl)benzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 37 as described for Example 1. Yield : 42 % 'H NMR (DMSOd 6 + CF,COOD, 400 MHz) δ : 1.72-2.13 (2H, m) ; 2.01 (3H, s) ; 2.1-2.4 (2H, m) ; 3.66 (2H, d) ; 4.23-4.44 (IH, m) ; 6.45-6.72 (2H, m) ; 7.08-7.30 (2H, m) ; 7.31-7.69 (6H, m) ; 9.06 (IH, s). Anal. Calculated for C 24 H 24 CN 3 O,S 0.9 H 2 O C 61.37 H 5.54 N 8.95 S 6.83 Found C 61.07 H 5.17 N 8.87 S 6.62 MS (ESI) m/z : 454 (MH + ) Example 37 tert-Butyl (2S)-2-{4-[rE)-3-πmidazoI-5-yπprop-l-en-l-yl]-2-(4-fluorophenyl)benzamido}- 4-methylsuIfanylbutyrate The title compound was prepared from 4-[(E)-3-(imidazol-5-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid and the appropriate amine as described for Example 2. Yield : 46 % ■ H NMR (CDCl, + CF,COOD, 400 MHz) δ : 1.48 (9H, s) ; 1.7-2.0 (2H, m) ; 2.06 (3H, s) ; 2.05-2.26 (2H, m) ; 3.62-3.81 (3H, m) ; 4.54-4.67 (IH, m) ; 6.26-6.45 (IH, m) ; 6.65 (IH, d) ; 7.03-7.66 (8H, m) ; 8.78 (IH, s). Anal. Calculated for C 28 H, 2 FN,O,S C 65.99 H 6.33 N 8.24 S 6.29 Found C 65.61 H 6.18 N 8.24 S 5.73 MS (ESI) m/z : 510 (MH + ) The starting material was prepared as follows: Ethyl magnesium bromide (3M solution in ether ; 5.7 ml ; 17 mmol) was added dropwise at 0°C under argon atmosphere to a solution of N-trityl 5-iodoimidazole (6.1 g ; 14 mmol). After stirring at 0°C for 1 hour, a solution of copper (I) cyanide (0.27 g ; 3 mmol) and lithium chloride (0.252 g ; 6 mmol) in THF (5 ml) was added. The mixture was cooled down to -78°C and a solution of methyl 4-(3-bromoprop-l-en-l-yl)-2-(4-fluorophenyl)benzoate (3.5 g ; 10 mmol) in THF (10 ml) was added. After stirring at -78°C for 15 minutes, the temperature was allowed to raise to room temperature. The mixture was stirred further overnight. After addition of aqueous ammonium chloride solution and evaporation to dryness, the residue was extracted with dichloromethane/distilled water. The organic layer was evaporated to give methyl 4-[(E)-3-(l-tritylimidazol-5-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoate which was used in the next step without further purification. ■ H NMR (CDC1 3 + CF 3 COOD, 400 MHz) δ : 1.48 (9H, s) ; 3.60-3.82 (5H, m) ; 7.00-7.85 (26H, m). A solution of methyl 4-[(E)-3-(l-tritylimidazol-5-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoate (7.8 g ; 10 mmol), 12N HCl (7.5 ml) and acetic acid (7.5 ml) in methanol (150 ml) was refluxed for 1 hour 30 minutes. After evaporation to dryness and neutralisation with an aqueous solution of ammonium hydroxide, the residue was extracted with dichloromethane and purified by flash chromatography, eluting with a gradient 2-5%o ethanol/dichloromethane to give methyl 4-[(E)-3-(imidazol-5-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoate. Yield : 20 % 'H NMR (CDC1 3 , 400 MHz) δ : 3.5-3.8 (5H, m) ; 6.58 (2H, m) ; 6.8-7.9 (9H, m). A solution of methyl 4-[(E)-3-(imidazol-5-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate (0.6 g ; 1.8 mmol) in IN HCl (15 ml) was refluxed for 20 hours. The mixture was evaporated to dryness to give 4-[(E)-3-(imidazol-5-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoic acid as the hydrochloride salt. 'H NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ : 3.6-3.7 (2H, m) ; 6.62 (2H, s) ; 7.1-7.9 (8H, m) ; 9.06 (IH, s). Example 38 f2SV2-(4-[rEV3-π-Methylimidazol-5-vnprop-l-en-l-yl]-2-(4-fluorophenynbenzamido}- 4-methylsulfanylbutyric acid The title compound was prepared from Example 39 as described for Example 1. 'H NMR (DMSO + CF 3 COOD, 400 MHz) δ : 1.74-2.03 (2H, m) ; 2.01 (3H, s) ; 3.69 (2H, d) ; 3.81 (3H, s) ; 4.28-4.35 (IH, dd) ; 6.50-6.66 (2H, m) ; 7.13-7.24 (2H, m) ; 7.37-7.60 (6H, m) ; 9.06 (lH, s). Anal. Calculated for C 25 H 26 FN 3 O 3 S, 1.2 H 2 O C 61.38 H 5.85 N 8.59 S 6.55 Found C 61.00 H 5.94 N 8.57 S 6.53 MS (ESI) m/z : 468 (MH + ) Example 39 tert-ButvI (2S 2-14-[(EV3-(l-methylimidazol-5-yllprop-l-en-l-yll-2-(4- fluoropheny0benzamido}-4-methylsulfanylbutyrate The title compound was prepared from 4-[3-(l-methylimidazol-5-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid and the appropriate amine as described for Example 2. 'H NMR (CDCl,, 400 MHz) δ : 1.42 (9H, s) ; 1.72-1.88 (IH, m) ; 1.89-2.02 (IH, m) ; 2.04 (3H, s) ; 2.14-2.26 (2H, m) ; 3.52 (2H, d) ; 3.57 (3H, s) ; 4.50-4.57 (IH, m) ; 5.97 (IH, d) ; 6.35-6.43 (2H, m) ; 6.80-7.52 (8H, m) ; 7.62 (IH, d). Anal. Calculated for C 29 H 34 FN 3 O 3 S, 0.6 H 2 OC 65.17 H 6.64 N 7.86 S 6.00 Found C 65.14 H 6.97 N 7.89 S 6.46 MS (ESI) m/z : 524 (MH + ) The starting material was prepared as follows : Methyl 4-[3-(l-methylimidazol-5-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate was prepared from methyl 4-(3-bromoprop-l-en-l-yl)-2-(4-fluorophenyl)benzoate and 5-iodo-l- methyl-imidazole using a similar method to that described for methyl 4-[(E)-3-(l- tritylimidazol-5-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate in Example 37. Yield : 59% MS (ESI) m/z : 351 (MH + ) 4-[3-(l-Methylimidazol-5-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoic acid was prepared from methyl 4-[3-( 1 -methylimidazol-5-yl)prop-l -en- 1 -yl]-2-(4-fluorophenyl)benzoate using a similar method to that described for 4-[(E)-3-(imidazol-5-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid in Example 37. MS (ESI) m/z : 337 (MH + ) Example 40 f2SV2-{4-[fE)-3-π-Benzylimidazol-2-yl)prop-l-en-l-yl]-2-(4-fluorophenyπbenzamido}-4- methylsulfanylbutyric acid The title compound was prepared from Example 41 as described for Example 1. 'H NMR (DMSO, 400 MHz) δ : 1.7-2.1 (2H, m) ; 2.01 (3H, s) ; 2.1-2.4 (2H, m) ; 4.02 (2H, d) ; 4.32 (IH, m) ; 5.49 (2H, s) ; 6.26-6.44 (IH, m) ; 6.60 (IH, d) ; 7.13-7.61 (12H, m) ; 7.72 (lH, d) ; 7.77 (lH, d). Anal. Calculated for C 3 ,H 30 FN 3 O,S 1.5 H 2 O C 65.24 H 5.83 N 7.36 Found C 65.04 H 5.42 N 7.21 MS (ESI) m/z : 544 (MH + ) Example 41 tert-Butyl (2SV2-{4-[(E 3- -benzylimidazol-2-ynprop-l-en-l-yl1-2-r4- fluorophenyl)benzamido}-4-methylsulfanyIbutyrate The title compound was prepared from 4-[3-(l-benzylimidazol-2-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid and the appropriate amine as described for Example 2. Yield : 17 % 'H NMR (CDCl,, + CF 3 COOD, 400 MHz) δ : 1.46 (9H, s) ; 1.7-2.3 (4H, m) ; 2.05 (3H, s) ; 3.95 (2H, d) ; 4.56-4.64 (IH, m) ; 5.28 (2H, s) ; 6.12-6.24 (IH, m) ; 6.55 (IH, d) ; 6.98-7.60 (14H, m). Anal. Calculated for C 35 H, 8 FN,O,S 0.6 H 2 O C 68.85 H 6.47 N 6.88 S 5.25 Found C 68.83 H 6.68 N 7.18 S 5.50 MS (ESI) m/z : 601 (MH + ) The starting material was prepared as follows : Methyl 4-[3-(l-benzylimidazol-2-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate was prepared from methyl 4-(3-bromoprop-l-en-l-yl)-2-(4-fluorophenyl)benzoate as described for methyl 4-[3-(l-methylimidazol-2-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoate in Example 19, but using N-benzylimidazole. Yield : 76 % 'H NMR (CDCl,, + CF 3 COOD, 400 MHz) δ : 3.69 (3H, s) ; 4.01 (2H, m) ; 5.28 (2H, s) ; 6.14 (IH, m) ; 6.52 (IH, m) ; 7.0-7.9 (14H, m). MS (ESI) m/z : 427 (MH + ) A solution of methyl 4-[3-(l-benzylimidazol-2-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate (3 g ; 7 mmol), sodium hydroxide (0.8 g ; 20 mmol) and distilled water (5 ml) in methanol (50 ml) was refluxed for 4 hours. After evaporation to dryness and acidification to pH 6 with 6N HCl, the resulting solid was triturated with water and ether to give 4-[3-(l-benzylimidazol-2- yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoic acid as a mixture of E and Z isomers. 'H NMR (DMSO, 400 MHz) δ : 4.04 (2H, m) ; 5.50 (2H, s) ; 6.3-7.9 (16H, m). MS (ESI) m/z : 413 (MH + ) Example 42 (2SV2-{4-[(EV3-(Imidazol-l-ynprop-l-en-l-yl]-2-r4-fluorophenynbenzamido}-4- methylsulfanylbutyric acid A solution of tert-butyl (2S)-2-{4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzamido}-4-methylsulfanylbutyrate (0.2 g ; 0.4 mmol) in dichloromethane (2 ml) was treated at 0°C with TFA (2 ml).The mixture was allowed to warm to ambient temperature and stirred for 1 hour. After evaporation ofthe solvent, the residue was taken up with distilled water (5 ml) ; the pH was adjusted to 6 with NH 4 OH and the solution was purified on reverse phase silica eluting with methanol/ammonium carbonate buffer (2 g / 1 ; pH 7) (40/60) to give the title compound after freeze-drying. Yield : 40%> 'H NMR (DMSO + CF,COOD, 400 MHz) δ : 1.8-2 (2H, m) ; 2 (3H, s) ; 2.15-2.4 (2H, m) ; 4.32 (IH, m) ; 5.05 (2H, m) ; 6.6-6.85 (2H, m) ; 7.20 (2H, m) ; 7.4-7.6 (5H, m) ; 7.7-7.85 (2H, m) ; 9.21 (IH, s). Anal. Calculated for C 24 H 24 N 3 O 3 SF 1.11 H 2 O C 60.90 H 5.58 N 8.88 S 6.77 Found C 60.80 H 5.32 N 8.83 S 6.37 MS (ESI) m/z : 454 (MH + ) Example 43 (2SV2-{4-[(El-3-rimidazoI-l-yl)prop-l-en-l-yl]-2-(4-fluorophenyπbenzamido}-4- methylsulfanylbutan-1-ol A solution of lithium borohydride (0,066 g ; 3 mmol) in diethyl ether (15 ml) was added at 0°C to a solution of Example 2 (0,74 g, 1.6 mmol) in THF (40 ml). After stirring at ambient temperature overnight the mixture was acidified at pH 8 with 12N HCl and evaporated to dryness. The residue was taken up in dichloromethane/methanol (90/10). After evaporation of the solvent, the compound was purified on reverse phase silica eluting with methanol/ammonium carbonate (2 g/1 pH 7) buffer. The appropriate fractions were concentrated under vacuum and extracted with dichloromethane and evaporated to give the title compound as a solid. Yield : 36 % Η NMR (CDC1 3 , 400 MHz) δ : 1.4-1.8 (2H, m) ; 2.04 (3H, s) ; 2.2-2.4 (2H, m) ; 3.48 (2H, m) ; 4.02 (IH, m) ; 4.74 (2H, m) ; 5.62 (IH, d) ; 6.3-6.6 (2H, m) ; 6.96 (IH, m) ; 7-7.7 (9H, m). Anal. Calculated for C 24 H 26 FNSO 2 S, 0.4 H 2 O C 64.52 H 6.07 N 9.41 S 7.18 Found C 64.75 H 6.10 N 9.50 S 7.23 MS (ESI) m/z : 440 (MH + ) Example 44 (3SV3-{4-[rEV3-(Tmidazol-l-ynprop-l-en-l-yll-2-(4-fluorophenvnbenzamido}-5- methylsulfanyl-l-phenyl-2-pentanone A mixture of 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoic acid (0.65 g, 2 mmol), (2S)-3-amino-5-methylsulfanyl-l-phenyl-2-pentanone (0.62 g, 2.4 mmol), HOBT (0.3 g, 2.2 mmol), EDC (0.425 g, 2.2 mmol), DMAP (0.245 g, 2 mmol) in dichloromethane (20 ml) was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane, evaporated to dryness and purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give the title compound. Yield : 35 %> Η NMR (CDCI 3 , 400 MHz) δ : 1.7-1.9 (2H, m) ; 2.05 (3H, s) ; 2-2.2 (2H, m) ; 3.78 (2H, m) ; 4.7-4.9 (3H, m) ; 6.12 (IH, m) ; 6.30-6.6 (2H, m) ; 6.96 (IH, s) ; 7-7.7 (14H, m). Anal. Calculated for C 31 H 30 FNO 3 O 2 S, 0.4 distilled water C 69.61 H 5.80 N 7.86 S 5.99 Found C 69.79 H 5.80 N 8.00 S 6.37 MS (ESI) m/z : 528 (MH + ) The starting material was prepared as follows : A solution of DIBAL in hexane (440 ml) was added dropwise at -70°C under argon atmosphere to a suspension of ethyl 2-(imidazol-l-yl)acetate (27.13 g ; 0.176 mole) in ether (1.2 1). The mixture was stirred at -70°C for 2 hours 30 minutes. Methanol (100 ml) and distilled water (8 ml) were then added at -70°C and the mixture was allowed to warm to ambient temperature and stirred for 2 hours. The resulting precipitate was filtered, washed with dichloromethane/methanol (2 x 400 ml) and the filtrate was evaporated and purified by flash chromatography eluting with a gradient 10-25%) methanol/dichloromethane to give 2- (imidazol-l-yl)acetaldehyde which was isolated as the hemiacetal 2-(imidazol-l-yl)-l- methoxy ethanol. Yield : 68% Η NMR (CDC1 3 , 400 MHz) δ : 3.48 (3H, s) ; 4.02 (2H, d) ; 6.9-7.5 (3H, m). A solution of 2-(imidazol-l-yl)acetaldehyde (2.6 g ; 0.018 mmol), 3-(4-fluorophenyl)-4- methoxycarbonylbenzyl triphenylphosphonium bromide (5.4 g ; 0.09 mmol), potassium carbonate (1.38 g ; 0.01 mmol) and 18 crown-6 (0.1 g ; 0.37 mmol) in THF (150 ml) was stirred under argon atmosphere at ambient temperature overnight. After filtration ofthe insoluble material and evaporation to dryness, the residue was purified by flash chromatography eluting with a mixture of dichloromethane/ethanol (98/2) to give methyl 4- [3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate as a mixture of E and Z isomers. Yield : 93%> A solution of methyl 4-[3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenyl)benzoate (E and Z isomers) (1.9 g ; 5.6 mmol) and 2N aqueous sodium hydroxide solution (8.5 ml ; 17 mmol) in methanol (100 ml) was refluxed for 9 hours. After evaporation and acidification with 12N HCl (1.5 ml), the resulting solid was washed with distilled water and ether, taken up in dichloromethane/methanol (99/1) to give 4-[(E)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenyl)benzoic acid (E isomer) after evaporation as a foam. Yield : 89%> 'H NMR (DMSO + CF 3 COOD, 400 MHz) δ : 5.06 (2H, d) ; 6.7-7.85 (2H, m) ; 7.1-7.9 (9H, m) ; 9.22 (IH, s). Example 45 f3SV3-{5-[(Z -3- midazol-l-vnprop-1 -en-1-yl|-2-(4-fluorophenethvnhenzamido}-5- methylsulfanyl-l-phenyl-2-pentanone A solution of pentafluorophenyl 5-[(Z)-3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenethyl)benzoate (0.25g, 0.5 mmol), (3S)-5-methylsulfanyl-2-oxo-l-phenylpentan-3- aniine (0.16 g, 0.6 mmol), l-hydroxy-7-azabenzotriazole (0.075 g, 0.55 mmol) in DMF (2 ml) was stirred at ambient temperature overnight. After evaporation ofthe solvent, the residue was taken up in ethyl acetate, washed with 5 % sodium hydrogen carbonate and saturated sodium chloride and evaporated to dryness. The residue was then purified by flash chromatography eluting with dichloromethane/ethanol (97/3) to give the title compound which was isolated as the hydrochloride salt by treatment with HCl/ether. Yield : 70 %> Η NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ : 1.83-2.20 (2H, m) ; 2.04 (3H, s) ; 2.05-3.11 (6H, m) ; 3.99 (2H, s) ; 4.74 (IH, dd) ; 5.23 (2H, d) ; 5.85-5.96 (IH, m) ; 6.81 (IH, d) ; 6.99- 7.10 (2H, m) ; 7.13-7.44 (10H, m) ; 7.73 (IH, s) ; 7.78 (IH, s) ; 9.21 (IH, s). Anal. Calculated for C 33 H 34 FN 3 O 2 S 1.25 HCl C 65.92 H 5.91 N 6.99 S 5.33 CI 7.37 Found C 66.03 H 6.20 N 6.97 S 5.57 CI 7.56 MS (ESI) m/z : 556 (MH + ) The starting material was prepared as follows : A solution of 2-(imidazol-l-yl)acetaldehyde (2.8 g ; 0.021 mmol), 4-(4-fluorophenethyl)-3- methoxycarbonylbenzyl triphenylphosphonium bromide (6.2 g ; 0.01 mmol), potassium carbonate (2.8 g ; 0.02 mmol) and 18 crown-6 (0.1 g ; 0.37 mmol) in dichloromethane (100 ml) was stirred under argon atmosphere at ambient temperature overnight. After extraction and evaporation to dryness, the residue was purified by flash chromatography eluting with a mixture of dichloromethane/ethanol (98/2) to give methyl 5-[3-(imidazol-l- yl)prop-l-en-l-yl]-2-(4-fluorophenethyl)benzoate as a mixture of E and Z isomers. Yield : 70% 'H NMR (CDC1 3 , 400 MHz) δ : 2.8-2.95 (2H, m) ; 3.15-3.30 (2H, m) ; 3.89 and 3.91 (3H, s) ; 4.7-4.85 (2H, m) ; 5.8-6.8 (2H, m) ; 6.9-7.85 (10H, m). A solution of methyl 5-[3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenethyl)benzoate (E and Z isomers) (2.4 g ; 6.6 mmol) in methanol (100 ml) was treated with a solution of sodium hydroxide (0.8g ; 20 mmol) in water (3 ml). The mixture was refluxed for 9 hours. After evaporation and acidification with 12N HCl (1.5 ml), the residue was extracted with dichloromethane to give after evaporation 5-[3-(imidazol-l-yl)prop-l-en-l-yl]-2-(4- fluorophenethyl)benzoic acid as a mixture of E and Z isomers. Η NMR (DMSOd 6 + CF 3 COOD) 400 MHz) δ : 2.75-2.90 (2H, m) ; 3.1-3.3 (2H, m) ; 4.95- 5.30 (2H, m) ; 5.90 and 6.5-6.85 (2H, m) ; 7-7.95 (10H, m) ; 9.2 (IH, m). MS (ESI) m/z : 351 (MH + ) Pentafluorophenyl trifluoroacetate (1.47 ml ; 8.6 mmol) was added to a solution of 5-[3- (imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenethyl)benzoic acid (2.5 g, 7.14 mmol) and pyridine (0.7 ml ; 8.6 mmol) in DMF (7 ml). After stirring at ambient temperature overnight, the mixture was evaporated to dryness and the residue extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate and saturated sodium chloride. After evaporation the reaction mixture was purified by flash chromatography eluting with dichloromethane/ethanol (99/1) to give E isomer pentafluorophenyl 5-[(E)-3-(imidazol-l- yl)prop-l-en-l-yl]-2-(4-fluorophenethyl)benzoate and Z isomer pentafluorophenyl 5-[(Z)-3- (imidazol-l-yl)prop-l-en-l-yl]-2-(4-fluorophenethyl)benzoate. Yield : 68 %> E isomer : 'H NMR (CDC1 3 , 400 MHz) δ : 2.88 (2H, m) ; 3.26 (2H, m) ; 4.76 (2H, m) ; 6.3-6.6 (2H, m) ; 6.9-7.8 (9H, m) ; 8.17 (lH, d). Z isomer : 'H NMR (CDC1 3 , 400 MHz) δ : 2.90 (2H, m) ; 3.27 (2H, m) ; 4.82 (2H, m) ; 5.89 (IH, m) ; 6.78 (IH, m) ; 6.9-7.6 (9H, m) ; 8.07 (IH, s). Example 46 (3S 3-{5-[(EV3-(ImidazoI-l-yπprop-l-en-l-yl]-2-(4-fluorophenethyπbenzamido}-5- methylsulfanyl-l-phenyl-2-pentanone The title compound was prepared from pentafluorophenyl 5-[(E)-3-(imidazol-l-yl)prop-l-en- l-yl]-2-(4-fluorophenethyl)benzoate using a similar method to that described in Example 3 and isolated as the hydrochloride salt by treatment with HCl/ether. Yield : 42 % Η NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ : 1.83-2.19 (2H, m) ; 2.04 (3H, s) ; 2.50-3.07 (6H, m) ; 3.98 (2H, s) ; 4.73 (IH, dd) ; 5.04 (2H, d) ; 6.46-6.59 -IH, m) ; 6.76 (IH, d) ; 6.96- 7.11 (2H, m) ; 7.12-7.37 (9H, m) ; 7.48 (IH, s) ; 7.74 (IH, s) ; 7.80 (IH, s) ; 9.22 (IH, s). Anal. Calculated for C 33 H 34 FN 3 O 2 S, 1.5 HCl C 64.93 H 5.86 N 6.88 S 5.25 CI 8.71 Found C 66.15 H 6.21 N 6.89 S 5.78 CI 8.74 MS (ESI) m/z : 556 (MH + ) Example 47 l-Methylpiperidin-4-vπ2 t y>-2-[(3-r4-πuorophenyn-5-[(E)-3-(lH-imidazol-l-ynprop-l- enyl]-2-thienylcarbonyπamino]-4-(methylsulfanyI)butanoate A solution of l-[3-(4-fluorophenyl)-5-[(E)-3-(lH-imidazol-l-yl)prop-l-enyl]-thien-2-yl] methanoic acid (4.2 g ; 12.8 mmol), EDC (3.19 g ; 16.6 mmol) and DMAP (0.313 g ; 2.6 mmol) in DMF (50 ml) was stirred under argon atmosphere for 15 minutes. l-(Methylpiperidin-4-yl)-4-(methylsulfanyl) butanoate (5.27 g ; 16.6 mmol) and N-methylmorpholine (3.65 ml ; 32.2 mmol) were then added. The mixture was stirred at room temperature overnight. After evaporation to dryness, the residue was taken up in CΗ 2 C1 2 / H 2 O and extracted. The organic phase was evaporated and purified by preparative HPLC on reverse phase silica eluting with MeOH / (NH 4 ) 2 CO 3 buffer (2 g/1, pH 7) 50/50 to give after evaporation ofthe appropriate fractions a solid which was redissolved in CH,C1 2 / ether and treated at 0°C with a solution of HCl / ether. After 10 minutes the resulting solid was filtered, washed with ether and dried to give the desired product. Yield : 14 % Η NMR (DMSOd 6 + TFA, 400 MHz) δ : 1.8-2.2 (6H, m) ; 2.0 (3H, m) ; 2.3-2.6 (2H, m) ; 2.78 (3H, s) ; 2.9-3.2 (2H, m) ; 3.25-3.5 (2H, m) ; 4.3-4.5 (IH, m) ; 4.8-5.2 (2H, m) ; 5.05 (2H, m) ; 6.4 (IH, m) ; 6.8 (IH, d) ; 7.2-7.6 (5H, m) ; 7.74 (2H, m) ; 9.2 (lH,s). Anal, calculated for C 28 H 33 N 4 O 3 S 2 F, 2 HCl, 0.6 H 2 O C 52.23 H 5.78 N 8.61 S 9.31 CI 11.15 Found C 52.51 H 5.70 N 8.75 S 10.01 CI 11.07 MS (ESI) m/s : 557 (MIT) l-[3-(4-Fluorophenyπ-5-[(E)-3-(lH-imidazol-l-yl)prop-l-enyl]-thien-2-yI] methanoic acid The starting material was prepared as follows : To a solution of methyl l-[5-methyl-3-hydroxy-thien-2-yl] methanoate (53.5 g ; 0.311 mmol) in pyridine (1 1), cooled at 0°C was added dropwise triflic anhydride (67.83 ml ; 0.40 mmol). After stirring at 0°C for 1 hour and then at room temperature for 1 hour, the mixture was evaporated to dryness and the residue extracted with CH 2 C1 2 / H 2 O. The organic phase was evaporated and purified by flash chromatography, eluting with petroleum ether / ethylacetate 95/5 to give methyl l-[5-methyl-3-triflate-thien-2-yl] methanoate. Yield : 90 % Η NMR (CDCl j , 400 MHz) δ : 2.51 (3H, s) ; 3.89 (3H, s) ; 6.71 (IH, s). To a solution of methyl l-[5-nιethyl-3-triflate-thien-2-yl] methanoate (10 g ; 0.033 mol) in a mixture of toluene (1 1) and ethanol (100 ml) was added 4-fluorobenzene boronic acid (6.9 g ; 0.049 mol), Na 2 CO 3 2M (41 ml ; 0.082 mol), LiCl (2.79 g ; 0.066 mol) and tetrakis(triphenylphosphine)palladium(0) (1.52 g ; 0.013 mmol). The mixture was refluxed under argon atmosphere for 2 h 30, extracted with ethyl acetate and purified by flash chromatography eluting with petroleum ether / AcOEt 95/5 to give after evaporation and trituration in ether to give methyl l-[5-methyl-3-(4-fluorophenyl)-thien-2-yl] methanoate as a white solid. Yield : 79 % Η NMR (CDClj, 400 MHz) δ : 2.51 (3H, s) ; 3.74 (3H, s) ; 6.75 (IH, s) ; 7.06 (2H, m) ; 7.40 (2H, m). A solution of methyl l-[5-methyl-3-(4-fluorophenyl)-thien-2-yl] methanoate (12.9 g ; 0.0516 mol), N-bromosuccinimide (11.02 g ; 0.0619 mol) and 2-2'-azobisisobutyronitrile (0.339 g ; 2.06 mmol) in CC1 4 (300 ml) was reflux under argon atmosphere for 90 minutes under UV irradiation. After filtration ofthe precipitate, the filtrate was evaporated to dryness to give methyl l-[5-bromomethyl-3-(4-fluorophenyl)-thien-2-yl] methanoate as a solid which was used in the next step without purification. Η NMR (CDC1 3 , 400 MHz) δ : 3.77 (3H, s) ; 4.65 (2H, s) ; 7.06 (3H, m) ; 7.40 (2H, m). A solution of methyl l-[5-bromomethyl-3-(4-fluorophenyl)-thien-2-yl] methanoate (10.6 g ; 0.032 mol) and triphenylphosphine (8.95 g ; 0.035 mol) in toluene (200 ml) was refluxed under argon atmosphere for 4 hours. After cooling, the precipitate was filtered, washed with toluene and petroleum ether and dried to give methyl l-[5-triphenylphosphine-3-(4- fluorophenyl)-thien-2-yl] methanoate. Yield : 93 % 'H NMR (CDCI 3 , 400 MHz) δ : 3.66 (3H, s) ; 6.08 (2H, d) ; 7.05 (2H, m) ; 7.1-7.3 (3H, m) ; 7.6-8 (15H, m). To a solution of methyl l-[5-tri-phenylphosphine-3-(4-fluorophenyl)-thien-2-yl] methanoate (17.6 g ; 0.03 mol) and 2-(imidazol-l-yl)acetaldehyde (8.46 g ; 0.06 mol) in CH 2 C1 2 (250 ml) was added under argon atmosphere, potassium t-butylate (3.34 g ; 0.03 mol). The mixture was stirred at room temperature for 3 hours, evaporated and purified by flash chromatography eluting with ethyl acetate and then with CH 2 C1 2 / MeOH 95/5 to give after trituration in ether methyl l-[5-(3-(lH-imidazol-l-yl)prop-l-enyl) -3-(4-fluorophenyl)-thien-2-yl] methanoate as a solid. Yield : 54 % 'Η NMR (CDCI 3 , 400 MHz) δ : 3.79 (3H, s) ; 5.0 (2H, d) ; 5.87 (IH, m) ; 6.72 (IH, m) ; 6.9- 7.8 (8H, m). A solution of methyl l-[5-[(E)-3-(lH-imidazol-l-yl)prop-l-enyl]-3-(4-fluorophenyl)-thien-2- yl] methanoate (9 g ; 0.026 mol) in methanol (100 ml) was treated with 2N aqueous sodium hydroxide solution (39.5 ml ; 0.079 mol). The mixture was heated at 60°C for 1 hour and evaporated. The residue was taken up in water (100 ml) / ether (100 ml). The aqueous phase was acidified with HCl 2N to pH 5 and the resulting precipitate was filtered, washed with H 2 O, dried over P 2 O 5 and triturated in ether to l-[3-(4-fluorophenyl)-5-[(E)-3-(lH-imidazol-l- yl)prop-l-enyl] -thienyl] methanoic acid as a solid. Yield : 66% Η NMR (CDC1 3 , 400 MHz) δ : 6.50 (IH, s) ; 6.86 (IH, m) ; 7.25 (3H, m) ; ; 7.50 (2H, m) ; 7.74 (IH, m) ; 7.8 ( IH, m) ; 9.2 (IH, s). Example 48 l-Methylpiperidin-4-yl (2,yi-2-K3-r4-fluorophenyn-5-[(E)-3- H-imidazol-l-ynprop-l- enyl]-2-thienylcarbonyI)amino]-4-(methyIsulfanyI)butanoate The compound was prepared using the same methodology as described for example 47 but was purified by flash chromatography eluting with CH 2 C1, / MeOH 98/2. Yield : 85 % 'H NMR (CDCI 3 , 400 MHz) δ : 1.4 (9H, m) ; 1.7-2.2 (2H, m) ; 2.03 (3H, s) ; 2.25 (2H, m) ; 4.6 (IH, m) ; 4.7 (2H, m) ; 6-6.5 (3H, m) ; 6.8-7.6 (8H, m). MS (ESI) m/z : 515 (MH + ) Example 49 (2S)-2-[r3-r4-Fluorophenvn-5-r( >-3-(lH-imidazol-l-vnprop-l-enyl]-2- thienylcarbonyDamino]-4-(methylsuIfanyl)butanoic acid A solution of example 48 (2 g ; 3.88 mmol) in CH 2 C1 2 (20 ml) was treated with TFA (20 ml). The mixture was stirred at room temperature for 2 hours. After evaporation, the residue was purified on reverse phase silica eluting with MeOH / (NH 4 ) 2 CO 3 buffer (2 g/1, pH 7) 40/60 to give the desired product. Yield : 33 % Η NMR (DMSO + CF 3 COOD, 400 MHz) δ : 1.8-2.1 (2H, m) ; 2.01 (3H, s) ; 2.2-2.5 (2H, m); 4.34 (IH, m) ; 5.02 (2H, d) ; 6.42 (IH, m) ; 6.88 (IH, d) ; 7.1-7.4 (3H, m) ; 7.52 (2H, m); 7.77 (2H, m) ; 9.19 (lH, s). Anal, calculated for C 22 H 22 N 3 O 3 S 2 F, 0.6 H 2 O, 0.3 ether C 56.57 H 5.36 N 8.53 S 13.02 Found C 56.28 H 5.10 N 8.71 S 12.76 MS (ESI) m/z : 460 (MH + )

Claims: CLATMS A compound of Formula (1): Formula (1) wherein Ar 1 represents: R 5 is hydrogen, C 1 -4 alkyl, phenylC] -4 alkyl; R is hydrogen, C ]- alkyl, hydroxyCι -4 alkyl, haloC, 4 alkyl, dihaloC, 4 alkyl, C, 4 alkoxy, C alkoxyC, 4 alkyl, sulfanylCι -4 alkyl, aminoC 1-4 alkyl, N-(C 1-4 alkyl)aminoCι -4 alkyl, N,N-di(C ] - alkyl)aminoCι -4 alkyl or phenylC, 4 alkyl; m is 0,1 or 2; R' 2 and R' 3 are independently hydrogen or C, 4 alkyl; Ar 2 is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, thiazolyl, furyl or oxazolyl, the ring being substituted on ring carbon atoms by R 2 and -(CH 2 )„R 3 , wherein Ar 2 is attached to Ar'C(R' )R n CH=CH- by a ring carbon atom; or Ar 2 is pyrrolyl, pyrazolyl or imidazolyl, substituted by R 2 and -(CH 2 )„R 3 (the pyrrolyl, pyrazolyl or imidazolyl rings can bear a substituent on the sp 3 hybridised ring nitrogen or Ar 2 can be attached to Ar'C(R' 2 )R' 3 CH=CH- by the sp 3 hybridised ring nitrogen); R is a group ofthe Formula (2): Formula (2) wherein R is hydrogen or C^alkyl, R 8 is -(CH 2 ) q -R 10 wherein q is 0-4 and R 10 is C| -4 alkylsulfanyl, C ) -4 alkylsulfinyl, Cι -4 alkylsulfonyl, hydroxy, C l -4 alkoxy, carbamoyl, N-C 1 - 4 alkyl carbamoyl, N,N-(diC] -4 alkyl)carbamoyl, C alkyl, phenyl, thienyl, or Cι -4 alkanoylamino, R" is hydroxy, C 1 -6 alkoxy, C, 9 cycloalkyloxy, heterocyclyloxy, heterocyclylC, 4 alkoxy or -NH-SO -R" wherein R" represents, trifluoromethyl, Cι -4 alkyl, phenyl, heteroaryl, arylC,- 4 alkyl or heteroarylC,- 4 alkyl; or R represents a lactone of Formula (3) "C °H V- O Formula (3) O the group of Formula (2) or (3) having L or D configuration at the chiral alpha carbon in the corresponding free amino acid; n is 0, 1 or 2; R is phenyl or heteroaryl; or R is a group ofthe Formula (4): -CONHCH(R' 4 )R 15 Formula (4) wherein R 14 is -(CH 2 ) q -R 16 wherein q is 0-4 and R' 6 is Cι -4 alkylsulfmyl, Cι. 4 alkylsulfonyl, hydroxy, C 1 -4 alkoxy, carbamoyl, N-C ] -4 alkyl carbamoyl, N,N-(diC 1 -4 alkyl)carbamoyl, C ] -4 alkyl, phenyl, thienyl, or R 15 is ofthe formula -CH 2 OR 17 (wherein R" is hydrogen, C,. 4 alkyl, phenyl, heteroaryl, C 2 - 5 alkanoyl, C,. 4 alkoxymethyl, phenoxymethyl or heteroaryloxymethyl), ofthe formula -COR 18 or ofthe formula -CH,COR' 8 (wherein R 18 is C, 4 alkyl (optionally substituted by halo, cyano, C 2 . 5 alkanoyloxy, hydroxy, C 1- alkoxy or Cι_4alkanoyl), phenyl, phenylC,- 3 alkyl, heteroaryl, heteroarylC,.,alkyl, C 5.7 cycloalkyl, C 5.7 cycloalkylC,_ 3 alkyl, 2-(phenyl)ethenyl, 2-(heteroaryl)ethenyl or N-methoxy-N-methylamino); or R" is morpholinoC, 4 alkyl, pyrrolidin-1-ylC, 4 alkyl or piperidin-1-ylC, 4 alkyl wherein the morpholine, pyrrolidine and piperidine rings are optionally substituted by C M alkyl or C 5 . 7 cycloalkyl; or R 15 is phenyl- 1 -hydroxy C alkyl or heteroaryl- l-hydroxyC,. 4 alkyl; phenyl and heteroaryl rings in R 3 , R\ R\ R", R" (including R and R 1S ) are independently optionally substituted on ring carbon atoms in by up to three substituents selected from CMalkyl, halogen, hydroxy, Cι_4alkoxy, C ^alkoxycarbonyl, Cι _4alkanoyl, C^alkanoyloxy, amino, Cι_4alkylamino, di(Cι_4alkyl)amino, Cι_4alkanoylamino, nitro, cyano, carboxy, thiol, C^alkylsulfanyl, Cι_4alkylsulfmyl, C]„4alkylsulfonyl, C, 4 alkanesulphonamido, N-(C, 4 alkylsulphonyl)-N-C, 4 alkylamino, aminosulfonyl, N-(C, 4 alkyl)aminosulfonyl, N,N-di(C, 4 alkyl)aminosulfonyl, carbamoyl, N-(C 1 -4 alkyl)carbamoyl, N,N-(diC i -4 alkyl)carbamoyl, carbamoy 1C i -4 alkyl, N-(C i -4 alkyl)carbamoylC ] - alkyl, N,N-(diCι -4 alkyl)carbamoylC]. 4 alkyl, hydroxyC 1 -4 alkyl and Cι -4 alkoxyCι -4 alkyl and on ring NH groups (replacing hydrogen) by C, alkyl, C, 4 alkanoyl, C, 4 alkylsulfonyl, haloC,. 4 alkyl, difluoromethyl or trifluoromethyl; or a pharmaceutically-acceptable salt, prodrug or solvate thereof. 2. A compound of Formula ( 1 ) : Formula (1) wherein Ar 1 represents: (A) (B) (C) R » 5 is hydrogen, Cι -4 alkyl, phenylC 1-4 alkyl; R 6 is hydrogen, C 1 -4 alkyl, hydroxyCι -4 alkyl, haloC, 4 alkyl, dihaloC, 4 alkyl, C 1 4 alkoxy, C, „alkoxyC, 4 alkyl, sulfanylC ]-4 alkyl, amino C ] -4 alkyl, N-(Cι -4 alkyl)aminoC ]-4 alkyl, N,N-di(Cι -4 alkyl)aminoC]. 4 alkyl or phenylC M alkyl; m is 0,1 or 2; R 12 and R' 3 are independently hydrogen or C, 4 alkyl; Ar 2 is phenyl, pyridinyl or thienyl, the ring being substituted on ring carbon atoms by R 2 and -(CH,),,R 3 and wherein Ar 2 is attached to Ar'C(R' 2 )R 1 CH=CH- by a ring carbon atom; R is a group ofthe Formula (2): Formula (2) wherein R .7 is hydrogen, R 8 is -(CH 2 ) 2 -R 10 wherein R 10 is C ! -4 alkylsulfanyl or C 1 -4 alkylsulfonyl, R 9 is hydroxy, Cι -6 alkoxy, C 3 ,cycloalkyloxy, heterocyclyloxy or heterocyclylC M alkoxy; or R represents a lactone of Formula (3) Formula (3) the group of Formula (2) or (3) having L or D configuration at the chiral alpha carbon in the corresponding free amino acid; n is 0, 1 or 2; R is phenyl or heteroaryl; or R 2 is a group ofthe Formula (4): -CONHCH(R' 4 )R' > Formula (4) wherein R" is -(CH 2 ) q -R 16 wherein q is 0-4 and R 16 is C i -4 alky lsulfanyl, C i -4 alkylsulfmyl, C ι . 4 alkylsulfonyl, hydroxy, C ] -4 alkoxy, carbamoyl, N-C 1-4 alkyl carbamoyl, N,N-(diCι -4 alkyl)carbamoyl, C 1 -4 alkyl, phenyl, thienyl, or C ] -4 alkanoylamino; R 1 " 5 is ofthe formula -CH 2 OR" (wherein R 17 is hydrogen, C, 4 alkyl, phenyl, heteroaryl, C 25 alkanoyl, C, 4 alkoxym ethyl, phenoxymethyl or heteroaryloxymethyl), ofthe formula -COR 18 or ofthe formula -CH,COR ,s (wherein R ,s is C, 4 alkyl (optionally substituted by halo, cyano, C 2 . 5 alkanoyloxy, hydroxy, Ci _4alkoxy or C^alkanoyl), phenyl, phenylC, ,alkyl, heteroaryl, heteroarylC, , alkyl, C 5 _ 7 cycloalkyl, C 5 . 7 cycloalkylC, 3 alkyl, 2-(phenyl)ethenyl, 2-(heteroaryl)ethenyl or N-methoxy-N-methylamino); or R" is morpholinoC, 4 alkyl, pyrrolidin-1-ylC, 4 alkyl or piperidin-1-ylC, 4 alkyl wherein the morpholine, pyrrolidine and piperidine rings are optionally substituted by C, 4 alkyl or C 5 . 7 cycloalkyl; or R 15 is phenyl- l-hydroxyC,. 4 alkyl or heteroaryl-l-hydroxyC, .4 alkyl; phenyl and heteroaryl rings in R R R"and R'are independently optionally substituted on ring carbon atoms in by up to three substituents selected from CMalkyl, halogen, hydroxy, C^alkoxy, C\ .4 alkoxycarbonyl, Cι_4alkanoyl, C^alkanoyloxy, amino, C^alkylamino, di(Cι_4alkyl)amino, Cι_4alkanoylamino, nitro, cyano, carboxy, thiol, C^alkylsulfanyl, Cι_4alkylsulfinyl, Cι_4alkylsulfonyl, C, 4 alkanesulphonamido, N^C.-.alkylsulphonyl N-C^alkylamino, aminosulfonyl, N-(C, 4 alkyl)aminosulfonyl, N,N-di(C,. 4 alkyl)aminosulfonyl, carbamoyl, N-(C 1-4 alkyl)carbamoyl, N,N-(diC ] -4 alkyl)carbamoyl, carbamoylC 1 -4 alkyl, N-(C 1 . 4 alkyl)carbamoylC] -4 alkyl, N,N-(diCι -4 alkyl)carbamoylC 1- alkyl, hydroxyCι- alkyl and Cι -4 alkoxyCι -4 alkyl and on ring NH groups (replacing hydrogen) by C 1 alkyl, C 1 4 alkanoyl, C, 4 alkylsulfonyl, haloC,. 4 alkyl, difluoromethyl or trifluoromethyl; or a pharmaceutically-acceptable salt, prodrug or solvate thereof. 3. A compound of Formula (I) as claimed in either claim 1 or claim 2 where in R 3 is phenyl. 4. A compound of Formula (I) as claimed in claim 3 wherein substituents on the ring carbon atom(s) ofthe phenyl ring R 3 are selected from C, 4 alkyl, halo, trifluoromethyl, C,_,alkoxy, nitro, cyano and C,. 4 alkoxyC, alkyl. 5. A compound of Formula (I) as claimed in Claim 4 wherein a carbon atom ofthe phenyl ring of R 3 is substituted by fluoro, chloro or cyano. 6. A compound of Formula (I) as claimed in any one of claims 1 to 5 wherein n is 0 or 2. 7. A compound of Formula (I) as claimed in any one of claims 1 to 6 wherein R 12 and R 13 are hydrogen. 8. A compound of Formula (IV), as defined in any one of claims 1 to 7, for use in medical therapy. 9. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically-acceptable salt thereof, as defined in any one of claims 1 to 7, with a pharmaceutically-acceptable diluent or carrier.

Inventors: ARNOULD JEAN-CLAUDE, OLIVIER ANNIE ANTOINETTE CHRIS, ARNOULD, JEAN-CLAUDE, OLIVIER, ANNIE, ANTOINETTE, CHRISTIANE
Applicants: ARNOULD JEAN CLAUDE, ASTRAZENECA UK LTD, OLIVIER ANNIE ANTOINETTE CHRIS, ZENECA PHARMA SA, ARNOULD, JEAN-CLAUDE, ASTRAZENECA UK LIMITED, OLIVIER, ANNIE, ANTOINETTE, CHRISTIANE, ZENECA-PHARMA S.A.
Application year: 1999
Main classification: G06F17
IPC codes: A61K31, A61P35, A61P43, C07D233, C07D409, C07D521