FARNESYL TRANSFERASE INHIBITORS

Abstract: The present invention relates to a compound of formula (1) wherein A is of formula (2), (3), (4), B is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, thiazolyl, furyl or oxazolyl, the ring being substituted on ring carbon atoms by R<1> and -(CH2)nR<2>; or B is pyrrolyl, pyrazolyl or imidazolyl, and when A is of formula (2) or (3), B can also be naphthyl substituted by R<1> and -(CH2)nR<2>; R<1> is of the formula -CONHCH(R<10>)R<11> wherein R<11> is of the formula -CH2OR<13>, -COR<14> or -CH2COR<14> or R<11> is morpholinoC1-4alkyl, pyrrolidin-1-ylC1-4alkyl or piperidin-1-ylC1-4alkyl; or R<11> is phenyl-1-hydroxyC1-4alkyl; or heteroaryl-1-hydroxyC1-4alkyl; R<2> is phenyl or heteroaryl; and n is 0, 1 or 2; or a prodrug, solvate or pharmaceutically-acceptable salt thereof. Processes for their preparation, their use as therapeutic agents and pharmaceutical compositions containing them. A particular use is in cancer therapy.

Description: FARNESYL TRANSFERASE INHIBITORS 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 farnesyl 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 farnesyl transferase is based on farnesyl pyrophosphate analogues; see for example European patent application EP 534546 from Merck. Inhibitors of farnesyl transferase based on mimicry of the CAAX box have been reported. Reiss (1990) in Cell 62, 81-8 disclosed tetrapeptides such as CVIM (Cys-Nal-Ile- Met). James (1993) in Science 260, 1937-1942 disclosed benzodiazepine based peptidomimetic compounds. Lemer (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 farnesyl transferase inhibitors having a 4-sulfanylpyrrolidine residue in the first position. More recently Intemational Patent Application No. PCT/GB96/01810 disclosed 2,4-thioproline compounds which contain phenyl, naphthyl or heteroaryl ring which can be substituted by a group of the formula -CONR13-CHR14-COOR17. We have now discovered a range of compounds containing non-acid groups which have farnesyl transferase inhibitory activity. According to one aspect of the present invention there is provided a compound of formula (1): wherein A is of the formula: R 4 S S R 4 Ar 1 CH 2 \ Ar 2' I I R 3 R 3 (2) (3) (4) wherein R 3 is hydrogen, C 2 - 5 alkanoyl, Cι. 4 alkoxycarbonyl, C 2 - 4 alkenyloxycarbonyl, phenylCι_ 3 alkyl, phenoxycarbonyl, phenylC^alkoxycarbonyl or Cι. 4 alkyl optionally substituted by carbamoyl, Cι. 4 alkylcarbamoyl, di(Cι. 4 alkyl)carbamoyl, carboxy or Cι_ 4 alkoxy carbonyl; R 4 is hydrogen, Cι_ 4 alkyl, C 2 - 5 alkanoyl, Cι_ 4 alkoxy carbonyl, phenylCι_ 3 alkyl, benzoyl, heteroarylC,. 3 alkyl or heteroaroyl; D is a linking moiety selected from the following groups written from left to right in formula (2) and (3): -3- K v. N N 77 . y K y (wherein the piperazine and perhydro-l,4-diazepine rings are optionally substituted by Cι. 4 alkoxyCι_ 4 alkyl, phenoxyCι. 4 alkyl or heteroarylCι. 4 alkyl); -CO-N(R5)-; -CH 2 -N(R5)-; - CH 2 S-; -CH 2 O-; -CH 2 -CH(R5); -CH=C(R5)-; -CH 2 N(R5)-T-; -CH 2 N(R5)-SO 2 -; -CH 2 -N(R5)- CO-T1-; -CO-N(R5)-T-; -CH 2 S-T-; -CH 2 O-T- (where R5 is hydrogen, Z, C^alkyl, Z- . 4 alkyl, Z-C 2 - 5 alkanoyl, C 2 - 7 alkanoyl or ZCO- and Z is alkoxy, phenyl, naphthyl or a monocyclic or bicyclic heteroaryl ring, T is -(CH 2 )m- wherein m is 1-4 and T is optionally monosubstituted with any value of R 5 other than hydrogen ; and Η represents -(CH 2 )mi- wherein ml is 0-4 and Tl is optionally monosubstituted with any value of R5 other than hydrogen); Ar 1 is of the formula (5), (6) or (7): R 6 / N==\ -N ^y y // N (R 7 ) D R 7 (5) (7) R is hydrogen, Ci^alkyl, phenylCι_ 4 alkyl; R is hydrogen, Ci^alkyl, hydroxyC 1 - 4 alkyl, haloC M alkyl, dihaloC M alkyl, C M alkoxy, Cι. 4 alkoxyCι. 4 alkyl, C 2 - 4 alkenyloxyCι_ 4 alkyl, C 2 - 4 alkynyloxyCι. 4 alkyl, sulfanylC alkyl, aminoC j . 4 alkyl, N-(C i ^alkyl)aminoC i ^alkyl or phenylC i . 4 alkyl; p is 0,1 or 2; Ar2 is phenyl or heteroaryl; E is of the formula >C=CH-, >CHCH 2 -, >CH-N(R8)-, >CH-O, >CH-N(R8)CH 2 - or >CH-OCH 2 -; wherein R 8 is hydrogen, Cj^alkyl or C 2 - 5 alkanoyl; B is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, thiazolyl, furyl or oxazolyl, the ring being substituted on ring carbon atoms by Ri and -(CH 2 ) n R 2 ; or B is pyrrolyl, pyrazolyl or imidazolyl, substituted by R 1 and -(CH 2 ) n R 2 (the pyrrolyl, pyrazolyl or -4- imidazolyl rings may bear a substituent on the sp 3 hybridised ring nitrogen); when A is of the formula (2) or (3), B can also be naphthyl substituted by Ri and -(CH 2 ) n R 2 ; R 1 is of the formula -CONHCH(Riθ)RH wherein Rio is hydrogen or -(CH 2 ) q -R 12 wherein q is 0-4 and R 12 is hydrogen Cι_ 4 alkylsulfanyl, Cj^alkylsulfinyl, Cj_ 4 alkylsulfonyl, hydroxy, C^alkoxy, carbamoyl, N-Ci^alkylcarbamoyl, N,N-(diC i . 4 alkvl ' )earbamovl. C^alkyl, phenyl, thienyl, phenylCj^alkoxy or C 2 . 5 alkanoylamino; RU is of the formula -CH 2 ORi3 (wherein R 13 is hydrogen, C 1 . alkyl, phenyl, heteroaryl, C 2 - 5 alkanoyl, Cι- alkoxymethyl, phenoxymethyl or heteroaryloxymethyl), of the formula -CORΪ4 or of the formula -CH 2 CORi4 (wherein Ri* is C 1 . 4 alkyl (optionally substituted by halo, cyano, C 2 . 4 alkanoyloxy, hydroxy, Cj_4alkoxy or Cι_4alkanoyl), phenyl, phenylCi- 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 11 is morpholinoC ϊ ^alkyl, pyrrolidin-l-ylCι. 4 alkyl or piperidin-l-ylCι- alkyl wherein the morpholine, pyrrolidine and piperidine rings are optionally substituted by Cι. 4 alkyl or C 5 . 7 cycloalkyl; or R 11 is phenyl- 1 -hydroxyC alkyl; or heteroaryl- 1 -hydroxyC M alkyl; R is phenyl or heteroaryl; n is 0, 1 or 2; and phenyl and heteroaryl groups in R 2 , R3, R4, R6, R7 ; Rii (including R 13 and R 14 ), R' 2 , Ar 2 and D are independently optionally substituted on ring carbon atoms by up to three substituents selected from C \ _4alkyl, halogen, hydroxy, C \ _4alkoxy, C j _4alkoxycarbonyl, C \ _4alkanoyl, Cι_4alkanoyloxy, amino, C^alkylamino, di(Cι_4alkyl)amino, Cj^alkanoylamino, nitro, cyano, carboxy, carbamoyl, N-Cι. 4 alkylcarbamoyl, N,N-(di-Cι- 4 alkyl)carbamoyl, Ci^alkoxycarbonyl, thiol, C^alkylsulfanyl, Cι_4alkylsulfinyl,Cι_4alkylsulfonyl, Cj. 4 alkanesulphonamido, N-(Cι- 4 alkylsulfonyl)-N-Cj. 4 alkylamino, aminosulfonyl, N- (C 1 _ 4 alkyl)aminosulfonyl, N,N-di (C 1 . 4 alkyl)aminosulfonyl, carbamoylC . - 4 alkyl, N- (C^alky carbamoylC alkyl, N,N-(diCι- 4 alkyl)carbamoylCι- 4 alkyL hydroxyCi^alkyl and C 1 ^alkoxy C j ^alkyl ; or a prodrug, solvate or pharmaceutically-acceptable salt 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" -5- are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain 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 "heteroaryl" refers to a 5 or 6-membered monocyclic heteroaryl ring containing upto 3 heteroatoms selected from nitrogen, oxygen and sulphur. The term 'bicyclic heteroaryl' refers to 8 to 10-membered bicyclic aromatic ring systems which contain up to 5 ring heteroatoms selected from nitrogen, oxygen and sulfur and comprises a 6- membered ring fused to a 5 or 6-membered ring. 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 Cι- 4 alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl and tert- butyl; examples of C^alkoxy include methoxy, ethoxy and propoxy; examples of Cj_4alkanoyl include formyl, acetyl and propionyl; examples of C 2 . 5 alkanoyloxy include acetyloxy and propionyloxy; examples of Cι- 4 alkylamino include methylamino, ethylamino, propylamino, isopropylamino, sec-butylamino and tert-butylamino; examples of i-(C 1 - 4 alkyl)amino include di-methylamino, di-ethylamino and N-ethyl-N-methylamino; examples of Cj^alkanoylamino include acetamido and propionylamino; examples of phenylCι_ 3 alkyl include benzyl and phenethyl; examples of alkenyloxycarbonyl include allyloxycarbonyl and vinyloxycarbonyl; examples of phenylCi^alkoxycarbonyl include benzyloxycarbonyl and phenethyloxy carbonyl; examples of C^alkoxy carbonyl include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of C^alkylsulfanyl include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, -yec-butylsulfanyl and tert-butylsulfanyl; examples of Cj^alkylsulfinyl include methylsulfinyl, ethylsulfinyl, -6- propylsulfinyl, isopropylsulfinyl, sec-butylsulfinyl and tert-butylsulfinyl; examples of Cχ_4alkylsulfonyl include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl; examples of N-(C 1 - alkyl)carbamoyl include N- methylcarbamoyl and N-ethylcarbamoyl; examples of N 1 N-(diC 1 . 4 alkyl)carbamoyl include N,N-dimethylcarbamoyl and N-methyl-N-ethylcarbamoyl; examples of phenyl- 1 - hydroxyC alkyl include 1 -phenyl- 1-hydroxymethyl and 2-phenyl-l-hydroxyethyl; examples of heteroaryl- 1 -hydroxy C h alky 1 include l-(pyrid-2-yl)-l-hydroxymethyl, 2-(pyrid-2-yl)-l- hydroxyethyl, l-(thiazol-2-yl)-l-hydroxymethyl and 2-(thiazo-2-yl)-l-hydroxyethyl; examples of Cj^alkanesulfonamido include methanesulfonamido, ethanesulphonamido and propanesulfonamido; examples of C1_4alkylsulfonyI-N-C 1 _ 4 alkyla.mi.110 include methylsulfonyl-N-methylamino, ethylsulfonyl-N-methylamino and propylsulfonyl-N- methylamino; examples of carbamoylCι- 4 alkyI include carbamoylmethyl, carbamoylethyl and carbamoylpropyl; examples of N-(Cι- 4 alkyl)carbamoylCι- 4 alkyl include N-methyl- carbamoylmethyl and N-ethyl-carbamoylethyl; examples of N,N-(diC i --.alkvDcarbamoyl-C i . 4 alkyl include N,N-dimethylcarbamoylethyl and N-methyl-N-ethylcarbamoylethyl; examples of hydroxyC 1 . 4 alkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, 2- hydroxypropyl, 2-(hydroxymethyl)propyl and hydroxy butyl; examples of C^alkoxy methyl include methoxymethyl, ethoxymethyl and propoxymethyl; examples of C^alkoxyC^alkyl include methoxyethyl, ethoxyethyl and methoxybutyl; examples of sulfanylC]. 4 alkyl include sulfanylmethyl, sulfanylethyl, sulfanylpropyl; and examples of N-(Cι- 4 alkyl)aminoC 1 - 4 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. Preferred heteroatoms in heteroaryl rings are N and S, especially N. In general, attachment of heterocyclic rings to other groups is via carbon atoms. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran, benzimidazole, ben^liiophene, benzthiazole, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine. -7- Heteroaroyl means heteroarylcarbonyl (heteroaryl-CO-). The ring sp 3 hybridised ring nitrogen in the pyrrolyl, pyrazolyl or imidazolyl rings is the ring nitrogen which can be substituted without becoming quatemised i.e. the ring >NH nitrogen. Examples of values for R 10 in Formula (2) are side chains of lipophilic amino acids including, for example, methionine, phenylglycine, phenylalanine, serine, leucine, isoleucine or valine. 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 phenyl phenylalanine benzyl thienylalanine thien-2-ylmethyl serine -CH 2 OH or a Ci^alkyl (preferably methyl) ether thereof. Leucine -CH 2 -CHMe 2 homoserine -CH 2 -CH 2 -OH or a Ci^alkyl (preferably methyl) ether thereof N-acetyl-lysine -CH 2 -CH 2 -CH 2 -CH 2 -NH-CO-CH 3 In one aspect A is of the formula (2) or (3). In another aspect A is of the formula (4). When A is of the formula (2) or (3): Preferably R 3 is selected from hydrogen, phenylCi. 3 alkoxy carbonyl, C 2 - 4 alkenyloxycarbonyl, C 2 - 5 alkanoyl, carbamoylCι_ 4 alkyl, N-C 1 . 4 alkylcarbamoylCι. 4 alkyl or di(C 1 _ alkyl)carbamoylC 1 . alkyl. Most preferably R 3 is hydrogen. Preferably R 4 is hydrogen, C 2 . 5 alkanoyl, C,. 4 alkoxy carbonyl or benzoyl. More preferably R 4 is hydrogen, C 2 - 5 alkanoyl or benzoyl. Most preferably R 4 is hydrogen. Preferably B is selected from phenyl, naphthyl, pyridyl or thienyl. Most preferably B is phenyl or naphthyl. -8- Suitable values for D, when it is of the formula -CHN(R5)-T-, include CH2.N(CO.CH2.CHMe2).CH2.CH2; CH2-N(CH2 CH2 CH2OMe).CH2-CH2; CH2.N(CH2.^Ph.OMe).CH2.CH2; CH2.N(CO.CH2.CHMe2).CH2; CH2N(CO.CH2.CH2.CH2.Me).CH2; CH2N(CO.CH2.CHMe.CH2Me).CH2; CH2N(CO.CH2-CH2.OMe)CH2; CH2N(CO.CH2.pyridin-3-yl).CH2; CH2N(4- methoxybenzyl)CH2; CH2N(CO.CH2.CHMe2)CH2.CH2.CH(Ph); CH2N(CO.CH3)CH2.CH2.CH(Ph); CH2N(CO.CH2.CHMe2)CH2; CH2N(CO.CH3)CH2; CH2N(CO.CH2.CHMe2)CH2.CH(Ph); CH2N(CO.CH2.CMe3)CH2.CH(Ph); CH2N(CO.CH2.pyridin-3-yl)CH2.CH(Ph); CH2N(CO.1 -hydroxy-6-methoxy-pyridin-3- yl)CH2.CH(Ph); CH 2 N (CO.CH 2 pyrid-3-yl)CH 2 CH(Ph); CH2N(CO.CH2CHMe2)CH2.CH2; CH2N(CO.CH2CMe3)CH2.CH2; CH 2 N(CO thiazol-2-yl)CH 2 CH 2 ; CH 2 N (CO l-oxido-6-hydroxypyridin-3-yl)CH 2 CH 2 ; CH2N(CO.CH2pyridin-3-yl)CH2.CH2 and CH2N(CO.4-methoxybenzyl)CH2.CH2. Preferred values for CH 2 N(R 5 )T include CH 2 N(CO.CH 2 .CHMe 2 )CH 2 .CH(Ph); CH 2 N (CO.CH 2 pyridin-3-yl)CH 2 CH(Ph); CH 2 N(CO.1 - hydroxy-6-hydroxypyridin -3-yl)CH 2 .CH(Ph); CH 2 N(CO thiazol-2-yl)CH 2 .CH 2 ; and CH 2 N (CO.1 -oxido-6-hydroxypyridin-3-yl) CH 2 .CH 2 . Suitable values for D when it is of the formula -CH2N(R ) - include CH2NH; CH2NMe; CH2N(CO.CH2.CHMe2) and CH2N(CO.CH2.CH2.OMe). A preferred value for - CH 2 NR 5 - is -CH 2 NH 2 -. When D is -CH N(R 5 )-T- a suitable value for m is 1. When D is -CH -N(R 5 )-CO-T 1 - a suitable value for m 1 is 1. When D is -CH 2 -NR5-T- a suitable value for m is 1. When D is -CH 2 -S-T- a suitable value for m is 1. When D is -CH 2 -O-T- a suitable value for m is 1. D is especially -CONH-, -CH 2 NH-, -CH 2 NHSO ., -CH 2 NHCO-, -CH 2 O- or -CH=CH- Preferably D is -CH 2 N(R 5 )-, -CH 2 N(R 5 )-T-, -CH 2 O-, -CH 2 O-T- or -CH=CH-. More preferably, D is -CH 2 NH-, -CH 2 O- or -CH=C(R 5 )-. Most preferably, D is -CH .NH- or -CH=C(R 5 )-. In another aspect D is of the formula: -9- y N wherein the piperazine ring is optionally substituted by C M alkoxyC M alkyl, phenoxyC^alkyl or heteroaryloxyC alkyl. In a preferred class of compounds wherein A is of the formula (2) or (3): R3 and R4 are hydrogen and D is of the formula -CH 2 O-, -CH=CH-, -CH 2 N(R5)-, -CH 2 N(R 5 )CH 2 -, -CH 2 N(R 5 )CH 2 CH 2 -, -CH 2 N(R 5 )CH 2 CH 2 - or -CH 2 N(R5)CH 2 CH(Ph)- wherein R5 is as hereinabove defined. Preferably substituents on the 2 and 3 (or 4 if A is of the formula (3)) positions of the pyrrolidine ring, in compounds of the Formula I, are in the cis configuration. S - H S - H " N CH, I and/or H Another suitable configuration is the trans configuration. S - H „ S _ H N CH 2 ■ and/or H When A is of the formula (4): In one aspect of the invention, R 7 is hydrogen, C M alkyl, hydroxyC M alkyl, C M alkoxyC M alkyl, C^alkenyloxyC.^alkyl, C 2^ ,alkynyloxyC M alkyl, sulfanylC M alkyl, aminoC M alkyl, N-(Cj. 4 alkyl)aminoC M alkyl or phenylC M alkyl. In another aspect of the invention R is hydrogen or methyl. In yet another aspect of the invention R is C^alkyl, hydroxyC^alkyl, sulfanylC 1 - 4 alkyl, aminoC]. 4 alkyl, N- -10- (monoCι- 4 alkyl)aminoC 1 . 4 alkyl or benzyl, more preferably hydroxyC^alkyl and especially hydroxymethyl or aminomethyl. Preferably R is benzyl (optionally substituted by cyano or nitro), methyl, ethyl or hydrogen. More preferably, R6 is 4-cyanobenzyl, 4-nitrobenzyl, methyl or hydrogen. When Ar' is imidazol-1-yl, then R 7 is preferably hydrogen or methyl. When Ari is imidazol-5-yl, then R 7 is preferably hydrogen and R5 is preferably methyl or cyanobenzyl. Preferably p is 1. A preferred heteroaryl value for Ar2 is pyridyl or thiazolyl, especially thiazol-2-yl. When Ar 2 is phenyl, more preferred optional substituents are fluoro, chloro and cyano. When Ar2 is phenyl, it is preferably unsubstituted or monosubstituted. In one aspect, when Ar 2 is phenyl, it is unsubstituted. In another aspect, when Ar2 is phenyl, it is monosubstituted in the para position. Preferably E is of the formula >C=CH-, >CHN(R 8 )-, >CHO-, >CHN(R8) CH 2 - or >CHOCH 2 -. More preferably E is of the formula >C=CH-, >CHN(R8)- or >CHO-. Most preferably E is of the formula >C=CH- or >CHN(R8)- Preferably R8 is hydrogen, methyl or acetyl. Most preferably R8 is hydrogen. Preferably B is phenyl, pyridyl, thienyl, thiazolyl, oxazolyl or pyrazolyl. More preferably B is phenyl or pyridyl. When A is of the formula (2), (3) or (4): Preferably B is phenyl or pyridyl. Most preferably B is phenyl. Preferably when n is 0, B is substituted by Ri in the 4-position and -(CH 2 ) n R 2 in the 3- or 5-position and when n is 1 or 2, then B is preferably substituted by R 1 in the 3- or 5-position and -(CH 2 ) n R 2 in the 4-position. Preferably q in R'O is 1-4, more preferably 1-3, most preferably 2-3 and especially 2. Preferably R12 in Rio is hydrogen, methyl, Cι_ 4 alkylsulfanyl, Cι_ 4 alkylsulfonyl, Ci- 4 alkoxy, hydroxy, phenyl or thienyl. More preferably R12 in Rio is methyl, methylsulfanyl or methylsulfonyl, methoxy, hydroxy or carbamoyl. -11- Yet more preferably R12 in Rio is methyl, methylsulfanyl or methylsulfonyl. Most preferably R 12 is methylsulfanyl or methylsulfonyl. Preferred values for Rio include 2-(methylsulfanyl)ethyl, 2-(methylsulfonyl)ethyl, 2-(methoxy)ethyl and methyl. Preferably R 13 in R 11 is hydrogen or phenyl. Most preferably R13 in RU is hydrogen. Preferably R14 in RU is Cι. 4 alkyl, phenyl, phenylC 1 . 3 alkyl, heteroaryl, heteroarylC^alkyl or C 5 - 7 cycloalkylCι- 3 alkyl. More preferably RI 4 in RH is Cj. 4 alkyl, phenyl, phenylCι_ 3 alkyl or heteroaryl. Most preferably R 1 in Ri 1 is Cι. 4 alkyl, phenyl or benzyl. Preferably when R 14 is C alkyl it is optionally substituted by halo, cyano or C 2 . 6 alkanoyloxy. Preferably morpholinoC 1 . 4 alkyl is morpholinomethyl, pyrrolidin- 1 -ylC 1 . 4 alkyl is pyrrolidin-1-ylmethyl and piperidin-l-ylC 1 . 4 alkyl is piperidin-1-ylmethyl. In one aspect Ri is morpholinomethyl. More preferably RU is hydroxymethyl, benzylcarbonyl, 3-(pyridyl)propionyl or morpholinomethyl. Preferably R 2 is optionally substituted phenyl, thienyl or thiazolyl. When R2 is phenyl more preferred optional substituents are fluoro, chloro and cyano. When R2 is phenyl, it is preferably unsubstituted or monosubstituted. In one aspect, when R2 is phenyl, it is unsubstituted. In another aspect, when R 2 is phenyl, it is monosubstituted in the para position. In one aspect of the invention, R is phenyl or 4-fluorophenyl. Preferred values for -(CH 2 )nR 2 include 4-fluorophenyl, phenyl, thiazol-2-yl, 2-(4- fluorophenyl)ethyl and 2-(thiazol-2-yl)ethyl. Particular compounds of the present invention include: (2S)-2-{ 2-(4-fluorophenyl)-4-[ 1 -(4-fluorophenyl)-2-(imidazol- 1 -yl)ethylamino]- benzoylamino}-4-methylsulfanylbutan-l-ol; (2S)-2-{4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenyl)benzamido } -4-methylsulfanylbutan-l-ol; -12- (2S)-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4-fluorophenyl)benzamido}- 4-methylsulfany lbutan-1-ol ; (2S)-2-{4-[l-(4-fluorophenyl)-2-(imidazol-l-yl)ethoxymethyl]-2-(4- fluorophenyl)benzamido } -4-methylsulfanylbutan-l-ol ; (2S)-3-{4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenyl)benzamido} -5-methylsulfanyl-2-oxo- 1 -phenylpentane; (2S)-3-{4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenyl)benzamido}-5-methylsulfonyl-2-oxo-l-phenylpentane; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 4-methylsulfany lbutan- 1 -ol ; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 5-methylsulfanyl- 1 -phenylpentan-2-one; (4S)-4-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 6-methylsulfanyl-l-(pyrid-3-yl)hexan-3-one; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 4-methylsulfanyl- 1 -morpholinobutane; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 4-methoxy- 1 -morpholinobutane; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 4-methoxybutan-l-ol; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamido]-l- phenylbutan-2-one; (3 S)-3 - [2-(4-fluorophenethyl)-5 -((2 S ,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido] - 1 -phenylpropan-2-one; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -pyridin-4-ylbutan-2-one; (3S)-3-{2-[2-(thiazol-2-yl)ethyl]-5-((2S,4S)-4-sulfanylpyrrolidin-2- ylmethy lamino)benzamido } - 1 -phenylpentan-2-one ; -13- (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- l-(2-fluorophenyl)-5-methylsulfanylpentan-2-one; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(2-fluorophenyl)-5-methylsulfanylpentan-2-ol; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(2-hydroxyphenyl)-4-methylsulfanylbutan- 1 -one; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(2-hydroxyphenyl)-4-methylsulfanylbutan- 1 -ol; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -one; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -ol; (3 S)-3 - [2-(4-fluorophenethyl)-5-((2 S ,4 S)-4-sulfanylpyrrolidin-2-ylmethy lamino)benzamido] - l-(pyridin-2-yl)-5-methylsulfanylpentan-2-ol; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamido]-5- methylsulfanylpentan-2-one; (4S)-4-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamido]-6- methylsulfanyl- 1 -(pyridin-3-yl)hex- 1 -en-3-one; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(thiazol-2-y l)-4-methylsulfanylbutan- 1 -ol ; 2- [2-(4-fluorophenethyl)-5 -((2 S ,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido] - 1 - (thiazol-2-yl)-4-methylsulfanylbutan- 1 -one; 2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]-3- hydroxypropan- 1 -ol; -14- (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -acetyloxybutan-2-one; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamido]-l- (triazol- 1 -yl)butan-2-one; (3S)-3-[2-(thiazol-2-yl)-4-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]-5- methylsulfanyl- 1 -(phenyl)pentan-2-one; (2S)-2-[2-(thiazol-2-yl)-4-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]-4- methylsulfanylbutan- 1 -ol; (3S)-3-[2-(4-fluorophenyl)-6-((2S,4S)-4-benzoylsulfanylpyrrolidin-2-ylmethoxy)pyridin-3- ylamido]-5-methylsulfanyl- 1 -phenylpentan-2-one; (2S)-2-[2-phenyl-5-((2S,4S)-4-tert-butoxycarbonylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-4-methylsulfanylbutan-l-ol; (3S)-3-{4-[(Z)-3-(imidazol-l-yl)-2-(thiazol-2-yl)prop-l-enyl]-2-(4-fluorophenyl)benzamido}- 5-(methylsulfanyl)- 1 -phenyl-2-pentanone; 1 -cyclohexyl-(2S)-2- {4-[(Z)-3-(2-methylimidazol- 1 -yl)-2-(thiazol-2-yl)prop- 1 -enyl]-2-(4- fluorophenyl)benzamido } -4-(methylsulfanyl)- 1 -butanone; l-cyclohexyl-(3S)-3-{4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenyl)benzamido}-5-methylsulfanyl-2-propanone; (3S)-3-{5-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenethyl)benzamido} -5 -methylsulfanyl- 1 -phenyl-2-propanone; (2S)-2-{5-[(E)-2-(4-Fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenethyl)benzamido } -4-methylsulfanylbutan- 1 -ol; or a pharmaceutically-acceptable salt thereof. In another aspect the present invention relates to an inhibitor of ras fanesylation of formula (1) : -15- wherein A is of the formula: R S S R 4 Ar 1 CH, \ .E— Ar 2' I I R 3 R 3 (2) (3) (4) wherein R 3 is hydrogen, C 2 - 5 alkanoyl, Ci^alkoxy carbonyl, C 2 - 4 alkenyloxycarbonyl, phenylCι- 3 alkyl, phenoxycarbonyl, phenylCι- 3 alkoxycarbonyl or C^alkyl optionally substituted by carbamoyl, C 1 . 4 alkylcarbam.oyl, di(Cι. 4 alkyl)carbamoyl, carboxy or C^alkoxy carbonyl; R 4 is hydrogen, Cι. 4 alkyl, C 2 - 5 alkanoyl, Cι- 4 alkoxycarbonyl or phenylCμ 3 alkyl; D is a linking moiety selected from the following groups written from left to right in formula (2) and (3): \ ° \_ N K v. N N N tf y -i . N— v_y \ yyy (wherein the piperazine and perhydro-l,4-diazepine rings are optionally substituted by Cι_ 4 alkoxyCι. 4 alkyl, phenoxyCι_ 4 alkyl or heteroarylCι- 4 alkyl); -CO-NR5-; -CH 2 -NR5-; - CH 2 S-; -CH 2 O-; -CH 2 -CHR5; -CH=CR5-; -CH 2 NR5-T-; -CH 2 NR5-SO 2 -; -CH 2 -NR5-CO-Ti-; -CO-NR5-T-; -CH 2 S-T-; -CH 2 O-T- (where R5 is hydrogen, Z, C M alkyl, Z-Cι. 4 alkyl, Z-C 2 . salkanoyl, C 2 - 7 alkanoyl or ZCO- and Z is alkoxy, phenyl, naphthyl or a monocyclic or bicyclic heteroaryl ring, T is -(CH 2 )m- wherein m is 1-4 and T is optionally monosubstituted with any value of R5 other than hydrogen ; and TJ represents -(CH 2 )mi- wherein ml is 0-4 and Tl is optionally monosubstituted with any value of R 5 other than hydrogen); -16- Ari is of the formula (5), (6) or (7): R 6 / -N — > * N (R 7 )„ R 7 (5) (7) R is hydrogen, Ci^alkyl, phenylCι. 4 alkyl; R is hydrogen, C h alky 1, hydroxyC^alkyl, Cι. 4 alkoxyCι. 4 alkyl, C 2 . 4 alkenyloxyCι_ 4 alkyl, C 2 - 4 alkynyloxyCι. 4 alkyl, sulfanylCi^alkyl, aminoCι. alkyl, N-(Cι- alkyl)aminoC 1 . 4 alkyl or phenylCι. 4 alkyl; p is 0,1 or 2; Aι*2 is phenyl or heteroaryl; E is of the formula >C=CH-, >CHCH 2 -, >CH-N(R8)-, >CH-O, >CH-N(R8)CH 2 - or >CH-OCH 2 -; wherein R 8 is hydrogen, Cι_ 4 alkyl or C 2 - 5 alkanoyl; B is phenyl, pyridyl, pyridazinyl, pyrimidyl or pyrazinyl the ring being substituted on ring carbon atoms by R i and -(CH 2 ) n R ; R 1 is of the formula -CONHCH(Riθ)Ri l wherein Rio is hydrogen -(CH 2 ) q -Ri2 wherein q is 0-4 and R1 is Cι. 4 alkylsulfanyl, C]- 4 alkylsulfinyl, Cι- 4 alkylsulfonyl, hydroxy, C 1 . 4 alkoxy, carbamoyl, N-C 1 - 4 alkylcarbamoyl, N.NJdiC i --.alkvDcarbamovh Ci^alkyl, phenyl, thienyl, phenylC^alkoxy or C alkanoylamino; RU is of the formula -CH 2 OR1 (wherein RI is hydrogen, C h alky 1, phenyl, heteroaryl, C 2 . salkanoyl, C^alkoxymethoxy, phenoxymethoxy, heteroaryloxymethoxy or C 2 - 5 alkanoyloxy), of the formula -CORI 4 or of the formula -CH 2 CORi4 (wherein RI 4 is C -alkyl, phenylCj. 3 alkyl, heteroarylCι- 3 alkyl, hydroxymethyl, Cj- 4 alkoxymethyl, 2-(phenyl)ethenyl, 2- (heteroaryl)ethenyl, 2,2-dihydroxy ethyl or N-methoxy-N-methylamino) or RU is morpholinoCι_ 4 alkyl, pyrrolidin-l-ylCι. 4 alkyl or piperidin-l-ylCι- 4 alkyl wherein the morpholine, pyrrolidine and piperidine rings are optionally substituted by Cj^alkyl or C 5 - 7 cycloalkyl; -17- R 2 is phenyl or heteroaryl; n is 0, 1 or 2; phenyl and heteroaryl groups in R 2 , R 3 , R4, R6, R7 ? Ri 1 5 R12 ? Ar 2 and D are independently optionally substituted on ring carbon atoms by up to three substituents selected from C i _4alkyl, halogen, hydroxy, C 1 _4alkoxy, C \ _4alkoxycarbonyl, C \ _4alkanoyl, Cι_4alkanoyloxy, amino, Cι_4alkylamino, di(Cι_4alkyl)amino, Cμ4alkanoylamino, nitro, cyano, carboxy, carbamoyl, N-Cι. 4 alkylcarbamoyl, N,N-(di-Cι. 4 alkyl)carbamoyl, C]. 4 alkoxycarbonyl, thiol, C^alkylsulfanyl, Cι_4alkylsulfinyl,Cι_4alkylsulfonyl, Cι_ 4 alkanesulphonamido, N-(Cι_ 4 alkylsulfonyl)-N-Cι. 4 alkylamino, aminosulfonyl, N- (C i . 4 alkyl)aminosulfonyl, N,N-di (C i . 4 alkyl)aminosulfonyl, carbamoylC } ^alkyl, N- (Cι^alkyl)carbamoylCj- alkyl, N.J -fdiCι.-ιalkyl carbamoylC 1 - 4 alkyl. hydroxy C^alkyl and C i ^alkoxy C i ^alky 1 ; or a prodrug, solvate or pharmaceutically-acceptable salt thereof. Compounds of Formula (1) may form salts which are within the ambit of the invention. Pharmaceutically acceptable salts are preferred 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 of the 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, morpholine or tris-(2-hydroxyethyl)amine. Solvates, for example hydrates, are also within the ambit of the invention and may be prepared by generally known methods. A prodrug is a compound which is converted in the human or animal body to a compound of the formula (1). Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: -18- 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 of the Formula I which contains either a carboxy or hydroxy group. Suitable pharmaceutically- acceptable esters for carboxy include Cj.salkyl esters, Cs-scycloalkyl esters, cyclic amine esters, Cι. 6 alkoxymethyl esters for example methoxymethyl, Cτ- 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 - 8 cycloalkoxycarbonyloxyCι- alkyl esters for example 1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5- methyl- 1 ,3 -dioxolen-2-onylmethyl; and C \ - 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. Prodrugs may also be formed on the sulfanyl group in compounds of the formula (1) wherein A is of the formula (2) or (3) to release in the human or animal body, a compound in which R 4 is hydrogen. According to another aspect of the 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 of the 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 -19- (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 of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well k . nown 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 absorption of the 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 carboxymethylcellulose, 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 -20- 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, antioxidants (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 of the 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 of the 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 -21- one or more of the 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 of the 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 -22- 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 of the dose for therapeutic or prophylactic purposes of a compound of the Formula (1) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. As mentioned above, compounds of the 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 of the Formula (1) for therapeutic or prophylactic purposes 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 of the 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 . -23- 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 farnesylated ras. A particular disease of interest is cancer. Specific cancers of interest include: - carcinoma, including that of the 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) of the 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 farnesyl protein transferase. Although the compounds of the 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. -24- In another aspect the present invention provides a process for preparing a compound of the formula (I) or a pharmaceutically-acceptable salt, prodrug or solvate thereof which comprises: deprotecting a compound of the formula (8): ^-^- (CH 2 ) n R 20 wherein A' is A or protected A, Ri 9 is Ri or protected Ri and R20 is R2 or protected R2 and B is as hereinabove defined; wherein at least one protecting group is present; and thereafter if necessary: (i) forming a pharmaceutically-acceptable salt, (ii) forming a prodrug, and/or (iii) forming a solvate. Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as appropriate for the protection of the 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 of the 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). -25- Examples of carboxy protecting groups include straight or branched chain Ci.^alkyl groups (for example isopropyl, tJ5utyl);Jower 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. 2 p-methoxybenzyl, o^nitrobenzyl, ^nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (for example trimethylsilyl and tJπityldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (for example trimethylsilylethyl); and C 2 - 6 al enyl 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 tJ3utoxycarbonyl); lower alkenyloxycarbonyl groups (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for example benzoyloxycarbonyl, r methoxybenzyloxycarbonyl, o^nitrobenzy loxy carbonyl, p^nitrobenzy loxy carbonyl) ; tri lower alkylsilyl (for example trimethylsilyl, ^butyldimethylsilyl) and phenyl lower alkyl (for example benzyl) groups. Examples of amino protecting groups include formyl, aralkyl groups (for example benzyl and substituted benzyl, pimethoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-p^anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (for example Jmtoxy carbonyl); lower alkenyloxycarbonyl (for example allyloxycarbonyl); phenyl lower alkoxycarbonyl groups (for example benzyloxycarbonyl, r methoxybenzyloxycarbonyl, C iitrobenzyloxycarbonyl, p^nitrobenzy loxy carbonyl; trialkylsilyl (for example trimethylsilyl and tbutyldimethylsilyl); alkylidene (for example methylidene); benzylidene and substituted bei-izylidene 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 -26- E^nitrobenzyloxycarbonyl, hydrogenation and for groups such as oHtiitrobenzyloxycarbonyl, 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 of the formula (1) and (8) can be formed by: a) reacting a compound of the formula (9) with a compound of the formula (10): NH 2 CH(R 21 )R 22 (10) b) when Ri 1 (or R22) is hydroxymethyl, reducing a compound of the formula (11): CONH 2 CH(R 21 )COOR 23 (CH 2 ) n R ° (11) wherein A 1 , B, n and R2 are as hereinabove defined and R 2i is Ri° or protected Ri°, R 22 is Ri or protected Ri i and R 3 is hydrogen or Cι. 6 alkyl; and thereafter if necessary: i) removing any protecting groups; ii) forming a pharmaceutically-acceptable salt, prodrug or solvate thereof. The reaction between compounds of the formulae (9) and (10) is carried out under standard conditions used in the formation of an amide bond. Suitable coupling conditions include the following: i) Use of EEDQ at ambient temperature in an organic solvent (e.g. dichloromethane, methanol). -27- ii) Use of oxalyl chloride in an organic solvent (e.g. dichloromethane), DMF in a catalytic amount, in the presence of an organic base (e.g. NMM, triethylamine, DMAP) at 0°C to ambient temperature for 0.5-16 hours. iii) Use of EDC/ HOBT in an organic solvent (e.g. DMF, dichloromethane). iv) Use of DCCI/ HOBT in an organic solvent (e.g. DMF, dichloromethane) in the presence of an organic base (e.g. triethylamine). v) Use of mixed anhydride reactions under standard conditions, for example isopropylchloroformate in an organic solvent (e.g. DMF, DMA, dichloromethane) in the presence of an organic base (e.g. NMM, DMAP, triethylamine). vi) Via an active ester under standard conditions e.g. pentafluorophenyl ester in an organic solvent (e.g. dichloromethane) in the presence of an organic base (e.g. triethylamine). vii) Via an acid chloride under standard conditions e.g. using thionyl chloride and heat for about 150 minutes followed by an organic base (e.g. triethylamine) in the presence of an organic solvent (e.g. acetonitrile). A compound of the formula (9) wherein A is of the formula (2) can be prepared using the methods described in Intemational patent application no. PCT/GB96/01810 or method similar thereto. A compound of the formula (9) wherein A is of the formula (3) can be prepared using the methods described in Intemational patent application no. PCT/GB97/02212 or methods similar thereto. For example a compound of formula (9) in which D (in the formulae A) is -CO-NR 5 - may be prepared by forming an amide bond between the appropriate thioproline substituted by carboxy in the 2-position and a compound of the formula (12): (12) -28- A compound of formula (9) in which D (in the formula A) is -CO-NR 5 -T- may be prepared by an analogous procedure. Suitable coupling conditions include those described above for the reaction between compounds of the formulae (9) and (10). A compound of formula (9) in which D (in the formulae A) is -CH2NR5-, -CH2O- or -CH2S- may be prepared by reacting the appropriate thioproline substitued in the 2-position by -CH 2 L with a compound of the formula (13): (13) wherein L is a leaving group (e.g. mesyloxy, tosyloxy, halogen) and X is S, O or NR 5 , as appropriate. Suitable coupling conditions include the following: i) Use of an inorganic base (e.g. NaHCO3, NaH, K2CO3, butyllithium) in an organic solvent (e.g. THF, DMF, DMSO) and a temperature of about 65° to 150°C ii) Use of an organic base (e.g. triethylamine, DMAP) in an organic solvent (e.g. THF, dichloromethane, DMA, DMF) at a temperature range of room temperature -150°C iii) Use of an inorganic base (e.g. KOH, NaOH, K-2CO3) in an aqueous (e.g. water) and organic solvents (e.g. dichloromethane) in a 2 phase system, optionally in the presence of a phase transfer catalyst (e.g. tetrabutylammoniumbromide). A compound of formula (9) in which D (in the formula A) is -CH=CR 5 - may be prepared by reacting together the appropriate thioproline substitued in the 2-position by a formyl group and a compound of the formula (14) using a Wittig reaction: (14) -29- wherein R24 is triphenylphosphine or -P(O)(O alkyl) 2 - Suitable reaction conditions include the following: i) Use of a base (e.g. potassium carbonate, metal hydride, metal alkoxide) in the presence of an organic solvent (e.g. THF, toluene, DMSO) optionally in the presence of an aqueous solvent (2-phase system) and optionally in the presence Of a catalyst complexing agent which solubilises alkali metal ions in non-polar solvents such as 1,4,7,10,13 -pentaoxacyclopentadecane ( also called 15-Crown-5) or 1,4,7,10,13, 16-hexaoxacyclooctadecane ( also called 18-Crown-6). A compound of formula (9) in which D (in the formula A) is -CH2-NR 5 - may be prepared by reacting a thioproline substituted in the 2-position by a formyl group with a compound of the formula (12). Suitable coupling conditions include the following: i) Use of a reducing agent (e.g. NaCNBH3, BH3, hydrogen plus catalyst, IJHBE13, di-isobutyl-aluminiumhydride, lithium aluminium hydride, sodium borohydride) in the presence of a suitable solvent e.g. ethanol and acetic acid. The thioproline aldehyde may be prepared by oxidation of the corresponding alcohol under suitable conditions such as use of an oxidising agent (e.g. TPAP, NMM-O) in the presence of an organic solvent (e.g. acetonitrile, dichloromethane) at room temperature. Other suitable oxidising agents include chromium oxide, pyridinium chlorochromate, pyridinium dichromate, sodium dichromate, pyridine sulfur trioxide complex and sodium hypochlorite. The thioproline aldehyde may also be prepared by reduction of the corresponding ester under standard conditions using for example diisobutyl-aluminium hydride. Alternatively, the thioproline aldehyde may be prepared by reducing the appropriate N- methoxy-N-methylcarboxamide with a strong reducing agent such as lithium aluminum hydride. A compound of formula (9) in which D (in the formulae A) is -CH2-NR5-T-, -CH2-O-T- or -CH2-S-T- may be prepared by reacting the appropriate thioproline which is substituted in the 2-position with -CH 2 L with a compound of the formula (15): -30- HXT in which R19, R20 5 β, n, L, T and X are as hereinabove defined. Suitable coupling conditions are as outlined above for the reaction between the thioproline substitued in the 2-position by -CH 2 L and a compound of the formula (13). Optionally the positions of L and XH can be reversed to give the same end product. A compound of formula (9) in which D (in the formula A) is -CH2_NR 5 -SO2- may be prepared by reacting the thioproline which is substituted in the 2-position by -CH 2 NHR5 and a compound of the formula (16): ^— ^- COOH CISO 2 h B J ^-^ (CH 2 ) n R ° (16) The reaction is carried out under standard conditions such as the following: i) Use of an organic base (e.g. di-isopropyl-ethylamine, triethylamine, 4-methyl-morpholine) in the presence of an organic solvent (e.g. dichloromethane) at a temperature range of 0 " 40 C ii) Use of an inorganic base (e.g. potassium carbonate) in the presence of an organic solvent (e.g. DMF) at a temperature range of 0°"150°C A compound of formula (9) in which D (in the formula A) is -CH2-NR5-CO-T- may be prepared may be prepared by reacting a thioproline which is substituted in the 2-positon by -CH 2 NHR5 and a compound of the formula (17): -31- COOH HOOC-T (CH 2 ) n R 2 o (17) This reaction is generally carried out under standard conditions such as those described above for the formation of compounds in which D is -CO-NR 5 - . A compound of formula (9) in which D (in the formulae A) is -CH2-CHR 5 - may be prepared by reduction of a compound in which D is -CH=CH-. The reduction is carried out under standard conditions with standard reagents for example using hydrogenation in the presence of a catalyst such as palladium on charcoal at ambient temperature. A compound of formula (9) in which D (in the formulae A) is -CH 2 NR5-, -CONR5, CH 2 N(R 5 )-T- or -CH 2 N(R5)COT- wherein R5 is not hydrogen, may be prepared from the appropriate compound wherein R5 is hydrogen by introducing the appropriate R 5 by acylation, alkylation etc. A compound of the formula (9) wherein A is of the formula (4) can be prepared using the methods described in European patent application no. 97400207.3 filed on 29 January 1997 and European patent application nos. 97402502.5, 97402503.3, 97402504.1 and 97402505.8 all filed on 22 October 1997. For example a compound of the formula (9) wherein E (in A) is > G=CH-. is of the formula >CHCH 2 or >C=CH- is conveniently prepared by reacting together compounds of the formulae (18) and (19): Ar i ' /^y- Ar2' 0 PPh, (CH 2 ) n R 2 ° (18) (19) wherein Ari' is Ari or protected Ari, Ar 2 ' is Ar or protected Ar and Pi is a carboxy protecting group and n, B and R 2 ' are as hereinabove defined, and optionally hydrogenating the double bond thus formed (to give compounds in which E is of the formula >CHCH 2 -). Suitable Wittig reaction conditions include using a polar aprotic organic solvent in the presence of a crown ether and an alkali metal cation, preferably at -50 to -5°C. Cl 8 HPLC -32- may be used to separate E and Z isomers at this stage or later if appropriate. Suitable hydrogenation conditions include use of a catalyst, preferably palladium on carbon in the presence of an organic solvent at a non-extreme temperature. A compound of the formula (18) can be prepared by introducing Ari' into a compound of the formula (20): O v CH 2 y ^ Ar z (20) wherein Ar2' is as hereinabove defined and Li is a leaving group such as halo, mesyloxy, tosyloxy or triflate, preferably bromo. The reaction is conveniently carried out in the presence of as sodium hydride, sodium hydroxide, butyl lithium, hydride or potassium carbonate. A compound of the formula (20) is conveniently formed from a compound of the formula (21): O CH 3 ^^ Ar 2 ' (21 ) wherein Ar ' is as hereinabove defined. The compound of the formula (21) may be converted to a compound in which L is bromo by bromination with, for example, N-bromosuccinimide, carbon tetrabromide or bromine, or to a compound in which Ll is chloro by chlorination with, for example, chlorine. When Ll is mesyloxy or tosyloxy by oxidising the compound of the formula (21) to an alcohol and converting the hydroxy group to mesyloxy or tosyloxy with a mesyl halide or tosyl halide. A compound of the formula (9) wherein E (in A) is of the formula >CH-N(R8)- is conveniently prepared by reacting together compounds of the formulae (18) and (22): -33- NHR 8 (22) wherein P', B, R8, R20 and n are as hereinabove defined. The compounds of the formula (18) and (22) are conveniently reacted together under conditions suitable for reductive amination, for example in the presence of a reducing agent and a dehydrating agent. Suitable reducing agents include sodium cyanoborohydride and sodium triacetoxyborohydride. When sodium cyanoborohydride is used, titanium tetrachloride is generally added dichloromethane or an alcohol used as solvent. When titanium tetrachloride is used, an organic base such as triethylamine is generally added. The reaction usually takes place in the temperature range of -20°C to ambient temperature. When sodium triacetoxyborohydride is used as the reducing agent, titanium tetrachloride is generally used as an activating agent, in an organic solvent such as dichloromethane, in a temperature range of -20°C to ambient temperature. (Also see Synthesis 135, 1975; Org. Prep. Proceed. Int. ϋ, 201, 1979). A compound of the formula (22) can be prepared by reducing the related nitro compound with a weak reducing agent such as ferric chloride in the presence of 1,1- dimethylhydrazine or tin chloride or hydrogenation under standard conditions known in the art. The related nitro compound can be formed by introducing -(CH 2 ) n R 20 into a compound of the formula (25): COOP 1 I-2 (25) wherein B and P are as hereinabove defined and L 2 is a leaving group. When n is 0 and R20 is phenyl, the compound of the formula (25) is conveniently reacted with phenyl boronic acid in the presence of a palladium catalyst such as palladium tetrakis (triphenylphosphine) palladium(O) under conditions known for the Suzuki reaction (Synth.Commun. 11, 513 (1981)). An aprotic organic solvent such as dimethyl ether (DME), -34- 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 of the base (J. Org. Chem. 1994, 59, 6095-6097). Preferably L2 is bromo. When n is 1 and R20 is phenyl, the compound of the formula (25), wherein L 2 is preferably bromo or chloro, is conveniently reacted with a benzylzinc bromide or a benzyl magnesium bromide in the presence of a nickel or palladium catalyst, such as bis(triphenylphosphine)palladium (II) chloride or Pd 2 (dibenzylideneacetone) 3 , in an inert organic solvent such as tetrahydrofuran (THF). For example see the conditions used for the 'Nagishi' reaction (J. Org. Chem. 42 (10), 1821-1822, 1977). When n is 2 and R20 is phenyl, the compound of the formula (25) 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 (Ace. Chem. Res. 12, 146-151 (1979) and J. Organometallic Chem. 486 (1995) 259-262). 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 compound of the formula (25) wherein L is triflate or bromo with a phenyl acetylene in the presence of an organic base such as triethylamine and a palladium catalyst such as tetrakis (triphenylphosphine)palladium. 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. A compound of the formula (9) wherein E (in A) is of the formula >CH-N(R8)CH 2 - is conveniently prepared by reacting together compounds of the formulae (18) and (26): (26) -35- wherein B, Pi, R 20 , n and R 8 are as hereinabove defined. The compounds of the formula (18) and (26) are conveniently reacted together under conditions suitable for reductive amination, for example in the presence of a reducing agent and a dehydrating agent. Suitable reducing agents include sodium cyanoborohydride and sodium triacetoxyborohydride. When sodium cyanoborohydride is used, titanium tetrachloride or 3A or 4A molecular sieves may be used as the dehydrating agent, in dichloromethane or an alcohol as solvent. When titanium chloride is used, an organic base such as triethylamine is generally added. The reaction usually takes place in the temperature range of -20°C to ambient temperature. When sodium triacetoxyborohydride is used as the reducing agent, 4A molecular sieves are generally used as the dehydrating agent, in an organic solvent such as dichloromethane, in a temperature range of -20°C to ambient temperature. (Also see Synthesis 135, 1975; Org. Prep. Proceed. Int. ii, 201, 1979). A compound of the formula (26) can be prepared by reducing the related nitro compound with a weak reducing agent such as ferric chloride in the presence of 1 , 1 - dimethylhydrazine or tin chloride or hydrogenation, under standard conditions known in the art. The related nitro compound can be formed by introducing -(CH 2 ) n R 3 into a compound of the formula (27): (27) wherein B, Pi and L 2 are as hereinabove defined using similar methods to those described above for the preparation of the nitro precursor of a compound of the formula (22). A compound of the formula (9) wherein E (in A) is of the formula >CHO- is conveniently prepared by reacting together compounds of the formulae (28) and (29): -36- (29) wherein Ari', AR 2 ', B, Pi, n and R 2 are as hereinabove defined. A compound of the formula (28) and a compound of the formula (29) are conveniently reacted together under conditions known for the Mitsunobu reaction. This typically involves reacting the reagents together in the presence of di(Cι. 4 alkyl)azodicarboxylate or V, V- (azodicarbonyl) dipiperidine and a phosphorous reagent such as tributylphosphine, triphenylphosphine or diphenylpyridylphosphine in an inert solvent such as toluene, benzene, tetrahydrofuran (THF) and dichloromethane, dioxan or diethylether, at non-extreme temperatures such as in the range -20°C to ambient temperature, (see Progress in the Mitsunobu Reaction. A Review, David L. Hughes, Organic Preparations and Procedures Int., 28 (2), 127-164 (1996)). A compound of the formula (28) can be prepared by reducing a compound of the formula (18) as hereinabove defined. Suitable reducing agents include sodium borohydride and lithium aluminium hydride. Typically, an alcohol is used as solvent in a temperature range of ambient temperature to 60°C with the former and ether or THF with the latter. The compound of the formula (29) can be formed by introducing -(CH 2 ) n R 20 into a compound of the formula (30): OP 2 wherein B, Pi and L2 are as hereinabove defined and P 2 is a hydroxy protecting group. Similar conditions are used to those described above for the preparation of the nitro precursor of a compound of the formula (22). -37- A compound of the formula (9) wherein E (in A) is of the formula >CHOCH 2 - is conveniently prepared by reacting together compounds of the formula (28) and (31): COOP 1 (CH 2 ) n R20 (31) wherein R 2 , n and P are as hereinabove defined and Ll is a leaving group. Compounds of the formula (28) and (31) are conveniently reacted together in the presence of a base such as sodium hydride, butyl lithium or potassium tert-butoxide, in .an aprotic solvent such as tetrahydrofuran (THF), dimethyl formamide (DMF) or dimethylacetamide (DMA), at a non-extreme temperature for example 0 ' C to ambient temperature. Li is preferably halo, mesyloxy or tosyloxy. A compound of the formula (31) is typically formed by introducing a leaving group into a compound of the formula CH 3 -B(-COOPi)-(CH 2 ) n R 20 . When L i is bromo, bromination can be carried out using N-bromosuccinimide, carbon tetrabromide or bromine. When L is chloro, a chlorinating agent such as chlorine could be used and when Ll is mesyloxy or tosyloxy, the methyl group is generally oxidised to the alcohol (or oxidised to the carboxylic acid and then reduced to the alcohol) and the hydroxy group converted to mesyloxy or tosyloxy with, for example, mesyl chloride or tosyl chloride. The compound of the formula CH3-B(-COOP i )-(CH 2 ) n R 20 could be formed by introducing -(CH 2 ) n R 2() into a compound of the formula (32): COOP 1 L 2 (32) wherein B, P and L2 are as hereinabove defined. When n is 0 and R 3 is phenyl, the compound of the formula (12) is conveniently reacted with phenyl boronic acid in the presence of a palladium catalyst such as palladium -38- tetrakis (triphenylphosphine) under conditions known for the Suzuki reaction (Synth.Commun. 11, 513 (1981)). An aprotic organic solvent such as dimethyl ether (DME), 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 of the base (J. Org. Chem. 1994, 59, 6095-6097). Preferably L 2 is bromo or triflate. When n is 1 and R 3 is phenyl, the compound of the formula (12), wherein L 2 is preferably bromo or chloro, is conveniently reacted with a phenylzinc chloride or a phenyl- magnesium bromide in the presence of a nickel or palladium catalyst, such as bis(triphenylphosphine)palladium (12) chloride or Pd 2 (dba) 3 , in an inert organic solvent such as tetrahydrofurna (THF). For example see the conditions used for the 'Nagishi' reaction (J. Org. Chem. 42 (10), 1821-1822, 1977). Similar conditions are used to those described above for the preparation of the nitro precursor of the compound of the formula (22). A compound of the formula (10) is typically prepared from a compound of the formula NH 2 CH(R2i)COOH. A compound of formula NH 2 CH(R 2 i)COOH can be reduced to a compound of the formula (10) wherein R 22 is hydroxymethyl with a reducing agent such as lithium aluminium hydride. The compound of the formula (10) wherein R 22 is hydroxymethyl and the amino group is suitably protected can then be alkylated or acylated as appropriate to form compounds of the formula (10) wherein R 22 is of the formula -CH 2 ORi 3 . A compound of the formula (10) wherein R 22 is of the formula -COR14 can be formed via the intermediate NH 2 CH(R 2 i)CON(OMe)Me which itself is formed by reacting NH 2 CH(R 2 i)COOH with N,O-dimethylhydroxylamine under standard amide bond forming conditions. A compound of the formula NH 2 CH(R 2 i)CON(OMe)Me is then conveniently reacted with a gringard reagent (such as PhC^MgCl) to form a compound of the formula (10). Alternatively, when R14 contains an alkyl chain linked to the carbonyl group, a compound of the formula NH 2 CH(R 2 i)CON(OMe)Me can be converted to the corresponding dimethylphosphono compound (NH 2 CH(R 2 i)COP(O)(OMe) 2 ) by reacting the former compound with dimethylmethylphosphonate in the presence of a strong base such as n-butyl -39- lithium. A compound of the formula (10) can be formed by reacting the dimethylphosphono compound with the appropriate aldehyde or ketone under conditions known for the Wittig or Emmons-Horner reactions. A compound of the formula (10) wherein R 22 is morpholinomethyl, pyrrolidin-1- ylmethyl or piperidin-1-ylmethyl is conveniently prepared by reacting NH 2 CH(R 2 i)COOH with the appropriate heterocyclic ring under standard amide bond forming conditions to form a compound of the formula (10), wherein RU is heterocyclylcarbonyl, and subsequently reducing the carbonyl group to a methyl group with a reducing agent such as lithium aluminium hydride. A compound of the formula NH 2 CH(R 2 i)COOH can be extended by one carbon length to produce a compound of the formula NH 2 CH(R 2 i)CH 2 COOH using the Amdt-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 of the formula NH 2 CH(R 2 i)CH 2 COOH and homologues may be used to prepare a compound of the formula NH 2 CH(R 2 i) R 22 wherein R 22 is of the formula -CH 2 CORi4, morpholino Cι_ 4 alkyl, pyrrolidin-l-ylC]. 4 alkyl or piperidin-l-ylCι_ 4 alkyl. A compound of the formula (11) can be reduced to a compound of the formula (1) or (4) using standard conditions. For example, when R 23 is hydrogen, the reduction can be carried out using sodium borohydride and ethylchloroformate (for example see Synthesis 1990, 299) and when R 23 is alkyl, using a reducing agent such as lithium borohydride or sodium borohydride in an organic soluent such as THF. The compound of the formula (11) can be prepared by forming an amide bond between a compound of the formula (9) and a compound of the formula NH 2 CH(R 2 i)COOPi wherein Pi is a carboxy protecting group and subsequently removing the protecting group. A compound of the formula (1) or (4) which contains a methylsulfinyl or methylsulfonyl group may be prepared by oxidising the appropriate methylsulfanyl compound. A methylsulfanyl group is typically oxidised to methylsulfinyl using sodium metaperiodate in an organic solvent such as methanol. A methylsulfanyl group can be oxidised to methylsulfonyl using metachloroperbenzoic acid or oxone. Many other suitable oxidising agents are known in the art. -40- Preferably, a compound of the formula (4) is prepared by reacting together compounds of the formulae (9) and (10). Optional substituents in a compound of the formula (1) and (4) and intermediates in their preparation may be converted into other desired optional substituents. For example, a nitro group could be 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 of the formulae (1) and (4) and intermediates in this prep.aration, 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 2 .6H 2 0, pH=8.0); Farnesyl 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 HCl). 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 -41- 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 farnesyl protein transferase enzyme preparation was stored at -80°C. The farnesyl transferase solution for the assay contained the following: dithiothreitol 5 (DTT)(0.6ml of 7.7mg/ml), TRIS buffer (0.6ml), aprotinin (0.48ml), distilled water (1.2ml), farnesyl transferase (0.6ml of the 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. 10 Assays were performed in 96 well plates as follows: lOμl of test compound solution was added to each well. Then 30μl farnesyl transferase solution (above) was added and the reaction started by addition of lOμl radiolabelled farnesyl 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 15 protein was then collected onto glass fibre filter mats (B) using a TomtecTM cell harvester and tritiated label was measured in a WallacTMi204 Betaplate scintillation counter. Test compounds were added at appropriate concentrations in DMSO (3% final concentration in test and vehicle control), (ii) Intracellular famesylation assay 20 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 2 the medium was removed and replaced with methionine-free minimal essential medium (MEM) and the cells 25 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 35 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 (1ml) (composed of 1000ml phosphate buffered saline, 30 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 -42- then clarified by centrifugation. To 0.8ml of the clarified lysate 80μl of Y13-259 pan-Ras antibody (isolated from the hybridoma - American Tissue Culture Collection Accession Number CRL-1742) (final concentration approximately 1 μg/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 ovemight 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) Morphology 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 ovemight at 37°C in 10% CO 2 . 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 of the compounds of the Formula (1) vary with structural change as expected, in general compounds of the 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 13 herein has an IC 50 of approximately 0.1 μM in test (i). Example 13 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 of the 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 argon; -43- (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Liohroprep 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 of the 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 of the 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:- BOC tert-butoxy carbonyl DEAD diethyl azodicarboxylate DCCI 1,3-dicyclohexylcarbodiimide DMA N,N-dimethylacetamide DMAP 4-dimethyl-aminopyridine DME 1 ,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDC 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide EEDQ 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline HOBT 1-hydroxybenzotriazole MCPBA m-chloroperoxybenzoic acid NMM N-methylmoφholine -44- NMM-O 4-methylmoφholine-N-oxide TFA trifluoroacetic acid THF tetrahydrofuran TMEDA N,N,N',N'-tetramethylethylenediamine TMSI trimethylsilyliodide TPAP tetrapropylammonium perruthenate Note in the Schemes only those hydrogen atoms thought to assist clarity have been illustrated (ie not all hydrogen atoms have been illustrated). - 45 - Example 1 (2SV2-{2-f4-Fluorophenvn-4-n-(4-fluorophenvn-2-(imidazol-l-yl)ethylamino1- benzoylamino } -4-methy lsulfanylbutan-1-ol Lithium borohydride (0.066 g ; 3J mmol) was added at 0°C to a suspension of methyl (2S)-2- { 2-(4-fluorophenyl)-4-[ 1 -(4-fluorophenyl)-2-(imidazol- 1 -yl)ethylamino jbenzoyl amino }-4-methylsulfanylbutyrate (0.846 mg ; 1.5 mmol) in a mixture of THF (40 ml) and ether (10 ml). After stirring at ambient temperature overnight, the mixture was acidified at pH with 12N HCl and evaporated to dryness. The residue was taken up in dichloromethane, washed with aqueous sodium hydrogen carbonate, evaporated and purified by flash chromatography eluting with dichloromethane / ethanol (95/50) to give the title compound. Yield = 44 % MP = 96-100°C Η NMR (CDC1 3 , 400 MHz) : δ 1.4-1.8 (3H, m) ; 2.02 (3H, s) ; 2.2-2.3 (2H, m) ; 3.47 (2H, m) ; 3.95 (IH, s) ; 4.28 (2H, m) ; 4.50 (IH, m) ; 4.76 (IH, m) ; 5.44 (IH, d) ; 6.36 (IH, m) ; 6.5 (IH, m) ; 6.77 (IH, s) ; 7-7.35 (10H, m) ; 7.50 (IH, d). Anal. Calcd for C 29 H 30 F 2 N 4 O 2 S, 1 H 2 O C 63.21 H 5.78 N 10.17 S 5.97 Found C 62.97 H 5.91 N 10.28 S 5.56 MS (ESI) m/z : 537 (MH + ) The starting material was prepared as follows: 4-Fluorophenylboronic acid (6.72 g ; 0.048 mol) was added to a suspension of 2- bromo-4-nitrotoluene (6.9 g ; 0.032 mol) and tetrakis(triphenylphosphine) palladium (1.5 g ; 1.4 mmol) in DME (90 ml). After addition of aqueous sodium carbonate solution 2M (120 - 46 - ml), the mixture was refluxed ovemight. After extraction with ether and evaporation, the residue was purified by flash chromatography (ethyl acetate / petroleum ether 95/5 to give 2- (4-fluorophenyl)-4-nitrotoluene (6.66 g ; 90%). Η NMR (CDC1 3 , 400 MHz) δ : 2.34 (3H, s) ; 7.1-7.5 (5H, m) ; 8.10 (2H, m). Potassium permenganate (23 g ; 0J45 mol) was added to a solution of 2-(4-fluoro- phenyl)-4-nitrotoluene (6.46 g ; 0.028 mol) in pyridine/water (100 ml / 60 ml). The solution was heated to reflux with care. After reflux ovemight, the insoluble material was filtered off and the mixture evaporated to dryness. The residue was taken up in a 2N aqueous sodium hydroxy de solution, washed with ether and acidified with 12N HCl. The mixture was extracted with ether ; the organic layer was evaporated to dryness to give 2-(4-fluorophenyl)- 4-nitrobenzoic acid (5.76 g; 79%). Η NMR (CDCI 3 + CF 3 COOD, 400 MHz) δ : 7.1-7.3 (4H, m) ; 8.1-8.35 (2H, m). Oxalyl chloride (9.35 g ; 0.074 mol) was added to a solution of 2-(4-fluorophenyl)-4- nitrobenzoic acid (17.5 g ; 0.067 mol) in methylene chloride (150 ml). After addition of DMF (3 drops), the mixture was stirred at ambient temperature for 2 hours. After evaporation to dryness the residue was redissolved in methylene chloride (100 ml) ; methanol (50 ml) and DMAP (8.2 g ; 0.067 mol) was added at 0°C. After stirring at ambient temperature for 2 hours, the mixture was evaporated to dryness. The residue was taken up in methylene chloride washed with a 2N HCl, saturated aqueous sodium bicarbonate and evaporated to give 2-(4- fluorophenyl)-4-nitrobenzoate (17.6 g; 95%). 'H NMR (CDCI 3 , 400 MHz) δ : 3.71 (3H, s) ; 7.05-7.4 (4H, m) ; 7.9 (IH, m) ; 8.26 (2H, m). A solution of methyl-2-(4-fluorophenyl)-4-nitrobenzoate (17 g ; 0.062 mol) in methylene chloride (60 ml) and methanol (400 ml) was hydrogenated on 10% Pd/C (2 g). After filtration of the catalyst, the mixture was evaporated and purified by flash chromatography eluting with methanol / methylene chloride 10/90 to give after evaporation methyl 4-amino-2-(4-fluorophenyl)benzoate (15 g; 100%). - 47 - Η NMR (CDCI 3 , 400 MHz) δ : 3.65 (3H, s) ; 4.05 (2H, s) ; 6.5 (IH, m) ; 6.65 (IH, m); 7-7.3 (4H, m) ; 7.84 (IH, d). Titanium chloride (2.86 ml ; 26 mmol) was added portionwise to a solution of methyl 4-amino-2-(4-fluorophenyl)benzoate (5 g ; 20 mmol), l-(4-fluorophenyl)-2-(imidazol-l-yl) ethanone (4.08 g ; 20 mmol) and triethylamine (8.4 ml ; 60 mmol) in dichloromethane (120 ml) at 0°C under argon atmosphere. After stirring overnight at ambient temperature, sodium cyanoborohydride (1.4 g ; 0.22 mmol) in solution in methanol (10 ml) was added at 0°C. The reaction mixture was stirred for 2 hours at ambient temperature, treated with 5% aqueous sodium hydrogen carbonate solution, filtered and extracted with dichloromethane. After evaporation to dryness of the organic phase, the residue was purified by flash chromatography eluting with dichloromethane / ethanol 95/5 to give methyl 4-[l-(4- fluorophenyl)-2-(imidazol- 1 -yl)ethylamino]-2-(4-fluorophenyl)benzoate. Yield 52%. Η NMR (CDC1 3 , 400 MHz) δ : 3.51 (3H, s) ; 4.22 (2H, m) ; 4.40 and 4.70 (IH, m) ; 6.30 (IH, m); 6.37 (IH, m) ; 6.68 (IH, s) ; 6.9-7.25 (10H, m) ; 7.68 (IH, d). MS (ESI) m/z 434 (MH + ) Methyl 4- [ 1 -(4-fluorophenyl)-2-(imidazol- 1 -y l)ethylamino] -2-(4- fluorophenyl)benzoate (4.36 g ; 10 mmol) in methanol (100 ml) was treated with 2N aqueous sodium hydroxide solution (20 ml ; 40 mmol) at reflux for 24 hours. After evaporation of the methanol, the residue was taken up in water, the pH adjusted to 4.5 with HCl 2N. The resulting precipitate was filtered, washed with water and pentane to give 4-[l-(4- fluorophenyl)-2-(imidazol-l-yl)ethylamino]-2-(4-fluorophenyl)benzoic acid as a solid (4 g ; 95%). M.P. : 195-200°C Η NMR (DMSO d 6 + CF 3 COOD, 400 MHz) δ : 4.52 (2H, m) ; 5J7 (IH, m) ; 6.45 (IH, s) ; 6.56 (IH, m) ; 7-7.3 (6H, m) ; 7.4-7.7 (4H, m) ; 7.80 (IH, s) ; 9.08 (IH, s). MS (ESI) m/z 420 (MH + ) A mixture of 4- { 1 -(4-fluorophenyl)-2-(imidazol- 1 -yl)ethylamino]-2-(4- fluorophenyl)benzoic acid (1.67 g; 4 mmol), L-methionine methyl ester hydrochloride 48 (0.96 g; 4.8 mmol), HOBT (0.65 g ; 4.8 mmol), EDC (0.925 g ; 4.8 mmol) and DMAP (0.54 g; 4.4 mmol) in dichloromethane (100 ml) was stirred at ambient temperature for 5 hours. The solution was diluted with dichloromethane (200 ml), washed with 5% aqueous sodium hydrogen carbonate solution and evaporated to dryness. The residue was purified by flash chromatography eluting with dichloromethane / ethanol 95/5 to give the title compound as a solid (1.8 g; 80%). M.P. : 94-98°C 'H NMR (CDC1 3 , 400 MHz) δ : 1.5-2.1 (2H, m) ; 2.01 (3H, s) ; 2.1-2.25 (2H, m) ; 3.64 (3H, s) ; 4.2-4.8 (5H, m) ; 5.77 (IH, m) ; 6.37 (IH, m) ; 6.48 (IH, m) ; 6.76 (IH, m) ; 6.95-7.35 (10H, m) ; 7.52 (IH, m). Anal. Calculated for C 30 H 30 F 2 N 4 O 3 S, 0.6 H 2 O C 62.52 H 5.46 N 9.74 S 5.57 Found C 62.86 H 5.68 N 9.86 S 5.35 Example 2 r2S)-2-(4-frE)-2-(4-Fluorophenvn-3-(imidazol-l-yl)proD-l-enyll-2-(4- fluorophenyl)benzamido)-4-methylsulfanylbutan-l-ol A mixture of 4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- florophenyl)benzoic acid (0.832 g , 2 mmol), L-methioninol (1 g , 4 mmol), DMAP (0.368 g, 3 mmol), EDC (0.575 g , 3 mmol) and N-methylmoφholine (0.44 ml , 4 mmol) in dichloromethane (15 ml) was stirred at room temperature for 3 hours. After evaporation to dryness, the residue was purified on reverse phase silica eluting a gradient of 50-60 % methanol / ammonium carbonate - 49 buffer (2 g/1 pH 7). Appropriate fractions were evaporated, extracted with dichloromethane, and evaporated to give after trituration in pentane/ether the desired starting material as a foam. Yield = 28% Η NMR (CDC1 3 + CF 3 COOD, 400 MHz) δ 1.4-1.7 (2H, m) ; 2.05 (3H, s) ; 2.15-2.35 (2H, m) ; 3.5-3.7 (2H, m) ; 4.15 (IH, m) ; 5.20 (2H, s) ; 6.87 (IH, s) ; 6.90-7.5 (13 H, m) ; 8.75 (IH, s). Anal calcd for C 30 H 29 F 2 N 3 O 2 S C 67.52 H 5.48 N 7.87 S 6.01 C 67.76 H 5.81 N 7.75 S 5.45 MS (ESI) m z : 534 (MH + ) Example 3 r2SV2-(4-rfZV2-(thiazol-2-yl)-3-(imidazol-I-vnprop-l-enyll-2-(4- fluorophenyl)benzamido}-4-methylsuIfanylbutan-l-ol The compound was prepared from the appropriate carboxylic acid using a similar method to that described in Example 2 Η NMR (CDCI 3 + CF 3 COOD, 400 MHz) δ 1.5-1.8 (2H, m) ; 2.06 (3H, s) ; 2.2-2.3 (2H, m) ; 3.6-3.8 (2H, m) ; 4.15 (IH, m) ; 5.56 (2H, s) ; 7-7.55 (10 H, m) ; 7.78 (IH, m) ; 8.07 (IH, m) ; 9.04 (IH, s). Anal calcd for C 27 H 27 FN 4 O 2 S 2 , 1.1 B-O C 59.78 H 5.43 N 10.33 S 11.82 C 59.65 H 5.10 N 9.92 S 11.91 MS (ESI) m/z : 523 (MH + ) - 50 - Example 4 f2SV2-{4-[l-(4-fluorophenvn-2-rimidazol-l-vnethoxymethyll-2-f4- fluorophenv0benzamido)-4-methylsulfanvIbutan-l-ol S Sodium borohydride (0.084 g ; 2.21 mmol) and lithium chloride (0.095 g ; 2.21 mmol) were added to a solution of methyl (2S)-2-{4-[l-(4-fiuorophenyl)-2-(imidazol-l- yl)ethoxymethyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutyrate (0.64 g ; 1J mmol) in THF (10 ml). After 5 minutes, ethanol (10 ml) was added to the mixture. After stirring ovemight and evaporation to dryness, the residue was taken up in water (2 ml) and acidified at pH 4 with 2N HCl. After extraction with dichloromethane, the organic phase was evaporated and purified on reverse phase silica eluting with a gradient of 40-60 % methanol / (NH 4 ) 2 CO 3 buffer (2 g/1 pH 7). Yield = 57 % Η NMR (DMSOd 6 + CF 3 COOD, 400 MHz) δ 1.45-1.85 (2H, m) ; 1.99 (3H, s) ; 2.2-2.35 (2H, m) ; 3.15-3.40 (2H, m) ; 3.80 (IH, m) ; 4.30-4.60 (4H, m) ; 4.95 (IH, m) ; 7.05-7.8 (13H, m) ; 9.07 (IH, s). Anal. Calcd for C 30 H 31 F 2 N 3 O 3 S C 65.32 H 5.66 N 7.62 S 5.81 C 65.03 H 5.93 N 7.38 S 5.32 MS (ESI) m/z : 552 (MH + ) The starting material was prepared as follows : Triflic anhydride (170 ml ; 1.01 mol) was added to a solution of methyl 2-hydroxy-4- methylbenzoate (153 g ; 0.92 mol) in pyridine (1.5 1), at 0°C, The mixture was stirred at ambient temperature ovemight. After evaporation of the pyridine, the residue was acidified to pH 3.5 with 6N HCl and extracted with ether. The organic phase was evaporated and the residue purified by flash column chromatography eluting with a gradient of 0-5% ethyl acetate - 51 - / petroleum ether to give methyl 2-trifluoromethylsulfonyloxy-4-methylbenzoate (245 g ; 90%). Η NMR (CDClj, 400 MHz) δ : 1.55 (3H,s) ; 2.45 (3H, s) ; 3.94 (3H, s) ; 7.09 (IH, s) ; 7.26 (IH, s) ; 7.98 (IH, d). Tetrakis(triphenylphosphine) palladium (9 g ; 7.8 mmol) and ethanol (780 ml) was added to a suspension of methyl 4-methyl-2-trifluoromethanesulphonyloxybenzoate (58 g; 0J95 mol), 2M aqueous solution of sodium carbonate (250 ml ; 0.5 mol), 4- fluorophenylboronic acid (30 g ; 0.214 mol) and lithium chloride (16.5 g ; 0.39 mol) in toluene (1.65 ml), under an argon atmosphere, The mixture was refluxed for 4 hours, diluted with ethyl acetate (1 1) and washed with aqueous sodium hydroxide solution IN (1 1). The organic phase was evaporated and the residue purified by flash column chromatography using ethyl acetate/petroleum ether (95:5) to give methyl 2-(4-fluorophenyl)-4-methylbenzoate (46.8 g ; 99%). Η NMR (CDCI 3 , 400 MHz) δ : 2.41 (3H, s) ; 3.64 (3H, s) ; 7-7.03 (6H, m) ; 7.7 (IH, d). A solution of methyl 2-(4-fluorophenyl)-4-methylbenzoate (54.18 g ; 0.22 mol), N- bromosuccinimide (39.6 g ; 0.22 mol), 2,2'-azobis(2-methylproprionitrile) (0.25 g; 1.5 mmol) and benzoylperoxide (0.25 g ; 1 mmol) in tetrachloromethane (550 ml) was heated at reflux for 6 hours. The solid was filtered and the filtrate evaporated to give methyl 4-bromomethyl- 2-(4-fluorophenyl)benzoate as an oil (79.7 g ; 79%) which was used in the next step without purification. Η NMR (CDCI 3 , 400 MHz) δ : 3.65 (3H, s) ; 4.51 (2H, s) ; 7-7.5 (6H, m) ; 7.82 (IH, m) To a solution of l-(4-fluorophenyl)-2-(imidazol-l-yl)ethanol (0.628 g ; 3 mmol) in THF (30 ml) was added sodium hydride, under an argon atmosphere, (0J5 g ; 3.6 mmol). After stirring for 10 minutes, methyl 4-bromomethyl-2-(4-fluorophenyl) benzoate (2 g ; 6.09 mmol) was added. The mixture was stirred at ambient temperature overnight. After evaporation to dryness, the residue was extracted with ethyl acetate and purified by flash column chromatography eluting with dichloromethane/ethanol (97:3) to give methyl 2-(4- fluorophenyl)-4-[2-(imidazol-l-yl)-l-(4-(fluorophenyl)ethoxymethyl]benzoate as an oil (0.635 g ; 46%). - 52 - Η NMR (CDCI 3 , 400 MHz) δ : 3.65 (3H, s) ; 4-4.6 (5H, m) ; 6.87 (IH, s) ; 6.98 (IH, s) ; 7- 7.3 (10H, m) ; 7.41 (IH, d) ; 7.80 (IH, d). Methyl 2-(4-fluorophenyl)-4-[2-(imidazol- 1 -yl)- 1 -(4- fluorophenyl)ethoxymethyl]benzoate (0.635 g ; 1.41 mmol) in methanol (15 ml) was treated with 2N aqueous sodium hydroxide solution (1.77 ml ; 3.54 mmol) at ambient temperature for 8 hours. After evaporation of the methanol, the residue was taken up in water, the pH adjusted to 4.8 with 2N HCl and extracted with dichloromethane to give 2-(4-fluorophenyl)-4-[2- (imidazol-l-yl)-l-(4-fluorophenyl)ethoxymethyl]benzoic acid after evaporation as a foam (0.522 g ; 85%). Η NMR (CDCI 3 , 400 MHz) δ : 4-4.25 (3H, m) ; 4.4-4.7 (2H, m) ; 6.9-7.5 (12H, m) ; 7.8 (2H, m). A mixture of 2-(4-fluorophenyl)-4-[2-(imidazol-l-yl)-l-(4- fluorophenyl)ethoxymethyl]benzoic acid (0.522 g ; 1.2 mmol), methyl (2S)-2-amino-4- methylsulfanyl)butanoate hydrochloride (L-methionine methyl ester hydrochloride) (0.24 g; 1.2 mmol), HOBT (0.163 g ; 1.2 mmol), EDC (0.23 g ; 1.2 mmol) and N-methylmoφholine (0J32 ml ; 1.2 mmol) in dichloromethane (15 ml) was stirred under an argon atmosphere for 5 hours. After evaporation to dryness, the residue was purified by flash column chromatography eluting with petroleum ether / ethanol (98:2). The resulting compound was dissolved in dichloromethane (2 ml), treated at 0°C with a 3.8N solution of HCl in ether (0.265 ml) and diluted with ether (100 ml) to precipitate the hydrochloride salt which was filtered and dried to give methyl (2S)-2-{2-(4-fluorophenyl)-4-[2-(imidazol-l-yl)-l-(4- fluorophenyl)ethoxymethyl]benzoylamino } -4-methylsulfanylbutyrate. Yield : 75% Η NMR (DMSO d 6 + CF 3 COOD, 400 MHz) δ : 1.8-1.95 (2H, m) ; 2 (3H, s) ; 2.15-2.35 (2H, m) ; 3.64 (3H, s) ; 4.3-4.55 (5H, m) ; 4.9 (IH, m) ; 7.1-7.7 (13H, m) ; 8.6 (IH, d) ; 9.05 (IH, s). Anal. Calculated for C 31 H 31 F 2 N 3 O 4 S, H 2 O , 0.9 HCl C 60.44 H 5.28 N 6.82 S 5.20 - 53 - Found C 60.07 H 5.39 N 6.69 S 4.95 MS (ESI) m/z 580 (MH + ) Example 5 (2S)-3-{4-r(E)-2-(4-fluorophenvn-3-αmidazol-l-vnprop-l-envIl-2-(4- fluorophenvI)benzamido}-5-methylsuIfanyl-2-oxo-l-phenylpentane and (2S)-3-(4-fflE)-2- (4-fluorophenyl)-3-(imidazol-l-v0prop-l-enyl]-2-(4-fluorophenyl)benzamido}-5- methyIsuIfonyl-2-oxo-l-phenylpentane J X 0 -^ ~ J H 9 A mixture of 4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2(4- fluorophenyl)benzoic acid (1.2 g ; 2.88 mmol), DMAP (0.423 g ; 3.46 mmol), EDC (0.663 g ; 3.46 mmol) and HOBT (0.468 g ; 3.46 mmol) in dichloromethane (15 ml) was stirred at room temperature for 30 minutes. (3S)-5-Methylsulfanyl-2-oxo-l-phenylpentan-3-amine was then added to the mixture. After stirring ovemight, extraction with dichloromethane and evaporation to dryness, the residue was purified by flash chromatography eluting with dichloromethane / ethanol (97/3) to give the title sulfanyl compound as a foam. Yield = 57 %. Η NMR (CDC1 3 + CF 3 COOD, 400 MHz) δ 1.65-2.15 (4H, m) ; 2.05 (3H, s) ; 3.82 (2H, m) ; 4.85 (IH, m) ; 5.19 (2H, s) ; 6.8-7.4 (16H, m) ; 8.74 (IH, s). Anal. Calcd for C 37 H 33 F 2 N 3 O 2 S C 71.48 H 5.35 N 6.76 S 5.16 C 71.87 H 5.64 N 7.35 S 4.26 MS (ESI) m/z : 622 (MH + ). - 54 - A solution of the above compound (0.644 g ; 1.03 mmol) and MCPBA (0.535 g ; 3J 1 mmol) in dichloromethane (15 ml) was stirred ovemight at ambient temperature. After extraction (dichloromethane / saturated sodium hydrogen carbonate), the organic phase was evaporated and the residue purified on reverse phase silica eluting with a gradient of 40-70 % methanol / (NH 4 ) 2 CO 3 buffer (2 g/1 pH 7). The compound was further purified by flash chromatography eluting with dichloromethane / ethanol (95/5) to give the title sulfonyl compound as a foam. Yield = 10 % 'H NMR (CDC1 3 , 400 MHz) δ 2.15-2.70 (4H, m) ; 2.80 (3H, s) ; 3.75 (2H, m) ; 4.80 (IH, m) ; 4.85 (2H, s) ; 6.15 (IH, m) ; 6.5 (IH, s) ; 6.8-7.5 (18H, m). Anal calcd for C 37 H 33 F 2 N 3 O 4 S, 0.35 H 2 O C 67.33 H 5.15 N 6.37 S 4.86 C 67.11 H 5.28 N 6.59 S 4.72 MS (ESI) m/z : 654 (MH + ). Example 6 (2SV2-[2-(4-Fluorophenethvn-5-(r2S.4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamido]-4-methylsuIfanylbutan-l-ol TFA (85 mL) was added to a stirred solution of (2S)-2-[2-(4-fluorophenethyl)-5- ((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-4- methylsulfanylbutan-1-ol (1.77 g, 2J2 mmol) in dichloromethane(5 mL) containing Et 3 SiH (3.2 mL, 20 J mmol) and the resulting solution allowed to stir for 1.5 h at room temperature under an inert atmosphere. The reaction mixture was evaporated to dryness and the residues treated with IM HCl diethyl ether to give a white solid. This solid was dissolved in a mixture - 55 - of water (50 mL and methanol (30 mL) and stirred for 4 h at room temperature under an inert atmosphere. The methanol was removed in vacuo and the resulting aqueous solution was lyophilised to give the title compound as a white foam (800 mg). (67%) Η NMR (DMSO-D 6 +CD 3 COOD,300MHz) δl.5-1.8(2H,m); 1.8-1.9(lH+CH 3 COOH,m);2.0(3H,s);2.3-2.6(lH+DMSO,m);2.6-2.9(6H,m); 3.0- 3J(lH,m);3.2-3.6(6H,m);3.6-3.8(lH,m);3.9-4J(lH,m)6.5-6.7(2H,m);6.8-7J(3H,m);7J- 7.25(2H,m). MS (ES+) m/z 492 (M+H) + Anal Calcd for C 25 H 34 N 3 O 2 S 2 F1.9HCl C,53.5;H,6.4;N,7.4;S,11.4 Found C,53.8;H,6.3;N,7.2;S,11.2 The starting material was prepared as follows: trans-4-Hydroxy-L-proline (50.0 g) was dissolved in 0.5M aqueous sodium hydroxide solution (763 mL) and THF (750 mL) and cooled to 4°C. Boc-O-Boc (91.5 g) was added and the reaction stirred ovemight, warming to RT. The THF was removed in vacuo and the solution diluted with water (1000 mL), acidified to pH2.5 with potassium hydrogen sulphate (51.9 g) and saturated with salt. The yellow emulsion was extracted twice with ethyl acetate (total 2500 mL). The combined organic phases were dried (MgSO 4 ) and evaporated to give (2S,4R)-l-tert-butoxycarbonyl-4-hydroxypyrrolidin-2-ylcarboxylic acid as an off-white gum (90.05 g, 95%). ■ H NMR (DMSO-D 6 , 300MHZ) d 1.3-1.35(9H,m);1.8-1.9(lH,m); 2.0-2J(lH,m);3J5-3.4(3H,m);4.05-4J5(lH,m);4.2(lH,br s);5.0(lH,br s) (2S,4R)-l-tert-butoxycarbonyl-4-hydroxypyrrolidin-2-ylcarboxylic acid (45.0 g) was dissolved in DCM (900 mL) and N,O-dimethylhydroxylamine.HCl (57.0 g), DCCI (44.2 g) and DMAP (2.38 g) were added. Triethylamine (81.4 mL) was added slowly (exotherm) which formed a thick white precipitate. The suspension was stirred ovemight under argon. The white suspension was filtered and the filtrate columned using silica (1 kg, eluting with 50% ethyl acetate in iso-hexane, increasing by 10% ethyl acetate each litre and then with 5% methanol in ethyl acetate). The appropriate fractions were combined and evaporated to give - 56 - (2S,4R)-N-methoxy-N-methyl-l-tert-butoxycarbonyl-4-hydroxypyrrolidin-2-ylcarboxamide as a white semi-solid (47.5 g, 95%). Η NMR (DMSO-D 6 , 300MHz) [rotamers] d 1.3 & 1.35 (9H,2 x s);1.7-1.8(lH,m); 2.0-2J5(lH,m);3.05(3H,2 x s);3.2-3.35(2H,m);3.65 & 3.7(3H,2 x s);4.2(lH,br s);4.55- 4.65(lH,m);5.0(lH,br s) (2S,4R)-N-methoxy-N-methyl-l-tert-butoxycarbonyl-4-hydroxypyrrolidin-2-ylcarboxamide (47.5 g) and triethylamine (48.3 mL) were dissolved in dichloromethane (1000 mL) and cooled to 0°C under argon. To this stirred solution was added methanesulfonyl chloride (14.7 mL) dropwise maintaining the reaction below 10°C. The reaction was stirred at 0°C for 45 min and then at room temperature ovemight. The solution was washed twice with water (total 480 mL), dried (MgSO 4 ) and evaporated to give (2S,4R)-N-methoxy-N-methyl-l-tert- butoxycarbonyl-4-methanesulfonyloxypyrrolidin-2-ylcarboxamide as a white resin (57.07 g, 87%). 'H NMR (DMSO-D 6 , 300MHz) [rotamers] d 1.3 & 1.35 (9H,2 x s);2.05-2J5(lH,m); 2.4-2.5(lH,m);3J(3H,2 x s);3.3(3H,2 x s);3.55(lH,dt);3.6(lH,m);3.7(3H,2 x s);4.6- 4.7(lH,m);5.2(lH,br s) To a suspension of 60% sodium hydride (36.4 g) in DMF (1200 mL) cooled to 0°C under argon was added dropwise a solution of triphenylmethylmercaptan (252.0 g) in DMF (1500 mL), maintaining the reaction below 5°C (hydrogen evolved). (2S,4R)-N-Methoxy-N- methyl- 1 -tert-butoxycarbonyl-4-methanesulfonyloxypyrrolidin-2-ylcarboxamide (247.0 g) dissolved in DMF (1700 mL) was added dropwise and the reacton stirred for 2 h at 40°C. The reaction was partitioned between 0.5M citric acid (7400 mL) and DCM (total 11000 mL), washing each extract with 0JM citric acid (3700 mL) and brine (2500 mL). The combined extracts were dried (MgSO 4 ) and evaporated to an oil. Purification by chromatography using 40% ethyl acetate/i-Hex gave (2S,4R)-N-methoxy-N-methyl-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylcarboxamide as a white solid (285.2 g, 77%). - 57 - A solution of LiAlH 4 in THF (1.OM) (62 mL, 62 mmol) was added dropwise to a stirred, cooled (-20°C) solution of (2S,4R)-N-methoxy-N-methyl-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylcarboxamide (30 g, 56.4 mmol) in THF (400 mL). The resulting mixture was allowed to warm to 10°C and stirred for 10 minutes. The mixture was cooled to - 35°C and carefully quenched by the dropwise addition of aqueous potassium hydrogen sulphate (15.3 g in 50 mL water) followed by extraction with diethyl ether (5x150 mL) and the combined organics were washed with IN citric acid (2x100 mL), saturated aqueous sodium bicarbonate solution (2x100 mL) and brine (100 mL), dried (MgSO 4 ), and evaporated to give a yellow oil. Purification by flash chromatography on silica (Merck 9385) eluting with 20% ethyl acetate/iso-hexane gave (2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylcarboxaldehyde as a colourless foam (19.7 g, 74%). MS (ES-) m/z 472 (M-H) ' Dried, powdered 3 A molecular sieve (50 g) was added to a stirred solution of (2S,4S)- l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylcarboxaldehyde (41 g, 86.4 mmol) and methyl 5-amino-2-(4-fluorophenylethyl)benzoate (21.4 g, 78.5 mmol) and the resulting suspension allowed to stir at room temperature for lh. Glacial acetic acid (23.6 g, 392.5 mmol), followed by sodium cyanoborohydride (7.45 g, 118 mmol) was added and the mixture stirred at room temperature under an inert atmosphere for 72 h. The mixture was filtered through celite (545) and evaporated. The residues were dissolved in ethyl acetate (600 mL), washed with saturated aqueous sodium bicarbonate solution (3x100 mL) and brine (3x100 mL), dried (MgSO 4 ), filtered and evaporated to give a brown oil (80 g). Purification by flash chromatography on silica (Merck 9385) eluting with 20% ethyl acetate/iso-hexane gave methyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxy-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoate as a light brown oil (66g, quantitative). MS (ES+) m/z 731 (M+H) + ,519,243. 2N Aqueous sodium hydroxide solution (159 mL, 318 mmol) was added to a solution of methyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxy-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoate (66 g,78.5 mmol estd.) in methanol (400 mL) and THF (100 mL) - 58 - and the resulting mixture heated at reflux for 18 h. The reaction mixture was reduced in volume, acidified to pH5 with IN citric acid and extracted with ethyl acetate (4x250 mL). The combined organics were dried (MgSO 4 ), filtered and evaporated to yield 2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoic acid as a brown gum (66 g, quantitative) MS (ES+) m/z 717 (M+H) + ,519,243. MS (ES-) m/z 715 (M-H)\ Methyl 5-amino-2-(4-fluorophenylethyl)benzoate was prepared as follows: A mixture of methyl 2-bromo-5-nitrobenzoate (5 g), 4-fluorostyrene (3.5 g), tributylamine (0.39 g), bis-(triphenylphosphine)-palladium(II)chloride (0.3 g), sodium bicarbonate(2.65 g) and water (30 ml) was stirred and heated at reflux under an argon atmosphere for 1.5 hours. The reaction was then cooled, suspended in dichloromethane (200 ml) and passed through a pad of silica (chromatography grade) eluting with more dichloromethane The dichloromethane was then evaporated away and the residue treated with iso-hexane (200 ml) to give as a yellow precipitate which was filtered and dried, (5.05 g). NMR (CDC1 3 ) d : 3.99(s, 3H), 7.08(t, 2H), 7J5(d, IH), 7.55(q, 2H), 7.88(d, IH), 8.0(d, IH), 8.32(2d, IH), 8.8(d, IH). A mixture of methyl 2-[2-(4-fluorophenyl)ethynyl]-5-nitrobenzoate (29 g), 10% Pd/C (3 g), and ethyl acetate (400 ml)was stirred under an hydrogen atmosphere for 6 hours. The catalyst was removed by filtration and replaced by fresh catalyst (3 g). The hydrogenation was then continued for another 16 hours, the catalyst was again filtered off , the filtrate evaporated to dryness and the residue treated with iso-hexane to give a white precipitate which was isolated by filtration and dried to give 45 (23.5 g). NMR (CDC1 3 ) d : 2.8(t, 2H), 3J(t, 2H), 3.62(s, 2H), 3.88(s, 3H), 6.72(dd, IH), 6.93(m, 3H), 7J3(m, 2H), 7.23(d, IH). Pentafluorophenyl trifluoroacetate (9 mL, 53 mmol) was added to a stirred solution of 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- - 59 - ylmethylamino)benzoic acid (30 g, 39.25 mmol estd.) in DMF (350 mL) and pyridine (4.3 mL,53 mmol) at room temperature under an inert atmosphere. The resulting solution was allowed to stir for 30 minutes. The reaction mixture was evaporated and the residue was redissolved in ethyl acetate (400 mL) and washed with 0.5N citric acid (3x100 mL), water (3x100 mL), saturated aqueous sodium hydrogen carbonate solution (3x100 mL) and brine (2x100 mL). The organics were dried (MgSO 4 ), filtered and evaporated to give a dark green oil (49 g). Purification by flash chromatography on silica (Merck 9385) eluting with 10% ethyl acetate/iso-hexane to give pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate as a yellow foam (30 g, 86.6%). MS (ES+) m/z 883 (M+H)\243. 2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoic acid (2J5 g, 3.0 mmol) was treated sequentially with EDC (864 mg, 4.5 mmol), DMAP (1.46 g, 12 mmol) and L-methioninol (810 mg, 6.0 mmol) in dichloromethane (50 mL) and the resulting solution was allowed to stir for 18 h at RT. The mixture was diluted with dichloromethane (100 mL), washed with IN citric acid (40 mL) and water (50 mL), dried (MgSO 4 ), filtered and evaporated to give a brown oil. Purification by flash chromatography on silica (Merck 9385) eluting with 50% ethyl acetate/iso-hexane gave (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-4-methylsulfanylbutan-l-ol as a white foam (1.75 g, 70%). MS (ES+) m/z 834(M+H) + - 60 - Example 7 (3SV3-r2-f4-Fluorophenethvn-5-((2S-4S)-4-sulfanylpyrrolidin-2- ylmethylamino " )benzamido1-5-methylsulfanyl-l-phenylpentan-2-one TFA (75 mL) was added to a stirred solution of (3S)-3-[2-(4-fluorophenethyl)-5- ((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-5- methylsulfanyl-l-phenylpentan-2-one (1.0 g, 1.09 mmol) in dichloromethane (5 mL) containing Et 3 SiH (3.2 mL, 20J mmol). The solution was stirred for 1.5 h at room temperature under an inert atmosphere. The reaction mixture was evaporated to dryness and the residue was re-dissolved in diethyl ether (80 mL) and treated with IM HCl diethyl ether to give the title compound as a white solid (582 mg), collected by centrifugation. Η NMR (DMSO-D 6 +CD 3 COOD,300MHz) dl.5-1.8(lH,m); 1.8-2.0(lH+CH 3 COOH,m);2.0-2.2(4H,m);2.4-2.6(2H+DMSO,m);2.6-2.9(5H,m); 3.0-3J(lH,m);3.2-3.6(4H,m);3.6-3.8(lH,m);3.95(2H,s)6.6-6.8(2H,m); 6.9-7.1 (3H,m);7.1 -7.3(7H,m). MS (ES+) m/z 580 (M+H) + Anal Calcd for C 32 H 38 N 3 O 2 S 2 F 2HCl lwater C,57.4;H,6.3;N,6.3;S,9.6 Found C,57.4;H,6.0;N,6.2;S,9.6 The starting material was prepared as follows: EDC (19.17 g, 100 mmol) was added to a stirred solution of N-a-BOC-L-methionine (20 g, 83.6 mmol) and HOBT (15.3 g, 100 mmol) in DMF (400 mL) at room temperature under an inert atmosphere. The mixture was stirred for 1 h until complete dissolution was achieved. N,O-Dimethylhydroxylamine HCl (9.75 g, 100 mmol) was added, followed by ΝMM (11 mL, 100 mmol), and the resulting mixture stirred for 72 h. The mixture was - 61 - evaporated and the residue partitioned between IN citric acid (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (3x100 mL) and the combined organics washed with IN citric acid (3x60 mL), saturated aqueous sodium bicarbonate solution (3x60 mL) and brine (2x60 mL), dried (MgSO 4 ), filtered and evaporated to yield (2S)-N-methoxy-N-methyl-2-tert-butoxycarbonylamino-4-methylsulfanylbutyramide as a yellow oil (24 g, 100%). Η NMR (CDCl 3 ,300MHz) dl.44(9H,s);1.72-1.88(lH,m);1.94-2J(lH,m);2J(3H,s); 2.48-2.62(2H,m);3.20(3H,s);3.78(3H,s);4.8(lH,br m);5.24(lH,br d). MS (ES+) m z 293 (M+H) + A solution of benzyl magnesium chloride in THF (2M) (15 mL, 30 mmol) was added dropwise to a cooled, stirred solution of (2S)-N-methoxy-N-methyl-2-tert- butoxycarbonylamino-4-methylsulfanylbutyramide (2.92 g, 10 mmol) in THF (75 mL) such that the internal temperature remained below 0°C. The reaction was warmed to room temperature and stirred for 4h ,cooled to 0°C and quenched with IN citric acid (30 mL). The aqueous phase was extracted with ethyl acetate (4x30 mL) and the combined organics washed with brine (2x50 mL), dried (MgSO 4 ), filtered and evaporated to a colourless gum (4.6 g). Purification by flash chromatography on silica (Merck 9385) eluting with 15% ethyl acetate/iso-hexane gave (3 S)-N-tert-butoxycarbonyl-5-methylsulfanyl-2-oxo- 1 -phenylpentan- 3-amine as a colourless oil (2.77 g, 86%). Η NMR (CDCl 3 ,300MHz) dl.44(9H,s);1.70-1.88(lH,m);2.0-2.2(lH,m);2.04(3H,s); 2.35-2.55(2H,m);3.78-3.9(2H,AB q);4.52(lH,br m);5.21(lH,br d);7.2-7.38(5H,m). MS (ES+) m/z 324 (M+H) + ,268,224. TFA (25 mL) was added to a solution of (3S)-N-tert-butoxycarbonyl-5- methylsulfanyl-2-oxo-l-phenylpentan-3 -amine (2.7 g, 8.4 mmol) in dichloromethane (10m L) and the solution to stirred for 30 min at room temperature under an inert atmosphere. The reaction mixture was evaporated to dryness and azeotroped with toluene (3x50 mL) to give the TFA salt of (3S)-5-methylsulfanyl-2-oxo-l-phenylpentan-3-amine as a brown oil (6.0 g), which was used without further purification. - 62 - MS (ES+) m z 224 (M+H) + . Compound 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoic acid (1.5 g, 2 J mmol) was coupled with (3S)-5-methylsulfanyl-2-oxo-l-phenylpentan-3-amine (3.0 g, 4.2 mmol estd.) to give (3S)-3- [2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-5-methylsulfanyl-l-phenylpentan-2-one as a colourless oil (1.05g, 54%). MS (ES+) m/z 922 (M+H) + . Example 8 r4SV4-[2-(4-Fluorophenethvn-5-((2S,4SV4-sulfanylpyrrolidin-2- ylmethylamino)benzamido)-6-methylsulfanvI-l-(pyrid-3-yl)hexan-3-one HS s" (4S)-4-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- trity lsulfanylpyrrolidin-2-ylmethylamino)benzamido] -6-methylsulfanyl- 1 -(pyrid-3 -yl)hexan- 3 -one (936 mg, 1 mmol) was deprotected using a similar method to that of Example 7 to give the title compound as an off-white, hygroscopic solid (166mg). 'H NMR (DMSO-D 6 +CD 3 COOD,300MHz) dl.5-1.7(lH,m); 1.7-1.9(lH+CD3COOD,m);1.9-2J(4H,m);2.4-2.6 (2H+DMSO,m); 2.6-2.9(4H,m);2.9-3.2(5,m);3.2-3.9(6H,m);4.5-4.6(lH,m);6.6-7J8(7H,m); 7.8-7.88(lHJ);8.28-8.36(lH,d);8.64-8.7(lH,d); 8.74(lH,s). MS (ES+) m z 595 (M+H) + Anal Calcd for C 32 H 39 N 4 O 2 S 2 F 3HC1J water C,53.2;H,6J;N,7.7;S,8.9 Found C,53.2;H,5.8;N,7.4;S,8.8 - 63 - The starting material was prepared as follows: n-Butyl lithium in hexane (1.6M) (33 mL, 52.8 mmol) was added to a stirred solution of dimethyl methylphosphonate (7.56 g, 61 mmol) in THF (100 mL) at -70°C under an inert atmosphere and the solution allowed to stir for lh. A solution of (2S)-N-methoxy-N-methyl- 2-tert-butoxycarbonylamino-4-methylsulfanylbutyramide (2.92 g, 10 mmol) in THF (20 mL) was added dropwise and the mixture stirred for an additional lh. The reaction was quenched by careful addition of saturated aqueous ammonium chloride solution (80 mL). The organics were separated and the aqueous phase re-extracted with ethyl acetate (4x30 mL). The combined organics were washed with brine (2x40 mL), dried (MgSO 4 ), filtered and evaporated to give a colourless oil. Purification by flash chromatography on silica (Merck 9385) eluting with 75% ethyl acetate/iso-hexane gave dimethyl (3S)-3-tert- butoxycarbonylamino-5-methylsulfanyl-2-oxopentylphosphonate as a colourless oil (3.38 g, 95%). 'H NMR (CDCl 3 ,300MHz) dl.47(9H,s);1.78-1.92(lH,m);2J6-2.3(4H,m); 2.5-2.6(2H,t);3.08-3.4(2H,m);3.78-3.82(6H,dd);4.4-4.5(lH,br m);5.5(lH,br d). MS (ES+) m/z 356 (M+H) + ,300,256. Pyridine-3-carboxaldehyde (1.49 g, 13.9 mmol) was added to a stirred mixture of dimethyl (3S)-3-tert-butoxycarbonylamino-5-methylsulfanyl-2-oxopentylphosphonate (3.3 g, 9.29 mmol) and potassium carbonate (1.54 g, 11.1 mmol) in acetonitrile (40 mL) at room temperature under an inert atmosphere and the resulting suspension to stirred for 18 h. The mixture was partitioned between brine (30 mL) and ethyl acetate (50 mL) and the aqueous was reextracted with ethyl acetate (2x50 mL). The combined organics were washed with brine(2x30 mL), dried (MgSO 4 ), and evaporated to give a solid. This solid was triturated with iso-hexane, filtered and dried to give (3S)-N-tert-butoxycarbonyl-l-methylsulfanyl-4-oxo-6- (pyrid-3-yl)hex-5-en-3-amine as a white solid (2.59 g, 83%). Η NMR (CDCl 3 ,300MHz) dl.46(9H,s);1.80-1.94(lH,m);2J-2.3(4H,m); 2.48-2.68(2H,m);4.75-4.9(lH,br m);5.3-5.45(lH,br d);6.9-6.95(lH,d);7.34-7.4(lH,dd); 7.7-7.75(lH,d);7.86-7.92(lH,m);8.61-8.67(lH,b d);8.8(lH,b s). - 64 - MS (ES+) m/z 337 (M+H) + . Ammonium formate (5.7 g, 90 mmol) was added to a stirred solution of (3S)-N-tert- butoxycarbonyl-l-methylsulfanyl-4-oxo-6-(pyrid-3-yl)hex-5-en-3-amine (3.03 g, 9.03 mmol) in methanol (200 mL) at room temperature under an inert atmosphere. When a solution had foimed 10% palladuim-on-carbon (2.5 g) was added and the resulting suspension was to stirred at room temperature under a balloon of Ar for 3hr. The mixture was filtered through celite (545) evaporated and the residue partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase extracted with ethyl acetate (4x50 mL) the combined organics washed with water (3x30 mL) and brine(2x30 mL), dried (MgSO 4 ), filtered and evaporated to give (3S)-N-tert-butoxycarbonyl-l-methylsulfanyl-4-oxo-6-(pyrid- 3-yl)hex-3-amine as a yellow oil (2.6 g, 86%). 'H NMR (CDCl 3 ,300MHz) dl.46(9H,s);1.68-1.88(lH,m);2.0-2.2(4H,m); 2.38-2.54(2H,m);2.85-3.0(4H,m);4.32-4.44(lH,br m);5.2-5.3(lH,br d); 7.2-7.26(lh,dd);7.5-7.56(lh,d);8.48(2h,b m). MS (ES+) m/z 339 (M+H) + ,283. TFA (15 mL) was added to a stirred solution of (3S)-N-tert-butoxycarbonyl-l- methylsulfanyl-4-oxo-6-(pyrid-3-yl)hex-3 -amine ( 2.9 g, 8.6 mmol) in dichloromethane (20 mL) and the resulting solution stirred for 4 h. The mixture was evaporated and azeotroped with toluene to give (3S)-l-methylsulfanyl-4-oxo-6-(pyrid-3-yl)hex-3-amine as a yellow oil (4.9g), which was used without further purification. MS (ES+) m/z 239 (M+H) + ,222. Pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (1J g, 1.25 mmol) was coupled with (3S)- l-methylsulfanyl-4-oxo-6-(pyrid-3-yl)hex-3 -amine (2J4 g, 3.75 mmol estd.) using a similar method to that of Example 9 give (4S)-4-[2-(4-fluorophenethyl)-5-((2S,4S)-lJert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-6-methylsulfanyl-l- (pyrid-3-yl)hexan-3-one as a colourless oil (1.0 g, 85%). - 65 - MS (ES+) m/z 937 (M+H) + 518,335,243,238,224. Example 9 r2SV2-r2-(4-Fluorophepethvn-5-f(2S.4SV4-sulfanylpyrrolidin-2- ylmethylamino)benzamidol-4-methylsulfanyl-l-morpholinobutane (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido] -4-methylsulfanyl- 1 -moφholinobutane (1.0 g, 1J3 mmol) was deprotected using similar methodology to that used in the equivalent step described in Example 7 to give the title compound as a white solid (596 mg) yield 75%. Η NMR (DMSO-D 6 + CD 3 COOD, 300MHz) d 1.6-1.7(lH,m);1.8-1.9(2H,m); 2.0(3H,s);2.4-2.6(2H,m);2.7-2.9(4H,m);3.0-3.2(3H,m);3.2-3.35(6H,m);3.35-3.5(3H,m);3.65- 3.8(2H,m); 3.8-3.95(3H,m);4.45-4.55(lH,m);6.65(lH,dd); 6.95-7.05(4H,m);7J-7.2(2H,m) MS (ESP+) 561 m z Anal Calcd for C 29 H 41 FN 4 O 2 S 2 .4HCl C,49.3;H,6.42;N,7.93;S,9.08 Found C,49.3;H,6.4; N,7.8;S,9.2 The starting material was prepare as follows: To a solution of BOC-L-methionine (10.0 g; 40.2 mmol) in dry DMF (50 mL) at 0°C under an inert atmosphere was added EDC (9.25 g; 48.2 mmol), HOBT (6.52 g; 48.2 mmol) and the mixture stirred for 30 min until a homogeneous solution resulted. Moφholine (7.7 mL, 88.4 mmol) was added dropwise and the reaction warmed to room temperature and stirred for 18 h. Solvent was removed in vacuo and the residue partitioned between ethyl acetate and IN citric acid, extracting three times with ethyl acetate. The combined organic extracts were washed with aqueous sodium bicarbonate, water and brine solution, dried (MgSO 4 ) and concentrated in vacuo to give a colourless oil (12.8 g) . - 66 - 'H NMR (CDC1 3 , 300MHz) d 1.4(9H,s);1.7-2.0(2H,m);2J(3H,s);2.5-2.6(2H,m);3.5- 3.7(8H,m);4.7-4.8(lH,m);5.4(lH,br d) MS (ESP+) m z 319 (M+H)J To a stirred solution of lithium aluminium hydride (50 ml; 50 mmol; IM solution in THF) in dry THF (200 mL) at 0°C under inert atmosphere was added dropwise a solution of (2S)-N-tert-butoxycarbonyl-4-methylsulfanyl- 1 -moφholino- 1 -oxobut-2-amine (12.7 g; 40 mmol) in dry THF (100 mL), such that the internal temperature did not exceed 10°C. Upon completion of the addition, the reaction was warmed to room temperature and allowed to stir for 3 h. The reaction was quenched with water (20 mL), followed by the addition of 15% aqueous aqueous sodium hydroxide solution (10 mL), and stirred for a further 1 h. The mixture was filtered and the filtrate concentrated in vacuo to give a colourless oil. Purification by flash chromatography (ethyl acetate: iso-hexane/ 1 : 1 ® 2:1) gave (2S)-N-tert-butoxycarbonyl-4-methylsulfanyl- 1 -moφholinobut-2-amine as a colourless oil (5.23 g; 43% over two steps). Η NMR (CDC1 3 , 300MHZ) d 1.45(9H,s);1.6-1.7(lH,m);1.8-1.95(lH,m);2J(3H,s); 2.25-2.6(8H,m);3.65(4H,t);3.7-3.85(lH,m);4.5(lH,br m) MS (ESP+) m/z 305 (M+H) + . To a stirred solution of (2S)-N-tert-butoxycarbonyl-4-methylsulfanyl- 1 - moφholinobut-2-amine (1.5 g, 4.9 mmol) and triethylsilane (3.15 ml; 19.7 mmol) in dichloromethane (5 mL) at room temperature under inert atmosphere was added trifluoroacetic acid (25 mL) and the reaction stirred for 1 h. Concentration and drying in vacuo gave the TFA salt of (2S)-4-methylsulfanyl-l-moφholinobut-2 -amine as a pale yellow oil (3.2 g), which was used without further purification. 'H NMR (DMSO-D 6 + CD 3 COOD, 300MHz) d 1.8-1.9(2H,m); 2.0(3H,s); 2.5-2.6(2H,m);3J-3.3(6H,m);3.7-3.85(5H,m) MS (ESP+) m/z 205 (M+H) + . - 67 - To a solution of 2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoic acid (1J5 g; 1.6 mmol) in DMF (20 mL) at 0°C under inert atmosphere was added EDC (369 mg; 1.9 mmol) and HOBT (257 mg; 1.9 mmol), and the mixture stirred for 30 min until a homogeneous solution resulted. NMM (5.5 ml; 50 mmol) was added, followed by a solution of (2S)-4-methylsulfanyl-l-moφholinobut- 2-amine (1.6 g; 2.5 mmol estd.) in DMF (5 mL), and the reaction allowed to warm to room temperature and stir for 18 h. Solvent was removed in vacuo and the residue partitioned between ethyl acetate and water, extracting with ethyl acetate (x3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine, filtered through PSl filter paper and concentrated in vacuo. Purification by flash chromatography (ethyl acetate:iso-hexane/ 1 :1) gave (2S)-2-[2-(4-fluoroρhenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-4-methylsulfanyl-l- moφholinobutane as a white foam (1.02 g, 71%). MS (ESP+) m/z 903 (M+H) + . Example 10 r2S)-2-r2-(4-Fluorophenethyn-5-((2S,4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamido1-4-methoxy-l-morpholinobutane SH (2S)-2-[2-(4-Fluoroρhenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-4-methoxy-l-moφholinobutane (453 mg, 0.51 mmol) was deprotected using similar methodology to that used in the equivalent step described in Example 7 to give the title compound as a white solid. 'H NMR (DMSO-D 6 + CD 3 COOD, 300MHz) d 1.55-1.7(lH,m);1.75-1.85(2H,m); - 68 - 2.5-2.6(2H,m);2.7-2.85(4H,m);3.0-3.2(3H,m);3J(3H,s);3.2-3.45(6H,m);3.5-3.6(3H,m);3.65- 3.8(2H,m);3.8-3.95(3H,m);4.45-4.55(lH,m);6.6(lH,dd); 6.9-7.0 (4H,m);7J-7.2(2H,dd) MS (ESP+) 545 m/z Anal Calcd for C 29 H 41 FN 4 O 3 S.3HCl C,53.3;H,6.78;N,8.57;S,4.90 Found C,53.6;H,6.8; N,8.6;S,5.0 The starting material was prepared as follows: To a solution of N-trityl-L-(O-methyl)homoserine (1.5 g; 4.0 mmol) in dry DMF (15 mL) at 0°C under an inert atmosphere was added ΝMM (500 mL; 4.55 mmol), EDC (922 mg; 4.8 mmol) and HOBT (648 mg; 4.8 mmol), and the mixture stirred for 30 min until a homogeneous solution resulted. Moφholine (767 mL, 8.8 mmol) was added and the reaction warmed to room temperature and stirred for 18 h. The reaction mixture was partitioned between ethyl acetate and IN citric acid, extracting three times with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution, water and brine, filtered through PSl filter paper and concentrated in vacuo to give an off- white solid. Purification by flash chromatography (ethyl acetate :iso-hexane/2:l) gave a white solid (1.49 g; 84%). Η ΝMR (CDC1 3 , 300MHZ) d 1.85-2.0(2H,m);2.55-2.65(lH,m);2.65-2.75(lH,m);3J- 3.2(lH,br m);3.25-3.4(4H,m);3.3(3H,s);3.45-3.55(3H,m);3.6-3.7(2H,m);7J- 7.25(9H,m);7.5(6H,dd) MS (ESP+) m z 445 (M+H) + . Reduction of (2S)-Ν-trityl- 1 -moφholino-4-methoxy- 1 -oxobutan-2-amine was achieved using similar methodology to that used in the equivalent step described in Example 9. Purification by flash chromatography (ethyl acetate :iso-hexane/l :4® 1 :2) gave (2S)-N- trityl-l-moφholino-4-methoxybutan-2-amine as a colourless oil (340 mg) yield 49%. Η NMR (CDC1 3 , 300MHZ) d 1.2-1.4(lH,m);1.5-1.6(lH,m);2.0-2J(2H,m);2J-2.2(4H,m);2.4- 2.5(lH,m);3J-3.25(2H,m);3.2(3H,s);3.5-3.6(4H,m);7J-7.3(9H,m);7.55(6H,dd) MS (ESP+) m z 431 (M+H) + . - 69 - Removal of the trityl group from (2S)-N-trityl-l-moφholino-4-methoxybutan-2-amine was carried out following similar methodology to that used in the removal of the BOC group in Example 9. The oily solid obtained was azeotroped with toluene to give a white solid which was used without further purification. MS (ESP+) m z 189 (M+H) + . To a solution of pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyπOlidin-2-ylmethylamino)benzoate (573 mg; 0.65 mmol) in DMF (5 mL) at room temperature under inert atmosphere was added NMM (514 mL; 4.7 mmol), HOBT (114 mg; 0.85 mmol) and a solution of (2S)-l-moφholino-4-methoxybutan-2- amine (0.78 mmol estd.) in DMF (5 mL), and the reaction allowed to stir for 18 h. Solvent was removed in vacuo and the residue partitioned between ethyl acetate and IN citric acid, extracting with ethyl acetate (x3). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine, filtered through PSl filter paper and concentrated in vacuo. Purification by flash chromatography (ethyl acetate: iso-hexane/ 1 :1 ® ethyl acetate) gave (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-4-methoxy- 1 -moφholinobutane as a white foam (453 mg, 79%). MS (ESP+) m/z 887 (M+H) + . Example 11 (2S)-2-r2-(4-Fluorophenethvn-5-fr2S-4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamido|-4-methoxybutan-l-ol - 70 - (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfany lpyrrolidin-2-y lmethylamino)benzamido] -4-methoxybutan- 1 -ol (500 mg, 0.61 mmol) was deprotected using similar methodology to that used in the equivalent step described in Example 10 to give the title compound as a white solid (293 mg) Yield 72%. ] H NMR (DMSO-D 6 + CD 3 COOD, 300MHz) d 1.55-1.7(lH,m);l .7-1.8(lH,m); 2.45-2.55(2H,m);2.65-2.8(4H,m);3.0-3J(lH,m);3J5(3H,s);3.3-3.45(6H,m);3.4- 3.6(lH,m);3.65-3.8(lH,m);3.98-4.0(0.5H,m);4.3-4.4(lH,m);4.45-4.55(0.5H,m); 6.55-6.65(2H,m); 6.9-7.05 (3H,m);7J-7.2(2H,m) MS (ESP+) 476 m/z Anal Calcd for C 25 H 34 FN 3 O 3 S.2HCl.TFA C,48.9;H,5.63;N,6.34;S,4.84 Found C,49.2;H,5.6; N,6.6;S,5.2 To a stirred solution of lithium aluminium hydride (5 ml; 5 mmol; IM solution in THF) in dry THF (20 mL) at 0°C under inert atmosphere was added dropwise a solution of N- trityl-L-(O-methyl)homoserine (1.5 g; 4.0 mmol) in dry THF (10 mL), such that the internal temperature did not exceed 10°C. Upon completion of the addition, the reaction was warmed to room temperature and allowed to stir for 18 h. The reaction was quenched with water (10 mL), followed by the addition of 15% aqueous sodium hydroxide solution (10 mL) and sodium potassium tartrate, and stirred vigorously for a further 2 h until no solid remained. The mixture was extracted with ethyl acetate; the organic extracts washed with water and brine, filtered through PSl filter paper and concentrated in vacuo to give a yellow oil (1.4 g) Yield 97%. 'HΝMR (CDC1 3 , 300MHz) d 1.4-1.5(lH,m);1.55-1.7(lH,m);2.6(lH,dd);2.7-2.8(lH,br m);3J(lH,dd);3.25-3.3(lH,m);3.25(3H,s);3.5(lH,dt); 7J5-7.3(9H,m); 7.55(6H,dd) MS (ESP+) m/z 362 (M+H) + . Removal of the trityl group from (2S)-2-tritylamino-4-methoxybutan-l-ol was carried out following similar methodology to that used in the equivalent step in Example 10. The solid obtained was used without further purification. 71 MS (ESP+) m/z 120 (M+H) + (2S)-2-amino-4-methoxybutan-l-ol was coupled with pentafluorophenyl 2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoate (2.0 g; 2.26 mmol) using a similar procedure to that used in the equivalent step in Example 10. Purification by flash chromatography (ethyl acetate: iso- hexane/ 1 :1 ® 2:1) gave (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-4-methoxybutan-l-ol as a white foam (1.55 g, 84%). MS (ESP+) m/z 818 (M+H) + . Example 12 (3SV3-[2-(4-Fluorophenethvn-5-(f2S.4SV4-sulfanylpyrrolidin-2-ylmethoxy)benzamidol- l-phenylbutan-2-one TFA (70mL) was added to a stirred solution of (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l- tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethoxy)benzamido]-l-phenylbutan-2-one (650mg,0.75mmol), in dichloromethane (5mL), containing triethylsilane 5.0mL,31.0mmol) and the resulting solution allowed to stir for 1 hour at room temperature under an inert atmosphere. The reaction mixture was evaporated to dryness and the residues treated with IM - 72 - HC1 in diethyl ether to give a yellow gum. This gum was re-dissolved in ethyl acetate and evaporated to give the title compound as a pale yellow foam, (300mg 62%). Η NMR (DMSO-D 6 ,400MHz) d 1.28-1.34(3H,d);1.65-1.75(lH,q);2.50-2.62(2H,m); 2.68-2.98(4H,m);3.00-3.10(1 H,m);3.40-3.70(2H,m);3.90-4.10(3H,m); 4.50-4.60(lH,q);6.90-7.30(12H,m) . Anal calc'd for C 30 H 33 N 2 O 3 SF , 2.0HC1 , 3.0H 2 O C 56.6 H 5.8 N 4.3 S 4.9 Found C56.6 H5.3 N 4.0 S 4.6 MS (ES+) m/z 521 (MH+). The starting material was prepared as follows : A solution of benzyl magnesium chloride (2M) in THF (30ml, 60mmol) was added dropwise to a cooled, stirred solution of (S)-2-(tert-butoxycarbonylamino)-N-methoxy-N- methylpropionamide (RN 87694-49-3) (4.64g, 20 mmol) in THF such that the internal temperature remained below 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours, then cooled to 0°C and quenched with a saturated aqueous solution of ammonium chloride (30 mL). The aqueous phase was extracted with ethyl acetate (3 x 40 mL) and the combined organic phases were washed with brine (2x40 mL), dried (MgSO4) , filtered and evaporated to give a pale yellow oil. Purification by flash chromatography on silica (Merck 9385), eluting with 15% ethyl acetate/ iso-hexane gave (3S)-3-(tert- butoxycarbonylamino)-l-phenylbutan-2-one as a pale yellow oil (4.6 g, 87%) ) . Η NMR (CDC1 3 ,300MHz) dl.30-1.36(3H,d);1.44,(9H,s);3.80(2H,narrow d ); 4.32-4.52(lH,bm);5.22,(lH,bm);7.20-7.40(5H,m). MS (ES+) m/z 264 (MH+) . TFA (25mL) was added to a solution of (3S)-3-(tert-butoxycarbonylamino)-l-phenylbutan-2- one (2.63g, lOmmol) in dichloromethane (50mL) and the solution stirred for 1 hour at room temperature under an inert atmosphere. The reaction mixture was evaporated to dryness and azeotroped with toluene (3x50 ml) to give the TFA salt of (3S)-3-amino-l-phenylbutan-2-one as a yellow oil, which was used without further purification assuming quantitative yield. 73 - 'H NMR (CDCI 3 ) dl.36-1.42 (3H,d );3.60-3.80(2H , AB,q );4J0-4J8(lH,q ); 6.80-7.30 (5H ,m ). MS (ES+) m/z l64 (MH+). 2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzoic acid (1.43g , 2.0 mmol ) was coupled with (3S)-3-amino-l-phenylbutan-2- one (1.48g , 4.0 mmol estd.) using a similar method to equivalent step in Example 7 to give (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzamido]-l-phenylbutan-2-one as a yellow oil (1.43g , 82% ). 'H NMR (CDCI 3 ) dl.35 (9H,s);1.44-1.48(3H,d);2.60-3.00(6H,m);3.88(2H,s); 3.80-4.20(4H,m);4.78-4.88(lH,quintet);6.42-6.50(lH,d);6.80-7J0(7H,m); 7J8-7.52(20H,m). MS (ES+) m/z 863 (MH+). Example 13 (3SV3-r2-(4-Fluorophenethvn-5-(r2S.4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamidol-l-phenylpropan-2-one TFA (75mL) was added to a stirred solution of (3S)-3-[2-(4-fluorophenethyl)-5- ((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 - - 74 - phenylpropan-2-one (1.00g;lJ8mmol) in dichloromethane (5mL) containing triethylsilane (5.0 mL, 31.0mmol). The reaction mixture was stirred for 1 hour at room temperature under an inert atmosphere. The mixture was evaporated to dryness and the residues dissolved in diethyl ether (50 mL), which was treated with IM HCl in diethyl ether, to give the title compound as a white solid, (464mg, 68%) . Η NMR (DMSO-D 6 ) d2.68-2.86(4H,m);2.98-3.06(2H,m);3.20-3.80(6H,m); 3.82(2H,s);4J4(2H,s);6.00-7.35(12H,m). MS (ES+) m/z 506 (MH+). The starting material was prepared as follows: l-Amino-3-phenyl-2-propanone (RN 135608-75-2 ) (2.05g , 5.45mmol ) was added to a stirred solution of pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)-l- tertbutoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (1.61g,1.82 mmol ), HOBT (320 mg , 2.37mmol ) and NMM (3.68g , 36.4mmol ) in DMF (25mL). The mixture was stirred under an inert atmosphere at room temperature for 18 hours. The reaction mixture was evaporated and the residues dissolved in ethyl acetate (150 mL) washed with sodium hydrogen carbonate (3x50 mL), brine (2x50mL), dried (MgSO 4 ), filtered and evaporated to a crude gum. Purification by chromatography on silica (Merck9385), eluting with 30% ethyl acetate/ iso-hexane, gave (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l- tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-l-phenylpropan- 2-one as a colourless oil (1.00g, 67%). Η NMR (CDC1 3 ) dl.36(s,9H),2.65-2.95(m,6H);3.05-3.30(m,3H);3.88(s,2H); 4.22-4.28(narrow d,2H),6.54 - 7.50(m,27H). MS (ES+) m/z 848 (MH+). Example 14 (3S)-3-r2-f4-FIuorophenethvn-5-((2S.4SV4-sulfanylpyrrolidin-2- ylmethylamino)benzamido1-l-pyridin-4-ylbutan-2-one 75 TFA (75mL) was added to a solution of (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-lJert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-l-pyridin-4-ylbutan- 2-one (431mg ,0.5 mmol) in dichloromethane (5 mL), containing triethylsilane (10 mL, 62.0mmol). The reaction mixture was stirred for 1 hour at room temperature under an inert atmosphere. The mixture was evaporated to dryness, dissolved in diethyl ether (30 mL) , and treated with IM HCl in diethyl ether to give the title compound as a white solid (240 mg, Η NMR (DMSO-D 6 ) dl.34-1.38( 3H ,d ); 2.60-2.90(4H,m);3.00-3J0(lH,dd); 3.30-3.80(10H,m);4.54-4.60(lH,q);6.60-7J5(7H,m);7.88-7.92(2H,d ); 8.80-8.84(2H,d). MS (ES+) m/z 521 (MH+). Anal cal'd for C 29 H 33 N 4 O 2 SF . 3.0HC1 1.0H 2 0 C 53.8 ; H5.8 ; N 8.6 ; S 4.9 Found C 53.8 ; H 5.8 ; N8.5 ; S 5.0 The starting material was prepared as follows : 1.6M n-Butyl-lithium in hexanes (32mL,50.0mmol) was added to a solution of 4-picoline (4.65g , 50.0 mmol) in THF (200mL) at -70C. After 10 minutes, a solution of (S)-2-(tert- butoxycarbonylamino)-N-methoxy- N-methylpropionamide (RN 87694-49-3), (2.92g, 10.0 mmol) in THF (75 mL ) was added and the mixture stirred for 2 hours at -70°C. The reaction was quenched with a saturated aqueous solution of ammonium chloride (200mL) and extracted with ethyl acetate (4xl00mL). The combined organic phases were washed with - 76 - brine (2xl00mL), dried (MgSO 4 ), filtered and evaporated. The products were purified by flash chromatography on silica (Merck 9385), eluting with 75% ethyl acetate/iso-hexane to give (3S)-3-(tert-butoxycarbonylamino)-l-pyridin-4-ylbutan-2-one as a yellow oil (2.05g, 78%). 'H NMR (CDC1 3 ) dl.34 - lJ8( 3H,d );1.46(9H,s );3.83(2H,s);4.30-4.48(lH,bm); 5J9 (lH,bm);7J2-7J6(2H,d);8.52-8.56(2H,d ). MS (ES+) m z 265 (MH+). (3S)-3-(tert-Butoxycarbonylamino)-l-pyridin-4-ylbutan-2-one (2.0g, 7.56mmol) was deprotected using a similar method to Example 12 to give (3S)-3-amino-l-pyridin-4-ylbutan- 2-one which was used without further characterisation assuming quantitative yield. 2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoic acid (2.78g, 4.0mmol) was coupled with (3S)-3-amino-l-pyridin-4- ylbutan-2-one (estd 7.5mmol) using a similar method to the equivalent step in Example 12 to give (3 S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-l-pyridin-4-ylbutan-2-one as a yellow gum, (1.95g, 57%). MS (ES+) m/z 863 (MH+) . Example 15 (3SV3-(2-r2-rThiazoI-2-vnethyll-5-r(2S.4S 4-sulfanylpyrrolidin-2- ylmethylamino)benzamido}-l-phenylpentan-2-one - 77. (3S)-3-{2-[2-(Thiazol-2-yl)ethyl]-5-((2S,4S)-lJert-butoxycarbonyl-4-fritylsulfanylpyrrolidin- 2-ylmethylamino)benzamido}-l-phenylpentan-2-one (330 mg , 0.36 mmol) was deprotected using a similar method to the equivalent step in Example 14 to give the title compound (170 mg, 68% ). 'H NMR (DMSO-D 6 +CD 3 COOD) dl.5-1.8(lH,m);1.80-1.95(lH+CHD 2 COOD,m); 2.00(3H,s);2.00-2J0(lH,m);2.40-2.60(4H+DMSO,m);2.95-3.09(2H,m); 3J8-3.32(2H,m);3.30-3.80(5H,m);3.90(2H,s);4.58-4.64(lH,m);6.60-6.70(2H,m); 7.00-7.30(6H,m);7.54-7.58(lH,m);7.70-7.75(lH,m). MS (ES+) m/z 569 (MH+). Anal calc'd for C 29 H 36 N 4 O 2 S 3 ,3.0 HC1,0.75 H2O C:50.5 ; H: 5.9 ; N: 8.1; S: 13.9 Found C.50.8 ; H: 6.1 ; N:7.9 ; S: 13.5 . The starting material was prepared as follows: A mixture of methyl-2-bromo-5-nitrobenzoate (50.0g , 192.0mmol ), TMS-acetylene (27.0mL , 192mmol), (Ph 3 P) 2 PdCl 2 (6.6g , 9.4mmol), copper (I) iodide (3.6g) in triethylamine (500mL) and DMF (800mL) was stirred at room temperature under an inert atmosphere for 18 hours. The solvent was evaporated and the residues treated with 2N HCl (500mL) and extracted with ethyl acetate (4 x 200mL). The combined organic phases were washed with sodium hydrogen carbonate (3xl50mL), brine (2x200mL), dried (MgSO 4 ), filtered and evaporated to give an oil. Purification by flash chromatography on silica (Merck 9385) eluting - 78 - with 5% ethyl acetate / iso-hexane, gave methyl 2-(2-trimethylsilylethynyl)-5-nitrobenzoate, as a pale yellow solid (26.7g, 51% ). Η NMR (CDC1 3 ) d 0.00( 9H, s) ; 3.70 (3H, s) ;7.42-7.46(lH, d);7.96-8.00(lH, dd ); (8.48,lH,narrow d ). MS (ES+) m/z 278 (MH+) . Sodium fluoride (24. Og , όlOmmol ) was added to a solution of methyl 2-(2- trimethylsilylethynyl)-5-nitrobenzoate (33.7g, 122mmol) in aqueous DMF (500mL) and water (lOOmL) and the mixture stirred at room temperature under an inert atmosphere for 30 minutes . The reaction mixture was diluted with water (600mL), extracted into ethyl acetate (5xl20mL) and the organic phases washed with brine (3 xl50mL), dried (MgSO 4 ), filtered and evaporated. The product was purified by flash chromatography on silica (Merck 9385), eluting with a gradient of 10-25% ethyl acetate / iso-hexane, to give methyl 2-ethynyl-5- nitrobenzoate as a yellow solid (2 l.Og, 84%) . Η NMR (CDCI 3 ) d 3.72 (IH, s) ; 4.00 (3H, s ) ;7.78-7.80(lH,d );8.30-8.34(lH ,dd ); 8.80 (IH ,narrow d ). MS (ES-) m/z 204 (M-H) " . A mixture of methyl 2-ethynyl-5-nitrobenzoate (2 l.Og , 102.5mmol ), 2-bromothiazole (66.8g , 410mmol), triethylamine (11.4g, 113mmol), (Ph 3 P) 2 PdCl 2 (3.62g, 5J5mmol), and copper (I) iodide (1.97g, 10.3mmol) in DMF (700mL) was stirred at room temperature under an inert atmosphere for 18 hours. The solvent was removed and the residues partitioned between IN HCl (300mL), and ethyl acetate (5xl50mL). The combined organic extracts were washed with brine (3x200 mL), dried (MgSO 4 ), filtered and evaporated. The product was purified by flash chromatography on silica (Merck 9385), eluting with a gradient of 30-50% ethyl acetate/ iso-hexane, to give methyl 2-[2-(thiazol-2-yl)ethynyl]-5- nitrobenzoate as a pale brown solid (11.6g, 39%) . Η NMR (CDCI 3 ) d4.05 (3H ,s ) ;7.50-7.54 (lH,d ) ; 7.94-7.98 (IH d); 7.88-7.92 (IH , d ) ;8.37-8.41 (IH, m ) ; 8.90 (IH , d ). MS (ES+) m/z 289(MH+) . - 79 - A solution of methyl 2-[2-(thiazol-2-yl)ethynyl]-5-nitrobenzoate (11.5g , 40.0mmol) in methanol (100 mL) was stirred under an atmosphere of hydrogen (5 Bar) for 24 hours at a temperature of 40°C, using 10% PαV C (2.5g) as the catalyst. The catalyst was removed by filtration through Celite, and the filtrate was evaporated to give methyl 2-[2-(thiazol-2- yl)ethyl]-5-aminobenzoate as a pale yellow oil (7.3g, 70%). Η NMR (CDC1 3 ) d3.30 (4H ,s ) ; 3.90(3H,S) ; 6.74-6.80 (IH d); 7.00-7.02(lH ,d ) ; 7J9-7.20 (IH, m ) ;7.30 (IH ,d ); 7.72-7.74(lH , d). MS (ES+) m/z 263 (MH+). (2S,4S)-l-tert-Butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylc--rboxaldehyde (10.4g,22mmol) was reductively animated with methyl 2-[2-(thiazol-2-yl)ethyl]-5-aminobenzoate (5.24g, 20mmol), using a similar method to the equivalent step in Example 6 to give methyl 5- ((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)-2-[2-(thiazol-2- yl)ethyl]benzoate as a pale yellow foam (5.5g, 38%). MS (ES+) m/z 720 (MH+). A mixture of methyl 5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)-2-[2-(thiazol-2-yl)ethyl]benzoate (5.5g, 7.7mmol ), 2N sodium hydroxide (15mL, 30mmol), THF (30mL), and methanol (80mL) was heated at reflux for 7 hours. The solvent was evaporated and the residues were acidified and extracted with ethyl acetate (5x70mL). The combined organic phases were washed with IN citric acid (50mL), brine (3x50mL), dried (MgSO 4 ), filtered and evaporated to give 5-((2S,4S)-l-tert-butoxycarbonyl- 4-tritylsulfanylpyrrolidin-2-ylmethylamino)-2-[2-(thiazol-2-yl)ethyl]benzoic acid as a yellow foam (5J8g, 96%). MS (ES-) m/z 704 (M-H)\ 5-((2S,4S)-l-tert-Butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)-2-[2-(thiazol- 2-yl)ethyl]benzoic acid (1.41g , 2.0mmol ), was coupled with (3S)-5-methysulfanyl-2-oxo-l- phenylpentan-3 -amine (1.24g , 3.0mmol estd.) using a similar method to the equivalent step in 80 - Example 7 to give (3S)-3-{2-[2-(thiazol-2-yl)ethyl]-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido}-l-phenylpentan-2-one, (1.33g, 71%>) as a yellow oil. MS (ES+) m/z 911 (MH+) . MS (ES-) m/z 909 (M-H) " . Example 16a f3S)-3-r2-(4-Fluorophenethvn-5-((2S.4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(2-fluorophenyl)-5-methylsulfanylpentan-2-one (3S)-3-[2-(4-Fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(2-fluorophenyl)-5-methylsulfanylpentan-2-one was deprotected (500mg , 0.53mmol ), using a similar method to the equivalent step in Example 15 ) to give the title compound (306 mg, 86% ). Η NMR (DMSO-D 6 ) dl.84-2.20(2H ,m);2.02 (3H ,s);2.40-2.62 (2H ,m); 2.68-2.88 (4H , m ) ; 4.60-4.72 (IH ,m ) ; 6.60-6.70 (2H , m ) ; 6.95-7.05 (3H ,m) ; 7.10-7.35 (6H , m ) ; 8.72-8.78 (lH , d ). MS (ES+) m/z 598 (MH+) . MS (ES-) m/z 596 (M-H) \ - 81 - Anal calc'd for C 32 H 37 N 3 O 2 S 2 F 2 ,2.0HC1 C:57.2 ; H:5.8 ; N:6.3 ; S : 9.5 Found C:56.9 ; H:6.2 ; N:6.2 ; S :9.5 . The starting material was prepared as follows: (2S) - N-Methoxy-N-methyl-2-tert-butoxycarbonylamino-4-methysulfanylbutyramide (8.76g ,30.0 mmol ) was treated with 2-fluorobenzyl magnesium chloride (100 mmol solution in THF) using a similar method to the equivalent step in Example 7 to give (3S)-3-tert- butoxycarbonylamino-l-(2-fluorophenyl)-5-methylsulfanylpentan-2-one as a colourless crystalline solid ,10.0g ( 98%). Η NMR (CDC1 3 ) dl.45 ( 9H, s ) ; 1.80-1.92 (IH , m ) ; 2.10-2.28 (IH , m ) ; 2.08 (3H , s ) ; 2.48-2.60 (2H , m) ; 3.80-3.96 (2H , q ) ; 4.48-4.60 (IH , m ) ; 5.18-5.26 (IH ,m ) ; 7.00-7.32 (4H , m ) . MS (ES+) m z 342 (MH+). (3S)-3-tert-Butoxycarbonylamino-l-(2-fluorophenyl)-5-methylsulfanylpentan-2-one (5J0g , 15.0mmol) was deprotected using a similar method to the equivalent step in Example 12, to give (3S)-3-amino-l-(2-fluorophenyl)-5-methylsulfanylpentan-2-one, which was used without further purification assuming quantitative yield. 2-(4-Fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoic acid (3.22g , 4.25mmol ) was coupled with (3S)-3-amino-l-(2- fluorophenyl)-5-methylsulfanylpentan-2-one (estd. 5.32mmol) using a similar method to the equivalent step in Example 7, to give (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-l-(2-fluorophenyl)- 5-methylsulfanylpentan-2-one as a yellow oil (3 J g, 77%). MS (ES+) m/z 940 (MH+) . Example 16b (3SV3-12-(4-Fluorophenethyl)-5-(f2S.4SV4-sulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-f2-fluorophenvO-5-methyIsulfanylpentan-2-ol 82 (3 S)-3-[2-(4-Fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(2-fluorophenyl)-5-methylsulfanylpentan-2-ol (450mg, 0.48mmol) was deprotected using a similar method to the equivalent step in Example 15 to give the title compound (185mg, 55%). 'H NMR (DMSO-D 6 ) d2.00( 3H , s ) ; 2.40-2.62 (4H , m ) ; 2.70-2.88 (4H , m ) ; 2.90-3.10 (IH , m ) ; 3.20-3.80 (7H , m ) ; 3.92-4.02 (IH , m ) ; 6.60 (IH , d ) ; 6.92-7.38 , (HH , m ) . MS (ES+) m/z 600 (MH+) . Anal calc'd for C 32 H 39 N 3 O 2 S 2 F 2 , 3.0HC1 C :54.5 ; H: 6.0 ; N: 6.0 ; S: 9.1 Found C: 54.9 ; H:6.0 ; N: 5.9 ; S: 9.2 . The starting materials was prepared as follows : A solution of (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-l-(2-fluorophenyl)-5- methylsulfanylpentan-2-one (470mg, 0.50mmol) in methanol (25 mL) was treated with sodium borohydride (76.0mg , 2.00mmol ) at 0°C under an inert atmosphere and left to stir for 1 hour. The solvent was evaporated and the residues partitioned between brine (25mL) , 83 and ethyl acetate (4x30mL). The combined organic phases were dried (MgSO 4 ), filtered, and evaporated to give (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-l-(2-fluorophenyl)-5- methylsulfanylpentan-2-ol as a colourless oil (460mg, 98%). MS (ES+) m/z 925 (MH+). Example 17a (2SV2-[2-(4-Fluorophenethyl)-5-f(2S,4S)-4-sulfanylpyrrolidin-2- ylmethyIamino)benzamido1-l-(2-hvdroxyphenvI)-4-methylsulfanylbutan-l-one (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4-fritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(2-hydroxyphenyl)-4-methylsulfanylbutan- 1 -one (220mg, 0.23mmol) was deprotected using a similar method to the equivalent step in Example 15 to give the title compound (150mg, 94%). 'H NMR (DMSO-D 6 ) dl.50-1.70 (IH , m ) ; 2.00 (3H , s ) ; 1.90-2.10 (2H , m ) ; 2.60- 2.80(6H , m) ; 3.00-3.05 (IH , m ) ; 3.20-4.00 (6H , m ) ; 5.56-5.64 (IH , m ) ; 6.30-8.00 (HH, m ). MS (ES+) m/z 582 (MH+) . Anal calc'd for C 31 H 36 N 3 O 3 S 2 F,2.0HC1 ,1.0H2O C:55.4 ; H:5.9 ; N:6.2 ; S : 9.5 . - 84 - Found C:55.4 ; H:5.7 ; N:6.2 ; S : 9.5 . The starting material was prepared as follows: 2-(Trimethylsilyl)ethoxymethyl chloride (13.3g,75mmol) was added to a solution of phenol (4.7g,50mmol) and ethyl di-isopropylamine (11.5gJ00mmol) in dichloromethane (lOOmL) at room temperature under an inert atmosphere. The mixture was stirred for 18 hours, washed successively with a 0.5N aqueous solution of citric acid (2x5 OmL), a saturated aqueous solution of sodium hydrogen carbonate (2x50mL) and water (2x50mL). The organic phase was dried (MgSO 4 ), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica (Merck 9385), eluting with 5% ethyl acetate/iso-hexane gave trimethylsilylethoxymethoxybenzene as a colourless oil (11.16g quantitative). Η NMR (CDC1 3 ) d0.00-0.04(9H,m);0.92-1.00(2H,m);3.72-3.80(2H,m);5.22(2H,s); 6.9- 7.08(3H,m) ;7.22-7.32(2H,m). 1.6M n-Butyl lithium in hexanes (15mL; 24.0mmol) was added to a solution of trimethylsilylethoxymethoxybenzene (5.5g , 25mmol ) in THF (25mL) at room temperature. The mixture was stirred for 2 hours then cooled to -70°C before the addition of (2S)-N- methoxy-N-methyl-2-tert-butoxycarbonylamino-4-methylsulfanylbutyramide ( 1.46g, 5.0mmol ) in THF(25mL) and the solution stirred for a further 2 hours. The mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride (50mL), and extracted with ethyl acetate (4x50 ml). The combined organic phases were washed with brine (2x50 ml), dried (MgSO 4 ), filtered and evaporated. The product was purified by flash chromatography on silica (Merck 9385), eluting with 10% ethyl acetate/ iso-hexane to give (2S)-2-tert-butoxycarbonylamino-l-[2-(trimethylsilylethoxymethoxy)phenyl]-4- methylsulfanylbutan-1-one as a colourless oil (1.20g, 53%). MS (ES+) m/z 456 (MH+) . (2S)-2-tert-Butoxycarbonylamino- 1 - [2-(trimethylsilylethoxymethoxy)phenyl]-4- methylsulfanylbutan-1-one (1.20g, 2.64mmol) was deprotected using a similar method to the equivalent step in Example 12 to give (2S)-2-amino-l-[2-hydroxyphenyl]-4- - 85 methylsulfanylbutan-1-one as an orange solid (l.OOg) which was used directly without further purification. 2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoic acid (1.43g, 2.00mmol) was coupled with (2S)-2-amino-l-[2- hydroxyphenyl]-4-methylsulfanylbutan-l-one (l.OOg estd. 2.64mmol) using a similar method to the equivalent step in Example 7 to give (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido] - 1 -(2- hydroxyphenyl)-4-methylsulfanylbutan-l-one as a yellow oil. (lJOg , 59%). MS (ES+) m/z 924 (MH+). Example 17b r2SV2-12-(4-Fluorophenethvn-5-rr2S.4SV4-sulfanylpyrrolidin-2- ylmethylamino)benzamidol-l-(2-hvdroxyphenyl)-4-methylsulfanylbutan-l-ol (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4-fritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(2-hydroxyphenyl)-4-methylsulfanylbutan-l-ol (800mg, 0.86mmol), was deprotected using a similar method to the equivalent step in Example 15 to give the title compound as a white solid (500mg, 82%). 86 MS (ES+) m/z 584 (MH+) Anal calc'd for C 31 H 38 N 3 O 3 S 2 F ,3.5HC1 C: 52.4 ; H:5.9 ; N:5.9 ; S: 9.0 . Found C:52.4 ; H: 5.9 ; N: 5.8; S: 8.7 . The starting material was prepared as follows : (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(2-hydroxyphenyl)-4-methylsulfanylbutan- 1 -one (840 mg, 0.90mmol), was reduced using a similar method to the equivalent step in Example 16 to give (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(2-hydroxyphenyl)-4-methylsulfanylbutan- 1 -ol as a pale yellow foam (800mg, 96%). MS (ES+) m/z 926 (MH+) . Example 18a (2S)-2-I2-(4-Fluorophenethvn-5-rr2S.4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(pyridin-2-yl)-4-methylsulfanylbutan-l-one (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-fritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(pyridin-2-yl)-4-methylsulfanylbutan-l-one (454mg, 0.5mmol) - 87 - was deprotected using a similar method to the equivalent step in Example 15 to give the title compound (285mg, 73%). Η NMR (DMSO-D 6 ) dl.90-2.28 (2H , m ) ; 2.04 (3H , s ) ; 2.50-2.85 (6H , m ) ; 3.00-3J0 (IH , m ) ; 3.20-4.05 (7H , m ) ; 5.85-5.95 (IH , dd ) ; 6.68-6.78 (2H , m) ; 6.95- 7.05 (3H , m ) ; 7J2-7.20 (2H , m ) ; 7.64-7.72 (IH , m ) ; 7.96-8.08 (IH , m ) ; 8.72-8.78 (lH, d ) . MS (ES+) m/z 566 (MH+) . Anal calc'd for C 30 H 35 N 4 O 2 S 2 F,3.0HC1,2.0H2O C: 50.6 ; H:5.6 ; N:7.8 ; S:9.0 . Found C: 50.7 ; H:5.6 ; N:7.8 ; S:8.8 . The starting material was prepared as follows: A solution of 2-bromopyridine(4.9mL, 50mmol) in THF(50mL) was cooled to -70°C under an inert atmosphere. 1.6M n-Butyl lithium in hexanes(3 lmL, 50mmol) was added and the mixture left to stir 30 minutes. (2S) - N-Methoxy-N- methyl-2-tert-butoxycarbonylamino-4- methanesulphanylbutyramide (2.92g, lO.Ommol) in THF (lOmL) was added and the mixture stirred for 1 hour. The reaction was quenched with a saturated aqueous solution of ammonium chloride (lOOmL) and extracted into ethyl acetate (4x50mL). The combined organic phases were washed with brine (2x50 mL), dried (MgSO 4 ), filtered and evaporated. The product was purified on silica (Merck 9385), eluting with 20% ethyl acetate / iso-hexane to give (2S)-2- tert-butoxycarbonylamino- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -one as a yellow oil (2.80 g, 90%). Η NMR (CDC1 3 ) dl.46(9H , s ) ;1.80-2.00 (IH , m ) 2.08(3H,s) ;2.25-2.40 (IH ,m) ; 2.52- 2.72 (2H,m) ;5.46-5.60 (IH ,bd) ;5.70-5.82 (IH ,bm) ;7.46-7.52 (IH , dd ) ; 7.80-7.90 ,(1H , t ) ; 8.04-8J0 , (IH , d ) ; 8.68-8.72 , (IH , d ) . MS (ES+) m/z 311 (MH+). MS (ES-) m/z 309 (M-H) " . (2S)-2-tert-Butoxycarbonylamino- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -one (2.7g, 8.7mmol), was deprotected using a similar method to the equivalent step in Example 12, to 88 give (2S)-2-amino-l-(pyridin-2-yl)-4-methylsulfanylbutan-l-one as a red oil which was used without further purification assuming quantitative yield. 'H NMR (DMSO-D 6 ) d 1.95 (3H , s ) ; 2.00-2.25 (2H , m ) ; 2.52-2.66 (2H , m ) ; 5.36 (IH , broad s ) ; 7.70-7.82 (IH , m ) ; 8.05-8.13 (2H , d ) ; 8.75-8.80 (IH , d ). MS (ES+) m/z 211 (MH+) . 2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoic acid (4.30g , 6.00mmol), was coupled with (2S)-2-amino-l-(pyridin- 2-yl)-4-methylsulfanylbutan-l-one (4Jg , estd. 8.7mmol) using a similar method to the equivalent step in Example 7, to give (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-l-(pyridin-2-yl)-4- methylsulfanylbutan-1-one as a pale yellow foam (2.3g, 42%). MS (ES+) m/z 909 (MH+) . Example 18b (2SV2-r2-(4-Fluorophenethvn-5-((2S.4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamido1-l-(pyridin-2-yl)-4-methvIsuIfanylbutan-l-oI - 89 (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -ol (450mg, 0.5mmol), was deprotected using a similar method to the equivalent step in Example 15 to give the title compound as a white solid (250mg, 73%). MS (ES+) m/z 569 (MH+) ; Anal calc'd for C 30 H 37 N 4 O 2 S 2 F, 3.0HC1 ,0.5H2O C:52.5 ; H:6.0 ; N:8J ; S:9.3 . Found C:52.7 ; H:6.5 ; N:8J ; S:9.3 . The starting material was prepared as follows : (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -one (454mg, 0.5mmol) was reduced using a similar method to the equivalent step in Example 16 to give (2S)-2-[2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(pyridin-2-yl)-4-methylsulfanylbutan-l-ol (450mg, 99%). MS (ES+) m z 911 (MH+) . Example 19 (3S)-3-12-(4-FluorophenethvIV5-f(2S.4SV4-sulfanylpyrroIidin-2- ylmethylamino)benzamido]-l-(pyridin-2-v0-5-methylsulfanylpentan-2-ol - 90 - (3S)-3-[2-(4-Fluoroρhenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-fritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l -(pyridin-2-yl)-5-methylsulfanylpentan-2-ol (430mg, 0.47mmol) was deprotected using a similar method to the equivalent step in Example 15 to give the title compound as a white solid (270mg, 79%). Η NMR (DMSO-D 6 ) d2.00 (3H , s) ; 2.40-2.64 (4H , m ) ; 2.70-2.92 (4H , m ) ; 3.00-3.10 (IH, m ) ; 3.20-4.30 (6H , m ) ; 6.60-7.20 (7H , m ) ; 7.88-7.94 (IH , t ) ; 7.96-8.00 (IH , d ) ; 8.48-8.56 (lH , t ) ; 8.80 (lH , d ). MS (ES+) m/z 583 (MH+) . Anal calc'd for C 31 H 39 N 4 O 2 S 2 F,4.0HC1 C:51.2 ; H:5.9 ; N:7.8 ; S:8.8 . Found C:51.6 ; H:6.0 ; N:7.6 ; S:8.8 . The starting material was prepared as follows: A solution of 2-picoline (4.65g, 50mmol) in THF (30mL ) was cooled to -20°C under an inert atmosphere, 1.6M n-butyl lithium in hexane (31.0mL, 50mmol ) was added dropwise and the mixture left to stir for 30 minutes. The reaction mixture was cooled to -70°C and to it added (2S) -N-methoxy-N-methyl-2-tert-butoxycarbonylamino-4-methylsulfanylbutyramide (2.92g , lO.Ommol ), in THF (50mL). After stirring for 2hours, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (lOOmL) and extracted with ethyl acetate (4x50mL). The combined organic phases were washed with brine (2x75mL), dried (MgSO 4 ), filtered and evaporated to give a yellow oil. Purification by flash chromatography on silica (Merck 9385), eluting with 50% ethyl acetate/ iso-hexane. gave (3S)-3-tert- butoxycarbonylamino-l-(pyridin-2-yl)-5-methylsulfanylpentan-2-one as a yellow oil (2.47g, 76%). Η NMR (CDC1 3 ) dl.45(9H , s ) ; 1.80-2.00 (IH , m ) ; 2.08-2.12 (3H , d ) ; 2.15-2.30 (IH , m ) ; 2.46-2.60 (2H , m ) ; 3.96-4.04 (IH , m ) ; 4.26-4.60 (IH , m ) ; 5.20- 5.54 (IH , m ) ; 6.86-6.96 (IH , m ) ; 7.04-7.24 (IH ,m ) ; 7.50-7.70 (IH , m ) ; 8.03-8.60 (IH, m ) . MS (ES+) m/z 325 (MH+) . (3S)-3-tert-Butoxycarbonylamino-l-(pyridin-2-yl)-5-methylsulfanylpentan-2-one (2.40g , 7.6mmol ) was deprotected using a similar method to the equivalent step in Example 12 to - 91 - give (3S)-3-amino-l-(pyridin-2-yl)-5-methylsulfanylpentan-2-one as a yellow oil. It was used without further purification assuming quantitative yield. MS (ES+) m/z 225 (MH+). 2-(4-Fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoic acid (4.30g, 6.00mmol), was coupled with (3 S)-3 -amino- l-(pyridin- 2-yl)-5-methylsulfanylpentan-2-one (4.3g, estd. 7.6mmol) using a similar method to the equivalent step in Example 7, to give (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-l-(pyridin-2-yl)-5- methylsulfanylpentan-2-one as a pale yellow foam (2.7g, 49%). MS (ES+) m/z 923 (MH+) . (3S)-3-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(pyridin-2-yl)-5-methylsulfanylpentan-2-one (461mg, 0.5mmol) was reduced using a similar method to the equivalent step in Example 16 to give (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-5-methylsulfanylpentan-2-ol, (440mg, 94%). MS (ES+) m/z 925 (MH+) . Example 20 (3S)-3-[2-(4-Fluorophenethyl)-5-((2S.4SV4-sulfanylpyrrolidin-2-ylmethoxy)benzamido1- 5-methylsulfanylpentan-2-one 92 (3S)-3-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzamido]-5-methylsulfanylpentan-2-one (1.03g,1.2mmol) was deprotected using a similar method to Example 7 to give the title compound as a white powder (546mg, 82%). 'H NMR (DMSO-D 6 ,300MHz) dl.5-1.9(2H,m);1.9-2J(4H,m);2J5(3H,s); 2.4-2.65(2H+DMSO,m);2.65-2.8(2H,m);2.8-2.95(2H,m);3.05(lH,bs); 3.2-3.6(5H+H 2 O,m);3.9(lH,bs);4.2-4.35(2H,m);4.4-4.6(lH,m);6.9-7.3(7H,m); 8.75(lH,d,NHCO),9.4-10.0(2H,bd,NH.HCl). MS (ES+) m/z 505 (M+H) + Anal Calcd for C 26 H 33 N 2 S 2 O 3 F,lHCl ,0.5H 2 O C,56.94;H,6.29;N,5J 1 Found C,56.7;H,5.9;N,4.8 The starting material was prepared as follows: (2S)-N-Methoxy-N-methyl-2-tert-butoxycarbonylamino-4-methylsulfanylbutyramide (8.2g, 28.0mmol) was treated with a solution of 3M methylmagnesium bromide in diethyl ether (28.0 mL, 84.0 mmol) using a similar method to the equivalent step in Example 7 to give (3S)-3-tert-butoxycarbonylamino-5-methylsulfanylpentan-2-one, (6.2g, 89%). MS (ES+) m/z 248 (M+H) + J92,148. - 93 - (3S)-3-tert-Butoxycarbonylamino-5-methylsulfanylpentan-2-one (3.0g, 12Jmmol) was deprotected using a similar method to the equivalent step in Example 7 to give (3S)-3-amino- 5-methylsulfanylpentan-2-one which was used assuming quantitative yield. MS (ES+) m/z 148(M+H) + J31. 2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzoic acid (1.43g, 2mmol) was coupled with (3S)-3-amino-5- methylsulfanylpentan-2-one (estd. όmmol), using a similar method to the equivalent step in Example 7 to give (3 S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethoxy)benzamido]-5-methylsulfanylpentan-2-one as a white foam, ((lJg, 65%). MS (ES+) m/z 848 (M+H) + Example 21 (4S)-4-[2-(4-Fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamidol- 6-methyIsulfanyl-l-(pyridin-3-yl)hex-l-en-3-one - 94 - (4S)-4-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzamido]-6-methylsulfanyl-l-(pyridin-3-yl)hex-l-en-3-one (300mg,0.32mmol) was deprotected using a similar method to Example 7 to give the title compound as a white powder (150mg, 65%). Η NMR (DMSO-D 6 +CD 3 COOD,300MHz) dl .5-2.2(6H+CH 3 COOH,m); 2.3-2.7(2H+DMSO,m);2.7-2.8(2H,m);2.8-2.95(2H,m);2.95-3J(lH,m); 3.2-4J(4H,m);4J-4.4(2H,m);4.8-5.0(lH,m)6.8-7.2(7H,m);7.4(lH,d); 7.6-7.8(2H,m);8.35-8.5(lH,m);8.6-8.8(lH,m);8.9-9J(lH,m). MS (ES+) m/z 594 (M+H) + Anal Calcd for C 32 H 36 N 3 S 2 O 3 F,3.5HCl C,53.27;H,5.52;N,5.83;S,8.89 Found C,53.6;H,5.3;N,5.5;S,8.6 The starting material was prepared as follows: (3 S)-N-tert-Butoxy carbonyl- 1 -methylsulfanyl-4-oxo-6-(pyrid-3 -yl)hex-5 -en-3 -amine was deprotected using a similar method to the equivalent step in Example 7 to give l-amino-6- methylsulfanyl-l-(pyrid-3-yl)hex-l-en-3-one wliich was used without further characterisation assuming quantitative yield. 2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzoic acid (1.44g, 2mmol) was coupled with l-amino-6-methylsulfanyl-l- (pyrid-3-yl)hex-l-en-3-one (estd 4.5mmol), using a similar method to the equivalent step in Example 7 to give (4S)-4-[2-(4-fluoroρhenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethoxy)benzamido]-6-methylsulfanyl-l-(pyridin-3-yl)hex-l-en- 3-one as a colourless gum (353mg, 18.9%). MS (ES+) m/z 936 (M+H) + ,243. Example 22a f2S 2-f2-(4-Fluorophenethvn-5-(r2S-4SV4-sulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(thiazol-2-yl)-4-methylsulfanylbutan-l-oI 95 (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4-fritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(thiazol-2-yl)-4-methylsulfanylbutan-l-ol (350mg, 0.38mmol) was deprotected using a similar method to Example 7 to give the title compound as a white powder (230mg,85%). Η NMR (DMSO-D 6 +CD 3 COOD,300MHz) dl.5-2J(7H+H2O,m); 2J-2.9(7H+DMSO,m);2.9-3.9(5H,m);4.4-4.6(lH,m);4.9-5.2(lH,m)6.6-6.8(2H,m); 6.9- 7.05(3H,m);7.05-7.2(2H,m);8.6(lH,m);8.8(lH,m). MS (ES+) m/z 575 (M+H) + MS (ES-) m/z 573 (M-) ' Anal Calcd for C 28 H 35 N 4 S 3 O 2 F,3.7HCl C,47.38;H,5.5;N,7.9;S,13.55 Found C,47.4;H,5.8;N,7.8;SJ3.5 HPLC:Waters S5 ODS2;lMl/min;1254nM;80%methanol/H 2 O(0J%TFA) RT@5Jmin (99%) The starting material was prepared as follows: (2S)-N-Methoxy-N-methyl-2-tert-butoxycarbonylamino-4-methylsulfanylbutyramide ( 1 Og, 34.25mmol) was deprotected using a similar method to the equivalent step in Example 7 to give (2S)-N-methoxy-N-methyl-2-amino-4-methylsulfanylbutyramide which was used assuming quantitative yield. ! H NMR (CDCl 3 ,300MHz) d2J(3H,s);2J-2.3(2H,m);2.55-2.75(2H,m); 3.25(3H,s); 3.75(3H,s); 4.55(lH,m);8J(3H,bs). - 96 - 2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzoic acid (10g,14mmol) was coupled with (2S)-N-methoxy-N-methyl-2- amino-4-methylsulfanylbutyramide (estd. 34mmol), using a similar method to equivalent step in Example 7 to give (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-N-methoxy-N-methyl-4- methylsulfanylbutyramide as a white crystalline solid (9.87g, 79.6%). MS (ES+) m/z 891 (M+H) + ,243. 1.6M n-Butyl lithium in hexanes (6.3mLJ0Jmmol) was added dropwise to a stirred solution of thiazole (800mL,l 1.3mmol) and TMEDA (1.5mL, 9.96mmol) in THF (lOOmL) at -70°C under an inert atmosphere. The internal temperature was allowed to warm to -50°C over 30 minutes and the solution was re-cooled to -70°C. A solution of (2S)-2-[2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- y lmethylamino)benzamido] -N-methoxy-N-methy 1-4-methylsulfanylbutyramide (1.0g,lJ2mmol) in THF (lOmL) was added dropwise at such a rate so as to maintain the temperature below -65 °C. The mixture was quenched with a saturated aqueous solution of ammonium chloride (lOOmL), extracted with ethyl acetate (lOOmL), and the combined organic phases washed with brine (50mL), filtered through phase separator paper and evaporated to give a yellow gum. Purification by flash chromatography on silica (Merck 9385) and elution with a gradient 0-100% ethyl acetate/i-hexane gave (2S)-2-[2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-(thiazol-2-yl)-4-methylsulfanylbutan-l-one as a white foam (950mg, 92.5%). MS (ES+) m/z 915 (M+H) + . Example 22b 2-[2-(4-FluorophenethylV5-((2S.4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamidol- l-(thiazol-2-vD-4-methylsulfanylbutan-l-one - 97 (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4-fritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(thiazol-2-yl)-4-methylsulfanylbutan- 1 -one (400mg, 0.44mmol) was deprotected using a similar method to Example 7 to give the title compound as a white powder (186mg, 63.4%). Η NMR (DMSO-D 6 +CD 3 COOD,300MHZ) dl.5-1.8(lH,m);1.9-2J(5H,m); 2J-2.3(lH,m);2.4-3.9(6H+DMSO,m);3.0-3J(lH,m);3.2-4J(5H,m);5.65(lH,m); 6.6-6.8(2H,m);6.9-7.05(3H,m);7.05-7.2(2H,m);8J 5(2H,s). MS (ES+) m/z 573 (M+H) + Anal Calcd for C 28 H 33 N 4 S 3 O 2 F,2.7HCl C,50J;H,5.36;N,8.35;S,14.33 Found C,50J;H,5.6;N,8.3;SJ4.4 HPLC:Waters S5 ODS2;lMl/min;1254nM;80%methanol/H 2 O(0J%TFA) RT@5.7min (98%) The starting material was prepared as follows : (2S)-2-[2-(4-Fluorophenethyl)-5-((2S,4S)- 1 Jert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]- 1 -(thiazol-2-yl)-4-methylsulfanylbutan- 1 -one (400mg, 44mmol) was reduced with sodium borohydride using a similar method to the equivalent step in Example 16 to give (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulf- ylpyιτolidin-2-ylmethylamino)benzamido]-l-(thiazol-2-yl)-4-methylsulfanylbutan- l-ol as a colourless gum (360mg, 90%). MS (ES+) m/z 917 (M+H) + 98 Example 23 2-f2-(4-Fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrroIidin-2-ylmethylamino)benzamido1- 3-hydroxypropan-l-ol 2-[2-(4-Fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-3-hydroxypropan-l-ol (690mg,0.87mmol) was deprotected using a similar method to Example 7 to give the title compound as a white powder (354mg, 67.5%). 1 H NMR (DMSO-D 6 +CD 3 COOD,300MHz) dl.5-1.8(lH,m);1.9-2J(5H,m); 2J-2.3(lH,m);2.4-3.9(6H+DMSO,m);3.0-3J(lH,m);3.2-4J(5H,m);5.65(lH,m); 6.6-6.8(2H,m);6.9-7.05(3H,m);7.05-7.2(2H,m);8J5(2H,s). MS (ES+) m/z 448 (M+H) + Anal Calcd for C^o^SO j F^.OHC^O TFA C,48.82;H,5.49;N,7.0;S,5.34 Found C,48.9;H,5.8;N,7J;S,5.5 HPLC:Waters S5 ODS2;lMl/min;1254nM;80%methanol/H 2 O(0J%TFA) RT@3.56min (99%) The starting material was prepared as follows: Pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tertbutoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (lg,lJ3mmol) was coupled with serinol 99 (210mg, 2.3mmol) using a similar method to the equivalent step in Example 8 to give 2-[2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-3-hydroxypropan-l-ol as a white foam (725mg, 81%). MS (ES+) m/z 790 (M+H) + ,243. Example 24 f3SV3-[2-f4-FluorophenethylV5-(f2S.4SV4-sulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-acetyloxybutan-2-one (3S)-3-[2-(4-Fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4-fritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-l-acetyloxybutan-2-one (lOOmg, 0J2mmol) was deprotected using a similar method to Example 7 to give the title compound as a white powder (25.2mg, 35.9%). Η NMR (DMSO-D 6 +CD 3 COOD,300MHZ) dl.25(3H,d);1.5-1.8(lH,m); 2.05(3H,s);2.3- 2.6(lH+DMSO,m);2.6-2.9(4H,m);2.95-3J(lH,m);3.2-4.(5H,m); 4.4-4.65(lH,m);4.95(2H,s)6.5-6.7(2H,m);6.9-7J(3H,m);7J-7.2(2H,m). MS (ES+) m z 502 (M+H) + Anal Calcd for C 26 H 32 N 3 SO 4 F,2.5HCl C,52.68;H,5.87;N,7.03 Found C,52.9;H,6J;N,7.3 HPLC:Waters S5 ODS2;lMl min;1254nM;90%methanol/H 2 O(0J%TFA) RT@3.0min (97%) - 100 - The starting material was prepared as follows: A solution of tetrabutylammonium acetate (1.9g, 6.3mmol) and tert-butyl [( lS)-3 -chloro- 1 - methyl-2-oxopropyl] carbamate (RN93371-30-3, 1.0g,4.5mmol) in acetone (75mL) was stirred at room temperature under an inert atmosphere for 2 hours. The mixture was evaporated to dryness and partitioned between ethyl acetate (lOOmL) and water (lOOmL). The organic phases were washed with water (3xl00mL) and brine (50mL), dried and evaporated to give an orange gum. Trituration with diethyl ether gave (3S)-3-[(tert-butoxycarbonyl)amino]-2-oxo- butyl acetate as a white powder which was filtered and dried (334mg, 30.2%). 'H NMR (CDCl 3 ,300MHz) dl.35(3H,d);1.42(9H,s);2J8(3H,s);4.3-4.5(lH,m); 4.8(2H,q AB );4.95-5.2(lH,m). MS (ES+) m/z 246 (M+H) + J90J46. 4.0M HCl in dioxane (lOmL, 40mmol) was added to a solution of (3S)-3-[(tert- butoxycarbonyl)amino]-2-oxo-butyl acetate (325mg, 1.32mmol) in THF (lmL) and the resulting solution left to stir for 2 hours at room temperature under an inert atmosphere. The mixture was evaporated to dryness and treated with diethyl ether (50mL) to give a white solid. Washing by decantation gave (1 S)-3 -acetyloxy- l-methyl-2-oxopropylamine as a hygroscopic white powder which was used assuming quantitative yield. MS (ES+) m z 146 (M+H) + . Pentafluorophenyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tertbutoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (lJ7g,1.32mmol) was coupled with (1S)- 3 -acetyloxy- l-methyl-2-oxopropylamine (estd. 1.32mmol) using a similar method to the equivalent step in Example 8 to give (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido] - 1 -acetyloxybutan-2- one as a colourless gum (132mg, 12%) which was used without further characterisation. Example 25 - 101 (3S)-3-[2-(4-Fluorophenethyπ-5-f(2S.4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamidol- 1 -(triazol-1 -y Dbutan-2-one CHIRAL S ! i\ 0 XX (3S)-3-[2-(4-Fluorophenethyl)-5-((2S,4S)-lJert-butoxycarbonyl-4Jritylsulfanylpyrrolidin-2- ylmethoxy)benzamido]-l-(tirazol-l-yl)butan-2-one (50.6mg, O.Oόmmol) was deprotected using a similar method to Example 7 to give the title compound as a white powder (28mg, 0 ). Η NMR (DMSO-D 6 +CD 3 COOD,300MHz) dl.35(3H,d);1.6-1.8(lH,m); 2.4-2.65(lH+DMSO,m);2.65-3.0(4H,m);3.0-3J5(lH,m);3.2-3.7(2H,m); 3.8-4J(lH,m)4J-4.4(2H,m);4.5-4.7(lH,m);5.45(2H,s);6.8-7.25(7H,m); 8.05(lH,s);8.55(lH,s). MS (ES+) m/z 512 (M+H) + Anal Calcd for C 26 H 30 N 5 SO 3 F,3HC1 C,50.28;H,5.36;N,11.28;S,5J6 Found C,50.4;H,5.8;N,11.4;S,5J HPLC:Waters S5 ODS2;lMl/min;1254nM;80%methanol/H 2 O(0J%TFA) RT@3.85min (95%) The starting material was prepared as follows: Sodium borohydride (2.3g,62.5mmol) was added portionwise to a stirred solution of (2S,4S)- 1 -tert-butoxycarbony 1-4-trity lsulfanylpyrrolidin-2-y lcarboxaldehyde ( 19.7g,41. όmmol) in - 102 - methanol (300mL) at room temperature under an inert atmosphere. The mixture was stirred for 20 minutes and evaporated to dryness. The residues were partitioned between water (75mL) and ethyl acetate (4x75mL) and the combined organic extracts were washed with water (2x75mL), brine (2x75mL), dried (MgSO 4 ), filtered and evaporated to give 2-[(2S,4S)- l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-yl] ethanol as a white foam (19.7g, 100%). MS (ES+) m/z 476 (M+H) + . A solution of DEAD (6.3mL,40mmol) in dichloromethane (50mL) was added dropwise to a stirred, cooled solution of 2-[(2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- yl]ethanol (19.0g, 40mmol), methyl 2-(4-fluorophenethyl)-5-hydroxybenzoate (lO.Og, 36.5mmol) and triphenylphosphine(10.5g,40mmol) in dichloromethane (200mL) containing powdered 4Ϊ molecular sieves (@10g) at such a rate as the internal temperature remained below 5°C. The mixture was stirred and allowed to warm to room temperature over 18 hours. The reaction was filtered through Celite (545) and evaporated to small volume. The product was purified by flash chromatography on silica (Merck 9385), eluting with a gradient of 0-20% ethyl acetate/i-hexane. Appropriate fractions were combined and evaporated to give methyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzoate as a white foam (19.15, 71.8%). MS (ES+) m/z 732 (M+H) + . Methyl 2-(4-fluorophenethyl)-5-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzoate (19Jg, 26Jmmol) was hydrolysed using a similar method to the equivalent step in Example 6 to give 2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl- 4-tritylsulfanylpyrrolidin-2-ylmethoxy)benzoic acid as a white foam (18.6g, 99%). MS (ES-) m z 716 (M-H) " . Iso-butylchloroformate (200mL,1.54mmol) was added dropwise to a stirred solution of 2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzoic acid (lJg,1.53mmol) and NMM (170mLJ.55mmol) in THF(20mL) at - 103 - -20°C. The mixture was stirred for 15 minutes cooled to -20°C and a solution of triethylamine (215mL, 1.55mmol) in THF (20mL) was added in one portion, followed by a cooled (-20°C) solution of 3-amino-l-chloro-2-butanone hydrochloride (RN36076-65- 0,250mg,1.55mmol) in DMF(lOmL), also in one portion. The reaction was left to warm to room temperature over 2 hours then quenched with a saturated aqueous solution of sodium hydrogen carbonate (250mL) and extracted with ethyl acetate (2xl00mL). The combined organic extracts were washed with water (4x5 OmL) and brine (5 OmL), dried and evaporated to give an orange gum. The product was purified by flash chromatography on silica (Merck 9385), eluting with a gradient of 0-50% ethyl acetate/i-hexane. Appropriate fractions were combined and evaporated to give (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethoxy)benzamido]- 1 -chlorobutan-2-one as a colourless gum (156mg, 12.4%). MS (ES+) m/z 821 (M+H) + ,243. Sodium 1,2,4-triazole, (35mg,0.38mmol) was added to a stirred solution of (3S)-3-[2-(4- fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)benzamido]-l-chlorobutan-2-one (150mg, 0J8mmol) in CH 3 CN (25mL) and the mixture stirred at room temperature under an inert atmosphere for 18 hours. The reaction was evaporated and the residues purified by flash chromatography on silica (Merck 9385), eluting with a gradient of 0-50% ethyl acetate/i-hexane. Appropriate fractions were combined and evaporated to give (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethoxy)benzamido]-l-(tirazol-l-yl)butan-2-one as a colourless glass (75.6mg, 48.5%). MS (ES+) m/z 854 (M+H) + . Example 26 (3S)-3-[2-rThiazol-2-vn-4-((2S.4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamidol-5- methylsulfanyl-l-(phenvI)pentan-2-one 104 - CHIRAL S \ ζ y y N ^ ? /\ S °y > (3S)-3-[2-(Thiazol-2-yl)-4-((2S,4S)-l-tert-butoxycarbonyl-4Jritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-5-methylsulfanyl-l-(phenyl)pentan-2-one (300 mg, 0.34 mmol) was deprotected using similar methodology to that described in Example 6 to give the title compound as a yellow powder (158 mg, 74%). Η NMR (DMSO-D 6 +CD 3 COOD,300MHz) dl.55-1.7(lH,m); 1.7-1.85(lH+CHD 2 COOD,m); 1.85-2.0(lH,m); 1.95(3H,s);2.3-2.6(2H+DMSO,m); 3.05(0.5H,dd);3.2-3.3(0.5H,m);3.4-3.6(4H,m); 3.7-3.8(2H,m);3.9(2H,s); 4.4(lH,dd);6.75(lH,dd); 6.9(lH,d);7J(2H,d);7J5-7.3(3H,m);7.35(lH,dd); 7.75(2H,dd). MS (ES+) m/z 541 (M+H) + Anal Calcd for C 27 H 32 N 4 O 2 S 3 2.3HC1 C,51.9;H,5.5;N,9.0;S,15.4 Found C,51.9;H,5.8;N,8.8;SJ5.3 The starting material was prepared as follows: n-Butyl lithium (39.4 ml, 0.39 mol; 10M solution in hexane) was added dropwise to a stirred solution of 2-bromothiazole (32 ml, 0.36 mol) in dry diethyl ether (350 ml) under nitrogen at -78°C maintaining the temperature below -65°C. The solution was stirred for 1 hour at -70°C and tributyltin chloride (97 ml, 0.36 mol) as a solution in diethyl ether (150 ml) was added. After stirring for 3.5 hours at -78°C, the reaction was allowed to warm to room temperature - 105 - and water (200 ml) added. The organic phase was separated and the aqueous phase re- extracted (x3) with diethyl ether. The combined ethereal extracts were dried (MgSO 4 ) and concentrated in vacuo to give a dark red oil. Fractional distillation under reduced pressure gave 2-(tri-n-butyltin)thiazole as a colourless oil (113g, 84%). Bpt. 295°C [102°C @ 0.5 mmHg] Η NMR (CDCl 3 ,300MHz) d0.9(9H,t); 1.2- 1.25(6H,m); 1.3-1.4(6H,m); 1.55-1.6(6H,m); 7.55(lH,d);8J(lH,d). bis-(Triphenylphosphine)palladium(II) chloride (2.6 g, 3.7 mmol) was added to a solution of methyl 2-bromo-4-nifrobenzoate (19.3 g, 74.3 mmol) and 2-(tri-n-butylstannyl)thiazole (30.6 g, 81.7 mmol) in dry, degassed THF (300 ml) under nitrogen and the solution heated at reflux for 18 hours. The reaction was cooled to room temperature and partitioned between a saturated aqueous solution of sodium hydrogen carbonate (150 ml) and ethyl acetate (300 ml). The organic phase was separated, washed with brine, filtered through phase separation filter paper and concentrated in vacuo to give a brown oil which, on trituration with iso-hexane, gave methyl 4-nitro-2-(thiazol-2-yl)benzoate as an off-white solid which was collected by filtration (19.2g, 98%). Η NMR (CDCl 3 ,300MHz) d3.85(3H,s);7.5(lH,d);7.85(lH,d); 7.9(lH,d);8.3(lH,dd);8.6(lH,d). MS (ES+) m/z 265 (M+H) + 10% Pd/C (5 g) was added to a solution of methyl 4-nifro-2-(thiazol-2-yl)benzoate (19.2 g, 72.7 mmol) in degassed ethyl acetate (800 ml) and 10% Pd/C (5 g) and the reaction stirred vigorously for 8 hours under a hydrogen atmosphere. The used catalysed was removed by filtration and fresh catalyst added to the reaction which was stirred under hydrogen for 16 hours. This process of refreshing the catalyst was repeated until the reaction was considered complete as determined by HPLC analysis. Removal of the catalyst and concentration of the filtrate in vacuo gave a yellow solid which on trituration with diethyl ether gave methyl 4-amino-2-(thiazol-2-yl)benzoate as a pale yellow powder (10.3 g, 61%). - 106 - 'H NMR (CDCl 3 ,300MHz) d3.6(3H,s);4J(2H,br s);6.7(lH,dd);6.8(lH,d); 7.4(lH,d);7.75(lH,d);7.85(lH,d). MS (ES+) m/z 235 (M+H) + The coupling of methyl 4-amino-2-(thiazol-2-yl)benzoate (5.0 g, 21.4 mmol) and (2S,4S)-1- tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylcarboxaldehyde (11.1 g, 23.5 mmol) was carried out using a similar method to the equivalent step in Example 6. Purification by flash chromatography (ethyl acetate: iso-hexane/ 1 :4->l : I) gave methyl 2-(thiazol-2-yl)-4-((2S,4S)- l-tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate as an off-white foam (7.03 g) and recovered methyl 4-amino-2-(thiazol-2-yl)benzoate (1.55 g). The yield (based on recovered starting material) was 69%. MS (ES+) m/z 235 (M+H) + Hydrolysis of methyl 2-(thiazol-2-yl)-4-((2S,4S)- 1 -tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethylamino)benzoate (7.0 g, 10J mmol) was achieved using similar methodology as for the equivalent step described in Example 6 to give 2-(thiazol-2- yl)-4-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzoic acid which was isolated as a yellow foam (6.8 g, quantitative). Η NMR (DMSO-D 6 ,300MHz) dl.25(9H,s);1.6-1.75(lH,m);2.35-2.45(2H,m); 2.6-2.7(2H,m);3.0-3.2(lH,br m);3.3-3.4(lH,m);3.65-3.75(lH,m);6.6-6.7(3H,m); 7J5-7.25(15H,m);7.6(lH,br d);7.7(lH,d);7.8(lH,d). MS (ES+) m/z 678 (M+H) + The coupling of 2-(thiazol-2-yl)-4-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin- 2-ylmethylamino)benzoic acid (3.5 g, 5.0 mmol) with (3S)-5-methylsulfanyl-2-oxo-l- phenylpentan-3 -amine (1.7 g, 7.8 mmol estd.) was carried out using a similar method to the analogous step in Example 7, followed by purification by flash chromatography (ethyl acetate:iso-hexane/l:2→l:l) to give (3S)-3-[2-(thiazol-2-yl)-4-((2S,4S)-l-tert- butoxy carbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido] -5 -methylsulfanyl- 1 - (phenyl)pentan-2-one as a yellow oil (2.1 g, 46%). 107 MS (ES+) m z 883 (M+H) + Example 27 r2SV2-12-(Thiazol-2-vn-4-(r2S.4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamidol-4- methylsulfanylbutan- 1 -ol (2S)-2-[2-(Thiazol-2-yl)-4-((2S,4S)-lJert-butoxycarbonyl-4-fritylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-4-methylsulfanylbutan-l-ol (500 mg, 0.63 mmol) was deprotected using the similar methodology to the equivalent step described in Example 6 to give the title compound as a yellow powder (277 mg, 77%). Η NMR (DMSO-D 6 +CD 3 COOD,300MHz) dl.55-1.7(2H,m); 1.7-1.85(lH+CHD 2 COOD,m);2.0(3H,s);2.3-2.6(2H+DMSO,m);3.05(0.5H,dd); 3.15-3.3(1.5H,m);3.35-3.6(5H,m); 3.65-3.85(2H,m);6.75(lH,dd); 6.9(lH,d); 7.3(lH,d); 7.75(lH,d);7.85(lH,dd). MS (ES+) m z 453 (M+H) + Anal Calcd for C 27 H 32 N 4 O 2 S 3 2HC1 0.4TFA C,43.7;H,5.4;N,9.8;S,16.8 Found C,43.8;H,5.8;N,9.7;SJ6.6 The starting material was prepared as follows: 108 - The coupling of 2-(thiazol-2-yl)-4-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin- 2-ylmethylamino)benzoic acid (3.5 g, 5.0 mmol) with L-methioninol (1J g, 7.8 mmol) was achieved using a similar method to the related compound in Example 6. Purification by flash chromatography (ethyl acetate:iso-hexane/l : 1 - ethyl acetate) gave (2S)-2-[2-(thiazol-2-yl)-4- ((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-4- methylsulfanylbutan-1-ol as a pale yellow foam (3.0 g, 72%). MS (ES+) m/z 795 (M+H) + . Example 28 (3S)-3-[2-(4-Fluorophenyl)-6-((2S,4S)-4-benzoyIsulfanylpyrrolidin-2-ylmethoxy)pyridin- 3-ylamidol-5-methylsulfanyl-l-phenylpentan-2-one (3S)-3-[2-(4-Fluorophenyl)-6-((2S,4S)-l-tert-butoxycarbonyl-4-benzoylsulfanylpyrrolidin-2- ylmethoxy)pyridin-3-ylamido]-5-methylsulfanyl-l-phenylpentan-2-one(290mg) was dissolved in dichloromethane (20ml). Triethylsilane (0J8ml) was added followed by trifluoroacetic acid (5ml), under an inert atmosphere at room temperature. After 40 minutes saturated aqueous sodium bicarbonate solution (100ml) was added, the organic layer separated and the aqueous layer extracted with dichloromethane (3x30ml). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under reduced pressure to yield a colourless solid. Purification on silica gel (6% methanol/ dichloromethane) gave the title compound as a colourless solid (0.20g). - 109 - 'H NMR (CDCI 3 ) δ 1.62-1.95 (3H, m), 1.97 (3H, s), 2.00-2.21 (3H, m), 2.49-2.63 (IH, m), 3.03 (IH, dd), 3.50 (IH, dd), 3.62-3.68 (IH, m), 3.77 (2H, s), 4.01-4.04 (IH, m), 4.37-4.47 (2H, m), 4.76-4.84 (IH, m), 6.08-6.14 (IH, m), 6.76 (IH, d), 7.01-7.10 (2H, m), 7.13-7.20 (2H, m), 7.26-7.37 (3H, m), 7.41-7.47 (2H, m), 7.53-7.63 (3H, m), 7.84 (IH, d), 7.90-7.95 (2H, m). MS (ES+) m/z 658 (M+H) + Elemental Analysis found C, 65.0 ; H, 5.4 ; N, 6J; + 0J5 dichloromethane requires C, 65.0 ; H, 5.4 ; N, 6.3. The starting material for was prepared as follows: DEAD (3.39g) was added dropwise over fifteen minutes to a stirred mixture of 2-[(2S,4S)-l- tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-yl]ethanol (7.7g), methyl 2-(4-fluorophenyl)- 6-hydroxypyridin-3-yl carboxylate (4.0g) and triphenylphosphine(5Jg) in THF (100 ml) under an inert atmosphere. After which the mixture was stirred for a further 18 hours at ambient temperature. The THF was evaporated under reduced pressure and the residue purified by silica flash chromatography, eluting with ethyl acetate/iso.hexane (4:1) to give methyl 2-(4-fluorophenyl)-6-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)pyridin-3-ylcarboxylate as a colourless foam (1 l.Og). Η NMR(CDC1 3 ) d 1.32 (9H, s), 1.80 (IH, m), 2.30 (IH, m), 2.76 (2H, m), 3.44 (IH, m), 3.70 (3H, s), 3.94 (IH, m), 4.47 (2H, m), 6.7 (IH, d), 7.09 (2H, t), 7.17-7.36 (9H, m), 7.46 (8H, m), 8.05 (IH, d). MS (ES+) m/z 705 (M+H) + A mixture of compound methyl 2-(4-fluorophenyl)-6-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethoxy)pyridin-3 -ylcarboxylate ( 11 g), sodium hydroxide (3 J g), water (60ml) and methanol (300ml) was stirred and heated at reflux under an inert atmosphere for 18 hours. The reaction was cooled to ambient temperature and the methanol removed by evaporation. The residue was diluted with water and acidified with IM aqueous citric acid solution and extracted with dichloromethane. The organic phase was dried and evaporated to - 110 - dryness to give compound 2-(4-fluorophenyl)-6-((2S,4S)-l-tert-butoxycarbonyl-4- tritylsulfanylpyrrolidin-2-ylmethoxy)pyridin-3-ylcarboxylic acid as a colourless foam (10.7 g). 2-(4-Fluorophenyl)-6-((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2- ylmethoxy)pyridin-3-ylcarboxylic acid (l.Og) and (3S)-5-methysulfanyl-2-oxo-l- phenylpentan-3 -amine (0.65g) were dissolved in dichloromethane (30ml), then DMAP (3.52g) and EDC (0.42g) were added under an inert atmosphere at room temperature. After 16 hours the solution was washed with IM citric acid (40ml) and purified on silica gel (20% ethyl acetate/ wø-hexane) to give (3S)-3-[2-(4-fluorophenyl)-6-((2S,4S)-l-tert- butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethoxy)pyridin-3-ylamido]-5-methylsulfanyl- l-phenylpentan-2-one as a colourless foam (0.52g). Η NMR(CDC1 3 ) δ 1.20-1.29 (IH, m), 1.31 (9H, s), 1.61-1.92 (2H, m), 1.96 (3H, s), 2.00-2.21 (3H, m), 2.62-2.83 (3H, m), 3.76 (2H, s), 3.81-4.05 (IH, m), 4.30-4.53 (2H, m), 4.75-4.84 (IH, m), 6.04-6J3 (IH, m), 6.71 (IH, d), 6.97-7.08 (2H, m), 7J3-7.34 (14H, m), 7.39-7.47 (6H, m), 7.54-7.63 (2H, m), 7.84 (IH, m). MS (ES+) m/z 896 (M) + Trifluoroacetic acid (1ml) was added to a stirred solution of (3S)-3-[2-(4-fluorophenyl)-6- ((2S,4S)- 1 -tert-butoxycarbonyl-4-tritylsulfanylpyrrolidin-2-ylmethoxy)pyridin-3-ylamido]-5- methylsulfanyl-l-phenylpentan-2-one (0.5g) and triethylsilane (0.27ml) in dichloromethane (50ml) under an inert atmosphere at room temperature. After 40 minutes saturated sodium bicarbonate solution (50ml) was added, the organic layer separated and the aqueous phase extracted with dichloromethane (2x20ml). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under reduced pressure to yield a yellow oil. Purification on silica gel (40% ethyl acetate/ wo-hexane) gave (3S)-3-[2-(4-fluorophenyl)-6-((2S,4S)-lJert- butoxycarbonyl-4-sulfanylpyrrolidin-2-ylmethoxy)pyridin-3-yl]-5-methylsulfanyl-l- phenylpentan-2-one as a colourless foam (0.27g). Η NMR (CDC1 3 ) δ 1.50 (9H, s), 1.63-1.76 (2H, m), 1.83-1.95 (IH, m), 1.97 (3H, s), 2.01- 2.22 (3H, m), 2.50-2.65 (IH, m), 3.04-3J4 (IH, m), 3J8-3.33 (IH, m), 3.76 (2H, s), 3.91- 111 4.25 (2H, m), 4.45-4.66 (2H, m), 4.75-4.84 (IH, m), 6.06-6.14 (IH, m), 6.75 (IH, d), 7.02- 7.10 (2H, m), 7.13-7.18 (2H, m), 7.24-7.39 (3H, m), 7.53-7.66 (2H, m), 7.85 (IH, d). MS (ES+) m/z 654(M+H) + Elemental Analysis found C, 62J ; H, 6.3 ; N, 6J; + 0.2 H 2 O requires C, 62.1 ; H, 6.2 ; N, 6.4. Benzoyl chloride (0.05ml) was added to a stirred solution of (3S)-3-[2-(4-fluorophenyl)-6- ((2S,4S)-l-tert-butoxycarbonyl-4-sulfanylpyπOlidin-2-ylmethoxy)pyridin-3-yl]-5- methylsulfanyl-l-phenylpentan-2-one (0.25g) and triethylamine (OJ lml) in dichloromethane (15ml) under an inert atmosphere at room temperature. After 80 minutes, a saturated aqueous solution of sodium bicarbonate (30ml) was added, the organic layer separated and the aqueous phase extracted with dichloromethane (2x20ml). The combined organic phases were dried (MgSO 4 ), filtered and concentrated under reduced pressure to give (3S)-3-[2-(4-fluorophenyl)- 6-((2S,4S)-l-tert-butoxycarbonyl-4-benzoylsulfanylpyrrolidin-2-ylmethoxy)pyridin-3- ylamido]-5-methylsulfanyl-l-phenylpentan-2-one as a colourless foam (0.29g). MS (ES+) m/z 758 (M+H) + Example 29 r2SV2-12-Phenyl-5-f(2S-4SV4-tert-butoxycarbonylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-4-methylsulfanylbutan-l-ol - 112 - Lithium borohydride (80mg,3.67mmol) and Pd(triphenylphosphine) 4 (25mg) were added to a stirred solution of methyl (2S)-2-[2-phenyl-5-((2S,4S)-l-allyloxycarbonyl-4-tert- butoxycarbonylsulfanylpyrrolidin-2-ylmethylamino)benzamido]-4-methylsulfanylbutyrate (Compound 33d in Intemational Patent Application No. PCT/GB96/01810) 580mg,0.883mmol) in THF (25mL) at room temperature under an inert atmosphere. After 1 hour the reaction was quenched with water (lOOmL) and extracted with ethyl acetate (3x50mL). The combined organic phases were washed with water (50mL) and brine (50mL), dried (MgSO 4 ), filtered and evaporated. The residues were purified by flash chromatography on silica (Merck 9385), eluting with 50% ethyl acetate/iso-hexane, ethyl acetate, 10% methanol/ethyl acetate and 20% methanol/ethyl acetate. Appropriate fractions were combined and evaporated to give the title compound as a white foam (343mg, 67.8%). 1 H NMR (CDCl 3 ,300MHz) dl.3-1.7(12H,m);2.0(3H,s);2J-2.3(3H,m);2.3-2.6(lH,m);2.8- 3.0(lH,m); 3.0-3.2(lH,m);3.2-3.3(lH,m);3.3-3.45(3H,m);3.45-3.6(lH,m);3.6-3.75(lH,m);3.85- 4.05(lH,m);5.5(lH,d);6.6-6.8(lH,m);6.8-7.0(lH,m);7J-7.2(lH,m);7.3-7.45(5H,m). MS (ES+) m z 546 (M+H) + . MS (ES-) m/z 544 (M-H) " . Example 30 (3S)-3-{4-r(Z)-3-(imidazol-l-vn-2-(thiazol-2-vn P rop-l-enyll-2-(4- fluorophenyl)benzamido)-5-(methylsuIfanyl)-l-phenyl-2-pentanone A mixture of pentafluorophenyl (2S)-2-{4-[(Z)-3-(imidazol-l-yl)-2-(thiazol-2-yl)prop-l- enyl]-2-(4-fluorophenyl)benzamido}-4-methylsulfanylbutanoate (4J3 g, 7 mmol), HOBT - 113 - (1.02 g, 7.6 mmol), (3S)-3-amino-5-(methylsulfanyl)-l-phenyl-2-pentanone (methionine benzylketone) (1.98 g, 7.6 mmol) and N-methylmoφholine (0.84 ml, 7.6 mmol) in DMF (40 ml) was stirred at ambient temperature ovemight. The mixture was diluted with ethyl acetate, washed with water, dried (MgSO 4 ), filtered and evaporated. The residue was purified by flash chromatography eluting with dichloromethane / ethanol (96/4) followed by chromatography on reverse phase silica eluting with a gradient 60-70 % methanol / ammonium carbonate buffer (2 g/1 pH 7). The appropriate fractions were concentrated and freeze-dried to give the title product as a foam. Yield = 86 %. 'H NMR (CDC1 3 , 400 MHz) δ 1.5-1.8 (2H, m), 1.9-2.2 (2H, m), 1.98 (3H, s), 3.76 (2H, m), 4.78 (IH, m), 5.20 (2H, s), 6.14 (IH, d), 6.69 (IH, s), 7-7.9 (17H, m). Anal calcd for C 34 H 35 FN 4 O 2 S 2 , 0J H 2 O C 66.67 H 5.13 N 9.15 S 10.47 Found C 66.30 H 5.22 N 9.24 S 10.62 MS (ESI) m/z : 611 (MH) + The starting material was prepared as follows : Pentafluorophenyl trifluoroacetate (9.92 ml, 57 mmol) was added to a solution of 4-[3- (imidazol-l-yl)-2-(thiazol-2-yl)prop-l-enyl]-2-(4-fluorophenyl)benzoic acid (18 g, 44 mmol) and pyridine (4.85 ml, 60 mmol) in DMF (100 ml). After stirring at ambient temperature overnight, the reaction mixture was evaporated to dryness and treated with 2N sodium hydroxide to adjust the pH 5. After extraction with dichloromethane and evaporation, the residue was purified by flash chromatography eluting with dichloromethane / ethanol (96/4) to give pentafluorophenyl (2S)-2- {4-[(Z)-3-(imidazol- 1 -yl)-2-(thiazol-2-yl)prop- 1 -enyl]-2-(4- fluorophenyl)benzamido}-4-methylsulfanylbutanoate Yield : 60 % Η NMR (CDC1 3 , 400 MHz) δ 5.32 (2H, m), 6.8-7.9 (12 H, m), 8.18 (IH, m). Example 31 r2SV2-(4-l(Z)-3-f2-Methylimidazol-l-vn-2-(thiazol-2-vnprop-l-enyll-2-(4- fluorophenvObenzamido -cyclohexyl-4-methylsulfanyl-l-butanone - 114 - The title compound was prepared from 4-[3-(2-methylimidazol-l-yl)-2-(thiazol-2-yl)prop-l- enyl]-2-(4-fluorophenyl)benzoic acid and (2S)-2-amino-l-cyclohexyl-4-(methylsulfanyl)-l- butanone using a similar method to that described for example 5. Yield = 6 %. 'H NMR (CDC1 3 , 400 MHz) δ 1.1-1.5 (6H, m), 1.5-1.95 (2H, m), 2-2.3 (6H, m), 2.03 (3H, s), 2.43 (3H, s), 2.4-2.55 (IH, m), 4.86 (IH, m), 5.10 (2H, d), 6.14 (IH, m), 6.40 (IH, s), 6.90- 7.35 (9H, m), 7.55 (IH, m), 7.82 (IH, m). Anal calcd for C 34 H 37 FN 4 O 2 S 2 C 66.21 H 6.05 N 9.08 S 10.40 Found C 65.83 H 6.21 N 9.02 S 9.96 MS (ESI) m/z : 617 (MH) + . The starting material was prepared as follows : A solution of 2-bromothiazole (5.3 ml, 59 mmol) in ether (80 ml) was added at -70°C to a solution of n-butyl lithium (solution (2.5 M in hexane), 26 ml, 64.9 mmol) in ether (45 ml). A solution of l-(ethoxycarbonylmethyl)-2-methylimidazole (12.9 g, 76 mmol) in ether (50 ml) was added at -70°C to the resulting mixture. The mixture was stirred at room temperature for two hours and subsequently treated with sat. ammonium chloride (250 ml) and extracted with dichloromethane. After evaporation to dryness the residue was purified by flash - 115 - chromatography eluting with dichloromethane / ethanol (97/3) to give 2-(2-methylimidazol-l- yl)-l-(thiazol-2-yl)-l-ethanone as an oil. Yield : 48 %. Η NMR (CDC1 3 , 400 MHz) δ 2.36 (3H, s), 5.47 (2H, m), 6.87 (IH, m), 6.98 (IH, m), 7.82 (IH, m), 8.09 (IH, m). Potassium tert-butoxide (3.21 g, 28.6 mmol) was added to a mixture of 2-(2-methylimidazol- l-yl)-l-(thiazol-2-yl)-l-ethanone (4.56 g, 22 mmol), [3-(4-fluorophenyl)-4- methoxycarbonylbenzyl] triphenylphosphonium bromide (16.67 g, 28.6 mmol) and 18-crown- 6 (0.25 g, 0.94 mmol) in methylene chloride (90 ml), at -40°C under an argon atmosphere. After stirring overnight at room temperature, the resulting mixture was treated with a saturated solution of ammonium chloride and extracted with dichloromethane to give Methyl 4-[3-(2-methylimidazol- 1 -yl)-2-(thiazol-2-yl)prop- 1 -enyl]-2-(4-fluorophenyl)benzoate as an oil. After evaporation it was dissolved in methanol (90 ml) and treated with 2N sodium hydroxide (30 ml) at reflux for 6 hours. After evaporation to dryness, the residue was taken up in ethyl acetate / H 2 O. The aqueous layer was acidified to pH 5.5 with 6N HCl and extracted with dichloromethane / ethanol (60/40) to give, after evaporation and trituration in ether, 4-[3- (2-methylimidazol-l-yl)-2-(thiazol-2-yl)prop-l-enyl]-2-(4-fluorophenyl)benzoic acid as a solid (E and Z mixture). Η NMR (DMSO-d 6 + CF 3 COOD, 400 MHz) δ 2.60 and 2.68 (3H, s), 5.38 and 5.45 (2H, m), 7-8 (12H, m). Cyclohexylmagnesium chloride (2M solution in ether, 6 ml, 12 mmol) was added at -40°C, under argon atmosphere to a solution of tert-butyl N-[(1S)-1- {[methoxy(methyl)amino]carbonyl}-3-(methylsulfanyl)propyl]carbamate (1J7 g, 4 mmol) in ether 35 ml. The mixture was stirred at room temperature for 3 hours; IN HCl (10 ml) was then added at 0°C. After stirring for 10 minutes the reaction mixture was extracted with ethyl acetate and purified by flash chromatography, eluting with petroleum ether / ethyl acetate (85/15) to give tert-butyl N-[(lS)-l-cyclohexylcarbonyl)-3-(methylsulfanyl)propyl]carbamate as an oil. Yield : 80 %. - 116 - Η NMR (CDCI 3 , 400 MHz) δ : 1.43 (9H, s), 1.1-2.2 (12H, m), 2.09 (3H, s), 2.4-2.65 (3H, m), 4.55 (IH, m), 5.22 (IH, m). A solution of tert-butyl N-[(lS)-l-cyclohexylcarbonyl)-3-(methylsulfanyl)propyl]carbamate (1 g, 3.3 mmol) in dichloromethane (8 ml) was treated with TFA (4 ml) at ambient temperature for 1 hour. After evaporation to dryness, the residue was purified by flash chromatography eluting with a gradient of 0-6 % ethanol in dichloromethane to give (2S)-2- amino-l-cyclohexyl-4-(methylsulfanyl)-l-butanone as an oil. Η NMR (CDCI 3 , 400 MHz) δ : 1.1-1.6 (7H, m), 1.7-2.2 (5H, m=, 2.12 (3H, s), 2.5-2.75 (3H, m), 4.37 (IH, m). Example 32 (3S)-3-(4-r(E)-3-αmidazol-l-vn-2-(4-fluorophenvnprop-l-enyll-2-(4- fluorophenyl)benzamido-l-cvclohexyl-5-methvIsulfanyl-2-pentanone /=\ The title compound was prepared from 4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l- enyl]-2-(4-fluorophenyl)benzoic acid and (3S)-3-amino-5-(methylsulfanyl)-l-cyclohexyl-2- pentanone using a similar method to that described for example 5. Yield = 35 %. Η NMR (CDCI 3 + CF 3 COOD, 400 MHz) δ : 0.8-1.5 (6H, m), 1.55-1.95 (7H, m), 2-2.2 (2H, m), 2.03 (3H, s), 2.3-2.5 (2H, m), 4.72 (IH, m), 5.19 (2H, s), 6.8-7.7 (14H, m), 8.69 (IH, s). Anal calcd for C 37 H 39 F 2 N 3 O 2 S C 70.79 H 6.26 N 6.69 S 5.11 Found C 70.72 H 6.26 N 7.22 S 4.63 MS (ESI) m/z : 628 (MH) + - 117 - The starting material was prepared as follows : A portion of bromomethylcyclohexane (1 ml, 0.7 mmol) was added to a suspension of magnesium (0.75 g, 3.2 mmol) and dibromoethane (0.05 ml) in THF (50 ml), under argon atmosphere. After stirring for 20 minutes, bromoethylcyclohexane (3.2 ml, 2.3 mmol) was added and the mixture was further stirred at ambient temperature for 1 hour. The resulting solution was then added at -70°C to a solution of tert-butyl N-[(1S)-1- {[methoxy(methyl)amino]carbonyl}-3-(methylsulfanyl)propyl]carbamate (2.92 g, 10 mmol) in THF (25 ml). After 1 hour at -70°C, the mixture was stirred at ambient temperature for 2 hours. IN HCl was then added at 0°C and the reaction mixture was extracted with ether and purified by flash chromatography eluting with petroleum ether / ethyl acetate (90/10) to give tert-butyl N-[(lS)-l-cyclohexylmethylcarbonyl)-3-(methylsulfanyl)propyl]carbamate as an oil. Yield = 42 %. 'H NMR (CDC1 3 , 400 MHz) δ : 0.8-2.2 (16H, m), 1.44 (9H, m), 2J0 (3H, s), 2.3-2.6 (4H, m), 4.38 (IH, m), 5.25 (IH, m). A solution of tert-butyl N-[(lS)-l-cyclohexylmethylcarbonyl)-3- (methylsulfanyl)propyl] carbamate (1.33 g, 4 mmol) in dichloromethane (8 ml) was treated with TFA (4 ml) at room temperature for 2 hours. After evaporation to dryness, the residue was purified by flash chromatography eluting with dichloromethane to give (3S)-3-amino-5- (methylsulfanyl)-l-cyclohexyl-2-pentanone as an oil. Yield = 75 %. 'H NMR (CDC1 3 , 400 MHz) δ : 0.8-1.4 (7H, m), 1.6-2.8 (12H, m), 2J2 (3H, s). Example 33 (3S)-3-(5-I(EV3-(ImidazoI-l-vn-2-f4-fluorophenvnprop-l-enyll-2-(4- fluorophenethvDbenzamidoM-phenyl-5-methylsulfanyl-2-pentanone 118 - The title compound was prepared from 5-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l- enyl]-2-(4-fluorophenethyl)benzoic acid and (3 S)-3-amino-5 -(methylsulfanyl)- 1-pheny 1-2- pentanone (methionine benzylketone) using a similar method to that described for example 5. Yield = 53 %. Η NMR (CDC1 3 , 400 MHz) δ : 1.7-2.6 (4H, m), 2.04 (3H, s), 2.7-3 (4H, m), 3.88 (2H, m), 4.8-5 (3H, m), 6.15 (IH, m), 6.48 (IH, s), 6.8-7.4 (19H, m). Anal calcd for C 39 H 37 F 2 N 3 O 2 S C 72.09 H 5.74 N 6.49 S 4.93 Found C 72.38 H 5.88 N 6.59 S 5.27 MS (ESI) m/z : 650 (MH) + The starting material, 5-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenethyl)benzoic acid, was prepared as described in Example 19 of Intemational Patent Application. Publication number WO 98/32741. Example 34 (2S)-2-(5-r(E)-3- midazol-l-vn-2-(4-fluorophenyl)prop-l-enyll-2-(4- fluorophenethyl)benzamido|-4-methylsulfanylbutan-l-ol - 119 - The title compound was prepared from methyl (2S)-2-{5-[(E)-2-(4-Fluorophenyl)-3- (imidazol- 1 -yl)prop- 1 -enyl] -2-(4-fluorophenethyl)benzamido } -4-methy Isulfanylbutanoate using a similar method to that described in example 4. Yield = 74 %. Η NMR (CDC1 3 , 400 MHz) δ : 1.6-2 (2H, m), 2.07 (3H, s), 2.4-2.6 (2H, m), 2.80 (2H, m), 2.94 (2H, m), 3.64 (2H, m), 4.14 (IH, m), 4.82 (2H, s), 5.65 (IH, m), 6.45 (IH, s), 6.8-7.1 (13H, m), 7.37 (lH, s). Anal calcd for C 32 H 33 F 2 N 3 O 2 S C 68.43 H 5.92 N 7.48 S 5.71 Found C 68.34 H 6.16 N 7.65 S 6.27 MS (ESI) m/z : 562 (MH) + The starting material, methyl (2S)-2-{5-[(E)-2-(4-Fluorophenyl)-3-(imidazol-l-yl)prop-l- enyl] -2-(4-fluorophenethyl)benzamido } -4-methylsulfanylbutanoate, was prepared as described in Example 19 of Intemational Patent Application, publication number WO 98/32741. - 120 - Example 35 Pharmaceutical compositions The following illustrate representative pharmaceutical dosage forms of the invention as defined herein (the active ingredient being termed "Compound X"), for therapeutic or prophylactic use in humans: (a) Tablet I mg/tablet Compound X 100 Lactose Ph.Eur 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25 Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/v paste) 2.25 Magnesium stearate 3.0 (c) Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur 93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75 Magnesium stearate 1.0 - 121 - (d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5 (e) Injection I (50 mg/mD Compound X 5.0% w/v IM Sodium hydroxide solution 15.0% v/v OJM Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100%) (f) Injection II flO mg/ml. Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v OJM Sodium hydroxide solution 15.0% v/v Water for injection to 100% (g) Injection III (lmg/ml, buffered to pH6 Compound X 0.1% w/v Sodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol 400 3.5% w/v Water for inj ection to 100% (h) Aerosol I mg/ml Compound X 10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0 - 122 - Dichlorodifluoromethane 490.0 (i) Aerosol II mg/ml Compound X 0.2 Sorbitan trioleate 0.27 Trichlorofluoromethane 70.0 Dichlorodifluoromethane 280.0 Dichlorotetrafluoroethane 1094.0 (j) Aerosol III mg/ml Compound X 2.5 Sorbitan trioleate 3.38 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (k) Aerosol IV mg/ml Compound X 2.5 Soya lecithin 2.7 Trichlorofluoromethane 67.5 Dichlorodifluoromethane 1086.0 Dichlorotetrafluoroethane 191.6 (1) Ointment ml Compound X 40 mg Ethanol 300 μl Water 300 μl 1 -Dodecylazacycloheptan-2-one 50 μl Propylene glycol to 1 ml - 123 - Note The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example for example to provide a coating of cellulose acetate phthalate. The aerosol formulations (h)-(k) may be used in conjunction with standard, metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soya lecithin may be replaced by an alternative suspending agent such as sorbitan monooleate, sorbitan sesquioleate, polysorbate 80, polyglycerol oleate or oleic acid.

Claims: 124 CLAIMS 1. A compound of formula ( 1 ) : wherein A is of the formula: R 4 S S R 4 Ar 1 CH 2 \ .E— ' NT Ό— ^ NT O— Ar 2' I I R 3 R3 (2) (3) (4) wherein R3 is hydrogen, C 2 - 5 alkanoyl, C^alkoxy carbonyl, C 2 - 4 alkenyloxycarbonyl, phenylCι- 3 alkyl, phenoxycarbonyl, phenylCj. 3 alkoxycarbonyl or Cι- 4 alkyl optionally substituted by carbamoyl, Cι. 4 alkylcarbamoyl, di(Cι- 4 alkyl)carbamoyl, carboxy or Ci^alkoxy carbonyl; R 4 is hydrogen, Cj_ 4 alkyl, C 2 - 5 alkanoyl, Cι- 4 alkoxycarbonyl, phenylCj. 3 alkyl, benzoyl, heteroarylCualkyl or heteroaroyl; D is a linking moiety selected from the following groups written from left to right in formula (2) and (3): O . ^ .0 N ^ , T ""N / N Α • N N \ • o y (wherein the piperazine and perhydro-1 ,4-diazepine rings are optionally substituted by Cι. 4 alkoxyC 1 . 4 alkyl, phenoxyCι. 4 alkyl or heteroarylCι. 4 alkyl); -CO-N(R5)-; -CH 2 -N(R5)-; - CH 2 S-; -CH 2 O-; -CH 2 -CH(R5); -CH=C(R5)-; -CH 2 N(R5)-T-; -CH 2 N(R5)-SO 2 -; -CH 2 -N(R5)- CO-T1-; -CO-N(R5)-T-; -CH 2 S-T-; -CH 2 O-T- (where R5 is hydrogen, Z, C M alkyl, Z-d- 4 alkyl, Z-C 2 - 5 alkanoyl, C 2 - 7 alkanoyl or ZCO- and Z is alkoxy, phenyl, naphthyl or a - 125 - monocyclic or bicyclic heteroaryl ring, T is -(CH 2 )m- wherein m is 1-4 and T is optionally monosubstituted with any value of R 5 other than hydrogen ; and T 1 represents -(CH 2 )mi- wherein m 1 is 0-4 and T 1 is optionally monosubstituted with any value of R 5 other than hydrogen); Ari i s of the formula (5), (6) or (7): R 6 / N — /> N (R 7 ) D R 7 R 7 (5) (6) (7) R is hydrogen, C^alkyl, phenylC^alkyl; R is hydrogen, Cj^alkyl, hydroxyC^alkyl, haloC,. 4 alkyl, dihaloC M alkyl, C M alkoxy, Cι. 4 alkoxyCι. 4 alkyl, C 2 - 4 alkenyloxyCι_ 4 alkyl, C 2 - 4 alkynyloxyCι- 4 alkyl, sulfanylC^alkyl, aminoCι. 4 alkyl, N^C^alky aminoC alkyl or phenylCj^alkyl; p is 0,1 or 2; Ax 1 is phenyl or heteroaryl; E is of the formula >C=CH-, >CHCH 2 -, >CH-N(R8)-, >CH-O, >CH-N(R8)CH 2 - or >CH-OCH 2 -; wherein R8 is hydrogen, C^alkyl or C 2 - 5 alkanoyl; B is phenyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, thiazolyl, furyl or oxazolyl, the ring being substituted on ring carbon atoms by Ri and -(CH 2 ) n R 2 ; or B is pyrrolyl, pyrazolyl or imidazolyl, substituted by R 1 and -(CH 2 ) n R 2 (the pyrrolyl, pyrazolyl or imidazolyl rings may bear a substituent on the sp3 hybridised ring nitrogen); when A is of the formula (2) or (3), B can also be naphthyl substituted by Ri and -(CH 2 ) n R 2 ; R 1 is of the formula -CONHCH(Riθ)RH wherein Rio is hydrogen or -(CH 2 ) q -R 2 wherein q is 0-4 and Ri 2 is hydrogen Ci^alkylsulfanyl, C^alkylsulfinyl, C^alkylsulfonyl, hydroxy, C M alkoxy, carbamoyl, N-C 1 - alkylcarbamoyl, N,N-(diC i ^alkvDcarbamovl, C alkyl, phenyl, thienyl, phenylCι_ 3 alkoxy or C 2 . 5 alkanoylamino; R 11 is of the formula -CH 2 OR13 (wherein R13 is hydrogen, C^alkyl, phenyl, heteroaryl, C 2 - 5 alkanoyl, Cj^alkoxymethyl, phenoxymethyl or heteroaryloxymethyl), of the formula - 126 - -CORI 4 or of the formula -CH 2 CORi 4 (wherein Ri4 is Cι. 4 alkyl (optionally substituted by halo, cyano, C^alkanoyloxy, hydroxy, Cj.4alkoxy or Cι _4alkanoyl), phenyl, phenylCi. 3 alkyl, heteroaryl, heteroarylCi^alkyl, C 5 . 7 cycloalkyl, C 5 . 7 cycloalkylC,. 3 alkyl, 2- (phenyl)ethenyl, 2-(heteroaryl)ethenyl, or N-methoxy-N-methylamino) or R l is morpholinoCι. 4 alkyl, pyrrolidin-l-ylCι. 4 alkyl or piperidin-l-ylCι_ 4 alkyl wherein the morpholine, pyrrolidine and piperidine rings are optionally substituted by Cj^alkyl or C 5.7 cycloalkyl; or R 11 is phenyl- 1 -hydroxy C M alkyl; or heteroaryl- 1 -hydroxy C M alkyl; R 2 is phenyl or heteroaryl; n is 0, 1 or 2; and phenyl and heteroaryl groups in R2, R3, R4, R6 s R7, RI 1 (including R 13 and R 14 ), R 2 , Ar2 and D are independently optionally substituted on ring carbon atoms by up to three substituents selected from Ci^alkyl, halogen, hydroxy, Cι _4alkoxy, Cι_4alkoxycarbonyl, Cι _4alkanoyl, Cι.4alkanoyloxy, amino, Cι_4alkylamino, di(Cι_4alkyl)amino, C^alkanoylamino, nitro, cyano, carboxy, carbamoyl, N-Cι_ 4 alkylcarbamoyl, N-N^di-C^-ialky^carbamoyl, C _ 4 alkoxycarbonyl, thiol, C \ _4alkylsulfanyl, C \ _4alkylsulfinyl,C \ _4alkylsulfonyl, Cι. 4 alkanesulphonamido, N-(Cι. 4 alkylsulfonyl)-N-Cι. 4 alkylamino, aminosulfonyl, N- (Cι. 4 alkyl)aminosulfonyl, N,N-di (C]. 4 alkyl)aminosulfonyl, carbamoylC j ^alkyl, N- (C^alky^carbamoylC alkyl, N,N-(diC 1 ^alkvDcarbamoylC 1 ^alkyl, hydroxyC^alkyl and C 1 ^alkoxy C 1 ^alky 1 ; or a prodrug, solvate or pharmaceutically-acceptable salt thereof. 2. A compound according to claim 1 wherein Ri is of the formula -CONHCH(R10)RH (wherein Ri° is of the formula -(CH 2 )q-R 12 , wherein q is 0-4 and R1 is hydrogen, methyl, Cμ alkylsulfanyl, Cj^alkylsulfonyl, methoxy, hydroxy or carbamoyl) and RU is of the formula - CH 2 OR1 (wherein R13 is hydrogen or phenyl) or Ri 1 is of the formula -COR 14 or - CH 2 COR 14 (wherein RI 4 is Cι_ 4 alkyl (optionally substituted by halo, cyano, or C 2 - 4 alkanoyloxy), phenyl, phenylCi^alkyl, heteroaryl, heteroarylCι- 3 alkyl or C 5 . 7 cycloalkylCι. 3 alkyl) or RU is morpholinomethyl, pyιτolidin-1-ylmethyl or piperidin-1-ylmethyl; or RU is phenyl- 1 -hydroxymethyl, pyridyl- 1 -hydroxymethyl or thiazolyl- 1-hydroxyethyl; wherein phenyl and heteroaryl rings in Ri 1 (including R13 and RI are optionally substituted as defined in claim 1). - 127 - 3. A compound according to either claim 1 or claim 2 wherein R 2 is phenyl, 4- fluorophenyl, thienyl or thiazolyl. 4. A compound according to any one of claims 1 to 3 wherein A is of the formula (2) or (3), B is phenyl or naphthyl, R3 is selected from hydrogen, phenylCι. 3 alkoxycarbonyl, C 2 - 4 alkenyloxycarbonyl, C 2 - 5 alkanoyl, carbamoylC^alkyl, N-Cι_ 4 alkylcarbamoylCι_ 4 alkyl or di(Cι- 4 alkyl)carbamoylCι. 4 alkyl, R 4 is hydrogen, C 2 . 5 alkanoyl, C M alkoxy carbonyl or benzoyl; and D is of the formula -CH 2 N(R5)-, -CH 2 N(R5)T-, -CH 2 O-, -CH 2 OT- or -CH=CH- wherein R5 is as defined in claim 1. 5. A compound according to any one of claims 1 to 3 wherein B is phenyl or pyridyl and A of the formula (3), wherein E is of the formula >C=CH-, >CHN(R8)-, >CHO-, >CHN(R8)CH 2 - or >CHOCH 2 - (wherein R8 is as defined in claim 1); Ari i s of the formula (5), (6) or (7) wherein R 6 is benzyl (optionally substituted on th ephenyl ring by cyano or nitro), methyl, ethyl or hydrogen and R? is hydrogen, C^alkyl, hydroxyCι. 4 alkyl, Ci. 4 alkoxyCι_ 4 alkyl, C 2 - 4 alkenyloxyCι_ 4 alkyl, C 2 - 4 alkylnyloxyCι. 4 alkyl, sulfanylCι. 4 alkyl, aminoCι- 4 alkyl, N-(Cι. 4 alkyl)aminoCι- 4 alkyl or phenylCj. 4 alkyl; p is 0, 1 or 2; and .Ar 2 is phenyl (optionally substituted by fluoro, chloro or cyano), pyridyl or thiazolyl. 6. A compound according to claim 1 which is: (2S)-2- { 2-(4-fluorophenyl)-4-[ 1 -(4-fluorophenyl)-2-(imidazol- 1 -yl)ethylamino]- benzoylamino } -4-methylsulfanylbutan-l-ol ; (2S)-2-{4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenyl)benzamido } -4-methylsulfanylbutan-l-ol ; (2S)-2-{4-[(Z)-2-(thiazol-2-yl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4-fluorophenyl)benzamido}- 4-methylsulfanylbutan-l-ol; (2S)-2-{4-[l-(4-fluoroρhenyl)-2-(imidazol-l-yl)ethoxymethyl]-2-(4- fluorophenyl)benzamido } -4-methylsulfanylbutan-l-ol ; - 128 - (2S)-3-{4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenyl)benzamido}-5-methylsulfanyl-2-oxo-l-phenylpentane; (2S)-3-{4-[(E)-2-(4-fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenyl)benzamido} -5-methylsulfonyl-2-oxo- 1 -phenylpentane; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 4-methylsulfanylbutan- 1 -ol; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 5 -methylsulfanyl- 1 -phenylpentan-2-one; (4S)-4-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 6-methylsulfanyl- 1 -(pyrid-3-yl)hexan-3-one; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 4-methylsulfanyl- 1 -morpholinobutane; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)ben.zamido]- 4-methoxy- 1 -mo holinobutane; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 4-methoxybutan- 1 -ol; (3 S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamido]- 1 - pheny lbutan-2-one ; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -pheny lpropan-2-one; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -pyridin-4-ylbutan-2-one; (3S)-3-{2-[2-(thiazol-2-yl)ethyl]-5-((2S,4S)-4-sulfanylpyrrolidin-2- ylmethylamino)benzamido } - 1 -pheny lpentan-2-one ; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- l-(2-fluorophenyl)-5-methylsulfanylpentan-2-one; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- l-(2-fluorophenyl)-5-methylsulfanylpentan-2-ol; - 129 - (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(2-hydroxyphenyl)-4-methylsulfanylbutan- 1 -one; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(2-hydroxyphenyl)-4-methylsulfanylbutan- 1 -ol; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -one; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-4-methylsulfanylbutan- 1 -ol; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(pyridin-2-yl)-5-methylsulfanylpentan-2-ol; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamido]-5- methylsulfanylpentan-2-one; (4S)-4-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamido]-6- methylsulfanyl- 1 -(pyridin-3-yl)hex- 1 -en-3-one; (2S)-2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -(thiazol-2-yl)-4-methylsulfanylbutan- 1 -ol; 2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]-l- (thiazol-2-yl)-4-methylsulfanylbutan- 1 -one; 2-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]-3- hydroxypropan-1-ol; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]- 1 -acetyloxybutan-2-one; (3S)-3-[2-(4-fluorophenethyl)-5-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethoxy)benzamido]-l- (triazol- 1 -yl)butan-2-one; - 130 - (3S)-3-[2-(thiazol-2-yl)-4-((2S,4S)-4-sulfanylρyrrolidin-2-ylmethylamino)benzamido]-5- methylsulfanyl- 1 -(phenyl)pentan-2-one; (2S)-2-[2-(thiazol-2-yl)-4-((2S,4S)-4-sulfanylpyrrolidin-2-ylmethylamino)benzamido]-4- methylsulfanylbutan- 1 -ol; (3S)-3-[2-(4-fluorophenyl)-6-((2S,4S)-4-benzoylsulfanylpyrrolidin-2-ylmethoxy)pyridin-3- ylamido]-5-methylsulfanyl- 1 -pheny lpentan-2-one; (2S)-2-[2-phenyl-5-((2S,4S)-4-tert-butoxycarbonylsulfanylpyrrolidin-2- ylmethylamino)benzamido]-4-methylsulfanylbutan- 1 -ol; (3 S)-3- {4-[(Z)-3-(imidazol- 1 -yl)-2-(thiazol-2-yl)prop- 1 -enyl]-2-(4-fluorophenyl)benzamido} - 5-(methylsulfanyl)-l-phenyl-2-pentanone; l-cyclohexyl-(2S)-2-{4-[(Z)-3-(2-methylimidazol-l-yl)-2-(thiazol-2-yl)prop-l-enyl]-2-(4- fluorophenyl)benzamido} -4-(methylsulfanyl)- 1 -butanone; 1 -cyclohexyl-(3 S)-3 - {4- [(E)-2-(4-fluorophenyl)-3-(imidazol- 1 -yl)prop- 1 -enyl]-2-(4- fluorophenyl)benzamido}-5-methylsulfanyl-2-propanone; (3 S)-3- { 5-[(E)-2-(4-fluorophenyl)-3-(imidazol- 1 -yl)prop- 1 -enyl]-2-(4- fluorophenethyl)benzamido}-5-methylsulfanyl-l-phenyl-2-propanone; or (2S)-2-{5-[(E)-2-(4-Fluorophenyl)-3-(imidazol-l-yl)prop-l-enyl]-2-(4- fluorophenethyl)benzamido } -4-methylsulfanylbutan- 1 -ol ; or a pharmaceutically-acceptable salt thereof. 7. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 6 and a pharmaceutically-acceptable carrier. 8. A method of treating a disease or medical condition mediated through famesylation of ras which comprises administering to a warm-blooded animal an effective amount of a compound according to any one of claims 1 to 6. 9. A compound according to any one of claims 1 to 6 for use as a medicament. - 131 - 10. A compound according to any one of claims 1 to 6 for use in the preparation of a medicament for treatment of a disease mediated through famesylation of mutant ras. 11. A process for preparing a compound of the formula (I) or a pharmaceutically- acceptable salt, prodrug or solvate thereof which comprises: deprotecting a compound of the formula (8): wherein A' is A (as defined in claim 1) or protected A, R19 is Ri (as defined in claim 1) or protected Ri and R20 is R2 (as defined in claim 1) or protected R 2 and B is as defined in claim i; wherein at least one protecting group is present; and thereafter if necessary: (i) forming a phaimaceutically-acceptable salt, (ii) forming a prodrug, and/or (iii) forming a solvate.

Inventors: DRAKE DAVID JOHN, WARDLEWORTH JAMES MICHAEL, DRAKE, DAVID, JOHN, WARDLEWORTH, JAMES, MICHAEL
Applicants: DRAKE DAVID JOHN, WARDLEWORTH JAMES MICHAEL, ZENECA LTD, ZENECA PHARMA SA, DRAKE, DAVID, JOHN, WARDLEWORTH, JAMES, MICHAEL, ZENECA LIMITED, ZENECA PHARMA S.A.
Application year: 1999
Main classification: C07D207
IPC codes: A61K31, A61P35, A61P43, C07D207, C07D231, C07D233, C07D401, C07D403, C07D417, C07D521