4-MERCAPTOPYRROLIDINE DERIVATIVES AS FARNESYL TRANSFERASE INHIBITORS

Abstract: Pharmaceutical compositions comprising an inhibitor of ras farnesylation of formula (I) wherein, R<1> is for example H and further values as defined in the specification; R<2> is for example H and further values as defined in the specification; R<3> is for example H or a substituent having values as defined in the specification; p is 0-3 in which R<3> values can be the same or different; L is a linking moiety for example -CO-NH2- and further values as defined in the specification; A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms where the heteroatoms are independently selected from O, N and S; or a -S-S- dimer thereof when R<2>=H; or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier. A particular use is cancer therapy.

Description: 4-MERCAPT0PYRR0LIDINE DERIVATIVES AS FARNESYL TRANSFERASE INHIBITORS This invention relates to compounds that inhibit famesylation of mutant ras gene products through inhibition of the enzyme famesyl-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, _£6: 779-827). Post translational modification of ras protein is required for biological activity. Famesylation of ras catalysed by FPTase is believed to be an essential step in ras processing. It occurs by transfer of the farnesyl group of famesyl pyrophosphate (FPP) to a cvsteine 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 cvsteine residue of the CAAX box and methylation of the cvsteine carbox l. 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, 2£Q: 1877-1878), possibly through being permanently in GTP activated form rather than cycled back to GDP inactivated form. Inhibition of famesylation of mutant ras gene products will stop or reduce activation. One class of known inhibitors of famesyl transferase is based on famesyl pyrophosphate analogues: see for example European patent application EP 534546 from Merck. Inhibitors of famesyl transferase based on mimicry of the CAAX box have been reported. Reiss (1990) in Cell £2, 81-8 disclosed tetrapeptides such as CVIM (Cys-Val- Ile-Met). James ( 1993) in Science 260. 1937-1942 disclosed benzodiazepine based peptidomimetic compounds. After earliest priority date of the present invention 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. Also after the earliest priority date of the present invention Bristol-Myers Squibb in European Patent Application EP 696593 disclosed for the first time famesyl transferase inhibitors having a 4-sulfanylpyrrolidine residue in the first position. According to one aspect of the present invention there is provided a pharmaceutical composition comprising an inhibitor of ras famesylation of Formula I Formula I wherein: R is selected from H; -Ci _4alkyl; -Ci _3alkylene-Ph optionally mono or di-substituted on Ph with substituents selected from Ci _4alkyl, halogen, OH, Ci _4alkoxy, C^alkanoyl, C]_4alkanoyloxy, amino, Cι _4alkylamino, di(Cι _4alkyl)amino, C1 _4alk_moylam.no, nitro, cyano, carboxy, carbamoyl, Cι _4alkoxycarbonyl, thiol, Cι _4alkylsulfanyl, Cι _4alkylsulfιnyl,Cι_4alkylsulfonyl and sulfonamido; -CO-C1 _.4a.kyl; -CO-O-C1.4a.kyl; -CO-O-C2_4alkenyl; -CO-O-(CH2) n Ph optionally substituted on Ph as defined for substitution on Ph in R 1 = -Ci _3alkylene-Ph above and n=0-4; -Ci _4alkylene-CONR 4 R 5 where R & R 5 are independently selected from H and C1.4a.kyl; and -Cι _4alkylene-COOR 6 where R 6 is selected from H, C1.4a.kyl; R is selected from H; -C1.4a.kyl; -C 1.3 alky lene-Ph optionally substituted on Ph as defined for substitution on Ph in R = -Cι _3alkylene-Ph above; -COC1.4a.kyl; and -COOCι_ 4 a-kyl; R 3 is selected from H; OH; CN; CF 3 ; NO 2 ; -C1.4 alkyl; -Cι _4alkylene-R 7 where R 7 is selected from phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O,N and S and any aryl ring in R is optionally substituted as defined for substitution on the Ph group in R = -Ci. _3alkylene-Ph above; R 7 ; C2-4alkenyl; halogen; -(CH2) n COOR 8 where n= 0-3 and R 8 represents H, - _> Cι_4alkyl. or C2-4alkenyl; -CONR 9 R 10 where R 9 and R 10 independently represent H. C _4alkyl. C2-4alkenyl, -O-C _4alkyl. -0-C2-4alkenyl. -C^alkylenePh optionally substituted as defined for this group for R 1 above:-CON(R' ')OR 12 where R 1 ' and R 12 independently represent H. Cj^alkyl and C2-4alkenyl; a group of Formula II. -CONR 13 -CHR 14 -COOR ! 7 . where R 13 is H or C 1 _ 4 alkyl. R 17 is H or C i .galkyl. R is selected from the side chain of a lipophilic amino acid. carbamoylC M alkyl, N-(monoC 1 . 4 alkyl)carbamoylC 1 _ 4 alkyl and N-(diC,. 4 alkyl)carbamoylC 1 . 4 alkyl. the group of Formula II having L or D configuration at the chiral alpha carbon in the corresponding free amino acid: a lactone of formula Cι_4alkyl monosubstituted on carbon with =N-OH; a group of Formula -X-R where X is selected from O, CO, CH2, S, SO. SO2 and R 1:3 is selected from Ci.galkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O.N and S and any aryl ring in R is optionally substituted as defined for the Ph group in R = -C \ _3alkylene-Ph; p is 0-3 in which R values can be the same or different; L is a linking moiety selected from the following groups written from left to right in Formula I: -CO-NR 16 - where R 16 is selected from H. C1.4a.kyl, C 1 _4alkylene-Z, -CO- C 1 _4alky lene-Z. -CO-C,. 6 alkyl, -COZ, Z and Z is selected from -0-Cι_4alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O. N and S and any aryl ring in R is optionally substituted as defined for the Ph 1 18 18 group in R = -Cι_3alkylene-Ph; -CH2-NR - where R represents any value defined for R 16 ; -CH 2 S-: -CH 2 0-: -CH 2 .CHR 19 - where R 19 represents any value defined for R 16 ; -CH=CR 2 - where R represents any value defined for R ; -CH2NR '-T- where R ' represents any value defined for R 16 , T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R where R " represents any value for R other than H: -CH NR 23 -S02- where R 23 represents any value defined for R 16 ; -CH2-NR 24 -CO-T- where R represents any value defined for R 16 . T represents -(CH2) n - where n is 0-4 and T is optionally monosubstituted with R 29 where R 2 represents any value for R 16 other than H: -CO-NR J -T- where R ^ represents any value defined for R . T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with represents any value for R other than H: -CH2S-T- where T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R 27 where R 27 represents any value for R 16 other than H: -CH2O-T- where T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R" where R represents any value for R other than H: A is selected from phenyl: naphthyl: a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms where the heteroatoms are independently selected from O. N & S; or a -S-S- dimer thereof when R =H: or a N-oxide thereof; or an enantiomer. diastereoisomer. pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier. Preferably R 1 is selected from H: -CO-O-(CH2) n Ph optionally substituted on Ph as defined for R 1 = -Cι_3alkylene-Ph and n=0-4; -CO-O-C 2 _4alkenyl; -CO-Cι_ 4 alkyl; -Cι_4alkylene-CONR 4 R 5 where R 4 & R 3 are independently selected from H. Cj^alkyl. Preferably R 2 is selected from H and -CO-C M alkyl. Preferably L is selected from -CH 2 -NR 18 -; -CH 2 NR 21 -T . Preferably A is selected from phenyl. naphthyl. pyridyl and thienyl. Preferably combinations of R and p are selected from: * i 7 7 7 1) R is selected from a group of Formula II; -C alkylR ; -O-R and; R : and p=l-3 with the proviso that one value of R is a group of Formula II; ii) p=0 with the proviso that A is naphthyl and L is -CH2NR 21 -T; iii) p=l with the proviso that R J = a group of Formula II and A is naphthyl. In another embodiment of the invention it is preferred that: R is selected from H; -Cι_4alkyl. -C 1.3 alky lene-Ph optionally mono or di-substituted on Ph with substituents selected from Ci^alkyl, halogen, OH. Ci^alkoxy. Cj^alkanoyl. Cι_4alkanoyloxy, amino. Chalky lamino, di(Cι_4alkyl)amino. Cι_4alkanoylamino. thiol. Cι_4alkylthio. nitro, cyano. carboxy. carbamoyl. C \ _4alkoxycarbonyl, C 1 _4alkylsulfinyl. Cι_4alkylsulfonyl. sulfonamido; -CO-CMalkyl: -CO-O-C1.4a.kyl; -CO-0-C2-4alkenyl; -CO-O-CH2-Ph optionally mono- or di-substituted on phenyl with substituents selected from Cι_4alkyl. halogen. OH. Cj^alkoxy. Cj^alkanoyl, C i _4alkanoyloxy. amino. C .4alky lamino. di(C ] _4alkyl)amino. Cι.4alkanoy lamino. thiol. C i _4alkylthio. nitro. cyano. carboxy. carbamoyl. Cι_4alkoxycarbonyl. C j^alkylthiono. Cι.4alkylsulfonyl, sulfonamido: -C \ .4alkylene-CONR R 5 where R & R "^ are independently selected from H. Cj^alkyl: -C i _4alkylene-COOR where R is selected from H. C1.4a.kyl; R 2 is selected from H: -C^alkyl; -Cι_3alkylene-Ph; -COC^alkyl; -COOCi^alkyl: R 3 is selected from H; OH; CN: CF 3 ; NO 2 ; -C1.4 alkyl, -C _4alkylene-R 7 where R 7 is selected from phenyl, naphthyl. a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 3 heteroatoms selected from O.N and S; C2-4 lkenyl; halogen: -(CH 2 ) n COOR 8 where n= 0-3 and R 8 represents H. C* _ 4 alkyl. C 2 -4alkenyl: -CONR 9 R 10 where R and R independently represent H, Cι_4alkyl. C2_4alkenyl. -0-Cι.4alkyl, -O-C2-4alkenyl: -CON(R' ')OR 12 where R 1 ' and R 12 independently represent H. C 1 _4alkyl and C2-4alkenyl; a group of Formula II. -CONR 13 -CHR 14 -COOR 17 , where R 13 is H or C^alkyl. R 17 is H or C j _6alkyl. R is the side chain of a lipophilic amino acid with L or D configuration at the chiral alpha carbon in the corresponding free amino acid: C \ _4alkyl monosubstituted on carbon with =N-OH; -SO-Cι.4alkyl; -Sθ2_Cι_4alkyl; a group of Formula -X-R 15 where X is selected from CO. CH2, S. SO. SO2 and R 15 is selected from Ci.^alkyl. phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 3 heteroatoms selected from O.N and S; p is 0-3 in which R 3 values can be the same or different; L is a linking moiety selected from the following groups written from left to right in Formula I: -CO-NR 16 - where R 16 is selected from H. Cι_4alkyl, C 1 _4alkylene-Z and Z is selected from -0-Cι_4alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 3 heteroatoms selected from O, N and S; -CH2-NR - where R represents any value defined for R ; -CH2S-; -CH2O-; -CH2.CHR - where R represents any value defined for R ; -CH=CR - where R represents any value defined for R ; -CH2NR -T- where R represents any value defined for R . T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R 22 where R " represents any value for . 16 least one of R 2 ' 1 ,22 • R 10 other than H. and provided at 1 and R is H: -CH NR ,23 -SO2- where R~ J represents any value defined for R 16 ; -CH2-NR 2 -CO-T- where R represents any value defined for R 16 . T represents -(CH2) n - where n is 0-4 and T is optionally monosubstituted with R 29 where R 29 represents any value for R 16 other than H. and provided at least one of R > 24 and R , 29 i.s H: -CO-NR >25 -T- where R ,2= represents any value defined for R 16. T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R , 16 other than H. and provided at least one of R and R is H; -CH2S-T where T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R ' 27 where R >27 represents any value for R , 16 other than H; -CH2O-T- where T represents 28 28 -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R 16 other than H; A is selected from phenyl: naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 3 or 5 heteroatoms in the case of monocyclic and bicyclic rings respectively where the heteroatoms are independently selected from O. N & S; or a -S-S- dimer thereof when R =H. A preferred pharmaceutical composition is in the form of a tablet. According to another aspect of the invention there is provided a compound of Formula I, III. IV or V for use as a medicament. According to another aspect of the invention there is provided a compound of Formula I. III. IV or V for use in preparation of a medicament for treatment of a disease mediated through famesylation of ras. Many compounds of Formula I are a feature of this invention and in particular according to another aspect of the invention there is provided a compound of any of the following classes i), ii) or iii): class i) whwpiir X is selected from H; C,. 6 alkyl: hydroxyC^alkyl. Cι. 6 alkoxyC,_ 6 alkyl: C,. 6 alkylcarbonyl: hydroxy C , . 6 alkylcarbony 1 : C , . 6 alkoxy C ■ . 6 alky lcarbony 1 : A is selected from phenyl. naphthyl or a 5-10 membered heterocyclic ring having upto 5 heteroatoms selected from O. N and S: X is selected from H: phenyl: phenylC^alkyl: a 5-6 membered heteroaryl ring containing upto 3 heteroatoms selected from O. N and S optionally linked to A by C,. 6 alkyl: and X is optionally substituted on any ring as defined for phenyl in R = -C].3alkylene-Ph in claim 1 ; X is selected from H; C 1-6 alkyl: X is selected from C 1-6 alkylsulfanyl; C,. 6 alkylsulfinyl; C|. 6 alkylsulfonyl; carbamoyl; N- (Cι_ 6 alkyl)carbamoyl; N-(diCι_ 6 alkyl)carbamoyl; and hydroxy or a C, -4 alkyl ether thereof: class ii) wherein: X 5 is selected from -CO-C 1-4 alkyl-Ph: -CO-C 1-6 alkyl; -CO-C 1-4 alkyl-heteroaryl where heteroaryl is a 5-10 membered heteroaryl ring containing upto 5 heteroatoms selected from 0. N and S and Ph or heteroaryl are optionally substituted as defined for Ph in R = -Cι_3alkylene-Ph; C i ^alky loxy C i ^alky 1 ; A is naphthyl or a 10 membered heterocyclic ring having upto 5 heteroatoms selected from O. N and S: R and p are as defined in claim 1 ; class iii) wherein: X 6 has any value defined for X ? in ii) above; X 7 is Ph optionally substituted as defined for Ph in R 1 = -C].3alkylene-Ph; A is Ph or naphthyl or a 5-10 membered heterocyclic ring having upto 5 heteroatoms selected from O. N and S; R and p are as defined above: or a N-oxide. pharmaceutically acceptable salt, prodrug or solvate thereof . Preferred values for compounds of class i) include, X 1 is selected from H and C 1 . 6 alkoxyC 1 . 6 alkyl; X 2 is selected from H; phenyl or phenylC^alkyl: X is C^alkylsulfanyl; A is selected from phenyl or naphthyl; Other preferred values for X are -OMe and the lactone which can be formed when X 4 is OH and X 3 is H. Preferred values for compounds of class ii) include p is 0. Preferred values for compounds of class iii) include. X 7 is Ph; A is Ph; p is 0. In another embodiment of the invention there is provided a compound of Formula I in which: R 1 is selected from H or C alkyl; R is selected from H. C alkyl, -COC 1 _ 4 alkyl; -C^alkylPh; L is selected from the following values as defined herein. CONR 16 , CH 2 S, CH 2 O, CH 2 CHR 19 . CH=CHR 20 . CH 2 NR 24 COT, CONR 25 T, CH 2 ST and CH 2 OT: and values for A, R and p are as defined herein, with the proviso that 2- (benzylcarbamoyl)-4-sulfanylpyrollidine and 4-(acetylsulfonyl)-2(benzylcarbamoyl)- pyrrolidine are excluded. It is believed that the excluded compounds were disclosed as intermediates for beta-lactam antibiotic synthesis in Japanese patent application 60233076 (Sumitomo Chemical). According to another aspect of the present invention there is provided any one of the following individual compounds or a pharmaceutically acceptable salt thereof: (2S)-2-{2-Benzyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-benzoylamino}-4- methylsulfanylbutyric acid methyl ester : (2S)-2-{2-Benzyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-benzoylamino}-4- methylsulfanylbutyric acid : (2S)-2-({2-phenyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-phenylcarbonyl}- __mino)-4-methylsulfanylbutyric acid methyl ester; (2S)-2-({2-phenyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-phenylcarbonyl}- amino)-4-methylsulfanylbutyric acid; (2S)-2-({3-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-naphthalene-l-carbonyl}- amino)-4-methylsulfanylbutyric acid methyl ester : (2S)-2-({3-[([2S_,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-naphthalene-l-carbonyl}- amino)-4-me thylsulfanylbutyric acid ; (2S)-2-({-3-phenyl-5[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-phenylcarbonyl}- amino)-4-methylsulfanylbutyric acid methyl ester; (2S_)-2-( {-3-phenyl-5[([2S,4S]-4-sulf_mylpyrrolidin-2-ylmethyl)-amino]-phenylcarbonyl}- amino)-4-methylsulfanylbutyric acid; (2S,4S)-2-[ {N-(4-methoxyben__yl)-_N-(naphthalen- 1 -ylmethyl)-amino } -methyl]- pyrrolidine-4-thiol ; N-(naphthalen- 1 -ylmethyl)-N-([2S,4S]-4-sulfanylpyπOlidin-2-ylmethyl)-pentanamide ; N-(naphthalen- 1 -ylmethyl)-N-([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-2-(pyridin-3-yl)- acetamide ; N-((2S,4S)-4-sulfanyl-pyrrolidin-2-ylmethyl)-3-methyl-N-(2-naphthalen-l-yl- ethyl)butyramide ; N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-N-(2-naphthalen-l-yl-ethyl)-2-pyridin-3-yl- acetamide ; (2S,4S)-2- { [(3-Methoxypropyl)-(2-naphthalen- 1 -ylethyl)amino]methyl } - pyrrolidine-4- thiol; N-([2S,4S_ . ]-4-sulfanyl-pyrrolidin-2-ylmethyl)-2-(4-methoxy-phenyl)-N-(2-naphthalen-2-yl- ethyl)-acetamide ; (2S,4S)-2- { [(2-(4-Methoxyphenyl)ethy l)-(2-naphthalen- 1 -y lethy l)amino] methyl } - pyrrolidine-4-thiol ; N-(2.2-Diphenyl-ethyl)-N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-3-methyl- butyramide : -([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-3.3-dimethyl-N-(2-naphthalen-2-yl-ethyl)- butyramide : N-(2.2-Diphenyl-ethyl)-N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-3.3-dimethyl- butyramide : (2S)-2-{3-[([2S_,4S]-4-Sulfanyl-pyrrolidin-2-ylmethyl)-(3-methoxy-propyl)-amino]- benzoylamino}-4-methylsulfanyl-butyric acid : N-([2S,4S]-4-Sulfanyl-pyrrolidin-2-ylmethyl)-3.3-dimethyl-N-(2-naphthalen-l-yl-ethyl)- butyramide : (2S)-4-Carbamoyl-2-({2-phenyl-5-[([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-amino]- phenylcarbonyl}-amino)-butyric acid; and (2S)-4-Carbamoyl-2-({2-phenyl-5-[([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-amino]- phenylcarbonyl}-amino)-butyric acid methyl ester. According to another aspect of the invention there is provided a pharmaceutical composition comprising a compound as defined in any one Formulas III, IV or V or an individual compound listed above together with a pharmaceutically acceptable diluent or carrier. According to another aspect of the invention there is provided a process for preparing compounds of classes i). ii) or iii) as defined above which comprises deprotecting a compound of Formula VI Formula VI wherein X represents the right hand side of compound classes i), ii) or iii) as defined above. Pr is H or an amino protecting group. Pr is H or a thio protecting group and any functional groups in X are optionally protected with the proviso that there is at least one protecting group and optionally, if desired, converting the product thus obtained into a pharmaceutically acceptable salt thereof. In an embodiment of the invention: SUBSTΓTUTE SHEET (RULE 26) Examples of values for R 1 include methyl: -CH 2 -Ph: -CH 2 -Ph substituted on Ph with nitro. especially 4-nitro: acetyl: BOC; allyloxycarbonyl: -CO-O-CH 2 -Ph substituted on Ph with nitro. especially 4-nitro: -CH2CONH2. Examples of values for R 2 include -COMe and -COOtertbutyl. Examples of values for R 3 include Cl: -COOH: -CONH 2 : -SOMe and: -S0 2 Me. When R J represents -(CH 2 ) n -COOR 8 a suitable value for n is 0. Examples of lipophilic amino acids which contribute their side chain (denoted R 14 within the definition of values for R J ) include 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. A preferred value for R 14 is -CH 2 -CH 2 -S-CH 3 . Further preferred values for R 14 are -CH 2 -OMe and -CH 2 -CH 2 - OMe. When R 17 is H to give a COOH group in Formula II. and R 14 is -CH 2 -CH 2 -OH then a lactone can be formed where R 17 and R 14 together form part of a dihydrofuran-2-one heterocyclic ring. The same lactone can be formed for compounds of Formula III where X 4 is OH and X 3 is H. Amino Acid Side Chain methionine -CH CH S-CH 3 phenylglycine Ph phenylalanine -CH Ph serine -CH 2 OH or a C alkyl (preferably methyl) ether thereof. leucine -CH 2 -CHMe 2 homoserine -CH 2 -CH 2 -OH or a C M alkyl (preferably methyl) ether thereof. A preferred value for p is 2. When L is -CH2NR 21 -T- a suitable value for n is 1. When L is -CH 2 -NR 24 -CO-T- a suitable value for n is 1. When L is -CH2"NR ^-T- a suitable value for n is 1. When L is -CH2"S-T- a suitable value for n is 1. When L is -CH2O-T- a suitable value for n is 1. L is especially -CONH-. -CH 2 .NH-. -CH 2 NHSO 2 -. -CH9NHCO-. Examples of values for A when A is heteroaryl are thienyl, pyridyl. quinolyl & quinoxalinyl. Further preferred values are set out below. For Rl ; 4-nitro-benzyloxycarbonyl; allyloxycarbonyl: carbamoylmethyl: acetyl: phenoxycarbonyl; H. For R2; Acetylsulfanyl: H. For R : Methoxy carbonyl; N-methyl-N-methoxy-carbamoyl: nitro: allyloxycarbonyl; N nethyl-allyloxycarbamoyl: ethoxycarbonyl: 3,4-dichloro-benzyl-carbamoyl: hydroxy: carboxy; (2S),4-methylsulfanyl-butyric acid methyl ester-2yl-carbamoyl: (2S),4-methylsulfanyl-butyric acid-2yl-carbamoyl; phenoxy. For p: 1-2. especially 2; a further preferred value is 0. For L: -C(O)-NH-: -CH .C(O)-NH-: -CH 2 .NH-C(O)-; -CH 2 -NH-SO2.: especially -C(O)-NH-. For A: phenyl; pyridyl. thienyl; naphthyl. For R 16 & R 18*26 : H, Cι_ 4 alkyl. especially H. In another embodiment of the invention preferred values are set out below. In compounds of Formula III: X is H or methoxyC 1-4 alkyl (especially H): X is H. phenyl or benzyl (especially benzyl); X is H or C alkyl (especially H); X is C alkylsulfanyl (especially methylsulfanyl); and A is phenyl. When A is a 6-membered aryl or heteroaryl ring then groups -NX - and the substituent comprising X are preferably in meta juxtaopsition relative to each other; and X . if present, is preferably positioned para relative to -NX 1 -. The chiral carbon to which -COOX J is attached is preferably in S configuration. The chiral carbons at the 2 and 4 positions of the pyrrolidine ring are preferably in S_configuration. In compounds of Formula IV: X 3 is -CO-C,_ 4 alkyl (especially -CO-CH 2 -CHMe 2 ) or -CH 2 -Ph-O-C alkyl (especially -CH 2 -Ph-OMe); heteroaryl is preferably pyridyl and a preferred aryl or heteroaryl substituent is -O-C M alkyl (especially methoxy); and A is naphthyl. The chiral carbons at the 2 and 4 positions of the pyrrolidine ring are preferably in S_configuration. The attachment point for A relative to -(CH 2 ), 2 - is preferably at the 1 position of napththalene and the equivalent position for heterocyclic values for A (regardless of ring numbering conventions for heterocycles). A preferred value for - (CH 2 ), .2 - is -(CH 2 ) 2 -. In compounds of Formula V: X 6 is -CO-C,. 5 alkyl (more preferably -CO-CH 2 - CHMe 2 or -CO-CH -butyl. especially -CO-CH 2 -CHMe 2 ) or -CH 2 -Ph-0-C,. 4 alkyl (especially -CH 2 -Ph-OMe): heteroaryl is preferably pyridyl and a preferred aryl substitution is -0-C alkyl (especially methoxy): and A is phenyl or naphthyl (especially phenyl). The chiral carbons at the 2 and 4 positions of the pyrrolidine ring are preferably in S_configuration. A preferred value for -(CH 2 )_ 2 - is -(CH 2 )j-. Suitable pairs of values for R 3 when p=2 are: -COOMe. -CO.N(Me).OMe; NO 2 . -CO.N(Me).OMe; -COOMe. allyloxycarbonyl: -CO.N(Me).OMe. allyloxycarbonyl; allyloxycarbonyl. -CO.N(Me).O.CH 2 CH=CH 2 : OH. COOH: -COOMe. COOMe: Ph. - CO.N-Methionine methyl ester: Ph. -CO.N-Methionine: benzyl. -CO.N-Methionine methyl ester: benzyl. -CO.N-Methionine; benzyl, -CO.N-Methionine isopropyl ester; Ph. -CO.Nα- Glutamine methyl ester; Ph, -CO.Nα-Glutamine. Suitable values for L= CHNR 21 T include CH 2 .N(CO.CH 2 .CHMe 2 ).CH 2 .CH 2 ; CH 2 .N(CH 2 CH 2 CH 2 OMe).CH 2 .CH 2 ; CH 2 .N(CH 2 ./. Ph.OMe).CH 2 .CH 2 ; CH 2 .N(CO.CH 2 .CHMe 2 ).CH 2 : CH 2 N(CO.CH 2 .CH 2 .CH 2 .Me).CH 2 ; CH 2 N(CO.CH 2 .CHMe.CH 2 Me).CH 2 ; CH 2 N(CO.CH 2 .CH 2 .OMe)CH 2 ; CH 2 N(CO.CH 2 .pyridin-3-yl).CH 2 ; CH 2 N(4-methoxybenzyl)CH 2 ; CH 2 N(CO.CH 2 .CHMe 2 )CH 2 .CH 2 .CH(Ph); CH 2 N(CO.CH 3 )CH 2 .CH 2 .CH(Ph); CH 2 N(CO.CH 2 .CHMe 2 )CH 2 ; CH 2 N(CO.CH 3 )CH 2 : CH 2 N(CO.CH 2 .CHMe 2 )CH 2 .CH(Ph); CH 2 N(CO.CH 2 .CMe 3 )CH 2 .CH(Ph); CH 2 N(CO.CH 2 .pyridin-3-yl)CH 2 .CH(Ph); CH 2 N(CO.1 -hydroxy-6-methoxy-pyridin-3-yl)CH 2 .CH(Ph); CH 2 N(CO.CH 2 CHMe 2 )CH 2 .CH 2 : CH 2 N(CO.CH 2 CMe 3 )CH 2 .CH 2 ; CH 2 N(CO.CH 2 pyridin-3-yl)CH 2 .CH 2 : CH 2 N(C0.4-methoxybenzyl)CH 2 .CH 2 ; Suitable values for L = -CH 2 NR 18 - include CH 2 NH: CH 2 NMe; CH 2 N(CO.CH 2 .CHMe 2 ) and CH 2 N(CO.CH 2 .CH 2 .OMe). Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs. edited by H. Bundgaard. (Elsevier. 1985) and Methods in Enzymology, Vol. 42, p. 309-396. edited by K. Widder. et al. (Academic Press. 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard. Chapter 5 "Design and Application of Prodrugs " . by H. Bundgaard p. 1 13-191 (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. An in vivo hydrolysable ester of a compound of the formula (I) containing carboxy group is. for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid. Suitable pharmaceutically- acceptable esters for carboxy include C| -6 alkoxymethyl esters for example methoxymethyl, C,. 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters. C 3 . g cycloalkoxycarbonyloxyC|. 6 alkyl esters for example 1-cyclohexylcarbonyloxy ethyl: 1,3- dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2-onylmethyl; and C,. 6 alkoxycarbonyloxyethyl esters for example 1 -methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. Particular substitutions on A for 6 membered rings are in the meta or para positions. Some compounds within the scope of Formula I are known as intermediates in carbapenem side chain synthesis but it is believed that they have not been previously described in forms suitable as pharmaceutical compositions nor had any pharmaceutical activity associated with them er se. The reader is referred to the following publications in this regard and also in respect of synthetic details for compound preparation: Matsumura. Heterocycles (1995), 41___147-59; European patent application EP 590885 (Zeneca; Betts et al); European patent application EP 592167 (Zeneca; Siret); European patent application EP 562855 (Zeneca; Jung et al); International patent application WO 92/17480 (Imperial Chemical Industries; Betts et al): European patent application EP 508682 (Imperial Chemical Industries: Betts et al): European Patent Application EP 280771 (Fujisawa Pharmaceutical, Murata et al): and International patent application WO 92/17479 (Imperial Chemical Industries; Betts et al). In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only and references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-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 I 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 " halogen " refers to fluorine, chlorine, bromine and iodine. The term " carbamoyl " refers to -C(O)NH2- The term " BOC " refers to tert 1 butyl-O-C(0)-. The term " allyl " refers to CH2=CH-CH2_. Bicyclic aryl and bicyclic heteroaryl rings refer to ring systems in which both rings of the bicyclic system are aromatic. Examples of C,. 6 alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl and pentyl: examples of C,_ 4 alkyl include methyl, ethyl, propyl, isopropyl, sec-butyl and tert-butyl; examples of C M alkyl include methyl, ethyl, propyl and isopropyl; examples of -Cι_ 3 aIkylenePh include benzyl, phenylethyl, phenylpropyl; examples of C,. alkoxy (also called -O-C_. 4 al.cyl herein) include methoxy, ethoxy and propoxy; examples of Cι_4alkanoyl include formyl, acetyl and propionyl; examples of Cj^alkanoyloxy include acetyloxy and propionyloxy; examples of C|. 4 aIkylamino include methy lamino. ethylamino. propylamino. isopropylamino, sec-butylamino and tert-buty lamino: examples of di-(Cι_ 4 alkyl)amino include di-methylamino. di-ethylamino and N-ethyl-N- methylamino: examples of C^alkanoylamino include acetamido and propionylamino: examples of C 1 _ 4 alkoxycarbonyl include methoxy carbonyl, ethoxycarbonyl and propoxycarbonyl: examples of C^alkylsulfanyl include methylsulfanyl. ethylsulfanyl. propylsulfanyl. isopropylsulfanyl. sec-butylsulfanyl and tert-butylsulfanyl; examples of Cι_4alkylsulfinyl include methylsulfinyl. ethylsulfinyl. propylsulfinyl. isopropylsulfinyl. sec-butylsulfinyl and /ert-butylsulfinyl: examples of Cj^alkylsulfonyl include methylsulfonyl. ethylsulfonyl. propylsulfonyl. isopropylsulfonyl. sec-butylsulfonyl and terr-butylsulfonyl; examples of -CO-C^alkyl include formyl. acetyl. propionyl. butyryl. and valeryl: examples of -CO-O-C_. 4 alkyI include ethyloxycarbonyl: propyloxycarbonyl and tert-butyloxycarbonyl (BOC); examples of -CO-O-C 2 _ 4 alkenyl include allyloxycarbonyl and vinyloxycarbonyl; examples of -CO-O-(CH 2 ) n Ph where n=0-4 include phenyloxycarbonyl. benzyloxycarbonyl, phenylethyloxycarbonyl and pheny lpropyloxycarbonyl: examples of -Cι_4alkyIene-CONR 4 R :> include carbamoylmethyl. carbamoylethyl, N- methylcarbamoylethyl, N-methyl-N-ethylcarbamoylethyl: examples of -Cι_4alkylene-COOR 6 include carboxymethyl. carboxyethyl. carboxypropyl, propionic acid methyl ester, acetic acid ethyl ester; examples of C 2 . 4 alkenyl include allyl and vinyl; examples of -O-C -4 alkenyl include allyloxy and vinyloxy; examples of lipophilic amino acids include valine, leucine. isoleucine. methionine, phenylalanine. serine, threonine and tyrosine; examples of carbamoylC aIkyl include carbamoylmethyl. carbamoylethyl and carbamoylpropyl; examples of N-(monoC,_ 4 alkyl)carbamoylC 1 _ 4 alkyI include N-methyl- carbamoylmethyl and N-ethyl-carbamoylethyl; examples of N-(diC 1 _ 4 alky_)carbamoyl- C^alkyl include N,N-dimethylcarbamoylethyl and N-methyl-N-ethylcarbamoylethyl; examples of Cj^alkyl monosubstituted on carbon with =N-OH include butyraldehyde oxime and propionaldehyde oxime; examples of hydroxyC,_ 6 alkyl include hydroxymethyl. hydroxyethyl. hydroxypropyl, 2-hydroxypropyl, 2-(hydroxymethyl)propyl and hydroxypentyl; examples of C|. 6 alkoxyC_. 6 aIkyl include methoxyethyl. ethoxyethyl and methoxybutyl; examples of C 1-6 alkylcarbonyl include methylcarbonyl. ethylcarbonyl. propylcarbonyl, isopropylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl and pentylcarbonyl: examples of hydroxyCι. 6 alkylcarbonyl include hydroxyacetyl. hydroxypropionyl, hydroxybutyryl, 3-hydroxybutyryl and hydroxypentanoyl; examples of Cι. 6 alkoxyCι. 6 alkylcarbonyl include methoxyacetyl. methoxypropionyl. ethoxybutyryl and butoxyacetyl; examples of phenylC_. 6 alkyl include benzyl, phenylethyl and phenyipropyl; examples of -CO-Cι_ 4 alky_-Ph include phenylacetyl and phenylpropionyl: examples of -CO-C 1. alkyl-heteroaryl include 2-(3-pyridyl)-acetyl and 2-(3-thienyl)- acetyl; examples of N-(C,. 6 alkyl)carbamoyl include N-methyl-carbamoyl and N-ethyl- carbamoyl: examples of N-(diC,. 6 alkyl)carbamoyl include _N,N-dimethylcarbamoyl and N-methyl-N-ethylcarbamoyl. Examples of 5-10 membered monocyclic or bicyclic heteroaryl rings containing upto 5 heteroatoms selected from O,N and S include the following. Examples of 5- or 6-membered heteroaryl ring systems include imidazole. triazole. pyrazine. pyrimidine. pyridazine. pyridine. isoxazole. oxazole. isothiazole. thiazole and thiophene. A 9 or 10 membered bicyclic heteroaryl ring system is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuran. benzimidazole. benzthiophene. benzthiazole. benzisothiazole. benzoxazole. benzisoxazole. pyridoimidazole, pyrimidoimidazole. quinoline. isoquinoline. quinoxaline. quinazoline. phthalazine. cinnoline and naphthyridine. Preferably monocyclic heteroaryl rings contain upto 3 heteroatoms and bicyclic heteroaryl rings contain upto 5 heteroatoms. Preferred heteroatoms are N and S. especially N. In general, attachment of heterocyclic rings to other groups is via carbon atoms. Suitable values of heterocycles containing only N as the heteroatom are pyrrole, pyridine, indole. quinoline. isoquinoline, imidazole, pyrazine, pyrimidine, purine and pteridine. Preferably any chiral carbon atoms at the 2 and 4 positions of the pyrrolidine ring in Formulas I and III-V are in S configuration. Compounds of Formula I and III-V 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. According to another aspect of the present invention there is provided a compound of Formula I for use as a medicament. According to another aspect of the present invention there is provided the use of a compound of Formula I in preparation of a medicament for treating ras mediated diseases, especially cancer. 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 I to a mammal in need of such treatment. According to a further feature of the invention there is provided a compound of Formula I. or a pharmaceutically-acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy. The invention also includes a method of treating a disease or medical condition mediated alone or in part by famesylated ras which comprises administering to a mammal requiring such treatment an effective amount of an active ingredient as defined above. The invention also provides the use of such an active ingredient in the production of a new medicament for use in a famesylated ras mediated disease or medical condition. 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 I 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 I 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 I may also be useful in the treatment of diseases associated with CAAX-containing proteins other than Ras (e.g., nuclear lamins and transducin) that are also post-translationally modified by the enzyme famesyl protein transferase. 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 (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 known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include. for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as com starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate. stearic acid or talc; preservative agents such as ethyl or propyl g-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 condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate. anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil. olive oil. sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a SUBSTTTUTE SHEET (RULE 26) 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 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 fluoπnated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. For further information on Formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board). Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I 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 I are useful in treating diseases or medical conditions which are due alone or in part to the effects of famesylation of ras. SUBSTTTUTE SHEET (RULE 26) In using a compound of the Formula I 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. Although the compounds of the Formula I 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. According to another aspect of the present invention there is provided individual compounds produced as end products in the Examples set out below and salts thereof. A compound of the invention, or a salt thereof, may be prepared by any process known to be applicable to the preparation of such compounds or structurally related compounds. Such processes are illustrated by the following representative schemes in which variable groups have any of the meanings defined for Formula I unless stated otherwise. Functional groups may be protected and deprotected using conventional methods. For examples of protecting groups such as amino and carboxylic acid protecting groups (as well as means of formation and eventual deprotection), see T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Second Edition, John Wiley & Sons, New York, 1991. Note abbreviations used have been listed immediately before the Examples below. 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). Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (e.g. isopropyl, t-butyl); lower alkoxy lower alkyl groups (e.g. methoxymethyl. ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (e.g. 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (e.g. p-methoxybenzyl, o-nitrobenzyl. g-nitrobenzyl. benzhydrvl and phthalidyl); tri(lower alkyl)silyl groups (e.g. trimethvlsilvl and t-butyldimethylsilyl): tri(lower alkyl)silyl lower alkyl groups (e.g. trimethylsilylethyl); and (2-6C)alkenyl groups (e.g. allyl and vinylethyl). Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis. Examples of hydroxy protecting groups include lower alkenyl groups (e.g. allyl); lower alkanoyl groups (e.g. acetyl); lower alkoxycarbonyl groups (e.g. t-butoxycarbonyl): lower alkenyloxycarbonyl groups (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g. benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl. p-nitrobenzyloxycarbonyl): tri lower alkyl/arylsilyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); aryl lower alkyl groups (e.g. benzyl) groups: and triaryl lower alkyl groups (e.g. triphenylmethyl). Examples of amino protecting groups include formyl. aralkyl groups (e.g. benzyl and substituted benzyl, e.g. p-methoxybenzyl. nitrobenzyl and 2.4-dimethoxybenzyl. and triphenylmethyl); di-p-anisylmethyl and furylmethyl groups: lower alkoxycarbonyl (e.g. t-butoxycarbonyl): lower alkenyloxycarbonyl (e.g. allyloxycarbonyl): aryl lower alkoxycarbonyl groups (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl. o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl: trialkylsilyl (e.g. trimethvlsilvl and t-butyldimethylsilyl): alkylidene (e.g. methylidene); benzylidene and substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include. for example, acid-, base, metal- or enzymicallv-catalysed hydrolysis, or photolyticallv for groups such as o-nitrobenzyloxycarbonyl. or with fluoride ions for silyl groups. Examples of protecting groups for amide groups include aralkoxymethyl (e.g.. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (e.g. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (e.g. trimethylsilyl, t-butyldimethylsily, t- butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (e.g. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (e.g. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (e.g. 2.4-dimethoxyphenyl); 4-alkoxybenzyl (e.g. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (e.g. 2,4-di(methoxy)benzyl); and alk-1-enyl (e.g. allyl, but-1-enyl and substituted vinyl e.g. 2-phenylvinyl). Aralkoxymethyl. groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation. Alkoxymethyl. tri alkyl/arylsilyl and tri alkyl/silyloxymethyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid; or in the case of the silyl containing groups, fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with eerie ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid. Compounds of Formula I in which L represents -CO-NR - may be prepared by forming an amide bond between compounds 1 and 2 as outlined in Scheme 23. Compounds of Formula I in which L represents -CO-NR S -T- may be prepared by an analogous procedure. Suitable coupling conditions include the following. i) Use of EEDQ at room temperature in an organic solvent (e.g. dichloromethane. methanol). ii) Use of oxalyl chloride in an organic solvent (e.g. DMF. CH2CI2) in the presence of an organic base (e.g. NMM. triethylamine. DMAP) at 0° to room temperature for 0.5-16h. iii) Use of EDC/ HOBT in an organic solvent (e.g. DMF. CH2CI2). iv) Use of DCCI/ HOBT in an organic solvent (e.g. DMF. CH 2 C1 2 ) 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 150min followed by an organic base (e.g. triethylamine) in the presence of an organic solvent (e.g. acetonitrile). Compounds of Formula I in which L represents -CH2NR -. -CH2O- or -CH2S- may be prepared as outlined in Scheme 24. LG represents a leaving group (e.g. 18 mesyloxy. tosyloxy. halogen) and X represents S. O or NR . 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 70° to 150° 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° iii) Use of an inorganic base (e.g. KOH. NaOH. K2CO3) 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). Compounds of Formula I in which L represents -CH=CR - may be prepared using a Wittig reaction as outlined in Scheme 25. Suitable reaction conditions include the following. SUBSTΓTUTE SHEET (RULE 26) 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). Compounds of Formula I in which L represents -CH2-NR - may be prepared as outlined in Scheme 26 by coupling aldehyde (2) with compound 4. Suitable coupling conditions include the following. i) Use of a reducing agent (e.g. NaCNBH3, BH3, hydrogen plus catalyst. LiHBEt3. di-isobutyl-aluminiumhydride. lithium aluminium hydride, sodium borohydride) in the presence of a suitable solvent e.g. ethanol & acetic acid. Aldehyde (2) may be prepared by oxidation of the corresponding alcohol ( 1 ) 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 and sodium hypochlorite. Aldehyde (2) may also be prepared by reduction of the corresponding ester (1) under standard conditions using for example diisobutyl-aluminium hydride. Compounds of Formula I in which L represents -CH2-NR' -T-. -CH2.O-T- or -CH2-S-T- may be prepared as outlined in Scheme 27 in which LG represents a leaving group (e.g. mesyloxy, tosyloxy, halogen) and X represents O, S or NR 21. Suitable coupling conditions are as outlined above in relation to Scheme 24. Optionally the positions of LG and XH in compounds 1 & 2 in Scheme 27 can be reversed to give the same end product. Compounds of Formula I in which L represents -CH2-NR 23 -SO2- may be prepared as outlined in Scheme 28. Compounds 1 & 2 may be coupled 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° 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° Compounds of Formula I in which L represents -CH2-NR -CO-T- may be prepared as outlined in Scheme 29. Compounds 1 & 2 may be coupled under standard conditions such as described above for L = -CO-NR - . Compounds of Formula I in which L represents -CH 2 -CHR 19 - may be prepared as by reduction of compounds of the type set out as compound 3 in Scheme 25 but substituting R 1 in lieu of R . 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 room temperature. Biological activity was tested as follows. Famesyl protein transferase (FPT) was partially purified from human placenta by ammonium sulphate fractionation followed by a single Q-Sepharose 'J (Pharmacia. Inc) anion exchange chromatography essentially as described by Ray and Lopez-Belmonte (Ray K P and Lopez-Belmonte J (1992) Biochemical Society Transations 20 494-497). The substrate for FPT was Kras (CVIM C-terminal sequence). The cDNA for oncogenic val 12 variant of human c-Ki-ras-2 4B was obtained from the plasmid pSWl 1-1 (ATCC). This was then subcloned into the polylinker of a suitable expression vector e.g. pIC147. The Kras was obtained after expression in the E. coli strain. BL21. The expression and purification of c-KI-ras-2 4B and the val 12 variant in E. coli has also been reported by Lowe et al (Lowe P N et al. J. Biol. Chem. (1991) 2£6 1672-1678). Incubations with enzyme contained 300nM tritiated famesyl pyrophosphate (DuPont New England Nuclear), 120nM ras-CVIM, 50mM Tris HC1 pH 8.0. 5mM MgCl 2 , lOμM ZnCl 2 , 5mM dithiotheitol and compounds were added at appropriate concentrations in DMSO (3% final concentration in test and vehicle control). Incubations were for 20 minutes at 37 ° and were stopped with acid ethanol as described by Pompliano et al. (Pompliano D L et al (1992) 31 3800-3807). Precipitated protein was then collected onto glass fibre filter mats (B) using a Tomtec® cell harvester and tritiated label was measured in a Wallac®1204 Betaplate scintillation counter. Although the pharmacological properties of the compounds of the Formula I vary with stmctural change as expected, in general compounds of the Formula I possess an IC5 in the above test in the range, for example. 0.01 to 200μM. Thus by way of example, the compound 5 { [(2S,4S).4-acetylsulfany 1- 1 -(4-nitro-benzy loxycarbonyl)-pyrrolidine-2-carbonyl]-amino } -3(Nzmethyl-methoxycarbamoyl)-benzoic acid allyl ester (see Example 7) has an IC50 of approximately 0.5μM. 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 room temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon; (iii) column chromatography (by the flash procedure) and medium pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phase silica obtained from E. Merck, Darmstadt. Germany; (iv) yields are given for illustration only and are not necessarily the maximum attainable; (v) the end-products of the Formula I 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, infra-red (IR) or NMR analysis; (vii) melting points are uncon n ected 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 I 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-butoxycarbonyl DCCI 1.3-dicyclohexylcarbodiimide DMA N.N-dimethylacetamide DMAP 4-dimethyl-aminopyridine DMF N,N dimethylformamide DMSO dimethylsulfoxide EDC 1 -(3-dimethylaminopropyl)-3-ethyl-carbodiimide EEDQ 2-ethoxy- 1 -ethoxycarbony 1- 1 ,2-dihydroquinoline HOBT 1 -hydroxybenzotriazole NMM Nzmethylmorpholine NMM-O 4-methylmoιpholine-N_.oxide TFA trifluoroacetic acid THF tetrahydrofuran 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). Example 1 (see Scheme 1 ) (2S,4S)-4-acetylsulfanyI-2[3-nitro-5-(N-methoxy-N-methyl- carbamoyI)-phenylcarbamoyl]-pyrrolidine-l-carboxylic acid 4-nitro-benzyl ester A mixture of 4-acetylsulfanyl-pyrrolidine- 1 ,2-dicarboxylic acid 1 -(4- nitrobenzyl) ester (1(c)) (0.2 g) and 3-amino-N-methoxy-N-methvl-5-nitro-benzamide (1(b)) (0.122 g) and EEDQ (0.201 g) in dichloromethane (20 ml) was stirred at ambient temperature for 16 hours. The solution was then stirred with 0.3M hydrochloric acid (20 ml) for ten minutes. The organic phase was separated, dried over magnesium sulphate and evaporated under reduced pressure to give a gum. This was purified by chromatography using 1. ethyl acetate/hexane (50:50) 2. ethyl acetate/hexane (75:25) to give the desired product (1) as a colourless gum (0.132 g). NMR Spectrum (CDC1 3 ) δ 2.35 (s. 3H). 2.62 (m. 2H). 3.4 (s, 3H). 3.44 (m. IH). 3.6 (s. 3H). 4.1 (m. 2H). 4.59 (t. IH). 5.3 (m. 2H). 7.55 (d. 2H). 8.09 (m.lH). 8.25 (d. 2H). 8.3 (m. IH). 8.6 (m.lH). 9.55 (br. s. IH). Starting material (1(c)) was synthesised as described in Reference Example 1-4 in European patent no 126587 (Sumitomo). Starting material (1(b)) was prepared as follows. A mixture of 3-amino-5-nitrobenzoic acid (10 g), pentafluoro-phenol (10 g) and DCCI (11.3 g) was stirred at ambient temperature for 24 hours. The reaction mixture was filtered and the filtrate poured onto a chromatography column which was then eluted with ethyl acetate/hexane (10:90) to give 3-amino-5-nitrobenzoic acid 2.3.4,5,6-pentafluorophenyl ester (1(a)) as a yellow solid (5.8 g). NMR Spectrum (CDC1 3 ) δ 4.3 (br. s, 2H), 7.7 (tr, IH), 7.8 (tr. IH), 8.36 (tr. IH). A mixture of (1(a)) (1.0 g), N,Ozdimethylhydroxylamine HC1 salt (0.84 g) and triethylamine (1.82 ml) in dichloromethane (50 ml) was stirred at ambient temperature for 48 hours. Water(50 ml) was added and the mixture stirred for a further 5 minutes. The organic phase was separated, dried over magnesium sulphate and evaporated under reduced pressure to give a gum. This was purified by chromatography using 1. ethyl acetate/hexane (10:90). 2. ethyl acetate/hexane (50:50) as eluents to give starting material 3-amino-]_±:methoxy-N:methyl-5-nitro benzamide (1(b)) as a yellow solid (0.55 g). NMR Spectrum: (CDCI3) δ 3.36 (s, 3H), 3.58 (s. 3H), 7.26 (tr. IH), 7.56 (tr, IH), 7.90 (tr, IH). Example 2 (see Scheme 2) ( S^^^-acetylsulfanyl- IS-^metho y-l methylcarbamoy -S-nitro- phenylcarbamoyl]-pyrroIidine-l -carboxylic acid allyl ester A mixture of (2S,4S).4-acetylsulfanyl-pyrrolidine-1.2-dicarboxylic acid 1 -allyl ester (1(d)) (0.2 g), 1(b) (0.165 g). and EEDQ (0.271 g), in dichloromethane (20 ml) was stirred at ambient temperature for 16 hours. The solution was then stirred with 0.3M hydrochloric acid for a further 10 minutes. The organic phase was then separated, dried over magnesium sulphate and evaporated under reduced pressure. The product obtained was purified by column chromatography using ethyl acetate/hexane (50:50) as eluent to give the desired product (2) as a colourless gum (0.152 g). 5 NMR Spectrum (CDCI3) δ 2.33 (s, 3H). 2.62 (m. 2H). 3.38 (m. IH). 3.4 (s, 3H). 3.6 (s, 3H). 4.05 (m. 2H), 4.59 (tr, IH). 4.69 (d. 2H). 5.3 (m. 2H). 5.95 (m. IH). 8.14 (t. IH). 8.28 (tr, IH). 8.6 (tr. IH), 9.7 (br.s. IH). Synthesis of starting material (1(d)) is described as "Compound (A)" on page 10 31 of International Patent Application No. WO 92/17479 (Imperial Chemical Industries). Synthesis of starting material (1(b)) is described in Example 1. Example 3 (see Scheme 3) 5-{[(2S,4S),4-acetylsulfanyI-l-(4-nitroben2_yloxycarbonyl)-pyrrolidine-2-carbonyl]- 15 amino}-isophthaIic acid 1 -allyl ester 3-methyl ester DMF (0.07 ml) was added to a stirred solution of oxalyl chloride (0.078 ml) in dichloromethane (20 ml) cooled to -20° under an argon atmosphere. After 15 minutes a solution of (1(c)) (0.3 g; see Example 1) in dichloromethane was added followed by a 0 solution of N-methylmorpholine (0.099 ml) in dichloromethane (2 ml). After a further 15 minutes a solution of 5-amino-isophthalic acid allyl ester methyl ester (3(b)) (0.192g) in dichloromethane (5 ml) was added again followed by a solution of N-methylmorpholine (0.099 ml) in dichloromethane (2 ml). The mixture was allowed to warm to ambient temperature and stirred for 16 hours. The reaction mixture was poured onto a flash column 5 and eluted with 1. ethyl acetate/hexane (50:50) and, 2. ethyl acetate/hexane (75:25) to give the desired end product (3) as a colourless gum (0.24 g). NMR Spectrum (CDCI3) δ 2.33 (s, 3H), 2.62 (m. 2H), 3.45 (m. IH), 3.95 (s, 3H). 4.03 (m. IH). 4.17 (m. IH), 4.57 (tr. IH), 4.85 (m. 2H), 5.32 (m. 2H). 5.36 (m. 2H). 6.05 (m, IH), 7.51 (m, 2H). 8.20 (m. 2H), 8.32 0 (m. 2H), 8.34 (s. IH). 9.2 (br. s, IH). - _> J - Starting material (3(b)) was synthesised as follows. A mixture of mono-methyl-5-nitroisophthalate (13.8 g), allyl bromide (7.96 g), potassium carbonate (13.94 g) and DMF (160ml) was stirred at ambient temperature for 4.5 h. The solid was filtered and DMF was evaporated away from the filtrate under reduced pressure. The residue was dissolved in diethyl ether (300 ml) and water (100 ml) and stirred for five minutes. The organic layer was separated and washed with saturated sodium bicarbonate solution (220 ml), brine (200ml), dried over magnesium sulphate and evaporated under reduced pressure to give 5-nitro-isophthalic acid allyl ester methyl ester (3(a)) as a yellow oil (14.74 g). NMR spectrum (CDC1 3 ) δ 4.0 (s. 3H), 4.9 (m. 2H), 5.4 (m, 2H), 6.1 (m. IH). 9.0 (m. 3H). A mixture of (3(a)) (15.46 g), tin (II) chloride dihydrate (65.78 g) and methanol (200 ml) was stirred at reflux for 4 hours. Methanol was evaporated under reduced pressure and the residue redissolved in ethyl acetate (400 ml). Ammonia solution (sp. g. 0.880) was added dropwise until the mixture reached pH 8 and no more precipitate was being formed. The solid was then filtered and the filtrate was washed with water (100 ml), brine(100 ml), dried over magnesium sulphate and evaporated under reduced pressure to give starting material 3(b) as a yellow solid (13.56 g). NMR spectmm (CDC1 3 ) δ 3.91 (s, 3H) , 3.94 (s ,2H) , 4.82 (m, 2H), 5.35 (m. 2H). 6.05 (m. IH), 7.52 (m. 2H), 8.08 (m ,1H). Example 4 (see Scheme 4) 5-{[(2S,4S),4-acetylsulfanyl-l-(carbamoylmethyl)-pyrroIidine-2-carbonyl]-amino}- isophthalic acid 1 -allyl ester 3-methyl ester A mixture of 5- { [(2S,4S),4-acetylsulfanyl-pyrrolidine-2-carbonyl]-amino } - -isophthalic acid 1 -allyl ester 3-methyl ester TFA salt (4(e)) (0.12 g), iodoacetamide (0.085 g), sodium bicarbonate (0.058 g) and DMF (3.0 ml) was stirred at ambient temperature for 16 h. The DMF was evaporated under reduced pressure and the residue purified by chromatography using 1. ethyl acetate/hexane (60:40), 2. ethyl acetate and, 3. methanol/ethyl acetate (5:95) as eluents to give the desired product 4 as a yellow solid (0.055 g). NMR spectmm δ 2.19 (2 tr.lH). 2.29 (s, 3H). 2.82 (m. IH). 3.22 (m. 2H). 3.48 (q, 2H). 3.6 (m, IH). 3.94 (s, 3H). 4.05 (m. IH), 4.85 (m. 2H). 5.35 (m. 2H), 6.04 (m.lH). 6.1 (br. s. IH), 6.30 (br. s. IH). 8.43 (m. IH), 8.55 (m. IH), 10.46 (br. s. IH). Starting material 4(e) was prepared as follows. A mixture of (2S,4S),4-hydroxy-pyrrolidine-1.2-dicarboxylic acid 1 -tert-butyl ester (1.0 g), EEDQ (1.6 g), Compound (3(b)) (see Example 3) and dichloromethane (100 ml) was stirred at ambient temperature for 16 hours. The mixture was poured onto a flash column and eluted with 1. ethyl acetate/hexane (80:20) and. 2. ethyl acetate to give 5- . [(2S.4S).4-hydroxy-l-( " tert-butoxycarbonyl)-pyrrolidine-2-carbonyl]-amino}-isophthalic acid 1 -allyl ester 3-methyl ester (4(a)) as a colourless gum (0.85 g.). NMR Spectmm (DMSOdό) δ 1.34 (2s. 9H), 1.97 (m, IH), 2.15 (m, IH), 3.30 (m, IH) 3.46 (m, IH), 3.9 (s, 3H), 4.32 (m, 2H), 4.84 (d, 2H), 5.06 (d, IH), 5.35 (m, 2H), 6.07 (m, IH), 8.18 (m, IH), 8.54 (m, 2H). A mixture of (4(a)) (0.8 g), methanesulphonyl chloride (0.152 ml), triethylamine (0.256 ml), and dichloromethane (20 ml) was stirred at 5° under an argon atmosphere for 10 minutes and then at ambient temperature for 2h. Water (20 ml) was then added and the mixture stirred for another 5 minutes. The organic phase was separated. dried over magnesium sulphate and evaporated under reduced pressure. The product was purified by chromatography using 1. ethyl acetate/hexane (30:70) and. 2. ethyl acetate/hexane (80:20) as eluents to give 5- { [(2S,4S),4-methanesulfanyloxy- 1 -(tej_t-butoxycarbonyl)-pyrrolidine- 2-carbonyl]-amino}-isophthalic acid 1 -allyl ester 3-methyl ester (4(b)) as a clear oil (0.8 g). NMR spectmm (CDC1 3 ) δ 1.5 (s, 9H). 2.4 (m, IH), 2.92 (m, IH), 3.07 (s, 3H). 3.63 (m. IH), 3.9 (m. IH). 3.95 (s. 3H), 4.66 (m. IH), 4.85 (m. 2H). 5.27 (m. IH). 5.36 (m. 2H), 6.05 (m. IH). 8.37 (m. 3H). 9.64 (br. s. IH). A mixture of 4(b) (0.74 g), potassium thioacetate (0.32 g) and acetone (25 ml) was maintained at reflux for 18 hours. The mixture was then cooled to room temperature and acetone evaporated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate (50 ml). 1.5M hydrochloric acid (25 ml), and ice (25 ml). The organic phase was separated, dried over magnesium sulphate and evaporated under reduced pressure to give a red gum. This was purified by chromatography using 1. ethyl acetate/hexane (30:70) and. 2. ethyl acetate/hexane(70:30) to give 5- { [(2S,4S),4-acetylsulfanyl- 1 -(terl butoxycarbonyl)-pyπ * olidine-2- carbonyl]-amino}-isophthalic acid 1 -allyl ester 3-methyl ester (4(c)) as an orange gum (0.48 g). NMR spectmm (CDC1 3 ) δ 1.5 (s. 9H). 2.32 (s. 3H). 2.56 (m. 2H). 3.33 (m. IH). 3.93 (s. 3H). 4.04 (m. 2H), 4.52 (tr. IH). 4.85 (m. 2H). 5.35 (m. 2H). 6.05 (m. IH), 8.38 (m. 3H), 9.63 (br. s. IH). A mixture of (4(c)) (3.6 g) and TFA (80 ml) was stirred at ambient temperature for 10 minutes. TFA was evaporated under reduced pressure and the residue dissolved in ethyl acetate (200 ml.) and saturated sodium bicarbonate solution (100 ml). This was then stirred for 10 minutes, the organic phase separated, washed with water (100 ml) and brine (100 ml) and dried over magnesium sulphate. The ethyl acetate was removed under reduced pressure and the residue purified by chromatography using 1. ethyl acetate/hexane (30:70). 2. ethyl acetate/hexane (80:20) as eluents to give 4(f) (the free base which is used in Example 6) as a brown oil (2.3 g). NMR Spectmm (CDC1 3 ) δ 2.05 (m, IH), 2.30 (s, 3H), 2.42 (br. s, IH), 2.78 (m, 2H), 3.58 (m, IH), 3.85 (m, IH), 3.94 (s, 3H), 3.99 (m, IH), 4.84 (m, 2H), 5.35 (m. 2H), 6.05 (m, IH), 8.47 (m, 3H), 9.83 (br. s, IH). A mixture of (4(c)) (0.45 g) and TFA (10 ml) was stirred at ambient temperature for 10 minutes. The TFA was evaporated away under reduced pressure and the residue purified by column chromatography using 1 ethyl acetate/hexane (30:70), 2 ethyl acetate/hexane (60:40), 3 ethyl acetate and, 4 methanol/ethyl acetate (10:90) as eluents to give the desired starting material (4(e)) as a brown gum (0.46 g). NMR Spectrum (CDC1 3 ) δ 2.15 (m, IH), 2.33 (s, 3H), 2.97 (m, IH), 3.44 (m. IH), 3.91 (s, 3H), 3.97 (m, IH), 4.08 (m, IH), 4.82 (d, 2H), 4.98 (tr. IH), 5.35 (m. 2H). 6.03 (m. IH). 8.12 (m. 2H). 8.26 (m. IH). Example 5 (see Scheme 5) 5-{[(2S,4S),4-acetylsuIfanyI-l-acetyl-pyrroIidine-2-carbonyl]-amino}-isophthalic acid 1 -allyl ester 3-methyl ester A mixture of (4(e)) (0.08 g: see Example 4). triethylamine (0.083 ml), acetic anhydride (0.056 ml) and dichloromethane (5 ml) was maintained at reflux for 16 hours. The mixture was cooled, evaporated under reduced pressure and purified by chromagraphy using 1 ethyl acetate/hexane (70:30). 2 ethyl acetate and. 3 methanol/dichloromethane (5:95) to give the desired product 5 as a colurless gum (0.048 g). NMR Spectmm (CDC1 3 ) δ 2.18 (s. 3H), 2.35 (s. 3H), 2.48 (m, IH). 2.77 (m. IH), 3.42 (m, IH), 3.95 (s. 3H), 4.1 (m, 2H), 4.85 (m. 3H). 5.35 (m. 2H). 6.06 (m. IH). 8.40 (m. 3H). 9.88 (br. s. IH). Starting material 4(e) was prepared as described in Example 4. Example 6 (see Scheme 6) 5-{[(2S,4S),4-acety_suIfanyI-l-phenyloxycarbonyI-pyrrolidine-2- carbonyI]-amino}-isophthaIic acid 1 -allyl ester 3-methyl ester A mixture of (4(f)) (0.07g), phenyl chloroformate (0.026 ml), triethylamine (0.07 ml) and dichloromethane (3 ml) was stirred at ambient temperature for 16 hours. The mixture was then evaporated under reduced pressure to give a gum which was purified by chromatography using 1 dichloromethane, 2 ethyl acetate/hexane (30:70) and. 3 ethyl acetate/hexane (60:40) to give the desired product as a colourless gum (0.048 g.). NMR Spectmm (DMSOdό) δ 1.93-2.24 (m, IH), 2.38 (s, H), 2.70 (m, IH), 3.63 (m. IH), 3.91 (d, 3H), 4.18 (m, 2H). 4.60 (m, IH), 4.87 (tr, 2H). 5.38 (m, IH), 6.08 (m. IH), 6.70-7.69 (m. 5H), 8.20-8.53 (m. 3H). 10.61 (d, IH). Starting material (4(f)) was prepared as described in Example 4. Example 7 (see Scheme 7) 5{[(2S,4S).4-acetylsulfanyl-l-(4-nitro-benzyloxycarbonyl)-pyrrolidine-2-carbonyl]- amino}-3(NLmethyl-methoxycarbamoy_)-benzoic acid allyl ester A mixture of (1(c)) (0.02 g; see Example 1). 3-amino- 5(N_:methyl- methoxycarbamoyl)-benzoic acid allyl ester (7(d)) (0.16 g.), EEDQ (0.25 g) and dichloromethane (20 ml) was stirred for 16 h at ambient temperature. The mixture was then washed with 0.3M hydrochloric acid (30 ml), the organic phase separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by column chromatography using ethyl acetate/hexane (75:25) as eluent to give the desired product 7 as a yellow solid (0.053 g). NMR Spectmm (CDC1 3 ) δ 2.33 (s, 3H), 2.60 (m. 2H). 3.38 (s. 3H), 3.42 (m, IH), 3.60 (s. 3H). 4.04 (m. IH). 4.15 (m. IH). 4.55 (m. IH). 4.83 (m, 2H), 5.30 (m. 2H). 5.35 (m. 2H). 6.04 (m. IH). 7.52 (m. 2H). 8.10 (m, 3H), 8.18 (m, 2H), 9.12 (br. s, IH). Starting material (1(c)) was prepared as described in Example 1. Starting material 7(d) was prepared as follows. A mixture of potassium carbonate (17.00 g), 5-nitroisophthalic acid (52.00 g), allyl bromide and dimethylacetamide (400 ml) was stirred at 90° for 4 h. Dimethylacetamide was evaporated away under reduced pressure and the residue was dissolved in ethyl acetate, washed with water (2 x 300 ml) and then extracted with aqueous saturated sodium bicarbonate solution (3 x 300 ml). The extracts were combined, acidified to pH 4 with concentrated hydrochloric acid and reextracted with ethyl acetate (2 x 300 ml). The extracts were combined, washed with water (300 ml), dried over magnesium sulphate and evaporated under reduced pressure to give 5-nitro-isophthalic acid 3-allyl ester (7(a)) as a cream solid (39.48 g). NMR Spectmm (CDCl 3 /DMSOd6) δ 4.90 (m. 2H). 5.42 (m. 2H). 6.08 (m. IH). 9.00 (m. 3H). A solution of 7(a) (10.00 g), N-hydroxysuccinimide (5.04 g) and DCCI (9.03 g) in dichloromethane(400 ml) was stirred at ambient temperature for 3.5 h. The white precipitate which formed was filtered off and the filtrate evaporated under reduced pressure to give a yellow oil. This was purified by flash chromatography eluting with ethyl acetate/hexane (75:25) to give 5-nitro-isophthalic acid l-(2.5-dioxo-pyrrolidin-l-yl) ester 3-allyl ester (7(b)) as a yellow solid (7.58 g). NMR Spectmm (CDC1 3 ) δ 2.95 (s. 4H). 4.92 (m. 2H). 5.43 (m. 2H). 6.07 (m. lH). 9.12 (m, 3H). A mixture of (7(b)) (2.00 g), N.O-dimethylhydroxvlamine hydrochloride (0.62 g), triethylamine (0.86 ml) and dichloromethane (60 ml) was stirred at 5° for 30 min and then allowed to warm to ambient temperature and stirred for a further 16 h. The mixture was poured onto a flash column and eluted with ethyl acetate/hexane (40:60)to give 3-(N_methyl-methoxycarbamoyl)-5-nitro benzoic acid allyl ester (7(c)) as a yellow oil. NMR Spectmm (CDC1 3 ) δ 3.43 (s. 3H). 3.58 (s. 3H), 4.90 (m. 2H), 5.40 (m. 2H). 6.07 (m. IH), 8.71 (m, IH). 8.76 (m. IH), 8.95 (m, IH). A mixture of (7(c)) (1.11 g), tin(II) chloride dihydrate (4.26 g) and methanol (60 ml) was heated under reflux for 1 hour. The reaction mixture was cooled and the methanol evaporated away under reduced pressure. The residue was redissolved in ethyl acetate (100 ml) and ammonia solution (sp. g. 0.880) was added dropwise until the solution reached pH 8. The precipitate that formed was filtered and washed with ethyl acetate (2 x 100 ml). The combined fitrate and washings were evaporated under reduced pressure to give the desired starting material 3-amino-5-(N methyl-methoxycarbamoyl)-benzoic acid allyl ester (7(d)) as a white solid (0.610 g). NMR Spectmm (CDC1 3 ) δ 3.35 (s, 3H). 3.59 (s, 3H). 3.90 (br. s, 2H). 4.82 (m. 2H), 5.35 (m, 2H). 6.04 (m, IH), 7.15 (m. IH). 7.45 (m. 1), 7.72 (m. IH). Example 8 (see Scheme 8) 5{[(2S . 4S),4-acetylsulfanyl-l-(4-nitro-benzyloxycarbonyI)-pyrroIidine-2-carbonyI]- amino}-3(_Vmethyl-allyIoxycarbamoyI)-benzoic acid allyl ester A mixture of (1(c)) (0.293 g; see Example 1), 3-amino- 5(N-methyl- -allyloxycarbamoyl)-benzoic acid allyl ester (8(c)) (0.210 g). EEDQ (0.268 g) and dichloromethane (20 ml) was stirred at ambient temperature for 16 hours. The mixture was then washed with 0.3M hydrochloric acid (30 ml), dried over magnesium sulphate and placed straight onto a flash column eluting with ethyl acetate/hexane (75:25). The product obtained was placed onto a flash column eluting with methanol/dichloromethane (2.5:97.5) to give the desired product 8 as a clear gum (0.153 g). NMR Spectmm (CDC1 3 ) δ 2.33 (s. 3H). 2.61 (m. 2H). 3.40 (s. 3H). 3.42 (m. IH). 4.04 (m. IH). 4.15 (m. IH). 4.26 (d. 2H). 4.55 (m. IH). 4.83 (m. 2H). 5.30 (m, 6H). 5.75 (m. IH). 6.04 (m. IH). 7.53 (m. 2H), 8.12 (m. 2H). 8.21 (m, 3H). 9.12 (br. s. IH). Starting material (8(c)) was prepared as follows. A mixture of 7(b) (2.00 g: see Example 7), N-methylhydroxylamine hydrochloride (1.06 g) triethylamine (1.72 ml) and dichloromethane (60 ml.) was stirred at 5° for 30 minutes. It was then allowed to warm to ambient temperature and stirred for a further 16 hours. The reaction mixture was then poured directly onto a flash column eluting with ethyl acetate/hexane (50:50) to give 3-(N_:methyl-hydroxycarbamoyl)-5-nitro-benzoic acid allyl ester (8(a)) as a cream solid (1.43 g). NMR Spectrum (CDC1 3 ) δ 3.48 (s, 3H), 4.90 (m. 2H). 5.42 (m. 2H), 6.05 (m, IH). 8.28 (br. s. IH), 8.55 (m. IH). 8.63 (m. IH), 8.96 (m. IH). A mixture of (8(a)) (0.60 g), allyl bromide (0.28 g), potassium carbonate (0.59 g) and DMF (20 ml) was stirred for 3 hours at ambient temperature under an argon atmosphere. The dimethyl formamide was then evaporated under reduced pressure and the residue dissolved in ethyl acetate (50 ml) and water (50ml). The organic phase was separated, washed with brine (50 ml), dried over magnesium sulphate and evaporated under reduced pressure to dryness to give 3-(N__methyl-allyloxycarbamoyl)-5-ni tro-benzoic acid allyl ester (8(b)) as a yellow oil (0.571 g). NMR Spectmm δ 3.47 (s. 3H). 4.25 (m. 2H), 4.90 (m. 2H). 5.35 (m. 4H), 5.65 (m, IH), 6.06 (m. IH), 8.73 (m. IH), 8.78 (m, IH). 8.95 (m. IH). SUBSTTΓUTE SHEET (RULE 26) A mixture of (8(b)) (0.523 g), tin(II) chloride dihydrate (1.84 g) and ethyl acetate (50 ml) was heated under reflux for 6 hours. The mixture was allowed to cool to ambient temperature and ammonia solution (sp. g. 0.880) was added dropwise until the solution reached pH 8. The white precipitate which had formed was filtered off. washed with ethyl acetate (2 x 50 ml) and the combined washings and filtrate evaporated to dryness to give the desired starting material (8(c)) as a yellow oil (0.472 g). NMR Spectmm (CDC1 3 ) δ 3.38 (s, 3H). 3.88 (m. 2H), 4.25 (d, 2H). 4.80 (m, 2H). 5.32 (m. 4H). 5.75 (m, IH), 6.03 (m. IH). 7.15 (m, IH), 7.45 (m, IH), 7.75 (m, IH). Example 9 (see Scheme 9) 5-{[(2S,4S),l-(allyloxycarbonyI)-4-suIfanyl-pyrrolidine-2-carbonyI]- amino}-3(Nrmethyl-allyloxycarbamoyl)-benzoic acid allyl ester An aqueous solution of 0.1 M sodium hydroxide (4.41 ml) was added to a solution of 5- { [(2S,4S_),4-acetylsulfanyl- 1 -(allyloxycarbonyl)-pyrrolidine-2- carbony l]-amino } -3 (N-methyl-allyloxycarbamoy 1 Vbenzoic acid allyl ester (9(a)) in allyl alcohol (15 ml) and the mixture was then stirred at ambient temperature for 1 hour. Hydrochloric acid (1.5M) was then added to bring the solution to pH3 and it was then evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (40 ml) and washed with water (2 x 40 ml). The organic phase was separated, dried over magnesium sulphate and evaporated to dryness to give a yellow foam. This was purified by chromatography using ethyl acetate/hexane (75:25) as eluent to give the desired product 9 as a yellow gum (0.148 g). NMR Spectrum (CDC1 3 ) δ 1.88 (d, 2H), 2.62 (m, 2H). 3.37 (s, 3H), 3.45 (m. 2H), 3.60 (s, 3H), 4.08 (m, IH), 4.52 (tr, IH). 4.65 (m, 2H), 4.83 (m, 2H), 5.35 (m, 4H). 6.00 (m, 2H), 8.10 (m. IH). 8.15 (m. IH), 8.21 (m, IH). 9.15 (br. s, IH). Starting material 9(a) was prepared as follows. A mixture of 7(d) (0.568 g: see Example 7). 1(d) (0.645 g; see Example 20), EEDQ (0.585 g) and dichloromethane (50 ml) was stirred at ambient temperature for 16 hours. The mixture was then washed with 0.3M hydrochloric acid(50 ml), dried over magnesium sulphate and applied to a flash column eluting with ethyl acetate/hexane (75:25). It was further purified with a second column eluting with ethyl acetate/hexane (50:50) to give the desired starting material (9(a)) as a colourless gum (0.401 g). NMR Spectmm (CDC1 3 ) δ 2.33 (s. 3H), 2.60 (m. 2H). 3.37 (s. 3H), 3.40 (m. IH). 3.61 (s. 3H). 4.02 (m. IH), 4.13 (m. IH). 4.58 (tr, IH). 4.68 (m. 2H). 4.83 (m. 2H). 5.35 (m. 4H). 6.00 (m. 2H). 8.10 (m. IH). 8.14 (tn. IH). 8.22 (m. IH). 9.30 (br. s. IH). Example 10 (see Scheme 10) 5-[((2S,4S),l-allyloxycarbonyl-4-suIfany.-pyrroIidin-2-yl-methyl)- carbamoyl]-pyridine-2-carboxylic acid methyl ester To a stirring solution of 5-[((2S,4S).l-allyloxycarbonyl-4-BOCsulfanyl-pyrrolidin-2-yl-methyl)- carbamoyl]-pyridine-2-carboxylic acid methyl ester (10(a)) (991 mg; 2.07 mmole) in dichloromethane. TFA (6 mL; 78 mmole) was added dropwise. The solution was stirred. under argon, for 4 hours. The solvent and excess TFA were removed in vacuo. The residue was azeotroped with toluene (2 x 10 mL). Keeping exposure to air to a minimum the resultant oil was triturated with diethyl ether (20 mL). The resultant solid was washed with cold diethyl ether (10 mL) and dried under high vacuum yielding the desired product 10 as a cream solid. 654 mg (76%). [4] has NMR (CDC1 3 ; 250 MHz) d 1.70 (m, IH). 1.75 (d, IH), 2.63-2.77 (m. IH). 3.15-3.50 (m. 3H), 3.90-4.00 (m. IH), 4.05 (s, 3H), 4.07-4.23 (m. 2H). 4.63 (m. 2H). 5.23-5.37 (m. 2H), 5.85-6.03 (m, IH), 8.22 (d, IH), 8.35 (dd, IH). 8.95 (s(br), IH). 9.20 (s, IH). MS (FAB) m/z 380 (M+H) + Anal. C17H21N3O5S. 0.33 C 2 HF 3 0 2 417: C 50.9 (50.8), H 5.3 (5.1). N 10.1 (10.1). Starting material (10(c)) was prepared as follows. Pyridine 2.5-dicarboxylic acid 2-methyl ester (10(a)) (9.0 g; 0.05 mole) was added to stirring thionyl chloride (25 mL) and the mixture refluxed gently for 2.5 hours. The excess thionyl chloride was removed in vacuo and the residual solid azeotroped with toluene (2 x 25 mL) to give 5-chlorocarbonyl-pyridine-2-carboxylic acid methyl ester (10(b)) which was used cmde in the next reaction. To a stirring solution of compound (15(b)) (Example 15)(220 mg; 0.7 mmole) in acetonitrile (6 mL) was added a solution of (10(b)) (0.7 mmole) in acetonitrile (4 mL). Triethylamine (0.29 mL; 2.1 mmole) was added and the solution stirred for 23 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water, aqueous sodiun hydrogen carbonate solution and brine, dried over magnesium sulphate and taken to dryness. The residual orange gum was flash chromatographed on kieselgel 9385. eluting initially with iso-hexane then with increasing proportions of ethyl acetate. The desired starting material 10(c) was isolated as a white foam (200 mg; 60%). NMR (CDC1 3 ; 250 MHz) 1.50 (s, 9H). 1.80 (m, IH), 2.62-2.75 (m. IH). 3.30-3.37 (m. IH), 3.39-3.50 (m. IH). 3.68-3.80 (m, IH), 3.83-3.95 (m, IH). 4.03 (s. 3H), 4.13-4.28 (m. 2H), 4.62 (m. 2H), 5.20-5.37 (m. 2H), 5.87-6.02 (m. IH), 8.2 (d. IH). 8.3 (dd. IH). 8.87 (s, IH), 9.2 (s, IH). MS (FAB) m/z 480 (M+H) Anal. C22H29N3O7S 479 :C 55.1 (55.1), H 6.4 (6.1), N 8.5 (8.8). Example 1 1 (see Scheme 1 1 ) (2S,4S)2-{[(5-ethoxycarbonyl-thiophene-2-carbonyl)-amino]-methyl}-4- sulfanyl-pyrollidine-1-carboxylic acid allyl ester TFA (2mL: 26 mmole) was added to a stirring solution of (2S,4S)2-{[(5-ethoxycarbonyl-thiophene-2-carbonyl)-amino]-methyl}-4- BOCsulfanyl-pyrollidine-1 -carboxylic acid allyl ester (1 1(b)) (130mg ; 0.26 mmole) in dichloromethane (20 mL). The solution was stirred under argon for 19 hours. The solvent and excess TFA were removed in vacuo and the residue dried under high vacuum to give the desired product 11 as a water-white gum (64%). NMR (CDC1 3 : 250 MHz) d 1.38 (t. 3H). 1.55-1.70 (m. IH). 1.75(d. IH). 2.60-2.76 (m. IH). 3.10-3.50 (m. 3H). 3.80-3.95 (m. IH). 4.05-4.25 (m, 2H). 4.38 (q. 2H). 4.70 (m. 2H). 5.20-5.40 (m. 2H). 5.85-6.05 (m. IH). 7.47 (d. IH). 7.73 (d. IH). 8.52 (s(br). IH) MS (FAB) m/z 399 (M+H) + Anal. C17H22N2O5S2 0.5 C2HF3 O 2 455: C 47.6 (47.5). H 5.2 (4.9), N 6.1 (6.15). Starting material 11 (b) was prepared in an analogous manner to the equivalent step in Example 10 but with addition of 5-chlorocarbonyl-thiophene-2-carboxylic -acid-ethyl-ester (1 1(a)) to compound (15(b)) (Example 15) with similar chromatographic work up. 11(b) is a tacky water white gum. Yield 60%. Preparation of (1 1(a)) is described in Journal of the American Pharmaceutical Association (Sci. Ed.) Vol. 41 pp 273-276 (1952). NMR of 1 1(b): (CDC1 3 ; 250 MHz) d 1.4 (t, 3H), 1.5 (s, 9H), 1.70-1.85 (m. IH). 2.57-2.73 (m, IH), 3.26-3.36 (m. IH), 3.38-3.50 (m. IH), 3.65-3.87 (m, 2H), 4.10-4.25 (m. 2H), 4.35 (q, 2H), 4.65 (m, 2H). 5.20-5.38 (m. 2H), 5.85-6.04 (m, IH), 7.47 (d, IH), 7.72 (d. IH), 8.45 (s(br), IH). MS (FAB) m/z 499 (M+H)+, other m z 183 Anal. C22H30N2O7S2 498 C 53.4 (53.0), H 6.3 (6.1). N 5.5 (5.6) Example 12 (see Scheme 12) N-(3,4-dichlorobenzyI)-Nl-((2S,4S),4-sulfanyl-pyrrolidin-2-yl-methyl) thiophene-2,5- dicarboxamide To a stirring solution of N-(3,4-dichlorobenzyl)-N_.-((2S,4S),- l-allyloxycarbonyl-4-sulfanyl-pyrrolidin-2-yl-methyl) thiophene-2.5-dicarboxamide (12(e)) (59 mg: 0.1 mmole) in dichloromethane (10 mL), under argon, was added trimethylsilyliodide (0.35 mL; 0.25 mmole). After 20 hours at ambient temperature the dichloromethane and excess trimethylsilyliodide were removed in vacuo and the residue treated with methanol (3 mL). The insoluble material was treated with further methanol (2 x 3 mL) and then triturated with diethyl ether to yield a solid which was filtered and dried to give the desired product 12 as a light brown solid (59%). NMR (DMSO-d 6 : 250 MHz) δ 1.65-1.90 (m. IH). 2.50-2.62 (m. IH). 3.20-3.40 (m. 2H), 3.55-3.70 (m. 2H). 3.75-3.90 (m. 2H). 4.45 (d. 2H). 7.32 (m. IH), 7.58 (m. 2H). 7.73 (d. IH). 7.78 (d. IH). 8.68 (br. IH). 8.88 (t, IH). 9.22 (t. IH). MS (FAB) m/z 444 (M+H) + other 111. 312 Anal. C18H19CI2N3O2S2 1 -25 HI 0.5 C4H10O 640 C 37.6 (37.5), H 3.5 (3.9), N 6.5 (6.6). Starting material (12(e)) was prepared as follows. To a stirring solution of 3.4-dichlorobenzylamine (0.53 mL: 4.0 mmole) in acetonitrile (10 mL) was added triethylamine (1.67 mL; 12.0 mmole) and a solution of (11(a)) (0.87g ; 4.0 mmole. see Example 11) in acetonitrile (20 mL). The solution was stirred at ambient temperature, under argon, for 22 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid ethyl ester (12(a)) as a cream solid ( 90% ). NMR (CDC1 3 ; 250 MHz) δ 1.40 (t, 3H), 4.38 (q, 2H), 4.57 (d, 2H), 6.47 (t(br). IH), 7.28 (m, IH), 7.42 (m, 2H). 7.48 (d, IH). 7.73 (d, IH) MS (CI) m/z 358 (M+H) + Anal. C 5H13CI2NO3S 358: C 50.4 (50.3), H 3.8 (3.7). N 3.9 (3.9). Aqueous IM sodium hydroxide (16.3 mL; 16.3 mmole) was added to a stirring solution of (12(a)) (1.17g; 3.3 mmole) in ethanol (70 mL). The reaction mixture was stirred at ambient temperature for 19 hours, reduced to a small volume, diluted with water and adjusted to pH 2 by addition of 2M hydrochloric acid. The filtered solid was washed with water and dried in vacuo to give 5-(3.4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid (12(b)) as a white solid (83%). NMR (DMSO d6: 200MHz) d 4.43 (d. 2H), 7.3 (dd, IH), 7.58 (m, 2H). 7.68 (d. IH). 7.78 (d, IH), 9.28 (t. IH) MS (CI) m z 330 (M+H) + Anal. C13H9CI2NO3S 330 C 47.3 (47.3). H 2.7 (2.7), N 4.2 (4.2). A stirring solution of (12(b)) (495mg; 1.5 mmole) in dichloromethane (25 mL) was cooled in an ice bath and DMF (1 drop) and oxalyl chloride (0.175 mL ; 2.0 mmole) added dropwise. The solution was stirred at ambient temperature under argon for 4 hours. The dichloromethane and excess oxalyl chloride were removed in vacuo. The residue was 5 azeotroped with toluene (2 x 15 mL) to give 5-(3.4-dichlorobenzyl-carbamoyl)- thiophene-2-carbonyl-chloride (12(c)) which was used cmde in the next step. Triethylamine (0.83 mL: 4.5 mmole) and a solution of compound (15(b)) (Example 15) (316 mg: 1.0 mmole) in acetonitrile (10 mL) were added to a stirring mixture of (12(c)) (1.5 mmole) in acetonitrile (15 mL) and stirred at ambient temperature under 10 argon for 19 hours. The acetonitrile and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give N-(3,4-dichlorobenzyl)-Nl-((2S,4S),- 1 -allyloxycarbonyl- 4-BOCsulfanyl-pyrrolidin-2-yl-methyl) thiophene-2.5-dicarboxamide (12(d)) as a tacky 15 brown solid (95%). NMR (CDC1 3 ; 200 MHz) δ 1.5 (s, 9H). 1.65-1.85 (m, IH), 2.47-2.73 (m, IH), 3.25-3.50 (m, 2H), 3.65-3.85 (m. 2H), 4.10-4.23 (m. 2H), 4.57 (d, 2H), 4.64 (m. 2H), 5.20-5.40 (m. 2H), 5.85-6.05 (m. IH). 6.45 (t. IH), 7.20 (dd. IH), 7.40 (m. 2H), 7.46 (d, IH), 7.53 (d. IH), 8.47 (br. IH) MS (FAB) m z 628 ( M+H ) + Anal. C27H31 CbN 3 O 6 S .H 2 O 20 646 C 50.2 (50.2), H 4.9 (5.1). N 6.5 (6.5). TFA (5 mL; 65 mmole) was added to a stirred solution of (12(d)) (600 mg; 0.93 mmole) in dichloromethane (25 mL). The solution was stirred at ambient temperature under argon for 4 hours, solvent and excess TFA were removed in vacuo and the residue 25 azeotroped with toluene to give the desired starting material (12(e)). NMR (CDCI3; 250 MHz) δ 1.55-1.75 (m. IH). 1.75 (d. IH), 2.50 - 2.72 (m, IH ), 3.12-3.43 (m. IH), 3.65-3.90 (m, 2H). 4.03-4.20 (m. 2H), 4.54 (d. 2H), 4.63 (m. 2H), 5.17-5.37 (m, 2H), 5.85-6.03 (m, IH 0, 6.63 (br, IH), 7.10-7.55 (m, 5H), 8.5 (br. 2H) MS (FAB) m/z 528 (M+H)+ Anal. C22H23CI2N3O4S2 0.33 C 4 Hι 0 O 0.3 C2HF3O2 30 586.5 C 49.0 (49.0). H 4.5 (4.6), N 7.2 (7.2). Example 13 (see Scheme 13) 5-[N-(3,4-dichlorobenzyl)carbamoyl]-N-((2S,4S)-4-sulfanylpyrrolidin-2-yI- methyl)pyridine-2-carboxamide 5-[N-(3.4-dichlorobenzyl)carbamoyl]-N-((2S,4S)-l-allyloxycarbonyl-4- sulfanylpyrrolidin-2-yl-methyl)pyridine-2-carboxamide (13(e)) was treated with trimethylsilyliodide in similar manner to compound (12(e)) in Example 12. The desired product 13 was obtained as a medium brown solid ( 26% ). NMR (DMSO-d6: 200 MHz) δ 1.70-1.82 (m. IH), 3.15-3.40 (m. 2H). 3.55-3.90 (m, ?H). 4.52 (d. 2H), 7.35 (dd. IH), 7.60 (m. 2H), 8.18 (d. IH), 8.47 (dd, IH). 8.75 (br. IH), 9.10 (d. IH). 9.28 (t -*- ?. 2H). 9.42 (t. IH). MS (FAB) m/z 439 (M+H) + . Anal. C19H20CI2N4O2S. 1.5 HI.0.33 C4H10O 655.7 C 37.4 (37.2), H 3.4 (3.7). N 8.1 (8.5). Starting material (13(e)) was prepared as follows. 5-chlorocarbonyl-pyridine- 2-carboxylic acid methyl ester was reacted with 3,4-dichlorobenzylamine analogously with preparation of compound (12(a)) in Example 12 to obtain 5(3,4-dichlorobenzylcarbamoyI)- pyridine-2-carboxylic acid methyl-ester (13(a)) as a cream solid (61%). NMR (CDCI3; 250 MHz), d 4.05 (s. 3H), 4.62 (d. 2H), 6.80 (t(br), IH). 7.22 (dd, IH), 7.43 (m. 2H). 8.20 (d, lH). 8.30 (m. lH), 9.08 (d, lH). MS (CI) m/z 339 (M+H) + Anal. C15H12CI2N2O3 339 C 53.2 (53.1), H 3.5 (3.6), N 8.1 (8.3). Compound (13(a)) was treated in an analogous manner to compound (12(a)) in Example 12 to obtain 5(3,4-dichlorobenzylcarbamoyl)-pyridine-2-carboxylic acid (13(b)) as an off-white solid (82%). NMR (DMSO-d 6 ; 200MHz) δ 4.50 (d. 2H), 7.33 (dd, IH), 7.58 (m, 2H), 8.13 (d, IH), 8.37 (dd, IH). 9.12 (d, IH), 9.40 (t. IH) MS (CI) m/z 325 (M+H)+ Anal. C 14 HιoCl2N 2 θ3. H 2 O 343 C 48.9 (48.9), H 3.5 (3.5), N 8.0 (8.2). Compound (13(b)) was treated in an analogous manner to compound (12(b)) in Example 12 to give 5(3,4-dichlorobenzylcarbamoyl)-pyridine-2-carbonylchloride (13(c)) which was used crude in the next reaction. Compound (13(c)) was reacted with compound (15(b)) (Example 15) in a similar manner to compound (12(c)) in Example 12 to give 5-[N-(3.4- dichlorober_zyl)carbamoyl]-N-((2S.4S)-l-allyloxycarbonyl-4-BOCsulfanylpyrrolidin-2-yl- methyl)pyridine-2-carboxamide as a light brown solid (13(d)) (81%). NMR (CDC1 3 ; 250 MHz) δ 1.50 (s. 9H). 1.73-1.90 (m. IH), 2.50-2.65 (m. IH). 3.20-3.30 (m, IH), 3.62-3.80 (m. 2H). 4.10-4.27 (m. 2H). 4.65 (d?, 4H). 5.18-5.38 (m. 2H). 5.83-6.05 (m, IH). 6.80 (t(br). IH), 7.20-7.28 (m. 2H), 7.40-7.48 (m, 2H), 8.23 (s. 2H). 8.75 (br. IH). 8.98 (d?. IH). MS (FAB) m z 623 (M+H) + Anal. C 2 8H32ChN 4 O 6 S 623 C 53.8 (53.9). H 5.1 (5.2). N 8.9 (9.0) mp l36-137.5°C. Compound (13(d)) was treated in a similar manner to compound (12(d)) in Example 12 to give the desired starting material (13(e)) as a light brown solid (64%). NMR (CDCI3; 250 MHz) δ 1.70 (d. IH), 1.80-2.00 (m, IH), 2.52-2.65 (m. IH). 3.05-3.25 (m, 2H). 3.60-3.85 (m. 2H). 4.05-4.20 (m, 2H). 4.60 (d?. 4H). 5.18-5.33 (m. 2H), 5.85-6.03 (m, IH), 6.80 (br, IH), 7.20 (dd. IH). 7.40-7.47 (m, 2H), 8.23 (s, 2H), 8.78 (br. IH), 9.0 (s, 1 H). MS (FAB) m/z 523 (M+H) + Anal. C23H24CI2N4O4S. 0.1 C 2 HF 3 0 2 534.4 C 52.4 (52.1), H 4.6 (4.5). n 10.3 (10.5) mp 101 -105°C Example 14 (see Scheme 14) l-hydroxy-4-[((2S,4S),4-sulfanyl-pyrrolidin-2yl-methyl)-amino- sulfonyl]naphthalene-2-carboxylic-acid To a stirring solution of l-hydroxy-4-[((2S,4S),l-allyloxycarbonyl-4-sulfanyl-pyrrolidin-2yl- methyl)-aminosulfonyl]-naphthalene-2-carboxylic-acid (14(c)) (47.5 mg; 0.1 mmole) in dichloromethane (10 mL) was added TMSI (0.56 mL; 0.4 mmole). The solvent and excess TMSI were removed in vacuo after 6 hours. Methanol (5 mL) was added to the residue and then removed in vacuo from the solution. The residue was triturated with diethyl ether, filtered and dried in vacuo to obtain the desired product 14 as a brown solid (74%). NMR (DMSO-d6; 250 MHz) δ 1.45-1.62 (m. IH). 2.25-2.45 (m, IH). 2.90-3.25 (m. 3H). 3.45-3.70 (m. 2H), 7.72 (m. IH). 7.85 (m. IH). 8.12 (m. IH). 8.38-8.60 (m. 2H). 9.15 (br. IH) MS (FAB) m/z 383 (M+H) + * Anal. Ci 6 Hi 8N 2 O5S 2 . 1.25 HI.0.5 C 4 H 0 O 579 C 37.0 (37.3), H 4.1 (4.2). N 4.8 (4.8). Starting material (14(c)) was prepared as follows. Compound (15(b)) (Example 15) and 1 -hydroxy-4-chlorosulfonyl-naphthalene-2-carboxylic acid (14(a)) were coupled in a similar manner to the equivalent step in Example 15 to give 0 l-hydroxy-4-[((2S,4S), l-allyloxycarbonyl-4-BOCsulfonyl-pyrrolidin-2yl-methyl)-aminosulfonyl]-naphthalene-2- carboxylic-acid (14(b)) as a light brown solid (80%). NMR (CDC1 3 ; 250 MHz) δ 1.45 (s. 9H). 1.50-1.75 (m. IH), 2.28-2.42 (m. IH), 2.96-3.10 (m, 2H), 3.48-3.60 (m. IH). 3.80-3.90 (m, IH). 3.95-4.05 (m. IH), 4.47 (m, 2H). 4.53-4.63 5 (m. IH), 7.55 (m, IH), 7.67 (m. IH), 8.50 (m, 2H), 8.70 (m, IH) MS (FAB) M+Na + 589, other 317. 261 Anal. C25H30N2O9S2.H2O.O.8 C3H15N 664.8 C 53.7 (53.8), H 6.7 (6.6), N 5.9 (5.9). 2M Aqueous sodium hydroxide (5 mL; 10.0 mmole) was added to a stirring 0 solution of (14(b)) (333mg; 0.5 mmole) in methanol (5 mL). The solution was evaporated to dryness after 42 hours and the residue dissolved in water (10 mL). The solution was adjusted to pH 2 with 2M hydrochloric acid and the solid was filtered, washed with water and dried in vacuo to give the desired starting material (14(c)) as a white solid (72%). NMR (CDCI3: 200 MHz) δ 1.48-1.70 (m, 2H). 2.38-2.52 (m, IH), 5 2.85-3.40 (m. ?H), 3.90-4.05 (m, 2H), 4.40-4.60 (m, 3H), 5.10-5.35 (m, 3H), 5.70-5.95 (m. 2H), 6.20-6.45 (br, IH). 7.57-7.90 (m. 3H), 8.43-8.70 (m, 4H) MS (FAB) m/z 467 (M+H) + Anal. C20H22 2O7S2. 0.5 H 2 O 475 C 50.6 (50.5). H 4.8 (4.8), N 6.0 (5.9). Example 15 (see Scheme 15) (2S)-2-{3-[([2S,4S]-4-suIfanyl-pyrrolidin-2-yl-methyl)-sulfamoyI]- benzoylamino}-4-methylsulfanyl-butyric acid methyl ester TFA (2.0 mL) was added to a stirred solution of (2S)-2-{3-[([2S,4S]-4-BOCsulfanyl-pyrrolidin-2-yl-methyl)-sulfamoyl]- benzoylamino}-4-methylsulfanyl-butyric acid methyl ester ( 15(d)) (101 mg. 0.18 mmol) in CH2CI2 (2.0 mL) at room temperature under argon. After 1 h the reaction mixture was concentrated to a dryness. azeotroped with toluene (3 x 10 mL) and dried to yield the desired product 15 as a colourless gum: 101.8 mg (99%). -H NMR (CDCI3. 250MH Z ) δ 1.6-1.8 (IH. m); 2.0 (IH. d. SH); 2.1-2.4 (5H. m): 2.52.65 (3H. m): 3.15-3.4 (3H. m) 3.45-3.65 (IH. m); 3.7-3.85 (4H. m) 3.9-4.1 ( IH. m): 4.85-5.0 (IH. m); 7.55-7.7 (2H. m) 7.8 (IH. s); 8.0 (IH. d); 8.1 (IH. d); 8.3 (IH. s); 9.0-9.4 (IH. s); 10.0-10.4 ( 1H. S). MS (ESP+) m/z 462 (M+H) + . Starting material (15(d)) was prepared as follows. Triethylamine (3.0mL, 21.5mmol) was added to a stirred suspension of L-methionine methyl ester. HC1(4.37 g, 21.8 mmol) in CH2CI2 (50 mL). The resulting mixture was left to stir for 30 min at room temperature then filtered. The filtrates were then added to a stirred solution of 3-chlorosulphonyl-benzoyl chloride (5.23 g, 21.9 mmol) and triethylamine (7.6 mL. 54.7 mmol) in CH2CI2 (50 mL) at 0° under argon. The reaction mixture was allowed to warm to room temperature and quenched with ice-water(100 mL). The organics were the dried over MgSO4. filtered and concentrated to a viscous brown gum. This was then purified by flash chromatography on 9385 Siθ2- eluting with 50% EtOAc/i-Hexane to give (2S)-2-(3-chlorosulfonyl-benzoylamino)-4-methylsulfonyl-butyric acid methyl ester (15(a)) as a viscous orange oil: 2.88 g (36%). l U NMR (CDCI3.25O MH Z ) δ 2.1-2.2 (5H. m); 2.65 (2H, t); 3.83 (3H. s); 4.95 (IH. m); 7.23 (IH. d); 7.74 (lH.t); 8.2 (2H.m): 8.47 (lH,m). MS (CI) m/z 366 (M+H) + . 332.300. A solution of 15(a) (1.53 g, 4.18 mmol) in CH2CI2 (20 mL) was added to a stirred solution of (2S,4S)-2-aminomethyl-4-BOCsulfanyl-pyrollidine-l -carboxylic acid allyl ester (15(b)) (prepared as described in International Patent Application WO 92/17480. see pages 39-41 ) (1.32g. 4.18 mmol) and iPr^NEt (1.5 mL. 9.0 mmol) in CH 2 Cl2 (30mL) at 0°C under argon. The resulting solution was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then washed with water ( 100 mL), dried over MgSO4. filtered and concentrated to a viscous white gum. This was then purified by flash chromatography on 9385 Siθ2- eluting with a gradient of 35-50% EtOAc/i-Hexane to give (2S,4S)-4-BOCsulfanyl-2-{[3-([l S]-l-methoxycarbonyl-3-methylsulfanyl- propylcarbamoyl)-benzenesulfonylamino]-methyl } -pyrrolidine- 1 - carboxylic acid allyl ester ( 15(c)) as a colourless foam: 2.19 g (81.3%). IH NMR (CDC1 3 .200MH Z ) δ 1.5 (9H. s); 1.65-1.9 (IH. s): 2.05-2.35 (5H. m); 2.4-2.7 (3H. m); 3.3-3.4 (3H, m); 3.55-3.75 (IH. m); 3.8 (3H. s); 3.9-4.2 (2H. m); 4.55 (2H. d); 4.98 (IH. m): 5.15-5.35 (2H, m); 5.8-6.0 (IH. m): 6.5 (IH. s); 7.4 (IH. s); 7.55 (IH. t); 7.9-8.05 (2H. m); 8.25 (IH, m). MS (FAB) m/z 646 (M+H)+. 590.568.546.230. Anal. Calcd for C27H39N3O9S3.O.3CH2CI2 :C. 48.8; H. 5.95; N, 6.26. Found C, 48.9; H, 6.2 N. 6.0. Tri-nButyl tin hydride (565 mL, 2.1 mmol) was added to a stirred solution of (15(c)) (1.18 g, 1.8 mmol) and (PPh)3PdC_2 (13 mg. 0.018 mmol) in a mixture of water (0.5 mL) and CH2CI2 (100 mL). The reaction mixture was left to stir for 10 minutes, dried over MgSO4, filtered and concentrated to a brown oil. This was then purified by flash chromatography on 9385 Siθ2- eluting with a gradient of 0-10% EtOAc/i-Hexane to give the desired starting material 15(d) as a white foam: 751 mg (73%). lH NMR δ 1.5 (9H, s): 1.85-1.97 (IH, m); 2.1-2.35 (5H, m); 2.45-2.7 (3H. m); 3.1-3.4 (3H. m): 3.65-4.25 (6H. m); 4.9-5.0 (IH, m); 7.63 (IH. t); 7.97-8.05 (IH, m); 8.1-8.17 (IH. m) 8.35-8.42 (IH, m). MS (ESP+) m z 562 (M+H) + , 462. Anal. Calcd for C23H35N3O7S3: C. 49.2; H. 6.28: N, 7.48. Found C. 49.4; H. 6.3: N. 7.2. Example 16 (see Scheme 16) (2S),2-{3-[([2S,4S]-4-sulfanyl-pyrrolidin-2-yl-methyl)-sulfamoyl]- benzoyIamino}-4-methylsulfanyl-butyric acid 2N NaOH(2.0 mL. 4.0 mmol) was added to a stirred solution of compound (15(d)) (prepared in Example 15) (200 mg, 0.36 mmol) in MeOH at room temperature under argon. After 18 h the reaction mixture was concentrated to remove the MeOH. The resulting residues were dissolved in H2θ(2.0 mL) and acidified to pH3 with 2N HC1. The resulting solution was purified by reverse phase HPLC (Dynamax C18.8μ prepcolumn). eluting with a gradient of 0-40% MeOH FbO. Product fractions were concentrated and azeotroped with toluene (3 x 25 mL) to give a colourless glass which was then triturated with Et2θ (25 mL), filtered and dried to yield the desired product 16 as a white powder: 85.2 mg (54%). l H NMR (DMSO-D 6 +CD 3 COOD.250 MH Z ) δl.45-1.65 (IH, m); 2.0-2.2 (5H. m); 2.3-2.7 (3H+DMSO, m); 2.95-3.2 (3H. m); 3.35-4.2 (3H. m); 4.5-4.65 (IH. m); 7.65-7.8 (IH, m); 7.9-8.05 (IH. m); 8.1-8.25 (IH. m); 8.3-8.4 (IH, m). MS (FAB) m z 448 (M+H) + . Anal. Calcd for C17H25N3O5S3: C. 45.6; H, 5.63; N. 9.39. Found C. 45.5; H, 5.8; N, 9.1. Example 17 (see Scheme 17) N_(3,4-dichlorophenyl)-3-[([2S,4S],4-sulfanyl-pyrrolidin-2-yl-methyl)-sulfamoyl]- benzamide N = (3,4-dichlorobenzyl)-3-[([2S,4S],4-BOCsulfanyl-pyrrolidin-2-yl-methyl)- sulfamoylj-benzamide (17(c)) was deprotected with TFA (analogously to compound (15(d)) in Example 15) to give the desired product 17 in 97% yield after trituration with Et2θ. *H NMR (CDC_3,200MHz) δl.5-1.8 (IH. m); 1.8-2.2 (2H+H 0,m.SH.NH); 2.5-2.7 (lH.m): 3.1-3.35 (3H. m); 3.4-4.1 (3H. m); 4.55 (2H. d); 7.15 (IH. dd); 7.2 (IH. s): 7.32 (1H, d); 7.4 (IH, d); 7.65 (lH+PPh PO. m); 7.9 (IH, m); 8.2 (IH. m): 8.35 (IH. m); 8.5-9.3 (IH. s, NH); 10.3-10.7 (IH. s. NH). MS (ESP+) m/z 474 (M+H)\ 279(Ph 3 PO) Starting material (17(c)) was prepared as follows. 3.4-Dichlorobenzylamine was coupled with 3-Chlorosulphonylbenzoyl chloride (analogously as for compound (15(a)) in Example 15) to give 3-(3.4-dichloro-benzylcarbamoyl)-benzene-sulfonyl-chloride (17(a)) in 28% yield. 1 H NMR (CDC1 3 ,250MH Z ) δ4.6 (2H. d); 6.6 ( 1 H. s, NH); 7.2 ( 1 H. dd). 7.4-7.5 (2H. m); 7.75 (IH. t): 8.15-8.25 (2H. m): 8.4 (IH. m) MS (FAB) m z 378 (M+Hr,380. Compound 15(b) (Example 15) was coupled with (17(a)) analogously as for the equivalent step in Example 15 to give N_;(3.4-dichlorobenzyl)-3-[([2S,4S],4-BOCsulfanyl-pyrrolidin-2-yl- methyl)-sulfamoyl]-benzamide (17(b)) in 72.5% yield. 1H NMR (CDC1 3 ,200MH Z ) δl.5 (9H, s); 1.6-1.9 (1H+H 2 0, m); 2.4-2.6 (IH, m); 3.1-3.3 (3H, m); 3.6-3.7 (IH, m); 3.8-4.1 (2H. m); 4.4 (2H, d); 4.6 (2H, d); 5.1-5.3 (2H, m); 5.7-5.95 (IH, m); 6.08 (IH. s, NH); 7.2 (IH, dd); 7.35-7.7 (4H. m); 7.95 (IH. d); 8.15 (IH, d); 8.25-8.35 (lH, s, NH). MS (FAB) m/z 658 (M+H) + Anal. Calcd for C28H33N3CI2O7S2: C 51.1 ; H, 5.05: N, 6.38. Found C, 50.8; H.5.2: N.6.2. Compound (17(b)) was deprotected, analogously as for the equivalent step in Example 15. to give the desired starting material (17(c)) in 70% yield. *H NMR (CDCI3, 250MH Z ) δ 1.15-1.45 (IH, m); 1.5 (9H. s); 2.25-2.4 (IH. m): 2.6-2.9 (4H, m); 3.02 (IH. dd); 3.25-3.4 (2H. m); 3.45-3.6 (IH. m); 4.6 (2H, m); 7.05 (IH. m); 7.2 (IH, dd); 7.4 (IH. d); 7.45 (IH, d); 7.6 (IH, t): 7.95 (IH, d); 8.1 (IH, d); 8.25 (IH, s). MS (ESP+) m/z 574 (M+H) + ,574,279 (PPh 3 O) Example 18 (see Scheme 18) N_:(3,4-dichlorobenzyI)-N'-([2S,4S],4-sulfanyl-pyrrolidin-2yl-methyl)- isophthalamide Nr(3.4-dichlorobenzyl)-N'-([2S,4S],4-BOCsulfanyl-pyrrolidin-2yl- methyl)-isophthalamide (18(e)) was deprotected with TFA (analogously to the equivalent step in Example 15) to give the desired product 18 in 100% yield after trituration with Et 2 O. *H NMR (CDCI3+CD3COOD. 250MH Z ) δl .75-1.9 (IH. m): 2.6-2.75 (IH. m): 3.2-3.35 (IH. m); 3.45-3.65 (IH. m): 3.7-3.95 (3H. m): 4.05-4.15 (IH. m); 4.6 (2H. s); 7.2 (IH. dd); 7.4 (IH. d): 7.55 (IH. t): 7.95-8.05 (IH. m); 8.1-8.2 (IH. m): 8.4 (IH. m). MS (ESP+) m/z 438 (M+H) + . Starting material (18(e)) was prepared as follows. A suspension of isophthalic acid monomethyl ester (18(a)), (2.65 g, 14.7 mmol) in CH2CI2 (100 mL) and DMF (10 drops) was treated with oxallyl chloride (2.6 ml, 29.8 mmol) at 0° under argon. The reaction mixture was allowed to warm to room temperature over 18h. The resulting solution was concentrated and azeotroped with toluene to give a crystalline yellow solid. This was then redissolved in CH2CI2 (100 mL) and added dropwise to a stirred solution of 3.4-dichlorobenzylamine (2.6 g. 14.7 mmol) and Et 3 N (5 mL. 35.9 mmol) in CH2CI2 (100 mL) at 0° under argon. The resulting solution was allowed to warm to room temperature over 4 hours, washed with IN HC1(50 mL), saturated NaHCO3 (aq) (50 mL), dried over MgSO4, filtered and concentrated to an orange oil. This was then purified by flash chromatography on 9385 Siθ2 eluting on a gradient of 25-50% EtOAc/i-Hexane to yield 3-(3,4-dichlorobenzyl-carbamoyl)-benzoic acid methyl ester (18(b)) as a pale yellow oil: 3.99g (80%). *H NMR (CDC_3,200MH Z ) δ3.9 (3H. s); 4.6 (2H, d); 6.6-6.8 (IH, NH); 7.18 (IH. dd): 7.38-7.45 (2H. m); 7.54 (lH.t): 8.0-8.1 (IH, m): 8.13-8.23 (IH. m); 8.35-8.42 (IH. m). MS (CI) m/z 338 (M+H) + . A stirred solution of (18(b)) (3.85 g. 1 1.4 mmol) in MeOH (100 mL) at room temperature under argon was treated with 2N NaOH (12 mL. 24 mmol). The reaction mixture was allowed to stir at room temperature for 4 h. concentrated to 1/5 volume and acidified to pH4 with 2N HC1. The resulting precipitate was then collected by filtration. washed with water (2 x 25 mL) and dried under high vacuum to yield 3-(3.4-dichlorobenzyl-carbamoyl)-benzoic acid (18(c)) as a white powder: 2.9 g (79%). IH NMR (DMSO-D 6 . 200MH Z ) δ4.49 (2H. d); 7.32 (IH. dd); 7.5-7.7 (3H. m); 8.0-8.2 (2H. m); 8.42-8.53 (IH, m); 9.27 (IH. t. NH); 13.0-13.4 (IH. s. COOH). MS (ESP+) m z 324 (M+H) + , 159. Anal. Calcd for C 15 Hι ιNO 3 Cl2.0.4H 2 O C. 54.4: H. 3.59; N, 4.23 Found C. 54.0: H. 3.2; N. 4.2 l-(3-Dimethylaminopropyl)-3-ethyl carbodiimide.HCl (655 mg, 3.4 mmol) and 1-Hydroxybenztriazole (463 mg, 3.4 mmol) were added portionwise to a stirred solution of (18(c)) (1.0 g, 3.1 mmol) in DMF (20 mL) at 0° under argon. After 30 mins a solution of compound (15(b)) (Example 15) (1.13 g, 3.57 mmol) in DMF (20 mL) was added dropwise. followed by N-methyl morpholine (375 ml. 3.4 mmol). The mixture was then allowed to warm to room temperature over 4 hours. The resulting reaction mixture was concentrated to 1/5 volume and diluted with EtOAc(100 mL). This solution was then washed successively with IN citric acid (100 mL). saturated NaHCO3(aq) (100 mL), water (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated to a white foam. This was then purified by flash chromatography on 9385 Siθ2, eluting on a gradient of 50-75% EtOAc/i-Hexane to yield (2S,4S),4-BOCsulfanyl-2- { [3 -(3 ,4-dichlorobenzylcarbamoyl)-benzoylamino]-methyl } -pyrrolidine- 1 -carboxylic acid allyl ester (18(d)) as a white foam: 1.57 g (82%). Ϊ H NMR (CDCI3, 250MH Z ) 61.5 (9H. s); 1.6-1.9 (IH. m); 2.55-2.75 (IH, m): 3.2-3.6 (2H.m); 3.65-3.9 (2H. m); 4.1-4.25 (2H, m); 4.5-4.65 (4H. m); 5.15-5.35 (2H, m): 5.38-6.0 (IH. m); 6.87 (IH, t. NH); 7.2 (IH. dd): 7.4 (IH. d); 7.45 (IH. d); 7.55 (IH, t); 7.95 (IH. d); 8.07 (IH. d); 8.25 (IH. s); 8.35-8.6 (IH. s, NH). MS (ESP+) m/z 622 (M+H) + ,566.522. Anal. Calcd for C29H33N3CI2O6S : C. 55.9: H. 5.34; N, 6.75 Found C. 56.1 : H. 5.6; N. 6.6 Compound (18(d)) was deprotected (analogously as for the equivalent step in Example 15) to give the desired starting material (18(e)) in 67% yield. IH NMR (CDC1 3 .200MH Z ) δl.2-1.6(10H. m): 2.25-2.55 (2H. mlH + INH): 2.9 (IH.q); 3.3-3.75 (5H. m); 4.6 (2H. d): 6.9-7.05 (IH. m. NH); 7.05-7.15 (IH. m. NH); 7.2 (IH. dd); 7.4 (IH. d); 7.45 (IH. d); 7.52 (IH. t); 7.9-8.05 (2H. m): 8.23 (IH. m). MS (ESP+) m/z 538 (M+H) + . 438. Example 19 (see Scheme 19) (2S,4S),4-sulfanyl-2-[(3-methoxycarbonyI-benzoylamino)-methyl_- pyrrolidin-l-carboxylic acid allyl ester (2S,4IS),4-BOCsulfanyl-2-[(3-methoxycarbonyl-benzoylamino)- methyl] -pyrrolidin-1 -carboxylic acid allyl ester (19(a)). (300 mg, 0.63 mmol) was dissolved in TFA (5 mL) at room temperature under argon. The reaction mixture was concentrated and azeotroped with toluene (3 x 20 mL) to yield the desired product ( 19) as a colourless viscous gum: 250 mg (105%). 'H NMR (CDCI3, 200MH ) δl.6-1.85 (2H, m. CH+SH); 2.55-2.85 (2H. m); 3.1-3.6 (3H. m): 3.92 (3H. bs); 4.0-4.4 (2H. m): 4.65 (2H. d); 5.15-5.4 (2H. m); 5.8-6.1 (IH. m): 7.53 (IH, t); 8.0-8.1 (IH, m): 8.1-8.25 (IH, m); 8.3-8.7 (2H, m. Aromatic-H + NH). MS (FAB) m z 379 (M+H) + , 163. Starting material (19(a)) was prepared as follows. A suspension of isophthalic acid monomethyl ester (compound 18(a), Example 18). (2.5 g. 13.89 mmol) in CH2CI2 (50 mL) and DMF (10 drops) was treated with oxallyl chloride (1.35mL.15.5mmol) at O° under argon. The reaction mixture was allowed to warm to room temperature over 18 h. The resulting solution was concentrated and azeotroped with toluene to give a crystalline yellow solid. This was then redissolved in CH2CI2 (50mL) and added dropwise to a stirred solution of (2S,4S)-2-aminomethyl-4-BOCsulfanyl-pyrollidine-l -carboxylic acid allyl ester (compound 15(b), Example 15) (2.0 g, 6.33 mmol) and (ΦrbNEt (2.2 mL. 12.66 mmol) in CH2CI2 (50 mL) at O° under argon. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, then washed with water (2 x 50 mL). dried over MgSO4. filtered and concentrated to a dark brown oil. This was then purified by flash chromatography on 9385 Siθ2 eluting with a gradient of 25-50%EtOAc/i-Hexane to yield the desired starting material (19(a)) as a pale yellow, viscous oil: 1.81 g (60%). *H NMR (CDC1 3 ,200MH Z ) δ 1.5 (9H. s); 1.65-1.9 (IH. m); 2.55-2.8 (IH. m): 3.3 (IH. q); 3.4-3.65 (IH. m); 3.65-3.9 (2H, m); 3.95 (3H. s); 4.05-4.35 (2H. m): 4.6-4.7 (2H.m); 5.15-5.4 (2H. m); 5.8-6.1 (IH. m); 7.52 (IH, t); 8.02 (IH, dd); 8.15 (IH. dd); 8.25-8.5 (IH. bs. NH); 8.55 (IH. bs). MS (FAB) m/z 479 (M+Hr. 423.163. Anal. Calcd for C23H30N2O7S : C, 57.7; H. 6.32: N, 5.85. Found C. 57.5; H, 6.4: N. 5.7. Example 20 (see Scheme 20) N:(I2S,4S],4-sulfanyl-pyrrolidin-2yl-methyI)-3-phenoxy-benzamide 3-Phenoxybenzoic acid was coupled with (2_E,4S>)-2-aminomethyl-4- BOCsulfanyl-pyrollidine-1 -carboxylic acid allyl ester (compound (15(b)), Example 15), followed by selective deprotection of the N-allyloxycarbonyl group and removal of the BOC group (analogously to the equivalent steps in Example 15) to give the desired product 20. NMR CDCI3 δ 1.8 (IH, m). 2.72 (IH. m). 3.01-3.31 (IH. bd). 3.69-3.97 (4H. m), 4.3 (IH, bs). 6.92-7.17 (4.5H. m. aromatics), 7.23-7.45 (5.5H. m. aromatics). 7.56 (IH, m), 7.68 (IH, t). 8.02-8.29 (IH, 2t), 9.02-9.29 (IH. 2bs). +ether. Analysis requires for C18H20N2O2S.HI C=47.33. H=4.6, N=6.13; Found C=47.8. H=4.5. N=6.1 Example 21 (see Scheme 21) 5-{(_2S.4S] . l-allyloxycarbonyI-4-suIfanyl-pyrrolidin-2yl-methyl)- carbamoyI}-isophthalic acid dimethyl ester Benzene- 1.3.5-tricarboxylic acid dimethyl ester was coupled to (2S.4S)-2-aminomethyl-4-BOCsulfanyl-pyrollidine-l -carboxylic acid allyl ester (compound (15(b)), Example 15). followed by removal of the BOC group (analogously to the equivalent steps in Example 15) to give the desired product 21. NMR CDC1 3 δ 1.67 (IH. m), 1.75 (IH. d), 2.66-2.89 (3H. m). 3.21 (IH. q), 3.27-3.37 (IH. m), 3.5 (IH. m). 3.9 (2H. bs), 3.97 (6H. s), 4.08-4.27 (2H. m). 4.68 (2H. d). 5.2-5.4 (2H. m). 5.88-6.06 (IH. m), 8.68 (2H. bs), 8.8 (IH, d). Analysis requires for C20H24N2O7S C = 55.0 H = 5.54 N = 6.42; Found C = 54.9 H = 5.6 N = 5.75 Example 22 (see Scheme 22) (2S)-2-{3-[([2S,4S]-4-sulfanyl-pyrrolidin-2-yl-methyI)-amino]-benzoyl-amino}-4- methylsulfanyl-butyric acid methyl ester (2S)-2-{3-[([2S,4S]-4-BOCsulfanyl-pyrrolidin-2-yl-methyl)-amino]- benzoylamino}-4-methylsulfanyl-butyric acid methyl ester (22g) was deprotected (analogously as for the equivalent step in Example 15) to yield the desired end product (22). 1 H NMR (CDCl3+CD3COOD)δl .7-1.9(lH,m);2.0-2.4(6H+CH 3 COOH.M);2.5-2.8(3h.M); 3.23(lh,Q);3.45-3.7(2H.m);3.7-3.9(4H.m);3.95-4.15(lH,m);4.8-4.95(lH.m);6.8(lH,d):7.0 5-7.18(2H.m):7.23(lH.t). MS (ESP) m/z 398 (M+H) + ,235. Anal.Calcd for Ci 8H27N 3 O3S2l .25TFA:C.45.6;H.5.27;N.7.78 Found C.45.2:H,5.3;N.7.4 Starting material 22g was prepared as follows. i) Preparation of (2S,4S_),4-BOCsulfanyl-2-formyl-pyrrolidine-l -carboxylic acid allyl ester (22b) TPAP (5.5mg.0.0156mmol) was added to a stirred mixture of (2S,4S).4-BOCsulfanyl-2-hydroxymethyl-pyrrolidine-l -carboxylic acid allyl ester (22a)(100mg.0.31mmol) and NMM-O (56mg.0.478mmol) in CH2Cl (2.0mL) and CH 3 CN (lOOμL) containing dried powdered 4A° molecular sieve(200mg). The reaction mixture was left to stir for lh then concentrated to dryness. This was then purified by flash chromatography on Siθ2 (Varian Mega Bond Elut Column) eluting with 50% EtOAc/i-Hexane to give compound 22b as a colourless gum: 66.3mg(66.7%). 1 H NMR (CDCl3.250MH Z ) δl .4-1.6(9H.m);2.0-2.25(lH,m);2.45-2.75(lH.m): 3.45-3.6(lH.m);3.75-3.9(lH.m);3.9-4.1(lH,m);4.1-4.35(lH,m):4.5-4.7(2H.m):5.15-5.4(2H ,m);5.75-6.05(lH,m):9.4(lH.s.CHO). MS (CI) m z 316 (M+H) + ,260.216. ii) Preparation of (2S),2-[(3-amino-ber_zoyl)-amino]-4-methylsulfanyl-butyric acid methyl ester (22e) 3-Nitro-benzoic acid (22c)(2.0g,l 1.9mmol) was coupled with L-methionine methyl ester hydrochloride (2.6g,13mmol) according to the method used to synthesise compound 18a. to give (2S),2-[(3-nitro-benzoyl)-amino]-4-methylsulfanyl-butyric acid methyl ester (22d) as a white solid:3.15g(93.4%) 1 H NMR (CDCl 3 ,200MH Z )Δ2.05-2.45(5H.m);2.63(2H.t);3.82(3H,s);4.96(lH,m); 7.2(lH.d.NH);7.65,lH.t);8.18(lH.m);8.39(lH.m);8.65(lH,m). MS (ESP) m z 313 (M+H) + ,265.253. Anal. Calcd for Ci3Hi6N2θ 5 S:C.50.0:H,5.16:N,8.97 Found C.50.3;H,5.1;N.8.9 A stirred solution of 22d (500mg.l .62mmol) in MeOH(lOmL) was treated portionwise with decolourising charcoal (50mg), and iron III chloride hexahydrate (7mg.0.026mmol). N,N-Dimethyl hydrazine (1.5mL. 19.8mmol) was then added dropwise and the resulting suspension was heated to reflux for a total of 18h. The reaction mixture was then concentrated to dryness and the residues purified by flash chromatography on Siθ2 (Varian Mega Bond Elut Column) eluting with 50%EtOAc/i-Hexane. Product fractions were then concentrated to yield a colourless oil which crystallised on standing. This was then triturated with E_2θ to give 22e as a white powder which was collected by filtration and dried:367mg (81.2%) ] H NMR (CDC1 3 ,250MH Z ) δ2.0-2.4(5H.m);2.5-2.65(2H.m);3.8(3H.s);4.9(lH.m); 6.75-6.95(2H.m.ArH+CONH);7.05-7.3(3H.m). MS (ESP) m/z 283 (M+H) + ,251.235.223. Anal. Calcd for Ci3Hi8N2θ3S:C.55.3:H.6.43:N.9.92 Found C.55.5;H.6.6;N.9.8 iii) Preparation of 22g A solution containing 22e (50mg,0.17mmol) and 22b (54mg,0.17mmol) in EtOH(2.5mL) was treated with powdered 4A° molecular sieves ( 1 OOmg) and the resulting suspension was stirred at room temperature for lh. Acetic acid (lOμL) and sodium cyanoborohydride(17mg,0.27mmol) were then added and the reaction mixture was left to stir for 18h at room temperature. The reaction mixture was then partitioned between EtOAc(50mL) and saturated NaHCθ3(aq)(50mL). The aqueous phase was then washed with EtOAc(50mL) and the combined organics dried over MgS04, filtered and concentrated to a colourless gum. This was then purified by flash chromatography on Siθ2 (Varian Mega Bond Elut Column) eluting a gradient of 25-40% EtOAc/i-Hexane to give (2S)-2-{3-[([2S,4S]-l-allyloxycarbonyl-4-BOCsulfanyl-pyrrolidin-2-yl- methyl)-amino]-benzoyl-amino}-4-methylsulfanyl-butyric acid methyl ester (22f) as a colourless gum:60.1mg(60.3%). IH NMR (CDC1 3 .200MH Z ) δl .45(9H.s, t Bu); 1.7-1.9(1 H,m); 2.0-2.4(5H.m); 2.45-2.7(3H.m); 3.1-3.35(2H,m); 3.4-3.6(lH.m); 3.6-3.85(4H,m); 4.0-4.3(2H.m); 4.6(2H.m); 4.8-4.95 (lH,m); 5.15-5.4(2H.m); 5.8-6.1(lH,m); 6.75(lH,d); 6.5-7.3(5H,m). MS (ESP) m/z 582 (M+H) + ,482. Compound 22f was deprotected (analogously as for the equivalent step in Example 15) to give the desired starting material 22g in 64% yield. 1 H NMR (CDCl3-*-D 2 O) δl .l5-1.95 (lOH. m); 1.95-2.15(4H.m,SMe+H): 2.15-2.35(lH.m); 2.35-2.5(lH.m): 2.55(2H,t): 2.75-2.95(lH.m); 2.95-3.15(lH.m); 3.15-3.55(3H.m); 3.55-3.7(lH.m); 3.78(3H.s.COMe); 4.9(lH.m): 6.73(lH.m); 6.98-7.13(2H.m):7.2(lH.t). MS (ESP) m/z 498 (M+H) + .398. Anal.Calcd for C 2 3H35N3θ5S2θ.35CH 2 Cl2:C.53.2;H.6.82.N,7.97 Found C.53.5:H.7.1:N.7.5 Example 23 (see Scheme 30) Preparation of N-((2S,4S)-4-suIfanyl-pyrroIidin-2-ylmethyl)-3-methyl-N-(2-naphthaIen-l-yl- ethyl)butyramide (compound 9); (2S . 4S)-2-{[(3-Methoxypropyl)-(2-naphthalen-l-y_ethyl)amino)methyl}- pyrrolidine- 4-thiol (compound 10) and; (2S,4S)-2-{[(2-(4-Methoxyphenyl)methyl)-(2-naphthalen-l-ylethyI)amino] methyl}- pyrrolidine-4-thiol (compound 11). Preparation of Compound 9 A solution of starting material N-((2S,4S)-4-BOCsulfanyl-pyrrolidin-2-ylmethyl)-3- methyl-N-(2-naphthalen-l-yl- ethyl)butyramide (6) (770 mg) in trifluoroacetic acid (40ml) was stirred at ambient temperature for 10 minutes. The trifluoroacetic acid was evaporated under reduced pressure and the residue redissolved in diethyl ether (90 ml). Ethereal HC1(1M .10ml) was added and the resulting suspension centrifuged. The diethyl ether was decanted off and more ether(90ml) added to the residue. This mixture was stirred for five minutes and then recentrifuged. The washing/centrifuging procedure was repeated once more and the resulting white solid dried under reduced pressure to give compound (9), (600mg) NMR. data in DMSOdό d 0.6(2d, 6H), 0.95(d, IH), 1.7(m. 3H), 2.15(m. IH), 1.9(m, IH), 3.0 to 3.85(m. lOh), 7.3 to 8.4(m. 7H). 8.9(br.s. IH), 9.5(br.s. IH) . SUBSTrTUTE SHEET (RULE 26) Micro Analysis: %Theory C64.9. H7.7. N6.9 (1.00 HC1 ) %Found C64.7. H7.9. N6.8 Starting material (6) was prepared as follows. (2S,4S)-2-Formyl-4-BOCsulfanyl-pyrrolidine- 1 -carboxylic acid allyl ester ( 1 ) ( 1.84 g) in dichloromethane(20ml) was added dropwise over 10 minutes to a mixture of 2- naphthalen- 1 -ylethylamine (l .Og). sodium triacetoxyborohydride(1.36g) and 4A powdered molecular sieve (3.0 g) in dichloromethane ( 130ml) cooled to -20 C. and stirred under an argon atmosphere. After the addition was complete the reaction was allowed to warm to ambient temperature and stirred for a further 18 hours. The molecular sieves were filtered off and the fitrate stirred with saturated aqueous sodium bicarbonate solution(100 ml) for 5 minutes. The mixture was separated . the organic phase dried over magnesium sulphate and applied to a silica flash column which was then eluted with 1. Ethyl acetate/Hexane(50:50), 2.Ethyl acetate/Hexane(80/20), 3. Ethyl acetate to give (2S,4S)-4-BOCsulfanyl-2[(2- naphthalen-l-ylethylamino)-methyl]pyrrolidine-l -carboxylic acid allyl ester (2) (2.2 g) as a colourless gum. NMR data in CDC1 3 , d 1.5(s, 9H), 1.85(m, IH), 2.5(m, IH). 2.8(m, IH), 3.0(m. 3H), 3.2(m, 3h). 3.7(m, IH). 4.05(m, 2H), 4.55(d, 2H), 5.25(m. 2H). 5.9(m, IH), 7.43(m, 4H), 7.7(d. IH). 7.83(m, IH). 8.05(m. IH). A mixture of compound (2)(1.2g), isovaleryl chloride(O.όlg) and triethylamine(0.77g) in dichloromethane(75ml) was stirred for lhour at ambient temperature. The reaction mixture was then applied to a silica flash colomn which was eluted with ethyl acetate/hexane(20:80) to give compound(3) as a colourless gum (1.3g). Tributyltin hydride(6.46g) was added dropwise over 5 minutes to a stirred mixture of compound(3)(1.23g) and bis(triphenylphosphine)palladium(0) chloride(20 mg) in dichloromethane(75ml). This mixture was stirred at ambient temperature for 30 minutes and then applied to a silica flash column which was eluted with 1.Ethyl acetate/Hexane(50:50). 2. Ethyl acetate. 3.Ethyl acetate/Methanol(95:5) . The product obtained was recolumned on an Isolute® C18(10g) column eluting with SUBSTTTUTE SHEET (RULE 26) methanol/water(80:20) to give starting material compound (6) as a white solid (769 mg). m.pt. 86°. NMR data (CDC1 3 ) d 0.9(2d. 6H). 1.3(m. IH). 1.5(s. 9H), 1.8-2.5(m. 6H). 2.9(m. IH). 3.05-3.9(m. 9H). 7.25-8.35(m. 7H). Preparation of Compound( 10) A solution of starting material (2S,4S)-2-{[(3-methoxypropyl)-(2-naphthalen-l- ylethyl)amino]methyl}- pyrrolidine-4-BOCthiol (compound 7) (78 mg) in trifluoroacetic acid(5 ml) was stirred at ambient temperature for 30 minutes. The trifluoroacetic acid was removed under reduced pressure and the residue treated with diethyl ether(5 ml). The ether was decanted off and the residue dried under reduced pressure for 24 hours to give the desired end product as a colourless gum (compound 10)(70 mg). NMR data (CDC1 3 ) d 1.95(m, 4H). 2.05(m, IH), 3.16-3.62(m. 10H), 3.29(s, 3H). 3.7(m. IH), 4.15(m, 2H), 7.3-7.65(m, 4H), 7.68((d. IH), 7.88(d, IH), 7.98(d, IH), 11.2(br.s. 2H). Micro Analysis: %Theory C48.2. H5.13, N4.32 (2.5TFA. 0.25H 2 O) %Found C48.5. H5.20, N4.40 Starting material (compound 7) was prepared as follows. A solution of 4-methoxy-butyraldehyde(140mg) in dichloromethane(10 ml) was added dropwise to a mixture of compound (2)(250 mg), sodium triacetoxyborohydride(338 mg) and 4A molecular sieves(1.0 g) in dichloromethane(30 ml) stirred under an argon atmosphere at -20°. After the addition was completed (5 minutes) the reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. The molecular sieves were filtered off and the filtrate washed with saturated sodium bicarbonate solution(20 ml). then brine and dried over magnesium sulphate. The solution was then applied to a silica column and eluted with ethyl acetate/hexane(50:50) to give a clear gum. compound(4)(260 mg). Compound(7) was synthesised from compound(4) analogously to the preparation of compound(6). NMR data (CDC1 3 ) d 1.35(m. IH). 1.48(s. 9H). 1.74(m. 2H). 2.31(m. IH). 2.42-3. l(m. 7H), 3.15-3.5(m. 9H). 3.65(m. IH). 7.28-8.1(m. 7H). Preparation of Compoundd 1 ) Compound(l 1) was synthesised from starting material (2S,4S)-2-{[(2-(4- methoxyphenyl)methyl)-(2-naphthalen-l-ylethyl)amino]methyl}- pyrrolidine-4-BOCthiol (compound 8) by the method described for the equivalent step in preparation of compound(lθ). NMR data (CDC1 3 ) d 1.9(m, IH), 2.05(m, IH), 2.3(m, IH), 3.1-3.8(m. 8H), 3.82(s, 3H). 4.25(m, 3H). 6.96(d, 2H), 7.42(m. 6H), 7.83(m. 3H). Micro Analysis: %Theory C55.7. H5.77. N4.06 (2TFA. 0.75diethyl ether) %Found C56.0, H5.40. N4.50 The starting material for compound( 11 ) was prepared as follows; A mixture of compound(2) (200mg), p -methoxybenzyl chloride(133 mg), saturated aqueous sodium bicarbonate(5ml) and dichloromethane(20ml) was stirred at ambient temperature for 24 hours. The layers were separated and the organic layer dried, applied to a silica flash column which was then eluted with ethyl acetate/hexane(80:20) to give (2S_,4SJ- 1 -allyloxycarbonyl-2- { [(2-(4-methoxyphenyl)methyl)-(2-naphthalen- 1 - ylethyl)amino]methyl}- pyrrolidine-4-BOCthiol compound(5) as a colourless gum(140 mg). NMR data (CDC1 3 ) d 1.45(s. 9H). 2.0(m. IH), 2.35(m. IH), 2.53-4.15(m, 1 OH), 3.8(s. 3H), 4.6(m. 4H), 5.25(m, 2H), 5.9(m. IH). 6.85(m.3H), 7.3(m. 6H). 7.75(m. 2H). The desired starting material (compound(8)) was synthesised from compound(5) by the same procedure used to prepare compound(6) from compound (3). Mass Spec.(ESP+) m/e 507.0 Example 24 (see Scheme 31) Preparation of a) 3-Methyl-N-(naphthalen-l-ylmethyl)-N-([2S,4S]4-sulfanylpyrrolidin-2- ylmethyl)-butanamide (compound 23): b) N-(naphthalen-l-ylmethyI)-N-([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)- pentanamide (compound 24); c) N-(naphthalen-l-ylmethyl)-N-([2S,4S]-4-suIfanylpyrroIidin-2-ylmethyl)-2- (pyridin-3-yl)-acetamide (compound 27); d) 3-Methyl-N-(naphthalen-l-ylmethyl)-N-([2S,4S]-4-sulfanylpyrroIidin-2- ylmethyl)-pentanamide (compound 25); e) 3-Methoxy-N-(naphthalen-l-ylmethyI)-l -([2S,4S]-4-sulfanylpyrrolidin-2- ylmethyI)-propanamide (compound 26) and; f) (2S,4S)-2-[{N-(4-methoxybenzyl)-J -(naphthalen-l-ylmethyl)-amino}-methyl]- pyrroIidine-4-thiol (compound 54). a) Preparation of Compound 23 A solution of starting material 3-methyl-N-(naphthalen-l-ylmethyl)-N-([2S,4S_]4- BOCsulfanyl- pyrrolidin-2-ylmethyl)-butanamide (compound(l 8)) (187mg) in trifluoroacetic acid (10ml) was stirred at ambient temperature for 5 minutes.The trifluoroacetic acid was evaporated under reduced pressure and the resulting residue was redissolved in ethyl acetate (5ml). A solution of hydrogen chloride (2ml/1.0M) was added to the solution followed by diethylether (5ml). The mixture was centrifuged, the solvent decanted off and the residue was washed with more diethylether (2x15ml) and dried to give the hydrochloride salt of compound(23) as an off-white solid (43mg). N.M.R. data (DMSO-d6) δ 0.83 (m.6H). 0.95(d.lH). 1.68(m.lH), 2.10(m.3H). 2.42(m.lH). 3.10(m.lH). 3.28-3.90(m.5H). 5.20(m.2H). 7.08(d.lH). 7.57(m.3H). 7.87(d.lH). 8.00(m.2H). 9.10-9.80(2br.s.2H) Micro Analysis : Theory % C62.7. H7.52. N6.97 (1HC1.0.5H 2 O) Found % C62.4. H7.6. N6.7 The starting material compound(18) was prepared as follows. A solution of (2S,4S)-2-formyl-4-BOCsulfanyl- pyrrolidine- 1 -carboxylic acid allyl ester (compound (1)) (3.1 lgrm. ) in dichloromethane(60 ml.) was added dropwise to a stirred mixture of of 1 -naphthalenemethylamine (1.71g), 4A molecular sieves(12grms) and sodium triacetoxyborohydride(2.3grms) in dichloromethane (200ml) under an argon atmosphere at -20°.The mixture was stirred for a further 30 minutes at -20°C and then allowed to warm to ambient temperature and stirred for a further 16 hours. The mixture was filtered and washed with aqueous sodium bicarbonate solution (2x200ml),the organic phase further washed with water (200ml), separated, dried over magnesium sulphate and purified by column chromatography, using ethyl acetate/hexane (30:70) as eluent to give (2S,4S)-2- { [naphthalen- 1 -ylmethyl]-amino)-methy 1 } -4-BOCsulfanyl- pyrrolidine- 1 - carboxylic acid allyl ester (compound(12)) as a pale yellow oil (2.09g). N.M.R. data (CDC1 3 ) δ 1.50(s,9H), 1.55(m.lH), 1.90(m,lH). 2.50(m,lH), 2.90(m,lH), 3.05(m.lH). 3.20(m,lH). 3.68(m.lH). 4.08(m.2H), 4.23(s,2H), 4.55(d.2H), 5.20(m.2H). 5.90(m.lH). 7.47(m.4H). 7.77(m.lH). 7.86(m.lH), 8.13(m.lH). A mixture of compound(12) (507mg). triethylamine(0.3 ml) and isovaleryl chloride(0.271ml) in dichloromethane (30ml) was stirred at ambient temperature for 1.5 hours and then applied directly to a silica flash column. This was eluted with ethyl acetate/hexane (25:75) and ethylacetate/hexane(35:65) to give 3-Methyl-N-(naphthalen-l- SUBSπrUTE SHEET (RULE 26) ylmethyl)-N-([2S,4S]-l-allyloxycarbonyl-4-BOCsulfanylpyrrolidin-2-ylmethyl)- butanamide (compound(13)) as a gum (475mg). N.M.R. data (DMSO-d6. 373°K) δ 0.90(m.6H). 1.45(s.9H). 1.78(m.lH). 2.18(m.3H). 2.50(m.lH). 3.15(q,lH). 3.45(m.lH). 3.70(m.2H). 4.03(q.lH). 4.20(m.lH). 4.45(m.2H). 5.10(m.4H). 5.80(m,lH). 7.20(d,lH). 7.50(m.3H). 7.80(d.lH). 7.92(m.lH). 8.00(m.lH). Tributyltin hydride(2.22 ml) was added dropwise to a mixture of compound(13) (446 mg), bis-triphenylphosphine palladium chloride(5.8 mg) in dichloromethane (10ml). The mixture was stirred at ambient temperature under an argon atmosphere for 70 minutes and then applied directly to a flash column which was eluted with (l)Ethyl acetate/hexane (50:50) and (2) Ethyl acetate. The product obtained was recolumned on an Isolute® C18 (lOg) column, eluting with methanol/water (1) (70:30), (2)(75:25) and (3)(80:20) to give the desired starting material (compound(18)) as a gum (197mg). N.M.R. data (DMSO-d6,373°.K) δ 0.90(m,6H), 1.45(m.5H), 1.60(m,lH), 1.68(m.2H). 2.12(m,2H). 2.25(d,2H), 2.40(m,lH), 2.60-3.85(m.8H), 5.14(s.2H), 7.20(d,lH), 7.50(m,3H). 7.83(m,lH), 7.93(m.lH). 8.03(m,lH). b) Preparation of Compound 24 Compound(24) was synthesised by the same procedure used for compound(23) but substituting appropriate compounds as indicated in Scheme 31. Compound 24: N.M.R. data (DMSO-d6) δ 0.85(m,3H), 1.15-1.75(m.5H). 2.28(t,2H), 3.10(m.lH), 3.33- 3.95(m,6H), 5.18(m,2H), 7.20(2d.lH). 7.55(m,3H), 7.85(d,lH), 8.00(m.2H), 8.95- 9.90(2br.s.2H) Micro Analysis : %Theory C62.7, H7.52. N6.97 (1HC1 ,0.5H 2 O) %Found C62.5, H7.80, N6.8 Compound(14): N.M.R. data (CDC1 3 ) δ 0.90(m.3H). 1.12-2.10(m,6H). 1.48(s.9H). 2.26(m.lH). 2.50(m.lH). 3.00-5.70(m.l2H). 5.87(m.lH). 7.07-8.06(m.7H). Compound(19): N.M.R. data (DMSO-d6.373°.K) δ 0.84(m.3H). 1.30(m.3H). 1.45(s.9H). 1.55(m.2H). 2.34(m.3H). 2.80(m.2H). 3.45(m.5H). 5.10(m.2H). 7.25(d.lH). 7.50(m.3H). 7.80(d.lH). 7.90(m.lH). 8.03(m.lH). c) Preparation of Compound(27) Compound(27) was synthesised. in the same manner as the equivalent step for compound(23). from starting material N-(naphthalen-l-ylmethyl)-N-([2S,4S]-4- BOCsulfanylpy_τolidin-2-ylmethyl)-2-(pyridin-3-yl)-acetamide (compound(22)). Compound(27): N.M.R. data (DMSO-d6) δ 1.70(m.lH), 2.50(m,lH), 3.14(m.lH), 3.28-5.10(m,7H), 5.35(m.2H). 7.20-9.00(m,l lH), 9.20(br.s.lH). 10.05-10.50(2br.s,lH) Micro Analysis : %Theory C55.10. H6.60, N7.97 (2HC1.2.25H 2 0. 0.3 diethyl ether) %Found C54.80. H6.10. N7.60 Starting material (compound(22)) was synthesised as follows. A mixture of compound(12)(345mg), 4-dimethylamino-pyridine(305mg), 3-pyridylacetic acid hydrochloride(262mg) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(348mg) in dichloromethane (30ml) was stirred at ambient temperature. under an argon atmosphere, for 16hours.The mixture was then purified by silica flash column chromatography, eluting with ethyl acetate/hexane(75:25) and then ethyl acetate to give N-(naphthalen-l -ylmethyl)-N-([2S,4S]-l -allyloxycarbonyl-4-BOCsulfanylpyrrolidin- 2-ylmethyl)-2-(pyridin-3-yl)-acetamide (compound(17)) as a colourless gum (394mg). Compound(17): N.M.R. data (DMSO-d6. 373°.K) δ 1.46(s,9H). 1.75(m.lH). 2.50(m.lH). 3.17(q,lH). 3.50(m.lH). 3.75(m.4H). 4.04(m,lH). 4.27(m.lH). 4.45(m.2H). 5.15(m.4H). 5.83(m.lH). 7.25(m.2H), 7.43(t,lH). 7.52(m,2H). 7.58(m.lH). 7.82(d.lH). 7.95(m.2H), 8.40(d.2H). Using the procedure previously described for the equivalent step in synthesis of compound 23. the desired starting material (compound(22)) was synthesised from compound(17). Compound(22) N.M.R. data (DMSO-d6. 373°.K) δ 1.45(s.9H). 2.38(m.lH). 2.55-4.00(m.lOH). 5.20(m.2H). 7.25(m.2H). 7.50(m.4H). 7.90(m.3H). 8.40(m.2H). d) Preparation of Compound(25) Compound(25) was synthesised using compounds 12, 15 and 20 as intermediates, in the same manner as the equivalent steps for synthesis of compound (27) (see Scheme 31). Compound(25): N.M.R. data (DMSO-d6) δ 0.80(m.6H), 0.95-4.80(m,14H), 5.18(m.2H), 7.08(d.lH). 7.55(m.3H). 7.95(m.3H). 8.90-10.15(2br.d.2H). Micro Analysis : %Theory C59.1, H7.30. N6.27 (2HC1. 0.2H 2 O) %Found C59.1. H6.90. N5.9 Compound(15): N.M.R. data (DMSO-d6. 373°.K) δ 0.85(m.6H), 1.15(m,lH), 1.35(m.lH), 1.45(s,9H). 1.75(m.lH), 1.90(m.lH). 2.17(m,lH). 2.30(m,lH), 2.50(m,lH). 3.15(q.lH). 3.45(m.lH). 3.70(m.2H). 4.03(q,lH). 4.20(m,lH). 4.44(d,2H), 5.10(m,4H). 5.80(m.lH), 7.20(d.lH). 7.50(m.3H), 7.80(d,lH). 7.90(m,lH). 8.00(m,lH). Compound(20): N.M.R. data (DMSO-d6. 373°.K) δ 0.85(m.6H). 1.25(m.3H). 1.45(s.9H). 1.93(m.lH). 2.27(m.3H). 3.40(m.6H), 5.13(m.2H). 7.25(d.lH). 7.50(m.3H). 7.80(d.lH). 7.90(m.lH). 8.04(m.lH). e) Preparation of Compound.26) Compound(26) was synthesised using compounds 12, 16 and 21 as intermediates in the same manner as the equivalent steps for synthesis of compound(27) (see Scheme 31 ). Compound(26): N.M.R. data (DMSO-d6) δ 1.70(m.lH). 2.40-4.15(m,14H). 5.20(m.2H). 7.20(2d.lH). 7.55(m.3H). 7.85(m.lH). 8.00(m.2H). 9.05-10.25(2br.d.2H). Micro Analysis : %Theory C59.5. H6.99. N6.93. (2HC1. 0.2H 2 O) %Found C59.3. H7.30. N6.70 Compound(16): N.M.R. data (DMSO-d6, 373°.K) δ 1.45(s,9hH). 1.78(m,lH). 2.40-3.80(m,12H), 4.00(m.lH). 4.20(m,lH). 4.45(m.2H). 5.10(m.4H), 5.80(m,lH), 7.20(d,lH). 7.45(t.lH). 7.50(m.2H). 7.80(d.lH). 7.90(m.lH), 8.00(m.lH). Compound(21): N.M.R. data (DMSO-d6. 373°.K) δ 1.30(m,lH), 1.48(s,9H). 2.30(m.lH). 2.56- 3.70(m,14H). 5.15(m.2H), 7.30(d,lH). 7.47(t,lH), 7.53(m,2H), 7.83(d,lH), 7.94(m.lH). 8.05(m.lH). f) Preparation of Compound(54) A mixture of starting material (2£,4S)-2-[{N-(4-methoxybenzyl)-J_i-(naphthalen-l- ylmethyl)-amino}-methyl]-pyrrolidine-4-BOCthiol (compound(53))(100mg) and trifluoroacetic acid(5ml) was stirred at ambient temperature for 1 hour. The trifluoroacetic acid was removed under reduced pressure and the residue coevaporated with diethylether to give compound(54) as a colourless gum (83 mg). NMR data (CDC1 3 ) d 1.5(m. IH), 1.75(br.d. IH). 1.95(m. IH). 2.6(t. IH). 3.05(m. IH). 3.2(d. IH). 3.35(m. 2H). 3.85(s. 3H). 4.2(s. 2H). 4.6(2d. 2H). 6.95(d. 2H). 7.4(d. 2H). 7.6(m. 4H). 7.9(m, 3H). Micro Analysis: %Theory C52.0. H5.40. N3.90 (2.5TFA. 0.4 diethyl ether) %Found C52.0. H4.92. N3.96. The starting material was prepared as follows. A mixture of compound(12)(240 mg), dimethylformamide(20 ml), anhydrous potassium carbonate(80 mg) and /. -methoxybenzylchloride(0.143ml) was stirred at 70° under an argon atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue purified by column chromatography eluting with ethyl acetate/hexane(20:80) to give a colourless gum (2S,4S l-allyloxycarbonyl-2-[{N-(4-methoxybenzyl)-_N-(naphthalen-l- ylmethyl)-amino}-methyl]-pyrrolidine-4-BOCthiol (compound(52)) (213 mg). NMR data (CDC1 3 ) d 1.45(s, 9H), 2.15(m. lH), 2.5(m, lH), 2.8(m, lH), 3.05(m, IH). 3.5(m. 2H), 3.8(br.s. 7H), 3.9(m, IH), 4.2(m, IH), 4.6(s, 2H). 5.25(m. 2H), 5.9(m. IH), 6.85(d, 2H). 7.2(d, 2H), 7.4(m, 4H), 7.8(2d. 2H), 8.1(d, IH). Tributyltin hydride(0.77ml) was added to a mixture of compound(52) and bis(triphenyl phosphine) palladium (O) chloride(2 mg) in dichloromethane( 10 ml). The solution was stirred at ambient temperature for 30 minutes.A second portion of tributyltin hydride(0.335 ml) and bis(triphenylphosphine) palladium (O) chloride(2 mg) were added and the stirring was continued for a further 30 minutes. The mixture was applied directly to a silica flash column which was eluted with ethyl acetate/hexane(25:75).(50:50) and finally ethyl acetate. The product obtained was further purified by reverse phase HPLC on a Cl 8 column eluting with water/methanol/TFA(20:80:0.2) to give the desired starting material (compound(53)) as a colourless gum. (168 mg.) NMR data (CDC1 3 ) d 1.45(s, 9H). 1.55(m. lH). 2.0(m. lH). 2.5(m. lH), 3.1(d. IH). 3.4(m. 3H), 3.6(t. IH). 3.8(.s, 3H), 4.1(2d, 2H). 4.4(d, IH). 4.6(d. IH). 6.95(d. 2H).m 7.4(d. 2H). 7.5(m. 4H). 7.9(m. 3H). Micro Analysis: %Theory C54.4. H5.40. N3.70 (2TFA) %Found C55.0. H5.31. N3.89 Example 25 (see Scheme 32) Preparation of a) (2S,4S)-2[(N-methylnaphthalen-l-ylamino)-methyl]-4-sulfanylpyrroIidine (compound 36) and: b) N-(naphthalen-l-yl)-N-((2S,4S)-4-sulfanylpyrrolidin-2-yI-methyI)-3- methylbutanamide (compound 37). Preparation of Compound 36 A mixture of starting material (2S,4S)-2[(N-methylnaphthalen-l-ylamino)-methyl]-4- BOCsulfanylpyrrolidine (compound (34)) (110 mg) and trifluoroacetic acid (5 ml) was stirred at ambient temperature for 1 hour. The trifluoroacetic acid was removed under reduced pressure and the residue dried under high vacuum to give compound(36) as a colourless gum(l 10 mg). N.M.R. data (CDC1 3 ) δ 1.7 (m.IH), 1.9 (d.IH). 2.6 (m,lH), 2.95 (s.3H). 3.1 (2d,lH). 3.5 (m.lH). 3.65 (m.3H). 4.05 (m.IH). 7.0 (br. s.lH). 7.4 (t.lH). 7.55 (m.3H), 7.7 (d.IH). 7.85 (m.lH). 8.2 (m.lH). Micro Analysis: %Found C 45.5. H 4.2. N 5.0 (2.0TFA. 1.0H 2 O) %Theory C 46.3. H 4.67. N 5.4 The starting material for compound(36) was prepared as follows; A mixture of (2S,4S)-2-formyl-4-BOCsulfanyl- pyrrolidine- 1 -carboxylic acid allyl ester (compound( 1 )) ( 711 mg), ethanol(25 ml), l-naphthylamine(333 mg) and 3 A molecular sieves(4.5 g.) was stirred under an argon atmosphere at ambient temperature for 6 hours. Acetic acid (0.4ml) was added followed by sodium cyanoborohydride(170 mg). The mixture was then stirred for a further 20 hours when the sieves were removed by filtration.The filtrate was concentrated under reduced pressure and the residue applied to a silica column and eluted with ethyl acetate/ hexane(20:80) to give (2S,4S)-1- allyloxycarbonyl-2[(naphthalen-l-ylamino)-methyl]-4-BOCsulfanylpyrrolidine (compound(31)) as a clear oil (560 mg). N.M.R. data (CDC1 3 ) δ 1.5 (s.9H). 1.85 (m.IH), 2.7 (m.IH). 3.35 (m.2H). 3.5 (m.IH). 3.8 (m.lH). 4.2 (m.IH). 4.5 (m,lH). 4.65 (d.2H). 5.3 (2d,2H), 5.95 (m.IH). 6.55 (m.IH). 7.2 (d.lH). 7.3 (t,lH). 7.4 (m.2H). 7.75 (m.IH). 7.9 (m.IH). A mixture of (compound(31 ))(218 mg), dimethylformamide(40ml). iodomethane(0.6 ml.) and anhydrous potassium carbonate(150 mg) was stirred at 80° for 20 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate(30 ml.) and washed with water(20ml). The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure to give (2S,4S)-l-allyloxycarbonyl-2[(N- methylnaphthalen- 1 -ylamino)-methyl]-4-BOCsulfanylpyrrolidine (compound(32)) as a yellow gum (183 mg). N.M.R. data (CDC1 3 ) δ 1.45 (s,9H), 2.0 (m.IH). 2.4 (m.IH). 2.85 (s.3H). 3.0 (2d.lH), 3.25 (m.lH), 3.7 (2d.lH). 3.8 (m.IH). 4.1 (m.2H), 4.6 (d.2H), 5.3 (9m.2h). 5.95 (m.IH). 7.45 (m.5H), 7.8 (m.IH). 8.25 (m.IH). To a solution of compound(32)(178 mg) in dichloromethane(10 ml) was added tri-n-butyl tin hydride(0.2 ml.) followed by bis(triphenyl phosphine) palladium chloride (2 mg) and the mixture then stirred at ambient temperature. After lOmin and 20min a second and third portion of tri-w-butyl tin hydride (0.2ml.) and bis(triphenyl phosphine) palladium chloride (2 mg) were added and stirring continued for a further 90 min. The reaction solution was applied direct to a silica column and eluted with ethyl acetate/hexane(25:75), (50:50) and ethyl acetate. The product was further purified on a reverse phase HPLC. C18 column which was eluted with water/methanol/ trifluoroacetic acid(20:80:0.2) to give as a colourless gum the desired starting material (compound(34))(l 60 mg). N.M.R. data (CDC1 3 ) δ 1.45 (s.9H). 2.2 (s,lH). 2.39 (m.IH). 2.85 (s.3H). 2.9 (2d,lH). 3.1 (2d.lH). 3.25 (m.2H). 3.4 (m.IH). 3.6 (m.IH). 7.15 (d.IH). 7.45 (m.4H). 7.8 (m.IH). 8.35 (m.IH). Micro Analysis: %Found C 50.8. H 5.20, N 4.6 (2.0TFA. 0.5H 2 O) %Theory C 49.3. H 5.13. N 4.6 b) Preparation of Compound (37) A mixture of starting material (compound(35))(187 mg) and trifluoroacetic acid(5 ml.) was stirred at ambient temperature for 1 hour. The trifluoroacetic acid was removed under reduced pressure and the residue dried under high vacuum to give a colourless gum. compound (37)(200 mg.). N.M.R. data (CDC1 3 ) δ 0.8 (m.6H). 1.6-2.2 (m.5H), 2.6 (m.IH). 3.2-5.0 (m,6H), 7.6 (m.5H). 8.0 (m.2H). Micro Analysis: %Found C 48.4, H 4.80. N 4.5 (2.0 TFA. 1.0H 2 0) %Theory C 49.0. H 5.14. N 4.76 The starting material was prepared as follows. Isovaleryl chloride(0.164 ml.) was added dropwise over 10 minutes to a stirred solution of compound(31)(297 mg.), dichloromethane(50 ml) and triethylamine(0.136 ml.). The solution was stirred at ambient temperature for 24 hours. The solvent was removed under reduced pressure and the residue applied directly to a silica column and eluted with ethyl acetate/hexane(25/75) to give a white foam, N-(naphthalen-l-yl)-N-((2S,4S_)-l- allyloxycarbonyl-4-BOCsulfanylpyrrolidin-2-yl-methyl)-3-methylbutanamide. (compound(33))(329 mg). N.M.R. data (CDC1 3 ) δ 0.75 (m.6H). 1.5 (s,9H), 1.65 -2.7 (m,5H), 3.15 -6.0 (m,9H), 7.25 (m.lH), 7.5 (m.3H), 7.7 (m.IH), 7.9 (m,2H). To a solution of compound(33)(296 mg.) in dichloromethane( 10 ml) was added tri-n-butyl tin hydride (0.3 ml.) followed by bis(triphenyl phosphine) palladium chloride(2 mg.). The solution was stirred at ambient temperature. After lOmin and 20min a second and third portion of tri-n-butyl tin hydride(0.3 ml.) and bis(triphenyl phosphine) palladium chloride(2 mg) were added and the stirring continued for a further 30 minutes. The reaction solution was applied directly to a silica column which was then eluted with ethyl acetate/hexane(25:75), (50:50) and ethyl acetate. The product was further purified on a reverse phase HPLC . C 18 column eluting with water/methanol/trifluoroacetic acid(20:80:0.2) to give the desired starting material, (compound (35))(216 mg.). N.M.R. data (CDC1 3 ) δ 0.8 (m.6H). 1.49 (s.9H). 1.1 -2.2 (m.6H), 2.9 -5.6 (m.6H). 7.4 - 8.0 (m.7H). Micro Analysis: %Found C 57.0. H 6.20. N 4.80 (1.0TFA. 0.75H 2 O) %Theory C 56.9, H 6.45; N 4.91 Example 26 (see Scheme 33) Preparation of a) 3-Methyl-N-(3,3-diphenylpropyl)-N-([2S,4S]-4-sulfanyIpyrrolidin-2-ylmethyl)- butanamide (compound 43) and; b) N-(3,3-diphenylpropyI)-N-([2S,4S]-4-suIfanylpyrroIidin-2-ylmethyI)- butanamide (compound 44) Compounds (43) and (44) were synthesised using the procedure described in Example 23 using appropriate starting materials and intermediates as set out in Scheme 33. a) Preparation of Compound (43) Compound (43) : NMR data (DMSOdό at 373 ° K.) d 0.9(d, 6H), 1.7(m. IH), 2.1(m, IH), 2.33(m. 2H), 2.45(m, IH). 2.9-4.00(m, 9H), 4.2-4.95(m, 2H), 7.3-8. l(m, 10H), 9.65(v.br.s. 2H) Micro Analysis: %Theory C64.8. H7.7. N5.9 1.00HC1. lH 2 O %Found C64.5, H7.9. N6.0 The starting material 3-Methyl-M-(3.3-diphenylpropyl)-N-([2S,4£]-4- BOCsulfanylpyrrolidin-2-ylmethyl)-butanamide (compound 41) was synthesised from compound (1) and 3.3-diphenylpropylamme using a similar procedure to that outlined in Example 23. Compound (38) : NMR data (CDC1 3 ) d 1.5(s, 9H). 1.8(m. IH). 2.19(m. 2H), 2.42(m. IH). 2.55(m, 2H). 2.7(m. IH), 2.82(m. IH). 3.19(m, IH). 3.67(m. IH), 4.0(m. 3H), 4.55(d. 2H). 5.2(2d. 2H). 5.9(m. IH). 7.2(m, 10H). Compound (39) : NMR data (CDC1 3 ) d 0.75-1.0(m. 6H). 1.22(m. IH), 1.5(s. 9H). 1.78-2.02(m. 2H). 2.3(m. 4H), 3.2(m, 3H), 3.4-4.2(m, 6H). 4.52(m. 2H), 5.21(m. 2H), 5.9(m. IH). 7.2(m. 10H) . Compound (41) : NMR data (CDC1 3 ) d 0.75-1.00(m, 6H), 1.25(m, IH). 1.5(s. 9H). 1.85-2.4(m, 6H), 2.83(m. IH), 3.05-3.47(m, 6H). 3.6(m. IH), 3.87(2t, IH), 7.25(m, 10H) . b) Preparation of Compound (44) Characterisation data is set out below: Compound (44): NMR data (DMSOd6 at 373° K) d 1.65(m, IH). 1.85(s, 3H). 2.32(q, 2H). 2.45(m, IH), 2.69-4.3(m, 9H), 7.2(m. 10H), 9.37(v.br.s. 2H). Micro Analysis: %Theory C 63.3. H 7.3. N. 6.6 1.00 HC1 , 0.75H2O %Found C63.1, H 7.3. N. 6.7 Compound (40): NMR data (CDC1 3 ) d 1.5(s, 9H), 1.82(s, 3H), 1.6-2.5(m, 4H). 3.2(m. 3H), 3.32-4.25(m. 6H), 4.54(m, 2H), 5.23(m, 2H). 5.9(m. IH), 7.23(m. 10H). SUBSTTTUTE SHEET (RULE 26) Compound (42): NMR data (CDC1 3 ) d 1.48(s, 9H). 1.8(m, IH). 1.87(s. 2H). 2.07(s. IH). 2.33(m. 3H). 2.83(m. IH). 3.28(m. 6H). 3.6(m. IH). 3.85(m. IH). 7.25(m. 10H). Example 27 (see Scheme 34) Preparation of a) 3-Methyl-N-(naphthalen-2-ylmethyl)-N-([2S,4S]-4-sulfanylpyrrolidin-2- ylmethyl)-butanamide (compound 50) and; b) N-(naphthalen-2-yImethyl)-N-([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)- acetamide (compound 51) Compounds (50) and (51 ) were synthesised using the procedure described in Example 23 using appropriate starting materials and intermediates as set out in Scheme 34. a) Preparation of Compound (50). Compound 50: NMR data (DMSOdό) d 0.75-1.1 (m. 6H), 1.63(m, lH), 2.1(m. lH), 2.48(m. lH). 2.83(m, 3H), 3.0-4.95(m, 8H). 7.17(m, 7H). Micro Analysis: %Theory C64.2. H7.44. N7.13. (1.0 HC1 ) %Found C64.0, H7.40. N7.10. Starting material 3-Methyl-N-(naphthalen-2-ylmethyl)-N-([2S,4S]-4- BOCsulfanylpyrrolidin-2-ylmethyl)-butanamide (compound (48)) was synthesised from compound (1) and 2-naphthylmethylamine. Compound (45): NMR data (CDC1 3 ) d 1.48(s, 9H). 1.92(m, IH). 2.5(m, IH), 2.82(m. IH), 2.96(m. IH). 3.2(2d, IH). 3.7(m. IH), 3.96(s. 2H), 4.08(m, 2H), 4.54(m, 2H). 5.2(m, 2H), 5.9(m. IH), 7.42(m, 3h). 7.8(m, 4H). Compound (46): NMR data (CDCl 3 ) d 0.96(2d. 6H). 1.48(s. 9H). 1.9(m. IH). 2.13-2.6(m. 4H). 3.3(m. IH). 3.72(m. 2H). 4.15(m. 2H). 4.5(m. 2H). 4.76(m. IH). 5.2(m. 2H). 5.9(m. IH). 7.48(m. 3H). 7.73(m. 4H). Compound (48): NMR data (CDCl 3 ) d 0.98(2d. 6H), 1.3(m. IH). 1.48(s. 9H). 2.3(m. 4H). 2.9(m. IH). 3.1- 3.7(m. 5H), 4.85(m. 2H). 7.15-7.9(m, 7H). b) Preparation of Compound (51 Characterisation data is set out below Compound 51 : NMR data (DMSOdό at 373 °K) d 1.7(m, IH), 2.14(s. 3H), 2.47(m. IH). 2.8-4.00(m, 6H), 4.8(m, 2H), 7.32-8. l(m. 7H). Micro Analysis: %Theory C64.2. H7.44. N7.13. (1.00 HC1) %Found C64.0. H7.40, N7.10. Compound (47): NMR data (CDCl 3 ) d 1.5(s, 9H), 1.9(m. IH). 2.12(s, 2H). 2.29(s. lH), 2.5(m. IH). 3.18- 5(m. 10H). 5.2(m. 2H). 5.95(m, IH), 7.2-7.89(m, 7H). Compound (49): NMR data (CDCl 3 ) d 1.3(m. IH), 1.47(s, 9H). 2.15(s. 2H), 2.3(s. IH), 2.35(m, IH), 2.88(m. IH). 3.1-3.7(m. 5H), 4.85(m. 2H), 7.4-7.9(m, 7H). Example 28 (see scheme 35) (2S)-2-({4-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-naphthalene-2- carbonyl}-amino)-4-methylsulfanylbutyric acid methyl ester (compound 30) Starting material (2S)-2-({4-[([2S,4S]-4-BOCsulfanylpyrrolidin-2-ylmethyl)-amino]- naphthalene-2-carbonyl}-amino)-4-methylsulfanylbutyric acid methyl ester 30e (72.1mg,0.132mmol) was deprotected (analogously as for the equivalent step in Example 15) to give the title compound 30.76mg (97.8%). 'H NMR (CDCl 3 +CD 3 COOD.200MHz) dl .75-2.0(lH.m); 2.0-2.5(5H+DMSO.m): 2.55-3.0(3H.m): 3.15-3.4(lH.m): 3.5-3.7(lH.m): 3.7-3.9(6H.m): 4.2-4.4(lH.m): 4.9-5.05(1 H.m): 7.0-8. K6H.rn.ArH). MS (ESP") m z 448 (M+Hf . Anal.Calcd for C 22 H 29 N 3 S 2 0 3 1.25 TFA C.49.9;H,5.17;N.7.12 Found C.49.6:H.5.3;N,6.7 Starting material 30e was prepared as follows. Compound 30a 2-Napthoic acid was nitrated with cone HNO 3 (Tetrahedron 49,17.3655.1993) to give a mixture of nitro-acids 30a.containing the required 4-Nitro-2-Napthoic acid. MS (ESP ' ) m z 216 (M-H) " . Compound 30b Oxalyl chloride (6.0mL,68.7mmol) was added dropwise to a stirred solution of the nitro acid mixture.30a(7.3g,33.6mmol) in a mixture of DMF(1.OmL) and CH 2 C1 2 (lOOmL) at 0°C under argon.The solution was allowed to warm to RT stirred 18hrs. evaporated to dryness and azeotroped with toluene(2x25mL).The resulting residues were redissolved in CH 2 C1 2 (lOOmL) and cooled to 0°C under argon. Et 3 N (7.0mL,50mmol) was then added, followed by L-Methionine methylester hydrochloride (7.4g,37mmol), portionwise, such that the internal temperature did not rise above 10°C.The reaction mixture was left to warm to room temperature and stirred for 18hr washed with water(lOOmL) ,dried over MgSO 4 ,fιltered and concentrated to a viscous brown gum.This was then purified by flash chromatography on SiO (Merck 9385).eluting with 25%EtOAc/i-Hexane.Appropriate fractions were combined and evaporated to give 30b as a viscous orange gum,490mg(4%). 'H NMR (CDCl 3 ,200MHz) d2.1-2.5(5H,m); 2.55-2.75(2H,m); 3.85(3H,s); 4.9-5.1(lH.m);7.32(lH,d); 7.6-8.0(2H.m); 8.05(lH.dd); 8.5-8.7(3H,m). MS (ESP") m/z 363 (M+H) + . SUBSTTTLΠΈ SHEET (RULE 26) Compound 30c 30b (450mg.l.24mmol) was reduced (analogously as for the equivalent step in Example 22) to give the corresponding aniline.30c as a yellow gum.310mg (75.3%) Η NMR (CDCl 3 ,250MHz) d2.0-2.45(5H.m): 2.5-2.75(2H.m): 3.83(3H.s); 5 4.3(2H.bs.NH 2 ); 4.9-5.05(lH.m); 7.0(1 H.d.NHCO): 7.2(lH.d):7.45-7.65(2H.m): 7.72(lH.s): 7.8-8.0(2H.m). MS (ESP") m/z 333 (M+H)",271.170. Compound 30d 10 30c (300mg,0.9mmol) was coupled with the aldehyde 22b(428mg, 1.36mmol) under the conditions employed to synthesise 22g using MeOH as solvent and in the presence of 3 A 0 molecular sieves as drying agent to give 30d as yellow gum.460mg (76.5%) MS (ESP + ) m/z 632 (M+H) " 15 Compound 30e 30d (450mg,0.7mmol) was deprotected (analogously as for the equivalent step in Example 15) to give the desired starting material 30e.220mg (56.4%) 'H NMR (CDC1 3 ,200MHZ) dl.4-1.9(10H+H 2 0.m); 2.0-2.75(9H.m); 2.95(lH.q): 3.1-3.35(lH.m); 3.35-3.55(2H.m); 3.55-3.8(2H.m): 3.82(3H.s.CO 2 Me); 4.98(lH.m); 20 5.15(lH.bs,NH); 6.9-7. l(2H.m.ArH+NHCO); 7.4-7.6(2H.m); 7.61(lH.d); 7.8-8.0(2H.m). MS (ESP") m/z 548 (M+H) + ,448. Example 29 (see scheme 36) 25 Preparation of a) (2S)-2-({3-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-naphthalene-l- carbonyl}-amino)-4-methylsulfanylbutyric acid methyl ester (compound 31) b) (2S)-2-({3-[( [2S,4S] -4-sulfany lpyrroIidin-2-y lmethy l)-amino] -naphthalene- 1 - carbonyl}-amino)-4-methylsulfanyIbutyric acid (compound 31 f) 30 a) Preparation of Compound 31 31e (55mg.0.1mmol)was deprotected (analogously as for the equivalent step in Example 15) then treated with Et 2 O.HCl to give the title compound.31 as a white solid. (37mg.64.8%) 5 'H NMR (DMSO-D 6 - CD 3 CO 2 D.250MHz) dl .05(lH.t. (CH 3 CH 2 ) 2 O):1.6-1.8(lH.m): 1.9-2.15(4H.m):2.3-2.7(4H+DMSO.m);3.0-4.0(9H+(CH 3 CH 2 ) 2 O);4.55-4.7(lH.m): 6.95(lH.s):7.1(lH.s);7.15(lH.t);7.32(lH,t);7.62(lH,d);7.92(lH.d) MS (ESP") m/z 448 (M+H)". Anal.Calcd for C 22 H 29 N 3 S 2 O 3 2.7HC1 0.3Et 2 O C,49.0;H,6.15:N.7.39 10 Found C,49.1;H.6.1;N,7.2 Compound 31 a 3-Nitro-l-napthoic acid 31a was synthesised from 3-nitro-l,8-napthalic anhydride according to the method of G.J.Leuck et al (Journal of the American Chemical Society 15 51,1831.1929). Compound 31b 3-Nitro-l-Napthoic acid 31a (5.0g,23.04mmol) was coupled with L-Methionine methvlester hydrochloride (analogously as for the equivalent step in Example 22) to give 20 31b as a white cyystalline solid.2.53g(30.3%) Η NMR (CDCl 3 .200MHz) d2.0-2.5(5H,m);2.55-2.75(2H.m);3.85(3H,s);5.05(lH,m); 6.9(lH,d.NH);7.6-7.85(2H,m);8.0-8.15(lH,m);8.3-8.5(2H.m);8.83(lH,m) MS (ESP") m z 363 (M+H)" 25 Compound 31 c 31b(2.3g.6.35mmol) was reduced (analogously as for the equivalent step in Example 22) to give the corresponding aniline 31c as a yellow gum.l.75g(83%) Η NMR (CDCl 3 .250MHz) d2.05-2.2(4H,m);2.25-2.45(lH.m):2.63(2H,m); 3.83(3H,s);5.03(lH.m);6.66(lH.d);7.05(lH,m);7.15(lH.m);7.28(lH.m);7.39(lH.m); 30 7.6(lH,m):8.15(lH,m) MS (ESP+) m z 333 (M+H)".170. Compound 3 Id 31c(1.7g,5.12mmol) was coupled with the aldehyde 22b(1.76g,5.59mmol). (analogously as for the equivalent step in Example 30) to give 31d as an off-white foam.2.95g(91.3%). Η NMR (CDCl 3 +CD 3 COOD.250MHz) dl.5(9H.s).1.9(lH,m); 2.0-2.25(4H+CH 3 COOH.m);2.25-2.44(lH.m);2.55-2.75(3H.m);3.25-3.53(2H.m): 3.55-3.7(lH.m);3.7-3.95(4H.m);4.1-4.25(lH.m);4.25-4.4(lH,m);4.55-4.8(2H.m): 5.03(lH.m):5.15-5.45(2H.m);5.96(lH,m):6.9-7.5(4H+CHCl 3 ,m);7.66(lH.m): 8.1(lH.m) MS (ESP+) m/z 632 (M+H)". Compound 31 e 31d (2.0g.3.17mmol) was deprotected (analogously as for the equivalent step in Examplel5) to give the desired starting material 31e as a pale yellow foam.l.62g(93.4%). Η NMR (CDCl 3 ,300MHz) d2.4-2.6(10H,m);1.85(4H.bs);2.0-2.2(4H.m); 2.35(lH.m):2.5(lH,m);2.65(2H,t);2.9(lH.m);3.1(lH,m);3.3(lH,m);3.4(lH.m): 3.55(lH.m):3.65(lH,m);3.8(3H,s):5.02(lH,m);6.65(lH,d);6.9(lH,m);7.1(lH.m); 7.2-7.3(lH+CHCl 3 ,m):7.4(lH,m):7.62(lH.m);8.1(lH.m) MS (ESP+) m/z 548 (M+H) + ,448. b) Compound 31 f 31e(180mg,0.33mmol) was hydrolysed (analogously as for Example 16) then purified by reverse phase HPLC (Dynamax® 60A,C 18 ,8m prep column), eluting with 50%MeOH/H 2 O (0.1% TFA) to give product 31f as a white foam,126mg(65.9%). 1 H NMR (DMSO-D 6 +CD 3 COOD.300MHz) dl.5-1.8(lH,m);1.9-2.1(5H,m); 2.4-2.7(3H+DMSO,m);3.0-3.1(lH.m);3.4-3.7(4H.m);3.75-3.9(lH,m);4.57(lH.m); 6.9(lH,m);7.07(lH.m);7.17(lH.m);7.35(lH,m);7.63(lH,m);7.95(lH,m) MS (ESP+) m/z 434 (M+H) + ,285. Anal.Calcd for C 21 H 27 N 3 S 2 O 3 .1.3TFA C.48.7;H,4.9;N,7.22 Found C,48.6:H,4.9;N,7.1 Example 30 (see Scheme 37) Preparation of a) (2S)-2-({-3-phenyl-5[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]- phenylcarbonyI}-amino)-4-methylsuIfanylbutyric acid methyl ester (compound 32) and: b) (2S)-2-({-3-phenyI-5[((2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]- phenylcarbonyl}-amino)-4-methylsulfanylbutyric acid (compound 32f) a) Preparation of Compound 32 Starting material compound 32e (55mg,0.096mmol) was deprotected (analogously as for the equivalent step in Example 15) to give the title compound 32 as a white foam (56mg). 1 H NMR (CDCl 3 .250MHz) dl .6-1.85(lH.m);1.9-2.4(6H+CH 3 C 5 H 6 );2.45-2.7(3H.m); 3.1-3.25(lH.m);3.35-4.1(l lH+H 2 O,m);4.75-4.95(lH.m);6.8(lH.m);6.9-7.05(lH.m); 7.1-7.55(6H+CH 3 C 6 H 5 +CHCl 3 ,m,) MS (ESP+) m/z 474 (M+H)". Anal.Calcd for C 24 H 3 I N 3 O 3 S 2 .2TFA.0.75toluene C,51.8;H.5.1;N,5.45 Found C,51.6;H,5.2;N,5.1 Starting material 32e was prepared as follows. Compound 32a Saturated NaHCO 3 (aq) (90mL) was added to a stirred solution of methyl-3-bromo-5-nitro- benzoate (4.0g,15.38mmol) (Mindl and Vecera, Coll.Czech.Chem.Comm. 38.3496.1973.) and phenyl boronic acid (2.0g,16.38mmol) in dimethoxyethane (180mL). Tetrakis(triphenylphosphine)palladium(0), (444mg,0.38mmol) was added and the mixture heated at reflux for lhr. The resulting black solution was allowed to cool to RT then quenched with saturated NaHCO 3 (aq)(400mL). The aqueous was extracted with EtOAc(200mL).then acidified to pH3 with 2N HC1. The resulting suspension was filtered. washed with water and azeotroped with toluene (3x25mL) to give 32a as an off- white solid which was triturated with i-Hexane.filtered and dried.2.6g(69.5%). Η NMR (DMSO-D 6 .300MHz) d7.5(3H.m);7.8(2H.m):8.4-8.7(3H.m) MS (ESP " ) m/z 242 (M-H) " . Anal. Calcd for C 13 H 9 N0 4 : C.64.2:H.3.73;N.5.76 Found C.64.0:H.3.7;N.5.6 5 Compound 32b 32a (3.1g,12.76mmol)was coupled with L-Methionine methylester hydrochloride (analogously as for the equivalent step in Example 22) to give 32b,4.9g(99%). Η NMR (CDCl 3 ,200MHz) d2.1-2.45(5H.m);2.65(2H.t);3.83(3H.s);4.99(lH.m); 7.2-7.35(lH+CHCl 3 ,m.);7.4-7.6(3H.m);7.6-7.7(2H.m);8.38(lH.m);8.58(2H.m) 10 MS (ESP+) m z 389 (M+H)". Anal. Calcd for C 19 H 20 N 2 O,S C.58.8:H.5.19;N.7.21 Found C.58.8;H.5.1 ;N.7.2 Compound 32c 15 32b(3.0g,7.73mmol) was reduced (analogously as for the equivalent step in Example 30) to give the corresponding aniline 32c.2.43g(87.8%). Η NMR (CDCl 3 ,250MHz) d2.0-2.2(4H.m);2.2-2.4(lH.m);2.6(2H,m);3.8(3H,s); 3.9(2H.bs.NH 2 );4.93(lH.m);6.93(lH.d.NHCO);7.03(lH.m);7.12(lH.m); 7.3-7.5(4H.m);7.5-7.65(2H.m) 20 MS (ESP+) m z 359 (M+H)". Compound 32d 32c (1.0g,2.8mmol) was coupled with the aldehyde 22b (880mg.2.8mmol) (analogously as for the equivalent step in Example 30) to give 32d .1.5 lg(82.3%) 25 1H NMR (CDCl 3 +CD 3 COOD.250MHz) dl.5(9H,s);1.8-2.0(lH.m); 2.0-2.4(5H+CH 3 COOH.m);2.5-2.75(3H.m);3.2-3.45(2H.m);3.5-3.7(lH,m); 3.7-3.9(4H,m);4.0-4.4(2H,m):4.5-4.75(2H,m);4.9-5.05(lH.m);5.1-5.45(2H.m); 5.8-6.1(lH,m);7.03(lH.m);7.1-7.5(5H+CHCl 3 ,m);7.55-7.7(2H.m) MS (ESP+) m/z 658 (M+H) + . 30 Anal.Calcd for C 33 H 43 N 3 O 7 S 2 0.1H 2 O C.59.9:H.6.61;N,6.35 Found C.59.7:H.6.8:N.6.2 Compound 32e 32d(l.lg.l.67mmol) was deprotected (analogously as for the equivalent step in Example 15) to give the desired starting material 32e.800mg(83.4%). 'H NMR (CDCl 3 ,250MHz) dl .25(1.5H.t,CH 3 CH 2 COCH 3 );l .4-1.6(10H.m); 1.9(2H.bs.NH+H 2 O);2.0-2.22(4H+CH 3 CH 2 CO 2 CH 3 );2.23-2.55(2H.m): 2.51 -2.65(2H.m);2.9( 1 H.m):3.12(1 H.m);3.2-3.75(4H.m);3.8(3H.m); 4.13(1.3H.q.CH 3 CH 2 C0 2 CH 3 );4.45(lH.bs.NH);4.95(lH,m); 6.85-7.0(2H.m.ArH+NHCO):7.07(lH,m);7.2-7.5(4H+CHC13.m);7.5-7.65(2H.m) MS (ESP+) m/z 574 (M+H) + .474. Anal.Calcd for C 29 H 39 N 3 O 5 S 2 0.5EtOAc C.60.3;H.7.02;N.6.8 Found C.59.9:H.7.1 ;N.6.6 b) Preparation of Compound 32f Starting material 32e (140mg,0.244mmol) was hydrolysed (analogously as for the equivalent step in Example 31) to give the desired product 32f as a white foam.96.3mg (64.9%). Η NMR (DMSO-D 6 +CD 3 COOD.250MHz) d 1.5-1.8(lH.m);1.9-2.2(5H,m); 3.05(lH.q);3.15-3.6(7H.m);3.65-3.9(lH,m);4.45-4.65(lH.m);6.95-7.05(lH.m); 7.05-7.2(1 H.m);7.25-7.5(4H.m):7.55-7.7(2H.m). MS (ESP+) m z 460 (M+H)",279. Anal.Calcd for C 23 H 29 N 3 S 2 O 3 1.3TFA C,50.6;H.5.02;N,6.91 Found C,50.6;H,5.1;N,7.2 The starting material was prepared as described in a) immediately above. Example 31 (see Scheme 38) Preparation of a) (2S)-2-({2-phenyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]- phenylcarbonyl}-amino)-4-methylsulfanylbutyric acid methyl ester (compound 33) and; b) (2S)-2-({2-phenyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]- phenylcarbonyl}-amino)-4-methylsulfanylbutyric acid (compound 33f) a) Preparation of Compound 33 Starting material 33e (53.4mg.0.093mmol) was deprotected (analogously as for the equivalent step in Example 31) to give the title compound 33 as a white solid.43.2mg(87%). 'H NMR (DMSO-D 6 +CD 3 COOD.300MHz) dl.5-1.9(3H+CH 3 COOH.m);1.95(3H.s); 2.0-2.3(2H.m);2.4-2.65(lH+DMSO.m);3.0-3.15(lH,m);3.3-3.9(8H.m): 4.25-4.4(lH.m):6.7(lH,m);6.78(lH.m);7.1-7.4(6H.m). MS (CI " ) m/z 474 (M+H) " . Anal.Calcd for C 24 H 3 I N 3 S 2 O 3 1.75TFA C,53.6:H,6.14;N,7.82 Found C,53.6:H.6.3;N,7.7 The starting material was prepared as follows. Compound 33a 2-Bromo-5-nitrobenzoic acid (12.28g,0.05mmol) was coupled with benzene boronic acid (6.7g.0.055mmol),(analogously as for the equivalent step in Example32) to give 33a as a white solid.10.95g(90.3%). Η NMR (DMSO-D 6 .300MHz) d7.3-7.5(5H.m);7.65(lH.m);8.35(lH.m);8.45(lH.m). MS (ESP-) m/z 242 (M-H) " ,198. Compound 33b 33a (3.58g,14.7mmol)was coupled with L-Methionine methyl ester hydrochloride (3.25.16.2mmol),(analogously as for the equivalent step in Example32) to give 33b as a pale yellow solid.3.02g(52.6%) 1H NMR (CDCl 3 .300MHz) dl .7-2.2(7H.m);3.7(3H.s);4.7(lH.m);6.05(lH.m.NH); 7.35-7.6(6H.m)8.33(lH.m);8.55(lH.m) MS (ESP+) m/z 389 (M+H) + . Compound 33c 33b(l .0g,2.6mmol) was reduced (analogously as for the equivalent step in Example 30) to give the corresponding aniline 33c.725mg(78.6%). 'H NMR (CDCl 3 ,300MHz) dl.6-1.8(lH.m);1.8-2.15(6H.m);3.6(3H,s): 5 3.7-3.9(2H.bs.NH 2 );4.6-4.7(lH,m);5.85(lH.d.NHCO):6.79(lH,m);7.0(lH.m); 7.15(lH,d);7.2-7.45(5H+CHCl 3 ,m). MS (ESP+) m z 359,(M+H) + ,196. Compound 33d 10 33c (71 Omg.1.98mmol) was coupled with the aldehyde 22b (625mg, 1.98mmol) (analogously as for the equivalent step in Example 30) to give 33d.l.lg(84.4%). Η NMR (CDCl 3 +CD 3 COOD,250MHz) dl.5(9H.s);1.6-2.2(8H+CH 3 COOH.m): 2.5-2.75(lH.m),3.2-3.4(2H,m);3.45-3.9(5H.m):4.05-4.35(2H,m);4.5-4.8(3H,m); 5.15-5.45(2H.m);5.8-6.1(lH,m);6.75-6.9(lH.m);6.9-7.05(lH.m);7.1-7.23(lH,m); 15 7.25-7.45(5H+CHCl 3 .m). MS (ESP+) m/z 658 (M+H) + . Anal.Calcd for C 33 H 43 N 3 S 2 O 7 C,60.3:H,6.59;N.6.39 Found C,60.0:H,6.9;N,6.2 20 Compound 33e 33d (1.0g,1.52mmol) was deprotected (analogously as for the equivalent step in example 15) to give the desired starting material 33e.658mg(75.4%). Η NMR (CDCl 3 +CD 3 COOD.250MHz) dl .5(9H,s);1.6-2.2(8H+CH 3 COOH,m); 2.55-2.75(lH,m);3.25-3.4(lH,m);3.5-3.75(5H.m);3.75-4.2(3H,m); 25 4.55-4.75(lH,m);6.7-6.85(lH,m);6.85-6.97(lH,m);7.1-7.25(lH,m); 7.25-7.48(5H+CHCl 3 ,m). MS (ESP+) m/z 574 (M+H) + ,474. Anal.Calcd for C 29 H 39 N 3 O 5 S 2 C,60.7:H.6.85;N,7.32 Found C.60.7;H.7.20;N,7.30 30 b) Preparation of Compound 33f Starting material 33e (100mg.0.174mmol) was hydrolysed (analogously as for the equivalent step in Example 31) to give 33f as a white foam.64.6mg(59.8%). Η NMR (DMSO-D 6 +CD 3 COOD.300MHz) dl .5-2.0(6H+CH 3 COOH.m); 2.0-2.3(2H.m):2.3-2.7(lH+DMSO);3.0-3.1(lH.m):3.2-3.9(5H.m);4.2-4.35(lH.m): 6.6-6.9(2H.m):7.1-7.4(6H.m). MS (ESP+) m z 460 (M+H)".31 1. Anal Calcd for C 23 H 29 N 3 O 3 S 2 1.4TFA C,50.0:H.4.95:N,6.79 Found C,49.9;H,5.1 :N.6.7 Starting material 33e was prepared as described in a) immediately above. Example 32 (see Scheme 39) Preparation of a) (2§)-2-{2-Benzyl-5-[(4-sulfanylpyrrolidin-2-ylmethyl)-amino]-benzoy_amino}- 4-methylsulfanyIbutyric acid methyl ester (compound 34) and: b) (2S)-2-{2-BenzyI-5-[(4-sulfanylpyrrolidin-2-ylmethyl)-amino]-benzoylamino}- 4-methylsulfanylbutyric acid (compound 34h) a) Preparation of Compound 34 Starting material 34g (500mg,0.85mmol) was deprotected (analogously as for the equivalent step in Example 31) to give the title compound 34 as a white solid, 454mg (89.3%). 'H NMR (DMSO-D 6 +CD 3 COOD.300MHz) dl.5-1.7(lH,m);1.85-2.1(5H,m); 2.35-2.6(3 H+DMSO.m);2.9-3.1 ( 1 H,m);3.1 -3.8(8H.m):3.9(2H.q);4.4-4.6( 1 H,m); 6.5-6.7(>lH,m);6.9-7.0(lH,m);7.0-7.3(6H.m). MS (ESP+) m/z 488 (M+H)",325. Anal.Calcd for C 25 H 33 N 3 S 2 O 3 .3HCl C,50.3;H.6.08;N.7.04 Found C,50.4;H,6.3:N,7.3 Starting material 34g was prepared as follows. Compound 34a A solution of 2-bromo-5-nitrobenzoic acid (9.0g.36.6mmol) in MeOH (200mL) was treated with SO 2 Cl 2 (2.0mL) and the resulting solution heated at reflux forl8hrs.The reaction mixture was then evaporated .pre-absorbed on SiO 2 (Merck.9385) and chromatographed. eluting with 10%EtOAc/i-Hexane. Appropriate fractions were combined and evaporated to give 34a as a crystalline white solid.8.38g(88.1%) Η NMR (CDCl 3 ,300MHz) d4.0(3H.s.CO 2 CH 3 );7.85(lH,m):8.18(lH.m);8.63(lH.m). Compound 34b A solution of benzyl bromide (2.0mL.17.3mmol) in THF( 1 OmL) was added dropwise at 0°C to a stirred suspension of zinc dust(1.7g.26mmol) in THF(lOmL) which had been activated according to the method described by Knochel (J.O.C. 51,2392.1988). The mixture was left to warm to RT and stir for 3hrs.An aliquot (6.5mmol) of the supematent containing the benzyl zinc reagent was then added to a stirred solution of 34a (1.0g,3.85mmol) and Pd(PPh 3 ) 2 Cl 2 (27mg,0.0385mmol) in THF(10mL) at RT under argon. After lhr a second aliquot (6.5mmol) of the benzyl zinc reagent was added.The resulting black reaction mixture was quenched with 2N HCl (250mL) and extracted with EtOAc (2xl00mL).The combined organics were washed with water (50mL) and brine (50mL),fιltered through phase separating paper and evaporated to an orange gum. This was chromatographed on SiO 2 (Merck.9385) eluting with 10%EtOAc/i-Hexane to give 34b as a yellow oil ,590mg(56.6%). Η NMR (CDCl 3 ,300MHz) d3.9(3H.s.CO2CH 3 );4.48(2H,s,CH 2 Ph);7.0-7.5(6H.m); 8.23(lH,m);8.75(lH,m). MS (ESP " ) m z 270 (M-H) " ,210. Compound 34c 2N NaOH (2.0mL,4mmol) was added to a solution of 34b (560mg.2.06mmol) in MeOH (lOmL) at RT. After 2hrs the RM was evaporated to remove the MeOH and then partitioned between Et 2 O (20mL) and 2N NaOH (20mL).The aqueous was acidified to pH2/3 with 2N HCl and extracted with EtOAc(3x20mL).The combined organics were washed with water (20mL) and brine (20mL) .filtered through phase separating paper and evaporated to yield 34c as a white solid.453mg(85.3%). Η NMR (DMSO-D 6 ,300MHz) d4.45(2H,s.CH 2 Ph):7.0-7.4(5H.m); 7.55(lH.m);8.3(lH.m);8.53(lH,m). MS (ESP " ) m z 256 (M-H) " ,212. Compound 34d 34c (630mg.2.45mmol) was coupled with L-Methionine methyl ester hydrochloride (540mg,2.7mmol). (analogously as for the equivalent step in Example 32) to give 34d as a pale yellow solid. 900mg (91.3%). Η NMR (DMSO-D 6 .250MHz) dl .9-2.25(5H.m);2.5-2.75(2H+DMSO.m); 3.74(3H.s.C02CH3);4.28(2H,q,CH 2 Ph);4.55-4.75(lH,m);7.15-7.5(5H.m); 7.6(lH,m);8.2-8.35(2H.m);9.13(lH.d.NHCO). MS (ESP+) m/z 403 (M+H)". Compound 34e SnCl 2 2H 2 O (2.5g,l 1.08mmol) was added to a stirred solution of 34d (900mg,2.24mmol) in EtOAc(50mL) and the resulting mixture heated at reflux for 18hrs.The RM was cooled to RT and treated with 0.88S0 SG NH 3 (aq) dropwise to pH8. The resulting heavy white precipitate was removed by filtration through celite(545). The filtrates were then evaporated and purified by chromatography (Mega Bond Elut.SiO 2 ),eluting with CH 2 C1 2 and then 50%EtOAc/ i-Hexane to give the corresponding aniline 34e.595mg(71.4%). Η NMR (CDCl 3 ,300MHz) dl.75-2.2(5H,m);2.25-2.45(2H,m); 3.6-3.8(5H.m.CO2CH 3 +NH 2 ).4.08(2H.q,CH 2 Ph); 4.65-4.85(lH.m);6.24(lH.d.NHCO);6.7(lH,m);6.78(lH.m):7.0(lH,m); 7.05-7.3(5H+CHCl 3 .m). MS (ESP+) m z 373 (M+H)",210. Compound 34f 34e (570mg,1.53mmol) was coupled with the aldehyde 22b (580mg.l.84mmol) (analogously as for the equivalent step in Example 30) to give 34f as a cmde pale green foam(1.54g). MS (ESP+) m/z 672 (M+H)". Compound 34g 34f (1.5g.2.24mmol) was deprotected (analogously as for the equivalent step in Example 15) to give the desired starting material 34g as a pale brown glass.550mg (41.9%). Η NMR (CDCl 3 ,300MHz) dl.3-1.65(10H,m);1.7-2.2(5H+H 2 O.m);2.25-2.6(3H.m); 2.8-3.9(9H.m):3.9-4.25(2H.m);4.6-4.9(lH.m);6.3(lH.d.NHCO);6.55-6.8(2H.m): 6.9-7.4(5H+CHCl 3 ,m). MS (ESP+) m/z 588 (M+H)",488. b) Preparation of Compound 34h Starting material 34g (52mg,0.087mmol) was hydrolysed (analogously as for the equivalent step in Example 16), then purified by reverse phase HPLC (Dynamax® 60A.C 18 ,8m prep column).eluting with 50%MeOH/H 2 O (0.1%TFA) to give 34h as a colourless glass.38.2mg(56.6%). 'H NMR (DMSO-D 6 +CD 3 COOD.300MHz) dl.5-1.7(lH,m); 1.8-2.1 (5H+CH 3 COOH,m);2.3-2.6(3H+DMSO,m);2.9-3.1 ( 1 H.m);3.2-4.1 (7H,m);4.3- 4.5(lH.m);6.5-6.7(2H,m);6.9-7.0(lH.m);7.05-7.25(5H.m). MS (ESP+) 474 (M+H) + . Anal.Calcd for C 24 H 3 I N 3 S 2 O 3 1.4TFA C.50.8;H,5.16:N,6.14 Found C.51.0:H,5.3;H.6.7 The starting material was prepared as described in a) immediately above. Example 33 (see Scheme 40) Preparation of a) (2S)2-{2-Benzyl-4-[([2S,4S]4-sulfanyIpyrrolidin-2-ylmethyl)-aminoj- benzoylamino}-4-methylsulfanylbutyric acid methyl ester (compound 35) and: b) (2S)2-{2-Benzyl-4-[([2S,4S]4-sulfanylpyrroIidin-2-ylmethyl)-aminol- benzoylamino}-4-methylsulfanyIbutyric acid (compound 35g) a) Preparation of Compound 35 The title compound 35 was synthesised from methyl-2-bromo-4-nitro-benzoate using the same methodology as described in Example 32 but using Pd (dba) 3 as a source of catalytic palladium in the benzylation reaction. 'H NMR (DMSO-D 6 +CD 3 COOD.300MH z ) dl.5-1.7(lH.m);1.8-2.1(5H.m); 2.3-2.6(3H+DMSO,m);2.9-3.1(lH.m);3.2-3.8(8H.m);4.05(2H.m);4.4-4.6(lH.m); 6.4-6.6(2H.m);7.0-7.35(6H.m) MS (ESP+) m/z 488(M+H) + ,325. Anal Calcd for C 25 H 33 N 3 S 2 O 3 .2HCl C.53.6:H.6.29;N,7.5 Found C,53.5:H.6.5;N,7.3 b) Preparation of Compound 35g Compound 35 (100mg.0.18mmol; see a) above) was hydrolysed (analogously as for the equivalent step in Example 32) to give 35g as a white solid.85.8mg(67.3%). Η NMR (DMSO-D 6 +CD 3 COOD.300MH Z ) dl .5- 1.7( 1 H,m); 1.8-2.1 (5H.m); 2.3-2.6(3H+DMSO,m);2.9-3.9(6H.m);3.95-4.2(2H,m);4.3-4.6(lH,m);6.4-6.5(2H.m); 7.0-7.3(6H,m) MS (ESP+) m z 474(M+H) + .325. Anal Calcd for C 24 H 3 I N 3 S 2 0 3 .1.3TFA C.51.4;H.5.24:N.6.76 Found C.51.2:H.5.4;N.6.7 SUBSTTΠΠΈ SHEET (RULE 26) Example 34 (see Scheme 41) (2S)2-{2-Benzyl-5-[([2S,4S]4-sulfanylpyrrolidin-2-ylmethyI)-amino]-benzoylamino}-4- methylsulfanylbutyric acid isopropyl ester (compound 36) The nitro compound 36b was reduced to the corresponding aniline, coupled with the thioproline aldehyde 22b using IPA as solvent and deprotected exactly analogously as for Example 32 to give the title compound 36. 1 H NMR (DMSO-D 6 +CD 3 COOD.300MH z ) dl.0-1.3(6H.m);1.5-1.7(lH,m); 1.8-2.1 (5H.m):2.3-2.6(3H+DMSO,m):2.9-4.1 (8H.m):4.3-4.6( 1 H.m):4.8-5.0( 1 H.m); 6.5-6.7(2H,m):6.8-7.3(6H,m) MS (ESP+) m/z 516(M+H) " ,325. Anal Calcd for C 27 H 37 N 3 S 2 O 3 .2HCl C.55.1;H.6.68;N.7.14 Found C,54.9:H.7.0;N,7.1 Compound 36a A solution of 34d (25.24g,62.78mmol) in MeOH (500mL) was treated with 2N NaOH (35mL.70mmol).The resulting solution was then evaporated to dryness and the solids partitioned between Et O (200mL) and water (500mL).The aqueous was then acidified to pH2 with 2N HCl and extracted with EtOAc(2x250mL).The combined organics were washed with water(2xl00mL),brine(100mL).filtered through phase separating paper and evaporated to give 36a as a white solid.23.57g(96.8%). Η NMR (DMSO-D 6 ,300MH Z ) dl .8-2.2(5H.m);2.3-2.6(2H+DMSO.m); 4.1-4.3(2H,m):4.4-4.6(lH.m);7.1-7.3(5H,m);7.4-7.6(lH.m);8.1-8.3(2H.m); 8.9-9.0(1 H,m.NHCO) MS (ESP-) m/z 387(M-H) " . Compound 36b Sulphuryl chloride (5.0mL.62mmol) was added to a stirred suspension of 36a(19.2g,50mmol) in IPA (500mL).The resulting mixture was then heated at reflux for 18hrs. The reaction mixture was then evaporated to 1/5 volume and partitioned between EtOAc (1L) and saturated NaHCO 3 (aq) (500mL).The organics were then washed with water (200mL).brine (200mL),filtered through phase separating paper and evaporated to give 36b as a white solid.21.25g(100%) Η NMR (DMSO-D 6 .300MH Z ) dl.0-1.3(6H.m);1.8-2.2(5H.m); 2.3-2.6(2H+DMSO.m):4.1-4.3(2H.m):4.4-4.6(lH.m);4.8-5.0(lH.m);7.1-7.3(5H.m); 7.4-7.6(lH.m);8.1-8.3(2H.m);9.0(lH.m.NHCO) MS (ESP+) m/z 431(M+H) " . Example 35 (see Scheme 42) (2S)2-{2-Benzyl-5-[N-([2S,4S]4-sulfanylpyrrolidin-2-ylmethyI)-N-(3- methoxypropionyl)-amino]-benzoylamino}-4-methylsulfanylbutyric acid isopropyl ester (compound 37) Starting material 37b was deprotected using the same methodology for the equivalent step described in Example 32 to give the title compound 37. 1 H NMR (DMSO-D 6 +CD 3 COOD.300MH Z ) d 1.0- 1.3(6H.m); 1.5-1.7(1 H.m); 1.8-2.1(5H.m);2.2-2.6(5H+DMSO.m);2.9-3.95(10H,m);4.0-4.2(3H,m). 4.4-4.6(lH.m);4.8-5.0(lH.m);7.0-7.5(8H,m) MS (ESP+) m/z 602 (M+H)". Anal Calcd for C 31 H 43 N 3 S 2 O 5 .1.5HCl C.56.7:H.6.83;N,6.4 Found C.56.7;H,7.0:N,6.0 The starting material was prepared as follows. EEDQ (530mg.2.15mmol) was added to a stirred solution of 36d (1.5g.2.15mmol; see Example 34) and 3-methoxy propionic acid (220mL. 2.36mmol) in CH 2 C1 2 (15mL). The mixture was left to stir 18hrs at RT then evaporated. The residues were then partitioned between IN citric acid(aq) (200mL) and EtOAc (lOOmL). The organics were washed with saturated NaHCO 3 (aq) (50mL), water(50mL) and brine(50mL). filtered through phase separating paper and evaporated to give a pale yellow gum. This was then purified by flash chromatography on SiO 2 (Merck 9385) eluting a gradient of 0-50%) EtOAc/i-Hexane. Appropriate fractions were filtered and evaporated to give starting material 37b as a colourless gum.l.l4g(67.7%). MS (ESP+) m/z 786 (M+H) + . Example 36 (see Scheme 43) Preparation of a) N-([2S,4S]-4-sulfanyl-pyrroIidin-2-ylmethyl)-3,3-dimethyl-N-(2-naphthalen-l- yl-ethyl)-butyramide (compound 56) and: b) IV-([2S,4S]-4-suIfanyl-pyrroIidin-2-ylmethyI)-i\-(2-naphthalen-l-yl-ethyl)-2- pyridin-3-yl-acetamide (compound 57) a) Preparation of compound 56 The method described in Example 23 for the synthesis of compound (6) was used to prepare compound (56) as set out in Scheme 43. NMR data in CDC1 3 δ 0.91(s. 9H), 1.5(m, IH). 1.75(m. IH). 1.82(d.lH). 1.91(d. IH). 2.52(m. IH). 2.92(m, IH). 3.33(m. 3H), 3.72(m, 4H). 4.15(m. IH), 7.26(d,lH). 7.4 l(t. IH). 7.56(m. 2H), 7.8(d, IH), 7.9(2d, 2H), 9.08(br.s. IH). Micro Analysis: %Theory C64.2, H7.97, N6.5 ( 1.00 HCl . 0.5H 2 O %Found C64.4, H7.90, N6.3 Starting material compound (54) was synthesised analogously with Example 23 using the appropriate intermediates: Compound (52). NMR data in CDC1 3 δ 1.00(2s. 9H). 1.46(d, 9H), 1.95(m. 2H), 2.4(m. 2H), 3.3(m. 4H), 3.7(m, 3H), 4.00(m, 3H), 4.57(d. 2H), 5.22(2d, 2H), 5.90(m. IH), 7.24-8.4(m, 7H). Compound (54). NMR data in CDC1 3 δ 1.00(2s, 9H), 1.35(m, IH), 1.49(s, 9H), 1.89(br.s,lH), 1.95(d, IH), 2.3(m, IH), 2.32(d, IH), 2.88(2q, IH), 3.1-3.9(m, 9H), 7.25-8.31(m, 7H). b) Preparation of Compound 57 The method described in Example 24 for the synthesis of compound (27) was used in a similar manner to prepare compound (57). NMR data in CDC1 3 δ 1.2(m, IH), 2.00(m, IH). 2.6(m. 2H). 3.15-4.40(m. 10H), 7.28- 8.70(m, l lH). 9.4(br.s. IH). Micro Analysis: %Theory C56.0, H6.20. N8.17 (2HC1. 2H 2 O) %Found C56.4, H6.46. N7.70 Starting material compound(55) was synthesised analogously with Example 24 using appropriate intermediates: Compound (53). NMR data inCDCl 3 δ 1.48(s. 9H). 1.84(m, IH), 2.42(m, IH). 2.87-3.45(m. 5H). 3.63- 4.26(m. 7H), 4.55(d, 2H), 5.22(2d. 2H), 5.9(m. IH). 7.1-8.7(m. 11H). Compound (55). NMR data in CDC1 3 δ 1.34(m. IH), 1.5(s. 9H). 1.95(m. IH), 2.32(m. 2H). 2.72-4.00(m. 10H), 7.1-8.6(m, 11H). Example 37 (see Scheme 44) Preparation of a) N-(2,2-Diphenyl-ethyl)-N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyI)-3-methyl- butyramide (compound 67); b) N-(2,2-Diphenyl-ethyl)-N-(|2S,4S]-4-sulfanyl-pyrroIidin-2-ylmethyI)-3,3- dimethyl-butyramide (compound 68); c) N-(2,2-Diphenyl-ethyl)-N-((2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-2-pyridin- 3-yl-acetamide (compound 69) and: d) N-(2 . 2-Diphenyl-ethyl)-l-oxy-N-([2S,4S]-4-sulfanyI-pyrrolidin-2-ylmethyI)-6- methoxy-nicotinamide (compound 70). a) Preparation of Compound 67 The method described in Example 23 for the synthesis of compound (6) was used in an analogous manner to prepare compound (67) using appropriate intermediates - see Scheme 44. NMR data in DMSO-d6 δ 0.75(m. 6H). 1.55(m,lH). 1.87(m. 2H), 2.05-2.45(m.lH). 3.05(m,lH), 3.25-3.70(m. 6H), 4.05(m. 2H), 4.20-4.55(m.lH), 7.30(m.lOH), 8.80- 9.80(2br.s. 2H) Micro Analysis: %Theory C63.9, H7.82. N6.21 (1.00HC1.1.00H 2 O) %Found C64.1. H7.70. N6.00 Compound (58). NMR data in CDC1 3 δ 1.50(s. 9H). 1.77(m,lH). 2.40(m.lH). 2.75(m.lH). 3.00(m,lH). 3.14(q.lH). 3.24(d. 2H). 3.67(m.lH). 3.93(m.lH). 4.10(m. 2H). 4.54(d. 2H). 5.25(m. 2H). 5.90(m.lH). 7.25(m,10H) Compound (59). NMR data in CDC1 3 δ 0.85(m. 6H), 1.48(m. 9H), 1.80(m, 2H). 2.10(m, 2H). 2.40(m.lH), 2.80-4.35(m, 9H), 4.55(m. 2H). 5.25(m, 2H). 5.90(m,lH). 7.25(m,10H) Compound (63). NMR data in CDC1 3 δ 0.85(2d, 6H). 1.24(m.lH). 1.48(s. 9H). 1.68(m.lH). 1.81 (d.IH). 1.95-2.35(m. 3H). 2.75-3.65(m. 6H). 3.90-4.55(m, 3H). 7.25(m,10H) b) Preparation of Compound 68 Similarly compound (68) was synthesised from compound (60) as set out in Scheme 44. Compound (68) NMR data in DMSO-d6 δ 0.85(m, 9H), 1.55(m,lH), 1.74-2.27(m, 2H). 2.37(m.lH), 3.05(m.lH), 3.45(m, 6H). 4.05(m, 2H), 4.18-4.55(m,lH), 7.28(m,10H), 8.90-9.90(m. 2H) Micro Analysis: %Theory C64.6. H8.02. N6.02 (1.0HC1.1.0H 2 0) %Found C64.8. H8.30. N5.70 Compound (60). NMR data in CDC1 3 δ 0.93(m, 9H), 1.50(s, 9H), 1.82(m. 2H). 2.35(m. 3H), 2.90-4.35(m, 8H), 4.55(m, 2H), 5.25(m,2H), 5.90(m.lH), 7.25(m.lOH). Compound (64). NMR data in CDC1 3 ) δ 0.93(s, 9H), 1.24(m,lH). 1.48(s, 9H). 1.80(q,lH), 2.23(d,lH), 2.30(m,lH). 2.75-3.70(m, 6H), 3.90-4.60(m, 3H), 7.25(m.lOH). c) Preparation of Compound 69 Compound (69) was synthesised from compound (61) (see Scheme 44) analogously with the procedure described in Example 24 for the preparation of compound (27). Compound (69). NMR data in CDC1 3 δ 1.95(m.1 H). 2.40(m.1 H). 2.60(m.1 H), 3.15-4.50(m.1 1 H). 7.28(m.lOH). 7.67(m.lH). 8.05(m.lH). 8.50(m.lH). 8.71(m.lH), 9.10-10.20(br.d. 2H). Micro Analysis: %Theory C55.1. H5.51. N7.01 (2.0 HC1.0.75TFA.0.5H 2 O) %Found C55.0. H5.60. N6.90 Compound (61). NMR data in CDC1 3 δ 1.47(s. 9H). 1.80(m.lH). 2.30-4.65(m.l4H), 5.23(m. 2H). 5.90(m.lH). 7.25(m,12H). 8.10-8.55(m, 2H). Compound (65). NMR data in CDC1 3 δ 1.25(m,lH), 1.48(s, 9H). 2.30(m.lH). 2.70-4.55(m,12H). 7.30(m,12H). 8.28(2d.lH). 8.45(m,lH). d) Preparation of Compound 70 Similarly compound (70) was synthesised from compound (62) using appropriate intermediates. NMR data in CDC1 3 δ 1.67(m,lH), 2.15(d,lH). 2.47(m.lH), 3.16(br.s. IH). 3.50(m. 2H), 3.85-4.40(m. 8H). 5.22(br.s.lH), 6.56(d,lH), 7.00-7.35(m,l lH), 7.90(s,lH), 8.85- 10.75(2br.s. 2H) Micro Analysis %Theory C57.2. H5.91. N7.70 (2.0HC1.0.5H 2 O) %Found C57.5. H5.60. N7.30 Compound (62). NMR data in CDC1 3 δ 1.50(s, 9H), 1.60(m,lH). 2.47(m,lH), 3.00-4.50(m,12H). 4.58(d. 2H), 5.25(m. 2H). 5.90(m.lH), 6.53(d,lH), 6.95(m.lH). 7.25(m,l lH). Compound (66). NMR data in CDC1 3 δ 1.20(m,lH), 1.45(s, 9H), 2.30(m,lH), 2.66(m,lH), 3.00-3.45(m. 4H), 3.55(m.lH). 3.95-4.25(m, 5H), 4.47(m.lH). 6.55(d,lH). 7.25(m,l IH), 7.65(m.lH). Example 38 (see Scheme 45) Preparation of a) N-([2S,4S]-4-suIfanyl-pyrrolidin-2-ylmethyl)-3-methyI-N-(2-naphthalen-2-yI- ethyl)-butyramide (compound 80): b) N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-3,3-dimethyl-N-(2-naphthalen-2- yl-ethyl)-butyramide (compound 81): c) N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-N-(2-naphthalen-2-yl-ethyl)-2- pyridin-3-yl-acetamide (compound 82) and: d) N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-2-(4-methoxy-phenyl)-N-(2- naphthalen-2-yl-ethyl)-acetamide (compound 83). a) Preparation of Compound 80 The method described in Example 23 for the synthesis of compound (6) was used to prepare compound (80). NMR data in DMSO-d6 δ 0.75(m. 6H). 0.87(d.lH). 1.65(m.lH). 1.92(m,lH). 2.02(d.lH), 3.03(m. 3H), 3.20-3.80(m. 9H). 7.48(m. 3H), 7.75(d,lH), 7.85(m, 3H). 8.90-9.90(br.d, 2H) Micro Analysis: %Theory C64.9, H7.68. N6.88 (1.00 HCl) %Found C64.9, H7.50, N6.80 Starting material compound (76) was synthesised analogously with Example 23 using appropiate intermediates - see Scheme 45. Compound (71). NMR data in CDC1 3 δ 1.50(s. 9H), 1.85(m,lH), 2.50(m,lH), 2.80(m,lH), 3.00(m, 5H), 3.20(m,lH), 3.65(m,lH), 4.00(m,lH). 4.10(m.lH), 4.53(d, 2H), 5.20(m. 2H). 5.90(m,lH). 7.32(m.lH), 7.42(m, 2H), 7.63(s,lH). 7.80(m. 3H). Compound (72). NMR data in CDC1 3 δ 0.90(m. 7H), 1.00-2.60(m, 14H). 3.00(m. 2H). 3.10-4.20(m. 7H). 4.60(m. 2H). 5.25(m. 2H), 5.90(m,lH). 7.30-7.50(m, 3H), 7.60(m,lH). 7.80(m. 3H). Compound (76). NMR data in CDC1 3 δ 0.90(m. 6H). 1.10-2.50(m.l5H). 2.80-3.80(m. 9H), 7.26-7.50(m. 3H), 7.60(m.lH), 7.80(m, 3H) b) Preparation of Compound 81 Compound (81) was synthesised from compound (73) as set out in Scheme 45 in a similar manner to preparation of compound 80 (see above). NMR data in DMSO-d6 δ 1.08(d, 9H), 1.80(m.lH). 2.15(m, 2H), 2.65(m.lH), 3.00- 4.00(m,10H), 7.63(m. 3H), 7.90(s,lH), 8.03(m. 3H). 9.50(br.d. 2H). Micro Analysis: %Theory C64.9. H7.93. N6.58 (1.0HC1.0.25H 2 O) %Found C64.8. H8.10. N6.50 Compound (73). NMR data in CDC1 3 δ 1.00(m, 9H), 1.47(s, 9H), 1.80-2.55(m. 4H), 3.00(m, 2H), 3.10- 4.20(m, 8H), 4.60(d, 2H). 5.25(m, 2H). 5.90(m,lH), 7.30-7.85(m. 7H) Compound (77). NMR data in DMSO-d6( 100°C) δ 0.95(m. 9H). 1.35-1.75(m. 9H), 2.15(s, 2H), 2.40(m,lH). 2.60-3.90(m.l2H), 7.40(m. 3H). 7.70(m.lH), 7.80(m. 3H). c) Preparation of Compound 82 Compound (82) was synthesised from compound (74) as set out in Scheme 45 by a similar procedure to that desribed in Example 24 for the preparation of compound (27). Compound (82). NMR data in DMSO-d6 δ 1.65(m,lH). 2.90-4.15(m.l4H), 7.35-8.90(m.l IH), 9.50(br.d. 2H). Micro Analysis: %Theory C51.9. H5.19, N6.99 (2.0HC1,1.0TFA.0.5H 2 O) %Found C52.2. H5.40. N.7.00 Compound (74). NMR data in DMSO-d6 ( 100°C) δ 1.45- 1.75(m.1 OH). 2.85-3.85(m.11 H). 4.03(m, 1 H). 4.20(m.lH). 4.45-4.65(m. 2H). 5.20(m, 2H). 5.90(m,lH), 7.23(m.lH). 7.45(m. 4H). 7.67(s.lH). 7.80(m. 3H). 8.35(m. 2H). Compound (78) NMR data in DMSO-d6 (100°C) δ 1.30-1.75(m, 9H), 2.40(m.lH), 2.55-3.90(m,14H). 7.10-8.45(m.l lH). d) Preparation of Compound 83 Similarly compound (83) was synthesised from compound (75) using appropriate intermediates as set out in Scheme 45. Compound (85). NMR data in DMSO-d6 δ 1.65(m,lH), 2.95(m, 2H), 3.08(m,lH), 3.25-4.00(m,13H), 6.80(m. 2H), 7.06(2d, 2H), 7.47(m, 3H). 7.68(d,lH), 7.85(m, 3H), 9.35(br.d. 2H). Micro Analysis: %Theory C62.7, H6.57, N5.62 (1.5 HC1.0.5H 2 O) %Found C62.4, H6.50, N5.40 Compound (75). NMR data in DMSO-d6 (100°C) δ 1.45(s, 9H), 1.75(m,lH), 2.75-3.85(m,14H), 4.00(m,lH), 4.14(m,lH), 4.45-4.65(m, 2H), 5.20(m, 2H), 5.90(m,lH), 6.80(m, 2H), 7.05(m. 2H), 7.33(m,lH), 7.45(m. 2H), 7.63(s,lH), 7.80(m, 3H). Compound (79). NMR data in DMSO-d6 (100°C) δ 1.30-1.75(m, 9H), 2.35(m,lH), 2.60-3.90(m,17H), 6.78(m. 2H), 7.05(m, 2H). 7.40(m. 3H). 7.65(m,lH), 7.80(m, 3H). SUBSTΓTUTE SHEET (RULE 26) Example 39 (see scheme 46) Preparation of a) (2S)-2-({2-phenyl-4-[((2S,4S)-4-sulfanyl-pyrroIidin-2-ylmethyl)-amino]- phenylcarbonyl}-amino)-4-methylsulfany_-butyric acid methyl ester (compound 38) and; b) (2S)-2-({2-phenyl-4-[((2S,4S)-4-sulfanyl-pyrrolidin-2-ylmethyl)-aminoj- phenylcarbonyl}-amino)-4-methylsulfanyI-butyric acid (compound 38f). a) Preparation of Compound 38 Methyl -2-bromo-4-nitro-benzoate was coupled with phenyl boronic acid (analogously as for the equivalent step in Example 30) then coupled and deprotected using the same methodology as previously described for Example 32 to give the title compound 38. 1 H NMR (DMSO-D 6 ,250MHz) δl.35-1.75(3H,m);1.8(3H,s);1.9-2.2(2H.m); 2.25-2.5(2H+DMSO.m);2.75-3.9(10H.m);4.0-4.25(lH.m);5.0-5.9(5H.bs,H 2 O); 6.3-6.6(2H,m);7.0-7.3(7H,m);7.95(lH,m);9.2-9.8(2H,bd). MS (ESP+) m/z 474 (M+H)",311.196. Anal.Calcd for C 24 H 31 N 3 O 3 S 2 .2HC1.1.5H 2 O C,50.3:H,6.3;N.7.3 Found C,50.4;H,6.1;N,7.3 b) Preparation of Compound 38f Compound 38 was hydrolysed to the corresponding acid (analogously as for the equivalent step in Example 33 )to give 38f. Η NMR (DMSO-D 6 +CD 3 COOD,300MHz) 61.5-1.9(3H+CD3COOD,m); 1.95(3H,s); 2.05-2.35(2H,m):2.4-2.6(2H+DMSO,m);3.0-3.1(lH,m);3.2-3.9(4H.m);4.2-4.3(lH.m); 6.5- 6.7(2H,m);7.2-7.4(6H.m). MS (ESP+) m/z 460 (M+H) + .311. Anal.Calcd for C 23 H 29 N 3 O 3 S 2 .1.35TFA C,50.3;H.4.99;N,6.85 Found C.50.2;H.5.1;N,6.8 Example 40 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 (d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur 488.5 Magnesium 1.5 (e) Injection I (50 mg/ml) Compound X 5.0% w/v IM Sodium hydroxide solution 15.0% v/v 0.1M Hydrochloric acid (to adjust pH to 7.6) Polyethylene glycol 400 4.5% w/v Water for injection to 100% (f) Injection II (10 mg/ml) Compound X 1.0% w/v Sodium phosphate BP 3.6% w/v 0.1M Sodium hydroxide solution 15.0% v/v Water for injection to 100% (g) Injection III (1 mg/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 injection to 100% (h) Aerosol I mg/ml Compound X 10.0 Sorbitan trioleate 13.5 Trichlorofluoromethane 910.0 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 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 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. 5 polyglycerol oleate or oleic acid. Example 41 (see Scheme 47) Preparation of a) (2S)-4-Carbamoyl-2-({2-phenyI-5-[([2S,4S]-4-sulfanyl-pyrroIidin-2-ylmethyl)- 10 amino]-phenylcarbonyl}-amino)-butyric acid (compound 39e): and b) (2S)-4-Carbamoyl-2-({2-phenyl-5-[([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)- amino]-phenylcarbonyi}-amino)-butyric acid methyl ester (compound 39) a) Preparation of Compound 39 15 Compound 39a 32a (1.5g,6.2mmol) was coupled with L-Glutamine methyl ester (analogously as for the equivalent step in Example 30) to give compound 39a as a white solid .1.2g(50.5%) MS (ESP)+ m/z 386 (M+H)+. Compound 39 20 39a was reduced.coupled with the aldehyde (22b) and selectively deprotected using the same methodology as previously described for Example 32 to give the title compound 39. MS (ESP+) m/z 471 (M+H) + . Anal.Calcd for C 24 H 30 N 4 O 4 S,3HC1.0.25H 2 O C,49.3;H,5.8;N.9.6 Found C,49.2;H,5.9;N,9.2 25 b) Preparation of Compound 39e 39 was hydrolysed (analogously as for the equivalent step in Example 32) to give the title compound 39e. MS (ESP-) m/z 455 (M-H) " . Anal.Calcd for C 23 H 28 N 4 O 4 S,2TFA C,47.4;H.4.4;N.8.2 30 Found C.47.0:H,4.5;N,7.9 Scheme 1 O 0 (B . N.Q-Dimethylhydroxylamine/Triethyl.imine.C^CI-, (C)EEDQ/CH 2 CI 2 SUBSTTTUTE SHEET (RULE 26) Scheme 2 Kb) (A) \ (A)EEDQ/CH 2 CI 2 Scheme 3 (B) OH (Free Base) Scheme 4 cont. (T.F.A. salt) (E) (A) EEDQ/CH 2 CI 2 (B)Methanesulphonyl chloride/triethylamine/CH 2 CI 2 (C)Potassium thioacetate/acetone (D)T.F.A. (EJIodoacetamide/Sodium Bicarbonate/DMF - I l l Scheme 5 TFA salt (A) (A) Acetic anhydride/triethyiamine/CH 2 CI 2 SUBSTTTUTE SHEET (RULE 26) Scheme 6 (Free Base) (A) (A)Phenyl chloroformate/triethylamine/CH 2 CI 2 SUBSTΓΓUTE SHEET (RULE 26) Scheme 7 Scheme 7(cont.) (A)Allyl bromide/potassium carbonate/DMA/90deg./4hrs (B)DCCI/N-Hydroxysuccinimide/CH Cl /R.T./3.5hrs. (C)N,O-Dimethylhydroxylamine HCI/Triethylamine/5degJ16hrs. (D)Tin(ll)Chloride/Methanol/Reflux/1hr (E)EEDQ/CH Cl /R.T./16hrs. 2 2 Scheme 8 1 (c) (A)N-Methylhydroxylamine HCI./Triethylamine/CH Cl /5deg./16hrs. (B)Allyl bromide/Potassium carbonate/R.t/DMF/3hrs. (C)Tin(ll) chloride/Ethvl acetate/70Deq. Scheme 9 7(d) 1 (d) 9(a) (B) (A) EEDQ/CH 2 CI 2 (B)0.1M Sodium hydroxide/Allyl alcohol/R.t . SCHEME 10 SCHEME 11 SUBSTTTUTE SHEET (RULE 26) 119 SCHEME 12 SUBSTTTUTE SHEET (RULE 26) SCHEME 12 (Cont'd) H SUBSTTTUTE SHEET (RULE 26) SCHEME 13 SCHEME 14 SUBSTTTUTE SHEET (RULE 26) SCHEME 15 SUBSTTTUTE SHEET (RULE 26) SUBSTTTUTE SHEET (RULE 26) SCHEME 16 SCHEME 17 SCHEME 18 SUBSTTTUTE SHEET (RULE 26) SUBSTTΓUTE SHEET (RULE 26) SCHEME 19 SUBSTTTUTE SHEET (RULE 26) SCHEME 20 SCHEME 21 SUBSTTTUTE SHEET (RULE 26) SCHEME 22 18hrs e 22f Scheme 23 R \ SUBSTTTUTE SHEET (RULE 26) Scheme 24 R' \ Scheme 25 R' Scheme 26 R' \ R * - Scheme 27 R < \ R SUBSTTTUTE SHEET (RULE 26) Scheme 28 R' \ R Scheme 29 Scheme 30 (1) (a) (d) (5) R= (CH 2 )paraPh0CH 3 (e) (8) R= (CH 2 )paraPhOCH 3 (e) (H)R=(CH 2 )paraPhOCH 3 (a)4A Molecular sieve/sodium triacetoxy borohydrιde/dιchloromethane/-20deg (b)lsovaleryl chlonde/tr lethylamine/dichloromethane/R T (c)R=(CH2)30CH3, 4A Molecular sieve/ sodium triacetoxy borohydride/dichloromethane (c)R=CH2paraPhOCH3, paraMethoxybenzyl chloride/sodium bιcarbonate/H2θ/dιchloromethane (d)Tπbutyltιn hydπde/bιs(tπphenylphosphιne)palladιum(0) chloride/dichloromethane (e)Tπfluroacetιc acid/R T SUBSTTTUTE SHEET (RULE 26) Scheme 31 (b) Me (c) (18)R=COCH 2 CH(Me) 2 e (23) R= COCH 2 CH(Me) 2 e (54) R= CH-,-4-methoxyPh (a)4A Molecular sieve/sodium triacetoxy borohydπde.dιchloromethane/-20deg (b)R=13. Isovaleryl chlonde/tπethylamine/dichloromethane/R T R=14, Valeryl chloπde/tπethylamine/dichloromethane/R T R=15. 3-Methylvaleπc acid/EDC/ /4-Dιmethylamιno- pyπdine/dichloromethane R=16, 3-Methoxypropιonιc acid/EDC /4-Dιmethylamιno-pyπdιne/dιchloromethane R=17, 3-Pyπdylacetιc acid HCI/EDC /4-Dιmethylamιno-pyrιdιne/dιchloromethane R=52, p-Methoxybenzyl chloride/potassium carbonate/DMF/70degs (c)Trιbutyltιn hydπde/bιs(tπphenylphosphιne)palladιum(0) chloride/dichloromethane (d)Tπfluoroacetιc acid/R T SUBSTTTUTE SHEET (RULE 26) Scheme 32 (1) (a) (b) (c) Isovaleryl chloride/triethylamine/dichloromethane/R.T. (c)Tributyltin hydride/bis(triphenylphosphine)palladium(0)chloride/dichloromethane (d)Trifluoroacetic acid/R.T. Scheme 33 (b) (c) (d) (a)4A Molecular sieve/sodium triacetoxy borohydrιde/dιchloromethane/-20deg (c)Trιbutyltιn hydrιde/bιs(tπphenylphosphιne)palladιum(0) chloride/dichloromethane Scheme34 (1) (a) (c) ( ) (a)4A Molecular sieve/sodium triacetoxy borohydπde/dιchloromethane/-20deg eryl chloπde/tπethylamine/dichloromethane/R T ichloromethane/tπethylamine/R T (c)Tπbutyltιn hydπde/bιs(tπphenylphosphιne)palladιum(0) chloride/dichloromethane (d)TrιfΙuroacetιc acid/R T SUBSTTTUTE SHEET (RULE 26) Scheme 35 30a 30b SUBSTTTUTE SHEET (RULE 26) i)HNO 3 ,50°C ii)(COCl) 2 .DMF/CH 2 Cl 2 Et 3 N.L-Methionine methyl ester hydrochloride iii)Me 2 NNH 2 .FeCl 3 6H 2 O/MeOH Δ Reflux iv)22b/MeOH.3A° sieves AcOH.NaCNBH 3 v)PdCl 2 (PPh 3 ) 2 , n Bu 3 SnH/CH 2 Cl 2 ,H 2 0 vi)TFA SUBSTTTUTE SHEET (RULE 26) 31e i)G.J.Leuck et al JACS 51,1831.1929 ii)EDC.HOBT/DMF 0°C NMM.L-Methionine methyl ester hydrochloride 0°C-RT iii) Me 2 NNH 2 .FeCl 3 6H 2 O/MeOH Δ Reflux iv) 22b/MeOH,3A° sieves AcOH.NaCNBH 3 v) PdCl 2 (PPh 3 ) 2 , n Bu 3 SnH/CH 2 Cl 2 .H 2 0 vi)TFA vii)2N NaOH/MeOH SUBSTTTUTE SHEET (RULE 26) iii) Δ Reflux NMM.L-Methionine methyl ester hydrochloride 0°C-RT iii) Me 2 NNH 2 .FeCl 3 6H,O/MeOH Δ Reflux iv) 22b/MeOH.3A° sieves AcOH.NaCNBH 3 v) PdCl 2 (PPh 3 ) 2 , n Bu 3 SnH/CH 2 Cl 2 .H 2 O vi)TFA vii)2N NaOH/MeOH SUBSTrrUTE SHEET (RULE 26) iii) i)PhB(OH) 2 , (PPh 3 ) 4 Pd° /DME,NaHCO 3 (aq) Δ Reflux ii) EDCHOBT DMF 0°C NMM,L-Methionine methyl ester hydrochloride 0°C-RT iii) Me 2 NNH 2 ,FeCl 3 6H 2 O/MeOH Δ Reflux iv) 22b/MeOH,3A° sieves AcOH.NaCNBH 3 v) PdCl 2 (PPh 3 ) 2 , n Bu 3 SπH/CH 2 Cl 2 .H 2 0 vi)TFA vii)2N NaOH/MeOH SUBSTTTUTE SHEET (RULE 26) i)SO 2 Cl 2 /MeOH Δ Reflux ii)BzZnBr, PdCl 2 (PPh 3 ) 2 /THF iii)2N NaOH/MeOH iv) EDCHOBT DMF 0°C NMM,L-Methionine methyl ester hydrochloride 0°C-RT v) SnCl 2 .2H 2 O/EtOAc Δ Reflux vi) 22b/MeOH.3A° sieves AcOH.NaCNBH 3 vii) PdCl 2 (PPh 3 ) 2 , n Bu 3 SnH/CH 2 Cl 2 ,H 2 O viii)TFA ix)2N NaOH/MeOH SUBSTTTUTE SHEET (RULE 26) SCHEME 40 i)BzZnBr,Pd 2 (dba) 3 /THF ii) 2N NaOH/MeOH iii) EDC.HOBT/DMF 0°C SUBSTTTUTE SHEET (RULE 26) NMM.L-Methionine methyl ester hydrochloride 0°C-RT iv) SnCl 2 .2H 2 O/EtOAc Δ Reflux v) 22b/MeOH.3A° sieves AcOH.NaCNBH 3 vi) PdCl 2 (PPh 3 ) 2 , n Bu 3 SnH/CH 2 Cl 2 .H 2 O vii) TFA viii)2N NaOH/MeOH SUBSTTTUTE SHEET (RULE 26) i) 2N NaOH/MeOH ii) SO 2 Cl 2 /IPA Δ Reflux iii) SnCl 2 .2H 2 O/EtOAc Δ Reflux iv) 22b/IPA.3A° sieves AcOH.NaCNBH 3 v) PdCl 2 (PPh 3 ) 2 , n Bu 3 SnH/CH 2 Cl 2 .H 2 0 vi)TFA SUBSTTTUTE SHEET (RULE 26) SCHEME 42 i)CH 3 O(CH 2 ) 2 CO 2 H.EEDQ/CH 2 Cl 2 ii) PdCl 2 (PPh 3 ) 2 , n Bu 3 SnH/CH 2 Cl 2 .H 2 0 iii)TFA SUBSTTTUTE SHEET (RULE 26) Scheme 43 (1) (a) (e) Sche e 43(cont.) (a)4A Molecular sieve/sodium triacetoxy borohydπde/dιchloromethane/-20deg (b)Tert butylacetyl chloπdel/tπethylamine/dichloromethane/R T (c)3-Pyrιdylacetιc acιd/EDC/HOBT/N-methylmorpholιne/dιchloromethane/0deg-R.T (d)Tributyltιn hydπde/bιs(trιphenylphosphιne)palladιum(0) chloride/dichloromethane (e)Trifluroacetιc acid/R.T SUBSTTTUTE SHEET (RULE 26) SUBSTTTUTE SHEET (RULE 26) Scheme 44(cont ) (a)4A Molecular sieve/sodium triacetoxy borohydπde/dιchloromethane/-20deg. (b) 2, Isovaleryl chloπde/tπethylamine/dichloromethane/R.T Tert.butylacetyl chloπde/dichloromethane/tπethylamine/R.T 3-Pyπdylacetιc acιd/EDC/HOBT/N-methylmorpholιne/dιchloromethane R=COCH2 6-Methoxy-1-oxo-nιcotιnιc acιd/EDC/HOBT/N-methylmorpholine/ \^ * \ dichloromethane 0 - (c)Tributyltιπ hydπde/bιs(trιphenylphosphιne)palladιum(0) chloride/dichloromethane (d)Trifluroacetιc acid/R.T. (71) (b) Scheme 45(cont ) (a)4A Molecular sieve/sodium triacetoxy borohydrιde/dιchloromethane/-20deg (b)R=COCH2CH(CH3)2 Isovaleryl chloride/tπethylamine/dichloromethane/R T R=COCH2C(CH3)3, Tert butylacetyl chloπde/dichlorometnane/tπethylamine/R T R=COCH2 3-Pyπdylacetιc acιd/EDC/HOBT/N-methylmorpholιne/dιchloromethane thoxyphenylacetιc acid/EDC/HOBT/N-methylmorpholine/dichloromethane (c)Tπbutyltιn hydπde/bιs(tπphenylphosphιne)palladιum(0) chloride/dichloromethane (d)Trιfluroacetιc acid/R T SUBSTTTUTE SHEET (RULE 26) 38 SUBSTTTUTE SHEET (RULE 26) SCHEME 46 (contd.) i)PhB(OH) 2 . (PPh 3 ) 4 Pd° DME.NaHC0 3 (aq) Δ Reflux ii) EDC.HOBT/DMF 0°C NMM.L-Methionine methyl ester hydrochloride 0°C-RT iii) SnCl 2 .2H 2 0/EtOAc Δ Reflux iv) 22b/MeOH.3A° sieves AcOH.NaCNBH 3 v) PdCl 2 (PPh 3 ) 2 . n Bu 3 SnH/CH 2 Cl 2 .H 2 O vi)TFA vii)2N NaOH/MeOH SUBSTTTUTE SHEET (RULE 26) SCHEME 47 v) SUBSTTTUTE SHEET (RULE 26) i) EDC.HOBT/DMF 0°C NMM.L-Glutamine methyl ester hydrochloride 0°C-RT ii) SnCl 2 .2H 2 O/EtOAc Δ Reflux iii) 22b/MeOH.3A° sieves AcOH.NaCNBH 3 iv) PdCl 2 (PPh 3 ) 2 , n Bu 3 SnH/CH 2 Cl 2 .H 2 O v)TFA vi)2N NaOH/MeOH

Claims: CLAIMS 1. A pharmaceutical composition comprising an inhibitor of ras famesylation of Formula I Formula I wherein: R is selected from H: -CMalkyl: -Cj_3alkylene-Ph optionally mono or di-substituted on Ph with substituents selected from CMalkyl. halogen. OH. C1.4a.koxy. C * .4alkanoyl. Cι _4alkanoyloxy. amino, C1_4alkylam.no. di(Cι_4alkyl)amino. Cι .4alkanoylamino. nitro, cyano. carboxy, carbamoyl, C * _4alkoxycarbonyl. thiol. C ] _4alkylsulfanyl. C].4alkylsulfιnyl,Cι.4alkylsulfonyl and sulfonamido; -CO-C1.4a.kyl; -CO-0-Cι.4alkyl; -CO-O-C2-4alkenyl; -CO-O-(CH2) n Ph optionally substituted on Ph as defined for substitution on Ph in R 1 = -Ci-3alkylene-Ph in this claim 1 and n=0-4; -C]_4alkylene-CONR 4 R 5 where R 4 & R 5 are independently selected from H. CMalkyl; and -C \ _4alkylene-COOR 6 where R 6 is selected from H. C \ _4alkyl: R is selected from H; -CMalkyl: -Cι_3alkylene-Ph optionally substituted on Ph as defined for substitution on Ph in R 1 = -C 1.3 alky lene-Ph in this claim 1: -COC* _4alkyl: and -COOCι_4alkyl; R 3 is selected from H; OH: CN: CF 3 ; NO 2 : -C1.4 alkyl: -C * .4alkylene-R 7 where R 7 is selected from phenyl, naphthyl. and a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O.N and S and any aryl ring in R is optionally substituted as defined for substitution on the Ph group in R = -C 1.3 alky lene-Ph in claim 1 : R 7 : C2-4alkenyl; halogen: -(CH2) n COOR 8 where n= 0-3 and R 8 represents H. Cι_4alkyl. C2-4alkenyl: -CONR 9 R 10 where R 9 and R 10 independently represent H. Cι_4alkyl. C2-4alkenyl, -O-Cι.4alkyl. -O-C2-4alkenyl. or -C,. alkylenePh optionally substituted as defined for this group for R 1 in this claim 1 :-CON(R )OR ] where R 1 ' and R independently represent H. C ι_4alkyl and C2_4alkenyl: a group of Formula II. -CONR 13 -CHR 14 -COOR 17 . where R 13 is H or C Malkyl. R 17 is H or I Cj.galkyl. R is selected from the side chain of a lipophilic amino acid. carbamoylC alkyl. N.-(monoC ! _ 4 alkyl)carbamoylCι_ 4 alkyl and N-(diC,. 4 alkyl)carbamoylC alkyl. the group of Formula II having L or D configuration at the chiral alpha carbon in the corresponding free amino acid: a lactone of formula CMalkyl monosubstituted on carbon with =N-OH; a group of Formula -X-R where X is selected from O. CO. CH2- S. SO. SO2 and R 15 is selected from CMalkyl, phenyl, naphthyl. a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O.N and S and any aryl ring in R is optionally substituted as defined for the Ph group in R' = -C 1 _3alkylene-Ph in this claim 1 ; p is 0-3 in which R J values can be the same or different; L is a linking moiety selected from the following groups written from left to right in Formula I: -CO-NR 16 - where R 16 is selected from H, C1.4a.kyl. C 1 _ 4 alkylene-Z, -CO- Cι_4alkylene-Z. -CO-Cι_ 6 alkyl. -COZ. and Z, and Z is selected from -O-C1.4a.kyl, phenyl, naphthyl. a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O. N and S and any aryl ring in R is optionally substituted as defined for the Ph group in R 1 = -C 1.3 alky lene-Ph in this claim 1 ; -CH2-NR 18 - where R 18 represents any value defined for R 1 ; -CH2S-; -CH2O-: -CH2-CHR - where R represents any value defined for R 16 : -CH=CR 20 - where R 20 represents any value defined for R 16 : -CH2NR -T- where R ' represents any value defined for R . T represents -(CH2)n- where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R 16 other than H: -CH2NR 23 -SO2- where R 23 represents any value defined for R 16 ; -CH2-NR -CO-T- where R 24 represents any value defined for R . T represents -(CH2) n - where n is 0-4 and T is optionally monosubstituted with R where R " represents any value for R other than H: -CO-NR " -T- where R 3 represents any value defined for R 16 . T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R' 6 where R 6 represents any value for R 16 other than H; -CH2S-T- where T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R 16 other than H: -CH2O-T- where T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R other than H: A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms where the heteroatoms are independently selected from O. N & S; or a -S-S- dimer thereof when R 2 =H: or a N-oxide thereof; or an enantiomer. diastereoisomer. pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier. 2. A pharmaceutical composition according to claim 1 in which R 1 is selected from H: -CO-0-(CH2) n Ph optionally substituted on Ph as defined for R 1 = -C 1 _3alkylene-Ph in claim 1 and n=0-4; -CO-O-C2_ _Jkenyl; -CO-C1.4a.kyl: -Cι^alkylene-CONR 4 R 5 where R & R 3 are independently selected from H, CMalkyl. 3. A pharmaceutical composition according to any one of claims 1-2 in which R is selected from H and -CO-C a_kyl. 4. A pharmaceutical composition according to any one of claims 1-3 in which L is selected from -CH 2 -NR 18 -; -CH 2 NR 2I -T . 5. A pharmaceutical composition according to any one of claims 1-4 in which A is selected from phenyl. naphthyl, pyridyl and thienyl. 6. A pharmaceutical composition according to any one of claims 1-5 in which combinations of R and p are selected from SUBSTTTUTE SHEET (RULE 26) i) R is selected from a group of Formula II; -C 1 _ 4 alkylR 7 ; -O-R 7 and; R ; and p=l-3 with the proviso that one value of R 3 is a group of Formula II; ii) p=0 with the proviso that A is naphthyl and L is -CH2NR 21 -T; iii) p=l with the proviso that R 3 = a group of Formula II and A is naphthyl. 7. A pharmaceutical composition according to claim 1 in which R is selected from H; -CMalkyl, -C _3alkylene-Ph optionally mono or di-substituted on Ph with substituents selected from CMalkyl, halogen, OH, C _4alkoxy, C]_4alkanoyl, C i _4alkanoyloxy, amino, C _4alkylamino, di(Cι_4alkyl)amino, Cι_4alkanoy lamino, thiol, C ] _4alkylthio, nitro, cyano, carboxy, carbamoyl, C ] _4alkoxycarbonyl. C1.4alkylsulf.nyl, Cι_4alkylsulfonyl, sulfonamido; -CO-C1.4a.kyl; -CO-O-C1.4a.kyl; -CO-O-C2_4alkenyl; -CO-O-CH2-PI1 optionally mono- or di-substituted on phenyl with substituents selected from CMalkyl, halogen, OH, Cι_4alkoxy, C _4alkanoyl, C _4alkanoyloxy, amino, C _4alky lamino, di(C _4alkyl)amino, Cι.4alkanoylamino, thiol, C _4alkylthio, nitro, cyano, carboxy, carbamoyl, Cι_4alkoxycarbonyl, C .4alkylthiono, C _4alky lsulfonyl, sulfonamido ; -C 1 _4alkylene-CONR 4 R 5 where R 4 & R 5 are independently selected from H, CMalkyl; -C .4alkylene-COOR where R is selected from H, Cι_4alkyl; R 2 is selected from H; -CMalkyl; -Ci^alkylene-Ph; -COCi^alkyl; -COOC^alkyl; R 3 is selected from H; OH; CN; CF 3 ; NO 2 ; alkyl, -Cι_4alkylene-R 7 where R 7 is selected from phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 3 heteroatoms selected from O,N and S; C2-4alkenyl; halogen; -(CH 2 ) n COOR 8 where n= 0-3 and R 8 represents H, CMalkyl, C ^alkenyl; -CONR 9 R 10 where R and R ° independently represent H, C _4alkyl, C2-4alkenyl, -O-C _4alkyl, -O-C2-4alkenyl; -CON(R n )OR 12 where R 1 ' and R 12 independently represent H, CMalkyl and C2-4alkenyl; a group of Formula II, -CONR I3 -CHR 1 -COOR 17 , where R 13 is H or CMalkyl, R 17 is H or CMalkyl, R is the side chain of a lipophilic amino acid with L or D configuration at the chiral alpha carbon in the corresponding free amino acid; C i _4alkyl monosubstituted on carbon with =N-OH; -SO-Cι_4alkyl: -SO2-Ci_4alkyl: a group of Formula -X-R 1 " where X is selected from CO. CH2. S. SO. SO2 and R 1 " is selected from CMalkyl. phenyl. naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 3 heteroatoms selected from O.N and S; p is 0-3 in which R values can be the same or different: L is a linking moiety selected from the following groups written from left to right in Formula I: -CO-NR 6 - where R 16 is selected from H. CMalkyl. Cj^alkylene-Z and Z is selected from -O-C 1 _4alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 3 heteroatoms selected from O, N and S; -CH2-NR 18 - where R 18 represents any value defined for R 1 ; -CH2S-; -CH2O-; -CH2-CHR - where R 1 represents any value defined for R ; -CH=CR - where R 2 represents any value defined for R ; -CH2NR 2I -T- where R 21 represents any value defined for R 16 . T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R 16 other than H. and provided at least one of R 21 and R 22 is H: -CH2NR 23 -SO 2 - where R 23 represents any value defined for R 16 ; -CH2-NR 24 -CO-T- where R 24 represents any value defined for R 16 , T represents -(CH2) n - where n is 0-4 and T is optionally monosubstituted 29 29 1 (\ with R where R represents any value for R other than H, and provided at least one of R and R is H; -CO-NR D -T- where R D represents any value defined for R , T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R 26 where R 26 represents any value for R 16 other than H, and provided at least one of R 24 and R 23 is H; -CH2S-T- where T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R 27 27 1 ft where R represents any value for R other than H; -CH2O-T- where T represents -(CH2) n - where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R 16 other than H; SUBSTTTUTE SHEET (RULE 26) A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 3 or 5 heteroatoms in the case of monocyclic and bicyclic rings respectively where the heteroatoms are independently selected from O. N & S: or a -S-S- dimer thereof when R =H. 8. A pharmaceutical composition according to any one of claims 1-7 or claim 14 which is in the form of a tablet. 9. A compound as claimed in any one of compound claims 11-13 or a compound defined in any one of pharmaceutical composition claims 1 -7 for use as a medicament. 10. A compound as claimed in any one of compound claims 11-13 or a compound defined in any one of pharmaceutical composition claims 1-7 for use in preparation of a medicament for treatment of a disease mediated through famesylation of ras. 11. A compound of any of the following classes i). ii) or iii): class i) wherein: X 1 is selected from H; C,. 6 alkyl; hydroxyC 1 . 6 alkyl, C 1-6 alkoxyC 1-6 alkyl; C| -6 alkylcarbonyl; hydroxy C ,. 6 alkylcarbonyl; C , . 6 alkoxyC ι. 6 alkylcarbonyl; A is selected from phenyl, naphthyl or a 5-10 membered heterocyclic ring having upto 5 heteroatoms selected from O. N and S; X 2 is selected from H; phenyl; phenylC,. 6 alkyl; and a 5-6 membered heteroaryl ring containing upto 3 heteroatoms selected from O, N and S optionally linked to A by C,. 6 alkyl; and X 2 is optionally substituted on any ring, as defined for phenyl in R = -Cι_3alkylene-Ph in claim 1 ; X is selected from H; C M alkyl; X 4 is selected from C^alkylsulfanyl; C 1-6 alkylsulfinyl; C 1-6 alkylsulfonyl; carbamoyl; N- (C 1-6 alkyl)carbamoyl; N-(diC|. 6 alkyl)carbamoyl; and hydroxy or a C M alkyl ether thereof; class ii) wherein: X 5 is selected from -CO-C^alkyl-Ph: -CO-C,. 6 alkyl; -CO-C alkyl-heteroaryl where heteroaryl is a 5-10 membered heteroaryl ring containing upto 5 heteroatoms selected from O, N and S and Ph or heteroaryl are optionally substituted as defined for Ph in R = -C ι_3alkylene-Ph in claim 1 : C alkyloxyC 1-4 alkyl; A is naphthyl or a 10 membered heterocyclic ring having upto 5 heteroatoms selected from O, N and S: R and p are as defined in claim 1 ; class iii) wherein: X has any value defined for X 5 in ii) above; X is Ph optionally substituted as defined for Ph in R 1 = -C \ _3alkylene-Ph in claim 1 ; A is Ph or naphthyl or a 5-10 membered heterocyclic ring having upto 5 heteroatoms selected from O, N and S; R and p are as defined in claim 1 ; or a N-oxide, pharmaceutically acceptable salt, prodrug or solvate thereof . 12. A compound according to claim 1 1 in which: in compounds of class i), X is selected from H and C^alkoxyC^alkyl; X is selected from H: phenyl or phenylC 1-6 alkyl; X is Cι. 6 alkylsulfanyl: A is selected from phenyl or naphthyl: in compounds of class ii), p is 0 and; in compounds of class iii) X 7 is Ph: A is Ph; p is 0. 13. Any one of the following compounds or a pharmaceutically acceptable salt thereof: (2S)-2-{2-Benzyl-5-[([2S,4S_]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-benzoylamino}-4- methylsulfanylbutyric acid methyl ester ; (2S)-2-{2-Benzyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-benzoylamino}-4- methylsulfanylbutyric acid ; (2S)-2-({2-phenyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-phenylcarbonyl}- amino)-4-methylsulfanylbutyric acid methyl ester: (2S)-2-({2-phenyl-5-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-phenylcarbonyl}- amino)-4-methylsulfanylbutyric acid; (2S)-2-({3-[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-naphthalene-l-carbonyl}- amino)-4-methylsulfanylbutyric acid methyl ester ; (2S)-2-( { 3 - [([2S_,4S]-4-sulfanylpyrrolidin-2-y lmethy l)-amino]-naphthalene- 1 -carbony 1 } - amino)-4-methylsulfanylbutyric acid : (2S)-2-( { -3-phenyl-5 [([2S, 4S]-4-sulfanylpyrrolidin-2-y lmethy l)-amino]-phenylcarbonyl } - amino)-4-methylsulfanylbutyric acid methyl ester; (2S)-2-({-3-phenyl-5[([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-amino]-phenylcarbonyl}- amino)-4-methylsulfanylbutyric acid; (2S,4S_)-2-[{N-(4-methoxybenzyl)-JU-(naphthalen-l-ylmethyl)-amino}-methyl]- pyrrolidine-4-thiol ; N-(naphthalen- 1 -ylmethyl)-N-([2jS,4S]-4-sulfanylpyrrolidin-2-y lmethy l)-pentanamide : N-(naphthalen-l-ylmethyl)-N-([2S,4S]-4-sulfanylpyrrolidin-2-ylmethyl)-2-(pyridin-3-yl)- acetamide ; N-((2S,4S)-4-sulfanyl-pyrrolidin-2-ylmethyl)-3-methyl-N-(2-naphthalen-l-yl- ethyl)butyramide : SUBSTTTUTE SHEET (RULE 26) N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-N-(2-naphthalen-l-yl-ethyl)-2-pyridin-3-yl- acetamide : (2S,4S)-2- { [(3-Methoxypropyl)-(2-naphthalen- 1 -ylethyl)amιno]methyl } - pyrrolidine-4- thiol: N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-2-(4-methoxy-phenyl)-H-(2-naphthalen-2-yl ethyl)-acetamide : (2S,4S)-2- { [(2-(4-Methoxyphenyl)ethyl)-(2-naphthalen- 1 -ylethyl)amino] methyl } - pyrrolidine-4-thiol ; N-(2.2-Diphenyl-ethyl)-N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-3-methyl- butyramide ; N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-3.3-dimethyl-N-(2-naphthalen-2-yl-ethyl)- butyramide ; N-(2,2-Diphenyl-ethyl)-N-([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-3.3-dimethyl- butyramide ; (2S)-2-{3-[([2S,4S]-4-Sulfanyl-pyrrolidin-2-ylmethyl)-(3-methoxy-propyl)-amino]- benzoylamino}-4-methylsulfanyl-butyric acid ; N-([2S,4S]-4-Sulfanyl-pyrrolidin-2-ylmethyl)-3.3-dimethyl-N-(2-naphthalen-l-yl-ethyl)- butyramide ; (2S)-4-Carbamoyl-2-({2-phenyl-5-[([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-amino]- phenylcarbonyl}-amino)-butyric acid; and (2S)-4-Carbamoyl-2-({2-phenyl-5-[([2S,4S]-4-sulfanyl-pyrrolidin-2-ylmethyl)-amino]- phenylcarbonyl}-amino)-butyric acid methyl ester. 14. A pharmaceutical composition comprising a compound as defined in any one of claims 11-13 together with a pharmaceutically acceptable diluent or carrier. 15. A process for preparing compounds of classes i). ii) or iii) as defined in claim 11 which comprises deprotecting a compound of Formula VI Formula VI wherein X 8 represents the right hand side of compound classes i), ii) or iii) as defined in claim 11. Pr 1 is H or an amino protecting group. Pr 2 is H or a thio protecting group and any functional groups in X are optionally protected with the proviso that there is at least one protecting group and optionally, if desired, converting the product thus obtained into a pharmaceutically acceptable salt thereof.

Inventors: BOYLE FRANCIS THOMAS, DAVIES DAVID HUW, KENNY PETER WEDDERBURN, MATUSIAK ZBIGNIEW STANLEY, SCHOLES PETER BEVERLEY, WARDLEWORTH JAMES MICHAEL, BOYLE, FRANCIS, THOMAS, DAVIES, DAVID, HUW, KENNY, PETER, WEDDERBURN, MATUSIAK, ZBIGNIEW, STANLEY, SCHOLES, PETER, BEVERLEY, WARDLEWORTH, JAMES, MICHAEL
Applicants: BOYLE FRANCIS THOMAS, DAVIES DAVID HUW, KENNY PETER WEDDERBURN, MATUSIAK ZBIGNIEW STANLEY, SCHOLES PETER BEVERLEY, WARDLEWORTH JAMES MICHAEL, ZENECA LTD, BOYLE, FRANCIS, THOMAS, DAVIES, DAVID, HUW, KENNY, PETER, WEDDERBURN, MATUSIAK, ZBIGNIEW, STANLEY, SCHOLES, PETER, BEVERLEY, WARDLEWORTH, JAMES, MICHAEL, ZENECA LIMITED
Application year: 1996
Main classification: C07D207
IPC codes: A61K31, A61P35, C07D207, C07D401, C07D409