BACKGROUND The enzyme dipeptidyl peptidase IV, herein abbreviated DP-IV (and elsewhere as DAP-IV or DPP-IV) and also known by the classification EC. 3.4. 14.5, is a serine protease that cleaves the N-terminal dipeptide from peptides that begin with the sequence H-Xaa-Pro (where Xaa is any amino acid, although preferably a lipophilic one, and Pro is proline). It will also accept as substrates peptides that begin with the sequence H-Xaa-Ala (where Ala is alanine). DP-IV was first identified as a membrane-bound protein. More recently a soluble form has been identified.

Initial interest in DP-IV focussed on its role in the activation of T lymphocytes. DP-IV is identical to the T cell protein CD26. It was proposed that inhibitors of DP-IV would be capable of modulating T cell responsiveness, and so could be developed as novel immunomodulators. It was further suggested that CD26 was a necessary co-receptor for HIV, and thus that DP-IV inhibitors could be useful in the treatment of AIDS.

Attention was given to the role of DP-IV outside the immune system. It was recognised that DP-IV has a key role in the degradation of several peptide hormones, including growth hormone releasing hormone (GHRH) and glucagon-like peptide-1 and - 2 (GLP-1 and GLP-2). Since GLP-1 is known to have a potentiating effect on the action of insulin in the control of post-prandial blood glucose levels it is clear that DP-IV inhibitors might also be usefully employed in the treatment of type 11 diabetes and impaired glucose tolerance. At least two DP-IV inhibitors are currently undergoing clinical trials to explore this possibility.

Several groups have disclosed inhibitors of DP-IV. While some leads have been found from random screening programs, the majority of the work in this field has been directed towards the investigation of substrate analogues. Inhibitors of DP-IV that are substrate analogues are disclosed in, for example, US 5,462, 928, US 5,543, 396, W095/15309 (equivalent to US 5,939, 560 and EP 0731789), W098/19998 (equivalent to US 6,011, 155), W099/46272 and W099/61431.

More recently a number of proteins have been found that share some of the enzymatic properties of DP-IV. Some, such as FAP and DPP-8, have sequence homology with DP-IV, while others, such as QPP, have no such homology but nevertheless mimic the aminodipeptidase activity of DP-IV. The physiological function of these newer proteases is still being investigated. FAP has been implicated in invasive processes such as cancer metastasis and endometriosis, and QPP appears to be involved in immune-cell apoptosis. It is also possible that some of these proteases share a common function. This redundancy would allow continuing normal physiological function in the event of a failure in the expression or function of one of the proteases.

In order to further define the roles of these newer proteases it is important to have the tools to manipulate selectively each one or the whole class. Therefore there exists a need for specific and potent inhibitors of each of these proteases, and also for potent non-specific inhibitors of the class of post-proline cleaving aminodipeptidases.

SUMMARY OF THE INVENTION We disclose herein a series of novel compounds that are inhibitors of one or more post-proline cleaving proteases, and specifically compounds according to general formula 1. In general formula 1, R'is H or CN, X'is O, S, CH2, CHF, CF2, CH (CH3), C (CH3) 2 or CH (CN), and b is 1 or 2. G'is H or a group according to the formula-CH2-X2-(CH2) a- G3 and G2 is H or a group according to the formula-CH2-(CH2) a-G3, provided that one of G1 and G2 is H and the other is not H. x2 is O, S or CH2, and a is 0,1 or 2, provided that when a is 1 then X2 is CH2. G3 is a group according to one of general formulae 2- 4.

X3, X4 and X5 are either nitrogen N or CH, provided that at least two of X3, X4 and X5 and N. X6 is either O or NH. R2 is either H or alkyl. R3 is selected from H, Cl, OH, O- alkyl, NH2, NH-alkyl and N (alkyl)2. R4, R6, R6, R7 and R8 are selected from H, Br, Cl, F, CF3, alkyl, acyl, OH, 0-alkyl, NH2, NH-alkyl, N (alkyl) 2, NO2, NH-acyl, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON (alkyl)2 and CN. X7 is CH2, O, S or NH. R9 is either H or alkyl. R10, R", R12, R13 and R14 are selected from H, Br, Cl, F, CF3, alkyl, acyl, OH, O- alkyl, NH2, NH-alkyl, N (alkyl) 2, NO2, NH-acyl, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON (alkyl) 2 and CN. R15 and R16 are each independently H, alkyl, alkenyl, polyfluoroalkyl, aralkyl, aryl or CH2-L-R17, where L is a covalent bond, CH=CH, C=C or- C6H4-, and R17 is H, alkyl or aryl, or R15 and R16 together are a group according to one of general formulae 5-7.

R18 is H, alkyl, aryl, OH, 0-alkyl, NH2, NH-alkyl or N (alkyl) 2, and R'9 is H, alkyl, aryl, F, Cl, Br, CF3, OH, 0-alkyl, NH2, NH-alkyl or N (alkyl) 2. The integers d and e are 0,1, 2 or 3 such that d+e is 3,4 or 5, and f is 1,2 or 3. When R15 and R16 are both H then X may not be S or CH2 if b is 1.

Preferred compositions are inhibitors of non-membrane associated post-proline cleaving proteases. The most preferred compositions are selective for non-membrane associated proteases (e. g. for example inhibitors of one or more of QPP, DPP-8 and/or DPP-9).

DETAILED DESCRIPTION OF THE INVENTION In a first aspect, the present invention relates to a series of novel a-amino acyl derivatives of saturated nitrogen-containing heterocycles according to general formula 1.

In general formula 1, the group R'is either a hydrogen atom H or a nitrile group CN.

The group X'is selected from an oxygen atom O, a sulphur atom S, a methylene group CH2, a monofluoromethylene group CHF, a difluoromethylene group CF2, an ethyliden group CH (CH3), a 2-propylidene group C (CH3) 2 and a cyanomethylene group CH (CN).

The integer b is either 1 or 2, such that the nitrogen-containing ring has 5 or 6 members.

The group G'is either H or a group according to the formula-CH2-X2- (CH2) a-G3 and the group G2 is either H or a group according to the formula-CH2- (CH2) a-G3, provided that one of G'and G2 is H and the other is not H. The group X2 is selected from 0, S and CH2. The integer a is 0,1 or 2, provided that when a is 1 then X2 is CH2.

The group G3 is selected from a group according to general formula 2, a group according to general formula 3 and a group according to general formula 4.

In general formula 2, the groups X3, X4 and X5 are selected from nitrogen N and methine CH, provided that at least two of X3, X4 and X5 are nitrogen. Preferably X3, X4 and X5 are all nitrogen. The group X6 is selected from O and NH. R2 is selected from H and alkyl. R3 is selected from H, Cl, OH, 0-alkyl, NH2, NH-alkyl and N (alkyl) 2. R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, CF3, alkyl, acyl, OH, 0- alkyl, NH2, NH-alkyl, N (alkyl) 2, NO2, NH-acyl, COzH, CO2-alkyl, CONH2, CONH-alkyl, CON (alkyl) 2 and CN.

In general formula 3, the group X7 is selected from CH2, O, S and NH. R9 is selected from H and alkyl. R'O, R11, R12,R13 and R14 are independently selected from H, Br, Cl, F, CF3, alkyl, acyl, OH, O-alkyl, NH2, NH-alkyl, N (alkyl) 2, NO2, NH-acyl, CO2H, CO2- alkyl, CONH2, CONH-alkyl, CON (alkyl) 2 and CN.

In general formula 4, R15 and R16 are each independently selected from H, alkyl, alkenyl, polyfluoroalkyl, aralkyl, aryl and CH2-L-R, where L is selected from a covalent bond, CH=CH, C#C and-C6H4-and R17 is selected from H, alkyl and aryl, or R15 and R16 together are a group selected from general formula 5, general formula 6 and general formula 7.

In these general formulae, the group R'8 is selected from H, alkyl, aryl, OH, 0-alkyl, NH2, NH-alkyl and N (alkyl) 2, and the group R'9 is selected from H, alkyl, aryl, F, Cl, Br, CF3, OH, O-alkyl, NH2, NH-alkyl and N (alkyl) 2. The integers d and e are selected from 0,1, 2 and 3 such that d+e is 3,4 or 5, and the integer f is selected from 1,2 and 3.

When R"s and R16 are both H then X'may not be S or CH2 if b is 1.

The term alkyl, as used herein, denotes saturated hydrocarbon groups with between 1 and 10 carbon atoms, including straight-chain, branched and mono-and polycycloalkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl, cyclohexylmethyl, 2-cyclohexyl-2-propyl, bicyclo [2.2. 2] octyl and the like.

The term alkenyl, as used herein, denotes monounsaturated hydrocarbon groups with between 2 and 10 carbon atoms, including straight-chain, branched and mono-and polycycloalkenyl groups, such as vinyl, allyl, methallyl, cyclohex-3-enyl and the like.

The term aryl, as used herein, denotes monocyclic and fused bicyclic aromatic groups, including carbocyclic groups, such as phenyl and naphthyl, and heteroaryl groups with up to three heteroatoms selected from nitrogen, oxygen and sulphur, such as pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl and the like. Unless otherwise specified, aryl groups may optionally be substituted with up to three groups independently selected from alkyl, OH, 0-alkyl, Cl, F, Br, NH2, NH-alkyl, N (alkyl) 2, CO2H, CO2-alkyl, CONH2, CONH-alkyl, CON (alkyl)2, NO2 and CN.

The term aralkyl, as used herein, denotes alkyl groups that are substituted by, or fused to, one or more aryl groups, including benzyl, phenethyl, indanyl, fluorenyl and the like.

The term acyl, as used herein, denotes a group selected from H-CO, alkyl-CO, aryi-CO and aralkyl-CO, including formyl, acetyl, benzoyl, phenylacetyl and the like.

The term polyfluoroalkyl, as used herein, denotes an alkyl group wherein all the hydrogen atoms on one or more of the carbon atoms are replaced by fluorine atoms, including trifluoromethyl, 2,2, 2-trifluoroethyl and the like.

In one preferred embodiment of the invention R'is H.

In another preferred embodiment of the invention R'is CN.

In another preferred embodiment of the invention X1 is CH2.

In another preferred embodiment of the invention X'is S.

In another preferred embodiment of the invention b is 1.

In another preferred embodiment of the invention b is 2.

In another preferred embodiment of the invention a is 0.

In another preferred embodiment of the invention a is 0 and X2 is CH2.

In another preferred embodiment of the invention a is 1.

In another preferred embodiment of the invention a is 1 and X2 is CH2.

In another preferred embodiment of the invention a is 2 and X2 is CH2.

In another preferred embodiment of the invention the compound is a compound according to general formula 8. In another preferred embodiment of the invention the compound is a compound according to general formula 9. In another preferred embodiment of the invention the compound is a compound according to general formula 10. In another preferred embodiment of the invention the compound is a compound according to general formula 11. In another preferred embodiment of the invention the compound is a compound according to general formula 12. In another preferred embodiment of the invention the compound is a compound according to general formula 13.

It will be recognised that certain of the compounds within the scope of the present invention are capable of forming salts with suitable acids or bases. To the extent that such salts are pharmaceutical acceptable they are included within the scope of this invention It will further be recognised that certain of the compounds within the scope of the present invention are capable of existing as optical isomers, such as enantiomers and diastereomers. All such optical isomers and mixtures thereof, including but not limited to racemates, are included within the scope of the invention.

The compounds of the present invention are inhibitors of post-proline cleaving proteases such as DPP-IV, QPP, FAP, DPP-8 (DPRP-1) and DPP-9 (DPRP-2). As such they may be useful in the treatment of diseases in which dysregulation of these enzymes or their endogenous substrates plays a role or the disease is ameliorated by inhibition of such enzymes. Accordingly, in further aspects, the present invention provides for the use of compounds according to the present invention in the preparation of pharmaceutical compositions, and for the use of such compositions a therapeutic agents.

Preferred compositions which are inhibitors for QPP may have G2=H, b = 1 or 2 and/or a = 0 or 1. Further preferred compositions having b=2 include G1 groups having a=0 or 1 and x2 is CH2. Further preferred compositions having b=2 have X'=CH2 or S, for example Example 38 of Table 2. Further preferred compositions having b=1 include G1 groups having a=0 or 1 and X2 is CH2 Further preferred compositions having b=1 have X1= S or CH2 or CF2, for example, Example 42 of Table 2.

The compounds of the present invention can be prepared by methods generally known in the art and illustrated in the following non-limiting examples.

EXAMPLES EXAMPLE 1 (2S)-(Dicinnamyl)-L-lysinylipyrrolidine-2-carbonitrile dihydrochloride A. (Nα-(tert-Butyloxycarbonyl)-N#-(9-fluorenylmethyloxycarbony l)-L-lysinyl)-L- prolinamide Nα- (tert-Butyloxycarbonyl)-IVm- (9-fluorenylmethyloxycarbonyl)-L-lysine (5g, 10. 7mmol) was dissolved in CH2Ci2 (100mL). The solution was cooled to 0°C, L-prolinamide (1.78g, 11. 7mmol) and PyBOPO (6.7g, 12. 8mmol) were added, and the pH adjusted to pH9 with triethylamine. After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (200mL). The solution was washed with 0.3M KHS04 (2 x 50mL), sat. NaHCO3 (2 x 50mL), water (2 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as (N°- (tert-butyloxycarbonyl)-N- (9- fluorenylmethyloxycarbonyl)-L-lysinyl)-L-prolinamide (4.05g, 7. 2mmol, 67%).

B. (2S)-1-(Nα-(tert-Butyloxycarbonyl)-N#-(9-fluorenylmethyloxy carbonyl)-L- lysinyl) pyrrolidine-2-carbonitrile <BR> <BR> <BR> <BR> (N (terf-Butyloxycarbonyl)-N"'- (9-fluorenylmethyloxycarbonyl)-L-lysinyl)-L-prolinamide (3.95g, 7. 02mmol) was dissolved in dry THF (100mL). The solution was cooled to 0°C, triethylamine (1.4g, 14mmol) was added followed by the slow addition of trifluoroacetic anhydride (2.97g, 14. 1mmol). The pH was adjusted to pH9 with triethylamine. After 30min the reaction mixture was diluted with ethyl acetate (100mL), washed with water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give an orange oil. The residue was purified by flash chromatography on silica gel (eluant : 60% pet ether, 40% ethyl acetate) to give a colourless oil identified as (2S)- <BR> <BR> <BR> <BR> 1-(Nα-(tert-butyloxycarbonyl)-N#-(9-fluoroenylmethyloxycarb onyl)-L-lysinyl)pyrrolidine-2- carbonitrile (3.3g, 6. 11 mmol, 87%).

C. (2S)-1-(Ng-(teff-Butyloxywarbonyl)-L-lysinyl) pyrrolidine-2-carbonitrile (2S)-1- «-(tert-Butyloxycarbonyl)-N-(9-fluorenylmethyloxyCarbonyl)- L-lysinyl)- pyrrolidine-2-carbonitrile (3.1g, 5. 7mmol) was dissolved in THF (80mL). Diethylamine (20mL) was added. After 2h at room temperature the solvent was removed in vacuo.

The residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a colourless oil identified as (2S)-1- (/"- (tert-butyloxycarbonyl)-L-lysinyl) pyrrolidine-2-carbonitrile (1.63g, 5. 03mmol, 89%).

D. (2S)-1=-(teff-Butyloxywarbonyl)-Nm-(dicinnamyl)-L-lysinyl) pyrrolidine-2- carbonitrile <BR> (2S)-1-(Nα-(tert-Butyloxycarbonyl)-L-lysinyl)pyrrolidine-2- carbonitrile (100mg, 0. 31mmol) was dissolved in methanol (25mL). To this solution was added trans- cinnamaldehyde (170mg, 1. 18mmol). After 30mins sodium triacetoxyborohydride (330mg, 1. 56mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as (2S)-1- (Nα-(tert-butyloxycarbonyl)-N#,N#-(dicinnamyl)-L- lysinyl) pyrrolidine-2-carbonitrile (38mg, 0. 068mol, 11%). Further elution with 9% methanol, 90% chloroform and 1 % acetic acid gave a colourless oil identified as (2S)- 1-(Nα-(tert-butyloxycarbonyl)-N#-(cinnamyl)-L-lysinyl)pyrro lidine-2-carbonitrile (32mg, 0. 073mmol, 12%) E. (2S)-1- [N#, No-(Dicinnamyl)-L-lysinyl] pyrrolidine-2-carbonitrile dihydrochloride (2S)-1- (Na- (tert-Butyloxycarbonyl)-N°', N°'- (dicinnamyl)-L-lysinyl) pyrrolidine-2- carbonitrile (32mg, 0. 057mmol) was dissolved in 4M HCI/dioxan (20mL). After 1 hat room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as (2S)-1-[N-(dicinnamyl)-L- lysinyl] pyrrolidine-2-carbonitrile dihydrochloride (37mg, 0. 053mmol, 93%).

[M+H] + = 457.3 'H NMR (CD30D) : 8 1. 35-1.55 (2H, m), 1.75-2. 00 (2H, m), 2.05-2. 23 (6H, m), 3.10-3. 29 (4H, m), 3.61-3. 68 (2H, m), 4.00-4. 03 (4H, m), 4.20-4. 30 (1H, m), 4.82-4. 93 (1H, m), 6.34-6. 39 (2H, m), 6.94 (2H, d, J = 5.8Hz), 7.31-7. 37 (6H, m), 7.39-7. 53 (4H, m) ppm.

EXAMPLE 2 (2S)-1 » (Cinnamyl)-L-lysinylipyrrolidine-2-carbonitrile dihydrochloride A. (2S)-1- [N°'- (Cinnamyl)-L-lysinyl] pyrrolidine-2-carbonitrile dihydrochloride (2S)-1-(Nα-(tert-Butyloxycarbonyl)-N#-(cinnamyl)-L-lysinyl) pyrrolidine-2-carbonitrile (32mg, 0. 057mmol). was dissolved in 4M HCUdioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as (2S)-1-[N#-(cinnamyl)-L-lysinyl]pyrrolidine-2- carbonitrile dihydrochloride (37mg, 0. 053mmol, 93%).

[M+H] + = 341. 5 'H NMR (CD30D): 6 1.29-1. 55 (2H, m), 1.72-1. 80 (2H, m), 1.90-2. 11 (2H, m), 2.16-2. 29 (6H, m), 3.02-3. 09 (2H, m), 3.65-3. 69 (2H, m), 3. 78-3. 82 (2H, m), 4.23-4. 27 (1H, m), 4.81-4. 82 (1H, m), 4.91-4. 99 (1H, m), 6.21-6. 32 (1H, m), 6.86 (1H, d, J=6. 1Hz), 7.26- 7.35 (3H, m), 7.37-7. 40 (2H, m) ppm.

EXAMPLE 3 <BR> <BR> (2S)-1-1N-(Dicinnamyl)-L-ornithinylipyrrolidine-2-carbonitri le dihydrochloride A. (2S)-1- (N"- (tert-Butyloxycarbonyl)-L-ornithyl) pyrrolidine-2-carbonitrile (2S)-l- (/V'- (tert-Butyloxycarbonyl)-L-ornithyl) pyrrolidine-2-carbonitrile was prepared by the method described for the lysine derivative in Example 1.

B. (2S)-1-(N-(teff-Butyloxywarbonyl)-Nm-(dicinnamyl)-L-ornithin yl) pyrrolidine- 2-carbonitrile (2S)-1- (N"- (terf-Butyloxycarbonyl)-L-ornithinyl) pyrrolidine-2-carbonitrile (200mg, 0. 65mmol) was dissolved in methanol (25mL). To this solution was added trans- cinnamaldehyde (180mg, 1. 25mol). After 30mins sodium triacetoxyborohydride (343mg, 1. 63mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as (2S)-1-(Nα-(tert-butyloxycarbonyl)-N#,N#-(dicinnamyl)-L-orn ithinyl)- pyrrolidine-2-carbonitrile (77mg, 0. 14mmol, 22%). Further elution with 9% methanol, 90% chloroform and 1% acetic acid gave a colourless oil identified as (2S)-1- (N"- (tert- butyloxycarbonyl)-N#-(cinnamyl)-L-ornithinyl)pyrroldiine-2-c arbonitrile (78mg, 0. 18mmol, 28%).

C. (2S)-1-[-(Dicinnamyl)-L-ornithinyllpyrrolidine-2-carbonitril e dihydrochloride (2S)-1-(N-(teff-Butyloxycarbonyl)-N-(dicinnamyl)-L-ornithiny l) pyrrolidine-2- carbonitrile (67mg, 0. 12mmol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as (2S)-1-[N#,N#-(dicinnamyl)-L- ornithinyl] pyrrolidine-2-carbonitrile dihydrochloride (82mg, 0. 12mmol, 100%).

[M+H] + = 443. 3 'H NMR (CD30D) : 5 1. 98-2.12 (4H, m), 2.22-2. 29 (4H, m), 3.27-3. 31 (4H, m), 3.62-3. 67 (2H, m), 3.96 (4H, d, J=7.5Hz), 4.30-4. 40 (1H, m), 4.80-4. 83 (1H, m), 6.34-6. 41 (2H, m), 6.96 (2H, d, J=15.6Hz), 7.31-7. 39 (6H, m), 7.49-7. 53 (4H, m) ppm.

EXAMPLE 4 (2S)-1-1NS-(Cinnamyl)-L-ornithinylipyrrolidine-2-carbonitril e dihydrochloride A. (2S)-1-[N#-(Cinnamyl)-L-ornithinyl]pyrrolidine-2-carbonitril e dihydrochloride (2S)-1-(Nα-(tert-Butyloxycarbonyl)-N#-(cinnamyl)-L-ornithin yl)pyrrolidine-2-carbonitrile (71mg, 0. 17mmol). was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as (2S)-1-[N#-(cinnamyl)-L-ornithinyl]pyrrolidine-2- carbonitrile dihydrochloride (91 mg, 0. 16mmol, 100%).

[M+H] + = 327.5 'H NMR (CD30D) : 8 1. 70-1. 88 (2H, m), 1.97-2. 01 (2H, m), 2.14-2. 32 (4H, m), 3.08-3. 13 (2H, m), 3.29-3. 31 (3H, m), 3.68-3. 71 (2H, m), 3.79-3. 82 (2H, m), 4.29-4. 31 (1H, m), 4.87-4. 91 (1H, m), 6.29-6. 31 (1H, m), 6.86 (1H, d, J=15. 8Hz), 7.29-7. 30 (3H, m), 7.44- 7.48 (2H, m) ppm.

EXAMPLE 5 3-[N#-N#-(Dicinnamyl)-L-lysinyl]thiazolidine dihydrochloride A. 3- [N- (tert-Butyloxycarbonyl)-W- (9-fluorenylmethyloxycarbonyl)-L-lysinyl]- thiazolidine N (tert-Butyloxycarbonyl)-N3-(9-fluorenylmethyloxycarbonyl)-L- lysine (2.73g, 6mmol) was dissolved in CH2CI2/DMF (9: 1, 100mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (1.53g, 10mol), water-soluble carbodiimide (1.34g, 7mmol), thiazolidine (1.28g, 18mmol) and N-methylmorpholine (1. 0g, 10mol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0.3M KHS04 (2 x 25mL), sat. NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a white solid identified as 3- [Al- (tert-butyloxycarbonyl)-Al- (9-fluorenylmethyloxycarbonyl)-L-lysinyi] thiazolidine (2.55g, 4. 85mmol, 81%).

B. 3- [N- (tert-Butyloxycarbonyl)-L-lysinyl] thiazolidine <BR> <BR> <BR> 3-[Nα-(tert-Butyloxycarbonyl)-N3-(9-fluorenylmethyloxycarbo nyl)-L-lysinyl]thiazolidine (1.15g, 2. 13mmol) was dissolved in acetonitrile (20mL). Diethylamine (5mL) was added. After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 3- [I\F- (tert- butyloxycarbonyl)-L-lysinyl] thiazolidine (530mg, 1. 67mmol, 78%).

C. 3-(Nα-(tert-Butyloxycarbonyl)-N#,N#-(dicinnamyl)-L-lysinyl) thiazolidine 3-(AIX-(tert-Butyloxycarbonyl)-L-lysinyl) thiazolidine (200mg, 0. 6mmol) was dissolved in methanol (25mL). To this solution was added trans-cinnamaldehyde (400mg, 3. 0mmol). After 30mins sodium triacetoxyborohydride (534mg, 2. 54mmol) was added.

After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as 3-(Nα-(tert-butyloxycarbonyl)-N#,N#-(di- cinnamyl)-L-lysinyl) thiazolidine (139mg, 0. 25mmol, 40%).

D. 3-[N#,N#-(Dicinnamyl)-L-lysinyl]thiazolidine dihydrochloride <BR> <BR> <BR> 3-(Nα-(tert-Butyloxycarbonyl)-N#,N#-(di-cinnamyl)-L-lysinyl )thiazolidine (139mg, 0. 25mol). was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a pale brown solid identified as 3-[N@, N@-(dicinnamyl)-L-lysinyl] thiazolidine dihydrochloride (127mg, 0. 24mmol, 96%).

[M+H] + = 450.2 'H NMR (CD30D) : 8 1.49-1. 55 (2H, m), 1.89-1. 98 (4H, m), 3.01-3. 30 (4H, m), 3.4-3. 5 (4H, m), 3.7-3. 9 (3H, m), 4.0-4. 2 (3H, m), 4.2-4. 8 (2H, br m), 6.38-6. 44 (2H, m), 6.99- 6.93 (2H, m), 7.34-7. 37 (5H, m), 7.51-7. 60 (4H, m) ppm.

EXAMPLE 6 3-[-(Cinnamyl)-L-lysinylithiazolidine dihydrochloride A. 3-(N-(tert-Butyloxywarbonyl)-Ne-(cinnamyl)-L-lysinyl) thiazolidine 3-(Na-(tert-Butyloxycarbonyl)-L-lysinyl) thiazolidine (200mg, 0. 6mmol) was dissolved in methanol (25mL). To this solution was added trans-cinnamaldehyde (400mg, 3. 0mmol). After 30mins sodium triacetoxyborohydride (534mg, 2. 54mmol) was added.

After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1% triethylamine, 5% methanol, 94% chloroform) to give a colourless oil identified as 3-(Nα-(tert- butyloxycarbonyl)-AlX-(cinnamyl)-L-lysinyl) thiazolidine (215mg, 0. 50mmol, 83%).

B. 3- [N, N- (Cinnamyl)-L-lysinyl] thiazolidine dihydrochloride 3-(Nα-(tert-Butyloxycarbonyl)-N#,N#-(cinamyl)-L-lysinyl)thi azolidine (215mg, 0. 5mmol). was dissolved in 4M HCI/dioxan (20mL). After 1 h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a pale brown solid identified as 3-[NX-(cinnamyl)-L-lysinyl] thiazolidine dihydrochloride (160mg, 0. 40mmol, 79%).

[M+H] + = 334. 4 'H NMR (CD30D) : 8 1.28-1. 30 (1H, m), 1.51-1. 53 (1H, m), 1.79-1. 78 (1 H, m), 1.93-1. 98 (2H, m), 2.9-3. 3 (5H, m), 3.6-3. 8 (5H, m), 4.30-4. 70 (5H, m), 6.2-6. 3 (1H, m), 6.85- 6.91 (1H, m), 7.1-7. 7 (5H, m) ppm.

EXAMPLE 7 1- [°- (Cyclohexylmethyl)-L-ornithinyl] pyrolidine dihydrochloride A. 1-[N#-(Benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-orni thinyl]pyrrolidine N#-(Benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L-ornithi ne (5.49g, 15mmol) was dissolved in CH2CI2/DMF (9: 1, 100mL). To this solution at 0°C was added 1-hydroxybenzotriazole hydrate (3.37g, 22mmol), water-soluble carbodiimide (3.46g, 18mmol), pyrrolidine (1.28g, 18mmol) and N-methylmorpholine (2. 0g, 20mol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (200mL). The solution was washed with 0.3M KHS04 (2 x 50mL), sat. NaHCO3 (2 x 50mL), water (2 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 90% ethyl acetate, 10% pet. ether) to give a colourless oil identified as 1-[N#-(benzyloxycarbonyl)-Nα-(tert-butyloxycarbonyl)-L- ornithinyl] pyrrolidine (5.15g, 12. 3mmol, 82%).

B. 1- [N"- (tert-Butyloxycarbonyl)-L-ornithinyl] pyrrolidine 1- [N°°- (Benzyloxycarbonyl)-N"- (tert-butyloxycarbonyl)-L-ornithinyl] pyrrolidine (2.15g, 5. 13mmol) was dissolved in methanol (80mL). This solution was hydrogenated over 10% Pd/C (400mg). After 2h the catalyst was filtered off and washed with methanol (50mL). The combined filtrates were evaporated in vacuo to give an off white solid identified as 1- [W- (tert-butyloxycarbonyl)-L-ornithinyl] pyrrolidine (1.35g, 4. 74mmol, 94%).

C. 1-(Nα-(tert-Butyloxycarbonyl)-N#-(cyclohexylmethyl)-L-ornit hinyl)pyrrolidine 1- [N"- (tert-Butyloxycarbonyl)-L-ornithinyl] pyrrolidine (100mg, 0. 35mmol) was dissolved in methanol (25mL). To this solution was added cyclohexanecarboxaldehyde (44mg, 0. 39mmol). After 30mins sodium triacetoxyborohydride (148mg, 0. 70mmol) was added.

After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1% triethylamine, 5% methanol, 94% chloroform) to give a colourless oil identified as 1-(Nα-(tert- ButyloxyCarbonyl)-N-(cyclohexylmethyl)-L-ornithinyl) pyrrolidine (51mg, 0. 18mmol, 52%).

D. 1- (Cyclohexylmethyl)-L-ornithinylipyrrolidine dihydrochloride 1- (N°- (fert-Butyloxycarbonyl)-N°- (cyclohexylmethyl)-L-ornithinyl) pyrrolidine (215mg, 0. 5mmol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1-[N#-(cyclohexylmethyl)-L-ornithinyl]pyrrolidine dihydrochloride (160mg, 0. 40mmol, 79%).

[M+H] + = 282.3 'H NMR (CD30D) : 8 0.93-1. 24 (3H, m), 1.66-1. 81 (15H, m), 2.50-2. 70 (2H, m), 2.71- 2.88 (2H, m), 3.2-3. 48 (6H, m), 4.08 (1H, m), 8.35-8. 38 (1H, m), 8.80-8. 85 (1H, m) ppm.

EXAMPLE 8 3-[N#-Me-N#-(2-napthylmethyl)-L-lysinyl]thiazolidine dihydrochloride A. Nα-(tert-Butyloxycarbonyl-N#-benzyl-L-lysine methyl ester Nα-(tert-Butyloxycarbonyl-L-lysine methyl ester (6.1g, 22. 2mmol) was dissolved in methanol (100mL). To this solution was added benzaldehyde (1.9g, 17. 5mmol). After 2 hours sodium triacetoxyborohydride (5.8g, 27. 3mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (200mL). This solution was washed with sat Na HC03 (1 x 50mL), water (12 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1 % acetic acid, 5% methanol, 94% chloroform) to give a colourless oil identified as Nα-(tert- butyloxywarbonyl-N-benzyl-L-lysine methyl ester (5.2g, 14. 2mmol, 82%).

B. Nα-tert-Butyloxycarbonyl-N#-benzyl-N#-methyl-L-lysine methyl ester A"-tert-Butyloxycarbonyl-N°'-benzyl-L-lysine methyl ester (5. 0g, 14. 2mmol) was dissolved in methanol (100mL). To this solution was added formaldehyde (37% solution in water, 10mL). After 2 hours sodium triacetoxyborohydride (3.9g, 18. 4mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (200mL). This solution was washed with sat. Na HC03 (1 x 50mL), water (12 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give a. colourless oil identified as W-tert-butyloxycarbonyl-/\r- benzyl-W-methyl-L-lysine methyl ester (5.2g, 14. 2mmol, 100%).

C. N°-tert-Butyloxycarbonyl-N-methyl-L-lysine methyl ester N"-fert-Butyloxycarbonyl-/°-benzyl-N-methyl-L-lysine methyl ester (5. 0g, 14. 2mmol) was dissolved in methanol/water (9: 1, 100mL). To this solution was added ammonium formate (1. 6, 19. 3mmol) and 10% palladium on charcoal (2g). After 3 hours at 60 °C the catalyst was filtered off through celite and the residue washed with methanol (50mL). The combined filtrates were evaporated in vacuo and the residue was taken up in chloroform (200mL). This solution was washed with sat Na HC03 (1 x 50mL), water (12 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as N «-(tert-butyloxycarbonyl-N"-methyl-L-lysine methyl ester (3.48g, 12. 5mmol, 93%).

D. Nα-tert-Butyloxycarbonyl-N#-(1,1-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-N°'- methyl-L-lysine methyl ester N"-tert-Butyloxycarbonyl-N°-methyl-L-lysine methyl ester (3. 1 g, 11. 1 mmol) was dissolved in dichloromethane (100mL). To this solution was added 1, 1-dimethyl-2, 2,2- trichloroethyl chloroformate (3. 0g, 12. 5mmol) and triethylamine (2. 3g, 23mmol). After 18 hours at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (200mL). This solution was washed with 0.3M KHS04 (1x 50mL), sat NaHCO3 (1 x 50mL), water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil purified by flash chromatography on silica gel (eluant : 30% ethyl acetate, 70% pet. ether) to give colourless oil identified as N"- (tert-butyloxycarbonyl-N#-(1,1-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-N'-methyl-L- lysine methyl ester (3. 28g, 6. 98mmol, 63%).

E. Nα-tert-Butyloxycarbonyl-N#-(1,1-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-N#- methyl-L-lysine No'- (tert-Butyloxycarbonyl-N#-(1,1-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-N°'-methyl-L- lysine methyl ester (3.1g, 6. 6mmol) was dissolved in tetrahydrofuran (100mL). 1M Lithium hydroxide (7mL, 7. Ommol) was added. After 3 hours at room temperature the reaction mixture was diluted with ethyl acetate (150mL), washed with 1 M HCI (1 x 50mL), water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give colourless oil identified as Nα- (tert-butyloxycarbonyl-N#-(1,1-dimethyl- 2,2, 2-trichloroethoxycarbonyl)-N#-methyl-L-lysine (2. 94g, 6. 45mmol, 98%).

F. 3-(Nα-tert-Butyloxycarbonyl-N#-(1,1-dimethyl-3, 2, 2-trichloroethoxycarbonyl)- N°'-methyl-L-lysinyl) thiazolidine N"- (tert-Butyloxycarbonyl-N#-(1,1-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-N'-methyl-L- lysine (700mg, 1.51 mmol) was dissolved in CH2CI2/DMF (9: 1,20mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (410mg, 3. 0mmol), water-soluble carbodiimide (250mg, 1. 3mmol), thiazolidine (170mg, 1. 9mmol) and N- methylmorpholine (1. 0g, 10mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0.3M KHS04 (1 x 25mL), sat. NaHCO3 (1 x 25mL), water (1 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 50% ethyl acetate, 50% pet. ether) to give a white solid identified as 3- (N#-tert-butyloxycarbonyl-N#-(1,1-dimethyl- 2,2, 2-trichloroethoxycarbonyl)-N#-methyl-L-lysinyl) thiazolidine (758mg, 1. 42mmol, 94%).

G. 3- «-fert-Butyloxycarbonyl-N@-methyl-L-lysinyl) thiazolidine 3- (Nα-tert-Butyloxycarbonyl-N#-(1,1-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-A'-methyl- L-lysinyl) thiazolidine (730mg, 1. 36mmol) was dissolved in acetic acid (30mL). Zinc powder (200mg) was added. After stirring at room temperature for 18 hours the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). The solution was washed with sat. NaHCO3 (1 x 25mL), water (1 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as 3- (N°-tert-butyloxycarbonyl-N°'-methyl-L-lysinyl) thiazolidine (438mg, 1. 32mmol, 97%).

H. 3- [Nα-tert-Butyloxycarbonyl-N#-methyl-N#-(2-napthylmethyl)-L- lysinyl] thiazolidine 3- «-teff-Butyloxycarbonyl-N@-methyl-L-lysinyl) thiazolidine (50mg, 0. 15mmol) was dissolved in 1, 2-dichloroethane (20mL). To this solution was added 2-naphthaldehyde (26mg, 0. 17mmol). After 2 hours sodium triacetoxyborohydride (36mg, 0. 17mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 4% methanol, 96% chloroform) to give a colourless oil identified as 3- «-teff- <BR> <BR> <BR> butyloxycarbonyl-N#-methyl-N#-(2-naphthylmethyl)-L-lysinyl]t hiazolidine (51mg, 0. 11 mmol, 72%). <BR> <BR> <BR> <BR> <BR> <BR> <P>1. 3-[N#-Methyl-N#-(2-napthylmethyl)-L-lysinyl]thiazolidine dihydrochloride<BR> <BR> <BR> <BR> <BR> 3- [Nα-tert-butyloxycarbonyl-N#-methyl-N#-(2-naphthylmethyl)-L -lysinyl]thiazolidine (44mg, 0. 093mmol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a pale brown solid identified as 3-[N#-methyl-N#-(2-napthylmethyl)-L- lysinyl] thiazolidine dihydrochloride (37mg, 0. 083mmol, 89%).

[M+H] + = 372.2 'H NMR (CD30D) : 8 1.50-1. 53 (2H, m), 1.91-1. 98 (4H, m), 2.82 (3H, s), 3.08-3. 19 (4H, m), 3.36-3. 75 (5H, m), 4.32-4. 47 (2H, m), 4.60-4. 71 (2H, m), 7.55-7. 59 (2H, m), 7.65- 7.68 (1H, m), 7.90-8. 00 (3H, m), 8.10-8. 12 (1H, m) ppm.

EXAMPLE 9 3- [W-Methyl-N'- (I-Napthylmethyl)-L-ornithyl] thiazolidine dihydrochloride A. 3- [N- (tert-Butyloxycarbonyl)-CP-methyl-L-glutamyl] thiazolidine N- (fert-Butyloxycarbonyl)-O-methyl-L-glutamic acid (6. 28g, 24mmol) was dissolved in CH2CI2/DMF (9: 1, 100moi). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (5.5g, 36mol), water-soluble carbodiimide (5. 38g, 28mol), thiazolidine (2. 48g, 28mmol) and N-methylmorpholine (3. 0g, 30mol). The mixture was stirred for 18h at 0°C to room temperature then the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150mi). The solution was washed with 0. 3M KHS04 (2 x 30ml), sat. NaHCO3 (2 x 30moi), water (2 x 30ml) and brine (1 x 30ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 70% ethyl acetate, 30% pet. ether 60-80) to give a brown oil identified as 3-[N-(tert-butyloxycarbonyl)-O#-methyl-L-glutamyl]thiazolidi ne (4. 0g, 12mmol, 50%).

B. 3- [N, N-Di- (tert-butyloxycarbonyl)-Om-methyl-L-glutamyl] thiazolidine 3-[N-(tert-Butyloxycarbonyl)-O#-methyl-L-glutamyl]thiazolidi ne (3. 2g, 9. 6mmol) was dissolved in acetonitrile (20mL). Di-tert-butyl dicarbonate (3. 14g, 14. 4mmol) and 4- dimethylaminopyridine (235mg, 1. 93mmol) were added. After 18 hours at room temperature further di-tert-butyl dicarbonate (3. 14g, 14. 4mmol) was added. After a further 3 days at room temperature the solvent was evaporated in vacuo the residue was purified by flash chromatography on silica gel (eluant : 70% ethyl acetate, 30% pet. ether 60-80) to give a colourless oil identified as 3-[N, N-di-(tert-butyloxycarbonyl)-O@- methyl-L-glutamyl] thiazolidine (2. 0g, 4. 63mmol, 48%).

C. 3-[N,N-Di-(tert-butyloxycarbonyl)-L-glutamyl]thiazolidine 3-[N,N-di-(tert-butyloxycarbonyl)-O#-methyl-L-glutamyl]thiaz olidine (950mg, 2. 22mmol) was dissolved in THF (50ml). 1M Lithium hydroxide (5. 5moi, 5. 5mmol) was added.

The mixture was stirred for 1 hour at room temperature then the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70moi). The solution was washed with 0.3M KHS04 (2 x 20mi), water (2 x 20mi) and brine (1 x 20mi), dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as 3-[N, N-di-(tert- butyloxycarbonyl)-L-glutamyl] thiazolidine (912mg, 2. 2mmol, 98%).

D. 3-[2-(N,N-Di-(tert-butyloxycarbonyl)amino)-5-hydroxypentaoyl ]thiazolidine 3- [N, N-Di- (tert-butyloxycarbonyl)-L-glutamyl] thiazolidine (912mg, 2. 2mmol) was dissolved in tetrahydrofuran (30 mL). This solution was cooled to-20 °C, N- methylmorpholine (300mg, 2. 96mmol) and isobutyl chloroformate (387mg, 2. 83mmol) were added. After 20 mins at-20 °C the reaction mixture was added to a solution of sodium borohydride (182mg, 4. 8mmol) in water (5mL) at 0°C. After 1 hour the reaction mixture was diluted with ethyl acetate (150 mL). This solution was washed with water (1 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as 3-[2-(N, N-di-(tert-butyloxycarbonyl) amino) -5-hydroxy- pentanoyl] thiazolidine (800mg, 2. Ommol, 92%).

E. 3-[2-(N,N-Di-(tert-butyloxycarbonyl)amino-5-oxopentanoyl]thi azolidine 3- [2-N, N- ( (Di-tert-butyloxycarbonyl) amino)-5-hydroxypentanoyl] thiazolidine (800mg, 2. Ommol) was dissolved in dichloromethane (50 mL). Dess-Martin periodinane (933mg, 2. 2mmol) was added. After 1 hour at room temperature the reaction mixture was diluted with ethyl acetate (150 mL). This solution was washed with water (1 x 20ml) and brine (1 x 20mi), dried (Na2SO4) and evaporated in vacuo to give a colourless oil. Purified by flash chromatography on silica gel (eluant : 50% ethyl acetate, 50% pet. ether 60-80) to give a colourless oil identified as 3-[2-(N, N-di-(tert- butyloxycarbonyl) amino-5-oxopentanoyl] thiazolidine (210mg, 0. 52mmol, 26%).

F. 3- [N,N-Di-(tert-butyloxycarbonyl-N#-methyl-N#-(1-napthylmethyl )-L-ornithyl]- thiazolidine 3- [N, N-Di- (tert-butyloxycarbonyl) amino-5-oxopentanoyl] thiazolidine was dissolved in 1, 2-dichloroethane (20mL). To this solution was added N-methyl-1- napthylmethylamine. After 2 hours sodium triacetoxyborohydride was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel to give a colourless oil identified as 3- [N, N-di- (tert-butyloxycarbonyl-/\r-methyl-N'- (l-napthylmethyl)-L-ornithyl] thiazolidine.

G. 3- [N-Methyl-N- (I-Napthylmethyl)-L-ornithyl] thiazolidine dihydrochloride 3-[N, N-Di-(teff-butyloxycarbonyl-N@-methyl-N@-(1-napthylmethyl)-L -ornithyl] thiazolidine was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a pale brown solid identified as 3-[N#-Me,N#-(1-napthylmethyl)-L-ornithyl]thiazolidine dihydrochloride.

EXAMPLE 10 3, 3-Difluoro-1-[N#-(2-methylbutyl)-L-lysinyl]pyrrolidine dihydrochloride A. 1- (tert-Butyloxycarbonyl)-3-pyrrolidone (3R)-1- (tert-Butyloxycarbonyl)-3-hydroxypyrrolidine (980mg, 5. 3mmol) was dissolved in CH2CI2 (40ml). Dess-Martin periodinane (2. 5g, 5. 8mmol) was added. The mixture was stirred for 3 hours at room temperature then the solvent was removed in vacuo and the residue was taken up in ethyl acetate (300moi). The solution was washed with sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil. The residue was purified by flash chromatography on silica gel (eluant : 20% ethyl acetate, 80% pet. ether 60-80) to give a colourless oil identified as 1-(tert- butyloxycarbonyl)-3-pyrrolidone (842mg, 4. 6mmol, 87%).

B. 1- (fert-Butyloxycarbonyl)-3, 3-difluoropyrrolidine 1- (tert-Butyloxycarbonyl)-3-pyrrolidone (810mg, 4. 4mmol) was dissolved in CH2Cl2 (30ml). (Diethylamino) sulphur trifluoride (2. 2g, 13. 7mmol) was added to this solution at 0°C. The mixture was stirred for 18 hours at 0°C to room temperature then carefully poured into sat. NaHCO3 (100ml). The mixture was stirred for 15min then extracted with CH2CI2. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give an orange oil. The residue was purified by flash chromatography (eluant : 10% ethyl acetate, 90% pet. ether 60-80) to give a colourless oil identified as 1- (tert-butyloxycarbonyl)-3, 3-difluoropyrrolidine (580mg, 2. 8mmol, 64%).

C. 3, 3-Difluoropyrrolidine hydrochloride 1- (tert-Butyloxycarbonyl)-3, 3-difluoropyrrolidine (540mg, 2. 6mmol) was dissolved in 4M HCI/dioxan (30ml). The solution was stirred for 1 hour at room temperature then the solvent was removed in vacuo to give an off white solid identified as 3,3- difluoropyrrolidine hydrochloride (370mg, 2. 6mmol, 100%).

D. 1- (N"- (tert-Butyloxycarbonyl)-N°'- (9-fluorenylmethyloxycarbonyl)-L-lysinyl]-3, 3- difluoropyrrolidine N°- (tert-Butyloxycarbonyl)-IV°'- (9-fluorenylmethyloxycarbonyl)-L-lysine (1.14g, 2. 4mmol) was dissolved in CH2Cl2/DMF (9: 1, 100mi). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (394mg, 2. 9mmol), water-soluble carbodiimide (680mg, 3. 4mmol), 3, 3-difluoropyrrolidine hydrochloride (380mg, 2. 43mmol) and N- methylmorpholine (400mg, 4mmol). The mixture was stirred for 18h at 0°C to room temperature then the solvent was removed in vacuo and the residue was taken up in ethyl acetate (200ml). The solution was washed with 0.3M KHS04, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 65% ethyl acetate, 35% pet. ether 60-80) to give a white solid identified as 1-[Nα-(tert-butyloxycarbonyl)-N#-(9- fluorenylmethyloxycarbonyl)-L-lysinyl]-3, 3-difluoropyrrolidine (1. 0g, 1. 8mmol, 75%).

E. 1- [W- (tert-Butyloxycarbonyl)-L-lysinyl]-3, 3-difluoropyrrolidine <BR> <BR> <BR> 1-[Nα-(tert-Butyloxycarbonyl)-N#-(9-fluorenylmethyloxycarbo nyl)-L-lysinyl]-3,3-difluoro- pyrrolidine (1. Olg, 1. 8mmol) was dissolved in THF (20mut). Diethylamine (5ml) was added. The mixture was stirred for 3 hours at room temperature then the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 1- «-(tert-butyloxycarbonyl)-L-lysinyl]-3, 3-difluoropyrrolidine (598mg, 1. 78mmol, 99%).

F. 1-[Nα-(tert-Butyloxycarbonyl)-Nα-(2-methylbutyl)-L-lysinyl ]-3,3-difluoro- pyrrolidine 1- [/"- (tert-Butyloxycarbonyl)-L-lysinyl]-3, 3-difluoropyrrolidine was dissolved in 1,2- dichloroethane (20mL). To this solution was added 2-methylbutanal. After 2 hours sodium triacetoxyborohydride was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel to give a colourless oil identified as 1- [I\r- (tert- butyloxycarbonyl)-N#-(2-methylbutyl)-L-lysinyl]-3,3-difluoro pyrrolidine.

G. 3, 3-Difluoro-1- [N- (2-methylbutyl)-L-lysinyl] pyrrolidine dihydrochloride 1-[Nα-(tert-Butyloxycarbonyl)-N#-(2-methylbutyl)-L-lysinyl] -3,3-difluoropyrrolidine was dissolved in 4M HCI/dioxan (20ml). The mixture was stirred for 1 hour at room temperature then the solvent was removed in vacuo to give a colourless oil identified <BR> <BR> as 3, 3-difluoro-l- [Al- (2-methylbutyl)-L-lysinyl] pyrrolidine dihydrochloride.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P>EXAMPLE 11<BR> <BR> <BR> <BR> 1-lNe-(3-Cyclohexenylmethyl)-L-lysinylithiomorpholine dihydrochloride A. 3- [W- (tert-Butyloxycarbonyl)-W- (94luorenylmethyloxycarbonyl)-L- lysinyl] thiomorpholine N (tert-Butyloxycarbonyl)-N'- (9-fluorenylmethyloxycarbonyl)-L-lysine (2. 5g, 5. 34mmol) was dissolved in CH2CIz/DMF (9: 1, 100mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (1. 44g, 10. 6mmol), water-soluble carbodiimide (1.35g, 6. 5mmol), thiomorpholine (710mg, 6. 9mmol) and N-methylmorpholine (800mg, 8mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0.3M KHS04 (2 x 25mL), sat. NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a white solid identified as 3- [/\r- (tert-butyloxycarbonyl)-/V- (9-fluorenylmethyloxycarbonyi)-L- lysinyl] thiomorpholine (2. 70g, 4. 88mmol, 91%).

B. 3- [N"- (tert-Butyloxycarbonyl)-L-lysinyl] thiomorpholine 3- [/V'- (tert-Butyloxycarbonyl)-N'- (9-fluorenylmethyloxycarbonyl)-L- lysinyl] thiomorpholine (2. 6g, 4. 7mmol) was dissolved in tetrahydrofuran (20mL).

Diethylamine (5mL) was added. After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 3-[Nα-(tert-butyloxycarbonyl)-L-lysinyl]thiomorpholine (1. 2g, 3. 637mmol, 77%).

C. 3-[Nα-(tert-butyloxycarbonyl)-N#-(3-cyclohexenylmethyl)-L-l ysinyl]- thiomorpholine 3-(Nα-(tert-Butyloxycarbonyl)-L-lysinyl)thiomorpholine (150mg, 0. 45mmol) was dissolved in methanol (25mL). To this solution was added 3- cyclohexenecarboxaldehyde (400mg, 0. 45mmol). After 30mins sodium triacetoxyborohydride (150mg, 0. 71mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL).

This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1 % acetic acid, 9% methanol, 90% chloroform) to give a colourless oil identified as 3- (AF- (tert-butyloxycarbonyl)-I\r- (3- cyclohexenylmethyl)-L-lysinyl) thiomorpholine (66mg, 0. 12mmol, 26%).

D. 1- [N- (3-Cyclohexenylmethyl)-L-lysinyl] thlomorpholine dihydrochloride 3-(Nα-(tert-Butyloxycarbonyl)-N#-(3-cyclohexenylmethyl)-L-l ysinyl)thiomorpholine (66mg, 0. 12mmol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1- [/\r- (3-cyclohexenylmethyl)-L- lysinyl] thiomorpholine dihydrochloride (62mg, 0. 12mmol, 100%).

[M+H] + = 326.2 EXAMPLE 12 <BR> (12S)-1-[N#-(2-(3'-trifluoromethylanilino)pyridyl-3-carbonyl )-L-ornithyl]thiazolidine dihydrochloride A. 3- [N'-tert-Butyloxycarbonyl-N"- (I, I-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-L- ornithytjthiazotidine Nez (tert-Butyloxycarbonyl-N#-(1,1-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-L-ornithine (2. 5g, 5. 9mmol) was dissolved in CH2CI2/DMF (9: 1,30mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (1. 6g, 11. 9mmol), water-soluble carbodiimide (1.4g, 7. 6mmol), thiazolidine (650mg, 7. 3mmol) and N-methylmorpholine (2. 0g, 20mol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0. 3M KHS04 (1 x 25mL), sat. NaHCO3 (1 x 25mL), water (1 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 70% ethyl acetate, 30% pet. ether) to give a colourless oil identified as 3-[Nα-tert-butyloxycarbonyl-N#-(1,1-dimethyl-2, 2,2- trichloroethoxycarbonyl)-L-ornithyl] thiazolidine (758mg, 1. 42mmol, 94%).

B. 3-(N-teff-Butyloxywarbonyl-L-ornithinyl) thiazolidine 3-[Na-teff-Butyloxycarbonyl-N@-(1, 1-dimethyl-2, 2, 2-trichloroethoxycarbonyl)-L- ornithyl] thiazolidine (130mg, 0. 26mmol) was dissolved in acetic acid (30mL). Zinc powder (100mg) was added. After stirring at room temperature for 18 hours the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). The solution was washed with sat. NaHCO3 (1 x 25mL), water (1 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as 3- (Na-tert-butyloxycarbonyl-L-ornithinyl) thiazolidine (80mg, 0. 26mmol, 100%).

C. 3-lNa-teff-Butyloxycarbonyl-N'°-(2-(3'-trifluoromethylanili no) pyridyl-3- carbonyl)-L-ornithinyl] thiazolidine 3- (Na-tert-Butyloxycarbonyl-L-ornithinyl) thiazolidine (80mg, 0. 26mmol) was dissolved in CH2CI2/DMF (9: 1,20mL). To this solution at 0°C was added 1-hydroxybenzotriazole hydrate (80mg, 0. 6mmol), water-soluble carbodiimide (65mg, 0. 32mol), niflumic acid (82mg, 0. 29mmol) and N-methylmorpholine (100mg, 1. 0mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0.3M KHS04 (1 x 20mL), sat.

NaHCO3 (1 x 20mL), water (1 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a yellow oil identified as 3- [N"-tert- butyloxycarbonyl-N#-(2-(3'-trifluoromethylanilino)pyridyl-3- carbonyl)-L-ornithinyl]- thiazolidine (60mg, 0. 12mmol, 45%).

D. (2S)-1-1Ne-(2-(3'-Trifluoromethylanilino) pyridyl-3-carbonyl)-L-ornithyll- thiazolidine dihydrochloride 3-[Nα-tert-Butyloxycarbonyl-N#-(2-(3'-trifluoromethylanilin o)pyridyl-3-carbonyl)-L- ornithinyl] thiazolidine (54mg, 0. 10mmol) was dissolved in 4M HCI/dioxan (20mL).

After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a pale brown solid identified as (2S)-1-[N#-(2-(3'- trifluoromethylanilino) pyridyl-3-carbonyl)-L-ornithyl] thiazolidine dihydrochloride (47mg, 0. 10mmol, 100%).

[M+H] + = 468.0 'H NMR (CD30D) : 81. 77-1.82 (2H, m), 1.84-2. 00 (2H, m), 3.03-3. 15 (4H, m), 3.41-3. 51 (2H, m), 3.65-3. 71 (2H, m), 3.80-3. 87 (1H, m), 4.46-4. 49 (2H, m), 4.65-4. 72 (2H, m), 7.06-7. 11 (1H, m), 7.61-7. 11 (3H, m), 7.95 (1H, s), 8.09 (1H, d, J=4.7Hz), 8.49 (1H, d, J= 4.2Hz) ppm.

EXAMPLE 13 3, 3-Difluoro-(2-(3'-chloroanilino) pyridyl-3-carbonyl)-L-ornithyl] pyrrolidine dihydrochloride A. 1-lNa-(teff-Butyloxywarbonyl)-L-ornithyl]-3, 3-difluoropyrrolidine 1- [N"- (tert-Butyloxycarbonyl)-L-ornithyl]-3, 3-difluoropyrrolidine was prepared as described for the lysine derivative in Example 9.

B. 3-Chloroanilinonicotinic acid 3-Chloroaniline was dissolved in xylene. 2-Aminonicotinic acid was added. The reaction mixture was heated at 150 °C for 18 hours after which time the reaction mixture was diluted with ethyl acetate giving an off-white solid identified as 3- chloroanilinonicotinic acid.

C. 3, 3-Difluoro-[Nα-tert-butyloxycarbonyl-N#-(2-(3'-chloroanilin o)pyridyl-3- carbonyl)-L-ornithinyl] pyrrolidine 1- [N"- (tert-Butyloxycarbonyl)-L-ornithyl]-3, 3-difluoropyrrolidine was dissolved in CH2CI2 /DMF (9: 1, 20mL). To this solution at 0°C was added 1-hydroxybenzotriazole hydrate, water-soluble carbodiimide, 3-chloroanilinonicotinic acid and N-methylmorpholine.

After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0.3M KHS04 (1 x 20mL), sat. NaHCO3 (1 x 20mL), water (1 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a yellow oil identified as 3, 3-difluoro- [N"-tert-butyloxycarbonyl-IV°'- (2- (3'- chloroanilino) pyridyl-3-carbonyl)]-L-ornithinyl) pyrrolidine.

D. 3, 3-Difluoro-1-[N#-(2-(3'-chloroanilino)pyridyl-3-carbonyl)-L- ornithyl] pyrrolidine dihydrochloride 3, 3-Difluoro- [Nc'-tert-butyloxycarbonyl-Ar- (2- (3'-chloroanilino) pyridyi-3-carbonyl)]-L- ornithinyl) pyrrolidine was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a pale brown solid identified as 3, 3-difluoro-1-[N'°-(2-(3'- chloroanilino) pyridyl-3-carbonyl)-L-ornithyl] pyrrolidine dihydrochloride.

EXAMPLE 14 3- [W-6-Chloro-4- (2', 5'-dichloroani li no)-I, 3, 5-triazinyl)-L-lysinyllthiazolidine dihydrochloride A. 4, 6-Dichloro-2- (2', 5'-dichloroanilino)-1, 3,5-triazine Cyanuric chloride (1.844g, 10mmol) was dissolved in acetonitrile (20mL). The solution was cooled to-20 °C. A solution of 2, 5-dichloroaniline (1. 62g, 10mmol) and triethylamine (1. Og, 10mol) was slowly added. After 1 hour at-20 °C the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150mL). The solution was washed with water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo. The residue was recrystallised from ethyl acetate/hexane to give an off white solid identified as 4, 6-dichloro-2- (2', 5'-dichloroanilino)-1, 3,5-triazine (1.86mg, 6. Ommol, 60%).

B. 3-[Nα-tert-Butyloxycarbonyl-N#-6-chloro-4-(2',5'-dichloroan ilino)-1, 3,5- triazinyl)-L-lysinyl] thiazolidine 3-(Na-(tert-Butyloxycarbonyl)-L-lysinyl) thiazolidine (800mg, 2. 58mmol) was dissolved in dichloromethane (30mL). To this solution was added 4, 6-dichloro-2-(2', 5'- dichloroanilino)-1, 3,5-triazine (810mg, 2. 6mmol) and triethylamine (300mg, 3. 0mmol).

After 2 hours at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150mL). This solution was washed with water (2 x 30mL) and brine (1 x 30mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (eluant : 60% ethyl acetate, 40% pet. ether) to give a white solid identified as 3- «-teff-butyloxycarbonyl-N@-6-chloro-4- (2', 5'-dichloroanilino)-1, 3, 5-triazinyl)-L-lysinyl] thiazolidine (1. 33g, 2. 23mmol, 86%).

C. 3-1NO-6-Chloro-4-(2', 5'-dichloroanilino)-1, 3, 5-triazinyl)-L-lysinyl] thiazolidine dihydrochloride 3- [Na-tert-Butyloxycarbonyl-/°'-6-chloro-4- (2', 5'-dichloroanilino)-1, 3, 5-triazinyl)-L- lysinyl] thiazolidine (59mg, 0. 10mmol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 3- [I\r-6-chloro-4- (2', 5'- dichloroanilino)-1, 3, 5-triazinyl)-L-lysinyl] thiazolidine dihydrochloride (55mg, 0. 098mmol, 98%).

[M+H] + = 492.2, 494.4 'H NMR (CD30D) : 51. 46-1.51 (2H, m), 1. 65-1. 67 (2H, m), 1.80-1. 96 (2H, m), 3.05-3. 14 (2H, m), 3.38-3. 42 (2H, m), 3.55-3. 75 (4H, m), 4.31-4. 36 (2H, mO, 4.40-4. 52 (1 H, m), 4.63- 4. 95 (2H, m), 7.15-7. 18 (1H, m), 7.40-7. 45 (1H, m), 8.15-8. 25 (1H, m) ppm.

EXAMPLE 15 <BR> <BR> 3- N'-4- (2', 5'-Dichloroanilino)-6-hydroxy-1, 3, 5-triazinyl)-L-lysinyl thiazolidine bis (trifluoroacetate) A. 3- [Nm-4- (2', 5'-Dichloroanilino)-6-hydroxy-1, 3, 5-triazinyl)-L-lysinyl] thiazolidine bis (trifluoroacetate) 3- [Nα-tert-Butyloxycarbonyl-N#-6-chloro-4-(2',5'-dichloroanil ino)-1, 3, 5-triazinyl)]-L- ornithinyl) thiazolidine (54mg, 0. 09mmol) was dissolved in trifluoroacetic acid (20mL) and water (2mL). After 2 hours at 70 °C the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 3- [W-4- (2', 5'- dichloroanilino)-6-hydroxy-1, 3, 5-triazinyl)-L-lysinyl] thiazolidine bis (trifluoroacetate) (63mg, 0. 089mmol, 97%).

[M+H] + = 472.1, 474.2 'H NMR (CD30D) : 81. 42-1.47 (2H, m), 1.62-1. 67 (2H, m), 1.82-1. 89 (2H, m), 3.04-3. 16 (4H, m), 3.70-3. 75 (2H, m), 3.84-3. 91 (1 H, m), 4.25-4. 32 (2H, m), 4.45-4. 54 (2H, m), 4.64- 4.70 (2H, m), 7.05-7. 15 (1H, m), 7.34-7. 38 (1H, m), 7.49-7. 55 (1H, m), 7.80-7. 92 (1H, m) ppm.

EXAMPLE 16 3-[N#-4-(2',5'-Dichloroanilino)-6-methylamino-1, 3, 5-triazinyl)-L-lysinyl] thiazolidine dihydrochloride A. 3- [N'-tert-Butyloxycarbonyl-W-4- (2', 5'-dichloroanilino)-6-dimethylamino-1, 3,5- triazinyl)-L-lysinyl] thiazolidine 3-[Nα-tert-Butyloxycarbonyl-N#-3-chloro-5-(2',5'-dichloroan ilino)-2, 4, 6-triazinyl)]-L- ornithinyl) thiazolidine (120mg, 0. 20mmol) was dissolved in 1 M dimethylamine in tetrahydrofuran (25mL). After 18 hours at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 70% ethyl acetate, 30% pet. ether) to give a white solid identified as 3- [Na-tert- butyloxycarbonyl-N#-4-(2',5'-dichloroanilino)-6-dimethylamin o-1, 3, 5-triazinyl)-L- lysinyl] thiazolidine (110mg, 0. 18mmol, 90%).

B. 3- NK-4-(2', 5'-Dichloroanilino)-6-dimethylamino-1, 3, 5-triazinyl)-L-lysinyl]- thiazolidine dihydrochloride 3- [Nα-tert-Butyloxycarbonyl-N#-4-(2',5'-dichloroanilino-6-dim ethylamino-1, 3, 5-triazinyl)- L-lysinyl] thiazolidine (110mg, 0. 18mmol) was dissolved in 4M HCl/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 3-[N'°-4-(2', 5'-dichloroanilino)-6- dimethylamino-1, 3, 5-triazinyl)-L-lysinyl] thiazolidine dihydrochloride (105mg, 0. 18mmol, 100%).

[M+H] + = 499.1, 501.1 'H NMR (CD30D) : 81. 52-1.55 (2H, m), 1.69-1. 71 (2H, m), 1.90-1. 98 (2H, m), 3.13-3. 22 (8H, m), 3.48-3. 62 (2H, m), 3. 65-3. 69 (4H, m), 4.37-4. 39 (2H, m), 4.46-4. 49 (1 H, m), 4.57- 4.77 (2H, m), 7.20-7. 22 (1H, m), 7.45-7. 50 (1H, m), 8.09-8. 12 (1H, m) ppm.

The following compounds were prepared by analogous methods.

TABLE 1 Example No n X Example No n X 17 3 s 22 3 23 4 o ND-Z N 18 3 F 24 3 3 F 19 my 25 zu 20 3 s 26 3 21 4 c 27 4 N-y N- TABLE 2 Example No n X Example No n X 28 2 vs 41 2 \,J 29 2 F 42 2 FF 30 3 43 3 31 4 45 4 32 2 46 2 /NX 33 3 47 3-N 34 4 48 4 35 2 CN 2 36 3 49 37 4 N 38 2 s 50 2 0 39 3 51 51 3 40 4 iN 52 4 iN TABLE 3 Ex a b X R3 R4 No 53 1 3 S H H3C CH2 54 1 4 H 3 2 55 1 3 H CH2 56 1 4 H 57 1 3 H CH2 58 1 4 H 59 1 4 S CH3 60 1 4 CH (CH3) 2 61 1 4 CH2 CH3 62 1 4 CH (CH3) 2 Ex a b X R3 R4 63 1 3 S CH (CH3) 2 64 1 3 CH2 CH (CH3) 2 65 2 3 H S 66 2 4 H 67 2 3 H 68 2 4 CH2 H 69 1 3 H S 70 1 4 H 71 1 3 H 72 1 4 H 73 1 3 H 73 1 3 H 74 1 4 CF2 H 75 1 4 S CH3 76 1 4 CH (CH3) 2 H CCH2 77 1 4 CHZ GH3 78 1 4 CH (CH3) 2 79 1 3 S CH (CH3) 2 80 1 3 CH2 CH (CH3) 2 81 2 3 H S 82 2 4 H 83 2 3 CH2 H 84 2 4 H 84 2 4 H 86 1 4 H 87 1 3 CH2 H 88 1 4 H 88 1 4 H 89 1 3 CF2 H 90 1 4 H 91 1 4 CH3 92 1 4 CH (CH3) 2 93 1 4 t-u CH3 94 1 4 CH (CH3) 2 95 1 3 S CH (CH3) 2 Ex b x R3 R4 96 1 3 CH2 CH (CH3) 2 97 2 3 H S 98 2 4 H 99 2 3 H 100 2 4 H 101 1 3 H s 102 1 4 H 103 1 3 H CHEZ 104 1 4 H 105 1 3 CF2 H 106 1 4 S CH3 107 1 4 CH (CH3) 2 CH3 108 1 4 CH2 CH3 H3Cx) CH 109 1 4 CH (CH3) 2 2 110 1 3 S CH (CH3) 2 111 1 3 CH2 CH (CH3) 2 112 2 3 H s 113 2 4 H 114 2 3 H 115 2 4 CH2 H 118 1 3 H 117 1 4 H H3C-_CH2 118 1 3 H 119 1 4 H 120 1 3 H 121 1 4 CF2 H 122 1 4 S CH3 123 1 4 CH (CH3) 2 124 1 4 CH3 125 1 4 CH (CH3) 2 126 1 3 S CH (CH3) 2 127 1 3 CH2 CH (CH3) 2 128 2 3 S H Ex a b X R5 R4 129 2 4 H 130 2 3 H 131 2 4 ICH2 H 132 1 3 H S 133 1 4 H 134 1 3 H 135 1 4 H 136 1 3 H 137 1 4 H 138 1 4 S CH3 CH 139 1 4 CH (CH3) 2 CH3 140 1 4 CH3 H3Co CH2 141 1 4 CH (CH3) 2 142 1 3 S CH (CH3) 2 143 1 3 CH2 CH (CH3) 2 144 2 3 H S 145 2 4 H 146 2 3 H 147 2 4H 148 1 3 s 149 1 4 150 1 4 CHU CHEZ 151 1 3 CF 152 1 4 153 1 4 CH3 154 1 4 CH (CH3) 2 155 1 4 CH3 CH2 156 1 4 CH (CH3) 2 157 1 3 S CH (CH3) z 158 1 3 CH2 CH (CH3) 2 159 2 3 H S 160 2 4 H 161 2 3 CH2 H Ex a b X R 4 No 163 1 4 H S 164 1 3 H 165 1 3 H 166 1 4 CH2 H 167 1 3 H 168 1 4 H 169 1 4 S CH3 170 1 4 CH (CH3) 2 171 1 4 CH2 CH3 aCH2 ce 172 1 4 CH (CH3) 2 173 1 3 S CH (CH3) 2 174 1 3 CH2 CH (CH3) 2 175 2 3 H S 176 2 4 H 177 2 3 H CH2 178 2 4 H 179 1 3 H S 180 1 4 H 181 1 3 H 182 1 4 CH2 H 183 1 3 H 184 1 4 H 185 1 4 S CH3 186 1 4 CH (CH3) 2 H C<CH 187 1 4 CH3 2 2 CH2 188 1 4 CH (CH3) 2 189 1 3 S CH (CH3) 2 190 1 3 CH2 CH (CH3) 2 191 2 3 H S 192 2 4 H 193 2 3 H 194 2 4 H Ex a b X R3 R4 No 195 1 3 H S 196 1 4 H 197 1 3 H 198 1 4 H 199 1 3 H 200 1 4 H 201 1 4 CH3 CH3 202 1 4 CH (CH3) 2 ICH3 203 1 4 CH2 CH3 H3CouCH z 204 1 4 CH (CH3) z 205 1 3 S CH (CH3) 2 206 1 3 CH2 CH (CH3) 2 207 2 3 H S 208 2 4 H 209 2 3 H 210 2 4 CH2 H 211 1 3 H S 212 1 4 H 213 1 3 H 214 1 4 CH2 H 215 1 3 H 216 1 4 CF2 H 217 1 4 CH3 CH3 218 1 4 CH (CH3) 2 cl2 219 1 4 CH3 CH3 CH2 220 1 4 CH (CH3) 221 1 3 S CH (CH3) 222 1 3 CH2 CH (CH3) 2 223 2 3 S H 224 2 3 H CHF 225 2 4 H 226 1 3 H S 227 1 4 H Ex a b X R3 R4 228 1 3 H 229 1 4 H 229 1 4H ! 230 1 3 H 9\CH2 231 1 4 CF2 H 232 1 4 S CH3 233 1 4 CH (CH3) 2 234 1 4 CH3 235 1 4 CH (CH3) 2 236 1 3 S CH (CH3) 2 237 1 3 CH2 CH (CH3) 2 238 2 3 H s 239 2 4 H 240 2 3 CH2 H 241 2 4 H 241 2 4 H 242 1 3 S H 243 1 4 H 244 1 3 H 244 1 3 H 245 1 4 CH2 H 246 1 3 H 247 1 4 CF2 H 248 1 4 CHUG 249 1 4 CH (CH3) 2 250 1 4 CH2 CH3 F CH2 251 1 4 CH (CH3) 2 252 1 3 S CH (CH3) 2 253 1 3 CH2 CH (CH3) 2 254 2 3 H 255 2 4 H 254 2 3 s H 256 2 3 H -- CH2 257 2 4 H 258 1 3 S H 259 1 4 H 260 1 3 CH2 H Ex | a | b | X R3 R4 Ex b x R3 R4 Nô 261 1 4 H 262 1 3 CF2 H 263 1 4 H CH2 264 1 4 S CH3 Cl 265 1 4 CH (CH3) 2 266 1 4 CH2 CH3 267 1 4 CH (CH3) 2 268 1 3 S CH (CH3) 2 269 1 3 CH2 CH (CH3) 2 270 2 3 H S 271 2 4 H 272 2 3 H CHEZ 273 2 4 H 274 1 3 H S 275 1 4 H 276 1 3 H 277 1 4H 278 1 3 H 279 1 4 CF2 H 280 1 4 CHUS 281 1 4 CH (CH3) 2 282 1 4 CH2 CH3 Cl CH2 283 1 4 CH (CH3) 2 284 1 3 S CH (CH3) 2 285 1 3 CH2 CH (CH3) 2 286 2 3 H S 287 2 4 H 288 2 3 H 289 2 4 H 290 1 3 S H CI 291 1 4 H 292 1 3 H CH2 292 1 3 H "CHg 293 1 4 CH2 H Ex a b X R3 R4 CF2 294 1 3 H 295 1 4 CF2 H 295 1 4 H 296 1 4 S CH3 297 1 4 CH (CH3) 2 298 1 4 CH2-CH3 299 1 4 CH (CH3) 2 300 1 3 S CH (CH3) 2 301 1 3 CH2 CH (CH3) 2 302 2 3 H S 303 2 4 H 304 2 3 H 305 2 4 CH2 H 306 1 3 H S 307 1 4 H 308 1 3 H 309 1 4H 310 1 3 H 311 1 4 CF2 H 312 1 4 s CH3 313 1 4 CH (CH3) 2 314 1 4 CH3 H3Cs <s c2 a 315 1 4 CH (CH3) 2 316 1 3 S CH (CH3) 2 317 1 3 CH2 CH (CH3) 2 318 2 3 H S 319 2 4 H 320 2 3 H 321 2 4 CH2 H 322 1 3 S H H O 323 1 4 H 324 1 3 H C2 325 1 4 H 326 1 3 CF2 H Ex a b X R3 R4 No 327 1 4 H 328 1 4 S CH3 329 1 4 CH (CH3) 2 330 1 4 CH2 CH3 331 1 4 CH (CH3) 2 332 1 3 S CH (CH3) 2 333 1 3 CH2 CH (CH3) 2 334 2 3 H S 335 2 4 H 336 2 3 H CH2 337 2 4 H 338 1 3 H S 339 1 4 H 340 1 3 H 341 1 4 CH2 H 342 1 3 H 343 1 4 CF2 H 344 1 4 CH3 S A 345 1 4 CH (CH3) 2 0 346 1 4 CH2 CH3 H3C O CH2 Qu DgU U UH 347 1 4 CH (CH3) 2 348 1 3 S CH (CH3) 2 349 1 3 CH2 CH (CH3) 2 350 2 3 H s 351 2 4 H 352 2 3 H 353 2 4 H 354 1 3 H H3C\/O 355 1 4 S H Y X 1 356 1 3 H CH2 357 1 4 H 358 1 3 H 359 1 4 H Ex a b X R3 R4 360 1 4 S CH3 361 1 4 CH (CH3) 2 362 1 4 CH3 CH2 363 1 4 CH (CH3) 2 364 1 3 S CH (CH3) 2 365 1 3 CH2 CH (CH3) 2 366 2 3 H s 367 2 4 H 368 2 3 H 369 2 4H 370 1 3 H S 371 1 4 H 372 1 3 H 373 1 4H 374 1 3 H 375 1 4 H 376 1 4 CHU CHUG 377 1 4 1 CH (CH3) 2 H3c N hic I 378 1 4 CHs. 1 379 1 4 2 CH (CH3) 2 380 1 3 S CH (CH3) 2 381 1 3 CH2 CH (CH3) 2 382 2 3 H S 383 2 4 H 384 2 3 H CHEZ 385 2 4 H 386 1 3 H H 387 H3C\/N 387 1 4CH 388 1 3 H I CH CH2 2 389 1 4 H 390 1 3 H CF2 391 1 4 H 392 1 4 S CH3 Ex b X R3 R4 393 1 4 CH (CH3) 2 394 1 4 CH2 CH3 395 1 4 CH (CH3) 2 396 1 3 S CH (CH3) 2 397 1 3 CH2 CH (CH3) 2 398 2 3 H s 399 2 4 H 400 2 3 H 401 2 4 H 402 1 3 H S 403 1 4 H 404 1 3 H 405 1 4 H 406 1 3 H CH2 407 1 4 H 408 1 4 S CH3 409 1 4 CH (CH3) 2 l l l O/ 410 1 4 CH2 CH3 H3C CCH2 411 1 4 CH (CH3) 2 O 412 1 3 S CH (CH3) 2 413 1 3 CH2 CH (CH3) 2 414 2 3 H S 415 2 4 H 416 2 3 H CH2 417 2 4 H 418 1 3 H 419 1 4 H 420 1 3 H H CH2 yu " 421 1 4 H CN 422 1 3 H 423 1 4 H 424 1 4 S CH3 425 1 4 CH (CH3) 2 Ex a b X CH3 R4 NO 426 1 4 CH2 CH3 427 1 4 CH (CH3) 2 428 1 3 S CH (CH3) 2 429 1 3 CH2 CH (CH3) 2 450 2 3 H S 451 2 4 H 452 2 3 H 453 2 4 CH2 H 454 1 3 H CH2 455 1 4 H 456 1 3 H 457 1 4 CH2 H 458 1 3 H 459 1 4 CF2 H 460 1 4 S CH3 461 1 4 CH (CH3) 2 462 1 4 CH2 CH3 NC 9 XCH2 463 1 4 CH (CH3) 2 464 1 3 S CH (CH3) 2 465 1 3 CH2 CH (CH3) 2 466 2 3 H s 467 2 4 H 468 2 3 H 469 2 4 H 470 1 3 H NC 471 1 4 H 472 1 3 CH2 lCH2 473 1 4 CH2 H 474 1 3 H CFZ 474 1 3 H 475 1 4 H 476 1 4 S CH3 477 1 4 CH (CH3) 2 478 1 4 CH2 CH3 Ex b X R'R4 No 479 1 4 CH (CH3) 2 480 1 3 S CH (CH3) 2 481 1 3 CH2 CH (CH3) 2 482 2 3 H S 483 2 4 H 484 2 3 H 485 2 4 H 486 1 3 H S 487 1 4 H 488 1 3 H CH2 489 1 4 H 490 1 3 H 491 1 4 H 492 1 4 CH3 S A 493 1 4 CH (CH3) 2 fol 494 1 4 CH2 CH3 9 CH2 495 1 4 CH (CH3) 2 496 1 3 S CH (CH3) 2 497 1 3 CH2 CH (CH3) 2 498 2 3 H S 499 2 4 H 500 2 3 H 501 2 4 H 502 1 3 S H 503 1 4 H 504 1 3 CH2 H CH2 505 1 4 H 506 1 3 H 507 1 4 H 508 1 4 CH3 S 509 1 4 CH (CH3) 2 510 1 4 CH2 CH3 511 1 4 CH (CH3) 2 Ex No a b X R3 R4 512 1 3 S CH (CH3) 2 513 1 3 CH2 CH (CH3) 2 514 2 3 H S 515 2 4 H 516 2 3 H CHEZ 517 2 4 H 518 1 3 H S 519 1 4 H 520 1 3 H CH2 521 1 4 H 522 1 3 H CF2 523 1 4 H 524 1 4 S CH3 525 1 4 CH (CH3) 2 526 1 4 CH2 CH3 N<CH2 527 1 4 CH (CH3) 2 528 1 3 S CH (CH3) 2 529 1 3 CH2 CH (CH3) 2 530 2 3 H S 531 2 4 H 532 2 3 H CH2 533 2 4 H 534 1 3 S H s 535 1 4 H N 536 1 3 H CH2 537 1 4 H 538 1 3 H 539 1 4 H 540 1 4 S CH3 541 1 4 CH (CH3) 2 542 1 4 CH3 543 1 4 CH (CH3) 2 544 1 3 S CH (CH3) 2 Ex b X R3 R4 No a 545 1 3 CH2 CH (CH3) 2 546 2 3 H s 547 2 4 H 548 2 3 H 549 2 4 H 550 1 3 H S 551 1 4 H 552 1 3 H 553 1 4 H 554 1 3 H CF2 555 1 4 H 556 1 4 S CH3 557 1 4 CH (CH3) 2 558 1 4 CH2 CH3 vCH2 ce 559 1 4 CH (CH3) 2 560 1 3 S CH (CH3) 2 561 1 3 CH2 CH (CH3) 2 562 2 3 H S 563 2 4 H 564 2 3 H 565 2 4 H 566 1 3 H S 1/ 567 1 4 H S CH2 N 568 1 3 H H 569 1 4 H 570 1 3 H 571 1 4 CF2 H 572 1 4 S CH3 573 1 4 CH (CH3) 2 574 1 4 CH3 CH2 575 1 4 CH (CH3) 2 576 1 3 S CH (CH3) 2 577 1 3 CH2 CH (CH3) 2 Ex b x R3 R 4 nô S 579 2 4 H 580 2 3 H 581 2 4 CH2 H 582 1 3 H S 583 1 4 H 584 1 3 H CH2 585 1 4H 586 1 3 H 587 1 4 CF2 H 588 1 4 S CH3 589 1 4 CH (CH3) 2 N-CH 2 590 1 4 CH CH3 591 1 4 CH (CH3) 2 592 1 3 S CH (CH3) 2 593 1 3 CH2 CH (CH3) 2 594 2 3 H S 595 2 4 H 596 2 3 H CH2 597 2 4 H 598 1 3 S | H s 599 1 4 H ts » CH2 S 600 1 3 H 601 1 4 H 602 1 3 H 603 1 4 H 604 1 4 S CH3 605 1 4 CH (CH3) 2 606 1 4 CH2 CH3 607 1 4 CH (CH3) 2 608 1 3 S CH (CH3) 2 609 1 3 CH2 CH (CH3) 2 610 2 3 S H Ex b x R 3 R4 611 2 4 H 612 2 3 H 613 2 4 H 614 1 3 H s 615 1 4 H 616 1 3 H 617 1 4 H 618 1 3 H 6191 4 H 620 1 4 CH3 621 1 4 CH (CH3) 2/=\ 622 1 4 CH3 SCHz 623 1 4 CH2 CH (CH3) 2 624 1 3 s CH (CH3) 2 625 1 3 CH2 CH (CH3) 2 626 2 3 H S 627 2 4 H 628 2 3 H 629 2 4 H 630 1 3 S H 631 1 4 H 632 1 3 C H CH2 H 633 1 4 H 634 1 3 H 6351 4 H 636 1 4 S CH3 637 1 4 CH (CH3) 2 638 1 4 CH2 CH3 639 1 4 CH (CH3) 2 640 1 3 S CH (CH3) 2 641 1 3 CH2 CH (CH3) 2 642 2 3 H s 643 2 4 H Ex a b X R3 R4 No 644 2 3 H 645 2 4 H 646 1 3 H S 647 1 4 H 648 1 3 H 649 1 4 CH2 H 650 1 3 CF2 H CFZ 651 1 4 H 652 1 4 S CH (CH3) 2 653 1 4 CH2 CH3 X CH 654 1 4 CH (CH3) 2 2 655 1 3 S CH (CH3) 2 656 1 3 CH2 CH (CH3) 2 657 2 3 H S 658 2 4 H 659 2 3 H 660 2 4 H 661 1 3 H S 662 1 4 H 663 1 3 H 664 1 4 H 665 1 3 H 666 1 4 CF2 H 667 1 4 S CH3 668 1 4 CH (CH3) z 669 1 4 CH2 CH3 vN CH2 670 1 4 CH (CH3) 2 671 1 3 S CH (CH3) 2 672 1 3 CH2 CH (CH3) 2 673 2 3 H s 674 2 4 H 675 2 3 H CH2 676 2 4H Ex b X R3 R4 677 1 3 S H 678 1 4 CH2 H 679 1 3 H 680 1 4 H 681 1 4 s CH3 N 682 1 4 CH (CH3) 2 Nq 683 1 4 CH2 CH3 +\CH2 684 1 4 CH (CH3) 2 685 1 3 S CH (CH3) 2 686 1 3 CH2 CH (CH3) Z 687 2 3 S H 688 2 4 CH2 H 689 1 3 H S 690 1 4 H 691 1 3 H CH2 692 1 4 H 693 1 3 H 694 1 4 H 695 1 4 s CH3 N S 696 1 4 CH (CH3) 2 697 1 4 CH3 i T CH2 CH2,, 698 1 4 CH (CH3) 2 699 1 3 S CH (CH3) 2 700 1 3 CH2 CH (CH3) 2 701 2 3 H S 702 2 4 H 703 2 3 H 704 2 4 CH2 H 705 1 3 H H S N 706 1 4 H 707 1 3 H CH2 \S 708 1 4 H "2 709 1 3 CF2 H Ex a b X R3 R4 710 1 4 H 711 1 4 CH3 S 712 1 4 CH (CH3) 2 713 1 4 CH2 CH3 714 1 4 CH (CH3) 2 715 1 3 S CH (CH3) 2 716 1 3 CH2 CH (CH3) 2 717 2 3 H s 718 2 4 H 719 2 3 H CH2 720 2 4 H 721 1 3 H S 722 1 4 H 723 1 3 H CHEZ 724 1 4 H 725 1 3 H 726 1 4 CF2 H 727 1 4 CH3 728 1 4 S CH (CH3) 2 w 729 1 4 CH2 CH3 o CH2 730 1 4 CH (CH3) 2 731 1 3 S CH (CH3) 2 732 1 3 CH2 CH (CH3) 2 733 2 3 H S 734 2 4 H 735 2 3 H CH2 736 2 4 H 737 1 3 S H 738 1 3 CH2 H 739 1 4 H CH2 CF2 740 1 3 H 741 1 H 741 1 4 H 742 1 4 S CH3 Eux b X R3 R4 743 1 4 CH (CH3) 2 744 1 4 CH2 CH3 745 1 4 CH (CH3) Z 746 1 3 S CH (CH3) 2 747 1 3 CH2 CH (CH3) 2 748 2 3 H s 749 2 4 H 750 2 3 H 751 2 4 CH2 H 752 1 3 H S 753 1 4 H 754 1 3 H CH2 755 1 4 H 756 1 3 H CF2 757 1 4 H 758 1 4 S CH3 NO2 759 1 4 CH (CH3) 2 < 760 1 4 H CH3 w CH2 761 1 4 CH (CH3) 2 762 1 3 S CH (CH3) 2 763 1 3 CH2 CH (CH3) 2 764 2 3 H S 765 2 4 H 766 2 3 H 767 2 4 CH2 H 768 1 3 S H 769 1 4 H-CH2 770 1 3 H 771 1 4H 772 1 3 H 773 1 4 CF2 H 774 1 4 CH3 s 775 1 4 CH (CH3) 2 Ex b x R3 No 776 1 4 CH2 CH3 777 1 4 CH (CH3) 2 778 1 3 S CH (CH3) 2 779 1 3 CH2 CH (CH3) 2 780 2 3 H s 781 2 4 H 782 2 3 H 783 2 4 CH2 H 784 1 3 H s 785 1 4 H 786 1 3 H 787 1 4 H 788 1 3 H 789 1 4 CF2 H 790 1 4 CH3 791 1 4 CH (CH3) 2 792 1 4 CH2 \-/\/ 793 1 4 CH (CH3) 2 794 1 3 S CH (CH3) 2 795 1 3 CH2 CH (CH3) 2 796 2 3 H S 797 2 4 H 798 2 3 H 799 2 4 H TABLE 4 Example X R Example X R No No 800 S CN-\ 841 S 801 CH2 842 CH2 -Ny 802 S n Y 843 S s 803 CH2 "y 844 CHZ 804 S , r, 845 Su 805 CH2 v Ny 846 CH2 wP Ny 806 s 847 s 807 CH2 CH2 808 S Y 848 s 809 CH2 N 849 CH2 810 S 850 S s A N 811 CH2 oNy 851 CH2 812 S IN 852 S 813 CH2 Ny 853 CH2 814 S 854 S l 815 CH2 Ny 855 CH2 816 S"°N', 856 S 817 CH2 ON"/857 CH2 Ny 818 S I 858 S 819 CH2 ~ Ny 859 CH2 ot 2 820 S 860 S 821 CH2 f <1 861 CH2 WNA N 9 O 4 Ny 4 Ny 822 S S NA 862 S A I 823 CH2 \/863 CH2 w owNy 824 S rah I 864 S S CI 824 S 825 CH2) Ny 865 CHZ 826 S n 866 S | N 827 CH2 867 N"/ -Ny 828 CH2 A I 868 S P 829 N"/869 CH2 830 S <1 870 S 631 CH2 s 671 CH2 832 s N 872 833 CH2 ON 873 873 CH2 aN k 834 S 874 S 835 CH2 e N 9 875 CH2 o0 4 Ny _ 836 S.. ruz 876 S 837 CH2 t) 877 CH2 t f xi 838 S 839 CH2 OIN k/ TABLE 5 Example n X Example n X R No No 878 3 S/°syo 933 3 S 879 4 934 4 880 3 CH2 N 935 3 CH2 H 881 4 936 4 882 3 S 937-3 S 883 4 1l 1 \ 938 4 884 3 CH2 ci N 939 3 CH2 rNA 885 4 940 4 886 3 S 941 3 S 887 4 942 4 DANA 888 3 CH2 H 943 3 CH2 H 889 4 944 4 890 3 S 945 3 s F zizi 892 3 CH2 N CH2 N 893 4 H 946 4 H 894 3 S 02N 947 3 S 895 4 948 4 896 3 CH2 N 949 3 CHZ oaN N 897 4 950 4 898 3 S 951 3 S 899 4 952 4 900 3 CH2 i t V 953 3 CH2 aN 901 4 H 954 4 H 902 3 S 955 3 S 903 4 956 4 904 3 CH2 ll l 957 3 CH2 NowNA 905 4 H 958 4 H 906-3 s ci 959 3 s ci 907 41 960 908 CH2 N 961 3 CH2 X 909 4 9 2 4 C ci H 910 3 S cl 963 3 S 911 4 1l I 964 4 912 3 CH2 Cl., aN 965 3 CH2 ci 913 4 966 4 cul 914 3 S r O 967 3 S 915 4 968 4 916 3 CH2 X 969 3 CH2 \eNS 917 4 N 970 4 H 918 3 S CF/°s E 971 3 S 919 4 3 A 972 4 A CH N 973 3 CH2 Y N 0 4 H 974 4 I H 921 3 S 975 4 s 922 4 , 976 922 4 1l 1 \ 976 11 1 923 3 CH2 aN 977 3 CH2 CF3 » H 924 4978 4 925 3 S 979 3 S MeS 926 4 t 980 4 927 3 CHz o 981 3 CH2 928 4 982 4 929 3 S Me 983 3 S MeO 930 4 984 4 931 3 CH2 985 3 CH2 932 4 986 4 TABLE 6 Example n X Example n X R No No 987 3 S 1044 3 S 988 4 1045 4 989 3 CH2 N 1046 3 CH2 N A 990 4 1047 4 991 4 S 1048 3 S 992 1049 4 993 3 CH2 N 1050 3 CHEZ'N 994 41051 40 995 3 S, +$ 1052 3 S 996 4 1053 4 N N 997 3 Chez"1054 3 CH2 H 998 4 1055 4 999 3 S 1056 3 S Fa 1000 4 1001 3 CH2 H CH2 N 1002 41057 4 1003 3 S O2Nsyz 1058 3 S 1004 4 1059 4 1005 3 CH2 N 1060 3 CH2 OaN N 1006 4 H 1061 4 H 1007 3 S 1062 3 S 1008 4 1063 4 1009 3 CHZ 1064 3 CH2/vH) \ 1010 4 N 1065 4 H 1011 3 S 1066 3 S 1012 4 1067 4 1013 3 CHZ 1068 3 CHZ o 1014 4,, 6NA 1069 4 H 1015 3 S 1070 3 S 1016 4 1071 4 1017 3 CH2 c N 1072 3 CH2 ff 1 1018 4 1073 4 ci H 1019 3 S ci 1074 3 S 1020 4 1l 1 \ 1075 4 1021 3 CHz ci N 1076 3 CH2 Cl NA 1022 4 H 1077-4 H 1023 3 S ro 1078 3 S 1024 4 1079 4 1025 3 CH2 1080 3 CH2 1026 4 N 1081 4 H 1027 3 S CFz°o 1082 3 S 1028----3 1083 4 1029 3 CH2 NA 1084 3 CH2 N 1030 41085 4 1031 3 S 1086 3 s 1032 4 A 1087 4 1033 3 CH,,, aN 1088 3 CH2 CF3 » NA 1034 41089 4 1035 3 S 1035 3 S 1090 3 S MeS 1036 4 1091 4 1037 3 CH2 0 1092 3 CH2 1038 4 1093 4 1039 3 S Me 1094 3 S MeO 1040 4 1095 4 1041 3 CH2 1096 3 CH2 1042 4 1097 4 TABLE 7 Example n X R Example N X R No No 1098 3 S/-0 1145 3 S 1099 4 ° 1146 4 1100 3 CH2 X 1147 3 CH2 ci 1101 4 N 1148 4 H 1102 3 S 1149 3 S 1103 4 1150 4 1104 3 CH2 < 2 1151 3 CH2 N 1105 4 Cl H 1152 4 1106 3 S F 1153 3 S 1107 4 1154 4 -N N 1108 3 CH2 H 1155 3 CH2 H 1109 4 1156 4 1110 3 S/% 1157 3 S i 1112 3 CHZ N CH2 F H 1113 4 l 1158 4 H 1113 41158 4 1114 3 S 1159 3 S 1115 4 116, 4 1116 3 CH2 N N 1117 4 H 1162 4 1118 3 S 1163 3 S 1119 4 S ß 1163 3 S < 1120 3 CH2 N 1165 3 CH2 N 1121 H 1166 4 F H 1122 3 S ro 1167 3 S cl 1123 4 0 1168 4 1124 3 CH2 ll l 1169 3 2 NA 1125 4 N 1170 4 J 1125a 3 S 1171 3 S 1126 4 ci 1172 4 1127 3 CH2 N-A 1173 3 CH2 1128 4 H 1174 4 0 1129 T S1175 3S ! o. 1130 4 S J 1176 4 1131 3 CH2 o N N 1177 3 z z H CHZ 1132 4 1178 4 1133 3 S 1179 3 s 1134 z 1180 4 1135 3 CH2 f sHK 1181 3 CH2 N 4 o° 1182 4 1136 1137 3 S 1183 3 S 1136 4 C H 2 f H 1164 4 CH 2 WHA 1138 4 1186 4 1139 3 CHAN 1185 3 CHF H n 1140 4-1186 4- 1141 3 S c- 1142 1143 3 CHz ci 1144 4 TABLE 8 Example n X Example n X R No No 1187 3 S | ro 1235 3 s ci 1188 4 0 1236 4 1189 3 CH2 11 l 1237 3 CH2 Cl NA 1190 4 aNA 1238 4 H 1191 3 S 1239 3 S 1192 4 1240 4 1 1193 3 CH2 cl"6 1241 3 CH2 NA 1194 4 Cl N 1242 4 H 1195 3 S F 1243 3 s 02N 1196 4 1244 4 ) aNl\ 1197 3 CHZ H 1245 3 CH2 H 1198 4 1246 4 1199 3 S 1247 3 S 1200 4 1201 3 CH N CH F 1202 41248 4 1203 3 S 1249 3 s 1204 4 1l l 1250 4 NA 1205 3 CH2 own N 1251 3 CH2 tNA 1206 4 1252 4 ci 1207 3 S 1253 3 S 1208 4 X t 2 1254 4 1209 3 CH2 N 1255 3 CH2 NA 1210 4 Cl 1256 4F 1211 3 S/-0 1257 3 S 1212 4 O 6 1258 4 1 1213 3 CH2 X 1259 3 CH2 N 1214 4 N 1260 4 H J 1215 3 S 1261 3 s 1216 4 ci 1262 4 _ s"v A 1217 3 CH2 2 NA 1218 4 T H 1264 4 l _/° 1219 3 S 1265 3 s 1220 4 1266 4 1220 4 1l 1 \ 1266 4 1221 3 CH2 OZN N 1267 3 CH2 NA 1222 4 1268 4 1223 3 S 1269 3 S 1224 4 1270 4 1225 3 CH2 \HA 1271 3 CH2 N 1226 4 1272 4 1227 3 S 1273 3 s 1228 4 1l tNA 1274 4 1229 3 CH2 f H 1275 3 CH2 CLNI\ 1230 4 1276 4 1231 3 S 1232 1 A 1233 3 CHZ ci 1235 4 EXAMPLE 1277 1-[2-(S)-Amino-4-(cyclohexylmethylamino)butanoyl]thiomorphol ine dihydrochloride A. 1-12- (S)-N- (tert-Butyloxycarbonyl) amino-4- (9- fluorenylmethyloxycarbonylamino)-butanoyl] thiomorpholine<BR> 1- [2- (S)-N- (tert-Butyloxycarbonyl) amino-4- (9-fluorenylmethyloxycarbonylamino)- butanoic acid (1. 0g, 2. 27mmol) was dissolved in CH2CI2/DMF (9: 1,20mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (461 mg, 3.41 mmol), water- soluble carbodiimide (521 mg, 2. 72mol), thiomorpholine (281mg, 2. 72mmol) and triethylamine (340mg, 3. 4mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0.3M KHS04 (2 x 25mL), sat. NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a white solid identified as 1- [2- (S)-N- (tert-butyloxycarbonyl) amino- 4- (9- fluorenylmethyloxycarbonylamino)-butanoyl] thiomorpholine (516mg, 0. 98mmol, 43%).

B. 1- [2- (S)-N- (tert-Butyloxycarbonyl)-4-amino)-butanoyl] thiomorpholine 1- [2- (S)-N- (tert-Butyloxycarbonyl) amino- 4- (9-fluorenylmethyloxycarbonylamino)- butanoyl thiomorpholine (500mg, 0. 95mmol) was dissolved in tetrahydrofuran (20mL).

Diethylamine (5mL) was added. After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 1- [2- (S)-N- (tert-butyloxycarbonyl)-4-amino)-butanoyl] thiomorpholine (162mg, 0. 54mmol, 56%).

C. 1- [2- (S)-N- (tert-Butyloxycarbonyl)-amino-4- (cyclohexylmethylamino) butanoyl] thiomorpholine 1- [2- (S)-N- (tert-Butyloxycarbonyl)-4-amino)-butanoyl] thiomorpholine (41mg, 0. 135mmol) was dissolved in dichloroethane (10mL). To this solution was added cyclohexanecarboxaldehyde (15mg, 0. 135mmol). After 30mins sodium triacetoxyborohydride (32mg, 0. 15mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL).

This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1 % acetic acid, 9% methanol, 90% chloroform) to give a colourless oil identified as 1- [2- (S)-N- (tert-butyloxycarbonyl)-amino-4- (cyclohexylmethylamino) butanoyl] thiomorpholine (25mg, 0. 063mol, 47%).

D. 1- [2- (S)-Amino-4- (cyclohexylmethylamino) butanoyl] thiomorpholine dihydrochloride 1- [2- (S)-N- (tert-Butyloxycarbonyl)-amino-4- (cyclohexylmethylamino) butanoyl] thiomorpholine (25mg, 0. 063mol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1- [2- (S)-amino-4- (cyclohexylmethylamino) butanoyl] thiomorpholine dihydrochloride (23mg, 0. 063mol, 100%).

[M+H] + = 300. 3 EXAMPLE 1278 1-12-(S)-Amino-4-((quinolin-2-ylmethyl) amino) butanoyllthiomorpholine dihydrochloride A. 1-[2-(S)-N-(tert-Butyloxycarbonyl)-amino-4-((quinolin-2- ylmethyl) amino) butanoyl thiomorpholine 1- [2- (S)-N- (tert-Butyloxycarbonyl)-4-amino)-butanoyl] thiomorpholine (41 mg, 0. 135mmol) was dissolved in 1, 2-dichloroethane (10mL). To this solution was added 2-quinolinecarboxaldehyde (32mg, 0. 15mmol). After 30mins sodium triacetoxyborohydride (36mg, 0. 17mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL).

This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1 % acetic acid, 9% methanol, 90% chloroform) to give a colourless oil identified as 1-[2-(S)-N-(tert-Butyloxycarbonyl)-amino-4-((quinolin- 2-ylmethyl) amino) butanoyl thiomorpholine (32mg, 0. 072mol, 53%).

B. 1-[2-(S)-Amino-4-((quinolin-2-ylmethyl) amino) butanoyl] thiomorpholine dihydrochloride 1- [2- (S)-N- (tert-Butyloxycarbonyl)-amino-4- ( (quinolin-2-ylmethyl) amino) butanoyl] thiomorpholine (12mg, 0. 027mol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1-[2-(S)-amino-4-((quinolin-2- ylmethyl) amino) butanoyl] thiomorpholine dihydrochloride (11. 3mg, 0. 027mol, 100%).

[M+HF= 345. 3 EXAMPLE 1279 <BR> <BR> <BR> 1-12- (S)-Amino-4- (cyclohexylmethylamino) butanoyllpiperldine dihydrochloride A. 1- [2- (S)-N- (tert-Butyloxycarbonyl) amino-4- (9- fluorenylmethyloxycarbonylamino)-butanoyl] piperidine 1-[2-(S)-N-(tert-Butyloxycarbonyl)amino-4-(9-fluoroenylmethy loxycarbonylamino)- butanoic acid (947mg, 2. 154mmol) was dissolved in CH2CI2/DMF (9: 1, 20mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (436mg, 3. 2mmol), water- soluble carbodiimide (495g, 2. 58mmol), piperidine (220g, 2. 58mmol) and triethylamine (320mg, 3. 2mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0.3M KHS04 (2 x 25mL), sat. NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a white solid identified as 1- [2- (S)-N- (tert-butyloxycarbonyl) amino- 4- (9- fluorenylmethyloxycarbonylamino)-butanoyl] piperidine (556mg, 1. 1 mol, 51 B. 1- [2- (S)-N- (tert-Butyloxycarbonyl)-4-amino)-butanoyl] piperidine <BR> <BR> <BR> <BR> 1- [2- (S)-N- (tert-Butyloxycarbonyl) amino- 4- (9-fluorenylmethyloxycarbonylamino)- butanoyl] piperidine (540g, 1. 1mmol) was dissolved in tetrahydrofuran (20mL).

Diethylamine (5mL) was added. After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 1-[2-(S)-N-(tert-butyloxycarbonyl)-4-amino)-butanoyl] piperidine (171mg, 0. 6mmol, 57%).

C. 1- [2- (S)-N- (tert-Butyloxycarbonyl)-amino-4- (cyclohexylmethylamino) butanoyl] piperidine 1- [2- (S)-N- (tert-Butyloxycarbonyl)-4-amino)-butanoyl] piperidine (43mg, 0. 15mmol) was dissolved in 1, 2-dichloroethane (20mL). To this solution was added cyclohexanecarboxaldehyde (17mg, 0. 15mmol). After 30mins sodium triacetoxyborohydride (36mg, 0. 17mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL).

This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1% acetic acid, 9% methanol, 90% chloroform) to give a colourless oil identified as 1- [2- (S)-N- (tert-butyloxycarbonyl)-amino-4- (cyclohexylmethylamino) butanoyl] piperidine (38mg, 0. 1mmol, 66%).

D. 1- [2- (S)-Amino-4- (cyclohexylmethylamino) butanoyl] piperidine dihydrochloride 1- [2- (S)-N- (tert-Butyloxycarbonyl)-amino-4- (cyclohexylmethylamino) butanoyl] piperidine (38mg, 0. 1mmol) was dissolved in 4M HCI/dioxan (2mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1- [2- (S)-amino-4- (cyclohexylmethylamino) butanoyl] piperidine dihydrochloride (33mg, 0. 093mmol, 93%).

[M+H] + = 282.3 EXAMPLE 1280 1-[2-(S)-Amino-4-((quinolin-2-ylmethyl) amino) butanoyllpiperidine dihydrochloride A. 1-[2-(S)-N-(teff-Butyloxywarbonyl)-amino-4-((quinolin-2- ylmethyl) amino) butanoyl piperidine 1-[2-(S)-N-(tert-Butyloxycarbonyl)-4-amino)-butanoyl] piperidine (24mg, 0. 15mmol) was dissolved in 1, 2-dichloroethane (25mL). To this solution was added 2- quinolinecarboxaldehyde (24mg, 0. 15mmol). After 30mins sodium triacetoxyborohydride (36mg, 0. 17mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL).

This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1% acetic acid, 9% methanol, 90% chloroform) to give a colourless oil identified as 1-[2-(S)-N-(tert-butyloxycarbonyl)-amino-4-((quinolin- 2-ylmethyl) amino) butanoyl] piperidine (35mg, 0. 082mol, 55%).

B. 1-[2-(S)-Amino-4-((quinolin-2-ylmethyl) amino) butanoyl piperidine dihydrochloride 1-[2-(S)-N-(tert-ButyloxyCarbonyl)-amino-4-((quinolin-2-ylme thyl) amino) butanoyl] piperidine (35mg, 0. 082mol) was dissolved in 4M HCI/dioxan (2mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1-[2-(S)-amino-4-((quinolin-2- ylmethyl) amino) butanoyl] piperidine dihydrochloride (26mg, 0. 065mol, 79%).

[M+H] + = 327. 3 EXAMPLE 1281 3-FluoroS 2-(S)-amino-4-(cyclohexenylmethylamino) butanoyllpyrrolidine dihydrochloride A. 1- (tert-Butyloxycarbonyl)-3-fluoropyrrolidine N- (tert-Butyloxycarbonyl)-3-hydroxypyrrolidine (21. Og, 10. 7mmol) was dissolved in CH2CI2 (30ml). (Diethylamino) sulphur trifluoride (1.72g, 10. 7mmol) was added to this solution at-78 °C. The mixture was stirred for 18 hours at-78 °C to room temperature then the reaction mixture was carefully poured into sat. NaHCO3 (100mi) and stirred for 15min and extracted with CH2CI2. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated in vacuo to give an orange oil. The residue was purified by flash chromatography (eluant : 28% ethyl acetate, 72% pet. ether 60-80) to give a colourless oil identified as 1- (tert-butyloxycarbonyl)-3-fluoropyrrolidine (1.14g, 5. 34mmol, 50%).

B 3-Fluoropyrrolidine hydrochloride 1- (tert-Butyloxycarbonyl)-3-fluoropyrrolidine (1.14g, 5. 34mmol) was dissolved in 4M HCI/dioxan (30ml). The mixture was stirred for 1 hour at room temperature then the solvent was removed in vacuo to give an off-white solid identified as 3-fluoropyrrolidine hydrochloride (640mg, 5. 2mmol, 95%).

C. 3-Fluoro-1- [2- (S)-N- (fert-butyloxycarbonyl) amino-4- (9- fluorenylmethyloxycarbonylamino)-butanoyl] pyrrolidine 1- [2- (S)-N- (tert-Butyloxycarbonyl) amino-4- (9-fluorenylmethyloxycarbonylamino)- butanoic acid (950mg, 2. 15mmol) was dissolved in CH2CI2/DMF (9: 1,20mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (395mg, 2. 6mmol), water- soluble carbodiimide (572mg, 3. 0mmol), 3-fluoropyrrolidine hydrochloride (270g, 2. 15mmol) and triethylamine (320mg, 3. 2mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0.3M KHS04 (2 x 25mL), sat. NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a white solid identified as 3-fluoro1-[2-(S)-N-(tert- butyloxycarbonyl) amino- 4- (9-fluorenylmethyloxycarbonylamino)-butanoyl] pyrrolidine (808mg, 1. 58mmol, 73%).

D. 3-Fluoro-1- [2- (S)-N- (tert-butyloxycarbonyl)-4-amino)-butanoyl] pyrrolidine <BR> <BR> <BR> 3-Fluoro-1- [2- (S)-N- (tert-butyloxycarbonyl) amino- 4- (9- fluorenylmethyloxycarbonylamino)-butanoyl] pyrrolidine (800mg ; 1. 58mmol) was dissolved in tetrahydrofuran (20mL). Diethylamine (5mL) was added. After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 3-fluoro-1-[2-(S)-N-(tert- butyloxycarbonyl)-4-amino)-butanoyl] pyrrolidine (316mg, 1. 04mmol, 66%).

E. 3-Fluoro-1-[2-(S)-N-(tert-butyloxywarbonyl)-amino-4- (cyclohexenylmethylamino) butanoyl] pyrrolidine 3-Fluoro-1- [2- (S)-N- (fert-butyloxycarbonyl)-4-amino)-butanoyl] pyrrolidine (150mg, 0. 52mmol) was dissolved in methanol (20mL). To this solution was added 3- cyclohexenecarboxaldehyde (63mg, 0. 57mmol). After 30mins sodium triacetoxyborohydride (220mg, 1. 04mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL).

This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1% acetic acid, 9% methanol, 90% chloroform) to give a colourless oil identified as 3-fluoro-1- [2- (S)-N- (tert-butyloxycarbonyl)-amino-4- (cyclohexenylmethylamino) butanoyl] pyrrolidine (176mg, 0. 46mmol, 77%).

F. 3-Fluoro-1-12-(S)-amino-4-(cyclohexenylmethylamino) butanoyl] pyrrolidine dihydrochloride 3-Fluoro-1- [2- (S)-N- (tert-butyloxycarbonyl)-amino-4- (cyclohexenylmethylamino) butanoyl] pyrrolidine (176mg, 0. 46mmol) was dissolved in 4M HCI/dioxan (2mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 3- <BR> <BR> <BR> fluoro-1-[2-(S)-amino-4-(cyclohexenylmethylamino) butanoyl] pyrrolidine dihydrochloride (140mg, 0. 39mmol, 963%).

[M+H] + = 284.3 EXAMPLE 1282 1- [2- (S)-Amino-4- (N-methyl-N- (2-methylbenzyl) amino) butanoyl] piperidine dihydrochloride A. N- (tert-Butyloxycarbonyl)-L-homoserine lactone L-Homoserine lactone 1.76g, 12. 8mmol) was dissolved in DMF (30 mL). This solution was cooled to 0 °C, triethylamine (1.41, 14.1 mmol) di-tert-butyl dicarbonate (3.35g, 15.35 mmol) was added. After 18 hours at room temperature the solvent was evaporated in vacuo, the residue was taken up in dichloromethane (200 mL). This solution was washed with 1M KHS04 (2 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo to give a white solid, recrystallised from EtOAc/pet. ether to give a white solid identified as N- (tert-butyloxycarbonyl)-L-homoserine lactone (2.25mg, 11. 2mmol, 87%).

B. 1- [2- (S)- (N- (tert-Butyloxycarbonyl) amino)-4-hydroxybutanoyl] piperidine N- (tert-Butyloxycarbonyl)-L-homoserine lactone (100mg, 0. 5mmol) was dissolved in tetrahydrofuran (30 mL). Piperidine (42mg, 0. 5mmol) was added. After 72 hours at room temperature the reaction mixture was diluted with ethyl acetate (150 mL). This solution was washed with water (1 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil identified as 1- [2- (S)- (N- (tert- butyloxycarbonyl) amino)-4-hydroxybutanoyl] piperidine (142mg, 0. 5mmol, 100%).

C. 1- [2- (S)- (N- (tert-Butyloxycarbonyl) amino)-4-oxobutanoyl] piperidine 1- [2- (S)- (N- (tert-Butyloxycarbonyl) amino)-4-hydroxybutanoyl] piperidine (142mg, 0. 5mmol) was dissolved in dichloromethane (50 mL). Dess-Martin periodinane (232mg, 0. 5mmol) was added. After 1 hour at room temperature the reaction mixture was diluted with ethyl acetate (150 mL). This solution was washed with water (1 x 20ml) and brine (1 x 20mi), dried (Na2SO4) and evaporated in vacuo to give a colourless oil.

Purified by flash chromatography on silica gel (eluant : 50% ethyl acetate, 50% pet. ether 60-80) to give a colourless oil identified as 1- [2- (S)- (N- (tert- butyloxycarbonyl) amino)-4-oxobutanoyl] piperidine (40mg, 0. 14mmol, 27%).

D. 1- [2- (S)- (N- (tert-butyloxycarbonyl) amino-4- (N-methyl-N- (2- methylbenzyl) amino) butanoyl] piperidine 1- [2- (S)- (N- (tert-Butyloxycarbonyl) amino)-4-oxobutanoyl] piperidine (40mg, 14mmol) was dissolved in methanol (20mL). To this solution was added N-methyl-2- methylbenzylamine (19mg, 0. 14mmol). After 2 hours sodium triacetoxyborohydride (64mg, 0. 3mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel to give a colourless oil identified as 1- [2- (S)- (N- (tert-butyloxycarbonyl) amino-4- (N- methyl-N- (2-methylbenzyl) amino) butanoyl] piperidine (36mg, 0. 09mmol, 64%).

E. 1- [2- (S)-Amino-4- (N-methyl-N- (2-methylbenzyl) amino) butanoyl piperidine dihydrochloride 1- [2- (S)- (N- (tert-Butyloxycarbonyl) amino-4- (N-methyl-N- (2-methylbenzyl) amino) butanoyl] piperidine (36mg, 0. 09mmol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a pale brown solid identified as 1- [2- (S)-amino-4- (N- methyl-N- (2-methylbenzyl) amino) butanoyl] piperidine dihydrochloride (43mg, 0. 09mmol, 100%) EXAMPLE 1283 1- [N- (2"- (Cyclohexylmethylaminoethyl) glycinyl)] thiomorpholine dihydrochloride A. 1- [N-2'- (tert-Butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)-glycinyl] thiomorpholine N-2'- (tert-Butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)-glycine (2.5g, 5. 7mmol) was dissolved in CH2CI2/DMF (9: 1, 100mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (833mg, 6. 3mmol), water-soluble carbodiimide (974mg, 6. 3mmol), thiomorpholine (617mg, 6. Ommol) and N- methylmorpholine (800mg, 8mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0.3M KHS04 (2 x 25mL), sat. NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a white solid identified as 1- [N-2'- (tert-butyloxycarbonyl)-N- (2"- (9- fluorenylmethyloxycarbonyl aminoethyl)-glycinyl] thiomorpholine (2.7g, 5. 1mmol, 90%).

B. 1- [N-2'- (tert-Butyloxycarbonyl)- (2"-aminoethyl)-glycinyl] thiomorpholine 1- [N-2'- (tert-Butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)- glycinyl] thiomorpholine (2.7g, 5. 1 mmol) was dissolved in tetrahydrofuran (20mL).

Diethylamine (5mL) was added. After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 1- [N-2'- (tert-butyloxycarbonyl)- (2"-aminoethyl)-glycinyl] thiomorpholine (1.44g, 4. 7mmol, 92%).

C. 1- [2'-N- (tert-Butyloxycarbonyl N- (2"- (cyclohexylmethylaminoethyl)-glycinyl] thiomorpholine 1- [N-2'- (tert-Butyloxycarbonyl)- (2"-aminoethyl)-glycinyl] thiomorpholine (100mg, 0. 3mmol) was dissolved in methanol (25mL). To this solution was added cyclohexanecarboxaldehyde (34mg, 0. 3mmol). After 30mins sodium triacetoxyborohydride (126mg, 0. 6mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL).

This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1 % acetic acid, 9% methanol, 90% chloroform) to give a colourless oil identified as 1- [2'-N- (tert-Butyloxycarbonyl N (2"- (cyclohexylmethylaminoethyl)-glycinyl] thiomorpholine (33mg, 0. 08mmol, 27%).

D. 1- [N- (2"- (Cyclohexylmethylaminoethyl) glycinyl)] thiomorpholine dihydrochloride 1- [2'-N- (tert-Butyloxycarbonyl-N (2"- (cyclohexylmethylaminoethyl)-glycinyl] thiomorpholine (33mg, 0. 081 mmol) was dissolved in 4M HCI/dioxan (20mL). After 1 h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1- [N- (2"- (cyclohexylmethylaminoethyl) glycinyl)] thiomorpholine dihydrochloride (31 mg, 0. 08mmol, 100%).

[M+H] + = 300. 3 EXAMPLE 1284 <BR> <BR> <BR> 1- [N- (2"- ( (Quinolin-2-ylmethyl) aminoethyl) glycinyl)] pyrrolidine dihydrochloride A. 1- [N-2'- (tert-Butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)-glycinyl] piperidine <BR> <BR> <BR> N-2'- (tert-Butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)-glycine (2.5g, 5. 7mmol) was dissolved in CH2CI2/DMF (9: 1, 100mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (1.5g, 11. lmmol), water-soluble carbodiimide (1.3g, 6. 8mmol), piperidine (484mg, 5. 69mmol) and N-methylmorpholine (800mg, 8mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0.3M KHS04 (2 x 25mL), sat. NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a white solid identified as 1- [N-2'- (tert-butyloxycarbonyl)-N- (2"- (9- fluorenylmethyloxycarbonyl aminoethyl)-glycinyl] piperidine (2.8g, 5. 5mmol, 96%).

B. 1- [N-2'- (tert-Butyloxycarbonyl)- (2"-aminoethyl)-glycinyl] piperidine 1- [N-2'- (tert-Butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)- glycinyl] piperidine (2. 8g, 5. 5mmol) was dissolved in tetrahydrofuran (20mL).

Diethylamine (5mL) was added. After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 1- [N-2'- (tert-butyloxycarbonyl)- (2"-aminoethyl)-glycinyl] piperidine (1.4g, 4. 9mmol, 89%).

C. 1- [2'-N- (tert-Butyloxycarbonyl N- (2"- ( (quinolin-2-ylmethyl) aminoethyl)- glycinyl] piperidine 1- [N-2'- (tert-Butyloxycarbonyl)- (2"-aminoethyl)-glycinyl] piperidine was dissolved in methanol (25mL). To this solution was added 2-quinolinecarboxaldehyde. After 30mins sodium triacetoxyborohydride was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL).

This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 1% acetic acid, 9% methanol, 90% chloroform) to give a colourless oil identified as 1- [2'-N- (tert-butyloxycarbonyl N (2"- ( (quinolin-2- ylmethyl) aminoethyl)-glycinyl] piperidine.

D. 1- [N- (2"- ( (Quinolin-2-ylmethyl) aminoethyl) glycinyl)] piperidine dihydrochloride 1- [2'-N- (tert-Butyloxycarbonyl-N (2"- ( (quinolin-2-ylmethyl) aminoethyl)-glycinyl] piperidine was dissolved in 4M HCI/dioxan (20mL). After 1 h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1- [N- (2"- ( (quinolin-2-ylmethyl) aminoethyl) glycinyl)] piperidine dihydrochloride.

EXAMPLE 1285 <BR> <BR> <BR> 1- [N, N- (2", 2"- ( (Dicinnamyl) aminoethyl) glycinyl)] thiomorpholine dihydrochloride A. 1- [2'-N- (tert-Butyloxycarbonyl N, N- (2", 2"- ( (dicinnamyl) aminoethyl)-glycinyl] thiomorpholine (2S)-1- (N"- (tert-Butyloxycarbonyl)-L-lysinyl)-pyrrolidine-2-carbonitril e (250mg, 0. 83mmol) was dissolved in dichloroethane (25mL). To this solution was added trans- cinnamaldehyde (108mg, 0. 83mmol). After 30mins sodium triacetoxyborohydride (350mg, 1. 6mmol) was added. After 18h at room temperature the solvent was removed in vacuo and the residue was taken up in chloroform (70mL). This solution was washed with water (2 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography on silica gel (eluant : 2% methanol, 98% chloroform) to give a colourless oil identified as 1- [2'-N- (tert-butyloxycarbonyl N, N- (2", 2"- ((dicinnamyl) aminoethyl)-glycinyl] thiomorpholine. Further elution with 9% methanol, 90% chloroform and 1% acetic acid gave a colourless oil identified as 1- [2'-N- (tert- butyloxycarbonyl N,- (2"- ( (cinnamyl) aminoethyl)-glycinyl] thiomorpholine (180mg, 0. 43mmol, 52%) B. 1- [N, N- (2--, 2"- ( (Dicinnamyl) aminoethyl) glycinyl)] thiomorpholine dihydrochloride 1- [2'-N- (tert-Butyloxycarbonyl N, N- (2", 2"- ( (dicinnamyl) aminoethyl)-glycinyl] thiomorpholine was dissolved in 4M HCI/dioxan (20mL). After 1 h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1- [N, N- (2", 2"- ( (dicinnamyl) aminoethyl) glycinyl)] thiomorpholine dihydrochloride.

EXAMPLE 1286 1- [N- (2"- ( (Cinnamyl) aminoethyl) glycinyl)] thiomorpholine dihydrochloride A. 1-[N-(2''-((Cinnamyl)aminoethyl)glycinyl)]thiomorpholine dihydrochloride 1- [2'-N- (tert-Butyloxycarbonyl N- (2"- ( (cinnamyl) aminoethyl)-glycinyl] thiomorpholine (180mg, 0. 43mmol) was dissolved in 4M HCI/dioxan (20mL). After 1h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a white solid identified as 1- [N- (2"- ( (cinnamyl) aminoethyl) glycinyl)] thiomorpholine dihydrochloride (168mg, 0. 43mmol, 100%).

[M+H] + = 320.3 EXAMPLE 1287 3, 3-Difluoro-1- [N-2"- (3'-trifluoromethylanilino) pyridyl-3-carbonyl aminoethyl) glycinyl)] pyrrolidine dihydrochloride A. 3, 3-Difluoro-l- [N-2'- (tert-butyloxycarbonyl)-N- (2"- (9- fluorenylmethyloxycarbonyl aminoethyl)-glycinyl] pyrrolidine <BR> <BR> <BR> N-2'- (tert-Butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)-glycine (1. 0g, 2. 27mmol) was dissolved in CH2CI2/DMF (9: 1, 100mL). To this solution at 0°C were added 1-hydroxybenzotriazole hydrate (620mg, 4. 6mmol), water-soluble carbodiimide (560mg, 2. 8mmol), 3, 3-difluoropyrrolidine hydrochloride (360mg, 2. 5mmol) and N-methylmorpholine (800mg, 8mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (100mL). The solution was washed with 0.3M KHS04 (2 x 25mL), sat.

NaHCO3 (2 x 25mL), water (2 x 25mL) and brine (1 x 25mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 60% ethyl acetate, 40% pet. ether) to give a white solid identified as 3,3- difluoro-1- [N-2'- (fert-butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)-glycinyl] pyrrolidine (934g, 1. 7mmol, 77%).

B. 3, 3-Difluoro-1- [N-2'- (tert-butyloxycarbonyl) aminoethyl)-glycinyl] pyrrolidine 3, 3-Difluoro-1- [N-2'- (tert-butyloxycarbonyl)-N- (2"- (9-fluorenylmethyloxycarbonyl aminoethyl)-glycinyl] pyrrolidine (890g, 1. 68mmol) was dissolved in tetrahydrofuran (20mL). Diethylamine (5mL) was added. After 90min at room temperature the solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (eluant : 90% chloroform, 7% methanol, 3% triethylamine) to give a pale yellow oil identified as 3, 3-difluoro-1- [N-2'- (tert-butyloxycarbonyl) aminoethyl)-glycinyl] pyrrolidine (470mg, 1. 5mmol, 91%).

C. 3, 3-Difluoro-1- [ N-2'- (tert-butyloxycarbonyl)-N-2"- (3'- trifluoromethylanilino) pyridyl-3-carbonyl aminoethyl) glycinyl)] pyrrolidine 3, 3-Difluoro-1- [N-2'- (tert-butyloxycarbonyl) aminoethyl)-glycinyl] pyrrolidine (50mg, 0. 16mmol) was dissolved in CH2CI2/DMF (9: 1,20mL). To this solution at 0°C was added 1-hydroxybenzotriazole hydrate (46mg, 0. 34mmol), water-soluble carbodiimide (40mg, 0. 2mmol), niflumic acid (49mg, 0. 17mmol) and N-methylmorpholine (40mg, 0. 4mmol). After 18h at 0°C to room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70mL). The solution was washed with 0.3M KHS04 (1 x 20mL), sat. NaHCO3 (1 x 20mL), water (1 x 20mL) and brine (1 x 20mL), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant : 75% ethyl acetate, 25% pet. ether) to give a yellow oil identified as 3, 3-difluoro-1- [N-2'- (tert-butyloxycarbonyl)-N-2"- (3'- trifluoromethylanilino) pyridyl-3-carbonyl aminoethyl) glycinyl)] pyrrolidine (63mg, 0. 11 mmol, 67%).

D. 3, 3-Difluoro-1- [N-2"- (3'-trifluoromethylanilino) pyridyl-3-carbonyl aminoethyl) glycinyl)] pyrrolidine dihydrochloride 3, 3-Difluoro-1- [N-2'- (tert-butyloxycarbonyl)-N-2"- (3'-trifluoromethylanilino) pyridyl-3- carbonyl aminoethyl) glycinyl)] pyrrolidine (55mg, 0. 10mmol) was dissolved in 4M HCI/dioxan (20mL). After 1 h at room temperature the solvent was removed in vacuo. The residue was lyophilised from water to give a pale brown solid identified as 3,3- difluoro-1- [N-2"- (3'-trifluoromethylanilino) pyridyl-3-carbonyl aminoethyl) glycinyl)] pyrrolidine dihydrochloride (52mg, 0. 10mmol, 100%).

[M+H] + = 472.3 EXAMPLE 1288 3, 3-Difluoro- [N-2"- (6-Chloro-4- (4'-fluoroanilino)-1, 3, 5-triazinyl) aminoethyl) glycinyl) lthiomorpholine dihydrochloride A. 4, 6-Dichloro-2- (4'-fluoroanilino)-1, 3, 5-triazine Cyanuric chloride (1.844g, 10mmol) was dissolved in acetonitrile (20mL). The solution was cooled to-20 °C. A solution of 4-fluoroaniline (1. 1g, 10mmol) and triethylamine (1. 0g, 10mmol) was slowly added. After 1 hour at-20 °C the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150mL). The solution was washed with water (1 x 50mL) and brine (1 x 50mL), dried (Na2SO4) and evaporated in vacuo. The residue was recrystallised from ethyl acetate/hexane to give an off white solid identified as 4, 6-dichloro-2- (4'-fluoroanilino)-1, 3,5-triazine 1.7g, 6. Ommol, 60%).

B. 1- [N-2'- (tert-butyloxycarbonyl)-N-2"- (6-Chloro-4- (4'-fluoroanilino)-1, 3,5- triazinyl aminoethyl) glycinyl)] thiomorpholine 1- [N-2'- (tert-butyloxycarbonyl) aminoethyl)-glycinyl] thiomorpholine (100mg, 0. 3mmol) was dissolved in dichloromethane (30mL). To this solution was added 4, 6-dichloro-2- (4'-fluoroanilino)-1, 3,5-triazine (90mg, 0. 3mmol) and triethylamine (50mg, 0. 5mmol).

After 2 hours at room temperature the solvent was removed in vacuo and the residue was taken up in ethyl acetate (150mL). This solution was washed with water (2 x 30mL) and brine (1 x 30mL), dried (Na2SO4) and evaporated in vacuo to give a yellow oil. The residue was purified by flash chromatography (eluant : 60% ethyl acetate, 40% pet. ether) to give a white solid identified as 1- [N-2'- (tert-butyloxycarbonyl)-N-2"- (6- chloro-4- (4'-fluoroanilino)-1, 3, 5-triazinyl aminoethyl) glycinyl)] thiomorpholine (20mg, 0. 032mol, 11 %).

C. 1- [N-2"- (6-Chloro-4- (4'-fluoroanilino)-1, 3, 5-triazinyl) aminoethyl) glycinyl) thiomorpholine dihydrochloride 1- [N-2'- (tert-butyloxycarbonyl)-N-2"- (6-chloro-4- (4'-fluoroanilino)-1, 3, 5-triazinyl aminoethyl) glycinyl)] thiomorpholine (18.8mg, 0. 03mmol) was dissolved in 4M HCI/dioxan (20mL). After 1 h at room temperature the solvent was removed in vacuo.

The residue was lyophilised from water to give a white solid identified as 1- [N-2"- (6- Chloro-4- (4'-fluoroanilino)-1, 3, 5-triazinyl) aminoethyl) glycinyl)] thiomorpholine dihydrochloride (18mg, 0. 03mmol, 100%).

[M+H] + = 526.4 TABLE 9 Ex No X a R 1289 S 1 \/y 1290 CF2 1291 CHF 1292 S 2 1293 CH2 1294 O 1295 S 1 1296 CF2 J 1297 CHF 1298 S 2 1299 CH2 1300 O 1311 S 1 1312 CF2 1313 CHF 1314 S 2 1315 CH2 1316 O 1317 S 1 l 1318 CF2 1319 CHF 1320 O 2 1321 S 1 1322 CF2 1323 CL-IF 1324 S 2 1325 CH2 1326 O 1327 S 1 1328 CF2 1329 CHF 1330 S 2 1331 CH2 1332 O 1333 S 1 1334 CF2 1335 CHF 1336 S 2 1337 CH2 1338 0 1339 S 1 1340 CF2 1341 CHF 1342 S 2 1343 CH2 1344 O 1345 S 1 1346 CF2 | t 1347 CHF 1348 S 2 1349 CH2 1350 O 1351 S 1 1352 CF2 1353 CHF 1354 S 2 1355 CH2 1356 0 1357 S I 1358 CF2 \ 1359 CHF 1360 S 2 1361 CH2 1362 O 1363 S 1 1364 CF2 1365 CHF 1366 S 2 1367 CH2 1368 O 1369 S 1 clou 1370 Caf2, 1371 CHF 1372 S 2 1373 CH2 1374 O 1375 S ci 1376 CF2 1377 CHF e 1378 S 2 1379 CH2 1380 1381 S 1 \ 1382 CF2 1383 CHF 1384 S 2 1385 CH2 1386 O 1387 S 1 1388 CF2 1389 CHF 1390 s 2 1391 CH2 1392 O 1393 S 1 1394 CF2 1395 CHF 1396 S 2 1397 CH2 1398 O 1399 S 1 1400 CF2 W 1401 CHF 1402 S 2 1403 CH2 1404 O 1405 S 1 1406 CF2/S/y 1407 CHF 1408 S 2 1409 CH2 1410 O 1411 S 1 1412 CF2 1413 CHF 1414 S 2 1415 CH2 1416 O 1417 S 1 1418 CF2 1419 CHF 1420 S 2 1421 CH2 1422 0 1423 S 1 1424 CF2 1425 CHF 1426 S 2- 1427 CH. JLJ 1428 O 1429 S 1 0 1430 CF. AJ 1431 CHF o 1432 S 2 1433 CH2 1434 O TABLE 10 Ex No 1614 s 1 1615 CF2 1616 S 1617 CH2 1618 S 1619 CF2 1620 S 2 1621 CH2 1622 s I 1623 CF2 1624 2 1625 CH2 1626 S 1 1627 CF2 1628 2 1629 CH2 1630 S 1 1631 c 2 1632 s 2 1633 CH2 1634 S 1 1635 CF2 1636 S 2 1637 CH2 1638 S 1 1639 CF2 1640 S 2 1641 CH2 1642 S 1 1643 CF2 1644 s 2 1645 CH2 1646 S 1647 CF2 1648 S 2 1649 CH2 1650 1651 CF2 b i 1652 S 2 1653 CH2 1654 s 1 1655 CF2 1656 S 2 1657 CH2 1658 S 1 1659 CF2 1l l 1660 S 2 cl 1661 CH2 1662 S 1 ci 1663 CF2 1664 S 2 1665 CH2 1666 S 1 Cl 1667 CF2 XY 1668 S 2 1669 CH2 1670 S 1/S 1671 CF2 1672 S 2 1673 CH2 1674 S 1 1675 CF2 1676S-2 ! 1677 CH2 1678 S 1 1679 CF2 V 1680S 2 1681 CH2 1682 S 1 1683 Caf2, 1684 S 2 1685 CH2 1686 S 1 1687 CF2 168 2 1690 CH2 1690 s 1 1691 CF2 1692 S 2 1693 CH2 1694 s I 1695 CF2 1696 S 2 1697 CH2 1698 s I 1699 COR 2 1700 S 2- 1701 CH2 1702 s 1 o 1703 CF2 1704 S 2 1705 CH2