META-BENZAMIDINE DERIVATIVES AS SERIN PROTEASE INHIBITORS

Abstract: The invention relates to serine protease inhibitor compound of formula (I), where R1 and R2 each independently is hydrogen or hydroxyl, alkoxyl, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl; each R3 independently is R1, R2, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulfonyl, alkylsulphenyl, alkylsulphonamido, alkylaminosulphonyl, haloalkoxy and haloalkyl; each X independently is C, N, O or S atom or a CO, CR1, C(R1)2 or NR1 group, at least one X being C, CO, CR1 or C(R1)2, with the proviso that if the benzamidine group is unsubstituted and the X-X group is -CH2C(R1)2-, then R1 is hydrogen or is attached to the alkylene carbon atom by a heteroatom; L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, O and S, or a branched alkyl or cyclic group; Y is a nitrogen atom or a CR1 group or Y and L taken together form a cyclic group; Cy is a saturated or unsaturated, mono or polycyclic, homo or heterocyclic group optionally subsituted by groups R3 or phenyl optionally substituted by R3; Lp is a lipophilic organic group, selected from an alkyl, heterocyclic, alkenyl, alkaryl, cycloalkyl, polycycloalkyl, cycloalkenyl, aryl, aralkyl or haloalkyl group or a combination of two or more such groups optionally substituted by one or more of oxa, oxo, aza, thio, halo, amino, hydroxy or R3 groups; D is a hydrogen bond donor group; and n is 0, 1 or 2 and salts thereof.

Description: META-BENZAMIDINE DERIVATIVES AS SERIN PROTEASE INHIBITORS This invention relates to compounds which are inhibitors of serine proteases and to pharmaceutical compositions thereof and their use m the treatment of the human or animal body. The serine proteases are a group of proteolytic enzymes which have a common catalytic mechanism characterized by a particularly reactive Ser residue. Examples of serine proteases include trypsm, tryptase, chymotrypsin, elastase, thrombm, plasmm, kallikrem, Complement Cl , acrosomal protease, lysosomal protease, cocoonase, α-lytic protease, protease A, protease B, serine carboxypeptidase II, subtilisin, urokmase, Factor Vila, Factor IXa, and Factor Xa. The serine proteases have been investigated extensively over a period of several decades and the therapeutic value of inhibitors of serine proteases is well understood. Serine protease inhibitors play a central role in the regulation of a wide variety of physiological process including coagulation, flbπnolysis, fertilization, development, malignancy, neuromuscular patterning and inflammation. It is well known that these compounds inhibit a variety of circulating proteases as well as proteases that are activated or released m tissue. It is also becoming clear that serine protease inhibitors inhibit critical cellular processes, such as adhesion, migration, free radical production and apoptosis. In addition, animal experiments indicate that intravenously administered serine protease inhibitors, variants or cells expressing serine protease inhibitors, provide a protective effect against tissue damage. Serine protease inhibitors have also been predicted to have potential beneficial uses m the treatment of disease m a wide variety of clinical areas such as oncology, neurology, haematology, pulmonary medicine, immunology, inflammation and infectious disease. In particular serine protease inhibitors may be beneficial in the treatment of thrombotic diseases, asthma, emphysema, cirrhosis, arthritis, carcinoma, melanoma, restenois, atheroma, trauma, shock and reperfusion injury. Thus for example an inhibitor of Factor Xa has value as a therapeutic agent as an anticoagulant, e.g. in the treatment and prevention of thrombotic disorders. The use of a Factor Xa inhibitor as an anticoagulant is desirable in view of the selectivity of its effect. Many clinically approved anticoagulants have been associated with adverse events owing to the non-specific nature of their effects on the coagulation cascade. Also, there are well-known associations of αl protease inhibitor deficiency with emphysema and cirrhosis and Cl esterase inhibitor deficiency with angioedema. We have now found that certain novel amidine compounds are particularly effective as inhibitors of serine proteases, especially proteases with negatively charged PI specificity pockets, and most especially the serine proteases thrombin, trypsin, urokinase and Factor Xa. Thus viewed from one aspect we provide serine protease inhibitor compounds having an m-benzamidine group and a lipophilic group coupled to a cyclic group- attached carbon or nitrogen atom (hereinafter the alpha atom) , the coupling of the m-benzamidine group to the alpha atom being by a linker group providing a two backbone atom linking chain, the backbone atoms being selected from C, N, 0 and S and at least one being C, optionally wherein one or both of the backbone atoms form part of a cyclic group and the coupling of the lipophilic group to the alpha atom being by a linker group capable of separating the alpha atom from the lipophilic group by a range of 2.3 to 6.5 A in length. In the compounds of the invention, the lipophilic group is itself optionally substituted by a hydrogen bond donor group. Where this is the case, the lipophilic group and its linker preferably are conformable to separate by from 7.5 to 15.0 A the alpha atom and the hydrogen bond donor atom of the donor group . Where distances from the alpha atom to the lipophilic group or to the hydrogen bond donor atom are mentioned, these relate to the distances between the centre of the alpha atom and the centre of the first atom of the lipophilic group or the centre of the hydrogen bond donor atom. Such distances can be calculated from crystallographic data for any given compound from the bond lengths and bond angles for individual bonds along the length of the molecule between the alpha atom and the first atom of the lipophilic group or the hydrogen bond donor atom. Similarly such distances may be calculated with reasonable accuracy from the bond lengths and bond angles known to be typical of such individual bonds . The linker between the alpha atom and the lipophilic group may itself be a lipophilic moiety, e.g. an alkylene chain. The nature of the linker may vary considerably - the primary requirement is that it be conformable to place part or all of the lipophilic group at a desired distance away from the alpha atom. The lipophilic group thus desirably is able to occupy at least part of a space 2.3 to 15.0 A from the alpha atom. The length of the linker generally corresponds to 1 to 5 backbone atoms and may be a chain, branched chain or cyclic linker (e.g. a cyclic amide or an aromatic heterocycle) . In one embodiment the alpha atom forms part of a cyclic group which also forms the linker to the lipophilic group. Thus viewed from an alternative aspect the invention provides serine protease inhibitor compounds of formula I (where R, and R 2 each independently is hydrogen or hydroxyl , alkoxy, alkyl, ammoalkyl , hydroxyalkyl alkoxyalkyl, alkoxycarbonyl , acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl; each R 3 independently is R 1( R 2 , ammo, halo, cyano, nitro, thiol , alkylthio, alkylsulphonyl , alkylsulphenyl , alkylsulphonamido, alkylaminosulphonyl, ammosulphonyl , haloalkoxy and haloalkyl; each X independently is a C, N, O or S atom or a CO, CRi, C(R ! ) 2 or NRj group, at least one X being C, CO, CR, or C(R 1 ) 2 , with the proviso that if the benzamidine group is unsubstituted (i.e. no non-hydrogen R 3 group is present) and the X-X group is -CH 2 C(R 1 ) 2 - then R λ is hydrogen or is attached to the alkylene carbon atom by a heteroatom; L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, 0 and S, or a branched alkyl or cyclic group; Y (the -atom) is a nitrogen atom or a CR-, group or Y and L taken together form a cyclic group; Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R 3 or phenyl optionally substituted by R, ; Lp is a lipophilic organic group, e.g. an alkyl, heterocyclic, alkenyl, alkaryl , cycloalkyl, polycycloalkyl, cycloalkenyl, aryl, aralkyl or haloalkyl group or a combination of two or more such groups optionally substituted by one or more of oxa, oxo, aza, thio, halo, amino, hydroxy or R 3 groups, preferably a group containing up to 25 carbon atoms ; D is a hydrogen bond donor group; and n is 0, 1 or 2) ; or a physiologically tolerable salt thereof, e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic amine such as ethylamine or meglumine . In the compounds of the invention, where the alpha atom is carbon it preferably has the conformation that would result from construction from a D- -aminoacid NH 2 - CRi (Cy) -COOH and a m-carboxyl benzamidine. Likewise the fourth substituent R λ at an alpha carbon is preferably a methyl or hydroxymethyl group or hydrogen. In compounds of formula (I) it is envisaged that the unsubstituted or substituted amidino group could be repalced by a substituted or unsubstituted aminomethyl group although an amidino derivative is preferred. In the compounds of the invention, unless otherwise indicated, aryl groups preferably contain 5 to 10 ring atoms optionally including 1, 2 or 3 heteroatoms selected from O, N and S; alkyl, alkenyl or alkynyl groups or alkylene moieties preferably contain up to 6 carbons; cyclic groups preferably have ring sizes of 3 to 8 atoms; and fused multicyclic groups preferably contain 8 to 16 ring atoms. The linker group from the benzamidine group to the alpha atom is preferably selected from -CH=CH-, -CONH-, -CONRi-, -NH-CO-, -NH-CH- 2 -, -CH 2 -NH-, -CH 2 0-, -OCH 2 -, - COO-, -OC=0- and -CH 2 CH 2 - . Preferably, the X moiety nearest to the alpha atom is an NH or O atom, most preferably a NH group. The X moiety alpha to the phenyl ] ring is preferably a carbon based group such as CH 3 or CO, preferably CO. Thus a particularly preferred linker X-X is -CONH-. The linker group from the alpha atom to the lipophilic group is preferably CO, CH 2 NH, CONRi (CH 2 ) m , (CH 2 ) m N(R 1 )CO(CH 2 ) m , (CH 2 ) m+2 , CO(CH 2 ) ra , (CH 2 ) ra CO, (CH 2 )-,OC=0, (CH 2 ) m O or CH=CH(CH 2 ) m (where each m is independently 0 or 1) . The linker may be optionally branched, for example, to incorporate a polar functionality. In a preferred embodiment Y and L taken together form a cyclic group and the alpha atom is therefore a carbon atom. The cyclic group can be unsubstituted or substituted and can have a ring size of from 3 to 8 atoms. Preferably, the cyclic group is a cyclic amide, most preferably wherein the amide nitrogen of the cyclic amide group is bound to the lipophilic group. The lipophilic group preferably comprises a cycloalkyl, azacycloalkyl , diazacycloalkyl , phenyl , naphthyl , adamantyl , decalinyl, tetrahydrodecalinyl, bicycloalkyl , mono- or diazabicycloalkyl , mono- or bicyclo heteroaromatic or a linear or branched alkyl, alkylene, alkenyl or alkenylene group all optionally substituted by one or more groups R 3 , or a combination of at least two such groups linked by a spiro linkage or a single or double bond or by C=0, O, S, SO, S0 2 , CONRi , NRi-CO-, NRi linkage. For example, representative lipophilic groups include a methyl -cyclohexyl , methylcyclohexylmethyl, methylphenylmethyl , phenylethyl, benzylpiperidinyl, benzoylpiperidinyl, bispiperidinyl or phenylpiperazinyl . Most preferably, the lipophilic group is selected from wherein R 3 is R lt aryl or cycloalkyl; m represents 0 or 1 ; R 4 represents hydrogen, (CH 2 ) w COOH, (CH 2 ) w CONH 2 , ;CH 2 ) w CON -AminoAcid; w represemts an integer from 0 to 4; and X represents CH or N. For example specific lipophilic groups include especially when R 8 represents H, OMe, F, N0 2 , OH or Cl The hydrogen bond donor group which may be attached to the lipophilic group preferably has a nitrogen or oxygen atom as the donor atom and conveniently is a hydroxyl group, a primary, secondary or tertiary amine, or a primary or secondary imine group (as part of an amidine or guanidine) or a saturated or unsaturated heterocyclic group containing a ring nitrogen, preferably a group containing 5 to 7 ring atoms. Where the donor atom is a ring nitrogen, the remote portion of the heterocyclic ring may be part of the lipophilic group . The cyclic group attached to the alpha carbon is preferably an optionally R 3 substituted phenyl or naphthyl group. The benzamidino group is preferably an unsubstituted m-benzamidino group, or a substituted m- benzamidino group bearing metabolically labile groups such as acyloxymethoxycarbonyl , alkoxycarbonyl or hydroxy . Accordingly, preferred compounds of the invention are of formula (wherein R lf R 2 and R 3 are as hereinbefore defined, Ri and R 2 preferably being hydrogen or one representing a metabolically labile group such as alkoxycarbonyl or hydroxy, R 3 preferably being hydrogen, OH or NH, and when other than hydrogen preferably being para to the amidine group) ; R 5 and R 6 are hydrogen or taken together with the carbon atom to which they are attached represent a carbonyl group; Ar is an unsubstituted or substituted aryl group, preferably phenyl; X-X is -CONH-, -CH 2 CH 2 -, CH 2 0-, -COO-, -CH 2 NH-, - 0CH 2 - or -NHCH 2 -; Li is a valence bond or an organic linker group containing 1 to 4 backbone atoms selected from C, N and 0; Lp α is a cycloalkyl, azacycloalkyl , diazacycloalkyl , phenyl, naphthyl , adamantyl , decalmyl, tetrahydrodecalinyl , bicycloalkyl , mono- or diazabicycloalkyl, mono- or bicyclo heteroaromatic or a linear or branched alkyl, alkylene, alkenyl or alkenylene group all optionally substituted by a group R 3 , or a combination of at least two such groups linked by a spiro linkage or a single or double bond or by C=0, 0, S, SO, S0 2 , C0NR 1; NR x -C0-, NR X linkage. For example, representative lipophilic groups include a methyl- cyclohexyl, methylcyclohexylmethyl , bispiperidinyl , methylphenylmethyl , phenylethyl , benzylpiperidinyl , benzoylpiperidinyl or phenylpiperazmyl and those as hereinbefore described; D is a hydrogen bond donor group; In one embodiment, Lj comprises the backbone of an alpha ammo acid, the lipophilic group being the side chain of the ammo acid. The carboxyl part of the alpha ammo acid may be optionally coupled via an amide bond to an ammo acid or to a primary or secondary cyclic or acyclic alkyl amme or diamme or via an ester bond to primary or secondary alcohols. In a preferred embodiment, L x represents a valence bond and the lipophilic group is bound directly to the carbonyl alpha to the alpha atom via a nitrogen atom which forms part of the lipophilic group. Suitable lipophilic groups m this case therefore include pipeπdmyl, pyrrolldinyl and piperazmyl. In a preferred embodiment the piperidme or piperazmyl group is further substituted by a phenyl, benzyl, piperidme, pyridme or benzoyl group, optionally substituted on the phenyl ring by one or more R 3 groups . In a further embodiment, the lipophilic group has attached a group of the formula -C00R : or -CON-ammoacid or ester derivative thereof. In another embodiment the group binding the alpha carbon atom to the lipophilic group comprises a heterocyclic group. Accordingly, preferred compounds of the invention also include (wherein R l t R 2 and R 3 are as hereinbefore defined R : and R 2 preferably being hydrogen or one representing a metabolically labile group such as alkoxycarbonyl or hydroxy, R 3 preferably being hydrogen, OH or NH 2 and when other than hydrogen preferably being para to the amidine group) ; Ar is an unsubstituted or substituted aryl group, preferably phenyl; X-X is -CONH-, -CH 2 CH 2 -, CH 2 0-, -COO-, -CH 2 NH- , - OCH 2 - or -NHCH 2 - ; m is 0, 1 or 2; Het is a 5 or 6-membered heterocyclic group interrupted by 1 , 2 or 3 heteroatoms selected from O, N and S optionally substituted by a group R 3 ; Lpj is a cycloalkyl, azacycloalkyl , diazacycloalkyl , phenyl, naphthyl , adamantyl , decalmyl, tetrahydrodecalmyl , bicycloalkyl , mono- or diazabicycloalkyl, mono- or bicyclo heteroaromatic or a linear or branched alkyl, alkylene, alkenyl or alkenylene group all optionally substituted by a group R 3 , or a combination of at least two such groups linked by a spiro linkage or a single or double bond or by C=0, 0, S, SO, S0 2 , CONRi, NRi-CO-, NR X linkage. For example, representative lipophilic groups include a methyl - cyclohexyl, methylcyclohexylmethyl , methylphenylmethyl , phenylethyl, benzylpiperidinyl, benzoylpiperidinyl, bispiperidinyl or phenylpiperazinyl ; D is a hydrogen bond donor group; and n is 0 , 1 or 2) . Where Het is a five membered ring, the two ring atoms at which it is connected are preferably separated by one ring atom. Where Het is a six-membered ring, the two ring atoms at which it is connected are preferably separated by one or two ring atoms. Representative heterocyclic groups include thiazole, oxazole, oxadiazole, triazole, thiadiazole or imidazole . Where the heterocyclic group is substituted by R 3 this is preferably a COOH or COORi connected to the heterocycle via a valence bond or alkylene chain. In a further embodiment, the lipophilic group has attached a group of the formula -COOR x or -CON-aminoacid or ester derivative thereof. The compounds of the invention may be prepared by conventional chemical synthetic routes, e.g. by amide bond formation to couple the benzamidine function to the alpha atom and to couple the lipophilic function to the alpha atom. Where the alpha atom is a carbon, the cyclic group-alpha atom combination may conveniently derive from an alpha amino acid with the benzamidine deriving from a m-amidino-benzoic acid. Amide formation from such reagents (in which the amidine function may if desired be protected during some or all of the synthesis steps) yields a compound of formula II. Bd-CONH-CH(Cy) -COOH (II) (where Cy is as defined above and Bd is an optionally protected m-benzamidine group) . The lipophilic group (and optionally simultaneously the hydrogen bond donor) may then conveniently be introduced by reaction of a compound of formula II (or another analogous carboxylic acid) optionally after transformation into an activated form, e.g. an acid chloride or active ester, with a lipophilic group carrying an amine, hydroxylamine, hydrazine or hydroxyl group, e.g. to produce compounds with linkages of -CO- NRx-, -CO-NRi-O-, -CO-NRi-NRi- and -CO-O- from the alpha atom (where it is a carbon) to the lipophilic group. Where Y and L taken together form a cyclic amide group the lipophilic group can be conveniently introduced by reacting the compound of formula (II) with a lipophilic group carrying a secondary amine with an active side chain. Cyclisation can be base induced via nucleophilic attack of the alpha atom on a leaving group on the active side chain. If necessary the amide linkage can be reduced using an appropriate reducing agent employing the necessary protection depending on whether concurrent reduction of the carboxylic acid moiety is also desired. Alternatively a compound of formula II or another analogous carboxylic acid may be transformed into an alcohol by reaction with isobutylchloroformate and reduction with sodium borohydride . Such an alcohol, e.g. of formula III Bd - CONH - CH ( Cy) CH 2 OH ( H i ; can be reacted to introduce the lipophilic group by reactions such as: alkylation with an alkyl halide in the presence of a base ; reaction with diethyl azodicarboxylate/triphenylphosphine and a hydroxylated aryl compound; by reaction with an activated carboxylic acid (e.g. an acid chloride) or with a carboxylic acid and diethylazodicarboxylate/triphenylphosphme; by reaction with an isocyanate; and by treatment with methanesulphonyl chloride or trifluoromethanesulphonic anhydride and reaction with an amine, or with a thiol optionally followed by oxidation, e.g. with potassium metapeπodate or hydrogen peroxide. In this way compounds with linkages of -CH 2 -0-, -CH,-0-CO-, -CHz-O-CO- Ri-, -CH^NR^, -CH 2 -S-, -CH 2 -S0- and -CH 2 -S0 2 - between the alpha carbon and the lipophilic group may be produced . Alternatively the alcohol can be oxidized to form a corresponding aldehyde (e.g. by oxidation with manganese dioxide or DMSO/oxalyl chloride or DMSO/S0 3 or Dess- Martm reagent) which may be reacted to introduce the lipophilic group by reactions such as: reaction with Wittig reagents or Horner-Emmons reagents, optionally followed by reduction of the resulting carbon: carbon double bond using H 2 /Pd-carbon; reaction with an organometallic, eg a Grignard reagent, optionally followed by reaction on the resulting hydroxyl group, such as oxidation (eg with Mn0 2 , DMSO/oxalyl chloride or Dess-Martin reagent) , alkylation (eg with an alkyl halide in the presence of a base in a solvent such as DMF) , arylation (eg with diethylazo dicarboxylate/triphenyl phosphme and a hydroxyaryl compound) , ester formation (eg with an acid chloride or with a carboxylic acid and diethylazido dicarboxylate/triphenyl phosphme) , or carbamate formation (eg with an isocyanate) ; by reaction with an amine followed by reduction, e.g. with sodium cyanoborohydπde; by reaction w th a hydrazine; or by reaction with a carbazide. In this way compounds with linkages of -CH=CR -, -CH,-CHR-, -CHOH-, -CHR,-0-, -CHR,-0-CO-, -CHR, -O-CO-NRj- , -CO-, -CH- 2 -NRi-, and -CH=N-NR 1 -CO-NR 1 - between the alpha carbon and the lipophilic group may be produced. The transformation of alcohol to amine referred to above may be used to produce an amine reagent for lipophilic group introduction, e.g. a compound Bd-CONH- Such an amine reagent may be reacted to introduce the lipophilic group, e.g. by acylation with an acid halide or activated ester, by reaction with isocyanate, by reaction with an isothiocyanate, or by reaction with a sulphonyl chloride. In this way compounds with linkages of -CHjNRj-CO-, and -CH 2 NR 1 -S0 2 - between the alpha carbon and the lipophilic groups may be produced. The transformation of acid to amide referred to above may be used to produce an amide reagent for introduction of the lipophilic group, e.g. a compound Bd-CONH-CH(Cy) -CON(R 1 ) 2 . Such amides may be reacted to introduce lipophilic groups, e.g. by reaction with a haloketone (e.g. phenacyl bromide) . This provides a linkage from alpha carbon to lipophilic group. Analogously the amide may be transformed to a thioamide by reaction with Lawesson's reagent and then reacted with a haloketone to form a linkage The amide reagent may likewise be transformed to a nitrile reagent by dehydration, e.g. with trifluoroacetic anhydride. The nitrile reagent may be reacted with hydrazine then with acyl halide and then cyclized, (e.g. with trifluoroacetic anhydride) to produce a linkage Alternatively it may be treated with hydroxylamine then reacted with acyl halide and cyclized (e.g. with trifluoroacetic anhydride) to produce a linkage The hydrazide produced by reaction of a carboxylic acid reagent with hydrazine discussed above may likewise be used as a reagent for lipophilic group introduction, e.g. as a compound of formula Bd-CONH-CH (Cy) -CO-NR^N ( Rι ) 2 - Thus the hydrazide reagent can be reacted with an acyl halide and cyclized, e.g. with trifluoroacetic anhydride to yield a linkage or reacted with an acyl halide or an isocyanate to yield linkages -CO-NRi . -NRi-CO- and -CO-NRj-NRi-CO-NRi- respectively . Alternatively the hydrazide may be transformed by reaction with Lawesson's reagent and then reacted with an acyl halide and cyclized (e.g. with trifluoroacetic anhydride) to produce the linkage // N An alternative route to these compounds is to carry out any of the above chemical reactions to incorporate the lipophilic group (an optional H bond donor) into a protected intermediate such as a compound of formula (IV) . PG = Protecting group The protecting group may then be removed before coupling of the m-amidino benzoic acid (optionally protected) . A starting reagent for lipophilic group introduction where the alpha atom is nitrogen may be produced for example by reaction of a beta protected hydrazine (such protection to be chosen as to be compatible with the subsequent reagents to be employed) with phosgene, diphosgene, triphosgene or N,N' carbonyl dnmidazole to give a reactive compound of the type: PG = Protecting group This intermediate may be used as has been described above for the carboxylic starting reagents where the alpha atom is carbon. Removal of the protecting group by standard methods and coupling with an activated m-carboxyl -benzamidine will give compounds of the type Bd-CONH-N (Cy) -L-Lp (D) n (where Bd, X, Y, Cy, L, Lp and D are as defined above) . Thus viewed from a further aspect the invention provides a process for the preparation of a compound according to the invention which process comprises coupling a lipophilic group to a compound of formula (V) Bd-(X),-Y(Cy)-Z (V) (where Bd, X, Y and Cy are as defined above and Z is a reactive functional group) , and optionally subsequently coupling a hydrogen bond donor group to said lipophilic group . The compounds of the invention may be administered Dy any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature or transdermally . The compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. Preferably the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention. Viewed from this aspect the invention provides a pharmaceutical composition comprising a serine protease inhibitor according to the invention together with at least one pharmaceutically acceptable carrier or excipient. Viewed from a further aspect the invention provides the use of a serine protease inhibitor according to the invention for the manufacture of a medicament for use in a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat (i.e. treat or prevent) a condition responsive to said inhibitor. Viewed from a further aspect the invention provides a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat a condition responsive to a serine protease inhibitor (e.g. a condition such as a thrombotic disorder responsive to a factor Xa inhibitor) , said method comprising administering to said body an effective amount of a serine protease inhibitor according to the invention. The dosage of the inhibitor compound of the invention will depend upon the nature and severity of the condition being treated, the administration route and the size and species of the patient. However m general, quantities of from 0.01 to 100 μmol/kg bodyweight will be administered. All publications referred to herein are hereby incorporated by reference. The invention will now be described further with reference to the following non-limiting Examples. Experimental Abbreviations used follow IUPAC-IUB nomenclature. Additional abbreviations are Hplc, high-performance liquid chromatography; DMF, dimethylformamide; DCM, dichloromethane; HOAt , 1-hydroxy-7-azabenzotπazole ; HATU, [O- (7-azabenzotrιazol-l-yl) -1, 1,3,3- tetramethyluronium hexafluorophosphate] ; Fmoc, 9- Fluorenylmethoxycarbonyl; HOBt, 1-hydroxybenzotrιazole; TBTU, 2- (IH- (benzotπazol-1-yl) -1,1,3,3- tetramethyluroniumtetrafluoroborate ; DIPEA, diisopropylethylamme; Boc , tertiary butyloxycarbony1 ; DIPCI, dnsopropylcarbodiimide; DBU, 1,8- diazabicyclo [5.4.0] undec-7-ene; TEA, triethylamme; Rmk linker, p- [ (R, S) -α- [1- (9H-Fluoren-9-yl) methoxy- formamido] -2 , 4 -dimethoxybenzyl] phenyl acetic acid; TFA, trifluoroacetic acid; MALDI-TOF, Matrix assisted laser desorption lonisation - time of flight mass spectrometry; and RT, retention time. Unless otherwise indicated, ammo acid derivatives, resins and coupling reagents were obtained from Novabiochem (Nottingham, UK) and other solvents and reagents from Rathburn (Walkerburn, UK) or Aldπch (Gill gham, UK) and were used without further purification. Purification: Purification was by gradient reverse phase Hplc on a Waters Deltaprep 4000 at a flow rate of 50 ml/ mm. using a Deltapak C18 radial compression column (40 mm x 210 mm, 10-15 mm particle size) . Eluant A consisted of aqTFA (0.1%) and eluant B 90% MeCN aqTFA (0.1%) with gradient elution (Gradient 1, 0 mm. 20%B then 20% to 100% over 36 mm., Gradient 2, 0 mm. 5%B for 1 mm. then 5%B to 20%B over 4 mm., then 20% to 60% over 32 mm. or Gradient 3, 0 mm. 20%B then 20% to 100% over 15 mm.) . Fractions were analysed by analytical Hplc and MALDI-TOF before pooling those with >95% purity for lyophilisation. Analysis: Analytical Hplc was on a Shimadzu LC6 gradient system equipped with an autosampler, a variable wavelength detector at flow rates of 0.4 ml/ mm. Eluents A and B as for preparative Hplc . Columns used were Techogell5 C18 (2x150mm) (Hplc Technology) , Jupiter 5 C18 column (2.1x150 mm, 5μm particle size) (Phenomenex) and Kromasil C4 (2.0x150 mm, 5 mm) (HPLC Technology) . Purified products were further analysed by MALDI-TOF and nmr. All Fmoc-protected ammo acids were purchased where available or prepared by known literature methods (1) with the exception of the following novel ammo acid: Preparation of (D,L) -N-Fluorenylmethyloxycarbonyl-4- phenylphenylglycine . A solution of 4-bιphenylcarboxaldehyde (4.6g 25mmol) , sodium cyanide (3.68g 75mmol) and ammonium carbonate (9.60g lOOmmol) m 50% aqueous ethanol (175ml) was heated at 50°C for 20 hours. The reaction mixture was cooled, concentrated under reduced pressure and acidified to pH 2.0 with concentrated hydrochloric acid (fume hood). The intermediate 4- (4-phenylphenyl) -2 , 5- lmidazolmedione was collected by filtration, washed with dilute (0.5%) HC1 and dried before using as crude m the next stage. (Filtrates were retained and treated with sodium hypochlorite solution before disposal) The intermediate 4- (4-phenylphenyl) -2 , 5-lmidazolmedione was refluxed in 16% aqueous sodium hydroxide (100ml, 16% w/v) for 24h. The reaction mixture was then filtered, cooled, diluted with water (100ml) and then shaken with ethyl acetate and separated. The aqueous solution was adjusted to pH 5.1 with concentrated hydrochloric acid and the solid obtained collected by filtration, washed with a little water and dried to give 4- phenylphenylglycme (2.36g, 42%). H nmr (d 6 DMSO) consistent with desired product . To a vigorously stirred solution of 4- phenylphenylglycme (500mg 2.2mmol) in DCM (20ml) was added DIPEA (614μl 4.4mmol) and then, carefully, chlorotπmethylsilane (558μl 4.4mmol) and the mixture refluxed for 1.5h. The reaction mixture was cooled m an ice bath and fluorenylmethoxycarbonyl chloride (742mg 2.2mmol) was added in one portion. After stirring at 0°C for 20mm the ice bath was removed and stirring was continued for 1.5h. The reaction mixture was concentrated under reduced pressure and the residue stirred with a mixture of diethyl ether (20ml) and saturated sodium carbonate solution (30ml) . A yellow solid which failed to dissolve m either layer was taken up m water (20ml) and acidified to pH 1 with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate and the organic layer washed with water (2 x 20ml) , dried with magnesium sulphate and evaporated to dryness . Recrystallisation from ethanol/water afforded (D, L) -N-fluorenylmethyloxycarbonyl-4-phenylphenylglycme (640mg, 65%) . H nmr (d 6 DMSO) 8.25 (IH, d, aromatics) ; 7.89 (2H, d, aromatics); 7.76 (2H d, aromatics); 7.67 (3H, d, aromatics); 7.57-7.25 (6H, m, aromatics); 5.23 (IH, d, - NH) ; ~4.27 (3H, m, H α + CH 2 ) . Preparation of 3-Amidinobenzoic acid TFA salt 3 Cyanobenzoic acid (lOg, 68 mmol) was refluxed m ethanol (300ml) on an isomantle fitted with reflux condenser and soxhlet extractor, the thimble being filled with A4 molecular sieve. Reflux was continued for 10 hours. The heating was then removed and the solution allowed to cool. The solution was then cooled m an ice bath and saturated with hydrogen chloride gas . The sealed flask was allowed to stand overnight then evaporated to dryness. To the dry product was added saturated ammonia/ethanol solution (400ml) and the flask sealed and allowed to stand overnight. The solution was then evaporated to dryness and then treated with 2M sodium hydroxide solution (3 eq. , 102ml) , the resulting solution was stirred for 2 hours then extracted with ethylacetate (100ml) . The aqueous layer was then acidified, with 10% aq hydrochloric acid (200ml) m one lot and extracted with ethylacetate (100ml) . Concentrated ammonia solution was added to pH 14 and the solution cooled m the fridge overnight. The precipitate formed was filtered off and washed with water, dissolved m 10%TFA water and lyophilised to a white powder (12g) . -H nmr (D 2 0) 8.40 (lH,s) ; 8.30 (IH, d, J=7.5Hz) ; 8.00 (IH, d, J=7.5Hz) ; 7.72 (IH, t) . Synthesis of inhibitors Method 1: Using a solid phase strategy on a Protein Technologies, Symphony Multiple Peptide Synthesiser by attachment of bis amino compounds to Peg-2-chlorotrityl chloride resin: 2-Chlorotrityl chloride resin was typically treated with greater than 2 fold excess of the di -amine in dry DCM .The resin was further modified by the attachment of acids. Activation of Fmoc protected amino acid (2-5eq) was by TBTU/ DIPEA, all couplings ( minimum 120 min.) were carried out in DMF. Deprotection of the Fmoc group was achieved with 20% (v/v) piperidine in DMF. Other acid substituents were added as the HOBt or HOAt esters either by activation with HBTU/HATU or DIPCI with or without Boc protection of amino groups. Cleavage of the products from the resin was by treatment (30 min., ambient) with 10% (v/v) triethylsilane in TFA, filtration, evaporation and trituration with diethylether . Synthesis using the Symphony Multiple Peptide Synthesiser. The Symphony Multiple Peptide Synthesiser is charged with DMF, DCM, TBTU in DMF(450 mM) , DIPEA in DMF (900 mM) , 20% (v/v) piperidine in DMF. Resins are held in plastic reaction vessels that allow the introduction of reagents and solvents and nitrogen for agitation or air drying . A typical synthesis cycle on the Symphony is as follows : - The reaction vessel containing the resm (0.1 mmol) is charged with the Fmoc protected ammo acid (0.5 mmol) and then this is dissolved m DMF (2.5ml), treated with TBTU (0.56 mmol, 1.25ml) and DIPEA (1.1 mmol, 1.25ml) and agitated with nitrogen for 2 hours (agitation times may vary) . After coupling the resm is washed with DMF (6x 5ml) then deprotected with 20% (v/v) piperidme m DMF (2x 5ml for 1 mm. each, then lx 5ml for 8 mm.) the resm is then washed with DMF (6x 5ml) . Example 1 : 3 -Amidino-benzoyl-D-phenylglycine 4- aminomethylcyclohexyl methylamide Bιs-1,4 ammomethylcyclohexane (2ml) was added to 2 chlorotπtyl chloride resm (1.2 mmol/g, 0.73g) pre swollen dry DCM (4ml) . After 2h the resm was washed with DCM (6x5ml) , DMF (6x5ml) and DCM (6x5ml) . The resm was then air dried to allow aliquots to be taken. The bis-1, 4 -ammomethylcyclohexane 2-chlorotrιtyl chloride resm (0.1 mmol) was treated with Fmoc-D- Phenylglycme (0.5 mmol, 187mg) , DMF (2.5ml), TBTU m DMF (1.25ml of a 450mM solution) and DIPEA DMF (1.25ml of a 900 mM solution) . The mixture was agitated with nitrogen for 2 hours. Deprotection and washing as above. HOBt (0.5 mmol, 68 mg) dissolved in DMF (4ml) at 0°C was treated with DIPCI (0.5 mmol, 80μl) , for 10 mm. 3-amιdmobenzoιc acid TFA salt (0.5 mmol, 139 mg.) was added and stirring continued for 10 mm. at room temperature. The mixture was transferred to the reaction vessel on the Symphony and agitated for 10 hours with nitrogen. The resm was washed with DMF (6x5ml) , DCM (6x5ml) and air dried. The product was cleaved from the resm with 10% triethylsilane in TFA (10ml) for 30 minutes, the resm filtered off and the TFA solution evaporated to dryness and triturated with diethyl ether to give the crude product . The crude product was dissolved in water (10ml) , filtered and purified by preparative reverse phase Hplc. Η nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 8.09 (IH, s) ; 8.05 (IH, d, J=7.5Hz); 7.90 (IH, d, J=7.5Hz); 7.66 (IH, t, J=7.5Hz); 7.43 (5H, m) ; 5.47 (IH, s) ; 3.05 (2H, m) ; 2.78 (2H, m) ; 1.48 (7H, m) ; 0.86 (3H, m) MS TOF 422 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 13.45 min. (major) and 13.62 mm. (minor) . Compounds made by the above method : - Example 2. 3-Amidino-benzoyl-DL-3-chloro-phenylglycine-4- .aminomethylcyclohexyl methylamide Η nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 8.19 (IH, s) ; 8.15 (IH, d, J=7.5Hz); 8.04 (IH, d, J=7.5Hz); 7.90 (IH, t, J=7.5Hz); 7.53 (4H, m) ; 5.63 (IH, s) ; 3.18 (2H, m) ; 2.90 (2H, m) ; 1.66 (7H, m) ; 1.00 (3H, m) . (MS TOF 457 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 16.53 min. Example 3. 3 -Amidino-benzoyl-DL-4-methoxyphenylglycine-4- aminomethylcyclohexyl methylamide X H nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 8.19 (IH, s) ; 8.12 (IH, d, J=7.5Hz); 8.01 (IH, d, J- 7.5Hz); 7.80(1H, t, J=7.5Hz); 7.50 ,(2H,d); 7.10, (2H,d); ;5.53 (IH, s) ; 3.86 (3H, s) ; 3.13 (2H, m) ; 2.90 (2H, m) ; 1.66 (7H, m) ; 0.95 (3H, m) . (MS TOF 452 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 13.87 min. (major) and 14.10 min. (minor) . Example 4 . 3 -Amidino-benzoyl-DL-4-hydroxyphenylglycine 4- aminomethylcyclohexyl methylamide : H nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 7.40 (IH, d) ; 7.25 (2H, dd) ; 7.08 (IH, d) ; 7.02 (IH, d);6.88 (2H, m) ; 6.82 (IH, d) ; 5.28 (IH, d) ; 5.10 (IH, d) ; 3.03 (2H, m) ; 2.83 (2H, m) ; 1.50 (7H, m) ; 0.85 (3H, m) . MS TOF 438 (M+l + ) Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 9.69 min. (major) and 14.10 min. (minor) . Example 5. 3 -Amidino-benzoyl-DL-1-naphthylglycine 4- aminomethylcyclohexyl methylamide X H nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers8.40 ,(lH,s); 8.25 (4H, 4); 8.132 (IH, d, J=7.5Hz); 7.81 (4H, m) ; 6.53 (IH, s) ; 3.70-3.10 (2H, m) ; 2.99 (2H, m) ; 2.0-1.3 (7H, m) ; 1.07 (3H, m) . (MS TOF 472 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 17.62 min. (major) and 18.03 min. (minor) . Example 6. 3 -Amidino-benzoyl-DL-4-phenyl phenylglycine 4- aminomethylcyclohexyl methylamide l E nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 8.11 (2H, m) ; 7.94 (IH, d, J=7.5Hz); 7.71 (5H, m) ; 7.51 (5H, m) ; 5.58 (IH, s) ; 3.3-2.90 (2H, m) ; 2.90-2.65 (2H, m) ; 1.8-1.2 (7H, m) ; 0.85 (3H, m) . MS TOF 498 (M+l + ) Hplc (Jupiterδ C18, Gradient 2, water/acetonitrile/ TFA) rt 19.37 min. (major), 21.69 min. (minor). Example 7. 3-Amidino-benzoyl-DL-4-trifluoromethyl phenylglycine 4- aminomethylcyclohexyl methylamide "H nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 8.12 (IH, s) ; 8.07 (IH, d, J=7.5Hz); 7.93 (IH, d, J=7.5Hz); 7.8-7.6 (5H, m) ; 5.61 (IH, s); 3.30-2.70 (4H, m) ; 1.50 (7H, m) ; 0.85 (3H, m) . MS TOF 490 (M+l + ) Hplc (Jupιter5 C18, Gradient 2, water/acetonitrile/TFA) rt 19.37 mm. Example 8. 3-Amidino-benzoyl-R, S-3-phenyl β-alanine 4- .aminomethylcyclohexyl methylamide Η nmr D 2 0 Mixture of cyclohexyl cis and trans isomers. 8.08 (2H, m) ; 7.96 (IH, d, J=7.5Hz); 7.73 (IH, t, J=7.5Hz); 7.44 (5H, m) ; 5.43 (IH, t, J=7.9Hz); 3.50 (2H, m) ; 2.88 (4H, m) ; 1.6-1.0 (7H, m) ; 0.77 (2H, m) . MS TOF 436 (M+l τ ) . Hplc (Jupιter5 C18, Gradient 2, water/acetonitrile/TFA) rt 13.22 mm. (major), 13.61 (minor) Example 9. 3-Amidino-benzoyl-DL-3-indolylglycine 4- aminomethylcyclohexyl methylamide H nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 8.1-7.85 (3H, m) ; 7.65 (IH, m) ; 7.47 (4H, m) ; 7.33 (IH, m) ; 4.85 (m, partially obscured by solvent); 4.3.3.80 (4H, m) ; 3.05 (2H, m) ; 2.78 (3H, m) ; 1.8-1.0 (7H, m) ; 1.0-0.65 (3H, m) . MS TOF 451 (M+l + ) . Hplc (Jupιter5 C18, Gradient 2, water/acetonitrile/TFA) rt 10.12 mm. Example 10. 3 -Amidino-benzoyl-DL-piperonylglycine 4- aminomethylcyclohexyl methylamide L H nmr D 2 0 Mixture of cyclohexyl cis and trans isomers. 8.13 (2H, m) ; 8.00 (IH, d, J=7.5Hz); 7.72 (IH, t, J=7.5Hz); 6.96 (5H, m) ; 5.98 (2H, s) ; 5.44 (IH, s) ; 3.4- 2.7 (4H, m) ; 1.9-1.25 (7H, m) ; 1.1-0.8 (3H, m) . MS TOF 466 (M+l + ) Hplc (Kromasil C4 , Gradient 2, water/acetonitrile/ TFA) rt 12.62 mm. Example 11. 3 -Amidino-benzoyl-DL-3 -methyl phenylglycine 4- aminomethylcyclohexyl methylamide " H nmr D 2 0 Mixture of cyclohexyl cis and trans isomers. 8.09 (2H, m) ; 7.96 (IH, d, J=7.5Hz); 7.70 (IH, t, J=7.5Hz); 7.25 (4H, m) ; 5.50 (IH, s) ; 3.4-2.7 (4H, m) ; 2.31 (3H, s) ; 1.9-1.1 (7H, m) ; 1.1-0.7 (3H, m) . MS TOF 436 (M+l τ ) Hplc (Kromasil C4 , Gradient 2, water/acetonitrile/ TFA) rt 14.41 min. Example 12. 3-Amidino-benzoyl-DL-2 -naphthylglycine 4- aminomethy1cyclohexyl methylamide Η nmr D 2 0 Mixture of cyclohexyl cis and trans isomers. 7.98 (2H, m) ; 7.83 (4H, m) ; 7.56 (IH, t, J=7.5Hz); 7.45 (4H, m) ; 5.58 (IH, s) ; 3.25-2.55 (4H, m) ; 1.7-0.9 (7H, m) ; 0.9-0.5 (3H, m) . MS TOF 472 (M+l + ) Hplc (Kromasil C4, Gradient 2, water/acetonitrile/ TFA) rt 17.44 min. (major) 17.69 (minor). Example 13. 3 -Amidino-benzoyl-1-aminocyclopentane-N- 4- όiminomethylcyclohexyl methyl - 1 - carboxamide " H nmr D 2 0 Mixture of cyclohexyl cis and trans isomers. 7.92 (2H, m) ; 7.81 (IH, d, J=7.5Hz) ; 7.57 (IH, t, J=7.5Hz) ; 3.6-3.1 (2H, m) ; 2.91 (2H, d, J=6.8Hz) ; 2.68 (2H, d, J=6.8Hz) ; 2.2-1.8 (4H, m) ; 1.8-1.2 (13H, m) ; 1.0-0.65 (3H, m) . MS TOF 400 (M+l + ) Hplc (Kromasil C4 , Gradient 2, water/acetonitrile/ TFA) rt 10.87 min. Example 14. 3 -Amidino-benzoyl-DL-cyclohexylglycine 4- aminomethylcyclohexyl methylamide "H nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 8.10 (IH, s) ; 8.05 (IH, d, J=7.5Hz) ; 7.85 (IH, d, J=7.5Hz); 7.66 (IH, t, J=7.5Hz); 4.25(1H, d) ; 3.05 (2H, m) ; 2.78 (2H, m) ; 1.48 -0.86 (19H, m) MS TOF 428 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 14.76 min. (major) and 15.09 min. (minor) . Example 15. 3 -Amidino-benzoyl-L-phenylglycine 4- .aminomethylcyclohexyl methylamide MS TOF 422 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/ TFA) rt 10.06 min. Example 16. 3 -Amidino-benzoyl-D-phenylglycine 3- aminomethylcyclohexyl methylamide MS TOF 422 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/ TFA) rt 8.81 min. Example 17. 3-Amidino-benzoyl-L-phenylglycine 3- aminomethylcyclohexyl methylamide MS TOF 422 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/ TFA) rt 8.79 min. Example 18. 3 -Amidino -benzoyl -DL- 2 - thienylglycine 4 - .aminomethylcyclohexyl methylamide MS TOF 429 (M+l + ) . Hplc (Jupiter5 C18 , Gradient 2 , water/acetonitrile/TFA) rt 12 . 73 min . Example 19 . 3 -Amidino-benzoyl-DL-4-chloro-phenylglycine 4- aminomethylcyclohexyl methylamide MS TOF 457 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 15.89 min. Example 20 3-Amidino-benzoyl-D-phenylglycine 4- aminomethylbenzylamide MS TOF 416 (M+r) Hplc (Techogell5 C18, Gradient 2, water/acetonitrile/ TFA) rt 12.34 min. Example 21. 3 -Amidino-benzoyl-D-phenylglycine 3- aminomethylbenzylamide MS TOF 416 (M+l + ) Hplc (Techogell5 C18, Gradient 2, water/acetonitrile/ TFA) rt 9.65 min. Example 22. 3-Amidino-benzoyl-L-phenylglycine 3- .aminomethylbenzylamide MS TOF 416 (M+l + ) Hplc (Techogell5 C18, Gradient 2, water/acetonitrile/ TFA) rt 10.26 min. Example 23. 3 -Amidino-benzoyl-L-phenylglycine 4- aminomethylbenzylamide l nmr (D 2 0) 8.10 (2H, m) ; 7.88 (IH, d, J=7.5Hz); 7.65(1H, t, J=7.5Hz); 7.4-7.1 (9H, m) ; 5.57 (IH, s) ; 4.37 (2H, ABq) ; 4.06 (2H, s) . MS TOF 416 (M+l + ) Hplc (Techogell5 C18, Gradient 1, water/acetonitrile /TFA) rt 12.34 min. Ex>aιtιple 24. 3 -Amidino-benzoyl-D-phenylglycine -4- (4-aminocyclohexyl methyl) cyclohexylamide : H nmr (D 2 0) 8.3-7.95 (3H, m) ; 7.85-7.6 (2H, m) ; 7.47 (4H, m) ; 5.55 (IH, s) ; 3.59 (IH, m) ; 3.06 (IH, m) ; 2.1- 1.5 (9H, m) ; 1.5-0.85 (11H, m) . MS TOF 490 (M+l + ) . Hplc (Kromasil C4 , Gradient 2, water/acetonitrile /TFA) rt 18.30 min. Example 25. 3-Amidino-benzoyl-L-phenylglycine -4- (4-aminocyclohexyl methyl) cyclohexylamide : H nmr (D 2 0) 8.3-7.95 (3H, m) ; 7.85-7.6 (2H, m) ; 7.47 (4H, m) ; 5.55 (IH, s) ; 3.59 (IH, m) ; 3.06 (IH, m) ; 2.1- 1.5 (9H, m) ; 1.5-0.85 (11H, m) . MS TOF 490 (M+l") . Hplc (Kromasil C4 , Gradient 2, water/acetonitrile /TFA) rt 18.39 min. Example 26. 3-Amidino-benzoyl-D-phenylglycinyl-D-2-naphthylalanine- 5 -aminopentamide Η nmr (d 4 methanol) d 8.21 (IH, s) ; 8.14 (IH, d, J=7.5Hz); 7.96 (IH, d, J=7.5Hz); 7.80-7.65 (6H, m) ; 7.45-7.15 (7H, m) ; 5.66 (IH, s) ; 4.56 (IH, m) ; 3.16 (2H, m) ; 3.02 (2H, m) ; 2.68 (2H, m) ; 1.45 (2H, m) ; 1.32 (2H, m) ; 1.12 (2H, m) . MS TOF 579 (M+l + ) . Hplc (Jupiterδ C18, Gradient 1, water/acetonitrile/TFA) rt 13.56 min. Example 27. 3 -Amidino-benzoyl-D-phenylglycinyl D-lysine-5- aminopentamide X H nmr (D 2 0) d 8.10 (IH, s) ; 8.05 (IH, d, J=7.5Hz); 7.94 (IH, d, J=7.5Hz); 7.68 (IH, t, J=7.5Hz); 7.45 (5H, m) ; 5.53 (IH, s) ; 4.22 (IH, t) ; 3.05 (2H, m) ; 2.90 (4H, dd) ; 1.8-1.0 (12H, m) . MS TOF 510 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.56 min. Example 28. 3 -Amidino-benzoyl-D-phenylglycine-5-aminopentamide X H nmr (D 2 0) d 7.85 (IH, s) ; 7.80 (IH, d, J=7.5Hz); 7.70 (IH, d, J=7.5Hz); 7.55 (IH, t, J=7.5Hz); 7.20 (5H, m) ; 5.30 (IH, s) ; 3.05 (2H, m) ; 2.60 (2H, m) ; 1.25 (4H, m) ; 0.90 ,(2H,m); MS TOF 382 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 11.26 min. Example 29. 3 -Amidino-benzoyl-D-phenylglycine-R, S-3 - aminopyrrolidinamide : H nmr (D 2 0) 8.18 (IH, s) ; 8.10 (IH, d) ; 7.88 (IH, d) ; 7.70 (IH, t) ; 7.50 (5H, m) ; 5.55 (IH, s) ; 4.50 (IH, m) ; 3 - 4 (4H, m) ; 2.33 (IH, m) ; 2.00 (IH, m) . MS TOF 366 (M+1 T ). Hplc (Jupιter5 C18, Gradient 2, water/acetonitrile/TFA) rt 10.38 + 10.79 mm. Example 30. 3-Amidino-benzoyl-D-phenylglycine 4-aminomethyl piperidinamide MS TOF 394 (M+l + ) . Hplc (Jupιter5 C18, Gradient 2, water/acetonitrile/TFA) rt 11.40 mm. (major) and 11.97 mm. (minor) . Method 2 : By solid phase strategy on a Protein Technologies, Symphony Multiple Peptide Synthesiser using Fmoc ammo acids attached to Peg-2-chlorotπtyl chloride resm: Typically the 2-chlorotrιtyl chloride resm was treated with a 2 fold excess of the Fmoc ammo acid m a 1:1 mixture of DMF and dry DCM and DIPEA (2eq.) . The resm was washed with DMF/DCM and deprotected with 20% piperidme m DMF before further modification. The resm was further modified by the attachment of acids. Activation of Fmoc protected ammo acids (2-5eq) was by activation with TBTU/ DIPEA, all couplings ( minimum 120 mm.) were carried out m DMF. Deprotection of the Fmoc group was achieved with 20% (v/v) piperidme m DMF. Other acid substituents were added as the HOBt or HOAt esters either by activation with HBTU/HATU or DIPCI with or without Boc protection of ammo groups. Cleavage of the products from the resm was by treatment (30 mm. , ambient) with 10% (v/v) triethylsilane m TFA, filtration, evaporation and trituration with ether. Example 31. 3-Amidino-benzoyl-D-phenylglycinyl-D-2-naphthylalaninyl- glycine Fmoc Glycine (0.2mmol, 59 mg.) in DMF (2ml) was added to 2 chlorotπtyl chloride resm (1.0 mmol/g, O.lg) pre swollen in dry DCM (2ml) , then DIPEA (0 . 2 mmol ) . After 2h the resin was washed with DCM (6x5ml) , DMF (6x5ml) and DCM (6x5ml) . The resin was then air dried to allow aliquots to be taken for further modification. On the Symphony Fmoc-Glycyl-2-chlorotrityl resin (0.1 mmol) was deprotected with 20% (v/v) piperidine in DMF and washed with DMF(6x 5ml) then treated with Fmoc-D-2- naphthylalanine (0.5 mmol 220 mg) , DMF (2.5ml), TBTU in DMF (1.25ml of a 450mM solution) and DIPEA in DMF (1.25ml of a 900 mM solution) . The mixture was agitated with nitrogen for 2 hours. Deprotection and washing as above. The resin was then treated Fmoc-D- henylglycine (0.5 mmol 187 mg) , DMF (2.5ml), TBTU in DMF (1.25ml of a 450mM solution) and DIPEA in DMF (1.25ml of a 900 mM solution) . The mixture was agitated with nitrogen for 2 hours. Deprotection and washing as above. HOBt (0.5 mmol, 68 mg) dissolved in DMF (4ml) was stirred at 0°C with DIPCI (0.5 mmol, 80μl) , for 10 min. 3-amidinobenzoic acid TFA salt (0.5 mmol, 139 mg.) was added and stirring continued for 10 min. at room temperature. The mixture was transferred to the reaction vessel on the Symphony and agitated for 10 hours with nitrogen. The resin was then washed with DMF (6x5ml) , DCM (6x5ml) and air dried. The product was cleaved from the resin with 10% (v/v) triethylsilane in TFA (10ml) for 30 minutes, the resin filtered off, the TFA solution evaporated to dryness and triturated with diethyl ether to give the crude product . The crude product was then dissolved in water (10ml) , filtered and purified by preparative reverse phase Hplc. "H nmr (DMSO) d 8.15 (IH, s) ; 8.12 (IH, d, J=7.5Hz); 7.85 (IH, d, J=7.5Hz); 7.74 (5H, m) ;7.65 (IH, t); 7.42 - 7.25 (7H,m) ; 5.73 (IH, s); 4.72 (IH, m) ; 3.75(2H, d) ; signals at 3.3 -3 -Oobscured by solvent. MS TOF 552 (M+l + ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/TFA) rt 14 . 88 mm . Compounds made by the above method: Example 32. 3 -Amidino-benzoyl-D-phenylglycinyl-D-2 -naphthylalaninyl N-methylglycine X H nmr (CD 3 CN) mixture of rotomers, major product quoted. d 7.95 (2H, m) ; 7.87 (IH, d, J=7.5Hz); 7.71 (4H, m) ; 7.62 (IH, t, J=7.5Hz); 7.36 (3H, m) ; 7.22 (5H, m) ; 5.57 (IH, s) ; 5.19 (IH, dd) ; 3.95 (2H, ABq) ; 2.98 (3H, s) . MS TOF 566 (M+l + ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/TFA) rt 14.86 mm. Example 33. 3 -Amidino-benzoyl-D-phenylglyciny1-D-2-naphthylalaninyl- D-proline X H nmr (CD 3 CN) d 8.15 (IH, s) ; 8.08 (IH, d) ; 7.95 (IH, d) ; 7.82 (5H, m) ; 7.62 ,(lH,m); 7.22 - 7.5 (7H,m); 5.63 (IH, s) ; 5.05 (IH, m) ; 4.35 (IH, m) ; 3.60 ,(2H,m); signals at 3.3 obscured by solvent; 3.1- , (lH,m); 2.22, (lH,m); 2.0 , (4H,m) ; . MS TOF 592 (M+l + ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/TFA) rt 15.32 mm. Method 3: By solid phase strategy on a Protein Technologies, Symphony Multiple Peptide Synthesiser using Fmoc ammo acids attached to TentaGel S- resm (Rapp Polymere) via the Rink amide linker: Typically the TentaGel resm was treated with a 5 fold excess of the Rmk linker, TBTU (leq.), DIPEA (2eq.). The resm was washed with DMF and deprotected with 20% piperidme in DMF before further modification. The resm was further modified by the attachment of acids. Activation of Fmoc protected ammo acid (2-5eq) was by TBTU/ DIPEA, all couplings ( minimum 120 mm.) were carried out m DMF. Deprotection of the Fmoc group was achieved with 20% piperidme m DMF. Other acid substituents were added as the HOBt or HOAt esters either by activation with HBTU/HATU or DIPCI with or without Boc protection of ammo groups. Cleavage of the products from the resm was by treatment (30 mm. , ambient) with 10% triethylsilane in TFA, filtration, evaporation and tπturation with ether. Example 34. 3 -Amidino-benzoyl-D-phenylglycinyl D-phenylalanine amide On the Symphony TentaGel S -NH2 resm (0.1 mmol, 400 mg, 0.24 mmol./g) was treated with Rmk linker (0.5 mmol, 270mg) , DMF (2.5ml), TBTU m DMF (1.25ml of a 450mM solution) and DIPEA m DMF (1.25ml of a 900 mM solution) . The mixture was agitated with nitrogen for 2 hours. Deprotection and washing as above. On the Symphony R k-TentaGel resm (0.1 mmol) was then treated with Fmoc-D-Phenylalanme- (0.5 mmol, 194mg) , DMF (2.5ml), TBTU m DMF (1.25ml of a 450mM solution) and DIPEA m DMF (1.25ml of a 900 mM solution) . The mixture was agitated with nitrogen for 2 hours. Deprotection and washing as above . The resm (0.1 mmol) was then treated with Fmoc-D- Phenylglycine (0.5 mmol, 187mg) , DMF (2.5ml), TBTU m DMF (1.25ml of a 450mM solution) and DIPEA in DMF (1.25ml of a 900 mM solution) . The mixture was agitated with nitrogen for 2 hours. Deprotection and washing as above. HOBt (0.5 mmol, 68 mg) dissolved DMF (4ml) was stirred at ice bath with DIPCI (0.5 mmol, 80μl) for 10 mm. 3- amidmo-benzoic acid TFA salt (0.5 mmol, 139 mg.) was added and stirring continued for 10 mm. at room temperature. The mixture was then transferred to the reaction vessel on the Symphony and agitated for 10 hours with nitrogen. The resm was then washed with DMF (6x5ml) , DCM (6x5ml) and air dried. The product was cleaved from the resm with 10% triethylsilane m TFA (10ml) for 30 minutes, the resm filtered off, the TFA solution evaporated to dryness and triturated with diethyl ether to give the crude product . The crude product was then dissolved m water (10ml) , filtered and purified by preparative reverse phase Hplc. H nmr (d^methanol) d 8.18 (IH, s) ; 8.10 (IH, d, J=7.5Hz); 7.87 (IH, d, J=7.5Hz); 7.72 (IH, t, J=7.5Hz); 7.40 (5H, m) ; 7.10 (5H, m) ; 5.53 (IH, s) ; 4.55 (dd, partially obscured by solvent); 3.08 (IH, dd) ; 2.87 (IH, dd) . MS TOF 444 (M+l + ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/TFA) rt 11.70 mm. Compounds made by the above method :- Example 35. 3 -Amidino-benzoyl-D-phenylglycinyl-L-asparagine amide IH nmr (D20) d 8.10 (IH, s) ; 8.04 (IH, d, J=7.5Hz); 7.91 (IH, d, J=7.5Hz); 7.66 (IH, t, J=7.5Hz); 7.42 (5H, m) ; 5.47 (IH, s) ; 4.73 (m, partially obscured by solvent); 2.71 (2H, m) ; 2.59 (2H, m) . MS TOF 411 (M+l + ) . Hplc (Jupιter5 C18, Gradient 2, water/acetonitrile/TFA) rt 10.49 mm. Example 36. 3-Amidino-benzoyl-D-phenylglycinyl-D-2-naphthylalanine amide X H nmr (d 4 methanol) d 8.18 (IH, s) ; 8.12 (IH, d, J=7.5Hz) ; 7.95 (IH, d, J=7.5Hz) ; 7.74 (5H, m) ; 7.42 (3H, m) ; 7.25 (5H,m) ; 5.63 (IH, s) ; 3.12 (IH, m) ; signals at ~4.8 and 3.3 obscured by solvent. MS TOF 494 (M+l ^ ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/TFA) rt 15.46 mm. Example 37. 3-Amidino-benzoyl-D-phenylglycinyl-D-valine amide : H nmr (d 4 methanol) d 8.44 (IH, s) ; 8.36 (IH, d, J=7.5Hz); 8.10 (IH, d, J=7.5Hz); 7.86 (IH, t, J=7.5Hz); 7.70 (2H, m) ; 7.55 (3H, m) ; 5.96 (IH, s) ; 4.40 (lH d); 2.21 (IH, m) ; 1.13 (6H, t). ). MS TOF 396 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 5.71 min. Example 38. 3 -Amidino-benzoyl-D-phenylglycinyl-D-lysine .amide X H nmr (D 2 0) d 8.10 (IH, s) ; 8.04) (IH, d, J=7.5Hz); 7.95 (IH, d, J=7.5Hz); 7.66 (IH, t, J=7.5Hz); 7.43 (5H, m) ; 5.56 (1H,S); 4.26 (IH, m) ; 2.91 (2H, t); 1.77(2H, m) ; 1.62 (2H, m) ; 1.42 (2H, m) . MS TOF 425 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 10.73 min. Example 39. 3-Amidino-benzoyl-D-phenylglycinyl-L-lysine .amide X H nmr (D 2 0) d 8.08 (IH, s) ; 8.00 (IH, d, J=7.5Hz); 7.99 (IH, d, J=7.5Hz); 7.61 (IH, t, J=7.5Hz); 7.40 (5H, m) ; 5.52 (IH, s) ; 4.21 (IH, m) ; 2.68 (2H, m) ; 1.74 (IH, m) ; 1.60 (IH, m) ; 1.40 (2H, m) ; 1.08 (IH, m) . MS TOF 425 (M+l τ ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 10.61 min. Example 40. 3-Amidino-benzoyl-D-phenylglycinyl-D,L-phenylglycinyl-L- valine amide H nmr (CD 3 CN) mixture of diastereomers d 8.39 (IH, m) ; 8.15 (IH, m) ; 7.93 (IH, m) ; 7.70 (IH, m) ; 7.41 (10H, m) ; 5.71 (IH, d) ; 5.46 (IH, m) ; 4.14 (IH, m) ; 2.77 (IH, m) ; 0.97 (3H, m) ; 0.65 (3H, m) . MS TOF 529 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 13.10 min. Example 41. 3 -Amidino-benzoyl -D-phenylglycinyl-D-asparagine-D- asparagine amide -H nmr (D 2 0) d 8.28 (IH, s) ; 8.20 (IH, d, J=7.5Hz); 8.08 (IH, d, J=7.5Hz); 7.82 (IH, t, J=7.5Hz); 7.59 (5H, m) ; 5.72 (IH, s) ; 4.70 (IH, dd) ; 2.85 (4H, m) .. MS TOF 526 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 11.14 min. Example 42. 3 -Amidino-benzoyl-D-phenylglycinyl-D-leucine amide -H nmr (CD 3 CN) d 8.23 (IH, s) ; 8.14 (IH, d, J=7.5Hz); 7.93 (IH, d, J=7.5Hz); 7.72 (IH, t, J=7.5Hz); 7.48 (5H, m) ; 5.62 (lH,s); 4.32 (IH, m) ; 1.58 (2H, m) ; 0.87 (6H, dd) . MS TOF 410 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 14.98 min. Example 43. 3-Amidino-benzoyl-D-phenylglycinyl-L-phenylalanine amide : H nmr (CD 3 CN) d 8.20 (IH, s) ; 8.14 (IH, d, J=7.5Hz); 7.96 (IH, d, J=7.5Hz); 7.72 (IH, t, J=7.5Hz); 7.35 (5H, m) ; 7.14 (3H, m) ; 7.04 (2H, m) ; 5.60 (IH, s); 5.46 (IH, dd) ; 3.15 (IH, dd) ; 2.80 (IH, m) . MS TOF 444 (M+1 * ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 12.78 min. Example 44. 3-Amidino-benzoyl-D-phenylglycinyl-L-2-naphthylalanine .amide : H nmr (d 4 methanol) d 8.26 (IH, s) ; 8.19 (IH, d, J=7.5Hz); 7.95 (IH, d, J=7.5Hz); 7.80 (IH, m) ; 7.67 (3H, m) ; 7.53 (IH, s) ; 7.45 (2H, m) ; 7.25 (lH,d); 7.08 (3H, m) ; 6.92 (2H,t); 5.61 (IH, s) ; 3.45 (IH, m) ; 3.0 (IH, m) signal at ~ 4.8 obscured by solvent. MS TOF 494 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 16.17 min. Example 45. 3-Amidino-benzoyl-D-phenylglycinyl-L-valine amide H nmr (CD 3 CN) d 8.17 (IH, s) ; 8.08 (IH, d, J=7.5Hz); 7.89 (IH, d, J=7.5Hz); 7.65 (IH, t, J=7.5Hz); 7.37 (5H, m) ; 5.64 (IH, s) ; 4.08 (lH d); 1.97 (m, partially obscured by solvent); 0.63 (6H, t) . MS TOF 396 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 9.34 min. Example 46. 3-Amidino-benzoyl-D-phenylglycinyl-D-asparagine amide H nmr (D 2 0) d 7.91 (IH, s) ; 7.86 (IH, d, J=7.5Hz); 7.63 (IH, d, J=7.5Hz); 7.48 (IH, t, J=7.5Hz); 7.23 (5H, m) ; 5.30 (IH, s) ; 4.42 (m, partially obscured by solvent); 2.57 (2H, m) . MS TOF 411 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 10.23 min. Example 47. 3 -Amidino-benzoyl-L-phenylglycinyl-D-2 -naphthylalanine amide l E nmr (CD 3 CN/D 2 0) 8.17 (IH, s) ; 8.10 (IH, d) ; 7.92 (IH, d) ; 7.81 (IH, m) ; 7.67 (3H, m) ; 7.53 (IH, s) ; 7.48 (2H, m) ; 7.22 (IH, d) ; 7.12 (3H, m) ; 6.98 (2H, m) ; 5.56 (lH,s); 4.70 (IH, dd) ; 3.35 (IH, dd) ; 3.00 (lH,dd). MS TOF 494 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 15.46 min. Example 48. 3 -Amidino-benzoyl-L-phenylglycinyl-L-2 -naphthylalanine amide l U nmr (CD 3 CN) 8.07 (IH, s) ; 8.01 (IH, d) ; 7.92 (IH, d) ; 7.78 (IH, m) ; 7.66 (2H, s) ; 7.41 (4H, m) ; 7.14 (6H, d) ; 5.46 (lH,s); 4.73 (IH, dd) ; 3.38 (IH, dd) ; 3.08 (lH,dd). MS TOF 494 (M+1") . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 14.51 min. Example 49 . 3 -Amidino-benzoyl-D-phenylglycinyl-D-4-chloro phenylalanine amide -H nmr (CD 3 CN) d 8.39 (IH, s) ; 8.32 (IH, d, J=7.5Hz); 8.13 (IH, d, J=7.5Hz); 7.90 (IH, t, J=7.5Hz); 7.51 (5H, m) ; 7.40 (4H, ABq); 5.70 (IH, s) ; 4.77 (IH, dd) ; 3.36 (IH, dd) ; 3.09 (IH, dd) . MS TOF 479 (M+l + ) . Hplc (Jupiterδ C18, Gradient 2, water/acetonitrile/TFA) rt 13.63 min. Example 50. 3-Amidino-benzoyl-D-phenylglycinyl-D-isoleucine .amide MS TOF 410 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 14.36 min. Example 51. 3 -Amidino-benzoyl-D-phenylglycinyl-D-tyrosine amide MS TOF 460 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 12.56 min. Example 52. 3 -Amidino-benzoyl-D-phenylglycinyl-D-l-naphthylalanine amide MS TOF 494 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 22.19 min. Example 53. 3 -Amidino-benzoyl-D-phenylglycinyl-D-threonine amide MS TOF 398 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 10.63 min. Example 54. 3 -Amidino-benzoyl-D-phenylglycinyl-D-histidine amide MS TOF 434 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 10.04 min. Example 55 . 3 -Amidino-benzoyl-D-phenylglycinyl-D-phenylalanine amide MS 444 TOF (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 14.82 min. Example 56. 3 -Amidino-benzoyl-D-phenylglycinyl-D-phenylalaninyl D- proline amide MS TOF 541 (M+l τ ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 11.54 min. Example 57. 3 -Amidino-benzoyl-D-phenylglycinyl-D-tryptophan amide MS TOF 483 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 17.14 min. Method 4: By solution phase strategy: Typically an activated Boc-amino acid was treated with an amine (primary or secondary) or alcohol (leq.) . Activation of Boc protected amino acid was by HATU or TBTU/ DIPEA(1:2), all couplings (minimum 120 min.) were carried out in DMF. After an aqueous work up the deprotection of the Boc group was achieved with TFA. Other acid substituents were added as the HOBt or HOAt esters either by activation with HBTU/HATU or DIPCI with or without Boc protection of amino groups. The final products were purified by preparative reverse phase Hplc. Example 58. 3 -Amidino-benzoyl-D-phenylglycine -1-adamantylamide Boc D-phenylglycine (251 mg, 1 mmol.) was dissolved in DMF (3ml) with HATU (380 mg . , 1 mmol.) and DIPEA(350μl ., 2 mmol.) . To this mixture was added 1-adamantylamine hydrochloride (187 mg . , 1 mmol.) and DIPEA (170μl., 1 mmol.) . The mixture was stirred overnight. The mixture was then taken up into ethylacetate and washed with water, sodium carbonate solution, water, 10% hydrochloric acid solution and water. The ethylacetate was evaporated without drying and treated immediately with TFA for 30 mm. The TFA was then evaporated to dryness and the product triturated with diethylether . TEA (lml) was added and evaporated to dryness. HOBt (1 mmol, 136 mg) dissolved DMF (4ml) was stirred at 0°C and treated with DIPCI (1 mmol, 160μl) , for 10 mm. 3 amidino benzoic acid TFA salt (1 mmol., 278 mg.) was added and stirring continued for 10 mm. at room temperature. The mixture was then added to the D- phenylglycme adamantyl amide and stirred overnight. The crude product was dissolved m water/acetonitrile (20ml) , filtered and purified by preparative Hplc to yield pure product (150 mg.) Η nir (D 2 0/CD 3 CN) 8.21 (IH, s) ; 8.13 (IH, d, J=7.5Hz); 7.92 (IH, d, J=7.5Hz) ;7.70 (IH, t, J=7.5Hz) ); 7.46 (2H, m) ; 7.34 (3H, m) ; 5.52 (IH, s); 2.15-1.52 (15H, m) . M.S. TOF 431 (M+l + ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/ TFA) rt 19.54 mm. Compounds made by the above method: Example 59. 3 -Amidino-benzoyl-D-phenylglycine -1- ad.amantylmethy1amide L H nmr (D 2 0/CD 3 CN) 8.23 (IH, s) ; 8.15 (IH, d, J=7.5Hz); 7.85 (IH, d, J=7.5Hz) ;7.71 (IH, t, J=7.5Hz); 7.46 (2H, m) 7.35 (3H, m) ; 5.59 (IH, d) ; 3.0 (2H,s obscured by solvent); 2.15-1.52 (15H, m) . M.S. TOF 445 (M+l τ ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/ TFA) rt 21.35 mm. Example 60 . 3 -Amidino-benzoyl-D-phenylglycine-2 -phenylethyl.amide H nmr (d 4 methanol) 8.18 (2H, m) ; 7.87 (IH, d, J=7.5Hz); 7.60 (IH, t, J=7.5Hz); 7.30 (5H, m) ; 7.02 (5H, m) ; 5.53 (IH, s) ; 3.32 (IH, m) ; IH signal at ~3.25 obscured by solvent); 2.68 (2H, t) . M.S. TOF 401 (M+l + ) . Hplc (Kromasil C4 , Gradient 1, water/acetonitrile/TFA) rt 15.56 mm. Example 61. 3-Amidino-benzoyl-D-phenylglycine-2- (1-adamantyl) ethyl ester H nmr (d 4 methanol) 8.27 (2H, m) ; 7.94 (IH, d J=7.5Hz); 7.72 (IH, t, J=7.5Hz); 7.42 (5H, m) ; 5.66 (IH, s) ; 4.25 (2H, m) ; 1.82 (3H, s) ; 1.61 (6H, m) ; 1.38 (8H, m) . M.S. TOF 459 (M+l + ) . Hplc (Kromasil C4 , Gradient 1, water/acetonitrile/ TFA) rt 23.17 mm. Example 62. 3 -Amidino-benzoyl-D-phenylglycine-2 -methylbenzylamide H nmr (CD 3 CN) 8.14 (2H, m) ; 7.88 (IH, d, J=7.5Hz); 7.65 (IH, t, J=7.5Hz); 7.45 (2H., m) ; 7.35 (3H, m) ; 7.04 (4H, m) ; 5.59 (IH, s) ; 4.30 (2H, AB q) ; 2.13 (3H, s). M.S. TOF 401 (M+l + ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/ TFA) rt 14.81 mm. Example 63. 3 -Amidino-benzoyl-D-phenylglycine-4-benzoyl piperidinamide H nmr (DMSO) 8.40 (2H, m) ; 8.10 (IH, d) ; 7.70 ,(lH,t); 7.50(10H, m) ; 5.55 (IH, s) ; 3.60 (IH, m) ; 2.5 (2H, m);.1.00, , (6H,m) ; .S. TOF 469 (M+l + ) . Hplc (JupiterS C18, Gradient 1, water/acetonitrile/ TFA) rt 11.43 mm. Example 64. 3 -Amidino-benzoyl-D-phenylglycine-4-methylbenzylamide H nmr (CD 3 CN) 8.30 (IH, s) ; 8.22 (IH, d, J=7.5Hz); 7.95 (IH, d, J=7.5Hz); 7.71 (IH, t, J=7.5Hz); 7.51 (2H., m) ; 7.34 (3H, m) ; 7.04 (4H, s) ; 5.76 (IH, s) ; 4.30 (2H, AB q) ; 2.30 (3H, s). M.S. TOF 401 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/ TFA) rt 15.20 min. Ex.am.ple 65. 3 -Amidino-benzoyl-D-phenylglycine-1-naphthylmethylamide Η nmr (CD 3 CN/D 2 0) 8.14 (IH, s) ; 8.02 (IH, d, J=7.5Hz); 7.84 (3H, m) ; 7.60 (IH, d, J=7.5Hz); 7.32 (5H, m, J=7.5Hz) ; 7.12 (5H., m) ; 5.58 (IH, s); 4.50 (2H, AB q) ; 3.03 (2H, s) . M.S. TOF 436 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/ TFA) rt 16.77 min. Example 66. 3 -Amidino-benzoyl-D-phenylglycinyl-D-phenylalanine -N- pyrrolidinamide : H nmr (CD 3 CN/D 2 0) 8.14 (IH, s) ; 8.03 (IH, d, J=7.5Hz); 7.94 (IH, d, J=7.5Hz); 7.70(1H, t,J=7.5Hz); 7.42 (5H, m) ; 7.42 (5H., m) ; 5.62 (IH, s) ; 4.80 (IH, t);3.40 ,( IH, m) ; 3.20 (2H, m);3.02 ,(2H,d); 2.80 ,(lH,m); 1.65 , (4H,m) ; . M.S. TOF 499 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/ TFA) rt 14.03 min. Example 67. 3 -Amidino-benzoyl-D-phenylglycine-3 -methylbenzylamide Η nmr (CD 3 CN) 7.95 (IH, s) ; 7.81 (IH, d, J=7.5Hz); 7.60 (IH, d, J=7.5Hz); 7.45 (IH, t, J=7.5Hz); 7.23 (2H., m) ; 7.12 (3H, m) ; 6.60-6.75 (4H, m) ; 5.40 (IH, s) ; 4.10 (2H, AB q) ; 1.95 (3H, s) . M.S. TOF 401 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/ TFA) rt 14.52 min. Example 68. 3 -Amidino-benzoyl-D-phenylglycine-2adamantylamide MS TOF 431 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.68 min. Method 5: By solid phase strategy using Boc amino acids attached to Kaiser Oxime resm (Novabiochem) : Typically the resm is treated with a 2 fold excess of the Boc phenylglycine symmetrical anhydride. The resm was washed with DCM/DMF then DCM and deprotected with 25%TFA DCM before further modification. The resm was further modified by the attachment of acids. Activation of Boc protected ammo acid (2-5eq) was by TBTU/ DIPEA, all couplings (minimum 120 mm.) were carried out in DCM/DMF. Deprotection of the Boc group was achieved with 25%TFA m DCM. Other acid substituents were added as the HOBt or HOAt esters either by activation with HBTU/HATU or DIPCI with or without Boc protection of ammo groups. Cleavage of the products from the resm was by treatment (1 day, ambient) with an amme or alcohol m chloroform, washing with chloroform and methanol/chloroform. Example 69. 3 -Amidino-benzoyl-D-phenylglycine cyclohexyl .amide Boc-D-Phenylglycme (0.5 mmol, 126 mg) was dissolved in DCM (5ml) and treated with DIPCI (0.5 mmol., 80μl) and stirred for 10 mm. A white precipitate forms which was dissolved by adding DMF. This mixture was added to Oxime resm (0.11 mmol, 330 mg, 0.33 mmol./g) previously swelled with DCM. 4 -Dimethyl ammo pyridme (10 mg, cat . ) was added and the mixture swirled for 2 hours . The resm was filtered and washed with DMF/DCM then DCM. The resm was then treated with 25% TFA/DCM (20ml) for 20 mm. , filtered and washed with DCM. HOBt (0.5 mmol, 68 mg) dissolved m DMF (4ml) was stirred at 0°C with DIPCI (0.5 mmol, 80μl) for 10 mm. 3 amidmo-benzoic acid TFA salt (0.5 mmol, 139 mg.) was added and stirring continued for 10 mm. at room temperature. The mixture was then added to the phenylglycine-oxime resm and agitated for 2 hours. The resm was filtered washed with DMF, DCM and chloroform then treated with cyclohexylamme (0.3 mmol. 40μl) in chloroform (2ml) and agitated for 1 day. The resm was then filtered off and washed with chloroform (10ml) and chloroform/methanol (1 : 1, 10ml). The combined organic extracts were evaporated to dryness and washed with 10% aqueous acetic acid (5-10ml) . The aqueous insoluble residue was dissolved m acetonitπle/water and lyophilised. MS TOF 379 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.62 mm. Example 70. 3 -Amidino-benzoyl-D-phenylglycine-3 , 3 -dimethylbutylamide MS TOF 382 (M+r) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 13.90 mm. Example 71. 3 -Amidino-benzoyl-D-phenylglycine-1, 2,3, 4-tetrahydro-1- naphthylamide MS TOF 427 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.74 mm. Example 72. 3-Amidino-benzoyl-D-phenylglycine-R, S 3-methyl-2- butylamide MS TOF 367 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.21 + 10.42 mm. Example 73. 3 -Amidino-benzoyl-D-phenylglycine-3 -phenylpropylamide MS TOF 415 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 14.00 mm. Example 74. 3 -Amidino-benzoyl-D-phenylglycine-3 -trifluoromethyl benzylamide MS TOF 455 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 14.32 min. Example 75. 3 -Amidino-benzoyl-D-phenylglycine-3-fluorobenzylamide MS TOF 405 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.56 min. Example 76. 3 -Amidino-benzoyl-D-phenylglycine-2-methyl propylamide MS TOF 353 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.10 min. Example 77. 3 -Amidino-benzoyl-D-phenylglycine-4-phenyl butylamide MS TOF 429 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 14.96 min. Example 78. 3-Amidino-benzoyl-D-phenylglycine-cyclohexylmethylamide MS TOF 493 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.52 min. Example 79. 3 -Amidino-benzoyl-D-phenylglycine-2 , 2 diphenylethylamide MS TOF 478 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.65 min. Example 80. 3 -Amidino-benzoyl-D-phenylglycine-R-1- (1- naphthyl) ethylamide MS TOF 450 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.26 min. Example 81. 3-Amidino-benzoyl-D-phenylglycine-S-l- (2- naphthyl) ethylamide MS TOF 450 (M+l τ ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.19 mm. Method 6: By solution phase strategy: Typically an activated Fmoc ammo acid was treated with an alcohol (leq.) which contains a Boc protected ammo group. Activation of Fmoc protected ammo acid was by HATU or TBTU/ DIPEA(1:2), all couplings (minimum 120 mm.) were carried out m DMF with DBU as catalyst After an aqueous work up the deprotection of the Fmoc group was achieved with 20% piperidme in DMF followed by evaporation and column chromatography. Other acid substituents were added as the HOBt or HOAt esters either by activation with HBTU/HATU or DIPCI with or without Boc protection of ammo groups. The products were purified by preparative reverse phase Hplc, followed by deprotection of the ammo groups with TFA. Further modification to acetamidme or amidine can be achieved by known literature methods . (2 , 3) Ex-ample 82. 3-Amidino-benzoyl-D-phenylglycine - (4-piperidinyl) methyl ester Fmoc D-Phenylglycine ( 1 mmol., 374 mg) was dissolved m DMF (5ml) with HATU (1 mmol., 380 mg) and DIPEA(2 mmol., 350μl) . To this mixture was added N-Boc 4-hydroxymethyl piperidme (215 mg, 1 mmol.) and DBU (lOOμl) . The mixture was stirred overnight. The mixture was then taken up into ethylacetate (50ml) and washed with water, sodium carbonate solution, water, 10% hydrochloric acid solution and water. The ethylacetate layer was dried over magnesium sulphate, filtered and evaporated. The product was then treated with 20% piperidme m DMF for 90 mm. this was then evaporated to dryness and then dissolved m methanol and adsorbed onto silica gel 60. The material was then chromatographed on silica gel 60, eluting first with hexane/ethylacetate (2:1) then hexane/ethylacetate (1:2), the required product eluting the second solvent. The combined fractions were evaporated to dryness . HOBt (1 mmol, 136 mg) dissolved m DMF (4ml) was stirred at 0°C with DIPCI (1 mmol, 160μl) for 10 mm. 3 amidmo-benzoic acid TFA salt (1 mmol., 278 mg.) was added and stirring continued for 10 mm. at room temperature. The mixture was then added to the D- phenylglycme N-Boc-4-pιperιdme methyl ester and stirred overnight. The mixture was evaporated to dryness on high vacuum, water and acetonitπle added to allow full dissolution and the whole lyophilised. The resulting crude product was treated with TFA/water (9:1) for 30 mm. and evaporated to dryness. The crude product was dissolved in water/acetonitrile (20ml) , filtered and purified by preparative reverse phase Hplc. Producing pure product (200mg) . L H nmr (D 2 0) 8.12 ,(lH,m); 8.05 (IH, d) ; 7.90 (IH, d) ; 7.65 (IH, t) ; 7.45 (5H, m) ; 5.65 ,(lH,s); 4.10 ,(2H,d); 3.30 (2H,m); 2.80 (2H, m) ; 1.90 (IH, m) ; 1.75 (2H, m) ; 1.30 (2H, m) ; MS TOF 395 (M+l + ) . Hplc (Jupιter5 C18, Gradient 2, water/acetonitrile/TFA) rt 12.48 mm. Compounds made by the above method :- Example 83 3 -Amidino-benzoyl-D-phenylglycine-2- (4-piperidinyl) ethyl ester l K nmr (D 2 0) 8.12 ,(lH,m); 8.05 (IH, d) ; 7.90 (IH, d) ; 7.65 (IH, t) ; 7.45 (5H, m) ; 5.65 ,(lH,s); 4.25 , (2H,m); 3.20 (2H,m) ; 2.60 (2H, m) ; 1.65 (2H, m) ; 1.50 (2H, m) ; 1.20 (3H, m) ; MS TOF 409 (M+l + ) . Hplc (Jupιter5 C18, Gradient 2, water/acetonitrile/TFA) rt 13.14 mm. Example 84 . 3 -Amidino-benzoyl-D-phenylglycine-2 - (N-acetimino-4 - piperidinyl) ethyl ester -H nmr (D 2 0) 8.22 ,(lH,m); 8.20 (IH, d) ; 8.02 (IH, d) ; 7.80 (IH, t) ; 7.60 (5H, m) ; 5.75 ,(lH,s); 4.35 ,(2H,m); 3.85 (2H,m) ; 3.00 (3H, m) ; 2.30 (3H,s); 1.65 (3H, m) ; 1.50 (IH, m) ; 1.20 (2H, m) ; MS TOF 450 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 14.92 min. Example 85. 3 -Amidino-benzoyl-D-phenylglycine- (N-acetimino-4- piperidinyl) methyl ester • H nrar (D 2 0) 8.12 ,(lH,m); 8.05 (IH, d) ; 7.90 (IH, d) ; 7.65 (IH, t) ; 7.40 (5H, m) ; 5.60 ,(lH,s); 4.05 ,(2H,m); 3.75 (2H,m) ; 3.10 (IH, m) ; 2.10 (3H,d); 1.90 (IH, m) ; 1.60 (2H, m) ; 1.20 (2H, m) ; 0.90 (lH,m); MS TOF 436 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 13.34 min. Example 86. 3 -Amidino-benzoyl-D-phenylglycine- (N-amidino-4- piperidinyl) methyl ester : H nmr (D,0) 8.02 ,(lH,m); 7.97 (IH, d) ; 7.80 (IH, d) ; 7.55 (IH, t) ; 7.40 (5H, m) ; 5.55 ,(lH,s); 4.05 , (2H,m); 3.65 (2H,m) ; 2.80 (2H, m) ; 1.80 (lH,m); 1.50 (2H, m) ; 1.10 (IH, m) ; 0.80 (lH,m); MS TOF 437 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 13.61 min. Example 87. 3-Amidino-benzoyl-D-phenylglycine-2- (N-.amidino-4- piperidinyl) ethyl ester : H nmr (D 2 0) 8.17 ,(lH,m); 8.07 (IH, d) ; 7.93 (IH, d) ; 7.70 (IH, t) ; 7.45 (5H, m) ; 5.60 ,(lH,s); 4.25 ,(2H,m); 3.55 (2H,m) ; 2.75 (2H, m) ; 1.60 (4H,m); 1.25 (IH, m) ; 1.00 (2H, m) ; MS TOF 451 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 14.97 min. Example 88. 2 -Hydroxy- 5-amidino-benzoyl D-phenylglycine-4- aminomethylcyclohexyl methylamide 5-Bromosalicylic acid (9.31mmol., 2.02g) was dissolved in DMF (4.5ml) and treated with copper (1) cyanide (11.33 mmol., 1.2eq., 1.015g) and heated under reflux for 4 hours. The solution was allowed to cool and poured into a solution of ferric chloride (2g) and concentrated hydrochloric acid (0.7ml) in water (3ml) . The mixture was heated for 10 min. at 60°C, then cooled and filtered, the solid was washed with water, then recrystallised ethanol/water . Product 0.73g, 48%. On the Symphony bis-1 , 4 -ammomethylcyclohexane 2 chlorotrityl chloride resin (0.1 mmol) (See method 1) was treated with Fmoc-D-Phenylglycine (0.5 mmol, 187mg) , DMF (2.5ml), TBTU in DMF (1.25ml of a 450mM solution) and DIPEA in DMF (1.25ml of a 900 mM solution) and agitated with nitrogen for 2 hours. Deprotection and washing as above . HOBt (0.5 mmol, 68 mg) dissolved in DMF (4ml) was stirred at 0°C with DIPCI (0.5 mmol, 80μl) for 10 min. 2- hydroxy-5-cyanobenzoic acid (0.5 mmol, 84 mg.) was added and stirring continued for 10 min. at room temperature. The mixture was then transferred to the reaction vessel on the Symphony and agitated for 10 hours with nitrogen. The resin was washed with DMF (6x5ml) , DCM (6x5ml) and air dried. The product was cleaved from the resin with 10% triethylsilane in TFA (10ml) for 30 minutes, the resin filtered off, the TFA solution evaporated to dryness and triturated with diethyl ether to give the crude product. The crude product was dissolved in saturated hydrogen chloride in ethanol (10ml) , sealed and allowed to stand overnight. The solution was evaporated to dryness and treated with saturated ammonia m ethanol (10ml) and allowed to stand overnight. The solution was then evaporated to dryness, dissolved m water and purified by reverse phase Hplc. H nmr (D 2 0) , 8.35 , (lH,s); 7.90 ,(lH,d); 7.55 ,(5H,m); 7.25 , (lH,d); 5.65 (IH, s) ; 3.20 (2H, m) ; 2.90 (2H, m) ; 1.40-1.80 (7H, m) ; 0.95 (3H, m) MS TOF 438 (M+l + ) . Hplc (Techogel5 C18, Gradient 2, water/acetonitrile/TFA) rt 14.11 mm. Example 89. 2-Amino-5-amidinobenzoyl-D-phenylglycine-4- aminomethylcyclohexyl methylamide 2-Ammo-5-bromo benzoic acid (1.6 mmol., 345mg) was dissolved m N-methylpyrrolidone (5ml) and treated with copper (1) cyanide (2.39 mmol., 1.5eq., 207mg) under reflux for 4.5 hours. The solution was allowed to cool and poured into water (10ml) . The mixture was acidified to pH3 with hydrochloric acid and extracted with ethylacetate, the ethylacetate was washed with water, dried over magnesium sulphate and evaporated to a yellow solid (145mg, 56%) . On the Symphony bιs-1 , 4-ammomethylcyclohexane-2- chlorotπtyl resm (0.1 mmol) (See method l)was treated with Fmoc-D-Phenylglycine (0.5 mmol, 187 mg) , DMF (2.5ml), TBTU m DMF(1.25ml of a 450mM solution) and DIPEA m DMF (1.25ml of a 900 mM solution) for 2 hours. Deprotection and washing as above. HOBt (0.5 mmol, 68 mg) dissolved m DMF (4ml) was stirred at 0°C with DIPCI (0.5 mmol, 80μl) for 10 mm. 2-ammo- 5 -cyanobenzoic acid (0.5 mmol, 84 mg . ) was added and stirring continued for 10 mm. at room temperature. The mixture was transferred to the reaction vessel on the Symphony and agitated for 10 hours with nitrogen. The resin was then washed with DMF (6x5ml) , DCM (6x5ml) and air dried. The product was cleaved from the resin with 10% triethylsilane in TFA (10ml) for 30 minutes, the resin filtered off, the TFA solution evaporated to dryness and triturated with diethyl ether to give the crude product . The crude product was then dissolved in saturated hydrogen chloride in ethanol (10ml) , sealed and allowed to stand overnight. The solution was then evaporated to dryness and treated with saturated ammonia in ethanol (10ml) and allowed to stand overnight. The solution was then evaporated to dryness, dissolved in water and purified by reverse phase Hplc. "H nmr (D 2 0) Mixture of cyclohexyl cis and trans isomers 7.80 (lH,s); 7.50 (IH, d, J=7.5Hz); 7.35 (5H, m) ; 6.75 (IH, d, J=7.5Hz) ; .5.35 (IH, s) ; 2.87 (2H, m) ; 2.60 (2H, m) ; 1.00-1.60 (7H, m) ; 0.70 (3H, m) MS TOF 437 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 13.11 min. (major) , 13.31 (minor). Prepared by Method 2 Example 90. 3 -Amidino-benzoyl-D-phenylglycinyl-D-2 -naphthylalanine : H nmr (CD 3 CN) 8.00 (IH, s) ; 7.95 (IH, d) ; 7.87 (IH, d) 7.72 (4H, m) ; 7.63 (2H, m) ; 7.38 (3H, m) ; 7.25 (4H, m) ; 5.60 (IH, s) ; 4.70 (IH, m) ; 3.25 (2H, m) . MS TOF 495 (M+l + ) . Hplc (Magellan C8, Gradient 3, water/acetonitrile/TFA) rt 10.19 min. Example 91. 3 -Amidino-benzoyl-D-phenylglycine- 1, 2,3,4, tetrahydoisoquinolin-2 -yl-3 -carboxylic acid " H nmr (DMSO) mixture of isomers and rotomers (only one isomer cited in nmr) 8.28 (IH, s) ; 8.18 (IH, d) ; 7.90 (IH, d) ; 7.69 (IH, t) ; 7.35 (4H, m) ; 7.15 (5H, m) ; 6.30 (IH, s) ; 5.15, (lH,m); 5.70 ,(2H,m); 3.15 , (2H,d) . MS TOF 457 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 13.84 and 14.33 min. Example 92. 3 -Amidino-benzoyl-D-phenylglycinyl-D-2 -naphthylalaninyl- D-proline : H nmr (CD 3 CN) d 8.15 (IH, s) ; 8.08 (IH, d) ; 7.95 (IH, d) ; 7.82 (5H, m) ; 7.62 ,(lH,m); 7.22 - 7.5 (7H,m); 5.68 (IH, s) ; 5.01 (IH, m) ; 4.25 (IH, m) ; 3.50 , (lH,m); 3.1,(2H,m); 2.22 ,(lH,m); 2.0 ,(3H,m); . MS TOF 592 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 16.04 min. Example 93. 3 -Amidino-benzoyl-D-phenylglycine-D-2 -naphthylalaninyl- L-pipecolic acid Η nmr (CD 3 CN) 7.95 (IH, s) ; 7.90 (IH, d) ; 7.85 (IH, d) ; 7.62 (5H, m) ; 7.25 (8H, m) ; 5.60 (IH, s) ; 5.15 (IH, t) ; 4.90 (IH, m) ; 3.60 , (lH,m); 3.00 (4H, m) ; 2.05 (IH, m) ; 1.45 , (2H,m) ; 1.15 ,(lH,m); 0.08 ,(lH,m). MS TOF 606 (M+l + ) . Hplc (Magellan C8 , Gradient 3, water/acetonitrile/TFA) rt 14.90 min. Example 94. 3 -Amidino-benzoyl-D-phenylglycine-D-2 -naphthylalaninyl- D-pipecolic acid Η nmr (CD 3 CN) 7.95 (IH, s) ; 7.90 (IH, d) ; 7.85 (IH, d) ; 7.62(5H, m) ; 7.25 (8H, m) ; 5.45 (IH, s) ; 5.10 (IH, t) ; 5.00 (IH, m) ; obscured by solvent3.60 ,(lH,m); 3.00 (4H, m) ; 2.05 (IH, m) ; 1.45 ,(2H,m); 1.25 , (lH,m); 1.10 , (lH,m) . MS TOF 606 (M+l + ) . Hplc (Magellan C8 , Gradient 3, water/acetonitrile/TFA) rt 14.71 min. Example 95. 3 -Amidino-benzoyl-D-naphthylglycinyl-D-2- naphthylalaninyl-D-proline Η nmr (CD 3 CN) d 8.13 (IH, s) ; 8.0 (2H, m) ; 7.85 (8H, m) ; 7.62 ,(lH,t); 7.45 (4H, m) ; 7.05 (2H,m); 6.35 (IH, s) ; 5.10 (IH, m) ; 4.34(1H, m) ; 3.67 ,(2H,m); 3.20, (2H,m); 2.22 , (lH,m) ; 2.0 (obscured by solvent) , (3H,m) . MS TOF 642 (M+1 * ). Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 18.14 min. Prepared by method 3 Example 96. 3 -Amidino-benzoyl-D-naphthylglycinyl-D-2 -naphthylalanine amide X H nmr (CD 3 CN) d 8.25 (IH, d) ; 8.13 (IH, s) ; 7.95 (H, m) ; 7.85 (H, m) ; 7.74 ,(H,m); 7.65 (lH,t); 7.50 (H,m); 7.39 (2H,d); 6.83 (H,m); 6.22 (IH, s); 4.85 (IH, m) ; 3.25, (2H,m). MS TOF 545 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 17.32 min. Prepared by method 4 Example 97. 3 -Amidino-benzoyl-D-phenylglycine-2- (4- methoxyphenyl) ethylamide H nmr (D4 methanol) 8.20 (2H, m) ; 8.00 (IH, d) ; 7.73 (IH, t) ; 7.40 (5H, m) ; 6.85 (4H, m) ; 5.60 (IH, m) ; 3.75 (2H, m) ; 2.70 (2H, m) ; 1.85 (3H, s) . MS TOF 431 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.09 min. Example 98. 3-Amidino-benzoyl-D-phenylglycine-2- (4- chlorophenyl) ethylamide Η nmr (D4 methanol) 8.28 (IH, s) ; 8.21 ,(lH,d); 7.97 (IH, d) ; 7.73(1H, t); 7.40(5H, m) ; 7.10 (4H, m) ; 5.61 (IH, m) ; 4.45 (2H, m) ; 2.78 (2H, m) . MS TOF 436 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.26 min. Exeimple 99 . 3 -Amidino-benzoyl-D-phenylglycine-4-chloro benzylamide : H nmr (D4 methanol) 8.20 (IH, s) ; 8.11 ,(lH,d); 7.90 (IH, d) ; 7.65(1H, t) ; 7.50(5H, m) ; 7.17 (4H, m) ; 5.60 (IH, m) ; 4.31 (2H, m) . MS TOF 422 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.81 min. Example 100. 3 -Amidino-benzoyl-D-phenylglycine-4-methoxy benzyl.am.ide : H nmr (D4 methanol) 8.22 (IH, s) ; 8.15 ,(lH,d); 7.93 (IH, d) ; 7.68 (IH, t ) ; 7.40 (5H, m) ; 6.95 (4H, m) ; 5.63 (IH, m) ; 4.30 (2H, m) ; 3.75 ,(3H,s). MS TOF 417 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 9.73 min. Example 101. 3 -Amidino-benzoyl-D-phenylglycine-3 -chloro benzylamide : H nmr (D4 methanol) 8.32 (IH, s) ; 8.25 ,(lH,d); 7.95 (IH, d) ; 7.75(1H, t) ; 7.50(5H, m) ; 7.20 (4H, m) ; 5.72 (IH, m) ; 4.40 (2H, m) . MS TOF 422 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.78 min. Example 102. 3 -Amidino-benzoyl-D-phenylglycine-4, 4' -dimethyl dibenzylamide ; H nmr (DMSO) 8.30 (IH, s) ; 8.21 ,(lH,d); 7.95 (IH, d) ; 7.70 (IH, t) ; 7.45 (5H, m) ; 7.10 (10H, m) ; 6.15 (IH, m) ; 4.41 (4H, m) ; 2.30 ,(6H,d). MS TOF 505 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 14.39 min. Example 103. 3-Amidino-benzoyl-D-phenylglycine-N-methyl-2- phenethylamide : H nmr (DMSO) 8.25 (IH, s) ; 8.20 ,(lH,d); 7.95 (IH, d) ; 7.70 (IH, t) ; 7.30 (10H, m) ; 6.02 (IH, m) ; 3.78 (IH, m) ; 3.54 (IH, m) ; 3.35 , (lH,m); 2.85 ,(3H,d); 2.72 ,(lH,m). MS TOF 415 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.65 mm. Example 104. 3 -Amidino-benzoyl-D-phenylglycine-N-methyl- 1- naphthylmethylamide l K nmr (DMSO) 8.35 (IH, s) ; 8.30 (IH, d) ; 8.10 (IH, d) ; 7.85(5H, m) ; 7.60 ,(4H,m); 7.45 (4H, m) ; 6.20 (IH, s) ; 5.15 (2H, m) ; 2.91 (3H, s) . MS TOF 451 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.53 mm. Example 105. 3 -Amidino-benzoyl-D-phenylglycine-S- 1-naphthylethylamide X H nmr (DMSO) 8.25 (IH, s) ; 8.19 (IH, d) ; 8.15 ,(2H,m); 7.95 , (2H,m) ; 7.85 (IH, d) ; 7.70(1H, t); 7.55(5H, m) ; 7.45 (3H, m) ; 5.75 (IH, s) ; 5.70 (IH, m) ; 1.45 (3H, d) . MS TOF 451 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.21 min. Example 106. 3 -Amidino-benzoyl-D-p enylglycine-1-S- cyclohexylethylamide 'H nmr (DMSO) 8.32 (IH, s) ; 8.20 (IH, d) ; 7.95 (IH, d) ; 7.70(1H, t) ; 7.50 (2H, m);7.30 ,(3H,m); 5.72 (IH, s) ; 3.55 (IH, m) ; 0.95-1.80 (11H, m) ; 0.9 (3H, d) . MS TOF 407 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.11 mm. Example 107. 3 -Amidino-benzoyl-D-phenylglycine-+/- (2- methyl) cyclohexylamide H nmr (DMSO) mixture of isomers (major isomer) 8.29 (IH, S); 8.18 (IH, d) ; 7.90 (IH, d) ; 7.70(1H, t); 7.50 (2H, m);7.30 (3H,m); 5.70 (IH, s); 0.9-1.8 (8H, m) ; 0.55 (3H, d) . MS TOF 3.93 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.45 mm. Example 108. 3-Amidino-benzoyl-D-phenylglycine-exo-2-norbornanamide H nmr (CD 3 CN) 8.25 (IH, s) ; 8.17 (IH, d) ; 7.90 (IH, d) ; 7.68(1H, t) ; 7.50 (2H, m);7.30 , (3H,m); 5.55 (IH, s) ; 3.62 (IH, m) ; 1.05-1.80 (10H, m) . MS TOF 391 (M+1 * ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.18 mm. Example 109. 3 -Amidino-benzoyl-D-phenylglycine-4- chlorobenzhydryl.am.ide -H nmr (DMSO) 8.35 (IH, s) ; 8. 29 (IH, d) ; 8.03 (IH, d) ; 7.79(1H, t) ; 7.62 (2H, d) ; 7.41(10H, s) ; 7.18 (2H, d) ; 6.23 , (lH,s); 6.00 , (lH,s). MS TOF 498 (M+1 * ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 13.50 mm. Example 110. 3 -Amidino-benzoyl-D-phenylglycine- 1, 1- diphenylmethylamide -H nmr (DMSO) 8.23 (IH, s) ; 8. 17 (IH, d) ; 7.95 (IH, d) ; 7.70(1H, t) ; 7.52 (2H, m) ; 7.35(11H, s) ; 7.05 (2H, m) ; 6.10 , (lH,s); 5.75 , (lH,s) . MS TOF 464 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.04 mm. Example 111. 3 -Amidino-benzoyl-D-phenylglycine-4 -ethylbenzylamide -H nmr (DMSO) 8.35 (IH, s) ; 8. 25 (IH, d) ; 7.95 (IH, d) ; 7.70(1H, t) ; 7.62 (2H, d) ; 7.41(5H, m) ; 7.21 , (lH,t); 6.90 , (lH,d); 5.90 , (lH,s); 2.60 , (2H,q); 1.20 , (3H,t) . MS TOF 401 (M+1 * ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.03 mm. Example 112. 3 -Amidino-benzoyl-D-phenylglycine-2 -tertiary butyl anilide H nmr (DMSO) 8.21 (IH, s) ; 8. 12 (IH, d) ; 7.85 (IH, d) ; 7.60(1H, t) ; 7.52 (2H, d) ; 7.25(4H, m) ; 7.10 , (2H,m); 6.90 , (lH,m); 5.90 ,(lH,s); 1.00 ,(9H,s). MS TOF 429 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.05 mm. Example 113. 3 -Amidino-benzoyl-D-phenylglycine-3- (1-hydroxyethyl) anilide H nmr (DMSO) 8.45 (IH, s) ; 8. 35 (IH, d) ; 8.08 (IH, d) ; 7.88 (IH, t) ; 7.75 (3H, m) ; 7.55 (4H, m) ; 7.38 , (lH,t); 7.20 , (lH,d); 6.02 ,(lH,s); 4.80 ,(lH,m); 1.45 ,(3H,d). MS TOF 417 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 9.12 mm. Example 114. 3-Amidino-benzoyl-D-phenylglycine-4- (4' - acetylphenyl) piperazinamide Η nmr (CD 3 CN) 8.12 (IH, s) ; 8.05 (IH, d) ; 7.87 (IH, d) ; 7.80 ,(2H,d); 7.65(1H, t) ; 7.41 (5H, m) ; 6.80 ,(2H,d); 6.05 (IH, s) ; 3.80 (lH,m); 3.65 (2H,m); 3.45 (2H,m); 3.35 (lH,m) ; 3.20 (lH,m); 2.75 (lH,m); 2.45 (3H,s). MS TOF 485 (M+l + ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/TFA) rt 12.96 mm. Example 115. 3-Amidino-benzoyl-D-phenylglycine-4- (4' - methoxypheny1) piperazinamide H nmr (CD 3 CN) 8.15 (IH, s) ; 8.08 (IH, d) ; 7.91 (IH, d) ; 7.68 , (2H,d); 7.45(1H, t) ; 7.41 (5H, m) ; 6.99 ,(2H,d); 6.12 (IH, s) ; 3.95 (3H,m); 3.78 (3H,s); 3.75 (2H,m); 3.55 (2H,m); 3.45 (lH,m); 2.92 (lH,m). MS TOF 473 (M+l + ) . Hplc (Jupιter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.34 mm. Example 116. 3-Amidino-benzoyl-D-phenylglycine-4- (4' - chloropheny1 ) piperazinamide Η nmr (CD 3 CN) 8.05 (IH, s) ; 8.00 (IH, d) ; 7.87 (IH, d) ; 7.55(1H, t) ; 7.31 (5H, m) ; 7.08 , (2H,d); 6.75 , (2H,d); 5.95 (IH, s) ; 3.70 (lH,m); 3.55 (2H,m); 3.45 (lH,m); 3.12 (lH,m); 3.00 (lH,m); 2.85 (lH,m); 2.35 (lH,m) . MS TOF 477 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 17.80 min. Example 117. 3 -Amidino-benzoyl-D-phenylglycine-4 -phenylpiperazinamide λ nmr (DMSO) 8.28 (IH, s) ; 8.21 (IH, d) ; 7.94 (IH, d) ; 7.71 (IH, t) ; 7.52 , (2H,d); 7.35 (3H, m) ; 7.21 (2H,m); 6.89 , (2H,d); 6.80 (lH,t); 6.15 (IH, s) ; 3.75 (3H,m); 3.55 (lH,m); 3.15 (2H,m); 3.00 (lH,m); 2.78 (lH,m). MS TOF 442 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 9.99 min. Ex.ample 118. 3 -Amidino-benzoyl-D-phenylglycine-4-toluenesulphonyl piperazinamide X H nmr (DMSO) 8.21 (IH, s) ; 8.11 (IH, d) ; 7.91 (IH, d) ; 7.69 (IH, t) ; 7.50 , (4H,m); 7.35 (2H, m) ; 7.31 (3H,m); 6.05 (IH, s) ; 3.60 (3H,m); 3.45 (2H,m); 2.90 (lH,m); 2.78 (lH,m) ; 2.70 (lH,m); 2.45 (3H,s); 2.25 (lH,m) . MS TOF 521 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.76 min. Example 119. 3 -Amidino-benzoyl-D-phenylglycine-4 -benzoyl piperazinamide X H nmr (CD 3 CN) 7.95 (IH, s) ; 7.88 (IH, d) ; 7.70 (IH, d) ; 7.45 (IH, t) ; 7.20 , (10H,m); 5.85 (IH, s, broad); 2.50- 3.60 (8H,m, broad signals) . MS TOF 470 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.78 min. Example 120 . 3 -Amidino-benzoyl-D-phenylglycine piperidinamide : H nmr (DMSO) 8.20 (IH, s) ; 8.10 (IH, d) ; 7.86 (IH, d) ; 7.65 (IH, t) ; 7.45 (5H, m) ; 6.02 (IH, s) ; 3.70 (IH, m) ; 3.40 (3H, m) ; 1.53 (3H, m) ; 1.41 (2H, m) ; 0.93 (lH,m). MS TOF 365 (M+1 * ). Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 9.29 min. Example 121. 3 -Amidino-benzoyl-D-phenylglycine- (IS, 2S, 3S, 5R) - isopinocamphyl amide Η nmr (DMSO) 8.30 (IH, s) ; 8.21 (IH, d) ; 7.98 (IH, d) ; 7.71(1H, t) ; 7.51 (2H, m) ; 7.35 (3H,m); 5.74 (IH, s); 4.05 (IH, m) ; 2.35 (2H, m) ; 1.90 (IH, m) ; 1.72 (2H, m) ; 1.60 (lH,m); 1.21 (3H,s); 1.01 (lH,d); 0.97 (3H,s); 0.83 (3H,d) . MS TOF 433 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 13.32 min. Example 122. 3 -Amidino-benzoyl-D-phenylglycine-3 -phenylanilide Η nmr (DMSO) 8.31 (IH, s) ; 8.24 (IH, d) ; 7.95 (2H, m) ; 7.53 (IH, t) ; 7.60 (5H, m) ; 7.4 (8H, m) ; 5.85 (IH, s) . MS TOF 449 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.42 min. Example 123. 3-Amidino-benzoyl-D-phenylglycine-3- (O-benzoyl hydroxymethyl) anilide : H nmr (DMSO) 8.40 (IH, d) ; 8.33 (IH, s) ; 8.31 (IH, d) ; 7.97 (2H,d); 7.75(1H, t); 7.64 (lH,m); 7.56 (2H,d); 7.40 (8H, m) ; 7.21 (lH,t); 5.75 (IH, s) ; 5.20 (2H,s). MS TOF 507 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 13.53 min. Example 124 . 3 -Amidino-benzoyl-D-phenylglycine-4- (4-chlorobenzoyl) piperidinamide : H nmr (DMSO) Mixture of rotomers 8.08 (2H, ) ; 7.80 (3H, m) ; 7.55(1H, t); 7.45 (2H, m) ; 7.25 (5H,m); 5.92 (IH, s) ; 4.25 (lH,m); 3.80 (IH, m) ; 3.55 (IH, m) ; 2.90 (lH,m) ; 2.68 (lH,m); 1.60 (IH, m) ; 1.55 (lH,m); 1.30 (IH, m) ; 0.83 (lH,m) . MS TOF 504 (M+1 * ). Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.21 min. Example 125. 3 -Amidino-benzoyl-D-phenylglycine-4- (4-fluorobenzoyl) piperidinamide l K nmr (DMSO) Mixture of rotomers 8.40 (2H, m) ; 8.22 (2H, m) ; 8.10 (lH,d); 7.88 (IH, t) ; 7.64 (2H, m) ; 7.54 (5H,m); 6.30 (IH, s) ; 4.65 (lH,m); 4.20 (IH, m) ; 3.82 (IH, m) ; 3.10 (2H,m); 1.98 (lH,m); 1.70 (IH, m) ; 1.40 (lH,m); 0.83 (lH,m) . MS TOF 487 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.37 min. Example 126. 3 -Amidino-benzoyl-D-phenylglycine-4-benzyl piperidinamide l K nmr (DMSO) Mixture of rotomers 7.98 (2H, m) ; 7.68 (IH, m) ; 7.45(1H, m) ; 6.60-7.25 (10H, m) ; 5.86 (IH, s) ; 4.15 (lH,m); 3.68 (IH, m) ; 2.63 (IH, m) ; 2.45 (lH,m); 2.21 (3H,m) ; 1.50 (IH, m) ; 1.33 (lH,m); 1.03 (IH, m) ; 0.45 (lH,m) . MS TOF 455 (M+l + ) . Hplc (Jupiterδ C18, Gradient 3, water/acetonitrile/TFA) rt 13.18 min. Example 127. 3 -Amidino-benzoyl-D-phenylglycinyl-D-2 -naphthylalanine pyrrolidinamide Η nmr (DMSO) 8.19 (IH, s) ; 8.11 (IH, d) ; 7.92 (IH, d) ; 7.75(5H, m) ; 7.41 (5H, m) ; 7.30 (3H,m); 5.81 (IH, s) ; 4.80 (IH, m) ; 3.20 (4H, ) ; 3.00 (2H, m) ; 1.55 (4H, m) . MS TOF 548 (M+l + ) . Hplc (Jupiterδ C18, Gradient 3, water/acetonitrile/TFA) rt 11.13 mm. Example 128. 3-Amidino-benzoyl-DL-l-naphthylglycinyl-D-2- naphthylalanine pyrrolidinamide H nmr (DMSO) mixture of isomers 8.25 (IH, s) ; 8.20 (IH, d) ; 8.15 (2H,m) ; 8.05 (IH, d); 6.90-8.00 complex multiplet (13H,m); 6.50 (IH, m) ; 4.90 (IH, m) ; 2.90- 3.50 broad, partially covered by solvent (H, m) ; 1.70 (4H, m) . MS TOF 598 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.18 and 12.37 mm. Example 129. 3 -Amidino-benzoyl-DL-1-naphthylglycine-4- methylbenzylamine X H nmr (DMSO) mixture of isomers 8.25 (IH, s) ; 8.20 (IH, d) ; 8.10 (lH,m) ; 7.90 (3H,m); 7.70 (IH, t); 7.55 (4H,m); 7.06 (4H,m) ; 6.45 (IH, s) ; 4.30 (2H, m) ; 2.25 (3H,s). MS TOF 451 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.30 mm. Example 130. 3 -Amidino-benzoyl-DL-1-naphthylglycine-4-benzoyl piperidinamide H nmr (DMSO) mixture of isomers 8.15 (2H, m) ; 8.00 (IH, d) ; 7.85 (5H,m) ; 7.45 (8H,m); 6.70 (IH, s) ; 4.50 (IH, m) ; 3.15 (lH,m); 2.80 (3H,m); 1.60 (2H,m); 1.42 (lH,m); 0.45 (lH,m) . MS TOF 519 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.67 mm. Example 131. 3 -.Amidino-benzoyl -DL-1 -naphthylglycine- 3- (1- hydroxyethyl) anilide X H nmr () mixture of isomers 8.10 (IH, s) ; 8.00 (IH, d) ; 7.80 (3H,m) ; 7.50 (7H,m) ; 7.30 (lH,m) ; 7.20 (lH,m) ; 7.00 (lH,m) ; 6.45 (IH, s) ; 4.65 (IH, m) ; 1.20 (3H,s) . MS TOF 467 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.67 min. Example 132. 3-Amidino-benzoyl-D-phenylglycine morpholinamide H nmr (DMSO) 8.25 (IH, s) ; 8.18 (IH, d) ; 7.91 (IH, d) ; 7.68(1H, t) ; 7.40 (5H, m) ; 6.09 (IH, s); 5.45 (4H, m) ; 3.63 (4H, m) . MS TOF 367 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 5.53 min. Example 133. 3 -Amidino-benzoyl-R, S-3 -amino-3 -phenylpropionic-1- adamantylamide : H nmr (CD 3 CN) 8.03 (IH, s) ; 7.97 (IH, d) ; 7.75 (IH, d) ; 7.55(1H, t) ; 7.20 (5H, m) ; 5.25 (IH, t) ; 2.50-1.70 (15H, m) . MS TOF 446 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.56 min. Example 134. 3-Amidino-benzoyl-DL-l-naphthylglycine- (Z,E) - (2- methyl) cyclohexylamide Mixture of isomers . MS TOF 443 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.57 and 12.75 min. Prepared by Method 5 Example 135. 3 -Amidino-benzoyl-D-phenylglycine cyclopropylmethylamide MS TOF 351 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 8.57 min. Example 136. 3-Amidino-benzoyl-D-phenylglycine-2-indanylamide MS TOF 413 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.13 min. Ex.am.ple 137 . 3 -Amidino-benzoyl-D-phenylglycine-3 -methylbutylamide MS TOF 367 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.81 min. Example 138. 3 -Amidino-benzoyl-D-phenylglycine-4-fluorobenzylamide MS TOF 405 (M+1 * ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.41 min. Example 139. 3-Amidino-benzoyl-D-phenylglycine trans-2- phenylcyclopropylamide MS TOF 413 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.25 min. Prepared by Method 6 Example 140. 3-Amidino-benzoyl-D-phenylglycine-2- (4-N-acetyl piperidinyl) ethyl ester l K nmr (DMSO) 8.13 (IH, s) ; 8.07 (IH, d) ; 7.92 (IH, d) ; 7.69 (2H,d); 7.45 (5H, m) ; 5.63 (IH, s) ; 4.25 (2H,m); 3.65 (lH,m) ; 3.45 (3H,m); 2.80 (lH,m); 3.35 (lH,m); 2.00 (3H,s); 1.50 (3H,m); 1.30 (lH,m); 0.95 (lH,m). MS TOF 451 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 19.00 min. Method 7 By solution phase strategy: Typically a Boc-amino alcohol with TEA is treated with an acid chloride to give an ester. Removal of the Boc protecting group with TFA followed by further extension of the compounds as in Method 4. Example 141. {R}-{ [N- (3 -amidino) benzoyl] amino}-2-phenylethyl-4- (methoxy) benzoate . To Boc- (D) -phenylglycmol (237mg, lmmol, leq) and TEA(153μl, 1. lmmol , leq) dry DCM (5ml) was added p- anisoyl chloride (188mg, 1. lmmol , 1. leq) . The reaction was stirred overnight. Ethylacetate (30ml) was added and the organic layer was washed successively with 2 x 10ml of 10%HC1 , NaHC0 3 solution, finally brine. Dried over magnesium sulphate, filtered and evaporated, to give the crude product (410mg) . After treatment with TFA to remove the Boc group the compound were extended as m Method 4. -H nmr (DMSO) 8.25 (IH, a); 8.21 (IH, d) ; 7.95 (IH, d) ; 7.85 (2H,d); 7.75 (IH, t) ; 7.45 (5H, m) ; 7.05 (2H,d); 5.55 (IH, q) ; 4.55 (2H, d) ; 3.85 (3H, a). MS TOF 418 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.01 mm. By analogoua methods the following were prepared Example 142. R-2-{ [N- (3 -amidino) benzoyl] amino}-2-phenylethyl-4- (methyl) benzoate -H nmr (DMSO) 8.25 (IH, a); 8.21 (IH, d) ; 7.95 (IH, d) ; 7.80 (2H,d); 7.75 (IH, t) ; 7.50 (2H,d); 7.34 (5H, m) ; 5.55 (IH, q) ; 4.55 (2H, d) ; 3.35 (3H, s) . MS TOF 402 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.87 mm. Example 143. R-2-{ [N- (3 -amidino) benzoyl] amino}-2-phenylethyl-4- (trifluoromethoxy) benzoate H nmr (DMSO) 8.45 (IH, a); 8.40 (IH, d) ; 8.25 (2H,d); 8.15 (IH, d) ; 7.95 (IH, t); 7.65 (7H, m) ; 5.78 (IH, q) ; 4.84 (2H, d) . MS TOF 472 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.85 min. Method 8 By solution phase strategy: Typically a Boc-amino alcohol and a carboxylic acid are treated with (4- dimethylamino) phenyldiphenyl phosphine and diethylazodicarboxylate to give an ester. Removal of the Boc protecting group with TFA followed by further extension of the compounds as in Method 4. Example 144. {R}-{ [N- (3 -amidino) benzoyl] amino}-2-phenylethyl-4- (acetimido) benzoate A dry solution of diethylazodicarboxylate (158μl, lmmol, leq) in THF (5ml) , was added dropwise to an anhydrous solution of (4 -dimethylamino) phenyldiphenyl phosphine (306mg, leq, lmmol), Boc- (D) -phenylglycinol ( 356mg, l,5eq, lmmol) and 4-acetimidobenzoic acid (179mg, lmmol, leq) in THF (5ml) at -78°C. The reaction allowed to warm to room temperature and stirred overnight. Reaction monitored by t.l.c, Si0 2 / 75% ethylacetate in hexane indicating formation of product. R f = 0.5. The solution was evaporated to remove THF and taken up into ethyl acetate (30ml) washed with.10% HCl solution, then brine. The solution was dried, filtered and evaporated to dryness. Crude yield ~650mg. Purifcation by column chromatography gave a yield of product of 200mg, (50%) . After treatment with TFA to remove the Boc group the compound were extended as in Method 4. X H nmr (DMSO) 8.48 (IH, s) ; 8.54 (IH, d) ; 8.15 (IH, d) ; 8.05 (2H,d); 7.95 (3H, m) ; 7.75 (2H,m); 7.55 (3H, m) ; 5.70 (IH, m) ; 4.70 (2H, m) ; 2.27 (3H, a). MS TOF 445 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 9.38 min. Example 145. R-2-{ [N- (3 -amidino) benzoyl] amino}-2-phenylethyl-4- (methylsulphonyl) benzoate Η nmr (DMSO) 8.25 (IH, a); 8.21 (IH, d) ; 8.10 (4H,q); 7.95 (IH, d) ; 7.75 (IH, t); 7.45 (5H, m) ; 5.60 (IH, q) ; 4.65 (2H, d) ; 2.08 (3H, s) . MS TOF 466 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 9.75 min. Example 146. R-2-{ [N- (3 -.amidino) benzoyl] amino}-2-phenylethyl-4- acetylbenzoate *H nmr (DMSO) 8.03 (IH, a); 8.00 (IH, d) ; 7.83 (4H,m); 7.73 (IH, d) ; 7.53 (IH, t) ; 7.25 (5H, m) ; 5.38 (IH, q) ; 4.41 (2H, d) ; 2.42 (3H, s) . MS TOF 430 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.46 min. Method 9 By solution phase strategy: Typically an activated Boc- amino acid was converted to the amide with ammonia and then to the thioamide using Lawessons reagent. Reaction of the thioamide with an acyl bromide to give a Boc protected thiazole. Deprotection of the thiazole with TFA allows further extension of the compound as in Method 4. Example 147. 2- [ (N-3-amidinobenzamido) - 1-phenyl] methyl-4- phenylthiazole To a solution of Boc-D-phenylglycine (875mg 3.5mmole) in a 1:1 mixture of DMF and DCM (40ml) was added 1- hydroxybenzotriazole (520mg l.lequiv.) and DIPCI (602ml l.lequiv.) and the mixture stirred for 30min at rt . Ammonia gas was bubbled in and the mixture left overnight before diluting with ethyl acetate and washing with 10% hydrochloric acid and sat. sodium bicarbonate. The organic solution was dried (magnesium sulphate) and evaporated. Flash chromatography (silica gel DCM/ethylacetate 0-50%) gave the amide 770mg 86%. To a solution of Boc-D-phenylglycine amide (740mg 2.96mmole) in THF 25ml was added Lawesson's reagent (1.2g) and the mixture stirred overnight. The solvent was evaporated off under reduced pressure and the residue purified by flash chromatography (silica gel - hexane/ethyl acetate 10 to 30%) to give the thioamide 67lmg . The thioamide (650mg) was dissolved in acetone (20ml) and phenacyl bromide (486mg 1 equiv) stirred for 30min and then diluted with chloroform/aqueous sod. bicarbonate (20ml each) , separated, dried (magnesium sulphate) and evaporated. The residue was dissolved in DCM (20ml) and treated with pyridine (350ml) and trifluoroacetic anhydride (360ml) . After 150min the solvent was removed under reduced pressure and the residues redissolved in DCM and washed with sat. sod. bicarbonate. Purification by flash chromatography (silica gel - hexane/ethyl acetate 10 to 30%) gave the thiazole intermediate 687mg. Deprotection of the amine was carried out using 50% TFA in DCM (30min) , evaporation of solvent under reduced pressure, dissolving in DCM, washing with sat sod. bicarbonate, drying (magnesium sulphate) and evaporation. Coupling of the thiazole intermediate to 3 -amidino benzoic acid was carried out using the standard method Method 4 to give 2- [ (N-3-amidinobenzamido) -1- phenyl] methyl - -phenylthiazole TFA salt. ' -HNMR (d 6 DMSO) 9.9 (IH, d) ; 9.48 (IH, a); 9.09 (IH, a); 8.40 (lH,s); 8.37 (IH, d) ; 8.16 (IH, a); 7.98 (3H, m) ; 7.80 (2H,t); 7.63 (2H, d) ; 7.5 (6H, m) ; 6.80 (IH, d) . MS TOF 413 (M+1 * ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.8 min. Method 10 By solution phase: Typically a compound prepared as Method 4 is further reacted with ethyl chloroformate to give the 3-Ethoxycarbonyl amidino compound Example 148. 3- (Ethoxycarbonyl) -amidinobenzoyl-D-phenylglycine-4- methylbenzyl amide . To a solution of 3 -Amidinobenzoyl- (D) -phenylglycine-4- methylbenzyl amide (125mg, 0.3lmmole) in DCM (20ml) was added DIPEA (163ml 0.94mmole) and then over 2min. ethyl chloroformate 33ml 0.34mmole). The reaction was stirred overnight and the solvent removed under reduced pressure. The residue was dissolved in ethylacetate and washed with water (x3), dried (magnesium sulphate) and evaporated to dryness. Flash chromatography (silica gel, DCM/Ethylacetate 0-100%) gave the title compound 98mg X HNMR (d 6 DMSO) 9.1 (2H, ba) ; 8.93 (lH,d); 8.82 (IH, t) ; 8.46 (IH, s) ; 8.08 (2H, t) ; 7.53 (3H, m) ; 7.36 (3H, m) ; 7.08 (4H, s) ; 5.76 (lH,d); 4.23 (2H, d) ; 4.07 (2H, q) ; 2.25 (3H, s) ; 1.22 (3H,t). MS TOF 473 (M+l + ) . Hplc (Jupiterδ C18, Gradient 3, water/acetonitrile/TFA) rt 11.06 min. By an analogous method Example 149 3- (Ethoxycarbonylamidino) -D-phenylglycine-4- (4- chlorophenyl) -piperazinamide -HNMR (d 6 DMSO) 9.01 (3H, bs+s) ; 8.40 (IH, a); 8.08 (2H, m) 7.52 (3H, m) ; 7.40 (3H, m) ; 7.25 (2H, d) ; 6.88 (2H, d) 6.15 (lH,d); 4.05 (2H, d) ; 3.70 (4H, m) ; 3.01 (4H, m) 1.20 (3H,t) . MS TOF 549 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.48 min. Method 11 By solution phase srategy: Typically 3 -cyanobenzoic acid is activated with carbonyl -diimidazole and reacted with R-phenylglycinol to give 3-cyanobenzoylphenylglycinol . Reaction with a trichloroacetimidate and BF 3 etherate, (4) , gives an ether. Reaction of the cyano group with HCl in ethanol followed by ammonia in ethanol gives the amidino compound. Example 150. 3-.Amidinobenzoyl-2- (4-methylbenzyloxy) -1- phenylethylamide 3 -Cyanobenzoic acid was condensed with (R) - phenylglycinol using N,N' -carbonyl -diimidazole as activator to give 3-cyanobenzoylphenylglycinol. : HNMR (CDC1 3 ) 8.05 (2H, d) ; 7.55 (IH, t) ; 7.4 (8H, m) ; 5.17 (2H, bs) ; 4.50 (2H, bs) . 3-Cyanobenzoylphenylglycinol in 1:1 DCM: cyclohexanol (50ml) was treated with 4-methylbenzyl trichloroacetimidate and BF 3 etherate and the crude product purified by flash chromatography to give 3- cyanobenzoyl-2- (4-methylbenzyloxy) -1-phenylethylamide which was then taken up in ethanol and saturated with HCl gas and left overnight at room temperature. The solvent and excess HCl gas were removed under reduced pressure and the residue redissolved in ethanol and the solution saturated with ammonia gas and left overnight. The solvent and excess ammonia were removed under reduced pressure and the residue treated with aqueous acetonitrile and trifluoroacetic acid. Preparative hplc gave the title compound approx 80% pure by hplc. ΗNMR (d 6 DMSO) 9.1 (5H, bs+d) ; 8.22 (2H, s+d) ; 7.90 (IH, d) ; 7.74 (IH, t); 7.35 (5H, m) ; 7.10 (4H, Abq) ; 5.35 (lH,q); 4.50 (2H, a); 3.70 (2H,m); 2.25 (3H, s) . MS TOF 389 (M+1 T ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.79 min. Miscellaneous Examples Example 151. N- (3 -Amidinobenzoyl) -2-amino-2 (R) -phenylethoxycarbonyl- 4-me hylaniline To a solution of Boc- (R) -phenylglycinol (500mg 3.65mmole) in DMF (20ml) was added 4- methylphenylisocyanate (500ml 4.0mmole) and the mixture warmed to 50°C before standing at room temperature overnight. Dilution with ethyl acetate and washing with sat. sodium bicarbonate gave after drying (magnesium sulphate) and evaporation of aolvent the crude intermediate which was purified by flash chromatography (silica gel, EtOAC 0-20% in DCM) Deprotection of the amine was carried out using 50% TFA DCM (30min) , evaporation of solvent under reduced pressure, dissolving in DCM, washing with sat sod. bicarbonate, drying (magnesium sulphate) and evaporation. Coupling of the thiazole intermediate to m-benzamidine was carried out using the standard method 4 to give N-(3- Amidinobenzoyl ) -2-amino-2 (R) -phenylethoxycarbonyl -4 - methylaniline . HNMR (d 6 DMSO) 8.2 (2H, m) ; 7.90 (IH, d) ; 7.72 (IH, t); 7.44 (2H, d) ; 7.35 (5H, m) ; 7.08 (2H, d) ; 5.35 (IH, m) ; 4.33 (2H, m) ; 2.25 (3H, s) . MS TOF 417 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.54 mm. Example 152. 3 -Amidinobenzyl-D-phenylglycine-cis/trans-4 -aminomethyl cyclohexylmethylamide Bιs-1 , 4 -ammomethylcyclohexane 2-chlorotrιtyl resm (0.2 mmol) (as prepared by method l)was treated with Fmoc-D- Phenylglycme (0.5 mmol, 187mg) , DMF (2.5ml), TBTU m DMF (1.25ml of a 450mM solution) and DIPEA in DMF (1.25ml of a 900 mM solution) . The mixture was agitated with nitrogen for 2 hours. Deprotection and washing as in method 1. The resm was then treated with 3- cyanobenzaldehyde (0.5mmol. 66mg) in DMF agitated over night . The resm was washed with DMF then with Dry THF to remove all DMF. Sodium cyanoborohydπde (lmmol. 63mg) THF and acetic acid (lθθμl)was then added to the resm and agitated for 4 hours. The resm was then washed with THF, the DMF and finally DCM. The resm was the treated with TFA containing 5% TES for 30 m s . The resm was then filtered off and the TFA evaporated then held under high vacuum to dry the product . The product was then taken up into saturated hydrogen chloride gas in ethanol (20ml.) overnight. The ethanol was then evaporated and the product treated with saturated ammonia gas in ethanol (20ml.) overnight. The ethanol was then evaporated and the product purified by preparative hplc. λ K nmr (CD 3 CN) Mixture of cyclohexyl cis and trans isomers 7.85 (2H, m) ; 7.79 (IH, d) ; 7.66 (IH, t) ; 7.50 (5H, m) ; 4.97 (IH, a); 4.22 (2H,s); 3.00 (2H,m); 2.78 (2H, m) ; 1.48 (7H, m) ; 0.86 (3H, m) MS TOF 407 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 9.78 min. Example 153. 4-Methylphenylacetyl-L-phenylglycine-3-amidino anilide Boc-L-phenylglycine(0.6mmol, 150mg) , HATU (O.δmmol, 230mg) and DIPEA (1.2mmol., 220μl) were dissolved in DMF (5ml) and stirred for 15mins. 3-Aminobenzonitrile (O.δmmol., 70mg) was added and the mixture stirred overnight. The DMF was then evaporated and the mixture taken into ethylacetate (50ml) and washed with water, sodium carbonate solution, water 10% hydrochloric acid and water. The ethylacetate was evaporated to give the product Boc-L- phenylglycine-3-cyano anilide. The product was treated with TFA (50ml) for 30mins. The TFA was evaporated to dryness. m-Tolylacetic acid (0.7mmol., lOOmg) , HATU (0.7mmol., 250mg) and DIPEA (1.4mmol., 250μl) were dissolved in DMF (5ml) and stirred for 15mins. This was then added to the above product with DIPEA (0.6mmol., llOμl) and stirred overnight. The DMF was evaporated and the mixture taken into ethylacetate (50ml) and washed as above . The ethyl acetate was then evaporated and the product treated with hydrogen chloride gas in ethanol and ammonia gas in ethanol as above. The product was purified by preparative hplc. : HNMR (d 4 MeOH) 8.23 (lH,s); 7.90 (IH, d) ; 7.72 (7H, m) ; 7.44 (IH, t) ; 7.29 (3H, m) ; 5.75 (IH, m) ; 3.80 (2H, s) ; 2.50 (3H, s) . MS TOF 401 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 14.59 min. Compounds synthesised by Method 4 Example 154 . 3-Amidino-benzoyl-D-phenylglycine-4- (4' -nitrophenyl) piperazinamide X H nmr (CD 3 CN) 8. 20 (IH, a); 8.05 (3H, m) ; 7.85 (IH, d) ; 7.70 (IH, t) ; 7.40 (5H, m) ; 6.82 ,(2H,d); 6.05 (IH, a); 3.75 (lH,m) ; 3.65(2H,m); 3.45(3H,m); 3.30 (lH,m); 2.85 (lH,m) . MS TOF 486 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 11.65 min. Example 155. 3-Amidino-benzoyl-D-phenylglycine-4- (4' -aminophenyl) piperazinamide Η nmr (CD 3 CN) 8.00 (IH, a); 7.85 (IH, d) ; 7.65 (IH, d) ; 7.45(1H, t) ; 7.20 (5H, m) ; 6.95 ,(2H,d); 6.70, (2H,d); 5.85 (IH, a); 3.55 (lH,m); 3.30(lH,m); 2.95 (3H,m); 2.80 (lH,m); 2.40 (lH,m). MS TOF 458 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 12.57 min. Example 156. 3 -Amidino-benzoyl-D-phenylglycine-4- (4' -fluorophenyl) piperazinamide l K nmr (CD 3 OD) 8.25 (IH, a); 8.20 (IH, d) ; 7.95 (IH, d) ; 7.75 (IH, t) ; 7.45(5H, m) ; 7.10 ,(4H,m); 6.20 (IH, a); 3.90 (3H,m) ; 3.70 (lH,m); 3.35 (2H,m); 3.15 (lH,m); 2.65 (lH,m) . MS TOF 460 (M+l + ) . Hplc (Jupiterδ C18, Gradient 1, water/acetonitrile/TFA) rt 14.88 min. Example 157. 3 -Amidino-benzoyl-D-phenylglycine-4- (4' -pyridyl) piperazinamide Η nmr (CD 3 CN) 8. 05 (IH, a); 7.95 (IH, d) ; 7. 90(2H,d); 7.80 (IH, d) ; 7.55(1H, t) ; 7.30 (5H, m) ; 6.80 ,(2H,d); 6.00 (IH, a); 3.70 (3H,m); 3.50 (3H,m); 3.40 (lH,m); 3.15 (lH,m) . MS TOF 444 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 11.54 min. Example 158. 3 -Amidino-benzoyl-D-phenylglycine-4- (2' -pyridyl) piperazinamide : H nmr (CD 3 OD) 8.30 (IH, a); 8.20 (IH, d) ; 8.10 (IH, m) ; 7.95 , (2H,m) ; 7.75(1H, t) ; 7.50 (5H, m) ; 7.30 ,(2H,d); 7.15(1H, t) ; 6.20 (IH, a); 3.95 (3H,m); 3.75 (4H,m); 3.40 (lH,m) . MS TOF 444 (M+l + ) . Hplc (Jupiter5 C18, Gradient 2, water/acetonitrile/TFA) rt 11.67 min. Example 159. 3 -Amidino-benzoyl-D-phenylglycine-4-benzylpiperazinamide : H nmr (CD 3 CN) 8.15 (IH, a); 8.05 (IH, d) ; 7.90 (IH, d) ; 7.65(1H, t) ; 7.40 (10H, m) ; 6.05 (IH, s) ; 4.20 (2H,s); 3.20(8H,v. broad m) . MS TOF 457 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 9.52 min. Example 160. 3 -Amidino-benzoyl-D-phenylglycine-4- (3 -chlorophenyl) piperazinamide Η nmr (CD 3 CN) 8.17 (IH, a); 8.07 (IH, d) ; 7.90 (IH, d) ; 7.65 (IH, t) ; 7.42 (5H, m) ; 7.15 (IH, m) ; 6.80 (3H,m); 6.08 (IH, a); 3.85 (lH,m); 3.55 (3H,m); 3.25 (lH,m); 3.10 (lH,m) ; 2.95 (lH,m); 2.40 (lH,m). MS TOF 477 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 15.39 min. Example 161 . 3 -Amidino-benzoyl-D-phenylglycine-4- (2-chlorophenyl) piperazinamide Η nmr (CD 3 CN) 8.15 (IH, s) ; 8.07 (IH, d) ; 7.90 (IH, d) ; 7.65(1H, t) ; 7.42 (5H, m) ; 7.20 (IH, m) ; 6.95 (3H,m); 6.05 (IH, a); 3.80 (lH,m); 3.65 (2H,m); 3.45 (lH,m); 3. 00(lH,m); 2.85 (2H,m); 2.40 (lH,m). MS TOF 477 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 15.02 min. Example 162. 3 -Amidino-benzoyl-D-phenylglycine- tetrahydroisoquinolin- 2 -amide l K nmr (CD 3 CN) 8.05 (IH, s) ; 8.00 (IH, d) ; 7.70 (IH, d) ; 7.45(1H, t) ; 7. 25(2H,m); 7.15 (3H, m) ; 6.90 ,(4H,m); 6.00 (IH, a); 4.45 (2H,m); 3.45 (2H,m); 2.55 (2H,m). MS TOF 413 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.92min. Example 163. 3-Amidino-benzoyl-D-phenylglycinyl-N-benzyl glycine ethyl ester Η nmr (CD 3 CN) 8.15 (IH, a); 8.10 (IH, d) ; 7.90 (IH, d) ; 7.70 (IH, t) ; 7.35 (10H, m) ; 6.10 (IH, a); 4.65 (2H,m); 4.45 (2H,m) ; 4.05 (2H,m); 1.15 (3H,m). MS TOF 473 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.32 min. Example 164. 3-Amidino-benzoyl-D-phenylglycinyl-l, 2, 3,4-DL- tetrahydroisoquinoline-3 -dimethylami.de : H nmr (CD 3 OD) mixture of isomers, major reported. 8.25 (IH, a); 8.20 (IH, d) ; 7.95 (IH, d) ; 7.75(1H, t); 7.70 - 7.00 (9H, m) ; 635 (IH, a); 5.20 (lH,m); 4.65 (2H,m); 3.15 (2H,m, obscured by solvent); 3.00 (6H,d). MS TOF 484 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 13.81 min. Compounds synthesised by Method 7 Example 165. R-2-{ [N- (3 -amidino) benzoyl] amino}-2-phenylethyl-4- (methyl) benzoate l K nmr (DMSO) 8.25 (IH, a); 8.21 (IH, d) ; 7.95 (IH, d) ; 7.80 (2H,d); 7.75 (IH, t); 7.50 (2H,d); 7.34 (5H, m) ; 5.55 (IH, q) ; 4.55 (2H, d) ; 3.35 (3H, s) . MS TOF 402 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.87 min. Example 166. R-2-{ [N- (3 -Amidino) benzoyl] amino}-2-phenylethyl-4- dimethylaminobenzoate X H nmr (CD 3 CN) 8. 20 (IH, a); 8.05 (lH,d); 7.90 (IH, d) ; 7.75 (2H,d); 7.65 (IH, t) ; 7.45 (2H,d); 7.35 (3H, m) ; 6.70 ,(2H,d); 5.50 (IH, m) ; 4.55 (2H,m); 1.95 (6H,s). MS TOF 431 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.11 min. Example 167. R-2-{ [N- (3 -Amidino) benzoyl] amino}-2-phenylethyl-4- aminosulphonylbenzoate l K nmr (CD 3 CN) 8. 15 (IH, a) ; 8.05 (3H,m) ; 7.90 (3H, m) ; 7.65 (IH, t) ; 7.55 (2H,d) ; 7.35 (3H, m) ; 5.50 (IH, m) ; 4.65 (2H,d) . MS TOF 467 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 9.80 min. Example 168. R-2-{ [N- (3 -Amidino) benzoyl] amino}-2-phenylethyl benzoate : H nmr (CD 3 CN) 8. 05 (IH, a); 8.00 (lH,d); 7.80 (2H,m); 7.70 (IH, d) ; 7.55 -7.00 (9H, m) ; 5.45 (IH, m) ; 4.55 (2H,m) . MS TOF 387 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.85 min. Example 169. R-2-{ [N- (3 -Amidino) benzoyl] amino}-2-phenylethyl-4- acetoxybenzoate : H nmr (CD 3 CN) 8. 00 (IH, a); 7.95 (lH,d); 7.85 (2H,d); 7.75 (IH, d) ; 7.55 (IH, t) ; 7.35 (2H,d); 7.20 (3H, m) ; 7.00 , (2H,d); 5.35 (IH, m) ; 4.55 (2H,m); 2.10 (3H,s). MS TOF 446 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.54 min. Example 170. R-2-{ [N- (3 -Amidino) benzoyl] amino} -2 -phenylethyl-4- isopropylbenzoate : H nmr (CD 3 CN) 8. 05 (IH, a); 8.00 (lH,d); 7.90 (IH, d) ; 7.75 (2H,d); 7.55 (IH, t); 7.40 (2H,d); 7.25 (5H, m) ; 5.45 (IH, m) ; 4.55 (2H,m); 2.85 (lH,m); 1.10 (6H,d). MS TOF 430 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 12.43 min. Example 171. R-2-{ [N- (3 -Amidino) benzoyl] amino}-2-phenylethyl-4- hydroxybenzoate Η nmr (CD 3 CN) 8. 15 (IH, s) ; 8.05 (3H,m); 7.85 (lH,d); 8.80 (2H,d); 7.65 (IH, t); 7.40 (5H, m) ; 6.80 (2H,d); 5.50 (IH, m) ; 4.55 (2H,d). MS TOF 404 (M+1 * ). Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.05 min. The following compounds were synthesised by Method 4 and elaborated as Example 89 Example 172. 2-Amino-5-amidino-benzoyl-D-phenylglycine benzylamide l K nmr (DMSO) 8.30 (IH, a); 7.80 (IH, d) ; 7.75 (2H, d) ; 7.45 (8H, m) ; 7.05 (lH,d); 5.95 (IH, a); 4.55 (2H,s). MS TOF 402 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.55 min. Example 173. 2-Amino-5-amidino-benzoyl-D-phenylglycine-2- methylbenzylamide X H nmr (DMSO) 8.15 (IH, a); 7.70 (IH, d) ; 7.60 (2H, d) ; 7.30 (7H, m) ; 6.90 (lH,d); 5.80 (IH, a); 4.30 (2H,s); 2.25 (3H,a). MS TOF 416 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.07 min. Example 174. 2 -Amino-5-amidino-benzoyl-D-phenylglycine-3 - methylbenzylamide l K nmr (DMSO) 8.15 (IH, a); 7.60 (IH, d) ; 7.50 (2H, d) ; 7.35 (4H, m) ; 7.15 (lH,m); 6.95 (2H,m); 6.80 (lH,d); 5.70 (IH, a); 4.30 (2H,s); 2.25 (3H,s). MS TOF 416 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.94 min. Example 175. 2 -Amino- 5-amidino-benzoyl-D-phenylglycine-R-α- methylbenzylamide : H nmr (DMSO) 8.15 (IH, a); 7.60 (IH, d) ; 7.50 (2H, d) ; 7.35 (5H, m) ; 7.15 (lH,m); 6.95 (2H,m); 6.80 (lH,d); 5.70 (IH, a); 5.00 (lH,m); 1.45 (3H,d). MS TOF 416 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.58 min. Example 176. 2 -Amino-5-amidino-benzoyl-D-phenylglycine-1- naphthylamide X H nmr (DMSO) 8.00 (IH, a); 7.85 (2H,m); 7.75 (lH,d); 7.50 (lH,d); 7.40 (4H,m); 7.25 (5H,m); 6.70 (lH,d); 5.60 (IH, a); 4.65 (2H,s). MS TOF 452 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 11.17 min. Example 177. 2 -Amino-5-amidino-benzoyl-D-phenylglycine-2- methylcyclohexylamide Η nmr (DMSO) 8.00 (IH, a); 7.50 (IH, d) ; 7.40 (2H, m) ; 7.25 (4H, m) ; 6.70 (lH,d); 5.55 (IH, a); 3.20 (lH,m); 1.7 -0.7 (9H, broad m)0.70 (3H,d). MS TOF 408 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.95 min. Compounds synthesised by Method 12 Example 178. R-2-{ [N- (3 -Amidino) benzoyl] amino} -2 -phenylethyl-4- methoxybenzamide Typically Boc- (R) -1, 2-diamino-l-phenylethane was prepared by the Method of O'Brien, P. et al . J " . Med . Chem. 37 (1994) 12, 1810-1822. The free amino group was reacted with an acid chloride or an activated acid, all couplings (minimum 120 min.) were carried out in DMF. After an aqueous work up the deprotection of the Boc group was achieved with TFA. Other acid substituents were added as the HOBt or HOAt esters either by activation with HBTU/HATU, EDC or DIPCI with or without Boc protection of amino groups. The final products were purified by preparative reverse phaae Hplc. Boc- (R) -1,2 diamino-1-phenylethane (2g) was dissolved in DCM (80ml) and toluoylchloride (1.2ml.) and TEA (1.1ml.) added. The mixture was stirred at room temperature under argon overnight . The mixture was then washed with 2M sodium hydroxide solution, water, 5% hydrochloric acid and brine, dried over magnesium sulphate, filtered and evaporated. The product was recrystallised from hexane dissolved in DCM (50ml.) and treated with TFA for 2hrs. The solvent was evaporated and the solid triturated with diethylether . Coupling to m-benzamidine as Method 4. : H nmr (DMSO) 8. 25 (IH, s) ; 8.20 (lH,d); 7.95 (IH, d) ; 7.75 (3H,m) ; 7.35 (5H, m) ; 6.90 (2H,d); 5.35 (IH, m) ; 3.80 (3H,s); 3.70 (2H,m). MS TOF 417 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.31 min. Example 179. R-2-{ [N- (3 -Amidino) benzoyl] amino}-2-phenylethyl-4- ethylbenzamide : H nmr (CD 3 CN) 8. 05 (IH, a); 8.00 (lH,d); 7.85 (IH, d) ; 7.65 (IH, t) ; 7.55 (2H,d); 7.35 (5H, m) ; 7.20 (2H,d); 5.30 (IH, m) ; 3.75 (2H,m); 2.30 (3H,a); MS TOF 401 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.58 min. Compounds synthesised by Miscellaneous Methods Example 180. 3-Amidino-benzoyl-DL- (4-methoxycarbonyl)phenylglycine-4- methylbenzylamine D, L-4-Carboxyphenylglycme was prepared from 4- cyanobenzaldehyde by a method described by Clark, B. P. et al Biorganic & Medicinal Chemistry Letters, 1997, 7, 2777-2780. D, L-4-Carboxyphenylglycme (600mg.) was suapended m methanol (30ml) at 0°C, aaturated with hydrogen chloride gaa and left at room temperature overnight. The reaction mixture was then evaporated to dryness under reduced pressure, resuspended methanol and evaporated twice more and the solid triturated with ether, filtered and dried to give D, L-4-methoxycarbonylphenylglycme methyl ester HCl salt 620mg. D, L-4-methoxycarbonylphenylglycme methyl ester HCl salt (600mg) was reacted with di-t-butyl dicarbonate m dioxane/ aqueous sodium bicarbonate to give after extraction with ethyl acetate and flash chromatography (Sι0 2 hexane/ethyl acetate) - D,L-Boc-4- methoxycarbonylphenylglycme methyl ester 590mg. - X H nmr (CDC1 3 ) 7.78 (2H, d) ; 7.20 (2H, d) ; 5.61 (IH, broad d) ; 5.13 (IH, broad d) ; 3.63 (3H, s) ; 3.44 (3H, a); 1.16 (9H, s) . D, L-Boc-4-methoxycarbonylphenylglycme methyl ester (400mg) was dissolved THF 10ml and treated with a solution of lithium hydroxide monohydrate 64mg. m water lml and the mixture stirred at room temperature for 30mm. The reaction mixture was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic solution was washed twice with water and dried (MgS0 4 ) . Evaporation of the solvent and purification by flash chromatography gave D, L-Boc-4-methoxycarbonyl- phenylglycine 282mg. : H nmr (CDC1 3 ) 8.0 (IH, broad d) ; 7.78 (2H, d) ; 7.20 (2H, d) ; 5.13 (IH, broad d) ; 3.80 (3H, s) ; 1.13 (9H, a) . D, L-Boc-4-methoxycarbonylphenylglycine was coupled to 4- methylphenyl-benzylamine using TBTU/DIPEA/DMF in the usual manner to give D,L-(4- methoxycarbonyl ) phenylglycine-4 -methylphenylbenzylamide . : H nmr (CDC1 3 ) 7.93 (2H, d) ; 7.35 (2H, d) ; 7.02 (2H, d) ; 6.93 (2H, d) ; 5.78 (2H, m) ; 5.08 (IH, broad s) ; 4.30 (2H,m); 3.86 (3H,s); 2.22 (3H,s); 1.30 (9H, s) . D,L- (4 -methoxycarbonyl) phenylglycine-4 - methylphenylbenzyl amide was deprotected using TFA/DCM and coupled to m-benzamidine carboxylic acid TFA salt as Method 4 Η nmr (DMSO) 8. 40 (IH, s) ; 8.30 (lH,d); 8.10 (3H, m) ; 7.80 (3H, m) ; 7.20 (4H,s); 6.00 (IH, a) ; 4.35 (2H,s); 4.00 (3H,s); 2.40 (3H,a);. MS TOF 459 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 10.88 min. Ex.am.ple 181. 3- (Trimethylacetyloxomethylcarbonylamidino) -benzoyl-D- phenylglycine-4- (4-chlorophenyl) piperazinamide Trimethylacetyloxymethyl carbonochloridate was prepared by the Method described by Folkmann and Lund, Synthesis , 1990, 1159., and reacted with 3 -amidino-benzoyl-D- phenylglycine-4- (4 ' -chlorophenyl) piperazinamide (Example 116) in acetonitrile/aqueous sodium bicarbonate to give, after flash chromatography (Si0 2 - DCM/ethylacetate) trimethylacetyloxymethylcarbonyl-3 -amidino-benzoyl -D- phenylglycine-4- (4 ' -chlorophenyl) piperazinamide . Η nmr (DMSO) 8. 35 (IH, a) ; 8.10 (IH, d) ; 8.00 (lH,d) ; 7.60 (IH, t) ; 7.55 (2H, m) ; 7.40 (3H, m) ; 7.20 (2H,d) ; 6.80 , (2H,d) ; 6.05 (IH, a) ; 5.75 (2H,a) ; 3.75 (lH,m) ; 3.65(2H,m) ; 3.45(3H,m) ; 3.30 (lH,m) ; 2.85 (lH,m) 1.20 (9H,s) . MS TOF no (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 13.30 min. Ex.ample 182. R-3 -Amidino- {2- (4-benzylpiperidin-l-yl) }-l-phenylethyl benzamide Boc-D-Phenylglycine-OH was coupled to 4-benzylpiperidine as Method 4 and the Boc group removed with TFA. The product was dissolved in dry THF and added dropwise to LiAlH 4 (1.2eq) suspended in dry THF (15ml) under nitrogen and refluxed under nitrogen for 20 hours. On cooling the reaction was carefully diluted with water, acidifed to pH 1 (HCl) , and washed with EtOAc . The aqueous solution was basified to pH 10 (solid Na 2 C0 3 ) , then extracted with EtOAc to obtain product which was further elaborated as Method 4. Ε nmr (CD 3 CN) 8. 25(1H, a); 8.15 (lH,d); 7.95 (lH,d); 7.70 (lH,t) 7.55 - 7.10 (10H,m); 5.60 (IH, m) ; 3.70 (2H,m) ; 3.30 (2H,m); 2.95 (2H,m); 2.55 (2H,m); 1.80 (3H,m) ; 1.50 (2H,m). MS TOF 441 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 13.34 min. Example 183. 3- (Benzyloxycarbonylamidino) -benzoyl-D-phenylglycine-4- (4-chlorophenyl) piperazinamide Example 116 was dissolved in DCM and DIPEA (2.2eq) , then benzyl chloroformate (l.leq) was added and stirred at room temperature for 45 mins . The reaction mixture was washed with water then chromatographed on silica gel 60 eluting with 65% EtOAc/Hexane to give the pure product. Η nmr (CD 3 OD) 8.25 (IH, a); 8.05 (IH, d) ; 7.95 (IH, d) ; 7.60(1H, t) ; 7.45(5H, m) ; 7.20 (2H,d); 6.80 (2H,d); 6.10 (IH, a); 5.20 (2H,s); 3.80 (lH,m); 3.60 (3H,m); 3.20 (2H,m); 2.95 (lH,m); 2.50 (lH,m). MS TOF 611 (M+l + ) . Hplc (Jupiterδ C18, Gradient 3, water/acetonitrile/TFA) rt 13.15 min. Example 184. 3- (tert-Butyloxycarbonylamidino) -benzoyl-D- phenylglycine-4- (4-chlorophenyl) piperazinamide Example 116 was dissolved in dioxane and NaHC0 3 (2.2eq.), di tertbutyl dicarbonate (l.leq) was added and stirred at room temperature for 1 week. The reaction mixture was extracted with ethyl acetate and evaporated to dryness. The product was chromatographed on silica gel 60 eluting with 75% EtOAc/Hexane to give the pure product . X H nmr (CD 3 OD) 8.25 (IH, a); 7.95 (2H, m) ; 7.55(1H, t) ; 7.45(5H, m) ; 7.15 (2H,d); 6.80 (2H,d); 6.10 (IH, a) ; 3.85 (3H,m) ; 3.60 (lH,m); 3.10 (2H,m); 2.90 (lH,m); 2.50 (lH,m) ; 1.45 (9H,s). MS TOF 577 (M+l + ) . Hplc (Jupiter5 C18, Gradient 1, water/acetonitrile/TFA) rt 12.72 min. Example 185. 3- (Acetylamidino) -benzoyl-D-phenylglycine-4- (4- chlorophenyl) piperazinamide Example 116 was dissolved in dichloromethane and DIPEA (2.2eq) added. Acetyl chloride (l.leq) was added and stirred at room temp for 45 mins . The reaction mixture was then washed with water and chromatographed on silica gel 60 eluting with EtOAc. The product was further purified by preparative hplc. Η nmr (CD 3 OD) 8.25 (IH, s) ; 8.05 (2H, m) ; 7.65 (IH, t); 7.45(5H, m) ; 7.25 (2H,d); 6.85 (2H,d); ; 6.15 (IH, a) ; 3.65 (3H,m); 3.60 (lH,m); 3.20 (2H,m); 3.00 (lH,m); 2.55 (lH,m) ; 2.40 (3H,s). MS TOF 519 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 14.53 min. Example 186. (R) -O- (3-Amidinobenzyl) -N- (4-methylbenzyl)mandelamide (R) -O- (3-Cyanobenzyl) mandelic acid (R) -Mandelic acid 91g, 6.57mmol.) was dissolved m THF (15ml.) and treated portionwise with sodium hydride (60%w/w, 0.798g, 19.7mmol.). The white suspension was heated at reflux and treated dropwise with 3- cyanobenzylbromide (1.93g, 9.86mmol.) in THF (20ml.) over 5mina . The mixture was refluxed for 2 days. The reaction mixture was cooled and treated with water (100ml.) . The aqueous phase was washed with diethyl ether then acidified to pH 1 with 10% HCl solution. The product was extracted with ethyl acetate. The extracts were waahed with brine and dried over magneaium aulphate, filtered and evaporated to give the product (1.5g) aa a gum. H nmr (CD 3 OD) 7.70 (3H,m); 7.40 (6H,m); 5.00 (lH,a); 4.65 (2H,m) . (R) -O- (3-Cyanobenzyl) -N- (4-methylbenzyl)mandelamide HOAt (0.27g, 1.96mmol.) and DBU (0.3g, 1.96mmol.) was dissolved in DMF (8ml.) and cooled in ice. EDC (0.38g, 1.96mmol.) was added in 3 portions and stirred for lOmins.. To this mixture was added (R) -O- (3-Cyanobenzyl) mandelic acid (0.5g, 1.87mmol.) m DMF (2ml.) and the mixture allowed to warm to room temperature for 5 mina . 4-Methylbenzylamine (0.23g, 1.96mmol.) was then added in one portion. The mixture was stirred for 1 hr. The reaction was quenched with water (100ml.) and basified with 2M sodium hydroxide solution. The product was extracted with ethylacetate. The combined extracts were washed with dilute (5%) lithium bromide solution, water and brine, dried over magneaium aulphate, filtered and evaporated to give a gum (0.58g) . The crude product was chromatographed on silica gel eluting with 35% ethylacetate in hexane . Η ninr (CDC1 3 ) 7.50 (2H,m); 7.30 (6H,m); 7.05 (4H,a); 6.90 (lH,m) ; 4.80 (lH,a); 4.55 (2H,m) 4.35 (2H,a); 2.25 (3H,s) . (R) -O- (3-Amidinobenzyl) -N- (4-methylbenzyl)mandelamide (R) -O- (3-Cyanobenzyl) -N- (4-methylbenzyl) mandelamide (0.16g) was diaaolved in ethanol (10ml) and treated with hydrogen chloride gas for 30 mins . The mixture was then stirred overnight at room temperature, evaporated to dryness and dissolved again in ethanol (10ml.) . The mixture was treated with ammonia gas for 5 mina . and allowed to atand overnight. The mixture was evaporated and the product purified by preparative hplc. l K nmr (CDC1 3 ) 7.65 (lH,s); 7.50 (lH,d ); 7.30 (7H,m); 7.00 (4H,s); 4.80 (lH,s); 4.55 (2H,m) 4.35 (2H,s); 2.25 (3H,s). MS TOF 387 (M+l + ) . Hplc (Jupiter5 C18, Gradient 3, water/acetonitrile/TFA) rt 11.24 min. Example 187. 2- (3 -Amidinobenzoyl) -1- (3-phenylpropanoyl) -1- phenylhydrazine . 1- (3-phenylpropanoyl) -1-phenylhydrazine 2-tert Butoxycarbonyl- 1-phenylhydrazine (1.3g) was dissolved in pyridine (6ml.) and treated with 3- phenylpropanoyl chloride (0.75ml.). The mixture was stirred overnight at room temperature under argon. The pyridine was then removed by evaporation and the reaidue taken up in ethyl acetate and washed with 10% hydrochloric acid, saturated aodium carbonate aolution and brine. The ethyl acetate fraction waa dried over magnesium aulphate, filtered and evaporated. The crude product waa chromatographed on silica eluting 5-25% ethyl acetate m hexane . The purified product was dissolved in DCM and treated with TFA before coupling to m-benzamidme by Method 4. X H nmr (CD,0D) 8.20 (IH, a); 8.05 (lH,d); 7.90 (lH,d); 7.65 (IH, t) ; 7.35 (5H, m) ; 7.10 (5H, m) ; 6.15 (IH, a); 2.60 (4H,m) . MS TOF 388 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 10.75 mm. Example 188. 3-{ [R] -N- (3-Amidinobenzamido) - 1-phenyl}methyl-5-benzyl- 1,2,4-triazole. EDC (1.6g) was dissolved in DMF (20ml.) and treated with HOAt (1.16g) m DMF (10ml.) and stirred for 10 mms . DIPEA (1.46ml.) was then added and the stirring continued for a further 15 mms. Boc-D-phenylglycme (2g) m DMF (10ml.) was then added dropwise and stirring continued for a further 25mms. 1M Hydrazine m THF (84ml.) was then added and the mixture stirred over night. The solvents were then evaporated and the residue treated with water (100ml.), basified with 2M sodium hydroxide solution and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried with magnesium sulphate, filtered and evaporated to give a yellow solid (1.38g) . Η nmr (CDC1 3 ) 7.20 (5H,s); 5.55 (lH,s); 1.25 (9H,s). The above product (0.3g, 1.13mmol . ) was disaolved in ethanol (6ml.) and added dropwiae to a aolution of benzyl ethyl lmidate hydrochloπde m ethanol (3ml.) at room temperature. The mixture was stirred for 30 mms. The solvent was then evaporated and the residue treated with dilute sodium bicarbonate solution and extracted with ethylacetate. The combined extracts were washed with brme, dried over magnesium sulphate, filtered and evaporated to give a yellow gum. (0.43g) . Η nmr (CDC1 3 ) 7.30 (10H,m); 5.80 (lH,s); 3.50 (2H,m); 1.45 (9H,s) . The above crude product (0.43g, 1.12 mmol.) was dissolved m xylene (60ml.) with para toluenesulphonic acid (cat.) and heated to 160°C for 1 day. The xylene waa removed under vacuo and the tπazole (0.35g) uaed without further purification. Η nmr (CDC1 3 ) 7.20 (10H,m); 5.70 (lH,s); 4.00 (2H,m); 1.30 (9H,s) . The above product was treated with TFA and coupled to m- benzamidme by Method 4 H nmr (CD 3 OD) 8.20 (lH,s); 8.05 (lH,d); 7.80 (lH,d ) ; 7.60 (lH,t); 7.20 (10H,m); 6.50 (lH,s); 4.10 (2H,s). MS TOF 411 (M+l + ) . Hplc (Jupιter5 C18, Gradient 3, water/acetonitrile/TFA) rt 14.38 mm. References: (1) (a) Bucherer, H. T. ; Sterner W. J. Prakt . Chem 1934, 140, 291-316. (b) Greene T. W.; Wuts P. G. M. Protective Groups m Organic Synthesis, (John Wiley and Sons, Inc. 1991) 318- 319 and references therein. (c) Bolm D. R..; Sytwu I.; Humiec F . ; Meienhofer J. Int . J. Peptide Protein Res . 1989, 33 , 353-359. (2) Shearer, B. G. , Oplinger, J. A., Lee, S. Tet. Letts. 38 (2) , 179-182 (1997) (3) Chandrakumar, . S . Synthetic Comms . , 26 (14) , 2613-2616 (1996) (4) Bundle et al J. Chem, Soc . Perkin Trans I 1985 2247) Assay protocols Enzyme Inhibition assays : Enzyme assays were carried out at room temperature in 0.1M phosphate buffer, pH7.4 according to the method of Tapparelli et al (J. Biol. Chem. 1993,268,4734-4741). Purified human factor Xa, trypsin, thrombin and plasmin were purchased from Alexis Corporation, Nottingham, UK. Urokinase waa purchased from Calbiochem, Nottingham, UK. Chromogenic substrates for these enzymes; pefachrome-FXA, pefachrome-TRY, pefachrome-TH, pefachrome-PL and pefachrome-UK were purchased from Pentapharm AG, Basel, Switzerland. Product (p- nitroaniline) was quantified by adsorption at 405nm in 96 well microplates using a Dynatech MR5000 reader (Dynex Ltd, Billingshurst , UK) . Km and Ki were calculated using SAS PROC NLIN (SAS Institute, Cary, NC, USA, Release 6.11) K-, values were determined as 100.9μM for factor Xa/pefachrome-FXA and 81.6μM for trypsin/pefachrome-TRY. Inhibitor stock solutions were prepared at 40mM in Me2S0 and tested at 500μM, 50μM and 5μM. Accuracy of Ki measurements was confirmed by comparison with Ki values of known inhibitors of factor Xa and trypsin. In agreement with published data, benzamidine inhibited factor Xa, trypsin, thrombin, plasmin and urokinase with Ki values of 155μM, 21μM, 330nM, 200nM and lOOnM respectively. NAPAP inhibited thrombin with a Ki value of 3nM. Compounds of the invention were found to have activity in these assays. Antithrombotic Activity The test material (Factor Xa inhibitor) was administered either intravenously, intraperitoneally or orally to a group of rats for experiment. A second group received vehicle (saline) only as a control, and a third group of animals received a standard antithrombotic (subcutaneoua lmw heparin) as a positive control . To perform the experiment male Sprague-Dawley rats (250-400g in weight) were anaesthetised by the inhalation of isoflurane with the addition of oxygen and nitrous oxide. The left or right femoral vein was carefully exposed and isolated from the femoral artery and saphenous nerve. Following removal of connective tissue a cannula containing physiological saline was inserted into the femoral vein. A segment of each of the left and right jugular vein was exposed and separated from the surrounding connective tissue. Each segment consisted of the section of vein between the exit point from the thorax to the vessel's first major junction. At the desired interval following the administration of the test material or vehicle a bolus injection of 'deactivated' human serum (1.32 ml. kg "1 ) was administered over less than 30 seconds, via the femoral vein cannula. Two minutes following the thrombus challenge both the jugular vein segments were ligatured at both ends and left in si tu for thrombi to form. After 10 min both jugular segments were carefully excised, and placed in a petri dish containing 0.9% saline. A blood aample (1.8 ml blood + 0.2 ml 3.8% sodium citrate) was obtained by cardiac puncture and the animal sacrificed by an overdose of Expiral (sodium pentobarbitone) administered intravenously via the femoral vein cannula or by cardiac puncture. The 2 segments of jugular vein were carefully dissected longitudinally along one surface to expose the lumen and dispel the vessel contents into the saline. The tissues were examined for the presence of any developed thrombi and scored accordingly. Thrombus score: 0 = No thrombus 1 = One or aeveral small thrombi 2 = Several larger thrombi 3 = Large thrombus occluding the vessel Compounds of the invention were found to have significant antithrombotic activity in these assays. Partial Thromboplastin Time Test Protocol Venous blood was collected into 3.2% (0.109m) trisodium citrate vacutainer tubes at 1 volume of anticoagulant to nine volumes of blood. The blood cells were separated by centrifugation at 700g for ten minutes to yield plasma, which was frozen at 70°C until required. To perform the test, lOOμl of plasma was pipetted into in a glass test tube, lμl of teat compound in DMSO was added, and allowed to warm to 37° over two minutes. lOOμl of warm (37°) Manchester (tissue thromboplasin) reagent (Helena Biosciences, UK) was added, allowed to equilibrate for sixty seconds. lOOμl of warm (37°) 25mM calcium chloride solution was added to initiate clotting. The test tube was tilted three times through a 90° angle every five seconds to mix the reagents and the time to clot formation recorded. Data from a series of observations and test compound concentrations are analysed by a SAS statistical analysis program and a CT2 (Concentration required to double clotting time) for each compound is generated. Compounds of the invention were found to significantly elongate the partial thromboplast time. Kaolin Activated Partial Thromboplastin Time Test Protocol Venous blood was collected into 3.2% (0.109m) trisodium citrate vacutamer tubes at 1 volume of anticoagulant to nine volumes of blood. The blood cells were separated by centπfugation at 700g for ten minutes to yield plasma, which was frozen at 70°C until required. To perform the test, lOOμl of plasma was pipetted into in a glass test tube, lμl of test compound in DMSO was added, and allowed to warm to 37° over two minutes. lOOμl of APTT reagent reauspended m Owren's buffer (Thrombosis Reference Centre University of Manchester, With gton Hospital, Manchester) was added, mixed thoroughly, and lOOμl of prewarmed kaolm suspension in Owren's buffer added. Thia mixture waa incubated for ten minutes at 37°, with regular gentle mixing by tilting through a 90° angle, three times sequentially at one minute intervals to maintain the kaol in suspension. After ten minutes lOOμl of 25mM calcium chloride solution was added, the suspension redispersed by mixing as above and the time to clot formation recorded. Data from a series of observations and test compound concentrations are analyaed by a SAS statistical analyaia program and a CT2 (Concentration required to double clotting time) for each compound is generated. T.able 1 Biological data for selected examples No FXa thrombin trypsin APTT PT pKi pKi pKi CT2 uM CT2 uM 84 7.98 5.04 5.61 5.8 1.9 89 7.85 5.99 6.61 NT NT 63 7.80 5.96 6.54 NT 3.7 87 7.62 5.10 5.89 14 4.2 33 7.50 6.14 6.39 NT 7.1 32 7.39 6.09 5.65 7.4 5.6 65 7.19 5.93 5.79 9.7 13 36 7.12 6.24 6.16 9.4 9 64 7.06 5.72 5.91 7.6 8.3 68 7.01 5.32 5.59 NT 17 66 6.94 6.66 6.55 4.5 4.6 31 6.80 6.98 5.56 3.7 3.2 37 6.79 4.77 5.84 36 15 80 6.57 5.16 5.73 NT 13 12 6.39 5.27 6.10 6.5 3.4

Claims: Claims 1. A serine protease inhibitor compound of formula I (where R λ and R 2 each independently is hydrogen or hydroxyl, alkoxy, alkyl, aminoalkuyl , hydroxyalkyl alkoxyalkyl , alkoxycarbonyl, acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl; each R 3 independently is R 1# R 2/ amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl , alkylsulphenyl , alkylsulphonamido, alkylaminosulphonyl, haloalkoxy and haloalkyl ; each X independently is a C, N, 0 or S atom or a CO, CRi, C(Rι 2 or NR X group, at least one X being C, CO, CR j or C(Rτ 2 , with the proviso that if the benzamidine group is unsubstituted and the X-X group is -CH 2 C(R ! ) 2 - then R- L is hydrogen or is attached to the alkylene carbon atom by a heteroatom; L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, O and S, or a branched alkyl or cyclic group; Y is a nitrogen atom or a CR X group or Y and L taken together form a cyclic group; Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group optionally substituted by groups R 3 or phenyl optionally substituted by R 3 ; Lp is a lipophilic organic group, selected from an alkyl, heterocyclic, alkenyl, alkaryl , cycloalkyl, polycycloalkyl, cycloalkenyl, aryl, aralkyl or haloalkyl group or a combination of two or more such groups optionally aubstituted by one or more of oxa, oxo, aza, thio, halo, amino, hydroxy or R 3 groups; D is a hydrogen bond donor group; and n is 0, 1 or 2) or a physiologically tolerable salt thereof. 2. A compound as claimed in claim 1 wherein R λ represents hydrogen. 3. A compound as claimed in either one of claims 1 or 2 wherein R 2 is hydrogen, alkoxycarbonyl or hydroxy. 4. A compound as claimed in any one of claims 1 to 3 wherein R 3 is hydrogen, amino, aminoalkyl, alkylamino, hydroxy, hydroxyalkyl, thiol, alkylthio or alkoxy. 5. A compound as claimed in claim 4 wherein R 3 is para to the amidino group. 6. A compound as claimed in claim 5 wherein R 3 is amino . 7. A compounds as claimed in any one of claima 1 to 6 wherein the linker X-X is -CH=CH- , -CONH- , -CONR : -, -NH- CO-, -NH-CH 2 -, -CH 2 -NH-, -CH 2 0-, -OCH 2 -, -COO-, -OC=0- or -CH 2 CH 2 - . 8. A compound as claimed in claim 7 wherein the X moiety nearest Y is NH. 9. A compound as claimed in claim 7 wherein the X moiety nearest the phenyl ring is CH 2 or CO. 10. A compound as claimed in claim 7 wherein X-X is -CONH- . 11. A compound as claimed in any one of claima 1 to 10 wherein Y ia CH. 12. A compound as claimed in any one of claims 1 to 11 wherein Cy represents aryl or heteroaryl optionally substituted by R 3 . 13. A compound as claimed in claim 12 wherein R 3 represents phenyl optionally substituted by R 3 or napthyl optionally subatituted by R 3 . 14. A compound as claimed in claim 13 wherein Cy repreaents phenyl . 15. A compounds as claimed in any one of claims 1 to 14 wherein the linker L represents CO, CH 2 NH, CONRi (CH 2 ) m , (CH 2 ) m N(R 1 )CO(CH 2 ) m , (CH 2 ) m+2 , (CH 2 ) m CO (CH 2 ) ra , (CH 2 ) m OC=0, (CH 2 ) m O or CH=CH(CH 2 ) m (where each m is independently 0 or 1) • 16. A compound as claimed in claim 15 wherein the linker L represents CONRi CH;,)-,, CO or where m is 0 or 1. 17. A compound as claimed in any one of claima 1 to 16 wherein aaid lipophilic group comprises cycloalkyl, azacycloalkyl , diazacycloalkyl , phenyl, naphthyl , adamantyl, decalinyl, tetrahydrodecalinyl , bicycloalkyl , mono- or diazabicycloalkyl, mono- or bicyclo heteroaromatic or a linear or branched alkyl, alkylene, alkenyl or alkenylene group all optionally substituted by one or more groups R 3 , or a combination of at least two such groups linked by a spiro linkage or a single or double bond or by C=0, 0, S, SO, S0 2 , CONR j , NRi-CO-, NR X linkage . 18. A compound as claimed in claim 17 wherein the lipophilic groups is a methyl -cyclohexyl , methylcyclohexylmethyl , methylphenylmethyl , phenylethyl, benzylpiperidinyl, benzoylpiperidinyl, biapiperidinyl or phenylpiperazinyl . 19. A compound as claimed in any one of claims 1 to 18 wherein the hydrogen bond donor group is attached to the lipophilic group. 20. A compound as claimed in claim 19 wherein nitrogen or oxygen is the hydrogen bond donor atom. 21. A compound as claimed in claim 20 wherein the hydrogen bond donor is formed from a hydroxyl group, a primary, secondary or tertiary amine, or a primary or secondary imine group as part of an amidine or guanidine or a saturated or unsaturated heterocyclic group containing 5 to 7 ring atoms and having a ring nitrogen. 22. A compound as claimed in any one of claims 1 to 21 wherein Y is carbon and preferably has the conformation that would result from construction from a D-α-aminoacid NHz-CRitCy) -COOH. 23. A compound as claimed in any one of claims 1 to 22 wherein the serine protease to be inhibited is trypsin, thrombin, urokinase or Factor Xa. 24. A compound as claimed in claim 1 being 3 -Amidinobenzoyl -D-phenylglycine-4 -benzoyl piperidinamide . 25. A pharmaceutical composition comprising a aerine protease inhibitor as claimed in any one of claima 1 to 24 together with at least one pharmaceutically acceptable carrier or excipient. 26. A serine protease inhibitor as claimed in any ome of claims 1 to 24 for use in combatting a condition responsive to said inhibitor. 27. Use of a serine protease inhibitor as claimed in any one of claims 1 to 24 for the manufacture of a medicament for use in a method of treatment of the human or non-human animal body to combat a condition responsive to said inhibitor. 28. A compound as claimed in claim 27 wherein said condition is a thrombotic disease, asthma, emphysema, cirrhosis, arthritia, carcinoma, melanoma, restenois, atheroma, trauma, shock and reperfusion injury. 29. A method of treatment of the human or non-human animal body to combat a condition responsive to a serine protease inhibitor, aaid method comprising administering to said body an effective amount of a serine protease inhibitor as claimed in any one of claims 1 to 24.

Inventors: JONES STUART DONALD, LIEBESCHUETZ JOHN WALTER, MORGAN PHILLIP JOHN, MURRAY CHRISTOPHER WILLIAM, RIMMER ANDREW DAVID, ROSCOE JONATHAN MICHAEL ERNEST, WASZKOWYCZ BOHDAN, WELSH PAULINE MARY, WYLIE WILLIAM ALEXANDER, YOUNG STEPHEN CLINTON, JONES, STUART, DONALD, LIEBESCHUETZ, JOHN, WALTER, MORGAN, PHILLIP, JOHN, MURRAY, CHRISTOPHER, WILLIAM, RIMMER, ANDREW, DAVID, ROSCOE, JONATHAN, MICHAEL, ERNEST, WASZKOWYCZ, BOHDAN, WELSH, PAULINE, MARY, WYLIE, WILLIAM, ALEXANDER, YOUNG, STEPHEN, CLINTON
Applicants: JONES STUART DONALD, LIEBESCHUETZ JOHN WALTER, MORGAN PHILLIP JOHN, MURRAY CHRISTOPHER WILLIAM, PROTEUS MOLECULAR DESIGN, RIMMER ANDREW DAVID, ROSCOE JONATHAN MICHAEL ERNEST, WASZKOWYCZ BOHDAN, WELSH PAULINE MARY, WYLIE WILLIAM ALEXANDER, YOUNG STEPHEN CLINTON, JONES, STUART, DONALD, LIEBESCHUETZ, JOHN, WALTER, MORGAN, PHILLIP, JOHN, MURRAY, CHRISTOPHER, WILLIAM, PROTEUS MOLECULAR DESIGN LTD., RIMMER, ANDREW, DAVID, ROSCOE, JONATHAN, MICHAEL, ERNEST, WASZKOWYCZ, BOHDAN, WELSH, PAULINE, MARY, WYLIE, WILLIAM, ALEXANDER, YOUNG, STEPHEN, CLINTON
Application year: 1998
Main classification: C07K5
IPC codes: A61K38, C07D217, C07D233, C07D249, C07D277, C07D401, C07D405, C07D409, C07K5