THROMBIN INHIBITORS

Abstract: The present invention relates to thrombin inhibitors of formula (I), wherein A, B, C, D, E, F and n have the meaning given in the description, that are useful as anticoagulants. In particular, this invention relates to peptide derivatives having high antithrombotic activity and high oral bioavailability.

Description: THROMBIN INHIBITORS TECHNICAL FIELD The present invention relates to thrombin inhibitors that are useful as anticoagulants In particular, this invention relates to peptide derivatives having high antithrombotic activity and high oral bioavailabihty BACKGROUND ART Thrombosis is characterized by excessive blood clotting The condition plays a significant role in cardiovascular and related diseases, and thrombotic events underlie a significant proportion of the mortality and morbidity associated with cardiovascular disease Thrombosis can cause a range of disease states which are characterized by the location of the blood vessel in which the clot is formed Thrombin is a trypsin-like seπne protease that plays a key role in the blood coagulation cascade by catalyzing the conversion of fibπnogen to insoluble fibrin This enzyme also activates Factor V and Factor VIII for its own production and potently activates platelets as well Therefore, thrombin has long been recognized as a central regulator in thrombosis and hemostasis, and its inhibition has become a major therapeutic target in the treatment of cardiovascular diseases such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism Indirect thrombin inhibitors such as hepaπn and warfarin (coumaπn) have been used as antithrombotic therapies with, however, several limitations Hepaπn demonstrates low bioavailabihty and is associated with side effects such as bleeding problems, moreover, it is not able to inhibit clot-bound thrombin Warfarin is an effective oral anticoagulant but it has a narrow therapeutic window and also requires patient monitoring A natural protein inhibitor, hirudin, has been associated with bleeding complications Most of the low molecular weight thrombin inhibitors are broadly based upon peptides or peptidomimetic templates which operate by a direct mechanism of action against the target enzyme Early examples are tπpeptidic aldehydes such as D-Phe- Pro-Arg-H and Me-D-Phe-Pro-Arg-H that have been reported to be effective thrombin inhibitors (Bajusz et al J Med Chem 1990, 33, 1729) Recently, D-Phe-Pro-Agmatine and its derivatives have been described as thrombin inhibitors in US 4,346,078 and WO93/11152 (agmatine = 1-amιno-4- guanidinobutane) These compounds are different from the earlier tπpeptidic compounds in that the agimatine compounds lack a carbonyl moiety found in similar compounds containing an Arg side chain More recently, certain tπpeptidic thrombin inhibitors in which 4- amidinobenzylamaine was incorporated at the P1 position in place of agmatine have been disclosed (WO 94/29336) These amidine-based compounds have been reported to possess good antithrombotic activity (WO 95/23609) However, this class of compounds has generally poor or low oral bioavailabihty Certain thrombin inhibitors bearing the unique ammo acid D-diphenylalanine at P3 position have been disclosed (WO 93/11152, US 5510369 WO 97/15190) These compounds have been reported to have higher potency against thrombin compared to the corresponding D-phenylalanine alalogs (J Med Chem 1992, 35, 3365, J Med Chem 1997, 40, 830) In addition, some of this class of compounds exhibited good oral bioavailabihty (J Med Chem 1997, 40, 3687, J Med Chem 1997, 40, 3726) In certain thrombin inhibitors and Factor Xa inhibitors, the amidinothiophene groups have been shown to be better para-benzamidine surrogates (WO 95/23609, WO98/24784 Bioorg Med Chem Lett 1998, 8 1683) In addition, 2, 5-thιophene and other 5-membered heterocyclic moieties have effectively served as a para-phenylene isostere in the inhibitors of other drug-targeting enzymes such as thymidylate synthase and glycinamide πobonuceotide formyltransferase (J Med Chem 1991 , 34, 1594, Cancer Research 1994, 54, 1021 , WO 97/41115) Therefore there is a need in the art for thrombin inhibitors which have improved oral bioavailabihty and stabhhty as compared to those described supra We have found that the compounds of the present invention, as defined below, are potent inhibitors of thrombin in vitro and in vivo In particular, certain compounds of this invention exhibit high bioavailabihty after oral administration DISCLOSURE OF THE INVENTION The present invention relates to compounds falling within formula I below which modulate and/or inhibit the serine protease thrombin, as well as to acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof (such compounds, prodrugs, metabolites and salts are collectively referred to as ' agents") The invention is also directed to pharmaceutical compositions containing such agents and their therapeutic use in treating diseases mediated by thrombin, such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism, as well as other disease states associated with blood clotting and associated clotting factors In one general aspect, the invention relates to thrombin inhibitors of the Formula I and pharmaceutically acceptable salts thereof wherein A is hydrogen, alkyl, C 3 7 cycloalkyl, aryl, -SO 2 R 1 , -SO 3 R 1 -COR 1 , -CO 2 R 2 , PO(OR 1 ) 2 , -(CH 2 ) m CO 2 R 1 , -(CH 2 ) m SO 2 R 1 , -(CH 2 ) m SO 3 R 1 , or -(CH 2 ) m PO(OR 1 ) 2 , wherein R 1 is hydrogen, C 1 6 alkyl, C 3 7 cycloalkyl, aryl, -(CH 2 ) m aryl, or -NR 3 R 4 , and R 2 is C, 6 alkyl, C 37 cycloalkyl, aryl, -(CH 2 ) m aryl, or alkenyl, m is 1 , 2, or 3, wherein aryl is unsubsituted or substituted phenyl or 5-6 membered aromatic heterocyclic ring, R 3 and R 4 are independently hydrogen, C, 6 alkyl, or C 37 cycloalkyl, and B is hydrogen or d 6 alkyl, and C and D are independently hydrogen unsubsituted or substituted phenyl with one or two substituents selected from C-, 4 alkyl, C-, 4 alkoxy, CF 3 , methylenedioxy, halogen, hydroxy, or -NR 3 R 4 , C 3 7 cycloalkyl or a 5-6 membered heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from the group consisting of N, O, and S, and wherein Y and Z are independently N or CR 6 wherein R 5 is hydrogen or d 4 alkyl and R 6 ιs hydrogen halogen, CF 3 or d alkyl, and F is -C(NH)N(R 7 ) 2 , -C(NH 2 )NN(R 7 ) 2 , -C(NH 2 )NOH or -CH 2 NH(R 7 ) 2 wherein R 7 is the same or different, R 7 ιs hydrogen, C 1-4 perfluoroalkyl or C, 4 alkyl The invention also relates to pharmaceutical compositions each comprising an effective amount of an agent selected from compounds of Formula I and pharmaceutically acceptable salts, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs thereof, and a pharmaceutically acceptable carrier or vehicle for such agent The invention further provides methods of treating cardiovascular diseases such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism, as well as other disease states associated with excess thrombin The inventive compounds of Formula I are useful for mediating the activity of trypsin-hke serine proteases More particularly, the compounds are useful as anticoagulant agents and as agents for modulating and/or inhibiting the activity of trypsin- like serine proteases, thus providing treatments for thrombosis and other cardiovascular diseases such as myocardial infarction unstable angina, deep vein thrombosis and pulmonary embolism The terms and abbreviations used in the instant disclosure have their normal meanings unless otherwise designated As used in the present application, the following definitions apply In accordance with a convention used in the art, is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure Where chiral carbons are included in chemical structures, unless a particular orientation is depicted, both stereoisomeπc forms are intended to be encompassed An "alkyl group" is intended to mean a straight or branched chain monovalent radical of saturated and/or unsaturated carbon atoms and hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl (Bu), isobutyl, t-butyl (t-Bu), ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl, and the like, which may be unsubstituted (i e , containing only carbon and hydrogen) or substituted by one or more suitable sustituents as defined below (e g , one or more halogens, such as F, Cl, Br, or I, with F and Cl being preferred) A "lower alkyl group" is intended to mean an alkyl group having from 1 to 8 carbon atoms in its chain A "cycloalkyl group" is intended to mean a non-aromatic monovalent monocyc c, bicyclic, or tricyclic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 carbon ring atoms, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more heterocycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more substituents A "heterocycloalky group" is intended to mean a non-aromatic monovalent monocychc, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 ring atoms, which includes 1 , 2, 3, 4, or 5 heteroatoms selected nitrogen, oxygen, and sulfur, where the radical is unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents An "aryl group" is intended to mean an aromatic monovalent monocychc, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents Thus, the term "aryl group" includes a benzyl group (Bzl) , or tricyclic radical containing 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 ring atoms including 1 2 3 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted by one or more suitable substituents as defined below, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups which themselves may be unsubstituted or substituted by one or more suitable substituents A "heterocycle" is intended to mean a heteroaryl or heterocycloalkyl group (each of which, as defined above, are optionally substituted) An "acyl group" is intended to mean a -C(O)-R radical, where R is a substituent as defined below A "thioacyl group" is intended to mean a -C(S)-R radical, where R is a substituent as defined below A "sulfonyl group" is intended to mean a -SO 2 R radical, where R is a substituent as defined below A "hydroxy group" is intended to mean the radical -OH An "ammo group" is intended to mean the radical -NH 2 An "alkylamino group" is intended to mean the radical -NHR a , where R a is an alkyl group A "dialkylamino group" is intended to mean the radical -NR a R b , where R a and R b are each independently an alkyl group An "alkoxy group" is intended to mean the radical -OR a , where R a is an alkyl group Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like An "alkoxycarbonyl group" is intended to mean the radical -C(O)OR a , where R a is an alkyl group An "alkylsulfonyl group" is intended to mean the radical -SO 2 R a , where R a is an alkyl group An "alkylaminocarbonyl group" is intended to mean the radical -C(O)NHR a , where R a is an alkyl group A "dialkylaminocarbonyl group" is intended to mean the radical -C(O)NR a R b where R a and R b are each independently an alkyl group A "mercapto group" is intended to mean the radical -SH An "alkylthio group' is intended to mean the radical -SR a , where R a is an alkyl group A "carboxy group" is intended to mean the radical -C(O)OH A "carbamoyl group" is intended to mean the radical -C(O)NH 2 An "aryloxy group" is intended to mean the radical -OR c , where R c is an aryl group A "heteroaryloxy group" is intended to mean the radical -OR d , where R d is a heteroaryl group An "arylthio group" is intended to mean the radical -SR C , where R c is an aryl group A "heteroarylthio group" is intended to mean the radical -SR d , where R d is a heteroaryl group A "leaving group" (Lv) is intended to mean any suitable group that will be displaced by a substitution reaction One of ordinary skill in the art will know that any conjugate base of a strong acid can act as a leaving group Illustrative examples of suitable leaving groups include, but are not limited to, -F, -Cl, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p- toluenesulfonates, alkyl methanesulfonates, tπflate, and any groups having a bisulfate, methyl sulfate, or sulfonate ion Typical protecting groups, reagents and solvents are well known in the art One skilled in the art would know possible protecting groups, reagents and solvents, these are intended to be within the scope of this invention The term "suitable organic moiety" is intended to mean any organic moiety recognizable, such as by routine testing, to those skilled in the art as not adversely affecting the inhibitory activity of the inventive compounds Illustrative examples of suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups alkylthio groups, alkoxy groups, carboxy groups, ammo groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like The term "substituent" or suitable substituent" is intended to mean any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art Illustrative examples of suitable substituents include hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, ammo groups, alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, and the like The term 'optionally substituted" is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents, unless the optional substituents are expressly specified, in which case the term indicates that the group is unsubstituted or substituted with the specified substituents As defined above, various groups may be unsubstituted or substituted (i e , they are optionally substituted) unless indicated otherwise herein (e g , by indicating that the specified group is unsubstituted) The terms "comprising" and "including" are used in an open, non-limiting sense A "pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound A "pharmaceutically active metabolite" is intended to mean a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those descibed herein A "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and htat is not biologically or otherwise undesirable A compound of the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salt Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a nimeral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dιoates, hexyne-1 ,6-dιoates, benzoates, chlorobenzoates, methylbenzoates, dmitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates phenylbutyrates, citrates lactates -hydroxybutyrates, glyco ates, tartrates, methane-sulfonates, propanesulfonates, naphthalene-1 -sulfonates, naphthalene-2-sulfonates, and mandelates Some abbreviations that appear in this application are as follows Boc t-butoxycarbonyl Pro prohne EDC 1 -ethyl-3-(3-dιmethylamιnopropyl)carbodιιmιde hydrochloride HOBT 1-hydroxybenzonιtrιle hydrate TFA trifluoroacetic acid AcOH acetic acid DMF dimethylformamide EtOAc ethyl acetate HCI hydrochloride rt room temperature TEA triethylamine FAB MS fast atom bombardment mass spectrum If the inventive compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid , such as acetic acid maleic acid, succmic acid, mandehc acid, fumaric acid malonic acid, pyrovic acid, oxalic acid, glyco c acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaπc acid, an ammo acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, or the like If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like Illustrative examples of suitable salts include organic salts derived from ammo acids such as glycme and argmine ammonia, primary secondary, and tertiary amines, and cyclic amines, such as piperidine, morpho ne and piperazme, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas Prefered compounds of the invention include, but are not limited to the following 1 N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, 2 N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-2-thιenyl)methyl]amιde, 3 N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, 4 N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdrazono-2-thιenyl)methyl]amιde, 5 N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-2-thιenyl)methyl]amιde, 6 N-benzylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, 7 N-t-butoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, 8 N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, 9 N-amιnosulfonyl-D-3 4-dιchlorophenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, 10 N-methoxycarbonyl-D-dιcyclohexylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, 1 1 N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιenyl)methyl]amιde 12 N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιnomethyl-2-thιenyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιenyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdrazono-3-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-3-thιenyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-cyclohexylsulfamoyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-allyloxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-benzylsulfonyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-cyclohexylsulfamoyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methylsulfamoyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-cyclohexylglycιnyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-(t-butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-(t-butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-hydroxyamιdιno-2- thιenyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methyl-N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-hydroxysulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-5-methyl-2- thιenyl)methyl]amιde N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-furanyl)methyl]amιde, N-methoxycabonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-furanyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-furanyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-1 -methyl-2- pyrrolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-[2-(methoxycarbonyl)ethyl]-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde N-(2-carboxyethyl)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-Boc-D-Dιphenylalanyl-L-prolyl-[(5-amιdrazono-2-thιenyl)methyl]amιde, D-dιphenylalanyl-L-prolyl-[(5-amιdrazono-2-thιenyl)methyl]amιde, N-methoxycabonyl-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-(2-carboxyethyl)-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-hydroxyamιdιno-2- thιenyl)methyl]amιde, N-(methoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-hydroxyamιdιno-2- thιenyl)methyl]amιde D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-(3-carboxypropyl)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-(MeO) 2 P(O)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-(Me) 2 P(O)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-(HO) 2 P(O)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-phenyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-[(N,N-dιethylcarboxamιdo)methyl]-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-[(N,N-dιethylcarboxamιdo)ethyl]-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-thιazolyl)methyl]amιde N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-thιazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-thιazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-thιazolyi)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιazolyl)methyl]amιde N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-thιazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-thιazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-oxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-oxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-oxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-oxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-oxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-oxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-oxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-oxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-oxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-oxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-oxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-oxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-oxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-oxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-oxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-oxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-ιsoxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-ιsoxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-ιsoxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-ιsoxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4- ιsoxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- ιsoxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-ιsoxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-ιsoxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- pyrazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-pyrrolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrrolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-pyrrolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-pyrrolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrrolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-pyrrolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- pyrrolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- pyrrolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3- pyrrolyl)methyl]amιde N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- pyrrolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- pyrrolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3- pyrrolyl)methyl]amιde, N-amιnosulfonyl-D-dιcyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιcyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-carboxymethyl-D-dιcyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-amιnosulfonyl-D-bιs-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methylsulfonyl-D-bιs-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methoxycarbonyl-D-bιs-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-carboxymethyl-D-bιs-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-amιnosulfonyl-D-bιs-(para-amιnophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methylsulfonyl-D-bιs-(para-amιnophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methoxycarbonyl-D-bιs-(para-amιnophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-carboxymethyl-D-bιs-(para-amιnophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-amιnosulfonyl-D-bιs-(para-chlorophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, 124 N-methylsulfonyl-D-bιs-(para-chlorophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, 125 N-methoxycarbonyl-D-bιs-(para-chlorophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, 126 N-carboxymethyl-D-bιs-(para-chlorophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde Compounds of the present invention can be prepared according to the general procedure outlined below As exemplified by Example 1 and Example 8 (Scheme 1 ), a protected ammo acid such as N-Boc-D-diphenylalnine is coupled to prohne methyl ester using a couplng agent such as EDC and HOBT The resultant dipeptide is treated with a strong acid such as hydrochloric acid gas or trifluoroacetic acid to remove the t-butoxycarbonyl (Boc) protecting group The resultant free amine is reacted with a sulfonylating reagent such as sulfamoyl chloride and a base such as triethylamine Carbamate-contaming compounds are prepared using chioroformates The product is then hydrolyzed with base such as lithium hydroxide and the resultant acid is coupled to the desired amine such as 5-(amιnomethyl)thιophene-2-carbonιtπle The coupled product is converted to the amidine by a three-step sequence involving sequential treatment with hydrogen sulfide, methyl iodide, and ammonium acetate The amidrazone compound is obtained by treatment with hydrazine in place of ammonium acetate in the final step The nitnle intermediate is also converted to the methylamine by catalytic hydrogenation in the presence of a strong acid such as hydrochloric acid Scheme 1 An alternative route, as depicted in Scheme 2, is to hydrolyze the Boc- protected dipeptide before functionalizing the ammo group and then couple the resultant acid with the desired amine The protecting group of the coupling product is removed and the free amine is then sulfonylated. Scheme 2 90 N-Boc-D-dιphenylalnιne can be coupled directly to the amine-coupled prohne as exemplified by Example 32 (Scheme 3) The product is then deprotected and subsequently sulfonylated Scheme 3 Another method for synthesizing compounds of the invention, particularly N- carboxyalkyl substituted compounds, is as exemplified by Example 28 and Example 29 (Scheme 4) The free ammo containing compound reacts with an alkylatmg agent such as t-butylbromoacetate and a base such as diisopropylethylamine (DIPEA) The resulting compound is treated with hydroxylamine hydrochloride in the presence of base such as sodium carbonate and the resultant amidoxime is catalytically hydrogenated in the presence of acetic anhydride to produce the amidine The t-butyl group is removed with acid such as trifluoroacetic acid and hydrochloric acid to give the product Scheme 4 Amide coupling used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclohexylcarbodπmide (DCC) or 1-ethyl-3-(3-dιmethylamιnopropyl) carbodiimide (EDC) Other method for forming the amide or peptide bond include, but not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester The addition and removal of one or more protecting groups are typical practice Methods for suitable protection and deprotection are provided in "Protective Groups in Organic Synthesis", 3rd Edition, by T W Green and Peter G M Wuts (1999), John Wiley & Sons, Inc , publishers The amide coupling reactions are carried out in an inert organic solvent such as dirmethylformamide, dimethylacetamide, tetrahydrofuran, dichloromethane, chloroform, and like common solvents or a mixture of such solvents Compounds that potently regulate, modulate, or inhibit the conversion of fibrmogen to fibrin via the enzyme thrombin and therefore inhibit thrombosis and clotting are desirable and represent preferred embodiments of the present invention The present invention is further directed to methods of modulating trypsin-hke serine protease activity, for example in mammalian tissue, by administering an inventive agent The activity of the inventive compounds as modulators of trypsm-hke serine protease activity, such as the activity of thrombin may be measured by any of the methods available to those skilled in the art including in vivo and/or in vitro assays These properties may be assessed, for example, by using one or more of the biological testing procedures set out in the examples below The active agents of the invention may be formulated into pharmaceutical compositions as described below Pharmaceutical compositions of this invention comprise an effective modulating, regulating, or inhibiting amount of a compound of Formula I and an inert, pharmaceutically acceptable carrier or diluent In one embodiment of the pharmaceutical compositions, efficacious levels of the inventive agents are provided so as to provide therapeutic benefits involving modulation of tyrpsin-hke serine proteases By "efficacious levels" is meant levels in which the effects of tyrpsin-hke serine proteases like thrombin are, at a minimum, regulated These compositions are prepared in unit-dosage form appropriate for the mode of administration, e g , parenteral or oral administration The compositions of the invention may be manufactured in manners generally known for preparing pharmaceutical compositions, e g , using conventional techniques such as mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophi zing Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically The pharmaceutical compositions also may comprise suitable solid- or gel- phase carriers or excipients Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g If a liquid carrier is used, the preparation will be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampule or vial or non-aqueous liquid suspension To obtain a stable water-soluble dose form, a pharmaceutically acceptable salt of an inventive agent is dissolved in an aqueous solution of an organic or inorganic acid, such as 0 3M solution of succmic acid or citric acid If a soluble salt form is not available, the agent may be dissolved in a suitable cosolvent or combinations of cosoivents Examples of suitable cosolvents include but are not limited to, alcohol, propylene glycol polyethylene glycol 300, polysorbate 80, gylceπn and the like in concentrations ranging from 0-60% of the total volume In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution A pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase The cosolvent system may be a VPD co-solvent system VPD is a solution of 3% w/v benzyl alcohol 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300 made up to volume in absolute ethanol The VPD co-solvent system (VPD 5W) contains VPD diluted 1 1 with a 5% dextrose in water solution This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration Naturally the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics Furthermore, the identity of the co-solvent components may be varied for example other low-toxicity nonpolar surfactants may be used instead of polysorbate 80, the fraction size of polyethylene glycol may be varied, other biocompatible polymers may replace polyethylene glycol, e g polyvmyl pyrro done, and other sugars or polysacchaπdes may be substituted for dextrose Alternatively other delivery systems for hydrophobic pharmaceutical compounds may be employed Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent Various sustained-release materials have been established and are known by those skilled in the art Sustained-release capsules may depending on their chemical nature, release the compounds for a few weeks up to over 100 days Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed It will be appreciated that the actual dosages of the agents used in the compositions of this invention will vary according to the particular complex being used, the particular composition formulated, the mode of administration and the particular site host and disease being treated Optimal dosages for a given set of conditions can be ascertained by those skilled in the art using conventional dosage-determination tests in view of the experimental data for an agent For oral administration, an exemplary daily dose generally employed is from about 0 001 to about 1000 mg/kg of body weight, more preferably from about 0 001 to about 50 mg/kg body weight, and most preferably 1-20 mg/kg, with courses of treatment repeated at appropriate intervals Administration of prodrugs are typically dosed at weight levels which are chemically equivalent to the weight levels of the fully active form Intravenously, the most preferred doses will range from about 0 01 to about 10 mg/kg/mmute during a constant rate infusion Advantageously, the thrombin inhibitors may be administered in divided doses of two, three, or four times daily Furthermore, they can be administered in mtranasal form vial topical use of suitable mtranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art To be administered in the form of a transdermal delivery system the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime Therapeutically effective amounts of the agents of the invention may be used to treat diseases mediated by modulation or regulation of trypsm-hke serine proteases An "effective amount" is intended to mean that amount of an agent that when administered to a mammal in need of such treatment, is sufficient to effect treatment for a disease mediated by the activity of one or more trypsm-hke serine proteases, such as thrombin Thus, e g , a therapeutically effective amount of a compound of the Formula I, salt, active metabolite or prodrug thereof is a quantity sufficient to modulate, regulate, or inhibit the activity of one or more protein kinases such that a disease condition which is mediated by that activity is reduced or alleviated The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e g , weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art "Treating" is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is affected, at least in part, by the activity of one or more trypsm-hke serine proteases, such as thrombin and includes preventing the disease condition from occurring in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but has not yet been diagnosed as having it, modulating and/or inhibiting the disease condition, and/or alleviating the disease condition Proper formulation is dependent upon the route of administration chosen The inventive compounds may be administered in intravenous (bolus or infusion), intrapeπtoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent For treating ocular build up of fibrin the compounds may be administered intraocularly or topically as well as orally or parenterally For injection, the agents of the invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution or physiological saline buffer For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation Such penetrants are generally known in the art For oral administration the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers known in the art Such carriers enable the compounds of the invention to be formulated as tablets pills dragees capsules liquids gels syrups slurries suspensions and the like, for oral ingestion by a patient to be treated Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent) optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose or polyvmylpyrrohdone (PVP) If desired, disintegrating agents may be added, such as crosslmked polyvmyl pyrrohdone, agar, or alginic acid or a salt thereof such as sodium algmate Dragee cores are provided with suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arable, polyvmyl pyrrohdone, Carbopol gel, polyethylene glycol and/or titanium dioxide lacquer solutions, and suitable organic solvents or solvent mixtures Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin as well as soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose binders such as starches and/or lubricants such as talc or magnesium stearate and optionally stabilizers In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols In addition, stabilizers may be added All formulations for oral administration should be in dosages suitable for such administration For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner For administration mtranasally or by inhalation the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuhser with the use of a suitable propellant, e g , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch The compounds may be formulated for parenteral administration by injection e g , by bolus injection or continuous infusion Formulations for injection may be presented in unit-dosage form, e g , in ampoules or in multi-dose containers, with an added preservative The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form Additionally suspensions of the active agents may be prepared as appropπate oily injection suspensions Suitable lipophihc solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides or liposomes Aqueous injection suspensions may contain substances which increase the viscosity of the suspension such as sodium carboxymethyl cellulose sorbitol, or dextran Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e g , sterile pyrogen-free water, before use The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e g, containing conventional suppository bases such as cocoa butter or other glycendes In addition to the formulations described above, the compounds may also be formulated as a depot preparation Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt The thrombin inhibitors can also be co-administered with suitable anti- coagulation agents or thrombolytic agents such as plasmmogen activators or streptokinase to achieve synergistic effects in the treatment of various ascular pathologies For example, thrombin inhibitors enhance the efficiency of tissue plasmmogen activator-mediated thrombolytic reperfusion Thrombin inhibitors may be administered first following thrombus formation, and tissue plasmmogen activator or other plasmmogen activator is administered thereafter They may also be combined with hepaπn aspirin, or warfarin Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions particularly coronary artery and cerebrovascular disease Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy The term patient used herein is taken to mean mammals such as primates, including humans sheep, horses cattle, pigs dogs cats, rats and mice The dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient, the severity of the condition to be treated, the route of administration, the renal and hepatic function of the patient, and the particular compound or salt thereof employed An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent counter or arrest the progress of the condition Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage Thus, the thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited e g when contacting the mammal s blood with material selected from the group consisting of vascular grafts stents orthopedic prothesis, cardiac prosthesis, and extracorporeal circulation systems The inventive agents may be prepared using the reaction routes and synthesis schemes as described below employing the techniques available in the art using starting materials that are readily available The preparation of preferred compounds of the present invention is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other protein kinase inhibitors of the invention For example, the synthesis of non-exemplified compounds according to the invention may be successfully perfomed by modifications apparent to those skilled in the art, e g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention. EXAMPLE 1 Preparation of N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA A) 5-(Bromomethyl)thιophene-2-carbonitrιle A mixture of 5-methylthiophene-2-carbonιtrile (9 9 g, 80.5 mmol), benzoylperoxide (0.23 g, 0 95 mmol), and N-bromosuccinimide (15 g, 84 3 mmol) in carbontetrachloπde (200 mL) was heated at reflux for 6 h The resulting suspension was filtered and the filtrate diluted with dichloromethane (400 mL), washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo The residue was purified by column chromatography (EtOAc n- hexane, 1 4) to give the title compound as a yellow oil (14 0 g, 86%) Η NMR (CDCI 3 ) δ 7 50 (d, 1 H), 7 13 (d, 1 H), 4 68 (s, 2H) FAB MS 203 [M+1] + B) 5-(Amιnomethyl)thιophene-2-carbonιtπle HCI To a cold solution of 5-(bromomethyl)thιophene-2-carbonιtrιle (4 2 g, 20 8 mmol) in THF (500 mL) was added sodium hydride (60% dispersion in oil, 1 0 g, 25 mmol) in portions To this suspension was added di-t-butyl iminodicarboxylate (4 9 g, 22 9 mmol) in portions After stirrng for 3 h, the resulting solution was diluted with ethyl acetate (400 mL) washed with water dried over magnesium sulfate and concentrated in vacuo The residue was purified by column chromatography (EtOAc n-hexane, 1 4) to give 5-(N,N-Boc 2 -amιnomethyl)thιophene-2-carbonιtrιle as a yellow foam This solid was dissolved in ethyl acetate (150 mL) and cooled to 0°C HCI gas was bubbled through the solution for 10 mm, and the mixture was allowed to warmed to room temperature The solvent was removed in vacuo to give the title compound as a pale yellow solid (2 4 g 86%) 1 H NMR (CD 3 OD) δ 7 48 (d, 1 H), 7 20 (d 1 H), 4 21 (s, 2H) FAB MS 175 [M+1] + C) N-Aminosulfonyl-D-diphenylalanyl-L-prohne methyl ester To a stirring solution of chlorosulfonyl isocyanate (6 3 g, 45 mmol) in dichloromethane (25 mL) was added dropwise formic acid (2 13 g, 45 mmol) The mixture was heated at reflux for 5 h and cooled to obtain 1 8 N solution of sulfamoyl chloride in dichloromethane To a cooled (0°C) solution of D-diphenylalanyl-L-prohne methyl ester HCI (2 5 g, 6 47 mmol) in dichloromethane (100 mL) was added the 1 8 N sulfamoylchloride solution (6 mL) and triethylamine (2 7 mL) After the reaction was completed the resulting solution was diluted with dichloromethane (40 mL) washed with brine, dried over magnesium sulfate, and concentrated in vacuo The residue was purified by column chromatography (EtOAc n-hexane 2 1 ) to give the title compound (1 88 g, 67%) Η NMR (CDCI 3 ) δ 7 38 - 7 20 (m 4H) 7 18 (m 6H) 5 85 (d 1 H) 5 29 (s 2H) 4 95 (dd, 1 H), 4 75 (m, 1 H), 4 14 (d, 1 H), 3 67 (s, 3H), 2 70 (m, 1 H), 1 74 (m, 3H), 1 38 (m, 1 H) FAB MS 431 [M+1] + D) N-Ammosulfonyl-D-diphenylalanyl-L-prohne To a suspension of N-ammosulfonyl-D-diphenylalanyl-L-prohne methyl ester (1 88 g, 4 36 mmol) in a mixture of water (100 mL) and methanol (150 mL) was added 0 5 N lithium hydroxide (40 mL) and the mixture stirred overnight at rt The resulting solution was acidified to pH 2 by addition of 1 N HCI and the solvent partially removed by evaporation in vacuo The precipitates were collected by filtration to give the title compound as a white crystalline solid (1 68 g 92%) 1 H NMR (CD 3 OD) δ 7 40 (m, 2H) 7 33 (m, 2H), 7 24 (m, 6H), 4 95 (dd, 1 H), 4 29 (d, 1 H), 4 05 (m, 1 H), 3 75 (m, 1 H), 2 87 (m, 1 H), 1 83 - 1 72 (m, 3H), 1 43 (m, 1 H) FAB MS 417 [M+1] + E) N-Amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde A mixture of N-aminosulfonyl-D-diphenylalanyl-L-prohne (0 2 g, 0 48 mmol), 5- (amιnomethyl)thιophene-2-carbonιtπle HCI (0 1 g, 0 57 mmol), EDC (0 14 g, 0 72 mmol), HOBT (0 08 g, 0 62 mmol), and triethylamine (0 2 mL, 1 44 mmol) in DMF (2 mL) was stirred for 2 h at rt The solvent was removed in vacuo and the residue dissovled in EtOAc and washed sequentially with a saturated sodium bicarbonate solution, 1 N HCI and brine After the solution was dried over magnesium sulfate and concentrated in vacuo, the residue was purified by column chromatography (EtOAc n- hexane, 2 1 ) to give the title compound (0 2 g, 78%) 1 H NMR (CDCI 3 ) δ 1 38 (m, 1 H), 1 50 (m, 1 H), 1 92 (m, 2H), 2 61 (m, 1 H), 3 63 (m, 1 H), 4 12 (m, 1 H), 4 40 (m, 2H), 4 52 (m, 1 H), 4 89 (m, 1 H), 5 25 (m, 2H), 6 87 (m, 1 H), 7 15-7 55 (m, 11 H) FAB MS 537 [M+1] + F) N-Amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde TFA A solution of the coupling compound prepared in Step E (0 2 g, 0 37 mmol) in pyridine (2 mL) was saturated with gaseous H 2 S After the mixture was allowed to stand for 1 day, the solvent was removed in vacuo to obtain the thioamide as a yellow solid To this material was added acetone (2 mL) and lodomethane (0 07 mL, 1 12 mmol), and the mixture was heated at reflux for 1 h After the solvent was evaporated in vacuo, the resulting methylthioamidate was dissolved in acetonitπle (2 mL) To this solution was added ammonium acetate (0 09 g, 1 12 mmol) over 10 mm and the mixture heated at reflux for 1 h The solution was cooled and concentrated and the residue purified by column chromatography using 10% methanol in chloroform to give the title compound which was further purified by preparative HPLC (TFA (0 1 %)-H 2 O- MeOH gradient) The pure fractions were lyophi zed to give a white solid (015 g, 60%) as a TFA salt Η NMR (CD 3 OD) δ 146 (m, 1H), 162 (m 1H) 173 (m, 1H), 185 (m, 1H), 290 ( , 1H), 376 ( , 1H), 405 (q, 1H), 431 (d 1H), 459 (m, 1H), 462 (m, 1H), 498 (m, 1H), 7.25-751 (m, 11 H), 777 (m, 1H) FAB MS 555[M+1] + EXAMPLE 2 Preparation of N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-2- thιenyl)methyl]amιde HCI N-Amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde prepared in Example 1 Step E (01 g 019 mmol) was dissolved in methanol (2 mL) To this solution was added 10% palladium-on-carbon (100 mg) and 3 drops of cone HCI and the mixture stirred for 2 days under H 2 (60 psi) The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo The residue was purified by preparative HPLC (TFA (01%)-H 2 0-MeOH gradient) to give the title compound (40 mg, 36%) as a white solid Η NMR (CD 3 OD) δ 141 (m, 1H), 150 (m, 1H), 172 (m, 1H), 182 (m, 1H), 298 (m, 1H), 375 (m, 1H), 405 (m, 3H), 438 (m, 3H), 498 (m, 1H), 720-751 (m, 12H) FAB MS 542 [M+1] + EXAMPLE 3 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA A) N-Methylsulfonyl-D-diphenylalanyl-L-prohne To a cooled (0°C) solution of D-diphenylalanyl-L-prolme methyl ester HCI (2 g, 5 67 mmol) in dichloromethane (100 mL) was added methanesulfonylchloπde (0 52 mL, 6 8 mmol) and triethylamine (3 1 mL, 22 7 mmol) and the mixture stirred for 2 h at rt After the reaction was completed, the resulting mixture was washed with 1 N HCI and then with brine, dried over magnesium sulfate, and concentrated in vacuo The residue was purified by column chromatography (EtOAc n-hexane, 1 2) to give N- methylsulfonyl-D-diphenylalanyl-L-prohne methyl ester (2 1g, 86%) This compound was then hydrolyzed essentially according to the procedure of Example 1 , Step D to give the title compound (1 8 g, 90%) Η NMR (CD 3 OD) δ 1 45 (m, 1 H), 1 70-1 90 (m, 3H), 2 91 (m, 4H), 3 85 (m, 1 H), 4 11 (m, 1 H), 4 32 (m, 1 H), 4 98 (m, 1 H), 7 18-7 42 (m, 10H) FAB MS 417 [M+1] + B) N-Methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde The title compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L- prohne and 5-(amιnomethyl)thιophene-2-carbonιtrιle HCI essentially according to the coupling procedure of Example 1, Step E, yield 88% 1 H NMR (CDCI 3 ) δ 145 (m, 2H), 172 (m 1H), 206 (m, 1H), 256 (m, 1H), 280 (s, 3H), 361 (m, 1H), 428 (m, 1H), 436 (d, 1H), 450 (m, 2H), 483 (m, 1H), 544 (m, 1H), 696 (m, 1H), 722-751 ( , 11H), FAB MS 537[M+1] + C) N-Methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde TFA The title compound was prepared from the compound obtained in Step B using the procedure described in Example 1, Step F, yield 54% Η NMR (CD 3 OD) δ 142 (m, 1H) 164 (m, 1H), 181 (m 2H), 287 (s, 3H), 295 ( , 1H), 372 (m, 1H), 404 (m, 1H), 431 (d, 1H) 458 (m 2H) 502 (m, 1H), 718-742 ( , 9H), 750(m, 2H), 778 (m, 1H) FAB MS 554[M+1] + EXAMPLE 4 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdrazono-2- thιenyl)methyl]amιde TFA A solution of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-2- thιenyl)methyl]amιde TFA prepared in Example 3, Step B (0 2 g, 0 37 mmol) in pyridine (2 mL) was saturated with gaseous H 2 S After the mixture was allowed to stand for 1 days, the solvent was removed in vacuo The yellow solid obtained was dissolved in acetone (2 mL) and lodomethane (0 07 mL, 1 12 mmol), and the mixture heated at reflux for 1 h After the solvent was evaporated in vacuo, the residue was dissolved in acetonitπle (2 mL) To this solution was added 80% hydrazine (0 07 mL, 1 12 mmol) over 10 mm, and the mixture was stirred for 1 h The solution was concentrated and the crude product purified by preparative HPLC (TFA (0 1 %)-H 2 0-MeOH gradient) to give the title compound as a white solid (0 14 g, 55%) 1 H NMR (CD 3 OD) δ 1 39 (m, 1 H), 1 52 (m, 1 H) 1 80 (m, 2H), 2 92 (m, 4H), 3 69 (m, 1 H), 4 03 (m, 1 H), 4 31 (d, 1 H), 4 50 (m, 2H), 5 02 (m, 1 H), 7 02 (m, 1 H), 7 21-7 55 (m, 11 H) FAB MS 569 [M+1] + EXAMPLE 5 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-2- thιenyl)methyl]amιde TFA The title compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L- prolyl-[(5-cyano-2-thιenyl)methyl]amιde TFA (see Example 3 Step B) essentially using the procedure described in Example 2, yield 42% Η NMR (CD 3 OD) δ 1 47 (m, 1 H), 1 60 (m, 1 H), 1 79 (m, 2H), 2.84 (s, 3H), 2 93 (m. 1 H), 3 71 (m, 1 H), 4 03 (m, 1 H), 4 31 (m,3 H), 4 46 (m, 2H), 4.98 (m, 1 H), 7.25-7.50 (m, 12H). FAB MS: 541 [M+1] + EXAMPLE 6 Preparation of N-benzylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde.TFA A) N-Benzylsulfonyl-D-diphenylalanyl-L-proline This compound was prepared by the same procedure as described in Example 3, Step A except that benzylsulfonylchloπde was used instead of methanesulfonylchloπde, yield 46% 1 H NMR (CD 3 OD) δ 1 40 (m, 1 H), 1 68-1 88 (m, 3H) 2 88 (m, 1 H) 3 93 (m, 1 H), 4.15 (m, 1 H), 4.37-4.43 (m, 3H), 5.02 (m, 1 H), 7.17-7 48 ( , 15H). FAB MS 493 [M+1] + B) N-Benzylsulfonyl-D-diphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde This compound was prepared from N-benzylsulfonyl-D-diphenylalanyl-L- prohne using the procedure described in Example 1, Step E, yield 85% 1 H NMR (CDCI 3 ) δ 138 (m, 1H), 146 (m, 1H), 169 (m, 1H), 215 (m, 1H), 257 (m, 1H), 360 (m, 1H), 399 (d, 1H), 413 (d, 1H), 428 (m, 2H), 447 (m, 2H), 469 (m, 1H), 488 (m, 1H), 689 (m, 1H), 718 (m 2H), 718-752 (m 14H) FAB MS 613[M+1] + C) N-Benzylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde TFA The title compound was prepared from the compound prepared in Step B using the procedure described in Example 1, Step F, yield 45% 1 H NMR (CD 3 OD) δ 146 (m, 1H), 162 (m, 1H), 182 (m, 2H), 300 (m, 1H), 378 (m, 1H), 403 ( , 1H), 421 (s, 2H), 432 (d, 1H), 459 (s, 2H), 512 (d, 1H), 709 (m, 1H), 715-745 (m 15H), 757 (m 1H) FAB MS 630[M+1] + EXAMPLE 7 Preparation of N-t-butoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA A) N-Boc-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde To a solution of N-Boc-D-diphenylalanyl-L-prohne (2 g, 48 mmol) in DMF (20 mL) was added 5-(amιnomethyl)thιophene-2-carbonιtrιle HCI (1 g, 5 7 mmol, prepared in Example 1 , Step B), EDC (1 4 g, 7 2 mmol), HOBT (0 8 g, 6 2 mmol) and triethylamine (2 mL, 14 4 mmol) and the mixture stirred overnight at rt The solvent was removed in vacuo and the residue dissolved in EtOAc and washed sequentially with a saturated sodium bicarbonate solution, 1 N HCI, and brine After the solution was dried over magnesium sulfate and concentrated in vacuo, the residue was purified by column chromatography (EtOAc n-hexane 2 1 ) to give the title compound (2 3 g, 86%) Η NMR (CD 3 OD) δ7 44 (m, 2H), 7 21 (m, 1 H) 4 98 (s, 2H), 4 40 (m, 2H), 3 79 (m, 1 H), 3 10-2 97 (m, 3H), 2 17-1 88 (m, 3H), 1 74 (m, 1 H) FAB MS 558 [M+1] + B) N-t-Butoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA The title compound was prepared from the compound obtained in Step A using the procedure described in Example 1 , Step F, yield 54% 1 H NMR (CD 3 OD) δ 7 78 (d, 1 H), 7 45 (m, 2H) 7 22 (m, 1 H), 7 16 (d, 1 H), 4 94 (s, 2H), 4 59 (s, 2H), 4 40 (m, 2H), 3 81 (m, 1 H), 3 09 (m, 1 H), 2 96 (m, 2H), 1 98 FAB MS 576 [M+1] + EXAMPLE 8 Preparation of N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA A) D-Dιphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde HCI To a cooled solution of N-Boc-D-dιphenylalanyl-L-prolyl-[(5-cyano-2- thιenyl)methyl]amιde prepared in Example 7, Step A (02 g, 037 mmol) in methanol (20 mL) was added dropwise acetylchloπde (2 mL) After stirring for 3 h at rt, the solution was removed to dryness to give the title compound as a white solid (0271 g, 100%) 1 H NMR (CDCI 3 ) δ 852 (m, 1H), 755-712 (m, 11 H), 684 (d, 1H), 477 (d, 1H), 457 (d, 1H), 450 (dd, 1H), 423 (d 1H) 418 (dd 1H), 377 (t, 1H), 243 (q, 1H), 194 (m, 1H), 162 (m, 1H), 148 (m, 1H), 130 (m, 1H) FAB MS 459[M+1] + B) N-Methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde D-Dιphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde HCI (0271 g) was dissolved in dichloromethane (2 mL) and cooled to 0°C To this was added triethylamine (0.22 mL, 159 mmol) and methyl chloroformate (004 mL, 067 mmol) and the mixture stirred at rt for 2 h The solution was concentrated and the residue purified by column chromatography (EtOAc n-hexane 21) to give the title compound (018g, 67%) Η NMR (CDCI 3 ) δ150 (m, 1H), 167 (m, 1H), 188 (m, 2H), 301 (m, 1H), 320 (s, 3H), 381 (m 1H), 409 (m, 1H) 429 (d, 1H), 455 (m 1H), 463 (m, 1H), 493 (m, 1H), 518 (m, 1H), 712-754 (m, 11H), 768 (m, 1H) FAB MS 516[M+1] + C) N-Methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde The title compound was prepared from the compound obtained in Step B essentially according to the procedure of Example 1 Step F yield 63% Η NMR (CD 3 OD) δ 1 49 (m, 1 H) 1 65 (m 1 H), 1 85 (m, 2H), 2 91 (m, 1 H), 3 30 (s, 3H), 3 84 (m, 1 H), 4 07 (m, 1 H), 4 36 (m, 1 H), 4 52 (m, 1 H), 4 66 (m, 1 H) 5 14 (m, 1 H), 7 18-7 52 (m, 11 H), 7 81 (m, 1 H) FAB MS 533 [M+1] + EXAMPLE 9 Preparation of N-amιnosulfonyl-D-3,4-dιchlorophenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA A) N-Amιnosulfonyl-D-3,4-dιchlorophenylalanyl-L-prohne The title compound was prepared from D-3,4-dιchlorophenylalanyl-L-prohne methyl ester (see J Med Chem 1997, 40, 3726) using the procedure described in Example 1 , Step C and D yield 60% Η NMR (CD 3 OD) δ 1 30 (m 1 H) 1 74 (m 1 H) 1 88-1 93 (m, 2H) 2 78 (m 3H), 3 71 (m, 1 H), 4 30-4 42 (m, 2H), 5 23 (m, 1 H), 7 11 -7 42 (m, 3H) FAB MS 410 [M+1] + B) N-Amιnosulfonyl-D-3 4-dιchlorophenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA The title compound was prepared from the compound obtained Step A using the procedure described in Example 1 , Step E and F yield 32% Η NMR (CD 3 OD) δ 1 38 (m, 1 H), 1 67 (m, 1 H), 1 84-2 01 (m, 2H), 2 84 (m, 2H), 3 02 (m, 1 H), 3 88 (m, 1 H), 4 25-4 52 (m, 4H), 7 18-7 62 (m, 5H) FAB MS 547 [M+1] + EXAMPLE 10 Preparation of N-methoxycarbonyl-D-dιcyclohexylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA The title compound was prepared from D-dicyclohexylalanyl-L-prohne methyl ester HCI (see J Med Chem 1997, 40, 3726) using the procedures described in Example 7, Step A and Example 8, yield 24% 1 H NMR (CD 3 OD) δ1 09-2 18 (m, 27H), 3 19-3 34 (m, 4H), 3 92 (m, 1 H), 4 21- 4 52 (m, 3H), 5 05 (m 1 H), 7 47 ( 1 H) 7 71 (m 1 H) FAB MS 546 [M+1] + EXAMPLE 11 Preparation of N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- thιenyl)methyl]amιde TFA A) 4-Bromo-2-(hydroxymethyl)thιophene 4-Bromothιophene-2-carboxaldehyde (4 g, 18 8 mmol) was dissolved in dichloromethane/methanol (9/1 , v/v, 100 L) and the solution was cooled to 0°C To this was added sodium borohydride (0 35 g 9 4 mmol) and the mixture stirred for 3 h at rt The reaction mixture was neutralized by addition of 1 N HCI, extracted with dichloromethane, and the extracts dried over magnesium sulfate and concentrated in vacuo The residue was purified by column chromatography (EtOAc n-hexane, 1 4) to give the title compound (3 5 g, 97%) Η NMR (CDCI 3 ) δ 4 52 (s, 2H), 7 19 (m, 1 H), 7 42 (m, 1 H) FAB MS 194 [M+1] + B) 2-(Hydroxymethyl)thιohene-4-carbonιtπle A mixture of 4-bromo-2-(hydroxymethyl)thιophene (3 5 g, 18 1 mmol) and cuprous cyanide (2 5 g, 28 2 mmol) in DMF (100 mL) was heated at reflux for 6 h The reaction mixture was diluted with dichloromethane (100 mL), washed with aqueous ammonia, dried over magnesium sulfate, and concentrated in vacuo The residue was purified by column chromatography (EtOAc n-hexane 2 1 ) to give the title compound (1 88 g, 75%) 1 H NMR (CDCI 3 ) δ 4 46 (s, 2H), 7 12 (m, 1 H), 7 46 (m, 1 H) FAB MS 140 [M+1] + C) 2-(Bromomethyl)thιophene-4-carbonιtrιle To a cooled (0°C) solution of 2-(hydroxymethyl)thιophene-4-carbonιtrιle (1 14 g 8 2 mmol) in dichloromethane (50 mL) was added tπphenylphosphine (2 8 g, 10 6 mmol) and carbon tetrabromide (3 3 g, 9 9 mmol) After strπng for 3 h at rt, the solvent was removed in vacuo and the residue chromatographed using EtOAc and n-hexane (1 4) to give the title compound (1 6 g 96%) 1 H NMR (CDCI 3 ) δ 4 38 (s, 2H), 7 15 (m, 1 H), 7 40 (m, 1 H) FAB MS 203 [M+1] + D) 2-(Amιnomethyl)thιophene-4-carbonιtrιle HCI This compound was prepared from 2-(bromomethyl)thιophene-4-carbonιtrιle (1 6 g, 8 0 mmol) using the procedure described in Example 1 , Step B, yield 80% H NMR (CD 3 OD) sm δ (m, 1 H) FAB MS 139 [M+1] + E) N-Amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιenyl)methyl]amιde TFA This compound was prepared from 2-(amιnomethyl)thιophene-4- carbonitπle HCI and and N-aminosulfonyl-D-diphenylalanyl-L-prohne using the procedure described in Example 1 Step E and F, yield 40% H NMR (CD 3 OD) δ 1 47 (m, 1 H), 1 65 (m, 1 H), 1 74 (m, 1 H), 1 89 (m, 1 H), 2 92 (m, 1 H), 3 86 (m, 1 H), 4 15 (m, 1 H), 4 31 (m, 1 H), 4 61 (m, 2H) 4 99 (m, 1 H), 7 25-7 51 (m, 11 H), 7 77 (m, 1 H) FAB MS 555 [M+1] + EXAMPLE 12 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- thιenyl)methyl]amιde TFA This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L- prohne (Example 3, Step A) and 2-(amιnomethyl)thιophene-4-carbonιtrιle HCI (Example 11 , Step D) essentially according to the procedure of Example 1 , Step E and F, yield 59% 1 H NMR (CDCI 3 ) δ 1 51 (m, 1 H), 1 64 (m, 1 H), 1 92 (m, 2H), 2 91-3 01 (m 4H) 3 72 (m, 1 H), 4 12 (m 1 H), 4 28 (d, 1 H) 4 55 (m, 2H), 5 07 (m 1 H), 7 18-7 52 (m, 11 H), 7 74 (m, 1 H) FAB MS 554 [M+1] + EXAMPLE 13 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιnomethyl-2- thιenyl)methyl]amιde HCI This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-prolyl- [(4-cyano-2-thιenyl)methyl]amιde (Example 12) according to the procedure of Example 2, yield 38% Η NMR (CD 3 OD) δ 142 (m, 1H), 165 (m, 1H), 181 (m, 2H), 278 (s, 3H), 290 ( , 1H), 382 (m, 1H), 411 (m, 1H) 435 (m,3 H) 445 (m, 2H) 502 (m, 1H), 720-755 (m, 12H) FAB MS 541 [M+1] + EXAMPLE 14 Preparation of N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- thιenyl)methyl]amιde TFA This compound was prepared from N-Boc-D-diphenylalanyl-L-prohne and 2- (amιnomethyl)thιophene-4-carbonιtrιle HCI (Example 11, Step D) using the procedure described in Example 1, Step E and F, yield 32% 1 H NMR (CD 3 OD) ό 149 (m, 1H), 165 (m, 1H), 182 (m, 2H), 292 (m, 1H), 345(s, 3H), 383(m, 1H), 407 ( , 1H), 436 (m, 2H), 459 (m, 1H), 514 (m, 1H), 718- 748(m, 11 H), 775 (m, 1H) FAB MS 516[M+1] + EXAMPLE 15 Preparation of N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3- thιenyl)methyl]amιde TFA A) 2-lodothιophene-4-carboxaldehyde To a solution of 3-thιophenecarboxaldehyde (500 mg, 4 46 mmol) in a 1 1 mixture of acetic acid and water (10 mL) was added 95% sulfuric acid (0 31 mL) To this was added sequentially HIO 4 (305 mg, 1 34 mmol) and iodine (680 mg, 2 67 mmol) and the mixture stirred for 3 h at 60 °C After the reaction was completed, aqueous NaHS0 3 solution (6 mL) was added, the mixture basified to pH 12 by addition of 10N NaOH, and extracted with dichloromethane The extracts were dried over magnesium sulfate and concentrated in vacuo The residue was purified by column chromatography (EtOAc n-hexane, 3 97) to give the title compound (390 mg, 37%) Η NMR (CDCI 3 ) δ 9 76 (s, 1 H), 8 08 (d, 1 H), 7 68 (d, 1 H) FAB MS 239 [M+1] + B) 4-(Hydroxymethyl)-2-ιodothιophene A solution of 2-ιodothιophene-4-carboxaldehyde (5 g, 21 mmol) in methanol (100 mL) was cooled to 0°C To this was added sodium borohydride (1 2 g, 31 5 mmol) and the mixture was stirred for 30 mim at 0°C The reaction mixture was quenched by addition of saturated ammonium chloride solution and concentrated The residue was dissolved in EtOAc, washed with brine, dried over magnesium sulfate, and concentrated in vacuo The crude material was purified by column chromatography (EtOAc n-hexane 1 4) yield 4 53 g (90%) 1 H NMR (CDCI 3 ) δ 7 15 (s, 2H), 4 52 (s, 2H) FAB MS 241 [M+1] + C) 4-(Hydroxymethyl)thιohene-2-carbonιtrιle This compound was prepared from 4-(hydroxymethyl)-2-ιodothιophene (1 2 g, 5 mmol) using the procedure described in Example 11 , Step A, yield 536 mg (77%) H NMR (CDCI 3 ) δ 7 58 (s, 1 H), 7 48 (s, 1 H), 4 47 (s, 2H) FAB MS 140 [M+1] + D) 4-(Bromomethyl)thιophene-2-carbonιtrιle This compound was prepared from 4-(hydroxymethyl)thιohene-2-carbonιtrιle (536 mg 3 85 mmol) using the procedure described in Example 11 Step C yield 754 mg (97%) Η NMR (CDCI 3 ) δ 7 59 (s, 1 H) 7 49 (s, 1 H), 4 89 (s, 2H) FAB MS 203 [M+1] + E) 4-(Amιnomethyl)thιophene-2-carbonιtrιle HCI This compound was prepared from 4-(bromomethyl)thιophene-2-carbonιtπle (188 mg, 4 7 mmol) using the procedure described in Example 1 Step B, yield 231 mg (95%) Η NMR (CD 3 OD) ό 7 75 (s 1 H), 7 64 (S 1 H) 4 65 (s 2H) FAB MS 139 [M+1] + F) N-Amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde TFA This compound was prepared from 4-(amιnomethyl) thιophene-2- carbonitπle HCI and N-ammosulfonyl-D-diphenylalanyl-L-prohne using the procedure described in Example 1 , Step E and F, yield 41 % Η NMR (CD 3 OD) δ 7 83(d, 1 H), 7 82(d, 1 H), 7 43 (m, 2H), 7 36 (m, 2H),7 24 (m, 6H), 4 45(dd, 1 H), 4 32 (d, 1 H), 4 21 (dd, 1 H), 4 04 (m, 1 H), 3 76 (m, 1 H), 2 88 (m, 1 H), 1 83-1 45 (m, 4H) FAB MS 555 [M+1] + EXAMPLE 16 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3- thιenyl)methyl]amιde TFA A) N-Methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-3-thιenyl)methyl]amιde This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L- prohne (Example 3, Step A) and 4-(amιnomethyl)thιophene-2-carbonιtrιle HCI (Example 15, Step E) using the procedure described in Example 1 , Step E, yield 89% 1 H NMR (CDCI 3 ) δ 7 60 (d, 1 H), 7 38 (m, 5H), 7 23(m, 6H), 4 81 (dd, 1 H), 4 39- 4 36 (m, 3H), 4 23 (m, 1 H), 3 58 (m, 1 H), 2 83 (s, 3H), 2 55 (m, 1 H), 1 70 (m, 2H), 1 41 (m, 2H). FAB MS. 537 [M+1] + B) N-Methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde TFA This compound was prepared from the compound obtained in Step A using the procedure described in Example 1 , Step F, yield 53% Η NMR (CD 3 OD) δ 7.62(d, 1 H), 7.51 (d, 1 H), 7 54-7.23(m, 10H), 4 99 (d, 1 H), 4.39(m, 4H), 4 11 (dd, 1 H), 3 78 (m, 1 H), 2.95(m, 1 H), 2.90(s, 3H), 1.82-1.43 (m, 4H) FAB MS 554[M+1] + EXAMPLE 17 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amidrazono-3- thienyl)methyl]amιde TFA This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-prolyl- [(5-cyano-3-thienyl)methyl]amide (Example 16, Step A) using the procedure described in Example 4, yield 63% Η NMR (CD 3 OD) δ 7 52(d, 1 H), 7 42 (d, 1 H), 7 34-7 10(m, 10H), 4 99 (d, 1 H), 4.29(m, 3H), 4 00 (dd, 1 H), 3 68 (m, 1 H), 3 27 (m, 1 H), 2 91 (m, 1 H), 2 80(s, 3H), 1 79- 1.32 (m, 4H) FAB MS 569 [M+1] + EXAMPLE 18 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-3- thιenyl)methyl]amιde TFA This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-prolyl- [(5-cyano-3-thιenyl)methyl]amιde (Example 16, Step A) using the procedure described in Example 2, yield 75% 1 H NMR (CD 3 OD) δ7 47 (d, 2H),7 36 (m, 2H), 7 26 (m, 6H), 6 93 (d,1 H), 6 87 (d, 1 H), 5 00 (d, 1 H), 4 44 (s, 2H), 4 30 (m, 2H), 4 12(s, 2H), 3 79 (m, 1 H) 2 92 (m, 1 H), 2 85 (s, 3H), 1 78-1 32 (m, 4H) FAB MS 541 [M+1] + EXAMPLE 19 Preparation of N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3- thιenyl)methyl]amιde TFA This compound was prepared from N-Boc-D-diphenylalanyl-L-prohne and 4- (amιnomethyl)thιophene-2-carbonιtrιle HCI (Example 15 Step E) using the procedure described in Example 7, Step A followed by Example 8, yield 47% 1 H NMR (CD 3 OD) δ 1 48 (m 1 H), 1 61 (m, 1 H), 1 83 (m, 2H), 2 92 (m, 1 H), 3 45 (s, 3H) 3 81 (m 1 H) 4 08 (m 1 H) 4 37 (d 1 H) 4 55 (q 2H) 5 15 (m 1 H) 7 15- 7 49 (m, 12H) FAB MS 516 [M+1] + EXAMPLE 20 Preparation of N-cyclohexylsulfamoyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA A) Cyclohexylsulfamoylchloπde To a solution of cyclohexylsulfamic acid (5 g 27 9 mmol) in benzene (30 mL) was added dropwise phosphorus pentachlonde (6 4 g, 30 7 mmol), and the mixture heated at reflux for 4 h After the solvent was removed, the residue was distilled under reduced pressure to give the title compound (5 g, 91 %) B) N-cyclohexylsulfamoyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA This compound was prepared from cyclohexylsulfamoylchloπde essentially according to the procedure of Example 3, yield 41% 1 H NMR (CD 3 OD) δ 776 (d, 1H), 749-710 (m, 10H), 703 (d, 1H), 497 (m, 1H), 460(dd, 1H), 450(dd, 1H), 430 (d, 1H), 404 (m, 1H), 385 (m, 1H), 305 (m, 1H), 273 (m, 1H), 186 (m, 3H) 175 (m, 2H) 155 (m, 3H), 128-100 (m, 6H) FAB MS 637[M+1] + EXAMPLE 21 Preparation of N-allyloxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA This compound was prepared from allylchloroformate essentially according to the procedure of Example 8, yield 56% 1 H NMR (CD 3 OD) δ 779 (d, 1H), 741-718 (m, 10H), 712(d, 1H), 574 (m, 1H), 515 (d, 2H), 508 (d, 1H), 486(dd, 1H) 465 (m, 1H), 453 (dd, 1H), 436 (d 2H) 423 (dd, 1H), 409 (dd, 1H), 381 (m, 1H), 292 (m, 1H), 185- 149 (m, 4H) FAB MS 560[M+1] + EXAMPLE 22 Preparation of N-methylsulfonyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA This compound was prepared from D-cyclohexylalanyl-L-prolme methyl ester HCI essentially according to the procedure of Example 3, yield 41 % 1 H NMR (CD 3 OD) δ7 77 (d, 1 H) 7 18 (d, 1 H) 5 05(m, 1 H) 4 58 (m, 2H), 4 41 (dd, 1 H), 4 30 (dd, 1 H), 3 85 (m, 1 H), 3 39 (m, 1 H), 2 85 (s, 3H), 2 23 (m, 1 H), 2 12- 1 15 (m, 15H), 1 10 (m, 2H) FAB MS 484 [M+1] + EXAMPLE 23 Preparation of N-benzylsulfonyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA This compound was prepared from D-cyclohexylalanyl-L-prohne methyl ester HCI and benzylsulfonylchloride using the procedure described in Example 3, yield 45% 1 H NMR (CD 3 OD) δ7.68 (d, 1H), 7.52-730 (m, 5H), 712 (d, 1H), 498 (m, 1H), 456 (s, 2H), 442 (d, 1H), 432 (d 1H), 422 (d, 1H) 412 (m.1H), 3.77 (m, 1H), 3.46 (m, 1H), 2.21 (m, 1H), 204 (m, 3H), 192-112 (m, 11 H), 095 (m, 2H) FAB MS 560[M+1] + EXAMPLE 24 Preparation of N-cyclohexylsulfamoyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdino-2- thienyl)methyl]amιde.TFA This compound was prepared from D-cyclohexylalanyl-L-prohne HCI and cyclohexylsulfamoylchloπde using the procedure described in Example 3; yield 39% Η NMR (CD 3 OD) δ 743 (d, 1H), 6.95 (d, 1H), 4.62 (m, 3H), 4.45 (dd, 1H), 4.27 (m, 1H), 412 (m, 1H), 342 (m, 1H), 322 (m, 1H), 237 (m, 1H), 220-110 (m, 24H), 091 (m, 2H) FAB MS: 567 [M+1] + EXAMPLE 25 Preparation of N-methylsulfamoyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amide TFA A) Methylsulfamoylchloπde This compound was prepared from methylsufamic acid (5 g, 45 9 mmol) using the procedure described in Example 20, Step A, yield 70% B) N-Methylsulfamoyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA This compound was prepared from D-cyclohexylalanyl-L-prohne HCI and methylsulfamoylchloπde using the procedure described in Example 3, yield 30% 1 H NMR (CD 3 OD) δ 7 84 (d, 1 H), 7 20 (d, 1 H), 4 59 (m, 2H), 4 42 (m, 1 H), 4 18 (m, 1 H), 3 92 (m, 1 H), 3 55 (m, 1 H), 2 53 (s, 3H), 2 22 (m, 1 H), 2 02 (m, 3H), 1 91-1 15 (m, 11 H), 1 01 (m, 2H) FAB MS 499 [M+1] + EXAMPLE 26 Preparation of N-methylsulfonyl-D-cyclohexylglycιnyl-L-prolyl-[(5-amιdιno-3- thιenyl)methyl]amιde TFA This compound was prepared from D-cyclohexylglycinyl-L-prohne methyl ester HCI and 4-(amιnomethyl)thιophene-2-carbonιtπle HCI (Example 15, Step F) essentially according to the procedure of Example 3, yield 46% Η NMR (CD 3 OD) δ 7 85(s, 1 H), 7 84 (s, 1 H), 4 45(dd, 1 H), 4 37(d, 2H), 4 01 (d, 1 H), 3 89 (m 1 H) 3 68 (m, 1 H) 2 90 (s, 3H) 2 24-1 05 (m, 14H) FAB MS 470 [M+1 ] + EXAMPLE 27 Preparation of N-methoxycarbonyl-D-cyclohexylglycιnyl-L-prolyl-[(5-amιdιno-3- thιenyl)methyl]amιde TFA This compound was prepared from N-Boc-D-cyclohexylglycinyl-L-prohne and 4-(amιnomethyl)thιophene-2-carbonιtπle HCI (Example 15 Step F) essentially according to the procedures of Example 7, Step A and Example 8 yield 42% Η NMR (CD 3 OD) δ 7 82(s, 1 H), 7 75 (s, 1 H), 4 55 (d, 2H), 4 48(d, 1 H), 4 33(d, 1 H), 4 14 (d, 1 H), 4 02 (m, 1 H) 3 69 (m, 1 H), 3 39 (s, 3H) 2 40-1 05 (m, 14H) FAB MS 450 [M+1] + EXAMPLE 28 Preparation of N-(t-butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2AcOH A) N-(t-Butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-2- thιenyl)methyl]amιde To a cooled (0°C) solution of D-Dιphenylalanyl-L-prolyl-[(5-cyano-2- thιenyl)methyl]amιde HCI prepared in Example 8 Step A (3 03 g, 6 06 mmol) in acetonitπle (60 mL) was added diisopropylethylamine (4 22 mL, 24 24 mmol) and t- butylbromoacetate (4 22 mL, 9 09 mmol), and the mixture stirred for 2 days at rt After the reaction mixture was concentrated in vacuo, the residue was purified by column chromatography (EtOAc n-hexane 7 3) to give the title compound (2 51 g 72%) Η NMR (CDCI 3 ) δ 8 12 (t, 1 H), 7 37 (m, 5H), 7 19 (m, 5H), 6 93 (d, 1 H), 4 61 (dd, 1 H), 4 49 (dd, 1 H), 4 25 (d, 2H), 4 12 (dd, 1 H), 3 24 (s, 2H), 2 67 (m, 1 H),2 07 (m, 1 H), 1 67 (m, 1 H), 1 43 (m, 2H), 1 37 (s, 9H), 1 25 (m, 1 H) FAB MS 573[M+1] + B) N-(t-Butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-hydroxyamιdιno-2- thιenyl)methyl]amιde To a solution of the compound obtained in Step A (2 31 g, 4 03 mmol) in a 4 1 mixture of ethanol and water (60 mL) was added hydroxylamine hydrochloride (1 04 g, 14 91 mmol) and sodium carbonate (726 mg, 6 85 mmol), and the mixture heated at reflux for 1 h After the reaction mixture was concentrated in vacuo, the residue was diluted with EtOAc, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound (2 36 g, 96%) 1 H NMR (CD 3 OD) δ 8 13 (t, 1 H), 7 42-7 35 (m, 4H), 7 27-7 11 (m, 6H), 7 01 (d, 1 H), 6 83 (d, 1 H), 4 87 (s, 1 H), 4 56 (dd, 1 H), 4 44 (dd, 1 H), 4 27 (m, 3H), 3 32 (m, 1 H), 3 25 (dd, 1 H), 2 73 (m, 2H), 1 80-1 42 (m, 4H), 1 41 (s, 9H) FAB MS 606 [M+1] + C) N-(t-Butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2AcOH The compound prepared in Step B (2 36 g, 3 89 mmol) was dissolved in methanol (45 mL) To this solution was added 10% palladium-on-carbon (240 mg), acetic anhydride (0 74 mL, 7 78 mmol) and the mixture was stirred for 8 h under H 2 (1 atm) The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo The residue was purified by preparative HPLC (H 2 0-MeOH gradient) to give the title compound (1 6 g, 70%) Η NMR (CD 3 OD) δ 7 81 (d, 1 H), 7 59 (d, 2H) 7 44 (t, 2H), 7 35-7 16 (m, 7H), 4 98 (d, 1 H), 4 61 (s, 2H), 4 44 (d, 1 H), 4 06 (m, 1 H), 3 62 (q, 2H), 3 62 (dd, 1 H), 2 91 (m, 1 H), 1 77 (m, 3H), 1 47 (s, 9H), 1 35 (m, 1 H) FAB MS 590 [M+1] + EXAMPLE 29 Preparation of N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2TFA To a cooled (0°C) solution of N-(t-butoxycarbonyl)methyl-D-dιphenylalanyl-L- prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde 2AcOH (1 4 g, 2 37 mmol, see Example 28) in dichloromethane (15 mL) was added TFA (15 mL) and the mixture stirred for 3 5 h After the reaction mixture was concentrated in vacuo, the residue was purified by preparative HPLC (TFA (0 1 %)-H 2 O-MeOH gradient) to give the title compound (1 2 g, 80%) Η NMR (CD 3 OD) δ 7 80 (d, 1 H), 7 62 (d, 2H), 7 48 (m 2H), 7 39-7 22(m, 6H) 7 18 (d, 1 H), 5 32 (d, 1 H), 4 60 (dd, 2H), 4 58 (d, 1 H), 4 06 (m, 1 H), 3 84 (dd, 2H), 3 49 (m, 1 H), 2 84 (m, 1 H), 1 80 (m, 3H), 1 30 (m, 1 H) FAB MS 534[M+1 ] + EXAMPLE 30 Preparation of N-methyl-N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2TFA A) N-Methyl-N-(t-butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2TFA A solution of N-(t-butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-2- thιenyl)methyl]amιde prepared in Example 28, Step A (0 18 g, 0 32 mmol) in pyridine (2 mL) was saturated with gaseous H 2 S After the mixture was allowed to stand for 1 day at rt, the solvent was removed in vacuo to obtain the thioamide as a yellow solid To this material was added acetonitπle (2 mL) and lodomethane (0 2 mL, 3 15 mmol), and the mixture was heated at reflux for 4 h After the solvent was evaporated in vacuo, the resulting methylthioamidate was dissolved in acetonitπle (2 mL) To this solution was added ammonium acetate (0 24 g, 3 15 mmol), and the mixture was heated at reflux for 2 h The solution was cooled and concentrated and the residue purified by preparative HPLC (TFA (0 1 %)-H 2 O-MeOH gradient) to give the title compound (0 14 g 64%) 1 H NMR (CD 3 OD) δ7 79 (d 1 H), 7 50 (m, 2H) 7 41 -7 10 (m, 9H) 5 01 (d, 1 H) 4 70-4 40 (m, 3H), 4 02 (m, 1 H), 3 59 (m, 1 H), 3 37 (s, 2H), 3 20 (m, 1 H), 2 91 (s, 3H), 1 78 (m, 3H), 1 56 (m, 10H) FAB MS 604 [M+1] + B) N-Methyl-N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2TFA This compound was prepared from the compound obtained in Step A using the procedure described in Example 29, yield 64% 1 H NMR (CD 3 OD) δ 7 81 (d, 1 H), 7 62 (d, 1 H), 7 43-7 12 (m, 10H), 5 22 (d, 1 H), 4 69 (d, 1 H), 4 61 (m, 2H), 3 93 (m, 1 H), 3 71 (s 2H), 3 50 (m, 1 H), 3 13 (m 1 H) 2 84 (s, 3H), 1 81 (m, 3H), FAB MS 548 [M+1] + EXAMPLE 31 Preparation of N-hydroxysulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA A) N-Hydroxysulfonyl-D-dιphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde DIPA To a cooled (0°C) solution of D-dιphenylalanyl-L-prolyl-[(5-cyano-2- thιenyl)methyl]amιde HCI (175 mg, 0 344 mmol) in dichloromethane (10 mL) was added chlorosulfonic acid (0 033 mL, 0 5 mmol) and dnsopropylethylamine (DIPA, 0 226 mL, 1 3 mmol) and the mixture stirred for 3 h at rt After the reaction was completed, the reaction mixture was diluted with dichloromethane washed with 1 N HCI and then with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound (230 mg 99%) Η NMR (CDCI 3 ) δ 1 20-1 35 (m, 15H), 1 44 (m, 2H), 1 63 (m, 1 H), 2 00 (m, 1 H), 2 62 (m, 1 H), 2 91 (m, 2H), 3 44 (m, 2H), 3 80 (m, 1 H), 4 24 (d, 1 H), 4 29 (d, 1 H), 4 40-4 58 (m 2H) 4 83 (d 1 H), 6 97 (d, 1 H), 7 12-7 45 (m, 9H), 7 39 (d, 1 H), 7 47 (m, 2H) FAB MS 539 [M+1] + B) N-Hydroxysulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde TFA To a solution of the compound prepared in Step A (230 mg) in ethanol (5 mL) was added hydroxylamine hydrochloride (74 mg 1 03 mmol) and diisopropylamme (195 mg, 1 4 mmol) and the mixture stirred overnight at rt The reaction mixture was concentrated in vacuo to give a white solid (380 mg) This solid was dissolved in methanol (5 mL) and 10% palladium-on-carbon (120 mg) and acetic acid (0 5 mL) were added After the mixture was stirred for 36 h under H 2 (1 atm), the reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo The residue was purified by preparative HPLC (TFA (0 1 %)-H 2 0-MeOH gradient) to give the title compound (130 mg, 57%) 1 H NMR (CD 3 OD) δ 1 45-1 90 (m, 4H), 2 88 (m, 1 H), 3 86 (m, 1 H), 4 06 (m, 1 H), 4 23 (d, 1 H), 4 43 (m, 1 H), 4 64 (m, 1 H), 5 00 (d, 1 H), 7 11 -7 40 (m, 9H), 7 45 (m, 2H), 7 70 (d, 1 H) FAB MS. 556 [M+1] + EXAMPLE 32 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA A) N-Boc-L-azetιdιne-2-carboxyl-[(5-cyano-2-thιenyl)methyl]amιde To a cooled (0°C) solution of N-Boc-L-2-azetιdιnecarboxylιc acid (0 5 g 4 94 mmol) in DMF (3 mL) was added 5-(amιnomethyl)thιophene-2-carbonιtπle HCI (0 48 g, 2 74 mmol) EDC (0 62 g 3 24 mmol) HOBT (0 40 g 2 99 mmol) and triethylamine (1 04 mL, 7 47 mmol) and the mixture stirred for 2 h at rt The solvent was removed in vacuo and the residue dissolved in EtOAc, washed sequentially with a saturated sodium bicarbonate solution, 1 N HCI, and brine After the solution was dried over magnesium sulfate and concentrated in vacuo the residue was purified by column chromatography (EtOAc n-hexane, 2 1) to give the title compound (0 54 g, 68%) Η NMR (CDCI 3 ) δ 7 46 (d, 1 H), 6 97 (d, 1 H), 4 75-4 50 (m, 3H), 3 92 (m, 1 H), 3 79 (m, 1 H), 2 52-2 40 (m, 2H), 1 42 (s, 9H) FAB MS 322 [M+1] + B) N-Boc-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-cyano-2-thιenyl)methyl]amιde To a cooled (0°C) solution of the compound prepared in Step A (1 4 g 2 37 mmol) in dichloromethane (15 mL) was added TFA (15 mL) and the mixture stirred for 3 h at rt The resulting solution was concentrated in vacuo to give Boc-deprotected compound as TFA salt (0 52 g, 93%) This product (0 2 g, 0 6 mmol) was dissolved in DMF (6 mL), and to this solution was added Boc-D-diphenylalanme (0 18 g, 0 54 mmol), EDC (0 13 g, 0 7 mmol), HOBT (0 09 g 0 54 mmol) The mixture was stirred until clear and then cooled to 0°C After triethylamine was added (0 3 mL, 2 16 mmol), the resulting mixture was stirred for additional 2 h at rt The solvent was removed in vacuo and the residue dissolved in EtOAc washed sequentially with a saturated sodium bicarbonate solution 1 N HCI, and brine After the solution was dried over magnesium sulfate and concentrated in vacuo, the residue was purified by column chromatography (EtOAc n-hexane, 2 1 ) to give the title compound (0 2 g, 69%) 1 H NMR (CDCI 3 ) δ 8 30 (bs, 1 H), 7 45-7 14 (m, 11 H), 6 96 (d, 1 H), 4 83 (bs, 1 H), 4 67-4 48 (m, 3H), 4 43 (m, 1 H), 4 32 (m, 1 H), 4 04 (m, 1 H), 2 97 (m, 1 H), 2 21 (m, 1 H), 2 02 (m, 1 H), 1 28 (s, 9H) FAB MS 545 [M+1] + C) N-Methylsulfonyl-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-amιdιno-2- thιenyl)methyl]amιde TFA This compound was prepared from the compound obtained in Step B using the same procedure as described in Example 8 except that methanesulfonylchlonde was used instead of methylchloroformate, yield 47% 1 H NMR (CD 3 OD) δ 7 78 (d, 1 H), 7 45-7 18 (m, 11 H), 4 65 (d, 1 H), 4 61 (s, 2H), 4 34-4 19 (m, 3H), 3 48 (m, 1 H), 2 81 (s, 3H), 2 09 (m, 2H) FAB MS 540 [M+1] + EXAMPLE 33 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-5-methyl-2- thιenyl)methyl]amιde TFA A) 5-Amιnomethyl-2-methylthιophene-3-carbonιtπle HCI This compound was prepared from 4-bromo-5-methylthιophene-2- carboxaldehyde using the procedure described in Example 11 , Step A through D, yield 22% 1 H NMR(CD 3 OD) δ 2 59 (s, 3H), 4 52 (s, 2H), 7 00 (s, 1 H), 7 25 (s, 1 H) FAB MS 153 [M+1] + B) N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-5-methyl-2- thιenyl)methyl]amιde TFA This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L- prohne (Example 3 Step A) and 2-amιnomethyl-5-methylthιophene-4-carbonιtπle HCI using the procedure described in Example 1 , Step E and F, yield 38% 1 H NMR (CD 3 OD) δ 1 48 (m, 1 H), 1 62 (m, 1 H), 1 90 (m, 2H), 2 65 (s, 2H), 2 90-3 03 (m, 4H) 3 62 (m, 1 H) 4 02 (m, 1 H), 4 34 (d, 1 H), 4 52 (m, 2H), 5 11 (m, 1 H), 7 19-7 56 (m, 11 H) FAB MS 568 [M+1] + EXAMPLE 34 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- furanyl)methyl]amιde TFA This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L- prohne (see Example 3, Step A) and 5-(amιnomethyl)furan-2-carbonιtrιle HCI using the procedure described in Example 1 Step E and F yield 20% Η NMR (CD 3 OD) δ 7.48(m, 3H), 7 35 (m, 2H), 7.25 (m, 6H), 6.62(d, 1 H), 5.02 (d, 1 H), 4.44 (m, 2H), 4.32 (d, 2H), 4 02(dd, 1 H), 3 71 ( , 1 H), 2.93 (m, 1 H), 2.85(s, 3H), 1 79-1 39 (m, 4H) FAB MS 538 [M+1 ] + EXAMPLE 35 Preparation of N-methoxycabonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- furanyl)methyl]amide.TFA This compound was prepared from N-Boc-D-diphenylalanyl-L-prohne and 5- (amιnomethyl)furan-2-carbonιtrile.HCI using the procedures described in Example 7, Step A and Example 8; yield 35%. H NMR (CD 3 OD) δ 7 49(d, 1 H), 7 39 (d, 2H), 7 34 (t, 2H), 7 25 (m, 6H), 6 57(d, 1 H), 5.15 (d, 1 H), 4 59 (d, 1 H), 4 37 (dd, 2H), 4 05(dd, 1 H), 3 85 (m, 1 H), 3.39 (s, 3H), 2 89(m, 1 H), 1.82-1 46 (m, 4H) FAB MS 518 [M+1] + EXAMPLE 36 Preparation of N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3- furanyl)methyl]amιde.TFA A) 4-(Amιnomethyl)furan-2-carbonιtrile.HCI This compound was prepared from 2-bromo-4-(hydroxymethyl)furan (see Acta Chemica Scandmavica 1991 , 45, 914) using the procedure described in Example 11 , Step B through D, yield 61 % 1 H NMR (CD 3 OD) δ 7 54 (s, 1 H), 7 12 (s, 1 H), 4 32 (s, 2H) FAB MS 159 [M+1] + B) N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-furanyl)methyl]amιde TFA This compound was prepared from N-aminosulfonyl-D-diphenylalanyl-L-proline (see Example 1 , Step D) and 4-(amιnomethyl)furan-2-carbonιtπle HCI using the procedure described in Example 1 Step E and F yield 36% Η NMR (CD 3 OD) δ 7 83 (s, 1 H), 7 47(s, 1 H), 7 43 (d 2H), 7 35 (t, 2H), 7 25 (m, 6H), 4 93 (d, 1 H), 4 31 (d, 2H), 4 11 (dd, 1 H), 4 02 (dd 1 H) 3 75 (m, 1 H), 2 88 (m 1 H), 1 84-1 45 (m, 4H) FAB MS 539 [M+1] + EXAMPLE 37 Preparation of N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl) methyl]amιde TFA A) 2-(Amιnomethyl)thιazole-4-carbonιtπle HCI To a cooled (0°C) solution of 2-(N-Boc-amιnomethyl)thιazole-4-carboxamιde (200 mg, 0 78 mmol, see Angew Chem Int Ed Engl 1996, 35 1503) in dichloromethane (7 mL) was added triethylamine (0 32 mL, 2 34 mmol) and acetic anhydride (0 22 mL, 1 56 mmol) and the mixture stirred for 1 h After the solvent was removed the residue was purified by column chromatography (EtOAc n-hexane, 3 7) 2-(N-Boc-amιnomethyl)thιazole-4-carbonιtπle (150 mg, 0 627 mmol) thus obtained was dissolved in methanol (10 mL) and cooled to 0°C To this was added dropwise acetylchloride (30 equivalent) and the mixture stirred for 1 h at rt The solvent was removed in vacuo to give the title compound (90 mg 81 %) Η NMR (CD 3 OD) δ 7 94 (s, 1 H) 5 44 (s 1 H), 4 59 (s, 2H) FAB MS 176 [M+1] + B) N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde TFA This compound was prepared from N-aminosulfonyl-D-diphenylalanyl-L- prohne (see Example 1 Step D) and 2-(amιnomethyl)thιazole-4-carbonιtπle HCI using the procedure described in Example 1 , Step E and F, yield 48% 1 H NMR (CD 3 OD) δ 8 56 (s, 1 H), 7 45(d, 2H), 7 35(t, 2H), 7 25 (m, 6H), 4 95 (d, 1 H), 4 67 (m, 2H), 4 34 (d, 1 H), 4 11 (dd, 1 H), 3 78 (m, 1 H), 2 89 (m, 1 H), 1 90- 1 45 (m, 4H) FAB MS 556 [M+1] + EXAMPLE 38 Preparation of N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-1 -methyl-2- pyrrolyl)methyl]amιde TFA This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L- prolme (see Example 3 Step A) and 5-(amιnomethyl)-1-methylpyrrole-2-carbonιtrιle using the procedure described in Example 1 Step E and F, yield 17% 5- (Amιnomethyl)-1-methyl-pyrrole-2-carbonιtrιle was prepared from 1 ,5-dιmethyl-pyrrole- 2-carbonιtrιle using the procedure described in Example 1 Step A and B 1 H NMR (CD 3 OD) ό 1 40 (m, 1 H), 1 65 (m, 1 H), 1 84 (m, 2H), 2 81 (s, 3H), 2 97 (m, 1 H), 3 69 (s, 3H), 3 78 (m, 1 H), 4 02 (m 1 H) 4 30 (d, 1 H), 4 56 (m, 2H), 5 00 (m, 1 H), 6 22 (d, 1 H), 6 88 (d, 1 H), 7 23-7 50 (m, 9H), 7 65 (m, 1 H) FAB MS 551 [M+1] + EXAMPLE 39 Preparation of N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3- thιenyl)methyl]amιde 2TFA This compound was prepared from D-dιphenylalanyl-L-prolyl-[(5-cyano-3- thιenyl)methyl]amιde HCI (obtained during the preparation of Example 19) using the procedures described in Examples 28 and 29, yield 41 % 1 H NMR (CD 3 OD) δ 7 91(s, 1 H), 7 88 (s, 1 H) 7 67(d, 2H), 7 50 (t, 2H), 7 38- 7 25 (m, 6H), 5 34 (d, 1 H), 4 58(d, 1 H), 4 42 (dd 2H), 4 07 (dd, 1 H), 3 78 (dd, 2H), 3 53 (m, 1 H), 2 89(m, 1 H), 1 83-1 72 (m, 3H), 1 31 (m, 1 H) FAB MS 534 [M+1] + EXAMPLE 40 Preparation of N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- thιazolyl)methyl]amιde 2TFA A) D-Dιphenylalanyl-L-prolyl-[(4-cyano-2-thιazolyl)methyl]amιde HCI This compound was prepared from 2-(amιnomethyl)thιazole-4-carbonιtπle HCI (see Example 37, Step A) using the procedures described in Example 7, Step A and Example 8, Step A Η NMR (CDCI 3 ) δ 8 56 (s, 1 H), 7 54-7 23 (m, 10H), 4 77 (d, 1 H), 4 57 (d, 1 H), 4 55 (dd, 1 H), 4 23 (m, 2H), 3 77 (m, 1 H), 2 41 (m, 1 H), 1 94 (m, 1 H), 1 62-1 35 (m, 3H) FAB MS 460 [M+1] + B) N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2- thιazolyl)methyl]amιde 2TFA This compound was prepared from the compound obtained in Step A using the procedures described in Examples 28 and 29, yield 35% overall Η NMR (CD 3 OD) δ 8 63(s, 1 H), 7 65 (d 2H), 7 52 (t, 2H), 7 45-7 23 (m 6H) 5 31 (d, 1 H), 4 74(s, 2H), 4 55 (d, 1 H), 4 13 (m, 1 H), 3 78 (dd, 2H), 3 52 (m, 1 H), 2 86 (m, 1 H), 1 81 (m, 3H) 1 37 (m, 1 H) FAB MS 535 [M+1] + EXAMPLE 41 Preparation of N-(2-carboxyethyl)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2TFA A) N-[2-(methoxycarbonyl)ethyl]-D-dιphenylalanyl-L-prolyl-[(5-cyano-2- thιenyl)methyl]amιde A mixture of D-Dιphenylalanyl-L-prolyl-[(5-cyano-2-thιenyl)methyl]amιde HCI (400 mg, 0 81 mmol, prepared in Example 8, Step A), sodium carbonate (690 mg, 6 5 mmol), sodium iodide (609 mg, 4 065 mmol), tetrabutylammonium bromide (79 mg, 0 244 mmol), and methyl 3-bromopropιonate (0 2 mL 1 626 mmol) in toluene (8 mL) was heated at reflux for 5 h The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (EtOAc n-hexane, 7 3) to give the title compound (180 mg, 41 %) 1 H NMR (CDCI 3 ) δ 7 97 (t 1 H) 7 42 (d 1 H) 7 38-7 13 (m 10H) 6 93 (d 1 H) 4 52(dd, 2H), 4 31 (d, 1 H), 4 22 (dd, 1 H), 4 14 (dd, 1 H), 3 61 (s, 1 H), 3 44 (m, 1 H), 2 87 (m, 1 H), 2 70 (m, 2H), 2 34 (m, 2H), 2 23 (m 1 H) 1 82 (m 1 H) 1 53 (m 1 H) 1 24(m 1 H) FAB MS 545 [M+1] + B) N-[2-(methoxycarbonyl)ethyl]-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2AcOH This compound was prepared from the compound obtained in Step A (160 mg) using the procedure described in Example 28, Step B and C, yield 54% Η NMR (CD 3 OD) δ 774 (d, 1H), 735-711 (m, 10H), 6.98 (d, 1H), 472 (dd, 1H), 430 (dd, 1H) 417(s 2H) 416 (dd 1H) 353 (s 3H), 352 (m 1H) 289 (m 2H), 275 (m, 1H), 238 (m, 2H), 189 (m, 2H), 162 (m, 1H), 140(m, 1H) FAB MS 562 [M+1] + C) N-(2-Carboxyethyl)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde 2TFA A mixture of the compound prepared in Step B (91 mg, 016 mmol), 05N LiOH (10 mL), and water (3 mL) was stirred for 3 h at rt The reaction mixture was neutralized with 1N HCI and concentrated in vacuo The residue was purified by preparative HPLC (TFA (01%)-H 2 0-MeOH gradient) to give the title compound (55 mg, 44%) 1 H NMR (CD 3 OD) δ 781 (d, 1H), 762 (d, 2H), 750 (t, 2H), 742-732(m, 6H), 721 (d, 1H), 512 (d, 1H), 461 (dd, 2H), 450 (d, 1H), 411 (m, 1H), 360 (m, 1H), 278 (m, 1H), 268(m, 2H) 183 (m, 3H), 130 ( , 1H) FAB MS 548[M+1] + EXAMPLE 42 Preparation of N-Boc-D-Dιphenylalanyl-L-prolyl-[(5-amιdrazono-2- thιenyl)methyl]amιde TFA This compound was prepared from N-Boc-D-dιphenylalanyl-L-prolyl-[(5- amιdιno-2-thιenyl)methyl]amιde (Example 7 Step A) using the procedure described in Example 4 1 H NMR (CD 3 OD) δ 7 67 (d, 1 H), 7 49-7 17 (m, 10H), 7 12 (d, 1 H), 5 10 (d, 1 H), 4 60 (dd, 2H), 4 33 (d, 1 H), 4 07 (m, 1 H), 3 80 (m, 1 H), 2 93 (m, 1 H), 1 89-1 73 (m, 2H), 1 58 (m, 1 H), 1 47 (m, 1 H), 1 29 (s, 9H) EXAMPLE 43 Preparation of D-dιphenylalanyl-L-prolyl-[(5-amιdrazono-2-thιenyl)methyl]amιde 2TFA To a solution of the compound obtained in Step A (0 05 g, 0 071 mmol) in methanol was added 0 4N HCI solution in methanol (0 9 mL) and the mixture stirred for 2 h The solvent was removed in vacuo and the residue was purified by preparative HPLC (TFA (0 1 %)-H 2 0-MeOH gradient) to give the title compound (45 mg, 88%) 1 H NMR (CD 3 OD) δ 7 69 (d, 1 H), 7 59 (m, 2H), 7 47 (m, 2H), 7 40 (m, 2H), 7 30 (m, 4H), 7 19 (d, 1 H), 5 10 (d, 1 H), 4 61 (dd 2H), 4 45 (d 1 H), 4 07 (m, 1 H), 3 58 (m, 1 H), 2 82 (m, 1 H), 1 78 (m, 3H), 1 33 (m, 1 H) EXAMPLE 44 Preparation of N-methylsulfonyl-D-phenylalanyl-L-prolyl-[(5-amιdrazono-2- thιenyl)methyl]amιde TFA The title compound was prepared from D-phenylalanyl-L-prohne methyl ester HCI using the procedures described in Example 7, Step A and B, followed by Example 4 1 H NMR (CD 3 OD) δ 8 52 (m, 1 H), 7 72 (d, 1 H), 7 19 (d, 1 H), 4 58 (m, 2H), 4 41 (dd, 1 H), 4 31 (m, 1 H), 3 85 (m, 1 H), 3 58 (m, 1 H), 2 87 (s, 3H), 2 28-0 85 (m, 17H) EXAMPLE 45 In vitro enzyme assays for determining inhibition constants The activity of thrombin was measured spectrophotometπcally using tosyl-Gly- Pro-Arg-p-nitroanihde acetate (Chromozym TH, Boehπnger Mannheim) as a substrate Thrombin used in this test was prepared from human plasma according to the protocol of Ngai and Chang (see, Biochem J 1991 , 280, 805) Each compound was dissolved in DMSO to make a 1 mM stock solution and dilutions were made thereof with assay buffer (0 1 M TπsHCI, 0 15 M NaCl, 0 1% polyethylene glycol 8000, pH 7 8) Different concentrations of inhibitor were mixed with 0 3 NIH units of thrombin in 0 8 mL of the buffer The mixture was incubated for 10 mm at room temperature before adding 0 2 mL of the substrate to a final concentration of 20 μM The release of p-nitroanihne by hydrolysis of the substrate was monitored for 5 mm by measuring the increase in optical density at 381 nm with a UV2100S spectrometer (Shimadzu) A graph for the reciprocal value of initial velocity to the inhibitor concentration was derived from progress curves by fitting the data using a linear regression program The inhibition constants (Ki values) were then obtained from the Dixon plot equation (see, Biochem J 1953, 55, 170) Under these conditions the Km value for the substrate hydrolysis was 5 2 μM as determined from a non-linear regression analysis of initial rate assuming Michaehs-Menten kinetics In certain studies with highly potent inhibitors (Ki < 0 1 nM) where the degree of thrombin inhibition was very high a more sensitive assay was employed In this assay the concentration of Chromozym TH and thrombin was set to 80 μM and 1 5 mU/mL, respectively, and the hydrolysis reaction was monitored for 1 5 hr Table 1 shows the thrombin inhibitory activity (Ki values) obtained with the exemplary compounds of the present invention It can be identified that the compounds of the present invention show excellent inhibitory activity against thrombin EXAMPLE 46 Pharmacokinetic studies for determining oral bioavailabihty Male Sprague-Dawley rats (250-300 g) were restrained individually in a surgical plate (Dae Jong Instrument Company, Seoul Korea) as supine position The femoral artery and the femoral vein (iv only) of rats were cannulated with polyethylene tubing (PE-50, Clay Adams, Parsippany NJ, USA) under light ether anesthesia After complete recovery from anesthesia rats were given 30mg/kg of test compound dissolved in distilled water via oral gavage or given 10mg/kg via the femoral vein for intravenous (iv) study Blood samples (0 25 mL) were collected from the femoral artery at 0 (for control), 1 (iv only) 5 15 30 60 90 (iv only) 120 180 and 240 mm after dosing Male beagle dogs (7-10 kg, Hazleton Research Product Inc , Kalamazoo, Ml, USA) were housed individually in a metabolic cage for plasma disposition study Dogs were orally administered with 10 mg/kg of test compound dissolved in distilled water via gavage or injected with 2mg/0 2 mL/kg via the cephalic vein using INTROCAN© Blood samples were withdrawn via the cephalic vein at 0 (for control), 1 , 5 (iv only), 15, 30, 60, 90, 120, 180, 240, 360 (po only) and 480 (po only) mm after dosing Blood samples were taken into hepaπnized tube (25 U/mL), deproteinized with 2 volumes of methanol, and centrifuged The resulting supernatant (60 μL) was analyzed by HPLC elutmg with a mixture of 0 1 % trifluoroacetic acid aqueous solution and acetonitπle with a ratio of 81 % to 19% Plasma concentration of test compound was recorded and used to calculate the pharmacokinetic parameters maximum plasma concentration of test compound (C max ), time of maximum plasma concentration (T max ), area under the curve (AUC), and fraction of test compound absorbed (F) The compounds of the present invention demonstrate generally good oral absorption in rats and dogs In particular, the compounds bearing D-diphenylalame moiety exhibit higher absorption compared to the corresponding compounds that contain D-cyclohexylalanme moiety Table 2 illustrates the pharmacokinetic results for some exemplary compounds of invention obtained upon oral dosing in rats EXAMPLE 47 In vivo studies of the compounds claimed herein were conducted using the following procedure Male Sprague-Dawley rats (body weights 250-300 g 3-4/group) were anaesthetized by intrapeπtoneal injection with urethane solution (1 25 g/kg) The abdomen was surgically opened by a midhne incision and the inferior venae cava was carefully dissected free from surrounding connective tissue The venae i olumbar and spermatica were hgated with a silk thread Thrombus formation was initiated by infusion of a thromboplastin preparation (Simplastm ® ) using an infusion pump (Model 100, IITC Life Science, USA) via the left femoral vein at 0 5 mL/kg/mm Simplastin ® (Organon Teknika, USA) was reconstituted with 4 mL of distilled water and then given diluted at 1 2 5 in distilled water At the start of infusion for 30 seconds, the vena cava was ligatured below the left renal vein After the end of infusion, vena cava was also ligatured above the iliac veins 16 mm apart from upper ligature After 15 mm of stasis, the thrombus formed inside the vessel was carefully removed and weighed Before wighing, the excess blood was removed by blotting the wet clot on the wet Whatman filter paper (see, Millet, J , Theveniaux, J , Brown, N L Thromb Haemost 1992, 67, 176) Saline (control) or test compounds (1 mg/kg) were injected as a bolus via the femoral vein starting 5 m before the thromboplastin infusion Bolus injection volume was 0 5 mL/kg Antithrombotic activity was expressed as a percentage where Antithrombotic activity (%) = 100 x (A - B) / A A = mean clot weight of control group B = mean clot weight of test compound group The results shows that the compounds of the present invention are effective in preventing thrombotic occlusions In particular, the compounds containing both D- diphenylalame and amidine moieties exhibit excellent antithrombotic activity For example, at a dose of 1 mg/kg, the compounds of Example 1 , 3, 11 , 15, 19, 29, and 41 , are 100% effective in inhibiting thrombus formation in the rat venous thrombosis model TABLE 1 TABLE 2 Pharmacokinetic parameters after oral dosing in rats (30 mg/kg) Example C max (μg/mL) T max (mm) AUC (μg min/mL) _ 22 60 253 5 18 32 280 8 96 60 1615 11 21 45 254 14 45 80 850 19 52 80 1297 29 95 15 1390 35 71 45 965 39 46 15 212 40 111 25 1126 41 49 20 503 All the documents cited herein, including the foreign priority documents, are hereby incorporated by reference It is to be understood that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments Through routine experimentation, the artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention Thus, the invention is intended to be defined not be the above description but by the following claims and their equivalents

Claims: WHAT IS CLAIMED IS 1. A compound having formula I. and pharmaceutically acceptable salts thereof wherein n is 1 , 2 or 3; A is hydrogen, alkyl, C 3 . 7 cycloalkyl, aryl, -SO 2 R\ -SO 3 R 1 , -COR 1 , -CO 2 R 2 , -PO(OR 1 ) 2 , - (CH 2 ) m CO 2 R 1 , -(CH 2 ) m SO 2 R 1 , -(CH 2 ) m SO 3 R 1 or -(CH 2 ) m PO(OR 1 ) 2 , wherein R 1 is hydrogen, C,. 6 alkyl, C 3 . 7 cycloalkyl, aryl, -(CH 2 ) m aryl, or -NR 3 R 4 , R 2 is C 1-6 alkyl, C 3 . 7 cycloalkyl, aryl, -(CH 2 ) m aryl or alkenyl , and wherein aryl is unsubsituted or substituted phenyl or 5-6 membered aromatic heterocyclic ring, and R 3 and R 4 are independently hydrogen, C,. 6 alkyl, or C 3 7 cycloalkyl, B is hydrogen or C, 6 alkyl, C and D are independently hydrogen, phenyl unsubsituted or substituted with one or two substituents selected from the group consisting of C-, 4 alkyl, d 4 alkoxy, CF 3 , methylenedioxy, halogen, hydroxy and -NR 3 R 4 , C 3 7 cycloalkyl, or a 5-6 membered heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from the group consisting of N, O, and S, E ιs X X-Y γ-x V V ^ s > 01 [ > Y-Z Z ^Z wherein Y and Z are independently N or CR )6 6 wherein R 5 is hydrogen or C, 4 alkyl , and R 6 is hydrogen, halogen, CF 3 or C, 4 alkyl, and F is -C(NH)N(R 7 ) 2 , -C(NH 2 )NN(R 7 ) 2 , -C(NH 2 )NOH or -CH 2 NH(R 7 ) 2 wherein R 7 is the same or different and is hydrogen, C, 4 perfluoroalkyl or C 1-4 alkyl 2 The compound of claim 1 , wherein C and D are independently selected from the group consisting of phenyl unsubsituted or substituted with one or two substituents selected from the group consisting of C 1 4 alkyl, C 1 4 alkoxy, methylenedioxy, halogen, hydroxy or NR 3 R 4 wherein R 3 and R 4 are as previously defined , C 3 7 cycloalkyl, and a 5-6 membered heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from the group consisting of N, O, and S The compound of claim 1 , wherein A is selected from the group consisting of hydrogen, aryl, -SO 2 R 1 , -SO 3 H, -COR 1 , -CO 2 R 2 , -PO(R 1 ) 2 -PO(OR 1 ) 2 and - (CH 2 ) m CO 2 R 1 wherein R and R 2 are as previously defined The compound of claim 3, wherein A is selected from the group consisting of -SO 2 NR 3 R 4 , -PO(R 1 ) 2 -PO(OR 1 ) 2 , -(CH 2 ) m CO 2 R 1 , or aryl, 5 The compound of claim 2, wherein A is selected from the group consisting of hydrogen, -SO 2 R 1 , -PO(C 1 6 alkyl) 2 -POfOC, 6 alkyl) 2 , -CO(C 1 6 alkyl), -CO 2 R 2 , -(CH 2 ) m CO 2 H and -(CH 2 ) m CO 2 (C 1 6 alkyl), wherein m is 1 or 2, and R 1 is C, 6 alkyl, aryl, -(CH 2 ) m aryl, hydroxy or -NR 3 R 4 wherein R 3 and R 4 are as previously defiened 6 The compound of claim 2, wherein C and D are independently selected from the group consisting of phenyl, pyridyl, or cyclohexyl unsubsituted or substituted with one or two substituents selected from the group consisting of C 1 4 alkyl, C 1 4 alkoxy, methylenedioxy, halogen hydroxy and NR 3 R 4 whereιn R 3 and R 4 are as previously defined 7 The compound of claim 2, wherein C and D are independently selected from the group consisting of phenyl or cyclohexyl 8 The compound of claim 1 , wherein E is selected from the group consisting of wherein when X is S, O or NR 5 , Y is CH and Z is CR 6 , or Y is CR 6 and Z is CH , when X is S, O or NH, Y is N and Z is CR 6 , or Y is CR 6 and Z is N wherein R 5 and R 6 are as previously defined 9 The compound of claim 8, wherein R 5 and R 6 are independently hydrogen or C 1 4 alkyl 10 The compound of claim 1 , wherein F is selected from the group consisting of -C(NH)NH 2 , -C(NH 2 )NOH, -C(NH 2 )NNH 2 and -CH 2 NH 2 11 The compound as defined in claim 1 , wherein the compound is selected from the group consisting of N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdrazono-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-2-thιenyl)methyl]amιde, N-benzylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-t-butoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-amιnosulfonyl-D-3,4-dιchlorophenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methoxycarbonyl-D-dιcyclohexylalanyl-L-prolyI-[(5-amιdιno-2-thιenyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιenyl)methyI]amιde N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιnomethyl-2-thιenyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιenyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdrazono-3-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιnomethyl-3-thιenyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-cyclohexylsulfamoyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-allyloxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-benzylsulfonyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-cyclohexylsulfamoyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfamoyl-D-cyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-cyclohexylglycιnyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methyl-N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-hydroxysulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-5-methyl-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-furanyl)methyl]amιde, N-methoxycabonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-furanyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-furanyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-1-methyl-2- pyrrolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-thιenyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-(2-carboxyethyl)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-Boc-D-Dιphenylalanyl-L-prolyl-[(5-amιdrazono-2-thιenyl)methyl]amιde, D-dιphenylalanyl-L-prolyl-[(5-amιdrazono-2-thιenyl)methyl]amιde, N-methoxycabonyl-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-(2-carboxyethyl)-D-dιphenylalanyl-L-azetιdιne-2-carboxyl-[(5-amιdιno-2- thιenyl)methyl]amιde, D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-(3-carboxypropyl)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-(MeO) 2 P(O)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-(Me) 2 P(0)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde N-(HO) 2 P(O)-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-phenyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-[(N,N-dιethylcarboxamιdo)methyl]-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-[(N,N-dιethylcarboxamιdo)ethyl]-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-thιazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-thιazolyl)methyl]amιde N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-thιazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-thιazolyl)methyl]amιde N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-thιazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-thιazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-thιazolyl)methyl]amιde N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-thιazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-oxazolyl)methyl]amιde N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-oxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-oxazolyl)methyl]amιde N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-oxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-oxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-oxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-oxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-oxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-oxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-oxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-oxazolyl)methyl]amιde N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-oxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-oxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-oxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-oxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-5-oxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-ιsoxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-ιsoxazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-ιsoxazolyl)methyl]amιde N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-ιsoxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-ιsoxazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-ιsoxazolyl)methyl]amιde N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-ιsoxazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(2-amιdιno-4-ιsoxazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrazolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrazolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrazolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrazolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-pyrrolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrrolyl)methyl]amιde, N-amιnosulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-pyrrolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-pyrrolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrrolyl)methyl]amιde, N-methylsulfonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-pyrrolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-pyrrolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrrolyl)methyl]amιde, N-methoxycarbonyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-pyrrolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2-pyrrolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(4-amιdιno-2-pyrrolyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-3-pyrrolyl)methyl]amιde, N-amιnosulfonyl-D-bιs-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methylsulfonyl-D-bιs-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde N-methoxycarbonyl-D-bιs-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-carboxymethyl-D-bιs-(para-methoxyphenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-amιnosulfonyl-D-bιs-(para-amιnophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methylsulfonyl-D-bιs-(para-amιnophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methoxycarbonyl-D-bιs-(para-amιnophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde N-carboxymethyl-D-bιs-(para-amιnophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-amιnosulfonyl-D-bιs-(para-chlorophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde N-methylsulfonyl-D-bιs-(para-chlorophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-methoxycarbonyl-D-bιs-(para-chlorophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde and N-carboxymethyl-D-bιs-(para-chlorophenyl)alanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-(t-butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-(t-butoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-hydroxyamιdιno-2- thιenyl)methyl]amιde, N-[2-(methoxycarbonyl)ethyl]-D-dιphenylalanyl-L-prolyl-[(5-amιdιno-2- thιenyl)methyl]amιde, N-carboxymethyl-D-dιphenylalanyl-L-prolyl-[(5-hydroxyamιdιno-2-thιenyl)methyl]amιde, N-(methoxycarbonyl)methyl-D-dιphenylalanyl-L-prolyl-[(5-hydroxyamιdιno-2- thιenyl)methyl]amιde, N-amιnosulfonyl-D-dιcyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, N-methylsulfonyl-D-dιcyclohexylalanyl-L-prolyl-[(5-amιdmo-2-thιenyl)methyl]amιde, N-carboxymethyl-D-dιcyclohexylalanyl-L-prolyl-[(5-amιdιno-2-thιenyl)methyl]amιde, and pharmaceutically acceptable salts thereof 12 A method of modulating trypsm-hke serine proteases comprising administering to a mammal an effective amount of the compound of claim 1 13 A method of inhibiting trypsm-hke serine proteases comprising administering to a mammal an effective amount of the compound of claim 1 14 A method of modulating thrombin comprising administering to a mammal an effective amount of the compound of claim 1 15 A method of inhibiting thrombin comprising administering to a mammal an effective amount of the compound of claim 1

Inventors: JUNG WON HYUK, LEE KOO, LEE SANG KOO, LEE SUN HWA, PARK CHEOL WON, PARK HEE DONG, JUNG, WON, HYUK, LEE, KOO, LEE, SANG, KOO, LEE, SUN, HWA, PARK, CHEOL, WON, PARK, HEE, DONG
Applicants: LG CHEMICAL LTD, LG CHEMICAL LTD.
Application year: 1999
Main classification: C07D409
IPC codes: A61K31, A61K38, A61P7, A61P9, A61P43, C07D205, C07D403, C07D407, C07D409, C07D413, C07D417, C07K5