NZ260127A - Sulphonamido azacycloalkyl derivatives and medicaments - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £601 £7 260 12 7 NO DRAWINGS Priority Date{s): Complete Specification Filed: ?.!£..

Class: tos>a.Q7./o«R+os:4....c«fS eM&MJ.9.s Publication t996 NEW ZEALAND PATENTS ACT, 1953 No.: Date: COMPLETE SPECIFICATION GUANIDINYL-SUBSTTTUTED HETEROCYCLIC THROMBIN INHIBITORS We, BRISTOL-MYERS SQUIBB COMPANY a corporation organized and existing under the laws of the State of Delaware, United States of America, having its offices at Lawrenceville-Princeton Road, Princeton, New Jersey, United States of America, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page la) 26 0 1 - la - STILFONAMTnO HETEROCYCLIC THROMBIN INHIBITORS The present invention relates to sulfonamide heterocyclic compounds which are thrombin inhibitors and thus useful in inhibiting formation of thrombi.

The sulfonamido heterocyclic thrombin inhibitors of the invention have the structure I z a wherein G is an amido moiety which is 260127 o=c I MH I CH, I «jHa)» CM, T I A HjM *H (Ol) ossc I or SB <CH2)p Q i A« (02) including all stereoisomers thereof; and including all pharniaceutically acceptable salts thereof; wherein R is hydrogen, hydroxyalkyl, aminoalkyl> amidoalfcyl, alkyl, cycloalkyl, aryl, arylalkyl, alkenyl, alkynyl, arylalko^alkyl, or an amino acid side chain, either protected or unprotected; R1 and R2 are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, keto, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R1 and R2 together with the carbons to which they are attached form a cycloalkyl, aryl, or heteroaryl ring; and R3 is lower all^l' aryl, arylalkyl, heteroaryl, quinolinyl or tetrahydroquinolinyl; n is 0, 1 or 2; m is 0, 1, 2 or 3; Y is NH or S; p is 0, 1 or 2; Q is a single bond or I c=o I A is arylene or cycloalkylene, or an azacycloalkylene ring - 3 260127 A of 3 to 7 carbons in the ring or an azaheteroalkylene ring A of 4 to 6 carbons in the ring, A T1 yi where R4 is attached to a nitrogen atom; X is CH2, 0, S or NH; q is 0, 1, 2, 3 or 4 if X is CH2; q is 2, 3 or 4 if X is 0, S or NH; Y1 and Y2 are independently H, lower alkyl, halo or keto; and R4 is guanidino, amidino or aminomethyl where A is arylene or cycloalkylene; R4 is amidino where A is azacycloalkylene or azaheteroalkylene; provided that where X is a hetero atom (that is, A is azaheteroalkylene), then there must be at least a 2-carbon chain between X and any N atom in the ring A or outside ring A; and provided that where G is G1, then if R3 is alkyl, the alkyl must contain at least 3 carbons.

Examples of the A ring (azacycloalkylene, or azaheteroalkylene) which may be employed herein include 4 - 260127, a- a • a- p „/ A cx and the like.

The term "alkyl" as employed herein by itself or as part of another group includes both straight and branched chain radicals of up to 18 carbons, preferably "lower alkyl" of up to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, penty 1, he^l, isohexy 1, heptyl, 4,4 -dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1, 2 or 3 halo substituents (for example, to form CF3 or CF3CH2) and/or 1 or 2 of the following substituents: an aryl substituent (for example, to form benzyl or phenethyl), an alkyl-aryl substituent, a haloaryl substituent, a cyclo-alkyl substituent, an alkylcycloalkyl substituent, an alkenyl substituent, an alkynyl substituent, hydroxy or a carboxy 260127 substituent. It will be appreciated that the same "alkyl" group may be substituted with one or more of any of the above substituents.

The term "cycloalkyl" by itself or as part of 5 another group includes saturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may 10 be substituted with substituents such as halogen, lower alkyl, alkoxy and/or hydroxy groups.

The term "aryl" or "Ar" as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, or naphthyl. Aryl (or Ar) , phenyl or naphthyl may include substituted aryl, substituted phenyl or substituted naphthyl, which may include 1 or 2 substituents on either the Ar, phenyl or naphthyl such as lower alkyl, cyano, amino, alkylamino, 20 dialkylamino, nitro, carboxy, carboalkoxy, trifluoro-methyl, halogen (CI, Br, I or F), lower alkoxy, aryl-alkoxy, hydroxy, alkylthio, alkylsulfinyl, alkyl-sulfonyl, arylthio, arylsulfinyl and/or arylsulfonyl.

The term "aralkyl", "aryl-alkyl" or "aryl-25 lower alkyl" as used herein by itself or as part of another group refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl.

The term "alkoxy", "lower alkoxy" or "aralkoxy" includes any of the above alkyl, lower alkyl or aralkyl groups linked to an oxygen atom.

The term "halogen" or "halo" as used herei 35 itself or as part of another group refers to - 6 26012 5rTLne chlorine, bromine, fluorine or iodine with chlo being preferred.

The term "alkenyl" as employed herein by itself or as part of another group includes a carbon 5 chain of up to 16 carbons, preferably "lower alkenyl" of 3 to 10 carbons, containing one double bond which will be separated from "N" by at least one saturated carbon moiety such as -(CH2)q- where q can be 1 to 14, such as 2-propenyl, 2-butenyl, 3-butenyl, 10 2-pentenyl, 4-pentenyl and the like, and may include „ a halogen substituent such as I, Cl, or F.

The term "alkynyl" as employed herein by itself or as part of another group includes a 15 carbon chain of up to 16 carbons, preferably "lower alkynyl" of 3 to 10 carbons, containing one triple bond which will be separated from "N" by at least one saturated carbon moiety such as - (CH2) q ■ - where q' can be 1 to 14, such as 2-propynyl, 2-butynyl, 3-20 butynyl and the like.

The term "heteroaryl" or heteroaromatic by itself or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1 or 2 hetero atoms such as nitrogen, oxygen or sulfur, such as CKV ■ /""X w . W ' i.JJ ' 260127 7 9 C£> H and the like. The heteroaryl rings may optionally be fused to aryl rings defined previously. The heteroaryl rings may optionally include 1 or 2 substituents such as halogen (CI, Br, F or CF3), lower alkyl, lower alkoxy, carboxy, amino, lower alkylamino and/or dilower alkylamino.

The term "amino acid side chain" refers to any of the known alpha-amino acids such as arginine, histidine, alanine, glycine, lysine, glutamine, leucine, valine, serine, homoserine, allothreonine, naphthylalanine, isoleucine, phenylalanine and the like.

Preferred cure compounds of formula I wherein G is ossc MB «jHa)p Q I A wherein Q is a single ring bond, A is an azacycloalkylene 26 0 127 HA619b 8 where q is 0 or 1; and R4 is amidino; R3 is lower alkyl or aryl; R is aralkyl or hydroxyalky 1 ; R1 and R2 are each H; n is 0 or 1.

A more preferred embodiment of the heterocyclic thrombin inhibitors of the invention has the structure IA IA where R is aralkyl (preferably benzyl) , aryl (preferably phenyl), or arylalkoxyalkyl (preferably benzyloxymethyl) and alkyl is preferably methyl, ethyl or propyl, including all stereoisomers thereof.

Other preferred compounds of formula I are those wherein G is Gl, n is 0 or 1; m is 2; R3 is aryl or alkyl; R is arylalkyl or hydroxyalkyl such as a: (•.a. cr3ca2 or C«H5CHa) 260 1 HA619b hydroxymethyl; R1 is hydrogen or lower alkyl such as methyl or ethyl; R2 is H; and Y is -NH-; and compounds of formula IB: IB _Ra O O II It « HOCHa- , HOCH (alkyl) - j U KH —CHaOCHa-, Ha«CCHaCHa. I i°r .r <i*" (or**-- T K3«aryl, alkyl or arylalkyl The compotinds of formula I of the invention wherein 6 is I 0=C—*H CHa (CH3)a CHa—T— and Y is NH may be prepared according to the following Reaction Sequence I. 260 1 HA619b Reachinn SemiennP T H B || »—-B—C—C—OB ♦ I R Ra 2 / C Coupling r\-« V raaotion IV zzx XX (»■ t-butoxyearbony1 (»OC), earbobonsyloxy (CBz)) o / sv H B || /^ £c 9—m—c—c—X) (CBj)n wac BOBT CO^aUcy! Sulfonamide Conation CVjCOOB i y«;,. — «- vi CO,.!**1 2) IV o o / || B B II /\ Byd*olya±» R>—0 M c—C—* V—*1 » VIX ■ I Y,«/ CO) alkyl VI O 0 , II 2 H II B»--S—B—C—C—B O 1 VCCHi), > COjB VII 26 0 1 2 7 HA619b H - HaV-CBa-(CHa)a-CHa-H-»1 (P^eMbobwtylosy, t-butoxyoarbonyl, pbthallaido) VZZZ VIZ IX wac HOBT 2 II / "" Reduction S-S-B-/ » »»• M/c > I \_#«/ ix 1 (CHa)* IX 2) Anidlno 0»C •ulfonlo I acid |"a / HH.

(CHa)» f ^ —SOaOH CHa \ Ha* L U R2 O ° ,11 * " || R3 B II C C O R V<CHi>i Y o-c I MH I CHa IB (CHa), I r (T - MH) I A HjM MH 2 6 0 ' 2 7 HA619b The compounds of formula I of the invention wherein G is I 0=C—KH CHa (CHj). CHj—*—c' MB, and Y is NH may also be prepared according to the following Reaction Sequence II Reaction Sequence II H HjK-CHJ- (CHj ) m-CHj-W-P (P^earbobansyloxy, t -,Ri butoxycarbonyl, phtbaliaido) VIII fc. zzx wac HOBT IIA IXA L ia->d/c I " ■ Daprotactions TFA (whan P-BOC) or (whan PaCBx) («a). - "8 CR, I KH I * 260 1 1 7 HA619b Ra HH " '(CHj), Y O-C I MB XXB I ,r (CHa).

I CHj L U o Coupling H H || raaction P * C C OH + XXB Ixc I It XXX (PbBOC or CBs) Jta o H H II p— M C C N — It1 wac HOBT i V(CHa), Y °"C Daprot actiom XXC HH I7A (whan P1 il BOC) or I Hj-Pd/C (whan P1 is CBx) CEj »- IID I (CHa)m a) Aaidina sulfonic acid I at, z 1h I 260 12 7 HA619b H *-M As seen in the above Reaction Sequence I, compounds of formula I wherein Y is -NH-, are 5 prepared as follows. The ester II is made to undergo a carbodiimide coupling reaction with protected amino acid III in the presence of ethyl 3-(3-dimethy1-amino)propyl carbodiimide hydrochloride (WSC) or dicyclohexylcarbodiimide (DCC), and 1-hydroxybenzo-10 triazole monohydrate (HOBT), and N-methylmorpholine (NMM), and in the presence of an inert organic solvent such as dimethylformamide (DMF), THF or N-methylpvrrolidone, to form the amide IV. Amide IV is deprotected by treatment with trifluoroacetic acid 15 with or without the presence of dry inert organic solvent such as dichloromethane, chloroform or THF at temperatures within the range of from about -15° to about 20°C. Sulfonyl chloride V is added followed by organic base such as triethylamine, pyridine or N,N-20 diisopropylethylamine to form the sulfonamide VI.

Sulfonamide VI is hydrolyzed by treatment with alkali metal base such as NaOH or LiOH in the presence of an o / H 11 t V_x -C C M >——Rx I R CZD Y O-C 1) Daprotaetions I T9X {wh«n F ia BOC) or | Hj-Pd/C (whan 9 ia CBs) CH, I .. ii | Ra8—-CI CBa II I ° MB I - ZB 260 1 2 ? HA619b alcohol solvent such as methanol or ethanol. The reaction mixture is acidified with HC1, KHSO4 or H2SO4, to form acid VII. The acid VII is then subjected to a carbodiimide coupling reaction wherein VII is treated with protected amine VIII in the presence of WSC or DCC, and HOBT, and NMM, in the presence of an inert organic solvent such as dimethylformamide, THF or N-methylpyrrolidone, to form sulfonamide IX. The sulfonamide IX is then dissolved in an alcohol solvent such as ethanol or methanol, to which HCl has been added and the mixture is hydrogenated over Pd-C or Pd(OH)2-C in the case where P1 is carbobenzyloxy. The crude material is separated by conventional procedures and the desired isomers are treated with amidine sulfonic acid X in the presence of an alcohol solvent such as ethanol to form the compound of the invention IB.

As seen in the above Reaction Sequence II, compounds of formula I wherein Y is -NH-, are prepared as follows. The protected acid I1A is made to undergo a carbodiimide coupling reaction with protected amino acid VIII in the presence of ethyl 3-(3 -dimethylamino) propyl carbodiimide hydrochloride (WSC) or dicyclohexylcarbodiimide (DCC), and 1-hydroxybenzotriazole monohydrate (HOBT), and N-methylmorpholine (NMM), and in the presence of an inert organic solvent such as dimethylformamide (DMF) , THF or N-methylpyrrolidone, to form the amide IXA. Amide IXA is deprotected by treatment with trifluoroacetic acid (TFA) when P is t-butoxycarbonyl (BOC) or H2-Pd/C when P is carbobenzyloxy (CBz) , with or without the presence of dry inert organic solvent such as dichloromethane, chloroform or THF, at temperatures within the range of from about -15° to 26 0 HA619b 16 - about 20°C to form amide XXB. The amide IXB is then subjected to a carbodiimide coupling reaction wherein IXB is treated with protected amine III in the presence of WSC or DCC, and HOBT, and NMM, in the 5 presence of an inert organic solvent such as dimethylformamide, THF or N-methylpyrrolidone, to form amide IXC. The amide IXC is then dissolved in an alcohol solvent such as ethanol or methanol, to which HCl has been added and the mixture is 10 hydrogenated over Pd-C or Pd(0H)2-C in the case where P1 is CBz or treated with trifluoroacetic acid when P1 is BOC. The crude material is separated by conventional procedures and the desired isomers are treated with amidine sulfonic acid X in the presence IS of an alcohol solvent such as ethanol to form IXD. Compound IXD is then deprotected by treatment with TFA when P is BOC or by treatment with H2-Pd/C when P is CBz, as described above, and sulfonyl chloride V is added followed by organic base such as triethyl-20 amine, pyridine or N,N-diisopropylethylamine to form the sulfonamide IB.

The compounds of formula I of the invention wherein G is I 0=C—MH CH2 (CH,)m CHa—Y—c' MH, and Y is S may be prepared according to the following Reaction Sequence III. 260 12 7 HA619b Reaction Seqnenca TTT VII BaMCBa (CHa)»CHaOH XI WSC BO»T o a II R1 8- II o H \\ , —C—H V— R1 XII (CHa)a CO,MHCBj (CH,) .CH,OH TsCl pyridine o II rV XIII R'SOaHBCHC—H. (CH,), i COMHCHa <CHa).CHaOT» 0 A.

SXF HaK HH IC HA619b -left3 2 6 0 1 2 7 o o , II H II - , R3—a—M—C—C—H H— Rl II I o R o-c Y •c I KB I ZC CH, I CB, I a I "^101 Referring to the above Reaction sequence III, compounds of formula I wherein Y=S can be prepared as 5 follows. The acid VII is subjected to a carbodiimide coupling reaction wherein VII is treated with an aminoalcohol XI in the presence of WSC or DCC, HOBT, and NMM, in the presence of an inert organic solvent such as dimethylformamide, THF or N-methylpyrroli-10 done, to form sulfonamide alcohol XII. The sulfonamide alcohol XII is reacted with p-toluene-sulfonyl chloride (TsCl) in pyridine, or in a solvent such as methylene chloride or chloroform, with N,N-dimethylaminopyridine to provide toluenesulfonate 15 XIII. The compound IC (Y=S) is prepared by treating XIII with thiourea in a solvent such as DMF or DMSO at temperatures within the range of from about 25°C to about 100°C.

The compounds of formulae I and IA of the 20 invention wherein G is 260 127 HA619b 0=C—MH (CHa)p—Q—A—R4 wherein A is azacycloalkyl or azaheteroalkyl, and R4 is amidine, may be prepared according to the following Reaction Sequence IV: Reaction Sequence TV XV Coupling Raaetion WSC or DCC HOBT MUM O-C XVX (vhtrt P1 is a protacting group such as BOC or CBx) O H H II P—M—C—C—M R1 R Y-<CB"a), I MB I <CHa)p K. X l\ ^ pi (CHj) Q XVXX HA619b DeproCeation of *l (Bydcoga&ation with Ha/Pd-c if V1 ia CBs) XVII RJ P—II—C—C—K W— R* O H B || Juaidinosulf onic .

Aold (x> R VfCHl) XVIII » * T-tCHj) V o-c I MB I XII "}»»'■> Q ■I.

V \ 26 0 1 2 HAS19b D«prot«etlen xzz H,N » X /\ / Ra XX 8ulfoustion ■ R380aCl V O O II H H H . R3—a—N—c—c—* II I O R ^-(CHa), Rl XD H2H O-C I MB I «=Ha)p MH As seen in the above Reaction Sequence IV, compounds of formula I wherein G is 0=C—HH (CH,)p—Q—A—R4 i".

HA619b and A is azacycloalkyl or azaheteroalkyl, are prepared as follows. The protected acid XV is made to undergo a carbodiimide coupling reaction with amine XVI in the presence of ethyl 3-(3-dimethy1-S amino)propyl carbodiimide hydrochloride (WSC) or dicyclohexylcarbodiimide (DCC), and 1-hydroxybenzo-triazole monohydrate (HOBT), and N-methylmorpholine (NMM), and in the presence of an inert organic solvent such as dimethylformamide (DMF), THF or N-10 methylpyrrolidone, to form the amide XVII. Amide XVII is deprotected by treatment with, for example, H2/Pd-C, if P1 is CBz, to form amine XVIII. Amine XVIII is treated with amidinesulfonic acid X in the presence of alcohol solvent, such as ethanol to form amine XIX. Amine XIX is deprotected by treatment with trifluoroacetic acid (if P=BOC), with or without the presence of dry inert organic solvent such as dichloromethane, chloroform or THF, at temperatures within the range of from about -15° to about 20°C. 20 Sulfonyl chloride V is added followed by organic base such as triethylamine, pyridine or N,N-diisopropyl-ethy1amine to form the sulfonamide ID of the invention.

The starting materials of formula XVI are 25 known in the art or may be prepared by those skilled in the art employing conventional techniques.

The compounds of formulae I and IA of the invention where G is 1 I 3Q OSSC—« (CKa) p—Q—-A—R4 where A is aryl or cycloalkyl and R4 is amidine or guanidine may be prepared according to the following Reaction Sequence V: 26 0 1 9 HA619b Reaction sequence V XV ♦ Ba*—(CH,) „—Q—A1-*4' XVXA (A1 ia axyl or eyeloalkyl R4' is UftidlM or gnaaidina) Coupling Raaetion XVXXA WSC or DCC HOBT *a O H H B,»—C—C—* I Deproteotlon ■ XVXXXA OmC I MB I (CI,), a i> I- R1 Sulfonation XVXXXA x3-aoaci V o o II H a H 'C- 11 o I * XX Ra ^-(CBa), o»c I MB I (CBa)p Q A* i- R1 26 0 lo * L*m HA619b As seen in Reaction Sequence V, compounds of formulae I and IA where G is 0=C—MH (CH, ) p—Q—A1-*4' are prepared as follows. The protected acid XV is subjected to a carbodiimide coupling reaction wherein XV is treated with protected amine XVIA in the presence of WSC or DCC, and HOBT, and NMM, in the 10 presence of an inert organic solvent such as dimethylformamide, THF or N-methylpyrrolidone, to form amide XVIIA. The amide XVIIA is then dissolved in an alcohol solvent such as ethanol or methanol, to which HC1 has been added and the mixture is 15 hydrogenated over Pd-C or Pd(OH>2-C in the case where P is carbobenzyloxy. The amide XVIIIA is treated with sulfonyl chloride V followed by base to form the compound of the invention IE.

The starting compound XVIA is known in the art 20 or may be prepared employing conventional procedures.

The compounds of formulae I and IA of the invention wherein G is 0=C—»H (CHa) p—Q—A1—R4' where A is aryl or cycloalkyl (that is A1) and R4 is aminomethyl (that is R*") may be prepared according to the following Reaction Sequence VI: 260 127 HA619b Reaction Sequence VI XV + Ha*—(CHa)p—Q—A1—CHjMHP1 XVZB R2 Coupling Rttotion wsc or DCC HOBT O H I II P—M—C—'C—H I R XVXIB ^(CHa), o*c I MB I <CHi>p Q I CBa-MBP1 R1 D*prot«ot«d XVI ZB o H || HaM—C—C—N I R XVXIXB ^-(CHa).

O-C I MH I (CH,)P Q {.

CHjMHP1 R1 26 0 1; HA619b XVXZXB u h h n / \_ x sulfonation **—jj—*—c—c—/~R *" o X V(CHa>» RSOjC1 OmC V | xr I (CHa)p Q I i CBaMHj As seen in the above Reaction Sequence VI, compounds of formulae I and IA wherein G is I 0=C—*H—(CHa)p—Q—Ax—CHjMHa are prepared as follows. The protected acid XV is made to undergo a carbodiimide coupling reaction with protected amino acid XVIB in the presence of ethyl 3-10 (3 -dimethylaraino) propyl carbodiimide hydrochloride (WSC) or dicyclohexylcarbodiimide (DCC), and 1-hydroxybenzotriazole monohydrate (HOBT), and N-methylmorpholine (NMM), and in the presence of an inert organic solvent such as dimethylformamide 15 (DMF) , THF or N-methylpyrrolidone, to form the amide XVIIB. Amide XVIIB is deprotected by treatment with trifluoroacetic acid (TFA) when P is t-butoxycarbony1 (BOC) or H2-Pd/C when P is carbobenzyloxy (CBz), with or without the presence of dry inert organic solvent 20 such as dichloromethane, chloroform or THF, at temperatures within the range of from about -15° to about 20°c to form amide XVIIIB. The amide XVIIIB is then subjected to a sulfonation reaction wherein amide XVIIIB is reacted with sulfonyl chloride V in 26 0 i ?^ HA619b the presence of organic base such as triethylamine, pyridine or N,N-diisopropylethylamine to form the sulfonamide IF of the invention.

The starting compounds XVIB are known in the 5 art or may be prepared employing conventional procedures. « The starting acid XV may be prepared from ester IV by hydrolyzing ester IV by treating with a base such as NaOH, KOH or LiOH and then neutralizing 10 the resulting alkali metal salt with strong acid such as HCl or oxalic acid.

The compounds of formula I of the invention can be obtained as pharmaceutically acceptable acid addition salts by reacting a free base with an acid, 15 such as hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, citric, maleic, succinic, lactic, tartaric, gluconic, benzoic, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic acid or the like. 20 The compounds of the present invention are serine protease inhibitors, and in particular may inhibit thrombin. Factor Xa, and/or trypsin. The compounds of the present invention are useful for the treatment or prophylaxis of those processes which 25 involve the production and/or action of thrombin.

This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis (DVT), disseminated 30 intravascular coagulopathy (DIC), Kasabach-Merritt syndrome, pulmonary embolism, myocardial infarction, stroke, thromboembolic complications of surgery (such as hip replacement and endarterectomy) and peripheral arterial occlusion. In addition to its effects on 260 HA619b the coagulation process, thrombin has been shown to activate a large number of cells (such as neutrophils, fibroblasts, endothelial cells, smooth muscle cells). Therefore, the compounds of the present invention may also be useful for the treatment or prophylaxis of adult respiratory distress syndrome, septic shock, septicemia, inflammatory responses which include, but are not limited to, edema, acute or chronic atherosclerosis, and reperfusion damage.

The compounds of the invention may also be useful in treating neoplasia/metastasis (in particular those which utilize fibrin) and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, in addition, the compounds of the present invention may be useful to prevent restenosis following arterial injury induced by endogenous (rupture of an atherosclerotic plaque) or exogenous (invasive cardiological procedure) events.

The compounds of the present invention may also be used as an anticoagulant in extracorpeal blood circuits, such as those necessary in dialysis and surgery (such as coronary artery bypass surgery).

The compounds of the present invention may also be used in combination with thrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinse, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, and the like. The compounds of the present invention may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to * A 26 0 1 2 HA619b reperfusion. The compounds of the present invention may also allow for reduced doses of the thrombolytic agent to be used and therefore minimize potential hemorrhagic side-effects.

The compounds of the present invention may also be used in combination with other antithrombotic or anticoagulant drugs such as thromboxane receptor antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, and the like. 10 Compounds of the present invention that inhibit trypsin may also be useful for the treatment of pancreatitis.

The compounds of the invention can be administered orally or parenterally to various IS mammalian species known to be subject to such maladies, e.g., humans, cats, dogs and the like in an effective amount within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg 20 (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses.

The active substance can be utilized in a composition such as tablet, capsule, solution or 25 suspension containing about 5 to about 500 mg per unit of dosage of a compound or mixture of compounds of formula I. They may be compounded in conventional matter with a physiologically acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, 30 flavor, etc., as called for by accepted pharmaceutical practice. 26 0 7 2 HA619b The following Examples represent preferred embodiments of the present invention. Unless otherwise indicated, all temperatures are expressed in degrees Centigrade.

Example 1 [1 (S), 2a,4|i]-N-[4-[ (Aminoiminomethyl) amino] butyl] -1-[3-hydroxy-2-[ (2-naphthalenylsulfonyl)amino] -1-oxo-propyl]-4-methyl-2-piperidinecarboxamide, trifluor-oacetate (1;1) salt A. (2R-trans)-1-t(Phenylmethoxy) carbonyl] - 4-methyl-2-piperidinecarboxylic acid, ethyl eater A(l) . 4-Met-hvl-2-pjperidinecarbonit:rile To 500 g of sodium hypochlorite solution (5% in CI, Aldrich) cooled in an ice bath was added dropwise 33.6 g (340 mmol, Aldrich) of 4-methyl-piperidine, over 40 minutes. The reaction mixture was stirred for 20 minutes then poured into a separatory funnel and extracted with two-400 mL portions of ether. The extracts were combined, dried (sodium sulfate) and concentrated in vacuo to give -44 g of N-chloro intermediate as a yellow liquid.

To a solution of 19.1 g (340 mmol) of potassium hydroxide in 140 mL of 95% ethanol heated to 80° was added dropwise over 40 minutes the solution of crude N-chloropiperidine from above in 20 mL of 95% ethanol. The addition was mildly exothermic and a precipitate formed. The reaction mixture was stirred for 10 minutes, cooled to room temperature, concentrated An vacuo. and to the residue was added 85 mL of 2N aqueous NaOH solution. 26 0 1 HA619b The resulting mixture was extracted with three 75 mL portions of ether. The ether extracts were combined, dried (sodium sulfate) and concentrated ill vacuo to give the crude imine as a viscous yellow oil.

To a solution of 110 g (1.7 mol, Mallinckrodt) of potassium cyanide in 400 mL of water cooled in an ice-bath was added over ~1 h 183 mL (2.20 mol) of concentrated HC1, followed by the crude imine from above. The reaction mixture was stirred between 10-20°C for 4 h then cooled in an ice-bath and basified to pH 12 by addition of -80 g of potassium hydroxide pellets, the resulting solution was poured into a separatozy funnel and extracted with three-300 mL portions of ether. The ether layers were combined, dried (sodium sulfate) and concentrated In vacuo to give a yellow oil. The crude material was purified by simple distillation at reduced pressure to afford 13.2 g (106 mmol, 31%) of title nitrile as a clear liquid, bp 72-74° (3mm).

A(2). 4-Methyl-2-piperidinecarboxylic acid, ethyl ester To 250 mL of 6N aqueous HCl solution was added 13.0 g (105 mmol) of Part A(l) nitrile at room temperature. The reaction mixture was heated to reflux (bath temp 145°) for 6 h then cooled to room temperature and concentrated in vacuo to give the crude acid hydrochloride as a solid.

To 250 mL of absolute ethanol cooled in an ice-bath was added dropwise 40 mL (550 mmol) of thionyl chloride over 30 minutes. The solution was stirred for an additional 15 minutes then added to the crude acid hydrochloride from above. The resulting slurry was heated to reflux for 4 h then 260127 HA619b cooled to room temperature and filtered to remove solids. The filtrate was concentrated in vacuo to give the crude ester amine hydrochloride as brown oil. The oil was partitioned between 150 mL of saturated aqueous potassium carbonate solution and 150 mL of chloroform. The aqueous layer was separated and extracted with two-100 mL portions of chloroform. The organic extracts were combined, dried (sodium sulfate) and concentrated to give crude title ester as a brown oil. The crude material was purified by distillation through a 10 cm packed column (glass helices, 3mm) at reduced pressure to afford 11.0 g (64.3 mmol, 61%) of title amine as a colorless liquid, bp 37-38° (0.4mm). The trans/cis ratio was determined as ~6:1 by 270 MHz lH NMR.

A(3). (2R-trans)-1-[(Phenylmethoxy)-carbonyl]-4-methyl-2-piperidinecarboxylic aeiri. enhvl eater To a solution of 10.0 g (58.5 mmol) of Part A(2) amine in 100 mL of methylene chloride cooled to 0° was added 9.8 mL (70 mmol, distilled from calcium hydride) of triethylamine in one portion then dropwise 11.9 g (70 mmol, Aldrich) of benzyl chloroformate over 20 minutes. The reaction mixture was stirred for 30 minutes then washed with 100 mL of IN aqueous HCl, 100 mL of saturated aqueous sodium bicarbonate solution, 50 mL of brine, dried (magnesium sulfate) and then concentrated in vacuo to give an oil. The crude oil was purified by flash chromatography (Merck silica, 30x10cm, 600 g, 1:9 EtOAc/hexane) to afford 12.7 g (41.6 mmol, 71%) of title compound (trans isomer) as a colorless oil. In 260 HAS19b addition 2.95 g (9.67 mmol, 17%) of a -1:1 mixture of trans/cis isomers was obtained as a colorless oil.

B. (2R-trans)-4-Methylpiperidinecarboxylic 5 acid, ethyl ester Part A racemic CBZ ester (2.36 g, 7.73 mmol) was dissolved in absolute ethanol (50 mL) and hydrogenated over Pd-C (10%, 250 mg) at RT and 1 atm. After 6 hrs additional catalyst (50 mg) was added, 10 the reaction continued for 2 hours, filtered, and evaporated in vacuo to provide the title free amine (1.22 g, 7.13 mmol, 92%).

C. (2R-trans)-1-[N-[(1,1-Dimethylethoxy)- carbonyl]-O-(phenylmethyl)-L-seryl]-4-methyl- 2-nineridinecarboxvlic acid, ethvl eater Part B pipecolic ester (1.22 g, 7.13 mmol) and BOC-Ser(OBn)-OH (2.3S g, 8.0 mmol) were dissolved in DMF (15 mL) at RT. HOBT (1.08 g, 8.0 mmol), WSC 20 (1.54 g, 8.0 mmol) and N-methyl morpholine (NMM) (0.88 mL, 8.0 mmol) were added. The pH was ca 8.5. The reaction was stirred for 90 min, partitioned between ethyl acetate and 10% KHSO4, the aqueous layer back-extracted, and the organic layers 25 combined. The combined organic layers were washed with saturated NaHC03 (2 X), saturated NaCl, dried over magnesium sulfate and stripped in vacuo to provide title ester as an oil (2.99 g, 6.67 mmol, 93%). 260 1 2 7 HA619b D. (2R-trans)-1-[N-(2-Naphthalenylsulfonyl)- O-(phenylmethy1)-L-seryl]-4-methy1-2- pjperldlnecarhoxvllc acid, ethvl eater Part C BOC-Ser-pipecolic ester (2.80 g, 6.25 5 mmol) was dissolved in trifluoroacetic acid (TFA) at 0°C, and allowed to warm to RT over 60 min. The TFA was evaporated in vacuo for two hours to provide the TFA salt as an oil (4.2 g). The crude TFA salt was dissolved in dichloromethane (15 mL) and 2-naphthyl-10 sulfonyl chloride (Aldrich, 1.58 g, 7.0 mmol) was added, followed by triethylamine (3.5 mL, 25 mmol). A vigorous exotherm developed, and the reaction was put into an ice bath for 10 min, then warmed to RT. After 6 hr the dichloromethane was evaporated, the IS reaction mixture partitioned between ethyl acetate and 10% KHSO4 (2 X), washed with saturated NaHCC>3 (2 X), dried over magnesium sulfate and evaporated to provide crude title ester (3.18 g). The crude product was chromatographed on silica gel 20 (1:3 ==> 1:2 ethyl acetate (EtOAc):hexanes to provide the two diastereomers as an oil (2.29 g, 4.25 mmol, 68% over two steps).

E. (2R-trans)-l-[N-(2-Naphthalenylsulfonyl)-25 O-(phenylmethy1)-L-seryl]-4-methyl-2-piper- idinecarho*vHr arid The Part D ester was dissolved in methanol (MeOH) (30 mL) and treated with in NaOH (10 mL, 10 mmol). The reaction was stirred for 12 hr, and 30 additional NaOH (5 mL) was added. After 24 hr the reaction was acidified with HC1 (50 mL, 1H). extracted with ethyl acetate (2 X), and dried in vacuo to give title free acid (1.99 g, 3.90 mmol, 99%). 26 0 1 HA619b F. (4-Aminobutyl)carbamic acid, phenylmethyl eater 1,4-butanediamine dihydrochloride (5.96 g, 37 5 mmol) was dissolved in water (15 mL), and DMF (50 mL) was added. With rapid stirring, CBZ-C1 (1.0 mL, 7.0 mmol) was added dropwise over 2 minutes. The cloudy solution had pH - 2.8. The pH was adjusted to 9.0 with 5 U NaOH, (clear solution) and stirred for 2 hr. 10 The reaction mixture was acidified to pH = 1.25, extracted with ether (2 X), made basic (pH > 10) with 5 N NaOH, and extracted with dichloromethane (2 X). The dichloromethane fractions were combined and washed with water (2 X), dried and evaporated in 15 vacuo to provide the crude mono-CBZ amine (0.72 g, 3.24 mmol, 46%) which was used as is in the next step.

G. (2R-trans)-1-[N-(2-Naphthalenylsulfonyl)-20 O-(phenylmethyl)-L-seryl]-N-[4-[[(phenyl- methoxy)carbony1]amino]butyl]-4-methyl-2-piperidinecarhQxamiflfi To a solution of Part E mono-CBZ amine (400 mg, 1.8 mmol) and Part E acid (640 mg, 1.25 mmol) in 25 DMF (5 mL) was added HOBT (170 mg, 1.25 mmol), WSC (0.25 g, 1.3 mmol), and NMM (138 ill, 1.3 mmol). The pH was - 8.5. The reaction was stirred for two hr (complete by HPLC), partitioned between ethyl acetate and 10% KHSO4, back-extracted, and the combined 30 organic layers washed with 10% KHSO4, saturated NaHC03 (2 X), saturated NaCl, and evaporated to provide the crude product in quantitative yield. The crude product was chromatographed on silica gel 26 0 1 2 HA619b (2:Is:EtOAc:hexanes) to provide a mixture of the title two diastereomers (671 mg, 0.94 mmol, 75%).

H. [1 (S) , 2a,4|J]-N-[4-[ (Aminoiminomethyl) -5 amino]butyl]-1-[3-hydroxy-2-[(2-naphthalen- ylsulfonyl)amino]-1-oxopropyl]-4-methyl-2-piperidinecarboxamide, trifluoroacetate (1:3.) salt.

The Part G O-benzyl CBZ derivative was 10 dissolved in ethanol (20 mL) to which acetyl chloride had been added (0.71 mL, 10 mmol, gives a 0.5 M solution of HCl), and the mixture hydrogenated over Pd-C (10%, 150 mg) at 1 atm and reflux temperature.

After 5 hr the reaction mixture was filtered, stripped and fresh ethanol and catalyst added. The reaction was determined to be ca 80% complete after an additional 2 hr, whereupon it was filtered and stripped to provide the crude amine (412 mg). The crude material was purified by preparative HPLC 20 (80:20 => 50:50) to provide the des-benzyl, des-CBZ diastereomers (281 mg, 0.57 mmol, 71%) and the O-benzyl, des-CBZ compounds (69 mg, 0.12 mmol, 15%).

The des-benzyl, des-CBZ material above (208 mg, 0.46 mmol) was dissolved in ethanol (5 mL), to 25 which amidinesulfonic acid (78 mg, 0.65 mmol) and triethyl amine (176 fiL, 1.26 mmol) were added. After 20 hr the solvent was evaporated and the material purified by preparative HPLC (80:20=>50:50).

Fractions containing the two major components were 30 combined and lyophilized to provide title compound as a 40:60 mixture of isomers A:B (255 mg, 78%). Purity £ 98%. [a]D (c = 1.0, MeOH) = -11.7°. 26 0 IP HA619b Analysis calc'd for 1.30 TFA + 0.80 H2O: C, 47.68; H, 5.64? N, 12.09; F, 10.66. Found: C, 47.68; H, 5.34;, N, 11.97; F, 10.83.

Example 2 [1 (S) ,2a,4(5]-N-[4-[ (Aminoiminomethyl)amino]butyl]-4-methyl-l-[2-[(2-naphthalenylsulfonyl)amino]-l-oxo-3-(phenylmethoxy)propyl]-2-piperidinecarboxamide, tri-10 fluoroacetate (1:1) salt The O-benzyl, des-CBZ compound described in Example 1 Part H (69 mg, 0.099 mmol) was dissolved in ethanol (2 mL), to which amidinesulfonic acid (22 IS mg, 0.18 mmol, prepared as described in Synthesis (1986) 777-779), and triethyl amine (50 JlL, 0.36 mmol) were added. After 20 hr the solvent was evaporated and the material purified by preparative HPLC (80:20=>50:50). Fractions containing the two 20 major components were combined and lyophilized to provide title compound as a 1:3 mixture of isomers A:B (76 mg, 100%). Purity ^ 98%. [<X]d (c = 1.0, MeOH) = -5.6°.

Analysis calc'd for 1.10 TFA + 0.30 H2O: C, 54.51; H, 5.84; N, 11.15; F, 8.32. Found: C, 54.19; H, 5.84;, N, 11.04; F, 8.29. ^60127 - 38 -Example 3 [2R-[1 (S*) ,2a, 4jJ] ]-N- [4 - [ (Aminoiminomethyl) amino] butyl] -1-13-hydroxy-2-[(2-naphthalenylsulfonyl)amino]-1-oxopropyl]-4-methyl-2-piperidinecarboxamide, tri-5 fluproacetate (1;1) salt Example 1 compound (ca 220 mg) was dissolved in water (15 mL) and chromatographed on a YMC S-10 20mm X 500 mm CDS column, using an 80:20 ==> 50:50 10 gradient. After lyophilization, the first peak to elute (isomer A) comprised 95 mg. The stereochemistry (2R, 4R) was assigned by comparison to a sample prepared form non-racemic starting material. [a]D (c = 1.00, MeOH) +11.0°.

Analysis calc'd for 1.16 H2O + 1.07 TFA: C, 48.25; H. 5.88; N, 12.44; F, 9.03; S, 4.75 Found: C, 48.25; H, 5.61; N, 12.25; F, 9.25; S, 5.19 £2S- [1 (R*) ,2a,4p]]-N-I4-[ (Aminoiminomethyl)amino]butyl] -1-[3-hydroxy-2-[(2-naphthalenylsulfonyl)amino]-1-oxopropyl]-4-methyl-2-piperidinecarboxamide, triflu-25 oroacetate (1;1) salt Example 1 compound (ca 220 mg) was dissolved in water (15 mL) and chromatographed on a YMC s-10 20mm X 500 mm ODS column, using an 80:20 ==> 50:50 30 gradient (acetonitrile:water). After lyophilization, the second peak to elute (isomer B) comprised 103 mg. The stereochemistry (2S, 4S) was assigned by comparison of the two isomers. 26 0 " 9 t^ HA619b [a]D (c = 1.00, MeOH) -29.0°.

Analysis calc'd for 1.39 H20 +1.17 TFA: C, 47.52; H, 5.83? N, 12.16; F, 9.65; S, 4.64.

Found: C, 47.52; H, 5.49; N, 11.96; F, 9.60; S, 5.25.

High resolution MS shows (M+H)+ = 533.2546 (C25H37O5N6S).

Example 5 (2S-trans) -N- [4 - [ (Aminoiminomethyl) amino ] butyl ] -4-methyl-l-[[[(1,2,3,4-tetrahydro-3-methyl-8-quinolin-yl) sulfonyl] amino]acetyl] -2-piperidinecarboxamide, trifluoroacefcate wait A. (2S-trans) -4-Methyl-2-piperidinecarboxylic acid, ethvl ester To a solution of dry EtOH (65 mL) and acetyl chloride (6.52 mL added dropwise at 0°C) was added (2S, 4S)-4-methyl pipecolic acid (2.8 g, 19.6 mmol) at room temperature. The reaction was stirred at room temperature for 16 hrs and then concentrated in vacuo to give the title compound, (3.01 g, 90%).

B. (2S-trans)-1-[[[(1,1-Dimethylethoxy)- carbony1]amino]acetyl]-4-methyl-2-pjperidinecarboxvlie acid, ethvl eater To a solution of L-Boc-Glycine (0.4 g, 2.25 mmol) and HOBT (0.31 g, 2.25 mmol) in 7 mL DMF was added WSC ( 0.44 g, 2.25 mmol) and Part A ethyl ester (0.35 g, 2.04 mmol), followed by NMM (240 fil, 2.25 mmol) to adjust the pH of the solution to 8. The reaction was stirred at room temperature for 16 hrs and worked up by washing with a saturated solution of 26 0 1 9 HA619b - 40 NaHC03, a saturated solution of KHSO4, brine, dried over NaaS04 and evaporated to give the title compound (0.60 g, 89%).

(M»H)+ 0329 C. (2S-trans)-1-5 *[(1,1-Dimethylethoxy)-car bony 1 ] amino ] acetyl ] - 4 -methyl- 2 -piper- iflinecarboxylic acid To a solution of Part B (560 mg, 1.71 mmol) in 10 6.5 mL EtOH was added IN NaOH (6.5 mL) at 0°C. The reaction was stirred at room temperature for 16 hrs and concentrated in vacuo. The reaction was acidified with IN HCl to pH 2 and extracted with EtOAc. Then the EtOAc was washed with a saturated 15 solution of KHSO4, brine, dried over Na2S04 and concentrated to give the title compound (512 mg, quantitative).

(M+H)+ © 301 D. (4-Aminobutyl)carbamic acid, phenylmethyl ester To a solution of 1,4-diaminopentane (25 g, 155 mmol) in 100 mL DMF/H20 (1:1) was added 5N NaOH to adjust the pH to 9. CBZ-Cl (3.7 mL, 26 mmol) was 25 added as one portion and stirred at room temperature for 16 hrs. The reaction was acidified to pH 1.25 and washed with diethyl ether. The pH of the reaction was then adjusted to 9.5 and the reaction extracted with EtOAc. The organic layer was washed 30 with H2O, brine, dried over Na2S04 and evaporated to give title compound (1.57 g, 30%). 26 Q i HA619b E. (2S-trans)-l-[[[(1,1-Dimethylethoxy)-carbonyl ] amino ] ace ty 1 ] - 4 -methyl -N- [ 4- [[(phenylmethoxy)carbonyl]amino]butyl]-2- piperiflinecarboxamide To a solution of Part C compound (516 mg, 1.72 mmol) and HOBT (256 mg, 1.89 mmol) in lOmL DMF was added WSC (363 mg, 1.89 mmol) and Part D CBZ amine, (381 mg, 1.72 mmol), followed by NMM (198|il, 1.89 mmol) to adjust the pH of the solution to 8. The reaction was stirred at room temperature for 16 hrs. The reaction was worked up by pouring into a saturated solution of NaHC03 and extracting with EtOAc. The EtOAc layer was washed with a saturated solution of KHS04, brine, dried over Na2S04 and concentrated in vacuo to give the title compound (900 mg, quantitative).

F. (2S-trans)-1-(Aminoacetyl)-4-methyl-N-[4-[[(phenylmethoxy)carbonyl]amino]butyl]-2- pipfiriflinfiCtirtoxamitifi. hydrochloride To a solution of Part E compound (0.76 g, 1.51 mmol) in 5 mL MeOH was added 4.5 mL of 4N HCl/dioxane at 0°C. After 2 hrs at room temperature, the reaction was worked up by adding Et20 to precipitate the title compound (0.70 g, quantitative).

G. (2S-trans)-4-Methyl-1-[[[(3-methyl-8-quinolinyl)sulfonyl]amino]acetyl]-N-[4- [[(phenylmethoxy)carbonyl]amino]butyl]-2-pjperidinecarboxamidfi To a solution of Part F compound (500 mg, 1.13 mmol) in 11 mL CHCI3 was added EtaN (475ml, 3.39 mmol) at 0'C. After 5 minutes, 6-methyl-8-quinoline-sulfonyl chloride, (273 mg, 1.13 mmol) was added. 26 0 1 27 HA619b The reaction was stirred at 0°C for another 5 minutes then stirred at room temperature for 3 hrs. The reaction was washed with a saturated solution of NaHC03, a saturated solution of KHSO4, brine, dried 5 over Na2S04 and evaporated to give the crude product which was purified by a silica gel column, using CH2CI2 : MeOH eluting solvent to give the title compound (150 mg, 22%).

H. (2S-trans) -N- (4-Aminobutyl)-4-methyl-l-[t[(l,2,3,4-tetrahydro-3-methyl-8-quinolinyl)sulfonyl]amino]acetyl]-2-piper-idinecarboxamide. hydrochloride A solution of Part G compound (140 mg, 0.23 15 mmol) and 230 |il IN HCl in 5 mL EtOH was hydrogenated at 1 atm over 10% Pd / C (40 mg) . After 16 hrs, the suspension was filtered through Celite and concentrated jja vacuo to give the title free amine, (130 mg, quantitative).

I. (2S-trans) -N- [4- [ (Aminoiminomethyl)amino] -butyl]-4-methyl-l-[[[(l,2,3,4-tetrahydro-3~ methyl-8-quinolinyl)sulfonyl]amino]acetyl]-2- pjperiflinecarbQxamifle ; To a solution of Part H compound (80 mg, 0.145 mmol) in 0.8 mL EtOH was added Et3N ( 60 ml, 0.43 mmol), followed by amidinesulfonic acid (27 mg, 0.22 mmol). After 16 hrs at room temperature, the reaction was concentrated jjl vacuo and was subjected to 30 preparative HPLC using an 80:20 to 50:50 gradient (H20: CH3CN) over 50 minutes to give the title compound (40 mg, 50%).

(M+H)+ @522 26 0 IP 7 HA619b Anal Calc'd for C24H39N7O4S • 1.2TFA • 1.1 H20 C, 43.54; H, 6.04; N, 13.46; F, 9.39 Found C, 43.87; H, 5.72; N, 13.09; F, 9.33. [a]d=-6.7 (c=0.51, methanol) Ryamnlp 6 trans-N- [4 - [ (Aminoiminomethyl) amino]butyl] -4- (methyl-thio)-l-[((2-naphthalenylsulfonyl)amino]acetyl]-L-10 nroli namide. r.rifhioroacetaf.e gait A. cis-4-Hydroxy-l- [ (phenylmethojqr) carbonyl]-L-prollne. methvl eater , N-CBZ-L-keto proline was dissolved in methanol 15 ( 150 mL), cooled to 0 to 5°C and treated dropwise with a solution of NaBH4 (2.875 g) in water (10 mL) . The mixture was kept at 0 to 5°C for 19 h. The methanol was removed in vacuo and the residue was treated with 75 mL of 3H NaOH and stirred at room 20 temperature for 40 min. After cooling in an ice bath, the mixture was acidified with conc HC1. The product was extracted into ethyl acetate (3x50 mL). The combined extracts were washed with brine (2x40 mL), dried (MgSO* ) and freed of solvent in vacuo to 25 give the cis-hydroxy acid. This was converted to the methyl ester by dissolving in methanol (75 mL), treating with acetyl chloride (7.5 mL), and stirring overnight at room temperature. The solvent was removed. The residue was dissolved in ethyl acetate 30 (75 mL), washed with sodium bicarbonate solution (2x25mL), dried (MgS04 ) and freed of solvent in vacuo to give title compound as a viscous oil (4.315 g, 81%). 260 1 2 HA619b B. cis-4-[[(4-Methylphenyl)sulfonyl]oxy]-1-[ (phenylmethoxy) carbonyl ] -L-proline, methyl ester The Part A alcohol (4.315g, 16.84 mmol) was 5 dissolved in dry pyridine (23mL), cooled in an ice bath and treated with tosyl chloride (6.8g). The mixture was allowed to warm slowly to room temperature and left stirring 60 h. After cooling, cold 2H HCl was added and the mixture was left at 0 10 to 5°C for 4 h. The solid was collected by filtration and dissolved in dichloromethane. This solution was washed with 1H HCl soln and brine, dried (MgS04 ) and freed of solvent in vacuo leaving title compound as a crystalline material.

C. 4- (Methylthio) -1-1 (phenylmethoxy) -carbonvll-li-proline, methyl eater Part B tosylate (2.09g, 4.8mmol) was dissolved in absolute ethanol (20mL) and acetone (20mL), under 20 an atmosphere of argon, and treated with sodium thicmethoxide (1.39g, 19.9mmol). The mixture was heated under reflux lh, cooled and most of the solvent was removed in vacuo. The residue was partitioned between IN HCl and ethyl acetate. The 25 ethyl acetate layer was washed with water, dried (MgSC>4 ), and freed of solvent in vacuo. NMR and TLC indicated the material was mainly the free acid. It was converted to the methyl ester by dissolving in methanol (20 mL), adding acetyl chloride (2mL) and 30 stirring at room temperature for two hours. After removal of the solvent, the product was purified by chromatography on silica gel, eluting with ethyl acetate:hexane (1:2) to give the title thiomethyl compound (1.364g, 99%). 260 1 HA619b D. 4-(Methylthio)-L-proline, methyl ester, hvflrobromifle Part C compound (945 mg, 3.3mmol) was treated with 30% HBr in HOAc (8mL) for 1 h and then concentrated in vacuo. Trituration of the residue with ether gave a solid which was harvested by filtration and washed with more ether leaving the title deprotected amine (749 mg, 89%).

E. trans-1-[[[(1,1-Dimethylethoxy)carbonyl]-amino]acetyl]-4-(methylthio)-L-proline, methyl eater ; and P. cis-l-[N-[(1,1-Dimethylethoxy)carbonyl)-alvcvll -4- (mefchvlf-hin) -L-proline. methvl ester Part D L-proline derivative (1.012 g, 3.95 mmol) and BOC-glycine (900mg, 5.1 mmol) were dissolved in DMF (20 mL) at RT. HOBT (688mg, 5.1 mmol), WSC (974mg, 5.1mmol) and NMM (1.0 mL, 9.1 mmol) were added. The reaction was stirred for 16 h, partitioned between ethyl acetate(50 mL) and 10% KHSO4 (100 mL) . The aqueous layer was extracted with ethyl acetate (2x50mL), and the organic layers were combined. The combined organic layers were washed with saturated NaHC03 , saturated NaCl, dried over magnesium sulfate and concentrated in vacuo to provide an oil. TLC indicated this was two major products. The crude material was purified by chromatography on silica gel. Elution with ethyl acetate:hexanes(1:2 followed by 1:1) gave the major product (tentatively assigned the trans configuration of the title compound, 603mg, 46%) and the minor product (tentatively assigned the cis configuration 26 0 12 7 HA619b of the title compound, 204mg, 16%) as well as some mixed fractions (438mg, 33%).

G. trans-4- (Methylthio) -1- [ [ (2-naphthalenyl-5 aulfonvl)amino1 acetyl!-L-proline« methyl eater The Part E BOC derivative (600 mg, 1.8 mmol) was dissolved in trifluoroacetic acid (TFA) (15 mL) and stirred at RT 1 h. The TFA was removed by distillation under reduced pressure and by 10 coevaporation with toluene. The crude TFA salt was dissolved in dichloromethane (20 mL), cooled in an ice bath, and 2-napthylsulfonyl chloride (Aldrich, 450mg, 2.0 mmol) was added, followed by triethylamine (1.5 mL). The solution was warmed to RT and stirred 15 1.5 h before diluting with dichloromethane (75 mL) . This solution was washed with potassium hydrogen sulfate solution(2x40mL) and saturated NaHC03 (2 x40mL), dried over magnesium sulfate, and evaporated to provide crude title compound. The crude product 20 was chromatographed on silica gel and eluted with 50% EtOAc in hexanes to provide title sulfonamide as a foam (700mg, 92% overall in two steps).

H. trans-4-(Methylthio)-1-[[(2-naphthalenyl-25 sulfonyl)amino!acetyl!-L-proline A solution of Part G methyl ester (700mg, 1.65 mmol) in methanol (20 mL) was treated with 1 N NaOH solution (8mL) and stirred at room temperature for three h. After acidification with IN HCl solution, 30 the product was extracted into dichloromethane (2x50 mL), dried over magnesium sulfate and freed of solvent in vacuo to give title compound as a white foam (687mg, 100%). 26 0 1 HA619b I. trans-4-(Methylthio)-1-[[(2-naphthalenyl-sulfonyl)amino]acetyl]-N-[4-t[(phenyl -mathoxv)rarbonvl1 amino1butvl1-L-prolinamide To a solution of mono-CBZ butyl diamine (484 mg, 2.18 mmol) and Part H acid (687 mg, 1.65 mmol) in DMF (25 mL) was added HOBT (230 mg, 1.7 mmol), WSC (325 mg, 1.7 mmol), and NMM (373 }IL, 3.4 mmol). The reaction was stirred at RT for 20 h, partitioned between ethyl acetate (50 mL) and KHSO4 solution (50 mL), back-extracted with ethyl acetate (2x50 mL), and the combined organic layers were washed with saturated NaHC03 and brine, dried (MgS04), filtered and concentrated. The crude product was chromatographed on silica gel and eluting with 50-67% EtOAc in hexanes followed by EtOAc to provide title compound (577mg, 58%).

J. trans-N-(4-Aminobuty1)-4-(methylthio)-1-[[(2-naphthalenylsulfonyl)amino]acetyl]-L- prnlinamide. hydrnbromide The CBZ group was removed from Part I compound (577 mg, 0.96mmol) by treating with 30%HBr in HOAc (lOmL) for 1.5 h and then concentrated A11 va£uo. Trituration of the residue with ether gave a solid which was harvested by filtration and washed with more ether leaving the title deprotected amine (100%) .

K. trans-N-[4-[(Aminoiminomethyl)amino]-butyl]-4-(methylthio)-1-[[(2-naphthalenyl-sulfonyl)amino]acetyl]-L-prolinamide, trifluoroacette salt The Part J compound (0.96 mmol) was dissolved in ethanol (20 mL), to which amidinesulfonic acid 26 0 1 HA619b (173 mg, 1.4 mmol) and triethyl amine (375 ILL, 2.7 mmol) were added. After 4 h the mixture was filtered through a pad of Celite, washed with ethanol and the filtrate was concentrated to dryness. The crude material was purified by preparative HPLC (YMC S-10 ODS 50 x 500 mm column, eluting with 54% methanol in water, containing 0.1% TFA). Fractions containing pure title compuond were combined and lyophilized to provide a white solid (279 mg, 44%), Purity 2. 98%. [a]D = -12.7°, (c = 0.7, MeOH).

Analysis calcd for 1.10 TFA + 0.90 H2O: C, 45.70; H, 5.31; N, 12.69; F, 9.68; S, 9.47. Found: C, 45.65; H, 5.09; N, 12.51; F, 9.74; S, 9.37.

Example 7 N- [4- [ (Aminoiminomethyl)aminojbutyl]-1-[N- (2-naphthalenylsulfonyl) -D-phenylalanyl] -L-prolinamide, triflnoroacehafce salt. hemihvriraf g A. N-[4-[ [ (1,1 -Dimethy le thoxy) carbonyl ] -amino 1 bur.yl 1 -L-prolinamiflfi, hyrochloridft A(l). (4-Aminobutyl)carbamic acid, 1,1-riimgfhvlef-hvl esfcsr To a stirred solution of 1,4-diaminobutane (50 g, 567 mmol) in 195 mL of dioxane under argon at room temperature was added dropwise a solution of Di-t-butyl dicarbonate (15.7 g, 71.9 mmol) in 195 mL of dioxane over 3.5 h. Some white precipitate appeared during the addition. The mixture was stirred at room temperature for 22 h and concentrated in vacuo. The residue was diluted with 320 mL of water and the \ 2 6 0 127 HA619b precipitate was filtered off. The aqueous filtrate was extracted with methylene chloride (3x300 mL). The combined methylene chloride extracts were washed with water (2x200 mL) and brine (1x200 mL). The 5 organic layer was dried (MgS04), filtered and concentrated in vacuo to give 9.79 g (72%) of title mono-BOC•amine.

TLC: silica gel, 2%NH40H in 10%CH30H/CH2Cl2, Rf 0.30, 10 Ninhydrin.

A(2). N-[4-[ [ (1,1-Dimethylethoxy) carbonyl] -amino]butyl] -1- [ (phenylmethoxy)carbonyl]-L- prolinamidfi : To a stirred solution of N-CBZ-L-proline (12.7 g, 50.9 mmol), 1-hydroxybenzotriazole monohydrate (6.49 g, 50.9 mmol) and Part A(l) BOC amine (9.57 g, 50.9 mmol) in 250 mL of EMF was added in order 4-methylmorpholine (11.2 mL, 102 mmol) and ethyl-3- (3-20 dimethylamino) propyl carbodiimide hydrochloride (9.76 g, 50.9 mmol). The reaction solution was stirred at room temperature for 22 h and concentrated under pump vacuum at 50°C. The residue was diluted with 600 mL of EtOAc and washed with IN HCl solution (2x250 mL), 25 saturated N&HCO3 solution (2x250 mL) and brine (1x250 mL). The EtOAc layer was dried (MgS04), filtered and concentrated in vacuo to give 20.7 g (97%) of title CBZ amine.

TLC: silica gel, 4%CH30H/CH2Cl2, Rf 0.44, UV, Ce(SO4)2* 260 1 2 7 HA619b A(3). N-[4-[ [ (1,1-Dimethylethoxy)carbonyl] - amino!tamvl 1 -L-prollnamirifl. hydrochloride To a stirred solution o£ Part A(2) CBZ amine (20.2 g, 48.2 mmol) in 250 mL of methanol under argon 5 was added 20%Pd(OK)2/C (4.04 g, 20% based on the weight of Part A(2) compound). The atmosphere was replaced by hydrogen with several vacuum-fill cycles. The reaction mixture was stirred at room temperature for 21 h. The catalyst was filtered off through a 4 10 1IM polycarbonate film and rinsed with methanol (3x50 mL). The filtrate was concentrated in vacuo. The oily residue was dissolved in 200 mL of ether and treated with IN HCl solution in ether (53.0 mL, 53.0 mmol). The solution was concentrated An vacuo. The IS residue was mixed with 200 mL of toluene and 30 mL of methanol and concentrated la vacuo to give title amine hydrochloride in quantitative yield (15.5 g) as an oil. b. N-[4-[[(1,1-Dimethylethoxy)carbonyl]- amino]butyl]-1-[N-I(phenylmethoxy)carbonyl]- D-phenvlalanyll-L-prolinamide a stirred solution of N-a-CBZ-D-phenylalanine (0.56 g, 1.9 mmol) in 6.5 mL of DMF at room 25 temperature under argon was treated with 1-hydroxy-benzotriazole (0.29 g, 1.9 mmol) and ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (0.36 g, 1.9 mmol). After 20 minutes, Part A compound was added (0.50 g, 1.6 mmol) and stirring was carried out 30 for 16 hours. The reaction was quenched by the addition of 75 mL of 0.25H khso4 solution. The suspension was washed with EtOAc (2 x 40 mL), the combined EtOAc layers were washed with 0.25M KHSO4 solution (2 x 40 mL), saturated aqueous khco3 £ o ■; z 1 HA619b solution (2 x 40 mL), brine, dried (Na2SC>4), and concentrated to yield 1.07 g of a white taffy, which by TLC analysis appeared to contain unreacted N-a- CBZ-D-phenylalanine. The crude product was 5 redissolved in 60 mL of EtOAc, washed with saturated aqueous KHCO3 solution (3 x 40 mL), brine, dried (Na2S04). concentrated, co-evaporated several times with ether and hexane and triturated with 50 mL of hexane to yield of title compound (0.78 g, 88%) as a 10 white solid.

C. N- [ 4- [ [ (1,1-Dimethylethoxy) carbonyl ] -amino! btifcvll -l-D-nhenvlalanvl-L-nrol inamidfr A solution of Part B compound (0.58 g, 1.0 15 mmol) with 0.12 g of Pd(OH)2/carbon in 5.0 mL of methanol was hydrogenated at 1 atm for 3.75 hours. The catalyst was removed by filtration through a porous membrane (Whatman 0. 2fi Nylon Autovial), and the filtrate was concentrated to yield title compound 20 (0.39 g, 88%) as a white, hygroscopic solid.

D. N- [4- [ [ (1,1 -Dimethylethoxy) carbonyl] -amino]butyl] -1- IN- (2-naphthalenylsulfonyl) -D-phenYlalanyll-L-nrnlinflmirip Triethylamine (0.25 mL, 1.8 mmol) was added dropwise to a stirred 0*C solution of Part C compound (0.39 g, 0.90 mmol) and 2-naphthalenesulfonyl chloride (0.21 g, 0.95 mmol) in 7.0 mL of CH2CI2. The reaction was carried out at room temperature for 45 30 minutes. Dichloromethane was removed under vacuum, the residue was partitioned between EtOAc (50 mL) and aqueous 0.25M KHSO4 solution (15 mL), the EtOAc layer was washed with 0.25M KHSO4 solution (3 x 15 mL), brine, dried (Na2S0«) > and concentrated to yield 0.61 2 6 0 1 z HA619b g of a colorless glaBS. Trituration with 50 mL of hexane yielded title compound (0.52 g, 93%) as a white solid.

E. N-(4-Aminobutyl)-1- [N-(2-naphthalenyl- sul f onyl) -D-phenylalanyl ] -L-prolinamide, trlfluoroacetate salt Trifluoroacetic acid (5.0 mL) was added to ice-cooled Part D compound (0.48 g, 0.77 mmol). The 10 reaction solution was stirred at room temperature for 45 minutes. Trifluoroacetic acid was removed under vacuum and co-evaporated several times with ether and hexane until title compound was obtained as a white solid (0.51 g, ca. 100%).

F. N-[4-[(Aminoiminomethyl) amino] butyl] -1-[N- (2-naphthalenylsulfonyl) -D-phenyl-alanyl]-L-prolinamide, trifluoroacetate salt, hemihydrate A solution of Part E compound (0.49 g, 0.77 mmol) in 6.0 mL of absolute ethanol was treated with amidine sulfonic acid (0.14 g, 1.2 mmol) followed by triethylamine (3.2 mL, 2.3 mmol). Within several minutes reaction time, a precipitate appeared. After 25 5 hours reaction time, TLC analysis of the reaction mixture (silica, 3:1:1 nBu0H:H0Ac:H20) indicated a small amount of unconsumed Part E compound. An additional portion of amidine sulfonic acid (0.05 g) and triethylamine (0.53 mL) were introduced, and the 30 reaction was continued for 16 hours. TLC analysis as above indicated complete consumption of Part E compound. The reaction mixture was concentrated, dissolved in 25 mL of CH3OH, and filtered through a porous membrane (Gelman Acrodisc CR PFTE, 0.45 ji.) . 260 1 HA619b preparative HPLC of the filtered solution (25%B to 100%B, 30 minute gradient) and subsequent lyophilization of the pooled fractions yielded title compound, (258 mg,48%) as a colorless solid, mp 100-5 120°C with foaming. [a]D = +19.4° (c = 0.5, CH3OH).

TLC: Rf a 0.70 (silica, 3:1:1 nBuOH ; H0Ac;H20).

Anal. Calc'd for C3lH37Ng06F3S»l.l C2HF3O2»0.50 H2O: C, 53.60; H, 5.49; N, 12.02; F, 8.97; S, 4.59 Found: C, 53.61; H, 5.50; N, 11.81; F, 9.03; S, 4.36 example 8 N-[4-[(Aminoiminomethyl)amino]butyl]-1-[N-(2- naphthalenYlsulfonyl)-D-qlutaminyll-L-prolinamide A. N-[4-[[(1,1-Dimethylethoxy)carbonyl]-aminojbutyl]-1-[N-[(phenylmethoxy)carbonyl]-20 D-alutaminvl 1 -L-prolinamide To a stirred solution of Example 7 Part A amine hydrochloride (0.56 g, 1.74 mmol), 1-hydroxy-benzotriazole monohydrate (0.29 g, 1.74 mmol) and N-CBZ-D-glutamine (0.49 g, 1.74 mmol) in 15 mL of DMF 25 was added 4-methylmorpholine (0.57 mL, 5.23 mmol) followed by ethy1-3-(3-dimethylamino)propyl carbodiimide hydrochloride (0.33 g, 1.74 mmol). The solution was stirred at room temperature for 19 h and concentrated under pump vacuum at 45°C. The oily 30 residue was diluted with 160 mL of EtOAc and washed with IN HCl solution (2x60 mL), saturated NaHC03 solution (2x60 mL) and brine (1x60 mL). The EtOAc layer was dried (MgS04), filtered and concentrated in vacuo to give 0.75 g (77%) of title CBZ amine. 26 0 i 2 HA619b TLC: silica gel, 6%CH30H/CH2Cl2, Rf 0.22, Ce(S04)2> B. N-[4-[[(1,1-Dimethylethoxy)carbonyl]- amino]butyl]-1-[N-(2-naphthalenylsulfonyl)- D-oliitaminvl1-L-prolinamide To a stirred solution of Part A CBZ amine (0.73 g, 1.33 mmol) in 12 mL of methanol under argon was added Pd(OH)2/C (146 mg, 20% based on the weight of Part A compound) . The atmosphere was replaced by hydrogen with several vacuum-fill cycles. The reaction solution was stirred at room temperature for 22 h and the catalyst was filtered off through a 4(iM polycarbonate film. The solid was rinsed with methanol (2x20 mL). The filtrate was concentrated in vacuo to give 0.54 g of the intermediate amine. To a stirred solution of this amine (0.44 g, 1.07 mmol) and 2-naphthalenesulfonyl chloride (0.27 g , 1.18 mmol, in 10 mL of dry methylene chloride under argon at 0°C was added Et3N (0.33 mL, 2.34 mmol). The reaction solution was stirred at room temperature for 2 h and diluted with 180 mL of EtOAc. This solution was washed with IN HCl solution (2x60 mL), saturated NaHC03 solution (1x60 mL) and brine (1x60 mL). The organic layer was dried (MgS04), filtered and concentrated in vacuo. Purification was effected by flash chromatography on 30 g of Merck silica gel 60 using 240 mL of 4%CH30H/CH2Cl2 and 480 mL of 6%CH30H/CH2Cl2 as eluants to give pure title sulfonamide (310 mg, 48%).

TLC: silica gel, 4%CH30H/CH2Cl2, Rf 0.20, UV, 12. 26 0 ' p HA619b C. N-[4-[(Aminoiminomethyl)amino]butyl]-1-[N-(2-naphthalenylsulfonyl)-D-glutaminyl]-L- prolinamifle To a stirred solution of Part B sulfonamide 5 (310 mg, 0.51 mmol) in 5 mL of dry methylene chloride was added 0°C 4N HCl in dioxane (6.00 mL, 24.0 mmol) . The solution was stirred at room temperature for 2 h and diluted with 120 mL of ether. The solid was filtered off and rinsed with ether (2x30 mL). The 10 solid was dissolved in 60 mL of methanol and concentrated in vacuo to give the intermediate amine hydrochloride. To a stirred mixture of this amine hydrochloride and Et3N (0.39 mL, 2.31 mmol) in 5 mL of absolute EtOH under argon was added aminoimino-15 methanesulfonic acid (204 mg, 1.64 mmol). The mixture was stirred at room temperature for 5 h and concentrated in vacuo. The reaction mixture was purified by preparative HPLC, eluting isocratically with a 37% composition of water:methanol (90:10 and 20 10:90) containing 0.2% H3PO4. The fractions were concentrated in vacuo and lyophilized to give 260 mg (93%) of title compound. m.p. 72-74°C 25 [cx]d=+5.80 (c=0.69, methanol).

Anal. Calc'd for C25H35N70sS»l.60 TFA»1.0 H20: C, 45.40; H, 5.21; N, 13.14; S, 4.30; F, 12.22 Found: C, 45.45; H, 4.98; N, 12.95; S, 4.32; F, 11.90 260127 56 - Following Che procedures of Examples 1 to 8 and those outlined above, the following additional examples may be prepared.

Melting Point °C, Optical Rotation and/or Elemental Analysis (where available) [a]D=+ll.o (c=l.09 MeOH) 9 * [2R-[l(S*),2a,4fl]]-N-[3-[ (Aminoiminomethyl)amino]propyl] - 1-[4-hydroxy-3-[(2-naphthalenylsulfonyl) amino} -1,2-dioxobutyl]- 2-piperidinecarboxamide, trifluoroacetate (1:1) salt Anal. Calc'd for C24H34N605S«1.1TFA»1.34 H2O: C, 47.10; H, 5.70; N, 12.58; S, 4.80; F, 9.38 Found: C, 47.39; H, 5.41; N, 12.29; S, 5.21; F, 9.56 . N-[4-[(Aminoiminomethyl) - amino]butyl]-1-[N- (2-naphthalenyl- [cxJd=-70.2 (c=0.5, sulfonyl) -L-seryl) -L-prolinamide MeOH) Anal. Calc'd for C23H32N60sS-1.15 TFA«0.5 H20: C, 47.13; H, 5.34; N, 13.03; S, 4.97; F, 10.17 Found: C, 46.83; H, 5.28; N, 12.84; S, 5.14; F, 10.43 11. N-[4-[(Aminoiminomethyl)- amino]butyl]-1-[N-(2-naphthalenyl- [a]d=-14.8 (c=0.5, 30 sulfonyl) -L-seryl] -D-prolin- MeOH) amide, trifluoroacetate (1:1) salt 26 0 1 2 7 HA619b Anal. Calc'd for C23H32N605S»1.15 TFA* 1.6 H20: C, 45.73; H, 5.51; N, 12.65; S, 4.82; F, 9.86 Found: C, 45.58; N, 5.19; N, 12.41; S, 5.14; F, 10.01 12. (2R-trans)-N-[4-[(Aminoiminomethyl )amino]butyl]-4-methy 1-1- [<X]d=+33.0 (c=1.08 [[(2-naphthalenylsulfonyl)amino]- MeOH) acetyl]-2-piperidinecarboxamide, trifluoroacetate salt, hydrate 10 Anal. Calc'd for C24H34N6O4S»1.35TFA.0.85 H2O: C, 47.73; H, 5.56; N, 12.51; S, 4.77; F, 11.45 Found: C, 47.73; H, 5.51; N, 12.13; S, 4.95; F, 11.42 13. [2R-[l(S*)2a,4p]]-N-[4- [ (Aminoiminomethyl)amino]butyl] - [<X]d=+18.8 (c=1.06 1-[3-hydroxy-2-[(2-naphthalenyl- MeOH) sulfonyl)amino]-1-oxopropyl]-4-methy1-2-piperidinecarboxamide, trifluoroacetate salt, hydrate 20 Anal. Calc'd for C26H38N60sS*1.36TFA*l. 00 H20: C, 47.93; H, 5.79; N, 11.68; S, 4.45; F, 10.77 Found: C, 47.92; H, 5.66; N, 11.53; S, 4.89; F, 10.75 14. [1(S)]-N-[4-[(Aminoimino- methyl)amino]butyl]-1,2,3,4- ta]c=-30.9 (c=0.5, tetrahydro-2-[3-hydroxy-2-[(2- MeOH) naphthalenylsulfonyl)amino]-1-oxopropyl]-3-isoquinoline-carboxamide, isomer A, trifluoroacetate salt, hydrate Anal. Calc'd for C28H34Ns05S*1.25 TFA* 1.0 H20: C, 50.37; H, 5.16; N, 11.56; S, 4.41; F, 9.80 Found: C, 50.31; H, 5.05; N, 11.58; S, 4.44; F, 9.65 260 1 27 HA619b [a]o=-22.8 MeOH) (c=0.6, . [1(S)]-N-[4-[(Amino imino-methyl)amino]buty1]-1,2,3,4- tetrahydro-2-[3-hydroxy-2-[ (2-naphthalenylsulfonyl)amino]-1-oxopropyl] -3-isoquinolinecarbox-amide, isomer B, trifluoroacetate salt, hydrate Anal. Calc'd for C28H34N60sS»1.25 TFA* 1.0 H2O: C, 50.15; H, 5.13; N, 11.47; S, 4.37; F, 10.11 Found; C, 50.04; H, 4.95; N, 11.36; S, 4.51; F, 10.17 [<X]d=-29.0 (c=0.6, MeOH) 16. (4S*) -N- [4- [. (Aminoiminomethyl )amino]butyl]-4-hydroxy-1- tN- (2-naphthalenylsulfonyl)-L-seiyll-L-prolinamide, trifluoroacetate (1:1) salt Anal. Calc'd for C23H32N606S» 1.15 TFA* 1.0 H2O: C, 45.25; H, 5.31; N, 12.51; S, 4.77; F, 9.76 Found: C, 45.28; H, 4.98; N, 12.52; S, 4.86; F, 9.86 [a]D=-24.5 (c=0.6, MeOH) 17. (4S*)-N-[4-[(Aminoiminomethyl) amino] butyl] -4-methoxy-l- [N- (2-naphthalenylsulfonyl)-L-seryl]-L-prolinamide, trifluoroacetate (1:1) salt Anal. Calc'd for C24H34N606S*1.1 TFA* 1.3 H20: C, 46.04; H, 5.56; N, 12.30; S, 4.69; F, 9.17 Found: C, 46.04; H, 5.48; N, 12.16; S, 4.78; F, 9.22 18. N- [4-[(Aminoiminomethyl)-amino]butyl] -1- [N- (2-naphthalenylsulfonyl) -L-phenylalanyl]-l-prolinamide, trifluoroacetate (1:1) salt m.p. 172-178°C with foaming [a]D=-27.0 (c=0.5, CH3OH) 26 0 1 HA619b Anal. Calc'd for C3lH37Ns06F3S*1.2 C2HF3O2-0.80 H20: C, 52.68; H, 5.46; N, 11.74; F, 9.55; S, 4.48 Found: C, 52.71; H, 5.35; N, 11.50; F, 9.33; S, 4.26 19. (2S-trans)-N-[4-I(Aminoiminomethyl) amino] butyl] -4-methyl-1- [<x]d=-36. 4 [[(2-naphthalenylsulfonyl)amino]- (c=0.98, MeOH) acetyl]-2-piperidinecarboxamide Anal. Cald'd for C26H35N606S»0.25TFA«1.20 H2O: 10 C, 47.74; H, 5.69; N, 12.60; F, 10.68; S, 4.81 Found: C, 47.75; H, 5.51; N, 12.62; F, 10.86; S, 4.95 . N-[4-[(Aminoiminomethyl)-amino]butyl]-l-tN-(2-naphthalen- [a]d=-48.1 ylsulfonyl) -L-glutaminyl] -L- (c=0.68, methanol) prolinamide, trifluoroacetate (1:1) salt Anal. Calc'd for C2sH35N705S»1.27 TFA* 1.57 H2O: C, 46.02; H, 5.53; N, 13.64; S, 4.46; F. 10.07 20 Found: C, 46.02; H, 5.18; N, 13.33; S, 4.86; F, 10.06 21. N-[4-[(Aminoiminomethyl)- m.p. 68-78°C amino]butyl]-1-IN-(2-naphthalen- [a]d=-72.6 ylsulfor^l)-L-threonyl]-L-prolin- (c=0.69, methanol) 25 amide, trifluoroacetate (1:1) salt Anal. Calc'd for C24H34N«;05S-1.25 TFA* 1.20 H2O; C, 46.62; H, 5.56; N, 12.31; S, 4.70; F, 10.43 Found: C, 46.75; H, 5.50; N, 12.08; S, 4.82; F, 10.40 22. N-[4-[ (Aminoiminomethyl)- m.p. 85-96°C amino]butyl]-1-[n-(2-naphthalen- [a]o=-70.8 ylsulfonyl)-L-allothreonyl]-L- (c=0.76, methanol) prolinamide, trifluoroacetate (1:1) salt L v \) i 2 HA619b Anal. Calc'd for C24H34N60sS«1.16 TFA-0.97 H2O: C, 47.30; H, 5.59; N, 12.57; S, 4.80; F, 9.89 Found: C, 47.30; H, 5.16; N, 12.39; S, 5.19; F, 9.48 23. (S)-N-[4-t(Aminoiminomethyl)- amino]butyl]-4-(methylthio)-1-IN- [a]n=+13.4 (c=0.6, (2-naphthalenylsulfonyl)glycyl]- MeOH) L-prolinamide, trifluoroacetate (1:1) salt Anal. Calc'd for C23H32N6O5S2»1.10 TFA«1.0 H20: C, 45.58; H, 5.33; N, 12.65; S, 9.44; F, 9.66 Found: C, 45.52; H, 5.11; N, 12.46; S, 9.49; F, 9.65 24. (R)-N-[4-[(Aminoiminomethyl)- amino]butyl]-4-(methylthio)-1-[N- [cx]d=-12.7 (c=0.7, (2-naphthalenylsulfonyl)glycyl] - MeOH) L-prolinamide, trifluoroacetate (1:1) salt Anal, calc'd for C23H32N604S2»1.10 TFA«0.9 H2O: 20 C, 45.70; H, 5.31; N, 12.69; S. 9.47; F, 9.68 Found: C, 45.65; H, 5.09; N, 12.51; S, 9.37; F, 9.74 . N-[4-[(Aminoiminomethyl)-amino]butyl]-1-[[(2-naphthalenyl- sulfonyl)amino]acetyl]-2-piperi-dinecarboxamide High Resolution Mass Spectrum: (M+H)+=489.2287. 2 6 0 1 2 7 HA619b 26. N-[4-[(Aminoiminomethyl)- m.p,100-160°C amino]butyl]-1-[N-(2-naphthalen- foam/dec ylsulfonyl)-D-tryptophyl]-L- [a]p=+44.4 (c=0.5, prolinamide, trifluoroacetate CH3OH) (1:1) salt Anal, calc'd for C3iH37N704S«l .06 C2HF302«1.35 H20: C, 53.12; H, 5.49; N, 13.09; F, 8.07; S, 4.28 Found: C, 53.51; H, 5.35; N, 12.73; F, 8.10; S, 4.28 27. (2S-trans)-N-[4-[(Aminoiminomethyl ) amino] butyl] -4-methyl-l- ta]p=-24.1 (c=0.99 [[[(3-methyl-8-quinolinyl)- MeOH) sulfony1]amino]acetyl]-2-piperi-dinecarboxamide, trifluoroacetate salt Anal. Calc'd for C24H35N704S«1.37TFA*1.00 H2O: C, 46.42; H, 5.59; N, 14.17; F, 11.29; S, 4.63 Found: C, 46.51; H, 5.32; N, 14.06; F, 11.28; S, 4.55 28. N-[4-[(Aminoiminomethyl)-amino] butyl]-1-[[(8-quinolinyl-sulfonyl)amino]acetyl]-2-piper-idinecarboxamide, trifluoroacetate salt Anal. Calc'd for C22H31N7O6S-202^302-2.20 H20: C, 41.21; H, 5.04; N, 12.84; F, 14.93; S, 4.20 Found: C, 41.34; H, 4.69; N, 12.39; F, 14.91; S, 4.55 260 1 2 7 HA619b 29. N-[4-[(Aminoiminomethyl)- amino] butyl ]-l-[N- (2-naphthalen- ta]p= (c=0.60, ylsulfonyl)-D-a-glutamyl]-L- methanol) prolinamide, trifluoroacetate 5 (1:1) salt Anal. Calc'd for C25H34N60«S.1.35 TFA* 1.13 H2O: C, 46.42; H, 5.31; N, 12.16; S, 4.35; F, 10.43 Found: C, 46.42; H, 5.33; N, 11.84; S, 4.6f, F, 10.50 Example 29 N-[4-[(Aminoiminomethyl)amino]butyl]-1-[N-(methyl-sulfonyl)-D-phenylalanyl]-L-prolinamide, trifluoroacetate fl;H salt A. N-[4-[ (Aminoiminomethyl) amino]butyl]-1- D-phenylalanyl-L-prolinamide, trifluoroacetate salt A(l) . N-[4-(Aminobutyl)]-1-[N-[(phenyl-20 methoxy) carbonyl ] -D-phenylalanyl -L- ornl i namidfl. fr-i flunroaffet.at.e The title compound of Example 7, Part B (0.78 g, 1.38 mmol) was dissolved in trifluoroacetic acid (3.2 mL)). After 3 hours the solvent was evaporated 25 and then co-evaporated with hexane/ether five times, and dried 16 hours in vacuo to provide a colorless taffy which was used in the next step.

A(2) . N- [4-[ (Aminoiminomethyl)amino]butyl] -30 1- [N- [ (phenylmethoxy) carbonyl] -D-phenylalanyl- 1,-Tvrol inamlde. trif lnarnarel-ate The Part A(l) compound (0.80 g, 1.38 mmol) was dissolved in absolute ethanol (10.9 mL) and treated with amidinesulfonic acid (0.26 g, 1.5 eg), followed 2 6 0 1 2 7 HA619b by triethylamine (0.58 mL, 3 eq). After stirring for two hours the solvent was evaporated and the crude product purified on reverse phase HPLC to provide a colorless solid (414 mg, 45%).

A(3). N-[4-[(Aminoiminomethyl)amino]butyl]-1-D-phenylalanyl-L-prolinamide, trifluoroacetate salt The title compound of Part A(2) (0.20 g, 0.30 mmol) was dissolved in methanol (1.5 mL) and hydrogenated at 1 atmosphere and room temperature for 3 hours with Pd(OH)2 (40 mg of 20% catalyst). The catalyst was removed by filtration, and the solvent stripped to provide an oil. The oil was dissolved in methanol, acidified with trifluoroacetic acid (0.2 mL) and evaporated to dryness, then dissolved in water and lyophilized to provide the title compound (152 mg).

Optical rotation: = -75.8° (c=0.5, CH3 OH) .

Anal. Calc'd for CigH30N6O2»2.07 C2HF302«0.90 H2O) : C, 44.35; H, 5.45; N, 13.41; F, 18.82 Found: C, 44.52; H, 5.01; N, 13.26; F, 18.52.

B. N-[4-[(Aminoiminomethyl)amino]butyl] -1-[N-(methylsulfonyl)-D-phenylalanyl]-L-prolin-amide. trifluoroacetate (1:1) salt — To a stirred solution of Part A amine (550 mg, 0.80 mmol) in 15 mL of dry CH2CI2 and 15 mL of dry THF under argon was added in order triethylamine (EtaN) (0.44 mL, 3.20 mmol) and methanesulfonyl chloride (68.0 |AL, 0.88 mmol). This turbid mixture was stirred at room temperature for 3 h and diluted 2 6 0 12 7 HA619b with 0.50 mL of water. The mixture was stirred at room temperature for 10 min and concentrated in vacuo. The residue was diluted with 30 mL of methanol, concentrated In vacuo and purified by 5 preparative HPLC. The fractions were concentrated in vacuo and lyophilized to give 300 mg (75%) of title compound.

Opt. rot.: [<X]d= -68.7° (C=1.00, methanol).

Elemental Analysis (%) Calc'd: C, 43.59; H, 5.31; N, 13.09; S, 4.99; F, 14.65 Found: C, 43.59; H, 5.33; N, 13.08; S, 4.80; F, 14.69 Example 3Q N- [ [1- (Aminoiminomethyl) -4-piperidinyl]methyl] -1- [N-(methyl suit onyl) -D-phenYlalanyll -L-prolinamifle A. 4-(Aminomethyl)-N,N'-bis[(1.1-dimethy1-20 ethoxy)carbonyll-l-piperiflinecarboximidamide To a stirred solution of 4-aminomethyl-piperidine (0.72 g, 6.31 mmol) in 40 mL of toluene was added benzaldehyde (0.78 inL, 6.94 mmol). The reaction solution was refluxed for 18 h and water was 25 removed by a Deem Stark trap. The reaction solution was cooled to room temperature at which time bis-Boc amidinopyrazole (1.96 g, 6.31 mmol) was added. The reaction solution was stirred at room temperature for 48 h and concentrated An vacuo. The oily residue was 30 diluted with 15 mL of 1M (ag) KHS04 solution and stirred at room temperature for 5 h. This aqueous solution was washed with ether (2x20 mL) and basified to pH 12 by the addition of IN NaOH solution. This basic solution was then saturated with NaCl and 260 1 2 7 HA619b extracted with dichloromethane (3x60 mL) . The combined dichloromethane extracts were dried (MgS04), filtered and concentrated in vacuo to give 2.10 g (93%) of title amine which was used for the next transformation without further purification.

B. (S*)-N-[[1-[[[(1,1-Dimethylethoxy)-carbonyl]amino][[(1,1-dimethylethoxy)-carbonyl]iminolmethyl]-4-piperidinyl]-methyl]-1-[1-[[(1,1-dimethylethoxy)carbon-Yllamino1-2-phenvlethvll-L-prolinamide To a stirred solution of N-Boc-D-Phe-L-Pro-OH (0.73 g, 2.02 mmol), Part A amine (0.72 g, 2.02 mmol) and 1-hydroxybenzotriazole monohydrate (0.34 g, 2.02 mmol) in 30 mL of DMF was added in order 4-methyl-morpholine (0.66 mL, 6.05 mmol) and ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (0.39 g, 2.02 mmol). The reaction solution was stirred at room tenqperature for 19 h and concentrated under pump vacuum at 45°C. The residue was diluted with 100 mL of saturated NaHC03 solution and extracted with dichloromethane (4x100 mL). The combined dichloromethane extracts were dried (MgS04), filtered and concentrated in vacuo. This was chromatographed on silica gel to give 0.70 g (50%) of title bis-Boc guanidine.

C. N-[[1-(Aminoiminomethyl)-4-piperidinyl]-methyl 1 -1 -P-phenv lalanyl -L -prol inamide To a stirred solution of Part B bis-Boc guanidine (0.68 g, 0.97 mmol) in 6.0 mL of dichloromethane was added trifluoroacetic acid (TFA) (6.00 mL, 77.9 mmol). The reaction solution was stirred at room temperature for 3 h and concentrated in vacuo. 260 12 7 HA619b This was purified by prep HPLC to give 310 mg (45%) of title compound.

D. N-[[1-(Aminoiminomethyl)-4-piperidinyl]-5 methyl] -1- [N- (methylsulfonyl) -D-phenylalanyl] - L-nrnlinamlde To a stirred solution of Part C guanidine (275 mg, 0.68 mmol) in 4.0 mL of dichloromethane and 2.0 mL of THF under argon at 0°C was added Et3N (0.38 mL, 10 2.74 mmol) and methanesulfonyl chloride (69 ML) in order. The reaction mixture was stirred at room temperature for 2.5 h and diluted with 2.0 mL of water. The mixture was concentrated in vacuo, and purified by prep HPLC to give 160 mg (37%) of title 15 compound.

Example 31 N-[[1-(Aminoiminomethyl)-3-piperidinyl]methyl]-1-[N-(methvlsulf onvl \ -D-nhenvlalanvl 1 -I.-nrr>linami A* A. N-Boc-3-hvdroxvmet:hvlplnerldinf» To a stirred solution of 3-hydroxyraethyl-piperidine (15.1 g, 131 mmol) and Et3N (21.9 mL, 158 mmol) in 100 mL of dichloromethane was added dropwise 25 a solution of di-t-butyl dicarbonate (31.5 g, 144 mmol) in 100 mL of dichloromethane over 1 h. The reaction was stirred at room temperature for 18 h and then diluted with 200 mL of dichloromethane. The resulting solution was washed with IN HCl solution 30 (3x100 mL), saturated NaHC03 solution (2x100 mL) and brine (1x100 mL). The organic layer was dried (MgS04), filtered and concentrated in vacuo to give N-Boc-3-hydroxymethylpiperidine (27.0 g, 96%). 260 127 HA619b B. 3-(Azidomethyl)-1-piperidinecarboxylic acid, ll-dlmethvlafchvl ester To a stirred solution of Part A N-Boc-3-hydroxymethylpiperidine (27.0 g, 126 mmol) in 150 mL 5 of dry dichloromethane under argon at 0°C was added in order triethylamine (22.7 mL, 163 mmol) and methanesulfonyl chloride (11.7 mL, 151 mmol). The reaction was stirred at room temperature for 1.5 h and diluted with 450 mL of dichloromethane. The 10 reaction was washed with 0°C IN HCl solution (2x100 mL) and brine (1x100 mL). The dichloromethane layer was dried (Na2S04), filtered and concentrated in vacuo - The residue was dissolved in 200 mL of DMF and combined with sodium azide (24.5 g, 377 mmol). IS The mixture was stirred at room temperature for 33 h and the solid was filtered off. The filtrate was concentrated under pump vacuum at 45°C. The residue was partitioned between 400 mL of EtOAc and 10% sodium thiosulfate solution (2x100 mL) and brine 20 (1x100 mL). The EtOAc layer was dried (MgS04), filtered and concentrated in vacuo. Purification was effected by a flash column chromatography on silica gel to give 19.5 g (65%) of title azide.

C. 3-(Aminomethyl)-1-piperidinecarboxylic acid. 1.1-dimethylethYl ester To a stirred solution of Part B azide (19.0g, 79.2 mmol) in 250 mL of methanol under argon was added 10%Pd/C (3.80 g, 20% based on the weight of 30 Part B azide). The atmosphere was replaced with hydrogen by several vacuum-fill cycles. The mixture was. stirred at room temperature for 15 h. The catalyst was filtered through a 4pM polycarbonate film and rinsed with methanol (4x30 mL). The 26 0 127 HA619b filtrate was concentrated in vacuo to give 16.3 g (96%) of title amine.

D. N-[[1-[(1,1-Dimethylethoxy)carbonyl]-3-5 piperidinyl]methyl]-1-[N-[(phenylmethoxy)- carhonvll-P-phenvlalanv]1-L-prolinamide To a stirred solution of Part C amine (2.00 g, 9,35 mmol), N-Cbz-D-Phe-L-Pro (3.70 g, 9.35 mmol), 1-hydroxybenzotriazole monohydrate (1.58 g, 9.35 mmol) 10 and 4-methylmorpholine (3.07 mL, 28.0 mmol) was added ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride (1.79 g, 9.35 mmol). The reaction solution was stirred at room temperature for 17 h and concentrated under pump vacuum at 45°C. The residue IS was dissolved in 360 mL of EtOAc and washed with IN HCl solution (2x120 mL), saturated NaHC03 solution (1x120 mli) and brine (1x120 mL) . The EtOAc layer was dried (MgS04), filtered, concentrated An vacuo and chromatographed on silica gel to give 1.30g (23%) of 20 title carbamate.

E. N-t[1-(Aminoiminometh' * *-3-piperidinyl]-methyl]-1-[N-[(phenylmethoxy)carbonyl]-D-phenvlalanYll-L-prQli.namj.de To a stirred solution of Part D carbamate (2.30 g, 3.89 mmol) in 10 mL of dry dichloromethane was added 0°C 4N HCl in dioxane (15.0 mL, 60.0 mmol). The solution was stirred at room temperature for 3 h and diluted with 300 mL of ether. The precipitate 30 was filtered off and rinsed with ether (3x30 mL). The precipitate was dried under pump vacuum at room temperature and purified by prep HPLC to give 1.39 g (59%) of intermediate amine*TFA salt. To a stirred solution of the intermediate amine*TFA salt (500 mg, 260 127 HA619b 0.83 mmol) and diisopropylethyl amine (0.35 mL, 1.98 mmol) in 2.0 mL of DMF w?s added lH-pyrazole-1-carboxamidine (133 mg, 0.91 mmol). The reaction solution was stirred at room temperature for 6 h and S diluted with 100 mL of ether. The desired oily precipitate was separated from the ether solution and purified by prep HPLC to give 250 mg (47%) of title Cbz-carbamate.

F. N-[[1-(Aminoiminomethyl)-3-piperidinyl]- methv11-1-D-Phenvlalanvl-L-orolinamide To a stirred solution of Part E Cbz-carbamate (240 mg, 0.37 mmol) in 10 mL of methanol under argon was added 20%Pd(OH)2/C (48 mg, 20% based on the IS weight of Part E Cbz-carbamate). The atmosphere was replaced with hydrogen by several vacuum-fill cycles. The reaction mixture was stirred at room temperature for 24 h. The catalyst was filtered off and rinsed with methanol (4x20 mL). The filtrate was 20 concentrated in vacuo. The residue was dissolved in 50 mL of a solution of 0.1%TFA in water and lyophilized to give 220 mg (82%) of title compound.

G. N-[[1-(Aminoiminomethyl)-3-piperidinyl]-25 methyl]-1-[N-(methylsulfonyl)-D-phenylalanyl]-T-nrr>1 inamide Following the procedure of Example 30 Part D except substituting the Part F amidine for the Example 30 Part C amidine, the title compound is 30 obtained. r-. 127 HA619b 70 - Example .12 N- [ [1- (Aminoiminomethyl) -4-piperidinyl]methyl] -1- [N-t (phenylmethyl) sulfonyl] -D-alanyl] -L-prolinamide, trifluoroacetate (1;1) salt ; A. N- [ t (Phenylmethoxy) -carbonyl] -D-alanyl] -L- proline methyl ester To a solution of N-CBZ-D-alanine (28.1 g, 0.149 mol) in DMF (250 mL) at 0°C, was added L-10 proline-methylester.HCl (24.6 g, 0.149 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine ( 22.6 g, 0.224 mmol). The reaction mixture was stirred for 12 IS h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (750 mL) and extracted with ethyl acetate (2x150 mL). The combined organic extracts were washed as follows: KHSO4 (0.25 M, 2x50 mL), water 20 (1x50 mL), saturated aqueous NaHC03 (2x50 mL) and saturated NaCl (1x50 mL). The organic layer was dried over MgS04, filtered and the solvent removed in vacuo to give the title compound, 41.16 g (92%), as an oil. MS (M+H) += 301+.

B. N- [ t [ (Phenylmethyl) sul fony 1 ] carbonyl ] -D-alam/11 -L-nrnline mefchvl Mter A solution of Part A compound (1.56 g, 5.2 mmol) in trifluoroacetic acid (3 mL) was stirred at 30 0°C for 1.5 hr and and concentrated in vacuo to give the corresponding TFA salt. This salt was dissolved in chloroform (10 mL), and triethylamine (2.2 mL, 15.6 mmol) and benzylsulfonyl chloride (1.48, 7.8 mmol) at 0°C were added to it. The reaction mixture 2 6 0 12 7 HA619b was stirred to room temperature overnight. After 25 h, the reaction mixture was poured into EtOAc (50 mL), washed with 0.25 M aqueous khso4 (2x20 mL) , H20 (1x20 mL) and saturated aqueous NaHC03 (2x20 mL), 5 successively; dried over MgS04, filtered and concentrated in vacuo to give title compound as an oil (1.56 g, 85%): MS (M + H)+ = 355+.

C. N-[[[(Phenylmethyl)sulfonyl]carbonyl]-D-10 alanvll-L-proline To a solution of Part B compound (1.33 g, 3.75 mmole) in THF (10 mL) at 0°C was added aqueous NaOH (1.0 N, 9.5 mL). After 30 min the reaction mixture was warmed to room temperature and stirring continued 15 for an additional 4 h. The organic solvent was removed in vacuo. The aqueous layer was acidified to pH of 2-3 and extracted with ethyl acetate (3x10 mL). The combined extracts were dried over MgS04, filtered and the solvent removed in vacuo to give title 20 compound, 1.21 g (94%), as a white solid.

MS (M+H) += 341+ .

D. N-[[[1-(1,1-Dimethylethoxy)carbonyl]- 4-piperidinyl]methyl]-1-[N-[(phenylmethyl)-25 gulfonvll -D-alanYn-L-prQli.nami.de To a solution of Part C compound (1.09 g, 3.2 mmol) in DMF (15 mL) at 0°C were added N-1,1-[ (dimethylethoxy)carboxyl]-4-methylaminopiperidine (prepared in Example 33 Part A) (0.685 g, 3.2 mmol), 30 1-hydroxybenzotriazole hydrate (0.476 g, 3.5 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (0.675 g, 3.5 mmol) and 4-methylmorpholine untill basic by pH paper. The reaction mixture was stirred for 12 h while allowing the reaction to warm to room L o 0 7 2 7 HA619b temperature. The reaction mixture was poured into 0.25 M aqueous KHSO4 (50 mL) and extracted with EtOAc (2x20 mL) . The organic layers were combined and washed with 0.25 M aqueous KHSO4 (1x30 mL), water (1x25 mL), saturated aqueous NaHC03 (2x25 mL) and water (1x20 mL). The organic layer was dried over MgS04, filtered and the solvent removed An vacuo to give title compound, 1.67 g (9%), as an oil.

MS (M+ H) += 537+.

E. N-1 [1- (Aminoiminomethyl) -4-piperidinyl] -methyl]-1- IN-[(phenylmethyl)sulfonyl]-D-alanyl]-L-prolinamide, trifluoroacetate <1;1) salt IS A solution of Part D compound (1.17 g, 2. 2 mmol) in trifluoroacetic acid (10.0 mL) was stirred at 0°c for 5 h. The reaction mixture was concentrated An vacuo to give the corresponding TFA salt. To a solution of this salt (2.2 mmol), 1H-20 pyrazole-l-carboxamidine hydrochloride (0.474 g, 3.3 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.5 mmol) in EMF (3.0 mL) were added and stirred for 3 days. The reaction mixture was concentrated An vacuo and purified by preparative HPLC (CH3CN/H2O with TFA 25 buffer using a C-18 silica gel column) . The appropriate fractions were combined, concentrated in vacuo, dissolved in H2O and lyophilized to yield title compound (0.486 g, 38 %) as a white solid: [a]p = +1.4 (c 1.0, MeOH) MS (M + H)+ = 479+ < T 26 0 12 7 HA619b Anal. Calc'd for C23H34N6O4S • 1.3 TFA • 0.7 H20: C, 45.21; H, 5.78; N, 13.14; S, 5.01; F, 11.59 Found: C, 46.42; H, 5,83; N, 12.88; S, 4.97; F, 11.82 N- [ II- (Aminoiminomethyl) -4-piperidinyl]methyl] -1- [N-[ (2,2,2-trifluoroethyl) sulfonyl] -D-phenylalanyl]-L- prolinamidR. nrifluoroacetate (1;1) salt.

A. N-l,l-[ (Dimethylethoxy) carbonyl]-4-mpfhvl ami im ninpririjr»> Benzaldehyde (14.j g, 0.138 mmol), 4-(aminomethyl)-piperdine (14.29 g, 0.125 mmol) and toluene (250 mL) were combined and heated at reflux 15 for 4.5 h with removal of water. The reaction mixture was cooled to -25°C and di-t-butyl dicarbonate (28.7 g, 0.131) was added. The reaction mixture was allowed to warm to room temperature and stirred an additional 8 h. To this reaction mixture 20 was added aqueous KHSO4 (1.0 M, 120 mL) and stirred for 3 h. The organic layer was removed and the remaining aqueous layer was extracted with ether (3x75 mL) . The aqueous layer was made basic through the addition of aqueous NaOH (1.0 M, 130 mL) and 25 extracted with ether (3x75 mL) . The combined organic extracts were dried over NaS04 filtered, and the solvent removed in vacuo to give title compound, 24.4 g (9 %), as a white solid.

B. N— £ t (Phenylmethoxy) - carbonyl ] -D-phenyl - alanyll-L-proline methyl eater To a solution of N-CBZ-D-phenylalanine (47.3 g, 0.158 mmol) in DMF (300 mL) at 0°C, was added L-proline-methylester.HCl (25.0 g, 0.151 mmol), 1- 260 12 HA619b hydroxybenzotriazole hydrate (20.28 g, 0.166 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.8 g, 0.166 mmol) and 4-methylmorpholine (16.0 g, 0.159 mmol). The reaction mixture was stirred for 0 5 h while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (1.2 L) and extracted with ethyl acetate (3x300 mL). The combined organic extracts were washed as follows: KHSO4 (0.25 M, 2x200 mL), water (1x200 mL), 10 saturated aqueous NaHC03 (2x200 mL) and saturated NaCl (1x200 mL). The organic layer was dried over MgS04, filtered and the solvent removed in vacuo to give title compound, 60.9 g (98%), as an oil. MS (M+ H) += 411+.

C. N-[t(Phenylmethoxy)-carbonyl]-D-phenyl- alanyll-L-proline To a solution of Part B compound (57.8 g, 0.141 mol) in MeOH (180 mL) and THF (60 mL) at 0°C 20 was added aqueous NaOH (1.0 N, 183 mL) . After 30 min the reaction mixture was warmed to room temperature and stirring continued for an additional 4 h.

Aqueous HCl (1.0 N, 42 mL) was added and the organic solvents removed An vacuo. The resulting aqueous 25 layer was acidified to pH of 2-3 and extracted with ethyl acetate (2x300 mL). The combined extracts were dried over MgSO*, filtered and the solvent removed in vacuo to give title compound, 45.53 g (97 %), as a white solid. MS (M+H)+= 397+. 26 0 127' HA619b D. N-[ [[1-(1,1-Dimethylethoxy)carbonyl]-4-piperidinyl]methyl] -1- [N- [ (phenylmethoxy) - carbonv!-D-phenvlalanvl1-L-nrolinamidP To a solution of Part C compound (19.39 g, 5 4a.90 mmol) in DMF (120 mL) at 0°C, was added Part A compound (9.98 g, 46.57 mmol), 1-hydroxybenzotriazole hydrate (6.26 g, 51.23 mmol) and ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (9.82 g, 51.23 mmol). The reaction mixture was stirred for 12 h 10 while allowing the reaction to warm to room temperature. The reaction mixture was poured in water (500 mL) and extracted with ethyl acetate (3x100 mL). The combined organic extracts were washed as follows: KHSO4 (0.25 M, 2x50 mL) , water 15 (1x75 mL), saturated aqueous NaHCC>3 (2x75 mL) and saturated NaCl (1x50 mL). The organic layer was dried over MgSC>4, filtered and the solvent removed in vacuo to give title compound, 23.4 g (85 %), as an oil. MS (M+ H) += 593+.

E. N- [[[ [1- (1,1-Dimethylethoxy) carbonyl] -4-piperidinyl]methyl]-1-D-phenylalanyl]-L- prolinamide To a stirred solution of Part D compound 25 (15.00 g, 25.3 mmol) in MeOH (150 mL) was added Pd/C (1.50 g) and the reaction mixture was placed under 1 atmosphere of hydrogen. An additional Pd/C (2.5 g) was added after stirring for 2 h. The reaction was complete after stirring 8 more hours. The reaction 30 mixture was filtered and the solvent removed in vacuo to give title compound, 11.41 g (91%), as a white solid. MS (M+H)+ = 459+. » 1 260i27 HA619b F. N-[[[1-(1#1-Dimethylethoxy)carbonyl]-4-piperidinyl]methyl]-l-[N-[(2,2,2-trifluoro-ethvl) aulfonvll -D-ohenvlalanvl 1 -L-prol Inamtde To a solution of Part E compound (1.71 g, 3.5 5 mmol) and txiethylamine (2.5 mL, 17.9 mmol) in chloroform (10 mL) at 0°C under argon was added trifluoroethylsulfonyl chloride (0.5 mL, 4.5 mmol). The reaction mixture was stirred to room temperature overnight. After 24 hr, triethylamine (2.0 mL, 14.3 10 mmol) and trifluoroethylsulfonyl chloride (0.5 mL, 4.5 mmol) were added at 0°C. The ice-water bath was removed, emd the reaction was stirred for 6 h. The mixture was diluted with 0.25 M aqueous khso4 and EtOAc. After separaton of the two layers, the IS organic layer was washed with 0.25 M aqueous khso4, H20, saturated aqueous NaHC03, and H20, successively; dried over NaS04, filtered and concentrated in vacuo to give title compound, (1.60 g, 75 %): MS (M + H)+ = 605+.

G. N- [ [ 1 - (Aminoiminomethyl) - 4 -piperidinyl ] -methyl]-1-[N-[(2,2,2-trifluoroethyl)sulfonyl]-D-phenylalanyl] -L-prolinamide, trifluoroacetate (1;1) salt To a solution of Part F compound (1.60 g, 2.6 mmol) in dichloromethane (4.4 mL) at 0°C under argon was added trifluoroacetic acid (3.0 mL, 38.9 mmol). After 5.5 h, the reaction mixture was concentrated in vacuo to give the corresponding TFA salt. To a 30 solution of this salt (1.3 mmol) and lH-pyrazole-1-carboxamidine hydrochloride (0.311 g, 2.1 mmol) in DMF (1.3 mL) under argon was added N,N-diisopropyl-ethylamine (0.7 mL, 4.0 mmol). After 2 days, 1H-pyrazole-l-carboxamidine hydrochloride (0.150 g, 1.0 * t HA619b 26 0 mmol) and N,N-diisopropylethy lamine (0.5 mL, 2.9 mmol) were added. After 1 day, lH-pyrazole-1-carboxamidine hydrochloride (0.150 g, 1.0 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.9 mmol) were 5 added. After 2 days, the reaction mixture was concentrated in vacuo and purified by preparative HPLC (ch3cn/h2o with TFA buffer using a C-18 silica gel column). The appropriate fractions were combined, concentrated in vacuo. dissolved in H2O and 10 lyophilized to yield title compound (0.256 g, 29 %) as a white solid: [a]D = -56.0 (c 0.50, MeOH) MS (M + H)+ = 547+ Anal. Calc'd for C23H33N6O4SF3 • 1.22 TFA • 1.14 H20: C, 43.26; H, 5.21; N, 11.90; S, 4.54; F, 17.92 Found: C, 42.82; H, 4.87; N, 11.48; S, 4.98; F, 17.52 Example 34 N- [ (1- (Aminoiminomethyl) -4-piperidinyl]methyl] -1- [N-[(phenylmethyl)sulfonyl]-L-alanyl]-L-prolinamide, triflnoynacetal-e (1;11 salt A. N-[[(t-Butoxy)-carbonyl]-L-alanyl]-L-nrnline methyl eater To a solution of N-BOC-L-alanine (150 mmol) in DMF (250 mL) at 0°C, is added proline methyl 30 ester.HCl (150 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine (22.6 g, 0.224 mmol). The reaction mixture is stirred for 12 h while allowing the ? E ? imt W %J HA619b reaction to warm to room temperature. The reaction mixture is poured in water (750 mL) and extracted with ethyl acetate (2x150 mL). The combined organic extracts are washed as follows: KKSO4 (0.25 M, 2x50 5 mL), water (1x50 mL), saturated aqueous NaHC03 (2x50 mL) and saturated NaCl (1x50 mL). The organic layer is dried over MgSO*, filtered and the solvent removed in vacuo to give title compound.

B. jtf-[[(Phenylmethyl>sulfonyl]carbonyl]-L-alanvll-L-proline methyl ester A solution of Part A compound (5.2 mmol) in trifluoroacetic acid (3 mL) is stirred at 0°C for 1.5 hr and and concentrated in vacuo to give the IS corresponding TFA salt. This salt is dissolved in chloroform (10 j0L), and triethylamine (2.2 mL, 15.6 mmol) and benzylsulfonyl chloride (1.48, 7.8 mmol) at 0°C are added to it. The reaction mixture is stirred to room temperature overnight. After 25 h, the 20 reaction mixture is poured into EtOAc (50 mu), washed with 0.25 M aqueous KHS04 (2x20 mL), H2O (1x20 mL) and saturated aqueous NaHC03 (2x20 mL), successively; dried over MgS04, filtered and concentrated in vacuo to give title compound.

C. N- [ [ (Phenylmethyl) sulfonyl] carbonyl] -L-alanvll-L-proline To a solution of Part B compound (3.75 mmole) in THF (10 mL) at 0°C is added aqueous NaOH (1.0 N, 30 9.5 mL). After 30 min the reaction mixture is warmed to room temperature and stirring continued for an additional 4 h. The organic solvent is removed in vacuo, the aqueous layer acidified to pH of 2-3 and extracted with ethyl acetate (3x10 mL). The combined VwOTES. ■i^ny ■ 26 0 1 HA619b extracts are dried over MgSC>4, filtered and the solvent removed in vacuo to give title compound.

D. N-[[[1-(1,1-Dimethylethoxy)carbonyl]-4-5 piperidinyl]methyl] -1- IN-1 (phenylmethyl) - aulfonvll -T.-a3anvil -L-pro linamidg To a solution of Part C compound (3.2 mmol) in EMF (15 mL) at 0°C is added Nl-B0C-4-methylamino piperidine (3.2 mmol), 1-hydroxybenzotriazole hydrate 10 (0.476 g, 3.5 mmol), ethyl-3-(3 -dimethylamino) -propyl carbodiimide.HCl (0.675 g, 3.5 mmol) and 4-methyl-morpholine until basic by PH paper. The reaction mixture is stirred for 12 h while allowing the reaction to warm to room temperature. The reaction IS mixture is poured into 0.25 M aqueous KHSO4 (50 mL) and extracted with EtOAc (2x20 mL). The organic layers are combined and washed with 0.25 M aqueous KHSO4 (1x30 mL), water (1x25 mL), saturated aqueous NaHCC>3 (2x25 mL) and water (1x20 mL), the organic 20 layer dried over MgSOj, filtered and the solvent removed in vacuo to give title compound.

E. N- [ [1- (Aminoiminomethyl) -4-piperidinyl] -methyl]-1-[N-I(phenylmethyl)sulfonyl]-L-25 alanyl]-L-prolinamide, trifluoroacetate (1:1) sail A solution of Part D compound (2. 2 mmol) in trifluoroacetic acid (10.0 mL) is stirred at 0°C for 5 h. The reaction mixture is concentrated in vacuo 30 to give the corresponding TFA salt. To a solution of this salt (2.2 mmol), lH-pyrazole-l-carboxamidine hydrochloride (0.474 g, 3.3 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.5 mmol) in DMF (3.0 mL) are added and stirred for 3 days. The reaction *0Q 127 HA619b mixture is concentrated In vacuo and purified by preparative HPLC (CH3CN/H2O with TFA buffer using a C-18 silica gel column). The appropriate fractions are combined, concentrated In vacuo, dissolved in H2O and lyophilized to yield title compound.

Example 3 5 N-1 [1- (Aminoiminomethyl) -4-piperidinyl]methyl] -1- [N-t (phenylmethyl)sulfonyl] -glycyl] -L-prolinamide, trifluoroacetate (hi) salt A. N-[[(t-Butoxy)-carbonyl]-glycyl]-L-proline methyl ester To a solution of N-BOC-glycine (150 mmol) in DMF (250 mL) at 0°C, is added proline methyl ester.HCl (150 mmol), 1-hydroxybenzotriazole hydrate (22.2 g, 0.164 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (31.4 g, 0.164 mmol) and 4-methylmorpholine ( 22.6 g, 0.224 mmol). The reaction mixture is stirred for 12 h while allowing the reaction to warm to room temperature. The reaction mixture is poured in water (750 mL) and extracted with ethyl acetate (2x150 mL). The combined organic extracts are washed as follows: KHSO4 (0.25 M, 2x50 mL), water (1x50 mL), saturated aqueous NaHC03 (2x50 mL) and saturated NaCl (1x50 mL). The organic layer is dried over MgS04, filtered and the solvent removed in vacuo to give title compound.

B. N- U[(Phenylmethyl)sulfonyl]carbonyl]-alvcvll -L-proline methvl eater A solution of Part A compound (5.2 mmol) in trifluoroacetic acid (3 mL) is stirred at 0°C for 1.5 hr and and concentrated in vacuo to give the 26Q 12T HA619b corresponding TFA salt. This salt is dissolved in chloroform (10 mL), and triethylamine (2.2 mL, 15.6 mmol) and benzylsulfonyl chloride (1.48, 7.8 mmol) at 0°C are added to it. The reaction mixture is stirred to room temperature overnight. After 25 h, the reaction mixture is poured into EtOAc (50 mL), washed with 0.25 M aqueous khso4 (2x20 mL), H2O (1x20 mL) and saturated aqueous NaHC03 (2x20 mL), successively; dried over MgS04, filtered and concentrated in vacuo to give title compound.

C. N-[[[(Phenylmethyl)sulfony1)carbonyl]- qlYCYll-L-proline To a solution of Part B compound (3.75 mmole) in THF (10 mL) at 0°C is added aqueous NaOH (1.0 N, 9.5 mL) . After 30 min the reaction mixture is warmed to room temperature and stirring continued for an additional 4 h. The organic solvent is removed in vacuo, the aqueous layer acidified to pH of 2-3 and extracted with ethyl acetate (3x10 mL). The combined extracts are dried over MgSOi, filtered and the solvent removed in vacuo to give title compound.

D. N- [ [ 11- (1,1 -Dimethylethoxy) carbonyl3.-4-piperidiny 1 ]methyl] -1- [N- [ (phenylmethyl) - sulfonyl1-glycyll-L-prolinamide To a solution of Part C compound (3.2 mmol) in DMF (15 mL) at 0°C is added N1-BOC-4-methylamino piperidine (3.2 mmol), 1-hydroxybenzotriazole hydrate (0.476 g, 3.5 mmol), ethyl-3-(3-dimethylamino)-propyl carbodiimide.HCl (0.675 g, 3.5 mmol) and 4-methyl-morpholine until basic by pH paper. The reaction mixture is stirred for 12 h while allowing the reaction to warm to room temperature. The reaction 26 0 1 HA619b mixture is poured into 0.25 m aqueous khso4 (50 mL) and extracted with EtOAc (2x20 mL). The organic layers are combined and vashed with 0.25 m aqueous khso4 (1x30 mL), water (1x25 mL), saturated aqueous 5 NaHC03 (2x25 mL) and water (1x20 mL), the organic layer dried over MgSO*, filtered and the solvent removed in vacuo to give title compound.

E. N-[[1-(Aminoiminomethyl]-4-piperidinyl]-10 methyl] -1- [N-1 (phenylmethyl) sulfonyl] - glycyl]-L-prolinamide, trifluoroacetate (1:1) salt ; A solution of Part D compound (2. 2 mmol) in trifluoroacetic acid (10.0 mL) is stirred at 0°C for IS 5 h. The reaction mixture is concentrated in vacuo to give the corresponding TFA salt. To a solution of this salt (2.2 mmol), lH-pyrazole-l-carboxamidine hydrochloride (0.474 g, 3.3 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.5 mmol) in DMF (3.0 20 mL) are added and stirred for 3 days. The reaction mixture is concentrated in vacuo and purified by preparative HPLC (ch3cn/h2o with TFA buffer using a C-18 silica gel column). The appropriate fractions are combined, concentrated in vacuo. dissolved in H2O 25 and lyophilized to yield title compound.

Following the procedures of Example 30 to 33, the following examples of compounds of the invention may be prepared. 260 12 7 HA619b B B B < ■< -< 2- 5 & o o v\" . o=i I MU-K I MM osaso I n o M O n m v n H O O M O n H O Ml M <• U <1 M U l e ■ M U H » • \v o v a » n • • Ma. ^3 & R2 &1 V -CH]C|Bj(8) 4 0 VH*^ -CH2CB3COHH2(S) H H a 41 CCHS -CB2CB3COMB3(lt) H CH3 A- 42 \=/ -CH(OH)CH3(S-Thr) -CBCB3CB3CB H O M. CH(OH)CH3(3-«lloThr) CH3 H -X* W v 44 ^ *—* SCB3 CB3 OCT 4 5 H ^ -CB3CBaC03B(R) B CH3 (V •H CO \ 7 y -CB3HB3 - J& rr CO -CBaHBa . isT HH m, —XH- m 00 «i o- -J* HH, .hh CO I "H, ro ? o> «o _>OT s ^ —< cr O ro MQ &3 A 4 6 CaH5 CH2OCH2Fh(X) 47 CSH5CH2 CH2CHaPh(S) 4* OCX -X!. -< MH -< MH, MH J- VHH, 00 ui cn M vo tr %7t o> o f\s *s| 260 12 7 HA619b Example 49 N- [ [ 1- (Aminoiminomethyl) -4-piperidinyl]methyl] -1- [N-(ethylsulfonyl) -D-phenylalanyl] -L-prolinamide, trifhinroarshafP (1:1) salt [a]o= -49.2 (c 1.08, MeOH) MS (M + H)+=493+ Anal. Calc'd for C23H36N6O4S • 1.4 TFA • 1.0 H20: C, 46.23; H, 5.92; N, 12.54; S, 4.78; F, 11.90 Foudn: C, 46.23; H, 6.08; N, 12.39; S, 4.71; F, 11.98 Example 50 N- [ [1- (Aminoiminomethyl) -4-piperidinyl]methyl] -1- [N-(propyl sulfonyl) -D-phenylalanyl ] -L-prolinamide, trifluoroacetate (1:1) salt [a]D= -47.0 (c 1.02, MeOH) MS (M + H) +=507+ Anal. Calc'd for C24H38N6O4S • 1.15 TFA • 1.2 H2O: C, 47.91; H, 6.35; N, 12.74; S, 4.86; F, 9.94 25 Found: C, 47.90; H, 6.21; N, 12.50; S, 4.82; F, 10.06 F.xamnlfl 5,1 N- [ [1- (Aminoiminomethyl)-4-piperidinyl]methyl] -1- [N-[(phenylmethyl)sulfonyl]-d-phenylalanyl]-L-30 prolinamide. frifluoroacetate (1:1) salt [o]d= -44.6 (c 0.8, MeOH) MS (M + H) +=555+ 260 127 HA619b Anal. Calc'd for C28H38N6O4S • 1.55 TFA • 0.67 H20: C, 50.31; H, 5.42; N, 11.32; S, 4.32; F, 11.90 Found: C, 50.31; H, 5.69; N» 11.24; S, 4.26; F, 11.97 N-t[1-(Aminoiminomethyl)-4-piperidinyl]methyl]-1-[N-(phenylsulfonyl)-D-phenylalanyl]-L-prolinamide, fcrlfluoroacet-afce (1;1) salt [a]D= +10.1 (C 1.0, MeOH) MS (M + H)+=541+ Anal. Calc'd for C27H36N6O4S • 1.3 TFA • 0.83 H2O: C, 50,51; H, 5.58; N, 11.94; S, 4.55; F, 10.53 Found: C, 50.51; H, 5.47; N, 11.83; S, 4.71; F, 10.52 Example 51 N-[[1-(Aminoiminomethyl)-4-piperidinyl]methyl]-1-[N-[(1-methylethyl)sulfonyl]-D-phenylalanyl]-L-prolinamide. trifiuoroacetate (2:3) salt. [a]D= -43.1 (c 1.10, MeOH) MS (M + H) +=507+ Anal. Calc'd for C24H38N6O4S • 1.5 TFA • 1.35 H2O: C, 46.20; H, 6.06; N, 11.97; S, 4.57; F, 12.18 30 Found: C, 46.61; H, 5.86; N, 11.95; S, 4.44; F, 12.02 260127

Claims (15)

WHAT WE CLAIM IS:

1. A compound having the structure o o : II b h II - R»—8—M— C«—C—V II I O X a including all stereoisomers, wherein n is 0, 1 or 2; G is an amido moiety which is I OSSC I I I MH OSC L, L ' <CHa)« or (CHa) p CHa Q \ I 1 | *4 syi MH (oi) <«) P. is hydrogen, hydroxyalkyl, aminoalkyl, alkyl, cycloalkyl, aryl, arylalkyl, alkenyl, alkynyl, amidoalkyl, arylalkoxyalkyl or an amino acid side chain, either protected or unprotected; R1 and R2 are independently hydrogen, lower alkyl, cycloalkyl, aryl, hydroxy, alkoxy, keto, thioketal, thioalkyl, thioaryl, amino or alkylamino; or R1 and R2 together with the carbons to which they are attached form a cycloalkyl, aryl or heteroaryl ring; R3 is lower alkyl, arylalkyl, aryl, heteroaryl, quinolinyl or tetrahydroquinolinyl; m is 0, 1, 2 or 3; Y is NH or S; - 89 - 10 26 0127 p is 0, 1 or 2; Q is a single bond or I csso I A is arylene or cycloalkylene or an azacycloalkylene ring of 3 to 7 carbons in the ring or an azaheteroalkylene ring of 4 to 6 carbons in the ring of the structure 15 where R4 is attached to a nitrogen atom; X is CH2, 0, S or NH; q is 0, 1 , 2, 3 or 4, provided that q is 0, 1 , 2, 3 or 4 if X is CH2; 20 q is 2, 3 or 4 if X is 0, S or NH; and Y1 and Y2 are independently H, lower alkyl, halo or keto; R4 is guanidino, amidino or aminomethyl, with the provisos that R4 is guanidino, amidino or 25 aminomethyl when A is arylene or cycloalkylene and R4 is amidino when A is azacycloalkylene or azaheteroalkylene; provided that where A is azaheteroalkylene, then there must be at least a 2-carbon chain between the 30 hetero atom X and any N atom in the ring or outside the ring; and provided that where G is G1, then if R3 is alkyl, the alkyl must contain at least 3 carbons; including pharmaceutically acceptable salts 35 thereof.

2. The compound as defined in Claim 1 wh G is an amido moiety of the structure - 90 - 260127 10 i ossc I MH (CHa)p Q i J, wherein p is 0, 1 or 2; Q is a single bond or I csso I A is arylene or cycloalkylene or an azacycloalkylene ring of 3 to 7 carbons in the ring or 15 an azaheteroalkylene ring of 4 to 6 carbons in the ring of the structure 20 where R4 is attached to a nitrogen atom; X is CH2, O, S or NH; 25 q is 0, 1, 2, 3 or 4, provided that q is 0, 1 , 2, 3 or 4 if X is CH;.; q is 2, 3 or 4 if X is O, S or NH; and Y1 and Y2 are independently H, lower alkyl, halo or keto; 30 R4 is guanidino, amidino or aminomethyl, with the provisos that R4 is guanidino, amidino or amino: ;ethyl when A is arylene or cycloalkylene and R4 is amidino when A is azacycloalkylene or azaheteroalkylene; 35 20 25 - 91 - 2601 provided that where A is azaheteroalkylene, then there must be at least a 2-carbon chain between the hetero atom X and any N atom in the ring or outside the ring.

3. The compound as defined in Claim 2 wherein A is arylene or cycloalkylene, Q is a single bond and q is 0 or 1.

4. The compound as defined in Claim 2 wherein A is ^.x 10 I (CHa), > *■/ I \ (CH

5. The compound as defined in Claim 4 wherein 15 X is CH2 or NH and Y1 and Y2 are each H.

6. The compound as defined in Claim 5 wherein G is ossc I MH (CHj) p y+v H HaH'-'^MH 30 g is 0 or 1, R1 and R2 are or aryl, n is 0 or 1 hydroxyalky1. each H, R3 is alJq^l, arylalkyl and R is aralkyl or 35 10 15 20 25 30 - 92 - 26

7. The compound as defined in Claim 2 which is N- [ [1- (aminoiminomethyl)-4-piperidinyl]methyl] -1- {N-fmethylsulfonyl) -D-phenylalanyl] -L-prolinamide or a salt thereof; N- [ [1- (aminoiminomethyl) -3-piperidinyl] -methyl] -1- [N- (methyl sulf onyl) -D-phenylalanyl] -L-prolinamide or a salt thereof; N-1 H- (aminoiminomethyl) -4-piperidinyl] -methyl] -1- [N- [ (phenylmethyl) sulfonyl] -D-alanyl] -L-prolinamide, or a salt thereof; N- [ 11- (aminoiminomethyl) -4-piperidinyl] -methyl]-1-[N- [(2,2,2-trifluoroethyl)sulfonyl]-D-phenylalanyl ] -L-prolinamide, or a salt thereof ; N- [ [1- (aminoiminomethyl) -4-piperidinyl] -methyl] -1- [N-[ (phenylmethyl) sulfonyl] -L-alanyl] -L-prolinamide, or a salt thereof ; N- [ [1- (aminoiminomethyl) -4-piperidinyl] -methyl] -1- (N- [ (phenylmethyl) sulfonyl]glycyl] -L-prolinamide, or a salt thereof ; N- [ [1- (aminoiminomethyl) -4-piperidinyl] -methyl] -1- [N- (ethylsulfonyl) -D-phenylalanyl] -L-prolinamide,' or a salt thereof ; N- [ [1- (aminoiminomethyl) -4-piperidinyl ] -methyl] -1- [N- (propylsulfonyl) -D-phenylalanyl] -L-prolinamide, or a salt thereof/; N- [ [1- (aminoiminomethyl) -4-piperidinyl] -methyl] -1- IN- [ (phenylmethyl) sulfonyl] -D-phenylalanyl]-L-prolinamide, or a salt thereof; N-[[1-(aminoiminomethyl)-4-piperidinyl]-methyl]-1-[N-(phenylsulfonyl)-D-phenylalanyl]-L-prolinamide, or a salt thereof ; or N-t[1-(aminoiminomethyl)-4-piperidinyl]-methyl]-1-[N-[(1-methylethyl)sulfonyl]-D-phenylalanyl] -L-prolinamide, or a salt thereof. - 93 260127

8. The compound as defined in Claim 1 wherein G is an amido moiety of the structure 10 ossc I HH I CHa I (CHa). > T I Ha*' m 15 wherein m is 0, 1 , 2 or 3; and Y is NH or S.

9. The compound as defined in Claim 8 having the structure R» 20 o o II H H || S—M—C—C—N I R ^-<CHa), Rl 25 30 ossc I nh I CHa I (CHa). cha I S I A HaH *H

10. The compound as defined in Claim 9 wherein n is 1 and m is 2, R3 is 2-naphthyl, lower alkyl having at least 3 carbons, or benzyl, R is 35 94 260 hydroxyalkyl or aralkyl, R1 is H or alkyl, R2 is H and Y is -NH-.

11. The compound as defined in Claim 9 having the structure

12. The compound as defined in Claim 9 which is [1 (S) ,2a,4(J]-N-[4-[ (aminoiminomethyl) amino]butyl] - 1- [3-hydroxy-2- [ (2-naphthalenylsulfonyl) amino] -1-oxopropyl]-4-methyl-2-piperidinecarboxamide, or a salt thereof; [1 (S) ,2a,40] -N- [4- [ (aminoiminomethyl)amino] -butyl] -4-methyl-l-[2[ (2-naphthalenylsulfonyl)amino] -l-oxo-3-(phenylmethoxy)propyl]-2-piperidinecarbox-amide, or a salt thereof; [2R-II (S*) ,2a, 4(i]]-N- [4- t (aminoiminomethyl) amino] butyl] -1- [3-hydroxy-2- [ (2-naphthalenylsul fonyl)amino] -1-oxopropyl] -4-methyl-2-piperidine-carboxamide, or a salt thereof; ossc mh 260 [2S- [1 (R*) ,2a, 4P1J-N-14- [ (aminoiminomethyl) -amino]butyl]-1-r3-hydroxy-2-[(2-naphthalenylsulfonyl) amino] -1-oxopropyl]-4-methyl-2-piperidine- carboxaraide, or a salt thereof; (2S-trans) -N-14- [ (aminoiminomethyl) amino] -butyl]-4-methyl-l-[[[(l,2,3,4-tetrahydro-3-methyl-8-quinolin-yl)sulfonyl1amino]acetyl]-2-piperidine- carboxamide, or a salt thereof; trans-N- [4-1 (aminoiminomethyl) amino ] butyl ] -4-(methylthio) -1- [ [ (2-naphthalenylsulfonyl)amino] - acetyl]-S-prolinamide, or a salt thereof; N- [4 - [ (aminoiminomethyl)aminojbutyl]-1-[N- (2-naphthalenylsulfonyl) -D-phenylalanyl] -L-prolinamide, or a salt thereof; N- [4- [ (aminoiminomethyl)amino]butyl] -1- [N- (2-naphthalenylsulfonyl) -D-glutaminyl ] -L-prolinamide or a salt thereof; [2R- [1 (S*) ,2a,4P)]]-N-[3- t (aminoiminomethyl) -amino]-propyl]-1-[4-hydroxy-3-t(2-naphthalenylsulfonyl) amino)]-l, 2-dioxobutyl] -2-piperidine-carboxamide, or a salt thereof; N-[4 -[ (aminoiminomethyl)aminojbutyl] -1-[N- (2-naphthalenylsulfonyl)-L-seryl]-L-prolinamide or a salt thereof; N-[4-I(aminoiminomethyl)amino]butyl]-1-[N-(2-naphthalenylsulfonyl)-L-seryl]-D-prolinamide, or a salt thereof; (-2R-trans) -N- [4-1 (aminoiminomethyl)amino] -butyl] -4-methyl-l-[ [ (2-naphthalenylsulfonyl)amino] -acetyl] -2-piperidinecarboxamide, or a salt thereof; [2R-[l(S*)2a,4fJ] ]-N-[4-[ (amVnoiminomethy 1) -amino]butyl] -1- [3-hydroxy-2- [ (2-naphthalenylsulfonyl) amino] -1-oxopropyl] -4-methyl-2-piperidine-carboxamide, or a salt thereof; - 96 - 10 25 30 260127 [1 (S) ] -N- [4 -1 (aminoiminomethyl)amino]butyl] -1,2,3,4-tetrahydro-2-[3-hydroxy-2-1 (2-naphthalenylsul f onyl) amino] -1-oxopropyl]-3-isoquinoline-carboxamide, isomer A, or a salt thereof*, [1 (S) ] -N- [4- [ (aminoiminomethv-mine]butyl] -1,2,3,4-tetrahydro-2-[3-hydroxy-2• [ i " .iaphthalenyl-sulfonyl)amino] -1-oxopropyl] -3-icoquinoline-carboxamide, isomer B, or a salt thereof; (4S *) -N- [ 4 - [ (aminoiminomethy.!.) amino] butyl ] -4 -hydroxy-1- IN- (2-naphthalenylsulfonyl) -L-seryl] -L-prolinemide, or a salt thereof*, (4S*)-N-[4- [ (aminoiminomethyl)amino]butyl] -4-15 methoxy-1- [N- (2-naphthalenylsulfonyl) -L-seryl] -L-prolinamide, or a salt thereof', N-[4 -[ (aminoiminomethyl)amino]butyl]-l-[N- (2-naphthalenylsulfonyl) -L-phenylalanyl] -L-prolinaraide, 20 or a salt thereof; (2S-trans) -N-[4-[ (aminoiminomethyl)amino] -butyl] -4-methyl-l- [ [ l2-naphthalenylsulfonyl) amino] -acetyl]-2-piperidinecarboxamide or a salt thereof; 35 N-[4-[(aminoiminomethyl)amino]butyl]-1-[N-(2-naphthalenylsulf ony 1) -L-glutaminyl ] -L-prolinamide, or a salt thereof? N- [4-[(aminoiminomethyl)amino]butyl]-1- IN-(2 -naphthalenylsulfonyl) -L-threonyl]-L-prolinamide, or a salt thereof; N- [4 - [ (aminoiminomethyl)amino]butyl] -1- [N- (2-naphthaleny lsulf onyl) -L-allothreonyl] -L-prolinamide, or a salt thereof', m 10 20 25 35 - 97 - 260127 (S) -N- [4- [ (aminoiminomethyl)amino]butyl] -4-(methylthio) -1- IN- (2-naphthalenylsulfonyl) glycyl] -L-prolinamide, or a salt thereof; (R) -N- [4- [ (aminoiminomethyl)amino]butyl] -4-(methylthio) -1- [N- (2-naphthalenylsulfonyl)glycyl] -L-prolinamide, or a salt thereof; N- [4-[(aminoiminomethyl)amino]butyl]-1-[[(2-naphthalenylsulfonyl) amino]acetyl]-2-piperidine-carboxamidc, or a salt thereof; N- [4-[(aminoiminomethyl)amino]butyl]-1-[N-(2-naphthalenylsulfonyl) -D-tryptophyl ] -L-prolinamide, or a salt thereof; 15 (2S-trans) -N- [4 - [ (aminoiminomethyl)amino] - butyl]-4-methyl-l-11[(3-methyl-8-quinolinyl)-sulfonyl]amino] acetyl] -2-piperidinecarboxamide, or a salt thereof; N- [4 - [ (aminoiminomethyl) aminojbutyl] -1- [ [ (8-quinolinylsulfonyl) amino]acetyl J-2-piperidinecarbox-amide, or a salt thereof; salt; N-14— [ (aminoiminomethyl)amino]butyl] -1- [N- (2-naphthalenylsulfonyl) -D-a-glutamyl] -L-prolinamide, or a salt thereof*, or N- [4- [ (aminoiminomethyl)aminojbutyl] -1- [N-(methyl-sulfonyl) -D-phenylalanyl] -L-prolinamide or a salt thereof. 30 t « • ' w 260127 98

13. The use of a compound as defined in any one of Claims 1 to 12 in the manufacture of a medicament for inhibiting or preventing formation of blood clots.

14. A pharmaceutical composition comprising a 5 compound as defined in any one of Claims 1 to 12 and a physiologically acceptable vehicle or carrier.

15. A process for the preparation of a compound as defined in Claim 1, substantially as hereinbefore described with particular reference to any one of the 10 foregoing Examples. dated this £ I PARK & SON 15 per agents for the app' "^ant9f 20 25 30