CARBOXAMIDE DERIVATIVES OF PYRROLIDINE, PIPERIDINE AND HEXAHYDROAZEPINE FOR THE TREATMENT OF THROMBOSIS DISORDERS

Abstract: Carboxamide derivatives of pyrrolidine, piperidine, and hexahydroazepine of formula (I) are disclosed as useful in treating platelet-mediated thrombotic disorders.

Description: CARBOXAMIDE DERIVATIVES OF PYRROLIDINE, PIPERIDINE, AND HEXAHYDROAZEPINE FOR THE TREATMENT OF THROMBOSIS DISORDERS BACKGROUND OF THE INVENTION Platelet aggregation constitutes the initial hemostatic response to curtail bleeding induced by vascular injury. However, pathological extension of this normal hemostatic process can lead to thrombus formation. The final, common pathway in platelet aggregation is the binding of fibrinogen to activated, exposed platelet glycoprotein llb/llla (GPIIb/llla). Agents which interrupt binding of fibrinogen to GPIIb/llla, therefore, inhibit platelet aggregation. These agents are, therefore, useful in treating platelet- mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, unstable angina, reocclusion following thrombolytic therapy and angioplasty, inflammation, and a variety of vaso- occlusive disorders. The fibrinogen receptor (GPIIb/llla) is activated by stimuli such as ADP, collagen, and thrombin exposing binding domains to two different peptide regions of fibrinogen: α-chain Arg-Gly-Asp (RGD) and fchain His-His-Lβu-Gly-Gly-Ala-Lys-Gln-Ala-Gly-Asp-Val (HHLGGAKQAGDV, γ400-411 ). Since these peptide fragments themselves have been shown to inhibit fibrinogen binding to GPIIb/llla, a mimetic of these fragments would also serve as an antagonist. In fact, prior to this invention, potent RGD-based antagonists have been revealed which inhibit both fibrinogen binding to GPIIb/llla and platelet aggregation e.g., Ro- 438857 (L. Alig, J. Med. Chem. 1992, 35, 4393) has an IC50 of 0.094 μM against in vitro thrombin-induced platelet aggregation. Some of these agents have also shown in vivo efficacy as antithrombotic agents and, in some cases, have been used in conjunction with fibrinolytic therapy e.g., t- PA or streptokinase, as well (J. A. Zablocki, Current Pharmaceutical Design 1995, 1, 533). As demonstrated by the results of the pharmacological studies described hereinafter, the compounds of the present invention show the ability to block fibrinogen binding to isolated GPIIb/lla (ICso's 0.0002- 1.39 μM), inhibit platelet aggregation in vitro in the presence of a variety of platelet stimuli (0.019-65.0 μM vs. thrombin), and furthermore, inhibit ex vivo platelet aggregation in animal models. Additionally, these agents exhibit efficacy in animal thrombosis models as their progenitors had shown ("Nipecotic Acid Derivatives As Antithrombotic Compounds," application Serial No. 08/213772, filed March 16, 1994). The compounds of the present invention show efficacy as antithrombotic agents by virtue of their ability to prevent platelet aggregation. Additionally, because the compounds of this invention inhibit integrin-mediated cell-cell or cell-matrix adhesion, they may also be useful against inflammation, bone resorption, tumor cell metastasis, etc. (D. Cox, Drug News&Perspectives 1995, 8, 197). DISCLOSURE OF THE INVENTION The present invention is directed to compounds represented by the following general formula (I): (I) wherein A, X, M, R5, R10, and n are as hereinafter defined. These platelet aggregation inhibitors are useful in treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardiε infarction, reocclusion following thrombolytic therapy and angioplasty, inflammation, unstable angina, and a variety of vaso-occlusive disorders. These compounds are also useful as antithrombotics used in conjunction with fibrinolytic therapy (e.g., t-PA or streptokinase). Pharmaceutical compositions containing such compounds are also part of the present invention. DETAILED DESCRIPTION OF THE INVENTION More particularly, the present invention is directed to compounds of the following formula (I): (I) wherein M is (CH2)m or piperidin-1-yl; wherein A is selected from any of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, NHR 2 , or R 9 wherein Rg is selected from any of H, alkyl, CH(NH), CMe(NH) or acyl, preferably Rg is hydrogen; wherein Rio is H or C(0)N(R 1 )YZ wherein Ri is selected from H or cycloalkyl; wherein R 2 is selected from any of H, alkyl or acyl. Preferably, R 2 is hydrogen; wherein R5 is H or C(0)NHQ(CHW)rCθ2R8; wherein Q is selected from CH2. CH-aryl, CH-heteroaryl, CH-substituted-heteroaryl or CH-alkyl; preferably Q is CH2, CH-substituted-heteroaryl or CH-heteroaryl; W is selected from H or N(Rβ)T-R7, preferably W is H when Q is CH, and N(Rβ)-T- R7 when Q is CH2; wherein RQ is selected from any of H, alkyl or acyl; preferably Re is hydrogen, T is selected fron C(O), C(N-CN) or SO2, preferably T is C(O) and R7 is selected from any of alkyl, aryl, aralkyl, alkoxy, or aminoalkyl; and Rβ is selected from H, alkyl or aralkyl; preferably Rβ is H. wherein m is the integer 1 , 2, or 3. Preferably m is 1 or 2; wherein X is selected from any of C(O), C(0)0, C(0)NH, CH2, or SO2; wherein n is the integer 1 , 2, or 3; wherein r is 0 or 1 ; wherein R 1 is selected from Η or cycloalkyl; wherein Y is selected from any of (CH2)p, CH(R 3 )(CH2)q, (CH 2 ) q CH(R3), (CH(COR4)CH2) q , (CH 2 ) q CHOH or piperidine-3-carboxylic acid; with the proviso that when Y is (CH2)p and p is 2, X is other than C(O) or when X is C(O) then either R 1 is other than H or R 2 is other than H, and with the proviso that when Y is (CH(C02R 4 )CH2)q X is other than C(O) or CH 2 ; wherein p is 2 or 3; wherein q is 1 , 2, or 3. Preferably, q is 1. wherein R 3 is alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, aralkyl or heteroaryl; wherein R 4 is H or alkyl or cycloalkyl. Preferably, R 4 is hydrogen. wherein Z is CO2H, Cθ2alkyl, SO3H, PO3H2 , or 5-tetrazole; provided that at least one of R5 and R10 is hydrogen; or the enantiomer or the pharmaceutically acceptable salt thereof. Preferably, the group C(0)N(R 1 )YZ is attached to the ring carbon of the central azacycle at the 3- or 4-position (4-position when larger than a five- membered ring), and most preferably the 3-position. As used herein, unless otherwise noted alkyl and alkoxy whether used alone or as part of a substituent group, include straight and branched chains having 1 -8 carbons. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, π-butyl, isobutyl, sec-butyl, f-butyl, D-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. Cycloalkyl groups contain 5-8 ring carbons and preferably 6-7 carbons. The term "aryl", "heteroaryl" or "substituted heteroaryl" as used herein alone or in combination with other terms indicates aromatic or heteroaromatic groups such as phenyl, naphthyl, pyridyl, thienyl, furanyl, or quinolinyl wherein the substituent is an alkyl group. The term "aralkyl" means an alkyl group substituted with an aryl group. The term "acyl" as used herein means an organic radical having 2-6 carbon atoms derived from an organic acid by removal of the hydroxyl group. The compounds of the present invention may also be present in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt generally takes a form in which the nitrogen on the 1 - piperidine (pyrrolidine, piperazine) substituent is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic. Particularly preferred compounds of the present invention include those compounds shown in Table I, where "Subst" indicates the position of attachment of the group C(0)N(R 1 )YCθ2H to the central azacycle and where the letter "R" after the numeral "3" indicates the absolute configuration (Cahn-lngold-Prelog rules). Those numerals not having any configuration specified are racemic mixtures. TABLE I fc Subst m n X Bl B£ 1 z 1 3 2 2 C(0) H H CH(Ph)CH2 CH 2 3 1 2 NHCO H H CH2CHMe CH 3 3 1 2 OC(O) H H (fl)-CH(Cθ2Me)CH 2 CH 4 3 2 1 C(O) H H CH(3-Me-Ph)CH2 CH 5 4 2 2 C(O) H H CH(Me)CH2 CH 6 4 2 2 C(O) H H CH(4-Cθ2H-Ph)CH 2 CH 7 3 2 2 C(O) H Me CH2CH2 CH 8 See structure 9 3 2 2 C{0) H H CH(Me3Si-ethynyl)CH2 CH 1 0 See structure 1 1 3R 2 2 CO H H CH 2 CH(OH) CH 1 2 3 2 2 so 2 H H CH 2 CH 2 CH 1 3 See structure 1 4 3 2 2 CO H Me CH(3,4-OCH2θ-Ph)CH2 N 1 5 3 2 2 CO H Me CH(3-quinolinyl)CH2 N 1 6 3R 2 2 CO H H S-CH(3,4-OCH2θ-Ph)CH2 CH 1 7 3 2 3 CO H H CH(3-quinolinyl)CH2 CH 1 8 3R 2 2 CO H H S-CH(3-quinolinyl)CH2 CH 1 9 3R 2 2 CO H H S-CH(f-butytethynyl)CH2 CH 2 0 3 2 2 CH2 H H S-CH(3,4-OCH2θ-Ph)CH2 CH 2 1 3R 2 2 CO H H S-CH(3-pyridyl)CH 2 CH 8 1 0 1 3 1 4 1 6 The compounds of the invention wherein R5 is H, Ri 0 is C(0)N(R 1 )YZ, M is (CH2)m and A is piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin- 1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl or NHR 2 may be prepared as shown in Scheme AA. In this scheme nipecotic acid allyl ester (either the racemic mixture or either separate enantiomer) may be treated with resin-bound 4- piperidinepropionic acid in the presence of DIC/HOBT and a tertiary amine. The allyl ester is then removed via palladium-mediated catalysis and the iterative coupling process continued to give final product upon saponification with potassium trimethylsilanolate (e.g., compound 1 ). By analogy, urea and urethane-based replacements for the tertiary amide (compounds 2 and 3) were prepared by reaction of solid-supported amine (alcohol) with p-nitrophenylchloroformate and then ethyl nipecotate (S. M. Hutchins, Tetrahedron Lett. 1994, 35, 4055). Three-substituted 3-aminopropionic acid ester intermediates were prepared utilizing a modified Knoevenagel procedure (Scheme AG; E. Profft, J. Prakt. Chem. 1965, 30, 18) followed by Fischer esterification of the carboxylic acid product (when not commercially-available). These intermediates were prepared in enantiomerically-enriched form by penicillin amidase resolution of racemic phenylacetamides such as intermediate AG3 (V. A. Soloshonok, Tetrahedron: Asymmetry 1995, 6, 1601). Here, the undesired R-enantiomer is hydrolyzed by amidase while the desired S- enantiomer retains the phenylacetyl group. Resolutions may also be performed on the (-)-ephedrine salts of racemic three-substituted 3-N-Boc- aminopropionic acids as published (J. A. Zablocki, J. Med. Chem. 1995, 38, 2378). Ethyl nipecotate and ethyl isonipecotate are commercially-available intermediates. Synthesis of 5- and 7-membered ring analogues of nipecotamides (4 and 17, respectively) were prepared by solid-phase synthesis using methyl pyrrolidine-3-carboxylate and methyl hexahydroazepine-3-carboxylate intermediates for the analogous conversion of AA2 to AA3 (Scheme AA). Methyl pyrrolidine-3-carboxylate and methyl hexahydroazepine-3- carboxylate were prepared as published (H. Rapoport, J. Org. Chem. 1974, 39, 893). For example, N-benzyl hexahydroazepin-2-one was reacted with lithium diisopropylamide/diethylcarbonate and this product then reduced with lithium aluminum hydride to afford N-benzyl-3-hydroxymethyl- hexahydroazepine. The benzyl group was removed by hydrogenolysis (H 2 , Pd-C, MeOH), the nitrogen protected (di-f-butyldicarbonate/sodium hydroxide), and the alcohol oxidized with chromium trioxide to give N-Boc- hexahydroazepine-3-carboxylic acid. The Boc group was removed concomitant with carboxylate esterification using HCI/MeOH to afford methyl hexahydroazepine-3-carboxylate. Piperazine analogs were prepared, as exemplified in Scheme AB, as published (S. G. Gilbreath, J. Am. Chem. Soc. 1988, 110, 6172). Tetrazoles (13) were prepared from the corresponding nitrites using azidotrimethylsilane/dibutyltin oxide as published (Scheme AC; S. J. Wittenberger, J. Org. Chem. 1993, 58, 4139). Here, the nitrile precursor AC2 was prepared by standard amide bond coupling with 3- aminopropionitrile, and reduced on the final synthetic step using platinum dioxide-mediated hydrogenation (W. J. Hoekstra, J. Med. Chem. 1995, 38, 1582). N-Methyipiperidine analogues can be prepared by Fmoc-based solid- phase peptide synthesis techniques as shown in scheme AD (P. Sieber, Tetrahedron Lett. 1987, 28, 6147). The Fmoc protecting groups were cleaved by 20% piperidine/DMF, couplings were effected using DIC/HOBT/DMF, and final products were removed from the resin with 95% TFA. Sulfonamido 12 was prepared as shown in Scheme AE. Intermediate AE1 was isolated in two steps from 4-pyridineethanesulfonic acid by hydrogenation/protection as described (J. I. DeGaw, J. Heterocyclic Chem. 1966, 3, 90), and then chlorinated using standard thionyl chloride conditions (P. J. Hearst, Org. Syn. 1950, 30, 58) to give AE2. Intermediate AE2 was then carried forward to final product using standard solution-phase synthesis (W. J. Hoekstra, J. Med. Chem. 1995, 38, 1582). Piperidinepropyl-nipecotamide 20 was prepared as shown in Scheme AF. Ester AF1 was Boc-protected using standard Boc-ON conditions (D. S. Tarbell, Proc. Natl. Acad. Sci. USA 1972, 69, 730), and then reduced to its corresponding primary alcohol with DiBAL-H/THF (E. Winterfeldt, Synthesis 1975, 617) to give intermediate AF2. This compound was converted to its corresponding tosylate AF3 using p-TsCI (L. F. Awad, Bull. Chem. Soc. Jpn. 1986, 59, 1587). Ethyl nipecotate was then alkylated with intermediate AF3 using standard conditions (benzene/heat; I. Seki, Chem. Pharm. Bull. Jpn. 1970, 18, 1104). Enantiomerically-enriched R-(-)-nipecotic acid ethyl ester was isolated by chiral resolution of racemic material as its corresponding D-tartaric acid salt (A. M. Akkerman, Rec. Trav. Chim. Pays-Bas 1951, 70, 899) SCHEME AA SCHEME AB H - AB3 14 10 -15 SCHEME AC N SCHEME AD DMF Fm ° C ~N AD3 AD4 2) TFA SCHEME AE AE1 AE2 12 SCHEME AF AF1 AF2 AF3 AF4 SCHEME AG AG1 AG2 AG3 AG4 AG5 Particularly preferred compounds of the present invention include those compounds shown in Table 1 (and Table 2), where the letter "FT after the numeral "3" indicates the absolute configuration (Cahn-lngold-Prelog rules). TABLE || 22 2 H H NHCONH(3-MeOPh) 23 2 H H NHCOOCH 2 Ph 24 2 H H NHCOOCH 2 (3-CIPh) 25 2 H H NHS0 2 CH 2 Ph 26 2 H H NHCONH(3,5-diMeOPh) 27 See structure below 28 2 H H NHCONH(2-naphthyl) 29 See structure below 30 2 H H NHCONHCHjCHaPh 31 2 H 6-Me-3-pyridyl H 32 2 H 5-Br-3-pyridyl H 33 2 CH(NH) 3-pyridyl H The diaminopropionic acid antagonists of the invention wherein R5 is C(0)NHQ(CHW)rC02R8, Ft10 is H, M is piperidin-1-yl and A is may be prepared as shown in Scheme AH. Methyl N-α-Z- diaminopropionate was acylated by HBTU-activated AH1, the Z group removed by hydrogenolysis to afford AH2 (for 23 the Z group was retained), and then the resultant primary amine reacted with the requisite isocyanate (or alkyl chloroformate for 24, alkylsulfonyl chloride for 25) to give AH3. The Boc group of intermediate AH3 was removed with HCI and the resultant secondary amine acylated with HBTU-activated AH4 to give AH5. This material was saponified with lithium hydroxide and the Boc group removed with HCI to give 22. SCHEME AH The bipiperidine-urea based antagonists of the invention may be prepared as shown in Scheme AJ. Intermediate AJ1 was prepared as described in Scheme AG. AJ1 was acylated with p-nitrophenyl chloroformate and then reacted with Boc-bipiperidine (for a synthesis, see W. Bondinell, patent application WO 94/14776). The ester AJ2 was saponified with lithium hydroxide and the Boc group removed with HCI to afford 27. Substituted piperidine aldehyde intermediates such as AK2 were prepared by lithium aluminum hydride reduction of their corresponding nicotinic acid methyl esters (AK1 ) followed by oxidation with manganese dioxide (Scheme AK). The aldehydes were then converted to β-amino acids as shown in Scheme AG. Formamidine AL3 was prepared as shown in Scheme AL. Amine AL1 was acylated with ethyl formimidate as described by M. K. Scott (J. Med. Chem. 1983, 26, 534). The ester AL2 was saponified with 4 N HCI (RT, 20 h) to afford 33. Three-substituted β-amino acid-type antagonists were synthesized as shown in Scheme AM. Resolved 6-methyl-pyridyl-β-amino ester was acylated with HBTU-activated AM1 , and the coupled product treated with HCI to afford amine AM2. The amine was acylated with HBTU-activated AM4, the ester saponified, and the Boc group removed with HCI to afford 31. SCHEME AJ SCHEME AK SCHEME AL SCHEME AM 31 To prepare the pharmaceutical compositions of this invention, one or more compounds of formula (i) or salt thereof of the invention as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed, if desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.03 mg to 100 mg/kg (preferred 0.1-30 mg/kg) and may be given at a dosage of from about 0.1-300 mg/kg/day (preferred 1-50 mg/kg/day). The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed. BIOLOGY The compounds of the present invention interrupt binding of fibrinogen to platelet glycoprotein llb/llla (GPIIb/llla) and thereby inhibit platelet aggregation. Such compounds are, therefore, useful in treating platelet- mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocciusion following thrombolytic therapy and angioplasty, and a variety of vaso-occlusivβ disorders. Because the final, common pathway in normal platelet aggregation is the binding of fibrinogen to activated, exposed GPIIb/llla, inhibition of this binding represents a plausible antithrombotic approach. The receptor is activated by stimuli such as ADP, collagen, and thrombin, exposing binding domains to two different peptide regions of fibrinogen: α-chain Arg-Gly-Asp (RGD) and γ-chain 400- 411. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds of the present invention show the ability to block fibrinogen binding to isolated GPIIb/lla (ICso's 0.0002-1.39 μM), inhibit platelet aggregation in vitro in the presence of a various of platelet stimuli (0.019-65.0 μM vs. thrombin), and furthermore, inhibit ex vivo platelet aggregation in animal models. IN VITRO SOLID PHASE PURIFIED GLYCOPROTEIN HB/IIIA BINDING ASSAY. A 96 well lmmulon-2 microtiter plate (Dynatech-lmmulon) is coated with 50 μl/well of RGD-affinity purified GPIIb/llla (effective range 0.5-10 μg/mL) in 10 mM HEPES, 150 mM NaCI, 1 mM at pH 7.4. The plate is covered and incubated overnight at 4°C. The GPIIb/lla solution is discarded and 150 μl of 5% BSA is added and incubated at RT for 1-3 h. The plate is washed extensively with modified Tyrodes buffer. Biotinylated fibrinogen (25 μl/well) at 2 x final concentration is added to the wells that contain the test compounds (25 μl/well). The plate is covered and incubated at RT for 2-4 h. Twenty minutes prior to incubation completion, one drop of Reagent A (Vecta Stain ABC Horse Radish Peroxidase kit, Vector Laboratories, Inc.) and one drop Reagent B are added with mixing to 5 mL modified Tyrodes buffer mix and let stand. The ligand solution is discarded and the plate washed (5 x 200 μl/well) with modified Tyrodes buffer. Vecta Stain HRP- Biotin-Avidin reagent (50 μl/well, as prepared above) is added and incubated at RT for 15 min. The Vecta Stain solution is discarded and the wells washed (5 x 200 μl/well) with modified Tyrodes buffer. Developing buffer (10 mL of 50 mM citrate/phosphate buffer <§> pH 5.3, 6 mg Q.- phenylenediamine, 6 μl 30% H2O2; 50 μl/well) is added and incubated at RT for 3-5 min, and then 2Λ/ H2SO4 (50 μl/well) is added. The absorbance is read at 490 nM. The results are shown in Tables III and IV. IN VITRO INHIBITION OF THROMBIN-INDUCED GEL- FILTERED PLATELET AGGREGATION ASSAY. The percentage of platelet aggregation is calculated as an increase in light transmission of compound-treated platelet concentrate vs. control- treated platelet concentrate. Human blood is obtained from drug free, normal donors into tubes containing 0.13Λf sodium citrate. Platelet rich plasma (PRP) is collected by centrifugation of whole blood at 200 x g for 10 min at 25°C. The PRP (5 mL) is gel filtered through Sepharose 2B (bed volume 50 mL), and the platelet count is adjusted to 2x10 7 platelets per sample. The following constituents are added to a siliconized cuvette: concentrated platelet filtrate and Tyrode's buffer (0.14/W NaCI, 0.0027/W KCl, 0.012M NaHCO3, 0.76 mM Na 2 HP04, 0.0055Λf glucose, 2 mg/mL BSA and δ.OmM HEPES @ pH 7.4) in an amount equal to 350 μl, 50 μl of 20 mM calcium and 50 μl of the test compound. Aggregation is monitored in a BIODATA aggregometer for the 3 min following the addition of agonist (thrombin 50 μl of 1 unit/mL). The results are shown in Tables III and IV. TABLE HI In Vitro Results Fibrinogen Binding Platelet Aggregation * Compound # % Inh. (50 uM). lCfiiUiMi % Inh. (50tιMl IC≥fl fuM) 1 95.0% 0.003 83.0% 3.6 2 93.0% 0.027 95.7% 54.0 3 81.0% NT 26.2% >100 4 89.9% 0.121 81.0% 26.0 5 89.0% 0.012 100% 10.0 6 90.7 0.197 71.2% 73.0 7 100% 0.006 75.6% 2.4 8 93.0% 0.332 94.8% 65.0 9 99.0% 0.002 90.9% 0.37 1 0 91.3% 0.019 85.0% 1.6 1 1 79.6% 0.004 99.2% 1.55 1 2 97.0% 0.025 88.0% 15.5 1 3 95.0% 1.39 67.0% 25.5 1 4 99.0% 0.004 91.0% 0.91 1 5 100% 0.0091 92.2% 1.9 1 6 100% 0.0005 94.0% 0.028 1 7 96.0% 0.005 89.6% 0.45 1 8 100% 0.0002 100% 0.019 1 9 99.0% 0.021 92.1% 0.079 20 99.0% 0.0007 89.7% 37.0 21 100% 0.0005 100% 0.060 Thrombin-induced aggregation of gel-filtered platelets. TABLE IY In Vitro Results Fibrinogen i Binding Platelet Aggregation * ComDound # % Inh. (50 uM) IC54 (nM) % Inh. f50uM) ICςrj (uMl 22 100% 0.0007 94.0% 0.046 23 100% 0.0003 97.0% 0.027 24 100% 0.0004 100% 0.018 25 100% 0.0003 97.0% 0.007 26 100% 0.0003 97.0% 0.016 27 100% 0.0006 100% 0.45 28 100% 0.0002 100% 0.17 29 100% 0.068 100% 42 30 100% 0.0008 100% 0.19 31 100% 0.0003 100% 0.045 32 100% 0.0004 100% 0.020 33 100% 0.0007 100% 0.30 * Thrombin -induced aggregation of gel-filtered platelets. EX VIVO DOG STUDY Adult mongrel dogs (8-13 kg) were anesthetized with sodium pentobarbital (35 mg/kg, i.v.) and artificially respired. Arterial blood pressure and heart rate were measured using a Millar catheter-tip pressure transducer inserted in a femoral artery. Another Millar transducer was placed in the left ventricle (LV) via a carotid artery to measure LV end diastolic pressure and indices of myocardial contractility. A lead II electrocardiogram was recorded from limb electrodes. Catheters were placed in a femoral artery and vein to sample blood and infuse drugs, respectively. Responses were continuously monitored using a Modular Instruments data aquisition system. Arterial blood samples (5-9 ml) were withdrawn into tubes containing 3.8% sodium citrate to prepare platelet rich plasma (PRP) and to determine effects on coagulation parameters: prothrombin time (PT) and activated partial thromboplastin time (APTT). Separate blood samples (1.5 ml) were withdrawn in EDTA to determine hematocrit and cell counts (platelets, RBC's and white cells). Template bleeding times were obtained from the buccal surface using a symplate incision devise and Whatman filter paper. Aggregation of PRP was performed using a BioData aggregometer. Aggregation of whole blood used a Chronolog impedance aggregometer. PT and APTT were determined on either a BioData or ACL 3000+ coagulation analyser. Cells were counted with a Sysmex K-1000. Compounds were solubilized in a small volume of dimethylformamide (DMF) and diluted with saline to a final concentration of 10% DMF. Compounds were administered by the intravenous route with a Harvard infusion pump. Doses was administered over a 15 min interval at a constant rate of 0.33 ml/min. Data were obtained after each dose and in 30 min intervals following the end of drug administration. Oral doses were administered as aqueous solutions via syringe. Compounds caused marked inhibition of ex vivo platelet aggregation responses. Thus, in whole blood, the compounds inhibited collagen-stimulated (or ADP) aggregation in doses of 0.1-10 mg/kg with marked inhibition of collagen stimulated platelet ATP release. In PRP, the compounds also inhibited collagen stimulated platelet aggregaton with marked activity at 0.1-10 mg/kg. Compounds had no measurable hemodynamic effect in doses up to 1 mg/kg, iv. The drugs produce an increase in template bleeding time at 0.1 -1 mg/kg with rapid recovery post treatment. No effects on coagulation (PT or APTT) were observed during treatment and platelet, white and RBC counts were unchanged at any dose of the compounds. The results indicate that the compounds are broadly effective inhibitors of platelet aggregation ex vivo (antagonizing both collagen and ADP pathways) following iv administration of doses ranging from 0.1-1 mg/kg or 1-10 mg/kg orally (Tables V and VI). The antiaggregatory effects are accompanied by increases in bleeding time at the higher doses. No other hemodynamic or hematologic effects are observed. TABLE Y Ex Vivo Dog Study Results Intravenous Dosing Oral Dosing Com p ound #Dose Duration * DΩSSL Duration' 1 5 1 mpk 30 min 10 mpk 120 min 1 6 0.1 mpk 60 min 1 mpk 60 min 0.3 mpk NT 3 mpk >180 min 1 8 0.1 mpk 30 min 1 mpk 150 min 1 9 1 mpk 30 min 10 mpk 90 min 21 0.3 mpk 150 min 1 mpk 180 min * Indicates duration of >50% inhibition of collagen- or ADP-induced ex vivo platelet aggregation. TABLE VI Ex Vivo Dog Study Results Intravenous Dosing Oral Dosing Cmpd # Dose Duration * Dose Djjialioϋ* 22 0.3 mpk 180 min 3 mpk 60 min 23 0.1 mpk 60 min 1 mpk 180 min 0.3 mpk NT 3 mpk 150 min 24 0.3 mpk 90 min 3 mpk 120 min 25 0.3 mpk 30 min 3 mpk 60 min 26 0.3 mpk NT 3 mpk 60 min 27 0.3 mpk 60 min 3 mpk 120 min 28 0.3 mpk NT 3 mpk 120 min 30 0.3 mpk 105 min 3 mpk 180 min 31 0.3 mpk 120 min 3 mpk >180 min 31 0.3 mpk 60 min 3 mpk 180 min * Indicates duration of >50% inhibition of collagen-induced ex vivo platelet aggregation. Compounds 16 and 18 have shown efficacy in a canine arteriovenous shunt model of thrombosis in a dose-dependent fashion ( method in "Nipecotic Acid Derivatives As Antithrombotic Compounds," application Serial No. 08/213772, filed March 16, 1994). For instance, compound 16 inhibits thrombus formation at 10, 30, and 100 μg/kg/min cumulative doses by iv infusion (75%, 37%, 12% of thrombus weight vs. vehicle control, respectively). Compound 18 inhibits thrombus formation at 3, 10, and 30 μg/kg/min cumulative doses by iv infusion (82%, 41%, 12% of thrombus weight vs. vehicle control, respectively). EXAMPLES Protected amino acids were purchased from Aldrich Chemical or Bachem Bioscience Inc. 2-Chlorotrityl resin and Wang resin were obtained from Novabiochem Corp. Enantiomerically-enriched cycloalkylidene-3- carboxylic acid ethyl esters were isolated by chiral resolution of racemic material as published (A. M. Akkerman, Rec. Trav. Chim. Pays-Bas 1951 , 70, 899). All other chemicals were purchased from Aldrich Chemical Company, Inc. Final product acid addition salts can be converted to free bases by basic ion exchange chromatography. High field 1 H NMR spectra were recorded on a Bruker AC-360 spectrometer at 360 MHz, and coupling constants are given in Herz. Melting points were determined on a Mel-Temp II melting point apparatus and are uncorrected. Microanalyses were performed at Robertson Microlit Laboratories, Inc., Madison, New Jersey. In those cases where the product is obtained as a salt, the free base is obtained by methods known to those skilled in the art, e.g. by basic ion exchange purification. In the Examples and throughout this application, the following abbreviations have the meanings recited hereinafter. Bn or Bzl = Benzyl Boc = t-Butoxycarbonyl BOC-ON = 2-(f-Butoxycarbonyloxyimino)-2-phenylacetonitrile BOP-CI = Bis(2-oxo-3-oxazolidinyl)phosphinic chloride CP = compound DCE = 1 ,2-Dichloroethane DCM = Dichloromethane DIBAL-H = Diisobutylaluminum hydride DIC = Diisopropylcarbodiimide DIEA = Diisopropylethylamine DMAP = 4-Dimethylaminopyridine DMF = N, N-Dimethylformamide EDC = Ethyl dimethylaminopropylcarbodiimide EDTA = Ethylenediaminetetraacetic acid Et2θ = Diethyl ether HBTU = 2-(1 H-Benzotriazole-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate HOBT = Hydroxybenzotriazole i-Pr = Isopropyl KOTMS = Potassium trimethylsilanolate NMM - N-Methylmorpholine Nip = Nipecotyl (unless noted otherwise, racemic at 3-position) NT = not tested PPT = precipitate PTSA = p-Toluenesulfonic acid RT = room temperature TFA = Trifluoroacetic acid TMSN 3 = Azidotrimethylsilane 2 = Benzyloxycarbonyl Allyl 3-(4-piperidine)propionate • HCI (AA1 precursor) To a mixture of 3-(4-pyridine)acrylic acid (10.0 g, 0.066 mol) and aqueous HCI (2.0 N, 50 mL) under a blanket of nitrogen was added platinum (IV) oxide (0.54 g). This mixture was hydrogenated at 50 psi and RT for 21 h, filtered through Celite, and evaporated to give 3-(4-piperidine)propionic acid • HCI as a white powder (12.9 g, 99%). This powder was treated with allyl alcohol (50 mL) and warmed at 50°C for 2 h. This solution was cooled to RT, evaporated to ca. 10 mL volume, and diluted with Et 2 0 (250 mL). The resultant precipitate was collected and washed with Et 2 0 to afford a white powder (14.5 g, 94%): 1 H NMR (DMSO-d 6 ) δ 8.7-9.1 (m, 2 H), 5.9 (m, 1 H), 5.25 (dd, J=7, 15, 2 H), 4.53 (d, J=4, 2 H), 3.21 (d, J=8, 2 H), 2.74 (t, J=7, 2 H), 2.35 (t, J=4, 2 H), 1.72 (d, J=8, 2 H), 1.5 (m, 3 H), 1.3 (m, 2 H); MS m/e 198 (MH+). Methvl fSΪ-3-amino-3-f3-pvridvn propionate « 2HCI (AG5Ϊ Phenylacetamide intermediate AG3 was prepared using standard methods as shown in Scheme AG (E. Profft, J. Prakt. Chem. 1965, 30, 18). A mixture of AG1 (0.47 mol), EtOH (100 mL), NH 4 OAc (0.47 mol), and malonic acid (0.70 mol) was heated at reflux for 6 h, cooled, and filtered. The white solid was washed with EtOH and MeOH and dried. This solid was dissolved in 2:1 acetone/water (360 mL), treated with triethylamine (0.72 mol) and phenylacetyl chloride (0.36 mol), and stirred for 22 h. The mixture was evaporated and the residue dissolved in water (500 mL) and adjusted to pH 12 (1 N NaOH). The aqueous layer was adjusted to pH 2 (cone. HCI), extracted with Et 2 0, and evaporated to a white foam. The foam was purified by silica gel chromatography (10% MeOH/DCM) to give AG3. A solution of compound AG3 (0.22 mol) in water (600 mL) at RT was adjusted to pH 7.5 using KOH (3.0 N) and treated with penicillin amidase (91520 units, Sigma). This mixture was stirred for 47 h, acidified to pH 1 with HCI (cone), and the resultant ppt filtered through Celite. The filtrate was extracted with Et2θ (3x300 mL), concentrated in vacuo, and treated with MeOH/conc. NH4OH (9:1). This product-containing solution was purified by silica gel chromatography (eluent DCM/MeOH/NH 4 OH, 78:18:4) to give (S)-3- phenylacetamido-3-(3-pyridyl) propionic acid ammonium salt (19.5 g, 58%). This product was treated with HCI (6.0 H, 292 mL), heated at reflux for 5 h, cooled to RT, and extracted with Et2θ (3x200 mL). The aqueous layer was adjusted to pH 12, concentrated in vacuo, and the resultant solid triturated with MeOH (2x300 mL). This solution was evaporated to give ca. 14 g sodium salt. This material was treated with MeOH (500 mL), 2,2- dimethoxypropane (44 mL), and HCI (4 N in dioxane, 84 mL), and stirred for 90 h at RT. This mixture was filtered and the filtrate concentrated in vacuo. The resultant off-white solid was triturated with Et2θ (2 x 150 mL) and dried to give compound AG5 (16.7 g, 96% ee) as a white, amorphous solid. EXAMPLE 1 N-3-(4-PipβridineDropionvn-nipecotvl-(3-amino-3-phenvn propionic acid • TFA (1 ) A 25 mL sintered glass vessel under nitrogen was charged with 2-chlorotrityl chloride resin (0.24 g, 0.36 mmol, Novabiochem) and DMF (5 mL). The resin was agitated with nitrogen for 5 min to swell and the DMF removed. The resin was treated with DMF (5 mL), DIEA (0.31 mL, 5 eq), and allyl 3-(4- piperidine)propionate • HCI (0.20 g, 2.4 eq), sequentially, and agitated for 8 h. The resultant dark green solution was removed, and the resin washed with DMF (3x5 mL), aqueous DMF (25%, 3x5 mL), THF (3x5 mL), DCM (3x5 mL), and Et2θ (5 mL). The resin was swelled with DCE (5 mL) and treated with a mixture of tetrabutylammonium fluoride hydrate (0.28 g, 3 eq), azidotrimethylsilane (0.38 mL, 10 eq), tetrakis(triphenylphosphine)palladium (0.084 g, 20 mol %), and DCE (5 mL). The resin was agitated for 15 h and the orange solution removed. The resin was washed with DCM (3x5 mL), DMF (3x5 mL), THF (3x5 mL), and Et2θ (5 mL). The resin was swelled with DMF (5 mL) and treated with DIEA (0.18 mL, 3 eq), allyl nipecotate • HCI (0.17 g, 3 eq), DIC (0.17 mL, 3 eq), and HOBT (1 mg). The resin was agitated for 15 h and then the reaction solution removed. The resin was washed with DMF (3x5 mL), aqueous DMF (25%, 3x5 mL), THF (3x5 mL), DCM (3x5 mL), and Et2θ (5 mL). The resin was swelled with DCE (5 mL) and treated with a mixture of tetrabutylammonium fluoride hydrate (0.28 g, 3 eq), azidotrimethylsilane (0.38 mL, 10 eq), tetrakis(triphenylphosphine) palladium (0.084 g, 20 mol %), and DCE (5 mL). The resin was agitated for 15 h and the orange solution removed. The resin was washed with DCM (3x5 mL), DMF (3x5 mL), THF (3x5 mL), and Et2θ (5 mL). The resin was swelled with DMF (5 mL) and treated with DIEA (0.18 mL, 3 eq), methyl D,L- 3-amino-3-phenylpropionate • HCI (0.23 g, 3 eq), DIC (0.17 mL, 3 eq), and HOBT (1 mg). The resin was agitated for 17 h and then the reaction solution removed. The resin was washed with DMF (3x5 mL), aqueous DMF (25%, 3x5 mL), THF (3x5 mL), DCM (3x5 mL), and Et2θ (5 mL). The resin was swelled with THF (5 mL) and treated with a solution of KOTMS (0.23 g, 10 eq) and THF (2 mL). The resin was agitated for 18 h and then the reaction solution removed. The resin was washed with DMF (3x5 mL), acetic acid/THF (1 :1 , twice), aqueous DMF (25%, 3x5 mL), THF (3x5 mL), DCM (3x5 mL), and Et2θ (5 mL). The resin was treated with TFA/DCM (1 :1 , 10 mL), agitated for 15 min, and the resultant red solution collected. This solution was evaporated and the resultant oil triturated with Et2θ (3x5 mL) and dried to afford compound 1 as a dear glass (0.11 g): 1 H NMR (DMSO- d 6 ) δ 8.6 (m, 1 H), 8.42 (d, J=7, 1 H), 8.2 (m, 1 H), 7.3 (m, 3 H), 7.2 (m, 2 H), 5.18 (d, J=6, 1 H), 4.3 (m, 1 H), 3.7 (m, 1 H), 3.2 (m, 3 H), 2.8 (m, 2 H), 2.6 (m, 2 H), 2.3 (m, 5 H), 1.1-1.9 (m, 11 H); MS m/e 416 (MH+). * * * Using the same general solid phase synthesis technique as described in Example 1, the compounds of indicated examples were made according to Scheme AA as recited in the particular example. EXAMPLE 2 N-M-Piperidinemethvlaminocarbonvn-nipecotvl-f3-amino-2-methyn propionic acid * TFA (2) Compound 2 was prepared as shown in Scheme AA. Resin-bound 4- piperidinemethylamine (0.36 mmol) was swelled with DCE (5 mL), treated with p-nitrophenylchloroformate (0.36 mmol) and DIEA (0.36 mmol), agitated for 1 h, and the solvent removed. The resin was washed (see Example 1 ), swelled with DCE (5 mL), treated with allyl nipecotate • HCI (0.36 mmol) and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1 ), and the allyl ester cleaved to the corresponding acid (see Example 1). The resin was swelled with DMF (5 mL), the acid coupled with methyl 3-amino-2-methylpropionatβ (0.36 mmol), and the synthesis completed as shown in Example 1. Compound 2 was isolated as a clear glass (0.11 g): 1 H NMR (CD 3 OD) δ 3.9 (m, 2 H), 3.2 (m, 4 H), 3.10 (d, J=7, 2 H), 2.9 (m, 3 H), 2.6 (m, 2 H), 2.3 (m, 1 H), 1.9 (m, 4 H), 1.7-1.9 (m, 5 H), 1.3-1.5 (m, 5 H), 1.11 (d, J=7, 3 H); MS m/e 355 (MH+). EXAMPLE 3 N-/4-Piperidinemethγloxvcarbonvn-nipecotvl-D-aspartic acid α-methvl ester - TFA (3) Compound 3 was prepared as shown in Scheme AA. Resin-bound 4- piperidinemethanol (0.36 mmol) was swelled with DCE (5 mL), treated with p-nitrophenylchioroformate (0.36 mmol) and DIEA (0.36 mmol), agitated for 1 h, and the solvent removed. The resin was washed (see Example 1 ), swelled with DCE (5 mL), treated with allyl nipecotate • HCI (0.36 mmol) and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1 ), and the allyl ester cleaved to the corresponding acid (see Example 1). The resin was swelled with DMF (5 mL), the acid coupled with H-D-Asp(OBn)-OMe (0.36 mmol), and the synthesis completed as shown in Example 1. Compound 3 was isolated as a yellow glass (0.019 g): 1 H NMR (CD3OD) δ 4.8 (m, 2 H), 3.9 (m, 3 H), 3.70 (d, J=9, 4 H), 3.39 (s, 3 H), 3.3 (m, 2 H), 2.9 (m, 4 H), 2.8 (m, 2 H), 1.9 (m, 4 H), 1.7 (m, 2 H), 1.4 (m, 4 H); MS m/e 400 (MH + ). EXAMPLE 4 N-3-M-Piperidinepropionyh-pvrrolidine-3-carboxy-f3-amino-3-r4-tolyn] propionic acid « TFA (4) Compound 3 was prepared as shown in Scheme AA. Intermediate AA2 (0.36 mmol) was swelled with DCE (5 mL), treated with methyl pyrrolidine-3- carboxylate • HCI (0.36 mmol), DIC (0.72 mmol), and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1), and the methyl ester cleaved to the corresponding acid with KOTMS (see Example 1). The resin was swelled with DMF (5 mL), the acid coupled with methyl 3-amino-3-(4-tolyl)propionatβ (0.36 mmol), and then the synthesis completed as shown in Example 1. Compound 4 was isolated as a clear glass (0.081 g): 1 H NMR (CD 3 OD) δ 7.19 (d, J=5, 2 H), 7.10 (d, J=5, 2 H), 5.31 (dd, J=3, 10; 1 H) 3.6 (m, 4 H), 3.3 (m, 2 H), 2.9 (m, 4 H), 2.7 (m, 2 H), 2.3 (m, 2 H), 2.1 (m, 3 H), 1.9 (m, 4 H), 1.6 (m, 4 H), 1.3 (m, 4 H); MS m/e 416 (MH+). EXAMPLE 5 N-3-(4-PiperidinepropionvlVisonipecotvl-(3-amino-3-metrtvn propionic acid « TFA (5) Compound 5 was prepared as shown in Scheme AA. Intermediate AA2 (0.36 mmol) was swelled with DCE (5 mL), treated with ethyl isonipecotate (0.36 mmol), DIC (0.72 mmol), and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1 ), and the ethyl ester cleaved to the corresponding acid with KOTMS (see Example 1 ). The resin was swelled with DMF (5 mL), the acid coupled with methyl 3-amino-3- methylpropionate (0.36 mmol), and then the synthesis completed as shown in Example 1. Compound 5 was isolated as a tan glass (0.033 g): 1 H NMR (CD3OD) δ 4.5 (m, 1 H), 4.2 (m, 1 H), 3.9 (m, 1 H), 3.3 (m, 2 H), 3.3 (m, 3 H), 3.1 (m, 1 H), 2.9 (m, 3 H), 2.7 (m, 2 H), 2.4 (m, 2 H), 2.0 (m, 2 H), 1.7 (m, 2 H), 1.5 (m, 6 H), 1.3 (m, 2 H), 1.15 (d, J=9, 3 H); MS m/e 354 (MH+). EXAMPLE 6 N-3-(4-PiDeridinepropionvn-isoniDecotvl-r3-amino-3-f4-carboxvphenvn] propionic acid * TFA (Bi Compound 6 was prepared as shown in Scheme AA. Intermediate AA2 (0.36 mmol) was swelled with DCE (5 mL), treated with ethyl isonipecotate (0.36 mmol), DIC (0.72 mmol), and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1 ), and the ethyl ester cleaved to the corresponding acid with KOTMS (see Example 1 ). The resin was swelled with DMF (5 mL), the acid coupled with methyl 3-amino-3- (4-carboxymethyl-phenyl)propionate (0.36 mmol), and then the synthesis completed as shown in Example 1. Compound 6 was isolated as a tan glass (0.034 g): 1 H NMR (CD 3 OD) δ 7.9 (m, 3 H), 7.43 (d, J=5, 2 H), 5.4 (m, 1 H), 4.5 (m, 1 H), 4.0 (m, 1 H), 3.3 (m, 4 H), 3.1 (m, 1 H), 2.9 (m, 2 H), 2.7 (m, 2 H), 2.7 (m, 1 H), 2.5 (m, 4 H), 2.0 (m, 2 H), 1.2-1.9 (m, 10 H); MS m/e 460 (MH+). EXAMPLE 7 N-3-f4-N-Methvl-piperidinepropionvM-nipecotvl-3-aminopropionic acid • TFA Compound 7 was prepared as shown in Scheme AD. Resin-bound Fmoc-β- Ala (1 mmol) was treated with 20% piperidine/DMF (10 mL), agitated for 2h, and the solvent removed. The resin was washed with DMF, swelled with DMF (10 mL), and treated with Fmoc-nipecotic acid (1 mmol), DIC (2 mmol), and DIEA (1 mmol). The resin was agitated for 16 h, the solvent removed, and the resin washed with DMF and DCM. The resin was treated with 20% piperidine/DMF (10 mL) for 2h, the solvent removed, and the resin washed with DMF. The resin was swelled with DMF (10 mL), treated with 4-N- methylpiperidinepropionic acid (1 mmol), DIC (2 mmol), and DIEA (1 mmol), and agitated for 16 h. The solvent was removed and the resin washed with DMF and DCM. The resin was cleaved with 95% TFA (10 mL) and the TFA evaporated to afford 7 as a white powder (0.26 g): mp 172-177°C; 1 H NMR (CDCI3) δ 4.4 (m, 1 H), 3.7 (m, 1 H), 3.4 (m, 1 H), 3.2 (m, 1 H), 3.1 (m, 1 H), 2.7 (m, 2 H), 2.3 (m, 6 H), 2.21 (s, 3 H), 1.9 (m, 4 H), 1.3-1.8 (m, 10 H); MS m/e 354 (MH+). EXAMPLE 8 N-3-M-Piperidinepropionvn-nipecotvl-4-oxonipecotic acid • TFA (B) Compound 8 was prepared as shown in Scheme AA. Intermediate AA2 (0.36 mmol) was swelled with DCE (5 mL), treated with ethyl nipecotate (0.36 mmol), DIC (0.72 mmol), and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1), and the ethyl ester cleaved to the corresponding acid with KOTMS (see Example 1). The resin was swelled with DMF (5 mL), the acid coupled with methyl 4-oxo- nipecotate (0.36 mmol), and then the synthesis completed as shown in Example 1. Compound 8 was isolated as a clear glass (0.04 g): 1 H NMR (DMSO-d 6 ) δ 8.5 (m, 1 H), 8.2 (m, 1 H), 6.5 (m, 1 H), 4.3 (m, 1 H), 3.4-3.8 (m, 4 H), 3.2 (m, 2 H), 3.0 (m, 1 H), 2.8 (m, 2 H), 2.2-2.6 (m, 6 H), 1.8 (m, 2 H), 1.1-1.7 (m, 11 H); MS m/e 394 (MH+). EXAMPLE 9 N-3-f4-Piperidinepropionvn-nipecotvl-r3-amino-3-f2-trimethvlsilvlethvnvni propionic acid » TFA (9) Compound 9 was prepared as shown in Scheme AA. Intermediate AA2 (0.36 mmol) was swelled with DCE (5 mL), treated with ethyl nipecotate (0.36 mmol), DIC (0.72 mmol), and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1 ), and the ethyl ester cleaved to the corresponding acid with KOTMS (see Example 1 ). The resin was swelled with DMF (5 mL), the acid coupled with methyl 3-amino-3- (2-trimethylsilylethynyl)propionate (for a preparation, see J. Zablocki, J. Med. Chem. 1995, 38, 2378; 0.36 mmol), and then the synthesis completed as shown in Example 1. Compound 9 was isolated as a yellow glass (0.12 g): 1 H NMR (CD 3 OD) δ 3.8 (m, 1 H), 3.2-3.4 (m, 4 H), 2.9 (m, 3 H), 2.7 (m, 2 H), 2.3-2.5 (m, 2 H), 1.9 (m, 4 H), 1.1-1.9 (m, 13 H), 0.0 (s, 9 H); MS m/e 436 (MH+). EXAMPLE 10 N-(6-Aminocaprovn-nipecotvl-3-amino.3-/3-pvridyhpropionic acid * 3TFA am Compound 10 was prepared as shown in Scheme AA. Resin-bound 6- aminocaproic acid (0.36 mmol) was swelled with DCE (5 mL), treated with ethyl nipecotate (0.36 mmol), DIC (0.72 mmol), and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1 ), and the ethyl ester cleaved to the corresponding acid with KOTMS (see Example 1 ). The resin was swelled with DMF (5 mL), the acid coupled with methyl 3-amino-3-(3-pyridyl)propionate (0.36 mmol), and then the synthesis completed as shown in Example 1. Compound 10 was isolated as a clear glass (0.008 g): 1 H NMR (DMSO-d 6 ) δ 8.6 (m, 2 H), 8.1 (s, 1 H), 7.0-7.7 (m. 5 H), 5.15 (t, J=3, 1 H), 4.4 (m, 1 H), 4.1 (m, 1 H), 3.7 (m, 2 H), 3.1 (m, 1 H), 2.7 (m, 4 H), 2.5 (m, 1 H), 2.3 (m, 2 H), 1.2-1.9 (m, 11 H); MS m/e 391 (MH+). Anal, calcd. for C20H30N4O4 • 3TFA • 2H 2 0 (768.60): C, 40.63; H, 4.85; N, 7.29; F, 22.25. Found: C, 40.81 ; H, 4.70; N, 6.12; F, 23.83. EXAMPLE 11 N-3-f4-Piperidinepropionvπ-R-M-nipecotyl-(3-amino-2-hvdroxvl propionic acid - TFA (1 1) Compound 11 was prepared as shown in Scheme AA. Intermediate AA2 (0.36 mmol) was swelled with DCE (5 mL), treated with ethyl R-nipecotate (0.36 mmol), DIC (0.72 mmol), and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1 ), and the ethyl ester cleaved to the corresponding acid with KOTMS (see Example 1 ). The resin was swelled with DMF (5 mL), the acid coupled with methyl 3-amino-2- hydroxypropionate (0.36 mmol), and then the synthesis completed as shown in Example 1. Compound 11 was isolated as a pink glass (0.05 g): 1 H NMR (DMSO-dβ) δ 8.5 (m, 1 H), 8.2 (m, 1 H), 7.6 (m, 1 H), 4.0-4.4 (m, 2 H), 3.7 (m, 1 H), 3.2 (m, 3 H), 2.8 (m, 3 H), 2.6 (m, 1 H), 2.1-2.3 (m, 3 H), 1.8 (m, 4 H), 1.0-1.4 (m, 10 H); MS m/e 356 (MH + ). EXAMPLE 12 N-3-f4-Piperidineethanesulfonyn-nipecotvl-3-aminopropionic acid • HCI αa Compound 12 was prepared as shown in Scheme AE. Intermediate AE1 was synthesized by the following procedure. 2-(4-Pyridine)ethanesulfonic acid (3.0 g, 0.016 mol) was dissolved in aq. HCI (2.0 M, 12 mL) and this solution treated with platinum dioxide (0.13 g) and hydrogenated at 50 psi and RT for 18 h. This mixture was filtered through Celite and evaporated to afford 2-(4-piperidine)ethanesulfonic acid • HCI (3.5 g, white powder). This powder was dissolved in aq. THF (1 :1 , 70 mL) at RT and treated with NMM (3.7 mL, 2.2 eq.) and benzyl chloroformate (2.2 mL, 1 eq.). This mixture was stirred for 15 h, acidified with aq. citric acid, and extracted with CHCI3 (2x100 mL). The organic layer was dried with Na 2 S0 4 and evaporated to afford 2- (4-N-Z-piperidine)ethanesulfonic acid (2.75 g, gold oil). This oil was converted to final product 12 in five synthetic steps (Scheme AE, W. J. Hoekstra, J. Med. Chem. 1995, 38, 1582) and isolated as a clear glass (0.060 g): 1 H NMR (DMSO-d 6 ) δ 8.9 (m, 1 H), 8.6 (m, 1 H), 3.5 (m, 2 H), 3.1 - 3.3 (m, 4 H), 3.0 (m, 2 H), 2.6-2.8 (m, 4 H), 2.3 (m, 3 H), 1.65-1.9 (m, 5 H), 1.6 (m, 3 H), 1.2-1.4 (m, 5 H); MS m/e 376 (MH+). EXAMPLE 13 N-3-(4-Pipflririinfipropionvh-nipecotvl-5H-f2-aminoethvntetrazole • HCI (1 3) Compound 13 was prepared as shown in Scheme AC. Intermediate AC1 (prepared as in W. J. Hoekstra, J. Med. Chem. 1995, 38, 1582; 1.9 mmol) was dissolved in DCM (50 mL) and treated with BOP-CI (1.9 mmol), NMM (1.9 mmol), and 3-aminopropionitrile (1.9 mmol). The reaction was stirred for 18 h, diluted with sat'd NH 4 CI, and the layers separated. The organic layer was evaporated and the product purified by silica gel chromatography (10%EtOH/DCM) to give an oil. The oil was dissolved in toluene (10 mL), treated with azidotrimethylsilane (2.4 mmol) and dibutyltin oxide (1.2 mmol), and heated at reflux for 16 h. Cooling gave a brown ppt which was triturated with Et 2 0. This solid was hydrogenated over platinum dioxide (0.08 g) in MeOH (12 mL) at 50 psi for 15 h, filtered, and evaporated to give 13 as a yellow foam (0.065 g): 1 H NMR (DMSO-d 6 ) δ 8.9 (m, 1 H), 8.6 (m, 1 H), 8.13 (d, J-28, 1 H), 4.2 (m, 2 H), 3.2 (m, 3 H), 3.0 (m, 4 H), 2.7 (m, 4 H), 2.31 (q, J=8, 2 H), 1.7-1.9 (m, 3 H), 1.4-1.6 (m, 5 H), 1.1-1.3 (m, 4 H); MS m/e 364 (MH+). EXAMPLE 14 N-3-(4-N-Methvl-piperazinepropionvn-nipecotvl-f3-amino-3-(3.4- methylenedioxyphenynipropionic acid « Na ii A) Compound 14 was prepared as shown in Scheme AB. Ethyl nipecotate (3 mmol) was dissolved in DCM (50 mL), treated with acryloyl chloride (3 mmol) and NMM (3 mmol), and stirred for 1 h. The solvent was evaporated and the residue dissolved in EtOH (50 mL) and treated with N- methylpiperazine (3 mmol). The solution was warmed at 60°C for 15 h, cooled to RT, and the solvent evaporated. The residue was partitioned between DCM (100 mL) and water (10 mL), and the layers separated. The organic layer was dried and evaporated to give a foam. The foam was dissolved in water, treated with NaOH (3 mmol), stirred for 1 h, and evaporated to give AB3*Na. The synthesis was completed as illustrated (W. J. Hoekstra, J. Med. Chem. 1995, 38, 1582) using methyl 3-amino-3-(3,4- methylenedioxyphenyl)propionate (2.5 mmol) to give 14 as a white, amorphous solid (0.14 g): 1 H NMR (D 2 0) δ 6.8 (m, 3 H), 5.91 (s, 2 H), 5.0 (m, 1 H), 4.0 (m, 1 H), 3.7 (m, 1 H), 2.8-3.4 (m, 11 H), 2.69 (s, 3 H), 2.4-2.6 (m, 7 H), 1.9 (m, 1 H), 1.7 (m, 2 H), 1.5 (m, 1 H); MS m/e 475 (MH + ). Anal, calcd. for C24H33N4O6 • Na • H 2 0 (514.56): C, 56.02; H, 6.86; N, 10.89. Found: C, 55.72; H, 6.78; N, 10.52. EXAMPLE 15 N-3-M-N-Methvl-piperazinepropionvn-nipecotvl-r3-amino-3-f3- guinolinvh]propionic acid * 3TFA IΛ 5) Compound 15 was prepared as described in Example 14. The synthesis was completed as illustrated (W. J. Hoekstra, J. Med. Chem. 1995, 38, 1582) using methyl 3-amino-3-(3-quinolinyl)propionate (6 mmol) with AB3. Compound 15 was isolated as a yellow powder (1.89 g): 1 H NMR (DMSO- d 6 ) δ 8.94 (s, 1 H), 8.12 (s, 1 H), 7.9 (m, 2 H), 7.6 (m, 2 H), 7.07 (d, J=4, 1 H), 5.2 (m, 1 H), 4.1 (m, 1 H), 3.7 (m, 1 H), 3.1-3.3 (m, 2 H), 2.9 (m, 2 H), 2.6 (m, 2 H), 2.43 (s, 3 H), 1.9-2.4 (m, 12 H), 1.2-1.5 (m, 4 H); MS m/e 482 (MH+). EXAMPLE 16 N-3-(4-Piperidinepropionvn-R-r-)-nipecotvl-ffS)-3-amino-3-r3.4- methvtenedioxvphenvn]propionic acid • HCI (1 61 To a cooled (5°C) solution of Boc-R-nipecotic acid (9 mmol) and methyl (S)- 3-amino-3-(3,4-methylenedioxyphenyl)]propionate (see AG5 example; 9 mmol) in MeCN (100 mL) was added HBTU (9 mmol), HOBT (9 mmol), and NMM (18 mmol). This mixture was stirred for 15 h, diluted with water (10 mL), and evaporated. The residue was diluted with EtOAc (100mL) and the organic layer dried and evaporated to give a white foam. The foam was treated with HCI (2 N in dioxane, 20 mL), stirred for 3 h, and evaporated to a foam. The foam was dissolved in MeCN (100 mL) and treated with Boc- piperidinepropionic acid (7 mmol), HBTU (7 mmol), HOBT (7 mmol), and NMM (14 mmol) with stimng for 6 h. The mixture was diluted with water (10 mL), evaporated, and diluted with EtOAc (100 mL). The organic layer was dried, evaporated, and purified by silica gel chromatography (7% EtOH/DCM) to give a foam. To a solution of the foam (4.6 mol) in THF cooled in an ice bath was added LiOH»H 2 0 (6.9 mmol dissolved in 30 mL water) dropwise. This mixture was stirred for 1.5 h, acidified with AcOH (1.7 mL), and warmed to RT. This solution was diluted with CHCI 3 (75 mL) and the layers separated. The organic layer was dried (Na 2 S0 4 ) and evaporated to give a white foam. The foam was dissolved in dioxane (20 mL) and anisole (0.3 mL), cooled in an ice bath, treated with HCI (15 mL, 4.0 N in dioxane), and stirred for 3 h to give a ppt. The ppt was filtered and washed with Et 2 0 (150 mL) and MeCN (20 mL) to give 16 as a white powder (1.78 g): mp 190- 200°C; 1 H NMR (DMSO-d 6 ) δ 8.9 (m, 1 H), 8.6 (m, 1 H), 8.4 (m, 1 H), 6.83 (d, J=5, 1 H), 6.79 (d, J=5, 1 H), 6.7 (m, 1 H), 5.95 (s, 2 H), 5.08 (dd, J=5, 11 , 1 H), 4.1-4.3 (m, 1 H), 3.7 (m, 1 H), 3.15 (d, J=10, 2 H), 3.0 (m, 1 H), 2.7 (m, 2 H), 2.6 (m, 3 H), 2.31 (d. J«7, 2 H), 1.81 (d, J-10, 2 H), 1.2-1.7 (m, 11 H); MS m/e 460 (MH+); [α]24 D -0.478° (c 1.00, MeOH). EXAMPLE 17 N-3-(4-Piperidinepropionvn-hexahvdroazepine-3-carboxv-r3-amino-3-f3- quinplinviηprppionic acid « 2TFA (1 7) Compound 17 was prepared as shown in Scheme AA. Intermediate AA2 (0.36 mmol) was swelled with DCE (5 mL), treated with methyl hexahydroazepine-3-carboxylate • HCI (0.36 mmol), DIC (0.72 mmol), and DIEA (0.72 mmoL), and agitated for 16 h. The solvent was removed, the resin washed (see Example 1 ), and the methyl ester cleaved to the corresponding acid with KOTMS (see Example 1 ). The resin was swelled with DMF (5 mL), the acid coupled with methyl 3-amino-3-(3- quinolinyl)propionate (0.36 mmol), and then the synthesis completed as shown in Example 1. Compound 17 was isolated as a glass (0.10 g): 1 H NMR (D 2 0) δ 9.06 (s, 1 H), 8.9 (m, 1 H), 8.2 (m, 1 H), 8.04 (s, 1 H), 8.0 (t, J=4, 2 H), 7.8 (t, J=4, 2 H), 5.5 (m, 1 H), 3.8 (m, 1 H), 3.3 (m, 4 H), 3.0 (m, 2 H), 2.7 (m, 4 H), 2.0-2.4 (m, 6 H), 1.7-1.9 (m, 4 H), 1.1-1.6 (m, 8 H); MS m/e 481 (MH+). EXAMPLE 18 N-3-(4-Piperidinepropionvn-R-f-Wnipecotvl-rfg)-3-amino-3-(3.- quinolinynipropionic acid « 2HCI M B) Compound 18, prepared as described in Example 16 starting with Boc-R- nipecotic acid (7.1 mmol) and methyl (S)-3-amino-3-(3-quinolinyl)propionate (see example AG5; 7.1 mmol), was isolated as white flakes (1.11 g): mp 142- 144°C; MS m/e 467 (MH + ); [α] 24 o -173° (c 0.1 , MeOH). Anal, calcd. for C26H34N4O4 • 2.25 HCI • H 2 0 (566.64): C, 55.11 ; H, 6.80; N, 9.89; Cl, 14.08. Found: C, 54.85; H, 6.62; N, 10.04; Cl, 13.68. EXAMPLE 19 N-3-(4-Piperidinepropionyn-R-^μnipecotvl-ffS^3-amino-3-(2-^butvlethvnvn^ propionic acid « HCI 11 9) Compound 19, prepared as described in Example 16 starting with Boc-R- nipecotic acid (3.2 mmol) and methyl (S)-3-amino-3-(2-f- butylethynyl)propionate (see J. A. Zablocki, J. Med. Chem. 1995, 38, 2378; 3.2 mmol), was isolated as a white powder (0.33 g): MS m/e 420 (MH + ). Anal, calcd. for C23H37N3O4 • 1.07 HCI • 0.43 H 2 0 (468.97): C, 59.21 ; H, 8.42; N, 8.96; Cl, 8.09. Found: C, 58.92; H, 8.58; N, 8.76; Cl, 7.82. EXAMPLE 2Q N-3-f4-Piperidinepropvn-nipecotvl-r(S -3-amino-3-(3.4- methvlenedioxvphenvnipropionic acid « 2TFA (20) Compound 20 was prepared as shown in Scheme AF. Intermediate AF3 (2.8 mmol) was dissolved in benzene (50 mL), treated with ethyl nipecotate (2.8 mmol), and heated at reflux for 7 h. The reaction was cooled, partitioned between water (15 mL) and EtOAc (70 mL), and the layers separated. The organic layer was dried and evaporated to give AF4. AF4 was converted to 20 as previously described (W. J. Hoekstra, J. Med. Chem. 1995, 38, 1582) and isolated as a white powder (0.33 g): 1 H NMR (CD3OD) δ 8.6-8.8 (m, 3 H), 6.7-6.9 (m, 3 H), 5.91 (s, 2 H), 5.1-5.2 (m, 1 H), 3.3-3.5 (m, 4 H), 2.8-3.1 (m, 6 H), 2.6-2.7 (m, 3 H), 1.5-2.0 (m, 11 H), 1.2-1.4 (m, 4 H); MS m/e 446 (MH+). EXAMPLE 21 N-3-(4-Piperidinepropionvn-R-r-V-ni p ecotvl-ffSW3-amino-3-f3-Pvridyn] propionic acid • 2TFA f211 Compound 21 , prepared as described in Example 16 starting with Boc-R- nipecotic acid (6.4 mmol) and methyl (S)-3-amino-3-(3-pyridyl)propionate (see example AG5; 6.4 mmol), was isolated as a white amorphous solid (1.60 g): mp 74-81 °C; MS m/e 417 (MH + ). Anal, calcd. for C22H32N4O4 • 2.1 C2HF3O2 • 0.7 H 2 0 (668.58): C, 47.07; H, 5.35; N, 8.38; F, 17.90; KF, 1.89. Found: C, 47.08; H, 5.31 ; N, 8.41 ; F, 17.68; KF, 2.00. EXAMPLE 22 N-3-(4-Piperidinepropionvn-R-Mnipecctvl-r(S)-2-f3- methoxvanilinotearhonvlamino-3-aminolpropionic acid (221 Methyl Boc-R-nipecotyl-[(S)-2-Z-amino-3-amino]propionate (prepared from methyl N-α-Z-L-diaminopropionate and Boc-R-nipecotic acid as shown in Example 16; 9.5 mmol) was dissolved in MeOH (40 mL) and hydrogenated at 50 psi over palladium hydroxide (0.4 g) for 24 h. The mixture was filtered and evaporated to give white solid AH2. AH2 (9.1 mmol) was dissolved in DCM (100 mL), cooled (5°C), treated with 3-methoxyphenylisocyanate (9.1 mmol) and NMM (9.1 mmol), and stirred for 17 h. The solution was diluted with sat'd NH 4 CI (10 mL), the layers separated, and the organic layer dried, evaporated to an oil, and purified by silica gel chromatography (4% EtOH/DCM) to give AH3. Intermediate AH3 was converted to 22 in four steps as in Example 16 to afford a white amorphous solid (1.35 g): mp 72- 76°C; 1 H NMR (DMSO-d 6 ) δ 8.7 (m, 3 H), 7.8 (m, 1 H), 7.1 (m, 2 H), 6.8 (d, 1 H), 6.5 (d, 2 H), 3.66 (s, 3 H), 3.4 (m, 2 H), 3.2 (d, 2 H), 2.7 (dd, 4 H), 2.3 (m, 3 H), 1.6 (m, 3 H), 1.1-1.7 (m, 11 H); MS m/e 504 (MH+). Anal, calcd. for C25H37N5O6 • 1.2 HCI • 1.0 H 2 0 (565.37): C, 53.11 ; H, 7.17; N, 12.39; Cl, 7.53. Found: C, 53.40; H, 7.44; N, 12.14; Cl, 7.66. Using the same general synthesis technique as described in Example 22, the compounds of Examples 26, 28-30 were made according to Scheme AH recited in the particular example. For carbamate analogues, the acylating agent employed was the appropriate alkyl chloroformate (analogous conversion of AH2 to AH3; one molar equivalent). For sulfonamides, the sulfonating agent employed was the appropriate sulfonyl chloride (one molar equivalent). EXAMPLE 23 N-3-r4-Piperidinepropionvn-R-Mnipecotvl-f(Sl-2-benzvloxvcarbonvlamino- 3-amino)propionic acid « HCI (231 Compound 23, prepared from methyl N-α-Z-L-diaminopropionate (8.8 mmol) and Boc-R-nipecotic acid (8.8 mmol) as shown in Example 16, was isolated as a white powder (1.65 g): mp 110-113°C; MS m/e 489 (MH+). Anal, calcd. for C25H36N4O6 • 1.15 HCI • 0.5 H 2 0 • 0.5 Dioxane (583.57): C, 55.56; H, 7.41 ; N. 9.60; Cl, 6.9g. Found: C, 55.23; H, 7.79; N, 9.85; Cl, 7.01. EXAMPLE 24 N-3-(4-Piperidinepropionvl1-R-Mnipecotvl-f(S1-2-f3- chlorobenzvloxvlcarbonvlamino-3-aminolpropionic acid * HCI (241 Compound 24, prepared by reacting 3-chlorobenzyloxycarbonyl chloride (6.6 mmol) with AH2 (6.6 mmol) as described in Example 22, was isolated as a white amorphous solid (1.33 g): mp 89-96°C; MS m/e 524 (MH + ). Anal. calcd. for C25H35CIN4O6 • 1.25 HCI • 0.5 H 2 0 • 1.0 Dioxane (637.20): C, 50.89; H, 7.08; N, 8.78; Cl, 12.52. Found: C, 51.10; H, 6.71 ; N, 8.38; Cl, 12.20. EXAMPLE 25 N-3-(4-PipQririinepropionyl1-R-(-1nipecotyl-ffS1-2-benzvlsulfonvlamino-3- amiπolpropioπic acid * HCI (25) Compound 25, prepared by reacting benzylsulfonyl chloride (5.2 mmol) with AH2 (5.2 mmol) as shown in Example 22, was isolated as a white powder (0.87 g): mp 145-14g°C; MS m/e 509 (MH+). Anal, calcd. for C24H36N4O6S • 1.3 HCI • 0.3 Dioxane (568.06): C, 50.75; H, 7.04; N, 9.86; Cl, 8.11. Found: C, 51.03; H, 6.03; N, 9.46; Cl, 7.85. EXAMPLE 26 N-3-(4-Piperidinepropionvl1-R-Mnipecotvl-f(S1-2-(3.5- dimethoxvanilinolcarbonvlamino-3-aminolpropionic acid * HCI (261 Compound 26, prepared by reacting 3,5-dimethoxyphenylisocyanate (10.2 mmol) with AH2 (10.2 mmol) as shown in Example 22, was isolated as a white powder (1.89 g): mp 190-ig3°C; MS m/e 534 (MH+). Anal, calcd. for C26H39N5O7 • 1.2 HCI • 0.2 Dioxane (585.40): C, 53.35; H, 7.20; N, 1 1.96; Cl, 7.27. Found: C, 53.48; H, 7.38; N, 12.05; Cl, 6.97. EXAMPLE 27 N-f(4.4'-Bipiperidin-1 -yl-1carbonyl]-R-(-l-nipecotyl-[(S1-3-amino-3-(3-pvridvl1] prooipnic acid * 3HCI (271 Intermediate AJ1 (5.5 mmol), prepared as shown in Example 16, was dissolved in DCM (140 mL), cooled (5°C), treated with p- nitrophenylchloroformate (5.5 mmol) and (16.5 mmol), and stirred for 2 h. The mixture was diluted with water (15 mL), the layers separated, and the organic layer dried and evaporated to an oil. The oil was dissolved in MeCN (70 mL). treated with N-Boc-4,4'-bipiperidine (7.5 mmol) and DMAP (5.5 mmol), and heated at reflux for 24 h. The mixture was cooled, evaporated to a solid, and partitioned between EtOAc (150 mL) and NaOH (1 N, 20 mL). The layers were separated, and the organic layer dried, evaporated to a solid, and purified by silica gel chromatography (8% EtOH/DCM) to give green glass AJ2 (1.5 mmol). AJ2 was saponified and deprotected as described in Example 16 to give 27 as a pale yellow powder (0.73 g): mp 121 -125°C; MS m/e 472 (MH+). Anal, calcd. for C25H37N5O4 • 3.6 HCI • 1.0 Dioxane (690.98): C, 50.41 ; H, 7.09; N, 10.14; Cl, 18.47. Found: C. 50.80; H, 7.31 ; N, 10.20; Cl, 18.78. EXAMPLE 28 N-3-(4-Piperidinepropionvl1-R-(-1nipecotvl-r(S1-2-(2- naphthvlammolcarbonvlamino-3-amino)propionic acid « HCI (281 Compound 28, prepared by reacting 2-naphthylisocyanate (8.5 mmol) with AH2 (8.5 mmol) as shown in Example 22, was isolated as a white powder (1.65 g): mp 187-193°C; MS m/e 524 (MH+). Anal, calcd. for C28H37N5O5 • 1.36 HCI • 0.72 Dioxane (602.07): C, 55.86; H, 7.3g; N, 11.63; Cl, 8.01. Found: C, 56.03; H, 7.11 ; N, 11.23; Cl, 7.g7. EXAMPLE 29 N-3-(4-Piperidinepropionyl1-R-(-lnipecotvl-aminomethvl-5-(S1-(3-N- benzvl1imidazoline-2.4-dione » HCI (291 N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(2- benzylamino)carbonylamino-3-amino]propionic acid hydrochloride (0.15 g), prepared from intermediate AH2 (4.4 mmol) and benzyl isocyanate (4.4 mmol) as described in Example 22, was dissolved in aq. HCI (3 N) and stirred for 18 h at RT. This solution was concentrated in vacuo to give a white solid. This solid was triturated and dried to give 29 as a white foam (0.144 g): ^H NMR (DMSO-d 6 ) δ 9.0 (m, 1 H), 8.6 (m, 1 H), 8.3 (m, 1 H), 7.2 (m, 5 H), 4.48 (s, 2 H), 4.2 (m, 2 H), 3.7 (m, 1 H), 3.4 (m, 1 H), 3.2 (d, 3 H), 2.7 (d, 3 H), 2.2 (m, 3 H), 1.7 (m, 3 H), 1.0-1.6 (m, 10 H); MS m/e 470 (MH + ). EXAMPLE 3Q N-3-(4-Piperidinepropionyl)-R-(-)nipecQtyl-[(S)-2-(2- pheπethylamiπQ)carpQπylaminQ-3-aminQ]propipnic acid • HCQ 2 H (3 Q) Compound 30, prepared by reacting 2-phenethylisocyanate (4.1 mmol mmol) with AH2 (4.1 mmol) as shown in Example 22, was isolated as a tan foam (0.41 g): mp 65-72°C; MS m/e 502 (MH+). Anal, calcd. for C26H39N5O5 • 1.2 HC0 2 H • 1.0 H 2 0 (574.87): C, 56.83; H, 7.61 ; N, 12.18. Found: C, 57.12; H, 7.80; N, 11.85. 6-Methyl-3-pvridine-carboxaldehvde (AK21 Aldehyde precursor AK2 was prepared in two steps using standard conditions. AK1 (0.066 mol) was dissolved in THF (100 mL), cooled (-78°C), treated with LiAIH 4 (0.066 mol), and stirred for 4 h. The reaction was quenched with sat'd NH 4 CI, warmed, filtered with CHCI 3 washes (250 mL), and the layers separated. The organic layer was dried and evaporated to give a clear oil (0.054 mol). The oil was dissolved in DCM (200 mL), treated with Mn0 2 (70 g), and heated at reflux for 6 h. The mixture was cooled, filtered, and the solvent evaporated to give AK2 (0.052 mol) as a brown oil. EXAMPLE 31 N-3-(4-PiperidineprQpionvl1-R-(-1nipecotvl-r(S1-3-amino-3-(β-methvl-3- pyridvlll propionic acid * 2HCI (311 Compound 31 , prepared as described in Example 16 starting with Boc-R- nipecotic acid (6.9 mmol) and methyl (S)-3-amino-3-(6-methyl-3- pyridyl)propionate (see examples AK5, AG5; 6.9 mmol). Compound 31 was isolated as a white foam (1.20 g): mp 9g-105°C; MS m/e 431 (MH + ). Anal. calcd. for C23H34N4O4 • 2.24 HCI • 1.0 H 2 0 • 0.24 Acetonitrile (534.33): C, 51.70; H, 7.35; N, 11.11 ; Cl, 14.82. Found: C, 51.32; H, 7.45; N, 11.23; Cl, 14.42. EXAMPLE 32 N-3-(4-Piperidinepropionyl1-R-(-1nipecotvl-r(S1-3-amino-3-(5-bromQ-3- pyridyl)] propionic acid ♦ 2HCI (32) Compound 32, prepared as described in Example 16 starting with Boc-R- nipecotic acid (4.8 mmol) and methyl 3-S-amino-3-(5-bromo-3- pyridyl)propionate (see examples AK5, AG5; 4.8 mmol), was isolated as a white foam (1.24 g): mp 98-101 °C; MS m/e 496 (MH+). Anal, calcd. for C22H 3 ιBrN 4 θ4 • 2.2 HCI • 1.0 H 2 0 (593.67): C, 44.51 ; H, 5.98; N, 9.44; Cl, 13.14. Found: C, 44.17; H, 6.37; N, 9.81 ; Cl, 13.10. EXAMPLE 33 N-3-(4-Formamidinopiperidinepropionyl1-R-(-1nipecotvl-f(S1-3-amino-3-(3- pyridvll] propionic acid • 2HCI (331 Formamidine 33 was prepared according to the procedure of M. K. Scott (J. Med. Chem. 1983, 26, 534) as shown in Scheme AL. Intermediate AL1 (see Example 21 ; 2.3 mmol) was dissolved in EtOH (20 mL), treated with ethyl formimidateΗCI (3.7 mmol), stirred for 22 h, and filtered. The filtrate was treated with Et 2 0 (40 mL), cooled in an ice bath, and filtered to give glassy AL2. AL2 was dissolved in aq. HCI (4 N, 15 mL), stirred for 28 h, and evaporated to give 33 as a white foam (0.75 g): mp 49-55°C. 1 H NMR (DMSO-de) δ 9.35 (s, 1 H), 9.1 (m, 2 H), 8.8 (m, 2 H), 8.70 (d, 1 H), 8.5 (m, 1 H), 7.8 (m, 2 H), 5.2 (dd, 1 H), 4.2 (m, 1 H), 3.8 (m, 2 H), 3.2 (m, 2 H), 2.8 (m, 2 H), 2.6 (m, 1 H), 2.3 (m, 2 H), 1.8 (m, 3 H), 1.0-1.7 (m, 12 H); MS m/e 444 (MH+).

Claims: WE CLAIM: 1. A compound represented by the general formula (I): (0 wherein M is (CH2)m or piperidin-1-yl; wherein A is selected from any of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1 -yl, pyrrolidin-2-yl, pyrrolidin-3-yl, NHR 2 , or "9 wherein Rg is selected from any of H, alkyl, CH(NH), CMe(NH) or acyl; wherein Rio is H or C(0)N(R1 )YZ wherein Ri is selected from H or cycloalkyl; wherein R2 is selected from any of H, alkyl or acyl; wherein R5 is H or C(0)NHQ(CHW)rCθ2Rβ; wherein Q is selected from CH2, CH-aryl, CH-heteroaryl, CH-substituted-heteroaryl or CH-alkyl; W is selected from H or N(R6)T-R7, wherein Re is selected from any of H, alkyl or acyl, T is selected fron C(O), C(N-CN) or SO2, and R7 is selected from any of alkyl, aryl, aralkyl, alkoxy, or aminoalkyl; and Rs is selected from H, alkyl or aralkyl. wherein m is the integer 1 , 2, or 3; wherein X is selected from any of C(O), C(0)0, C(0)NH, CH 2 , or S0 2 ; wherein n is the integer 1 , 2, or 3; wherein r is 0 or 1 ; wherein R 1 is selected from H or cycloalkyl; wherein Y is selected from any of (CH2)p, CH(R 3 )(CH 2 ) q , (CH 2 )qCH(R3), (CH(COR 4 )CH2) q , (CH 2 ) q CHOH or piperidine-3-carboxyiic acid; with the proviso that when Y is (CH2)p and p is 2, X is other than C(O) or when X is C(O) then either R 1 is other than H or R 2 is other than H, and with the proviso that when Y is (CH(Cθ2R 4 )CH2)q X is other than C(O) or CH 2 ; wherein p is 2 or 3; wherein q is 1 , 2, or 3; wherein R 3 is alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, aralkyl or heteroaryl; wherein R 4 is H or alkyl or cycloalkyl; wherein Z is CO2H, Cθ2alkyl, SO3H, PO3H2 , or 5-tetrazole; provided that at least one of R5 and Ri 0 is hydrogen; or the enantiomer or the pharmaceutically acceptable salt thereof. 2. The compound of claim 1 , wherein R5 is H, R-| rj is H or C(0)N(R 1 )YZ , M is (CH2)m and A is selected from any of piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl or NHR 2 . 3. The compound of claim 1 , wherein R5 is H and R 2 is hydrogen. 4. The compound of claim 1 , wherein R5 is H and m is 1or 2. 5. The compound of claim 1 , wherein R5 is H and X is C(O). 6. The compound of claim 1 , wherein R5 is H and R 1 is hydrogen. 7. The compound of claim 1 , wherein R5 is H and Y is 4-oxo-nipecotic acid. 8. The compound of claim 1 , wherein R5 is H and q is 1. 9. The compound of claim 1 , wherein R5 is H and R 3 is aryl. 10. The compound of claim 1 , wherein R5 is H and R 4 is hydrogen. 11. The compound of claim 1 , wherein R5 is H and Z is CO2H. 12. The compound of claim 1 , wherein the group C(0)N(R 1 )YZ is attached at the 3- or 4-position of the central azacycle. 13. The compound of claim 1 , wherein the group C(0)N(R 1 )YZ is attached at the 3-position of the central azacycle. 14. The compound of claim 1 , selected from any of: N-3-(4-Piperidinepropionyl)-nipecotyl-(3-amino-3-phenyl) propionic acid N-(4-Piperidinemethylaminocarbonyl)-nipecotyl-(3-amino-2-methyl) propionic acid N-(4-Piperidinemethyloxycarbonyl)-nipecotyl-D-aspartic acid α-methyl ester N-3-(4-Piperidinepropionyl)-pyrrolidine-3-carboxy-[3-amino-3-(4-tolyl)] propionic acid N-3-(4-Piperidinepropionyl)-isonipecotyl-(3-amino-3-methyl) propionic acid N-3-(4-Piperidinepropionyl)-isonipecotyI-[3-amino-3-(4-carboxyphenyl)] propionic acid N-3-(4-N-Methyl-piperidinepropionyl)-nipecotyl-3-aminopropionic acid N-3-(4-Piperidinepropionyl)-nipecotyl-4-oxonipecotic acid N-3-(4-Piperidinepropionyl)-nipecotyl-[3-amino-3-(2-trimethylsilylethynyl)] propionic acid N-(6-Aminocaproyl)-nipecotyl-3-amino-3-(3-pyridyl)propionic acid N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-(3-amino-2-hydroxy) propionic acid N-3-(4-Piperidineethanesulfonyl)-nipecotyl-3-aminopropionic acid N-3-(4-Piperidinepropionyl)-nipecotyl-5H-(2-aminoethyl)tetrazole N-3-(4-N-Methyl-piperazinepropionyl)-nipecotyl-[3-amino-3-(3,4- methylenedioxyphenyl)]propionic acid N-3-(4-N-Methyl-piperazinepropionyl)-nipecotyl-[3-amino-3-(3,- quinolinyl)]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3,4- methylenedioxyphenyl)]propionic acid N-3-(4-Piperidinepropionyl)-hexahydroazepine-3-carboxy-[3-amino-3-(3- quinolinyl)]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3- quinolinyl)]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(2-f-butylethynyl)] propionic acid N-3-(4-Piperidinepropyl)-nipecotyl-[(S)-3-amino-3-(3,4- methylenedioxyphenyl)]propionic acid, and N-3-(4-Piperidinepropionyl)-R-(-)-nipecotyl-[(S)-3-amino-3-(3-pyridyl)] propionic acid. 15. The compound of claim 1, wherein Rι 0 is H, R5 is H or C(0)NHQ(CHW) r COOR 8 , M is piperidin-1 -yl and A is 16. The compound of claim 1 , wherein R 10 is H and X is C(O). 17. The compound of claim 1 , wherein R 10 is H and Q is (CH 2 ). 18. The compound of claim 1 , wherein R 10 is H and W is N(R 6 )-T-R 7 . 19. The compound of claim 1 , wherein R 10 is H and T is C(O). 20. The compound of claim 1 , wherein R 10 is H and R 9 is H. 21. The compound of claim 1 , wherein R 10 is H and R 6 is H. 22. The compound of claim 1 , wherein R 10 is H and R 7 is NH(CH 2 )zPh. 23. The compound of claim 1 , wherein R 10 is H and R 7 is H. 24. The compound of claim 1 , wherein n is 2. 25. The compound of claim 1 , selected from any of: N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(3- methoxyanilino)carbonylamino-3-amino]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-benzyloxycarbonylamino- 3-amino]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(3- chlorobenzyloxy)carbonylamino-3-amino]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-benzylsulfonylamino-3- amino]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(3,5- dimethoxyanilino)carbonylamino-3-amino]propionic acid N-[(4,4'-Bipiperidin-1-yl-)carbonyl]-R-(-)-nipecotyl-[(S)-3-amino-3-(3-pyridyl)] propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(2- naphthylamino)carbonylamino-3-amino]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-aminomethyl-5-(S)-(3-N- benzyl)imidazoline-2,4-dione • HCI N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-2-(2- phenethylamino)carbonylamino-3-amino]propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-3-amino-3-(6-methyl-3- pyridyl)] propionic acid N-3-(4-Piperidinepropionyl)-R-(-)nipecotyl-[(S)-3-amino-3-(5-bromo-3- pyridyl)] propionic acid, and N-3-(4-Formamidinopiperidinepropionyl)-R-(-)nipecotyl-[(S)-3-amino-3-(3- pyridyl)] propionic acid. 26. A composition for treating platelet-mediated thrombotic disorders comprising the compound of Claim 1 in an effective amount for treating such disorders in combination with a pharmaceutically acceptable carrier. 27. A method of treating platelet-mediated thrombotic disorders comprising administering to a patient afflicted with such disorder an effective amount of the compound of Claim 1 to treat such disorder. 28. The method of Claim 17, wherein the amount is 0.1 -300 mg/kg/day. 29. A process for preparing a compound of the formula AG4 AG4 comprising treating a compound of the formula AG3 AG3 with penicillin amidase. 30. The process of claim 19, wherein the compound of the formula AG3 was placed in a water solution and the pH was adjusted to about 7.5 prior to treatment with penicillin amidase. 31. A compound of the formula AG4: AG4

Inventors: COSTANZO MICHAEL J, HOEKSTRA WILLIAM J, MARYANOFF BRUCE E, COSTANZO, MICHAEL, J., HOEKSTRA, WILLIAM, J., MARYANOFF, BRUCE, E.
Applicants: ORTHO PHARMA CORP, ORTHO PHARMACEUTICAL CORPORATION
Application year: 1997
Main classification: C07D211
IPC codes: A61K31, A61P7, C07D211, C07D213, C07D215, C07D241, C07D401, C07D405, C07F7, C12P17