JP2001504810A - Selective factor Xa inhibitor - Google Patents

Abstract

(57) SUMMARY Disclosed are novel compounds, their salts, and their related compositions having activity against mammalian factor Xa. The compounds are useful for preventing or treating coagulopathies in vitro or in vivo. These formulas are (I) and the meaning of the various symbols is provided in the description.

Description

DETAILED DESCRIPTION OF THE INVENTION                           Selective factor Xa inhibitor Field of the Invention   The present invention relates to factor Xa or factor Xa assembled in a prothrombinase complex. And novel heterocyclic compounds that are potent and highly selective inhibitors. This These compounds may be coagulated (eg, thrombin, Factor VIIa, Factor IXa) or Cascade of fibrinolysis (eg, plasminogen activator, plasmin Show selectivity for factor Xa compared to other proteases for                                Background of the Invention   When intact vascular walls are damaged and uncontrolled bleeding threatens survival, Blood clotting protects mammalian species. Clotting, which results in blood clotting, is an important factor in hemostasis. It is a component. In normal haemostatic situations, clot formation and clot removal (five The acute balance of phosphorus dissolution is maintained. The blood clotting cascade can Involves the conversion of inactive enzymes (enzymes) to active enzymes, and ultimately, soluble plasma proteins. Colifibrinogen into highly crosslinked fibrin insoluble matrix Convert. Davie, et al., "The Coagulation Cascade: Initiation, Maintenanc e and Regulation ”Biochemistry 30: 10363-10370 (1991). Damaged blood Platelets adhering to the tube are activated and taken up by the clot, thus leading to the initiation of a hemostatic “plug”. It plays a major role in phase formation and stabilization. In certain diseases of the cardiovascular system The balance between clot formation and clot lysis can be compromised by deviations from normal hemostatic action. Squeezed towards a threatening thrombus formation, in which case intracoronary (myocardial infarction) or Thrombus in the extremities and pulmonary veins (venous thrombosis) blocks blood flow. Platelets and blood Although coagulation is both involved in thrombus formation, certain components of the coagulation cascade are In the process of amplification or promotion of processes involving platelet aggregation and fibrin deposition is there.   The key enzyme in both the coagulation cascade and hemostasis is thrombin . Thrombin is deeply involved in the process of thrombus formation, but in normal circumstances thrombin Through the ability to convert protein C to active protein C in a modulin-dependent manner, It can also play an anticoagulant role in hemostasis. Thrombin is the penultimate Ability to catalyze the conversion of fibrinogen to fibrin It plays a central role in hemostasis through powerful platelet activation. Thrombi Direct or indirect inhibition of protein activity is due to Claeson “Synthetic Peptides and Peptides idominetics as Substrates and Inhibitors of Thromibin and Other Protease s in the Blood coagulation System ”,Blood Coag . Fibrinol. 5: 411-436 (19 As reviewed in 94), is the focus of recent various anticoagulation strategies. Current, The major class of anticoagulants used in the clinic is thrombi, either directly or indirectly. (Ie, heparin, low molecular weight heparin and coumarin). Tron Bins are activated by the prothrombinase complex at the point of convergence of the intrinsic and extrinsic coagulation pathways. Generated. Mann, et al., “Surface-Dependent Reactions of the Vitamin  K-Dependent Enzymes ”,Blood As reviewed in 76-1-16 (1990), Rothrombinase complex activates factor X (factor Xa) and its non-enzymatic aids Factor Va, which is a factor⁺²It is formed when dependently gathered. Professional The thrombinase complex converts the proenzyme prothrombin into an active procoagulant. To thrombin.   Prothrombinase complex position at the convergence point of the intrinsic and extrinsic coagulation pathways And a limited number of target catalytic units at the site of vascular injury Amplification of thrombin generation mediated by uncomplexed factor Xa 393,000 times) inhibits thrombin generation and prevents dysregulated procoagulant activity. Suggest that this is the ideal way to Various proteins also in specific receptors Unlike thrombin, which also acts on a qualitative substrate, factor Xa has a single physiological substrate, That is, it seems to have prothrombin.   Factor VIIa-tissue factor (TF) complex called tissue factor pathway inhibitor (TFPI) Plasma contains endogenous inhibitors of both the body and factor Xa. TFPI Kunitz-type protease inhibitor with three Nunit Kunitz domains It is. TFPI is the initial site between the second Kunitz domain of TFPI and the active site of factor Xa. Inhibits the TF / Factor VIIa complex by a two-step mechanism involving the interaction of It further inhibits the proteolytic activity of factor Xa. Girard, et al., “Functional  Significance of the Kunitz-type Inhibitory Domeins of Lipoprotein-associated Coagulation Inhibitor ”,Nature 338: 518-520 (1989 ), The second stage consists of a quaternary complex TF / Factor VIIA / TF Involved in the inhibition of the TF / Factor VIIa complex by formation of PI / Factor Xa.   A very potent and specific inhibitor of factor Xa, Ripeptides have been reported. United States Patent Number 4,588,5 to Gasic No. 87 describes the anticoagulant activity in saliva of Mexican hill Haementeria officinalis. It is listed. The major component of this saliva is the polypeptide factor Xa inhibitor a Nutt, et al., “The Amino Acid Sequence of Antis tasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Struc ture ”,J . Biol. Chem.263: 10162-10167 (1988).   Waxman, et al., “Tick Anticoagulant Peptide (TAP) is a Novel Inhibito r of Blood Coagulation Factor Xa ”,Science 248: 593-596 (1990) As noted, it is another potent and very specific inhibitor of factor Xa. Mite anticoagulant peptide isolated from body extract of the soft mite Ornithidoros moubata Was done.   Another inhibitor of the polypeptide type for factor Xa has been reported, References to Condra, et al., “Isolation and Structural Character ization of a Potent Inhibitor of Coagulation Factor Xa from the Leech Ha ementeria ghilianii ”,Thromb. Haemost. 61: 437-441 (1989); Blankenship, et  al., “Amino Acid Sequence of Ghilanten: Anti-coagulant-antimetastatic P rinciple of the South American Leech, Haementeriaghilianii ”,Biochem. B iophys. Res. Commum. 166: 1384-1389 (1990); Brankamp, et al., "Ghilantens: Anticoagulants, Antimetastatic Proteins from the South American Leech Ha ementeria ghilianii ”,J. Lab. Clin. Med. 115: 89-97 (1990); Jacobs, et al. , “Isolation and Characterization of a Coagulation Factor Xa Inhibitor from Black Fly Salivary Glands ”,Thromb. Haemost. 64: 235-238 (1990); Rigb i, et al., “Bovine Factor Xa Inhibiting Factor and Pharmaceutical Compo sitions Containing the Same ", European Patent Application No. 352,903 (1990); Cox, “Coagulation Factor X Inhibitor From the Hundred-pace Snake Deinagkistrodon acutus venom ”,Toxicon 31: 1445-1457 (1993); Cappello, et al., “Ancylostoma Factor Xa Inhibitor: Partial Purification and its Iden tification as a Major Hookworm-derived Anticoagulant In Vitro ”,J. Infe ct. Dis. 167: 1474-1477 (1993); Seymour, et al., "Ecotion is a Potent Anti coagulant and Reversible Tight-binding Inhibitor of Factor Xa ”,Biochem istry  33: 3949-3958 (1994).   Factor Xa inhibitory compounds that are not large polypeptide-type inhibitors have also been reported Tidwell, et al., “Strategies for Anticoagulation With Syn thetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors ”,Thromb. Res. 19: 339-349 (1980); Turner, et al., “P-Amidino Esters as Irre versible Inhibitors of Factor IXa and Xa and Thrombin ”,Biochemistry twenty five : 4929-4935 (1986); Hitomi, et al., “Inhibitory Effect of New Synthetic Pr otease Inhibitor (FUT-175) on the Coagulation System ”,Haemostasis 15: 1 64-168 (1985); Sturzebecher, et al., “Synthetic Inhibitors of Bovine Fact. or Xa and Thrombin. Comparison of Their Anticoagulant Efficiency ”,Thro mb. Res. 54: 245-252 (1989); Kam, et al., “Mechanism Based Isocoumarin Inh ibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagu lants ”,Biochemistry 27: 2547-2557 (1988); Hauptmann, et al., “Comparison  of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin a nd Factor Xa Inhibitors ”,Thromb. Haemost. 63: 220-223 (1990); Miyadera et al. , Japanese Patent Application JP 6327488 (1994); Nagahara, et al., “Dibasic (Amidinoaryl) p. ropanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitor s ”,J. Med.Chem. 37: 1200-1207 (1994); Vlasuk, et al., “Inhibitors of Th. rombosis "European Patent Application, WO 93/15756 (1993); and Brunck, et al.," Novel Inhibitors of Factor Xa ”, European patent application, WO 94/13693 (1994) included. Al-obeidi, et al., “Factor Xa Inhibitors”, WO Patent 95/29189 Discloses a pentapeptide X1-Y-I-R-X2 derivative as a factor Xa inhibitor. The compound inhibits blood coagulation in the treatment of thrombosis, stroke, and myocardial infarction Useful for   WO 96/18644 to Tamura et al. Describes aromatic heterocyclic thrombin inhibitors are doing. WO 95/35313 to Semple et al. Is 3-amino-2-oxo-1-piperidine Acetate derivatives are related to thrombin inhibitors.   EP 0,512,831 and U.S. Patent No. 5,281,58 both to Duggan et al. 5 describes fibrinogen receptor antagonists.                                Summary of the Invention   The present invention relates to novel peptides and analogs that mimic the peptides, their pharmaceutically Relates to acceptable isomers, salts, hydrates, solvates and prodrug derivatives .   In another aspect, the invention provides a pharmaceutically effective amount of a compound of the invention and a pharmaceutical agent. Pharmaceutical compositions that include a chemically acceptable carrier are included. These compositions are It is useful as a potent and specific blood coagulation inhibitor in milk individuals.   In yet another aspect, the invention relates to refractory angina, refractory angina, myocardial infarction, Pandemic, including treatment of transient ischemic attacks, thrombotic attacks, embolic attacks, septic shock Treatment or prophylaxis of deep vein thrombosis in the prevention of primary intravascular coagulation syndrome and pulmonary embolism Prevention or treatment of reocclusion or restenosis of reperfused coronary arteries These inhibitors as therapeutic agents for disease states in mammalian individuals with abnormal coagulation Related to the method of using the harmful agent. These compositions may optionally contain anticoagulants, anticoagulants, It may include a platelet agent, and a thrombolytic agent.   In another aspect of the present invention, there is provided a compound useful as a diagnostic reagent.   In a preferred embodiment, the present invention provides a compound of general formula I:Where:   R¹Is H, C_1-6Alkyl or C_1-3Alkylaryl;   R^TwoIs H, C_1-6Alkyl, C_3-6Cycloalkyl, C_1-3Alkylaryl, C_1-3A Ruki Le-C_3-8Cycloalkyl or aryl and R^ThreeIs H, C_1-6Is alkyl Or R^TwoAnd R^ThreeTogether form a carbocyclic ring;   m is an integer from 0-3;   n is an integer from 0-6;   p is an integer from 0-4;   s is an integer from 0-2;   q is an integer from 0-2;   A is a 5-membered group containing 1-4 heteroatoms selected from the group consisting of N, O and S A 10-membered heterocyclic ring system; R^Four; -NR^FourR^Five; Selected from the group consisting of^Four, R^Five, R¹⁶And R¹⁷Is H, -OH, C_1-6Archi , Aryl and C_1-4Independently selected from the group consisting of alkylaryl; R¹⁸ Is H, -OH, C_1-6Alkyl, aryl and C_1-4Group consisting of alkylaryl Selected from or R¹⁶Or R¹⁷And form a 5- to 6-membered ring Can; and R¹⁹Is H, -OH, C_1-6Alkyl, aryl and C_1-4Alkyl ally Selected from the group consisting of¹⁷And form a 5- to 6-membered ring Can be;   W is a direct bond, C_1-6Alkyl, C_3-8Cycloalkyl, C_1-6Alkenyl, C_{1- 6} Alkylaryl, aryl, or 1- selected from the group consisting of N, O and S A 5-10 membered heterocyclic ring system containing 4 heteroatoms;   D is a direct bond, -CO-, SO_Two-, -CH_Two-, -O-CO-, -NR^FifteenSO_Two-Or-NR^Fifteen-CO- Yes, where R^FifteenIs H, -OH, C_1-6Alkyl, aryl and C_1-4Alkyl ally Selected from the group consisting of   K is a direct bond, C_3-8Consists of cycloalkyl, aryl or N, O and S A 5- to 10-membered heterocyclic ring system containing 1-4 heteroatoms selected from the group R;   E is R²⁶, NR²⁶R²⁷, Selected from the group consisting of²⁶, R²⁷, R²⁸And R²⁹Is H, -OH, C_1-6Archi , Aryl and C_1-4Independently selected from the group consisting of alkylaryl; R³⁰ Is H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl Or R²⁸Or R²⁹Can form a 5-6 membered ring with And R³¹Is H, C_1-6Alkyl, aryl and C_1-4Group consisting of alkylaryl Selected from or R²⁹Can form a 5- to 6-membered ring with But E is R²⁶K must contain at least one N atom if Conditional;   Y is H, Selected from the group consisting of¹³And R¹⁴Is H, C_1-3Alkyl and ally Independently selected from the group consisting of²⁰, -CONR²⁰R^{twenty one}, -CF_Three, -C F_TwoCF_ThreeOr a group having the following formula: Where:   R^{twenty two}Is H, C_1-6Alkyl, C_2-6Alkenyl, C_0-6Alkylaryl, C_2-6Arche Nylaryl, C_0-6Alkylheterocyclo, C_2-6Alkenylheterocyclo, -CF_Three , And -CF_TwoCF_ThreeSelected from the group consisting of:   U is -O-, -S-, -N- or -N (H)-; and   V is -O-, -S-, -N- or -N (H)-; provided that at least one of U or V is Conditional on being -N- or -N (H)-;   J is -S-, -SO-, -SO_Two-, -O- or -NR⁶-Where R⁶Is H, C_1-6Alkyl Or benzyl; and   L is R⁹And R^Ten1-4 heteroatoms selected from N, S and O, replaced by C with children_6-10Selected from the group consisting of heterocyclic ring systems; wherein r is an integer from 0-2 Yes; R⁷And R⁸Is H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, -COOR¹¹ , -CONR¹¹R¹², -CN, and -CF_ThreeIndependently selected from the group consisting of: R⁹And R^Ten Is H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, C_1-4Alkyloxy, Halogen, -NO_Two, -NR¹¹R¹², -NR¹¹COR¹², -O-R¹¹, -O-COR¹¹, -COOR¹¹, -CONR¹¹ R¹², -CN, -CF_Three, -SO_TwoNR¹¹R¹²And C_1-6Alkyl-O-R¹¹Independently of the group consisting of Selected; and R¹¹And R¹²Is H, C_1-6Alkyl, C_1-3Alkylaryl and Independently selected from the group consisting of: And all their optical isomers are provided.                             Detailed description of the invention Definition   In accordance with the present invention, and as used herein, unless expressly stated otherwise. The following terms are defined with the following meanings.   The term “alkyl” refers to straight-chain, branched-chain, cyclic groups, and combinations thereof. With the specified number of carbon atoms or unspecified number Case means a saturated aliphatic group having up to 12 carbon atoms. “Cycloalkyl The term "has 3 to 12 carbon atoms, preferably 3 to 7 carbon atoms. Means a di-, bi- or tricyclic aliphatic ring.   The term “alkenyl” refers to straight-chain, branched-chain, cyclic groups, and combinations thereof. Containing at least one double bond and having the specified number of carbon atoms Unsaturated aliphatic group.   The term "aryl" refers to one or more aromatic rings that are unsubstituted or substituted. , By way of example and not limitation, C_1-6Alkoxy, C_1-6Alkyl, C_{1 -6} Alkylamino, hydroxy, halogen, cyano (-CN), hydroxyl, mel Capto, nitro (-NO_Two), Thioalkoxy, carboxaldehyde, carboxyl, Carboalkoxy, carboxamide, -NR'R ", -NR'COR", -OR, -OCOR, -COOR , -CONR'R ", CF_Three, -SO_TwoNR'R "and C_1-61, 2 or 3 such as alkoxy-OR; Aryl, heterocyclic aryl, biaryl substituted with 3 substituents Ants, including, but not limited to, and triaryl groups and the like. , C_1-6Alkylaryl wherein the R group is H, C_1-6Alkyl, C_1-3Alkyl ants (All of which may be optionally substituted.) Means Preferred aryl groups include phenyl, halophenyl, C_1-6Alkyl Phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and phenyl Includes aromatic heterocycles or heteroaryls, the latter being derived from nitrogen, oxygen and sulfur An aryl group containing from 1 to 4 heteroatoms selected from the group consisting of: Ants The hydroxyl group preferably has 5 to 14 carbon atoms making up the ring structure, while the The teloaryl preferably has 1-4 heteroatoms and the remaining 4-10 atoms are Is a carbon atom.   The terms “heterocyclo” and “heterocyclic ring system” are used herein 1 to 4 selected from the group consisting of nitrogen, oxygen and sulfur Means any saturated or unsaturated, mono- or bicyclic ring system containing two heteroatoms I do. A typical heterocyclic ring system has 5 to 10 members, of which 1-4 The individual will be a heteroatom. Typical examples of monocyclic ring systems include piperidinyl, pyrrolidini , Pyridinyl, piperidonyl, pyrrolidonyl and thiazolyl, On the other hand, examples of bicyclic ring systems include benzimidazolyl, benzothiazolyl and benzene Includes zoxyazolyl, all of which may be substituted.   The term "carbocyclic ring", as used herein, refers to 3-6 Means any saturated or unsaturated ring containing two carbon atoms.   The terms "alkylaryl" and "alkenylreel" are used herein. As used in 1, 2, or 3 aryl groups, Means an alkyl or alkenyl group, respectively, having the indicated number of carbon atoms You. The term benzyl, as used herein, refers to -CH_Two-C₆H_FiveTo means.   The term “alkoxy,” as used herein, refers to methoxy , Ethoxy, etc., means an alkyl bonded to an oxygen atom.   The term "halogen" as used herein refers to Cl, Br, F Or I substituent.   The term "direct bond", as used herein, refers to a direct bond. A bond directly connecting the substituents on each side of the bond. Two adjacent substituents If each is defined as a "direct bond", it is considered a single bond .   Two substituents "combined to form a 5-6 membered ring" are defined as ethylene or ethylene, respectively. Or that a propylene bridge is formed between the two substituents.   The term “pharmaceutically acceptable salt” refers to a compound and an organic or non-organic acid. Salts of compounds derived from combinations of acids are included. These compounds are free salts It is useful in both group and salt form. In practice, salt forms The use is substantially equivalent to the use of the base form, both acid and base addition salts according to the invention Is within the range.   “Pharmaceutically acceptable acid addition salts” refer to the biological effectiveness and properties of the free base. Maintained, non-organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and Acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malo Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid , Methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In combination with other organic acids to form biologically or otherwise harmful Means salt that has not been used.   “Pharmaceutically acceptable base addition salt” refers to sodium, potassium, lithium, Ammonium, calcium, magnesium, iron, zinc, copper, manganese, and Includes those derived from non-organic bases such as luminium bases. Particularly preferred are ammo The potassium, sodium, calcium and magnesium salts. Pharmacy Non-toxic salts derived from non-toxic organic bases include isopropylamine, trimethyl Amine, diethylamine, triethylamine, tripropylamine, ethanol Amine, 2-diethylaminoethanol, trimetamine, dicyclohexylamine , Lysine, arginine, histidine, caffeine, procaine, hydrabamine, Choline, betaine, ethylenediamine, glucosamine, methylglucamine, theo Bromine, purine, piperidine, piperazine, N-ethylpiperidine, polyamine Including primary, secondary, tertiary amines, naturally occurring substituted amines such as resins Substituted amines, cyclic amines and salts of basic ion exchange resins are included. Especially preferred New non-toxic organic bases include isopropylamine, diethylamine, and ethanolamine. , Trimethamine, dicyclohexylamine, choline, and caffeine .   As used herein, “biological properties” refers to those directly related to the compounds of the present invention. Effectors or antigenic functions performed in vivo or indirectly Or activity. Effector functions include receptor or ligand binding, Any enzyme activity or enzyme regulating activity, any carrier binding activity, any Activity, promoting cell adhesion to extracellular matrix or cell surface molecules or Includes any activity in inhibition, or any structural role. Antigenic Functions include epitopes or antibodies that can react with the antibodies raised against them. Includes possession of a site of origin. The biological properties of the compounds of the present invention are described in Example 14 and 15 and by other methods well known in the art. Can be easily described.   In addition, the following abbreviations are used in the present application. That is,   "Boc" means t-butoxycarbonyl.   “BOP” means benzotriazol-1-yloxy-tris- (dimethylamino) phos Means honium hexafluorophosphoric acid.   “CBZ” means benzyloxycarbonyl.   "DIEA" means diisopropylethylamine.   “DMF” means N, N-dimethylformamide.   “Et_Two"O" means diethyl ether.   “EtOAc” means ethyl acetate.   "HF" means hydrogen fluoride.   “HOAc” means acetic acid.   "MeI" means methyl iodide.   “MeOH” means methanol.   "MeSEt" means methylethyl sulfide.   “TFA” means trifluoroacetic acid.   “THF” means tetrahydrofuran.   "Tos" refers to p-toluenesulfonyl.   In the compounds of the present invention, a carbon atom bonded to four non-identical substituents Is asymmetric. Thus, the compounds may be diastereomers, enantiomers or May be present as a mixture of these. The syntheses described herein are racemic, enantiomer Omars or diastereomers can be used as starting materials or intermediates. That The diastereomeric product resulting from such a synthesis may be chromatographed or Separation by crystallization method or by other methods known in the art I can do it. Mixtures of enantiomeric products can also be prepared using the same technique or with this technique. Separation may be by other methods known in the art. Each asymmetric carbon atom can be Can be in one of two configurations (R or S) when present in a compound of formula , Both are within the scope of the present invention. In the process described above, the final product In some cases, containing small amounts of diastereomeric or enantiomeric products However, these products do not affect their therapeutic or diagnostic applications.   Of all the peptides of the invention, one or more amide bonds (-CO-NH -) Is -CH_TwoNH-, -CH_TwoS-, -CH_Two-O-, -CH_TwoCH_Two-, -CH = CH- (cis and trans), -COCH_Two-, -CH (OH) CH_Two-, -CH_TwoSO-, and -CH_TwoSO_Two-Is an equidistant electron such as another May be interchanged if appropriate. This replacement can be done by those known in the art. Method. The following references include peptides containing these alternative binding moieties The preparation of analogs has been described. Spatola, “Peptide Backbone Modifications "(Review)Vega Data, Vol. 1, Issue 3, (March 1983); Spatola, “Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, "(Review) B. Wei nstein, eds., Marcel Dekker, New York, p. 267 (1983); Morley,Trends Pharm . Sci. (Review) pp. 463-468 (1980); Hudson, et al.,Int. J. Pept.Prot.Re s . 14: 177-185 (1979) (-CH_TwoNH-, -CH_TwoCH_Two-); Spatola, et al.,Life Sci. 38: 1 243-1249 (1986) (-CH_TwoS-); Hann,J. Chem. Soc.Perkin Trans.I pp.307-314 (1982) (-CH = CH-, cis and trans); Almquist, et al.,J.Med.Chem. twenty three : 1392-1398 (1980) (-C0CH_Two-); Jennings-White, et al.,Tetrahedron Lett. twenty three : 2533 (-COCH_Two-) (1982); Szelke, et al., European application EP 45665; CA:97: 3940 5 (1982) (-CH (OH) CH_Two-); Halladay, et al.,Tetrahedron Lett 24: 4401-4404 ( 1983) (-CH (OH) CH_Two-); And Hruby,Life Sci. 31: 189-199 (1982) (-CH_TwoS-).                               Preferred embodiment   The present invention relates to general formulas I, which are potent and selective inhibitors of Xa: Where:   R¹Is H, C_1-6Alkyl or C_1-3Alkylaryl;   R^TwoIs H, C_1-6Alkyl, C_3-6Cycloalkyl, C_1-3Alkylaryl, C_1-3A Lucil-C_3-8Cycloalkyl or aryl and R^ThreeIs H, C_1-6With alkyl Yes or R^TwoAnd R^ThreeTogether form a carbocyclic ring;   m is an integer from 0-3;   n is an integer of O-6;   p is an integer of O-4;   s is an integer from 0-2;   q is an integer from 0-2;   A is a 5-membered group containing 1-4 heteroatoms selected from the group consisting of N, O and S A 10-membered heterocyclic ring system; R^Four; One NR^FourR^Five;Selected from the group consisting of^Four, R^Five, R¹⁶And R¹⁷Is H, -OH, C_1-6Archi , Aryl and C_1-4Independently selected from the group consisting of alkylaryl; R¹⁸ Is H, -OH, C_1-6Alkyl, aryl and C_1-4Group consisting of alkylaryl Selected from or R¹⁶Or R¹⁷And form a 5- to 6-membered ring Can; and R¹⁹Is H, -OH, C_1-6Alkyl, aryl and C_1-4Alkyl ally Selected from the group consisting of¹⁷And form a 5- to 6-membered ring Can be;   W is a direct bond, C_1-6Alkyl, C_3-8Cycloalkyl, C_1-6Alkenyl, C_{1- 6} Alkylaryl, aryl, or 1- selected from the group consisting of N, O and S A 5-10 membered heterocyclic ring system containing 4 heteroatoms;   D is a direct bond, -CO-, SO_Two-, -CH_Two-, -O-CO-, -NR^FifteenSO_Two-Or-NR^Fifteen-CO- Yes, where R^FifteenIs H, -OH, C_1-6Alkyl, aryl and C_1-4Alkyl ally Selected from the group consisting of   K is a direct bond, C_3-8Consists of cycloalkyl, aryl or N, O and S 5- to 10-membered heterocyclic ring systems containing 1-4 heteroatoms selected from the group Is;   E is R²⁶, NR²⁶R²⁷,Selected from the group consisting of²⁶, R²⁷, R²⁸And R²⁹Is H, -OH, C_1-6Archi , Aryl and C_1-4Independently selected from the group consisting of alkylaryl; R³⁰ Is H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl Or R²⁸Or R²⁹Can form a 5-6 membered ring with And R³¹Is H, C_1-6Alkyl, aryl and C_1-4Group consisting of alkylaryl Selected from or R²⁹Can form a 5- to 6-membered ring with But E is R²⁶K must contain at least one N atom if Conditional;   Y is H, Selected from the group consisting of¹³And R¹⁴Is H, C_1-3Alkyl and ally Independently selected from the group consisting of: G is -COOR²⁰, -CONR²⁰R^{twenty one}, -CF_Three, -CF_TwoCF_Three Or a group having the following formula: Where:   R^{twenty two}Is H, C_1-6Alkyl, C_2-6Alkenyl, C_0-6Alkylaryl, C_2-6Arche D Ruaryl, C_0-6Alkylheterocyclo, C_2-6Alkenylheterocyclo, -CF_Three, And -CF_TwoCF_ThreeSelected from the group consisting of:   U is -O-, -S-, -N- or -N (H)-; and   V is -O-, -S-, -N- or -N (H)-; provided that at least one of U or V is Conditional on being -N- or -N (H)-;   J is -S-, -SO-, -SO_Two-, -O- or -NR⁶-Where R⁶Is H, C_1-6Alkyl Or benzyl; and   L is R⁹And R^Ten1-4 and selected from N, S and O C containing B atom_6-10Selected from the group consisting of heterocyclic ring systems; wherein r is 0-2 A number; R⁷And R⁸Is H, C_1-6Alkyl, aryl, C_1-6Alkylaryl,- COOR¹¹, -CONR¹¹R¹², -CN, and -CF_ThreeIndependently selected from the group consisting of: R⁹And And R^TenIs H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, C_1-4Alkyloxy Si, halogen, -NO_Two, -NR¹¹R¹², -NR¹¹COR¹², -O-R¹¹, -O-COR¹¹, -COOR¹¹, -CO NR¹¹R¹², -CN, -CF_Three, -SO_TwoNR¹¹R¹²And C_1-6Alkyl-O-R¹¹From the group consisting of Germany Selected; and R¹¹And R¹²Is H, C_1-6Alkyl, C_1-3Alkylaryl And aryl are independently selected from the group consisting of: And all of their optical isomers; A new class of peptide derivatives selected from, pharmaceutically acceptable compositions thereof, and As a therapeutic for disease states in mammalian individuals, characterized by abnormal thrombosis Related to how to use them.   Preferred R¹Substituents are H and C_1-6Alkyl, and more preferably H.   Preferred R^TwoSubstituents are H and C_1-6Alkyl, and more preferably H.   R^ThreeIs preferably H.   The integer "m" is preferably 0-1, more preferably 0.   The integer "n" is preferably 1-4.   The integer "p" is preferably 3.   The integer "s" is preferably 0.   The integer "q" is preferably 0-1.   A preferred "A" substituent is R^Four, -NR^FourR^Five, It is.   R^FourIs preferably H, -OH, or C_1-6Alkyl, more preferably H, -OH Or methyl.   R^FiveIs preferably H, -OH, or C_1-6Alkyl, more preferably H, -OH Or methyl.   Preferred "W" substituents are C_1-4Alkyl, C_5-6Cycloalkyl, aryl, Or a 5- to 10-membered heterocyclic ring system containing at least one N heteroatom More preferably C_1-4Alkyl, aryl, or at least one N heteroatom 5- to 10-membered heterocyclic ring systems, including offspring.   Preferred "D" substituents are -CO-, -SO_Two-And-CH_Two-; More preferably -CO- And -SO_Two-Yes.   K is preferably a direct bond.   In the “E” substituent, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰And R³¹Is H and C_1-6A Alkyl, more preferably independently selected from the group consisting of H and methyl preferable. Particularly preferred "E" substituents are -NH_Two, -NHC (= NH) -NH_TwoAnd -SC (= NH) -NH_Two And more preferably -NHC (= NH) -NH_TwoAnd -SC (= NH) -NH_TwoIt is.   Preferred "Y" substituents are It is.   R¹³Is preferably H.   R¹⁴Is preferably H.   The “G” substituent is preferably a group having the formula:   The "J" substituent is preferably -S-, -O- or -NR⁶-Yes.   R⁶Is preferably H.   The “L” substituent is preferably And more preferably, It is.   R⁷Is preferably H.   R⁸Is preferably H.   R⁹Is preferably H, -O-R¹¹, -COOR¹¹, -CONR¹¹R¹²Or -CF_ThreeAnd more preferred Or H.   R^TenIs preferably H, -O-R¹¹, -COOR¹¹, -CONR¹¹R¹²Or -CF_ThreeAnd better Preferred is H.   R¹¹Is preferably H.   R¹²Is preferably H.   In one embodiment of the present invention, R¹, R^TwoAnd R^ThreeIs H, p = 3, s = 0, K is a direct bond, E Is -NHC (= NH) -NH_TwoAnd Y is -CO-G, where G is where J and L are defined above The following formula is as follows: Is a group having It has the following general structure II: Where:   m is an integer from 0-3;   n is an integer from 0-6;   q is an integer from 0-2;   A is R^Four, -NR^FourR^Five, Selected from the group consisting of^Four, R^Five, R¹⁶, R¹⁷, R¹⁸And R¹⁹Are H, -OH and And C_1-6Independently selected from the group consisting of alkyl;   W is C_1-6Alkyl, C_3-8Cycloalkyl, C_1-6Alkenyl, aryl, or N 5 to 10 membered members containing 1-4 heteroatoms selected from the group consisting of, O and S A heterocyclic ring system; wherein A is R^FourW contains at least one N atom With the condition that they must be;   D is -CO- or -SO_Two-   J is -S-, -SO-, -SO_Two-, -O- or -NR⁶And R⁶Is H; and   L is R⁹And R^Ten1-4 and selected from N, S and O C containing B atom_6-10Selected from the group consisting of heterocyclic ring systems; wherein r is an integer of 0-1 A number; R⁷And R⁸Is H, C_1-6Alkyl, aryl, C_1-6Alkylaryl,- COOR¹¹, -CONR¹¹R¹², -CN, and -CF_ThreeIndependently selected from the group consisting of: R⁹And And R^TenIs H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, C_1-4Alkyloxy Si, halogen, -NO_Two, -NR¹¹R¹², -NR¹¹COR¹², -O-R¹¹, -O-COR¹¹, -COOR¹¹, -C0 NR¹¹R¹², -CN, -CF_Three, -SO_TwoNR¹¹R¹²And C_1-6Alkyl-O-R¹¹From the group consisting of Germany Selected; and R¹¹And R¹²Is H, C_1-6Alkyl, C_1-3Alkylaryl And aryl are independently selected from the group consisting of: And preferred groups of compounds defined by all their optical isomers Is also explained.   Preferred embodiments of the compounds of general formula II have the following stereochemistry.  In yet another preferred embodiment of the present invention, R¹, R^TwoAnd R^ThreeIs H, p = 3, s = 0, K Is a direct bond, E is -NHC (= NH) -NH_Two, Y is -CO-G, and G is the following formula: Where J is -S- and L is⁹And R^TenIs H Is a group having It has the following general structure III: Where:   m is an integer from 0-3;   n is an integer from 0-6;   q is an integer from 0-2;   A is R^Four, -NR^FourR^Five, Selected from the group consisting of^Four, R^Five, R¹⁸And R¹⁹Is H, -OH and C_1-6A Independently selected from the group consisting of   W is C_1-6Alkyl, C_3-8Cycloalkyl, C_1-6Alkenyl, aryl, or N , A 5- to 10-membered heteroatom containing 1-4 heteroatoms selected from the group consisting of O and S A telocyclic ring system; where A is R^FourW contains at least one N atom With the condition that they must be;   D is -CO- or -SO_Two- And preferred groups of compounds defined by all their optical isomers Is also explained.   Preferred embodiments of the compounds of general formula III have the following stereochemistry.   The present invention relates to all pharmaceutically acceptable isomers of the compounds of formulas I, II and III, Also encompasses salts, hydrates and solvates. In addition, compounds of formulas I, II and III It can exist in various isomeric and tautomeric forms, and such isomers and Pharmaceutically acceptable salts, hydrates and solvates of tautomers as well as their forms Are meant to be included in the present invention.   The compounds of the present invention can be isolated as free acids or bases or It can be converted to salts of non-organic and organic acids and bases. Such salts are used in the present invention. Within range. Other less preferred salts may help in the isolation and purification process. Salts that can stand, but are non-toxic and have no physiological effects are particularly useful.   Numerous methods are useful for preparing the salts described above and are known to those of skill in the art. Have been. For example, the free acid or free base form of a compound of one of the above formulas is In a solvent or solvent mixture in which the salt is insoluble, or in a solvent such as water, 1 or It can be reacted with a higher molar equivalent of the desired acid or base and then the solvent Is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or salt of the product The prototype can be passed through an ion exchange resin to form the desired salt, or the product One form of the salt may be converted to another using a similar general procedure.   The present invention also encompasses prodrug derivatives of the compounds included herein. The term “prodrug” refers to the natural occurrence in an organism to release an active drug. Pharmaceutically unreacted parent drug molecules that require biotransformation, either bioactive or enzymatic Refers to active derivatives. Prodrugs have groups that can be cleaved under metabolic conditions A variant or derivative of the compound of the invention. Prodrugs are physiological conditions Solvolysis or enzymatic degradation below It becomes a compound of the present invention which is active. The prodrug compounds of the present invention Single or double depending on the number of biotransformation steps required to release the active drug , Triples, etc., of the functional groups present in the precursor type form. A number can be indicated. Prodrug forms are often soluble, histocompatible, or mammalian. Provides the advantage of slow release in living organisms (Bundgard, Design of Prodrugs , Pp. 7-9, 21-24, Elsevler, Amesterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, S an Diego, CA, 1992). Prodrugs commonly known in the art Include, for example, the sulphide prepared by the reaction of the base acid with a suitable alcohol. Amides prepared by the reaction of an amine with a tellurium or base acid compound , Or a basic group reacted to form an acylated base derivative, Includes acid derivatives well known to those skilled in the art. In addition, the book Prodrug derivatives of the invention enhance bioavailability herein Can be combined with other features taught.   The structures below are illustrative of the compounds of the present invention and are in no way limiting. Not intended:   As mentioned above, the compounds of the present invention are useful in unstable angina, unresponsive angina, Includes treatment of infarction, transient ischemic attacks, thrombotic attacks, embolic attacks, and septic shock Treatment of deep vein thrombosis in the prevention of generalized intravascular coagulation syndrome and pulmonary embolism Or in the prevention or treatment of reocclusion or restenosis of a reperfused coronary artery A therapeutic agent for a disease state in a mammalian individual having a coagulation disorder, such as in Available. In addition, these compounds are associated with the factor Xa / prothrombinase complex. Useful for treating or preventing diseases associated with the production and / or action of coalescence You. This includes many thrombosis and prothrombosis where the coagulation cascade is activated Conditions include, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, surgical thromboembolism Including but not limited to thrombotic complications and peripheral artery occlusion.   Thus, preventing conditions in mammalian individuals characterized by undesirable thrombosis Alternatively, a method of treating comprises administering to a mammalian individual a therapeutically effective amount of a compound of the present invention. For example. In addition to the disease states mentioned above, the administration of the compounds of the invention Other diseases that can be treated or prevented are thrombolytic therapy or percutaneous transluminal coronary artery Obstructive coronary thrombosis resulting from any of the coronary angioplasty, venous vasculature Thrombosis, generalized intravascular coagulation, rapid consumption of coagulation factors and microvascular Systemic coagulation resulting in life-threatening thrombus formation that occurs anywhere and occurs through multiple organ failure Solid condition, hemorrhagic stroke, renal dialysis, blood oxygenation, and cardiac catheterization Including, but not limited to.   Compounds of the invention inhibit the coagulation of a biological sample, including administration of a compound of the invention. Also available for the method.   The compounds of the present invention may also be used in combination with other therapeutic or diagnostic agents. specific In a preferred embodiment of this, according to generally accepted medical practice Other compounds typically prescribed for these conditions, such as anticoagulants, thrombolytics, Or platelet aggregation inhibitor, tissue plasminogen activator, urokinase, pro Urokinase, streptokinase, heparin, aspirin, or warfari The compounds of the present invention may be administered together with other antithrombotic agents, including but not limited to, the drug. Of the present invention Compounds act synergistically to prevent recoagulation following successful thrombolytic therapy And / or may reduce reperfusion time. These compounds are used for The dose of thrombolytics that should be present can also be reduced, and therefore possible bleeding side effects Can be minimized. The compounds of the present invention can be used in vivo, usually primates (e.g., humans), Mammals such as sheep, horses, cows, pigs, dogs, cats, rats and mice It can be used in the body or in vitro.   The biological properties of the compounds of the invention can be measured, for example, in an in vitro protease activity assay. And in the art, such as in vivo studies to evaluate antithrombotic effects Hemostasis and hemostasis, such as those described in the Examples, and by known methods. And its effect on hematological parameters can be easily described.   For diagnostic applications of the compounds of the present invention, formulations will typically be used in the form of a solution or suspension. Would use. In the treatment technique for thrombotic diseases, the compound of the present invention is used for oral administration. Tablets, capsules or elixirs, suppositories, sterile solutions or suspensions for injection administration It can be used in compositions, such as liquids, or can be incorporated into molded articles. Optimal for subjects (typically mammals) in need of treatment with compounds of the present invention. A dose that will provide efficacy can be administered. Dosage and method of administration Depending on the subject, the type of mammal being treated, gender, weight, diet, concomitant medications, The overall clinical conditions, the specific compounds used, and the specific Depends on factors such as use and other factors that medical technology professionals will understand will do.   Formulations of the compounds of the present invention allow for the preparation of compounds having the desired degree of purity in a physiologically acceptable manner. For storage or administration by mixing with active carriers, excipients, stabilizers, etc. And may be provided in a sustained release or timed release formulation. For therapeutic use The acceptable carriers or diluents are well known in the pharmaceutical art. For example, Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R.G. ennaro, 1985). Such substances depend on the dosage used and It is nontoxic to recipients at concentrations and contains phosphate, citrate, acetate and And other organic acid salts, antioxidants such as ascorbic acid, polyarginine Low-molecular-weight (less than about 10 residues) peptides such as serum albumin, gelatin, Or proteins such as immunoglobulins, hydrophilic properties such as polyvinylpyrrolidinone Polymer, glycine, glutamic acid, aspartic acid, or arginine Amino acids, monosaccharides, disaccharides, cellulose or its derivatives, glucose, Chelating agents such as other hydrocarbons including nonose or dextrin, EDTA, Sugar alcohols such as mannitol or sorbitol, sodium On and / or with Tween, Pluronics or polyethylene glycol A nonionic surfactant.   Dosage forms of the compounds of the invention for use in therapeutic administration must be sterile. Absent. Sterilization can be by filtration through a sterile membrane, such as a 0.2 micron membrane, or by other means. It is easily achieved by conventional methods. Formulations are typically packaged in lyophilized form. Or stored as an aqueous solution. The pH of the preparations of the invention is typically 3-11, more preferably. Preferably it can be 5-9, most preferably 7-8. The above excipients, carriers, Or the use of some of the stabilizers, resulting in cyclic polypeptide salts It will be understood that it will be formed. The preferred route of administration is injection Suppositories, implant pellets or small cylinders, aerosols, orally Variety of drug preparations and topical preparations such as ointments, drops and skin patches Oral, intravenous (bolus and / or infusion), subcutaneous, intramuscular Other modes of administration, such as intra-, colonic, rectal, nasal, transdermal or intraperitoneal, are also contemplated. The compounds of the invention may be biodegradable polymers or, for example, Inert, such as synthetic silicon such as rubber or other commercially available polymers It is incorporated as desired into molded articles such as implants that can use various materials.   The compounds of the present invention can be used to transport liposomes such as small, large and multilamellar vesicles. It can also be administered in the form of a system. Liposomes are cholesterol, stearylamido Or phosphatidylcholine.   The compound of the present invention may be an antibody, an antibody fragment, a growth factor, an antibody to which a compound molecule is bound. It can also be transported by Remon or other targeting moieties. Compound of the present invention Can be combined with a suitable polymer as a targetable drug carrier. it can. Such polymers include polyvinylpyrrolidinone, pyran copolymer , Polyhydroxy-propyl-methacrylamide-phenol, polyhydroxy Poly-substituted with tyl-aspartamide-phenol or palmitoyl residues Ethylene oxide-polylysine may be included. Furthermore, the compounds of the present invention Polylactic acid, polyglycol useful for achieving controlled release of objects Acid, copolymer of polylactic acid and polyglycolic acid, polyepsilon caprolactone , Polyhydroxybutyric acid, polyorthoester, polyacetal, polydialdehyde Ropyran, polycyanoacrylic acid and crosslinked or amphiphilic hydrogen And certain biodegradable polymers, such as protected copolymers of thiol. Poly Polymers and matrices of semipermeable polymers can be used for valves, stents, tubing, It can be formed into any molded article.   Therapeutic liquid compound formulations are generally prepared by puncturing, for example, with a hypodermic injection needle. A sterile device, such as an intravenous solution bag or vial with a stopper that can Place in container with access port.   Therapeutically effective dose is determined by either in vitro or in vivo methods I can do it. For each particular compound of the invention, determine the optimal dosage required. However, individual decisions can be made. The range of dosages that are effective over treatment depends on the route of administration, Will be affected by the target and the condition of the patient. Injection with hypodermic needle In some cases, it may be assumed that the medication is transported into a body fluid. For other routes of administration The absorption efficiency of each compound is determined by the well-known method in pharmacy. Must be determined individually. Therefore, the dosage is determined and the optimal therapeutic effect It is necessary for the therapist to modify the route of administration as necessary to obtain Can get. Determination of effective dosage levels, i.e., to achieve the desired result, is necessary. The required dosage level will be readily determined by one skilled in the art. Typically, compounds The application of the substance should be started at a lower dosage level, and the dosage level should be maintained until the desired effect is achieved. Increase with.   The compounds of the present invention may be administered in a therapeutic program at about 0.1 to 100 mg / kg, preferably about 0.5 mg / kg. An effective amount within the dosage range of from 1 to 50 mg / kg, more preferably from about 1 to 20 mg / kg. Daily or single to 2 to 4 divided doses and / or continuous infusion Can be administered orally or parenterally.   Typically, in free acid or base form or as a pharmaceutically acceptable salt From about 5 to 500 mg of a compound or mixture of compounds of the present invention Physiologically acceptable vehicles, carriers, as required by pharmaceutical practice , Excipients, binders, preservatives, stabilizers, dyes, flavors and the like. These pairs The amount of active ingredient in the composition is such that a suitable dosage in the range indicated is obtained.   Typical adjuvants that can be incorporated into tablets, capsules, etc. are acacia, corn Binders such as starch or gelatin, and microcrystalline cellulose Excipients such as, disintegrants such as corn starch or alginic acid, stearic acid Lubricants such as magnesium, sweeteners such as sucrose or lactose, or flavoring agents It is. When the dosage form is a capsule, in addition to the above substances, water, saline or the like Or a liquid carrier such as a fatty oil. Various types of other substances It can be used as a coating agent or as a conditioning agent in the physiological form of a dosage unit. Injection The sterile composition for use can be formulated according to the usual pharmaceutical practice. For example, In a vehicle such as oil or a synthetic fat vehicle such as ethyl oleate, Or it may be necessary for the active compound to be dissolved or suspended in liposomes. . Buffers, preservatives, antioxidants and the like may be mixed depending on accepted pharmaceutical practice .                             Preparation of disclosed compounds   The compounds of the present invention may be in solid or liquid phase as described and referenced in standard reference books. Or by a combination of both methods. These methods are well known in the art. Bodanszky, “The Princ iples of Peptide Synthesis ”, Hafner, et al., Eds., Springer-Verlag, Ber. See lin, 1984.   The starting materials used in any of these methods were Aldrich, Sigma, Commercially available from chemical trading companies such as Nova Biochemicals and Bachem Biosciences. It is accessible or can be easily synthesized by known techniques.   Reactions were run under standard conditions of reaction at standard temperature and pressure unless otherwise noted. Performed in laboratory glassware and in reaction vessels.   During the synthesis of these compounds, the functional groups of the amino acid derivatives used in these methods Is protected with a protecting group to prevent cross-reaction during the coupling process. Examples of suitable protecting groups And its use are described in “The Peptides: Analysis, Synthesis, Biology”, Academic Press, Vol. 3 (Gross, et al., Eds., 1981) and Vol. 9 (1987) And its disclosure is incorporated herein by reference.   Two typical synthetic schemes are outlined immediately below, and specific syntheses are described in the examples. . Isolate reaction products by standard methods, typically by solvent extraction into compatible solvents Purify. By column chromatography or other suitable methods, the product is It can be further purified.  Peptide derivative is continuous from protected fragment 3 to protected fragment 2 By coupling, followed by coupling with the protected fragment 1 (Scheme I). Alternatively, fragment 2 first To produce an intermediate, from which fragment 3 is added. Can be coupled (Plan II). Protecting groups are finally removed by HF cleavage .   Most compounds are purified by reverse phase HPLC and characterized by ion spray MS spectroscopy. I can.                                  Plan I                           P is a protecting group.                                  Plan II                           P is a protecting group.   The chemistry described in Schemes I and II can be readily modified and is well known in the art. Combined with other approaches to produce other compounds within the family of Formula I be able to.   R^Four, -NR^FourR^Five, Methods for attaching such "A" substituents are well known in the art. Mr Various R substituents (H, -OH, C_1-6Alkyl, aryl and C_1-4Alkylaryl) Chemistry using is also well known in the art. C_1-6Alkyl, C_3-8Shiku 1-4 alkyl, aryl, or 1-4 selected from the group consisting of N, O and S Attaches a "W" substituent, such as a 5- to 10-membered heterocyclic ring system containing a heteroatom Methods are well known in the art. In addition, additional A and W substituents This will be described in Examples 8 and 13.   The “D” substituent described in fragment 1 is —CO. D is -SO_Two-, -CH_Two-, -O- CO-, NR^FifteenSO_Two-Or NR^FifteenFragment similar to the structure of Fragment 1 which is -CO- Can be performed by techniques such as those described in Simple, et al., WO 95/35311. It can be easily synthesized.   "R" described in fragment 2¹”And“ R^Two"The substituent is -H. R¹Is C_1-6 Alkyl or C_1-3Alkylaryl and / or R^TwoIs C_1-6Alkyl , C_3-6Cycloalkyl, C_1-3An alkylaryl or an aryl fragment Fragments similar to the structure of event 2 can be prepared using techniques well known in the art. Can be easily synthesized.   The "E" substituent described in fragment 3 (-NHC (= NH) -NH_Two) Is included in the present invention. It is merely one example of the various "E" substituents that are performed. E is -NH_Two, -SC (= NH) -NH_Two, Or -C (= NH) -NH_TwoA fragment similar to the structure of fragment 3 The compound can be easily synthesized by a technique well known in the technical field.   The “Y” substituent described in fragment 3 is —CO-G, where G is Where J is -S- and L is And R⁹And R^TenIs H. G isAnd J is -SO- or -SO_TwoFragment similar to the structure of fragment 3 Can be readily synthesized by techniques well known in the art. J is -O- Is a fragmentJ. Am. Chem. Soc. 114: 1854-1863 (1992),J. Med.Che m .38: 76-85 (1995), andJ. Med.Chem. 37: 3492-3502 (1994). Can be synthesized by the following method. Finally, J is -NR₆-And R₆Is H, C_1-6Alkyl Or a fragment that is benzyl,J. Med.Chem. 37; explained in 3492-3502 (1994) It can be synthesized by the method described. All these references are referred to herein. Incorporated for reference.   G is Where L is R⁷, R⁸, R⁹And R^TenIs not H Fragments similar to the structure of Fragment 3 are also well known in the art. It can be easily synthesized by a known method.   G is -COOR²⁰, -CONR²⁰R^{twenty one}, -CF_ThreeOr -CF_TwoCF_ThreeTo the structure of fragment 3 Similar fragments can be readily prepared using techniques well known in the art. Can be synthesized.   G isWherein U and V are various substituents (-O-, -S-, -N-, -N (H)-) The fragment similar to the structure ofJ. Med.Chem. 38: 1355-1371 (1995) AndJ. Med.Chem. 37: 2421-2436 (1994). Can be easily synthesized.   A fragment similar to the structure of fragment 3 in which “Y” is a group containing boron Can be readily synthesized by techniques well known in the art. For example, J.Org .Chem. 60: 3717-3722 (1995).   Coupling various fragments used to synthesize compounds of the present invention Mechanisms are also well known in the art.   Without further elaboration, those skilled in the art will be able to utilize the invention to its fullest extent. it can. Therefore, the following preferred specific embodiments are to be interpreted merely illustratively and It does not limit the rest in any way.                                 Example 1   To a suspension of Boc-Arg (Tos) -OH (2 g, 4.7 mmol) in DMF (20 mL) at 0 ° C. was added MeNHOMe HCl ( 1 g, 10.3 mmol), DIEA (6 mL) and BOP (2.5 g, 5.6 mmol) are added. Solution at 0 ° C And stir for 10 hours. DMF is evaporated by reduced pressure. The oily residue was treated with EtOAc (200m L) and water (20 mL). NaHCO saturated organic layer_Three, Water (20 mL), 1M HCl (10 mL) and saturated NaCl (2X20mL). MgSO_FourDried on, filtered Evaporate to obtain a suspension. The suspension was filtered, washed with cold EtOAc (10 mL) and dried To obtain Boc-Arg (Tos) -N (Me) OMe shown above (1.5 g, yield 70%). FAB-MS (M + H) + = 472.Example 2   To a solution of thiazole (2.5 g, 29 mmol) in THF (25 mL) at -78 ° C was added n-BuL1 (hexane 1.6M, 19mL) is added dropwise. Stir the mixture for 30 minutes. Then, Example 1 A solution of Boc-Arg (Tos) -N (Me) OMe (1.7 g, 3.6 mmol) from THF (50 mL) at -78 ° C Add to the thiothiazole mixture. The solution is stirred for 2 hours. Reaction with 1M HCl (30mL) Add to the mixture and warm to room temperature. Extract the mixture with EtOAc (100 mL). The organic layer was washed with saturated NaCl (30 mL),_FourDry over, filter and evaporate. Crude oily residue is SiO_Two(50% EtOAC CH_TwoCl_Two) On a flash column. The indicated Boc-Arg (Tos) thiazole (1.5 g, 84% yield) is obtained as a powder. DCI-MS (M + H) + = 496.                                 Example 3   Boc-Arg (Tos) thiazole from Example 2 (300 mg, 0.6 mmol) CH 2 at 0 ° C._TwoCl_Two (10 mL) To the solution is added TFA (10 mL). The solution is stirred at 0 ° C. for 2 hours. Solvent And the excess TFA was evaporated to give an oily residue which was used directly without further purification You.Example 4   N-α-Boc-N-δ-CBZ-L-ornithine (10 g, 0.027 mol) was added to MeOH (45 mL), water (30 mL). ) And acetic acid (5 mL). After purifying with argon, 10% Pd / C (1 g) and hydrogenate on a Parr apparatus at 35 psi for 3 hours. N-α-Bo by TLC Pure conversion to c-L-ornithine was shown.   After purifying with argon, glyoxylic acid (3 g, 0.03 mol) was added, and the mixture was added. After stirring at room temperature for 50 hours, the mixture was hydrogenated on a Parr apparatus at 35 psi for 17 hours. , The catalyst is removed by filtration. A fresh 10% Pd / C (0.5 g) portion is added and the mixture is Hydrogenate at 40 psi time. The catalyst is removed by filtration and the filtrate is evaporated to dryness under reduced pressure. And concentrate. The residue is dissolved in MeOH and re-evaporated. Repeat this process and remove the residue Pump overnight to give a yellow foam.   Dissolve the crude intermediate in dry DMF (60 mL) and warm to 50-60 ° C. for 2.5 hours. Under reduced pressure And remove the solvent. The oily residue is taken up in 50 mL CH_TwoCl_TwoAnd extracted with 50 mL of 1N NaOH Put out. 50 mL CH_TwoCl_TwoAnd then acidify with 50 mL of 1N HCl while cooling. 5 X 50 mL CH_TwoCl_TwoExtract again. The combined organic layers were dried over MgSO_FourDried on Filtered and evaporated to give 5 g of the compound shown above as a solidified oil.                                 Example 5   Compound (1 mmol) of Example 3 and compound (1 mmol) of Example 4 were added to DMF (5 mL). Dissolve and cool to 0 ° C. Neutralize the solution with DIEA (1 mL), then The drug BOP (1.1 mmol) is added. Stir the solution for 1-2 hours and react by HPLC analysis Showed completion. The solvent is removed at 30 ° C. by reduced pressure. The residue was treated with EtOAc-H_TwoO (50mL: 10 Dissolve in the mixture (mL). NaHCO saturated organic layer_Three(2 × 10 mL) and saturated NaCl (2 × 10 mL) and wash with MgSO_FourDry over, filter and evaporate the solvent. S oily residue iO_TwoTo give the above compound as a powder.                                 Example 6   CH of the compound of Example 5 (1 mmol) at 0 ° C._TwoCl_Two(10mL) solution to TFA (10mL) Add. The solution is stirred at 0 ° C. for 2 hours. Evaporate solvent and excess TFA to oil The residue is used without further purification.                                 Example 7   Compound of Example 6 (1 mmol) and N-Boc-4-piperidine-propanoic acid (1 mmol) Is dissolved in DMF (5 mL) and cooled to 0 ° C. Neutralize the solution with DIEA (1 mL), then Add coupling reagent BOP (1.1 mmol). Stir the solution for 1-2 hours for HPLC analysis To indicate the completion of the reaction. The solvent is removed at 30 ° C. by reduced pressure. The residue was treated with EtOAc-H_TwoO (50m L: 10 mL) and discard the aqueous layer. NaHCO saturated organic layer_Three(2X10mL) And saturated NaCl (2 × 10 mL),_FourDried on, filtered, Allow to evaporate. Oily residue SiO_TwoPurified by flash column As a powder.Example 8   100 mg of the compound of Example 7, 1 ml of anisole and 4 drops of MeSEt in an HF cutting vessel Put in liquid N_TwoCool down. Then 10 ml of HF is concentrated and the mixture is 1.25 Stir for hours. A rubber-like residue is obtained, except for decompression bandits. Residue in 20 ml of 50% Et_TwoO- Triturate with hexane and remove the solvent by filtration. Remove the gummy residue with 30 ml of 30% HOAc Dissolve in aqueous solution and filter through upper sinter funnel. The filtrate is freeze-dried to obtain a powder, It is purified by RP-HPLC to give the above compound as a powder.                                 Example 9   The compound of Example 4 (1 mmol) was dissolved in 1 mL of MeOH, cooled to 0 ° C., Treat dropwise with MeOH solution (4 mL). The solution was stirred at 0 ° C. for 1 hour, then Warm to room temperature and stir for 14 hours. Concentrate the solution under reduced pressure to clear the above compound Oil, which is used directly in the next example.Example 10   Example 9 (1 mmol) and 4- (Di-CBZ-guanidine) -butanoic acid (1 mmol) ) Is dissolved in DMF (5 mL) and cooled to 0 ° C. Neutralize the solution with DIEA (1 mL) Post coupling reagent BOP (1.1 mmol) is added. Stir solution for 1-2 hours and analyze by HPLC Indicates the completion of the reaction. The solvent is removed at 30 ° C. by reduced pressure. The residue was treated with EtOAc-H_TwoO ( Dissolve in a mixture (50 mL: 10 mL) and discard the aqueous layer. NaHCO saturated organic layer_Three(2X10mL) And saturated NaCl (2 × 10 mL),_FourDried on, filtered and evaporated . Oily residue SiO_TwoAnd purified using a flash column Get it.                                 Example 11   The compound of Example 10 (1 mmol) is dissolved in MeOH (1 mL) and cooled to 0 ° C. 5mL of 1N  LiOH is added dropwise to the mixture and the solution is stirred at 0 ° C. for 2 hours. By TLC analysis The reaction was complete. Concentrate the mixture and acidify with 1N HCl (5 mL). Crude generation The product is purified by reverse phase HPLC to give the compound shown above as a powder.                                 Example 12   The compounds of Example 11 (1 mmol) and Example 3 (1 mmol) were dissolved in DMF (5 mL) and Cool down to ° C. The solution was neutralized with DIEA (5 mL), and then coupling reagent BOP (1. 1 mmol). The solution was stirred for 1-2 hours and HPLC analysis indicated the completion of the reaction. Dissolution The medium is removed at 30 ° C. by reduced pressure. The residue was treated with EtOAc-H_TwoDissolved in a mixture of O (50 mL: 10 mL) Disassemble and discard the aqueous layer. NaHCO saturated organic layer_Three(2X10mL) and saturated NaCl (2X10mL) Wash with MgSO_FourDry over, filter and evaporate. Oily residue SiO_TwoHula The product is purified by a flash column to obtain the above compound as a powder.Example 13   100 mg of the compound of Example 12, 1 ml of anisole and 4 drops of MeSEt in an HF cutting vessel Put in liquid N_TwoCool down. Then 10 ml of HF is concentrated and the mixture is 1.25 Stir for hours. Removal of HF under reduced pressure gives a rubber-like residue. Residue in 20 ml of 50% Et_TwoO-F Triturate with xane and remove the solvent by filtration. 30 ml of 30% HOAc water with rubbery residue Dissolve in solution and filter through an upper sinter funnel. The filtrate is freeze-dried to obtain a powder, which Is purified by RP-HOLC to obtain the above compound as a powder. Example 1-12 and actual By going through the same synthetic procedure as in Example 13, the following compound was also prepared: . Example 14 (Determination of IC ₅₀ )   The compound of the invention is first dissolved in buffer to give an assay concentration in the range 0-100 μM. A solution containing such a concentration is obtained. For thrombin assays, the prothrombiner Enzyme, factor Xa, and synthetic dye substrate in a solution containing the test compound and the target enzyme. In addition, the remaining catalytic activity of the enzyme is then determined with a spectrophotometer.   Compound IC₅₀Is determined from the substrate turnover. I c₅₀Is the substrate turn-over The concentration of test compound that inhibits the bar by 50%. Preferred compounds of the present invention Desirably less than 500 nM, preferably less than 200 nM, more preferably Preferably, IC of 100nM or less₅₀Having. A preferred compound of the present invention is prothrombi Desirably 4.0 μM or less, preferably 200 nM in the enzyme assay Less than, more preferably less than 10 nM IC₅₀Having. Preferred compounds of the invention are In a thrombin assay, desirably 1.0 μM or more, preferably 10.0 nM μM or less. Above, more preferably more than 100.0 μM IC₅₀Having.          Amidolytic assay to determine protease inhibitory activity   Factor Xa and thrombin assays are performed at room temperature with 0.02 M Tris HC containing 0.15 M NaCl. Perform in l buffer, pH 7.5. Pre-incubate enzyme and test compound for 5 minutes at room temperature After addition, the paranitroanilide substrate for factor Xa S-2765 (Chromogenix), The hydrolysis rate of Chromozym TH (Boehringer Mannheim) Monitor at 405 nm using a x96-well plate reader (Molecular Devices). By determining the time-dependent appearance of p-nitroanilide.   Prothrombinase inhibition assays are described in Sinha, et al.,Thromb.Res., 75: 427- 436 (1994), in a modified, plasma-free system. Prothrombin complex The activity of the coalescence was determined through thrombin generation using the p-nitroanilide substrate Chromozym TH. It is determined by measuring the time change. The assay attempts to test as an inhibitor Selected compounds, Factor Xa (0.5 nM), Factor Va (2 nM), phosphatidylserine: Complexes formed from phosphatidylcholine (25:75, 20 μM) were combined with 0.15 M NaCl , 5mM CaCl_TwoAnd 20 mM Tris-HCl buffer containing 0.1% bovine serum albumin, pH 7.5 Pre-incubation for 5 minutes in water. Complex-test compound mixture The injection is added to prothrombin (1 nM) and Chromozym TH (0.1 mM). Substrate cleavage The speed is monitored at 405 nM for 2 minutes. Duplicate several concentrations of a particular test compound. Assay in duplicate. Then thrombi with an equal amount of untreated complex A standard curve of protein production is used to determine percent inhibition.                                 Example 15   The antithrombotic effect of the compounds of the present invention has been described in a series of studies in rabbits described below. Can be easily evaluated using These studies are based on hemostasis and its hematological parameters. It is also useful for assessing the effect of a compound on a compound.              Antithrombotic effect in a rabbit model of venous thrombosis   Hollenbach, et al.,Thromb.Haemost. 71: 357-362 (1994) Rabbit depth Using a venous thrombosis model, the in vivo antithrombotic activity of the compound of the present invention is determined. Rabbits are injected intramuscularly with ketamine, xylazine, and acepromazine cocktail Anesthetize with   A standardized protocol consists of an anesthetized thrombogenic cotton thread and a copper wire device. Including insertion into the abdominal vena cava of a giant. Non-occlusive thrombus forms in central venous circulation Thrombus growth as a measure of the antithrombotic activity of the compound to be evaluated. Use inhibition. Test substance or control saline via marginal ear vein catheter Administer. Blood sampling before and during routine infusion of the compound to be evaluated Use a femoral vein catheter to perform the procedure. As soon as the cotton thread device has advanced into the central venous circulation Later, the onset of thrombus formation will occur. Compound to be evaluated, from time = 30 minutes Administer until the end of the experiment = 150 minutes. Euthanize rabbits and surgically dissect thrombi And characterized by weight and histology. Then, a blood sample Analyze for changes in humoral and coagulation parameters.   Although the invention has been described with reference to the disclosed embodiments, detailed and specific experiments are merely illustrative of the invention. Those skilled in the art will readily recognize that this is an illustrative example. Spirit of the invention It should be understood that various modifications can be made without departing from You. Accordingly, the invention is limited only by the following claims.

────────────────────────────────────────────────── ─── Continuation of front page    (31) Priority claim number 08 / 948,672 (32) Priority Date October 10, 1997 (Oct. 10, 1997) (33) Priority country United States (US) (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, S D, SZ, UG, ZW), EA (AM, AZ, BY, KG) , KZ, MD, RU, TJ, TM), AL, AM, AT , AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, F I, GB, GE, GH, HU, IL, IS, JP, KE , KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, M X, NO, NZ, PL, PT, RO, RU, SD, SE , SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Scarborough, Robert M             94002 California, United States of America,             Belmont, Belmont Canyon Lo             Mode 2544

Claims (1)

[Claims] 1. The following formula:   Where:   R¹Is H, C_1-6Alkyl or C_1-3Alkylaryl;   R^TwoIs H, C_1-6Alkyl, C_3-6Cycloalkyl, C_1-3Alkylaryl, C_1-3A Lucil-C_3-8Cycloalkyl or aryl and R^ThreeIs H, C_1-6With alkyl Yes or R^TwoAnd R^ThreeTogether form a carbocyclic ring;   m is an integer from 0-3;   n is an integer from 0-6;   p is an integer from 0-4;   s is an integer from 0-2;   q is an integer from 0-2;   A is a 5-membered group containing 1-4 heteroatoms selected from the group consisting of N, O and S A 10-membered heterocyclic ring system; R^Four; -NR^FourR^Five; Selected from the group consisting of^Four, R^Five, R¹⁶And R¹⁷Is H, -OH, C_1-6Archi , Aryl and C_1-4Independently selected from the group consisting of alkylaryl; R¹⁸Is H , -OH, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl Selected or R¹⁶Or R¹⁷Can form a 5- to 6-membered ring ; And R¹⁹Is H, -OH, C_1-6Alkyl, aryl and C_1-4Alkyl aryl Selected from the group consisting of¹⁷And form a 5- to 6-membered ring Can;   W is a direct bond, C_1-6Alkyl, C_3-8Cycloalkyl, C_1-6Alkenyl, C_{1- 6} Alkylaryl, aryl, or 1- selected from the group consisting of N, O and S A 5-10 membered heterocyclic ring system containing 4 heteroatoms;   D is a direct bond, -CO-, SO_Two-, -CH_Two-, -O-CO-, -NR^FifteenSO_Two-Or-NR^Fifteen-CO- Yes, where R^FifteenIs H, -OH, C_1-6Alkyl, aryl and C_1-4Alkyl ally Selected from the group consisting of   K is a direct bond, C_3-8From cycloalkyl, aryl, or N, O and S 5 to 10-membered heterogeneous intellectuals, including 1-4 heteroatoms selected from the group Selected from the group consisting of:   E is R²⁶, NR²⁶R²⁷, Selected from the group consisting of²⁶, R²⁷, R²⁸And R²⁹Is H, -OH, C_1-6Archi , Aryl and C_1-4Independently selected from the group consisting of alkylaryl; R³⁰ Is H, C_1-6Alkyl, aryl and C_1-4Select from the group consisting of alkylaryl Or R²⁸Or R²⁹Can form a 5-6 membered ring with And R³¹Is H, C_1-6Alkyl, aryl and C_1-4Group consisting of alkylaryl Selected from or R²⁹Can form a 5- to 6-membered ring with But E is R²⁶K must contain at least one N atom if Conditional;   Y is H, Selected from the group consisting of¹³And R¹⁴Is H, C_1-3Alkyl and ally Independently selected from the group consisting of²⁰, -CONR²⁰R^{twenty one}, -CF_Three, -C F_TwoCF_ThreeOr a group having the following formula, Where:   R^{twenty two}Is H, C_1-6Alkyl, C_2-6Alkenyl, C_0-6Alkylaryl, C_2-6Arche Nylaryl, C_0-6Alkylheterocyclo, C_2-6Alkenylheterocyclo, -CF_Three , And -CF_TwoCF_ThreeSelected from the group consisting of:   U is -O-, -S-, -N- or -N (H)-; and   V is -O-, -S-, -N- or -N (H)-; provided that at least one of U or V is Conditional on being -N- or -N (H)-;   J is -S-, -SO-, -SO_Two-, -O- or -NR⁶-Where R⁶Is H, C_1-6Alkyl Or benzyl; and   L is R⁹And R^Ten1-4 and selected from N, S and O C containing B atom_6-10Selected from the group consisting of heterocyclic ring systems; wherein r is 0-2 A number; R⁷And R⁸Is H, C_1-6Alkyl, aryl, C_1-6Alkylaryl,- COOR¹¹, -CONR¹¹R¹², -CN, and -CF_ThreeIndependently selected from the group consisting of: R⁹And And R^TenIs H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, C_1-4Alkyloxy , Halogen, -NO_Two, -NR¹¹R¹², -NR¹¹COR¹², -O-R¹¹, -O-COR¹¹, -COOR¹¹, -CONR¹¹ R¹², -CN, -CF_Three, -SO_TwoNR¹¹R¹²And C_1-6Alkyl-O-R¹¹Independent of the group consisting of Selected; and R¹¹And R¹²Is H, C_1-6Alkyl, C_1-3Alkyl aryl And aryl are independently selected from the group consisting of: And all optical isomers thereof. 2. R¹Is H or C_1-62. The compound of claim 1, which is an alkyl. 3. R^TwoIs H or C_1-62. The compound of claim 1, which is an alkyl. 4. R^ThreeIs H. 2. The compound of claim 1, wherein 5. 2. The compound of claim 1, wherein m is an integer from 0-1. 6. 2. The compound of claim 1, wherein n is an integer from 1-4. 7. 2. The compound of claim 1, wherein p is 3. 8. 2. The compound of claim 1, wherein s is 0. 9. 2. The compound of claim 1, wherein q is an integer from 0-1. 10. A is R^Four, -NR^FourR^Five, 2. The compound of claim 1, wherein the compound is selected from the group consisting of: 11. R^FourIs H, -OH or C_1-611. The compound of claim 10, which is an alkyl. 12. R^FiveIs H, -OH or C_1-611. The compound of claim 10, which is an alkyl. 13. W is C_1-4Alkyl, C_5-6Cycloalkyl, aryl, or at least 2. The compound of claim 1 which is a 5 to 10 membered heterocyclic ring system containing one N heteroatom. Compound. 14． D is -CO-, -SO_Two-Or-CH_Two2. The compound of claim 1, which is-. 15. 2. The compound of claim 1, wherein K is a direct bond. 16. E is -NH_Two, -NHC (= NH) -NH_TwoOr -SC (= NH) -NH_Two2. The compound of claim 1, which is . 17． Y is 2. The compound of claim 1, which is 18. R¹³Is H. 18. The compound of claim 17, wherein 19. R¹⁴Is H. 18. The compound of claim 17, wherein 20. G is the following formula, 18. The compound according to claim 17, which is a group having 21. J is preferably -S-, -O- or -NR⁶21. The compound of claim 20, which is-. 22. R⁶Is H. 22. The compound of claim 21, wherein 23. L is 21. The compound of claim 20, which is 24. R⁹Is H, -O-R¹¹, -COOR¹¹, -CONR¹¹R¹²Or -CF_Three24. The method of claim 23, wherein Compound. 25. R^TenIs H, -O-R¹¹, -COOR¹¹, -CONR¹¹R¹²Or -CF_Three24. Compound. 26. R¹¹Is H. 2. The compound of claim 1, wherein 27. R¹²Is H. 2. The compound of claim 1, wherein 28. The following formula:   Where:   m is an integer from 0-3;   n is an integer from 0-6;   q is an integer from 0-2;   A is R^Four, -NR^FourR^Five, Selected from the group consisting of^Four, R^Five, R¹⁶, R¹⁷, R¹⁸And R¹⁹Are H, -OH and And C_1-6Independently selected from the group consisting of alkyl;   W is C_1-6Alkyl, C_3-8Cycloalkyl, C_1-6Alkenyl, aryl, or N 5 to 10 membered members containing 1-4 heteroatoms selected from the group consisting of, O and S A heterocyclic ring system; wherein A is R^FourW contains at least one N atom With the condition that it must be;   D is -CO- or -SO_Two-   J is -S-, -SO-, -SO_Two-, -O- or -NR⁶And R⁶Is H; and   L is R⁹And R^Ten1-4 and selected from N, S and O C containing B atom_6-10Selected from the group consisting of heterocyclic ring systems; wherein r is an integer of 0-1 A number; R⁷And R⁸Is H, C_1-6Alkyl, aryl, C_1-6Alkylaryl,- COOR¹¹, -CONR¹¹R¹², -CN, and -CF_ThreeIndependently selected from the group consisting of: R⁹And And R^TenIs H, C_1-6Alkyl, aryl, C_1-6Alkylaryl, C_1-4Alkyloxy Si, halogen, -NO_Two, -NR¹¹R¹², -NR¹¹COR¹², -O-R¹¹, -O-COR¹¹, -COOR¹¹, -CO NR¹¹R¹², -CN, -CF_Three, -SO_TwoNR¹¹R¹²And C_1-6Alkyl-O-R¹¹From the group consisting of Germany Selected; and R¹¹And R¹²Is H, C_1-6Alkyl, C_1-3Alkylaryl And aryl are independently selected from the group consisting of: And all optical isomers thereof. 29. A is R^Four, -NR^FourR^Five, 29. The compound of claim 28, selected from the group consisting of: 30. R^FourAnd R^FiveIs independently selected from the group consisting of H, -OH and methyl; 29. The compound of claim 29. 31. W is C_1-4Alkyl, C_5-6Cycloalkyl, aryl, at least one N 29. The compound of claim 28 which is a 5- to 10-membered heterocyclic ring system containing atoms. 32. J is preferably -S-, -O- or -NR⁶-And R⁶Is H Compound of 8. 33. L is 29. The compound of claim 28, which is 34. R⁹Is H, -O-R¹¹, -COOR¹¹, -CONR¹¹R¹²Or -CF_Three34. The method of claim 33, wherein Compound. 35. R^TenIs H, -O-R¹¹, -COOR¹¹, -CONR¹¹R¹²Or -CF_Three34. Compound. 36. The following stereochemistry: 29. The compound of claim 28 having the formula: 37. The following formula:   Where:   m is an integer from 0-3;   n is an integer from 0-6;   q is an integer from 0-2;   A is R^Four, -NR^FourR^Five, Selected from the group consisting of^Four, R^Five, R¹⁸And R¹⁹Is H, -OH and C_1-6Al Independently selected from the group consisting of kills;   W is C_1-6Alkyl, C_3-8Cycloalkyl, C_1-6Alkenyl, aryl, or N 5 to 10 membered members containing 1-4 heteroatoms selected from the group consisting of, O and S A heterocyclic ring system; wherein A is R^FourW contains at least one N atom With the condition that it must be;   D is -CO- or -SO_Two- And all optical isomers thereof. 38. A is R^Four, NR^FourR^Five, 38. The compound of claim 37, wherein the compound is selected from the group consisting of: 39. R^FourAnd R^FiveIs independently selected from the group consisting of H, -OH and methyl; 38. The compound of claim 38. 40. W is C_1-4Alkyl, C_5-6Cycloalkyl, aryl, or at least 38. The method of claim 37, which is a 5 to 10 membered heterocyclic ring system containing one N heteroatom. Compound. 41. The following stereochemistry: 38. The compound of claim 37 having the formula: 42. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1. To prevent or treat a condition in a mammalian individual characterized by unwanted thrombosis Pharmaceutical composition. 43. Claims 1. A therapeutically effective amount of a compound of claim 1 characterized by unwanted thrombosis. Preventing or treating the condition in said mammal individual, comprising administering to said mammal individual. How to treat. 44. State is: Unstable angina, refractory angina, myocardial infarction, transient ischemic attack, thrombotic attack, embolus For seizures, generalized intravascular coagulation including treatment of septic shock, pulmonary embolism Deep vein in the prevention or treatment of reperfusion or restenosis of reperfused coronary arteries Thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, surgery Complications and peripheral artery occlusion, thrombolytic treatment or percutaneous transluminal coronary angioplasty Obstructive coronary thrombus formation, thrombus formation in the venous vasculature Treating or preventing disseminated intravascular coagulation; 44. The method of claim 43, wherein the method is selected from the group consisting of: 44. A method of inhibiting coagulation of a biological sample, comprising administering a compound of claim 1.