MXPA00001568A - SELECTIVE FACTOR Xa INHIBITORS CONTAINING A FUSED AZEPINONE STRUCTURE - Google Patents

Abstract

Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders. They have structure (I), where the meanings of the substituents are as indicated in the text.

Description

SELECTING FACTOR Xa INHIBITORS THAT CONTAIN A FUSED AZEPINONE STRUCTURE FIELD OF THE INVENTION This invention relates to a novel class of fused aryl diazepinone compounds which are potent and highly selective inhibitors of factor Xa or factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other coagulation proteases (e.g., thrombin, fVlla, flXa) or fibrinolytic cascades (e.g., plasminogen activators, plasmin).

BACKGROUND OF THE INVENTION The coagulation of the blood protects the species of mammals when the integrity of the wall of the blood vessels is damaged and the uncontrolled loss of blood threatens survival. Coagulation, which results in the agglutination of blood, is an important component of hemostasis. Under normal haemostatic conditions, an acute balance of clot formation and clot removal (fibrinolysis) is maintained. The blood coagulation cascade involves the conversion of a variety of inactive enzymes (zymogens) into active enzymes, which ultimately convert the protein fibrinogen into the soluble plasma into an insoluble, highly entangled fibrin matrix (see Davie, et al., "The Coagulation Cascade: Initiaton, Maintenance and Regulation "Biochemistry 30: 10363-10370 (1991)). Blood platelets that adhere to damaged blood vessels are activated and incorporated into the clot and thus play an important role in the initial formation and stabilization of hemostatic "plugs". In some diseases of the cardiovascular system, deviations from normal hemostasis break the equilibrium of clot formation and clot dissolution to the formation of life-threatening thrombi when thrombi obstruct blood flow in the coronary vessels (myocardial infarctions) or veins of the extremities and lungs (venous thrombosis). Although platelets and blood coagulation are both involved in the formation of thrombi, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition. A key enzyme in the coagulation cascade, as well as in hemostasis, is thrombin. Thrombin is strictly involved in the process of thrombus formation, but under normal circumstances it can also play an anticoagulant role in hemostasis through its ability to convert protein C into activated protein C in a thrombomodulin-dependent manner. Thrombomodulin plays a central role in thrombosis through its ability to catalyze the penultimate conversion of fibrinogen to fibrin and through its potent platelet activation activity. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson "Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coaq. Fibrinol. 5: 411-436 (1994). The main classes of anticoagulants currently used in medicine directly or indirectly affect thrombin (ie, heparins, low molecular weight heparins and coumarins). Thrombin is generated at the convergence of intrinsic and extrinsic coagulation pathways by the prothrombinase complex. The prothrombinase complex is formed when the activated factor X (factor Xa) and its nonenzymatic cofactor, factor Va, is assembled on phospholipid surfaces in a Ca + 2 dependent manner as reviewed by Mann, et al., "Surface- Dependent Reactions of the Vitamin K-Dependent Enzymes, Blood 76: 1-16 (1990) Prothrombinase complex converts the prothrombin of zymogen into the active procoagulant thrombin The site of the prothrombinase complex at the convergence of intrinsic coagulation pathways and extrinsic, and significant amplification of thrombin generation (393,000 fold over factor Xa that does not form complex) mediated by the complex in a limited number of target catalytic units present at vascular injury sites, suggests that generation inhibition of thrombin is an ideal method to block «ASÜfet uncontrolled procoagulant activity. Unlike thrombin, which acts on a variety of protein substrates as well as a specific receptor, factor Xa appears to have a single physiological substrate, namely, prothrombin. Plasma contains an endogenous inhibitor of both the tissue factor factor (TF) factor VI complex and the tissue factor pathway inhibitor factor TF (TFPI). TFPI is a Kunitz-type protease inhibitor with three chain Kunitz domains. TFPI inhibits the TF / fVlla complex in a two-step mechanism that includes the initial interaction of the second Kunitz domain of TFPI with the active factor Xa site, thereby inhibiting the proteolytic activity of factor Xa. The second step involves the inhibition of the TF / fVlla complex by the formation of a TF / fVlla / TFPI / fX quaternary complex as described by Girard, et al., "Functional Significance of the Kunitz-type Inhibitory Domains of Lipoprotein-associated Coagulation Inhibitor ", Nature 338: 518-520 (1989). Polypeptides derived from hematophagous organisms that are highly potent and specific inhibitors of factor X have been reported. The U.S. patent. No. 4,588,587 issued to Gasic, describes anticoagulant activity in the saliva of the Mexican leech Haementeria officinalis. A major component of this saliva has been shown as the factor Xa inhibitor polypeptide, antistasin, by Nutt, et al., "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveates to Repeated Internal Structure," J. Biol. Chem. 263: 10162-10167 (1988). mb ^^^^ u ^ g¡ £ Another powerful and highly specific inhibitor of factor Xa, the tick anticoagulant peptide, has been isolated from the whole body extract of the soft-bodied tick Ornithidoros moubata, as reported by Waxman, al., "Tick Anticoagulant Peptide (TAP) sa Novel Inhibitor of Blood Coagulation Factor Xa", Science 248: 593-596 (1990). Other inhibitors of factor Xa polypeptide type have been reported by the following citations: Condra, et al., "Isolation and Structural Characterization of a Potent Inhibitor of Coagulation Factor Xa from the Leech Haementeria ghilianiP," Thromb. Haemost 61: 437- 441 (1989); Blankenship, et al., "Amino Acid Sequence of Ghilanten: Anti-coagulant-antimetastatic Principle of the South American Leech, Haementeria ghilianif, Biochem. Biophvs. Res. Commun. 166: 1384-1389 (1990); Brankamp, et al., "Guilantens: Antociagulants, Antimetastatic Proteins from the South American Leech Haementeria ghilianif, 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); Rigbi, et al.," Bovine Factor Xa Inhibiting Factor and Pharmaceutical Compositions Containing the same ", European Patent Application, 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 Identification as Major Hookworm-derived Anticoagulant In Vitro ", J. Infect. Dis 167: 1474-1477 (1993); Seymour, et al.," Ecotin is a Potent Anticoagulant and Reversible Tight-binding Inhibitor of Factor Xa ", Biochemistry 33: 3949-3958 (1994) Factor Xa inhibitor compounds that are not polypeptide type inhibitors. Also, large numbers have been reported in the following citations: Tidwell, et al., "Strategies for Anticoagulation With Synthetic Protease Inhibitors Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res. 19: 339-349 (1980); Turner et al., "P-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry 25: 4929-4935 (1986); Hitomi et al., "Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System", Haemostasis 15: 164-168 (1985); Sturzebecher, et al., "Synthetic Inhibitors of Bovine Factor Xa and Thrombin, Comparison of Their Anticoagulant Efficiency", Thromb. Res. 54: 245-252 (1989); Kam, et al., "Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants", Biochemistry 27: 2547-2557 (1988); Hauptmann, et al., "Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors", Thromb. Haemost. 63: 220-223 (1990); Miyadera, ei al., Japanese Patent Application JP 6327488 (1994); Nagahara, et al., "Dibasic (Amidinoaryl) propanoic Acid Derivates as Novel Blood Coagulation Factor Xa Inhibitors", L Med. Chem. 37: 1200-1207 (1994); Vlasuk, et al., "Inhibitors of Thrombosis", WO 93/15756; and Brunck, e to al., "Novel Inhibitors of Factor Xa". WO 94/13693. AI-obeid, et al., "Factor Xa Inhibitors", WO 95/29189, discloses pentapeptide XI-Y-I-R-X2 derived as factor Xa inhiitors. Said compounds are useful for inhibiting blood coagulation in the treatment of thrombosis, stroke and myocardial infarction.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to mimetic analogs of novel peptides, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives. In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. These compositions are useful as potent and specific inhibitors of blood coagulation in mammals. In another aspect, the invention relates to methods for using these inhibitors as therapeutic agents for pathological conditions in mammals having coagulation disorders such as the treatment or prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, vascular accident. cerebral thrombotic, embolic cerebral vascular accident, disseminated intravascular coagulation including the treatment of septic shock, deep vein thrombosis in the prevention of pulmonary embolism or the treatment of reocclusion or restenosis of reperfused coronary arteries. These compositions may optionally include anticoagulants, antiplatelet agents and thrombolytic agents.

In other aspects of the invention, compounds that are useful as diagnostic reagents are provided. In preferred embodiments, the present invention provides compounds of the general formula I: wherein: R1 and R4 are independently selected from the group consisting of H, C- | _6 alkyl, C3.8 cycloalkyl, C-1.3 alkylaryl, C < C3.8 cycloalkyl and aryl; R3 is H, alkyl of C < \ .Q, or R2 and R3 are taken together to form a carbocyclic ring; q is an integer of 0-1; r is an integer of 0-4; s is an integer of 0-1; t is an integer of 0-4; A is selected from the group consisting of R ^, -NR8R9, 3 £ «s g ^^^^^^? £? K ^ wherein Rβ, Rp, R 10 and R 1 1 are independently selected from the group consisting of H, -OH, C-j.β alkyl, aryl and alkylaryl of C < | __ ?; R ^ 2 is selected from the group consisting of H, C-β alkyl, aryl and alkylaryl of C- | _4, or it can be taken together with R10 or R ^ to form a ring of 5 to 6 members; and R ^ is selected from the group consisting of H, C 1-6 alkyl, aryl and C 1-4 alkylaryl, or it may be taken together with R 5 to form a 5 to 6 membered ring; D is selected from the group consisting of a direct bond, C3_8 cycloalkyl, aryl and a five to ten member heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; E is selected from the group consisting of a direct link, -CO-, -SO2-, -O-CO-, -NR1 -S02- and -NR -CO-, wherein R14 is independently selected from the group consisting of H, -OH, C-β alkyl, aryl and | 8 ^^ j ^^? ^^^ alkylaryl of C- | _4; G is selected from the group consisting of a direct bond, C3.8 cycloalkyl, aryl and a five to ten member heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; J is selected from the group consisting of R15I -NR ^ Rl ^ wherein R.sub.5, R 16, R 7 and R 18 are independently selected from the group consisting of H, -OH, C- | _g alkyl, aryl and C 1-4 alkylaryl; R19 is selected from the group consisting of H, C-β alkyl, aryl, and alkylaryl of C < | _4, or it can be taken together with R17 or R18 to form a ring of 5 to 6 members; and R 2 is selected from the group consisting of H, C 1-6 alkyl, aryl and C 1-4 alkylaryl, or it may be taken together with R 18 to form a 5- to 6-membered ring; with the proviso that when J is R1 5, then G must contain at least one atom of N; K ', K ", K'" and K "" are independently selected from the group consisting of -CH-, -CR4-, -CR5- and -N-; with the proviso that no more than one of K ', K ", K and K" "are -CR4-and no more than one of K \ K", K "' and K" "are -CR5-, R4 and R5 are selected from the group consisting of C- | _g alkyl, aryl, C1.4 alkylaryl, C1.4 alkylalkoxy, halogen, -NO2- NR R7, - NR6COR7, -OR6, -OCOR6 -COOR6, -CONR R7, -CN, -CF3 > -S02NR6R7 and C alquilo_g-OR6 alkyl, wherein R6 and R7 are selected from the group consisting of H, alkyl of Cj.g, alkylaryl of C- | _4 and aryl; is selected from the group consisting of R33, -NR 3R34, wherein R33, R34, R35 and R36 are independently selected from the group consisting of H, -OH, C-μg alkyl, aryl, and C 1-4 alkylaryl; R37 is and is selected from the group consisting of H, C 1 6 alkyl, aryl and alkylaryl.

C -] _ 4, or it can be taken together with R35 or R36 to form a ring of 5 to 6 members; and R3 ^ is selected from the group consisting of H, C-μβ alkyl, aryl and alkylaryl of C- | _4, or it may be taken together with R36 to form a 5-6 membered ring; M is selected from the group consisting of a direct bond, C- | _6 alkyl, 03.3 cycloalkyl, C-.beta.-alkenyl, C-.beta.-alkenylaryl, aryl, and a five to ten membered heterocyclic ring system containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; Q is selected from the group consisting of H, wherein R2 and R22 are independently selected from the group consisting of H, C-1.3 alkyl and aryl; and T is selected from the group that consists of H, -COOR23, -CONR23R24, -CF3, -CF2CF3, and a group having the formula: wherein R23 and R24 are independently selected from the group consisting of H, C < | _6, aryl and alkylaryl of C1.4; U "and U" are independently selected from the group consisting of -O-, -S-, -N- and -NH-; with the proviso that at least one of U 'and U "is -N- or -NH-; R25 is selected from the group consisting of H, C-μ alkyl, C2-6 alkenyl, alkylaryl of CQ. Q, C2-6 alkenylaryl, CrH-6 alkylheterocycle, C2-6 alkenylheterocycle, -CF3, -CF2CF3, V is selected from the group consisting of -S-, -SO-, -SO2-, -O- and -NR26-, wherein R26 is selected from the group consisting of H, C-β alkyl and benzyl, and W is selected from the group consisting of: a heterocyclic system of Cß_? o substituted by R2 ^ and R30 and containing from 1 to 4 heteroatoms selected from N, S and O; where a is an integer from 0 to 2; R27 and R2 ^ are independently selected from the group consisting of H, C < | 6, aryl, alkylaryl of C < | 6, -COOR31 -CONR31 R32, -CN, -CF3, and R and R36 are independently selected from the group consisting of H, C-μg alkyl, aryl, C- | 6 alkylaryl, C 1-4 alkylalkoxy; , Halogen, -NO2- NR 1 R32, -NR31COR32, -OR31, -OCOR31, -COOR31, - CONR31 R32, -CN, -CF3, -S? 2NR31 R32 and C < | 6-OR31; where R31 and R32 are selected from the group consisting of H, C? _6 alkyl, C-alkylaryl; .3 and aryl; and all pharmaceutically acceptable salts and optical isomers thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. The term "alkyl" refers to saturated aliphatic groups that include straight chain, branched chain, cyclic groups and combinations thereof, having the specified number of carbon atoms, or if a number is not specified, having up to 12 carbon atoms. The term "cycloalkyl" refers to a mono, bi or tricyclic aliphatic ring having from 3 to 12 carbon atoms, preferably from 3 to 7 carbon atoms. The term "alkenyl" refers to unsaturated aliphatic groups that include straight chain, branched chain, cyclic groups and combinations thereof, which have at least one double bond and which have the specified number of carbon atoms. The term "aryl" refers to a substituted or unsubstituted aromatic ring (s), which is substituted with one, two or three substituents such as, by way of example but not limitation, C 1-6 alkoxy, C < | 6, C-μβ alkylamino, hydroxy, halagen, cyano (-CN), mercapto, nitro (-NO2), thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy, carboxamide, -NR'R ", -NR'COR", - OR, -OCOR, -COOR, -CONR'R ", -CF3, -S? 2NR'R" and C < | _6-OR; aryl, alkylaryl of C? _6 (wherein the R groups can be H, C-j.β alkyl, C1.3 alkylaryl and aryl) including but not limited to carbocyclic aryl, heterocyclic aryl, biaryl, triaryl groups and the like, all of which may be optionally substituted. Preferred aryl groups include phenyl, halogenphenyl, C- | 6 alkylphenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl and aromatic or heteroaryl heterocyclics, the last of which is an aryl group containing one or four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The aryl groups preferably have from 5 to 14 carbon atoms constituting the structure of the ring, while the heteroaryls preferably have from 1 to 4 heteroatoms with the remaining 4-10 carbon atoms. The terms "heterocycle" and "heterocyclic ring system" as used herein refer to any saturated or unsaturated mono or bicyclic ring system containing 1 to 4 heteroatoms, selected from the group consisting of nitrogen, oxygen and sulfur. Typical heterocyclic ring system will have from five to ten members, 1-4 of which are heteroatoms Typical examples of monocyclic ring system include piperidinyl, pyrrolidinyl, pyridinyl, piperidonyl, pyrrolidonyl and thiazolyl, while examples of bicyclic ring systems include benzimidazolyl, benzothiazolyl and benzoxazolyl, all of which may be substituted The term "carbocyclic ring" as used herein refers to any saturated or unsaturated ring containing from three to six carbon atoms The terms "alkylaryl" and "alkenylaryl" as used herein they refer to an alkyl group or alkenyl group, respectively, which has the number or of designated carbon atoms, attached to one, two or three aryl groups. The term "benzyl" as used herein refers to -CH2-C6H5. The term "alkyloxy" as used herein refers to an alkyl group linked to an oxygen atom such as methoxy, ethoxy, etc. The term "halogen" as used herein refers to Cl, Br, F or I substituents. The term "direct bond", as used herein refers to a bond that directly binds the substituents on either side of the direct link . When two adjacent substituents are defined as a "direct link" each, it is considered to be a single link. Two substituents are "taken together to form a 5-6 membered ring" means that an ethylene or propylene bridge, respectively, is formed between the two substituents. The term "pharmaceutically acceptable salts" includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful both in free base and in salt form. In practice, the use of the salt form is almost equivalent to the use of the base form; Acid and basic addition salts are within the scope of the present invention. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid , nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. "Pharmaceutically acceptable basic addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum bases and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines including substituted amines as they occur in nature, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine , triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, resins of polyamine and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine. "Biological property" for the purposes of the present invention means an in vivo effector or an antigenic function or antigenic activity directly or indirectly performed by a compound of this invention. The function of the effector includes a ligand receptor or link, any enzymatic activity or enzymatic modulator activity, any carrier binding activity, any hormonal activity, any activity in the promotion or inhibition of cell adhesion to an anti-cell matrix or molecules of the cellular surface, or any structural function. Antigenic functions include the possession of an epitope or antigenic site that is capable of reacting with antibodies that are produced against it. The biological properties of the compounds of the present invention can be easily characterized by the methods described in Examples 6 and 7 and by other methods as is known in the art. In addition, the following abbreviations are used in this application: "Bn" refers to benzyl. "Boc" refers to t-butoxycarbonyl. "BOP" refers to benzotriazol-1-yloxy-tris- (dimethylamino) phosphonium hexafluorophosphate. "Bu" refers to butyl. "DCM" refers to dichloromethane. "DIEA" refers to diisopropylethylamine. "DMF" refers to N, N-dimethylformamide. "Et" refers to ethyl. "Et2?" it refers to diethyl ether. "EtOAc" refers to ethyl acetate "Fmoc" refers to 9-fluorenylmethyloxycarbonyl. "HBTU" refers to O- (1 H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyl-uronium hexafluorophosphate. "HF" refers to hydrofluoric acid. "Me" refers to methyl. "MeOH" refers to methanol. "Ph" refers to phenyl. "TFA" refers to trifluoroacetic acid. "THF" refers to tetrahydrofuran.

"Cough" refers to p-toluenesulfonyl. In the compounds of this invention, the carbon atoms bonded to four non-identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof. The synthesis described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. The diastereomeric products resulting from such synthesis can be separated by chromatography or crystallization methods, or by other methods known in the art. Also, mixtures of enantiomeric products can be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, can be in one of two configurations (R or S) and both are within the scope of the present invention. In the methods described above, the final products, in some cases, may contain a small amount of diastereomeric or enantiomeric products; however, these products do not affect their therapeutic or diagnostic application. In all the peptides of the invention, one or more amide bonds (-CO-NH-) can be optionally replaced by another linkage which is isostero such as -CH2NH-, -CH2S-, -CH2-O-, CH2CH2-, -CH = CH (cis and trans), -COCH2-, -CH (OH) CH2-, -CH2SO-, and -CH2SO2-. This replacement can be done by methods known in the art. The following references describe the preparation of peptide analogs that include those alternative linkages: Spatola, "Peptide Backbone Modifications" (general review) Vega Data, Vol. 1, Issue 3, (March 1983); Spatola, "Chemistry and Biochemistry of Amino Acids, Peptides and Proteins", (general review) B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983); Morley, Trends Pharm. Sci. (General review) pp. 463-468 (1980); Hudson, ei al.,] R Pept. Prot. Res. 14: 177-185 (1979) (-CH2NH-, -CH2CH2-); Spatola, ei al., Ufe Sc 38: 1243-1249 (1986) (-CH2-S); Hann, J, Chem. Soc. Perkin Trans. _ \ pp.307-314 (1982) (-CH = CH-, cis and trans); Almquist, et al., Med. Chem. 23: 1392-1398 (1980) (-COCH2-); Jennings-White, e al., Tetrahedron Lett. 23: 2533 (-COCH-2) (1982); Szelke, ei al., European Application EP 45665; CA: 97: 39405 (1982) (-CH (OH) CH2-); Halladay, e. Al., Tetrahedron Lett 24: 4401-4404 (9183) (-CH (OH) CH2); and Hruby, Ufe Sci. 31: 189-199 (1982) (-CH2-S-).

PREFERRED MODALITIES This invention relates to a new class of fused aryldiazopinone compounds selected from those of the general formula I which are potent and specific Xa inhibitors, pharmaceutically acceptable compositions thereof and methods for using them as therapeutic agents for disease states in mammals characterized by abnormal thrombosis: wherein: R1 and R2 are independently selected from the group consisting of H, C-β alkyl, C3_8 cycloalkyl, C-1.3 alkylaryl, C3_3-C3_3-cycloalkyl, and aryl; R3 is H, C- | _6 alkyl, or R2 and R3 are taken together to form a carbocyclic ring; q is an integer of 0-1; r is an integer of 0-4; s is an integer of 0-1; t is an integer of 0-4; A is selected from the group consisting of RP, -NR6R9, • α &ßiSL -Y-i wherein R 3, R 9, R 16 and R 1 1 are independently selected from the group consisting of H, -OH, C 1-6 alkyl, aryl and C 1-4 alkylaryl; R 2 is selected from the group consisting of H, C-β alkyl, aryl and alkylaryl C- | _4, or it can be taken together with R1 ^ or R1 1 to form a ring of 5 to 6 members; and R13 is selected from the group consisting of H, C-μβ alkyl, aryl and alkylaryl of C- | _4, or it may be taken together with R1 1 to form a 5-6 membered ring; D is selected from the group consisting of a direct bond, cycloalkyl of 03.3, aryl and a five to ten member heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; E is selected from the group consisting of a direct link, -CO-, -SO2-, -O-CO-, -NR14-S? 2- and -NR -CO-, wherein R14 is independently selected from the group consisting of H, -OH, C-.beta.-alkyl, aryl and alkylaryl of C- | .4; G is selected from the group consisting of a direct bond, C3_8 cycloalkyl, aryl and a five to ten member heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; J is selected from the group consisting of R15, -NR15R16, wherein R15, R16, R17 and R18 are independently selected from the group consisting of H, -OH, C-β alkyl, aryl and C-1.4 alkylaryl; R 19 is selected from the group consisting of H, C 1-6 alkyl, aryl, and C 1-4 alkylaryl, or it may be taken together with R 1 7 or R 13 to form a 5- to 6-membered ring; and R2 ^ is selected from the group consisting of H, C-μg alkyl, aryl, and C 1-4 alkylaryl, or it may be taken together with R 13 to form a ring of 5 to 6 members; with the proviso that when J is R15, then G must contain at least one atom of N; K ', K ", K'" and K "" are independently selected from the group consisting of -CH-, -CR4-, -CR5- and -N-; with the proviso that no more than one of K ', K ", K"' and K "" are -CR4-and no more than one of K \ K ", K" 'and K "" are -CR5-; R4 and R5 are selected from the group consisting of C-μβ alkyl, alkylaryl, alkylaryl of C- | _4, alkylalkoxy of C- | _4, halogen, -NO2- NR6R7, - NR6COR7, -OR6, -OCOR6, -COOR6, -CONR6R7 -CN, -CF3, -SO2NR6R7 and C-μg-OR6 alkyl; wherein R6 and R7 are selected from the group consisting of H, C-μg alkyl, C-1.4 alkylaryl and aryl; L is selected from the group consisting of R33, -NR33R34, wherein R33, R34, R35 and R36 are independently selected from the group consisting of H, -OH, alkyl of C-j.g, aryl and alkylaryl of C-1.4; R37 is selected from the group consisting of H, C-μg alkyl, aryl and alkylaryl C- | _4, or can be taken together with R35 or R36 to form a ring of 5 to 6 members; and R33 is selected from the group consisting of H, C-μg alkyl, aryl and alkylaryl of C- | _4, or it may be taken together with R36 to form a 5-6 membered ring; M is selected from the group consisting of a direct bond, C- [g] alkyl, C3.8 cycloalkyl, C-μg alkenyl, Cj.g alkenylaryl, aryl and a five to ten membered heterocyclic ring system contains from 1 to 4 heteroatoms selected from the group consisting of N, O and S; Q is selected from the group consisting of H, wherein R2 and R22 are independently selected from the group consisting of H, C- alkyl; _3 and aryl; and T is selected from the group that consists of H, -COOR23, -CONR23R24, -CF3, -CF2CF3, and a group having the formula: wherein R23 and R24 are independently selected from the group consisting of H, C- | _g alkyl, aryl and alkylaryl of C- | _4; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-, with the proviso that at least one of U' and U" is -N- or - NH-; R25 is selected from the group consisting of H, C- | _g alkyl, C2-g alkenyl, Cr-g alkylaryl, C2- alkenylaryl, Cr-g alkylheterocycle, C2-6 alkenylheterocycle. -CF3, -CF2CF3; V is selected from the group that consists of -S-, -SO-, -SO2-, -O- and -NR26-, wherein R26 is selected from the group consisting of H, C < | g and benzyl; and W is selected from the group consisting of: a heterocyclic Cg_? o system substituted by R29 and R3 ^ and containing from 1 to 4 heteroatoms selected from N, S and O; where a is an integer from 0 to 2; R27 and R23 are independently selected from the group consisting of H, C-μg alkyl, aryl, alkylaryl of C- | _g, -COOR31 -CONR R32, -CN, - CF3, and R29 and R3 ^ are independently selected from the group consisting of H, alkyl of C-j.g, aryl, alkylaryl of C- | _g, alkylalkoxy of C- | _4, Halogen, -NO2- NR31 R32, -NR31COR32, -OR31, -OCOR31, -COOR31, - CONR3 R32, -CN, -CF3, -S? 2NR31 R32 and C-) _6-OR31 alkyl; where R31 and R32 are selected from the group consisting of H, C-μg alkyl, C- | _3 alkylaryl and aryl; and all pharmaceutically acceptable salts and optical isomers thereof. A preferred embodiment of compounds of general structural formula I has the following stereochemistry: Preferred substituents of R1 and R2 are H and C- | g; most preferably H and methyl; most preferably H. R3 is preferably H. The integer "r" is preferably 3. The integer "s" is preferably 0. The integer "t" is preferably from 0 to 1. In the various substituents of "A", it is preferred that R3, R9, R1 ^ and R1 1 are independently selected from the group consisting of H and C- | _g alkyl; and most preferably are selected independently of the group which consists of H and methyl. It is also preferred that R12 is H, C-μg alkyl or it is taken together with R1 ^ or R1 1 to form a ring of 5 to 6 members; and most preferably it is H or methyl. It is also preferred that R13 is H, C- | _g alkyl or taken together with R1 ^ to form a 5- to 6-membered ring; and most preferably it is H or methyl. D is preferably selected from the group consisting of a direct bond, cycloalkyl of 03.3, aryl and a heterocyclic ring system ^^ _ ¿____ five to ten members containing 1 to 4 heteroatoms selected from the group consisting of N, O and S. E is preferably a direct bond, -CO-, -SO2-. G is preferably a direct link. In the "J" substituent, it is preferred that R 5, R 16, R 17, R 18 R19 and R20 are independently selected from the group consisting of H, and C- | _g alkyl, most preferably H and methyl. Preferably at least three of K ', K ", K"' and K "" are -CH-; most preferably K ', K ", K'" and K "" are all -CH-. When one of the K is -CR4- or -CR5-, then R4 and R5 is preferably halogen. In the various "L" substituents, it is preferred that R33, R34, R35 and R36 are independently selected from the group consisting of H and C- | _g alkyl; and most preferably they are selected independently from group consisting of H and methyl. It is also preferred that R37 is H, C- | _g alkyl or is taken together with R35 or R36 to form a ring of 5 to 6 members; and is most preferably H or methyl. It is also preferred that R38 is H, C-μg alkyl or taken together with R36 to form a 5- to 6-membered ring; and is most preferably H or methyl. M is preferably a direct bond, C-μg alkyl, cycloalkyl of 03.3, aryl or a heterocyclic ring system of five to ten members. Most preferably, M is C- [g] alkyl, aryl or a five to ten membered heterocyclic ring system. The input q is preferably 0.

Q is preferably: wherein R21 is preferably H and R22 is preferably H. T is preferably H, -COOR23 -CONR23R24 or a group having the formula: R23 is preferably H. R24 is preferably alkylaryl C- | _4- V is preferably -S-, -O- or -NR26-, wherein R26 is preferably H or methyl, most preferably H. W is preferably selected from the group consisting of: W is very preferably R29 and R30 are independently selected from the group consisting of H, -O-R31, -COOR31 -CONR31 R32 or -CF3; very preferably H. When W is: then R27 is preferably H and R28 is preferably H. When T is: then U 'is preferably O, U "is preferably N and R25 is preferably -CF3 or -CF2CF3.

In a preferred embodiment of the invention, s is 0; R2 and R3 are H; K \ K ", K, p and K" "are -CH-; and Q is -C (O) -T. This is also illustrated as a group of compounds defined by general structural formula II as: A preferred embodiment of compounds of general structural formula II has the following stereochemistry: ÉÉYÍY In another preferred embodiment of the invention, s is 0; r is 3; R1, R2 and R3 are H; K ', K ", K"' and K "" are -CH-; G is a link; J is: NR18 ^ N ^ NR15R19 R17 wherein R17, R18, R19 and R20 are all H; Q is -C (O) -T. This is also illustrated as a preferred group of compounds defined by the general structural formula III as: A preferred embodiment of compounds of general structural formula III has the following stereochemistry: This invention also encompasses all pharmaceutically acceptable isomers, salts, hydrates and solvates of the compounds of formulas I, II and III. In addition, the compounds of formulas I, II and III may exist in various isomeric and tautomeric forms, and all such forms are intended to be included in the invention, together with pharmaceutically acceptable salts, hydrates and solvates. The compounds of this invention can be isolated as the base or free acid or converted to salts of various bases and inorganic and organic acids. Said salts are within the scope of this invention. The non-toxic and physiologically compatible salts are particularly useful although other less desirable salts can be used in the isolation and purification procedures. Various methods can be used for the preparation of the salts described above and are known to those skilled in the art. For example, the base and free acid form of a compound of one of the above formulas can be reacted with one or more equivalents of the desired base or acid in a solvent or mixture of solvents in which the salt is insoluble, or a solvent such as water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free base or acid form of the product can be passed over an ion exchange resin to form the desired salt or a salt form of the product can be converted to another using the same general procedure. The invention also includes prodrug derivatives of the compounds contained herein. The term "prodrug" refers to a pharmacologically inactive derivative of an original drug molecule that requires biotransformation, either spontaneous or enzymatic, within the body to release the active drug. Prodrugs are variations or derivatives of the compounds of this invention that have digestible groups under metabolic conditions. The prodrugs are converted to the compounds of the invention which are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. The prodrug compounds of this invention can be called single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor type form. . Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drugs Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA, 1992). Prodrugs commonly known in the art include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reaction of the original acids with a suitable alcohol, or amides prepared by reaction of the original acid compound with a amine, or basic groups that react to form an acetylated base derivative. In addition, the prodrug derivatives of this invention can be combined with other features taught herein to increase bioavailability. The following structures are illustrative of the compounds of the present invention and are not intended to be limiting in any way. It should be noted that in the compounds of the invention, some substituents are present among two other substituents. For example, D is located between A- and - (CH2) fE. Accordingly, substituents such as D are illustrated below having two "hanging" bonds, the left bond representing a direct link to the substituent A- and the right link representing a direct link to - (CH 2) t-E. Therefore, the general formula of A-D- (CH2) fE- where D is phenyl, can be written as: D, a phenyl group, would then be written as follows in the tables below: Other substituents in the following table can also be presented having one or two adjacent "hanging" links. It is understood that these represent direct links to the adjacent substituents. It is also understood that the compounds shown below can exist as other isomers, and it is not intended that the isomeric form illustrated herein be limiting in any way. The invention encompasses compounds of general structural formula IV, wherein R1, R2 and R3 are H; r is 3; q and s are 0; G is a direct link; J K ", K '" and K "" are -CH-; L is H; M is a direct link; The invention encompasses compounds of general structural formula, R2 and R3 are H; r is 3; q and s are 0; G is a direct link; J) NH2; K \ K ", K" 'and K "" are -CH-; L is H; Month The invention encompasses compounds of general structural formula VI, wherein R1, R2 and R3 are H; q is 0; t is 1; A is H; D is phenyl; E is -SO2-; K \ K ", Km and K, m are -CH-, L is H, M is a direct link, and Q is (SAW) The invention encompasses compounds of general structural formula VII, where q is 0; r is 3; s is 0; t is 1; A is H; D is phenyl; E is -SO2-; G is a direct link; J is -NH-C (NH) NH2; K \ K ", K '" and K, m are -CH-; L is H; M is a The invention encompasses compounds of general structural formula VIII, wherein R1, R2 and R3 are H; q is 0; r is 3; s is 0; t is 1; A is H; D is phenyl; E is -SO2-; G is a direct link; J is -NH-C (NH) NH2; K ', K ", K, H and K" "are -CH-; L is H; and M is a direct link: 15 20 The invention encompasses compounds of general structural formula IX, wherein R1, R2 and R3 are H; q and s are 0; r is 3; t is 1; A and L are H; D is phenyl; E is -SO2-; G and M are direct links; J is -NH-C (NH) NH2¡ and Q is The invention encompasses compounds of general structural formula X, wherein R1, R2 and R3 are H; s is 0; r is 3; t is 1; A is H; D is phenyl; E is -SO2-; G is a direct link; K ', K ", K'" and K '"are -CH-, J is -NH-C (NH) NH2, and Q is As mentioned above, the compounds of this invention find utility as therapeutic agents for pathogenic states in mammals having coagulation disorders such as in the treatment and prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, cerebral vascular accident. thrombotic, embolic cerebral vascular accident, disseminated intravascular coagulation including the treatment of septic shock, deep vein thrombosis in the prevention of pulmonary embolism or the treatment of reocclusion or restenosis of reperfused coronary arteries. In addition, these compounds are useful for the treatment or prophylaxis of those diseases that involve the production and / or action of the factor Xa / prothrombinase complex. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated including, but not limited to, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, thromboembolic complications of surgery and peripheral arterial occlusion. Accordingly, a method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprises administering to the mammal a therapeutically effective amount of a compound of this invention. In addition to the pathological conditions indicated above, other diseases treatable or preventable by administration of compounds of this invention include, without limitation, occlusive coronary thrombi formation resulting from thrombolytic therapy or percutaneous transluminal coronary angioplasty, formation of thrombi in the venous vasculature, disseminated intravascular coagulopathy, a condition in which there is a rapid consumption of coagulation factors and systemic coagulation that results in the formation of life-threatening thrombi that occur throughout the microvasculature leading to disseminated organ failure, hemorrhagic cerebral vascular accident, renal dialysis, oxygenation of the blood and cardiac catheterization. The compounds of the invention also find utility in a method for inhibiting biological coagulation samples, which comprises the administration of a compound of the invention. The compounds of the present invention can also be used in combination with other therapeutic or diagnostic agents. In some preferred embodiments, the compounds of this invention can be coadministered together with other compounds typically prescribed for these conditions in accordance with generally accepted medical practice such as anticoagulant agents, thrombolytic agents; or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of the present invention can act in a synergistic manner to prevent reocclusion after successful thrombolytic therapy and / or reduce the time of reperfusion. These compounds may also consider reduced doses of thrombolytic agents to be used and thus minimize potential hemorrhagic side effects. The compounds of this invention can be used in vivo, ordinarily in mammals such as primates (e.g., humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro. The biological properties of the compounds of the present invention can be easily characterized by methods that are well known in the art, for example by in vitro protease activity tests and in vivo studies to assess antithrombotic efficacy, and effects on hemostasis and hematological parameters such as illustrated in the examples. Diagnostic applications of the compounds of this invention will typically use formulations in the form of solutions or suspensions. In the management of thrombotic disorders, the compounds of this invention can be used in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or sterile suspensions, or injectable administration and the like, or incorporated into shaped articles. Subjects in need of treatment (typically mammals) using the compounds of this invention can receive doses that provide optimal efficacy. The dose and method of administration will vary from one subject to another and will depend on factors such as the type of mammal being treated, sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds used, the specific use for These compounds and other factors that will be recognized by experts in medical techniques. Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable vehicles, excipients, stabilizers, etc., and can be provided in sustained release and controlled release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro, 1985). Said materials are non-toxic to the receptors at the doses and concentrations employed, and include pH regulators such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight peptides (less than about ten residues) such as polyarginine, proteins, such as serum albumin, gelatin or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamic acid, aspartic acid or arginine, monosaccharides, disaccharides and other carbohydrates including cellulose or its derivatives, glucose , mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and / or nonionic surfactants such as Tween, Pluronics or polyethylene glycol. The dose formulations of the compounds of this invention that are to be used for therapeutic administration must be sterile. Sterility is easily achieved by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional means. The formulations will typically be stored in lyophilized form or as an aqueous solution. The pH of the preparations of this invention will typically be 3-11, very preferably 5-9 and most preferably still 7-8. It will be understood that the use of some of the above excipients, vehicles or stabilizers will result in the formation of salts of cyclic polypeptides. Although the preferred route of administration is with injection, other methods of administration such as orally, intravenously (bolus and / or infusion), subcutaneous, intramuscular, colonic, rectal, nasal, transdermal or intraperitoneal are also provided, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, microencapsulation, oral dose formulations and topical formulations such as ointments, drops and skin patches. The compounds of this invention are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other commercially available polymers. The compounds of the invention can also be administered in the form of liposome assortment systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholines. The compounds of this invention can also be delivered by the use of antibiotics, antibiotic fragments, growth factors, hormones or other target portions, to which the molecules of the compound are coupled. The compounds of this invention can also be coupled with suitable polymers as target drug vehicles. Such polymers can include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroethyl-aspartamide-phenol, or polyethylene-polylysine oxide substituted with palmitoyl residues. In addition, the compounds of the invention can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid copolymers, polyepsilon-caprolactone, polyhydroxybutyl acid, polyorthoesters , polyacetals, polydihydropyrans, polycyanoacrylates and interlaced or amphiphilic block copolymers of hydrogels. Semipermeable polymer polymers and matrices can be formed into shaped articles, such as valves, stents, tubes, prostheses and the like. Liquid formulations of therapeutic compounds are generally placed in a container having a sterile access port, for example, an intravenous solution bag or intravenous solution bottle having a plug pierceable by a hypodermic injection needle. Therapeutically effective doses can be determined either by in vitro or in vivo methods. For each particular compound of the present invention, individual determinations can be made to calculate the optimum dose required. The scale of therapeutically effective doses will be influenced by the route of administration, the therapeutic objectives and the condition of the patient. For injection by hypodermic needle, it can be stated that the dose is supplied in body fluids. For other routes of administration, the absorption efficiency must be determined individually for each compound by methods well known in pharmacology. Therefore, it may be necessary for the therapist to titrate the dose and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dose levels, i.e., the dose levels necessary to achieve the desired result, will be readily determined by one skilled in the art. Typically, compound applications will start at lower dose levels, with the dose levels increased until the desired effect is achieved. The compounds of the invention can be administered orally or parenterally in an effective amount within the dose range of about 0.1 to 100 mg / kg, preferably from about 0.5 to 50 mg / kg and most preferably from about 1 to 20 mg / kg on a regimen in a single dose or from 2 to 4 divided daily doses and / or continuous infusion. Typically, about 5 to 500 mg of a compound or ^ S-. The mixture of compounds of this invention, such as the free acid or base form or as a pharmaceutically acceptable salt, is combined with a carrier, carrier, excipient, binder, preservative, stabilizer, colorant, flavoring, etc. physiologically acceptable, as required in accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dose is obtained in the indicated scale. Typical adjuvants that can be incorporated into tablets, capsules and the like are binders such as acacia, corn starch or gelatin, and excipients such as microcrystalline cellulose, disintegrating agents such as corn starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents. When a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline or a fatty oil. Other materials of various types can be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated in accordance with conventional pharmaceutical practice. For example, the solution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle such as ethyl oleate, or in a liposome may be desired. PH regulators, preservatives, antioxidants and the like can be incorporated in accordance with accepted pharmaceutical practice. -rnirr- - - * "• ^ aa» - Preparation of the described compounds The compounds of the present invention can be synthesized by solid or liquid phase methods described and referenced in standard textbooks, or by a combination of several methods. These methods are well known in the art, see Bodanszky, "The Principles of Peptide Synthesis", Hafner, et al., Eds., Springer-Verlag, Berlin, 1984. The starting materials used in any of these methods are commercially available. of chemical suppliers such as Aldrich, Sigma, Nova Biochemicals, Bachem Biosciences, and the like or can be easily synthesized by known methods.The reactions are carried out in standard laboratory instruments and reaction vessels under standard temperature and pressure reaction conditions. except when otherwise indicated, the reaction products are isolated and purified by conventional methods, typically by e. xtraction with solvents in a compatible solvent. The products can be further purified by column chromatography or other appropriate methods. Most compounds are purified by reverse phase HPLC and are characterized by ion spray mass spectrometry. During the synthesis of these compounds, the functional groups of the amino acid derivatives used in these methods are protected by blocking groups to avoid collateral reactions during the coupling procedure. Examples of suitable blocking groups and their use are described in "The peptides: Analysis, Synthesis, Biology", Academic Press, Vol. 3 (Gross, et al., Eds., 1981) and Vol. 9 (1987), whose description it is incorporated here by reference. The compounds of this invention can be prepared preferably by coupling the carboxylic acid of the formula (a) to the amine of the formula (b) by the standard amide bond formation strategies: (a) (b) The compounds of the formula (b) wherein Q is H can be prepared by the methods described in WO 96/01338; WO 96/24609; Feng, et al., WO 96/31504; and WO 96/32110, the descriptions of which are incorporated herein by reference. The compounds of the formula (b) wherein Q is a boron-containing compound can be prepared by methods described in J. Orq. Chem. 60: 3717-3722 (1995) and of Nanteuil, et al., EP 688,788, the disclosures of which are incorporated herein by reference. The compounds of the formula (b) wherein Q is -C (O) -T, where T is H, can be prepared by methods described in WO 93/15756, supra; Vlasuk, ei al., WO94 / 17817; Abelman, et al., WO 94/21673; Webb, e. Al., WO 94/08941; Veber, ei al., WO 94/25051; Levy, e. Al., WO 95/35312; Semple e al., WO 95/35313; Abelman, et al., WO 95/28420; and Abelman, et al., WO 96/19493, the descriptions of which are incorporated herein by reference. The compounds of the formula (b) wherein Q is -C (O) -T, wherein T is -COOR23 or -CONR23R24, can be prepared by the methods described in WO 94/25051, supra, WO 94/08941, supra, and WO 94/21673, supra, the descriptions of which are incorporated herein by reference. The compounds of the formula (b) wherein Q is -C (O) -T, where T is -CF-3 or -CF2CF3, can be prepared by the methods described in Schacht ket al., GB 2287027, whose description they are incorporated here by reference. The compounds of the formula (b) wherein Q is -C (O) -T, where T is: and V is -S-, -O-, -SO- or -SO2- can be easily synthesized by the methods described in Costanzo, et al., US Pat. No. 5,523,308; Di Maio, ei al., WO 96/19483; Patent of E.U.A. No. 5,164,371; J. Am. Chem. Soc. 114: 1854-1863 (1992); J. Med. Chem. 38: 76-85 (1995); and J. Med. Chem. 37: 3492-3502 (1994). Finally, fragments in which V is -NR21-, where R21 is H, C- | 6 alkyl or benzyl, can be synthesized by techniques illustrated in J. Med. Chem. 37: 3492-3502 (1994). All of these references are incorporated herein by reference. The compounds of the formula (b) wherein Q is -C (O) -T, where T is: and U 'and U "are the various substituents (-O-, -S-, -N-, -NH-) can be prepared by the methods described in J. Med. Chem. 38: 1355-1371 (1995) and J. Med. Chem. 37: 2421-2436 (1994), the descriptions of which are incorporated herein by reference The starting compound of the formula (a) is either a known compound or can be produced by known methods (Heitsch, et al. al., Canadian Patent No. 2,071, 744, Sugihara, et al., Canadian Patent No. 2,126,026, Baker, et al., EP 365,992, US Patent No. 4,251, 438; Carr, et al., US Patent. No. 4,341, 698; Goldman, et al., US Patent No. 5,120,718; Biswanath, et al., US Patent No. 5,164,388; Duggan, et al., US Patent No. 5,281, 585; Sugihara, et al. al., U.S. Patent No. 5,294,713, Bovy, etal., WO 95/06038, WO 95/35308, J. Chem. Soc. Perkin Trans., 1687-1689 (1989), and Int L Peptide Protein Res. 37: 468-475 (1991) or can be prepared by the methods shown in the following formulas of area The following reaction schemes are more specific illustrations of the above reaction formulas. The chemical reactions described in each scheme can be easily modified and combined with _ 3 ^. ' other techniques that are well known in the art to produce other compounds within the scope of the invention. SCHEME I Neosystem Labórateme FB02201 wherein R is any desired substituent "A-D- (CH2) r" ^ ¿^ SCHEME II Neosystem Laboratone FB02201 wherein R is any desired substituent "A-D- (CH2) r" The reagent used in the fifth step of schemes I and II can be synthesized as follows: Without further elaboration, it is believed that one skilled in the art can use the present invention to its fullest extent. Therefore, the following preferred specific embodiments should be considered merely as illustrative and not to limit the remainder of the description in any way. - - - - - "" "" ^ - *** - < - • -•* -" EXAMPLE 1 Preparation of: 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). The solution was stirred at 0 ° C for 10 hours. DMF was evaporated in vacuo. The oily residue was dissolved in EtOAc (200 ml) and water (20 ml). The organic layer was washed with saturated NaHC 3, water (20 ml), 1 M HCl (10 ml) and saturated NaCl (2 X 20 ml). The organic layer was dried over MgSO filtered and evaporated to give a suspension. The suspension was filtered and the solid was washed with cold EtOAc (10 ml) and dried to give Boc-Arg (Tos) -N (Me) OMe, which was shown above, (1.5 g, 70% yield). FAB-MS (M + H) + = 472 Preparation of: To a solution of thiazole (2.5 g, 29 mmol) in THF (25 mL) at -78 ° C was added n-BuLi (1.6 in hexane, 19 mL) dropwise. The mixture was stirred for 30 minutes. Then a solution of Boc-Arg (Tos) -N (Me) OMe, from Example 1 (1.7 g, 3.6 mmol) in THF (50 ml) was added to the lithiathiazole mixture at -78 ° C. The solution was stirred for 2 hours. 1 M HCl (30 ml) was added to the reaction mixture and warmed to room temperature. The mixture was extracted with EtOAc (100 mL). The organic layer was washed with saturated NaCl (30 ml), dried over MgSO filtered and evaporated. The crude oily residue was purified by flash column chromatography over SiO2 (50% EtOAc in CH2Cl2) to give Boc-Arg (Tos) -thiazole, shown above, (1.5 g, 84% yield) as a powder. DCI-MS (M + H) + = 496 EXAMPLE 3 Preparation of: To a solution of Boc-Arg (Tos) -thiazole of Example 2 (300 mg, 0. 6 mmol) in CH2Cl2 (10 mL) at 0 ° C, TFA (10 mL) was added. The solution was stirred at 0 ° C for 2 hours. The solvent and excess TFA were evaporated to give an oily residue which was then used directly without further purification.

EXAMPLE 4 Part 1. Preparation of 2- (3 - (((9H-9-fluorenylmethoxy) carbonylamino) -2-oxo-5-phenyl-2,3-dihydro-1 H-1,4-benzodiazepine-1 L) methyl acetate: A solution of (R, S) Fmoc-3-amino-N-1-carboxymethyl-2-oxo-5-phenyl-1,4-benzodiazepine from Neosystem Laboratorie (Strasbourg, France) (212 mg, 0.4 mmol) in MeOH at 0 ° C was treated with an excessive amount of thionyl chloride (20 eq). The mixture was stirred at room temperature overnight and evaporated to give the title compound (100% yield). ES-MS (M + H) + = 546.2.

«He * t- - Part 2. Preparation of methyl 2- (3-amino-2-oxo-5-phenyl-2,3-dihydro-1 H-1,4-benzodiazepin-1-yl) acetate A solution of the compound of Part 1 (226 mg, 0.4 mmol) in DMF (2 ml) was treated with piperidine (0.5 ml, 5 mmol) to make a final solution of 20% piperidine / DMF and stirred at room temperature overnight. The reaction mixture was evaporated under vacuum, then acidified with 10% HCl and extracted with CH2Cl2. The aqueous layer was then neutralized with 1 N NaOH and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 and evaporated under vacuum to give the title compound (99% yield). ES-MS (M + H) + = 324.2.

Part 3. Preparation of methyl 2- (3 - ((benzyl sulfonyl) amino) -2-oxo-5-phenyl-2,3-dihydro-1 H-1,4-benzodiazepin-1-yl) acetate: To a solution of the compound from Part 2 (128 mg, 0.4 mmol) and DIEA (0.092 ml, 0.5 mmol) in CH 2 Cl 2 (2 ml) at -78 ° C, was added α-toluenesulfonyl chloride (92 mg, 0.48 mmol) ). The mixture was stirred at -78 ° C for three hours and evaporated under vacuum. The residue was dissolved in EtOAc and washed with H2O, saturated NaHC3, saturated NaCl, dried over Na2S4 and evaporated to give the title compound as a solid (67% yield). ES-MS (M + H) + = 478.3.

Part 4. Preparation of 2- (3 - ((benzylsulfonyl) amino) -2-oxo-5-phenyl-2,3-dihydro-1 H-1,4-benzodiazepin-1 -peacetic acid: A solution of the compound of Part 3 (128 mg, 0.27 mmol) in THF (2 ml) was treated with 2 N LiOH (0.54 ml, 10.08 mmol). The mixture was stirred at room temperature overnight. The organic solvent was evaporated under vacuum. The aqueous layer was acidified to pH of 2-3 with 1 N aqueous HCl, extracted with EtOAc and the organic layer was dried over Na 2 SO 4 and evaporated to give the title compound (100% yield).

ES-MS (M + H) + = 464.0.

Part 5. Preparation of N1- (1 R) -4 - ((imino (((4-methylphenyl) sulfonyl) amino) -methyl) amino) -1- (1,3-thiazol-2-ylcarbonyl) ) butyl) -2- (3 - ((benzyl sulfonyl) amino) -2-oxo-5-phenyl-2,3-dihydro-1 H-1,4-benzodiazepin-1 Dacetamide: The compound from Part 4 (0.3 mmol) was dissolved in DMF (2 ml) and cooled to 0 ° C. The solution was neutralized with DIEA followed by the addition of the compound of Example 3 (142 mg, 0.36 mmole) and coupling reagent HBTU (136 mg, 0.36 mmole). The solution was stirred at room temperature overnight. The reaction mixture was diluted in a mixture of EtOAc / H2 ?. The organic layer was washed with saturated NaHC 3 3, NaCl saturated, dried over Na 2 S 4, and the solvent was evaporated to give the title compound (82% yield). ES-MS (M + H) + = 841.4.

H Part 6. Preparation of N1 - ((1 R) -4 - ((amino (imino) methyl) amino) -1- (1,3-thiazole-2-alkylcarbonyl) -2- (3- ((benzylsulfonyl) amino) -2-oxo-5-phenyl-2,3-dihydro-1 H-1,4-benzodiazepin-1-yl) acetamide (Compound X (8)) : The compound of Part 5 (206 mg, 0.25 mmol), anisole (1 ml) and ethylmethyl sulfide (two drops) were placed in an HF separation vessel and cooled under liquid N2. HF (10 ml) was then condensed and the mixture was stirred at -10 ° C for half an hour and 0 ° C for half an hour. HF was removed under vacuum to give a residue as a gum. The residue was triturated with Et2? 50% in hexane (20 ml) and the solvent was removed by filtration. The gum residue was dissolved in 0.1% aqueous TFA (15 ml) and filtered through the above-specified funnel. The filtrate was lyophilized to a powder which was purified by RP-CLAR to give the title compound as inseparable diastereomers as a white powder (85% yield). ES-MS (M + H) + = 686.8. ^^ 4 ^ EXAMPLE 5 Part 1. Preparation of N- (1- (2 - (((1 R) -4- (pmino (((4-methylphenyl) sulfonyl) amino) -metl) amino) -1- (1, 3-Tazo-2-ylcarbonyl) butyl) amino) -2-oxoethyl) -2-oxo-5-phenyl-2,3-dihydro-1 H-1,4-benzodiazepine-3-yl ) 9H-9-fluorenylmethyl carbamate (R, S) Fmoc-3-amino-N-1-carbozimethyl-oxo-5-phenyl-1,4-benzodiazepine from Neosystem Laboratorie (134 mg, 0.25 mmol) was dissolved in DMF (2 ml) and cooled to 0 ° C. the solution was neutralized with DIEA followed by the addition of the compound of Example 3 (118 mg, 0.3 mmol) and the coupling reagent HBTU (114 mg, 0.3 mmol). The solution was stirred overnight at room temperature. The reaction mixture was diluted in a mixture of EtOAc / H2 ?. the organic layer was washed with saturated NaHC 3, saturated NaCl, dried over NaS 4, filtered and the solvent was evaporated to give the title compound (93% yield) ES-MS (M + H) + = 909.3.

Part Preparation of N1 - ((1 R) -4 - ((imino (((4-methylenephosphonyl) amino) -methyl) amino) -1- (1,3-thiazol-2-yl) ilcarbonyl) butyl) -2- (3-amino-2-oxo-5-phenyl-2,3-dihydro-1 H-1,4-benzodiazepin-1-i-acetamide: A solution of the compound from Part 1 (211 mg, 0.232 mmol) in DMF (2 ml) was treated with piperidine (0.5 ml, 5 mmol) to make a final solution of 20% piperidine / DMF and stirred at room temperature overnight. The reaction mixture was evaporated in vacuo then acidified with 10% HCl and extracted with CH2Cl2. The aqueous layer was then neutralized with 1 N NaOH and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated under vacuum to give the title compound (100% yield). ES-MS (M + H) + = 687.1.

Part 3. Preparation of N1 - ((1 R) -4 - ((amine (imino) methyl) amine) -1- (1,3-thiazol-2-ylcarboninbutyl) -2- (3-Amino-2-oxo-5-phenyl-2,3-d, H-dro-1 H-1,4-benzodiazepin-1-iPacetamide (Compound V (D): The compound from Part 2 (0.232 mmol), anisole (1 ml) and ethylmethyl sulfide (two drops) were placed in an HF separation vessel and cooled under liquid N2. HF (10 ml) was then condensed and the mixture was stirred at -10 ° C for half an hour and 0 ° C for half an hour. HF was removed under vacuum to give a residue as a gum. The residue was triturated with Et2? 50% in hexane (20 ml) and the solvent was removed by filtration. The gum residue was dissolved in 0.1% aqueous TFA (15 ml) and filtered through the above-specified funnel. The filtrate was lyophilized to a powder which was purified by RP-CLAR to give the title compound as inseparable diastereomers as a white powder (88% yield). ES-MS (M + H) + = 533.1.

EXAMPLE 6 (Determination of Cl. ^ N) The compounds of the present invention are first dissolved in a pH regulator to give solutions containing concentrations such that the test concentrations vary from 0-100 μM. In tests for thrombin, prothrombinase and factor Xa, a chromogenic substrate would be added to a solution that would contain a test compound and the enzyme of interest and the residual catalytic activity of the enzyme would then be determined by spectrophotometer. The IC50 of a compound is determined from substrate production. The IC50 is the concentration of the test compound that gives 50% inhibition of substrate production. Preferred compounds of the invention desirably have an IC50 of less than 500 nM in the factor Xa test, preferably less than 200 nM, and most preferably less than 100 nM. Preferred compounds of the invention desirably have an IC50 of less than 4.0 μM in the prothrombinase test, preferably less than 200 nM and most preferably less than 10 nM. The preferred compounds of the invention desirably have IC50 greater than 1.OμM in the thrombin test, preferably greater than 10.0μM and most preferably greater than 100. OμM.

Amidolytic tests to determine protease inhibition activity Factor Xa and thrombin tests are carried out at room temperature, in pH buffer of 0.02 M Tris HCl, pH 7.5, containing 0.15 M NaCl. The hydrolysis rates of the paranitroanilide substrate S-2765 (Chromogenix) for Factor Xa and the substrate Chromozym TH (Boehringer Mannheim) for thrombin after preincubation of the enzyme with the test compound during Five minutes at room temperature were determined using a Softmax 96-well plate reader (Molecular Devices), monitored at 405 nm to measure the appearance of time-dependent p-nitroanilide. The prothrombinase inhibition test is performed in a plasma-free system with modifications to the method as described in Sinha, et al., Thromb. Res., 75: 427-436 (1994). The activity of the prothrombinase complex is determined by measuring the time course of thrombin generation using the p.nitroanilide substrate Chromozym TH. The test consists of a pre-incubation of 5 minutes of selected compounds that are to be tested as inhibitors with the complex formed from factor Xa (0.5 nM), factor Va (2 nM), phosphatidylserine: phosphatidylcholine (25:75, 20 μM ) in pH buffer of 20 mM Tris HCl, pH 7.5, containing 0.15 M NaCl, CaCl2 5mM and 0.1% bovine serum albumin. Aliquots of the complex-compound test mixture were added to prothrombin (1 nM) and Chromozym TH (0.1 mM). The substrate separation rate is monitored at 405 nm for two minutes. Various concentrations of a given test compound are tested in duplicate. A standard thrombin generation curve for an equivalent amount of untreated complex is then used to determine the percent inhibition. The compounds of the invention showed inhibitory activity in the factor Xa test described above. Preferred compounds of the invention have IC 50 values less than 100 nM.

EXAMPLE 7 The antithrombotic efficacy of the compounds of this invention can be easily evaluated using a series of studies in rabbits, as described above. These studies are also useful to evaluate the effects of the compounds on hemostasis and its haematological parameters.

Antithrombotic efficacy in rabbit model in venous thrombosis A model of deep vein thrombosis of rabbit as described in Hollenbach, et al., Thromb. Haemost. 71: 357-362 (1994), is used to determine the in vivo antithrombotic activity of the compounds of the present invention. Rabbits are anesthetized with intramuscular injections of a mixture of Ketamine, Xylazine and Acepromazine. A standardized protocol consists of the insertion of an apparatus of thrombogenic cotton thread and copper wire into the abdominal cava vein of the anesthetized rabbit. A non-occlusive thrombus is allowed to develop in the central venous circulation and inhibition of thrombus growth is then used as a measure of the antithrombotic activity of the compound being evaluated. The test or saline control agents are administered through a marginal ear vein catheter. A femoral vein catheter is used for blood sampling before and during steady-state infusion of the compound being evaluated. The onset of thrombus formation will begin immediately after advancing the cotton thread apparatus into the central venous circulation. The compounds that are being evaluated are administered at a time = 30 minutes at a time = 150 minutes in which the experiment is completed. The rabbits are sacrificed and the thrombus is removed by surgical dissection and characterized by weight and histology. The blood samples are then analyzed for changes in the hematological and coagulation parameters. Although the invention has been described with reference to the embodiments described, those skilled in the art will readily appreciate that specific detailed experiments are only illustrative of the invention. It should be understood that several modifications must be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims (6)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound that has the formula: wherein: R1 and R2 are independently selected from the group consisting of H, C-β alkyl, C3.8 cycloalkyl, C- | 3 alkylaryl, C- | 3-cycloalkyl of C3_8 and aryl; Rp is H, C-j.β alkyl, or R 2 and R 3 are taken together to form a carbocyclic ring; q is an integer of 0-1; r is an integer of 0-4; s is an integer of 0-1; t is an integer of 0-4; A is selected from the group consisting of R8, -NR8R9, wherein R 8, R p, R 10 and R 11 are independently selected from the group consisting of H, -OH, C-j.β alkyl, aryl and C 1-4 alkylaryl; R ^ 2 is selected from the group consisting of H, C? _6 alkyl, aryl and alkylaryl of C < | _4, or it can be taken together with R10 OR R ^ to form a ring of 5 to 6 members; and R ^ 8 is selected from the group consisting of H, C-μg alkyl, aryl and C 1-4 alkylaryl, or it can be taken together with R 11 to form a 5- to 6-membered ring; D is selected from the group consisting of a direct bond, C3_8 cycloalkyl, aryl and a five to ten member heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; E is selected from the group consisting of a direct bond, -CO-, -SO2-, -O-CO-, -NRl4-SO2- and -NR14-CO-, wherein R ^ is independently selected from the group consisting of H, -OH, C? _6 alkyl, aryl, and alkylaryl of C < | _4; G is selected from the group consisting of a direct bond, C3.8 cycloalkyl, aryl and a five to ten member heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; J is selected from the group consisting of R15. -NR15 16, J wherein R15I R16 R17 and R18 are independently selected from the group consisting of H, -OH, C] _Q alkyl, aryl, and C-1.4 alkylaryl; R1 9 is selected from the group consisting of H, C < | _6, aryl and alkylaryl C- | _4, or it can be taken together with R ^ 7 or R ^ 8 to form a ring of 5 to 6 members; and R2 ^ is selected from the group consisting of H, C < | _6, aryl and alkylaryl of C- | _4, or can be taken together with R18 to form a 7 ^ 7 fc. É ^^^^^ ring of 5 to 6 members; with the proviso that when J is R ^ 5, then G must contain at least one atom of N; K ', K ", K'" and K "" are independently selected from the group consisting of -CH-, -CR4-, -CR5- and -N-; with the proviso that no more than one of K ', K ", K"' and K "" are -CR4-and no more than one of K \ K ", K '" and K "" are -CR5-; R4 and R5 are selected from the group consisting of C? _6 alkyl, aryl, C? _4 alkylaryl, C- | _4 alkylalkoxy, halogen, -NO2- NR6R7, -NR6COR7, -OR6, -OCOR6, -COOR6, -CONR6R7, -CN, -CF3, -S? 2NR6R7 and C-μe-OR6 alkyl; wherein R6 and R7 are selected from the group consisting of H, alkyl of C-j.g, alkylaryl of C1.4 and aryl; L is selected from the group consisting of R88, -NR R84, wherein R88, R84, R85 and R86 are independently selected from the group consisting of H, -OH, C-j.g alkyl, aryl, and C1.4 alkylaryl; R87 is selected from the group consisting of H, C- | _g alkyl, aryl and alkylaryl C-j_4, or it can be taken together with R85 or R86 to form a ring of 5 to 6 jfc. Sv., AI »*« tana, «g., > .-. > J mμJW '"ii *» - -. • -s. -c -u-.. ».". V * ir, Bu-members, and R88 is selected from the group consisting of H, C-alkyl μg, aryl and alkylaryl of C- | _4, or it may be taken together with R86 to form a 5- to 6-membered ring; M is selected from the group consisting of a direct bond, alkyl of C-μg, cycloalkyl of 03.3, alkenyl of C-μg, alkenylaryl of C- | _g, aryl and a heterocyclic ring system of five to ten members containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; Q is selected from the group consisting of H, wherein R21 and R22 are independently selected from the group consisting of H, C- | _3 alkyl and aryl; and T is selected from the group consisting of H, -COOR28, -CONR28R24, -CF3, -CF2CF3, and a group having the formula: wherein R28 and R24 are independently selected from the group consisting of H, C- | _g alkyl, aryl and alkylaryl of C- | _4; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-, with the proviso that at least one of U' and U" is -N- or - NH-; R25 ^ ^^ - ~ ¿> i ^ _ selected from the group consisting of H, C-μg alkyl, C2_ alkenyl, Cryj-alkylaryl, C2- alkenylaryl, Cryj-alkylheterocycle, C2- alkenylheterocycle, -CF3, -CF2CF3; V is selected from the group consisting of -S-, -SO-, -SO2-, -O- and -NR26-, wherein R26 is selected from the group consisting of H, C- | g alkyl and benzyl; and W is selected from the group consisting of: a heterocyclic Cg_? o system substituted by R29 and R8 ^ and containing from 1 to 4 heteroatoms selected from N, S and O; where a is an integer from 0 to 2; R27 and R28 are independently selected from the group consisting of H, alkyl of Cj.g, aryl, alkylaryl of C-μg, -COOR81 -CONR81 R82, -CN, -CF3, and R29 and R80 are independently selected from the group consisting of H, alkyl of C-μg, aryl, alkylaryl of C-μg, alkylalkoxy of C-1.4, halogen, -NO2- NR8"l R82, -NR81COR82, -OR8"! , -OCOR8-! , -COOR8"!, -CONR31 R82, -CN, -CF3, -SO2NR81 R82 and C-μg-OR81 alkyl, wherein R31 and R32 are selected from the group consisting of H, C-μg alkyl, alkylaryl C- | _3 and aryl, and all pharmaceutically acceptable salts and optical isomers thereof. 2. - The compound according to claim 1, further characterized in that R1 is H or C- | g alkyl. 3. The compound according to claim 2, further characterized in that R1 is H or methyl. 4. The compound according to claim 3, further characterized in that R1 is H. 5. The compound according to claim 1, further characterized in that R2 is H or C-μg alkyl. 6. The compound according to claim 5, further characterized in that R2 is H or methyl. 7. The compound according to claim 6, further characterized in that R2 is H. 8. The compound according to claim 1, further characterized in that R8 is H. 9. The compound according to claim 1, further characterized in that R4 is halogen. 10. The compound according to claim 1, further characterized in that R5 is halogen. 11. The compound according to claim 1, further characterized in that the integer "r" is 3. 12. The compound according to claim 1, further characterized in that the integer "s" is 0. 13. - The compound according to claim 1, further characterized in that the integer "t" is from 0 to 1. 14. The compound according to claim 1, further characterized in that R8, R9, R10 and R1 1 are independently selected of the group consisting of H and C-μg alkyl. 15. The compound according to claim 1, further characterized in that R8, R9, R10 and R11 are independently selected from the group consisting of H and methyl. 16. The compound according to claim 1, further characterized in that R12 is H, alkyl of C-μg or can be taken together with R10 OR R1 1 to form a ring of 5 to 6 members. 17. The compound according to claim 16, further characterized in that R12 is H or methyl. 18. The compound according to claim 1, further characterized in that R18 is H, alkyl of C- | _g or can be taken together with R ^ or R ^ to form a ring of 5 to 6 members. 19. The compound according to claim 18, further characterized in that R18 is H or methyl. 20. The compound according to claim 1, further characterized in that D is selected from the group consisting of a direct bond, C3_8 cycloalkyl, aryl and a five to ten member heterocyclic ring system containing 1 to 4 heteroatoms selected from the group consisting of N, O and S. 21. The compound according to claim 1, further characterized in that E is a direct bond, -CO-, -SO2-. 22. The compound according to claim 1, further characterized in that G is a direct bond. 23. The compound according to claim 1, further characterized in that R1, R1, R17, R18, R19 and R2 ^ are independently selected from the group consisting of H, and C-μg alkyl. 24. The compound according to claim 23, 10 further characterized in that R 15, R "16, R 7, R18, R19 and R2 ^ are independently selected from the group consisting of H, and methyl. 25. The compound according to claim 1, further characterized by the minus three of K ', K ", K"' and K "" are -CH- 26.- The compound according to claim 25, characterized further because K ', K ", K"' and K "". are -CH-. 27. the compound according to claim 1, further characterized in that R88, R84, R85 and R86 are independently selected from the group consisting of H and alkyl C-g 28.- the compound according to Claim 27, Further characterized in that R88, R84, R85 and R86 are independently selected from the group consisting of H and methyl. 29. The compound according to claim 1, ^ ^^^ --te ^^^^^^^ stia ^^^^^^ ssi ^^^ ^ ik ^ u ^ m H wherein R87 is also H, alkyl of C-j.g or taken together with R35 OR R36 to form a ring of 5 to 6 members. 30. The compound according to claim 29, further characterized in that R87 is H or methyl. 31. The compound according to claim 1, further characterized in that R88 is H, C-μg alkyl or is taken together with R86 to form a ring of 5 to 6 members. 32. The compound according to claim 31, further characterized in that R88 is H or methyl. 33. The compound according to claim 1, further characterized in that M is a direct bond, alkyl C- | _g, C3_8 cycloalkyl, aryl or a heterocyclic ring system of five to ten membered. 34. The compound according to claim 33, further characterized in that M is C < | g, aryl or a heterocyclic ring system of five to ten members. The compound according to claim 1, further characterized in that the integer q is 0. 36. The compound according to claim 1, further characterized in that Q is: 37. The compound according to claim 36, further characterized in that R21 is H. 38. The compound according to claim 37, further characterized in that R22 is H. 39. The compound according to claim 36, further characterized because T is H, -COOR28 -CONR28R24 or a group having the formula: 40. The compound according to claim 39, further characterized in that R28 is H. 41. The compound according to claim 39, further characterized in that R24 is alkylaryl of C < | _4. 42. The compound according to claim 39, further characterized in that V is -S-, -O- or -NR26-. 43. The compound according to claim 42, further characterized in that R26 is H or methyl. 44. The compound according to claim 43, further characterized in that R26 is H. The compound according to claim 39, further characterized in that W is selected from the group consisting of: 46. - The compound according to claim 45, further characterized in that W is: 47. The compound according to claim 45, further characterized in that R29 is independently selected from the group consisting of H, -O-R81, -COOR31 -CONR81 R32 or -CF3. 48. The compound according to claim 47, further characterized in that R29 is H. 49. The compound according to claim 45, further characterized in that R8 ^ is independently selected from the group consisting of H, -O-R81 , -COOR81 -CONR81R82 or -CF3. 50.- The compound according to claim 49, further characterized in that R8 ^ is H. 51. The compound according to claim 39, further characterized in that W is: and R27 is H. 52. The compound according to claim 51, further characterized in that R28 is H. 53. The compound according to claim 36, further characterized in that T is: U 'is O, U "is N and R25 is -CF3 or -CF2CF3 54.- A compound having the formula: wherein: R1 is selected from the group consisting of H, C-i.g.alkyl, C3.8 cycloalkyl, C- | _3 alkylaryl, C3_8-C3_3alkyl, and aryl; q is an integer of 0-1; r is an integer of 0-4; t is an integer of 0-4; A ÉM¡ ^ | t ^ M | i¡j | ¡^ ¿jaa ^ _, - - r - - -. select from the group consisting of R8, -NR R9, wherein R8, R9, R10 and R1 1 are independently selected from the group consisting of H, -OH, C- | _g alkyl, aryl and alkylaryl of C- | _4¡R12 is selected from the group consisting of H, alkyl of C- | _g, aryl and alkylaryl C- | _4, or it can be taken together with R1 ^ or R1 1 to form a ring of 5 to 6 members; and R18 is selected from the group consisting of H, C-μg alkyl, aryl and C-1,4 alkylaryl, or it may be taken together with R to form a 5- to 6-membered ring; D is selected from the group consisting of a direct bond, cycloalkyl of 03.8, aryl and a five to ten member heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; E is selected from the group consisting of a direct bond, -CO-, -SO2-, -O-CO-, -NR1 -SO2- and -NR1 -CO-, wherein R14 is independently selected from the group consisting of H , -OH, alkyl of Cj.g, aryl and alkylaryl of C-1.4; G is selected from the group consisting of a Iááááá direct bond, C3_8 cycloalkyl, aryl and a five to ten member heterocyclic ring system containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; J is selected from the group consisting of R15-NR15R16 wherein R15, R16, R17 and R18 are independently selected from the group consisting of H, -OH, C- | _g alkyl, aryl and alkylaryl of C- | _4¡R19 Is selected from the group consisting of H, C-μg alkyl, aryl and alkylaryl C < ? _4, or it can be taken together with R17 or R18 to form a ring of 5 to 6 members; and R2 ^ is selected from the group consisting of H, C-μg alkyl, C-1.4 aryl and alkylaryl, or it can be taken together with R18 to form a ring of 5 to 6 members; with the proviso that when J is R15, then 20 G must contain at least one N atom; L is selected from the group consisting of R38, -NR38R34, a * j wherein R33, R34, R35 and R36 are independently selected from the group consisting of H, -OH, C-μg alkyl, aryl and C- | 4 alkylaryl; R37 is selected from the group consisting of H, C- | _g alkyl, aryl and alkylaryl C- | _4, or it can be taken together with R35 or R36 to form a ring of 5 to 6 members; and R38 is selected from the group consisting of H, C- | _g alkyl, aryl, and C-1.4 alkylaryl, or it may be taken together with R36 to form a 5-6 membered ring; M is selected from the group consisting of a direct bond, C- [g] alkyl, C3.8 cycloalkyl, C- [g] alkenyl, C- [g] alkenylaryl, aplo and a five-membered heterocyclic ring system ten members containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; T is selected from the group consisting of H, -COOR23, -CONR23R24, -CF3, -CF2CF3, and a group having the formula: sg? á * ¿.. wherein R23 and R24 are independently selected from the group consisting of H, C-μg alkyl, aryl, and C-1.4 alkylaryl; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-, with the proviso that at least one of U' and U" is -N- or - NH-; R25 is selected from the group consisting of H, C-j.g alkyl, C2-g alkenyl, Cryg-alkylaryl, C2_g alkenylaryl, Cryg-alkylheterocycle, C2_g alkenylheterocycle, -CF3, -CF2CF3; V is selected from the group that consists of -S-, -SO-, -SO2-, -O- and -NR26-, wherein R26 is selected from the group consisting of H, C- | g alkyl and benzyl; and W is selected from the group consisting of: a heterocyclic Cg_? o system substituted by R29 and R3 ^ and containing from 1 to 4 heteroatoms selected from N, S and O; where a is an integer from 0 to 2; R27 and R28 are independently selected from the group consisting of H, C-μg alkyl, aryl, C-μg alkylaryl, -COOR31 -CONR31 R32 -CN, -CF3, and R29 and R30 are independently selected from the group consisting of H, C-μg alkyl, aryl, alkylaryl of C-μg, alkylalkoxy of C-j_4, halogen, -NO2- NR31 R32, -NR31COR32, -OR31 , -OCOR31, -COOR31, - gjyg CONR31 R32, -CN, -CF3, -SO2NR31R32 and C-γ-g-OR31 alkyl; wherein R31 and R32 are selected from the group consisting of H, C- | _g alkyl, C- | _3 alkylaryl, and aryl; and all pharmaceutically acceptable salts and optical isomers thereof. 55.- A compound of the formula where: q is an integer of 0-1; t is an integer of 0-4; A is selected from the group consisting of R8, -NR8R9, wherein R8, R9, R19 and R1 1 are independently selected from the group consisting of H, -OH, C- | g alkyl, aryl and C-1.4 alkylaryl; R 12 is selected from the group consisting of H, C-μg alkyl, aryl and alkylaryl C- | _4, or it can be taken together with R19 or R1 to form a ring of 5 to 6 members; and R13 is selected from the group consisting of H, C-μg alkyl, aryl and alkylaryl of C- | _4, or it may be taken together with R1 1 to form a 5-6 membered ring; D is selected from the group consisting of a direct bond, C3_8 cycloalkyl, aryl and a five to ten member heterocyclic ring system containing from 1 to 4 heteroatoms selected from the group consisting of N, O and S; E is selected from the group consisting of a direct bond, -CO-, -SO2-, -O-CO-, -NR14-S? 2- and -NR14-CO-, wherein R14 is selected from the group consisting of H, -OH, C- | g alkyl, aryl, and C-1.4 alkylaryl; L is selected from the group consisting of R33, -NR33R34, ^ a ^ fe- ^ s ^ where R33, R34, R35 and R36 are independently selected from the group consisting of H, -OH, C-μg alkyl, aryl and C-1.4 alkylaryl; R37 is selected from the group consisting of H, C-μg alkyl, aryl and alkylaryl C- | _4, or can be taken together with R35 or R36 to form a ring of 5 to 6 members; and R38 is selected from the group consisting of H, C- | _g alkyl, aryl and alkylaryl of C- | _4, or it may be taken together with R36 to form a 5-6 membered ring; M is selected from the group consisting of a direct bond, alkyl of C-μg, cycloalkyl of C3_8, alkenyl of C-μg, alkenylaryl of C- | _g, aryl and a heterocyclic ring system of five to ten members containing 1 to 4 heteroatoms selected from the group consisting of N, O and S; T is selected from the group consisting of H, -COOR23, - CONR23R24, -CF3, -CF2CF3, and a group having the formula: wherein R23 and R24 are independently selected from the group consisting of H, C- | g alkyl, aryl and C- | 4 alkylaryl; U 'and U "are independently selected from the group consisting of -O-, -S-, -N- and -NH-, with the proviso that at least one of U' and U" is -N- or - NH-; R25 is selected from the group consisting of H, C- | _g alkyl, C2_ alkenyl, Cryg-alkylaryl, C2- alkenylaryl, Cryg-alkylheterocycle, C2-6 alkenylheterocycle. -CF3, -CF2CF3; V is selected from the group that consists of -S-, -SO-, -SO2-, -O- and -NR26-, wherein R26 is selected from the group consisting of H, C < | g and benzyl; and W is selected from the group consisting of: a heterocyclic system of Cg_- | Q substituted by R29 and R39 and containing from 1 to 4 heteroatoms selected from N, S and O; where a is an integer from 0 to 2; R27 and R28 are independently selected from the group consisting of H, C-μg alkyl, aryl, C-μg alkylaryl, -COOR31 -CONR3 R32, -CN, -CF3, and R29 and R39 are independently selected from the group consisting of H, C-μg alkyl, aryl, C-j.g alkylaryl, C- | _4 alkylalkoxy, Halogen, -NO2- NR31 R32, -NR31COR32, -OR31, -OCOR31, -COOR31, - CONR31 R32, -CN, -CF3, -SO2NR31 R32 and alkyl of C-μg-OR31; wherein R31 and R32 are selected from the group consisting of H, C-μg alkyl, C-1.3 alkylaryl and aryl; and all pharmaceutically acceptable salts and optical isomers thereof. 56.- A pharmaceutical composition for preventing or treating a condition in a mammal characterized by unwanted thrombosis that they contain a pharmaceutically acceptable carrier and the compound of claim 1. The use of the compound of claim 1, for the manufacture of a medicament for preventing or treating a condition in a mammal suffering from undesirable thrombosis. 58.- The use according to claim 57, wherein the condition is selected from the group consisting of: the treatment or prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, thrombotic stroke, vascular accident cerebral embolic, disseminated intravascular coagulation including the treatment of septic shock, deep vein thrombosis in the prevention of pulmonary embolism or the treatment of reocclusion or restenosis of reperfused coronary arteries, deep vein thrombosis, pulmonary embolism, myocardial infarction, cerebral vascular accident, complications thromboembolic of surgery and peripheral arterial occlusion, formation of occlusive coronary thrombi that result either from thrombolytic therapy or percutaneous transluminal coronary angioplasty, thrombus formation in the venous vasculature and disseminated intravascular quadulopathy. 59. The use of the compound of claim 1, for the manufacture of a medicament for inhibiting the coagulation of biological samples. _ál0Mé? MÍB