MXPA06003914A - Thioether-substituted benzamides as inhibitors of factor xa - Google Patents

Abstract

Thioether-substituted benzamide compounds having the formula:are provided that exhibit exceptionally strong inhibition of Factor Xa in combination with weak hERG binding.

Description

BENZAMIDES REPLACED WITH TIOETER AS INHIBITORS OF THE FACTOR Xa REFERENCE TO RELATED REQUESTS This application claims the benefit of the provisional patent application serial number 60 / 510,264, filed on October 9, 2003, the description of which is incorporated in the present application by reference.

DECLARATION AS RIGHTS FOR INVENTIONS CARRIED OUT UNDER INVESTIGATION AND DEVELOPMENT SPONSORED FEDERALLY Not applicable REFERENCE TO A "LIST OF SEQUENCES". A TABLE. O UN LIST OF COMPUTER PROGRAM PRESENTED AS APPENDIX IN A COMPACT DISC Not applicable BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to novel compounds that are potent and highly selective inhibitors of factor Xa isolated or when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa against other coagulation proteases (e.g., thrombin, fVlla, FlXa) or fibrinolytic cascades (e.g., plasminogen activators, plasmin). In another aspect, the present invention relates to novel compounds containing monoamidino, their pharmaceutically acceptable salts, and compositions thereof acceptable for pharmaceutical use, which are useful as potent and specific inhibitors of blood coagulation in mammals. In yet another aspect, the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals, characterized by coagulation disorders.

BACKGROUND OF THE INVENTION Hemostasis, the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation. This invention particularly concerns the coagulation of blood, and the ways in which it helps maintain the integrity of the circulation of mammals after damage, inflammation, disease, congenital defect, dysfunction or other disturbance. 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. Thrombin is a key enzyme in the coagulation cascade, as well as in hemostasis. Thrombin plays a central role in thrombosis because of its ability to catalyze the 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 discussed by Claeson, G. , "Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol. 5: 41-1-436 (1994). Several classes of anticoagulants currently used in clinical activity directly or indirectly affect thrombin (ie, heparins, low molecular weight heparins, heparin-like compounds, and coumarins). A prothrombinase complex, which includes Factor Xa (a serine protease, the activated form of its precursor Factor X, and a member of the calcium ion bond, the family of blood coagulation glycoprotein containing gamma carboxylglutamyl (GLA), vitamin dependent K), converts zymogen prothrombin into active procoagulant thrombin. 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, that is, prothrombin. Since a factor Xa molecule can be capable of generating up to 138 thrombin molecules (Elodi and co-authors, Thromb Res 15: 617-619 (1979)), the direct inhibition of factor Xa as a form of inhibition indirectly the formation of thrombin, it can be an efficient anticoagulant strategy. Therefore, it has been suggested that compounds that selectively inhibit factor Xa may be useful as in vitro diagnostic agents, or for therapeutic administration in certain thrombotic disorders, see, for example, WO 94/13693. Polypeptides derived from hematophagous organisms that are highly potent and specific inhibitors of factor Xa have been reported. U.S. Patent No. 4,588,587 describes the anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. It was shown that a major component of this saliva was the factor Xa inhibitor polypeptide, antistasin (ATS), by Nutt, E. and co-authors, "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveáis a Repeated I nterna! Structure ", J. Biol. Chem., 263: 10162-10167 (1988). Another powerful and highly specific inhibitor of factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole-body extract of the soft tick Ornithitdoros moubata, as reported by Waxman, L., and co-authors, "Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa "Science, 248: 593-596 (1990). Compounds which are not large polypeptide type inhibitors have also been reported, including: Tidwell, R. R. and co-authors, "Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res., 19: 339-349 (1980); Turner, A. D. and co-authors, "p-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry, 25: 4929-4935 (1986); Hitomi, Y. and co-authors, "Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System", Haemostasis, 15: 164-168 (1985); Sturzebecher, J. and coauthors, "Synthetic Inhibitors of Bovine Factor Xa and Thrombin, Comparison of Their Anticoagulant Efficiency", Thromb. Res., 54: 245-252 (1989); Kam, C. M. and co-authors, "Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants", Biochemistry, 27: 2547-2557 (1988); Hauptmann, J. and co-authors, "Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors", Thromb. Haemost., 63: 220-223 (1990); and similar. Others have reported factor Xa inhibitors that are small molecule organic compounds, such as nitrogen-containing heterocyclic compounds, which have amidino substituted groups, where two functional groups of the compounds can bind factor Xa to two of their active sites . For example, WO 98/28269 describes pyrazole compounds having a C-terminal group (= NH) -NH2; WO 97/21437, describes benzimidazole compounds substituted by a basic radical, which is connected to a naphthyl group by means of a straight or branched chain alkylene linking group -C (= O) or -S (= O) 2; WO 99/10316 describes compounds having a 4-phenyl-EN-alkylamidine-piperidone and 4-phenoxy-N-alkylamidine-piperidine group connected to a 3-amidinophenyl group by means of a carboxamidoalkyleneamido bridge; and EP 798295 describes compounds having a 4-phenoxy-EN-alkylamidino-piperidine group connected to an amidinonaphthyl group by means of a substituted or unsubstituted sulfonamide or carboxamide bridging group. Still further, it has recently been recognized that drug-induced QT prolongation in hearts produces adverse and fatal side effects in many clinical procedures (Netzer, R., and co-authors, Drug Discovery Today, 6: 78 (2001)) . Several drugs were withdrawn from the market due to their binding to hERG and to the attention of the prolongation of the QT interval, for example, Terfenadine (Seldane®), Cisapride (Propulsid®, and astemizole (Hismanal®).) See Pearlstein, RA, and co-authors, Bioorg Med. Chem. Lett.13: 1829 (2003) .The potassium channel hERG is a human a-go-go ether gene that is expressed in the human heart, and is a key effector of cardiac repolarization, and it contributes to the QT interval measured by ECG It has been shown that the inhibition of the hERG potassium channel can lead to prolongation of the QT interval, widely considered a critical risk factor for the arrhythmia Torsades de Pointes (TdP). The hERG link has become a major obstacle in current drug development.Fortunately, high-throughput in vitro preclinical assays that measure the compound's ability to inhibit the hERG channel have become powerful tools. s detection for medical chemists, to obtain first-hand information about SAR and to evaluate its potential side-effect in the discovery of early-stage drugs. See Haverkamp, W. and co-authors. Cardiovasc. Res. 47: 219 (2000). Finlayson, K.; and co-authors, European Journal of Pharmacology 430: 147 (2001). Significant progress has been made in recent years in the understanding of electrophysiology of hERG channels, drug-induced QT prolongation mechanisms, structural understanding of drugs that bind to the hERG channel, hERG link power ratio with preclinical studies of QT prolongation in vivo (Redfern, WS, and co-authors, Cardiovasc Res. 58:32 (2003)). Thus, it is highly desirable to find new compounds that provide beneficial antithrombotic activity with little or no binding to hERG. There is a need for effective therapeutic agents for the regulation of hemostasis, and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature, induced by thrombin, such as restenosis and inflammation. In particular, there continues to be a need for compounds that selectively inhibit factor Xa or its precursors. Compounds having different combinations of bridging groups and functional groups are required, than previously discovered compounds, particularly compounds that selectively or preferably bind to Factor Xa. Compounds with a higher degree of binding to factor Xa than thrombin are preferred, especially those compounds that have good bioavailability and / or solubility.

BRIEF DESCRIPTION OF THE INVENTION In one aspect, the present invention provides compounds having the formula (I): C or a salt of them acceptable for pharmaceutical use. In formula I, the symbol R 1 a represents H, halogen, hydroxy, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) 0-2 amino or alkylcarbonyl of 1 to 6 carbon atoms; the symbols R1b and R1c independently represent H or alkyl of 1 to 6 carbon atoms, or optionally, R1b and R1c combine with the nitrogen atom to which each is bound to form a 5, 6 or 7 membered monocyclic ring which has from 0 to 1 additional heteroatom members in the ring, or a bicyclic ring of 8, 9, 10 or 11 members having 0 to 2 heteroatom members in the ring, the heteroatom members of the ring are selected from O, IN, S , S (O) and S (O) 2, and the ring is further substituted with from zero to two substituents, independently selected from alkyl of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) 0-2arnino , oxo and an amine protecting group. The symbols R1d and R1e each independently represent H, halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) 0. 2-amino, or amino-alkyl of 1 to 6 carbon atoms; or R1d and R1e can be combined to form a 5 to 6 membered fused ring having from 0 to 2 heteroatoms in the ring selected from EN, O and S. The letter X in formula I represents O or S, or together with the carbon atoms to which it is attached is CH2. The letter Y in the formula I represents CH or EN; and the letter Z represents a group that has the formula: wherein the symbols R2a, R2b and R2c each independently represent H, hydroxy, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, and (alkyl of 1 to 6 carbon atoms) 0-2 amino; or optionally, any two of R2a, R2b and R2c are taken together with its intervening atom or atoms to form a 3, 4, 5, 6 or 7 member ring having from 0 to 1 additional heteroatom members in the ring, selected from O, N, S, S (O) and S (O) 2, the ring is further substituted with from zero to two substituents, independently selected from alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms. carbon, CO2H, oxo and (alkyl of 1 to 6 carbon atoms) amino. In addition to the compounds of the present invention, pharmaceutical compositions are provided, along with methods for the treatment of conditions characterized by undesired thrombosis, such as acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring after thrombolytic therapy or after coronary angioplasty, a thrombotic-mediated cerebrovascular syndrome, embolic attack, thrombotic attack, transient ischemic attacks, venous thrombosis, deep vein thrombosis, pulmonary embolism, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intra-aortic balloon pump ica, coronary stent or cardiac valve, and conditions that require the placement of prosthetic devices.

BRIEF DESCRIPTION OF THE DRAWINGS Not applicable.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term "alkyl" by itself or as part of another substituent means, unless otherwise stated., a straight or branched chain hydrocarbon radical having the number of designated carbon atoms (i.e., C1-8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, N-propyl, isopropyl, N-butyl, t-butyl, isobutyl, sec-butyl, N-pentyl, N-hexyl, N-heptyl, N-octyl and the like. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Examples of these unsaturated alkyl groups include vinyl, 2-propienyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl, 1-3-propynyl, 3-butynyl, and the higher homologs and isomers. The term "cycloalkyl" refers to hydrocarbon rings having the indicated amount of atoms in the ring (eg, cycloalkyl of 3 to 6 carbon atoms), and are fully saturated or have no more than one double bond between the vertices of the ring. ring. When "cycloalkyl" is used in combination with "alkyl", as in cycloalkyl of 3 to 5 carbon atoms-alkyl, it means that the cycloalkyl portion has from three to five carbon atoms, while the alkyl portion is an alkylene portion which has one to three carbon atoms (eg, -CH2-, -CH2CH2- or -CH2CH2CH2- .The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups that are attached to the rest of the molecule by means of an oxygen atom, an amino group, or a sulfur atom, respectively For more briefness, the term "alkylamino" of 1 to 6 carbon atoms means that it includes straight chain, branched or cyclic alkyl groups, or combinations thereof, such as methyl, ethyl, 2-methylpropyl, cyclobutyl and cyclopropylmethyl.The terms "halo" or "halogen" by themselves or as part of another substituent, mean, unless another is declared thing, an atom of fluorine, chlorine, bromine or iodine. Additionally, terms such as "haloalkyl", mean that they include monohaloalkyl and polyhaloalkyl. For example, the term "haloalkyl of 1 to 4 carbon atoms" means that it includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like. The term "aryl", unless otherwise indicated, refers to a poly-unsaturated hydrocarbon group, typically aromatic, which may have a single ring or multiple rings (up to three rings), which are fused together or covalently linked . Examples of aryl groups are phenyl, naphthyl, biphenyl and the like. The term "heteroaryl" refers to aryl groups (or rings) containing from one to five heteroatoms selected from EN, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom or atoms are quaternized optionally. A heteroaryl group can be attached to the rest of the molecule through a heteroatom. Non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-pyrazolyl, 5-oxazolyl, 3-isoxazole, 4-oxazolium, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, - pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, 1-isoquinolyl, 5-isoqinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3 -q-quinolinyl and 6-quinolyl. The substituents for each of the aforementioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. As used herein, the term "heteroatom" includes oxygen (O), nitrogen (EN), sulfur (S) and silicon (Si). The term "pharmaceutically acceptable salts" includes salts of the active compounds that are prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds of the present invention contain relatively acidic functionalities, the base addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of base addition salts acceptable for pharmaceutical use include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt, when the compounds of the present invention contain relatively basic functionalities , the acid addition salts can be obtained by contacting the neutral form of these compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, monohydric, phosphoric, monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogen sulfuric, hydroiodic, or phosphorous acids. and the like, as well as salts derived from relatively non-toxic organic acids, such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic and Similar. Also included are amino acid salts, such as arginate and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, eg, Berge, SM and co-authors, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977 , 66, 1-19). Certain specific compounds of the present invention contain both basic and acid functionalities, which allow the compounds to be converted into base addition or acid addition salts. The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the original compound in the conventional manner. The original form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but on the other hand, the salts are equivalent to the original form of the compounds for the purposes of the present invention. In addition to the salt forms, the present invention provides compounds that are in the form of a prodrug. The prodrugs of the compounds described herein, are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a reservoir in a transdermal patch with an appropriate enzyme or chemical reagent. Certain compounds of the present invention can exist in unsolvated forms, as well as in solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be within the scope of the present invention. Certain compounds of the present invention can exist in multiple or amorphous crystalline forms. In general, all physical forms are equivalent for the uses contemplated by the present invention, and are intended to be within the scope of the present invention. Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; it is intended that racemates, diastereomers, geometric isomers and individual isomers (e.g., separate enantiomers) fall within the scope of the present invention. The compounds of the present invention may also contain unnatural proportions of atomic isotopes in one or more of the atoms that make up these compounds. For example, the compounds can be radioactively labeled with radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125l) or carbon-14 (14C). It is intended that all isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

GENERAL The present invention stems from the surprising discovery that the compounds of the formula I show strong inhibition of factor Xa, but show only weak linkage with h ERG. Compounds that have reduced inhibition of h ERG are less likely to cause prolongation of the QT interval, which is associated with certain types of arrhythmia. Therefore, the present compounds are useful for the treatment or prophylaxis of unwanted thrombosis, while providing a lower risk of side effects related to QT.

DESCRI PTION OF THE MODALI DADES COMPOUNDS In one aspect, the present invention provides compounds having the formula (I): © or a salt thereof acceptable for pharmaceutical use, in formula I, the symbol R 1a represents H, halogen, hydroxy, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms. carbon, haloalkoxy of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) 0-2amino, or alkylcarbonyl of 1 to 6 carbon atoms. Preferably, R1a is H or halogen. The symbols R1b and R1c independently represent H or alkyl of 1 to 6 carbon atoms, or optionally R1b and R1c are combined with the nitrogen atom to which each is attached, to form a 5, 6 or 7 membered monocyclic ring which have from 0 to 1 additional heteroatom members in the ring, or a bicyclic ring of 8, 9, 10 or 11 members having 0 to 2 additional ring heteroatom members, the ring heteroatom members are selected from O, N, S, S (O) and S (O) 2, and the ring is further substituted with from zero to two substituents, independently selected from alkyl, (alkyl of 1 to 6 carbon atoms) 0-2 amino, oxo and a protecting group amine, in a group of preferred embodiments, R1b and R1c are independently selected from H and alkyl of 1 to 4 carbon atoms. The symbols R1d and R1e each independently represent H, halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms; haloalkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, haloalkoxy of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) 0-2amino or aminoalkyl of 1 to 6 carbon atoms carbon; or R1d and R1e may be combined to form a fused 5 to 6 membered ring having from 0 to 2 heteroatoms in the ring selected from E, O, and S. In certain preferred embodiments, R1d is selected from halogen, hydroxy, alkyl of 1 to 3 carbon atoms, haloalkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, amino-alkyl of 1 to 3 carbon atoms. In other preferred embodiments, R1e is hydrogen. The letter X in the formula I represents O or S, or together with the carbon atoms to which it is attached, is CH2. Preferably, X is O, or together with the carbon atom to which it is attached, is CH2. The letter Y in the formula I represents CH or N, preferably N. The letter Z represents a group that has the formula: wherein the s each independently represents H, hydroxy, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and (alkyl of 1 to 6 carbon atoms) 0.2 amino, or optionally any two of R2a, R2b and R c are taken together with its intervening atom or atoms, to form a 3, 4, 5, 6 or 7 member ring having from 0 to 1 additional heteroatom members in the ring , selected from O, N, S, S (O) and S (O) 2, the ring is further substituted with from zero to two substituents independently selected from alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, CO2H, oxo and (alkyl of 1 to 6 carbon atoms) 0.2 amino. In preferred embodiments, Z is selected from Certain combinations of X, Y, Z and R1a through R1e are also disclosed as preferred embodiments. In a first group of preferred embodiments, X is O and Z is selected from Within this first group of preferred embodiments, R1b and R1c are preferably H or alkyl of 1 to 3 carbon atoms, or are combined with the nitrogen atom to which each is attached to form a 5, 6 or 7 membered ring having 0 to 1 additional heteroatom members in the ring, selected from O, N and S, wherein the ring is selected from pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, homopiperazine and thiomorpholine. More particularly, the portion -EN (R1b) (R1 °) is preferably selected from - NHfe - Nfvte - WMBZ In still other preferred embodiments, R1a is preferably selected from H, F, Cl and Br; R1 d is preferably -F, Cl, -Br, -OCH3, -OH, -CH3, -CF3 or -CH2NH2; and Y is preferably EN. In other preferred combinations in the first group, Z is preferably selected from and the -EN (R) (R) portion is preferably selected from In a second group of preferred embodiments, X and the carbon atom to which it is attached, is CH2. It is further preferred those modalities in which Z is selected from more preferably, Z is selected from fßSegN In still other preferred embodiments, the portions - EN (R1b) (R1 °), R1a, R1 and R1e are selected from the preferred groups provided with respect to the first group of preferred embodiments, or with reference to formula I, previous. Among the most preferred embodiments of the invention are the compounds provided in the examples below.

M ETHODS OF SYNTHES IS Schemes 1 and 2 illustrate methods for the preparation of compounds of formula I, exemplified by compounds viii and xii. A person skilled in the art will realize that similar routes can be used to prepare a quantity of related derivatives simply by substituting various reactant species. For example, by replacing 2-amino-chloropyridine with other appropriately substituted 2-aminopyridines, compounds of the formula I are provided in which R1d and R1e are portions such as alkyl, haloalkyl, alkoxy, alkylamino, and the like. Additionally, the replacement of 4-cyanobenzoyl chloride with other substituted 4-cyanobenzoyl chlorides provides compounds of the formula I in which R a is halogen, alkyl, haloalkyl, alkoxy, and the like. With reference to Scheme I, amide formation between 5-fluoro-2-nitrobenzoic acid (i) and 2-amino-5-chloropyridine in the presence of POCI3 provides ii. The treatment of ii with methyl thioglycolate in the presence of cesium carbonate provides the thioether derivative iii. The reduction of the nitro group present in iii can be efficiently achieved with tin (II) chloride dihydrate to produce the iv amine, which, when treated with 4-cyanobenzoyl chloride, provides scaffolding v. A three step conversion of the nitrile present in v to an N, N-dimethylamidine, can be achieved using hydrogen sulfide in pyridine, followed by methyl iodide in acetone and finally dimethylamine in methanol and acetic acid, to provide vi. The saponification of the methyl ester vi to the acid vii is easily accomplished using aqueous lithium hydroxide in methanol. The conversion of the carboxylic acid vii to an NN-dimethylamide (shown as compound viii) or a general amide (shown as ix) occurs smoothly using an appropriate amine or cyclic amine (eg, piperidine, morpholine and similar) and standard coupling conditions.

SCHEME 1 Using slight variations of the methods provided in Scheme 1, cyclic amidines (eg, x, xi, xii and xiii) can be prepared as outlined in Scheme 2.

SCHEME 2 While the above formulas can be readily adapted by a person skilled in the art to prepare other compounds of the present invention, reference is made to the examples presented below for a more complete discussion of solvent, amounts and proportions of reagents and other reaction conditions for the preparation of the compounds of the claims.

COMPOSITION IS In another aspect of the invention, pharmaceutical compositions are provided in which the compounds of Formula I, alone or in combination, are combined with an acceptable carrier for pharmaceutical use.

The pharmaceutical compositions of the invention can take the form of solutions or suspensions. In the management of thrombotic disorders, the compounds or pharmaceutical compositions of the invention may also be in forms such as for example, tablet, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions for injectable administration, and the like, or may be incorporated in trained articles. Typical adjuvants that can be incorporated into tablets, capsules and the like include, but are not limited to, 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 in capsule, in addition to the above materials it may also contain liquid carriers such as water, saline or 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 dissolution 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 desirable. PH regulators, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice. Additionally, dosage formulations of compounds of Formula I, or pharmaceutical compositions containing a compound of the invention, to be used for therapeutic administration, must be sterile. Sterility can be easily achieved by filtration through sterile membranes such as 0.2 micron membranes, preferably in a lyophilized form. Although the preferred route of administration is orally, dose formulations of the compounds of Formula I, or pharmaceutical compositions of the invention, can also be administered by injection, intravenously (bolu and / or infusion), subcutaneously, intramuscularly , colonic, rectally, Nasally, transdermally or intraperitoneally. A variety of dosage forms may be employed, as well as, without limitation, suppositories, granules or small implanted cylinders, aerosols, oral dose formulations and topical formulations such as ointments, drops and dermal patches. The compounds of Formula I, and the pharmaceutical compositions of the invention, may also be incorporated into forms and articles such as implants that may employ inert materials such as biodegradable polymers or synthetic silicones, such as, for example, SI LASTIC, silicone rubber. or other commercially available polymers. The compounds and pharmaceutical compositions of the invention may also be provided in the form of liposome delivery systems, such as unilamellar vesicles and large multilamellar vesicles. Liposomes can be formed from a variety of lipids, such as cholesterol, stearylamine or phosphatidylcholine, used methods well known to those skilled in the art.

METHODS OF TREATMENT AND ADMINISTRATION In yet another aspect, the present invention provides methods for treating or reducing the risk of rhombosis in a mammal by administering to the mammal a therapeutically effective amount of a compound of formula I, alone or as part of a pharmaceutical composition of the invention such as described earlier. The compounds of Formula I, and pharmaceutical compositions of the invention containing a compound of Formula I of the invention, are suitable for use alone or as part of a multi-component treatment regimen for the prevention or treatment of cardiovascular diseases, particularly with the related to thrombosis. For example, a compound or pharmaceutical composition of the invention can be used as a drug or therapeutic agent for any thrombosis, particularly a platelet-dependent thrombotic indication, including, if not limited to, acute myocardial infarction, unstable angina, angina. stable chronic, transient ischemic attacks, strokes, peripheral vascular disease, preeclampsia / eclampsia, deep vein thrombosis, embolism, disseminated intravascular coagulation and cytopenic thrombotic purpura, thrombotic and restenotic complications after invasive procedures, for example, angioplasty, carotid endarterectomy , post surgery CABG (coronary artery bypass graft), vascular graft surgery, stent placement and insertion of devices and endovascular prostheses. The compounds and pharmaceutical compositions of the invention may also be used as part of a multi-component treatment regimen in combination with other therapeutic or diagnostic agents in the prevention or treatment of thrombosis in a mammal. In certain preferred embodiments, the compounds or pharmaceutical compositions of the invention may 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 inhibitors. of plasminogen aggregation, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin or warfarin. Coadministration may also allow the application of reduced dose of thrombolytic agents and thus minimize potential hemorrhagic side effects. The compounds and pharmaceutical compositions of the invention can also act in a synergistic manner to prevent reocclusion after successful thrombolytic therapy and / or reduce the time for reperfusion. The compounds and pharmaceutical compositions of the invention can be used in vivo, ordinarily in mammals such as primates (eg, humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro. The biological properties, as defined below, of a compound or pharmaceutical composition of the invention, can be easily characterized by methods that are well known in the art, such as, for example, in vivo studies to evaluate the antitromotic efficacy, and Effects on haemostasis and hemotological parameters. Subjects (typically mammals) that need treatment using the compounds or pharmaceutical compositions of the invention, may receive doses that will provide optimal efficacy. The dose and method of administration will vary from subject to subject, and will depend on such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, general clinical condition, the particular compound of Formula I employed , the specific use for which the compound or pharmaceutical composition is employed, and other factors that will be recognized by those skilled in the art. Therapeutically effective doses can be determined either by in vivo methods or by in vitro methods. For each particular compound or pharmaceutical composition of the invention, individual determinations can be made to determine the optimum dosage required. The scale of effective doses therapeutically 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 assumed that the dose is supplied in body fluids. For other administration routes, the absorption efficiency has to be determined individually for each compound by well-known methods in pharmacology. Accordingly, it may be necessary for the therapist to adjust the dose and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dose levels, that is, the dose levels necessary to achieve the desired result, i.e., inhibition of Factor Xa, will be readily determined by a person skilled in the art. Typically, the applications of a compound or pharmaceutical composition of the invention start at lower dose levels, with increasing dose levels until the desired effect is achieved. The compounds and compositions of the invention can be administered orally in an effective amount within the dose range from about 0.01 to 1000 mg / kg in a single dose regimen or several divided doses daily. If a carrier acceptable for pharmaceutical use is used in a pharmaceutical composition of the invention, typically, about 5 to 500 mg of a compound of Formula I is com pounded with a carrier acceptable for pharmaceutical use in accordance with accepted pharmaceutical practice. , but without limitation to them, a vehicle, carrier, excipient, binder, preservative, stabilizer, colorant, flavoring, etc. , physiologically acceptable. The amount of active ingredient in these compositions is such that an appropriate dose is obtained on the indicated scale. The following preparations and examples are provided to enable those skilled in the art to understand more clearly and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as illustrative and representative of it.

EXAMPLES EXAMPLE 1 This example illustrates the sulfanyl-phenylcarboxamide preparation of N- (5-chloro-2-pyridinyl) -2- (4-N, N-dimethylaminophenylcarbonyl) amino-5-acetic acid dimethylamide STEP 1: A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0 equiv.), 2-amino-5-chloropyridine (9.02 g, 1.3 equiv.), In 80 mL of pyridine, was treated with sodium oxychloride. phosphorus (25.3 g, 3.0 equiv.) for 30 minutes. The volatile part was evaporated and the residue was redissolved in EtOAc, washed with 1 N HCl, saturated aqueous NaHCO 3, and saturated aqueous NaCl. The organic layer was dried over Na 2 SO, filtered and evaporated + o. The product was triturated with diethyl ether to give N- (5-chloro-2-pyridinyl) - (2-nitro) -5-fluorophenylcarboxamide (11.5 g, 72%). MS found for C 12 H 7 ClFN 303 (M + H) +: 296, (M + 2 + H): 298.

STEP 2: A solution of N- (5-chloro-2-pyridinyl) - (2-nitro) -5-fluorophenylcarboxamide (0.60 g, 2.03 mmol, 1.0 equiv.) In 10 mL of DMF with methyl thioglycolate (0.24 grams, 1.1 equiv.) And cesium carbonate (1.65 g, 2.5 equiv.) For 30 minutes at 50 ° C. The reaction was added to 40 mL of water. The product was then extracted into EtOAc and washed with 1N HCl and saturated aqueous NaCl. The organic layer was dried over Na 2 SO 4, filtered and evaporated to give sulfanyl-phenylcarboxamide of N- (5-chloro-2-pyridinyl) - (2-nltro) -5-acetic acid methyl ester (0.65 g, 84% ). MS found for dsH ^ CINsOsS? (M + H) +: 382, (M + 2 + H): 384. STEP 3: A solution of sulfanyl-phenylcarboxamide of N- (5-chloro-2-pyridinyl) - (2-nitro) -5-acetic acid methyl ester (0.62 g, 1.63 mmol, 1.0 equiv.) In 10 mL of acetate was treated. of ethyl with tin (II) chloride dihydrate (1.83 g, 5.0 equiv.) for 30 minutes at reflux. The solution was cooled to room temperature and added to 40 mL of a 1: 1 mixture of saturated aqueous sodium carbonate / saturated aqueous sodium sulfate. The resulting precipitate was filtered. The organic layer was washed with saturated aqueous sodium chloride, dried over Na 2 SO 4, filtered and evaporated to give sulfanyl-phenyl-N- (5-chloro (2-pyridyl)) carboxamide of 2-amino acid methyl ester. 5-acetic) (0.51 g, 90%). MS found (M + H) +: 352, (M + 2 + H): 354.

STEP 4: To a solution of sulfanyl-phenyl-N- (5-chloro (2-pyridyl)) carboxamide of 2-amino-5-acetic acid methyl ester) (0.50 g, 1.42 mmol, 1.0 equiv.) In 10 mL of tetrahydrofuran. anhydrous, 4-cyanobenzoyl chloride (0.28 g, 1.2 equiv.) was added at room temperature. After 30 minutes, the precipitated suspension was diluted with 10 mL of hexanes and filtered, to give sufanyl-2 - [(4-cyanophenyl) carbonylamino] phenyl-carboxamide of N- (5-chloro-2-methyl) methyl ester pyridyl)) 5-acetic (0.52g, 75%). MS found for C21 H15CIN402S1 (M + H) +: 481, (M + 2 + H): 483.

STEP 5: A suspension of sufanyl-2 - [(4-cyanophenyl) carbonylamino] phenyl-carboxamide of N- (5-chloro (2-pyridyl)) 5-acetic acid methyl ester (500 mg, 1.04 mmol, 1. 0 eq uiv), in 12 mL of 5: 1 pridine / triethylamine was stirred at room temperature while bubbling gaseous hydrogen sulfide into the mixture for more than 10 minutes. After 3 hours, the volatile ocmptonnes were evaporated and the solid was suspended again in 4 μL of acetone. To this mixture was added iodomethane (0.12 mL, 8.0 equiv.) The solution was refluxed for 1.5 hours, and the volatile component was evapourated to give sufanyl-2 - [(4-cyanophenyl) carbonylamino] phenyl-carboxamide. of N- (5-chloro (2-pyridinyl)) 5-acetic acid methyl ester. The raw material was used immediately.

STEP 6: To a suspension of N- (5-chloro (2-pyridinyl)) -5-acetic acid methyl ester (based on the previous step: 0.52 mmol, 1) sufanyl-2 - [(4-cyanophenyl) carbonylamino] phenyl-carboxamide .0 equiv.) In 6 mL of methanol, was added a pre-mixed solution of glacial acetic acid (0.37 mL, 12.0 equiv.) And dimethylamine (2N in THF) (1.56 mL, 6.0 equiv.) In 4 mL of methanol The reaction was stirred under reflux for 40 minutes and then the volatile components were evaporated. The crude mixture was purified by HPLC (C18 reverse phase) eluting with 0.1% TFA in H2O / CH3CN to give sulfanyl-phenylcarboxamide of N- (5-chloro-2-pyridinyl) -2- (4-N, N-dimethylaminopropylcarbonyl) amino-5-acetic acid (140 mg, 51%). MS found for C 23 H 22 Cl 1 N 5 O 2 S 1 (M + H) +: 526, (M + 2 + H) +: 528.

STEP 7: A solution of sulfanyl-phenylcarboxamide of N- (5-chloro-2-pyridinyl) -2- (4-N, N-dimethylamidophenylcarbonyl) amino-5-acetic acid methyl ester (95 mg, 0.181 mmol, 1. 0 equiv.) In 5 mL of a 1: 1 mixture of water and methanol with lithium hydroxide monohydrate (19 mg, 2.5 equiv.) For 30 minutes at room temperature. The volatile materials were evaporated. The aqueous solution was treated with 1N HCl and the resulting precipitate was filtered, dried and collected to give sulfanyl-phenylcarboxamide of N- (5-chloro-2-pyridinyl) -2- (4-EN, E N-dimethylamide mofen i Ica rbon il) to mino-S-acetic (55mg, 59%). MS found for C 24 H 22 CIN 5 O 4 S 1 (M + H) +: 512, (M + 2 + H): 514.

STEP 8: A suspension of sulfanyl-phenylcarboxamide of N- (5-chloro-2-pyridinyl) -2- (4-EN, IN-dimethylamidophenylcarbonyl) -amino-5-acetic acid (40 mg, 0.078 mmol, 1.0 equiv.) Was treated. in 5 mL of acetonitrile and 1 mL of DMF, with EDC (45 mg, 3.0 equiv.), HOAT (16 mg, 1.5 equiv.), dimethylamine-HCl (32 mg, 5.0 equiv.), and N-methylmorpholine (79 mg. , 10 equiv.) For 2 h. at 60 ° C. The volatiles were evaporated and the crude mixture was purified by HPLC (C18 reverse phase) eluting with 0.1% TFA in H20 / CH3CN to give sulfanyl-phenylcarboxamide of N- (5-chloro-2-pyridinyl) dimethyl-amide -2- (4-N, N-dimethylamidophenylcarbonyl) amino-5-acetic acid (20mg, 47%). MS found for C26H27CIN6? 3S1 (M + H) +: 539, (M + 2 + H): 541.

EXAMPLES 2-9 The following compounds were prepared according to the general procedures described above.

Example 3 Example 7 Example 8 Example 5 Example 9 EXAMPLE 10 This example provides the biological activity for the representative compounds of the invention. The compounds were evaluated for their ability to inhibit Factor Xa, as well as to inhibit hERG. In the following table, the activity is represented as follows: (For Ki, factor Xa), +++ indicates a value of less than 10 nM; (for Ki, hERG), the activity is indicated either as > 10 micromolar or as < 10 micromolar.

TABLE 1 FACTOR DATA Xa Ki and hERG FOR EXAMPLES 1 - 9 The examples in Table 1 above show that the present compounds are potent inhibitors of factor Xa while having relatively weak hERG binding. In the lace assay with hERG, almost all compounds tested gave a Ki greater than 1.0 micromolar and many were greater than 10 micromolar. This desirable selectivity is an improvement on the selectivity of other factor Xa inhibitors that have a related chemical structure. It was found that the -SCH2C (= X) EN (Rlb) (Rie) bound to the middle ring compounds of the formula I was a critical feature for the improved selectivity. In comparison, most of the compounds tested with factor Xa lacked the -SCH2C (= X) N (R1b) (R1 c) portion provided with the hERG link below 1.0 millimolar. For the present compounds, the propoation of Ki (hERG) / Ki (factor Xa) ranges from about 4000 to more than about 80,000. Preferably, the ratio is greater than about 10,000. The previous tests were performed as described below: PROCEDIMI TION FOR THE TEST OF I N HI BI DORS OF FACTOR Xa Determinations of IC50 and Ki Substrate: Substrate S-2765 (Z-D-Arg-Gly-Arg-pNA-HCI) was obtained in Diapharma (West Chester, OH). Enzyme: Factor Xa of plasma protein hum anus was purchased in Haematologic Technologies (Essex Junction, VT). METHODS: DETERMITIONS OF IC50 All assays, which were carried out in 96 receptacle microtiter plates, measure the proteolytic activity of the enzyme (factor Xa) after the substrate cleavage paranitroanilide (20mM Tris, 150mM NaCl, 5mM CaCl2, 0.1% bovine serum albumin ( BSA), 5% dimethyl sulfoxide (DMSO) pH 7.4). In a 96-well microtiter plate, the inhibitor was serially diluted to give a range of concentrations from 0.01 nM to 10 μM (final). Duplicate receptacle assemblies were tested and conrol receptacles without inhibitor were included. Enzyme was added to each receptacle (concentration fXa = 1 nM), the plate was shaken for 5 seconds and then incubated for 5 minutes at room temperature. S2765 (final 100 μM) was added, and the plate was shaken for 5 seconds (the final volume of the liquid in each well was 200 μL). The degree of substrate hydrolysis was measured at 450 nm in a Thermomax plate reader (Molecular Devices, Sunnyvale, CA) for 2 minutes. The initial velocities (mOD / min), for each scale of inhibitor concentrations, were fitted to a four parameter equation using the Softmax data analysis software. Parameter C, derived from the adjustment of the resulting curve, corresponded to the maximum average inhibition concentration (IC50) DETERMINATION OF Kl The test regulator for these series of tests was: Hepes regulatory saline solution (20mM Hepes, 150mM NaCl, 5mM CaCl2, 0.1% PEG-8000, pH 7.4). In a microtiter plate of In 96 wells, the inhibitor was serially diluted in a set of receptacles in duplicate, to give a range of final concentrations from 5 μm to 3 μM final. Controls without inhibitor were included (8 receptacles =.) The enzyme fXa (1 nM final) was added to the receptacles, Substrate S-2765 (200 μM final) was added and the degree of hydrolysis of the substrate at 405 nm was measured in a reader. Thermomax plate reader for 5 minutes, using Softmax software Initial velocities (mOD / min) were analyzed by non-linear least squares regression in Pia Ki software (BioKin Ltd, Pullman, WA) (Literature reference: Kusmic P , and co-authors, "High-throughput screening of enzyme inhibitors: Automatic determination of tight-binding inhibition constants" Anal. Biochemistry 2000, 281: 62-67.) The model used to adjust the response curves to the inhibitor was the equation of Morrison An apparent Ki (Ki *) was determined, the total Ki was calculated using the following equation: where [S] is the substrate concentration (200 μM) and Km the Michelis constant for S2765.

THE MEMBRANE A HERG UNION ASSAY (PROTEIN ETHER TO GO-GO HUMANA) Embryonic human kidney cells (HEK293) stably transfected with hERG cDNA for membrane preparation were used (Literature reference: Zhou, Z., and co-authors, "Properties of HERG stably expressed in HEK293 cells studied at physiological temperature . "Biophys. J, 1998, 74: 230-241). The assay regulator consisted of 50 mM Tris, 10 mM KCl, 1 mM MgCl 2, pH 7.4. Competence assays were performed for hERG binding in a 96-well plate, with 50 μL of 3H-dofetilide, at a concentration of 3.5 nM (final concentration of 0.01% ethanol). The test compound was added in final concentrations of 100 μM, 33.33 μM, 1 1 .1 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.14, μM, 0.046 μM, 0.015 μM, and 0.005 μM (1. 0% DMSO). Each compound was run in duplicate in each of the two plates. The total binding was determined by the addition of 50 μL of regulator for the assay in place of the compound. The non-specific binding was determined by adding 50 μL of 50 μM of terfenadine in place of the test compound. All assays were initiated by the addition of 150 μL of membrane homogenates (15 μg protein / receptacle as the final concentration) to the wells (total volume = 250 μML per well), and the plates were incubated at room temperature for 80 minutes at room temperature. a platform with agitation. All tests were completed by vacuum filtration on glass fiber filters, followed by two cold controller washings. The filter plates were dried at 55 ° C for 90 minutes, after which, Microscint 0 (50 μL) was added to each receptacle of the dry filter plate. Plates were counted in a Packard Topcount counter (Perkin Elmer, Boston, MA) using a one-minute procedure. The flash reading data (counts per minute, CPM) generated by the Packard TopCount device was used to calculate the percent inhibition curve generated using Excel XL Fil software (Microsoft). The equilibrium dissociation constant (K) was calculated using the Cheng and Prusoff equation.

K¡ = lc50 / [1 + ([L] / KD) (Reference in the literature: Cheng Y, Prusoff WH., "Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction," Biochem Pharmacol., 1973, 22 ( 23), 3099-108 The following compounds can be prepared according to the procedures described above.

It should be understood that the foregoing description, embodiments and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention. All patents, journal articles and other documents described or cited herein are incorporated by reference to the present application.

Claims (30)

1. A compound that has the formula: or a salt of it acceptable for pharmaceutical use. characterized in that R1a is a member selected from the group consisting of H, halogen, hydroxy, alkyl of 1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms, all of 1 to 6 carbon atoms, haloal of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) 0-2amino and alkylcarbonyl of 1 to 6 carbon atoms; R1b and R1c are each members independently selected from the group consisting of H and alkyl of 1 to 6 carbon atoms, or optionally R by R1c are combined with the nitrogen atom to which each is attached, to form a monocyclic ring of 5, 6 or 7 members having from 0 to 1 additional heteroatom members in the ring, or a bicyclic ring of 8, 9, 10 or 11 members having 0 to 2 additional ring heteroatom members, said ring heteroatom members are selected from O, N, S, S (O) and S (0) 2, said ring is further substituted with from zero to two substituents, independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, ( alkyl of 1 to 6 carbon atoms) 0. 2amino, oxo and an amine protecting group; R1d and R1e are each members independently selected from the group consisting of H, halogen, hydroxy, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms; haloalkyl of 1 to 6 carbon atoms, al of 1 to 6 carbon atoms, haloal of 1 to 6 carbon atoms, (alkyl of 1 to 6 carbon atoms) 0. 2-amino and amino-alkyl of 1 to 6 carbon atoms; or R1d and R e combine to form a fused 5 to 6 membered ring having from 0 to 2 heteroatoms in the ring selected from N, O and S; X is O, S, or together with the carbon atom to which it is attached, is CH

2. And it is CH or N; and Z is a group that has the formula: wherein R2a, R2b and R2c are each members independently selected from the group consisting of H, hydroxy, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, al of 1 to 6 carbon atoms and ( alkyl of 1 to 6 carbon atoms) 0-2arnino, or optionally any two of R2a, R2b and R2c are taken together with its atom or atoms involved, to form a ring of 3, 4, 5, 6 or 7 members having from 0 to 1 additional heteroatom members in the ring, selected from O, N, S, S (O) and S (O) 2, said ring is further substituted with from zero to two substituents independently selected from the group consisting of 1 to 6 carbon atoms, hydroxy, al of 1 to 6 carbon atoms, C02H, oxo and (alkyl of 1 to 6 carbon atoms) 0-2amino. The compound of claim 1, further characterized in that X is O.

3. The compound of claim 1, further characterized in that Y is N.

4. The compound of claim 1, further characterized in that R a is H or halogen .

5. The compound of claim 1, further characterized in that R1b and R1c are each members independently selected from the group consisting of H and alkyl of 1 to 4 carbon atoms.

6. The compound of claim 1, further characterized in that R1d is selected from the group consisting of halogen, hydroxy, alkyl of 1 to 3 carbon atoms, haloalkyl of 1 to 3 carbon atoms, al of 1 to 3 carbon atoms and amino-alkyl of 1 to 3 carbon atoms.

7. The compound of claim 1, further characterized in that S is O, and Z is a member selected from the group consisting of

8. The compound of claim 7, further characterized in that the -N (R1b) (R1c) portion is a member selected from the group consisting of - A > - * -O * » - r ~ "j3 -H -NMßa -l - T -N ^ J> - NHj.

9. The compound of claim 8, further characterized in that Z is a member selected from the group consisting of

10. The compound of claim 7, further characterized in that R1a is selected from the group consisting of H, F, Cl and Br.

The compound of claim 7, further characterized by Y being N; R1a is selected from the group consisting of H, F, Cl and Br; and R1d is selected from the group consisting of -F, -Cl, -Br, -OCH3, -OH, -CH3, -CF3 and -CH2NH2.

12. The compound of claim 11, further characterized in that R1b and R1c are each independently selected from the group consisting of H and alkyl of 1 3 carbon atoms.

The compound of claim 11, further characterized in that R1b and R1c are combined with the nitrogen atom to which each is attached to form a 5, 6 or 7 membered ring having from 0 to 1 additional heteroatom member in the ring, selected from O, N and S, said ring is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, homopiperazine and thiomorpholine.

14. The compound of claim 1, further characterized in that X and the carbon atom to which it is attached, is CH2.

15. The compound of claim 14, further characterized in that Z is a member selected from the group consisting of

16. The compound of claim 15, further characterized in that the -N (R1b) (R1c) portion is a member selected from the group consisting of - - \ > -? * 9 ~ \ _J OG

17. The compound of claim 16, further characterized in that Z is a member selected from the group consisting of

18. The compound of claim 15, further characterized in that R1a is selected from the group consisting of H, F, Cl and Br.

The compound of claim 15, further characterized in that Y is N; R1a is selected from the group consisting of H, F, Cl and Br; and R1d is selected from the group consisting of -F, -Cl-Br, -OCH3, -OH, -CH3, -CF3 and -CH2NH2.

The compound of claim 19, further characterized in that R b and R 1c are each independently selected from the group consisting of H and alkyl of 1 to 3 carbon atoms.

The compound of claim 19, further characterized in that R by R c are combined with the nitrogen atom to which they are attached, to form a ring of 5, 6 or 7 members having from 0 to 1 heteroatom member in the ring, selected from O, N and S, said ring is selected from the group consisting of pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, homopiperazine and thiomorpholine.

22. The compound of claim 1, selected from the group consisting of

23. The compound of formula 1, selected from the group consisting of

24. A composition containing an excipient acceptable for pharmaceutical use and a compound of any one of claims 1 to 23.

25. A method for treating or reducing the risk of a condition in a mammal, said condition characterized by unwanted thrombosis, comprises step of administering to said mammal an effective amount for therapeutic use of a compound of claim 1.

26. The method according to claim 25, further characterized in that said condition is selected from the group consisting of acute coronary syndrome, myocardial infarction. Unstable angina, refractory angina, occlusive coronary thrombus that occurs after thrombolytic therapy or after coronary angioplasty, a thrombotic-mediated cerebrovascular syndrome, embolic attack, thrombotic attack, transient ischemic attacks, venous thrombosis, deep vein thrombosis, pulmonary embolism, coagulopathy, intravascular coagulation d iseminated, thrombotic thrombocytopenic purpura, thromboangitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve, and conditions that require the placement of prosthetic devices.

27. The method for inhibiting the coagulation of biological samples, comprising contacting said sample with a computed one of claim 1.

28. The method according to claim 25, further characterized in that said compound is administered orally or intravenously.

29. The method according to claim 25, further characterized in that said compound is administered in combination with a stent.

30. The method according to claim 25, further characterized in that said compound is administered in combination with a second therapeutic agent.