MXPA99002396A - Benzamidine derivatives substituted by cyclic amino acid or cycl ic hydroxy acid derivatives and their use as anti-coagulants - Google Patents

Abstract

This invention is directed to benzamidine derivatives substituted by cyclic amico acid and cyclic hydroxy acid derivatives which are useful as anti-coagulants as represented by formulae (I), (II), (III), (IV), (V), (VI), (VII) wherein:A is -C(R8)=or -N=;Z1 and Z2 are independently -O-, -N(R9)-, -S-, -S(O)-, -S(O)2-, or -OCH2-;R2 is -C(NH)NH2, -C(NH)N(H)OR9, -C(NH)N(H)C(O)OR12, -C(NH)N(H)C(O)R9, -C(NH)N(H)S(O)2R12, or -C(NH)N(H)C(O)N(H)R9;R7 is -N(R9)-(C(R9)(R10))n-R13 (where n is 0 to 4), -O-(C(R9)(R10))n-R13 (where n is 0 to 4), or -N(R14)R15;R1 and R3 - R6 are as defined in the description. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.

Description

DERIVATIVES OF BE ZAMIDINE REPLACED BY CYCLIC AMINO ACIDS OR DERIVATIVES OF CYCLIC HYDROXYDICS, AND ITS USE AS -_NGIX) AGULA - ?? S FIELD OF THE INVENTION The present invention is directed to monocyclic N-heterocyclics which are substituted by cyclic amino acids or cyclic hydroxy acid derivatives, and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, and are therefore useful as anticoagulants. It is also related to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods for their use.

Factor Xa is a member of the class of serine protease enzymes, similar to trypsin. The one-to-one binding of Xa and Va factors with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin into thrombin. Thrombin, in turn, converts fibrinogen to fibrin, which polymerizes to form insoluble fibrin. In the coagulation cascade, the prothrombinase complex is the point of convergence of intrinsic (surface-activated) and extrinsic (tissue-factor-tissue damage) pathways (Biochemist? Y (1991), Vol. 30, p.10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been further refined with the discovery of the mode of action of the tissue factor pathway inhibitor (TFPI) (Seminars in Hematology (1992), Vol. 29, pp. 159-161). TPFI is a circulating, multiple-domain serine protease inhibitor with three Kunitz-type domains, which compete for factor Va by free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of factor Vlla and the tissue factor complex. Factor Xa can be activated by two different complexes, by the tissue factor-VIIa complex in the "Xa delivery" pathway and by the factor IXa-VIIIa complex (TENase) of the pathway "sustained by Xa" in the cascade of coagulation. After damage to the vessels, the "Xa delivery" pathway is activated via tissue factor (TF). The upregulation of the coagulation cascade occurs via the production of "increased factor Xa via the" sustained Xa "pathway.The down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex , which not only removes factor Xa, but also inhibits the additional formation of factor by means of the "Xa delivery" pathway, therefore, the coagulation cascade is naturally regulated by factor Xa. of inhibitor factor Xa on thrombin in order to avoid coagulation is the main role of factor Xa versus the multiple functions of thrombin.Thrombin not only catalyzes the conversion of fibrinogen to fibrin, from factor VIII to VIIIA, from factor V to It goes from factor XI to Xla, but also activates platelets, is a monocyte and mitogenic chemotactic factor for lymphocytes and smooth muscle cells.Thrombin activates protein C, the anticoagulant activator gulante in vivo of factors Va and Villa, when it is united to trombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other glycosaminoglycans associated with proteoglycan, whereas thrombin in tissues is inactivated by protease nexin Thrombin carries out multiple functions of cellular activation through a single "ligand-bound" thrombin receptor (Cell (1991), Vol 64, p.1057), which requires the same anionic binding site and site. active used in the binding and separation of fibrinogen, and by the binding of thrombomodulin and activation of protein C. Therefore, a diverse group of molecular targets in vivo are related to thrombin binding and subsequent proteolytic events will have very physiological consequences different based on the type of cell and receptor, modulator, substrate or inhibitor to which the thrombin binds. Published data with antistasin proteins and coarse anticoagulant peptide (TAP) demonstrate that factor Xa inhibitors are effective anticoagulants (Thropíbosis and Haemostasis (1992), Vol. 67, pp. 371-376; and Science (1990), Vol. 248, pp. 593-596). The active site of factor Xa can be blocked by any inhibitor based on mechanism or firm binding (a firm binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent linkage between the enzyme and the inhibitor). Two types of inhibitors are known based on mechanism, reversible and irreversible, which are differentiated by their ease of hydrolysis of the enzyme-inhibitor binding (Thrombosis Res (1992), Vol 67, pp. 221-231; and Trends Pharmacol.

Sci, (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of strong binding inhibitors (Throrribosis Res. (1980), Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives have also been shown to be inhibitors that bind tightly to thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series of compounds containing arylamidine, including 3 -amidinophenylaryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and bis (amidino) benzylcycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548 ). However, these compounds demonstrate poor selectivity for factor Xa.

DESCRIPTIONS P CT.Artnt_Ar > A.q The published European patent application 0 540 051 (Nagahara et al.) Describes aromatic amidine derivatives which are said to be able to show a strong anticoagulant effect by the reversible inhibition of factor Xa. The synthesis of a, a '-bis (amidinobenzylidene) cyclo-alkanones and, a' -bis (amidino-benzyl) cycloalkanones is described in Pha.rma.zie (1977), Vol. 32, No. 3, pp. 141-145. These compounds are described as serine protease inhibitors.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa, and therefore are useful as pharmacological agents for the treatment of disease states characterized by thrombotic activity. Accordingly, in one aspect, this invention provides compounds selected from the group consisting of the following formulas: , wherein: A is -C (R8) = or -N =; Z1 and Z2 are independently -0-, -N (R9) -, -S-, -S (0) -, -S (0) 2-, or -OCH2-; R1 and R4 are each independently hydrogen, halo, alkyl, nitro, -OR9, -C (0) OR9, -C (O) N (R9) R1Q, -N (R9) R10, -N (R9) C ( 0) R9, or -N (H) S (0) 2R12; R2 is • C (NH) NH, -C (NH) N (H) 0R? ' -C (NH) N (H) CfOOR1 -C (NH) N (H) C (0) R9, -C (NH) N (H) S (0) 2R12, or -C (NH) N (H) C (O) N (H) R9; R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, -OR9, -C (NH) NH2, -C (NH) N (H) OR9, -C (O) N (R9) R10, -CH (OH) C (0) N (R9) R10, -N (R9) R10, -Rlx-N (R9) R10, -C (0) OR9, -Ru-C (0) OR9, -N (R9) C (0) R9, (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl), - R5 and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, -N (R9) R10, -C (0) OR9, -C (O) N (R9) R10, -C (0) N (R9) CH2C (0) N (R9) R10, -N (R9) C (O) N (R9) R10, -N (R9) C (O) R10 or -N (R9) S (0) 2R12, R7 is -N (R9) - (C (R9) (R10)) n-Rx3 (where n is 0 to 4), -0- (C (R9) (R10) n-R13 (where in is 0 to 4), or -N (R1) R15; R8 is hydrogen, alkyl or halo, each R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl ', monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tri-cyclic carbocyclic ring system containing 3 to 15 carbon atoms which may be partially or fully saturated, or be aromatic, wherein the carbon atoms may optionally be oxidized and wherein the carbocyclic ring system is substituted by - (C (R9) (R10) m-R16 (wherein m is 0 to 4) and optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9, or -C (0) N (R9) R10, or R13 is a mono- or tri-cyclic heterocyclic ring system containing from 3 to 15 members in the ring and including carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be saturated partially or completely, or be aromatic, and is substituted -C (R9) (R10)) -R16 (wherein m is 0 to 4), and optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) 0R9, or -C (0) N (R9) R10; R14 and R15, together with the nitrogen atom, form a mono-, bi- or tri-cyclic heterocyclic ring system containing from 3 to 15 members in the ring including carbon and 1 to 3 additional heteroatoms which are selected from atoms of nitrogen, oxygen and sulfur, wherein the carbon, nitrogen or sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be partially or completely saturated or aromatic, and is substituted by -C (R9) (R10) )) m-R16 (wherein m is 0 to 4), and optionally is substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C ( 0) 0R9, or -C (0) N (R9) R10; and R16 is -C (0) 0R9 O -C (0) N (R9) R10; with the proviso that when R7 is -N (R9) - (C (R9) (R10) n -R13 (where n is 0), R13 can not be phenyl, naphthyl or piperidinyl substituted by -C (0) 0R9 when R7 is -0- (C (R9) (R10)) n -R13 (where n is 0), R13 can not be phenyl, naphthyl, piperidinyl or pyrrolidinyl substituted by -C (0) 0R9; is -N (R14) R15, R14 and R15, together with the nitrogen atom, can not be piperazinyl or piperidinyl substituted by -C (0) 0R9, -as a single stereoisomer or a mixture thereof, or a pharmaceutically salt In another aspect, this invention provides compositions useful for treating a human having a disease state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound of the invention as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient In another aspect, this invention provides a method for treating a human having a disease state characterized by thrombotic activity, which method comprises administering to the human in need thereof a therapeutically effective amount of a compound of the invention as described above. In another aspect, this invention provides a method for treating a human having a disease state, alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention. invention as described above. In another aspect, this invention provides a method for inhibiting human factor Xa in vitro or in vivo by administering a compound of the invention.

DESCRIPTION DETAT.T.?D? ? THE INVENTION Definitions As used in the specification and appended claims, unless otherwise specified, the following terms have the indicated meaning: "Alkyl" refers to a monovalent or divalent radical, straight or branched chain consisting solely of carbon and hydrogen , which does not contain unsaturation and has from one to six carbon atoms, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-) butyl) and the like. "Alkoxy" refers to a radical of the formula -0Ra where Ra is alkyl as defined above, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, (isopropoxy), n-butoxy, n-pentoxy , 1, 1-dimethylethoxy (t-butoxy) and the like. "Alkylene" refers to a divalent straight or branched chain radical consisting solely of carbonyl and hydrogen that does not contain unsaturations and having one to six carbon atoms, for example, methylene, ethylene, propylene, n-butylene and the like . "Aryl" refers to a phenyl or naphthyl radical. "Aralkyl" refers to a radical of the formula -RaRb wherein Ra is alkyl as defined above, and Rb is aryl as defined above, for example benzyl. "Aryloxy" refers to a radical of the formula -ORb wherein Rb is aryl as defined in the preceding, for example phenoxy and naphthoxy. "Aralkoxy" refers to a radical of the formula -ORc, wherein Rc is aralkyl as defined above, for example benzyloxy and the like. "Amidino" refers to the radical -C (NH) -NH2, "Carbocyclic ring system" refers to a stable 3 to 15 membered ring radical consisting solely of carbon and hydrogen atoms. For purposes of this invention, the radical of the carbocyclic ring system may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridging ring systems, and the ring system may be partially or completely saturated or be aromatic, and the carbon atoms in the ring system may optionally be oxidized. Examples of such carbocyclic ring system radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornane, norbornene, adamantyl, bicyclo [2.2.2] octane and the like. "Dialkylamino" refers to a radical of the formula -NRaRa wherein each Ra is independently an alkyl radical as defined above, for example dimethylamino, methylethylamino, diethylamino, dipropylamino, ethylpropylamino and the like. "Dialkylaminocarbonyl" refers to a radical of the formula -C (0) NRaRa wherein each Ra is independently an alkyl radical as defined above, for example, dimethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl and the like. "Halo" refers to bromine, chlorine, iodine or fluorine. "Haloalkyl" refers to an alkyl radical, as defined above, which is substituted by one or more halo radicals, as defined above, for example trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 2-bromo-2-fluoropropyl, l-bromomethyl-2-bromoethyl and the like. "Haloalkoxy" refers to a radical of the formula -0Rf wherein Rf is haloalkyl as defined above, for example trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2 -fluoropropoxy, 2-bromomethyl-2-bromoethoxy and the like. "Heterocyclic ring system" refers to a stable 3 to 15 membered ring radical which consists of carbon atoms and 1 to 4 heteroatoms which are selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridging ring systems; and the nitrogen, carbon or sulfur atoms in the radical of heterocyclic ring systems may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the ring system may be partially or completely saturated or aromatic. The radical of a heterocyclic ring system can be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic ring system radicals include, but are not limited to, aziridinyl, azetidinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolinyl. , pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl , isoindole inyl, octahydroindolinyl, octahydroisoindolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, decahydroisoquinolinyl, dihydroisoquinolinyl, tetrahydro-isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, sulfoxide of thiamorpholinyl, thiamorpholinyl sulfone, 2-azabicyclo [2.2.2] heptyl and oxadiazolyl. "(1,2) -imidazolyl" refers to an imidazolyl radical attached at any position, 1 or 2. "(1, 2) -imidazolinyl" refers to a 4,5-dihydroimidazolyl radical attached at any of positions 1 or 2. "Monoalkylamino" refers to a radical of the formula -NHRa wherein Ra is an alkyl radical as defined above, for example methylamino, propylamino, and the like. "Monoalkylaminocarbonyl" refers to a radical of the formula -C (0) NHRa wherein Ra is an alkyl radical as defined above, for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl and the like. "(1,2) -tetrahydropyrimidinyl" refers to a tetrahydropyrimidinyl attached at any position I or 2. "Optional" or "optionally" means that the event described subsequently of the circumstances may or may not occur, and that the description includes cases where such an event or circumstance occurs and cases in which it does not. For example, "optionally substituted aryl" means that the aryl radical can not be substituted and that the description includes both substituted aryl radicals and aryl radicals that have no substitution. "Pharmaceutically acceptable salt" includes both acid addition salts and base salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are 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, trifluoroacetic 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 base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically undesirable or in some other way. These salts are prepared from the addition of an inorganic base or an organic base to the free acid. Salts derived from such bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. The preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases, include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including substituted amines that occur naturally, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, thiobromine, purines, pyrazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine.

"Therapeutically effective amount" refers to that amount of a compound of formula (I) which, when administered to a human in need thereof, is sufficient to carry out the treatment, as defined below, for conditions of disease characterized by thrombotic activity. The amount of a compound of formula (I) which constitutes a "therapeutically effective amount" will vary based on the compound, the disease state and its severity, and the age of the human to be treated, but can usually be determined by a person familiar with the technique when considering his own knowledge and that of this description. "Treat" or "Treatment" as used herein, covers the treatment of a disease state in a human, disease state which is characterized by thrombotic activity, and includes: (i) preventing the state from being present; disease in a human, in particular when such a human is predisposed to the state of disease, but has not yet been diagnosed as a person suffering from it; (ii) inhibit the disease state, that is, suppress its development; or (iii) alleviate the disease state, that is, cause the regression of the disease state.

The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield. The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sulfur atoms or quaternary nitrogen atoms in their structure. The compounds of the invention and their pharmaceutically acceptable salts can therefore exist as simple stereoisomers, racemates and as mixtures of enantiomers and diastereomers. The totality of such stereoisomers, racemates and mixtures thereof is intended to be within the scope of this invention. The nomenclature used herein is a modified form of the I.U.P.A.C. system. wherein the compounds of the invention are named as benzamidine derivatives. For example, a compound of the invention selected from formula (I) wherein A is -N =; Z1 and Z2 are both -O-, R1 is hydroxy; R2 is -C (NH) NH2 / - R3 is l-methylimidazolin-2-yl; R4 is hydrogen; Rs and R6 are both fluoro; R7 is -N (R9) - (C (R9) (R10)) n -R13 wherein n is 0, R9 is hydrogen and R13 is l-carboxyclohex-4-yl, i.e., it is referred to herein as 4-hydroxy-3 - [(4-N- (1-carboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine.

Utility and Administration A. Utility The compounds of the invention are inhibitors of factor Xa and are therefore useful in disease states characterized by thrombotic activity based on the role of factor Xa in the coagulation cascade (see background of the invention, in the above). A primary indication for the compounds is prophylaxis for long-term risk after myocardial infarction. Additional indications are prophylaxis of deep vein thrombosis (DVT) after orthopedic surgery or prophylaxis of selected patients after transient ischemic attack. The compounds of the invention may also be useful for indications in which coumarin is currently used, such as for DVT or other types of surgical intervention such as coronary artery bypass graft and percutaneous transluminal coronary angioplasty. The compounds are also useful for the treatment of thrombotic complications associated with acute promyelucitic leukemia, diabetes, multiple myelomas, disseminated intravascular coagulation associated with septic shock, fulminant purpura-associated infection, adult respiratory distress syndrome, unstable angina and thrombotic complications associated with the aortic valve or vascular prosis. The compounds are also useful for prophylaxis for thrombotic diseases, particularly in patients who are at high risk of developing such a disease. In addition, the compounds of the invention are useful as in vitro and in vivo diagnostic reagents to selectively inhibit factor Xa without inhibiting the other components of the coagulation cascade.

B. Tests The primary bioassays used to demonstrate the inhibitory effect of the compounds of the invention on the factor Xa are simple chromogenic assays involving only serine protease, the compound of the invention to be tested, a substrate and a buffer (see, for example, Thrombosis Res. (1979), Vol. 16, pp. 245-254). For example, four human tissue serine proteases can be used in the primary bioassay, free factor Xa, prothrombinase, thrombin (bundle) and tissue plasminogen activator (tPA). The tPA assay has been successfully used before to demonstrate unwanted side effects in the inhibition of the fibrinolytic process (see, for example, J. "Med. Chem. (1993), Vol. 36, pp. 314-319). useful bioassay to demonstrate the utility of the compounds of the invention for inhibiting factor Xa demonstrates the potency of the compounds against free factor Xa in citrated plasma For example, the anticoagulant efficacy of the compounds of the invention will be tested using either the time of prothrombin (PT), or activated partial thromboplastin time (aPTT), while the selectivity of the compounds is verified with the thrombin coagulation time (TCT) assay. The correlation of Ki in the primary enzyme assay with the Kx for free factor Xa in citrated plasma will be examined against compounds which interact, or are inactivated by other plasma components. The correlation of K. with the extension of PT is a necessary in vitro demonstration that the potency in the inhibition assay of free factor Xa is translated into potency in a clinical coagulation assay. In addition, the extension of PT in citrated plasma can be used to measure the duration of the action in subsequent far acodynamic studies. For additional information regarding assays for demonstrating the activity of the compounds of the invention, see R. Lottenberg et al., Methods in Enzymology (1981), Vol. 80, pp. 341-361 and H. Ohno et al. , Thrombosis Research (1980), Vol. 19, pp. 579-588.

C. General Administration The administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out by any of the accepted modes of administration or the agents for providing similar facilities. Thus, administration can be, for example, orally, nasally, parenterally, topically, transdermally or rectally, in the form of solid, semi-solid, lyophilized powder or liquid dosage forms, such as, for example, tablets, suppositories , pills, soft, elastic and hard gelatine capsules, powders, solutions, suspensions or aerosols, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention such as the agent or an active agent and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Generally, based on the proposed mode of administration, the pharmaceutically acceptable compositions will contain from about 1% to about 99% by weight of a compound or compounds of the invention, or a pharmaceutically acceptable salt thereof, and from 99% to 1% by weight of a pharmaceutically suitable excipient. Preferably, the composition will be from about 5% to about 75% by weight of the compound or compounds of the invention, or a pharmaceutically acceptable salt thereof, the remainder being comprised of pharmaceutically suitable excipients. The preferred route of administration is oral, using a convenient daily dosage regimen, which can be adjusted according to the degree of severity of the disease state to be treated. For such oral administration, a pharmaceutically acceptable composition is prepared which contains the compound or compounds of the invention, or a pharmaceutically acceptable salt thereof, by the incorporation of any of the excipients normally used, such as, for example, pharmaceutical grades of mannitol, lactose, starch , pregelatinized starch, magnesium stearate, sodium saccharin, talcum, cellulose, ether derivative, glucose, gelatin, sucrose, citrate, propyl gallate and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. Preferably, such compositions will take the form of a capsule, caplet (capsule-tablet) or tablet and will therefore also contain a diluent such as lactose, sucrose, dicalcium phosphate and the like.; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as starch, acacia gum, polyvinyl pyrrolidone, gelatin, cellulose ether derivatives and the like. The compounds of the invention, or their pharmaceutically acceptable salts, can also be formulated in a suppository using, for example, from about 0.5% to about 50% of active ingredient placed in a carrier that dissolves slowly within the body, for example, polyoxyethylene glycols and polyethylene glycols (PEG), for example, PEG 1000 (96%) and PEG 4000 (4% 9. The pharmaceutically administrable compositions in liquid form can be prepared, for example, by dissolving, dispersing, etc., a compound or compounds of the invention (from about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension If desired, a pharmaceutical composition of the invention may also contain Examples of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants and the like such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc. Current methods for preparing such dosage forms are known, or will be apparent from those familiar in the art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pennsylvania, 1990). The composition to be administered will, in any case, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease state alleviated by inhibition of factor Xa in accordance with the teachings of this invention. The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary based on a variety of factors including the activity of the specific compound used, the metabolic stability and the duration of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, speed of expression, combination with medications, the severity of the particular disease states and the therapy to which the host is subjected. Generally, a therapeutically effective daily dose is between about 0.14 mg and about 14.3 mg / kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably from about 0.7 mg to about 10 mg / kg of body weight per day; and more preferably from about 1.4 mg to about 7.2 mg / kg of body weight per day. For example, for administration to a 70 kg person, the dosage range will be from about 10 mg to about 1.0 grams per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and more preferably from about 100 mg to about 500 mg per day.

Preferred Modalities Of the compounds of the invention as set forth in the above Brief Description of the Invention, several groups of compounds are preferred. A preferred group of compounds is that group in which the compound is selected from formula (I): as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof. A preferred subgroup of this group is that subset of components where A is -N =; Z1 and Z2 are independently -O-, or -OCH2-; R1 and R4 are each independently hydrogen, halo, alkyl, or -OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (O) OR12, -C (NH) N (H) C (0) R9, R3 is ureido, guanidino, -OR9, -C (NH) NH2, -C (0) N (R9) R10, -N (R9) R10, (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl) , or (1, 2) -imidazolinyl (optionally substituted by alkyl); R5 and R6 are independently hydrogen, halo, alkyl or haloalkyl; R7 is -N (R9) - (C (R9) (R10)) n -R13 (wherein n is 0 to 4), each R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy) , alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxysarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl) 0 aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tri-cyclic carbocyclic ring system containing 3 to 15 carbon atoms which may be partially or completely saturated, or be aromatic, wherein the carbon atoms may optionally be oxidized and wherein the carbocyclic ring system is substituted by - (C (R9) (R10) m-R16 (wherein m is 0 to 4) and optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkox, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) 0R9, or -C (O) N (R9) R10, - or R13 is a mono- or tri-cyclic heterocyclic ring system containing 3 to 15 members in the ring and that includes carbon and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be partially or completely saturated, or aromatic, and is substituted -C (R9) (R10)) _, - R16 (wherein m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) 0R9, or -C (0) N (R9) R10; and R16 is -C (0) OR9 or -C (O) N (R9) R10. A preferred class of this subgroup is that class of compounds where A is -N =; Z1 and Z2 are each -O-; Rx is hydrogen or -OR9; R2 is -C (NH) NH, -CCNH? NÍHJSÍO R1 -C (NH) N (H) C (0) R9; R3 is (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; R5 and R6 are each halo, R7 is -N (R9) - (C (R9) (R10) n -R13 (where n is 0 to 4), - each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tri-cyclic carbocyclic ring system containing from 3 to 15 carbon atoms which may be partially or completely saturated or aromatic, wherein the carbon atoms may optionally be oxidized and wherein the carbocyclic ring system is substituted by -C (R9) (R10) mR? s (wherein m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy , hydroxy, -N (R9) R10, -C (0) OR9, or -C (0) N (R9) R10; and R16 is -C (0) R9 or -C (O) N (R9) R10. A preferred subclass of this class is that subclass of compounds where A is -N =; Z1 and Z2 are each -O-; R1 is hydrogen -OR9; is -C (NH) NH, RJ is (1,2) -tetrahydropyrimidinyl (optionally substituted by methyl), (1, 2) -imidazolyl (optionally substituted by methyl), or (1,2) -imidazolinyl (optionally substituted by methyl), - R 4 is hydrogen; R5 and R6 are each halo, R7 is -N (R9) - (C (R9) (R10) n-R13 (where n is 0); each of R9 and R10 is independently hydrogen, alkyl or aralkyl; R13 is a carbocyclic ring system that is selected from the group consisting of cyclopentyl, cyclohexyl, cyclobutyl, norbornene, norbornane and adamantyl, and wherein the ring system is substituted by - (C (R9) (R10)) m-R16 (where m is 0); and optionally substituted by hydroxy, -N (R9) R10, -C (0) OR9, or -C (O) N (R5) R10; and R1"is -C (0) OR9 or - C (0) N (R9) R10. Preferred compounds of this subclass of compounds are those compounds wherein R 1 is hydrogen, benzyloxy or hydroxy; R3 is l-methylimidazolin-2-yl; and R5 and R6 are both fluoro. Particularly preferred compounds of this subclass are selected from the following: 4-hydroxy-3- [(4- (N- (l-carboxycyclopent-2-yl) amino) -6- (3- (1-methyl) imidazolin- 2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4-. {N- (1,3-dicarboxycyclopent-1-yl) amino) -6 - (3 - (1-methyl) imidazolin-2-yl) phenoxy -3.5 -difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (1-carboxycyclopropyl-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2 -yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (1-carboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 - il) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (l-carboxycyclohex-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 - il) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (l-carboxycyclohex-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 - il) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (l-carboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin - 2 -yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (1,3-dicarboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazole in 2-yl) phenoxy-3, 5- dif luoropyr idin-2-yl) oxy] -benzamidine; 4-hydroxy -3- [(4- (N- (1, 1-dicarboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (2-carboxynorbornan-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin- 2-yl) oxy] -benzamidine; 4-hydroxy -3- [(4- (N- (1 -carboxybicyclo [2.2.2] oct-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (JV-met il-N- (1-carboxycyclopent-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-meth) N- (1-ethoxycarboxycyclopent-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-Hydroxy -3- [(4- (N-methyl-N- (1,3-dicarboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxycyclopropyl-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyr idin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-ethoxycarboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (JV-methyl-V- (1-carboxycyclohex-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxycyclohex-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-ethyl-N- (1-carboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoro ir idin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1,3 -dicarboxiciclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy -3 - [(4- (N-ethyl-N- (1, l-dicarboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (2-carboxinorbornan-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; and 4-hydroxy-3- [(4- (JV-methyl-N- (1-carboxybicyclo [2.2.2] oct-2-yl) amino) -6- (3- (1-methyl) imidazolin-2- il) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine. Of these compounds, the following are the most preferred: 4-hydroxy-3- [(4- (N-methyl-N- (1 -carboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; and 4-hydroxy-3- [(4- (N-methyl-N- (1-ethoxycirbonylcyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine. Another preferred subclass of this class of compounds is the subclass wherein A is -N =; Z1 and Z2 are each -O-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2, "-C (NH) N (H) S (0) 2R 12 -C (NH) N (H) C (O) R9; R3 is (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; R5 and Rs are each halo, R7 is -N (R9) - (C (R9) (R10) n -R13 (wherein n is 0 to 4), each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl) amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl , aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tri-cyclic heterocyclic ring system containing from 3 to 15 members in the ring, which includes carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the atoms carbon, nitrogen "and sulfur may optionally be oxidized and wherein the heterocyclic ring system may be partially or completely saturated, or is aromatic, and is substituted by -C (R9) (R10) m-R16 (wherein m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9, or -C (O) N (R9) R10; and R1S is -C (0) R9 or -C (0) N (R9) R10.

Another preferred subgroup of the group of compounds is the subgroup where A is -N =; Z1 and Z2 are independently -O-, -S-, or -OCH2-; R1 and R4 are each independently hydrogen, halo, alkyl or OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (O) 2R12 or -C (NH) N (H) C (0) R9; R3 is ureido, guanidino, -OR9, -C (NH) NH2, -C (O) N (R9) R10, -N (R9) R10, (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1 , 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); Rb and R5 are independently hydrogen, halo, alkyl or haloalkyl; R7 is -0 - (- C (R9) (R10) n -R13 (wherein n is 0 to 4), each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy , alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tri-cyclic carbocyclic ring system containing from 3 to 15 carbon atoms which may be partially or completely saturated or aromatic, wherein the carbon atoms may optionally be oxidized and wherein the carbocyclic ring system is substituted by -C (R9) (R10) mR? s (wherein m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy , hydroxy, -N (R9) R10, -C (0) OR9, or -C (0) N (R9) R10; or R13 is a mono- or tri-cyclic heterocyclic ring system containing from 3 to 15 ring members including carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the atoms carbon, nitrogen and sulfur may optionally be oxidized and wherein the heterocyclic ring system may be partially or fully saturated or aromatic and is substituted by - (C (R9) (Ri0)) ra-R16 (where m is 0 a 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9 or -C (O) N ( R9) R10, - and R16 is -C (0) OR9 or -C (0) N (R9) R10. A preferred class of this subgroup is that class of compounds in which A is -N =; Z1 and Z2 are each -0-, R1 is hydrogen or -OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (O) 2R12 or -C (NH) N (H) C (0) R9; R3 is (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; R5 and R6 are each halo, R7 is -0 (C (R9) (R10) n -R13 (wherein n is 0 to 4), - each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, amino arbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono-, bi- or tri-cyclic carbocyclic ring system containing from 3 to 15 carbon atoms, which may be partially or fully saturated or aromatic, in which the carbon atoms may optionally be oxidized and wherein the carbocyclic ring system is substituted by -C (R9) (R10) mR, 16 > wherein m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9, or - C (O) N (R9) R10; and R16 is -C (0) OR9 or -C (0) N (R9) R10. A preferred subclass of this class is that subclass of compounds where A is -N =; Z1 and Z2 are each -O-, - R1 is hydrogen or -OR9; R2 is • C (NH) NH 2 'RJ is (1,2) -tetrahydropyrimidinyl (optionally substituted by methyl), (1, 2) -imidazolyl (optionally substituted by methyl), or (1,2) -imidazolinyl (optionally substituted by methyl); R4 is hydrogen; R5 and R6 are each halo, R7 is -0- (C (R9) (R10) n -R13 (where n is 0), each of R9 and R10 is independently hydrogen, alkyl or aralkyl; R13 is a system of carbocyclic ring which is selected from the group consisting of cyclopentyl, cyclohexyl, cyclobutyl, norbornene, norbornane and adamantyl, and wherein the ring system is substituted by -C (R9) (R10)) m-R16 (wherein m is 0), and is optionally substituted by hydroxy, -N (R9) R10, -C (0) OR9, or -C (O) N (R9) R10; and R16 is -C (0) OR9, -C (0) N (R9) R10. Preferred compounds of this subclass are those compounds wherein R 1 is hydrogen, benzyloxy or hydroxy; R3 ES 1-methylimidazolin-2-yl; and R5 and R6 are both fluoro. Particularly preferred compounds of this subclass of compounds are selected from the following: -hydroxy -3- [(4- (l-carboxycyclopent-2-yl) oxy -6- (3- (1-methyl) imidazolin-2-yl) ) phenoxy-3,5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-carboxycyclohex-2-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (l-carboxycyclohex-4-yl) oxy- 6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (1-dicarboxycyclopent-3-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy -3- [(4- (1 -carboxycyclobut -3-yl) oxy-6- (3 - (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (l-carboxy-l-hydroxycyclobut-3-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 -yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-carboxynorbornan-3-yl) oxy- 6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-methoxycarbonyl-2-hydroxynylohexa-3,5-dien-l-yl) oxy-6- (3- (1-methyl) -imidazolin-2-yl) phenoxy - 3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonylcyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-l-methyl-2-ethenylcyclohex-2-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-methoxycarbonylcyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (9-methoxycarbonylfluoren-9-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (9-methoxycarbonyl-2-chlorofluoren-9-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-3,4,5-trihydroxycyclohex-1-yl) oxy-6- (3- (1-methyl ') imidazolin-2-yl) phenoxy-, -difluoropyridin-2-yl) oxy] -benzamidine; 4-Hydroxy-3- [(4- (1-methoxycarbonylcycloprop-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-Hydroxy-3- [(4- (1-methoxycarbonylcyclohept-1-yl) oxy-6- (3 - (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonylcyclopent-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (3-methoxycarbonylbicyclo [3.2.1] oct-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridine -2-yl) oxy] -benzamidine; 4-Hydroxy -3- [(4- (4-methoxycarbonylbicyclo [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridine -2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (methoxycarbonylbicyclo [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-2-hydroxycyclobut-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 -yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridine -2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (4-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridine -2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-methoxycarbonylamantyl-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] - benzamidine; 4-hydroxy-3- [(4- (2-carboxy-2-hydroxycyclohexa-3,5) -dien-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-carboxycyclohex-1-yl) oxy- 6- (3- (1-methyl) imidazol-2-yl) phenoxy-3,5-dif luoropyridin-2-yl ) oxy] -benzamidine; 4-hydroxy-3- [(4- (l-carboxy-l-methyl-2-ethenyl-cyclohex-2-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-carboxycyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-Hydroxy-3 - [(4- (9-carboxyluoren-9-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (9-carboxy-2-chlorofluoren-9-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 -yl) oxy] -benzamidine; 4-Hydroxy -3- [(4- (1-carboxy-3,4,5-trihydrocyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -difluoropyridin-2-yl) oxy] benzamidine; 4-Hydroxy -3- [(4- (1-carboxycycloprop-1-yl) oxy -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (1-carboxycyclohept-1-yl) oxy-6- (3-imethyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-carboxycyclopent-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (3-carboxylicicylic [3.2.1.] Oct-l-yl) oxy- 6- (3 - (1-methyl) imidazolin-2-yl) phenoxy -3,5- difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (4-carboxycyclo [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridine -2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-carboxybicyclo [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridine -2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-carboxy-2-hydroxycyclobut-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-di-fluoropyridine -2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-carboxybicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridine -2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (carboxybicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 -yl) oxy] -benzamidine; and 4-hydroxy-3- [(4- (3-carboxymantmant-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] -benzamidine. Another preferred subgroup of the group of compounds is that subgroup where A is -N =; Z1 and Z2 are independently -0-, -S-, or -0CH2-; R1 and R4 are each independently hydrogen, halo, alkyl or OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (O) 2R12 or -C (NH) N (H) C (0) R9; R3 is ureido, guanidino, -OR9, -C (NH) NH2, -C (O) N (R9) R10, -N (R9) R10, (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1 , 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R5 and R5 are independently hydrogen, halo, alkyl or haloalkyl; R7 is -N (R14) R15; each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), - R 12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy , alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), - R14 and R15, together with the nitrogen atom, form a mono-, bi- or tri-cyclic heterocyclic ring system containing from 3 to 15 members in the ring which includes carbon and 1 to 3 additional heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon atoms rbonus, nitrogen or sulfur may optionally be oxidized and wherein the heterocyclic ring system may be partially or completely saturated or aromatic, and is substituted by - (C (R9) (R10)) ,, - R16 (where m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9 or -C (O) N (R9) R10; and R16 is -C (0) OR9 or -C (0) N (R9) R10. A preferred subclass of this subgroup is that class of compounds in which A is -N =; Z1 and Z2 are each -O-, - R1 is hydrogen or -OR9; R 2 is -C (NH) NH- -C (NH) N (H) S (O) 2 R 12 -C (NH) N (H) C (O) R 9; R3 is (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; R5 and Rd are each halo, each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl) or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), - R14 and R15 together with the nitrogen atom, form a heterocyclic ring system selected from the group consisting of dihydroisocyanilinyl, tetrahydrolsoquinolinyl, 2-azabicyclo [2.2.1] heptyl, azetidyl, thiazolidinyl, pyrrolyl, pyrrodinyl, pyridinyl and 2-oxopiperazinyl; and R1 is -C (0) OR9 or -C (0) N (R9) R10. A preferred subclass of this class of compounds is that subclass of compounds wherein A is -N =; Z1 and Z2 are each -0-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2; R3 is (1,2) -tetrahydropyrimidinyl (optionally substituted by methyl), (1, 2) -imidazolyl (optionally substituted by methyl), or (1,2) -imidazolinyl (optionally substituted by methyl), - R4 is hydrogen; R5 and R6 are each halo, - each of R9 and R10 is independently hydrogen, alkyl or aralkyl; and R1S is -C (0) OR9 or -C (0) N (R9) R10. Preferred compounds of this subclass are those compounds wherein R 1 is hydrogen, benzyloxy or hydroxy; R3 is l-methylimidazolin-2-yl; and R5 and R6 are both fluoro. Particularly preferred compounds of this subclass are those compounds which are selected from the following: 4-hydroxy-3- [(4- (2-carboxymethyl-3-oxopiperazin-1-yl) -6- (3- (1-methyl) ) imidazolin-2-yl) phenoxy-3,5-dif luoropyr idin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-carboxydihydroisoquinolin-2-yl-6- (3- (1-methyl) imidazole ind 2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine; 4-hydroxy-3- [(4- (7-carboxy-2-azabicyclo [2.2.1] hept-2-yl) -6- (3- (1-methyl) imidazole in 2-yl) phenoxy-3, 5-dif luoropyr idin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-carboxytetrahydroisoquinolin-2-yl) -6- (3- (1-methyl) imidazolin- 2-yl) phenoxy-3,5-dif luoropyr idin-2-yl) oxy] benzamidine; 4-hydroxy-3 - [(4- (3-carboxy ace idin-1-yl) -6- (3 - ( 1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine;4 - . 4-Hydroxy -3- [(4- (4-carboxy-thiazole idin-3-yl) -6- (3- (l-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl ) oxy] benzamidine; 4-Hydroxy -3 - [(4- (2-carboxypyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine; 4-hydroxy-3- [(4- (methoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-ethoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-carboxy-4-hydroxypyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2 -yl) oxy] benzamidine; and 4-hydroxy-3 - [(4- (4-carboxy-5,5-dimethyl-thiazolidin-3-yl) -6- (3- (1-methyl) imidazole ind 2-yl) phenoxy -3,5 -dif luoropyr idin-2-yl) oxy] benzamidine. The most preferred compounds of this subclass are selected from the following: 4-hydroxy-3- [(4- (2-carboxypyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) ) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-methoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine; and 4-hydroxy-3- [(4- (2-ethoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] benzamidine.

Preparation of the Compounds of the Invention As an important topic, the following description of the preparation of the compounds of the invention is directed to the preparation of compounds of formula (I) wherein A is -N =, Z1 and Z2 are both -O-, R2 is- C (NH) NH2 and R7 is -N (R9) - (C (R9) (R10) n -R13 wherein R9 is alkyl or aralkyl, n is 0, and R13 is cyclopentyl substituted by -C (0) OR9. However, it should be understood that a similar synthesis process can be used to prepare other compounds of formulas (I), (II), (III), (IV), (V), (VI) and (VII). it should be understood that the following description, combinations of substituents and / or variables (for example R3 and R4) of the formulas shown are permissible only if such combinations result in chemically stable compounds.

A. Preparation of Compounds of Formulas (la) and (Ib) The compounds of formulas (la) and (Ib) are compounds of the invention, as described above in the brief description of the invention and can be prepared as illustrated below in reaction scheme 1, wherein each X is independently halo, R9 is alkyl or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); and R1, R3, R4, R5 and R6 are as described in the above in the brief description of the invention: REACTION SCHEME 1 0R '(E) 0R (J) The amino acids of formula (B) are commercially available, for example from Aldrich Chemical Co., Sigma Co., or ICN Biomedicals, Inc., or can be prepared in accordance with - methods known to those familiar with the art.

In addition, other amino acids and hydroxy acids of the formula N (H) (R9) - (C (R9) (R10)) n-R13, H0- (C (R9) (R? A)) n-R13 and HN (R14) ) R1S wherein each of R9, R10, R13, R14 and R15 are as defined above in the brief description of the invention, are also commercially available, for example from Aldrich Chemical Co., Maybridge Co., and Jannsen Co. , or can be prepared according to methods known to those familiar in the art, and can be used similarly in the above Reaction Scheme in place of the compound of formula (B) to produce the corresponding compounds of the invention wherein R7 is -N (R9) -C (R9) (R10) n -R13, -0-C (R9) (R10) n -R13 and -N (R14) R: S. The compounds of formulas (A), (D); (F) and (H) are commercially available, for example from Aldrich Chemical Co., or can be prepared according to methods known to those familiar with the art. In general, the compounds of formula (la) and (Ib) are prepared by first treating a compound of formula (A) with a compound of formula (B) in an aprotic solvent, for example, DMSO, in the presence of a base, for example triethylamine from -20 ° C to 50 ° C, preferably at room temperature, for about 20 to 40 hours. Subsequently, the compound of formula (C) is isolated from the reaction mixture by standard or conventional techniques, such as extraction, filtration and solvent removal in vacuo. The resulting compound of formula (C) is then treated with a compound of formula (D) under standard alkylation conditions, for example, in an aprotic solvent, preferably in acetonitrile in the presence of a base, for example, sodium hydride, room temperature for 1 to 24 hours, preferably for about 2 hours. Subsequently, the compound of formula (E) is isolated from the reaction mixture by standard techniques such as extraction, solvent removal in vacuo and flash chromatography.

The resulting compound of formula (E) in an aprotic solvent, for example acetonitrile, is treated with an equimolar amount of a compound of formula (F) in the presence of a base, for example cesium carbonate, at temperatures between about 20 ° C. and 120 ° C, preferably at room temperature, for a sufficient period of time to complete the desired reaction and monitored by thin layer chromatography (CCD). The compound of formula (G) is then isolated from the reaction mixture by standard isolation techniques such as extraction, solvent removal in vacuo and flash chromatography. The compound of formula (G) in an aprotic solvent, for example DMSO, is then treated with an equimolar amount of a compound of formula (H) in the presence of a base, for example, cesium carbonate, at a temperature between about 20 ° C and 120 ° C, preferably at about 35 ° C for a sufficient period of time to complete the desired reaction, for example for about 13 hours. The reaction mixture is cooled to room temperature and the compound of formula (J) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, solvent removal in vacuo and flash chromatography. The compound of formula (J) is dissolved in anhydrous alkanol, preferably ethanol, and then anhydrous mineral acid, preferably HCl, is added to the solution for a period of time sufficient to incorporate the acid into the solution while maintaining the reaction temperatures. at about -78 ° C. After the incorporation is complete, the reaction vessel is sealed and the reaction mixture is allowed to warm to room temperature and stir between 12 and 24 hours, preferably for about 16 hours, at room temperature. The solvent is removed in vacuo and the resulting residue is dissolved in fresh anhydrous alkane, preferably ethanol, and then treated with anhydrous (gaseous) ammonia at temperatures between about room temperature and 100 ° C for about 1 to about 5 hours, preferably for about 2 hours. The compound of formula la, is then isolated from the reaction mixture by standard isolation techniques, for example, solvent removal in vacuo and purification by high performance liquid chromatography (CLAP). Alternatively, instead of treating the above resulting residue with anhydrous ammonia (gaseous), the resulting residue can be treated with a compound of formula NH2OR9 to provide the corresponding compound of formula (la) wherein R2 is -C (NH) N (H) OR9. The compound of formula (la) is then hydrolyzed under acidic conditions, for example, treatment with a strong mineral acid such as HCl, to produce the compound of formula (Ib). In addition, during this step, any of the compounds of formula (la) produced in this manner which may contain an ester such as R1, R3, R5, R5, R9, R10, R12 or R14 and R: 5 (together with the nitrogen atom) substituent is hydrolyzed to compounds containing the corresponding acid substituent. In addition, the compounds of formula (la) can be treated under standard transesterification conditions with an alcohol of the formula R9OH wherein R9 is aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro) , carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl) to produce compounds of the invention wherein R9 is optionally substituted aryl. The compounds of formula (la) wherein R3 is -C (NH) NH2 or -C (NH) N (H) OR9 are produced from the corresponding cyano compounds in a manner similar to that described above for the compound of formula (J). In addition, the compounds of formula (Ia) wherein R x, R 3, R 4, R 5, R 6, R 13 or R 14 and R 15 (together with the nitrogen atom) contain a group -C (O) N (R 9) R 10 or a group -C (0) 0R9 (wherein each of R9 or R10) is independently alkyl, optionally substituted aryl or optionally substituted aralkyl) can be hydrolyzed under acidic conditions to prepare the corresponding compounds of the invention wherein R1, R3, R4, R5, R6, R13 or R14 and R1S (together with the nitrogen atom) contain a -C (0) 0H group.

In addition, compounds of the formula (Ia) wherein R 1, R 3, R 4, Rs, R 6, R 13 or R 14 and R 15 contain a group -C (0) OR 9 wherein R 9 is hydrogen, optionally substituted aryl or optionally substituted aralkyl, they can be amidated under standard amidation conditions to form the corresponding compounds of formula (Ia) wherein R 1, R 3, R 4, R 5, R 6, R 13 or R 14 and R 15 (together with the nitrogen atom) contain a -C (0) group ) N (R5) R10 wherein R9 and R10 are independently hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl. In addition, the compounds of formula (Ia) wherein R 1, R 3, R4, R5, R6 contain a nitro group can be reduced under standard conditions to produce the corresponding compounds of formula (Ia) wherein R1, R3, R4, R5, R6 contain an amino group, which can be treated with the alkylating agents suitable or the acylating agents to provide the corresponding compounds of formula (Ia) wherein R1, R3, R4, R5, R6 contain -N (R9) R10 or -N (R9) C (0) R10 wherein each R9 and Rlc is independently hydrogen, alkyl, optionally substituted aryl or optionally substituted aralkyl. The compounds of formula (la) can be further treated with the appropriate acid halide, preferably acid chloride, or with the appropriate acid anhydride or equivalent, to provide compounds of the invention wherein R2 is -C (NH) N (H) C (0) R9 wherein R9 is hydrogen, optionally substituted alkyl or optionally substituted aralkyl.

Alternatively, the compounds of formula (la) can be further treated with carbamoyl chlorides or their equivalents to provide compounds of the invention wherein R2 is C (NH) N (H) C (0) 0R12 wherein R12 is as described in the above in the brief description of the invention. Alternatively, the compounds of formula (la) can be further treated with compounds of the formula R12-S (0) 2-imidazole (wherein R12 is as described in the brief description of the invention) in a polar solvent such as methylene chloride, at room temperature, to provide the compounds of the invention wherein R12 is -C (NH) N (H) S (0) 2R 12 Alternatively, compounds of formula (la) can be further treated with a phenylcarbamate substituted with N-R9, suitably, in a polar solvent, preferably methylene chloride, at room temperature, for about 6 to 24 hours, preferably for about 12 hours, to provide compounds of the invention wherein R2 is -C (NH) N (H) C (O) N (H) R9. Further, if the compounds of formula (B) are already substituted on the amino radical by substituents R9 as described above, in the brief description of the invention, such compounds do not require the alkylation process of step 2, as described in the above in the Reaction Scheme 1.

In addition, the compounds of formula (B) which contain additional reactive amino or hydroxy groups can be treated with the appropriate oxygen or nitrogen protecting groups before step 1 and then can be deprotected as desired to provide the hydroxy groups or free amino.

***** The following specific preparations and examples are provided as a guide to assist in the practice of the invention, and are not intended to be a limitation on the scope of the invention.

PREPARATION 1 Compounds of formula '(B) A. A solution of 1-amino-1-cyclopentanecarboxylic acid (2.0 g, 16 mmol) in absolute ethanol (30 ml) is cooled to -78 ° C and HCl (g) is bubbled for 10 minutes.

The flask is sealed with a septum and stirred at room temperature.

After 22 hours, the mixture is concentrated in vacuo to give 3.0 g (100% yield) of the hydrochloric acid salt of 1-ethoxycarbonyl-1-aminocyclopentane, as a white solid: NMR (CDCl 3) 9.0 (broad s, 3), 2.4-1.8 (m, 8), 1.4 (t, 3) ppm.

B. In a similar manner, the following esters were prepared: l-ethoxycarbonyl-2-aminocyclopentane; l-ethoxycarbonyl-2-aminocyclohexane; l-ethoxycarbonyl-3-aminocyclohexane; l-ethoxycarbonyl-4-aminociclohexane: 3-ethoxycarbonylmethyl-2-oxopiperazine, -1, l-diethoxycarbonyl-4-aminociclohexane, 1,3-diethoxycarbonyl-4-aminociclohexane, 1-ethoxycarbonyl-l, 2-dihydrocyclobutane, l-ethoxycarbonyl -3-hydroxycyclobutane; l-ethoxycarbonyl-2-hydroxycyclopentane; 1,2-diethoxycarbonyl-4-hydroxycyclopentane, 1-ethoxycarbonyl-2-hydroxycyclohexane; l-ethoxycarbonyl-4-hydroxycyclohexane; 3-ethoxycarbonyldihydroisoquinoline; 3-ethoxycarbonyltetrahydroisoquinoline; 6-ethoxycarbonyl-2-azabicyclo [2.2.1] heptane; 7-ethoxycarbonyl-2-azabicyclo [2.2.1] heptane; 2-ethoxycarbonyl-3-aminonorbornane; 3-ethoxycarbonylazetidine; 4-ethoxycarbonylthiazolidine; 2-ethoxycarbonylpyrroline, -2-ethoxycarbonylpyrrolidine; 2-ethoxycarbonyl-4-hydroxypyrrolidine, 4-ethoxycarbonyl-5,5-dimethylthiazolidine; 1-ethoxycarbonyl-1-aminociclopropane; 2-ethoxycarbonyl-2-aminonaborbornane, -1,3-diethoxycarbonyl-1-aminociclobutane; 4-ethoxycarbonyl-4-aminoquinuclidine; 1-benzyloxycarbonyl -1,2-dihydrocyclohexa-3,5-diene; 1-benzyloxycarbonyl -1-hydroxycyclohexane, -9-methoxycarbonyl-9-hydroxylfluorene; 9-methoxycarbonyl-2-chlorofluorene; 1-methoxycarbonyl-l, 3,4,5-tetrahydrocyclohexane; 1-methoxycarbonyl-1-hydroxycyclopropane; 1-methoxycarbonyl-1-hydroxycycloheptane, -1-methoxycarbonyl-1-hydroxycyclopentane; 1-methoxycarbonyl-1-hydroxycyclobutane, -l-methoxycarbonyl-3-hydroxy-cyclo [3.2.1] octane; l-methoxycarbonyl-3-hydroxycyclo [2.2.1] heptane; l-methoxycarbonyl-4-hydroxy cyclo [2.2.1] heptane; 1-methoxycarbonyl-3-hydroxydamantane; 1,3-dimethoxycarbonyl-2,2-dithylene-4-hydroxy-6-oxocyclohex-5-ene; l-methoxycarbonyl-3-hydroxymethylbicyclic [2.2.2] octane; l-methoxycarbonyl-4-hydroxy-cyclo [2.2.2] octane; and 1-methoxycarbonyl-1-methyl-2-hydroxy-2-ethenylcyclohexyl.

PREPARATION 2 Compounds of formula (C) A. A solution of the hydrochloric acid salt of ethyl 1-amino-1-l-cyclopentanecarboxylate (1.0 g, 5.2 mmol) prepared as above, in acetonitrile (50 ml) was cooled to -15 ° C and added pentafluoropyridine (0.57 ml, 0.87 g, 5.2 mmol) and triethylamine (3.6 ml, 2.6 g, 26 mmol). The resulting mixture was allowed to warm slowly to room temperature and was stirred. After 3 days, the mixture was poured into 100 ml of 50% brine in water and 100 ml of ethyl acetate. The aqueous layer was separated and extracted with another 100 ml of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to provide 1.3 g (82% yield) of 4-IV- (1-ethoxycarbonylcyclopent-1-yl) amino-2,3,5,6-tetrafluoropyridine. , a compound of formula (C), as a crystalline solid: NMR (CDC13) 4.8 (broad s, 1), 4.2 (c, 2), 2.5-1.7 (m, 8), 1.3 (t, 3) ppm.

B. In a similar manner, the following compound of formula (C) was prepared: 4-\ 7- (2-methoxycarbonylpyrrolidin-1-yl) amino-2, 3,5,6-tetrafluoropyridine.

C. In a similar manner, the following compounds of formula (C) were prepared: 4 - . 4-N- (2-ethoxycarbonylcyclopent-1-yl) amino-2,3,5,6-tetrafluoropyridine; 4-N- (2-ethoxycarbonylcyclohex-1-yl) amino-2, 3, 5, 6 -tetrafluoropyridine; 4-N- (3-ethoxycarbonyl-cyclohex-1-yl) amino-2,3,5,6-tetrafluoropyridine; 4-N- (4-ethoxycarbonyl-cyclohex-1-yl) amino-2,3,5,6-tetrafluoropyridine, - A-N- (, -dietoxycarbonyl-cyclohex-1-yl) amino-2, 3,5,6-tetrafluoropyridine; 4-17- (2,4-diethoxycarbonylcyclohex-l-yl) amino-2, 3,5,6-tetrafluoropyridine; 4-N- (1-ethoxycarbonylcycloprop-1 -yl) amino-2, 3,5,6-tetrafluoropyridine; 4-N- (2-ethoxycarbonylnorbornane-2-yl) amino-2, 3, 5, 6-tetrafluoropyridine; -N- (3-ethoxy carbon ilnorbornan-2-yl) amino-2, 3,5,6-tetraf luoropyridine; 4-JV- (1, 3-diethoxycarbonylcyclobut-1-yl) amino-2, 3,5,6-tet raf luoropyridine; 4- (2-ethoxycarbonyl-2-benzyloxybutyl-1-yl) oxy-2, 3,5,6-tetraf luoropyridine; 4- (3-ethoxycarbonylcyclobut-1-yl) oxy-2, 3, 5, 6-tetraf luoropyridine, 4- (2-ethoxycarbonylcyclopent-1-yl) oxy-2, 3, 5, 6-tetraf luoropyridine; 4- (3,4-Diethyloxycarbonyl-cyclo-ent-1-yl) -oxi-2,3,5,6-tetraf-luoropyridine; 4- (2-ethoxycarbonylcyclohex-l-yl) oxy-2,3,6,5-tetraf luoropyridine; 4- (4-ethoxycarbonylcyclohex-1-yl) oxy-2, 3,5,6-tetraf luoropyridine; 4 - (4-ethoxy carbon i 1 c ic lohe'x -1-yl) oxy-2, 3,5,6-tetraf luoropyridine; 4- (2-ethoxycarbonyltetrahydroisoquinolin-3-yl) -2,3,5,6-tetraf luoropyridine; 4- (6-ethoxycarbonyl-2-azabicyclo [2.2.1] hept-2-yl) -2,3,5,6-tetraf luoropyridine, 4- (7-ethoxycarbonyl-2-azabicyclo [2.2.1] hept -2-il) -2.3.5, 6 -tetraf luoropyridine; 4- (3-ethoxycarbonylacetidin-1-yl) -2, 3, 5, 6 -tet raf luoropyridine; 4- (4-ethoxycarbonylthiazolidin-3-yl) -2, 3, 5, 6 -tetraf luoropyridine; 4- (2-ethoxycarbonylpyrrolidin-1-yl) -2,3,5,6-tetraf luoropyridine; 4- (2-ethoxycarbonylpyrrolidin-1-yl) -2,3,5,6-tetraf luoropyridine; 4- (2-ethoxycarbonyl-4-benzyloxypyrrolidin-1-yl) -2,3,5,6-tetraf luoropyridine; 4- (4-ethoxycarbonyl-5,5-dimethylthiazolidin-3-yl) -2,3,5,6-te raf luoropyridine; 4- (3-methoxycarbonyl-2-benzyloxycyclohexa-3,5-dien-l-yl) oxo-2, 3,5,6-tetraf luoropyridine; 4- (1-methoxycarbonylcyclohex-l-yl) oxy-2,3,6,6-tetraf luoropyridine; 4- (l-methoxycarbonyl-l-methyl-2-ethenyl-cyclohex-2-yl) oxy-2,3,5,6-tetraf luoropyridine; 4- (2-methoxycarbonylcyclohex-l-yl) oxy-2,3,6,6-tetraf luoropyridine; 4- (9-methoxycarbonylfluoren-9-yl) oxy-2,3,5,6-tetrafluoropyridine; 4- (9-methoxycarbonyl-2-chlorofluoren-9-yl) oxy-2, 3,5,6-tetrafluoropyridine; 4- (1-methoxycarbonyl-3,4,5-benzyloxycyclohexyl-1-yl) oxy-2,3,5,6-tetraf luoropyridine; 4- (1-methoxycarbonylcycloprop-1-yl) oxy-2, 3, 5, 6-tetraf luoropyridine; 4- (1- metoxicarbonylcyclohept-1-yl) oxy-2, 3,5,6-tetraf luoropyridine; 4- (1-methoxycarbonylcyclopent-1-yl) oxy-2, 3, 5, 6-tetraf luoropyridine; 4- (3-methoxycarbonylbicyclo [3.2.1] oct-l-yl) oxy-2, 3,5,6-tetraf luoropyridine; 4- (4-methoxycarbonylbicyclo [2.2.2] oct-l-yl) oxy -2, 3,5,6-tetraf luoropyr idin; 4- (3-methoxycarbonylbicyclo [2.2.2] oct-l-yl) oxy-2, 3,5,6-tet raf luoropyridine; 4- (1-methoxycarbonyl-2-benzyloxycyclobut-1-yl) oxy-2,3,5,6-tetraf luoropyridine; 4- (3-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-2, 3,5,6-tet raf luoropyr idine; 4- (4-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-2, 3,5,6-tetraf luoropyridine; and 4- (3-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-2, 3,5,6-tetraf luoropyridine.

PREPARATION 3 Compounds of formula (E) A. To a solution of A-N- (1-ethoxycarbonylcyclopent-1-yl) amino-2, 3, 5, β-tetrafluoropyridine (1.3 g, 4.2 mmol) in acetonitrile (40 ml) was added sodium hydride (0.8 g, 20 mmol, 60% dispersion in mineral oil). After gas production ceased, iodomethane (0.32 ml, 0.72 g, 5.1 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then poured into 100 ml of 50% brine / water and 100 ml of ethyl acetate. The aqueous layer was separated and extracted with another 100 ml of ethyl acetate. The combined organic extracts were dried over MgSO, filtered and concentrated in vacuo to give a light orange oil. Purification by flash chromatography on silica gel provided 0.89 g (65% yield) of 4- (N-methyl-N- (1-ethoxycarbonylcyclopent-1-yl) amino) -2,3,5,6-tetrafluoropyridine, a compound of formula (E), as a clear and colorless liquid: NMR (CDC13) 4.2 (c, 2), 3.2 (s, 3), 2.3-1.7 (m, 8), 1.3 (t, 3) ppm.

B. In a similar manner, the following compounds of formula (E) were prepared: 4- (N-methyl-N- (2-ethoxycarbonyl-cyclope-1-yl) amino) -, 3,5,6-tetrafluoropyridine; 4-dV-methyl-IV "- (2-ethoxycarbonylcyclohex-1-yl) amino) -, 3,5,6-tetrafluoropyridine; 4 - (iV-methyl-JV- (3-ethoxycarbonyl iclohex-1-yl) amino ) -, 3,5,6-tetrafluoropyridine, 4- (_V-methyl-_V- (4-ethoxy-carbonyl-hexyhex-1-yl) -amino) -, 3,5,6-tetrafluoropyridine, 4-dV-methyl-IV- ( 4,4-diethoxycarbonylcyclohex-1-yl) amino) -, 3,5,6-tetrafluoropyridine, 4- (JV-methyl-JV- (2,4-diethoxycarbonylcyclohex-1-yl) amino) -, 3,5, 6-tetrafluoropyridine; 4- (N-methyl-N- (1-ethoxycarbonylcycloprop-1-yl) amino) -, 3,5,6-tetrafluoropyridine, 4- (W-methyl-iV- (2-ethoxycarbonylnorbornane-2) - il) amino) -, 3,5,6-tetrafluoropyridine, - 4- (-V-methyl-IV- (3-ethoxycarbonyl-norborphan-2-yl) amino) -, 3,5,6-tetrafluoropyridine; (N-methyl-N- (1, 3-diethoxycarbonylcyclobut-1-yl) amino) -, 3, 5, 6 -tetrafluoropyridine.

PREPARATION 4 Compounds of formula (G) A. To a solution of A - (N-meth i 1 - A - (1-ethoxycarbonylcyclopent-1-yl) amino-2, 3,5,6-tetrafluoropyridine (0.89 g, 2.8 mmol) in acetonitrile (30 ml) was added 2-benzyloxy-5-cyanophenol (0.63 g, 2.8 mmol) and cesium carbonate. (1.2 g, 3.6 mmol). The resulting mixture is stirred at 60 ° C for 1 day. The mixture is then cooled to room temperature and poured into 100 ml of water and 100 ml of ethyl acetate. The aqueous layer is separated and extracted with another 100 ml of ethyl acetate. The organic extracts are washed with a 1 M aqueous KOH solution (100 ml), brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography on silica gel provides 0.87 g (60% yield) of 4-benzyloxy-3- [(4- (N-methyl-N- (1-e-oxycarbonyl-cyclopent-1-yl) amino) -3 , 5,6-trifluoropyridin-2-yl) oxy] benzonitrile, a compound of formula (G), as a colorless and clear oil; NMR (CDC13) 7.6-7.1 (m, 8), 5.2 (s, 2), 4.2 (c, 2), 3.1 (s, 3), 2.3-1.6 (m, 8), 1.3 (t, 3) ppm.

B. In a similar manner, the following compound of formula (G) is made: 4-benzyloxy-3 - [(4-N- (2-methoxycarbonylpyrrolidin-1-yl) amino-3,5,6-trifluoripyrin-2) -yl) oxy] benzonitrile.

C. In a similar manner, the following compounds of formula (G) are prepared: 4 - . 4-benzyloxy-3 - [(4-N- (2-ethoxycarbonylcyclopent-1 -yl) amino-3,5,6,6-trifluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4-N- (2-ethoxycarbonylcyclohex-1-yl) amino-3,5,6,6-trifluoropyridin-2-yl) oxylbenzonitrile; 4-benzyloxy-3- [(4-N- (3-ethoxycarbonylcyclohex-1-yl) amino-3,5,6,6-trifluoropyridin-2-yl) oxybenzonitrile; 4-benzyloxy-3- [(4-N- (4-ethoxycarbonylcyclohex-1-yl) amino-3,5,6,6-trifluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy -3 - [(4-N- (4,4-diethoxycarbonylcyclohex-1-yl) amino-3,5,6-trifluoropyridin-2-yl) oxy] benzonyl ester; 4-benzyloxy-3 - (4-N- (2,4-diethyloxycarbonyl-cyclohex-1-yl) amino-3,5,6-trifluoropyridin-2-yl) oxybenzonitrile: 4-benzyloxy-3 - [(4-N- (1-ethoxycarbonyl-cycloprop-1-yl) amino-3,5,6-trifluoropyridin-2-yl) oxy] benzonitrile: 4-benzyloxy-3 - [(4-N- (2-ethoxycarbonylnorbornan-2-yl) amino- 3, 5, 6-trifluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3 - [(4-N- (3-ethoxycarbonylnorbornan-2-yl) amino-3,5,6,6-trifluoropyridin-2-yl) oxy] benzonitrile; -benzyloxy -3- [(4-N- (1, 3-diethoxycarbonit-cyclobut-l -yl) amino-3,5,6-trifluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (2-ethoxycarbonyl-2-benzyloxycyclobut-1-yl) oxy -3,5,6-trifluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3-. { (4- (3-ethoxycarbonylcyclobut-1-yl) oxy] -3,5,6-trif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3 - [(4- (2-ethoxycarbonylcyclopent-1-yl) oxy] -3,5,6-trif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy -3 - [(4 - (3,4-diethylcarbonylocyclopent-1-yl) oxy] -3,5,6-trif luoropyr idin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (2-ethoxycarbonylcyclohex-1-yl) oxy] -3,5,6-trif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (4-ethoxycarbonyl-cyclohex-1-yl) oxy] -3,5,6-trifluoropyridin-2-yl) oxylbenzonitrile; 4-benzyloxy-3- [(4- (4-ethoxycarbonylcyclohex-1-yl) oxy] -3,5,6-trif luoropyridin-2-yl) oxylbenzonitrile; 4-benzylloxy-3 - [(4- (2-ethoxycarbonyl-1-rahydro-isoquinolin-3-yl) -3,5,6-trif luoropyr idin-2-yl) oxy] benzonitrile; 4-benzyloxy -3 - [(4- (6-ethoxycarbonyl-2-azabicyclo- [2.2.1] hept-2-yl) -3,5,6-trifluoropyridin-2-yl) oxylbenzonitrile; 4-benzyloxy -3- (4- (7-ethoxycarbonyl-2-azabicyclo- [2.2.1] hept-2-yl) -3,5,6-rifluoropyridin-2-yl) oxylbenzonitrile; 4-benzyloxy-3- [14- (3-ethoxycarbonylazetidin-1-yl) -3,5,6-trif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (4-ethoxycarbonyl-thiazolidin-3-yl) -3,5,6-trif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (2-ethoxycarbonyl-pyrrolin-1-yl) -3,5,6-trifluoropyridin-2-yloxy] benzonitrile; 4-benzyloxy-3 - [(4- (2-ethoxycarbonylpyrrolidin- l-il) -3,5,6-trif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (2-ethoxycarbonyl-4-benzyloxy-pyrrolidin-1-yl) -3,5,6-trifluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (4-ethoxycarbonyl-5,5-dimethyl-thiazolidin-3-yl) -3,5,6-trifluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (N-methyl-N- (2-ethoxycarbonyl-cyclopent-1-yl) amino-3,5,6-trifluoropyridin-2-yl) oxy] -benzonitrile; benzyloxy-3- [(4- (N-methyl-N- (2-ethoxycarbonyl-cyclohex-1-yl) amino) -3,5,6-trifluoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy -3- [4- (N-methyl-N- (3-ethoxycarbonyl-cyclohex-1-yl) amino) -3,5,6-trif luoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy -3-1 (4- [N-methyl-N- (4-ethoxycarbonyl-cyclohex-1-yl) amino) -3,5,6-trifluoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy-3- [(4- (N-methyl-N- (4,4-di-ethoxy-carboni-1-cyclohex-1-yl) amino) -3,5,6-trifluoropyridin-2-yl) oxy ] -benzonitrile; 4 - . 4-benzyloxy -3 - [(4- (N-ethyl-N-2,4-di etoxycarboni 1 -cyclohex-1-yl) amino) -3,5,6-trifluoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy-3- [(4- (N-etyl-N- (1-ethoxycarbonyl-cycloprop-1-yl) amino) -3,5,6-trifluoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy-3- [(4- (N-ethyl-N- (2-ethoxycarbonyl-norbornan-2-yl) amino) -3,5,6-trifluoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy-3- [(4- (N-ethyl-N- (3-ethoxycarbonyl-norbornate-2-yl) amino) -3,5,6-trifluoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy -3 -1 (4- [(N-ethyl-N- (1,3-di-ethoxycarbonyl-cyclobut-1-yl) amino) -3,5,6-trifluoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy-3- [(4- (2-methyl-oxocarboni-1-2-benzyloxy-cyclohexa-3,5-dien-l-yl) oxy-6, 3, 5-trifluoropyridin-2-yl) -oxi] benzonitrile; 4-benzyloxy-3-l (4- (1-methoxycarbonylcyclohex-1-yl) oxy-6.3, 5-trifluoropyr idin-2-yl) oxy] benzonitrile: 4-benzyloxy-3 - [(4 - ( 1-methoxycarbonyl-l-methyl-2-ethenyl-cyclohex-2-yl) oxy-6, 3, 5-trif luoropyr idin-2-yl) oxy-benzoniyl; 4-benzyloxy-3- [(4 (2-methoxycarbonylcyclohex-1-yl) oxy-6,3,5-trifluoropyridin-2-yl) oxylbenzonitrile; 4-benzyloxy-3- [(4- (9-methoxycarbonylfluoren-9-yl) oxy-6, 3, 5-trif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3 - [(4- (9-methoxycarbonyl-2-chlorofluoren-9-yl) oxy-6, 3, 5-trif luoropyr idin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (1-methoxycarbonyl-3, 4,5, -tribenzyl-oxycyclohex-1-yl) oxy-6, 3, 5-trif luoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy -3- [(1-methoxy carbonyl cyclopropyl-1-yl) oxy-6.3, 5-trif luoropyridin-2-yl) oxylbenzonitrile; 4-benzyloxy-3 - [(4- (1-methoxycarbonylcyclohept-1-yl) oxy-6, 3, 5-trif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (1-methoxycarbonylcyclopent-1-yl) oxy -6,5,5-trifluoropyridin-2-yl) oxy] benzonitrile; -benzyloxy -3 - [(4 - (3-methoxycarbonylbicyclo [3.2.1] -oct-l-yl) oxy- 6, 3, 5-trif luoropyridin-2-yl) oxylbenzonitrile; 4-benzyloxy -3 - [(4- (4-methoxycarbonylbicyclo [2.2.2] -oct-l-yl) oxy-6, 3, 5-trif luoropyr idin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (3-methoxycarbonylbicyclo- [2.2.2] oct-l-yl) oxy-6, 3, 5-trif luoropyridin-2-yl) oxy] -benzonitrile; 4- benzyl oxy-3 - [(4 - (1-methyl toxic rbonyl-2-benzyloxy-cyclobut-1-yl) oxy- 6, 3, 5-trif luoropyridin-2-yl) oxylbenzonitrile; Benzyloxy-3- [(4- (3-methoxycarbonylbicyclo- [2.2.1] hept-1-yl) oxy-6, 3, 5-trifluoropyridin-2-yl) oxy] -benzonitin, -4-benzyloxy-3 [(4- (4-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-6, 3, 5-trif luoropyridin-2-yl) oxy] -benzonitrile; 4-benzyloxy-3 - [(4- (3-methoxycarbonyl-ladamant-1-yl) oxy-6,3,5-trifluoropyridin-2-yl) oxylbenzonitrile.

PREPARATION 5 Compounds of formula (J) A. To a solution of 4-benzyloxy-3- [(4-methyl-N- (1-ethoxycarbonyl-cyclopent-1-yl) amino] -3,5,6-trifluoro-iridin-2-yl) oxy] benzonitrile (0.87) g, 1.7 mmol) in DMSO (17 ml), 3- (l-methylimidazolin-2-yl) phenol (0.32 g, 1.8 mmol) and cesium carbonate (0.7 g), 2.1 mmol) are added. The resulting mixture is stirred at 35 ° C. After 4 days, the mixture is cooled to room temperature and poured into 100 ml of water and 100 ml of ethyl acetate. The aqueous layer is separated and extracted with another 100 ml of ethyl acetate. The combined organic extracts are washed with a 0.5 M aqueous KOH solution (100 ml), brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to provide 4-benzyloxy-3 - [(4- ( N-methyl-N- (1-ethoxycarbonyl-cyclopent-1-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzonitrile as a solid foam: NMR (CDC13) 7.4-6.8 (m, 12), 5.0 (s, 2), 4.2 (c, 2), 3.9 (t, 2), 3.5 (t, 2), 3.2 (s, 3), 2.8 (s, 3), 2.4-1.7 (m, 8), 1.3 (t, 3) ppm.

B. In a similar manner, the following compound of formula (J) is made: 4-benzyloxy-3- [(4-iV- (2-methoxycarbonylpyrrolidin-1-yl) 6- (3- (1-metridazol-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy ] benzonitrile.

C. In a similar manner, the following compounds of formula (J) are prepared: 4 - . 4 - . 4-benzyloxy-3 - [(4-N- (2-ethoxycarbonylcyclopent-1-yl) amino -6 - (3- (1-methyl-imidazol-2-yl) phenoxy-3,5-difluoro-pyridine- 2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4-N- (2-ethoxycarbonyl-cyclohex-1-yl) amino -6- (3- (1-methyl-imidazolin-2-yl) phenoxy) -3,5-difluoro-pyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [4-N- (3-ethoxycarbonyl-cyclohex-1-l) amino-6 -3- (1-methylimidazolin-2) - il) f enoxy) -3,5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3-l (4-N- (4-ethoxycarbonylcyclohex-l-yl) amino-6- (3- (l-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin-2-yl ) oxy] benzonitrile; 4-benzyloxy -3 - [(N- (4, 4 -dietoxycarbonylcyclohex-1-yl) amino-6- (3- (l-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin-2-yl ) oxy] benzonitrile; 4-benzyloxy -3 - [(4-N- (2, 4 -dietoxycarbonylcyclohex-1-yl) amino-6- (3- (l-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(N- (1-ethoxycarbonylcycloprop-1-yl) amino-6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy ] benzonitrile; 4-benzyloxy -3- (4-N- (2-ethoxycarboni lnorbornyan-2-yl) amino-6- (3- (l-methylimidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3-4-N- [(3-ethoxycarbonylnorbornane-2-yl) amino-6-3- (l-methylimidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2- il) oxy] benzonitrile; 4-benzyloxy -3 - [(4-N- (1,3-diethyloxy carbonyl cyclobu-1-yl) amino-6- (3- (l-methylimidazolih-2-yl) phenoxy-3, 5 -dif luoropyridin -2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (2-ethoxycarbonyl-2-benzyloxy-cyclobut-1-yl) oxy-S- (3 - (1-methylimidazolin-2-ylphenoxy)) - 3, 5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (3-ethoxycarbonylcyclobut-1-yl) oxy-6 - (3 - (1-methylimidazolin-2-yl) ) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (2-ethoxycarbonylcyclopent-yl) oxy-6- (3- (l-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy -3 - [4- (3,4-diethylcarbonylocyclopent-1-yl) oxy-6 - (3- (l-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin-2 -yl) oxy] benzonitrile; 4-benzyloxy-3- (4- (2-ethoxycarbonylcyclohex-1-yl) oxy-6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(1 (4-ethoxycarbonylcyclohex-1-yl) oxy-6-3- (1-methylimidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (4-ethoxycarbonylcyclohex-1-yl) oxy-6- (3-l-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4 -benz i loxi-3 - [(4- (2-e-toxi-carboni-11 and rahydro-isoquinolin-3-yl) -6-3-l-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin -2-yl) oxy] benzonitrile; 4-Benzyloxy-3- [(4- (6-ethoxycarbonyl-2-azabicyclo [2.2.1] hept-2-yl) -6- (3- (1-methylimidazolin-2-yl) -phenoxy) -3 , 5-dif luoropyr idin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (7-ethoxycarbonyl-2-azabicyclo- [2.2.1] hept-2-yl) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-Benzyloxy-3- [4- (3-ethoxycarbonylazetidin-1-yl) - (6 -) 3 - (1-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4 - be nc il ox i - 3 - [4 - (4-ethoxybo rbo ni 1-thiazolidin-3-yl) -6- (3- (l-methylimidazolin-2-yl) phenoxy) -3,5 -dif luoropyr idin-2-yl) oxy] benzonitrile; 4-Benzyloxy-3- [(4- (2-ethoxycarbonylpyrrolin-1-yl) - 6 - (3 - (1-methylimidazolin-2-yl) -3-yl) -3,5-dif luoropyridin-2-yl) ethoxy] benzonitrile; 4-benzyloxy-3- [(4- (2-ethoxycarbonylpyrrolidin-1-yl) -6- (3 - (l -methylimidazolin-2-yl) f-enoxy) -3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (2-ethoxycarbonyl-4-benzyloxy-pyrrolidin-1-yl) -6- (3- (1-methyl-imidazol-2-yl) phenoxy) - 3, 5 -dif luoropyridin-2-yl) oxy] benzonitrile: 4-benzyloxy-3- [(4- (4-ethoxycarboni 1 -5,5-dimethyl-thiazolidin-3-yl) -6- (3- ( l-Methylimidazoin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (N-methyl-N- (2, -ethoxycarbonyl-cyclopent-1-yl) amino- 6 - (3 - (l-methyl-imidazol-2-yl) phenoxy] 3, 5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- (4- (N-methyl-N- (2-ethoxycarbonyl-cyclohex-1-yl) amino-6- (3- ( l-methylimidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzonitrile; 4- benzyl oxy-3- [(4- (N-methyl-N- (3-ethoxycarbonyl-cyclohex-l-yl) amino-6- (3- (l-methylimidazolin-2-yl) f enoxy-3, 5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3 - [(4- (N-methyl-N- (4-ethoxycarbonyl-cyclohex-1-yl) ami or -6- (3- ( l-methylimidazolin-2-ylphenoxy) -3,5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3 - [(4- (N-methyl-N- (4,4-di ethoxycarboni 1 - cic lohex-1-yl) amino) -6- (3- (l-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [4 - (N-Ethyl-N- (2,4-diethoxycarbonyl-cyclohex-1-yl) amino) -6- (3- (1-methylimidazolin-yl) phenoxy) -3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (N-ethyl-N- (1-ethoxycarbonyl-cycloprop-1-yl) amino-6 - (3 - (1-methyl imidazolin-2-yl) f] enoxy-3, 5-dif luoropyr idin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (N-ethyl-N- (2-ethoxycarbonyl-norbornan-2-yl) amino) -6 - (3 - (l-Methylimidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzonitri the; 4-benzyloxy-3- ((N-ethyl-N- (3-ethoxycarbonyl-norbornyan-2-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyr idin-2-yl) oxy] benzoni rilo; 4-benzyloxy -3 - [4- (N-ethyl-N- (1,3-diethoxycarbonyl-cyclobut-1-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3 , 5-difluoropyridin-2-yl) oxy] benzonitrile; 4 - . 4-benzyloxy-3 - [(4- (2-methoxycarbonyl-2-benzyloxy-cyclohexa-3, 5-dien-l-yl) oxy -6 -3- (1-methyl) -imidazole in 2-yl) -fer.oxi-3, 5-dif luoropyr idin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (1-methoxycarbonylcyclohex-1-yl) oxy-6 - (3 - (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy -3 - [(4 - (1-methoxycarbonyl-l-methyl-2-ethenylcyclohex-2-yl) oxy- 6- (3- (1-methyl) imidazolin-2-yl) f enoxi-3 , 5-difluoropyridin-2-yl) oxy] benzonitrile: 4-benzyloxy-3- [(4- (2-ethoxycarbonylcyclohex-1-yl) oxy-6- (3 - (1-methyl) imidazolin-2-yl) ) phenoxy-3,5-dif luoropyr idin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (9-methoxycarbonylfluoren-9-i 1) oxy-6- (3- (l-methylimidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy -3 - [(4 - (9-methoxycarbonyl-2-chlorofluoren-9-yl) -oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoro-pyridin-2-yl) oxy] benzonitrile: 4-benzyloxy-3- [4- (1-methoxycarbonyl-3, 4,5, -tribenzyl-oxycyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) -phenoxy-3, 5-difluoropyr idin-2-yl) oxylbenzonitrile; 4-benzyloxy-3- [(4- (1-methoxycarbonylcycloprop-1-yl) -oxy-6 - (3 - (1-methyl) imide zol in-2-yl) fe nox i-3, 5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (1-methoxycarbonylcyclohept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 difluoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (1-methyl) rbonylcyclopent-1-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2- il) oxy] benzonitrile; 4-benzyloxy-3- [(4- (3-methoxycarbonylbicyclo- [3.2.1] oct-l-yl) oxy] -6- (3- (1-methyl) imidazole in 2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (4-methoxycarbonylbicyclo- [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazole in 2-yl) phenoxy -3,5 -dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy -3 - [(4 - (3-methoxycarbonylbicyclo- [2.2.2] -oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3 - [(4- (1-methoxycarbonyl-2-benzyloxy-cyclobut-1-yl) oxy- 6- (3-methyl) imidaz? Lin-2-yl) phenoxy-3, 5-dif luoropyridin -2-yl) oxy] benzonitrile; 4-benzyloxy -3 - [(4- (3-methoxycarbonylbicyclo- [2.2.1-hepty-1-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 - dif luoropyridin-2-yl) oxy] benzonitrile; 4-benzyloxy-3- [(4- (4-methoxycarbonylbicyclo- [2.2.1] hept-1-yl) oxy -6- (3- (1-methyl) imidazo lin-2-yl) phenoxy -3,5 -dif luoropyridin-2-yl) oxy] benzonitrile; and 4-benzyloxy-3- [(4- (3-methoxycarbonydamantyl-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 difluoropyridin-2-yl) oxylbenzonitrile .

EXAMPLE 1 Compounds of formula (la) A. A solution of 4-benzyloxy-3- [(4- (N-methyl- (1-ethoxycarbonylcyclopent-1-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3 , 5-difluoropyridin-2-yl) oxy] benzonitrile (1.1 g, 1.6 mmol) in absolute ethanol (30 ml) is cooled to -78 ° C and HCl (g) is bubbled through the mixture for 15 min. The resulting mixture is stirred in a sealed vessel at room temperature for 22 hours, and then all the volatile fractions are concentrated in vacuo without heating to provide a solid white foam. This foam is dissolved in absolute ethanol (40 ml) and heated to reflux as NH3 (g) is gently bubbled through the mixture.After 3 hours, the mixture is cooled to room temperature and concentrated in vacuo. Purification by CLAP on a C18 Dynamax column with 20-80% acetonitrile in a gradient of water with 0.1% trifluoroacetic acid provides the trifluoroacetic acid salt of 4-hydroxy-3- [(4- (N-methyl- N- (1-ethoxycarbonyl-cyclopent-1-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzamidine, as a solid white: NMR (DMSO-d6 / TFA) 10.2 (broad s, 1), 9.0 (broad s, 2), 8.8 (broad s, 2), 7.3-7.6 (m, 6), 7.0 (d, 2), 3.9-4.2 (m, 6), 3.2 (s, 3), 3.0 (s, 3), 2.9 (s, 3), 2.1 (m, 4), 1.6-1.8 (m, 4), 1.2 (t, 3) ppm.

B. In a similar manner, the following compounds of formula (I) are prepared: Trifluoroacetic acid salt of 4-hydroxy-3- [(4- (2-ethoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2 -yl) oxy] benzamidine; NMR (DMSO-d) 10.2 (broad s, 1), 9.0 (broad s, 2), 8.8 (broad s, 2), 7.3-7.6 (m, 6), 7.0 (d, 2), 4.8 (m, 1), 3.8-4.2 (m, 8), 3.0 (s, 3), (s, 3) 2.3 (m, 1), 1.9 (m, 3), 1.2 (t, 3) ppm; Trifluoroacetic acid salt of 4-hydroxy-3- [(4- (2-methoxycarbonylpyrrolidin-1-yl) -6- (3 - "(1-methylimidazolin-2-yl) phenoxy) -3,5-dif luoropyridin -2-yl) oxy] benzamidine; NMR (DMSO-d6) 10.2 (broad s, 1), 9.0 (broad s, 2), 8.8 (broad s, 2), 7.3-7.6 (m, 6), 7.0 ( d, 2), 4.8 (m, 1), 3.8-4.2 (m, 6), 3.6 (s, 3), 2.9 (s, 3), 2.3 (m, 1), 1.9 (m, 3), ppm .

C. In a similar manner, the following compounds of formula (I) are made: 4-hydroxy-3- [(4- (N-methyl-N- (1-ethoxycarbonyl-cyclopent-2-yl) amino) -6- ( 3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4-N- (1-methoxycarbonylcyclopent-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (1,3-dimethoxycarbonylcyclopent-1-yl) amino) -6- (3- (1-methyl) imidazole ind 2-yl) phenoxy-3,5- difluoro-pyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (1-methoxycarbonylcyclopropyl-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin- 2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (l-methoxycarbonylcyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin- 2-yl) oxy] benzamidine; 4-Hydroxy -3- (4- (N- (1-methoxycarbonyl-cyclohex-2-yl) amino -6- (3-l-methyl) imidazolin-2-yl) -f-enoxy-3, 5-dif luo-pyridin-2- il) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (l-methoxycarbonyl-cyclohex-3-yl) -amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin -2-yl) oxy] benzamidine; 4-hydroxy-3- [(4-N- (1-methoxycarbonylcyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2 -yl) oxy] benzamidine; 4 - . 4-hydroxy-3- [(4- (Nl, 3-dicarboxycyclohex-4-ii) -ami) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridine -2-yl) oxy] benzamidine; hydroxy -3 - [(4- (N- (1,1-diethyloxycarbonylcyclohex-4-yl) amino) -6-3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (2-ethoxycarbonylnorbornan-3-yl) lamino-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4 (N- (l-ethoxycarbonylbicyclo- [2.2.2] oct-2-yl) amino- 6- (3- (1-methyl) imidazolin- 2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (l-ethoxycarbonyl-cyclopent-2-yl) amino-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5- dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy -3 - [(4- (N-methyl-N- (1,3-diethoxysarbonyl-cyclopent-1-yl) amino) -6- (3- ( 1-methyl] imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4-N-methyl-N- (1-ethoxycarbonylcyclopropyl-1- il) amino-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- (4- (N-methyl) -N- (l-ethoxycarbonylcyclohex-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; -hydroxy-3- [(4- (N-methyl-N- (l-ethoxycarbonyl-cyclohex-3-yl) amino) -6- (3- (l-methylimidazolin-2-yl) phenoxy-3, 5-dif luoropyridin -2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-ethoxycarbonyl-cyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin- 2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1, 3 -dietoxycarbonyl-cyclohex-4-yl) amino) -6- (3-yl-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy -3 - [(4- (N-methyl-N- (1, 1-diethoxycarbonyl-cyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy -3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (2-ethoxycarbonyl-norbornan-3-yl) amino) -6- (3- (1-methyl) imidazole-2-yl) phenoxy - 3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [. (4- (N-methyl-N- (1-ethoxycarbonylbicyclo- [2.2.2] oct-2-yl) amino) -6- (3- (1-methyl) imidazole 2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-cyclopent-2-yl) oxy-6- (3- (1-methyl) imide-zolin-2-yl) -phenoxy-3,5-difluoro-pyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonyl-cyclohex-2-y1) -oxy-6 -3- (1-methyl) imidazole-2-yl) phenoxy-3, 5-dif luoropyr idin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-cyclohex-4-yl) -oxy-6- (3- (1-methyl) imidazole-2-yl) phenoxy-3,5-dif luoropyridin- 2 - il) oxy] benzamidine; 4-hydroxy-3 - [(4 - (1, 2-dimethoxycarbonyl-cyclopen-3-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridine -2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonyl-cyclobut-3-yl) oxy- 6- (3- (1-methyl) imidazo-lin-2-yl) -phenoxy-3,5-difluoro-pyridin-2- il) oxy] benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-l-hydroxycyclobut-3-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin -2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-methoxycarbonylnorbonan-3-yl) oxy-6- (3-l-methylimidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-ethoxycarbonylmethyl-3-oxopiperazin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-ethoxycarbonyldihydroisoquinolin-2-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridin-2-yl) oxy] enzymidine; 4-Hydroxy -3 - [(4- (7-ethoxycarbonyl-2-azabicyclo- [2.2.1] hept-2-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-difluoropyridin-2-yl) oxy] benzamidine; 4 - . 4 - . 4-hydroxy -3 - [(4 - (3-ethoxy carbonyl tet) rahydroiso-quinolin-2-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin- 2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-ethoxycarbonylazetidin-1-yl) -6- (3- (1-methyl) imidazole ind 2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (4-ethoxycarbonyl-thiazolidin-3-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy ] benzamidine: 4-hydroxy-3- [(4- (2-ethoxycarbonylpyrrolidin-1-yl-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl ) oxy] benzamidine; 4-hydroxy-3- [(4- (2-methoxycarbonylpyrrole idin-1 -yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-ethoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazole) 2-yl) phenoxy- 3, 5-difluoropyridin-2-yl) oxy] benzamidine: 4-hydroxy-3- [(4- (2-ethoxycarbonyl-4-hydroxy-pyrrolidin-1-yl) -6- (3 (1-methyl)] imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (4-ethoxycarbonyl-5,5-dimethyl-thiazolidin-3-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-Hydroxy -3-14- (2-methoxycarbonyl-2-hydroxycyclohex-3,5-di in -1-yl) oxy-6- (3- (1-methyl) -imidazole ind 2-yl) phenoxy - 3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonylcyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridin-2-yl ) oxy] benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-l-methyl-2-et eni l-cyclohex-2-yl) oxy- 6- (3- (1-methyl) imidazole in-2-yl) phenoxy -3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3 - [(4- (2-methoxycarbonylcyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridin-2-yl ) oxy] benzamidine, • 4-hydroxy -3 - [(4 - (9-methoxycarbonyl fluoren-9-yl) oxy-6- (3- (1-methyl) imidazole) 2- (2-yl) phenoxy -3,5 -dif luoro iridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (-methoxycarbonyl-2-chlorofluoren-9-yl) oxy-6-3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonyl-3, 4, 5, -trihydroxycyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonylcycloprop-1-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonylcyclohept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridin-2-yl ) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonylcyclopent-1-yl) oxy-6 - (3 - (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridin-2- il) oxy] benzamidine; 4-Hydroxy -3- [(4- (3-methoxycarbonylbicyclo [3.2.1] oct-l-yl) oxy-6- (3- (1-methyl) imide zolin-2-yl) phenoxy-3, 5- difluoro-pyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [4- (4-methoxycarbonylbicyclo [2.2.2] oct-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro- pyridin-2-yl) oxy] benzamidine; 4-Hydroxy-3- [(4- (3-methoxycarbonylbicyclo- [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy- 3, 5 - dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonyl-2-hydroxycyclobut-1-yl) oxy-6- (3 - (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin- 2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (4-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; and 4-hydroxy-3 - [(4 - (3-methoxycarboni ladamant-1-i 1) -oxy-6 - (3 - (1-methyl) imidazole ind 2-yl) phenoxy-3,5-dif luoropyridin - 2-yl) oxy] -benzamidine.

EXAMPLE 2 Compounds of formula (Ib) A. A solution of trifluoroacetic acid salt of 4-hydroxy-3- [(4- (N-methyl-N- (1-ethoxycarbonyl-cyclopent-1-yl) amino) -6- (3 - (1-methylimidazolin-2) -yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzamidine, (0.80 g, 1.2 mmol) in 25 ml of 6 N aqueous HCl is stirred at 60 ° C for 1 hour. It is then cooled to room temperature, diluted with acetonitrile and trifluoroacetic acid and purified by CLAP on a Dynamax C18 column with 20-80% acetonitrile in a water gradient, with 0.1% trifluoroacetic acid to provide the acid salt. trifluoroacetic acid 4-hydroxy-3 - [(4 - (N- me tyl-N- (1 -carboxycyclopent-1-yl) amino) -6- (3- (l-methylimidazolin-2-yl) phenoxy) - 3, 5-difluoropyridin-2-yl) oxy] benzamidine, as a white solid: NMR (DMSO-ds) / TFA 10.2 (broad s, 1), 9.0 (s broad, 2), 8.8 's broad, 2) , 7.3-7.6 (m, 6), 7.0 (d, 2), 4.1 (m, 2), 3.9 (, 2 !, 3.2 (s, 3), 3.0 (s, 3), 2.9 (s, 3) , 2.1 (m, 4), 1.6-1.8 (m, 4) ppm.

B. In a similar manner, the following compound of formula (I) was prepared: Trifluoroacetic acid salt of 4-hydroxy-3- [(4- (N- (2-carboxypyrroleidin-1-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3, 5-dif luoropyridin-2-yl) oxy] benzamidine, NMR (DMSO-d?) 10.2 (broad s, 1), 9.0 (broad s, 2), 8.8 (broad s, 2), 7.3-7.6 (m, 6), 7.0 (d, 2), 4.7 (m, 1), 3.8-4.1 (m, 6), 3.0 (s, 3), 2.3 (m, 1), 1.9 (m, 3) ppm.

C. In a similar manner, the following compounds of formula (I) were prepared: 4-hydroxy-3- [(4- (N- (1-carboxycyclopent-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin- 2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (1,3-dlcarboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4 (N- (1-carboxycyclopropyl-1-yl) amino) -6- (3- (1-methyl) imidazole in 2-yl) phenoxy-3, 5-dif luoro- pyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (l-carboxycyclohex-2-yl) amino) -6- (3- (1-methyl) imidazole in 2-yl) phenoxy-3,5-dif luoropyr idin -2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (1-carboxycyclohex-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (l-carboxycyclohex-4-yl) amino- 6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin- 2 - iloxy] -benzamidine; 4-hydroxy-3- [(4- (N- (1,3-dicarboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy 3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3 - [(4- (N- (1, 1-dicarboxycyclohex-4-yl) amino) -6- (3 - (1 - met il) imida zol in-2-yl) f enoxi-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N- (2-carboxynorbornan-3-yl) ) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine: 4-hydroxy-3- [(4- (N- (1-carboxybicyclo [2.2.2] -oct-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxic ic lopent-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy -3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1,3-dicarboxycyclopentyl-1-yl) ) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxycyclopropyl-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 - dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxycyclohex-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (l-carboxycyclohex-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-Hydroxy -3- [(4- (N-methyl-N- (l-carboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] enzamidine; 4-hydroxy -3 - [(4- (N-methyl-N- (1,3-di carboxycyclohexyl-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1, 1 -dicarboxiciclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy 3, 5-difluoro-pyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (2-carboxinorbornan-3-yl) amino-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 - dif luoropyridin-2-yl) oxy] benzamidine: 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxybicyclo- [2.2.2] oct-2-yl) amino) -6- ( 3- (1-methyl) imidazo lin -2-yl) f enoxi -3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (l-carboxycyclopent-2-yl) oxy-6 - (3-thymyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (l-carboxycyclohex-2-yl) oxy -6- (3 - (1-methyl) imid zolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] -benzamidine; -hydroxy-3- [(4 - (l-carboxycyclohex-4-yl) oxy -6 - (3- (1-methyl-yl) imidazolin-2-yl) phenoxy-3,5-difluoro-iridin-2-yl ) oxy] -benzamidine; 4-Hydroxy -3- [(4- (1, 2 -dicarboxiciclopen-3-yl) -oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2- il) oxy] benzamidine; 4-hydroxy-3 - [(4- (l-carboxycyclobut-3-yl) oxy -6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-iridin-2-yl ) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-carboxy-1-hydroxycyclobut-3-yl) oxy-6- (3 - (l-methyl-imidazole-2-yl) phenoxy-3,5-difluoropyridine] -2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-carboxynorbornan-3-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-carboxymethyl-3-oxopiperazin-1-yl) -6- (3- (1-methyl) imidazolin-2 -yl) phenoxy-3,5-difluoro-pyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-carboxydihydroisoquinol in-2-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridin-2- il) oxy] benzamidine; 4-hydroxy-3- [(4- (6-carboxy-2-azabicyclo [2.2.1] hep-2-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-carboxy-tetrahydroisoquinolin-2-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy ] benzamidine; 4-Hydroxy -3 - [(4- (3-carboxiazet idin-1-yl) -6- 3 - (1-methyl) imidazole in- 2-yl) phenoxy-3, 5-dif luoropyr idin -2 -il ) oxy] -benzamidine; 4-Hydroxy -3 - [(4- (4-carboxy thiazole idin -3-yl) -6- (3- (1-ethyl) imidazole ind 2-yl) phenoxy-3,5-dif luoropyridin- 2 - il) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-carboxy-pyrrolidin-1-yl) -6- (3- (1-methyl) imidazole-2-yl) phenoxy-3,5-dif-luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [((2-methoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine : 4-hydroxy-3 - '[(4- (2-ethoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoro-pyridin-2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-carboxy-4-hydroxypyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro-pyridine- 2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (4-carboxy-5,5-dimethylthiazolidin-3-yl) -6- (3- (1-methyl) imidazole-2-yl) phenoxy-3, 5-dif luoro-pyridin-2-yl) oxy] benzamidine; 4-Hydroxy -3- (4 - (2-carboxy-2-hydroxycyclohexa-3,5-dien-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-carboxycyclohex-1-yl) oxy-6- (3-timethyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yloxy] -benzamidine; 4-hydroxy-3- [(4- (l-carboxy-l-methyl-2-ethenyl-cyclohex-2-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -difluoro-pyridin-2-yl) oxy] benzamidine; 4-Hydroxy-3- [((2-carboxycyclohex-1-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] - benzamidine; 4-hydroxy-3- [(4- (9-carboxyfluoren-9-yl) oxy-6- (3- (l-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (9 -carboxy-2-chlorofluoren-9-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin- 2 -yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-carboxy-3,5-trihydroxycyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoro -pyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-carboxycycloprop-1-yl) oxy-β- (3-1-methyl) imidazole ind 2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-Hydroxy -3- [(4- (1-carboxycyclohept-l-yl) oxy- 6- (3- (l -me il) imidazole in 2-yl) phenoxy -3,5-dif luoropyr idin -2 - il) oxy] -benzamidine; 4-Hydroxy-3- [(4- (1-carboxycyclopent-1-yl) oxy- 6- (3- (1-methyl) imidazole ind 2-yl) phenoxy-3, 5-dif luoro iridin- 2- il) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-carboxybicyclo [3.2.1] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoro-pyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (4-carboxybicyclo [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5- dif luoro-pyridin-2-yl) oxy] benzamidine; 4-Hydroxy -3- [(4- (3-carboxybicyclo [2.2.2 [oct-1-yl] oxy -6- (3- (1-methyl) imi zolin-2-yl) phenoxy -3,5 -difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (l-carboxy-2-hydroxycyclobut-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-ylf-enoxy-3, 5-dif luoropyridin-2 - il) oxy] benzamidine; 4-hydroxy-3- [(4- (3-carboxybicyclo [2.2.1] hept-1-yl) oxy -6- (3- (1-methyl) imid-zolin-2-yl) -phenoxy-3, 5- difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (4-carboxybicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridine -2-yl) oxy] benzamidine; and 4-hydroxy-3- [(4- (3-carboxiadamant-1-yl) oxy -6- (3-time-tyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] -benzamidine.

EXAMPLE 3 This example illustrates the preparation of representative pharmaceutical compositions for oral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for example, 4-hydroxy-3- [(-N-methyl-N- (1-ethoxycarbonylcyclopent -l-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzamidine; A. Ingredient% weight / weight Compound of the invention 20.0! Lactose 79.5; Magnesium stearate 0.5% The above ingredients are mixed and supplied in hard shell gelatin capsules containing 100 mg each, one capsule is approximately a total daily dosage.

B. Ingredient. in weight / weight Compound of the invention 20.0% Magnesium stearate 0.9% Starch 8.6% Lactose 69.6% PVP (polyvinylpyrrolidine) 0.9% The above ingredients are combined and granulated, with the exception of magnesium stearate, using water as a granulating liquid. The formulation is then dried, mixed with the magnesium stearate and formed into tablets with the appropriate tabletting machine.

C. Ingredients Compound of the invention 0.1 g Propylene glycol 20.0 g Polyethylene glycol 400 20.0 g Polysorbate 80 1.0 g Water c.s. 100 ml The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient amount of water is then added with stirring, to provide 100 ml of the solution, which is filtered and bottled.

D. Ingredient in weight / weight Compound of the invention 20.0 !, Peanut oil 78.0% Span 60 2.0% The above ingredients are melted, mixed and filled into soft elastic capsules.

Ingredient% weight / weight Compound of the invention 1.0% Methyl or carboxymethylcellulose 2.0% 0.9% saline solution is. 100 ml The compound of the invention is dissolved in the cellulose / saline solution, filtered and bottled for use.

EXAMPLE 4 This example illustrates the preparation of a representative pharmaceutical formulation for parenteral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for example, 4-hydroxy-3 - [(4- (N- (2-ethoxycarbonylpyrrolidin- 1-yl) -amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzamidine: Ingredients Compound of the invention 0.02 g Propylene glycol 20.0 g Polyethylene glycol 400 20.0 g Polysorbate 80 1.0 g 0.9% saline solution. 100 ml The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient amount of 0.9% saline is then added with stirring to provide 100 ml of the IV solution, which is filtered through a membrane filter. 0.2 μ, and packed under sterile conditions.

EXAMPLE 5 This example illustrates the preparation of a representative pharmaceutical composition in the form of a suppository containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for example, 4-hydroxy-3- [(4- (N- (2-ethoxycarbonylpyrrolidine -1-yl) -amino) -6- (3- (3-methylimidazolidin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzamidine: Ingredient in weight / weight Compound of the invention 1.0% Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5% The ingredients are melted together and mixed in a steam bath, and poured into molds containing a total weight of 2.5 g.

EXAMPLE 6 This example illustrates the preparation of a representative pharmaceutical formulation for insufflation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, eg 4-hydroxy-3- [4- (N- (2-methoxycarbonylpyrrolidin-1) -yl) -amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzamidine: in weight / weight Micronized compound of the invention 1.0% micronized lactose 99.0! The ingredients are ground, mixed and packed in an insufflator equipped with a dosing pump.

EXAMPLE 7 This example illustrates the preparation of a representative pharmaceutical formulation in nebulized form containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for example 4-hydroxy-3 - [4 - (- (2-methoxycarbonylpyrrolidin-1-yl ) -amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzamidine; Ingredient in weight / weight Compound of the invention 0.005% Water 89.995% Ethanol 10,000% The compound of the invention is dissolved in ethanol and mixed with water. The formulation is then packed in a nebulizer equipped with a dosing pump.

EXAMPLE 8 This example illustrates the preparation of a representative aerosol formulation containing a compound of the invention, or a pharmaceutically acceptable salt thereof, for example, 4-hydroxy-3- [(4- (N-methyl-N- ( 1-carboxycyclopent-1-yl) amino) -6- (3- (1-methylimidazolin-2-yl) phenoxy) -3,5-difluoropyridin-2-yl) oxy] benzamidine: Ingredient% weight / weight Compound of the invention 0.10% Propellant 11/12 98.90! Oleic acid 1.00% The compound of the invention is dispersed in oleic acid and the propellants. The resulting mixture is then poured into an aerosol container to which a metering valve is placed.

EXAMPLE 9 (In vitro assay for Factor Xa and Thrombin) This assay demonstrates the activity of the compounds of the invention towards factor Xa, thrombin and tissue plasminogen activator. The activities were determined as the initial rate of separation of the peptide p-nitroalinide by the enzyme. The separation product, p-nitroaniline, absorbs at 405 nm with a molar extinction coefficient of 9920 M'W.

Reagents and Solutions: Dimethyl sulfoxide (DMSO) (Analytical Grade Baker) Test Damper: 50 mM Tris HCl, 150 mM NaCl, 2.5 mM CaCl2 and 0.1% polyethylene glycol 6000, pH 7.5.

Enzymes (Enzyme Research Lab.) Concentrated solution of human factor Xa; 0.281 mg / ml in assay buffer, stored at -80 ° C (working solution (2X): 106 ng / ml or 2 nM in assay buffer, prepare before use). 2. Concentrated human thrombin solution: stored at -80 ° C (working solution (2X): 1200 ng / ml or 40 nM in assay buffer, prepare before use). 3. Human tissue plasminogen activator (tPA) (Two chains, Sigma) concentrated solution: 1 mg / ml, stored at -80 ° C (working solution (2X): 1361 ng / ml in assay buffer, prepare before use) .

Chromogenic substrates (Pharmacia Hepar Inc.): ? l Concentrated S2222 solution (FXa assay): 6 mM in deionized H20, store at 4 ° C (working solution) (4X): 656 μM in assay buffer). Concentrated solution S2302 (thrombin assay): 10 mM in deionized H20, stored at 4 ° C (working solution (4X): 1200 μM in assay buffer). 3 Concentrated solution S2288 (tPA assay): 10 mM in deionized H20, stored at 4 ° C (working solution) (4X): 1484 μM in "test" buffer.

Concentrated solution of standard inhibitor compound: 5 mM in DMSO stored at -20 ° C.

Concentrated solutions of test compounds (compounds of the invention): 10 mM in DMSO, stored at -20 ° C.

Test procedure: The assays were performed in 96-well microtiter plates in a total volume of 200 μl. The components of the assay were in a final concentration of 50 mM Tris HCl, 150 mM NaCl, 2.5 mM CaCl2, 0.1% polyethylene glycol 6000, pH 7.5, in the absence or presence of the standard inhibitor or test compounds and the enzyme and substrate , at the following concentrations: (1) Factor Xa 1 nM and S2222 164 μM; (2) 20 nM thrombin and 300 μM S2302; and (3) 10 nM tPA and 372 μM S2288. The concentrations of the standard inhibitor compound in the assay were from 5 μM to 0.021 μM in a 1 to 3 dilution. The concentration of test compounds in the assay typically ranged from 10 μM to 0.041 μM in a 1 to 3 dilution. the power tests of the compounds, the concentrations used in the factor Xa assay were further diluted 100-fold (100 nM to 0.4i hM) or 1000-fold (10 nM to 0.041 nM). All substrate concentrations used are equal to their values of _ under the present test conditions. The tests were carried out at room temperature. The first step in the test was the preparation of the concentrated solutions of the 10 M test compound in DMSO (For the potency test of the compounds, the 10 mM concentrated solutions were further diluted to 0.1 or 0.01 mM for the factor Xa assay), followed by the preparation of the working solutions of the test compounds (4X) by dilutions. Serial solutions of concentrated 10 mM with Biomek 1000 (or Multiprobe 204) in 96 deep well plates, as follows: (a) A 40 μM working solution is prepared by diluting the concentrated solution 10 mM 1 to 250 in 2-stage assay buffer: 1 to 100 and 1 to 2.5. (b) Five other serial dilutions (1: 3) of the 40 μM solution (600 μl for each concentration) are made. A total of six diluted test compound solutions were used in the assay. The standard inhibitor compound (5 mM concentrate) or DMSO (control) were carried through the same dilution steps as described above for the test compounds. The next step in the assay was to deliver 50 μl of working solutions of the test compound (4X) (from 40 μM to 0.164 μM) in duplicate, to microtiter plates with Biomek or MP204. To this is added 100 μl of working enzyme solution (2X) with Biomek or MP204. The resulting solutions are incubated at room temperature for 10 minutes. To the solutions, 50 μl of substrate working solution (4X) is added with Biomek or MP204.

Enzymatic kinetics were measured at 405 nm at 10 second intervals for five minutes in a THERMOmax plate reader at room temperature.

Calculation of Kj. of the compounds of the invention: Enzyme rates were calculated as mOD / min based on the readings of the first two minutes. The IC50 values were determined by fitting the data to the log-logit (linear) equation or to the Morrison equation (non-linear) with an EXCEL worksheet. The Ki values were then obtained by dividing CIfC by 2. Usually, the Ki (factor Xa) values less than 3 nM were calculated from the Morrison equation. The compounds of the invention, when tested in this assay, demonstrated the selective ability to inhibit human factor Xa and human thrombin.

EXAMPLE 10 (In vitro assay for Human Prothrombinase) This test demonstrates the ability of the compounds of the invention to inhibit prothrombinase. Prothrombinase (PTase) catalyzes the activation of prothrombin to provide fragment 1.2 plus thrombin with meizothrombin as the intermediate. This test is an endpoint or titration test. Prothrombinase activity is measured by thrombin activity (one of the reaction products) or by the amount of thrombin formed / time based on a standard thrombin curve (nM versus mOD / min). For the determination of the IC53 (PTase) of the compounds of the invention, the PTase activity is expressed by thrombin activity (mOD / min). materials Enzymes Working solution of human factor Va (Haematologic Technologies Inc., Cat # HCVA-0110): 1.0 mg / ml in 50% glycerol, CaCl2 mM, stored at -20 ° C. Working solution of human factor Xa (Enzyme Res. Lab. Cat # HFXa 1011): 0.281 mg / ml in assay buffer (without BSA), stored at -80 ° C. Human prothrombin working solution (FII) (Enzyme Res. Lab., Cat # HP1002): FU diluted to 4.85 mg / ml in assay buffer (without BSA) stored at -80 ° C.

Phospholipid vesicles (PCPS): PCPS vesicles (80% PC, 20% PS) were prepared by modification of the method reported by Barenholz et al., Biochemistry (1977), Vol. 16, p. 2806-2810. Phosphatidylserine (Avanti Polar Lipids, Inc., Cat # 840032): 10 mg / ml in chloroform, purified from brain, stored at -20 ° C under nitrogen or argon. Phosphatidylcholine (Avanti Polar Lipids, Inc., Cat # 850457): 50 mg / ml in chloroform, palmitoyl-oleoyl 16: 0-18: 1 synthetic, stored at -20 ° C under nitrogen or argon.

Work solution Spectrozyme-TH (American Diagnostica Inc., Cat # 238L, 50 μmol, stored at room temperature): dissolve 50 μmol in 10 ml of deionized H20. BSA (Sigma Chem Co., Cat # A-7888, Fraction V, RIA grade). Test buffer: 50 mM TrisHCl, pH '7.5, l50 mM NaCl, CaCl, 2. 5 mM, 0.1% PEG 6000 (BDH), 0.05% BSA (Sigma, Fr.V, grade RIA).

For testing on a plate, the following working solutions are prepared: 1. Prothrombinase complex: (a) 100 μM PCPS (27.5 μl of PCPS concentrate (4.36 mM) diluted up to 1200 μl final with assay buffer. (B) factor human Va 25 nM: 5.08 μl of Va concentrate (1 mg / ml) diluted to final 1200 μl with assay buffer. (c) human factor Xa 5 pM: dilute factor Xa concentrate (0.281 mg / ml) 1: 1,220,000 with Test buffer Prepare at least 1200 μl.

Equal volumes (1,100 μl) of each component are combined in the order of PCPS, Va and Xa. Allow to stand at room temperature for 5 to 10 minutes and use immediately or store on ice (bring it to room temperature before use).

Human prothrombin FII) 6 μM: dilute 124 μl of FII concentrate (4.85 mg / ml) up to 1400 μl final with assay buffer. 3 20 mM EDTA / assay buffer: 0.8 ml of 0.5 M EDTA (pH 8.5) plus 19.2 ml of assay buffer. 0.2 mM Spectrozyme-TH / EDTA buffer: 0.44 ml of SPTH concentrate (5 mM) plus 10.56 ml of 20 mM EDTA / assay buffer. Test compounds (compounds of the invention): Prepare a working solution (5X) from the 10 mM concentrate (DMSO) and make a series of 1: 3 dilutions. The compounds are tested in 6 concentrations in duplicate.

Test conditions and procedure The prothrombinase reaction is performed in 50 μl final mixture containing PTase (20 μM PCPS, 5 nM hfVa and 1 pM hFXa), human factor II 1.2 μM and variable concentration of test compounds (concentration range of 5 μM to 0.021 μM or less). The reaction was initiated by PTase reaction and incubated for 6 minutes at room temperature. The reaction was stopped by reaction of EDTA / buffer to final 10 mM. Thrombin activity (product) was subsequently measured in the presence of 0.1 mM Spectrozyme-TH as a substrate at 405 nM for 5 minutes (10 second intervals) at room temperature in a THEROmax microplate reader. The reactions were performed in 96-well microtiter plates. In the first stage of the assay, 10 μl of diluted (5X) test compound or buffer was added to the plates in duplicate. 10 μl of prothrombin (hFII) (5X) was then added to each well. Subsequently, 30 μl of PTase was added to each well, and mixed for approximately 30 seconds. The plates were then incubated at room temperature for 6 minutes.

In the next step, 50 μl of 20 mM EDTA (in assay buffer) was added to each well to stop the reaction. The resulting reactions were then mixed for about 10 seconds. Then, 100 μl of 0.2 mM Spectrozyme were added to each well. The thrombin reaction rate was subsequently measured at 405 nm for 5 minutes, at 10 second intervals in a Molecular Devices microplate reader.

Calculations: The thrombin reaction rate was expressed as mOD / min, using OD readings from the five minute reaction. The IC50 values were calculated with the log-logit curve fitting program. The compounds of the invention demonstrated ability to inhibit prothrombinase when tested in this assay.

EXAMPLE 11 (In vivo test) The following test demonstrates the ability of the compounds to act as anticoagulants. Male rats (250-330 g) were anesthetized with sodium pentobarbital (90 mg / kg, i.p.) and prepared for surgery. The left carotid artery was cannulated to measure blood pressure as well as to take blood samples and monitor the coagulation variables (prothrombin time (PT) and activated partial thromboplastin time (aPTT)). The tail vein was cannulated for the purpose of administering the test compounds (i.e., the compounds of the invention and the standards), and the thromboplastin infusion. The abdomen was opened via an incision in the midline, and the abdominal vena cava was isolated by a distance of 2-3 cm distal to the renal vein. All venous branches in this 2-3 cm segment of the abdominal vena cava were ligated. After all the surgery, the animals were allowed to stabilize before beginning the experiment. The test compounds were administered as an intravenous bolus (t = 0). Three minutes later (t = 3) a 5-minute thromboplastin infusion was started. Two minutes into the infusion (t = 5) the abdominal vena cava was ligated at both ends, proximal and distal. The vessel was left in place for 60 minutes, after which it was excised from the animal, opened longitudinally, the clots were carefully removed (if any) and weighed. We performed a statistical analysis of the results using the concordant mixed sign test with ilcoxin. The compounds of the invention, when tested in this assay, demonstrated the ability to inhibit blood coagulation.

Although the present invention has been described with reference to the specific embodiments thereof, it should be understood by those familiar with the art that various changes can be made and equivalents can be substituted without departing from the true spirit and scope of the invention. In addition, many modifications can be made to adapt to a particular situation, material, composition of matter, process, stage or process steps, to the purpose, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (22)

REVIEWS

1. A compound characterized in that it is selected from the group consisting of the following formulas: (i; (n: (V), (VI), where: A is - C (R8) = or -N =; Z1 and Z2 are independently -0-, -N (R9) -, -S-, -S (0) -, - S (0) 2-, or -0CH2-; R1 and R4 are each independently hydrogen, halo, alkyl, nitro, -OR9, -C (0) 0R9, -C (O) N (R9) R10 ', -N (R9) R10, -N (R9) C (0) R9, or -NÍHÍSÍO) ^ 1 R2 is -C (NH) NH 2 '-C (NH) N (H) OR9, -C (NH) N (H) C (0) ) OR12, -C (NH) N (H) C (0) R9, -C (NH) N (H) S (0) 2R12, or -C (NH) N (H) C (O) N (H) R9; R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, -OR9, -C (NH) NH2, -C (NH) N (H) OR9, -C (O) N (R9) R10, -Rxl -C (0) N (R9) Rx °, -CH (0H) C (0) N (R9) R10, -N (R9) RX \ -R1X-N (R9) Rx0, -C (0) 0R9, -Ru-C (0) 0R9, -N (R9) C (0) R9, (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or ( 1, 2) -imidazolinyl (optionally substituted by alkyl); R5 and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, -N (R9) R10, -C (0) 0R9, -C (0) N (R9) Rx0, -C (O) N (R9) CH2C (O) N (R9) RX0, -N (R9) C (0) N (R9) R10, -N (R9) C (0) R10 or -N (R9) S (0) 2R12, R7 is -N (R9) - (C (R9) (R10)) n-R13 (where n is 0 to 4), -0- (C (R9) (R10) n-R13 (where n is 0 to 4), or -N (RX4) RXS; R8 is hydrogen, alkyl or halo, each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro) , carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); is a straight or branched alkylene chain, R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy , alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tri-cyclic carbocyclic ring system containing 3 to 15 carbon atoms which may be partially or completely saturated, or be aromatic, wherein the carbon atoms may optionally be oxidized and wherein the carbocyclic ring system is substituted by - (C (R9) (Rx0) m-R16 (where m is 0 to 4) and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy , hydroxy, -N (R9) R10, -C (0) OR9, or -C (0) N (R9) R10, -0 R13 is a mono- or tricyclic heterocyclic ring system containing from 3 to 15 members in the ring and including carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be saturated partially or completely, or be aromatic, and is substituted by -C (R9) (R10)) m-R15 (in which em is 0 to 4), and optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) 0R9, or -C ( O) N (R9) R10; R14 and R15, together with the nitrogen atom, form a mono-, bi- or tri-cyclic heterocyclic ring system containing from 3 to 15 members in the ring including carbon and 1 to 3 additional heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen or sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be partially or completely saturated or aromatic, and is substituted by -C (R9) (R10)) ra -R16 (wherein m is 0 to -4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy , -N (R9) R10, -C (0) 0R9, or -C (0) N (R9) R10; and R16 is -C (0) 0R9 or -C (0) N (R9) R10; with the proviso that when R7 is -N (R9) - (C (R9) (Ri0) n -R13 (where n is 0), R13 can not be phenyl, naphthyl or piperidinyl substituted by -C (0) 0R9 When R7 is -0- (C (R9) (R10)) n-R13 (where n is O), R13 can not be phenyl, naphthyl, piperidinyl or pyrrolidinyl substituted by, -C (0) 0R9; R7 is -N (R14) R15, R14 and R15, together with the nitrogen atom, can not be piperazinyl or piperidinyl substituted by -C (0) 0R9, -as a single stereoisomer or a mixture thereof, or a salt pharmaceutically acceptable thereof.

2. The compound according to claim 1, characterized in that it is selected from the formula (I): as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2, characterized in that A is -N =; Z1 and Z2 are independently -O-, -S-, or -OCH2 -, - R1 and R4 are each independently hydrogen, halo, alkyl, or -OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (0) 2OR12, or -C (NH) N (H) C (O) R9, R3 is ureido, guanidino, -OR9, - C (NH) NH2, -C (0) N (R9) R10, -N (R9) R10, (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl) ), or (1,2) -imidazolinyl (optionally substituted by alkyl); R5 and R6 are independently hydrogen, halo, alkyl or haloalkyl; R7 is -N (R9) - (C (R9) (R10)) n-R13 (wherein n is 0 to 4); each R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl) or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy) , alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tricyclic carbocyclic ring system containing 3 to 15 carbon atoms which may be partially or fully saturated, or aromatic, wherein the carbon atoms may optionally be oxidized and wherein the carbon carbocyclic ring is substituted by - (C (R9) (R10) ra-R? s (where m is 0 to 4) and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy , hydroxy, -N (R9) R10, -C (0) 0R9, or -C (0) N (R9) R10; or R13 is a mono- or tricyclic heterocyclic ring system containing from 3 to 15 members in the ring and including carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen and atasulfur atoms can be oxidized and wherein the system heterocyclic ring can be partially or completely saturated, or be aromatic, and is substituted by -C (R9) (R10)) m-R16 (wherein m is 0 to 4), and optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9, or -C (O) N (R9) R1 •; and R16 is -C (0) OR9 or -C (O) N (R9) R10.

4. The compound according to claim 3, characterized in that: A is -N =; Z1 and Z2 are each -0-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (O) 2R12 or -C (NH) N (H) C (O) R9; R3 is (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; R5 and R6 are each halo, R7 is -N (R9) - (C (R9) (R10)) n-R13 (where n is 0 to 4), each R9 and R10 is independently hydrogen, alkyl , aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy , aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a carbocyclic ring system mono- bi- or tricyclic containing 3 to 15 carbon atoms which may be partially or fully saturated or aromatic, and wherein the carbon atoms may optionally be oxidized and wherein the system carbocyclic ring is substituted by -C (R9) (R10) m-R16 (where m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) 0R9, O -C (O) N (R9) R1", and R16 is -C (0) R9 or -C (O) N (R9) R10.

5. The compound according to claim 4, characterized in that: A is -N =; Z1 and Z2 are each -0-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2; R3 is (1,2) -tetrahydropyrimidinyl (optionally substituted by methyl), (1, 2) -imidazolyl (optionally substituted by methyl), or (1, 2) -imidazolinyl (optionally substituted by methyl); R4 is hydrogen; R5 and R6 are each halo; R7 is -N (R9) - (C (R9) (R10)) n -R13 (wherein n is 0); each of R9 and R10 is independently hydrogen, alkyl or aralkyl; R13 is a carbocyclic ring system that is selected from the group consisting of cyclopentyl, cyclohexyl, cyclobutyl, norbornene, norbornane, and adamantyl, and wherein the ring system is substituted by -C (C (R9) (R10)) mR: '(wherein m is 0) and optionally substituted by hydroxy, -N (Ra) R1, -C (0) 0R9, or -C (0) N (R9) R10; and Rld is -C (0) OR9 or -C (O) N (R9) R10.

6. The compound according to claim 5, characterized in that: R1 is hydrogen, benzyloxy or hydroxy; R3 is l-methylimidazolin-2-yl; and R5 and R6 are both fluoro.

7. The compound according to claim 6, characterized in that it is selected from the following: 4-hydroxy-3- [(4- (N- (l-carboxycyclopent-2-yl) amino) -6- (3- (1- methyl) imidazole ind 2-yl) phenoxy-3, 5-difluoropyr idin-2-yl) oxy] benzamidine; 4-hydroxy -3 - [(4- (_V- (1,3-dicarboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (1-carboxycyclopropyl-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin- 2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (1-carboxycyclopent-1-yl) amino) -6- (3 - (1-methyl) imidazole in- 2-yl) phenoxy-3, 5-dif luoropyr idin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (l-carboxycyclohex-2-yl) amino) -6- (3- (1-methyl) imidazole ind 2-yl) phenoxy-3,5-dif luoropyridin -2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (l-carboxycyclohex-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridine - 2 -yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (l-carboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin- 2-yl) oxy] -benzamidine; 4-hydroxy -3- [(4- (N- (1, 3-dicarboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy -3- [(4- (N- (1, 1-dicarboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(A- (N- (2-carboxynorbornan-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin- 2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (N- (1-carboxybicyclo [2.2.2] oct-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxycyclopent-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-ethyl-N- (1-ethoxycarboxycyclopent-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (_V-methyl-iV- (1,3-dicarboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-dif luoropyridin-2-yl) oxy] benzamidine, 4-hydroxy-3- [(4- (N-ethyl-N- (1-carboxycyclopropyl-1-yl) amino) -6- (3- ( 1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1-carboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4 -.hydroxy -3- [(4- (IV-methyl-27- (1-ethoxycarboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (_7-methyl-27- (l-carboxycyclohex-2-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3 - [(4- (N-me ti 1-N- (1-carboxycyclohex-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (l-carboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (N-methyl-N- (1,3-dicarboxy-cyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3 , 5-dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (17-methyl-27- (1, 1-dicarboxycyclohex-4-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy- 3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (27-methyl-27- (2-carboxynorbornan-3-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; and 4-hydroxy-3 - [(4 - (2-V-methyl-2V- (1-carboxycyclo [2.2.2] oct-2-yl) amino) -6- (3- (1-methyl) imidazole in 2 -yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzamidine.

8. The compound according to claim 7, characterized in that it is selected from the following: 4-hydroxy-3- [(4-N-methyl-N- (1-carboxycyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] benzamidine; and 4-hydroxy-3- [(1-ethoxycarbonylcyclopent-1-yl) amino) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine.

9. The compound according to claim 3, characterized in that: A is -N =; Z1 and Z2 are each -0-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (0) 2R12 or -C (NH) N (H) C (O) R9; R3 is (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; R5 and R6 are each halo; R7 is -N (R9) - (C (R9) (R10)) n-R13 (wherein n is 0 to 4); each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tricyclic heterocyclic ring system containing from 3 to 15 members in the ring, including carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon atoms , nitrogen and sulfur may optionally be oxidized and wherein the heterocyclic ring system may be partially or fully saturated or aromatic, and is substituted by -C (R9) (R10) m -R16 (where m is 0 to 4) , and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) 0R9, or -C (0) N (R9) R10; and R16 is -C (0) R9 or -C (O) N (R9) R10.

10. The compound according to claim 2, characterized in that: A is -N =; Z1 and Z2 are independently -0-, -S-, or -0CH2 -, - R1 and R4 are each independently hydrogen, halo, alkyl or OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (0) 2R12 or -C (NH) N (H) C (0) R ';', - R3 is ureido, guanidino, - OR9, -C (NH) NH2, -C (O) N (R9) R10, (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or ( 1, 2) -imidazolinyl (optionally substituted by alkyl); Rs and R6 are independently hydrogen, halo, alkyl or haloalkyl; R7 is -0 - (- C (R9) (R10)) n -R13 (wherein n is 0 to 4); each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tri-cyclic carbocyclic ring system containing from 3 to 15 carbon atoms which may be partially or completely saturated or aromatic, wherein the carbon atoms may optionally be oxidized and wherein the The carbocyclic ring system is substituted by -C (R9) (R10) m-R16 (wherein m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9, or -C (0) N (R9) R10; or R16 is a mono- or tricyclic heterocyclic ring system containing from 3 to 15 ring members including carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon atoms , nitrogen and sulfur optionally may be oxidized and wherein the heterocyclic ring system may be partially or completely saturated or aromatic and is substituted by - (C (R9) (R10)) m-R16 (where m is 0 to 4) ), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9 or -C (O) N (R9) R10; and R16 is -C (0) OR9 or -C (0) N (R9) R10.

11. The compound according to claim 10, characterized in that: A is -N =; Z1 and Z2 are each -O-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (O) 2R12 or -C (NH) N (H) C (0) R9; R3 is (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; R5 and R6 are each halo; R7 is -0 (C (R9) (R10)) n-R13 (wherein n is 0 to 4); each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono-, bi- or tricyclic carbocyclic ring system containing from 3 to 15 carbon atoms, which may be partially or fully saturated or aromatic, in which the carbon atoms may optionally be oxidized and wherein the carbocyclic ring system is substituted by -C (R9) (R10) ra -R16 (wherein m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) 0R9, or -C (O) N (R9) R10; and R16 is -C (0) R9 or -C (0) N (R9) R10.

12. The compound according to claim 11, characterized in that: A is -N =; Z1 and Z2 are each -O-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2; R3 is (1, 2) -tetrahydropyrimidinyl (optionally substituted by methyl), (1, 2) -imidazolyl (optionally substituted by methyl), or (1, 2) -imidazolinyl (optionally substituted by methyl); R4 is hydrogen; R5 and R6 are each halo; R7 is -0- (C (R9) (R10)) n-R13 (wherein n is 0); each of R9 and R10 is independently hydrogen, alkyl or aralkyl; R13 is a carbocyclic ring system which is selected from the group consisting of cyclopentyl, cyclohexyl, cyclobutyl, norbornene, norbornane and adamantyl, and wherein the ring system is substituted by -C (R9) (R10)) m-R16 (wherein m is 0), and is optionally substituted by hydroxy, -N (R9) R10, -C (0) 0R9, or -C (0) N (R9) R10; and R16 is -C (0) N (R9) R10.

13. The compound according to claim 12, characterized in that: R1 is hydrogen, benzyloxy or hydroxy; R3 is l-methylimidazolin-2-yl; and Rs and Rs are both fluoro.

14. The compound according to claim 13, characterized in that it is selected from the following: 4-hydroxy-3- [(4- (l-carboxycyclopent-2-yl) oxy -6- (3- (1-methyl) imidazolin- 2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (l-carboxycyclohex-2-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (l-carboxycyclohex-4-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (1-dicarboxycyclopent-3-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (l-carboxycyclobut-3-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] -benzamidine; 4-hydroxy-3- [(4- (1-carboxy-l-hydroxycyclobut -3-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin- 2-yl) oxy] -benzamidine; 4-hydroxy -3- [(4- (2-carboxy-borbornan-3-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif-luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-methoxycarbonyl-2-hydroxynylohexa-3,5-dien-l-yl) oxy-6- (3- (1-methyl) -imidazolin-2-yl) phenoxy - 3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonyl) -cyclohex-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2- il) oxy] -benzamidine; 4 - . 4-Hydroxy -3 - [(4- (1-methyl-rbonyl-1-methyl-2-ethenylcyclohex-2-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy - 3, 5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-methoxycarbonyl-cyclohex-1-yl) oxy-6- (3- (1-methyl) imidazole-2-yl) phenoxy-3, 5-dif luoropyr-idin 2- il) oxy] -benzamidine; 4-hydroxy-3- [(4- (9-methoxycarbonylf-luoren-9-yl) oxy-6- (3- (1-methyl) imidazole-2-yl) phenoxy-3,5-dif-luoropyridin- 2 - il) oxy] -benzamidine; 4-hydroxy-3- [(4- (9-methoxycarbonyl-2-chlorofluoren-9-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin -2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-3,4,5-trihydroxycyclohex-1-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonylcycloprop-1-yl) oxy-6- (3 - (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin-2-yl ) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-methoxycarbonylcyclohept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin-2-yl ) oxy] -benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonylcyclopent-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin-2-yl ) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-methoxycarbonylbicyclo [3.2.1] oct-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (4-methoxycarbonylbicyclo [2.2.2] oct-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (methoxycarbonylbicyclo [2.2.2] oct-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin- 2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (l-methoxycarbonyl-2-hydroxycyclobut-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2 -yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (4-methoxycarbonylbicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-methoxycarbonylantamant-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyr idin-2-yl) ox ¿] -benzamidine; 4-hydroxy-3- [(4- (2-carboxy-2-hydroxycyclohexa-3, 5-dien-1-yl) oxy-6- (3- (1-methyl) imidazole in 2-yl) phenoxy - 3, 5-difluoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-carboxycyclohex-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (l-carboxy-l-methyl-2-ethenyl-cyclohex-2-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (2-carboxycyclohex-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropir idin- 2-il ) oxy] -benzamidine; 4-hydroxy-3- [(4- (9-carboxyfluoren-9-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin-2- il) oxy] -benzamidine; 4-hydroxy-3- [(4- (9-carboxy-2-chlorofluoren-9-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-carboxy-3, 4, 5-trihydrocyclohex-1-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 -dif luoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (1-carboxycycloprop-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) f enoxy-3, 5-dif luoropyridin-2-yl ) oxy] -benzamidine; 4-Hydroxy -3- [(4- (1-carboxycyclohept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1-carboxycyclopent-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-carboxylicicylic [3.2.1]] oct-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5 - dif luoropyridin-2-yl) oxy] -benzamidine; 4-Hydroxy -3- [(4- (4-carboxycyclo [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (3-carboxycyclo [2.2.2] oct-l-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (1 -carboxy-2-hydroxycyclobut-1-yl) oxy-6 - (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyridin- 2-yl) oxy] -benzamidine; 4-Hydroxy -3 - [(4- (3-carboxycyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2-yl) oxy] -benzamidine; 4-hydroxy-3- [(4- (carboxybicyclo [2.2.1] hept-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin - 2-yl) oxy] -benzamidine; and 4-hydroxy-3- [(4- (3-carboxy-adamant-1-yl) oxy-6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin- 2-yl) oxy] -benzamidine.

15. The compound according to claim 2, characterized in that: A is -N =; Z1 and Z2 are independently -O-, -S-, or -OCH2-; R1 and R4 are each independently hydrogen, halo, alkyl or OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (O) 2R12 or -C (NH) N (H) C (O) R9; R3 is ureido, guanidino, -OR9, -C (NH) NH2, -C (O) N (R9) R10, -N (R9) R10, (1, 2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1 , 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R5 and R6 are independently hydrogen, halo, alkyl or haloalkyl; R7 is -N (R14) R15; each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R14 and R15, together with the nitrogen atom, form a mono-, bi- or tri-cyclic heterocyclic ring system containing from 3 to 15 carbon ring members and 1 to 3 additional heteroatoms that are selected from atoms of nitrogen, oxygen and sulfur, wherein the carbon, nitrogen or sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be partially or completely saturated or aromatic, and is substituted by - (C (R9)) R10)) ra-R16 (wherein m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9 or -C (O) N (R9) R10; and R16 is -C (0) 0R9 or -C (0) N (R9) R10.

16. The compound according to claim 15, characterized in that: A is -N =; Z1 and Z2 are each -O-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2, -C (NH) N (H) S (O) 2R12 or -C (NH) N (H) C (O) R9; R3 is (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); R4 is hydrogen; R5 and R6 are each halo; each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl) or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R14 and R15 together with the nitrogen atom, form a ring of heterocyclic system which is selected from the group consisting of dihydrosoqualinyl, tetrahydroisoquinolinyl, 2-azabicyclo [2.2.1] heptyl, azetidenyl, thiazolidinyl, pyrrolyl, pyrrolidinyl and 2-oxopiperazinyl; and R16 is -C (0) OR9 or -C (O) N (R9) R10.

17. The compound according to claim 16, characterized in that: A is -N =; Z1 and Z2 are each -O-; R1 is hydrogen or -OR9; R2 is -C (NH) NH2; R3 is (1, 2) -tetrahydropyrimidinyl (optionally substituted by methyl), (1, 2) -imidazolyl (optionally substituted by methyl), or (1, 2) -imidazolinyl (optionally substituted by methyl); R4 is hydrogen; Rs and R6 are each halo; each of R9 and R10 is independently hydrogen, alkyl or aralkyl; and R16 is -C (0) OR9 or -C (0) N (R9) R10.

18. The compound according to claim 17, characterized in that: R1 is hydrogen, benzyloxy or hydroxy; R3 is l-methylimidazolin-2-yl; and R5 and R6 are both fluoro.

19. The compound according to claim 18, characterized in that it is selected from the following: 4-hydroxy-3- [(4- (2-carboxymethyl-3-oxop iperaz in-l-yl) -6- (3- (1 -methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyr idin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(A- (3-carboxydihydroisoquinolin-2-yl-6- (3 - (1-methyl) imidazolin-2-yl) phenoxy-3,5-dif luoropyr idin -2-yl) oxy ] benzamidine; 4-hydroxy-3- [(4- (6-carboxy-2-azabicyclo [2.2.1] hept-2-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy -3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-carboxy-tetrahydroisoquinolin-2-yl) -6- (3- (1-methyl) imidazolin-2- il) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (3-carboxiacet idin-1-yl) -6- (3 - (1-methyl) ) imidazolin-2-yl) phenoxy -3,5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (4-carboxythiazolidin-3-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-carboxypyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-difluoropyridin-2-yl) oxy ] benzamidine; 4-hydroxy-3- [(A- (methoxycarbonylpyrrolidin-1-yl) -6- (3 - (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin -2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-ethoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr-idin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-carboxy-4-hydroxypyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyridin-2 -yl) oxy] benzamidine; and 4-hydroxy -3- [(4- (4-carboxy-5,5-dimethylthiazolidin-3-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3, 5-dif luoropyr idin-2-yl) oxy] benzamidine.

20. The compound according to claim 19, characterized in that it is selected from the following: 4-hydroxy-3- [(4- (2-carboxypyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2] -yl) phenoxy -3,5-di f luoropyr idin-2-yl) oxy] benzamidine; 4-hydroxy-3- [(4- (2-methoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy] benzamidine; and 4-hydroxy-3- [(4- (2-ethoxycarbonylpyrrolidin-1-yl) -6- (3- (1-methyl) imidazolin-2-yl) phenoxy-3,5-difluoropyridin-2-yl) oxy ] benzamidine.

21. A pharmaceutical composition useful for the treatment of a human having a disease state defined by thrombotic activity, which position is characterized in that it comprises a therapeutically effective amount of a compound that is selected from the group consisting of the following formulas: (I): ID wherein: A is -C (R8) = or -N =; Tr and Z2 are independently -O-, -N (R9) -, -S-, -S (O) -, -S (0) 2-, or -0CH2-; R1 and R4 are each independently hydrogen, halo, alkyl, nitro, -OR9, -C (0) ORs, -C (O) N (R9) R10, -N (R9) R10, -N (R9) C ( 0) R9, or -N (H) S (0) 2R12; R2 is -C (NH) NH 2 / -C (NH) N (H) OR 9, -C (NH) N (H) C (0) 0R 12 -C (NH) N (H) C (0) R9, -C (NH) N (H) S (0) 2R12, or -C (NH) N (H) C (O) N (H) R9; R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, -OR9, -C (NH) NH2, -C (NH) N (H) OR9, -C (O) N (R9) R10, -R11-C (0) N (R9) R10, -CH (OH) C (0) N (R9) R10, -N (R9) R10, -Rxl-N (R9) R10, -C (0) OR9 , -Ru-C (0) OR 9, -N (R 9) C (O) R 9, (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1, 2) -imidazolyl (optionally substituted by alkyl), or (1, 2) -imidazolinyl (optionally substituted by alkyl); Rs and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, -N (R9) R10, -C (0) OR9, -C (O) N (R9) R10, -C (0) N (R9) CH2C (0) N (R9) R10, -N (R9) C (O) N (R9) R10, -N (R9) C (0) R ^ or R7 is -N (R9) - (C (R9) ( R10)) n-R13 (where n is 4), -0- (C (R9) (R10) p-R13 (wherein n is 0 to 4), or -N (R14) R15; R8 is hydrogen, alkyl or hale-each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R11 is a straight or branched alkylene chain; R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy) , amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkyl, ilamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tricyclic carbocyclic ring system containing 3 to 15 carbon atoms which may be partially or fully saturated, or aromatic, wherein the carbon atoms may optionally be oxidized and wherein the carbon carbocyclic ring is substituted by - (C (R9) (R10) m-R16 (where m is 0 to 4) and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy , -N (R9) R10, -C (0) 0R9, or -C (O) N (R9) R10, or R13 is a mono- or tri-cyclic heterocyclic ring system containing from 3 to 15 members in the ring and including carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be partially saturated or completely, or be aromatic, and is substituted by -C (R9) (R10)) m-R16 (where m is 0 to 4), and optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) OR9, or -C ( O) N (R9) R10, - R14 and R15, together with the nitrogen atom, form a mono-, bi- or tri-cyclic heterocyclic ring system containing from 3 to 15 members in the ring including carbon and 1 to 3 additional heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen or sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be partially or fully saturated or aromatic, and is substituted by -C (R9) (R10)) m-R16 (wherein m is 0 to 4), and optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, - N (R9) R10, -C (0) OR9, or -C (O) N (R9) R10; and R16 is -C (0) OR9 or -C (O) N (R9) R10; with the proviso that when R7 is -N (R9) - (C (R9) (R10) n -R13 (where n is 0), R13 can not be phenyl, naphthyl or piperidinyl substituted by -C (0) OR9 when R7 is -O- (C (R9) (R10)) n -R13 (where n is 0), R13 can not be phenyl, naphthyl, piperidinyl or pyrrolidinyl substituted by -C (0) 0R9, - and when R7 is -N (R14) R15, R14 and R15, together with the nitrogen atom, can not be piperazinyl or piperidinyl substituted by -C (0) 0R9, -as a single stereoisomer or a mixture thereof, or a salt pharmaceutically acceptable thereof, and a pharmaceutically acceptable excipient.

22. A method for treating a human having a disease state defined by thrombotic activity, which method is characterized in that it comprises administering to a human in need thereof a therapeutically effective amount of a compound selected from the group consisting of the following formulas: (i: (ID , (V), (VI) wherein: A is -C (R8) = or -N =; Z1 and Z2 are independently -0-, -N (R9) -, -S-, -S (0) -, -S (0) 2-, or -OCH2-; R1 and R4 are each independently hydrogen, halo, alkyl, nitro, -OR9, -C (0) 0R9, -C (O) N (R9) R10, -N (R9) R10, -N (R9) C (0) R9, or -N (H) S (0) 2R12; R 'is -C (NH) NH 2' -C (NH) N (H) 0R9 -C (NH) N (H) C (0) 0R12, -C (NH) N (H) C (0) R9, -C (NH) N (H) S (0) 2R12, or -C (NH) N (H) C (O) N (H) R9; R3 is hydrogen, halo, alkyl, haloalkyl, nitro, ureido, guanidino, -OR9, -C (NH) NH2, -C (NH) N (H) OR9, -C (O) N (R9) R10, -R11 -C (0) N (R9) R10, -CH (0H) C (0) N (R9) R10, -N (R9) R10, -Rlx-N (R9) R10, -C (0) 0R9, - Ru-C (0) OR 5, -N (R 9) C (O) R 9, (1,2) -tetrahydropyrimidinyl (optionally substituted by alkyl), (1,2) -imidazolyl (optionally substituted by alkyl), or (1) , 2) -imidazolinyl (optionally substituted by alkyl); R5 and R6 are independently hydrogen, halo, alkyl, haloalkyl, nitro, -N (R9) R10, -C (0) 0R9, -C (O) N (R9) R10, -C (0) N (R9) CH2C (0) N (R9) R10, -N (R9) C (O) N (R9) R10, -N (R9) C (0) R10 or -N (R9) S (0) 2R12, R7 is -N (R9) - (C (R9) (R10)) n-R13 (where n is 0 to 4), -0- (C (R9) (R10) n-R13 (where n is 0 to 4), or -N (R14) R15; R8 is hydrogen, alkyl or halo, each of R9 and R10 is independently hydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro) , carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); is a straight or branched alkylene chain, R12 is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, nitro, carboxy, alkoxycarbonyl, aminocarbonyl, monyalkylaminocarbonyl or dialkylaminocarbonyl), or aralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino, monoalkylamino, nitro, carboxy , alkoxycarbonyl ', aminocarbonyl, monoalkylaminocarbonyl or dialkylaminocarbonyl); R13 is a mono- or tricyclic carbocyclic ring system containing 3 to 15 carbon atoms which may be partially or fully saturated, or aromatic, wherein the carbon atoms may optionally be oxidized and wherein the carbon carbocyclic ring is substituted by - (C (R9) (R10) m-R16 (where m is 0 to 4) and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy , -N (R9) R10, -C (0) OR9, or -C (O) N (R9) R10, or R13 is a mono- or tricyclic heterocyclic ring system containing from 3 to 15 members in the ring and including carbon and 1 to 4 heteroatoms which are selected from nitrogen, oxygen and sulfur atoms, wherein the carbon, nitrogen and sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be partially or completely saturated , or be aromatic, and is substituted by -C (R9) (R10)) ra-R16 (in m is 0 to 4), and is optionally substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C (0) 0R9, or -C (0) N (R9) R10; R14 and R15, together with the nitrogen atom, form a mono-, bi- or tri-cyclic heterocyclic ring system containing from 3 to 15 members in the ring including carbon and 1 to 3 additional heteroatoms which are selected from atoms of nitrogen, oxygen and sulfur, wherein the carbon, nitrogen or sulfur atoms may optionally be oxidized and wherein the heterocyclic ring system may be partially or completely saturated or aromatic, and is substituted by -C (R9) (Rxo) )) m-R16 (wherein m is 0 to 4), and optionally is substituted by alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, -N (R9) R10, -C ( 0) 0R9, or -C (0) N (R9) R10; and R16 is -C (0) 0R9 or -C (0) N (R9) R10; with the proviso that when R7 is -N (R9) - (C (R9) (R10) n -R13 (where n is 0), R13 can not be phenyl, naphthyl or piperidinyl substituted by -C (0) 0R9 when R7 is -0- (C (R9) (R10)) n -R13 (where n is 0), R13 can not be phenyl, naphthyl, piperidinyl or pyrrolidinyl substituted by -C (0) 0R9; is -N (R14) R15, R14 and R15, together with the nitrogen atom, can not be piperazinyl or piperidinyl substituted by -C (0) 0R9, as a single stereoisomer or a mixture thereof, or a pharmaceutically acceptable salt of the same.