ZA200200560B

ZA200200560B - Benzenamine derivatives as anti-coagulants.

Info

Publication number: ZA200200560B
Application number: ZA200200560A
Authority: ZA
Inventors: William J Guilford; Steven T Sakata; Kenneth J Shaw; Shung Wu; Wei Xu; Zuchun Zhao
Original assignee: Berlex Lab
Priority date: 1999-07-30
Filing date: 2002-01-22
Publication date: 2003-04-22
Also published as: BG106363A

Description

BENZENAMINE DERIVATIVES AS ANTI-COAGULANTS

This application claims the benefit of U.S. Provisional Application No. 60/146,572, filed July 30, 1999, which is incorporated herein in full by reference. .

Field of the invention

The present invention is directed to benzenamine derivatives and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, thereby being useful as anti-coagulants. It also reiates to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods of their use.

BACKGROUND OF THE INVENTION

Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin which polymerizes to form insoluble fibrin. in the coagulation cascade, the prothrombinase complex is the convergent point of the intrinsic (surface activated) and extrinsic (vessel injury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in Hernatology (1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serine protease inhibitor with three Kunitz-type domains which competes with factor Va for free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of the factor Via and tissue factor complex.

Factor Xa can be activated by two distinct complexes, by tissue factor-Vlla complex on the "Xa burst" pathway and by the factor IXa-Vllla complex (TENase) of the "sustained

Xa" pathway in the coagulation cascade. After vessel injury, the "Xa burst” pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the "sustained Xa" pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFP! complex, which not only removes factor Xa but also inhibits further factor formation via the "Xa burst" pathway.

Therefore, the coagulation cascade is naturally regulated by factor Xa. ; The primary advantage of inhibiting factor Xa over thrombin in order to prevent 1 coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor Vil to VIIA, factor V to Va, and factor XI to Xla, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inactivator of factors Va and Villa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin li (ATI) and heparin cofactor ! (HCI) in a reaction which is catalyzed by heparin or other proteoglycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin.

Thrombin carries out its multiple cellular activation functions through a unique "tethered ligand" thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin : binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.

Published data with the proteins antistasin and tick anti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors are efficacious anti-coagulants (Thrombosis 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 either a mechanism-based or a tight binding inhibitor (a tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor link (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 tight-binding inhibitors ( Thrombosis Res. (1980),

Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidine-carboxylic acid derivatives have also been shown to be tight-binding inhibitors of thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compounds demonstrate poor selectivity for factor Xa.

Related Disclosures J

European Published Patent Application 0 540 051 (Nagahara et al.) describes aromatic amidine derivatives. These derivatives are stated to be capable of showing a strong anticoagulant effect through reversible inhibition of factor Xa.

The synthesis of a,a-bis(amidinobenzylidene)cycloalkanones and a,a'-bis(amidinobenzyl)cycloalkanones is described in Pharmazie (1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.

U.S. Patent No. 5,451,700 (Morrissey et al.) describes amidino compounds. These compounds are stated to be useful as selective LTB, receptor antagonists.

U.S. Patent No. 5,612,363 (Mohan et al.) describes N,N-di(aryl) cyclic urea derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants. :

U.S. Patent No. 5,633,381 (Dallas et al.) describes (2,2), (Z,E) and (E,Z) isomers of substituted bis(phenyimethylene)cycloketones. These compounds are disclosed as being . factor Xa inhibitors, thereby being useful as anticoagulants.

PCT Published Patent Application WO/96/28427 (Buckman et al.) describes benzamidine derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.

PCT Published Patent Application WO/97/21437 (Arnaiz et al.) describes naphthyl- substituted benzimidazole derivatives. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.

PCT Published Patent Application WO/97/29067 (Kochanny et al.) describes benzamidine derivatives that are substituted by amino acid and hydroxy acid derivatives.

These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.

U.S. Patent No. 5,869,501 (Hirayama et al.) describes amidinonaphthyl derivatives and their use as factor Xa inhibitors.

The above references, published patent applications and U.S. patents are herein incorporated in full by reference.

SUMMARY OF THE INVENTION

] This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa and are therefore useful as pharmacological agents for the ‘ treatment of disease-states characterized by thrombotic activity. ) 5 Accordingly, in one aspect, this invention provides compounds of formula (1): 6

Ege Na

PRA JR Tr —R 0] (CH), A R’ A wherein:

Ais -O- or -N(R')-;

Wis -N(R*)-, -S- or -O-; } 10 each mis independently 0, 1, 2, 3 or 4; nisQorft;

R' is hydrogen, alkyl, alkylcarbonyl, phenylalylidenyl (wherein the phenyl group is ’ optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, : -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R®, -C(NH)N(H)S(O),R?, or -C(NH)N(H)C(O)N(H)R’), alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkoxycarbonyl, phenylcarbonyl (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R?®, -C(NH)N(H)S(0),R®, or -C(NH)N(H)C(O)N(H)R’), mono[dialkoxycarbonylJalkylaminocarbonyl, monol[dicarboxy]alkylaminocarbonyl; alkylsulfonyl, arylsulfonyl or dialkylaminosulfonyit;

R%is [C(R")y]m -[C(R"),1n-C(O)-N(R®)-, or {C(R")2}-[C(R®)]=CH-; or R%is 7\ (8 x 1CR)R ~ 7

R? is -C(NH)NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR®, -C(NH)N(H)C(O)R®, -C(NH)N(H)S(O),R?®, or -C(NH)N(H)C(O)N(H)R”; )

R* is hydrogen, alkyl, alkylcarbonyl, aminocarbonyl, monoalkylaminocarbonyt, ’ dialkylaminocarbonyl, aminosulfonyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, or -C(NH)CH,. ) each R® is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbony!;

R® is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the ary! group is optionally substituted by alkyl, halo or alkoxy); each R7 and R? is independently hydrogen, alkyl, aryl, or aralkyl; and each Ris alkyl or aralkyl; as a single stereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

In another aspect, this invention provides a method of treating a human having a . disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (1) as : described above.

In another aspect, this invention provides a method of 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 formula (I) as described above.

In another aspect, this invention provides a method of inhibiting human factor Xa in vitro by the administration of a compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION Definitions -

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated: "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl}, n-butyl, n-pentyl, 1,1-dimethylethy! (t-butyl), and the like. . "Alkylcarbonyl" refers to a radical of the formula -C(O)R, where R, is an alkyl radical , as defined above, e.g., acetyl, ethylcarbonyl, n-propylcarbonyl, and the like. "Alkoxy" refers to a radical of the formula -OR, where R, is an alkyl radical as ) 5 defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), and the like.

"Alkoxycarbony!" refers to a radical of the formula -C(O)OR, where R, is an alkyl radical as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbony!, 1-methylethoxycarbony! (iso-propoxycarbonyl), n-butoxycarbonyl, n-pentoxycarbonyl,

1,1-dimethylethoxycarbonyl (t-butoxycarbonyl), and the like.

"Alkoxycarbonylalkyl" refers to a radical of the formula -R,C(O)OR, where each Ris independently an alkyl radical as defined above, e.g., methoxycarbonyimethyl, 2- (ethoxycarbonyi)ethyl, (n-propoxycarbonylmethyl, 1-methylethoxycarbonylmethy!

. (iso-propoxycarbonylmethyl), n-butoxycarbonylmethyl, n-pentoxycarbonyimethyl,

1,1-dimethylethoxycarbonyimethyl (t-butoxycarbonyimethyl), and the like.

"Alkoxycarbonylalkylcarbonyl” refers to a radical of the formula -C(O)R,C(O)OR,

where each R, is independently an alkyl radical as defined above, e.g., methoxycarbonylmethylicarbonyl, 2-(ethoxycarbonyl)ethylcarbonyl, (n-propoxycarbonylmethyicarbonyl, 1-methylethoxycarbonylmethyicarbony!

(iso-propoxycarbonylmethylcarbonyl), n-butoxycarbonylmethylcarbonyl, n-pentoxycarbonylmethylcarbonyl, 1,1-dimethylethoxycarbonylmethylcarbony! (t-butoxycarbonyimethyl)carbonyl, and the like.

"Aryl" refers to a phenyl or naphthyl radical.

"Aralky!" refers to a radical of the formula -R,R, where R, is an alkyl radical as defined above, substituted by R,, an aryl radical, as defined above, e.g., benzyl.

“Aralkoxy"” refers to a radical of the formula -OR_ where R_ is an aralkyl radical as defined above, e.g., benzyloxy, and the like.

"Amidino” refers to the radical -C(NH)NH.,.

"Aminocarbony!” refers to the radical -C(O)NH,.

"Aminosulfonyl” refers to the radical -S(O),NH,.

“"Aminocarbonylalkyl" refers to the radical -R,C(O)NH,, where R, is an alkyl radical as defined above, e.g., aminocarbonyimethyl, 2-(aminocarbonyi)ethyl, and the like.

"Aminocarbonylalkylicarbony!" refers to the radical -C(O)R,C(O)NH,, where R, is an alkyl radical as defined above, e.g., aminocarbonyimethylcarbonyl!, 2- . (aminocarbonyl)ethylcarbonyl, and the like. "Alkylsulfonyl” refers to a radical of the formula -S(0),-R, where R, is an alkyl radical ' 5S as defined above, e.g., methylsulfonyl, ethylsulfonyl, t-butyisulfonyl, and the like. ) "Arylsulfonyl" refers to a radical of the formula -5(0),-R, where R, is an aryl radical as defined above, e.g., phenylsulfonyi or naphthylsulfonyl. "Carboxy" refers to the radical -C(O)OH. "Carboxyalky!" refers to a radical of the formula -R,C(O)OH, where R, is an alkyl radical as defined above, e.g., carboxymethyl, 2-(carboxy)ethyl, 3-(carboxy)propyl, and the like. "Carboxyalkylcarbonyl" refers to a radical of the formula -C(O)R,C(O)OH, where R, is an alkyl radical as defined above, e.g., carboxymethylcarbonyl, 2-(carboxy)ethylcarbonyl, 3-(carboxy)propylcarbonyl, and the like. ] "Dialkylamino” refers to a radical of the formula -N(R,)R, where each R, is independently an alkyl radical as defined above, e.g., dimethylamino, methylethylamino, diethylamino, dipropylamino, ethylpropylamino, and the like. "Dialkylaminocarbonyl” refers to a radical of the formula -C(O)N(R,)R, where each

R, is independently an alkyl radical as defined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethyipropylaminocarbonyl, and the like. "Dialkylaminosulfonyl” refers to a radical of the formula -S(0),-N(R,)R, where each

R., is independently an alkyl radical as defined above, e.g., dimethylaminosulfonyl, methylethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosutfonyl, ethylpropylaminosulfonyl, and the like. "Dialkylaminocarbonylalky!” refers to a radical of the formula -R,C(O)N(R,)R, where each R, is independently an alkyl radical as defined above, e.g., dimethylaminocarbonylmethyl, 2-(methylethylaminocarbonyl)ethyl, diethylaminocarbonylmethy!, 3-(dipropylaminocarbonyl)propy!, 4- (ethylpropylaminocarbonyi)butyl, and the like. "Halo" refers to bromo, chloro, iodo or fluoro. "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethy!, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. ’ “Monoalkylamino" refers to a radical of the formula -NHR, where R, is an alkyl ’ 5 radical as defined above, e.g., methylamino, ethylamino, propylamino, and the like. "Monoalkylaminocarbonyl” refers to a radical of the formula -C(O)NHR, where R, is an alkyl radical as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like. "Mono[dialkoxycarbonyl]alkylaminocarbonyl” refers to a radical of the formula

-C(O)N(H)[R,(C(O)OR,),] where each R, is independently an alkyl radical as defined above,

e.g., [1,2-diethoxycarbonyl)ethyllaminocarbonyl, and the like. "Monol[dicarboxy]alkylaminocarbony!" refers to a radical of the formula -C(O)N(H)[R,(C(O)OH),] where R, is an alkyl radicai as defined above, e.g., [1,2- ] dicarboxy)ethyllaminocarbonyl, and the like.

"Monoalkylaminocarbonylalky!" refers to a radical of the formula -R,C(O)NHR, where each R, is independently an alkyl radical as defined above, e.g.,

’ methylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl, 3-(propylaminocarbonyl)propyl, : and the like. "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

For example, "optionally substituted aryl" means that the ary! radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

"Phenylalkylidenyl" refers to a radical of the formula -R.R, where Ry is a phenyl radical and R, is a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule, e.g., ethylidene, propylidene,

n-butylidene, and the like.

"Phenylcarbony!" refers to a radical of the formula -C(O)R, where R, is a phenyl radical.

- g ~~ "Pharmaceutically acceptable salt” includes both acid and base addition 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-toluenesuifonic 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 or otherwise undesirable.

These salts are prepared from addition of an inorganic base or an organic base to the free acid.

Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, . manganese, aluminum salts and the like.

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 naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, ftripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol. dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.

Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. "Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for disease-states characterized by thrombotic activity.

The amount of a compound of the invention which constitutes a "therapeutically effective amount” will vary depending on the compound, the disease-state and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

"Treating" or "treatment" as used herein covers the treatment of a disease-state in a ; human, which disease-state is characterized by thrombotic activity, and includes: (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having if (i) inhibiting the disease-state, i.e., arresting its development; or (iii) relieving the disease-state, i.e., causing 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 quaternized nitrogen atoms in their ‘structure. The compounds of the invention and their pharmaceutically acceptable salts may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and . diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are 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 benzenamine derivatives: For example, a compound of formula (I) wherein A is -O-, Wis -N(R*)-, nis 1, R'is 2- (carboxy)ethylcarbonyl, R? is -CH,-CH=CH-, R® is -C(NH)NH,, R* is methyl, R® is trifluoromethyl, and R® is hydroxy, i.e., a compound of the following formula: rg ho” TY N ~YY NH, 2 HO

C(O)OH is named herein as 4-(N-(methyl)piperidin-4-yi)oxy-3-trifiuoromethyl-N-(2- (carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine.

Utility and Administration

A. Utility i

The compounds of the invention are inhibitors of the serine protease, factor Xa, and are therefore useful in disease-states characterized by thrombotic activity based on factor

Xa'srole in the coagulation cascade (see Background of the Invention above). A primary indication for the compounds is prophylaxis for long term risk following myocardial infarction.

Additional indications are prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery or prophylaxis of selected patients following a transient ischemic attack. The compounds of the invention may also be useful for indications in which coumadin 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 promyelocytic leukemia, diabetes, multiple myelomas, disseminated intravascular coagulation associated with septic shock, purpura fulminanas associated infection, adult . respiratory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular prosthesis. The compounds are also useful for prophylaxis for thrombotic diseases, in particular in patients who have a high risk of developing such disease.

In addition, the compounds of the invention are useful as in vitro and in vivo } 20 diagnostic reagents for selectively inhibiting factor Xa without inhibiting other components of the coagulation cascade.

B. Testing

The primary bioassays used to demonstrate the inhibitory effect of the compounds of the invention on factor Xa are simple chromogenic assays involving only serine protease, the compound of the invention to be tested, substrate and buffer (see, e.g., Thrombosis

Res. (1979), Vol. 16, pp. 245-254). For example, four tissue human serine proteases can be used in the primary bioassay, free factor Xa, prothrombinase, thrombin (lla) and tissue plasminogen activator (tPA). The assay for tPA has been successfully used before to demonstrate undesired side effects in the inhibition of the fibrinolytic process (see, e.g., J.

Med. Chem. (1993), Vol. 36, pp. 314-319).

Another bioassay useful in demonstrating the utility of the compounds of the invention in 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 prothrombin time (PT), or activated partial thromboplastin time (aPTT) while selectivity of the compounds is checked with the thrombin clotting time (TCT) assay. Correlation of the K; in the primary enzyme assay with the K; for free factor Xa in citrated plasma will screen against compounds which interact with or are inactivated by other plasma components. Correlation of the K; with the extension of the PT is a necessary in vitro demonstration that potency in the free factor Xa inhibition assay translates into potency in a clinical coagulation assay. In addition, extension of the PT in citrated plasma can be used to measure duration of action in subsequent pharmacodynamic studies.

For further information on assays to demonstrate 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

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 via any of the accepted modes of administration or agents for serving similar utilities. 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 gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, 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 as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, efc. .

Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. Preferably, the composition will be about 5% to 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical 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 5S containing a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, 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 capsule, caplet or tablet and therefore will 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 a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.

The compounds of the invention, or their pharmaceutically acceptable salts, may : also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, efc., a compound(s) of the invention (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 minor amounts 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.

Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pennsylvania, 1990). The composition to be administered will, in any event, 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 the inhibition of factor Xa in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptable salts, are ) 5 administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.14 mg to 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 most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for i administration to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram 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 most preferably from about 100 ) mg to about 500 mg per day. :

Preferred Embodiments

Of the compounds of formula (1) as described in the Summary of the Invention, one preferred group of compounds are those compounds wherein A is -O-; W is -N(R*)-; each mis independently 0, 1 or 2; nis 1; R?is -[C(R"),],.-C(O)-N(R®)-; and R® is -

C(NH)NH,.

Of this group of compounds, more preferred compounds are selected from the group consisting of the foliowing: 4-(N"-(1-iminoethy!)piperidin-4-yoxy-N-(N"-(3- amidinophenyl)aminocarbonyl)methylbenzenamine: 4-(piperidin-4-yl)oxy-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4~(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(N-(6-hydroxy-3-amidinophenyl)aminocarbonyl)- methylbenzenamine; 4-(N"-(acetyl)piperidin-4-yt)oxy-N- (N-(6-hydroxy-3-amidinophenyl)aminocarbonyl)-

methylbenzenamine; 4-(N"-(1-iminoethyl)piperidin-4-ylJoxy-N-(aminocarbonylmethyl)-N-((N-(3- . amidinophenyl)amino)carbonyl)methylbenzenamine: 4-(N"-(1-iminoethyl)piperidin-4-ylyoxy-N-(1-( N'-(3-amidinophenyl)aminocarbonyl)- ) ethyl)benzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yt)oxy-N-(ethoxycarbonyimethy!)-N-((N~(3- amidinophenyl)amino)carbonyl)methylbenzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(methyl)-N-((N-(3- amidinophenyl)amino)carbonyl)methylbenzenamine; 4-{N"-(1-iminoethyl)piperidin-4-yhoxy-N-(ethoxycarbonylmethyl)-N-(N'"-(6-hydroxy-3- amidinophenyl)aminocarbonyl)-methylbenzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(methyl)-N-(N"-(6-hydroxy-3- amidinophenyl)aminocarbonyl)-methylbenzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(N"-(6-hydroxy-3- ' amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(N"-(6-hydroxy-3- ] amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yljoxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N- (N-(3-amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N- (N'-(6-hydroxy-3-amidinophenyi)aminocarbonyl)methylbenzenamine; 4-(N"-(methyl)piperidin-4-yl)oxy-N-(N"-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(methyl)piperidin-4-yi)oxy-3-trifluoromethyl-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(methyl)piperidin-4-yi)oxy-N-(1-methylethyl)-N-(N'-(6-benzyloxy-3- amidinophenyl)aminocarbonyl}methylbenzenamine; 4-(N"-(methyl)piperidin-4-yhoxy-N-(1-methylethyl)-N-(N'-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(methyl)piperidin-4-yloxy-3-trifluoromethyl-N-(1-methylethyt)-N-(N*-(6-hydroxy-3- amidinophenyllaminocarbonyl)methylbenzenamine; and 4-(N"-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(N'-(6-hydroxy-3-

amidinophenyl)aminacarbonyl)methylbenzenamine. ) Another preferred group of compounds of the compounds of formula (I) as defined above in the Summary of the Invention is the group of compounds wherein A is -O-; W is -N(R*)-; each m is independently 0, 1 or 2; nis 1; R?is -[C(R"),],-; and R® is -C(NH)NH,, ’ 5 Of this group of compounds, mare preferred compounds are those compounds selected from the list consisting of the following: 4-(piperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy ethylcarbonyl!)-N-(3- (6-hydroxy-3-amidinophenyl)propyl)benzenamine; 4-(N-methylipiperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine: 4-(piperidin-4-yl)oxy-3-trifiuoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)propyi)benzenamine; 4-( N'-(1-iminoethyl)piperidin-4-yl)oxy-3-trifiuoromethyl-N-(3-(6-hydroxy-3- . amidinophenyl)propyl)benzenamine; 4-(piperidin-4-yl)oxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-1-yl)benzenamine; 4-(N'-(1-iminoethyl)piperidin-4-yi)oxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-1- yl)benzenamine; 4-(N'-(actyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethyicarbonyi)-N-(2- methyl-3-(6-hydroxy-3-amidinophenyl)prop-1-yl)benzenamine; and 4-(N-(actyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl- 3-(6-hydroxy-3-amidinophenyl)prop-1-yl)benzenamine.

Another preferred group of compounds of the compounds of formula (1) as defined above in the Summary of the Invention is the group of compounds wherein A is -O-; W is -N(R*)-; each m is independently 0, 1 or 2; n is 1; R?is -[C(R"),],-[C(R®)]=CH-; R® is -

C(NH)NH,; and R® is hydrogen.

Of this group of compounds, more preferred compounds are those compounds selected from the list consisting of the following: 4-(N-(1-iminoethyl)piperidin-4-ylyoxy-3-nitro-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yloxy-N-(3-(3-amidinophenyl)prop-2-en-1-yl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(carboxymethy!)-N-(3-(3- amidinophenyl!)prop-2-en-1-yl)benzenamine; . 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-trifiuoromethyl-N-(3-(3-amidinophenyl)prop-2-en- 1-yhbenzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-ethoxycarbonyl-N-(3-(3-amidinophenyl)prop-2-en- 1-yhbenzenamine; 4-(N-(1-iminoethyl)piperidin-4-yloxy-3-ethoxycarbonyl-N-(3-(3-amidinophenyl)prop-2-en- 1-yl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-(ethoxycarbonyl)propy!)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-(ethoxycarbonyi)-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine, : 4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl}-N-(3-(3-amidinophenyl)prop-2-en-1-yl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-ethoxycarbonyl-N-(ethoxycarbonyimethyl)-N-(3-(3- : amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1- : yhbenzenamine; 4-(N'-(1-iminoethy!)piperidin-4-yl)oxy-3,5-difluoro-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N*-acetylpiperidin-4-yl)oxy-3-triflucromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2- en-1-yl)benzenamine, 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyi-N-(3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(piperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinopheny!)prop-2-en-1-yl)benzenamine; 4-(N-(1-iminoethy!)piperidin-4-yl)oxy-3,5-difluoro-N-(3-(3-amidinopheny!)prop-2-en-1- yl)benzenamine; 4-(N'-(1-iminoethyl)piperidin-4-y))oxy-N-(1-methylethyl)-N-(3-(3-amidinophenyl)prop-2-en-

1-yl)benzenamine; ] 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(6-hyd roxy-3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(methoxycarbonylmethy!)-N-(3-(3- ) 5 amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-( methoxycarbonyimethyl)-N-(3- (3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(methyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(aminocarbonylmethy!)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(aminocarbonylmethyl)-N-(3-(3- amidinophenyi)prop-2-en-1-yl)benzenamine: } 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-methoxycarbonyi-N-{3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N*-(1-iminoethy!)piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-methoxycarbonyl-N-(3-(3-amidinophenyl)prop-2- en-1-yl)benzenamine; 4-(N*-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyli)prop-2- en-1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-acetyl-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'~(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-((1-methylethyl)carbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbony!)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(benzyl)-N-(3-(6-hydroxy-3-amidinophenylyprop- 2-en-1-yl)benzenamine; ] 4-( N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(( 1-methylethyl)carbonyl)-N-(3- (6-hydroxy-3-amidinopheny!)prop-2-en-1-yi)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-ylJoxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-triflucromethyl-N-(benzyl)-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl Jethylcarbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; : 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hyd roxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyi-N-acetyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2- en-1-yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3- (6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N -(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(methoxycarbonyl)ethylcarbony!)-N- (3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-acetyl-N-(3-(6-hydroxy-3- amidinopheny!)prop-2-en-1-yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(methoxycarbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(benzyl)-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbony!)-N-(3-(3- _ amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-((1-methylethyl)carbonyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'-(aminocarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-(methoxycarbony!)-N-(2- . (methoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amid inophenyl)prop-2-en-1- yl)benzenamine; 4-(N-(1 -iminoethy!)piperidin-4-yl)oxy-3-carboxy-N-(2-(aminocarbonyl)ethylcarbonyl)-N-(3- ] 5 (6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(methylsulfonyl)piperidin-4-yl)oxy-3-trifl uoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'-(methylsuifonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1 -methylethyl)carbonyl)-N-(3- (6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;

4~(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2- (ethoxycarbonyl)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1- yh)benzenamine;

4-(N*-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N- : (3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(N(acetyl)piperidin-4-yl)oxy-3-trifluoromethyi-N-(2-(ethoxycarbony!)ethylcarbonyl)-N-(3-

(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;

4~(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2- (ethoxycarbonyl)ethylcarbonyl)-N-(3~(6-hydroxy-3-amidinophenyl)prop-2-en-1- yhbenzenamine;

4-(N-(ethoxycarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-(nitro)-N-(aminocarbonylmethyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(ethoxycarbonyimethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-

(ethoxycarbonyl)ethyicarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1- yl)benzenamine;

4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1,2- di(ethoxycarbonyl)ethyl)aminocarbonyl)-N-(3-(3-amidinopheny!)prop-2-en-1- yhbenzenamine;

4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1,2- di(carboxy)ethyl)aminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine;

Claims

WHAT IS CLAIMED IS:

1. A compound of formula (1): 6 CN JA JR mT —R '()] (CH) A R! A wherein: Ais -O- or -N(R')-; Wi is -N(R?)-, -S- or -O-; each mis independently 0, 1, 2, 3 or 4; nisOor1,; R'is hydrogen, alkyl, alkylcarbonyl, phenylalylidenyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, -C(NH)N(H)OR', -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R®, -C(NH)N(H)S(O),R®, or ‘ -C(NH)N(H)C(O)N(H)R’), alkoxycarbonylalky, carboxyalkyl, aminocarbonyialkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalky!, alkoxycarbonyl, phenylcarbonyl (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbony!, aminocarbonylalkylcarbonyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R?, -C(NH)N(H)S(O),R®, or -C(NH)N(H)C(O)N(H)R7), monol[dialkoxycarbonyljalkylaminocarbonyl, mono[dicarboxylalkylaminocarbonyl, alkylsulfonyl, arylsulfonyl or dialkylaminosulfonyl; R? is -[C(R")ln-, -[C(R")Jm-C(O)-N(R®)-, or -[C(R"),],-[C(R*)]=CH-; or R%is 7/8 pd C(R')(R i ) ;

R? is -C(NH)NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR?®, -C(NH)N(H)C(O)R®, . -C(NH)N(H)S(0),R?®, or -C(NH)N(H)C(O)N(H)R’, R* is hydrogen, alkyl, alkylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, or -C(NH)CH,. each R® is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyi; R® is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the aryl group is optionally substituted by alkyl, halo or alkoxy); each R” and R® is independently hydrogen, alkyl, aryl, or aralkyl; and each R® is alkyl or aralkyl; as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof. 2, The compound of Claim 1 wherein Ais -O-; Wis -N(R%)-; each mis independently 0, 1 or 2; nis 1, R? is -[C(R"),].-C(O)-N(R®)-; and R? is -C(NH)NH,.

3. The compound of Claim 2 selected from the group consisting of the following: : 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(N'-(3- amidinophenyl)aminocarbonyi)methylbenzenamine; 4-(piperidin-4-yl)oxy-N-(N'-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N'~(1-iminoethyl)piperidin-4-yl)oxy-N-(N"-(6-hydroxy-3-amidinophenyl!)aminocarbonyl)- methylbenzenamine; 4-(N"-(acetyhpiperidin-4-yl)oxy-N- (N-(6-hydroxy-3-amidinophenyl)aminocarbonyi)- methylbenzenamine;

4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(aminocarbonylmethyi)-N-((N-(3- amidinophenyl)amino)carbonyl)methylbenzenamine; ’ 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(1-(N"-(3-amidinophenyl)aminocarbonyl)- ethyl)benzenamine; . 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(ethoxycarbonylmethyl)-N-((N'-(3- amidinophenyl)amino)carbonyl)methylbenzenamine,; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(methyl)-N-((N*-(3- amidinophenyl)amino)carbonyl)methylbenzenamine, 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(ethoxycarbonylmethyl)-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbonyl)-methylbenzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(methyl)-N-(N"-(6-hydroxy-3- amidinophenyl)aminocarbonyl)-methylbenzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; ’ 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; . 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy )ethylcarbonyt)-N- (N'-(3-amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(1-iminoethy!)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N- (N*-(6-hydroxy-3-amidinophenyl}aminocarbonyl)methyibenzenamine; 4-(N"-(methyl)piperidin-4-yl)oxy-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(methy!)piperidin-4-yhoxy-3-trifluoromethyl-N-(N'-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(methyl)piperidin-4-yl)oxy-N-(1-methylethyl)-N-(N"-(6-benzyloxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(methyl)piperidin-4-yi)oxy-N-(1-methyiethyi)-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; 4-(N"-(methyl)piperidin-4-yl)oxy-3-triflucromethyl-N-(1-methylethyl)-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbonyl)methylbenzenamine; and 4-(N"-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(N-(6-hydroxy-3- amidinophenyl)aminocarbony!)methylbenzenamine.

4, The compound of Claim 1 wherein . Ais -O-; Wis -N(R%-; each mis independently 0, 1 or 2; nist; R?is -[C(R"),]..-; and R® is -C(NH)NH,.

5. The compound of Claim 4 selected from the group consisting of the following: 4-(piperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine; 4~(N-(1-iminoethyl)piperidin-4-ylyoxy-3-trifiuoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3- (6-hydroxy-3-amidinophenyl)propyl)benzenamine; } 4~(N*-methylpiperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)propyl)benzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)propyl)benzenamine; 4-( N'-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)propyl)benzenamine; 4-(piperidin-4-yl)oxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl!)prop-1-yl)benzenamine: 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-methyl-3-(6-hyd roxy-3-amidinophenyl)prop-1- yl)benzenamine; 4-(N*(actyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2~(ethoxycarbonyl)ethylcarbony!)-N-(2- methyl-3-(6-hydroxy-3-amidinophenyl)prop-1-yl)benzenamine; and 4-(N*(actyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethyicarbonyl)-N-(2-methyl- 3-(6-hydroxy-3-amidinophenyl)prop-1-yl)benzenamine.

8. The compound of Claim 1 wherein Ais -O-; Wiis -N(R%)-; each mis independently 0, 1 or 2; nis 1, R?is -[C(R"),]-[C(R®)]=CH-;

R® is -C(NH)NH,; and R® is hydrogen.

7. The compound of Claim 6 selected from the group consisting of the following: 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(3-(3-amidinophenyl)prop-2-en-1- yhbenzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(3-amidinophenyl)prop-2-en-1-yi)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(3-amidinophenyl)prop-2-en-1-yl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(carboxymethyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-imincethy!)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(3-amidinophenyl)prop-2-en- 1-yl)benzenamine; 4-(N"-(1-iminoethyi)piperidin-4-yl)oxy-3-ethoxycarbonyl-N-(3-(3-amidinophenyl)prop-2-en- 1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-ethoxycarbonyl-N-(3-(3-amidinophenyl)prop-2-en- 1-yh)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(3-(3-amidinophenyl)prop-2-en-1- : yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-(ethoxycarbonyl)propyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1- yllbenzenamine, 4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)}-N-(3-(3-amidinophenyl!)prop-2-en-1-yl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl}benzenamine; 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-ethoxycarbonyl-N-(ethoxycarbonylmethyl )-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1- yhbenzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3,5-difluoro-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine;

4-(N"-acetylpiperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2- en-1-yl)benzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yloxy-3-trifluoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(piperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3,5-difluoro-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-N-(1-methylethy!)-N-(3-(3-amidinophenyl)prop-2-en- 1-yl)benzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-N-(3-(6-hydroxy-3-amidinopheny!)prop-2-en-1- yhbenzenamine; . 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(methoxycarbonylmethy!)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; } 4-(N*-(1-iminoethy!)piperidin-4-yl)oxy-3-triflucromethyi-N-(methoxycarbonylimethyl)-N-(3- (3-amidinophenyl)prop-2-en-1-yl}benzenamine: 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(methyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(aminocarbonylmethyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-fluoro-N-(aminocarbonylmethyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4~(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-nitro-N-(2-(carboxy Jethylcarbonyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinopheny!)prop-2-en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-methaxycarbonyl-N-(3-(3-amidinopheny!)prop-2-an-1- yl)benzenamine; 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-methoxycarbonyl-N-(3-(3-amidinophenyl)prop-2- en-1-yl)benzenamine;

4-(N-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hyd roxy-3-amidinophenyl)prop-2- en-1-yl)benzenamine;

4-(N-(1 -iminoethy!)piperidin-4-yl)oxy-3-trifluoromethyl-N-acetyl-N-(3-(6-hyd roxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; .

4-(N~(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1 -yl)benzenamine;

4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(( 1-methylethyl)carbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1 -yllbenzenamine;

4-(N-(1 -iminoethyl)piperidin-4-yloxy-3-carboxy-N-(2-(carboxy )ethylcarbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1 -yl)benzenamine;

4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(benzyi )-N-(3-(6-hydroxy-3-amidinopheny!)prop- 2-en-1-yl)benzenamine;

4-( N-(1 -iminoethyl)piperidin-4-yljoxy-3-trifluoromethy!-N-((1 -methylethyl)carbonyl)-N-(3- (6-hydroxy-3-amidinophenyl)prop-2-en-1 -yl)benzenamine; ’

4-(N*-(1 -iminoethyl)piperidin-4-yl)oxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine: }

4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-triflucromethyl-N-(benzyf)-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine:

4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-acetyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2- en-1-yl)benzenamine;

4-(N'-(1-iminoethyl)piperidin-4-yl Joxy-3-trifluoromethyl-N-(2-(carboxy )ethylcarbony!)-N-(3- (6-hydroxy-3-amidinopheny!)prop-2-en-1-yl)benzenamine;

4-(N-(acetyl )piperidin-4-yl)oxy-3-trifluoromethyi-N-(2-(carboxy Jethylcarbony!)-N-(3-(6- hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(N-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(methoxycarbonyl)ethylcarbonyl)-N- (3~(6-hydroxy-3-amidinopheny!)prop-2-en-1-yl)benzenamine:

4-(N -(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-acetyl-N-(3-(6-hyd roxy-3- amidinopheny!)prop-2-en-1-yl)benzenamine:

4-(N-(1-iminoethyl )piperidin-4-yl)oxy-3-trifluoromethyl-N-(methoxycarbonyl)-N-(3-(6- : hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(benzyl)-N-(3-(6-hydroxy-3- ) amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-((1-methylethyl)carbonyt)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(aminocarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-( methoxycarbonyl)-N-(2- (methoxycarbonyl)ethylcarbonyi)-N-(3-(6-hydroxy-3-amidinophenyl) prop-2-en-1- yh)benzenamine; . 4-(N"-(1-iminoethyl)piperid in-4-yl)oxy-3-carboxy-N-(2-(aminocarbonyl)ethylcarbonyt)-N-(3- (6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; } 4-(N"-(methylsulfonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hyd roxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(methylsulfonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1-methylethyl)carbonyl)-N-(3- (6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine: 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2- (ethoxycarbonyi)ethylcarbony!)-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N-(methyl)piperidin-4-yl)oxy-3-trifiuoromethyl-N-(2-(ethoxycarbonyl)ethylcarbonyl )-N- (3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(acety!)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(ethoxyca rbonyl)ethylcarbonyl)-N-(3- (6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2- (ethoxycarbonyl)ethylcarbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N"-(ethoxycarbonyl)piperidin-4-yl)oxy-3-trifluorometnyl- N-(3-(6-hydroxy-3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-(nitro)-N-(aminocarbonylmethy!)-N-(3-(3-

amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*(ethoxycarbonylmethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2- (ethoxycarbonyl)ethyica rbonyl)-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1 - yl)benzenamine; . 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-trifiucromethyl-N-((1 ,2- di(ethoxycarbonyl)ethyl)aminocarbonyl )-N-(3-(3-amidinophenyi)prop-2-en-1- yl)benzenamine; 4-(N-(1 -iminoethyf)piperidin-4-yl)oxy-3-triflucromethyl-N-(( 1,2- di(carboxy)ethyl)aminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1 - yl)benzenamine; 4-(piperidin-4-ylJoxy-3-carboxy-N~(2-(carboxy)ethylcarbonyl)-N-(3-(3-amidinophenyl)prop- 2-en-1-yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(3-(6- hydroxy-3-amidinopheny!)prop-2-en-1 -yl)benzenamine; 4-(N*-(1-iminoethy!)pi peridin-4-ylJoxy-3-carboxy-N-(2-(carboxy)ethylca rbonyl)-N-(3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine: . : 4-(N*-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1,2- di(ethoxycarbonyl)ethylyaminocarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1 - yl)benzenamine; 4-(N'-(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4- di(ethoxycarbonyl)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1 - yhbenzenamine, 4-(N*(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N- (3~(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*(acetyl)piperidin-4-yl)oxy-3-trifluoromethyt-N-((1 ,2-di(carboxy)ethyl)aminocarbonyl)- N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N*-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4- di(carboxy)phenyl)carbonyi)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((1 ,2-di(carboxy)ethyl)aminocarbonyl)- N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N -(acetyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(carboxy)phenyl)carbony!)-N-( 3- (3-amidinophenyl)prop-2-en-1-yl)benzenamine;

4-(N'-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4- : di(ethoxycarbonyl)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; ) 4-(N'-(methyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4-di(carboxy)phenyl)carbony!)-N- (3-(3-amidinophenyi)prop-2-en-1-yl)benzenamine; 4-(N-(methy!)piperidin-4-yl)oxy-3-triftuoromethyl-N-((3,4- di(ethoxycarbonyl)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1- yl)benzenamine; 4-(N’-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbony!)-N- (3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-((3,4- di(carboxy)phenyl)carbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N'-(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyi-N-(3-(3-amidinopheny!)prop-2- . en-1-yl)benzenamine; 4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)prop-2-en-1-yl)-N-(3-(3- ] amidinophenyl)prop-2-en-1-yl)benzenamine; and 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1-yl)- N-(3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1-y!)benzenamine.

8. The compound of Claim 1 wherein Ais -O-; Wis -N(R*)-; each mis independently 0, 1 or 2; nis 1; R?is -[C(R),).-[C(R®)]=CH-; R? is -C(NH)NH,; and R? is methyl.

o. The compound of Claim 8 selected from the group consisting of the following: 4-(N'-(1-iminoethyl)piperidin-4-yhoxy-3-(nitro)-N-(2-methyl-3-(3-amidinopheny!)prop-2-en- 1-yl)benzenamine,

4-(piperidin-4-yhoxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-2-en-1- ylbenzenamine; ’ 4-(piperidin-4-yl)oxy-N-(2-methyl-3-(6-benzyloxy-3-amidinophenyl)prop-2-en-1- yl)benzenamine; . 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-N-(2-methyl-3-(6-hydroxy-3-amidinophenyl)prop-2- en-1-yl)benzenamine; 4-( N*-(acetyl)piperidin-4-yl)oxy-N-(2-methyl-3-(6-hydroxy-3-amid inophenyl)prop-2-en-1- y)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-N-(2-methyi-3-(6-benzyloxy-3-amidinophenyi)prop- 2-en-1-yh)benzenamine; 4-(piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl-3-(3- amidinophenyl)prop-2-en-1-yl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yt)oxy-3-carboxy-N-(2-(carboxy)ethylcarbonyl)-N-(2-methyl- 3-(6-hydroxy-3-amidinopheny!)prop-2-en-1-yl)benzenamine; ‘ 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(2-(carboxy)ethyicarbony!)-N-(2-methyl- 3-(3-amidinophenyl)prop-2-en-1-yl)benzenamine; and . 4-(N*(carboxymethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(2-(carboxy)ethylcarbonyl)-N- (2-methyl-3-(6-hydroxy-3-amidinopheny!)prop-2-en-1-yl)benzenamine.

10. The compound of Claim 1 wherein Ais -O-; Wis -N(R%)-; each m is independently 0, 1 or 2; nis 1; R?is ew) : and R® is -C(NH)NH.,.

11. The compound of Claim 12 selected from the group consisting of the following: 4~(N-(1-imincethy!)piperidin-4-yl)oxy-3-nitro-N-(3-(3-amidinophenyl)benzyl)benzenamine;

4-(N-(acetyl)piperidin-4-yl)oxy-3-methoxy-N-(3-(3-amidinophenyl)benzyl)benzenamine; . 4-(N'~( 1-iminoethyl)piperidin-4-yl)oxy-N-(3-(3-amidinopheny!)benzyl)benzenamine:; 4-(piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)benzyl)benzenamine; } 4-(N~(1-iminoethyl)piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3- amidinophenyl)benzyl)benzenamine; 4-(N-(1-iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(3-(3- amidinophenyl)benzyl)benzenamine; 4-(piperidin-4-yl)oxy-3-(ethoxycarbonyi)-N-(ethoxycarbonylmethyl)-N-(3-(3- amidinophenyl)benzyl)benzenamine; 4-(N"-(1-iminoethy!)piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(ethoxycarbonyimethyl)-N-(3- (3-amidinophenyl)benzyl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(carboxymethyl)-N-(3-(3- amidinophenyl)benzyl)benzenamine; . 4-(N"-(1-iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(3- amidinophenyl)benzyl)benzenamine; } 4-(piperidin-4-yljoxy-3-trifluoromethyl-N-(3-(3-amidinophenyl)benzyl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(ethoxycarbonyimethy)-N-(3-(3- amidinophenyl)benzyl)benzenamine; 4-(N-(1 -iminoethyl)piperidin-4-yl)oxy-3-(ethoxycarbonyl)-N-(3-(3-amidinophenyl)benzy)- N-(3-(3-amidinophenyl)benzyl)benzenamine; and 4-(N-{1 -iminoethyl)piperidin-4-yl)oxy-3-carboxy-N-(3-(3-amidinophenyl)benzy!)-N-(3-(3- amidinophenyl)benzyl)benzenamine.

12. The compound of Claim 1 wherein Ais -O-; Wis -O- or -S-; each mis independently 0, 1 or 2; nis 1; R? is -[C(R7),],-{C(R®)]=CH-; and R? is -C(NH)NH,,.

13. The compound of Claim 14 selected from the group consisting of the

- 91 ~- following: 4-(tetrahydropyran-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinaphenyl)prop-2-en- ) 1-yl)benzenamine; and 4-(thian-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1 - . yl)benzenamine.

14. A pharmaceutical composition useful in treating a human having a disease- state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound of formula (1): RN ASE -S Fm i TAT NEVE 2 gs 0 (CH), A lL A wherein: Ais -O- or -N(R")-; - Wiis -N(R*)-, -S- or -O-; each mis independently 0, 1, 2, 3 or 4; nis 0 or 1; R'is hydrogen, alkyl, alkylcarbonyl, phenylalylidenyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, -C(NH)N(H)OR', -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R®, -C(NH)N(H)S(O),R®, or -C(NH)N(H)C(O)N(H)R"), alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkoxycarbonyl, phenylcarbonyl (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR?®, -C(NH)N(H)C(O)R®, -C(NH)N(H)S(O),R®, or -C(NH)N(H)C(O)N(H)R"), monol[diatkoxycarbonyllalkylaminocarbonyl, monof{dicarboxylalkylaminocarbonyl, alkylsulfonyl, arytsutfonyl or dialkylaminosulfonyl;

PCT/US00/20390 R%is -[C(R") m= -[C(R)dm-C(O}N(R®)-, or -[C(R"),}-[C(R*)}=CH-; or R%is 7\ 8 rd -[CR' XR) \ / ° R? is ~C(NH)NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R®, : -C(NH)N(H)S(O).R", or -C(NH)N(H)C(Q)N(H)R; R*is hydrogen, alkyl, alkylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, or -C(NH)CH,. each R® is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl; R® is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the aryl group is optionally : substituted by alkyl, halo or alkoxy); each R7 and R? is independently hydrogen, alkyl, aryl, or aralkyl; and . each R? is alkyl or aralkyl; _ as a single sterecisomer or a mixture thereof; or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient.

15. Use of a compound of formula (I): 6 Ww (Rm (Rm NL, Nl 3 JA (J = J 1); (cH Zn NF wherein: Ais -O- or N(R"); W is -N(R%-, -S- or -O-; AMENDED SHEET each mis independently 0, 1, 2, 3 or 4; :

nisQor1;

R' is hydrogen, alkyl, alkylcarbonyl, phenylalylidenyi (wherein the phenyl! group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, ~-C(NH)}-NH,, -C(NH)N(H)OR', -C(NH)N(H)C(Q)OR?, -C(NH)N(H)C(O)R?, -C(NH)N(H)S(O),R®, or

) -C(NH)N(H)C(ON(H)R"), alkoxycarbonylalkyl, carbaxyalkyl, aminocarbonytalkyl,

monoalkylaminacarbonylalkyl, dialkylaminocarbonylatkyl, alkoxycarbonyl, phenylcarbony! (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, benzyl (wherein the phenyl group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R®, -C(NH)N(H)S(O).R?, or -C(NH)N(H)C(O)N(H)R’), mono[dialkoxycarbonyllalkylaminocarbonyl, monofdicarboxylalkylaminocarbonyl, alkylsuifonyl, arylsuifony! or dialkylaminosulfonyt;

R? is -[C(R Jw, -[C(R)Am-C(O}N(R®)-, or {C(R")Jn-[C(R®)]=CH-;

or R?is

7\ 78 — x LER <7 S R? is -C(NH)NH,, -C(NH)N(H)OR?, -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R®, -CINH)N(H)S(O),R?, or -C(NH)N(H)C(ON(H)R™:

R* is hydrogen, alkyl, alkylcarbonyl, aminocarbonyl, monoaikylaminocarbonyl, ’ dialkylaminocarbonyl, aminosulfonyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, or -C(NH)CH. each R® is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy, alkoxy, carboxy,

alkoxycarbonyl, amino, monoalkylamino, dialkylamino, aminocarbanyl, monoalkylaminocarbonyl, or dialkylaminocarbonyf;

R® is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the aryl group is optionally substituted by alkyl, halo or alkoxy);

each R” and R? is independently hydrogen, alkyl, aryl, or aralkyl; and each R? is alkyl or aralkyl; )

CLEAN COPY

PCT/US00/20390 as a single stereoisomer of a mixture thereof; or a pharmaceutically acceptable salt i thereof in the manufacture of a medicament for treating a human having a disease- state characterized by thrombotic activity.

16. A substance or composition for use in a method of treating a human having a disease-state characterized by thrombotic activity, said substance or composition comprising a compound of formula (1): Ww (R%m (Rm I GF OA B (CHa 0 wherein: A is -O- or N(R"); ’ W is -N(R%)-, -S- or -O-; AMENDED SHEET

. PCT/US00/20390 each mis independently 0, 1, 2, 3 or 4; nisOor1, R' is hydrogen, alkyl, atkylcarbonyl, phenyialylideny! (wherein the phenyi group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(Q)OR?, -C(NH)N(H)C(O)R®, -C(NH)N(H)S(O),R®, or -C(NH)N(H)C(O)N(H)R"), alkoxycarbanylalkyl, carboxyalky!, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, alkoxycarbonyl, phenylcarbonyl (wherein the phenyl group is optionally substituted by carboxy or alkoxycarbonyl), carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, aminocarbonylalkylcarbonyl, benzyl! (wherein the pheny! group is optionally substituted by alkyl, halo, alkoxy, aralkoxy, -C(NH)-NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)ORS®, -C(NH)N(H)C(O)R?, -C(NH)N(H)S(O),R®, or -C(NH)N(H)C(Q)N(H)R"), mono[dialkoxycarbonyf]alkylaminocarbonyl, monoldicarboxylalkylaminocarbonyl, alkylsulfonyl, arylsulfonyl or dialkylaminosulfonyt; R? is -[C(R") lm, -IC(R")Jm-C(OFN(R®)-, or -[C(R"),]{C(R*)}=CH-; or R?is 7\ (8 — Xx CRIR 2, R?® is -C(NH)NH,, -C(NH)N(H)OR’, -C(NH)N(H)C(O)OR?, -C(NH)N(H)C(O)R®, -C(NHIN(H)S(Q),R®, or -C(NH)N(H)C(O)N(H)R'; _ R*is hydrogen, alkyl, alkylcarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, or -C(NH)CH. each R? is independently hydrogen, alkyl, halo, haloalkyl, nitro, hydroxy; alkoxy, carboxy, alkoxycarbonyl, amino, monaalkylamino, dialkylamino, aminocarbonyl, - monoalkylaminocarbonyl, or dialkylaminocarbonyt; R® is hydrogen, alkyl, hydroxy, alkoxy, aralkoxy (wherein the aryl group is optionally substituted by alkyl, halo or alkoxy); each R’ and R? is independently hydrogen, alkyl, aryl, or aralkyl; and ] each R® is alkyl or aralkyl; AMENDED SHEET

PCT/US00/20390 as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof, and said method comprising administering to a human in need thereof a therapeutically effective amount of said substance or composition.

17. A compound as claimed in Claim 1, substantially as herein described and illustrated.

18. A composition as claimed in Claim 14, substantially as herein described and illustrated. ) 19. Use as claimed in Claim 15, substantially as herein described and illustrated.

20. A substance or composition for use in a method of treatment as claimed in Claim 16, substantially as herein described and illustrated.

21. Anew compound, a new composition, a new use of a compound as claimed in Claim 1, or a substance or composition for a new use in a method of ) treatment, substantially as herein described. ) AMENDED SHEET