THE INVENTION This application relates to compound and compositions for treating diseases associated with serine protase activity, particularly factor Xa activity.

DESCRIPTION OF THE FIELD Hemostasis is a function of the physiological processes which initiate and modulate blood coagulation and fibrinolysis. Blood coagulation involves a series of highly complex, inter-related proteolytic events which culminate in the formation of a fibrin clot surrounding the platelet aggregate which makes up the primary hemostatic plug that forts to prevent loss of blood when a vessel is damage. Fibrin is the product of a proteolytic rection catalyzed by thrombin, a serine protase, which in turn is the product of a proteolytic activation of prothrombin by factor Xa, also a serine protase. Thrombin also is a potent activator of platelet aggregation.

Factor Xa is converted from inactive factor X by two distinct mechanisms referred to as the intrinsic and extrinsic coagulation pathways. The intrinsic pathway comprises a series of proteolytic rections catalyzed by factors originating in blood and culminates in the formation of factor IXa. The extrinsic pathway comprises the activation of factor VII by tissue factor, a membrane bound protein, which is available at the site of vessel injury and culminates in the formation of factor VICIA. Factor IXa and factor VIIa, in consert with tissue factor, catalyzes the conversion of factor X to factor Xa. Thus, the formation of factor Xa represents a convergence of the entrinsic and extrinsic pathways in the cascade of events which lead to blood coagulation.

Fibrinolysis is the mechanism by which the platelet aggregate and fibrin clot is dissolve after the vessel injury has healed. The normal physiological condition results in an equilibrium between blood coagulation and anticoagulation mechanisms preventing hemorrhage while maintaining blood fluidity. A pathological condition leading to the occlusion of a blood vessel, i. e., thrombosis, is the equilibrium tipped in the direction of procoagulation. Arterial thrombosis which deprives tissue of oxygen will result in ischemic

necrosis of that tissue. Venous thrombosis may result in a pulmonary embolism. Agents which shift the equilibrium towards anticoagulation provide a method for treating and/or preventing thrombosis. Agents which inhibit factor Xa provide a valid pharmacological mechanism for effecting anticoagulation.

The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.

SUMMARY OF THE INVENTION This application relates to a compound of Formula 1 : in which: <BR> <BR> <BR> <BR> <BR> <BR> n2isl, 2or3;<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> n3 is l, 2. 3 or 4; n4 is 1 or 2; A together with B comprises a fused heterobicyclic radical containing 8 to 12 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, Xl and x2 are adjacent annular members of an aromatic ring and X'is a heteroatom moiety selected from-N=,-NR5-,-0-and-S-, wherein R 5 is-R6or -X6-R6, wherein X6 is a linking group containing 1 to 12 contiguous linking atoms and R6 is hydrogen, (C6-14) aryl, cyclo(C3-14) alkyl, hetero (C5 l4) aryl, heterocyclo (C3 l4) alkyl, hetero (C8 l4) polycycloaryl or (C9-14)polycycloaryl ; C comprises a heteromonocyclic or fused heteropolycyclic radical containing 5 to 18 annular atoms, wherein each ring contains 5 to 7 annular members, each annular atom optionally is a heteroatom, X4 and X5 are adjacent annular members of an aromatic ring and X5 is a heteroatom moiety selected from-N=,-NRS-,-0-and-S-, wherein R5 is as defined

above, and any carbocyclic ketone, thioketone and iminoketone derivative thereof; X3 represents a linking group of Formula (a) or (b): in which D comprises a monocyclic or polycyclic divalent radical containing 5 to 10 <BR> <BR> annular atoms, wherein X6, XI, X8 and X9 are contiguous annular carbon atoms and one or more other annular atoms optionally is a heteroatom moiety heteroatom moiety selected from-N=,-NRS-,-0-and-S-, wherein R5 is as defined above, X10 and X"together represent a linking group containing two contiguous linking atoms and R'is-R6 or-X6-R6, wherein X6 and R6 are as defined above, with the proviso that when X3 is a linking group of Formula (b) and R'is-R6, wherein R6 is substituted or unsubstituted heteroaryl or heteropolycycloaryl, then the annular atom of R6 to which X10 or X"is attache is not adjacent to an annular heteroatom moiety; R'is amidino and bonded to any annular carbon atom with an available valence comprising B; each R2is independently hydrogen, (C1-3)alkylsulfonyl,(C1-3)alkyloxy, (C1.3) alkylthio, carboxy, halo, (C2, 2) heteroalkyl, hydroxy, mercapto or nitro and bonded to any annular atom with an available valence comprising B; each R3 is independently hydrogen, cyano, halo, nitro, perhalo (C1-3) alkyl or perhalo (C, 3) alkyloxy and bonded to any annular atom with an available valence comprising C; and each R'is independently-R6or _X6-R 6, wherein X6 and R6 are as defined above, and bonded to any annular atom with an available valence comprising C;

wherein aliphatic or alicyclic moities with an available valence comprising each x6 and R6 optionally are substituted with 1 to 5 substituents independently selected from (Cl 6) alkyl, (Cl 6) alkylamino, di (Cl 6) alkylamino, (Cl 6) alkylcarbamoyl, di(C1-6)alkylcarbamoyl,(C1-6)alkylsulfinyl,(C1-6)alkyloxycar bonyll, (C1-6) alkylsulfonyl, (CI_6) alkylthio, amino, carbamoyl, carboxy, cyano, guanidino, halo, hydroxy, mercapto, perhalo (Cl 3) alkyl, perhalo (Cl 3) alkyloxy and uriedo; and aromatic moities with an available valence comprising each X6 and R6 optionally are substituted with one to three substituents independently selected from (Cl 3) alkyl, (C1-3) alkylamino, di (C, 3) alkylamino, (C1-3) alkyloxy, (Cl 3) alkyloxycarbonyl, (Cl 3) alkylimino, amino, carboxy, cyano, guanidino, halo, hydroxy, perhalo (Cl 3) alkyl and perhalo (C, _3) alkyloxy; and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof.

A second aspect of this invention is a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer, mixture of isomers or pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.

A third aspect of this invention is a method of treating a disease in an animal in which contributes to the pathology and/or symptomatology of the disease, which method comprises administering to the animal a therapeutically effective amount of compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer, mixture of isomers or pharmaceutically acceptable salt thereof.

A fourth aspect of this invention is the processes for preparing compound of Formula I and the N-oxide derivatives, prodrug derivative, protected derivatives, individual isomers, mixtures of isomers and pharmaceutically acceptable salts thereof as set forth in "Detailed Description of the Invention".

DETAILED DESCRIPTION OF THE INVENTION Definitions: Unless otherwise stated, the following terms used in the specification and claims have the meanings given in this Section:

"Alicyclic moiety"means any saturated or unsaturated, monocyclic or polycyclic portion of a radical and inclues cycloalkyl, cycloalkylene, heterocycloalkyl and heterocycloalkylene, as defined in this Section. For example, alicyclic moiety refers to cycloalkyl as well as to the alicyclic portions comprising cycloalkylalkyl, cycloalkyloxy, cycloalkylcarbonyl, cycloalkylcarbamoyl, polycycloaryl, and the like.

"Aliphatic moiety"means any straight or branche, saturated or unsaturated portion of a radical and inclues alkyl, alkylene, heteroalkyl and heteroalkylene, as defined in this Section. For example, aliphatic moiety refers to alkyl as well as to aliphatic portions comprising alkyloxy, arylalkyl, alkylcarbamoyl, and the like.

"Alkyl", for the purposes of this application, means a straight or branche, saturated or unsaturated aliphatic radical having the number of carbon atoms indicated, and any ketone, thioketone or iminoketone derivative thereof (e. g., (C1-6) alkyl inclues methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, l-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, l-propynyl, 2-propynyl, 3-oxopentyl, 3-thioxopentyl, 3-iminopentyl, etc.).

"Alkylene"means a saturated or unsaturated divalent radical having the number of carbon atoms indicated and any ketone, thioketone, iminoketone and substituted derivative thereof (e. g., (C1-10) alkylene inclues methylene (-CH2-), ethylene (-CH2CH2-), methylethylene, vinylene, ethynylene, trimethylene (-CH2CH2CH2-), 2-oxotrimethylene (-CH2C (O) Chez), 2-thiatrimethylene (-CH2C (S) Chez), 2-iminotrimethylene (-CH2C (NH) Chez), propenylene (-CH2CH=CH-or-CH=CHCH2-), propanylylidene (=CHCH2CH2-), propendiylene (=CHCH=CH-), l-aminotetramethylene, pentamethylene, etc.).

"Alkyloxy"means the radical-OR, wherein R is alkyl as defined in this Section, having the number of carbon atoms indicated (e. g., (Cl 6) alkyloxy inclues the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, vinyloxy, allyloxy, 1-propenyloxy, isopropenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-methylallyloxy, ethynyloxy, l-propynyloxy, 2-propynyloxy, etc.).

"Alkylsulfonyl"and"alkylthio"mean the radicals-S (0) 2R and-SR, respectively, wherein R is alkyl as defined in this Section, having the number of carbon atoms indicated (e. g., (C1-6) alkylsulfonyl inclues methylsulfonyl, ethylsulfonyl, propylsulfonyl,

isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, vinylsulfonyl, allylsulfonyl, 1-propenylsulfonyl, isopropenylsulfonyl, 1-butenylsulfonyl, 2-butenylsulfonyl, 3-butenylsulfonyl, 2-methylallylsulfonyl, ethynylsulfonyl, 1-propynylsulfonyl, 2-propynylsulfonyl, etc.).

"Amidino"means the radical-C (NH) NH2.

"Amino"means the radical-NH2.

"Animal"includes humans, non-human mammals (e. g., dogs, cats, rabbis, cattle, horses, sheep, goats, swine, deer, etc.) and non-mammals (e. g., birds, etc.).

"Aryl"means an aromatic monocyclic or fused polycyclic radical containing the number of annular carbon atoms indicated, wherein each ring contained therein is comprise of 6 annular members (e. g., (C6_4) aryl inclues phenyl, naphthalenyl, anthracenyl, phenanthrenyl, etc.).

"Arylene"means an aromatic monocyclic or fused bicyclic divalent radical containing 6 to 10 annular atoms, wherein each ring contained therein is comprise of 6 annular members (e. g., arylene inclues 1,4-phenylene, 1,2-phenylene, 1,5-naphthalenylene, 1,8-naphthaleylene,etc.).

"Aromatic moiety"means any aromatic portion of a radical and inclues aryl and heteroaryl, as defined in this Section. For example, aromatic moiety refers to aryl as well as the aromatic portions comprising arylalkyl, polycycloaryl, and the like.

"Carbamoyl"means the radical-C (O) NE2' "Carboxy"means the radical-C (O) OH.

"Cyano"means the radical-CN.

"Cycloalkyl"means a saturated or unsaturated, monocyclic or fused polycyclic radical containing the number of annular carbon atoms indicated, wherein each ring contained therein is comprise of 3 to 8 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e. g., (C3, 4) cycloalkyl inclues cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo [2.2.2] octyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo [2.2.1] hept-1-yl, 1-azabicyclo [2.2.2] oct-3-yl, etc.).

"Cycloalkylene"means a saturated or unsaturated, monocyclic or fused bicyclic divalent radical containing 3 to 14 annular atoms, wherein each ring contained therein is

comprise of 3 to 8 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e. g., cycloalkylene inclues cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cyclohexenylene, 2,5-cyclohexadienylene, bicyclo [2.2.2] octylene, oxocyclohexylene, dioxocyclohexylene, thiocyclohexylene, 2-oxobicyclo [2.2.1] hept-1-ylene, 1-azabicyclo [2.2.2] oct-3-ylene, etc.).

"Disease"specifically inclues any unhealthy condition of an animal or part thereof and inclues an unhealthy condition which may be caused by, or incident to, medical or veterinary therapy applied to that animal, i. e., the"side effects"of such therapy.

"Fused heteropolycyclic radical"includes"fused heterobicyclic radical"and means a heterocyclic radical containing two or more rings having the number of annular members indicated, wherein at least two annular members of one ring are common to a second ring (e. g., a heteropolycyclic radical containing from 5 to 18 annular atoms and the carbocyclic ketone and thioketone derivatives thereof inclues lH-benzimidazol-2-yl, 1H naphtho [2,3-dlimidazol-2-yl, lH-imidazo [4,5-flquinolin-2-yl, 1H imidazo [4,5-b] pyridin-2-yl, lH-phenanthro [9,10-d] imidazol-2-yl, 1H-imidazo [4,5-g] quinoxalin-2-yl, 2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl, 2,6-dithioxo-2,3,6,9-tetrahydro-lH-purin-8-yl, 7H-purin-8-yl, 1,6-dihydrocyclopentaimidazol-2-yl, 4-quinolin-2-yl, etc.) "Guanidino"means the radical-NHC (NH) NH2.

"Halo"means fluoro, chloro, bromo or iodo.

"Heteroatom"means an atom selected from N, O, S and P.

"Heteroatom moiety", unless indicated otherwise, means a moiety selected from -N=, -NR8-, -O-, -S-, -S(O)-, -S(O)2-, -P(O)(OR8)-, wherein R8 is hydrogen or (CI-6) alkyl.

"Heteroalkyl"means alkyl, as defined in this Section, except one or more of the carbon atoms indicated is replace by a heteroatom moiety, as defined in this Section, and any ketone, thioketone or iminoketone derivative thereof (e. g., hetero (C2 l2) alkyl inclues methoxy, ethoxy, ethylthio, 2- (2-methoxyethoxy) ethoxy, 3-methoxymethoxycarbonylmethoxy, 2- (N-ethyl-N-methylamino) ethyl, 2-ethyliminoethyl, ethoxymethoxyphosphoryloxy, etc.).

"Heteroalkylene"means alkylene, as defined in this Section, except one or more of the carbon atoms indicated is replace by a heteroatom moiety, as defined in this Section, or

any suitable combination thereof (e. g., -OS (0) 2,-S (0) 20-,-N (Rg) S (O)2-, -S(O)2NR8-, -OP (O) (OR8) 0-, and the like, wherein R8 is hydrogen or (C, _6) alkyl), and any ketone, thioketone or iminoketone derivative thereof (e. g., hetero (C2, 0) alkylene inclues azaethylene (-CH2NH-), 2-azapropenylene (-CH2N=CH2-), l-oxatrimethylene (-CH2CH2O-), 2-oxo-3-azapentamethylene, 3-aza-2-thiopentamethylene, 2-oxa- 3-oxopentamethylene, 3-aza-2-iminopentamethylene (-CH2CH2NHC (NH) Chez), 2,4-aza- 2-methyl-3,3-dioxo-3-thiapentamethylene (-CH2NHS (0) 2N (CH3) Chez), 3-hydroxy-2,4-oxa- 3-oxo-3-phosphapentamethylene (-CH20P (O) (OH) OCH2-), 3-aza- 2-oxo-4-carboxyhexamethylene, 1-thia-3-oxo- 4-azahexamethylene, 1-thia-1,1,3-trioxo-4-azahexamethylene (-CH2CH2NHC (O) CH2S(O)2-), 3-aza-4-oxoheptamethylene, 1,4,7-trioxaoctamethylene, 6-aza-1-oxa-2,5-dioxooctamethylene (-CH2CH2NHC (O) CH2CH2C(O)O-), 3-aza- 4-oxodecamethylene, etc.).

"Heteroaryl"means an aromatic monocyclic or fused polycyclic divalent radical having the number of annular atoms indicated, wherein each ring contained therein is comprise of 5 to 6 annular members and one or more of the annular atoms is a heteroatom moiety selected from-N=,-NRg-,-O-or-S-, and each ring contained therein is comprise of 5 to 6 annular members (e. g., hetero (C5-, 4) aryl inclues thienyl, furyl, pyrrolyl, pyrimidinyl, isoxazolyl, oxaxolyl, indolyl, benzo [b] thienyl, isobenzofuranyl, purinyl, isoquinolyl, pterdinyl, perimidinyl, imidazolyl, pyridyl, pyrazolyl, pyrazinyl, quinolyl, etc.).

"Heteroarylene"means an aromatic monocyclic or fused bicyclic divalent radical containing 5 to 10 annular atoms, wherein each ring contained therein is comprise of 5 to 6 annular members and one or more of the annular atoms is a heteroatom moiety selected from -N=, -NR8-, -O- or -S-, (e. g., heteroaryl inclues thienylene, furylene, pyrrolylene, pyrimidinylene, isoxazolylene, oxaxolylene, indolylene, benzo [b] thienylene, isobenzofuranylene, purinylene, isoquinolylene, imidazolylene, pyridylene, pyrazolylene, pyrazinylene, quinolylene, etc.).

"Heterocycloalkyl"means cycloalkyl, as defined in this Section, except one or more of the annular carbon atoms indicated are replace by a heteroatom moiety, as defined in this Section, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e. g., the term heterocyclo (C5-1 4) alkyl inclues piperidyl, pyrrolidinyl, pyrrolinyl,

imidazolidinyl, quinuclidinyl, morpholinyl, etc.).

"Heterocycloalkylene"means cycloalkylene, as defined in this Section, except one or more of the annular carbon atoms indicated is replace by a heteroatom moiety, as defined in this Section, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e. g., the term heterocyclo (C3, 4) alkylene inclues piperidylene, pyrrolidinylene, pyrrolinylene, imidazolidinylene, quinuclidinylene, morpholinylene, etc.).

"Heteropolycycloaryl"means polycycloaryl, as defined below, except one or more of the annular carbon atoms indicated are replace by a heteroatom moiety, as set defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e. g., heteropolycyclo (C8, 0) alkyl inclues 3,4-dihydro-2H-quinolinyl, 5,6,7,8-tetrahydroquinolinyl, 3,4-dihydro-2H- [1,8] naphthyridinyl, 2,4-dioxo-3,4-dihydro-2H-quinazolinyl, 3-oxo- 2,3-dihydrobenzo [1,4] oxazinyl, etc.).

"Heteropolycycloarylene"means polycycloarylene, as defined below, except one or more of the annular carbon atoms indicated is replace by a heteroatom moiety, as set defined in the Detailed Description of the Invention, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e. g., heteropolycyclo (C8, 0) alkylene inclues 3,4-dihydro-2H-quinolinylene, 5,6,7,8-tetrahydroquinolinylene, 3,4-dihydro-2H- [1,8] naphthyridinylene, 2,4-dioxo-3,4-dihydro-2H-quinazolinylene, 3-oxo- 2,3-dihydrobenzo [1,4] oxazinylene, etc.).

"Hydroxy"means the radical-OH.

"Imino"means the radical =NH.

"Iminoketone derivative"refers to a radical containing the moiety-C (NR)-, wherein R is hydrogen or (C, _) alkyl.

"Isomers"mean compound of Formula I having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "steroisomers". Stereoisomers that are not mirror images of one another are termed "diastereomers"and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers"or sometimes"optical isomers". A carbon atom bonded to four nonidentical substituents is termed a"chiral center". A compound with one chiral center has two

enantiomeric forms of opposite chirality is termed a"racemic mixture". A compound that has more than one chiral center has 2"-'enantiomeric pairs, where n is the number of chiral centers. Compound with more than one chiral center may exist as ether an individual diasteromer or as a mixture of diastereomers, termed a"diastereomeric mixture". When one chiral center is present a stereoisomer may be characterized by the absolut configuration of that chiral center. Absolut configuration refers to the arrangement in space of the substituents attache to the chiral center. Enantiomers are characterized by the absolut configuration of their chiral centers and described by the R-and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (e. g., see"Advanced Organic Chemistry", 3rd edition, March, Jerry, John Wiley & Sons, New York, 1985). It is understood that the names and illustration used in this application to describe compound of Formula I are meant to be encompassed all possible stereoisomers.

Thus, for example, compound of Formula I in which R4 is 1-carboxy- 2-methylpropylcarbamoyl contains a chiral center and can exist as the (R)-or (S)-isomer or a mixture thereof, racemic or otherwise. For the purposes of the present application when referring to a compound of Formula I by name or by formula and the configuration is designated, it is to be understood that the reference is to all possible configurations of the compound.

"Ketone derivative"refers to a radical containing the moiety-C (O)-.

"Leaving group"has the meaning conventionally associated with it in synthetic organic chemistry, i. e., an atom or group displaceable under alkylating conditions, and inclues, halogen, hydroxy, alkyloxy, alkylsulfonloxy (e. g., mesyloxy, ethanesulfonyloxy, etc.), arylsulfonyloxy (e. g., benzenesulfonyloxy and tosyloxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphaoxy, and the like.

"Linking group"means a saturated or unsaturated divalent radical having the number of contiguous linking atoms indicated, wherein"contiguous linking atoms"refers to the minimum number of connecting atoms linking the free valences, and any substituted, ketone, thioketone or iminoketone derivative thereof. The linking group may contain one or more heteroatom moities, as defined in this Section, one or more suitable combinations of heteroatom moities (e. g., -OS (0) 2,-S (0) 20-,-N (R8) S (O) z,-S (O) ZNRg-,

-OP (O) (OR8) 0-, etc.), alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, polycycloarylene, heteropolycycloarylene, and any combination and carbocyclic ketone, thioketone and iminoketone derivative thereof (e. g., -C (O},-C (O) O-, <BR> <BR> <BR> -OC (O)-,-N (R8) C (O)-,-C (O) NR8-,-N (R8) C (O)O-, -OC (O) NR8-,-N (R8) C (O) NR8-,<BR> <BR> <BR> <BR> -N (R8) C (N)-, etc.). Hence, a linking group containing 1 to 12 contiguous linking atoms may include one or more heteroatom moities, one or more suitable combinations of heteroatom moities and one or more groups selected *om (C2, 0) alkylene, hetero (C2 l0) alkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, polycycloarylene and heteropolycycloarylene, and any combination thereof (e. g., methylenephen-1,4-ylene (-C6H4CH2 or-CHzC6H4), methylenepiperazin-1,4-ylene (-NzC4H8CH2 or-CHZNZC4H8), methyleneoxaphen-1,4-ylene (-OC6H4CH2-or -CHZC6H40-), etc.).

"Mercapto"means the radical-SH.

"Nitro"means the radical-N02' "Optional"or"optionally"means that the subsequently described event or circumstance may or may not occur, and that the description inclues instances where the event or circumstance occurs and instances in which it does not. For example, the phrase "optionally are substituted with one to three radicals"means that the group referred to may or may not be substituted in order to fall within the scope of the invention.

"N-oxide derivatives"means a derivatives of compound of Formula I in which nitrogens are in an oxidized state (i. e., O~N) and which possess the desired pharmacological activity.

"Pathology"of a disease means the essential nature, causes and development of the disease as well as the structural and functional changes that result from the disease processes.

"Pharmaceutically acceptable"means that which is userul in preparing a pharmaceutical composition that is generall safe, non-toxic and neither biologically nor otherwise undesirabale and inclues that which is acceptable for veterinary use as well as human pharmaceutical use.

"Perhalo (C, 3) alkyl"means alkyl, as defined in this Section, except all of the hydrogen atoms are replace by haloatoms (e. g., trifluoromethyl, etc.).

"Pharmaceutically acceptable salts"means salts of compound of Formula I which are pharmaceutically acceptable, as defined in this Section, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic aicd, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.

Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydoxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

"Polycycloaryl"means a fused polycyclic radical containing the number of annular carbon atoms indicated, wherein at least one, but not all, of the fused rings comprising the radical is aromatic and each ring contained therein is comprise of 5 to 6 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e. g., polycyclo (C9_, o) aryl inclues indanyl, indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2-dihydronaphthalenyl, 2,4-dioxo-1,2,3,4-tetrahydronaphthalenyl, etc.).

"Polycycloarylene"means a fused bicyclic divalent radical containing 10 to 12 annular atoms, wherein at least one, but not both, of the fused rings comprising the radical is aromatic and each ring contained therein is comprise of 5 to 6 annular members, and any carbocyclic ketone, thioketone or iminoketone derivative thereof

(e. g., polycyclo (Cg, O) arylene inclues indanylene, indenylene, 1,2,3,4-tetrahydronaphthalenylene, 1,2-dihydronaphthalenylene, 2,4-dioxo-1,2,3,4-tetrahydronaphthalenylene, etc.).

"Prodrug derivatives"means derivatives of compound of Formula I which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I.

For example, suitable prodrug derivatives include compound of Formula I wherein the R' amidino group is hydroxy-or (CI-6) alkyloxy-substituted.

"Protected derivatives"means derivatives of compound of Formula I in which a reactive site or sites are blocked with protective groups. Protected derivatives of compound of Formula I are useful in the preparation of compound of Formula I or in themselves may be active inhibitors of factor Xa. For example, a compound of Formula I may have one or more reactive amino groups. Suitable protecting groups for reactive nitrogen atoms include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protective groups (e. g., see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).

"Therapeutically effective amount"means that amount which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.

"Thioketone derivative"refers to a radical containing the moiety-C (S)-.

"Treatment"or"treating"refers to any administration of a compound of the present invention and inclues: (1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i. e., arresting further development of the pathology and/or symptomatology), or (3) amelorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i. e., reversing the pathology and/or symptomatology).

"Sulfo"means the radical-S (O) OH.

"Uriedo"means the radical-NHC (O) NE2' The compound of Formula I and the intermediates and starting materials used in

their preparation are named in accordance with IUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides and amidines. For example, a compound of Formula I in which: A together with B comprises 5-amidino-lH-benzimidazol-2-yl, C comprises 6-methoxycarbonyl-1-methyl-lH-benzimidazol-2-yl and X3 is ethylene is named methyl 2- [2- (5-amidino-IH-benzimidazol-2-yl)ethyl]-3-methyl-3H-benzimida zole-5-carboxylate; A together with B comprises 5-amidino-lH-benzimidazol-2-yl, C comprises 5-(4-aminophenoxy)-lH-benzimidazol-2-yl(4-aminophenoxy)-lH-b enzimidazol-2-yl and X3 is ethylene is named 2-[2-(5-(4-aminophenoxy)-1-H-benzimidazol-2-yl) ethyl]-lH-benzimidazole- 5-carboxamidine; and A together with B comprises 5-amidino-lH-benzimidazol-2-yl, C comprises 1H-benzimidazol-2-yl and X3 is ethylene is named 2-{2-[2-(5-amidino- lH-benzimidazol-2-yl) ethyl]-lH-benzimidazol-5-ylcarbonylamino}-3-methylbutyric acid.

Certain compound of Formula I exist in tautomeric equilibrium. For example, compound of Formula I in which C comprise a 1H-imidazol-2-yl exist in equilibrium between tautomers of the following formulae: wherein R4 is not hydrogen. Compound of Formula I which exist as tautomers are named, illustrated or otherwise described in this application as one possible tautomer. However, it

is to be understood that the all possible tautomers are meant to be encompassed by such names, illustrations and descriptions. Thus, the name 2- [2- (5-chloro- 1H-benzimidazol-2-yl)ethyl]-1H-benzimidazole-5-carboxamidine is meant to include its tautomers 2-[2-(6-chloro-1H-benzimidazol-2-yl)ethyl]-1H-benzimidazole- 5-carboxamidine, 2- [2-(6-chloro-1 H-benzimidazol-2-yl) ethyl]-3H-benzimidazole-5-carboxamidine and 2- [2- (5-chloro-lH-benzimidazol-2-yl)ethyl]- 3H-benzimidazole-5-carboxamidine.

Presently Preferred Embodiments: While the broadest definition of this Invention is set forth in the Summary of the Invention, certain aspects of the Invention are preferred. A preferred aspect of the Invention are compound of Formula I in which: n2 is 1; A together with B comprises a fused heterobicyclic radical containing 8 to 10 annular atoms, wherein each ring contains 5 to 6 annular members; C comprises a fused heteropolycyclic radical containing from 9 to 13 annular atoms, wherein each ring contains 5 to 6 annular atoms; X3 represents a linking group of Formula (a) or (b) in which D comprises a monocyclic divalent radical containing 6 annular carbon atoms; each R3 is independently hydrogen, halo or hydroxy; and each R4, R5 and R7 is independently -R6 or -X6-R6, wherein x6 is a linking group containing 1 to 10 contiguous linking atoms and R6 is hydrogen, (C6-10) aryl, cyclo(C3-6) alkyl, hetero (CS_, o) aryl, heterocyclo (C5 6) alkyl or hetero (C8_, o) polycycloaryl.

A further preferred aspect of the Invention is a compound of Formula II:

in which E together with the vinylene moiety to which it is fused comprises a monocyclic or heteromonocyclic divalent radical containing 6 annular atoms; X3 is ethylene, carbamoylethylene, methoxycarbonylethylene, trans-1,2-methylvinylene, 1,2-phenylene or 1-cyclohexen-1,2-ylene; and X'and X5 are independently a heteroatom moiety selected -O-and-S-.from-NR5-, A further preferred aspect of the Invention is a compound of Formula 11 in which each R4, R5and/or R'is independently-R 6, wherein R6 is (C6-, 4) aryl, cyclo(C3-14) alkyl, hetero (C5-14) aryl, heterocyclo (C3_14) alkyl, hetero (C8-14)polycycloaryl or (C9-14)polycycloaryl, or -X6-R6, wherein X6 is (Cl 10) alkylene, or (CZ_, o) heteroalkylene and R6 is hydrogen, hetero(C5-14)aryl,heterocyclo(C3-14)alkyl,(C6-14)aryl,cyclo( C3-14)alkyl, (C9-14)polycycloaryl.hetero(C8-14)polycycloarylor A further preferred aspect of the Invention is a compound of Formula 11 in which each R3 is independently cyano, halo, nitro, perhalo (C, _3) alkyl or perhalo (C1-3) alkyloxy and/or each R4 is independently hydroxy, mercapto, sulfo,-NHRg or-OP (O) (OR8) OH, wherein R8 is hydrogen or (C1-6) alkyl.

A further preferred aspect of the Invention is a compound of Formula 11 in which one of X'and X5 iS-NR5-and the other is a heteroatom selected from-0-and-S- ; in particular, compound of Formula 11 wherein X'is-S-and XS is-NR5-.

Further preferred are the following compound of Formula I : methyl 2-[2-(5-amidino-1H-benzimidazol-2-yl)ethyl]-3-methyl-3H-benz imidazole- 5-carboxylate; 2-[2-(5-amidino-1H-benzimidazol-2-yl)ethyl]-N-benzyl-3H-benz imidazole-5- carboxamide;

3-(5-amidino-lH-benzimidazol-2-yl)-2-(lH-benzimidazol-2-yl)( 5-amidino-lH-benzimidazol-2-yl)-2-(lH-benzimidazol-2-yl) propionamide;<BR> <BR> <BR> <BR> <BR> <BR> 2-[2-(5-imidazol-1-yl-1-H-benzimidazol-2-yl) ethyl]-lH-benzimidazole- 5-carboxamidine; 2- [2- (5-amidino-IH-benzimidazol-2-yl) ethyl]-3-methyl-3H-benzimidazole-5- carboxylic acid; 2- [2- (I-benzyl-IH-benzimidazol-2-yl) ethyl]-IH-benzimidazole-5-carboxamidine; 2- [2- (lH-benzimidazol-2-yl) ethyl]-3- (3-phenylpropyl)-3H-benzimidazole- 5-carboxamidine; 2-{2-[2-(5-amidino-1H-benzimidazol-2-yl)ethyl]-1H-benzimidaz ol-5- ylcarbonylamino}-3-methylbutyric acid; 2- [2- (5-amidino-IH-benzimidazol-2-yl) ethyl]-IH-benzimidazole-5-carboxylic acid; 2- {2-[2-(5-amidino-lH-benzimidazol-2-yl) ethyl]- 3H benzimidazol-5-ylcarbonylamino} pentandioic acid; 6-amino-2- {2-[2-(5-amidino-lH-benzimidazol-2-yl) ethyl]- lH-benzimidazol-5-ylcarbonylamino}-3-methylhexanoic acid; 2- {2-[2-(5-amidino-lH-benzimidazol-2-yl) ethyl]- lH-benzimidazol-5-ylcarbonylamino} propionic acid ; and 2- {2- [2- (5-amidino-lH-benzimidazol-2-yl) ethyl]-1H-benzimidazol-5- ylcarbonylamino}-3-phenylpropionic acid.

Pharmacology and Utility: The compound of this invention are factor Xa inhibitors and, as such, are useful for treating diseases in which factor Xa activity contributes to the pathology and/or symptomatology of the disease. Uses for factor Xa inhibitors include therapy in treating venous thromboembolism (obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vesse), to reduce the risk of myocardial infarction in patients with unstable angina, to ameliorate further loss of cardiac function in patients with acute myocardial infarction, to reduce the risk of occlusion of saphenous grafts, to reduce periprocedural thrombosis in patients undergoing angioplasty procedures, to reduce the risk of ischemic stroke in patients with atrial fibrillation, to reduce the risk of embolism associated with mechanical heart valves and valvular heart disease, to

prevent ischemic strokes in patients with cerebrovascular atherosclerosis, in patients with peripheral vascular disease, and the like.

Suitable in vitro assays for measuring factor Xa activity and the inhibition thereof by test compound are known. Typically, the assay mesures factor Xa induced hydrolysis of a peptide base substrat. Suitable in vivo and ex vivo models for measuring the anti-coagulation activity of test compound are known to those of ordinary skill in the art.

For further details of the assays for measuring factor Xa inhibitor and/or anticoagulant activity see Examples 17,18 and 19, infra.

Administration and Pharmaceutical Compositions: In general, compound of Formula I will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in <BR> <BR> <BR> <BR> combination Aith another therapeutic agent. A therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. For example, therapeutically effective amounts of a compound of Formula I for anticoagulant therapy may range from 0.1 micrograms per kilogram body weight (, ug/kg) per day to 1 milligram per kilogram body weight (mg/kg) per day, typically 1 llg/kg/day to 0.1 mg/kg/day. Therefore, a therapeutically effective amount for a 80 kg human patient may range from 10 Fg/day to 10 mg/day, typically 0.1 mg/day to 10 mg/day. In general, one of ordinary skill in the art, acting in relance upon personal knowledge and the disclosure of this application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.

The compound of Formula I can be administered as pharmaceutical compositions by one of the following routes: oral, systemic (e. g., transdermal, intranasal or by suppository) or parenteral (e. g., intramuscular, intravenous or subcutaneous). Compositions can take the form of tables, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprise of, in general, a compound of Formula I in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient.

Such excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e. g., peanut oil, soybean oil, mineral oil, sesame oil, etc.). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.

The amount of a compound of Formula I in the composition may vary widely depending upon the type of formulation, size of a unit dosage, kind of excipients and other factors known to those of skill in the art of pharmaceutical sciences. In general, a composition of a compound of Formula I for treating a given disease will comprise from 0.01% w to 10% w, preferably 0.3% w to I % w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. Representative pharmaceutical formulations containing a compound of Formula I are described in Example.

Chemistry: Compound of Formula I in which X4 and X5 are adjacent members of an oxazol-2- yl, lH-imidazol-2-yl or thiazol-2-yl ring and C comprises a fused polycyclic radical can be prepared by the methods depicted in the following rection scheme: Schème 1

in which R9 is-C (O) L or-CN, wherein L is a leaving group, E together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and optionally one or more annular members is a heteroatom moiety, X12 is -O-, -N(R5)- or -S -, R10 is -OH, -NHR5 or -SH and heteroatom moiety, n2, n3, n4, A, B, X1, X2, X3, R', R2, R3, R4 and R5 are as defined in the Summary of the Invention.

Compound of Formula I in which X4 and X5 are adjacent members of an oxazol-2- yl, 1H-imidazol-2-yl or thiazol-2-yl ring comprising a fused polycyclic radical (Formula I (a)) can be prepared by reacting a compound of Formula 1 with a compound of Formula 2 (a). The rection may be carried out neat, but preferably is carried out in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone (DMPU) or polyphosphoric acid, at 160 to 200°C preferably 170-180 °C, and requires 2 to 3 hours to complete (e. g., see Examples 3 and 4, infra.). Compound of Formula I in which C comprises oxazol-2-yl, 1H-imdazol-2-yl or thiazol-2-yl can be prepared by proceeding as in Scheme I, but replacing the compound of Formula 2 (a) with a compound of Formula 2 (b):

in which R'° is-OH,-NHRS or-SH and each p, q, R3, R4 and R5 is as defined in the Summary of the Invention.

In a similar fashion, compound of Formula I in which X'and x2 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring can be prepared by the methods depicted in the following rection scheme: Scheme 2 in which R is-C (O) L or-CN, wherein L is a leaving group, x'2 is N (RS), O or S, R10 is -OH,-NHRS or-SH and n2, n3, n4, B, C, X3, X4, X5, R1, R2, R3, R4 and R5 are as defined in

the Summary of the Invention (e. g., see Example 5, infra.).

Compound of Formula I can be prepared by the methods depicted in the following rection scheme: Scheme 3 X2. X XR4) n4 NC X, x A X1 X5 C R) n3 (R') n3 hydroxylamine HCl Zn/HOAc NH2 XZ. XXR4) n4 B A XI X5/\ 3 (R2). 2 l (c) in which n2, n3, n4, A, B, C, X', X2, XI, X4, X5, R2, R3, R4 and R5 are as defined in the Summary of the Invention.

Compound of Formula I can be prepared by reacting a corresponding nitrile with hydroxylamine hydrochloride to give a N-hydroxy amidine and then dehydroxylating to give the unsubstituted amidine. The rection with the hydroxylamine may be carried out in the presence of sodium bicarbonate and in a suitable solvent (e. g., ethanol) at reflux temperature and requires 12 to 18 hours. The dehydroxylation can be effected by reacting the N-hydroxy amidine with zinc in the presence of acetic acid at reflux temperature and requires 3 to 4 hours to complet.

In general, the starting materials required for preparing the compound of Formula I are either commercially available or can be readily prepared by methods known to those of

ordinary skill in the art or as described herein. For example, compound of Formula 1 or <BR> <BR> Formula 3 in which L is hydroxy and X'and Xz or X4 and XS are adjacent members of an oxazole, imidazole or thiazole ring can be prepared by reacting an appropriate compound of Formula 4 or Formula 2, respectively, with an anhydride of Formula 4: in which X3 is as defined in the Summary of the Invention (e. g., dihydrofuran-2,5-dione, furan-2,5-dione, 3,4-dimethylfuran-2,5-dione, isobenzofuran-1,3-dione, 4,5,6,7-tetrahydroisobenzofuran-1,3-dione, etc.). The rection is carried out in a suitable solvent (e. g., acetic acid, etc.) 80 to 100°C, and requires 6 to 10 hours (for further details see Example 1, infra.).

Compound of Formula 2 (a) in which R4 is-OR,-NRR'or-SR, wherein R and R' are independent or together with the nitrogen atom to which they are attache form heterocycloalkyl, can be prepared by reacting a correspondingly appropriate amine, alcool, thiol or heterocycloalkane with a corresponding halo-subsituted nitroaniline and then reducing. The rection with the halo-substituted nitroaniline typically is carried out in a suitable solvent (e. g., THF) at 25 to 60°C and requires 4 to 5 hours to complet.

Additional procedures: Compound of Formula I in which R4, R5 or R7 comprises -X13C(O)NR8X14R6 can be prepared by reacting a corresponding compound of Formula I in which R4, R5 or R7 comprises-X'3C (O) OH with a compound having the formula R6X14NHR8, wherein X13 and X14 are linking groups containing n13 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R8 is hydrogen or (C1-6) alkyl and R6 is as defined in the Summary of the Invention. The rection typically is carried out in the presence of 1-hydroxybenzotriazole (HOBT) and a coupling agent (e. g., benzotriazol-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP),

1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 1, 1-carbonyldiimidazole, etc.) and a non-nucleophillic base (e. g., N methylmorpholine, N, N diisopropylethylamine, etc.) and in a suitable solvent (e. g., N, N dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, etc., preferably DMF) at 20 to 25°C and requires 12 to 24 hours to complete (e. g., see Example 3, infra.).

Compound of Formula I in which R4, R5 or R7 comprises -X13NR8C(O)X14R6 can be prepared by reacting a corresponding compound of Formula I in which R4, R5 or R' comprises-X'3NHR8 with a compound having the formula R6X'4C (O) OH, wherein X13 and X14 are linking groups containing nul 3 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R8 is hydrogen or (C, _6) alkyl and R6 is as defined in the Summary of the Invention. The rection typically is carried out in the presence of a coupling agent (e. g., PyBOP, EDCI, 1, 1-carbonyldiimidazole, etc.) and a non-nucleophillic base (e. g., N-methylmorpholine, N,N-diisopropylethylamine, etc.) and in a suitable solvent (e. g., DMF, THF, dichloromethane, etc., preferably DMF) at 20 to 25°C and requires 6 to 24 hours to complet.

Compound of Formula I in which R4, R5 or R7 comprises -X13NR8S(O)2X14R6 can be prepared by reacting a corresponding compound of Formula I in which R4, R5 or R7 comprises -X3-NHR8 with a compound having the formula R'X 14S (0) 2C" wherein X13 and X14 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of nul 3 and nl4 is 0 to 10, R8 is hydrogen or (C1-6) alkyl and R6 is as defined in the Summary of the Invention. The rection typically is carried out in the presence of a non-nucleophillic base (e. g., N methylmorpholine, N, N diisopropylethylamine, etc.) and in a suitable solvent (e. g., DMF, THF, dichloromethane, etc., preferably DMF) at 20 to 25°C and requires 12 to 24 hours to complet.

Compound of Formula I in which R4, R5 or R7 comprises -X13NR8CH2X14R6 can be prepared by reacting a corresponding compound of Formula I in which R4, R5 or R7 comprises-X'3NHR8 with a compound having the formula R6X'4C (O) H under reducing conditions, wherein X13 and X14 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of n7 and n8 is 0 to 10, Ru ils hydrogen or (Cl 6) alkyl and R6 is as defined in the Summary of the Invention. The rection typically is carried out in the presence of a reducing agent (e. g., sodium cyanoborohydride) and in a

suitable solvent (e. g., methanol) at 20 to 25 °C and requires 12 to 24 hours to complet.

Compound of Formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable base addition salts of compound of Formula I may be prepared by reacting the free acid forms of compound of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of the pharmaceutically acceptable salts of compound of Formula I are set forth in the definitions section of this application. Alternatively, the salt forms of the compound of Formula I may be prepared using salts of the starting materials or intermediates.

The free acid or free base forms of the compound of Formula I can be prepared from the corresponding base addition salt or acid addition salt form. For example, compound of Formula I in an acid addition salt form may be converted to the corresponding free base by treating with a suitable base (e. g., ammonium hydroxide solution, sodium hydroxide, etc.). Compound of Formula I in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid (e. g., hydrochloric acid, etc).

The N-oxides of compound of Formula I can be prepared by methods known to those of ordinary skill in the art. For example, N-oxides can be prepared by treating an unoxidized form of the compound of Formula I with an oxidizing agent (e. g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (e. g., a halogenated such as methylene chloride) at approximately 0 °C. Alternatively, the N-oxides of the compound of Formula I can be prepared from the N-oxide of an appropriate starting material.

Compound of Formula I in unoxidized form can be prepared from N-oxides of compound of Formula I by treating with a reducing agent (e. g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in an suitable inert organic solvent (e. g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 OC.

Prodrug derivatives of the compound of Formula I can be prepared by methods

known to those of ordinary skill in the art (e. g., for further details see Saunier et al. (1994), Bioorganic and Medicinal Chemistry Lettes. 4: 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e. g., lol-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, etc.).

Protected derivatives of the compound of Formula I can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protective groups and their removal can be found in T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.

Compound of Formula I can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compound, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of compound of Formula I, dissociable complexes are preferred (e. g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties (e. g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking avantage of these dissimilarities. The diastereomers can be separated by chromotography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compound from their racemic mixtures can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc.

(1981).

In summary, an aspect of this Invention is a process for preparing a compound of Formula I, which process comprises: (a) reacting a compound of Formula 1:

or a protected derivative thereof, with a diamine of Formula 2 (a) or 2 (b):

or a protected derivative thereof, in which R9 is-C (O) L or-CN, wherein L is a leaving group, E together with the vinylene moiety to which it is fused comprises a monocyclic or fused bicyclic divalent radical containing from 5 to 15 annular atoms, wherein each ring contains 5 to 7 annular atoms and optionally one or more annular members is a heteroatom, , X5 is N (RS), O or S, R10 is -OH, -NHR5 or -SH and heteroatom n2, n3, n4, B, X', XZ, X3, R1, R2, R3, R5 and R4 are as defined in the Summary of the Invention, to give a compound of <BR> <BR> <BR> Formula I in which X4 and X5 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring; or (b) reacting a compound of Formula 3:

or a protected derivative thereof, with a compound of Formula 4:

or a protected derivative thereof, which R is-C (O) L or-CN, wherein L is a leaving group, R10 is -OH, -NHR5 or -SH and n2, n3, n3, B, C, XI, X4, X5, R', R2, R3, R4 and R5 are as defined in the Summary of the Invention, to give a compound of Formula I in which X'and X2 are adjacent members of an oxazol-2-yl, lH-imidazol-2-yl or thiazol-2-yl ring; or (c) reacting a compound of Formula 5:

with hydroxylamine hydrochloride, wherein n2, n3, n3, A, B, C, XI, X2, X3, X4, X5, R1, R2, R3 and R4 are as defined above, to give a corresponding N-hydroxycarboxamidine and then dehydroxylating; (e) optionally further reacting a compound of Formula I in which R4, R5 or R7 comprises -X'3C (O) OH with a compound having the formula R6X'4NHR8 to give a compound of Formula I in which R4, R5 or R7 comprises -X13C(O)NR8X14R6, wherein X'3 and X'4 are

linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R8 is hydrogen or (Cl 6) alkyl and R6 is as defined in the Summary of the Invention; (f) optionally further reacting a compound of Formula I in which R4, R5 or R7 comprises -X'3NHRg with a compound having the formula R6Xl4C (O) OH to give a compound of Formula I in which orR7comprises-X13NR8C(O)X14R6,whereinX13andX14areR5 linking groups containing nul 3 and nul 4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R8 is hydrogen or (CI_6) alkyl and R6 is as defined in the Summary of the Invention; (g) optionally further reacting a compound of Formula I in which R4, R5 or R7 comprises -X'3NHRg with a compound having the formula R6X'4S (O) ZCl to give a compound of Formula I in which R4, R5 or R7 comprises -X13NR8S(O)2X14R6, wherein X13 and X'4 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R8 is hydrogen or (Cl 6) alkyl and R6 is as defined in the Summary of the Invention; (h) optionally further reacting a compound of Formula I in which R4, R5 or R7 comprises -X'3NHRg with a compound having the formula R6Xl4C (O) H under reducing conditions to give a compound of Formula I in which R4, R or R7 comprises -X13NR8CH2X14R6, wherein X13 and X14 are linking groups containing nl3 and nl4 contiguous linking atoms, respectively, wherein the sum of nl3 and nl4 is 0 to 10, R8 is hydrogen or (Cl 6) alkyl and R6 is as defined in the Summary of the Invention; (i) optionally converting a non-salt form of a compound of Formula I to a pharmaceutically acceptable salt with a pharmaceutically acceptable inorganic or organic acid or base; (j) optionally converting an acid addition salt or base addition salt form of a compound of Formula I to the corresponding free base or free acid, respectively, with a suitable base or acid; (k) optionally separating a mixture of stereoisomers of a compound of Formula I to give a single stereoisomer; (1) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;

(ion) optionally converting an N-oxide form of a compound of Formula I its unoxidized form; (n) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative; and (o) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form.

In any of the above processes, a reference to Formula I refers to such Formula wherein each X, R1, R2, R3, R4 and Rus are as defined in their broadest definitions set forth in the Summary of the Invention, with the processes applying particularly well to the presently preferred embodiments.

Examples: EXAMPLE 1 3-(5-Amidino-1H-benzimidazol-2-yl)propionicacid, a compound of Formula 1 in which L is hydroxy, A together with B comprises 5-amidino- lH-benzimidazol-2-yl and X3 is-CH2CH2- A mixture comprising succinic anhydride (2.0 g, 19.98 mmol, 1.2 eq.), 3,4-diaminobenzamidine hydrochloride (3.1 g, 16.65 mmol., 1 eq.) and acetic acid (50 mL) was heated at 80 °C for 6 hours to give a precipitate. The precipitate was filtered, washed with excess ethyl acetate and diethyl ether and dried under vacuum to give 3- (5-amidino- lH-benzimidazol-2-yl) propionic acid (2.8 g, 11.86 mmol) as an off-white solid.

EXAMPLE 2 Methyl 3- (8-benzyloxyquinolin-2-yl) propionate, a compound of Formula 3 in which L is methoxy, C comprises 3- (8-benzyloxyquinolin-2-yl) and X3 is-CHZCHZ (a) A mixture comprising 2-methylquinolin-8-ol (8.9 g, 50 mmol), potassium carbonate

(18.8 g, 100 mmol), DMF (85 mL) and benzyl bromide (8.9 mL, 75 mmol) was heated at 60 °C for approximately 12 hours, filtered and concentrated. The residue was dissolve in ethyl acetate and the solution was extracted into 1 N hydrochloric acid. The aqueous layer was made basic with sodium bicarbonate and the product was extracted into ether. The ether solution was dried (MgS04) and concentrated to provide 8-benzyloxy-2-methylquinoline (10 g, 80 %) as a white solid.

(b) A solution comprising selenium dioxide (3.3 g, 30 mmol) in dioxane (60 mL) and water (1.5 mL) was warmed in a water bath and then 8-benzyloxy-2-methylquinoline (5.0 g, 20 mmol) was added portion-wise to the solution over 15 minutes. The mixture was heated at 50° C for 7 hours, cooled in an ice bath, filtered and concentrated to give orange crystals.

The crystals were dissolve in hot hexanes, leaving a red residue behind. The solution was cooled to provide yellow crystals. The crystals were isolated and dried to provide 8-benzyloxyquinoline-2-carbaldehyde (3.9 g, 74%).

(c) A solution comprising potassium hydride (448 mg, 11.2 mmol), THF (10 mL), and trimethylphosphonoacetate (1.81 mL, 11.2 mmol) was stirred for 45 minutes, then added over 15 minutes to a solution comprising 8-benzyloxyquinoline-2-carboxaldehyde (1.34 g, 5.6 mmol) in THF (10 mL). The mixture was quenched with ammonium chloride after 2 hours and then extracted with methylene chloride. The extract was washed with 0.5 N sodium hydroxide, dried (MgS04), and concentrated to provide methyl 3- (8-benzyloxyquinolin-2-yl) acrylate (1.5 g, 94%) as a yellow solid.

(d) A mixture comprising methyl 3- (8-benzyloxyquinolin-2-yl) acrylate (1.5 g, 4.7 mmol), methanol (50 mL) and a catalytic amount of 10% palladium on carbon was stirred under hydrogen balloon at room temperature for 15 hours, filtered through Celite and concentrated. The residue was purifie by chromatography on silica (25% ethyl acetate in hexanes) to provide methyl 3- (8-benzyloxyquinolin-2-yl) propionate (550 mg, 51%).

EXAMPLE 3 2-[2-(1H-Benzimidazol-2-yl)ethyl]-1H-benzimidazole-5-carboxa midine (Compound 1), a compound of Formula I in which A together with B comprises 5-amidino- 1H-benzimidazol-2-yl, C comprises lH-benzimidazol-2-yl and X3 is-CHZCHZ A mixture comprising 3- (5-amidino-lH-benzimidazol-2-yl) propionic acid (1 g, 5.26 mmol), 1,2-benzenediamine dihydrochloride (0.98 g, 5.26 mmol) and polyphosphoric acid (3 mL) was heated at 180°C for 3 hours. The mixture was cooled, diluted with water (2 mL) and basified with ION sodium hydroxide to pH 8 to give a precipitate. The precipitate was collecte and washed with water. The residue was purifie by reverse phase HPLC (1% trifluoroacetic acid/acetonitrile) with a 2-27% gradient. The resulting pure fractions were lyophilized to provide 2-[2-(1H-benzimidazol-2-yl)ethyl-1H-benzimidazole- 5-carboxamidine (1.4 g, 3.34 mmol) as a white solid, MS (ESI): Calculated for C, 7H, 6N6: MH+: 304.35 Found: MH+ 304.9.

Proceeding as in Example 3, but substituting different starting materials, provided the following Formula I : 2- [2- (I-methyl-lH-benzimidazol-2-yl) ethyl]-lH-benzimidazole-5-carboxamidine (Compound 2), Calculated for C, 8H18N6: MH+: 318.16 Found: MH+ 318.8; 2-[2-(1-benzyl-1H-benzimidazol-2-yl)ethyl]-1H-benzimidazole- 5-carboxamidine (Compound 3), Calculated for C24H22N6 : MH+: 394.19 Found: MH+ 394.6; 2- [2- (l-pyrid-4-yl-lH-benzimidazol-2-yl) ethyl]-IH-benzimidazole-5-carboxamidinc (Compound 4), Calculated for C22HlgN7: MH+: 381.2 Found: MH+ 381.9; 2- [2- (IH-imidazo [4,5-c] pyrid-2-yl) ethyl]-lH-benzimidazole-5-carboxamidine (Compound 5); Calculated for C16H15N7 : MH+: 305. 14 Found: MH+ 306. 1; 2- [2- (9H-purin-8-yl) ethyl]-lH-benzimidazole-5-carboxamidine (Compound 6); Calculated

for C16Hl5N7: MH+: 306.13 Found: MH+ 307. 2; 2-[2-(5-imidazol-1-yl-1-H-benzimidazol-2-yl)ethyl]-1H-benzim idazole- 5-carboxamidine (Compound 7); Calculated for C20H18N8 : MH+: 370.17 Found: MH-370.9; 2- [2- (lH-naptho[2,3-dlimidazol-2-yl) ethyl]-lH-benzimidazole-5-carboxamidine (Compound 8); Calculated for C,, H, 8N6: MH+: 354.16 Found: NH+ 355. 0; 2- [2-(5-benzoyl-1-H-benzimidazol-2-yl) ethyl]-1 H-benzimidazole-5-carboxamidine (Compound 9); Calculated for C24H20N6O : MH+: 408.17 Found: MH+ 409. 0; 2-[2-(5-chloro-1H-benzimidazol-2-yl)ethyl]-1H-benzimidazole- 5-carboxamidine (Compound 10); Calculated for C, 7H, 5ClN6: MH+: 338.1 Found: MH+ 338. 8; 2-[2-(5-fluoro-1-H-benzimidazol-2-yl)ethyl]-1H-benzimidazole -5-carboxamidine (Compound 11); Calculated for C17Hl5N5F: MH+: 322.13 Found: MH+ 322. 9; 2- [2- (5- (4-aminophenoxy)-l-H-benzimidazol-2-yl) ethyl]-lH-benzimidazole- 5-carboxamidine (Compound 12); Calculated for C23H2lN70: MH+: 411.18 Found: MH- 412; 2-[2-(5,6-difluoro-1-H-benzimidazol-2-ylethyl]-1H-benzimidaz ole- 5-carboxamidine (Compound 13); Calculated for C17H14N6F2 : MH+: 340.12 Found: MH 341.0; methyl 2- [2- (5-amidino-lH-benzimidazol-2-yl) ethyl]-IH-benzimidazole-5- carboxylate (Compound 14); Calculated for C, 9H18N6O2 : MH+: 362.39 Found: MH+ 363. 2; 2- [2- (5-amidino-lH-benzimidazol-2-yl) ethyl]-lH-benzimidazole-5-carboxylic acid (Compound 15); Calculated for C18H, 6NbOZ: MH+: 348.36 Found: MH+ 348. 9; methyl 2- [2- (5-amidino-IH-benzimidazol-2-yl) ethyl]-3-methyl-3H-benzimidazole- 5-carboxylate (Compound 16); Calculated for C20H20N6O2 : MH+: 376.42 Found: MH- 377.1; 2- [2- (5-amidino-IH-benzimidazol-2-yl) ethyl]-3-methyl-3H-benzimidazole-5- carboxylic acid (Compound 17); Calculated for C19H18N6O2 : MH+: 362.39 Found: MH+ 363; 2- [2- (5-amidino-IH-benzimidazol-2-yl) ethyl]-l-methyl-lH-benzimidazole-5- carboxylic acid (Compound 18); Calculated for C, 9H, 8N602 : MH+: 362.39 Found: MH+ 363;

2- [2- (lH-benzimidazol-2-yl) ethyl]-3- (3-phenylpropyl)-3H-benzimidazole- 5-carboxamidine (Compound 19); Calculated for C26H26N6: MH+: 422. 53 Found: MH+ 423 ; trans-2-[2-(lH-benzimidazol-2-yl)-1-methylpropenyl]-3H-benzi midazole- 5-carboxamidine (Compound 20); Calculated for C, gH,, N6: MH+ : 330.16 Found: MHt 331.0; 2-[2-(1H-benzimidazol-2-yl)cyclohex-1-enyl]-3H-benzimidazole -5-carboxamidine (Compound 21); Calculated for C21H20N6 : MH+ : 356.17 Found: MH+ 357 ; 2-[2-(1H-benzimidazol-2-yl)phenyl]-3H-benzimidazole-5-carbox amidine (Compound 22); Calculated for C2, H, 6N6: MH+ : 352.14 Found: MHt 352.9; 2-[2-(lH-imidazo [4,5-c] pyrid-2-yl) phenyl]-3H-benzimidazole-5-carboxamidine (Compound 23); Calculated for CZOHISNy MH+: 353.14 Found: MH+ 353. 9; and 2-(2-benzothiazol-2-ylethyl)-lH-benzimidazole-5-carboxamidin e(2-benzothiazol-2-ylethyl)-lH-benzimidazole-5-carboxamidine (Compound 24); Calculated for C, 7HI5N5S: MH+: 321.1 Found: MH+ 321.9.

EXAMPLE 4 2- [2- (8-Hydroxyquinolin-2-yl) ethyl]-1H-benzimidazole-5-carboxamidine (Compound 35), a compound of Formula I in which A together with B comprises 5-amidino- 1H-benzimidazol-2-yl, C comprises 8-hydroxyquinolin-2-yl and X3 is-CHZCHZ A mixture comprising methyl 3- (8-benzyloxyquinolin-2-yl) acrylate (550 mg, 2.4 mmol), DMPU (2 mL) and diaminobenzamidine hydrochloride (448 mg, 2.4 mmol) in a sealed pressure tube was heated at 180 °C for 3 hours, allowed to cool to 100 °C, and diluted with acetonitrile to give a yellow precipitate (790 mg, 99%). The product was further purifie by reverse phase HPLC using a two solvent system (solvent A: 20 mM HUI in H20; solvent B: CH3CN) with programme elution at 50 mL/min (0 min, 98% A, 2% B; 15 min, 98% A, 2% B; 50 min, 73% A, 27% B) on a C18 preparatory column. 1H NMR 8 <BR> <BR> <BR> <BR> 10.6 (bs, 1 H), 9.5 (s, 2 H), 9.1 (s, 2H), 8.5 (d, 1 H, J= 10 Hz), 8.2 (s, 1 H), 7.9 (d, 1 H, J=

10 Hz), 7.8 (d, 1 H, J=10 Hz), 7.7 (d, 1 H, J=10 Hz), 7.5 (s, 2 H), 7.2 (s, 1 H), 3.7 (s, 4 H). LRMS (Bioion) calcd ClgHl7N50 + H 332.1; found 332.2.

EXAMPLE 5 3-(5-Amidino-lH-benzimidazol-2-yl)-2-(lH-benzimidazol-2-yl)( 5-Amidino-lH-benzimidazol-2-yl)-2-(lH-benzimidazol-2-yl) propionamide (Compound 31), a compound of Formula I in which A together with B comprises 5-amidino- lH-benzimidazol-2-yl, C comprises lH-benzimidazol-2-yl and X3 is carbamoylethylene A mixture of ethyl 2- (lH-benzimidazol-2-yl)-3-cyanopropionate (0.5 g, 2.06 mmol) and 3,4-diaminobenzamidine hydrochloride (0.32 g, 1.71 mmol) was heated at 180 °C for 2 hours and concentrated. The residue was taken up in 0.1 N hydrochloric acid and purifie by reverse HPLC (1% TFA/acetonitrile) with a 2-27% gradient to provide 3- (5-amidino- lH-benzimidazol-2-yl)-2-(lH-benzimidazol-2-yl)(lH-benzimidaz ol-2-yl) propionamide (0.15 g) as a white solid, Electrospray MS (ESI): Calculated for C,, H, 6N60,: MH+ : 332.36 Found: MH+ 333.

EXAMPLE 6 Methyl 3- (5-amidino-lH-benzimidazol-2-yl)-2-(lH-benzimidazol-2-yl) propionate (Compound 32), a compound of Formula I in which A together with B comprises 5-amidino- lH-benzimidazol-2-yl, C comprises lH-benzimidazol-2-yl and X3 is methoxycarbonyl A solution comprising 3-(5-amidino-lH-benzimidazol-2-yl)- 2-(lH-benzimidazol-2-yl)(lH-benzimidazol-2-yl) propionamide (50 mg) hydrogen chloride/dioxane (4M, 5 mL) and methanol (lOmL) in a sealed tube was heated overnight and concentrated. The residue was purifie by reverse HPLC (1% TFA/acetonitrile) with a 2-27% gradient to provide methyl 3-(5-amidino-lH-benzimidazol-2-yl)-2-(lH-benzimidazol-2-yl)( 5-amidino-lH-benzimidazol-2-yl)-2-(lH-benzimidazol-2-yl) propionate (0.01 g) as an off-white solid, Calculated for C, gH,, N602: MH+: 326.39 Found: MH+ 362. 9. <BR> <BR> <BR> <BR> <BR> <BR> <P> EXAMPLE 7<BR> <BR> <BR> <BR> <BR> <BR> 2- [2- (5-Amidino-IH-benzimidazol-2-yl) ethyl]-N-benzyl-3H-benzimidazole-5-carboxamide (Compound 25), a compound of Formula I in which A together with B comprises 5-amidino- 1H-benzimidazol-2-yl, C comprises 5-benzylcarbamoyl-lH-benzimidazol-2-yl and X3 is -CH2CH2- A mixture comprising 2- [2- (5-amidino-IH-benzimidazol-2-yl) ethyl]- 3H-benzimidazole-5-carboxylic acid (0.4 g, 1.15 mmol), EDC (0.265 g, 1.38 mmol), HOBT (0.187 g, 1.38 mmol), NMM (0.35 g, 3.45 mmol, 0.38 mL) and THF (20 mL) was stirred at room temperature 1 hour and then benzylamine (0.25 g, 2.3 mmol) was added. The mixture was over night, poured into ether and decanted. The residue was taken up in 0.01 N hydrochoric acid and purifie by reverse HPLC (1% TFA/acetonitrile) with a 2-27% gradient to provide 2- [2- (5-amidino-IH-benzimidazol-2-yl) ethyl]-N-benzyl- 3H benzimidazole-5-carboxamide (0.18 g) as a bright yellow solid, MS (ESI): Calculated

for C25H23N70: MH+: 437.5 Found: MH+ 438.

Proceeding as in Example 7, but substituting different starting materials, provided the following compound of Formula I : 2-{2-[2-(5-amidino-1H-benzimidazol-2-yl)ethyl]- lH-benzimidazol-5-ylcarbonylamino} propionic acid (Compound 26); Calculated for C21H21N7O3 : MH+: 419.44 Found: MH+ 420 ; 2-{2-[2-(5-amidino-1H-benzimidazol-2-yl)ethyl]- 3H benzimidazol-5-ylcarbonylamino} pentandioic acid (Compound 27); Calculated for C23H23N705: MH+: 477.48 Found: MH+478.4; 2-(2- [2- (5-amidino-IH-benzimidazol-2-yl) ethyl]-lH-benzimidazol-5- ylcarbonylaminp}-3-phenylpropionic acid (Compound 28); Calculated for C27H25N703: MH+: 496.5 Found: MH+495.54; 2-{2-[2-(5-amidino-1H-benzimidazol-2-yl)ethyl]-1H-benzimidaz ol-5- ylcarbonylaminp}-3-methylbutyric acid (Compound 29); Calculated for C23HZSNgO3: MH+: 447.5 Found: MH+ 448. 4; and 6-amino-2- {2- [2- (5-amidino-1H benzimidazol-2-yl)ethyl]- 1H-benzimidazol-5-ylcarbonylamino}-3-methylhexanoic acid (Compound 30).

EXAMPLE 8 In Vitro Enzyme Inhibitor Assay The following represents an assay for determining the Factor Xa inhibitory activity of compound of Formula I.

Mixtures of human Factor Xa (0.5-5 nM) and test compound (varying concentrations) in assay medium (comprising: Tris, 50 mM (pH 8); NaCl, 1M; CaCl2, 5 mM; polyoxyethylenesorbitan monolaurate (Tween-20), 0.05%; DMSO, 10%; and zinc chloride, 150 µM) were incubated for 1 hour at room temperature and then substrate, MesOC-Norleu-Gly-Arg-pNA, was added such that the final concentration of the assay mixture was between 0.5 and 5 mM. Hydrolysis of the substrate was followed spectrophotometrically at (405 A) for 5 minutes. Apparent inhibition constants (Kj) were calculated from the enzyme progress curves using standard mathematical models.

Proceeding as described in this application or by methods known to those of ordinary skill the following compound of Formula I were prepared and tested for factor Xa inhibitory activity: Compound 3, Ki=0.002µM ; Compound 7, Ki=0.0009µM ; Compound 9, Ki=0.0008µM ; Compound 12, =0. 0007pM; Compound 15, Ki=0.006µM ; Compound 16, 17,Ki=0.001µM;Compound19,Ki=0.003µM;Compound Compound 20, Ki=0.003µM ; Compound 21, Ki=0.004µM ; Compound 22, =0. 0031lM; Compound 25, 26,Ki=0.003µM;Compound27,Ki=0.004µM;Compound Compound 28, Ki=0.006µM ; Compound 29, Ki=0.003µM ; Compound 30, Kj=0. 005pM; and Compound 31, =0. 002pM.

EXAMPLE 9 Ex vivo ACT Assay Rabbits were sedated with HypnormO (fluanisone 10 mg/mL and phentanylcitrate 0.315 mg/mL; 0.05 mL/kg, i. m.). A catheter (VenflonOO2, 0.8/25 mm) was inserted into a marginal ear vein for adminstration of test compound. A second catheter (Venflon#2, 1.0/32 mm) was inserted into the artery of the other ear for blood sampling. Test compound were administered by i. v. bolus injection. Blood samples were collecte (0.5 mL) prior to adminstration of test compound and at various time points thereafter.

The activating clotting time (ACT), the amount of time for clot formation, was measured with a Medtronic Automate Coagulation Timer ACT II. An aliquot (200 iL) of the blood sample was added to each of two rection chambers of a disposable two-channel test cartridge containing assay buffer (comprising: 0.75% kaolin, as the activator, and 0.0025M CaCl2 in 0.1 mL HEPES buffer for non-citrated blood and 2.2% kaolin and 0. 05M CaCl2 in 0.1 mL HEPES buffer for citrate blood). Clot formation was measured as a decrease in the downward motion of a plunger assembly contained by the test cartridge.

The decrease in downward motion of the plunger was detected by a photo-optic system.

Proceeding as described in Example 9 compound of the present Invention were assayed and found to increase ACT.

EXAMPLE 10 In vitro ACT Assay Rabbit blood was collecte from an indwelling catheter in a ear artery into plastic containers. Human blood was collecte via venipuncture into vacutainers, some of which contained 0.5 mL of 3.8% citrate. ACT was measured as described in Example 7. Blood samples were mixed with varying concentrations of test compound dissolve in physiological saline (30RL for non-citrated blood and 15gL for citrate blood). Non- citrate blood was used in the assay immediately upon its collection. Citrate blood was kept at ambient temperature for 0.5 to 2 hours and then incubated at 37 °C before used.

Proceeding as described in Example l Ocompounds of the present Invention were assayed and found to increased ACT.

EXAMPLE 11 The following are representative pharmaceutical formulations containing a compound of Formula I.

ORAL FORMULATION 10-100 mg Compound of Formula I 105 mg Citric Acid Monohydrate 18 mg Sodium Hydroxide Flavoring q. s. to 100 mL Water

INTRAVENOUS FORMULATION Compound of Formula I 0.1-10 mg Dextrose Monohydrate q. s. to make isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mg Water for Injection q. s. to 1.0 mL TABLET FORMULATION Compound of Formula I 1% Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica 1%.