Patent Publication Number: US-2003225131-A1

Title: Thrombin inhibitors

Description:
BACKGROUND OF THE INVENTION  
       [0001] Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.  
       [0002] Edwards et al., J. Amer. Chem. Soc., (1992) vol. 114, pp. 1854-63, describes peptidyl a-ketobenzoxazoles which are reversible inhibitors of the serine proteases human leukocyte elastase and porcine pancreatic elastase. European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group of the substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety. Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or a-keto carboxyl derivatives. R. J. Brown et al., J. Med. Chem., Vol. 37, pages 1259-1261 (1994) describes orally active, non-peptidic inhibitors of human leukocyte elastase which contain trifluoromethylketone and pyridinone moieties. H. Mack et al., J. Enzyme Inhibition, Vol. 9, pages 73-86 (1995) describes rigid amidino-phenylalanine thrombin inhibitors which contain a pyridinone moiety as a central core structure. U.S. Pat. Nos. 5,536,708, 5,672,582, 5,510,369 and 5,741,485 describe proline-based thrombin inhibitors having cyclohexylamino end groups.  
       SUMMARY OF THE INVENTION  
       [0003] The invention includes compounds for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compounds may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. The compounds can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.  
       [0004] The invention also includes a compound for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compounds may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.  
       [0005] The invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound of the invention.  
       [0006] The invention also includes a method for treating an inflammatory disease in a patient which comprises treating the patient with a compound of the invention.  
       DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS  
       [0007] Compounds of the invention are useful as thrombin inhibitors and have therapeutic value in for example, preventing coronary artery disease.  
       [0008] This invention includes compounds of the general formula  
                 
 
       [0009] wherein  
       [0010] n, m and p are independently selected from the group of integers consisting of 0 and 1, provided that n+m+p is 1 or 2;  
       [0011] u is N or CH;  
       [0012] v is N or CH;  
       [0013] w is CH 2 , SO 2 , or C(O);  
       [0014] R 10  and R 11  are independently selected from the group consisting of hydrogen, ═CH 2 , —CH 3 , F, —CH 2 CH 3 , and —CH 2 OH;  
       [0015] R 1  is  
                 
 
       [0016] R 8  is hydrogen, —CH 2 R 9 , or —C(O)OCH 2 R 9 ;  
       [0017] R 9  is selected from the group consisting of  
       [0018] a) —C 1-3  alkyl,  
       [0019] b) —C 1-3  alkanol,  
       [0020] c) —C 6 H 5 ,  
       [0021] d) —CF 3 ,  
       [0022] e) —C(O)OH,  
       [0023] f) —CHF 2 ,  
       [0024] g) —C(O)OCH 2 C 6 H 5 , and  
       [0025] h) —C(O)OCH 2 CH 3 ;  
       [0026] R 2  and R 3  are independently selected from the group consisting of hydrogen, halogen, CN, and C 1-4  alkyl;  
       [0027] R 4  is hydrogen or halogen;  
       [0028] R 5  is hydrogen, halogen or a 5-membered heterocyclic ring having 2, 3 or 4 nitrogen atoms; and  
       [0029] R 6  and R 7  are independently selected from the group consisting of hydrogen and halogen, and pharmaceutically acceptable salts thereof.  
       [0030] In a class of these compounds or pharmaceutically acceptable salts thereof,  
       [0031] R 1  is  
                 
 
       [0032] In a subclass of this class, R 2  and R 3  are indepenently selected from the group consisting of hydrogen, Cl and CH 3 .  
       [0033] In a group of this subclass, R 4  is selected from hydrogen and Cl.  
       [0034] In a subgroup of this group, R 5  is selected from the group consisting of hydrogen, triazole, or tetrazole.  
       [0035] In a family of this subgroup, R 6  and R 7  are independently selected from the group consisting of hydrogen and F.  
       [0036] Examples of this collection are selected from the group consisting of  
                 

                 

                 

                 

                 

                 

                 

                 

                 

                 

                 

                 
 
       [0037] Compounds shown above which inhibit thrombin at Ki IC 50  concentration of ≦10 μM and which also inhibit Factor Xa at Ki IC 50  concentration of ≦15 μM are marked with “*”. Compounds shown above which inhibit thrombin at Ki IC 50  concentration of ≦10 μM and which also inhibit Factor Xa at Ki IC 50  concentration of &gt;15 μM are marked with “**”.  
       [0038] Compound names corresponding to the above structures are as follows:  
       [0039] (1) N-(2,2-difluoro-2-pyridin-2-ylethyl)-2-[2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0040] (2) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2,2-difluoro-2-piperidin-2-ylethyl)-1,3-benzoxazol-4-amine  
       [0041] (3) N-(2,2-difluoro-2-pyridin-2-ylethyl)-2-{[3-(1H-tetraazol-1-yl)pyridin-2-yl]methyl)}[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0042] (4) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2-piperidin-2-ylethyl)[1,3]oxazolo [4,5c]pyridin-4-amine  
       [0043] (5) N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-2-{1-[2-(1H-tetraazol-1-yl)phenyl]ethyl}[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0044] (6) ethyl {2-[2-({2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo [4,5c]pyridin-4-yl }amino)ethyl]piperidin-1-yl }acetate  
       [0045] (7) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-{2-[1-(2,2,2-trifluoroethyl)piperidin-2-yl]ethyl}[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0046] (8) 2-{2-[2-({2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-yl}amino)ethyl]piperidin-1-yl}ethanol  
       [0047] (9) N-[2-(1-benzylpiperidin-2-yl)ethyl]-2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4amine  
       [0048] (10) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)-6-methyl[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0049] (11) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2,2-difluoro-2-piperidin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0050] (12) 2-[5-chloro-2-(1H-1,2,4-triazol-4-ium-1-yl)benzyl]-4-[(2,2-difluoro-2-pyridinium-2-ylethyl)amino]-1,3-benzoxazol-3-ium tris(trifluoroacetate)  
       [0051] (13) N-[2-(1-benzylpiperidin-2-yl)-2,2-difluoroethyl]-2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0052] (14) {2-[2-({2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-yl}amino)ethyl]piperidin-1-yl}acetic acid  
       [0053] (15) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0054] (16) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-{2-[1-(2,2-difluoroethyl)piperidin-2-yl]ethyl}[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0055] (17) N-(2,2-difluoro-2-piperidin-2-ylethyl)-2-[2-(1H-tetraazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0056] (18) N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-6-methyl-2-[2-(1H-1,2,4-triazol-1yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0057] (19) N-(2-piperidin-2-ylethyl)-2-[2-(1H-tetraazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0058] (20) 2-(3-chlorobenzyl)-N-(2-piperidin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0059] (21) 2-[[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl](fluoro)methyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0060] (22) N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-2-[2-(1H-tetraazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0061] (23) 4-[(2,2-difluoro-2-pyridinium-2-ylethyl)ammonio]-2-[2-(4H-tetraazol-2-ium-4-yl)benzyl]-1,3-benzoxazol-3-ium tetrachloride  
       [0062] (24) 2-(3-chlorobenzyl)-N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-6-methyl[1,3]oxazolo[4,5-c]pyridin-4amine  
       [0063] (25) 2-(3-chlorobenzyl)-6-methyl-N-(2-piperidin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0064] (26) 2-(3-chlorobenzyl)-N-(2,2-difluoro-2-piperidin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4amine  
       [0065] (27) 2-(2,5-dichlorobenzyl)-N-(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-4-amine  
       [0066] (28) 2-{1-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]propyl}-N-[2-(1ethylpiperidin-2-yl)ethyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0067] (29) N-(2,2-difluoro-2-piperidin-2-ylethyl)-2-[2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0068] (30) 6-chloro-2-(3-chlorobenzyl)-N-(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-4-amine  
       [0069] (31) 2-(3-chlorobenzyl)-N-(2,2-difluoro-2-pyridin-2-ylethyl)-6-methyl[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0070] (32) 2-{1-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]vinyl}-N-(2,2-difluoro-2-pyridin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0071] (33) N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-2-[2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0072] (34) N-(2,2-difluoro-2-pyridin-2-ylethyl)-2-[2-(1H-1,2,4-triazol-1-yl)benzyl]-1,3-benzoxazol-4-amine  
       [0073] (35) N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-2-{[3-(1H-tetraazol-1-yl)pyridin-2-yl]methyl }[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0074] (36) 2-(3-chlorobenzyl)-N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0075] (37) 2-(3-chlorobenzyl)-N-(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-4-amine  
       [0076] (38) 2-[1-(3-chlorophenyl)ethyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-4-amine  
       [0077] (39) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]-2-{4-[(2,2-difluoro-2-pyridin-2-ylethyl)amino][1,3]oxazolo[4,5-c]pyridin-2-yl}ethanol  
       [0078] (40) 2-(3-chlorobenzyl)-N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-1,3-benzoxazol-4-amine  
       [0079] (41) 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]-2-{4-[(2,2-difluoro-2-pyridin-2-ylethyl)amino][1,3]oxazolo[4,5-c]pyridin-2-yl}propane-1,3-diol  
       [0080] (42) 2-(3-chlorobenzyl)-N-(2,2-difluoro-2-pyridin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4amine  
       [0081] (43) N 2 -(3-chlorobenzyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine  
       [0082] (44) 2-benzyl-N-(2,2-difluoro-2-piperidin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0083] (45) 2-(2-chlorobenzyl)-N-(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-4-amine  
       [0084] (46) 6-chloro-N 2 -(3-chlorophenyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine  
       [0085] (47) N-[6-chloro-2-(3-chlorobenzyl)-1,3-benzoxazol-4-yl]-1-phenylmethanesulfonamide  
       [0086] (48) 7-chloro-N 2 -(3-chlorobenzyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-2,4-diamine  
       [0087] (49) N 2 -(3-chlorophenyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine  
       [0088] (50) N-(2,2-difluoro-2-piperidin-2-ylethyl)-2-[2-(1H-1,2,4-triazol-1-yl)benzyl]-1,3-benzoxazol-4-amine  
       [0089] (51) N-{2-[(3-chlorobenzyl)amino]-1,3-benzoxazol-4-yl}-1-phenylmethanesulfonamide  
       [0090] (52) N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-N 2 -phenyl-1,3-benzoxazole-2,4-diamine  
       [0091] (53) N-(2,2-difluoro-2-pyridin-2-ylethyl)-2-(pyridin-2-ylmethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine  
       [0092] (54) N 2 -(3-chlorophenyl)-N 4 -(2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine  
       [0093] (55) 7-chloro-N 2 -(3-chlorophenyl)-N 4 -(2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine  
       [0094] (56) 2-[2-(3-chlorophenyl)ethyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-4-amine  
       [0095] (57) N-{2-[(3-chlorophenyl)amino]-1,3-benzoxazol-4-yl}-2-pyridin-2-ylacetamide  
       [0096] (58) benzyl 2-(2-{[2-(3-chlorobenzyl)[1,3]oxazolo[4,5-c]pyridin-4-yl]amino}-1,1-difluoroethyl)piperidine-1-carboxylate  
       [0097] The compounds of the invention may have asymmetric centers. Compounds of the invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. The compounds of the present invention may also have polymorphic crystalline forms, with all polymorphic crystalline forms being included in the present invention.  
       [0098] When any variable occurs more than one time in any constituent or formula for a compound, its definition on each occurrence is independent of its definition at every other occurrence. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.  
       [0099] Some abbreviations that may appear in this application are as follows:  
       ABBREVIATIONS  
       [0100] Designation  
       [0101] AcOH acetic acid  
       [0102] (Boc) 2 O di-t-butyl dicarbonate  
       [0103] BOP reagent benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate  
       [0104] Cs 2 CO 3  cesium carbonate  
       [0105] DIAD diisopropyl azodicarboxylate  
       [0106] DIEA N,N-diisopropylethylamine  
       [0107] DMA N,N-dimethylacetamide  
       [0108] DMAP dimethylaminopyridine  
       [0109] DMF dimethylformamide  
       [0110] EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride  
       [0111] EtOAc ethyl acetate  
       [0112] EtOH ethanol  
       [0113] H 2  hydrogen  
       [0114] HCl hydrochloric acid  
       [0115] HOAc acetic acid  
       [0116] HOAt 1-hydroxy-7-azabenzotriazole  
       [0117] HOBt 1-hydroxybenzotriazole  
       [0118] HPLC high pressure liquid chromatography  
       [0119] KCl potassium chloride  
       [0120] KOH potassium hydroxide  
       [0121] LiOH lithium hydroxide  
       [0122] MeOH methanol  
       [0123] NaBH 4  sodium borohydride  
       [0124] NaCN sodium cyanide  
       [0125] NaHCO 3  sodium hydrogen carbonate  
       [0126] Na 2 CO 3  sodium carbonate  
       [0127] NH 4 Cl ammonium chloride  
       [0128] NH 4 OH ammonium hydroxide  
       [0129] Ph 3 P triphenyl phosphine  
       [0130] Pd-C palladium on activated carbon catalyst  
       [0131] PhCH 3  toluene  
       [0132] PPTS pyridium p-toluenesulfonate  
       [0133] POCl 3  phosphorous oxychloride  
       [0134] TFA trifluoroacetic acid  
       [0135] THF tetrahydrofuran  
       [0136] SnCl 2  tin chloride  
       [0137] “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted”is replaced with a selection from the indicated group(s), provided that the indicated atom&#39;s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is a keto (i.e., ═O) group or a methylene (i.e., ═CH 2 ) group, then 2 hydrogens on the atom are replaced.  
       [0138] As used herein except where noted, “alkyl” or “alkylene” is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C 1-4  alkyl (or alkylene) includes C 1 , C 2 , C 3  and C 4  alkyl (or alkylene) groups Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyle, t-butyl, n-pentyl, and s-pentyl. Alkyl groups may optionally be represented as follows: “Me” for methyl, “Et” for ethyl, “Pr” for propyl, and “Bu” for butyl).  
       [0139] “Alkoxy” represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge. C 1-4  alkoxy includes C 1 , C 2 , C 3  and C 4  alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy.  
       [0140] “Halogen”, as used herein, means fluoro, chloro, bromo and iodo; and  
       [0141] “Counterion” is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.  
       [0142] The term “cycloC 3-7  alkyl” refers to saturated carbocyclic ring systems containing 3, 4, 5, 6, or 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like. “Partially unsaturated carbocyclic ring” systems, e.g. partially unsaturated C 3-12  carbocyclic ring systems, refers to partially unsaturated ring systems containing the specificied number of carbon atoms, e.g., cyclopentadiene, cycloheptatriene, indene, and flourene ring systems. The term “aryl” as used herein except where noted, represents a stable 6- to 14-membered mono-, bi- or tricyclic unsaturated ring system such as phenyl, naphthyl and anthryl. Unless otherwise specified, he ring systems can be unsubstituted or substituted with one or more of C 1-4  alkyl, C 1-4  alkoxy, halogen, hydroxy or amino.  
       [0143] “Alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C 2-4  alkenyl includes C 2 , C 3  and C 4  alkenyl groups.  
       [0144] “Alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C 2-4  alkynyl (or alkynylene) includes C 2 , C 3  and C 4  alkenyl groups.  
       [0145] The term “heterocycle” or “heterocyclic ring”, as used herein except where noted, represents a stable 5, 6, or 7-membered mono- or bicyclic or stable 7, 8, 9, or 10-membered bicyclic ring system any ring of which may be saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized (e.g. pyridyl N-oxides), and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Especially useful are rings containing one oxygen or sulfur, one to four nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The heterocyclic ring may be substituted on a carbon or on a nitrogen atom, e.g. with one or more of C 1-4  alkyl, C 1-4  alkoxy, halogen, hydroxy or amino, if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocyclic ring exceeds 1, then these heteroatoms are not adjacent to one another. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzthiazolyl, benzoxazolyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, acridinyl, azocinyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furazanyl, 1Hindazolyl, indolenyl, indolinyl, indolizinyl, 3Hindolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, methylenedioxyphenyl, naphthyridinyl, octahydroisoquinolinyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazolinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, thianthrenyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.  
       [0146] Pyridyl N-oxides (e.g., where R 1  is a pyridyl N-oxide) are structurally depicted using conventional representations  
                 
 
       [0147] which have equivalent meanings.  
       [0148] The term “5-membered heterocyclic ring having 3 or 4 nitrogen atoms” includes unsubstituted and substituted rings, including but not limited to, rings such as triazoles and tetrazoles.  
       [0149] In this specification methyl substituents may be represented by  
                 
 
       [0150] For example, the structures  
                 
 
       [0151] have equivalent meanings.  
       [0152] The pharmaceutically-acceptable salts of the compounds of the invention (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfamic, phosphoric, nitric and the like, or the quaternary ammmonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.  
       [0153] Thrombin Inhibitors—Therapeutic Uses—Method of Using  
       [0154] Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy. The term “patient” used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.  
       [0155] Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus, the thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal&#39;s blood with material selected from the group consisting of vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems.  
       [0156] Compounds of the invention are useful for treating or preventing venous thromboembolism (e.g. obstruction or occlusion of a vein by a detached thrombus; obstruction or occlusion of a lung artery by a detached thrombus), cardiogenic thromboembolism (e.g. obstruction or occlusion of the heart by a detached thrombus), arterial thrombosis (e.g. formation of a thrombus within an artery that may cause infarction of tissue supplied by the artery), atherosclerosis (e.g. arteriosclerosis characterized by irregularly distributed lipid deposits) in mammals, and for lowering the propensity of devices that come into contact with blood to clot blood.  
       [0157] Examples of venous thromboembolism which may be treated or prevented with compounds of the invention include obstruction of a vein, obstruction of a lung artery (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombophilic diseases such as Protein C deficiency, Protein S deficiency, antithrombin III deficiency, and Factor V Leiden, and thrombosis resulting from acquired thrombophilic disorders such as systemic lupus erythematosus (inflammatory connective tissue disease). Also with regard to venous thromboembolism, compounds of the invention are useful for maintaining patency of indwelling catheters.  
       [0158] Examples of cardiogenic thromboembolism which may be treated or prevented with compounds of the invention include thromboembolic stroke (detached thrombus causing neurological affliction related to impaired cerebral blood supply), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber muscular fibrils), cardiogenic thromboembolism associated with prosthetic heart valves such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease.  
       [0159] Examples of arterial thrombosis include unstable angina (severe constrictive pain in chest of coronary origin), myocardial infarction (heart muscle cell death resulting from insufficient blood supply), ischemic heart disease (local anemia due to obstruction (such as by arterial narrowing) of blood supply), reocclusion during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass grafts, and occlusive cerebrovascular disease. Also with regard to arterial thrombosis, compounds of the invention are useful for maintaining patency in arteriovenous cannulas.  
       [0160] Examples of atherosclerosis include arteriosclerosis.  
       [0161] Examples of devices that come into contact with blood include vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems  
       [0162] The thrombin inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.  
       [0163] The thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Corporation.  
       [0164] The thrombin inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.  
       [0165] The thrombin inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The thrombin inhibitors may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the thrombin inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.  
       [0166] The dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.  
       [0167] Oral dosages of the thrombin inhibitors, when used for the indicated effects, will range between about 0.01mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis). For example, an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg/day, more preferably 8-200 mg/day, and most preferably 8-40 mg/kg/day. A suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg. Advantageously, the thrombin inhibitors may be administered in divided doses of two, three, or four times daily. For administration twice a day, a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.  
       [0168] Intravenously, the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day. Such quantities may be administered in a number of suitable ways, e.g. large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g. once a day. Typically, a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/ml, e.g. 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml, and administered in amounts per day of between 0.01 ml/kg patient weight and 10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg. In one example, an 80 kg patient, receiving 8 ml twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/ml, receives 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers. Consideration should be given to the solubility of the drug in choosing an The choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.  
       [0169] The compounds can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.  
       [0170] The thrombin inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as “carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixers, syrups and the like, and consistent with convention pharmaceutical practices.  
       [0171] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.  
       [0172] The invention also includes a method for treating an inflammatory disease in a patient which comprises treating the patient with a composition comprising a compound of the present invention. Such diseases include but are not limited to nephritis, systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis, and sacoidosis.  
       [0173] The invention is also a method for treating an inflammatory disease in a patient that comprises treating the patient with a combination comprising a compound of the invention and an NSAID, e.g., a COX-2 inhibitor. Such diseases include but are not limited to nephritis, systemic lupus, erythematosus, rheumatoid arthritis, glomerulonephritis, vasculitis and sacoidosis.  
       [0174] The present invention is a method for relieving pain, fever and inflammation of a variety of conditions including nephritis, systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis, sacoidosis, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures in a patient by administering to the patient a therapeutically effective amount of a compound of the invention. Thrombin inhibitors may also be useful for the treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer Disease.  
       [0175] In inflammatory diseases wherein fibrin formation is prominent, the fibrin may be a determinant of the pathology. Fibrin serves as a matrix onto which inflammatory cells can migrate and adhere. (see Sherman et al., 1977  J. Exp. Med . 145:76-85; Altieri et al., 1986  J. Clin. Invest . 78:968-976; Wright et al., 1983  Proc. Natl. Acad. Sci . 85:7734-7738; Altieri et al., 1993  J. Biol. Chem . 268;1847-1853). Fibrin also enhances expression of the inflammatory cytokine IL-1beta and decreases expression of IL-1 receptor antagonist by human peripheral blood mononuclear cells (see Perez 1995  J. Immunol . 154:1879-1887). The anticoagulants warfarin and heparin attenuate delayed-type hypersensitivity reactions and experimental nephritis in animals. (see Jasain et al., Immunopathogenesis of Rheumatoid Arthritis Eds. G. S. Panayi et al., Surrey, UK, Reedbooks, Ltd. and Halpern et al., 1965  Nature  205:257-259). Enzymatic defibrination with ancrod diminishes the degree of experimental nephritis (Naish et al., 1972  Clin. Sci . 42:643-646), systemic lupus erythematosus (Cole et al., 1990  Kidney Int . 37:29-35, and rheumatoid arthritis (see Busso et al., 1998  J. Clin. Invest . 102:41-50) in animals, and glomerulonephritis in man (see Kim et al., 1988  Q. J. Med . 69:879-905). Additionally, intra articular injection of fibrin induces arthritis in rabbits immunized with fibrin Dumonde et al., 1961  British Journal of Experimental Pathology  XLIII:373-383), and antigen-induced arthritis in mice is exacerbated in urokinase-deficient mice wherein fibrinolysis synovial fibrin is compromised (see Busso et al., 1998  J. Clin. Invest . 102:41-50).  
       [0176] In diseases where fibrin deposition is prominent such as, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, vasculitis and sacoidosis, lowering the steady state concentration of fibrin by administration of a compound of the invention will, according to the instant invention, diminish the pathological inflammatory responses associated with these diseases.  
       [0177] Similarly, compounds of the invention will be useful as a partial or complete substitute for conventional NSAIDs in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating inflammatory diseases as defined above comprising a non-toxic therapeutically effective amount of a compound of the invention as defined above and one or more ingredients such as another pain reliever including acetominophen or phenacetin; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone; a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating or non-sedating antihistamine. In addition the invention encompasses a method of treating inflammatory diseases comprising administration to a patient in need of such treatment a non-toxic therapeutically effect amount of a compound of the invention, optionally co-administered with one or more of such ingredients as listed immediately above.  
       [0178] The instant invention also involves a novel combination therapy comprising the administration of a therapeutically effective amount of an NSAID such as a COX-2 inhibitor in combination with a therapeutically effective amount of a compound of the invention to a mammal, and more particularly, to a human. The combination therapy is used to treat inflammatory diseases.  
       [0179] The instant pharmaceutical combinations comprising a compound of the invention in combination with an NSAID such as a COX-2 inhibitor include administration of a single pharmaceutical dosage formulation which contains both a compound of the invention and the NSAID, as well as administration of each active agent in its own separate pharmaceutical dosage formulation. Where separate dosage formulations are used, the compund of the invention and the NSAID can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e, sequentially. The “instant pharmaceutical combination” is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial pharmaceutical effect of the compound of the invention and the NSAID are realized by the patient at substantially the same time. Such beneficial effect is preferably achieved when the target blood level concentrations of each active drug are maintained at substantially the same time. It is preferred that the compound of the invention and the NSAID be co-administered concurrently on a once-a-day dosing schedule; however, varying dosing schedules, such as the compound of the invention once per day and the NSAID once, twice or more times per day, or the NSAID once per day and the compound of the invention once, twice or more times per day, is also encompassed herein. A single oral dosage formulation comprised of both the compound of the invention and the NSAID is preferred. A single dosage formulation will provide convenience for the patient.  
       [0180] The instant invention also provides pharmaceutical compositions comprised of a therapeutically effective amount of an NSAID, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. One embodiment of the instant compositions is a single composition adapted for oral administration comprised of a therapeutically effective amount of a COX-2 inhibitor in combination with a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The combination can also be administered in separate dosage forms, each having one of the active agents. If administered in separate dosage forms, the separate dosage forms are administered such that the beneficial effect of each active agent is realized by the patient at substantially the same time.  
       [0181] Common NSAIDs include salicylates such as aspirin, sodium salicylate, choline salicylate, salicylsalicylic acid, diflunisal, and salsalate; indoleacetic acids such as indomethacin and sulindac; pyrazoles such as phenylbutazone, oxyphenbutazone; pyrrolealkanoic acids such as tolmetin; phenylacetic acids such as ibuprofen, feroprofen, flurbiprofen, and ketoprofen; fenamates such as mefanamic acid, and meclofenamate; oxicams such as piroxicam; and naphthaleneacetic acids such as naproxen. Cyclo-oxygenase inhibitors such as COX-1 and COX-2 inhibitors are also NSAIDs.  
       [0182] Employing the human whole blood COX-1 assay and the human whole blood COX-2 assay described in C. Brideau et at,  Inflamm. Res . 45: 68-74 (1996), herein incorporated by reference, preferably, the compounds have a cyclooxygenase-2 IC 50  of less than about 2 μM in the human whole blood COX-2 assay, yet have a cyclooxygenase-1 IC 50  of greater than about 5 μM in the human whole blood COX-1 assay. Also preferably, the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 10, and more preferably of at least 40. The resulting selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.  
       [0183] The inhibitor of cyclooxygenase-2 may be administered at a dosage level up to conventional dosage levels for NSAIDs. Suitable dosage levels will depend upon the antiinflammatory effect of the chosen inhibitor of cyclooxygenase-2, but typically suitable levels will be about 0.001 to 50 mg/kg per day, preferably 0.005 to 30mg/kg per day, and especially 0.05 to 1mg/kg per day. The compound may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, and especially once per day.  
       [0184] The dosage regimen utilizing a compound of the invention in combination with the NSAID is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. Since two different active agents are being used together in a combination therapy, the potency of each of the agents and the interactive effects achieved by combining them together must also be taken into account. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amounts needed to prevent, counter, or arrest the progress of the condition.  
       [0185] Administration of the drug combination to the patient includes both self-administration and administration to the patient by another person.  
       [0186] Additional active agents may be used in combination with the compound of the invention in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration. Examples of additional active agents which may be employed include HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol absorption inhibitors; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; vitamin B 6  (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCl salt; vitamin B 12  (also known as cyanocobalamin); β-adrenergic receptor blockers; folic acid or a pharmaceutically acceptable salt or ester thereof such as the sodium salt and the methylglucamine salt; and anti-oxidant vitamins such as vitamin C and E and beta carotene.  
       [0187] The thrombin inhibitors can also be co-administered with suitable anti-platelet agents, including, but not limited to, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), anticoagulants such as aspirin, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies, or lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as lovastatin and simvastatin, HMG CoA synthase inhibitors, etc.) to treat or prevent atherosclerosis. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and thrombin inhibitors. Also, thrombin inhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion. Thrombin inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter.  
       [0188] Typical doses of thrombin inhibitors of the invention in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient&#39;s therapeutic needs.  
       [0189] Unless otherwise stated, all NMR determinations were made using 400 MHz field strength.  
       [0190] The following general schemes describe methods for preparing compounds of the invention. Unless otherwise indicated, variables have the meanings defined in Formula I.  
                 
 
                 
 
                 
 
                 
 
                 
 
     
    
    
     EXAMPLE 1  
     [0191] Preparation of N 2 -(3-chlorobenzyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1.3-benzoxazole-2,4-diamine  
                 
 
     [0192] Step A:  
     [0193] N-(3-chlorobenzyl)-4-nitro-1,3-benzoxazol-2-amine  
     [0194] 2-Amino-3-nitrophenol (1.00 g, 6.49 mmol) and 1-chloro-3-(isothiocyanatomethyl)benzene (1.31 g, 7.13 mmol) in 5 mL of acetic acid was heated at 70° C. for 16 h. The solvent was evaporated and the residue was redissolved in ethyl acetate. The ethyl acetate solution was washed with 1N HCl, saturated NaHCO 3  solution and water. The organic layer was dried (over Na 2 SO 4 ) and concentrated to give the title compound as solid. MS: MH + =304.5.  
     [0195] Step B:  
     [0196] N 2 -(3-chlorobenzyl)-1,3-benzoxazole-2,4-diamine  
     [0197] To a solution of N-(3-chlorobenzyl)-4-nitro-1,3-benzoxazol-2-amine (0.33 g, 1.09 mmol) in 15 mL of THF was added sodium hydrosulfite (0.68 g, 3.27 mmol, 85%) in 5 mL of water. The mixture was stirred for 16 h and the solvent was evaporated. The residue was dissolved in EtOAc, washed with water, concentrated and purified by silica chromatography using 10%-70% EtOAc/Hexane gradient:  1 H NMR (CDCl 3 ) δ4.57 (s, 2H), 6.49-6.51 (dd, 1H), 6.69-6.71 (dd, 1H), 6.83-6.87 (t, 1H), 7.20-7.25 (m, 3H), 7.32 (s, 1H). MS: MH + =274.4  
     [0198] Step C:  
     [0199] N 2 -(3-chlorobenzyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine  
     [0200] To a solution of N 2 -(3-chlorobenzyl)-1,3-benzoxazole-2,4-diamine (55 mg, 0.201 mmol) in 0.25 mL of DMA was added 2,2-difluoro-2-pyridin-2-ylethyl trifluoromethanesulfonate (0.048 mL, 0.221 mmol) and DIEA (0.039 mL, 0.221 mmol). After 16 h at 60° C., the reaction was concentrated and purified with 5%-50% EtOAc-hexane on silica chromatography:  1 H NMR (CDCl 3 ) δ4.13-4.23 (td, 2H, 13.6 Hz, 7.0 Hz), 4.56-4.58 (d, 2H, 5.7 Hz), 4.62-4.66 (t, 1H, 7.0 Hz), 5.29 (b, 1H), 6.51-6.53 (d, 1H, 8.1 Hz), 6.65-6.67 (d, 1H, 8.1Hz), 6.86-6.90 (t, 1H, 8.1 Hz), 7.21-7.26 (m, 3H), 7.31-7.34 (m, 2H), 7.63-7.66 (d, 1H, 7.8 Hz), 7.71-7.76 (td, 1H, 7.8 Hz, 1.7 Hz),8.66-8.67 (d,1H, 4.4 Hz). MS: MH + =415.6.  
     EXAMPLE 2  
     [0201]                   
     [0202] Preparation of N-(2,2-difluoro-2-pyridin-2-ylethyl)-2-[2-(1H-tetraazol-1-yl)benzyl]-1,3-benzoxazol-4-amine  
     [0203] Step A:  
     [0204] Ethyl (2-aminophenyl)acetate  
     [0205] Ethyl (2-nitrophenyl)acetate (2.50 g, 12.0 mmol) in 50 mL of EtOAc was degased (with N 2 ), 0.60 g of Pd-C (10%) was added and the mixture was hydrogenated under 60 psi H 2 . After 14 h the reaction was filtered through celite and concentrated to yield the title compound. MS: MH + =180.4.  
     [0206] Step B:  
     [0207] Ethyl [2-(1H-tetraazol-1-yl)phenyl]acetate  
     [0208] To a solution of ethyl (2-aminophenyl)acetate (1.15 g, 6.42 mmol) and trimethyl orthoformate (1.54 mL, 14.1 mmol) in 60 ml of AcOH was added sodium azide (0.834 g, 12.8 mmol). The solution was stirred under N 2  at 75° C. for 16 h then concentrated. The residue was paritioned between EtOAc and sat. aq. NaHCO 3 , the layers separated, and the aqueous phase backwashed with EtOAc (2×). The combined organics were dried, concentrated and and purified by 5%-95% EtOAc-Hexane on silica chromatography to afford title compound as a pink oil.  1 H NMR (CDCl 3 ) δ1.19-1.22 (t, 3H), 3.59 (s, 2H), 4.04-4.09 (q, 2H), 7.37-7.39 (m, 1H), 7.49-7.56 (m, 3H), 8.93 (s, 1H). MS: MH + =233.5  
     [0209] Step C:  
     [0210] [2-(1H-tetraazol-1-yl)phenyl]acetic acid  
     [0211] To a solution of ethyl [2-(1H-tetraazol-1-yl)phenyl]acetate (1.40 g, 6.02 mmol) in 20 mL of THF was added LiOH monohydrate (0.78 g, 18.1 mmol) at room temperature. After 16 h the reaction was concentrated, and the residue was redistributed between 1N HCl and EtOAc. The EtOAc solution was dried and concentrated to yield the title compound as of solid:  1 H NMR (CDCl 3 ) δ3.65 (s, 2H), 7.36-7.38 (d, 1H), 7.51-7.55 (m, 2H), 7.58-7.60 (t, 1H), 8.95 (s, 1H). MS: MH + =205.4.  
     [0212] Step D:  
     [0213] N-(2-hydroxy-6-nitrophenyl)-2-[2-(1H-tetraazol-1-yl)phenyl]acetamide  
                 
 
     [0214] To a solution of [2-(1H-tetraazol-1-yl)phenyl]acetic acid (0.162 g, 0.793 mmol) and 2-amino-3-nitrophenol (0.134 g, 0.873 mmol) in 5 mL of DMF was added EDC (0.167 g, 0.873 mmol), HOBt (0.118 g, 0.873 mmol) and DIEA (0.152 mL, 0.873 mmol). The reaction was stirred at room temperature for 16 h, concentrated and purified by 15%-85% of EtOAc/Hexane on silica chromatography: MS: MH + =341.5.  
     [0215] Step E:  
     [0216] 4-nitro-2-[2-(1H-tetraazol-1-yl)benzyl]-1,3-benzoxazole  
     [0217] A solution of N-(2-hydroxy-6-nitrophenyl)-2-[2-(1H-tetraazol-1-yl)phenyl]acetamide (0.200 g, 0.587 mmol) in 10 mL of AcOH was heated at 70° C. for 24 h. The reaction was concentrated, diluted with EtOAc and was washed with saturated NaHCO 3  solution. Removal of the EtOAc under reduced pressure afforded the title compound was obtained as a pink solid: MS: MH + =323.5.  
     [0218] Step F:  
     [0219] 2-[2-(1H-tetraazol-1-yl)benzyl]-1,3-benzoxazol-4-amine  
     [0220] A solution of 4-nitro-2-[2-(1H-tetraazol-1-yl)benzyl]-1,3-benzoxazole (0.310 g, 0.961 mmol) and 90 mg of 10% Pd-C in 15 mL of EtOAc was degased and hydrogenated at 55 psi H 2 . After 4 h the solution was filtered through celite and concentrated to give title compound: MS: MH + =293.6.  
     [0221] Step G:  
     [0222] N-(2,2-difluoro-2-pyridin-2-ylethyl)-2-[2-(1H-tetraazol-1-yl)benzyl]-1,3-benzoxazol-4-amine  
     [0223] To a solution of 2-[2-(1H-tetraazol-1-yl)benzyl]-1,3-benzoxazol-4-amine (0.214 g, 0.732 mmol) and 2,2-difluoro-2-pyridin-2-ylethyl trifluoromethanesulfonate (0.180 mL, 0.879 mmol) in 0.5 mL of DMA was added DIEA (0.153 mL, 0.879 mmol). This mixture was heated at 55° C. under N 2  for 16 h and concentrated. The residue was purified with 10% isopropanol/dichloromethane on silica chromatography. The product-containing fractions were concentrated and further purifed by reverse phase prep-HPLC to yield the title compound:  1 H NMR (CDCl 3 ) δ4.11 (s, 2H), 4.17-4.23 (t, 2H,13.6 Hz), 6.54-6.56 (d, 1H, 8.1 Hz), 6.75-6.77 (d, 1H, 8.3 Hz), 7.07-7.11 (dd, 1H, 8.3 Hz, 8.1 Hz), 7.36-7.42 (m, 2H), 7.49-7.53 (td, 1H, 1.4 Hz, 7.9 Hz), 7.55-7.59 (m, 2H), 7.66-7.68 (d, 1H, 7.9 Hz), 7.77-7.81 (td, 1H, 1.4 Hz, 7.7 Hz), 8.69-8.70 (d, 1H, 4.8 Hz), 9.09 (s, 1H). MS: MH + =434.7.  
     EXAMPLE 3  
     [0224] Preparation of 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-4-amine  
                 
 
     [0225] Step A:  
     [0226] Tert-butyl 2-hydroxy-6-nitrophenylcarbamate  
     [0227] To a solution of 2-amino-3-nitrophenol (6.90 g, 44.8 mmol) in 40 mL of DMF was added di(tert-butyl) dicarbonate (10.3 g, 47.0 mmol), DMAP (5.80 g, 47.0 mmol) and DIEA (8.20 mL, 47.0 mmol). The reaction was stirred at ambient temperature for 16 h then concentrated. The residue was paritioned between EtOAc and sat. aq. NaHCO 3 , the layers separated, and the aqueous phase backwashed with EtOAc (2×). The combined organics were dried, concentrated and and purified by 5%-95% EtOAc-Hexane on silica chromatography: MS: MH + -BOC=155.4.  
     [0228] Step B:  
     [0229] Tert-butyl 2-amino-6-hydroxyphenylcarbamate  
     [0230] To a degassed solution of tert-butyl 2-hydroxy-6-nitrophenylcarbamate (2.50 g, 9.84 mmol) in 20 mL of EtOAc was added 0.50 g of 10% Pd-C. The mixture was hydrogenated at 40 psi of H 2  for 16 h. The reaction was filtered through celite and concentrated to give 2.0 g of title compound as white solid.  1 H NMR (CDCl 3 ) δ1.53 (s, 9H), 3.58 (b, 2H), 6.18 (b, 1H), 6.35-6.38 (d, 1H, 8.1 Hz), 6.49-6.51(d, 1H, 8.2 Hz), 6.91-6.95 (dd, 8.1 Hz, 8.2 Hz). MS: MH + =225.5  
     [0231] Step C:  
     [0232] Tert-butyl 2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-6-hydroxyphenylcarbamate  
                 
 
     [0233] Tert-butyl 2-amino-6-hydroxyphenylcarbamate (0.622 g, 2.77 mmol) and 2,2-difluoro-2-pyridin-2-ylethyl trifluoromethanesulfonate (0.682 mL, 3.32 mmol) were dissolved in 4 mL of DMA and DIEA (0.577 mL, 3.32 mmol) was added. The mixture was stirred at 70° C. under N 2  for 16 h, concentrated and purified by 5%-50% EtOAc-Hexane on silica chromatography:  1 H NMR (CDCl 3 ) δ1.53 (s, 9H), 3.91-3.99 (dt, 2H), 4.18 (b, 1H), 6.38-6.6.40 (d, 1H, 8.0 Hz), 6.48-6.50 (d, 1H, 8.0 Hz), 6.95-6.99 (t, 1H, 8.0 Hz), 7.39-7.44 (m, 1H), 7.68-7.72 (d, 1H, 8.0 Hz), 7.82-7.87 (t, 1H, 8.0 Hz), 8.68-8.69 (d, 1H, 4.7 Hz). MS: MH + =366.7.  
     [0234] Step D:  
     [0235] 2-Amino-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]phenol  
     [0236] Tert-butyl 2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-6-hydroxyphenylcarbamate (1.20 g, 3.28 mmol) was dissolved in 5 mL of 1,4-dioxane and 5 mL of 4 N HCl in 1,4-dioxane was added. The reaction was stirred at ambient temperature for 16 h and concentrated to yield the title compound as the HCl salt: MS: MH + =266.5.  
     [0237] Step E:  
     [0238] 5-Chloro-2-(1H-1,2,4-triazol-1-yl)benzonitrile  
     [0239] A solution of 2,5-dichlorobenzonitrile (6.8 g, 39.5 mmol), imidazole (8.2 g, 119 mmol), Cs 2 CO 3  (38.6 g, 119 mmol) and tetrabutylammonium iodide (2.90 g, 7.90 mmol) in 60 mL of DMF was heated at 90° C. for 16 h. After cooling to ambient temperature, the reaction was filtered. The filtrate was concentrated to a solid under reduced pressure and washed with 50 mL of water (3×). The residue was vaccum dried to give the title compound:  1 H NMR (CD3OD) δ7.82-7.84 (d, 1H, 8.6 Hz), 7.89-7.90 (dd, 1H, 8.6 Hz, 2.2 Hz), 8.07-8.08 (d, 1H, 2.2 Hz), 8.23 (s, 1H), 9.06 (s, 1H). MS: MH + =205.0.  
     [0240] Step F:  
     [0241] 5-chloro-2-(1H-1,2,4-triazol-1-yl)benzoic acid  
     [0242] 5-Chloro-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.26 g, 1.27 mmol) in 15 mL of concentrated HCl was heated to reflux for 48 h. The reaction was concentrated and redistributed between 1N HCl and dichloromethane. The dichloromethane layer was concentrated to give the title compound: MS: MH + =223.9  
     [0243] Step G:  
     [0244] [5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]methanol  
     [0245] To a solution of 5-chloro-2-(1H-1,2,4-triazol-1-yl)benzoic acid (0.91 g, 4.07 mmol) and BOP (2.16 g, 4.88 mmol) in 40 mL of dry THF was added DIEA (1.84 mL, 10.6 mmol) followed by NaBH 4  (0.46 g, 12.2 mmol). After 16 h the reaction was quenched with 15 mL of saturated NaHCO 3  solution and the organics removed via a rotary evaporator. This mixture was diluted with 150 mL of EtOAc, separated and washed with 100 mL water and 100 mL brine. The organic layer was dried, concentrated and purified by 5%-95% of EtOAc-Hexane on silica chromatography to give the title compound: 1H NMR (CD3OD) δ4.51 (s, 1H), 7.45-7.50 (m, 2H), 7.71-7.72 (d, 1H, 1.3 Hz), 8.20 (s, 1H), 8.81 (s, 1H). MS: MH + =210.0.  
     [0246] Step H:  
     [0247] 1-[2-(bromomethyl)-4-chlorophenyl]-1H-1,2,4-triazole  
     [0248] To a solution of [5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]methanol (2.34 g, 11.2 mmol) in 60 mL of chloroform was slowly added thionyl bromide (1.30 mL, 16.7 mmol). After stirring at ambient temperature for 1 h, the reaction was concentrated at reduced pressure, the residue dissolved in 150 mL of EtOAc and washed with 150 mL of saturated NaHCO 3  solution, water and brine, respectively. The title compound was obtained after removal of the solvent.  1 H NMR (CD3OD) δ4.45 (s, 2H), 7.29-7.33 (d, 1H, 10.6 Hz, 8.4 Hz), 7.41-7.46 (dd, 1H, 8.4 Hz, 2.2 Hz), 7.57-7,58 (d, 1H, 2.2 Hz), 8.18 (s, 1H), 8.44 (s, 1H). MS: MH + =273.0.  
     [0249] Step I:  
     [0250] [5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]acetonitrile  
     [0251] 1-[2-(Bromomethyl)-4-chlorophenyl]-1H-1,2,4-triazole (2.20 g, 8.07 mmol) and NaCN (1.20 g, 24.2 mmol) in a mixture of 20 mL 1,4-dioxane and 20 mL water was heated to reflux for 6.0 h. The solvent was removed under reduced pressure and the residue was dissolved in 150 mL of EtOAc. The EtOAc solution was concentrated and washed with 100 mL of water and brine, respectively. The title compound was purified with 30%-100% EtOAc-Hexane on silica chromatography: 1H NMR (CD3OD) δ3.85 (s, 2H), 7.31-7.35 (d, 1H, 8.4 Hz), 7.47-7.50 (dd, 1H, 8.4 Hz, 2.2 Hz), 7.66-7.67 (d, 1H, 2.0 Hz), 8.17 (s, 1H), 8.36 (s, 1H). MS: MH + 219.0  
     [0252] Step J:  
     [0253] [5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]acetic acid  
     [0254] To [5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]acetonitrile (1.0 g, 4.58 mmol) in 15 mL of acetic acid was added 15 mL of concentrated HCl. The reaction was refluxed for 5 h at 120° C. and concentrated under reduced pressure to give title compound as white solid:  1 H NMR (CD3OD) δ3.73 (s, 1H), 7.50-7.58 (m, 2H), 7.60 (s, 1H), 8.51 (s, 1H), 9.25 (s, 1H). MS: MH + =238.0  
     [0255] Step K:  
     [0256] 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]-N-{2-[(2,2-difluoro-2-pyridin-2-ylethyl)amimo]-6-hydroxyphenyl}acetamide  
     [0257] To the HCl salt of 2-amino-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]phenol (0.152 g, 0.460 mmol) and [5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]acetic acid (0.115 g, 0.483 mmol) in 10 mL of DMF was added EDC (0.106 g, 0.552 mmol), HOAt (0.075 g, 0.552 mmol) and DIEA (0.200 mL, 1.15 mmol). After 16 h at ambient temperature, the reaction was concentrated and dissolved in 200 mL of dichloromethane. The dichloromethane solution was washed with 150 rnL of saturated sodium bicarbonate solution followed by 150 mL of brine. The organics were dried, concentrated and purified with 15%-99% of EtOAc-Hexane on silica chromatography:  1 H NMR (CD3OD) δ3.67 (s, 2H), 3.91-3.98 (t, 2H, 13.4 Hz), 6.17-6.20 (d, 2H, 8.2 Hz), 6.82-6.87 (t, 1H, 8.2 Hz), 7.39-7.52 (m, 3H), 7.60-7.63 (d, 1H, 7.9 Hz), 7.68 (s, 1H), 7.78-7.83 (dd, 1H, 7.9 Hz, 7.7 Hz), 8.19 (s, 1H), 8.54-8.56 (d, 1H, 4.2 Hz), 8.79 (s, 1H). MS: MH + =485.3.  
     [0258] Step L:  
     [0259] 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazol-4-amine  
     [0260] To a solution of 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]-N-{2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-6-hydroxyphenyl}acetamide (0.110 g, 0.227 mmol) in 10 mL of THF was added triphenyl phosphine (0.115 g, 0.439 mmol), followed by DIAD (0.085 mL, 0.432 mmol). After 3.0 h the reaction was concentrated and purified by reverse-phase preparative HPLC to give the TFA salt of title compound:  1 H NMR (CD3OD) δ4.12-4.19 (t, 2H, 13.7 Hz), 4.29 (s, 2H), 6.46-6.48 (d, 1H, 8.1 Hz), 6.69-6.71 (d, 1H, 8.1 Hz), 6.98-7.03 (t, 1H, 8.1Hz), 7.46-7.56 (m, 3H), 7.65-7.66 (d, 1H, 2.4 Hz), 7.68-7.71 (d, 1H, 7.9 Hz), 7.88-7.93 (td, 1H, 7.9 Hz, 1.7 Hz), 8.14 (s, 1H), 8.61-8.63 (d, 1H, 4.8 Hz), 8.77 (s, 1H). MS: MH + =467.3.  
     EXAMPLE 4  
     [0261] Preparation of N-(2,2-difluoro-2-pyridin-2-ylethyl)-2-[2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
                 
 
     [0262] Step A:  
     [0263] 2-Chloro-3-nitropyridin-4-ol  
     [0264] A mixture of 3-nitropyridine-2,4-diol (12.0 g, 76.9 mmol), benzyltriethylammonium chloride (53.0 g, 231 mmol) and POCl 3  (21.5 mL, 231 mmol) in 250 mL of acetonitrile was heated at reflux for 24 h. The reaction was concentrated, diluted with 300 mL H 2 O, and neutralized by careful addition of solid Na 2 CO 3 . This mixture was extracted with 400 mL DCM (4×). The combined organics were dried, concentrated and the product precipitated with H 2 O to afford the title compound:  1 H NMR (CDCl 3 ) δ7.47 (d, 1H, 5.3 Hz); 8.45 (d, 1H, 5.3 Hz).  
     [0265] A solution of 2,4-dichloro-3-nitropyridine (6.5 g, 33.7 mmol) and cesium acetate (16.2 g, 84.2 mmol) in 100 mL of DMF was heated at 80° C. for 2 h. The reaction was cooled to room temperature, 50 mL of sat. aq. NH 4 Cl was added and the mixture was concentrated. The residue was partitioned between 200 mL DCM, 100 mL sat. aq. NH 4 Cl and 50 mL H 2 O. The layers were separated and the aqueous layers was backwashed with 200 mL DCM (4×). The combined organics were dried and concentrated (high vacuum) to afford the title compound as a tan solid:  1 H NMR (CD 3 OD) δ6.97 (d, 1H, 5.9 Hz); 8.14 (d, 1H, 5.6 Hz). MS: MH + =174.9.  
     [0266] Step B:  
     [0267] 2-Chloro-1-(methoxymethyl)-3-nitropyridin-4(1H)-one  
     [0268] To a solution of 2-chloro-3-nitropyridin-4-ol (0.722 g, 4.14 mmol) in 20 mL of dichloroethane and 0.5 mL DMF, was added DIEA (2.20 mL, 12.4 mmol) followed by chloro(methoxy)methane (0.63 mL, 8.28 mmol). After 1.0 h at ambient temperature, the reaction was concentrated and redisolved in 150 mL DCM. The DCM solution was washed with 100 mL of saturated sodium bicarbonate solution, 100 mL water and 100 mL of brine, respectively. The organics were dried and concentrated to afford the title compound as a white solid:  1 H NMR (CDCl 3 ) δ3.47 (s, 3H), 5.37 (s, 2H), 6.58-6.60 (d, 1H, 7.9 Hz), 7.54-7.57 (d, 1H, 7.9 Hz). MS: MH + =219.0  
     [0269] Step C:  
     [0270] 2-[(2,2-Difluoro-2-pyridin-2-ylethyl)amino]-1-(methoxymethyl)-3-nitropyridin-4(1 H)-one  
     [0271] A mixture of 2-chloro-1-(methoxymethyl)-3-nitropyridin-4(1H)-one (0.44 g, 2.01 mmol), 2,2-difluoro-2-pyridin-2-ylethanamine (0.46 mL, 4.02 mmol) and DIEA (1.05 mL, 6.03 mmol) in 5 mL of DMF was heated at 50° C. for 2.0 h. The reaction was concentrated, the residue diluted 150 mL of DCM and washed with 150 mL saturated sodium bicarbonate solution (2×). The organic layer was dried, concentrated and purified with 15% MeOH/DCM on silica chromatography:  1 H NMR (CDCl 3 ) δ3.46 (s, 3H), 3.87-3.95 (m, 2H), 5.16 (s, 2H), 6.28-6.30 (d, 1H, 7.9 Hz), 6.97-7.00 (b, 1H), 7.13-7.16 (d, 1H, 7.9 Hz). 7.43-7.46 (m, 1H), 7.67-7.70 (d, 1H, 7.9 Hz), 7.86-7.90 (td, 1H, 7.9 Hz, 1.7 Hz), 8.58-8.60 (d, 4.8 Hz). MS: MH + =341.0.  
     [0272] Step D:  
     [0273] 2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-3-nitropyridin-4-ol  
     [0274] 2-[(2,2-Difluoro-2-pyridin-2-ylethyl)amino]-1-(methoxymethyl)-3-nitropyridin-4(1H)-one (0.30 g, 0.880 mmnol) was dissolved in 10 mL of 1:1 mixture of 1N HCl/methanol and stirred at ambient temperature for 16 h. Evaporation of solvent yielded the HCl salt of the title compound: MS: MH + =297.0.  
     [0275] Step E:  
     [0276] b  3 -Amino-2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]pyridin-4-ol  
     [0277] A degassed solution of 2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-3-nitropyridin-4-ol (0.26g, 0.880 mmol) in 15 mL of EtOH was added 0.10 g of 10% Pd-C. The mixture was hydrogenated under 55 psi hydrogen for 4.0 h. The reaction was filtered and concentrated to give the title compound: MS: MH + =267.0.  
     [0278] Step F:  
     [0279] 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]-N-{2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino-4-hydroxypyridin-3-yl }acetamide  
     [0280] A mixture of 3-amino-2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]pyridin-4-ol (0.160 g, 0.600 mmol), [5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]acetic acid (0.160, 0.660 mmol), EDC (0.140 g, 0.720 mmol), HOAt (0.100 g, 0.720 mmol) and DIEA (0.230 mL, 1.32 mmol) in 15 mL of DMF was stirred at ambient temperature for 16 h. The reaction was concentrated and redistributed between 50 mL of saturated sodium bicarbonate solution and 100 mL DCM. The DCM solution was dried, concentrated and purified by 0%-15% MeOH-DCM to give the title compound:  1 H NMR (CD3OD) δ3.65 (s, 2H), 4.16-4.23 (t, 2H, 13.7 Hz), 6.11-6.13 (d, 1H, 7.0 Hz), 7.34-7.36 (d, 1H, 7.0 Hz), 7.40-7.50 (m, 2H), 7.63-7.66 (d, 1H, 8.1Hz), 7.68-7.69 (d, 1H, 2.2 Hz), 7.80-7.83 (td, 1H, 7.9 Hz, 1.5 Hz), 8.20 (s, 1H), 8.51-8.53 (d, 1H, 4.4 Hz), 8.79 (s, 1H). MS: MH + =486.3  
     [0281] Step G:  
     [0282] 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)[1,3]oxazolol4,5-c]pyridin-4-amine  
     [0283] To a solution of 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]-N-{2-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-4-hydroxypyridin-3-yl}acetamide (0.190 g, 0.391 mmol) in 10 mL of DCM was added triphenylphosphine (0.41 g, 1.56 mmol) and DIAD (0.23 mL, 1.17 mmol). After 16 h the solvent was removed and the reaction was purified by 0%-5% MeOH-DCM to yield the title compound:  1 H NMR (CDCl 3 ) δ4.22 (s, 2H), 4.53-4.63 (td, 2H, 14.1 Hz, 6.4 Hz), 6.75-6.77 (d, 1H, 5.9 Hz), 7.33-7.40 (m, 2H), 7.43-7.47 (dd, 1H, 8.4 Hz, 2.4 Hz), 7.52-7.53 (d, 1H, 2.4 Hz), 7.68-7.70 (ddd, 1H, 7.9 Hz, 2.0 Hz, 0.9 Hz), 7.78-7.83 (td, 1H, 7.9 Hz, 1.8 Hz), 7.93-7.95 (d, 1H, 5.9 Hz), 8.12 (s, 1H), 8.39 (s, 1H), 8.67-8.69 (dd, 1H, 4.8 Hz, 0.7 Hz). MS: MH + =468.1.  
     [0284] Step H:  
     [0285] N-(2.2-difluoro-2-pyridin-2-ylethyl)-2-[2-(1H-, 1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-amine  
     [0286] To a degassed solution of 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2,2-difluoro-2-pyridin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine (0.050 g, 0.107 mmol) in 0.15 mL of triethylamine and 10 mL EtOH was added 0.055 g of 10% Pd-C. The mixture was hydrogenated under a hydrogen balloon for 3.0 h. The reaction was filtered through celite and concentrated. The residue was partitioned between 50 mL of DCM and 50 mL of sodium bicarbonate solution, separated and the organics concentrated. The residue was purified with 5% of MeOH-DCM on silica chromatography to give title compound:  1 H NMR (CD3OD) δ4.54 (s, 2H), 4.59-4.67 (t, 2H, 13.9 Hz), 7.35-7.38 (d, 1H, 7.1 Hz), 7.61-7.76 (m, 5H), 7.84-7.87 (d, 1H, 7.8 Hz), 7.94-7.96 (d, 1H, 7.1 Hz), 8.08-8.12 (td, 1H, 7.7 Hz, 1.4 Hz), 8.71-8.74 (d, 1H, 4.5 Hz), 8.78 (s, 1H), 9.88 (s, 1H). MS: MH + =434.3.  
     EXAMPLE 5  
     [0287] Preparation of N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-2-{[3-(1 H-tetraazol-1-yl)pyridin-2-yl]methyl}[1,3]oxazolo[4,5-c]pyridin-4-amine  
                 
 
     [0288] Step, A:  
     [0289] 2-chloro-3-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridin-4(1H)-one  
     [0290] To a solution of 2-chloro-3-nitropyridin-4-ol (0.305 g, 1.75 mmol) in 10 mL DCM and 0.5 mL of DMF, was added DIEA (0.460 mL, 2.63 mmol) followed by [2-(chloromethoxy)ethyl](trimethyl)silane (0.370 mL, 2.10 mmol). The reaction was stirred at ambient temperature for 1.0 h, diluted with 100 mL of DCM, and washed with saturated sodium bicarbonate solution (2×). The organic layer was dried, concentrated and purified with 15%-100% EtOAc-Hexane on silica chromatography to give the title compound as white solid:  1 H NMR (CDCl 3 ) δ0.034 (s, 9H), 0.96-1.02 (m, 2H), 3.63-3.68 (m, 2H), 5.39 (s, 2H), 6.59-6.62 (d, 1H, 7.9 Hz), 7.51-7.54 (d, 1H, 7.9 Hz).  
     [0291] Step B:  
     [0292] 2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-3-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridin-4(1H)-one  
     [0293] A solution of 2-chloro-3-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridin-4(1H)-one (0.17 g, 0.558 mmol), 2,2-difluoro-2-(1-oxidopyridin-2-yl)ethanamine (0.12 g, 0.670 mmol) and DIEA (0.15 mL, 0.837 mmol) in 3 mL of EtOH was heated at 50° C. for 16 h. The mixture was concentrated and the residue purified with a 0%-9% MeOH-DCM gradient on silica chromatography to give the title compound:  1 H NMR (CDCl 3 ) δ0.000 (s, 9H), 0.93-0.98 (m, 2H), 3.55-3.59 (t, 2H, 8.3 Hz), 4.19-4.27 (td, 2H, 13.4 Hz, 5.0 Hz), 5.21 (s, 2H), 6.24-6.26 (d, 1H, 7.9Hz), 7.07 (b, 1H), 7.16-7.19 (d, 1H, 7.9 Hz), 7.35-7.41 (m, 2H), 7.59-7.62 (m, 1H), 8.15-8.17 (m, 1H). MS: MH + =443.3.  
     [0294] Step C:  
     [0295] 3-amino-2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridin-4(1H)-one  
     [0296] To a solution of 2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-3-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridin-4(1H)-one (0.15 g, 0.339 mmol) in 20 mL of MeOH and 3.4 mL of 1N HCl was added zinc (0.168 g, 2.52 mmol) at 55° C. in three portions over 1 h. The reaction was filtered after 2 h at 55° C. and concentrated. The residue was purified with 1%-15% of Methanol (containing 1% NH 4 OH)-DCM on silica gel to give the title compound:  1 H NMR (CDCl 3 ) δ0.00 (s, 9H), 0.90-0.94 (t, 2H, 8.2 Hz), 3.50-3.55 (t, 2H, 8.2 Hz), 4.04-4.13 (td, 2H, 14.4 Hz, 7.0 Hz), 4.52-4.56 (t, 1H, 7.0 Hz), 5.24 (s, 2H), 6.21-6.24 (d, 1H, 7.3Hz), 7.05-7.08 (d, 1H, 7.5 Hz), 7.41-7.44 (m, 1H), 7.68-7.71 (d, 1H, 7.9 Hz), 7.84-7.89 (td, 1H, 7.7 Hz, 1.7 Hz), 8.64-8.65 (d, 1H, 4.8 Hz). MS: MH + =413.3.  
     [0297] Step D:  
     [0298] Ethyl (3-aminopyridin-2-yl)acetate  
     [0299] To a degassed solution of ethyl (3-nitropyridin-2-yl)acetate (3.40 g, 16.2 mmol) in 25 mL of EtOH was added 0.68 g 10% Pd-C. This mixture was hydrogenated at 40 psi for 3.0 h and filtered through celite to give 3.0 g of the title compound after evaporation of solvent:  1 H NMR (CDCl 3 ) δ1.21-1.28 (t, 3H), 3.83 (s, 2H), 4.10-4.20 (q, 2H), 6.98-7.04 (m, 2H), 7.98-8.00 (m, 1H). MS: MH + =181.0  
     [0300] Step E:  
     [0301] Ethyl [3-(1H-tetraazol-1-yl)pyridin-2-yl]acetate  
     [0302] To ethyl (3-aminopyridin-2-yl)acetate (3.0 g, 16.6 mmol) in 60 mL of AcOH was added trimethyl orthoformate (9.00 mL, 83.0 mmol) and sodium azide (5.40 g, 83.0 mmol). The mixture was heated at 65° C. for 16 h and then concentrated. The residue was diluted with 200 mL of DCM, washed with 100 mL saturated sodium bicarbonate solution (2×) and concentrated. The residue was purified with 2%-85% EtOAc-Hexane on silica gel:  1 H NMR (CDCl 3 ) δ1.21-1.28 (t, 3H, 7.1 Hz), 3.85 (s, 2H), 4.09-4.14 (q, 2H, 7.1 Hz), 7.49-7.53 (dd, 1H, 8.0 Hz, 4.8 Hz), 7.78-7.81 (dd, 1H, 8.0 Hz, 1.6 Hz), 8.79-8.81 (dd, 1H, 4.8 Hz, 1.6 Hz), 9.06 (s, 1H). MS: MH + =234.0  
     [0303] Step F  
     [0304] [3-(1H-tetraazol-1-yl)pyridin-2-yl]acetic acid  
     [0305] A solution of ethyl [3-(1H-tetraazol-1-yl)pyridin-2-yl]acetate (0.286 g, 1.23 mmol) in 10 mL of methanol and 1.35 mL of 1N KOH was stirred for 2 h at ambient temperature. The solution was titrated to pH=7.0 with 1N HCl and concentrated to give the title compound containing KCl:  1 H NMR (DMSO-D 6 ) δ3.77 (s, 2H), 7.61-7.64 (dd, 1H, 8.0 Hz, 4.8 Hz), 8.09-8.11 (dd, 1H, 8.0 Hz, 1.0 Hz), 8.74-8.76 (dd, 1H, 4.8 Hz, 1.0 Hz), 9.90 (s, 1H). MS: MH + =206.0.  
     [0306] Step G  
     [0307] N-(2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydropyridin-3-yl)-2-[4-(2H-tetraazol-2-yl)pyridin-2-yl]acetamide  
     [0308] A mixture of 3-amino-2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-1-{[2-(trimethylsilyl)ethoxy]methyl}pyridin-4(1H)-one (0.030 g, 0.0727 mmol), [3-(1H-tetraazol-1-yl)pyridin-2-yl]acetic acid (0.028 g, 0.0873 mmol, 65% remainder KCl), HOBt (0.015 g, 0.109 mmol), EDC (0.021 g, 0.109 mmol) and DIEA (0.028 mL, 0.160mmol) was stirred in 4 mL of dry DMF at ambient temperature for 5.0 h. The reaction was concentrated and purified with 1%-15% of MeOH-DCM on silica chromatography to give title compound: MS: MH + =600.3.  
     [0309] Step H:  
     [0310] N-(2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-4-hydroxypyridin-3-yl)-2-[3-(2H-tetraazol-2-yl)pyridin-2-yl]acetamide  
     [0311] N-(2-{[2,2-Difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-4-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydropyridin-3-yl)-2-[4-(2H-tetraazol-2-yl)pyridin-2-yl]acetamide (0.29 g, 0.484 mmol) was dissolved in 6mL of 1:1 of EtOH: 2N HCl and heated at 55° C. for 2.0 h. Concentation of the solvent gave the title compound: MS: MH + =470.3.  
     [0312] Step I:  
     [0313] N-[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]-2-{[3-(1H-tetraazol-1-yl)pyridin-2-yl]methyl}[1,3]oxazolo[4,5-c]pyridin-4-amine  
     [0314] A solution of N-(2-{[2,2-difluoro-2-(1-oxidopyridin-2-yl)ethyl]amino}-4-hydroxypyridin-3-yl)-2-[3-(2H-tetraazol-2-yl)pyridin-2-yl]acetamide (0.23 g, 0.490 mmol) in 15 ml of DCM was added to a mixture of triphenyl phosphine (0.514 g, 1.96 mmol) and DIAD (0.290 mL, 1.47 mmol) in 5 mL of DCM. This mixture was stirred at ambient temperature for 16 h, concentrated and purified with 10% MeOH-DCM on silica chromatography:  1 H NMR (CDCl 3 ) δ4.39 (s, 2H), 4.69-4.77 (m, 2H), 5.90-5.94 (t, 1H, 6.4 Hz), 6.72-6.74 (d, 1H, 5.9 Hz), 7.25-7.29 (m, 1H), 7.32-7,37 (dd, 1H, 8.0 Hz, 1.9 Hz), 7.52-7.56 (dd, 1H, 8.0 Hz, 4.8 Hz), 7.60-7.63(dd, 1H, 8.1 Hz, 2.0 Hz), 7.82-7.88(m, 2H), 8.32-8.34 (d, 1H, 6.2 Hz), 8.80-8.82 (dd, 1H, 4.8 Hz, 1.5 Hz), 9.38 (s, 1H). MS: MH + =4.52.3  
     EXAMPLE 6  
     [0315] Preparation of 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2-piperidin-2-ylethyl)[1,3]oxozolo[4.5-c]pyridin-4-amine  
                 
 
     [0316] Step A:  
     [0317] Tert-butyl 2-{2-[(4-hydroxy-3-nitropyridin-2-yl)amino]ethyl}piperidine-1-carboxylate  
     [0318] To a solution of tert-butyl 2-(2-aminoethyl)piperidine-1-carboxylate (1.50 g, 6.59 mmol) and 2-chloro-3-nitropyridin-4-ol (0.959 g, 5.50 mmol) in 5 mL of EtOH, was added DIEA (1.50 mL, 8.25 mmol). The reaction was refluxed at 78° C. for 3 days, diluted with 200 mL of DCM, washed with 100 mL of saturated sodium bicarbonate solution (2× 0  and concentrated. The residue was purified with 10% MeOH-DCM to give the title comnpound:  1 H NMR (CDCl 3 ) δ1.36-1.71 (m, 16H), 2.05-2.15 (b, 1H), 2.76-2.84 (t, 1H), 3.37 (b, 1H), 3.80 (b, 1H), 4.00 (b, 1H ), 4.39 (b, 1H), 6.24-6.25 (d, 1H, 5.5 Hz), 8.06-8.08 (d, 1H, 5.5 Hz), 12.4 (b, 1H). MS: MH + =367.2.  
     [0319] Step B:  
     [0320] Tert-butyl 2-{2-[(3-amino-4-hydroxypyridin-2-yl)amino]ethyl}piperidine-1-carboxylate  
     [0321] To a degassed solution of tert-butyl 2-{2-[(4-hydroxy-3-nitropyridin-2-yl)amino]ethyl}piperidine-1-carboxylate (1.45 g, 3.96 mmol) in 30 mL of EtOAc was added 0.42 g of 10% Pd-C. The mixture was hydrogenated at 45 psi for 16 h, filtered through celite, and concentrated to give the title compound: MS: MH + =337.1  
     [0322] Step C:  
     [0323] Tert-butyl 2-(2-{[3-({[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]acetyl}amino)-4-hydroxypyridin-2-yl]amino}ethyl)piperidine-1-carboxylate  
     [0324] To a solution of tert-butyl 2-{2-[(3-amino-4-hydroxypyridin-2-yl)amino]ethyl}piperidine-1-carboxylate (0.612 g, 1.82 mmol), [5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]acetic acid (0.454 g, 1.91 mmol) in 6 mL of DMF was added EDC (0.42 g, 2.18 mmol), HOBt (0.30 g, 2.18 mmol) and DIEA (0.70 mL, 4.00 mmol). The reaction was stirred at ambient temperature for 16 h, concentrated and the residue purified with 20% MeOH-DCM on silica gel: MS: MH + =556.4.  
     [0325] Step D:  
     [0326] Tert-butyl 2-[2-({2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-yl}amino)ethyl]piperidine-1-carboxylate  
     [0327] A solution of tert-butyl 2-(2-{[3-({[5-chloro-2-(1H-1,2,4-triazol-1-yl)phenyl]acetyl}amino)-4-hydroxypyridin-2-yl]amino}ethyl)piperidine-1-carboxylate (0.300 g, 0.539 mmol) in 30 mL of dichloroethane was added to a mixture of triphenylphosphine (0.565 g, 2.16 mmol) and DIAD (0.318 mL, 1.62 mmol) in 20 mL of dichloroethane. The reaction was stirred at ambient temperature for 16 h and concentrated. The residue was purified with 5% MeOH-DCM on silica gel to give the title compound: MS: MH + =538.1.  
     [0328] Step E:  
     [0329] 2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-N-(2-piperidin-2-ylethyl)[1,3]oxazolo[4,5-c]pyridin-4-amine:  
     [0330] To a solution of tert-butyl 2-[2-({2-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl][1,3]oxazolo[4,5-c]pyridin-4-yl}amino)ethyl]piperidine-1-carboxylate (0.480 g, 0.892 mmol) in 10 mL of DCM was added 0.96 mL of TFA at ambient temperature. After 1 h, the reaction was diluted with 200 mL of DCM and washed with 100 mL saturated sodium bicarbonate solution (2×). The organic layer was concentrated and purified with 1%-50% MeOH-DCM gradient on silica gel to afford the title compound:  1 H NMR (CDCl 3 ) δ1.15-1.22 (m, 1H), 1.32-1.42 (m, 2H), 1.56-1.60 (m 1H), 1.65-1.79 (m, 4H), 2.17 (b, 1H), 2.54-2.64 (m, 2H), 3.06-3.09 (d, 1H, 12.1 Hz), 3.53-3.59 (dd, 1H, 12.1Hz, 6.5 Hz), 3.70-3.75 (dd, 1H, 13.2 Hz, 6.4 Hz), 4.21 (s, 2H), 5.63-5.67 (t, 1H, 5.1 Hz), 6.69-6.71(d, 1H, 5.9 Hz), 7.33-7.36 (d, 1H, 8.4 Hz), 7.43-7.46 (dd, 1H, 8.4 Hz, 2.2 Hz), 7.52-7.53 (d, 1H, 2.2 Hz), 7.94-7.96 (d, 1H, 5.9 Hz), 8.13 (s, 1H), 8.42(s, 1H). MS: MH = 438.3.  
     EXAMPLE 7  
     [0331] Typical tablet cores suitable for administration of thrombin inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:  
                                               General   Preferred   Most Preferred       Excipient   Range (%)   Range (%)   Range (%)                  mannitol   10-90   25-75   30-60       microcrystalline cellulose   10-90   25-75   30-60       magnesium stearate   0.1-5.0   0.1-2.5   0.5-1.5                  
 
     [0332] Mannitol, microcrystalline cellulose and magnesium stearate may be substituted with alternative pharmaceutically acceptable excipients.  
     [0333] In Vitro Assay For Determining Proteinase Inhibition  
     [0334] Assays of human α-thrombin, human trypsin, and factor Xa were performed by the methods substantially as described in Lewise et al., (1993) Inhibition of Thrombin and Other Trypsin-Like Serine Proteinases by Cyclotheonamide-A. Thrombosis Research, 70; pages 173-190. The compounds of the invention inhibit thrombin at an IC 50  concentration of ≦10 μM. In addition, select compounds also inhibit factor Xa in an IC 50  concentration of ≦15 μM.  
     [0335] The assays were carried out at 25° C. in 0.05 M TRIS buffer pH 7.4, 0.15 M NaCl, 0.1% PEG. Trypsin assays also contained 1 mM CaCl2. In assays wherein rates of hydrolysis of a p-nitroanilide (pna) substrate were determined, a Thermomax 96-well plate reader was used was used to measure (at 405 nm) the time dependent appearance of p-nitroaniline. sar-PR-pna was used to assay human α-thrombin (K m =125 μM) and bovine trypsin (K m =125 μM). p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm −1 M −1 .  
     [0336] In certain studies with potent inhibitors (K i &lt;10 nM) where the degree of inhibition of thrombin was high, a more sensitive activity assay was employed. In this assay the rate of thrombin catalyzed hydrolysis of the fluorogenic substrate benzyloxycarbonyl-Gly-Pro-Arg-7-amino-4-trifluoromethylcoumarin (Z-GPR-afc, Lewis S. D. et al. (1998) J. Biol. Chem. 273, pp. 4843-4854) (K m =7 μM) was determined from the increase in fluorescence at 500 nm (excitation at 400 nm) associated with production of 7-amino-4-trifluoromethyl coumarin. Concentrations of stock solutions of Z-GPR-afc were determined from measurements of absorbance at 380 nm of the 7-amino-4-trifluoromethyl coumarin produced upon complete hydrolysis of an aliquot of the stock solution by thrombin.  
     [0337] Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration ≦0.1 K m  into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (V o ) or presence of inhibitor (V i ) were measured. Assuming competitive inhibition, and that unity is negligible compared K m /[S], [I]/e, and [I]/e (where [S], [I], and e respectively represent the total concentrations, of substrate, inhibitor and enzyme), the equilibrium constant (K i ) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of V o /V i  on [I]shown in the following equation. 
       V   o   /V   i  =1 +[I]/K   i   
     [0338] The activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels.  
     [0339] EXAMPLE 8  
     [0340] Tablet Preparation  
     [0341] Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the following active compounds are prepared as illustrated below (compositions A-C). Active I is compound N 2 -(3-chlorobenzyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine.  
                                              Amount-(mg)                                     Component   A   B   C                                                 Active I   25   50   100           Microcrystalline cellulose   37.25   100   200           Modified food corn starch   37.25   4.25   8.5           Magnesium stearate   0.5   0.75   1.5                      
 
     [0342] All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.  
     [0343] EXAMPLE 9  
     [0344] Tablet Preparation  
     [0345] Exemplary compositions of compound N 2 -(3-chlorobenzyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine (Active I) tablets are shown below:  
                                               Component   0.25 mg   2 mg   10 mg   50 mg                  Active I   0.500%   1.000%   5.000%   14.29%       mannitol   49.50%   49.25%   47.25%   42.61%       microcrystalline cellulose   49.50%   49.25%   47.25%   42.61%       magnesium stearate   0.500%   0.500%   0.500%   0.500%                  
 
     [0346] 2, 10 and 50 mg tablets were film-coated with an aqueous dispersion of hydroxypropyl cellulose, hydroxypropyl methylcellulose and titanium dioxide, providing a nominal weight gain of 2.4%.  
     [0347] Tablet preparation Via Direct Compression  
     [0348] Active I, mannitol and microcrystalline cellulose were sieved through mesh screens of specified size (generally 250 to 750 μm) and combined in a suitable blender. The mixture was subsequently blended (typically 15 to 30 min) until the drug was uniformly distributed in the resulting dry powder blend. Magnesium stearate was screened and added to the blender, after which a precompression tablet blend was achieved upon additional mixing (typically 2 to 10 min). The precompression tablet blend was then compacted under an applied force, typically ranging from 0.5 to 2.5 metric tons, sufficient to yield tablets of suitable physical strength with acceptable disintegration times (specifications will vary with the size and potency of the compressed tablet). In the case of the 2, 10 and 50 mg potencies, the tablets were dedusted and film-coated with an aqueous dispersion of water-soluble polymers and pigment.  
     [0349] Tablet Preparation Via Dry Granulation  
     [0350] Alternatively, a dry powder blend is compacted under modest forces and remilled to afford granules of specified particle size. The granules are then mixed with magnesium stearate and tabletted as stated above.  
     [0351] EXAMPLE 10  
     [0352] Intravenous Formulations  
     [0353] Intravenous formulations of compound N 2 -(3-chlorobenzyl)-N 4 -(2,2-difluoro-2-pyridin-2-ylethyl)-1,3-benzoxazole-2,4-diamine (Active I) were prepared according to general intravenous formulation procedures.  
                                                   Component   Estimated range                                                        Active I   0.12-0.50   mg           D-glucuronic acid*   0.5-5   mg           Mannitol NF   50-53   mg                             1 N Sodium Hydroxide   q.s. pH 3.9-4.1           Water for injection   q.s. 1.0 mL                      
 
     [0354] Various other buffer acids, such as L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be substituted for glucuronic acid.