INHIBITORS OF FACTOR Xa

Abstract: The present application relates to compounds of the general formula A-Y-D-E-G-J-K-L, wherein A, Y, D, E, G, J, K and L have the meanings given in the description, having activity against mammalian factor Xa. The compounds are useful <i>in vitro</i> or <i>in vivo</i> for preventing or treating coagulation disorders.

Description: INHIBITORS OF FACTOR Xa Related Applications This application claims benefit of priority under 35 USC § 119(e) to U.S. Provisional Application No. 60/135,819 filed on May 24, 1999, which is herein incorporated in its entirety by reference. Field of the Invention This invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa or when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation (e.g. thrombin, fNIIa, fIXa) or the fibrinolytic cascades (e.g. plasminogen activators, plasmin). In another aspect, the present invention relates to novel monoamidino-containing compounds, their pharmaceutically acceptable salts, and pharmaceutically acceptable compositions thereof which are useful as potent and specific inhibitors of blood coagulation in mammals. In yet another aspect, the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals characterized by coagulation disorders. Background of the Invention Hemostasis, the control of bleeding, occurs by surgical means, or by the physiological properties of vasoconstriction and coagulation. This invention is particularly concerned with blood coagulation and ways in which it assists in maintaining the integrity of mammalian circulation after injury, inflammation, disease, congenital defect, dysfunction or other disruption. Although platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of the processes involved in platelet aggregation and fibrin deposition. Thrombin is a key enzyme in the coagulation cascade as well as in hemostasis. Thrombin plays a central role in thrombosis through its ability to catalyze the conversion of fibrinogen into fibrin and through its potent platelet activation activity. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies as reviewed by Claeson, G., "Synthetic Peptides and Peptidomimetics as Substrates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System", Blood Coag. Fibrinol. 5, 411-436 (1994). Several classes of anticoagulants currently used in the clinic directly or indirectly affect thrombin (i.e. heparins, low-molecular weight heparins, heparin-like compounds and coumarins). A prothrombinase complex, including Factor Xa (a serine protease, the activated form of its Factor X precursor and a member of the calcium ion binding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent, blood coagulation glycoprotein family), converts the zymogen prothrombin into the active procoagulant thrombin. Unlike thrombin, which acts on a variety of protein substrates as well as at a specific receptor, factor Xa appears to have a single physiologic substrate, namely prothrombin. Since one molecule of factor Xa may be able to generate up to 138 molecules of thrombin (Elodi et al., Thromb. Res. 15, 617- 619 (1979)), direct inhibition of factor Xa as a way of indirectly inhibiting the formation of thrombin may be an efficient anticoagulant strategy. Therefore, it has been suggested that compounds which selectively inhibit factor Xa may be useful as in vitro diagnostic agents, or for therapeutic administration in certain thrombotic disorders, see e.g., WO 94/13693. Polypeptides derived from hematophagous organisms have been reported which are highly potent and specific inhibitors of factor Xa. United States Patent 4,588,587 describes anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. A principal component of this saliva was shown to be the polypeptide factor Xa inhibitor, antistasin (ATS), by Nutt, E. et al., "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveals a Repeated Internal Structure", J. Biol. Chem., 262, 10162-10167 (1988). Another potent and highly specific inhibitor of Factor Xa, called tick anticoagulant peptide (TAP), has been isolated from the whole body extract of the soft tick Ornithidoros moubata, as reported by Waxman, L., et al, "Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa" Science, 248, 593-596 (1990). Factor Xa inhibitory compounds which are not large polypeptide-type inhibitors have also been reported including: Tidwell, R.R. et al, "Strategies for Anticoagulation With Synthetic Protease Inhibitors. Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res., 12, 339-349 (1980); Turner, A.D. et al, "p-Amidino Esters as Irreversible Inhibitors of Factor IXa and Xa and Thrombin", Biochemistry, 25, 4929-4935 (1986); Hitomi, Y. et al, "Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation System", Haemostasis, 15., 164- 168 (1985); Sturzebecher, J. et al, "Synthetic Inhibitors of Bovine Factor Xa and Thrombin. Comparison of Their Anticoagulant Efficiency", Thromb. Res., 54_, 245- 252 (1989); Kam, CM. et al, "Mechanism Based Isocoumarin Inhibitors for Trypsin and Blood Coagulation Serine Proteases: New Anticoagulants", Biochemistry, 22, 2547-2557 (1988); Hauptmann, J. et al, "Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors", Thromb. Haemost., 61, 220-223 (1990); and the like. Others have reported Factor Xa inhibitors which are small molecule organic compounds, such as nitrogen containing heterocyclic compounds which have amidino substituent groups, wherein two functional groups of the compounds can bind to Factor Xa at two of its active sites. For example, WO 98/28269 describes pyrazole compounds having a terminal C(=NH)-NH 2 group; WO 97/21437 describes benzimidazole compounds substituted by a basic radical which are connected to a naththyl group via a straight or branched chain alkylene,-C(=O) or -S(=O) 2 bridging group; WO 99/10316 describes compounds having a 4-phenyl-N-alkylamidino- piperidine and 4-phenoxy-N-alkylamidino-piperidine group connected to a 3- amidinophenyl group via a carboxamidealkyleneamino bridge; and EP 798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidine group connected to an amidinonaphthyl group via a substituted or unsubstituted sulfonamide or carboxamide bridging group. There exists a need for effective therapeutic agents for the regulation of hemostasis, and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature induced by thrombin such as restenosis and inflammation. In particular, there continues to be a need for compounds which selectively inhibit factor Xa or its precursors. Compounds that have different combinations of bridging groups and functional groups than compounds previously discovered are needed, particularly compounds which selectively or preferentially bind to Factor Xa. Compounds with a higher degree of binding to Factor Xa than to thrombin are desired, especially those compounds having good bioavailabihty and/or solubility. Summary of the Invention The present invention relates to novel compounds which inhibit factor Xa, their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives, and pharmaceutically acceptable compositions thereof which have particular biological properties and are useful as potent and specific inhibitors of blood coagulation in mammals. In another aspect, the invention relates to methods of using these inhibitors as diagnostic reagents or as therapeutic agents for disease states in mammals which have coagulation disorders, such as in the treatment or prevention of any thrombotically mediated acute coronary or cerebrovascular syndrome, any thrombotic syndrome occurring in the venous system, any coagulopathy, and any thrombotic complications associated with extracorporeal circulation or instrumentation, and for the inhibition of coagulation in biological samples. In certain embodiments, this invention relates to novel compounds which are potent and highly selective inhibitors of isolated factor Xa when assembled in the prothrombinase complex. These compounds show selectivity for factor Xa versus other proteases of the coagulation cascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and are useful as diagnostic reagents as well as antithrombotic agents. In a preferred embodiment, the present invention provides a compound of the formula I: A-Y-D-E-G-J-Z-L wherein: A is selected from: (a) C.-Q-alkyl; (b) C 3 -C 8 -cycloalkyl; (c) phenyl, which is independently substituted with 0-2 R 1 substituents; (d) naphthyl, which is independently substituted with 0-2 R 1 substituents;and (e) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R 1 substituents; R 1 is selected from: Halo, C alkyl, C 2 . 6 alkenyl, C 2.6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl,-CN, -NO 2 , (CH 2 ) m NR 2 R 3 , SO 2 NR 2 R 3 , SO 2 R 2 , CF 3 , OR 2 , and a 5- 6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C C 4 -alkyl, -CN C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 - 4 alkylC 3 . 8 cycloalkyl and -NO 2 ; R 2 and R 3 are independently selected from the group consisting of: H, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3.8 cycloalkyl, ^alkylphenyl and ^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3.8 cycloalkyl, C 0 - 4 alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ; m is an integer of 0-2; Y is a member selected from the group consisting of: a direct link, -C(=O)-, -N(R 4 )-, -C(=O)-N(R 4 )-, -N(R 4 )-C(=O)-, -SO 2 -, -O-, -SO 2 -N(R 4 )- and -N(R 4 )-SO 2 -; R 4 is selected from: H, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C (M alkylC 3 . 8 cycloalkyl, C 0^ ,alkylphenyl and C^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3.8 cycloalkyl, C M alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ;. D is a direct link or is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R la substituents; (b) naphthyl, which is independently substituted with 0-2 R la substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R la substituents; R la is selected from: Halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C θJ ,alkylC 3. gcycloalkyl, -CN, -NO 2 , (CH 2 ) m NR 2a R 3a , SO 2 NR 2a R 3a , SO 2 R 2a , CF 3 , OR 2a , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, C 3 . 8 cycloalkyl, C (M alkylC 3 . 8 cycloalkyl, -CN and -NO 2 . R 2a and R 3a are independently selected from the group consisting of: H, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl, Co^alkylphenyl and C^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0Jf alkylC 3 . 8 cycloalkyl, -CN and -NO 2 ;. E is a member selected from the group consisting of: -N(R 5 )-C(=O)-, -C(=O)-N(R 5 )-, -N(R 5 )-C(=O)-N(R 6 )-, -SO 2 -N(R 5 )-, -N(R 5 )-SO 2 -N(R 6 )- and -N(R 5 )-SO 2 -N(R 6 )-C(=O)-; R 5 and R 6 are independently selected from: H, C 1-4 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C (M alkylC 3 . 8 cycloalkyl, Co^alkylphenyl, C 0^ ,alkylnaphthyl, Co^alkylheteroaryl, C M alkylCOOH and C^alkylCOOC^alkyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3.8 cyclόalkyl, C 0^ ,alkylC 3 . 8 cycloalkyl, -CN and -NO 2 ; G is selected from: -CR 7 R 8 - and -CR^-CR^R 8 "- wherein R 7 , R 8 , R 7a , R 8a , R 70 and R 8b are independently a member selected from from the group consisting of: hydrogen, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C (M alkyl-C 3 . 8 cycloalkyl, C^alkylphenyl, C 0 ^alkylnaρhthyl, -OR 9 ,-C 0 ^alkylCOOR 9 , -C 0 ^alkylC(=O)NR 9 R 10 , -C 0 ^alkylC(=O)NR 9 -CH 2 -CH 2 -O-R 10 , -C M alkylC(=O)NR 9 (-CH 2 -CH 2 -O-R 10 -) 2 , -N(R 9 )COR 10 , -N(R 9 )C(=O)R 10 , -N(R 9 )SO 2 R 10 , and a naturally occurring or synthetic amino acid side chain, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 _ gcycloalkyl, C 0^ ,alkyl-C 3 . 8 cycloalkyl, -CN and -NO 2 ; R 9 and R 10 are independently selected from: H, C alkyl, C h alky lphenyl and C 0^ ,alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C M alkyl-C 3 . 8 cycloalkyl, -CN and -NO 2 , and wherein R 9 and R 10 taken together can form a 5-8 membered heterocylic ring; J is a member selected from the group consisting of: a direct link, -CH(R")- and -CH(R U )-CH 2 -; R 11 is a member selected from the group consisting of: hydrogen, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkyl-C 3 . gcycloalkyl, C 0^ ,alkylphenyl, C M alkylnaphthyl, C 0^ ,alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH 2 COOC lJ( alkyl, CH 2 COOC alkylphenyl and CH 2 COOC lJ( alkylnaρhthyl; Z is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R lb substituents; (b) naphthyl, which is independently substituted with 0-2 R lb substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R lb substituents; R lb is selected from: Halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3 . gcycloalkyl, -CN, -NO 2 , NR 2b R 3b , SO 2 NR 2b R 3b , SO 2 R 2b , CF 3 , OR 2b , O-CH 2 - CH 2 -OR 2b , O-CH 2 -COOR 2b , N(R 2b )-CH 2 -CH 2 -OR 2b , N(-CH 2 -CH 2 -OR 2b ) 2 , N(R 2b )-C(=O)R 3b , N(R 2b )-SO 2 -R 3b , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C (M alkylC 3 . gcycloalkyl, -CN and -NO 2 ; R 2b and R 3b are independently selected from the group consisting of: H, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3 . 8 cycloalkyl, . Co^alkylphenyl and C 0^ ,alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3.8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl, -CN and -NO 2 ; L is selected from: H, -CN, C(=O)NR ,2 R 13 , (CH 2 ) n NR 12 R 13 , C(=NR 12 )NR 12 R 13 , NR ,2 R'\ OR 12 , -NR 12 C(=NR 12 )NR 12 R 13 , and NR 12 C(=NR 12 )-R 13 ; R 12 and R 13 are independently selected from: hydrogen, -OR 14 , -NR 14 R 15 , C alkyl, C 0 ^alkylρhenyl, C 0^ ,alkylnaphthyl, COOC alkyl, COO-C^alkylphenyl and COO-C 0 ^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 - 4 alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ; R 14 and R 15 are independently selected from: H, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C θJ ,alkylC 3 . 8 cycloalkyl, C^alkylphenyl and C 0J( alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3.8 cycloalkyl, -CN, and -NO 2 ; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. In certain aspects of this invention, compounds are provided which are useful as diagnostic reagents. In another aspect, the present invention includes pharmaceutical compositions comprising a pharmaceutically effective amount of the compounds of this invention and a pharmaceutically acceptable carrier. In yet another aspect, the present invention includes methods comprising using the above compounds and pharmaceutical compositions for preventing or treating disease states characterized by undesired thrombosis or disorders of the blood coagulation process in mammals, or for preventing coagulation in biological samples such as, for example, stored blood products and samples. Optionally, the methods of this invention comprise administering the pharmaceutical composition in combination with an additional therapeutic agent such as an antithrombotic and/or a thrombolytic agent and/or an anticoagulant. The preferred compounds also include their pharmaceutically acceptable isomers, hydrates, solvates, salts and prodrug derivatives. Detailed Description of the Invention Definitions In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise. The term "alkenyl" refers to a trivalent straight chain or branched chain unsaturated aliphatic radical. The term "alkinyl" (or "alkynyl") refers to a straight or branched chain aliphatic radical that includes at least two carbons joined by a triple bond. If no number of carbons is specified alkenyl and alkinyl each refer to radicals having from 2-12 carbon atoms. The term "alkyl" refers to saturated aliphatic groups including straight-chain, branched-chain and cyclic groups having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms. The term "cycloalkyl" as used herein refers to a mono-, bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms. As used herein, the terms "carbocyclic ring structure " and " C 3 . 16 carbocyclic mono, bicyclic or tricyclic ring structure" or the like are each intended to mean stable ring structures having only carbon atoms as ring atoms wherein the ring structure is a substituted or unsubstituted member selected from the group consisting of: a stable monocyclic ring which is aromatic ring ("aryl") having six ring atoms; a stable monocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring; a stable bicyclic ring structure having a total of from 7 to 12 ring atoms in the two rings wherein the bicyclic ring structure is selected from the group consisting of ring structures in which both of the rings are aromatic, ring structures in which one of the rings is aromatic and ring structures in which both of the rings are non-aromatic; and a stable tricyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein the tricyclic ring structure is selected from the group consisting of: ring structures in which three of the rings are aromatic, ring structures in which two of the rings are aromatic and ring structures in which three of the rings are non- aromatic. In each case, the non-aromatic rings when present in the monocyclic, bicyclic or tricyclic ring structure may independently be saturated, partially saturated or fully saturated. Examples of such carbocyclic ring structures include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3J.0]bicyclooctane, [4J.0]bicyclononane, [4.4.0]bicyclodecane (decalin), 2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any carbon atom which results in a stable structure. The term "substituted" as used in conjunction with carbocyclic ring structures means that hydrogen atoms attached to the ring carbon atoms of ring structures described herein may be substituted by one or more of the substituents indicated for that structure if such substitution(s) would result in a stable compound. The term "aryl" which is included with the term "carbocyclic ring structure" refers to an unsubstituted or substituted aromatic ring, substituted with one, two or three substituents selected from loweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl, carboalkoxy and carboxamide, including but not limited to carbocyclic aryl, heterocyclic aryl, and biaryl groups and the like, all of which may be optionally substituted. Preferred aryl groups include phenyl, halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl and naphthacenyl. The term "arylalkyl" which is included with the term "carbocyclic aryl" refers to one, two, or three aryl groups having the number of carbon atoms designated, appended to an alkyl group having the number of carbon atoms designated. Suitable arylalkyl groups include, but are not limited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, and the like, all of which may be optionally substituted. As used herein, the term "heterocyclic ring" or "heterocyclic ring system" is intended to mean a substituted or unsubstituted member selected from the group consisting of stable monocyclic ring having from 5-7 members in the ring itself and having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S; a stable bicyclic ring structure having a total of from 7 to 12 atoms in the two rings wherein at least one of the two rings has from 1 to 4 hetero atoms selected from N, O and S, including bicyclic ring structures wherein any of the described stable monocyclic heterocyclic rings is fused to a hexane or benzene ring; and a stable tricyclic heterocyclic ring structure having a total of from 10 to 16 atoms in the three rings wherein at least one of the three rings has from 1 to 4 hetero atoms selected from the group consisting of N, O and S. Any nitrogen and sulfur atoms present in a heterocyclic ring of such a heterocyclic ring structure may be oxidized. Unless indicated otherwise the terms "heterocyclic ring" or "heterocyclic ring system" include aromatic rings, as well as non-aromatic rings which can be saturated, partially saturated or fully saturated non-aromatic rings. Also, unless indicated otherwise the term "heterocyclic ring system" includes ring structures wherein all of the rings contain at least one hetero atom as well as structures having less than all of the rings in the ring structure containing at least one hetero atom, for example bicyclic ring structures wherein one ring is a benzene ring and one of the rings has one or more hetero atoms are included within the term "heterocyclic ring systems" as well as bicyclic ring structures wherein each of the two rings has at least one hetero atom. Moreover, the ring structures described herein may be attached to one or more indicated pendant groups via any hetero atom or carbon atom which results in a stable structure. Further, the term "substituted" means that one or more of the hydrogen atoms on the ring carbon atom(s) or nitrogen atom(s) of the each of the rings in the ring structures described herein may be replaced by one or more of the indicated substituents if such replacement(s) would result in a stable compound. Nitrogen atoms in a ring structure may be quatemized, but such compounds are specifically indicated or are included within the term "a pharmaceutically acceptable salt" for a particular compound. When the total number of O and S atoms in a single heterocyclic ring is greater than 1, it is preferred that such atoms not be adjacent to one another. Preferably, there are no more that 1 O or S ring atoms in the same ring of a given heterocyclic ring structure. Examples of monocylic and bicyclic heterocylic ring systems, in alphabetical order, are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H- 1,5,2- dithiazinyl, dihydrofuro[2J-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyπolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-l,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structures include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyπolidinyl, imidazolyl, indolyl, benzimidazolyl, lH-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocyhc ring structures. As used herein the term "aromatic heterocyclic ring system" has essentially the same definition as for the monocyclic and bicyclic ring systems except that at least one ring of the ring system is an aromatic heterocyclic ring or the bicyclic ring has an aromatic or non-aromatic heterocyclic ring fused to an aromatic carbocyclic ring structure. The terms "halo" or "halogen" as used herein refer to CI, Br, F or I substituents. The term "haloalkyl", and the like, refer to an aliphatic carbon radicals having at least one hydrogen atom replaced by a CI, Br, F or I atom, including mixtures of different halo atoms. Trihaloalkyl includes trifluoromethyl and the like as preferred radicals, for example. The term "methylene" refers to -CH2-. The term "pharmaceutically acceptable salts" includes salts of compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both free base and salt form. In practice, the use of the salt form amounts to use of the base form; both acid and base addition salts are within the scope of the present invention. "Pharmaceutically acceptable acid addition salt" refers to salts retaining the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine. "Biological property" for the purposes herein means an in vivo effector or antigenic function or activity that is directly or indirectly performed by a compound of this invention that are often shown by in vitro assays. Effector functions include receptor or ligand binding, any enzyme activity or enzyme modulatory activity, any carrier binding activity, any hormonal activity, any activity in promoting or inhibiting adhesion of cells to an extracellular matrix or cell surface molecules, or any structural role. Antigenic functions include possession of an epitope or antigenic site that is capable of reacting with antibodies raised against it. In the compounds of this invention, carbon atoms bonded to four non- identical substituents are asymmetric. Accordingly, the compounds may exist as diastereoisomers, enantiomers or mixtures thereof. The syntheses described herein may employ racemates, enantiomers or diastereomers as starting materials or intermediates. Diastereomeric products resulting from such syntheses may be separated by chromatographic or crystallization methods, or by other methods known in the art. Likewise, enantiomeric product mixtures may be separated using the same techniques or by other methods known in the art. Each of the asymmetric carbon atoms, when present in the compounds of this invention, may be in one of two configurations (R or S) and both are within the scope of the present invention. Preferred Embodiments In a prefened embodiment, the present invention provides a compound according to the formula I: A-Y-D-E-G-J-Z-L wherein: A is selected from: (a) C,-C 6 -alkyl; (b) C 3 -C 8 -cycloalkyl; (c) phenyl, which is independently substituted with 0-2 R 1 substituents; (d) naphthyl, which is independently substituted with 0-2 R 1 substituents; and (e) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R 1 substituents; R 1 is selected from: halo, C M alkyl, -CN, (CH 2 ) m NR 2 R 3 , SO 2 NR 2 R 3 , SO 2 R 2 , CF 3 , OR 2 , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S; R 2 and R 3 are independently selected from the group consisting of: H, C alkyl and C h alky laryl, m is an integer of 0-2; Y is a member selected from the group consisting of: a direct link, -C(=O)-, -N(R 4 )-, -C(=O)-N(R 4 )-, -N(R 4 )-C(=O)-, -SO 2 -, -O-, -SO 2 -N(R 4 )- and -N(R 4 )-SO 2 -; R 4 is selected from: H, C alkyl and C^alkylaryl;. D is absent or is a member selected from the group consisting of: (a) aryl, which is independently substituted with 0-2 R la substituents; and (b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R l substituents; R la is selected from: Halo, C M alkyl, -CN, -NO 2 , (CH 2 ) m NR 2a R 3a , SO 2 NR 2a R 3a , SO 2 R 2a , CF 3 , OR 2a , and a 5-6 membered aromatic heterocyclic ring containing from 1-4 heteroatoms selected from N, O and S; R 2a and R 3a are independently selected from the group consisting of: H, C M alkyl and C^alkylaryl; E is a member selected from the group consisting of: -N(R 5 )-C(=O)-, -C(=O)-N(R 5 )-, -N(R 5 )-C(=O)-N(R 6 )-, -SO 2 -N(R 5 )-, -N(R 5 )-SO 2 -N(R 6 )- and -N(R 5 )-SO 2 -N(R°)-C(=O)-; R 5 and R 6 are independently selected from: H, C M alkyl, C^alkylaryl, C 0 ^alkylheteroaryl, C^alkylCOOH and C alkylCOOC M alkyl; G is selected from: -CR 7 R 8 - and -CR'R^-CR^R 8 "- wherein R 7 , R 8 , R 7 , R 8a , R n and R 8b are independently a member selected from from the group consisting of: hydrogen, C, .4 alkyl, C 0 ^alkyl-C 3 . 8 cycloalkyl, C^alkylaryl, -OR 9 , -C^alkylCOOR 9 , -C 0J( alkylC(=O)NR 9 R 10 , -N(R 9 )COR 10 , -N(R 9 )C(=O)R 10 , -N(R 9 )SO 2 R 10 , and common amino acid side chains; R 9 and R 10 are independently selected from: H, C M alkyl and C 0Jl alkylaryl; J is a member selected from the group consisting of: a direct link, -CH(R U )- and -CH(R π )-CH 2 -; R 11 is a member selected from the group consisting of: hydrogen, C alkyl, C 2 . 6 alkenyl, C 2.6 alkynyl, C 3.8 cycloalkyl, C^alkylaryl, C M alkylheterocyclics, CH 2 COOC,^alkyl, CH 2 COOC,^alkylaryl; Z is a member selected from the group consisting of: (a) aryl, which is independently substituted with 0-2 R lb substituents;and (b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R lb substituents; R ,b is selected from: halo, C M alkyl, -CN, -NO 2 , NR 2b R 3b , SO 2 NR 2b R 3b , SO 2 R 2 \ CF 3 , OR 2b , O-CH 2 - CH 2 -OR 2b , O-CH 2 -COOR 2 \ N(R 2b )-CH 2 -CH 2 -OR 2b , N(-CH 2 -CH 2 -OR 2b ) 2 , N(R 2b )-C(=O)R 3b , N(R 2b )-SO 2 -R 3b , and a 5-6 membered aromatic heterocyclic ring containing from 1-4 heteroatoms selected from N, O and S; R 2b and R 3b are independently selected from the group consisting of: H, C alkyl and C 0 ^alkylaryl; L is selected from: H, -CN, C(=O)NR 12 R 13 , (CH 2 ) n NR 12 R 13 , C(=NR 12 )NR 12 R 13 , NR 12 R 13 , OR 12 , -NR 12 C(=NR 12 )NR 12 R 13 and NR 12 C(=NR 1 )-R 13 ; R 12 and R 13 are independently selected from: hydrogen, -OR 14 , -NR 14 R 15 , C M alkyl, C 0 ^alkylaryl COOC M alkyl, and COO-C M alkylaryl; R 14 and R 15 are independently selected from: H and C M alkyl; and and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. In a further preferred embodiment, the present invention provides a compound according to the formula I: A-Y-D-E-G-J-Z-L wherein: A is selected from: (a) phenyl, which is independently substituted with 0-2 R 1 substituents; and (b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R 1 substituents; R 1 is selected from: halo, (CH 2 ) m NR 2 R 3 , SO 2 NR 2 R 3 and SO 2 R 2 ; R 2 and R 3 are independently selected from the group consisting of: H and C,. 4 alkyl; Y is a member selected from the group consisting of: a direct link, -C(=O)-, - SO 2 - and -O-; D is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R la substituents; and (b) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R la substituents; R la is selected from: Halo and C alkyl; R 2a and R 3a are independently selected from the group consisting of: H, C M alkyl, C^alkylaryl; E is a member selected from the group consisting of: -N(R 5 )-C(=O)- and -C(=O)-N(R 5 )-; R 5 and R 6 are independently selected from: H, C alkyl, C 0^ ,alkylaryl and C 0^ ,alkylheteroaryl; G is selected from: -CR 7 R 8 - and -CR 7 R 8a -CR 7b R 8b - wherein R 7 , R 8 , R 7a , R 8a , R n and R 8b are independently a member selected from from the group consisting of: hydrogen, C M alkyl, Co- 4 alkyl-C 3 . 8 cycloalkyl, C 0^ ,alkylaryl, -OR 9 , -C 0 ^alkylCOOR 9 , -C 0 . 4 alkylC(=O) NR 9 R 10 , -C 0 ^alkylC(=O)NR 9 -CH 2 -CH 2 -O- R 10 , -C 0Jl alkylC(=O)NR 9 (-CH 2 -CH 2 -O-R 10 -) 2 , -N(R 9 )COR 10 , -N(R 9 )C(=O)R 10 , -N(R 9 )SO 2 R 10 , and common amino acid side chains; R 9 and R 10 are independently selected from: H and C M alkyl, wherein the NR 9 R 10 group of R 7 , R 8 , R 7a , R 8a , R 7 " and R 8b is optionally cyclized to form a 5-8 membered heterocyclic group; J is a member selected from the group consisting of: a direct link, -CH(R")- and -CH(R U )-CH 2 -; R 11 is a member selected from the group consisting of: hydrogen, C M alkyl, C 2 . 6 alkenyl, Co^alkylaryl and a C h alky lheterocyclic ring; Z is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R lb substituents; (b) an aromatic heterocyclic ring having from 5 to 10 ring atoms, wherein 1-4 ring atoms are selected from N, O and S, and wherein the ring may be subsituted independently by from 0-2 R lb substituents; and (c) a fused aromatic bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, wherein the bicyclic ring system may be substituted with 0-2 R lb substituents; R lb is selected from: halo, C M alkyl, OH, OBn, O-CH 2 -CH 2 -OH, O-CH 2 -CH 2 -OCH 3 , O-CH 2 -COOH, O-CH 2 -C(=O)-O-CH 3 , NH 2 , NH-CH 2 -CH 2 -O-CH 3 , NH-C(=O)-O-CH 3 , and NH-SO 2 -CH 3 ; L is selected from: H, C(=O)NR 12 R 13 , (CH 2 ) n NR 12 R 13 and C(=NR 12 )NR 12 R 13 ; R 12 and R 13 are independently selected from: hydrogen and C M alkyl; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. In a further preferred embodiment, the present invention provides a compound according to formula I: A-D-E-G-J-Z-L wherein A is a member selected from the group consisting of: D is a member selected from the group consisting of: E is a member selected from the group consisting of:: -C(=O)-NH-, -C(=O)-N(-CH 3 )-, C(=O)-N(-Bn)-, -NH-C(=O)-, -N(-CH 3 )- C(=O)- and -N(-Bn)C(=O)-; G is selected from: -CH-(-NH 2 )-CH 2 -, -CH-(-NH(C(=O)-CH 3 ))-CH 2 -, -CH-(-NH(C(=O)-Ph))-CH 2 -, -CH-(C(=O)-OR 8 )-, -CH(-R 7 )-, -CH 2 -CH(C(=O)-OR 8 )-, and -CH 2 -CH(C(=O)-N(-R 8 , -R 8 ))-; R 7 is a member selected from the group consisting of : H, phenyl, Bn, -O-loweralkyl and cyclohexyl; R 8 is a member selected from the group consisting of: H, C,. 6 alkyl, -O-loweralkyl and C 3 . 6 cycloalkyl; J is a member selected from the group consisting of; a direct link, -CH(R U )- and -CH(R n )-CH 2 -; R 11 is a member selected from the group consisting of: H, methyl, phenyl and benzyl; and Z and L taken together are a member selected from the group consisting of: and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. The following non-limiting tables illustrate representative compounds of the present invention: Table 1 Formula II Formula II Table 2 Formula III Table 2a Formula El Table 3 Formula IN ,1b Me -OH Br -ΝH2 A OCH2Ph CH CH 2 * JJ- OCH2CH20MΘ CH 2 CH 2 A- ^ N,HMe CH 2 CH Λ NMe, Formula IN Table 4 Formula V Table 4a Formula V Table 5 Formula VI Table 5 a Formula VI Table 6 Formula Nil Table 6a Formula Nil Table 7 Formula VIE Table 8 Formula DC wherein R3 is a member selected from the group consisting of H, F, -OH, Br, CI, -NH 2 , -O-CH 2 -O-Ph and -O-CH 2 -CH 2 -O-CH 35 Table 9 Formula X Table 10 Formula XI Table 11 Formula XH Table 12 Formula XIE Formula XIV Table 14 Formula XN Table 15 Formula XVI Table 16 Formula XVII Table 17 Formula XVIE Table 18 Table 19 Formula XX Table 20 Table 21 Formula XXII Table 22 Table 23 Formula XXIV Table 24 Formula XXV 10 Table 25 Formula XXVI Table 26 Formula XXVII Table 27 Formula XXVIII Table 28 Formula XXX Table 29 Formula XXX Table 30 Formula XXXI Table 31 Formula XXXII Table 32 Formula XXXIII Table 33 Formula XXXIV Table 34 Formula XXXV Table 35 Formula XXXVI Table 36 Formula XXXVII ,7a 3 7b Me -NH 2 Me -NHAc Me NHS02Me Me Table 37 Formula XXXVIII Table 38 Formula XXIX Table 39 Formula XXXX ,7a • ,7b Me CH 2 OH -NH 2 Me -NHAc Me NHS02Me Me Table 40 Formula XXXXI Table 41 Formula XXXXII Table 42 Table 43 Formula XXXXIV ,7b -C(= θ)NCH 2CH 20C H3 CH 2 OH -COOH Me -COOC H3 Me -C(=0)N(CH3)2 Me Table 44 Formula XXXXV ,7b ,11 -C(=0)NCH2CH20CH3 CH, OH -COOH Me -COOC H3 Me -C(=0)N(CH3)2 Me Table 45 Formula XXXXVI ,7b ,11 -C(= θ)NCH 2CH 20C H3 OH -COOH Me -COOC H3 Me -C(=0)N(CH3)2 Me Table 46 Formula XXXXVII ■ ,7b ?11 -C(= θ)NCH 2CH 20C H3 OH -COOH Me -COOC H3 Me -C(=0)N(CH3)2 Me Table 47 Formula XXXXVEI ,7b ,11 -C(=0)NCH 2CH 20CH3 -COOH Me -COOC H3 Me -C(=0)N(CH3)2 Me Table 48 Formula XXXXIX 5 7b ,11 -C(=θ)NCH 2CH20CH3 OH -COOH Me -COOC H3 Me -C(=0)N(CH3)2 Me Table 49 Formula L Table 50 Formula LI Table51 Formula LII Table 52 Formula LEI 3 7a 37b Me Me Me "-0 Bn H 2 C * -CH200H Λ ^ Me -CH2CH2C00Me ^ Bn -CH2CH2CONMe2 H ' C→ 0 Table 53 Formula LIV Table 54 Formula LV Table 55 Formula LVI Table 56 Formula LVII Table 57 Formula LVIII Table 58 Formula LIX Table 59 Formula LX Table 60 Formula LXl Table 61 Formula LXII Table 62 Formula LXI Table 63 Formula LXIV Table 64 Formula LXV Table 65 Formula LXVI Table 66 Table 67 Formula LXVIE j 7b Me Me Me H 2 C Bn H 2 C -CH 200H / -OH Me -CH 2CH 2COOM e Λ Bn -CH2CH2CONMe2 H2C ^) Table 68 Formula LXVIX Table 69 Formula LXX Table 70 Formula LXXI Table 71 Formula LXXE Table 72 Formula LXXIII Table 73 Table 74 Other prefened compounds of formula I, having the sub-formula la, are set forth in Table 75, below. Table 75 Formula la l58 Other preferred compounds of formula I, having the sub-formula lb, are set forth in Table 76, below. Table 76 Formula III This invention also encompasses all pharmaceutically acceptable isomers, salts, hydrates and solvates of the compounds of formulas I, II and III. In addition, the compounds of formulas I, II and III can exist in various isomeric and tautomeric forms, and all such forms are meant to be included in the invention, along with pharmaceutically acceptable salts, hydrates and solvates of such isomers and tautomers. The compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification. A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, the free acid or free base form of a compound of one of the formulas above can be reacted with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process. Prodrug Derivatives of Compounds This invention also encompasses prodrug derivatives of the compounds contained herein. The term "prodrug" refers to a pharmacologically inactive derivative of a parent drug molecule that requires biotransformation, either spontaneous or enzymatic, within the organism to release the active drug. Prodrugs are variations or derivatives of the compounds of this invention which have groups cleavable under metabolic conditions. Prodrugs become the compounds of the invention which are pharmaceutically active in vivo, when they undergo solvolysis under physiological conditions or undergo enzymatic degradation. Prodrug compounds of this invention may be called single, double, triple etc., depending on the number of biotransformation steps required to release the active drug within the organism, and indicating the number of functionalities present in a precursor-type form. Prodrug forms often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA, 1992). Prodrugs commonly known in the art include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acids with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative. Moreover, the prodrug derivatives of this invention may be combined with other features herein taught to enhance bioavailabihty. As mentioned above, the compounds of this invention find utility as therapeutic agents for disease states in mammals which have disorders of coagulation such as in the treatment or prevention of unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, thrombotic stroke, embolic stroke, disseminated intravascular coagulation including the treatment of septic shock, deep venous thrombosis in the prevention of pulmonary embolism or the treatment of reocclusion or restenosis of reperfused coronary arteries. Further, these compounds are useful for the treatment or prophylaxis of those diseases which involve the production and/or action of factor Xa/prothrombinase complex. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated which include but are not limited to, deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, thromboembolic complications of surgery and peripheral arterial occlusion. Accordingly, a method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprises administering to the mammal a therapeutically effective amount of a compound of this invention. In addition to the disease states noted above, other diseases treatable or preventable by the administration of compounds of this invention include, without limitation, occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty, thrombus formation in the venous vasculature, disseminated intravascular coagulopathy, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure, hemorrhagic stroke, renal dialysis, blood oxygenation, and cardiac catheterization. The compounds of the invention also find utility in a method for inhibiting the coagulation biological samples, which comprises the administration of a compound of the invention. The compounds of the present invention may also be used in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this invention may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of the present invention may act in a synergistic fashion to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. These compounds may also allow for reduced doses of the thrombolytic agents to be used and therefore minimize potential hemorrhagic side-effects. The compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro. The biological properties of the compounds of the present invention can be readily characterized by methods that are well known in the art, for example by the in vitro protease activity assays and in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters, such as are illustrated in the examples. Diagnostic applications of the compounds of this invention will typically utilize formulations in the form of solutions or suspensions. In the management of thrombotic disorders the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incoφorated into shaped articles. Subjects in need of treatment (typically mammalian) using the compounds of this invention can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize. Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol. Dosage formulations of the compounds of this invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution. The pH of the preparations of this invention typically will be 3-11, more preferably 5-9 and most preferably 7-8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as orally, intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally, transdermally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds of this invention are desirably incorporated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available. The compounds of the invention may 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 lipids, such as cholesterol, stearylamine or phosphatidylcholines. The compounds of this invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled. The compounds of this invention may also be coupled with suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidinone, pyran copolymer, polyhydroxy- propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, compounds of the invention 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. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like. Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle. Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will be influenced by the route of administration, the therapeutic objectives and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absorption efficiency must be individually determined for each compound by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be readily determined by one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved. The compounds of the invention can be administered orally or parenterally in an effective amount within the dosage range of about 0J to 100 mg kg, preferably about 0.5 to 50 mg/kg and more preferably about 1 to 20 mg/kg on a regimen in a single or 2 to 4 divided daily doses and/or continuous infusion. Typically, about 5 to 500 mg of a compound or mixture of compounds of this invention, as the free acid or base form or as a pharmaceutically acceptable salt, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained. Typical adjuvants which may be incoφorated into tablets, capsules and the like are binders such as acacia, corn starch or gelatin, and excipients such as microcrystalline cellulose, disintegrating agents like corn starch or alginic acid, lubricants such as magnesium stearate, sweetening agents such as sucrose or lactose, or flavoring agents. When a dosage form is a capsule, in addition to the above materials it may also contain liquid carriers such as water, saline, or a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives, antioxidants and the like can be incoφorated according to accepted pharmaceutical practice. Preparation of Compounds The compounds of the present invention may be synthesized by either solid or liquid phase methods described and referenced in standard textbooks, or by a combination of both methods. These methods are well known in the art. See, Bodanszky, "The Principles of Peptide Synthesis", Hafiier, et al, Eds., Springer- Verlag, Berlin, 1984. Starting materials used in any of these methods are commercially available from chemical vendors such as Aldrich, Sigma, Nova Biochemicals, Bachem Biosciences, and the like, or may be readily synthesized by known procedures. Reactions are carried out in standard laboratory glassware and reaction vessels under reaction conditions of standard temperature and pressure, except where otherwise indicated. During the synthesis of these compounds, the functional groups of the amino acid derivatives used in these methods are protected by blocking groups to prevent cross reaction during the coupling procedure. Examples of suitable blocking groups and their use are described in "The Peptides: Analysis, Synthesis, Biology", Academic Press, Nol. 3 (Gross, et al, Eds., 1981) and Vol. 9 (1987), the disclosures of which are incoφorated herein by reference. Νon-limiting exemplary synthesis schemes are outlined directly below, and specific steps are described in the Examples. The reaction products are isolated and purified by conventional methods, typically by solvent extraction into a compatible solvent. The products may be further purified by column chromatography or other appropriate methods. Scheme 1 1.HCI, methanol 2.NH4OAC, methanol, reflux H 2 , 10%Pd/C, methanol Scheme 2 Scheme 3 Sche e 4 (CF 3 CH 2 0)2P(0)CH2Cθ 2 Me KN(SiMe 3 ) 2 , 18-crown-6 AIMeg, DCM Scheme 5 LDA, DMF (CF 3 CH 2 0)2P(0)CH2C0 2 Me THF KN(SiMe 3 ) 2 , 18-crown-6 AIMes, DCM Scheme 6 1. HCI, MeOH 2. NH 4 OAc, MeOH H 2 , 10% Pd/C MeOH Scheme 7 (CF 3 CH2θ)2P(0)CH 2 Cθ 2 Me KN(SiMe 3 ) 2 , 18-crown-6 Compositions and Formulations The compounds of this invention may be isolated as the free acid or base or converted to salts of various inorganic and organic acids and bases. Such salts are within the scope of this invention. Non-toxic and physiologically compatible salts are particularly useful although other less desirable salts may have use in the processes of isolation and purification. A number of methods are useful for the preparation of the salts described above and are known to those skilled in the art. For example, reaction of the free acid or free base form of a compound of the structures recited above with one or more molar equivalents of the desired acid or base in a solvent or solvent mixture in which the salt is insoluble, or in a solvent like water after which the solvent is removed by evaporation, distillation or freeze drying. Alternatively, the free acid or base form of the product may be passed over an ion exchange resin to form the desired salt or one salt form of the product may be converted to another using the same general process. Diagnostic applications of the compounds of this invention will typically utilize formulations such as solution or suspension. In the management of thrombotic disorders the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensions or injectable administration, and the like, or incoφorated into shaped articles. Subjects in need of treatment (typically mammalian) using the compounds of this invention can be administered dosages that will provide optimal efficacy. The dose and method of administration will vary from subject to subject and be dependent upon such factors as the type of mammal being treated, its sex, weight, diet, concurrent medication, overall clinical condition, the particular compounds employed, the specific use for which these compounds are employed, and other factors which those skilled in the medical arts will recognize. Formulations of the compounds of this invention are prepared for storage or administration by mixing the compound having a desired degree of purity with physiologically acceptable carriers, excipients, stabilizers etc., and may be provided in sustained release or timed release formulations. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field, and are described, for example, in Remington 's Pharmaceutical Sciences, Mack Publishing Co., (A.R. Gennaro edit. 1985). Such materials are nontoxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate and other organic acid salts, antioxidants such as ascorbic acid, low molecular weight (less than about ten residues) peptides such as polyarginine, proteins, such as serum albumin, gelatin, or immunoglobulins, hydrophilic polymers such as polyvinalpyrrolidinone, amino acids such as glycine, glutamic acid, aspartic acid, or arginine, monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, counterions such as sodium and/or nonionic surfactants such as Tween, Pluronics or polyethyleneglycol. Dosage formulations of the compounds of this invention to be used for therapeutic administration must be sterile. Sterility is readily accomplished by filtration through sterile membranes such as 0.2 micron membranes, or by other conventional methods. Formulations typically will be stored in lyophilized form or as an aqueous solution. The pH of the preparations of this invention typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of cyclic polypeptide salts. While the preferred route of administration is by injection, other methods of administration are also anticipated such as intravenously (bolus and/or infusion), subcutaneously, intramuscularly, colonically, rectally, nasally or intraperitoneally, employing a variety of dosage forms such as suppositories, implanted pellets or small cylinders, aerosols, oral dosage formulations and topical formulations such as ointments, drops and dermal patches. The compounds of this invention are desirably incoφorated into shaped articles such as implants which may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers commercially available. The compounds of this invention may 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 lipids, such as cholesterol, stearylamine or phosphatidylcholines. The compounds of this invention may also be delivered by the use of antibodies, antibody fragments, growth factors, hormones, or other targeting moieties, to which the compound molecules are coupled. The compounds of this invention may also be coupled with suitable polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy- propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the factor Xa inhibitors of this invention 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. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like. Therapeutic compound liquid formulations generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by hypodermic injection needle. Therapeutically effective dosages may be determined by either in vitro or in vivo methods. For each particular compound of the present invention, individual determinations may be made to determine the optimal dosage required. The range of therapeutically effective dosages will naturally be influenced by the route of administration, the therapeutic objectives, and the condition of the patient. For injection by hypodermic needle, it may be assumed the dosage is delivered into the body's fluids. For other routes of administration, the absoφtion efficiency must be individually determined for each inhibitor by methods well known in pharmacology. Accordingly, it may be necessary for the therapist to titer the dosage and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dosage levels, that is, the dosage levels necessary to achieve the desired result, will be within the ambit of one skilled in the art. Typically, applications of compound are commenced at lower dosage levels, with dosage levels being increased until the desired effect is achieved. A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg, preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferably from about 0J0 mg/kg to about 20 mg/kg. Advantageously, the compounds of this invention may be administered several times daily, and other dosage regimens may also be useful. Typically, about 0.5 to 500 mg of a compound or mixture of compounds of this invention, as the free acid or base form or as a pharmaceutically acceptable salt, is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, dye, flavor etc., as called for by accepted pharmaceutical practice. The amount of active ingredient in these compositions is such that a suitable dosage in the range indicated is obtained. Typical adjuvants which may be incoφorated into tablets, capsules and the like are a binder such as acacia, corn starch or gelatin, and excipient such as microcrystalline cellulose, a disintegrating agent like corn starch or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose, or a flavoring agent. When a dosage form is a capsule, in addition to the above materials it may also contain a liquid carrier such as water, saline, a fatty oil. Other materials of various types may be used as coatings or as modifiers of the physical form of the dosage unit. Sterile compositions for injection can be formulated according to conventional pharmaceutical practice. For example, dissolution or suspension of the active compound in a vehicle such as an oil or a synthetic fatty vehicle like ethyl oleate, or into a liposome may be desired. Buffers, preservatives, antioxidants and the like can be incoφorated according to accepted pharmaceutical practice. In practicing the methods of this invention, the compounds of this invention may be used alone or in combination, or in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this inventions may be coadministered along with other compounds typically prescribed for these conditions according to generally accepted medical practice, such as anticoagulant agents, thrombolytic agents, or other antithrombotics, including platelet aggregation inhibitors, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin. The compounds of this invention can be utilized in vivo, ordinarily in mammals such as primates, such as humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro. The preferred compounds of the present invention are characterized by their ability to inhibit thrombus formation with acceptable effects on classical measures of coagulation parameters, platelets and platelet function, and acceptable levels of bleeding complications associated with their use. Conditions characterized by undesired thrombosis would include those involving the arterial and venous vasculature. With respect to the coronary arterial vasculature, abnormal thrombus formation characterizes the rupture of an established atherosclerotic plaque which is the major cause of acute myocardial infarction and unstable angina, as well as also characterizing the occlusive coronary thrombus formation resulting from either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTC A). With respect to the venous vasculature, abnormal thrombus formation characterizes the condition observed in patients undergoing major surgery in the lower extremities or the abdominal area who often suffer from thrombus formation in the venous vasculature resulting in reduced blood flow to the affected extremity and a predisposition to pulmonary embolism. Abnormal thrombus formation further characterizes disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer, a condition wherein there is rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout the microvasculature leading to widespread organ failure. The compounds of this present invention, selected and used as disclosed herein, are believed to be useful for preventing or treating a condition characterized by undesired thrombosis, such as (a) the treatment or prevention of any thrombotically mediated acute coronary syndrome including myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post- thrombolytic therapy or post-coronary angioplasty, (b) the treatment or prevention of any thrombotically mediated cerebrovascular syndrome including embolic stroke, thrombotic stroke or transient ischemic attacks, (c) the treatment or prevention of any thrombotic syndrome occurring in the venous system including deep venous thrombosis or pulmonary embolus occurring either spontaneously or in the setting of malignancy, surgery or trauma, (d) the treatment or prevention of any coagulopathy including disseminated intravascular coagulation (including the setting of septic shock or other infection, surgery, pregnancy, trauma or malignancy and whether associated with multi-organ failure or not), thrombotic thrombocytopenic puφura, thromboangiitis obliterans, or thrombotic disease associated with heparin induced thrombocytopenia, (e) the treatment or prevention of thrombotic complications associated with extracoφoreal circulation (e.g. renal dialysis, cardiopulmonary bypass or other oxygenation procedure, plasmapheresis), (f) the treatment or prevention of thrombotic complications associated with instrumentation (e.g. cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve), and (g) those involved with the fitting of prosthetic devices. Anticoagulant therapy is also useful to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus the compounds of this invention can be added to or contacted with any medium containing or suspected to contain factor Xa and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material such as vascular grafts, stents, orthopedic prostheses, cardiac stents, valves and prostheses, extra coφoreal circulation systems and the like. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure. EXAMPLES Example 1 To a solution of bis(2,2J-trifluoroethyl)(methoxylcarbonylmethyl)phosphate (0.665ml, 3J4mmol) and 18-crown-6 (4J4g, 15.7mmol) in tetrahydrofuran (50ml) at -78 °C was added potassium bis(trimethylsilyl)amide (6.3ml, 3J5mmol) dropwise. After the addition was complete, 3-cyanobenzaldehyde (0.412g, 3 J 4mmol) in tetrahydrofuran ( 10ml) was added at -78 °C. The mixture was stirred at -78 °C for additional 1 hr. Saturated ammonia chloride solution was added to quench the reaction. Ether and water were added. The organic layer was separated, and the aqueous layer was extracted with ether once more. The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by silica gel column chromatography using solvent system 5- 10% ethyl acetate in hexane as eluent to give the title compound as a white solid (1.12g, 100%). ES-MS (M+H)+ = 188. Example 2 To a solution of tert-butylamine (5.73g, 78.4mmol) and triethylamine (16.6ml, 119mmol) in dichloromethane (200ml) in an ice bath was added benzenesulfonyl chloride (13.85g, 78.4mmol) dropwise. The mixture was stirred at room temperature overnight. It was washed with saturated sodium carbonate (60ml) and brine (60ml). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2x50ml). The combined organic extracts were dried over magnesium sulfate. The solvent was evaporated in vacuo to give the title compound as a light yellowish solid (15.92g, 95%). ES-MS (M+H)+ = 214. Example 3 To a solution of the compound of example 2 (15.92g, 74.7mmol) in tetrahydrofuran (200ml) in an ice bath was added 1.6M n-butyllithium in hexane (100ml, 164mmol) dropwise over 30 minutes. The mixture remained a clear solution. In an ice bath it was added triisopropylborate (24.1ml, 104mmol) dropwise. The mixture was stirred at room temperature for 3.5hrs, solution becoming cloudy. After it was cooled in an ice bath, IN hydrochloride (200ml) was added. The mixture was stirred at room temperature overnight. It was extracted with ether (2x50ml). The organic extract was washed with IN sodium hydroxide (2x60ml). The aqueous solution was acidified to pH=l with 6N hydrochloride, and then extracted with ether (2x100ml). The ether extract was dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a while solid (11.5g, 60%). ES-MS (M+H)+ = 258. Example 4 To a solution of the compound of example 3 (2.06g, 8mmol) in toluene (60ml) was added water (4ml), 8N sodium hydroxide (8ml), isopropanol (16ml), 2-fluoro-4- iodoaniline (3.8g, lόmmol) and tetrakis(triphenylphosphine)palladium(0) (464mg, 0.4mmol). The mixture was refluxed for 3-4 hrs, cooled to room temperature, and diluted with ethyl acetate. The organic layer was washed with water (25ml), and dried over magnesium sulfate. After the evaporation of the solvent in vacuo, the crude reside was purified by silica gel column chromatography using solvent system 20-30% ethyl acetate in hexane as eluent to give the title compound as a white solid (1.49g, 58%). ES-MS (M+H)+ = 323. Example 5 To a solution of compound of example 4 (161mg, 0.5mmol) in dichloromethane (5ml) was added 2.0M trimethylaluminum in hexane (0.75ml, 1.5mmol). The mixture was stirred at room temperature for 30 minutes, methane gas evolved. A solution of the compound of example 1 (94mg, 0.5mmol) in dichloromethane (1ml) was added. The mixture was stirred at room temperature overnight. IN hydrochloride was added to acidify the solution to pH=2. After the addition of water and dichloromethane, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a yellow oil (260mg, 100%). ES-MS (M+H)+ = 478. Example 6 To a solution of the compound of example 5 (lOOmg, OJlmmol) in absolute methanol (3ml) in an ice bath was saturated with hydrochloride gas for 10 minutes. The mixture was stirred at room temperature for 3 hrs. After the evaporation of solvent in vacuo, the residue was dissolved in absolute methanol (3ml), and ammonia acetate (97mg, 1.26mmol) was added. The mixture was refluxed for 3 hrs. The solvent was evaporated in vacuo. The crude residue was purified by RP-HPLC to give the title compound as a white powder (53mg, 58%). ES-MS (M+H)+ = 439. Example 7 To a solution of the compound of example 6 (30mg, 0.07mmol) in absolute methanol (2ml) was added 10% Pd/C (catalytic amount). The mixture was hydrogenated under balloon for lhr. After the filtration through Celite, the solvent was evaporated in vacuo. The residue was purified by RP-HPLC to give the compound as a white powder (25mg, 81%). ES-MS (M+H)+ = 441. Example 8 To a solution of the compound of example 3 (2.06g, 8mmol) in toluene (60ml) was added water (4ml), 8N sodium hydroxide (8ml), isopropanol (16ml), 2-chloro-4- iodoaniline (4.06g, 16mmol) and tetrakis(triphenylphosphine)palladium(0) (464mg, 0.4mmol). The mixture was refluxed for 3-4 hrs, cooled to room temperature, and diluted with ethyl acetate. The organic layer was washed with water (25ml), and dried over magnesium sulfate. After the evaporation of the solvent in vacuo, the crude reside was purified by silica gel column chromatography using solvent system 20-30% ethyl acetate in hexane as eluent to give the title compound as a white solid (1.43g, 53%). ES-MS (M+H)+ = 339. Example 9 To a solution of the compound of example 8 (lOOmg, OJmmol) in dichloromethane (5ml) was added 2.0M trimethylaluminum in hexane (0.45ml, 0.9mmol). The mixture was stirred at room temperature for 30 minutes, methane gas evolved. A solution of the compound of example 1 (55mg, OJmmol) in dichlodomethane (1ml) was added. The mixture was stirred at room temperature overnight. IN hydrochloride was added to acidify the solution to pH=2. After the addition of water and dichloromethane, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a greenish solid (1 lOmg, 70%). ES-MS (M+H)+ = 494. Example 10 To a solution of the compound of example 9 (lOOmg, OJmmol) in absolute methanol (3ml) in an ice bath was saturated with hydrochloride gas for 10 minutes. The mixture was stirred at room temperature for 3 hrs. After the evaporation of the solvent in vacuo, the residue was dissolved in absolute methanol (3ml), and ammonia acetate (92mg, 1 Jmmol) was added. The mixture was refluxed for 3 hrs. The solvent was evaporated in vacuo. The crude residue was purified by RP-HPLC to give the title compound as a white powder (46mg, 51%). ES-MS (M+H)+ = 456. Example 11 Production of 3-[(2-2-furyl)-5-oxo- 1 ,3-oxazolin-4-ylidene)methyl] benzenecarbonitrile. A mixture of 3-cyanobenzaldehyde (2J02g, 15J20mmol), N-2-furoylglycine (1.846g, 10.914mmol), and sodium acetate (0.636g, 7.753mmol) in 15ml acetic anhydride was refluxed for 7 hours. The mixture was then cooled to room temperature before cooling in the freezer over night. The solid was washed with ice cold water then filtered (0.472g, 1.788mmol, 16%). ES-MS(M+H)+=265. Example 12 Production of (2E)-N-[4(2- {[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)-2-(2-furylcarbonylamino)prop-2-enamide To a solution of {[2-(4-aminophenyl)phenyl]sulfonyl}(tert-butyl)amine (0J52g, 0.500mmol) in 9ml DCM was added trimethylaluminum (lml, 2M solution in hexanes, 2mmol) which was allowed to stir for l A hour. Then 3-[(2-(2-furyl)-5-oxo- lJ-oxazolin-4-ylidene)methyl]benzenecarbonitrile (O.Hg, 0.417mmol) was added drop wise as a solution in 3ml DCM. Three hours later 6M HCI was added drop wise to pH=0. 10ml portions of water and DCM were also added and the aqueous layer was extracted twice with 10ml portions of DCM. The organic layers were dried over MgSO4, filtered and concentrated in vaccu to yield the desired product (0.259, 0.456, 109%). ES-MS(M+H)+=569. Example 13 Production of 3-(2- {N-[4-(2- {[(tert- butyl)amino]sulfonyl}phenyl)phenyl]carbamoyl}-2- (2-furylcarbonylamino)ethyl)benzenecarboxamidine To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)-2-(2-furylcarbonylamino)prop-2-enamide (0.259g, 0.456mmol) in 7ml ethanol was added hydroxyamine (0J92g, 2J63mmol) and triethyl amine (0.762ml, 5.407mmol). This mixture was refluxed for 2 hours before it was concentrated in vaccu. The residue was dissolved in AcOH (5ml), then acetic anhydride (0.30ml, 3J82mmol) was added and the mixture was allowed to stir for 1.5 hours. The mixture was concentrated in vaccu. The residue was dissolved in dry MeOH (3ml), 5%Pd/C (22.7mg) was added. A balloon filled with hydrogen gas was fitted to the flask with an adapter. The flask was evacuated and backfilled with hydrogen gas three times before being run for 0.75 hour. The mixture was then filtered over a bed of celite and concentrated in vaccu. The residue was purified via Preparative HPLC to yield the desired product (0.075g, 0.128mmol, 28%). ES-MS(M+H)+=588. Example 14 Production of 3-(2-(2-furylcarbonylamino)-2- {N-[4-(2-sulfamoylphenyl)phenyl]- carbamoyl } ethyl)benzenecarboxamidine 3-(2-{N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]carbamoyl}-2-(2-furyl- carbonylamino)ethyl)benzenecarboxamidine (0.075g, 0.128mmol) was dissolved with TFA (6ml) for 2hours. The mixture was concentrated in vaccu and the residue was purified via Preparative HPLC, (0.040g, 0.075mmol, 58%). ES- MS(M+H)+=532. Example 15 Production of (tert-butyl)(phenylsulfonyl)amine To a solution of benzenesulfonyl chloride (30.00g, 169.86mmol) in 100ml DCM, in an ice bath, was added butyl amine (18ml, 171J8mmol), then triethylamine(35ml, 251 J lmmol), drop wise via addition funnel. This was allowed to warm to room temperature over 3hr. The mixture was then filtered and the filtrate was concentrated in vaccu. The pale yellow solid (35.03g, 164.46mmol, 97%) was then rinsed with minimal amounts of DCM. ES-MS (M+Na)+=236. Example 16 Production of (tert-butyl)(phenylsulfonyl)amine To (tert-butyl)(phenylsulfonyl)amine (17.43g, 81.83mmol) in 180ml dry THF in an ice bath was added nBuLi (66ml, 2.5M in hexanes) via addition funnel. Then triisopropyl borate (33ml, 143.06mmol) was added via addition funnel. The mixture was warmed to room temperature and allowed to stir for 4hr. The reaction mixture was then cooled in an ice bath before HCL (82ml, 3M) was added drop wise. This was allowed to stir at room temperature for 3hr. The mixture was then put in the freezer over the weekend. The reaction was then warmed to room temperature and extracted with ether. The aqueous layers were washed twice more with ether. The combined organic layers were washed three times with 5M NaOH aqueous solution. The combined basic layers were acidified to pH=l with 6M HCL solution. These acidified layers were then extracted three times with ether. These ether layers were then dried over MgSO4, filtered, then concentrated in vaccu to about 50ml solution. To this solution was added hexanes and a minimal amount of ethyl acetate. A white precipitate is observed and the mixture in stored in the freezer to allow for crystallization. The white solid is then filtered and collected (14.65g, 57mml, 70%) ES-MS(M+H)+=258. Example 17 Production of {[2-(4-aminophenyl)phenyl]sulfonyl}(tert-butyl)amine To a solution of 2- [(tert-butyl amino)sulfonyl] phenyl boronic acid (6.00g, 23J5mmol) in 120ml toluene was added water (16ml), isopropanol (60ml), and NaOH (40ml, 5M aqueous solution). To this were added 4-bromoaniline and Pd(Ph3P)4. This heterogeneous mixture is then refluxed for 6hr, then stirred at room temperature over night before refluxing for another 1.5hr. The reaction mixture is then extracted with water and ethyl acetate. The aqueous layer is extracted twice with ethyl acetate. The organic layers are then dried over MgSO4, filtered and concentrated in vaccu. The crude residue is purified by silica gel flash chromatography. The desired product can be eluded with 30% ethyl acetate in hexanes and concentrated to an orange solid (5.06g, 16.65, 71%). ES- MS(M+H)+=305. Example 18 Step (a): To a 0°C solution of 4-((2-N-t-butylamonisulfonyl)phenyl) aniline (74.1 mg, 0J mmol, 1.0 equiv) in 5 mL of CH 2 C1 2 was added a solution of AlMe 3 (2M in hexanes, 0.7 mL, 5 equiv). After 15min, methyl 2-(3-cyanophenyl)acrylate (56J mg, 1.0 equiv) was added. The resulting solution was stirred overnight, carefully quenched with water, diluted with ethyl acetate. The organic layer was dried, evaporated and chromatographied on silica gel to give the product in 55% yield. LRMS found for C 23 H 19 N 2 O 3 S (M+H) + : 403.1. Step (b): The compound obtained in step (a) (25 mg) was dissolved in 5 mL of methanol . The reaction mixture was cooled to 0°C and HCI gas was bubbled in until saturation. The mixture was stirred at rt overnight. The solvent was evaporated and the resulting residue was treated with ammonium acetate and 10 ml methanol at reflux temperature for 2 h. The solvent was removed at reduced pressure and the crude benzamidine was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H 2 O/CH 3 CN to give the desired salt in 77% yield. LRMS found for C 23 H 22 N 3 O 3 S (M+H) + : 420J. Step (c): The compound obtained in step (b) (8 mg) and 5 mg of 10% Pd/C was suspended in 1 mL of methanol . The reaction mixture was stirred under latm hydrogen balloon for 2h and filtered. The solvent was removed at reduced pressure and the crude benzamidine was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H 2 O/CH 3 CN to give the desired salt in 63% yield. LRMS found for 3 H 24 N 3 O 3 S (M+H) + : 422J. Example 19 2-Fluoro-5-methyl benzonitrile (1.26g, 9.32 mmol) was mixed with NBS (1.66 g, 9.32 mmol), benzoyl peroxide (79 mg, 0J3 mmol) in CC1 4 (45mL). The mixture was refluxed for 2.5 hrs. It was cooled to room temperature, filtered and concentrated in vacuo to give the title compound. ES-MS (M+H)+ = 213.1. Example 20 To a solution of compound of example 19 (9.32 mmol) in CHC1 3 (50 mL), was added trimethylamino N-oxide (1.7 g, 23.3 mmol). The mixture was refluxed for 3 hrs. Water was added. The organic layer was dried over MgSO 4 , filtered and filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using solvent system 20% EtOAc in hexane as eluant to give the title compound. ES-MS (M+H)+ = 150.1. Example 21 To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl) phosphonate (0J2 mL, 0.58 mmol) and 18-crown-6 (770 mg, 2.92 mmol) in THF (5 mL) at - 78°C, was added potassium bis(trimethylsilyl)amide (1 J 7 mL, 0.57 mmol) dropwise. After the addition was complete, compound of example 2 (87 mg, 0.58 mmol) in THF (2 mL) was added. The mixture was stirred at -78°C for 1 hour. Aqueous NH 4 C1 solution was added to quench the reaction. Water and EtOAc was added to the mixture. The organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. This was purified by silica gel column chromatography using solvent system 20% EtOAc in hexane as eluant to give the title compound (85 mg, 71%). ES-MS (M+H)+ = 206.L Example 22 To a solution of compound of example 3 (6.4 g, 25 mmol) in toluene (120 mL) was added water (15 mL), 5N NaOH solution (38.5 mL), isopropanol (60 mL) 4- bromoaniline and tetrakis(triphenylphosphine)palladium(0). The mixture was refluxed for six hours, cooled to room temperature, diluted with EtOAc. The organic layer was washed with water, dried with MgSO 4 , filtered and concentrated. This was purified by silica gel column chromatography using solvent system 30% EtOAc in hexane as eluant to give the title compound (5g, 66%). ES-MS (M+H)+ = 305J. Example 23 To a solution of compound of example 22 (121.6 mg, 0.4 mmol) in DCM (3 mL) was added trimethylaluminum (0.6 mL, 2M in hexane) dropwise. The reaction mixture was stirred at room temperature for 30 min. Compound of example 21 (82 mg, 0.4 mmol) in DCM (2 mL) was added dropwise. The mixture was stirred at room temperature overnight. 2N HCI was added to pH 2. Water and DCM were added. The organic layer was dried over MgSO 4 and concentrated in vacuo. It was purified by silica gel column chromatography using solvent system 50% EtOAc in hexane as eluant to give the title compound. ES-MS (M+Na)+ = 500. L Example 24 A solution of the compound of example 23 (99 mg, 0.208 mmol) in MeOH (10 mL) was treated with a stream of HCI gas for 10 min. at 0°C. The resulting solution was capped, stirred at room temperature overnight and evaporated in vacuo. The residue was reconstituted in MeOH (10 mL) and the mixture was treated with NH 4 OAc (80 mg, 1.04 mmol). The reaction mixture was refluxed for 2 hrs. and concentrated in vacuo. The obtained residue was purified by RP-HPLC to give the title compound as a white powder. ES-MS (M+H)+ = 439.1. Example 25 The compound of example 24 (10 mg, 0.022 mmol) was dissolved in MeOH (5 mL) and 10% Pd/C (catalytic amount) was added. The mixture was hydrogenated under balloon overnight, filtered through Celite to remove the catalyst and the filtrate was evaporated. The obtained residue was purified by RP-HPLC to give the title compound as a white powder. ES-MS (M+H)+ = 441 J . Example 26 To a solution of LDA (2.6 mL, 2N solution in hexane, 5.2 mmol) in THF (10 mL) at -78°C, was added 4-fluorobenzonitrile in THF (10 mL) dropwise. The mixture was stirred at -78°C for 1 hour. To this was added DMF (0.4 mL, 0.55 mmol). The mixture was stirred at -78°C for another 15 min., quenched rapidly with AcOH (2 mL) and water (10 mL), extracted with ether (50 mL). The ether extracts were washed with IN HCI (10 mL), brine (10 mL), dried over MgSO 4 , filtered and concentrated in vacuo to give the title compound. (M+H)+ = 150. Example 27 To a solution of bis(2JJ-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (0.875 mL, 4J4 mmol) and 18-crown-6 (5.46 g, 20.7 mmol) in THF (20 mL) at - 78°C, was added potassium bis(trimethylsilyl)amide (8J mL, 4J5 mmol) dropwise. After the addition was complete, compound of example 26 (616 mg, 4J4 mmol) in THF (10 mL) was added. The mixture was stirred at -78°C for 1 hour. Aqueous NH 4 C1 solution was added to quench the reaction. Water and EtOAc was added to the mixture. The organic layer was dried over MgSO 4 , filtered and concentrated in vacuo. This was purified by silica gel column chromatography using solvent system 20% EtOAc in hexane as eluant to give the title compound (375 mg, 44%). ES-MS (M+H)+ = 206.1. Example 28 To a solution of compound of example 22 (553 mg, 1.82 mmol) in DCM (9 mL) was added trimethylaluminum (2.73 mL, 2M in hexane, 5.46 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. Compound of example 27 (373 mg, 1.82 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at room temperature overnight. 2N HCI was added to pH 2. Water and DCM were added. The organic layer was dried over MgSO 4 and concentrated in vacuo. It was purified by silica gel column chromatography using solvent system 50% EtOAc in hexane as eluant to give the title compound (283 mg). ES-MS (M+Na)+ = 500.1. Example 29 A solution of the compound of example 28 (283 mg, 0.593 mmol) in MeOH (10 mL) was treated with a stream of HCI gas for 10 min. at 0°C. The resulting solution was capped, stirred at room temperature overnight and evaporated in vacuo. The residue was reconstituted in MeOH (10 mL) and the mixture was treated with NH 4 OAc (228 mg, 2.97 mmol). The reaction mixture was refluxed for 2 hrs. and concentrated in vacuo. The obtained residue was purified by RP-HPLC to give the title compound as a white powder. ES-MS (M+H)+ = 439. L Example 30 Compound of example 29 (12 mg, 0.027 mmol) was dissolved in MeOH (5 mL) and 10% Pd/C (catalytic amount) was added. The mixture was hydrogenated under balloon overnight, filtered through Celite to remove the catalyst and the filtrate was evaporated. The obtained residue was purified by RP-HPLC to give the title compound as a white powder. ES-MS (M+H)+ = 441 J . Example 31 To a solution of methyl-3-cyano-4-methoxybenzoate (5g, 26.2 mmol) in THF (50 mL) was added lithium borohydride (53 mL, 2.00M solution in THF, 105 mmol) at room temperature. The mixture was stirred at room temperature overnight. IN HCI was slowly added until bubbling stopped. THF was removed in vacuo and EtOAc and water were added. The organic layer was washed with water, saturated NaHCO 3 solution, brine, dried with Na^ , and solvent evaporated in vacuo to give the title compound (3.7 g, 86.7%). Example 32 To a solution of compound of example 31 (2g, 12.3 mmol) in DMSO (50 mL) was added IBX (4.673g, 17.7 mmol) slowly. The mixture was stirred at room temperatxire overnight. EtOAc and water were added. The formed precipitate was removed. The organic layer was washed with IN HCI, water, saturated NaHCO 3 , brine, dried over Na 2 SO 4 and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography using DCM as eluant to give the title compound (l.lg, 56%). ES-MS (M+H)+ = 162.1. Example 33 To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl) phosphonate (139 mL, 6.57 mmol) in THF (130 mL) at -78°C was added 18-crown- 6 (8.6, 33.9 mmol), potassium bis(trimethylsilyl)amide (14.4 mL, 7.22 mmol) dropwise. The mixture was stirred at at -78°C for 30 min. Compound of example 32 (1.06 g, 6.57 mmol) was then added. The mixture was warmed to room temperature and stirred for 1 hour. Aqueous NH 4 C1 solution was added to quench the reaction. Water and EtOAc was added to the mixture. The organic layer was dried over MgSO 4 , filtered and concentrated in vacuo to give the title compound (1.175g, 87%). ES-MS (M+H)+ = 218.1. Example 34 To a solution of compound of example 22 (457 mg, 1.5 mmol) in DCM (4 mL) was added trimethylaluminum (0.9 mL, 2M in hexane, 1.8 mmol) dropwise. The reaction mixture was stirred at room temperature for 1 hour. Compound of example 33 (326 mg, 1.5 mmol) in DCM (5 mL) was added dropwise. The mixture was heated to reflux briefly. IN HCI was added to pH 2. Water and DCM were added. The organic layer was washed with brine, dried over MgSO 4 and concentrated in vacuo. It was purified by silica gel column chromatography using solvent system 30-50% EtOAc in hexane as eluant to give the title compound (450 mg, 61.3%). ES- MS (M+H)+ = 490.1. Example 35 A solution of the compound of example 34 (200 mg, 0.408 mmol) in MeOH (10 mL) was treated with a stream of HCI gas for 10 min. at 0°C. The resulting solution was capped, stirred at room temperature overnight and evaporated in vacuo. The residue was reconstituted in MeOH (10 mL) and the mixture was treated with NH 4 OAc (650 mg, 8J6 mmol). The reaction mixture was refluxed for 2 hrs. and concentrated in vacuo. The obtained residue was purified by RP-HPLC to give the title compoxmd as a white powder. ES-MS (M+H)+ = 451 J . Example 36 Compound of example 35 (6 mg, 0.027 mmol) was dissolved in MeOH (2 mL) and 10% Pd/C (catalytic amount) was added. The mixture was hydrogenated under balloon overnight, filtered through Celite to remove the catalyst and the filtrate was evaporated to give the title compound as a white powder. ES-MS (M+H)+ = 443.1. Example37 Boc-m-CN-Phenylalanine -OH (200 mg, 0.69 mmol) and compound of example 22 (210 mg, 0.69 mmol) were dissolved in DMF (3 mL). DIEA (0.24 mL, 1.4 mmol) was added followed by the addition of the coupling reagent PyBOP (572 mg, 1.1 mmol). The solution was stirred at room temperature for 12 hours. The reaction mixture was diluted in a mixture of EtOAc/H 2 O. The organic layer was washed with water, saturated Na 2 CO 3 , water, IM KHSO 4 , brine, dried over MgSO 4 , filtered and solvent evaporated to give the title compound. ES-MS (M+H)+ = 521.1. Example 38 A solution of the compound of example 37 (132 mg, 0.23 mmol) in MeOH (10 mL) was treated with a stream of HCI gas for 10 min. at 0°C. The resulting solution was capped, stirred at room temperature overnight and evaporated in vacuo. The residue was reconstituted in MeOH (10 mL) and the mixture was treated with NH 4 OAc (540 mg, 7 mmol). The reaction mixture was refluxed for 2 hrs. and concentrated in vacuo. The obtained residue was purified by RP-HPLC to give the title compoxmd as a white powder. ES-MS (M+H)+ = 438.L Example 39: To a solution of ethyl 2-oxocyclopentane carboxylate (1.56g, lOmmol) in 20ml anhydrous dichloromethane was added triethylamine (1.06g, 10.5mmol). Reaction was cooled under argon to -78°C to which trifluoro-methanesulfonic anhydride (2.96g, 10.5mmol) was added dropwise via syringe over 5 minutes. Reaction was allowed to warm to room temperature and stirred over night. Next morning the reaction was diluted with 25ml dichloromethane, organic was washed with 2x50ml water, 2x50ml IN HCI, dried over magnesium sulfate, filtered and concentrated to give ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}-l-cyclopentene-l-carboxylate (2.8g, 97%) as a light brown oil after drying. H'NMR (CDC1 3 ) : 1.21 - 1.56 (t, 3H); 1.97- 2.01 (m, 2H); 2.6-2J4 (m, 4H); 4.21-4.26 (m, 2H). Example 40: To a solution of ethyl 2-{[(trifluoromethyl)sulfonyl]oxy}-l-cyclopentene-l- carboxylate (1.2g, 4J6mmol) in 10ml anhydrous dioxane was added potassium phosphate (1.32g, 6Jmmol), 3-cyanophenyl boronic acid (0.612g, 4J6mmol), and tetrakis (triphenylphosphine)palladium(O) (0J2g, OJOmmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50ml ethyl acetate, washed with 2x50ml water, 2x50ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl 2-(3-cyanophenyl)-l-cyclopentene-l-carboxylate (0.7g, 71%) as a light yellow oil after drying. ES-MS (M+H + ): 242.15. H'NMR ^DC^) : 1.09-1.13 (t, 3H); 1.96-2.01 (m, 2H); 2.80-2.84 (m, 4H); 7.39-7.59 (m, 4H). Example 41: To a solution of 2'-tert-butylaminosulfonyl-4-amino-[l, ]-biphenyl (60mg, 0J97mmol) in 4ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.3ml, 0.59mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl 2-(3-cyanophenyl)-l- cyclopentene-1-carboxylate (48mg, 0J97mmol) in 1ml anhydrous dichloromethane. Reaction was stirred at room temperature overnight. Reaction was quenched with 15ml IN HCI after which an additional 10ml dichloromethane was added. Organic was washed with 2x20ml water, dried over magnesium sulfate and concentrated to give N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl][2-(3- cyanophenyl)cyclopent-l-enyl]carboxamide (80mg, 80%) as a white powder which was sufficiently pure to be used without further purification. To a solution of N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl][2-(3- cyanophenyl)cyclopent-l-enyl]carboxamide (70mg, 0J37mmol) in 5ml anhydrous methanol cooled in an ice bath was bubbled HCI gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5ml anhydrous methanol to which ammonium acetate (77mg, lmmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2x25cm Nydac C 18 HPLC column to give 3-(2- {Ν-[4-(2-sulfamoylphenyl)phenyl]carbamoyl} cyclopent- 1 - enyl)benzenecarboxamidine (40mg, 63%) as a fluffy white powder after lyophilization. ES-MS (M+H + ): 461.15 Example 42: To a solution of the 3-(2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl} cyclopent- 1- enyl)benzenecarboxamidine (7mg, 0.015mmol) in 4ml methanol was added 10% Pd on carbon (1.5mg). Mixture was treated with 50psi hydrogen on the PARR apparatus for lhr. Reaction was filtered through a pad of Celite, concentrated and lyophilized to give the 3-(2-{N-[4-(2-sulfamoylphenyl)phenyl]- carbamoyl}cyclopentyl)benzenecarboxamidine (5mg, 71%) as a fluffy white powder. ES-MS (M+H + ): 463.15 Example 43: To a solution of ethylacetoacetate (lJg, lOmmol) in 10ml anhydrous dichloromethane was added triethylamine (1.46ml, 10.5mmol). The reaction was cooled to -78°C under argon to which trifluoromethanesulfonic anhydride (2.96g, 10.5mmol) was added dropwise via syringe over 5 minutes. Reaction was allowed to warm to room teperature and stirred over night. Next morning the reaction was diluted with 25ml dichloromethane, organic was washed with 2x50ml water, 2x50ml 1N HCI, dried over magnesium sulfate, filtered and concentrated. Crude oil was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give 1) ethyl (E)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (800mg, 60%) as a clear oil: H'NMR (CDC1 3 ) : 1.247-1.282 (t, 3H); 2.471 (s, H); 4.155-4.209 (m, 2H); 5.912 (s, H); and 2) ethyl (Z)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (450mg, 30%) as a clear oil: H'NMR (CDC1 3 ) : 1.247-1.283 (t, 3H); 2J31 (s, 3H); 4.18-4.233 (m, 2H); 5.736 (s, H). Example 44: To a solution of ethyl (E)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (390mg, 1.49mmol) in 5ml anhydrous dioxane was added potassium phosphate (474mg, 2.24mmol), 3-cyanophenyl boronic acid (217mg, 1.49mmol), and tetrakis (triphenylphosphine)palladium(O) (43mg, 0.038mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50ml ethyl acetate, washed with 2x50ml water, 2x50ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl (E) 3-(3-cyanophenyl)-2-propenoate (240mg, 71%) as a clear yellow oil after drying. H'NMR (CDC1 3 ) : 1.2-1.32 (t, 3H); 2.547 (s, 3H); 4.18-4.24 (m, 2H); 6J 13 (s, H); 7.47-7.725 (m, 4H). NOE confirmed stereo orientation. Example 45: To a solution of ethyl (Z)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (330mg, 1.25mmol) in 5ml anhydrous dioxane was added potassium phosphate (398mg, 1.88mmol), 3-cyanophenyl boronic acid (185mg, 1.25mmol), and tetrakis (triphenylphosphine)palladium(O) (36mg, 0.031 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50ml ethyl acetate, washed with 2x50ml water, 2x50ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl (Z) 3-(3-cyanophenyl)-2-propenoate (240mg, 71%) as a clear oil after drying. ES-MS (M+H + ): 216.05 Example 46: To a solution of 2'-tert-butylaminosulfonyl-4-amino-[lJ']-biphenyl (79mg, 0.26mmol) in 4ml anhydrous dichloromethane was added a solution of 2M trimethylalxxminum in hexane (0.39ml, 0.78mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl (E) 3-(3-cyanophenyl)-2- propenoate (56mg, 0J6mmol) in 1ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5ml IN HCI after which an additional 10ml dichloromethane was added. Organic layer was washed with 2x20ml water, dried over magnesium sulfate, filtered and concentrated to give the (2E)-N- [4-(2- { [(tert-buty l)amino] sulfonyl } phenyl)pheny 1] - 3-(3-cyanophenyl)but-2-enamide (90mg, 72%) as an off-white powder which was sufficiently pure to be used without further purification. To a solution of (2E)-N-[4-(2-{ [(tert-buty l)amino] sulfonyl }phenyl)phenyl] -3 -(3- cyanophenyl)but-2-enamide (90mg, 0J9mmol) in 5ml anhydrous methanol cooled in an ice bath was bubbled HCI gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5ml anhydrous methanol to which ammonium acetate (77mg, lmmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2x25cm Vydac C, 8 HPLC column to give 3-((lE)-l-methyl-2-{N-[4- (2-sulfamoylphenyl)phenyl]carbamoyl} vinyl)benzene-carboxamidine (15mg, 20%) as a fluffy white powder after lyophilization. ES-MS (M+H + ): 435 J Example 47: To a solution of 2'-tert-butylaminosulfonyl-4-amino-[l,l']-biphenyl (198mg, 0.65mmol) in 5ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.98ml, 1.95mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl (Z) 3-(3-cyanophenyl)-2- propenoate (140mg, 0.65mmol) in 1ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5ml IN HCI after which an additional 20ml dichloromethane was added. Organic was washed with 2x25ml water, dried over magnesium sulfate and concentrated to give (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)but-2-enamide (200mg, 65%) as a light brown residue which was sufficiently pure to be used without further purification. To a solution of (2Z)-N-[4-(2- {[(tert-butyl)amino] sulfonyl }phenyl)phenyl] -3 -(3- cyanophenyl)but-2-enamide (90mg, 0J9mmol) in 5ml anhydrous methanol cooled in an ice bath was bubbled HCI gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5ml anhydrous methanol to which ammonium acetate (144mg, 2mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2x25cm Vydac C 18 HPLC column to give 3-((lZ)-l-methyl-2-{N-[4- (2-sulfamoylphenyl)phenyl]carbamoyl} vinyl)-benzenecarboxamidine (35mg, 20%) as a fluffy white powder after lyophilization. ES-MS (M+H + ): 435J Example 48: To a solution of the 3-((lZ)-l-methyl-2-{N-[4-(2- sulfamoylphenyl)phenyl]carbamoyl}vinyl)-benzenecarboxamidine (5mg, 0.0115mmol) in 4ml methanol was added 10% Pd on carbon (2mg). Mixture was treated with 50psi hydrogen on the PARR apparatus for lhr. Reaction was filtered through a pad of Celite, concentrated and lyophilized to give 3-(l-methyl-2-{N-[4- (2-sulfamoylphenyl)phenyl]carbamoyl}-ethyl)benzenecarboxamidine (3mg, 60%) as a fluffy white powder. ES-MS (M+H + ): 437J Example 49: To a solution of ethyl trifluoroacetoacetate (5g, 27.2mmol) in 20ml anhydrous dichloromethane was added triethylamine (5.7ml, 40.7mmol). Reaction was cooled under argon to -78°C to which trifluoro-methanesulfonic anhydride (11.5g, 10.5mmol) was added dropwise via syringe over 5 minutes. Reaction was allowed to warm to room temperature and stirred over night. Next morning the reaction was diluted with 25ml dichloromethane, organic was washed with 2x50ml water, 2x50ml IN HCI, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude oil was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl (Z)-4,4,4-trifluoro-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-butenoate (7.7g, 90%) as a clear light yellow oil after drying. H'NMR CDCl,) : 1.31-1.35 (t, 3H); 4.33-4.35 (m, 2H); 6.535 (s, H). Example 50: To a solution of ethyl (Z)-4,4,4-trifluoro-3-{[(trifluoromethyl)sulfonyl]-oxy}-2- butenoate (250mg, 0J9mmol) in 5ml anhydrous dioxane was added potassium phosphate (251mg, lJ9mmol), 3-cyanophenyl boronic acid (116mg, 0.79mmol), and tetrakis (triphenylphosphine)palladium(O) (23mg, 0.02mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50ml ethyl acetate, washed with 2x50ml water, 2x50ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 20% EtOAc in hexane as the eluent to give ethyl (2E)-3-(3-cyanophenyl)-4,4,4-trifluorobut-2-enoate (150mg, 79%) as a yellow residue after drying. H'NMR (CDC1 3 ) : 1.107-1.142 (t, 3H); 4.05- 4.107 (m, 2H); 6.684 (s, H); 7.38-7.72 (m, 4H). Example 51: To a solution of 2'-tert-butylaminosulfonyl-4-amino-[l,l']-biphenyl (79mg, 0J6mmol) in 5ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.39ml, 0.78mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl (Z) 3-(3-cyanophenyl)-4,4,4- trifluoro-2-butenoate (70mg, 0.26mmol) in 1ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5ml IN HCI after which an additional 20ml dichloromethane was added. Organic was washed with 2x25ml water, dried over magnesixxm sulfate, filtered and concentrated to give (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)-4,4,4-trifluorobut-2-enamide (120mg, 88%) as a yellow foam which was sufficiently pure to be used without further purification. To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)-4,4,4-trifluorobut-2-enamide (90mg, 0.19mmol) in 10ml 1:1 ethyl acetate: anhydrous methanol cooled to -78°C was bubbled HCI gas until saturation was achieved. Reaction was placed in the refrigerator at 0°C over the weekend. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5ml anhydrous methanol to which ammonium acetate (144mg, 2mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated then treated with 10ml trifluoroacetic acid for 2hrs, concentrated and purified on a 2x25cm Nydac C 18 HPLC colximn to give 3- ((1 E)-2- {Ν-[4-(2-sulfamoylphenyl)phenyl]carbamoyl} - 1 - (trifluoromethyl)vinyl)benzenecarboxamidine (57mg, 47%) as a fluffy white powder after lyophilization. ES-MS (M+H + ): 489.15 Example 52: To a solution of 3-((lE)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}-l- (trifluoromethyl)vinyl)-benzenecarboxamidine (lOmg, 0.02mmol) in 4ml methanol was added 10% Pd on carbon (2mg). Mixture was treated with hydrogen at 1 atmosphere under balloon for lhr. Reaction was filtered through a pad of Celite, concentrated and lyophilized to give 3-[2,2,2-trifluoro-l-({N-[4-(2- sulfamoylpheny l)phenyl] carbamoy 1 } -methy l)ethyl]benzenecarboxamidine (8mg, 82%) as a fluffy white powder. ES-MS (M+H + ): 491 J Example 53: To a solution of ethyl (Z) 3-(3-cyanophenyl)-2-propenoate (2g, 9Jmmol) in 50ml carbon tetrachloride was added N-bromosuccinimide (1.74g, 9J7mmol) and benzoyl peroxide (40mg, 0J65mmol). Reaction mixture was heated to reflux and stirred over night. Reaction was allowed to cool to room temperature to which 50ml dichloromethane was added. Organic was washed with 2x50ml water, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude residue was chromatographed on silica gel using 2.5% EtOAc in hexane as the eluent to give ethyl (Z) 3-(3-cyanophenyl)-4-bromo-2-butenoate (0.77g, 29%) as a clear oil (note: NOE experiment showed compound isomerized during bromination). H'NMR (CDC1 3 ) : 1.311-1.347 (t, 3H); 4.239-4.292 (m, 2H); 4.92 (s, 2H); 6J8 (s, H); 7.514-7.801 (m, 4H). ES-MS (M+H + ): 293.95 and 296.0 Example 54: To a solution of ethyl (Z) 3-(3-cyanophenyl)-4-bromo-2-butenoate (103mg, 0J5mmol) in 5ml anhydrous di-methylformamide was added pyrazole (24mg, 0J5mmol) and cesium carbonate (228mg, OJmmol). Reaction mixture was stirred for 1.5 hours at room temperature after which 25ml ethyl acetate was added. Organic was washed with 3x25ml water, 3x50ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to give ethyl (Z)-3-(3-cyanophenyl)-4- (lH-l-pyrazolyl)-2-butenoate (70mg, 71%) as a brown residue which was sufficiently pure to be used without further purification. ES-MS (M+Η + ): 282J Example 55: To a solution of 2'-tert-butylaminosulfonyl-4-amino-[l, ]-biphenyl (76mg, 0J5mmol) in 4ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.38ml, 0.75mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl (Z)-3-(3-cyanophenyl)-4- (lH-l-pyrazolyl)-2-butenoate (70mg, 0J5mmol) in 1ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5ml IN ΗC1 after which an additional 20ml dichloromethane was added. Organic was washed with 2x20ml water, dried over magnesium sulfate and concentrated to give the tButyl nitrile of the title compound (120mg, 89%) as a brown foam which was sufficiently pure to use in the next step. To a solution of the above nitrile compound (120mg, 0.22mmol) in 10ml 1:1 ethyl acetate : anhydrous methanol cooled to -78°C was bubbled HCI gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried xxnder hi vacuum. The dried methyl imidate residue was dissolved in 5ml anhydrous methanol to which ammonium acetate (77mg, lmmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated, then treated with trifluoroacetic acid (10ml) for 2 hours, concentrated and purified on a 2x25cm Nydac C 18 HPLC column to give 3-((lZ)-l-(pyrazolylmethyl)-2-{Ν-[4-(2-sulfamoylphenyl)phenyl]- carbamoyl}vinyl)benzenecarboxamidine (lOmg, 9%) as a fluffy white powder after lyophilization. ES-MS (M+H + ): 501 J Example 56: To a solution of 3-acetobenzonitrile (5g, 0.0344mol) in 45ml glacial acetic acid was added pyridinium tribromide (11.3g, 0.0355mol). Reaction was stirred at room temperature under argon overnight. Reaction was then quenched with a saturated sodium sulfite solution (20ml) and extracted with 3x25ml dichloromethane. Combined organic phases were washed with 2x25ml water, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude oil was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give 3-(2-bromoacetyl) benzonitrile (4.5g, 58%) as a white solid. H'NMR : 4.371-4.403 (s, 2H); 7.613-7.664 (m, H); 7.838-7.888 (m, H); 8.192-8.261 (m, 2H). To a solution of 3-(2-bromaceto)benzonitrile (500mg, 2.23mmol) in 5ml dichloromethane was added pyrazole (304mg, 4.46mmol) and triethylamine (03 lml, 2.23mmol). Reaction was stirred at room temperature over night. Reaction was then diluted with 20ml dichloromethane, washed with 2x25ml water, 2x25ml IN HCI, dried over magnesium sulfate, filtered and concentrated in vacuo. Crude residue was chromatographed on silica gel using 2.5% EtOAc in hexane to give 3- [2-(7H-l-pyrazolyl)acetyl]benzonitrile (330mg, 70%) as a clear oil after drying. ES- MS (M+Η + ): 212.05 Example 57: To a solution of bis(2J,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (0.39ml, 1.87mmol) in 5ml anhydrous tetrahydrofuran was added a solution of 18- crown-6 (2g, 7.8mmol) in 5ml anhydrous tetrahydrofuran. Reaction was cooled to - 78° C to which a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (0.93ml, 1.87mmol) was added all at once. The reaction mixture was stirred at -78° C for 20 minutes after which a solution of 3-[2-(7H-l-pyrazolyl)acetyl]- benzonitrile (330mg, 1.56mmol) in 5ml anhydrous tetrahydrofuran was added dropwise over several minutes. Reaction was gradually allowed to warm to room temperature and stirred for 5 hours. Reaction was then quenched with a saturated ammonixim chloride solution (10ml) and extracted with 2x25ml diethyl ether. Combined organic layers were washed with 2x25ml water, 2x25ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to a brown residue. Crude residue was chromatographed on silica gel using a gradient of 5% EtOAc in hexane containing 0.1% triethylamine to 20% EtOAc in hexane contaning 0.1% triethylamine to give methyl (E)-3-(3-cyanophenyl)-4-(iH-l-pyrazolyl)-2-butenoate (135mg, 32%) as a clear oil after drying. Η'NMR (CDC1 3 ) : 3.521 (s, #Η); 4.98 (s, 2H); 5.694 (s, H); 6.237-6.247 (t, H); 7.296-7.593 (m, 6H). NOE experiment confirmed stereoconfiguration. Example 58: To a solution of 2'-tert-butylaminosulfonyl-4-amino-[l,l']-biphenyl (105mg, 0.34mmol) in 4ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.5ml, 1.02mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of methyl (E)-3-(3-cyanophenyl)-4- (lH-l-pyrazolyl)-2-butenoate (90mg, 034mmol) in 1ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5ml IN ΗC1 after which an additional 20ml dichloromethane was added. Organic was washed with 2x20ml water, dried over magnesium sulfate, filtered and concentrated to give (2E)-N-[4-(2- {[(tert- buty l)amino] sulfonyl } phenyl)phenyl] -3 -(3 -cy anophenyl)but-2-enamide ( 155mg, 85%>) as an off-white foam which was sufficiently pure to be used without further purification. To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino] sulfonyl }phenyl)phenyl] -3 -(3- cyanophenyl)but-2-enamide (155mg, 0.287mmol) in 10ml 1:1 ethyl acetate: anhydrous methanol cooled to -78°C was bubbled ΗC1 gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried xmder hi vacuum. The dried methyl imidate residue was dissolved in 5ml anhydrous methanol to which ammonium acetate (77mg, lmmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10ml) for 2hrs, concentrated and purified on a 2x25cm Vydac C 18 HPLC column to give 3-((lE)-l-(pyrazolylmethyl)-2- {N-[4-(2- sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (40mg, 28%) as a fluffy white powder after lyophilization. ES-MS (M+H + ): 501 J Example 59: To a solution of 3-((lE)-l-(pyrazolylmethyl)-2-{N-[4-(2- sulfamoylphenyl)phenyl]carbamoyl}vinyl)-benzenecarboxamidine (5mg, O.Olmmol) in 4ml methanol was added 10% Pd on carbon (lmg). Mixture was treated with hydrogen at 1 atmosphere under balloon for lhr. Reaction was filtered through a pad of Celite, concentrated and lyophilized to give 3-(l-(pyrazolylmethyl)-2-{N-[4- (2-sulfamoylphenyl)phenyl]-carbamoyl} ethyl)benzenecarboxamidine (5mg, 100%) as a fluffy white powder. ES-MS (M+H + ): 503 J Example 60: To a solution of ethyl R-oxo-3-furanpropionate (lg, 5.49mmol) in 5ml anhydrous dichloromethane was added triethylamine (0.847ml, 6.04mmol). Reaction was cooled under argon to -78°C to which trifluoromethanesulfonic anhydride (1.02ml, 6.04mmol) was added dropwise via syringe over 5 minutes. Reaction was allowed to warm to room temperature and stirred over night. Next morning the reaction was diluted with 25ml dichloromethane, organic was washed with 2x50ml water, 2x50ml IN HCI, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was chromatographed on silica gel using 20% EtOAc in hexane as the eluent to give ethyl (Z)-3-(2-furyl)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2- propenoate (1.6g, 93%) as a light brown solid after drying. H'NMR (CDC1 3 ) : 1.31- 1.35 (t, 3H); 4.26-4.314 (m, 2H); 6.065 (s, H); 6.522 (s, H); 7.47 (s, H); 7.76 (s, H). Example 61: To a solution of ethyl (Z)-3-(2-furyl)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2- propenoate (500mg, 1.59mmol) in 7ml anhydrous dioxane was added potassium phosphate (506mg, 2.4mmol), 3-cyanophenyl boronic acid (234mg, 1.59mmol), and tetrakis (triphenylphosphine)palladium(O) (46mg, 0.04mmol). Reaction mixtxire was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50ml ethyl acetate, washed with 2x50ml water, 2x50ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was chromatographed on silica gel using a gradient from 5% EtOAc in hexane to 10% EtOAc in hexane as the eluent to give ethyl (E) 3-(3-cyanophenyl)-3- (2-ftxryl)-2-propenoate (lOOmg, 24%) as a clear yellow oil after drying. H'NMR (CDC1 3 ) : 1.1-1.14 (t, 3H); 4,016-4.035 (m, 2H); 5.293 (s, H); 7.45-7.549 (m, 3H); 7.669 (m, H). ES-MS (M+H + ): 268.05 Example 62: To a solution of 2'-tButylaminosulfonyl-4-amino-[l,l']-biphenyl (102mg, 0336mmol) in 4ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.5ml, 1.Ommol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl (E) 3-(3-cyanophenyl)-3-(2- furyl)-2-propenoate (90mg, 0336mmol) in 1ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5ml IN HCI after which an additional 20ml dichloromethane was added. Organic was washed with 2x20ml water, dried over magnesium sulfate and concentrated to give (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)-3-(2-furyl)prop-2-enamide (200mg, 112%) as a brown foam which was sufficiently pure to be used without further purification. To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)-3-(2-furyl)prop-2-enamide (176mg, 0336mmol) in 10ml 1:1 ethyl acetate: anhydrous methanol cooled to -78°C was bubbled HCI gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried xmder hi vacuum. The dried methyl imidate residue was dissolved in 5ml anhydrous methanol to which ammonium acetate (144mg, 2mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10ml) for 2hrs, concentrated and purified on a 2x25cm Vydac C, 8 HPLC column to give 3-((lE)-l-(2-furyl)-2-{N-[4-(2- sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (60mg, (37%) as a fluffy off-white powder after lyophilization. ES-MS (M+H + ): 487.15 Example 63: To a solution of 3-((lE)-l-(2-furyl)-2-{N-[4-(2- sulfamoylphenyl)phenyl]carbamoyl} vinyl)benzenecarboxamidine (1 Omg, 0.02mmol) in 4ml methanol was added 10% Pd on carbon (2mg). Mixture was treated with hydrogen at 1 atmosphere under balloon for lhr. Reaction was filtered through a pad of Celite, concentrated and lyophilized to give 3-(l-(2-furyl)-2-{N-[4- (2-sulfamoylphenyl)phenyl]carbamoyl}ethyl)benzenecarboxamidine (9mg, 90%) as a fluffy white powder. ES-MS (M+H + ): 489.15 Example 64: To a solution of methyl 4-methoxy-3-oxobutanoate (5g, 34.2mmol) in 20ml anhydrous dichloromethane was added triethylamine (5.24ml, 37.6mmol). Reaction was cooled under argon to -78°C to which trifluoromethane-sulfonic anhydride (10.6gml, 37.6mmol) was added dropwise via syringe over 5 minutes. Reaction was allowed to warm to room temperature and stirred over night. Next morning the reaction was diluted with 25ml dichloromethane, organic was washed with 2x50ml water, 2x50ml IN HCI, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was chromatographed on silica gel using a gradient of 5% EtOAc in hexane to 10% EtOAc in hexane as the eluent to give methyl (Z)-4- methoxy-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-butenoate (5Jg, 54%) as a clear colorless oil after drying. H'NMR (CDC1 3 ) : 3.342 (s, 3H); 3.711 (s, 3H); 3.99 (s, H); 6.02 (s, H). Example 65: To a solution of methyl (Z)-4-methoxy-3-{[(trifluoromethyl)sulfonyl]-oxy}-2- butenoate (246mg, l.Ommol) in 5ml anhydrous dioxane was added potassium phosphate (318mg, 1.5mmol), 3-cyanophenyl boronic acid (162mg, l.Ommol), and tetrakis (triphenylphosphine)palladium(O) (29mg, 0.025 lmmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 20ml ethyl acetate. Organic was washed with 2x20ml water, 2x20ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give methyl (E)-3-(3-cyanophenyl)-4-methoxy-2-butenoate (220mg, 75%) as a clear brown oil which was sufficiently pure to be used without further purification. ES-MS (M+H + ): 232J Example 66: To a solution of 2'-tButylaminosulfonyl-4-amino-[l,l ']-biphenyl (105mg, 035mmol) in 4ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.53ml, 1.05mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of methyl (E) 3-(3-cyanophenyl)-4- methoxy-2-butenoate (80mg, 035mmol) in 1ml anhydrous dichloromethane was added. Reaction was stirred at room temperature overnight. Reaction was quenched with 5ml IN HCI after which an additional 20ml dichloromethane was added. Organic was washed with 2x20ml water, dried over magnesium sulfate and concentrated to give (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)-4-methoxybut-2-enamide (150mg, 85%) as a white foam after drying which was sufficiently pure to be used without further purification. To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3- cyanophenyl)-4-methoxybut-2-enamide (150mg, 0J98mmol) in 10ml 1:1 ethyl acetate: anhydrous methanol cooled to -78°C was bubbled HCI gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5ml anhydrous methanol to which ammonium acetate (77mg, lmmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10ml) for 2hrs, concentrated and purified on a 2x25cm Vydac C 18 HPLC column to give 3-((lE)-l-(methoxymethyl)-2- {N-[4-(2- sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (34mg, (25%) as a fluffy off-white powder after lyophilization. ES-MS (M+H + ): 465.15 Example 67: To a solution of 3-((lE)-l-(methoxymethyl)-2-{N-[4-(2- sulfamoylphenyl)phenyl]carbamoyl} vinyl)-benzenecarboxamidine (5mg, 0.01 mmol) in 4ml methanol was added 10% Pd on carbon (lmg). Mixture was treated with hydrogen at 1 atmosphere under balloon for lhr. Reaction was filtered through a pad of Celite, concentrated and lyophilized to give 3-(l-(methoxymethyl)-2-{N-[4- (2-sulfamoylphenyl)phenyl]carbamoyl}-ethyl)benzenecarboxamidine (5mg, 100%) as a fluffy white powder. ES-MS (M+IT): 467.15 BIOLOGICAL ACTIVITY EXAMPLES Evaluation of the compounds of this invention is guided by in vitro protease activity assays (see below) and in vivo studies to evaluate antithrombotic efficacy, and effects on hemostasis and hematological parameters. The compounds of the present invention are dissolved in buffer to give solutions containing concentrations such that assay concentrations range from 0 to 100 μM. In the assays for thrombin, prothrombinase and factor Xa, a synthetic chromogenic substrate is added to a solution containing test compound and the enzyme of interest and the residual catalytic activity of that enzyme is determined spectrophotometrically. The IC50 of a compoxmd is determined from the substrate turnover. The IC50 is the concentration of test compound giving 50% inhibition of the substrate turnover. The compounds of the present invention desirably have an IC50 of less than 500 nM in the factor Xa assay, preferably less than 200 nM, and more preferred compounds have an IC50 of about 100 nM or less in the factor Xa assay. The compounds of the present invention desirably have an IC50 of less than 4.0 μM in the prothrombinase assay, preferably less than 200 nM, and more preferred compounds have an IC50 of about 10 nM or less in the prothrombinase assay. The compounds of the present invention desirably have an IC50 of greater than 1.0 μM in the thrombin assay, preferably greater than 10.0 μM, and more preferred compounds have an IC50 of greater than 100.0 μM in the thrombin assay. Amidolytic Assays for determining protease inhibition activity The factor Xa and thrombin assays are performed at room temperature, in 0.02 M Tris-HCl buffer, pH 7.5, containing 0J5 M NaCl. The rates of hydrolysis of the para-nitroanilide substrate S-2765 (Chromogenix) for factor Xa, and the substrate Chromozym TH (Boehringer Mannheim) for thrombin following preincubation of the enzyme with inhibitor for 5 minutes at room temperature, and were determined using the Softmax 96-well plate reader (Molecular Devices), monitored at 405 nm to measure the time dependent appearance of p-nitroaniline. The prothrombinase inhibition assay is performed in a plasma free system with modifications to the method described by Sinha, U. et al, Thromb. Res., 25, 427-436 (1994). Specifically, the activity of the prothrombinase complex is determined by measuring the time course of thrombin generation using the p- nitroanilide substrate Chromozym TH. The assay consists of preincubation ( 5 minutes) of selected compounds to be tested as inhibitors with the complex formed from factor Xa (0.5 nM), factor Va (2 nM), phosphatidyl serine:phosphatidyl choline (25:75, 20 μM) in 20 mM Tris-HCl buffer, pH 7.5, containing 0J5 M NaCl, 5 mM CaCl2 and 0.1% bovine serum albumin. Aliquots from the complex-inhibitor mixture are added to prothrombin (1 nM) and Chromozym TH (0J mM). The rate of substrate cleavage is monitored at 405 nm for two minutes. Eight different concentrations of inhibitor are assayed in duplicate. A standard curve of thrombin generation by an equivalent amount of untreated complex are used for determination of percent inhibition. Antithrombotic Efficacy in a Rabbit Model of Venous Thrombosis A rabbit deep vein thrombosis model as described by Hollenbach, S. et al., Thromb. Haemost. 71, 357-362 (1994), is used to determine the in-vivo antithrombotic activity of the test compounds. Rabbits are anesthetized with I.M. injections of Ketamine, Xylazine, and Acepromazine cocktail. A standardized protocol consists of insertion of a thrombogenic cotton thread and copper wire apparatus into the abdominal vena cava of the anesthetized rabbit. A non-occlusive thrombus is allowed to develop in the central venous circulation and inhibition of thrombus growth is used as a measure of the antithrombotic activity of the studied compounds. Test agents or control saline are administered through a marginal ear vein catheter. A femoral vein catheter is used for blood sampling prior to and during steady state infusion of test compound. Initiation of thrombus formation begins immediately after advancement of the cotton thread apparatus into the central venous circulation. Test compounds are admimstered from time = 30 min to time = 150 min at which the experiment is terminated. The rabbits are euthanized and the thrombus excised by surgical dissection and characterized by weight and histology. Blood samples are analyzed for changes in hematological and coagulation parameters. Effects of Compounds in Rabbit Venous Thrombosis model Administration of compounds in the rabbit venous thrombosis model demonstrates antithrombotic efficacy at the higher doses evaluated. There are no significant effects of the compound on the aPTT and PT prolongation with the highest dose (100 μg/kg + 2.57 μg/kg/min). Compoxmds have no significant effects on hematological parameters as compared to saline controls. All measurements are an average of all samples after steady state administration of vehicle or (D)-Arg-Gly-Arg-thiazole. Values are expressed as mean ± SD. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods.

Claims: WHAT IS CLAIMED IS: 1. A compound according to the formula: A-Y-D-E-G-J-K-L wherein: A is selected from: (a) C r C 6 -alkyl; (b) C 3 -C 8 -cycloalkyl; (c) phenyl, which is independently substituted with 0-2 R' substituents; (d) naphthyl, which is independently substituted with 0-2 R' substituents;and (e) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R' substituents; R 1 is selected from: Halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3 . 8 cycloalkyl,-CN, -NO 2 , (CH 2 ) m NR 2 R 3 , SO 2 NR 2 R 3 , SO 2 R 2 , CF 3 , OR 2 , and a 5- 6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C,-C 4 -alkyl, -CN C 1-4 alkyl, C 2 . 6 alkenyl, C 2- 6 alkynyl, C 3.8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl and -NO 2 ; R 2 and R 3 are independently selected from the group consisting of: H, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C (M alkylC 3 . 8 cycloalkyl, Co^alkylphenyl and C^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ; m is an integer of 0-2; Y is a member selected from the group consisting of: a direct link, -C(=O)-, -N(R 4 )-, -C(=O)-N(R 4 )-, -N(R 4 )-C(=O)-, -SO 2 -, -O-, -SO 2 -N(R 4 )- and -N(R 4 )-SO 2 -; R 4 is selected from: H, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylphenyl and C 0^ ,alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ;. D is a direct link or is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R l substituents; (b) naphthyl, which is independently substituted with 0-2 R la substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R la substituents; R la is selected from: Halo, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . gcycloalkyl, -CN, -NO 2 , (CH 2 ) m NR 2a R 3a , SO 2 NR 2a R 3a , SO 2 R 2a , CF 3 , OR 2a , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 - 4 alkylC 3 . 8 cycloalkyl, -CN and -NO 2 . R 2a and R 3 are independently selected from the group consisting of: H, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C θJ ,alkylC 3 . 8 cycloalkyl, C o ^alkylphenyl and C h alky lnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl, -CN and -NO 2 ;. E is a member selected from the group consisting of: -N(R 5 )-C(=O)-, -C(=O)-N(R 5 )-, -N(R 5 )-C(=O)-N(R 6 )-, -SO 2 -N(R 5 )-, -N(R 5 )-SO 2 -N(R 6 )- and -N(R 5 )-SO 2 -N(R 6 )-C(=O)-; R 5 and R 6 are independently selected from: H, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 _ 4 alkylC 3 .gCycloalkyl, C 0.4 alkylphenyl, C θJ( alkylnaphthyl, C 0^ ,alkylheteroaryl, C M alkylCOOH and C M alkylCOOC, ^ ,alkyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3 . 8 cycloalkyl, -CN and -NO 2 ; G is selected from: -CR 7 R 8 - and -CR 7 R 8a -CR 7b R 8b - wherein R 7 , R 8 , R 7a , R 8a , R 70 and R 8b are independently a member selected from from the group consisting of: hydrogen, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, gcycloalkyl, C^alkylphenyl, C 0 ^alkylnaphthyl, -OR 9 , - ^alkylCOOR 9 , -C 0 ^alkylC(=O)NR 9 R 10 , -C 0-4 alkylC(=O)NR 9 -CH 2 -CH 2 -O-R 10 , -C 0 ^alkylC(=O)NR 9 (-CH 2 -CH 2 -O-R'°-) 2 , -N(R 9 )COR 10 , -N(R 9 )C(=O)R 10 , -N(R 9 )SO 2 R 10 , and a naturally occurring or synthetic amino acid side chain, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 - 6 alkynyl, C 3 . 8 cycloalkyl, C h alky l-C 3 . 8 cycloalkyl, -CN and -NO 2 ; R and R are independently selected from: H, C M alkyl, C^alkylphenyl and C^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkyl-C 3 . gcycloalkyl, -CN and -NO 2 , and wherein R 9 and R 10 taken together can form a 5-8 membered heterocyhc ring; J is a member selected from the group consisting of: a direct link, -CH(R π )- and -CH(R π )-CH 2 -; R 11 is a member selected from the group consisting of: hydrogen, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, Co^alkyl- . gcycloalkyl, C^alkylphenyl, C 0^ ,alkylnaphthyl, Co^alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH 2 COOC alkyl, CH 2 COOC M alkylphenyl and CH 2 COOC alkylnaphthyl; K is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R lb substituents; (b) naphthyl, which is independently substituted with 0-2 R lb substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R lb substituents; R Ib is selected from: Halo, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C^alkyl . gcycloalkyl, -CN, -NO 2 , NR 2b R 3b , SO 2 NR 2b R 3b , SO 2 R 2b , CF 3 , OR 2b , O-CH 2 - CH 2 -OR 2b , O-CH 2 -COOR 2b , N(R 2b )-CH 2 -CH 2 -OR 2b , N(-CH 2 -CH 2 -OR 2b ) 2 , N(R 2b )-C(=O)R 3b , N(R 2b )-SO 2 -R 3b , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, C 3 _ 8 cycloalkyl, C 0^ ,alkylC 3 . gcycloalkyl, -CN and -NO 2 ; R 2b and R 3b are independently selected from the group consisting of: H, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3 . 8 cycloalkyl, C 0 ( alkylphenyl and C^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2.6 alkynyl, C 3 . 8 cycloalkyl, C (M alkylC 3 . 8 cycloalkyl, -CN and -NO 2 ; L is selected from: H, -CN, C(=O)NR 12 R 13 , (CH 2 ) n NR ,2 R 13 , C(=NR 12 )NR 12 R 13 , NR ,2 R 13 , OR 12 , -NR ,2 C(=NR ,2 )NR 12 R 13 , and NR 12 C(=NR 12 )-R 13 ; R 12 and R 13 are independently selected from: hydrogen, -OR 14 , -NR 14 R 15 , C M alkyl, C 0J( alkylρhenyl, C^alkylnaphthyl, COOC M alkyl, COO-C^alkylphenyl and COO-C 0 ^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0J ,alkylC 3. gCycloalkyl, -CN, and -NO 2 ; R 14 and R 15 are independently selected from: H, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3.8 cycloalkyl, C h alky lC 3-8 cycloalkyl, ^alkylphenyl and C 0^ ,alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2-6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0J( alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 2. A compound of claim 1, wherein: A is selected from: (a) C,-C 6 -alkyl; (b) C 3 -C 8 -cycloalkyl; (c) phenyl, which is independently substituted with 0-2 R 1 substituents; (d) naphthyl, which is independently substituted with 0-2 R ! substituents;and (e) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0-2 R 1 substituents; R 1 is selected from: Halo, C 1-4 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C^aU ylC^ 8 cycloalkyl,-CN, -NO 2 , (CH 2 ) m NR 2 R 3 , SO 2 NR 2 R 3 , SO 2 R 2 , CF 3 , OR 2 , and a 5- 6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C,-C 4 -alkyl, -CN C M alkyl, C 2 . 6 alkenyl, C 2 _ 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl and -NO 2 ; R 2 and R 3 are independently selected from the group consisting of: H, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C o _ 4 alkylphenyl and C 0^ ,alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ; m is an integer of 0-2; Y is a member selected from the group consisting of: a direct link, -C(=O)-, -N(R 4 )-, -C(=O)-N(R 4 )-, -N(R 4 )-C(=O)-, -SO 2 -, -O-, -SO 2 -N(R 4 )- and -N(R 4 )-SO 2 -; R 4 is selected from: H, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3 . 8 cycloalkyl, C 0Jt alkylphenyl and C^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C 1-4 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ;. D is a direct link or is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R la substituents; (b) naphthyl, which is independently substituted with 0-2 R la substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0- 2 R la substituents; R la is selected from: Halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C θJ ,alkylC 3 . gcycloalkyl, -CN, -NO 2 , (CH 2 ) m NR 2a R 3a , SO 2 NR 2a R 3a , SO 2 R 2a , CF 3 , OR 2a , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C I-4 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0J ,alkylC 3 .gCycloalkyl, -CN and -NO 2 R 2a and R 3a are independently selected from the group consisting of: H, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 - 4 alkylC 3 .gCycloal.kyl, C o ^alkylphenyl and C θJ ,alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3.8 cycloalkyl, C 0 ^alkylC 3-8 cycloalkyl, -CN and -NO 2 ;. E is a member selected from the group consisting of: -N(R 5 )-C(=O)-, -C(=O)-N(R 5 )-, -N(R 5 )-C(=O)-N(R 6 )-, -SO 2 -N(R 5 )-, -N(R 5 )-SO 2 -N(R 6 )- and -N(R 5 )-SO 2 -N(R 6 )-C(=O)-; R 5 and R 6 are independently selected from: H, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 . 4 alkylC 3 . 8 cycloalkyl, C 0 ^alkylphenyl, C^alkylnaphthyl, C 0^ ,alkylheteroaryl, C^alkylCOOH and C alkylCOOC alkyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl and heteroaryl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0J ,alkylC 3 . 8 cycloalkyl, -CN and -NO 2 ; G is selected from: -CR 7 R 8 - and -CR 7 R 8a -CR 7b R 8b - wherein R 7 , R 8 , R 7a , R 8a , R n and R 8b are independently a member selected from from the group consisting of: hydrogen, C M alkyl, C 2 . 6 alkenyl, C 2.6 alkynyl, C 3 . 8 cycloalkyl, ^al-kyl^. gcycloalkyl, Co^alkylphenyl, Co^alkylnaphthyl, -OR 9 ,-C 0^ ,alkylCOOR 9 , -C 0Jl alkylC(=O)NR 9 R ,0 , -C 0 . 4 alkylC(=O)NR 9 -CH 2 -CH 2 -O-R ,() , -C 0 ^alkylC(=O)NR 9 (-CH 2 -CH 2 -O-R 10 -) 2 , -N(R 9 )COR 10 , -N(R 9 )C(=O)R 10 , -N(R 9 )SO 2 R 10 , and a naturally occurring or synthetic amino acid side chain, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . gcycloalkyl, C 0 - 4 alkyl-C 3 .gCycloalkyl, -CN and -NO 2 ; R 9 and R 10 are independently selected from: H, C M alkyl, C 0 ^alkylphenyl and Co^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, Co ^ ,alkyl-C 3 . gcycloalkyl, -CN and -NO 2 , and wherein R 9 and R 10 taken together can form a 5-8 membered heterocyhc ring; J is a member selected from the group consisting of: a direct link, -CH(R U )- and -CH(R π )-CH 2 -; R u is a member selected from the group consisting of: hydrogen, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, Co^alkyl-C 3 . g cycloalkyl, C 0 ^alkylphenyl, C θJ ,alkylnaphthyl, C 0^ ,alkylheterocyclic ring having from 1 to 4 hetero ring atoms selected from the group consisting of N, O and S, CH 2 COOC,. 4 alkyl, CH 2 COOC alkylphenyl and CH 2 COOC M alkylnaphthyl; Z is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R lb substituents; (b) naphthyl, which is independently substituted with 0-2 R lb substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0- 2 R lb substituents; R lb is selected from: Halo, C 1-4 alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0 ^alkylC 3 . 8 cycloalkyl, -CN, -NO 2 , NR 2b R 3b , SO 2 NR 2b R 3b , SO 2 R 2b , CF 3 , OR 2b , O-CH 2 - CH 2 -OR 2b , O-CH 2 -COOR 2b , N(R 2b )-CH 2 -CH 2 -OR 2b , N(-CH 2 -CH 2 -OR 2b ) 2 , N(R 2b )-C(=O)R 3b , N(R 2b )-SO 2 -R 3b , and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, 8 cycloalkyl, -CN and -NO 2 ; R 2b and R 3b are independently selected from the group consisting of: H, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0-4 alkylC 3 . 8 cycloalkyl, C 0 ^alkylphenyl and C 0^ ,alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2.6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0^ ,alkylC 3 . g cycloalkyl, -CN and -NO 2 ; L is selected from: H, -CN, C(=O)NR 12 R 13 , (CH 2 ) n NR 12 R 13 , C(=NR 12 )NR 12 R 13 , NR 12 R 13 , OR 12 , -NR 12 C(=NR 12 )NR 12 R 13 , and NR ,2 C(=NR 12 )-R 13 ; R 12 and R 13 are independently selected from: hydrogen, -OR 14 , -NR ,4 R 15 , C M alkyl, C 0 ^alkylphenyl, C^alkylnaphthyl, COOC^alkyl, COO-C^alkylphenyl and COO-C^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . g cycloalkyl, C 0Jt alkylC 3 . 8 cycloalkyl, -CN, and -NO 2 ; R 14 and R 15 are independently selected from: H, C M alkyl, C 2 . 6 alkenyl, C 2.6 alkynyl, C 3 . 8 cycloalkyl, Co^alkylC 3 _ 8 cycloalkyl, ^alkylphenyl and C^alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties may be independently replaced with a member selected from the group consisting of halo, C alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3.8 cycloalkyl, C 0 ^alkylC 3.8 cycloalkyl, -CN, and -NO 2 ; and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof. 3. A compound of claim 1, wherein: A is selected from: (a) phenyl, which is independently substituted with 0-2 R 1 substituents; (b) naphthyl, which is independently substituted with 0-2 R 1 substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0- 2 R 1 substituents; Y is a direct link; D is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R la substituents; (b) naphthyl, which is independently substituted with 0-2 R la substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0- 2 R la substituents; E is a member selected from the group consisting of: -NH-C(=O)-, and -C(=O)-NH-; G is -CHR 7a -CHR 7b -; J is a direct link; Z is a member selected from the group consisting of: (a) phenyl, which is independently substituted with 0-2 R lb substituents; (b) naphthyl, which is independently substituted with 0-2 R lb substituents; and (c) a monocyclic or fused bicyclic heterocyclic ring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system are selected from N, O and S, and wherein the ring system may be substituted with 0- 2 R lb substituents; R lb is selected from: N(R 2b )-C(=O)R 3b and a 5-6 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system may be independently replaced with a member selected from the group consisting of halo, C M alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, C 3 . 8 cycloalkyl, C 0-4 alkylC 3 .gCycloalkyl, -CN and - NO 2 ; and L is H. 4. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a compound of claim 1. 5. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a compound of claim 2. 6. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a compound of claim 3. 7. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising the step of administering to said mammal a therapeutically effective amount of a compound of claim 1. 8. The method of claim 7, wherein the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopema, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve, and conditions requiring the fitting of prosthetic devices. 9. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising the step of administering to said mammal a therapeutically effective amount of a compound of claim 2. 10. The method of claim 9, wherein the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopema, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve, and conditions requiring the fitting of prosthetic devices. 11. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising the step of administering to said mammal a therapeutically effective amount of a compound of claim 3. 12. The method of claim 11, wherein the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopema, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation such as cardiac or other intravascular catheterization, intra-aortic balloon pump, coronary stent or cardiac valve, and conditions requiring the fitting of prosthetic devices. 13. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 1. 14. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 2. 15. A method for inhibiting the coagulation of biological samples, comprising the step of administering a compound of claim 3.

Inventors: CLIZBE LANE, MARLOWE CHARLES, SCARBOROUGH ROBERT M, SONG YONGHONG, SU TING, ZHU BING-YAN, CLIZBE, LANE, MARLOWE, CHARLES, SCARBOROUGH, ROBERT, M., SONG, YONGHONG, SU, TING, ZHU, BING-YAN
Applicants: COR THERAPEUTICS INC, COR THERAPEUTICS, INC.
Application year: 2000
Main classification: C07C311
IPC codes: A61K31, A61K33, A61P7, A61P9, A61P43, C07C311, C07C317, C07D209, C07D213, C07D217, C07D231, C07D233, C07D295, C07D307, C07D413, C07D521