WO2013049591A2

WO2013049591A2 - Dual inhibitor compounds and methods of use thereof

Info

Publication number: WO2013049591A2
Application number: PCT/US2012/057951
Authority: WO
Inventors: Kevin Michael Short; Son Minh Pham; David Charles Williams
Original assignee: Verseon Corporation
Priority date: 2011-09-29
Filing date: 2012-09-28
Publication date: 2013-04-04
Also published as: WO2013049591A3

Abstract

There are provided inter alia multisubstituted aromatic compounds which exhibit dual inhibitory action against thrombin (activated blood-coagulation factor II; EC 3.4.21.5) and coagulation factor Xa (activated Stuart-Prower factor, factor Xa, EC 3.4.21.6), and method of use thereof.

Description

DUAL INHIBITOR COMPOUNDS AND METHODS OF USE THEREOF

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 61/540,653, filed September 29, 201 1, the entire contents of which is hereby incorporated herein and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] NOT APPLICABLE

REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER

PROGRAM LISTING APPENDIX SUBMITTED ON A COMPACT DISK

[0003] NOT APPLICABLE

BACKGROUND OF THE INVENTION

[0004] There are provided multisubstituted aromatic compounds, which exhibit dual inhibitory action against thrombin (i.e., activated blood-coagulation factor II; EC 3.4.21.5) and coagulation factor Xa (i.e., "fXa," activated Stuart-Prower factor, factor Xa, EC 3.4.21.6).

[0005] In mammalian systems, blood vessel injuries result in bleeding events, which are dealt with by the blood coagulation cascade. The cascade is comprised of the extrinsic and intrinsic pathways, involving the activation of over 13 interconnected factors and a variety of co-factors and other regulatory proteins. Upon vascular injury, plasma factor VII (fVIIa) interacts with exposed tissue factor (TF), and the resultant TF-fVIIa complex initiates a complex series of events. Factor Xa (fXa) is produced directly 'downstream' from the TF-fVIIa complex, and amplified manifold via the Intrinsic Pathway. FXa then serves as the catalyst for formation of thrombin (flla), which in turn is the direct precursor to fibrinolysis. The outcome is a fibrinolytic clot, which stops the bleeding. Fibrinolysis of the polymeric clot into fibrin monomers leads to dissolution and a return of the system to 'normal' The cascade is a complex balance of factors and co-factors and is tightly regulated.

[0006] In disease states, undesired up- or down-regulation of any factor leads to conditions such as bleeding or thrombosis. Historically, anticoagulants have been used in patients at risk of suffering from thrombotic complications, such as angina, stroke and heart attack. Warfarin has enjoyed dominance as a first-in-line anticoagulant therapeutic. Developed in the 1940s, it is a vitamin K antagonist and inhibits factors II, VII, IX and X, amongst others. It is administered orally, but its ease of use is tempered by other effects: it has a very long half life (greater than 2 days) and has serious drug-drug interactions. Importantly, since vitamin K is a ubiquitous cofactor within the coagulation cascade, antagonism results in the simultaneous inhibition of many clotting factors and thus can lead to significant bleeding complications.

[0007] Much attention has been focused on heparin, the naturally-occurring polysaccharide that activates antithrombin III (AT III), the endogenous inhibitor of many of the factors in the coagulation cascade. The need for parenteral administration for the heparin-derived therapeutics, and the inconvenient requirements for close supervision for the orally available warfarin, has resulted in a drive to discover and develop orally available drugs with wide therapeutic windows for safety and efficacy.

[0008] The position of thrombin within the coagulation cascade has made it a popular target for drug discovery. The ultimate development of direct thrombin inhibitors (DTIs) is based upon the classical d-Phe-Pro-Arg motif, a sequence that mimics fibrinogen, thrombin's natural substrate. The development of DTIs is very well established, such as with the hirudin-based anticoagulants, and thus there is strong commercial interest in the discovery and development of novel DTIs. [0009] Recent studies show that fXa is a promising therapeutic target, with potential advantages over thrombin. For example, thrombin also promotes platelet activation, promoting concern that thrombin inhibition may result in thrombocytopenia, a lack of platelets.

Conversely, fXa is centrally located in the coagulation cascade, and its sole function is in the promotion of coagulation. The previously described generation and subsequent amplification of fXa has led to the recognition that generation of a single molecule of fXa leads to the generation of greater than 1000 molecules of thrombin. Thus, as a drug discovery strategy, fXa inhibition has been reasoned to be more effective than thrombin inhibition.

[0010] Development of small molecule therapeutics that inhibit either thrombin or factor Xa has recently led to the introduction of marketed drugs as well as a number of candidates in late- stage clinical trials. However, no small molecule therapeutics that inhibit both proteins simultaneously have been advanced to clinical trials. Some preclinical data has been published on dual inhibitors, however, with the suggestion that the combined inhibition of both thrombin and factor Xa results in a favorable pharmacology. Such work can be found in a variety of references including the following: Giardino, E. C, et al, Blood Coagul Fibrinolysis 2010, 21, 128-34; Young, R. J., et al, Bioorg. Med. Chem. Lett. 2007, 17, 2927-2930; Deng, J. Z., et al, Bioorg. Med. Chem. Lett. 2005, 15, 4411-16; and Kranjc, A. & Kikelj, D., Curr Med Chem 2004, 11, 2535-47.

[0011] A discussion of thrombin, fXa and their roles in the coagulation process can be found in the literature. See e.g., Wieland, H. A., et al, 2003, Curr Opin Investig Drugs, 4:264-71. See also: Gross, P. L. & Weitz, J. I., 2008, Arterioscler Thromb Vase Biol, 28:380-386; Hirsh, J., et al, 2005, Blood, 105:453-63; Prezelj, A., et al, 2007, Curr Pharm Des, 13:287-312. [0012] Accordingly, there are provided compounds which are dual inhibitors of thrombin and coagulation factor Xa (fXa).

BRIEF SUMMARY OF THE INVENTION

[0013] In a first aspect, there is provided a compound with structure of Formula (II)

or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof. For Formula (II), R¹ and R² are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. R³ is hydrogen, -NH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. R⁴ is unsubstituted alkyl. L¹ and L² are each independently a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene. L³ is a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or -L^3a-L^3b-. L^3a is substituted or unsubstituted heterocycloalkylene, and L^3b is -C(O)-, -S(0)₂-, or -C(0)0. The compound inhibits both thrombin and coagulation factor Xa (fXa). [0014] In another aspect, there is provided a method for inhibiting thrombin or coagulation factor Xa (fXa). The method includes contacting thrombin or fXa with a compound according to Formula (II), thereby inhibiting thrombin or fXa.

[0015] In another aspect, there is provided a method for treating a thrombotic disorder. The method includes administering to a subject in need thereof an effective amount of a compound according to Formula (II), thereby treating the thrombotic disorder.

[0016] In another aspect, there is provided a method for ameliorating wound healing,. The method includes administering to a subject in need thereof an effective amount of a compound according to Formula (II), thereby ameliorating wound healing.

[0017] In another aspect, there is provided a method for mediating tissue repair. The method includes administering to a subj ect in need thereof an effective amount of a compound according to Formula (II), thereby mediating tissue repair.

[0018] In another aspect, there is provided a method for treating a disease or disorder in a subject. The method includes administering a compound according to Formula (II) to a subject in need thereof in an amount effective to treat the disease or disorder. [0019] In another aspect, there is provided a pharmaceutical composition including a compound according to Formula (II) and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] NOT APPLICABLE

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

[0021] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0022] The term "attached" signifies a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art.

[0023] Unless indicated otherwise, the term "about" in the context of a numeric value refers to the nominal numeric value ± 10% thereof. [0024] The terms "halogen" and "halo" include fluorine, chlorine, bromine, and iodine.

Combinational terms such as "haloalkyl" include all levels of halogenation, e.g., monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3- bromopropyl, and the like. [0025] The term "alkyl," alone or in combinational form, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3 -(1,4- pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. Accordingly, the term "alkyl" can refer to Q-Ci₆ straight chain saturated, Q-C16 branched saturated, C3-C8 cyclic saturated and O-C16 straight chain or branched saturated aliphatic hydrocarbon groups substituted with C₃-C₈ cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (t-Bu), sec -butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropylmethyl, and the like.

[0026] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, e.g., -CH2CH2CH2CH2- and the like. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

[0027] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to: -CH₂-CH₂-0-CH₃, -CH₂-CH₂-NH-CH₃, -CH₂-CH₂-N(CH₃)-CH₃, -CH₂-S-CH₂-CH₃, -CH₂-CH₂, -S(0)-CH₃, -CH₂-CH₂-S(0)₂-CH₃, -CH=CH-0-CH₃, -Si(CH₃)₃, -CH₂-CH=N-OCH₃,

-CH=CH-N(CH₃)-CH₃, -0-CH₃, -0-CH₂-CH₃, and -CN. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃.

[0028] Similarly, the term "heteroalkylene," alone or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, e.g., -CH₂-CH₂-S-CH₂-CH₂-, -CH₂-S-CH₂-CH₂-NH-CH₂-, and the like. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)₂R'- represents both -C(0)₂R'- and -R'C(0)₂-, wherein "R"' represents the remainder of the alkylene or heteroalkylene. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R, -C(0)NR, -NR'R", -OR', -SR', -S0₂R, and the like. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like wherein "R"' and "R"" represent substituents, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.

[0029] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic "alkyl" and "heteroalkyl," respectively. For heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, aziridine, azetidine, pyrrolidine, azepane, l-(l,2,5,6-tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like. The terms "cycloalkylene" and "heterocycloalkylene," alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. As customary in the art, the term

"heterocyclyl" is generic to and synonymous with "heterocycloalkyl," and the term

"heterocyclyl" is further generic to and synonymous with "heteroaryl." Heterocyclyl functionalities may be optionally substituted with one or more substituents selected from the group consisting of hydrogen, halo, haloalkyl, alkyl, alkenyl, oxo, alkyloxy, alkylthio, alkyloxycarbonyl, alkylamino, alkylaminoalkyl, alkyloxy(alkyl)amino, alkylcarbonyl, alkylcarboxy, alkylcarboxyalkyl, alkylcarbonylamino, and the like.

[0030] The term "alkenyl" includes C₂-Ci₆ straight chain unsaturated, C₂-Cn branched unsaturated, Cs-Cs unsaturated cyclic, and C2-C16 straight chain or branched unsaturated aliphatic hydrocarbon groups substituted with C3-C8 cyclic saturated and unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Double bonds may occur in any stable point along the chain and the carbon-carbon double bonds may have either the cis or trans configuration. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5- octadienyl, 1,4,7-nonatrienyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, l-pentenyl-3 -cyclohexenyl, and the like. The term "cycloalkenyl" refers to cycloalkyl additionally having one or more double bonds. The term "heterocycloalkenyl" refers to heterocycloalkyl additionally having one or more double bonds. [0031] The term "alkynyl" refers in the customary sense to alkyl additionally having one or more triple bonds.

[0032] The term "acyl" means, unless otherwise stated, -C(0)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0033] The term "alkyloxy" (e.g., methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) refers in the customary sense to an alkyl group attached through an oxygen bridge. [0034] The term "alkylthio" (e.g., methylthio, ethylthio, propylthio, cyclohexylthio and the like) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge.

[0035] The term "alkylamino" represents one or two alkyl groups as defined above having the optionally indicated number of carbon atoms attached through an amine bridge. The two alkyl groups maybe taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one Ci-Ci₆alkyl, arylCo-Ci₆alkyl, or C₀- Ci₆alkylaryl substituent.

[0036] The term "alkylaminoalkyl" represents an alkylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms.

[0037] The term "alkyloxy(alkyl)amino" (e.g., methoxy(methyl)amine, ethoxy(propyl)amine) represents an alkyloxy group as defined above attached through an amino group, the amino group itself having an alkyl substituent.

[0038] The term "alkylcarbonyl" (e.g., cyclooctylcarbonyl, pentylcarbonyl, 3-hexylcarbonyl) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.

[0039] The term "alkylcarboxy" (e.g., heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen. [0040] The term "alkylcarboxy alkyl" represents an alkylcarboxy group attached through an alkyl group as defined above having the indicated number of carbon atoms.

[0041] The term "alkylcarbonylamino" (e.g., hexylcarbonylamino,

cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group.

[0042] The nitrogen group may itself be substituted with an alkyl or aryl group.

[0043] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term "heteroaryl" includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. The term "furanyl," "thiophenyl," "pyridinyl," "pyrimidinyl," and "pyridazinyl" refer to the combinational forms of the terms furan, thiophene, pyridine, pyrimidine, and pyridazine, respectively. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5- benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2- quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. Accordingly, the term "aryl" can represent an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl). The aryl substituents are independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, Ci_i₆alkyl, arylCi_i₆alkyl, Co-i₆alkyloxyCo- i₆alkyl, arylCo-i6alkyloxyCo-i6alkyl, Co-i6alkylthioCo-i6alkyl, arylCo-i6alkylthioCo-i6alkyl, Co-i6alkylaminoCo-i6alkyl, arylCo-i6alkylaminoCo-i6alkyl, di(arylCi-i6alkyl)aminoCo-i6alkyl, Ci-i6alkylcarbonylCo-i6alkyl, arylCi_i6alkylcarbonylCo-i6alkyl, Ci-i6alkylcarboxyCo-i6alkyl, arylCi-i₆alkylcarboxyCo-i₆alkyl, Ci_i₆alkylcarbonylaminoCo-i₆alkyl,

arylCi-i₆alkylcarbonylaminoCo-i₆alkyl, -Co-i₆alkylCOOR₄, -Co-i₆alkylCO R₅R₆ wherein R₄, R₅ and R-6 are independently selected from hydrogen, Ci-Cualkyl, arylCo-Cn alkyl, or R5 and Re are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with or without one Ci_i₆alkyl, arylCo-Ci₆alkyl, or Co-Cli₆alkylaryl substituent. The definition of aryl includes but is not limited to triazolyl. [0044] As used herein, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl," "aralkyl" and the like are meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l- naphthyloxy)propyl, and the like), or a sulfur atom. Accordingly, the terms "arylalkyl" and the like (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group attached through an alkyl group having the optional indicated number of carbon atoms. [0045] The term "alkylsulfonyl," as used herein, means a moiety having the formula -S(02)- , where R is an alkyl group as defined above. R may have a specified number of carbons (e.g., "C1-C4 alkylsulfonyl").

[0046] The term "arylalkyl" (e.g. (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexyl, pyridylcyclopentyl) represents an aryl group attached through an alkyl group having the optional indicated number of carbon atoms.

[0047] The term "carbonyloxy" represents a carbonyl group attached through an oxygen bridge.

[0048] The term "oxo," as used herein, means an oxygen that is double bonded to a carbon atom. [0049] In the above definitions, the terms "alkyl" and "alkenyl" may be used interchangeably in so far as a stable chemical entity is formed, as obvious to those skilled in the art.

[0050] The term "linker" refers to divalent attachment groups interposed between substituents, e.g., R¹, R², R³ of Formula (I) described herein, e.g., Formula (II), generically referred to following as Rⁿ, and the group which is substituted, e.g., the triazole ring of Formula (II). In some embodiments, the linker includes amido (-CONH-R" or -NHCO-R"), thioamido

(-CSNH-R" or -NHCS-R"), carboxyl (-C0₂-Rⁿ or -OCOR"), carbonyl (-CO-R"), urea (-NHCONH-R"), thiourea (-NHCSNH-R¹), sulfonamido (-NHS0₂-Rⁿ or -S0₂NH-Rⁿ), ether (-0-R¹), sulfonyl (-S0₂-Rⁿ), sulfoxyl (-SO-R"), carbamoyl (-NHC0₂-Rⁿ or -OCONH-R"), or amino (-NHR") linking moieties. In some embodiment, a linker is a bond, -NH-, -NR^m- wherein "R^m" is a nitrogen substituent as disclosed herein, -CONH-, -CSNH-, -C(O)-, -C(0)0-, - NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or

unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene.

[0051] A "substituent group," as used herein, means a group selected from the following moieties:

(A) -OH, -NH₂, -SH, -CN, -CF₃, -N0₂, oxo, halogen, -COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:

(i) oxo, -OH, -NH₂, -SH, -CN, -CF₃, -N0₂, halogen, -COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:

(a) oxo, -OH, -NH₂, -SH, -CN, -CF₃, -N0₂, halogen, -COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and

(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, substituted with at least one substituent selected from: oxo, -OH, -NH₂, -SH, -CN, -CF₃, -N0₂, halogen, -COOH, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

[0052] A "size-limited substituent" or " size-limited substituent group," as used herein, means a group selected from all of the substituents described above for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C₂o alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C4-C8 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or

unsubstituted 4 to 8 membered heterocycloalkyl.

[0053] A "lower substituent" or " lower substituent group," as used herein, means a group selected from all of the substituents described herein for a "substituent group," wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl. [0054] The compounds of the present invention also include racemic mixtures, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds. See e.g., Goding; MONOCLONAL ANTIBODIES PRINCIPLES AND PRACTICE, Academic Press, p. 104 (1986). Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral chromatography. See e.g., Eliel, E. L. & Wilen S. H., 1993,

STEREOCHEMISTRY IN ORGANIC COMPOUNDS; John Wiley & Sons, New York.

[0055] The terms "therapeutically effective amount," "effective amount" and the like refer to an amount of a compound, drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. II. Compounds

[0056] We have discovered that multisubstituted aromatic compounds exhibit dual inhibitory action against thrombin and fXa. In turn, this inhibits the blood coagulation process.

[0057] Accordingly, in one aspect there are provided compounds having the structure of Formula I following:

[0058] For Formula (I), "Ar" is an aryl group. Linker groups L¹ and L² are each independently a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0₂-, -Ο-, -S-, -S(O)-, -SO2-, -NHCO2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene. L³ is a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, - NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or

unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or -L^3a-L^3b-. If present, L^3a is substituted or unsubstituted heterocycloalkylene, and L^3b is -C(O)-, -S(0)₂-, or -C(0)0-. R¹ and R² are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. R³ is hydrogen, -NH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. R⁴, if present, is alkyl, preferably C1-C6 alkyl, more preferably methyl, or ethyl. Contemplated compounds of Formula (I) inhibit both thrombin and fXa.

[0059] In one aspect, there are provided compounds of Formula (I) having the structure of Formula (II) following:

[0060] For Formula (II), linker groups L¹ and L² are each independently a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or unsubstituted alkylene, substituted or unsubstituted

heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene. L³ is a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-,

-NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or -L^3a-L^3b-. If present, L^3a is substituted or unsubstituted heterocycloalkylene, and L^3b is -C(O)-, -S(0)₂-, or -C(0)0-. R¹ and R² are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. R³ is hydrogen, -NH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. R⁴, if present, is alkyl, preferably C -Ce alkyl, more preferably methyl, or ethyl. Contemplated compounds of Formula (II) inhibit both thrombin and fXa.

[0061] In one embodiment, the compound has IC5₀ > 1.0 μΜ for thrombin inhibition. In one embodiment, the compound has IC5₀ > 1.0 μΜ for fXa inhibition. In one embodiment, the compound has IC5₀ > 0.1 μΜ and < 1.0 μΜ for thrombin inhibition. In one embodiment, the compound has IC50 > 0.1 μΜ and < 1.0 μΜ for fXa inhibition. In one embodiment, the compound has IC5₀ < 0.1 μΜ for thrombin inhibition. In one embodiment, the compound has IC5₀ < 0.1 μΜ for fXa inhibition. The term "IC5₀" refers in the customary sense to half maximal inhibitory concentration. Methods for determining IC5₀ are well known in the art. [0062] In one embodiment, L¹ is a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, - NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or

unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene. In one embodiment, L¹ is a bond, -NH-, or substituted or unsubstituted heteroalkylene.

[0063] In one embodiment, the compound of Formula (II) has the structure of Formula (Ha) following, wherein L¹ is -NH-(CH₂)_n-, n is 0 to 6, preferably 1-2, more preferably 1 , and R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.

[0064] In one embodiment of the compound of Formula (Ha), L¹ is -NHCH₂- or -NH(CH₂)₂-, and R¹ is substituted or unsubstituted aryl. In one embodiment, R¹ is unsubstituted aryl, preferably phenyl. In one embodiment, R¹ is aryl, preferably phenyl, substituted with halogen. In one embodiment, R¹ is unsubstituted alkyl, preferably lower alkyl, more preferably methyl or ethyl. In one embodiments, n is 0, and R¹ is hydrogen. In one embodiment, R¹ is substituted or unsubstituted heteroaryl. In one embodiment, R¹ is unsubstituted heteroaryl, preferably thiophenyl. In one embodiment, R¹ is substituted heteroaryl, preferably thiophenyl substituted with halogen.

[0065] In one embodiment, the compound of Formula (II) has the structure of Formula (lib) following, wherein L¹ is -S-(CH₂)_n-, n is 0 to 6, preferably 1-2, more preferably 1, and R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocycloalkyl.

[0066] In one embodiment, n is 0, and R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. In one embodiment, R¹ is unsubstituted alkyl, preferably methyl.

[0067] In one embodiment, n is 1, and R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl. In one embodiment, R¹ is substituted or unsubstituted aryl, preferably phenyl. In one embodiment, R¹ is halogen substituted phenyl.

[0068] Further to any embodiment disclosed herein, in one embodiment, L² is a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -SO2-, -NHCO2-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene. [0069] In one embodiment, L² is -C(O)-, and the compound of Formula (II) has the structure of Formula (lie) following:

[0070] In one embodiment of the compound of Formula (lie), R² is substituted or unsubstituted aryl. In one embodiment, R² is unsubstituted aryl, preferably phenyl. In one embodiment, R² is substituted aryl, preferably substituted phenyl. In one embodiment, R² is aryl substituted with alkyl (preferably methyl), alkyloxy (preferably methoxy at 1 or 2 substitutions), halogen, or heteroalkyl. In one embodiment, R² is aryl substituted at two positions with alkyl (preferably methyl), alkyloxy (preferably methoxy at 1 or 2 substitutions), or halogen. In one embodiment, R² is 2,3-dihydrobenzo[b][l,4]dioxine. In one embodiment, R² is substituted or unsubstituted alkyl. In one embodiment, R² is unsubstituted alkyl, preferably methyl, ethyl, propyl, or tert- butyl. In one embodiment, R² is substituted alkyl, preferably phenylmethyl. In one embodiment, R² is substituted or unsubstituted heteroaryl. In one embodiment, R² is unsubstituted heteroaryl, preferably furanyl, thiophenyl, or pyridinyl. In one embodiment, R² is substituted heteroaryl, preferably substituted furan or substituted thiophene. In one embodiment, R² is furan substituted with halogen. In one embodiment, R² is thiophene substituted with halogen.

[0071] In one embodiment, L² is a bond, and R² is hydrogen.

[0072] Further to any embodiment disclosed herein, in one embodiment of the compound of Formula (II), L³ is a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or -L^3a-L^3b-.

[0073] In one embodiment, L³ is a bond, and R³ is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl. [0074] In one embodiment, R³ is substituted or unsubstituted alkyl. In one embodiment, R³ is unsubstituted alkyl, preferably C₁-C₄ alkyl.

[0075] In one embodiment, R³ is substituted or unsubstituted cycloalkyl. In one embodiment, R³ is unsubstituted cycloalkyl, preferably cyclopentyl or cyclohexyl. [0076] In one embodiment, R³ is substituted or unsubstituted aryl. In one embodiment, R³ is unsubstituted aryl, preferably phenyl. In one embodiment, R³ is aryl, preferably phenyl, substituted with alkyl or halogen.

[0077] In one embodiment, R³ is substituted or unsubstituted heterocycloalkyl. In one embodiment, R³ is unsubstituted heterocycloalkyl, preferably tetrahydrofuran or tetrahydrogen- 2H-pyran. In one embodiment, R³ is substituted heterocycloalkyl, preferably tetrahydrofuran or tetrahydrogen-2H-pyran substituted with alkyl or halogen.

[0078] In one embodiment, R³ is substituted or unsubstituted heterocycloaryl. In one embodiment, R³ is unsubstituted heterocycloaryl, preferably furanyl, thiophenyl, pyridinyl, or pyrimidinyl, or pyridazinyl. In one embodiment, R³ is furanyl, thiophenyl, pyridinyl, pyrimidinyl, or pyridazinyl.

[0079] In one embodiment, L³ is -L^3a-L^3b-, and the compound of Formula (II) has the structure of Formula (lid):

L² M )-^3b R³

^L (lid).

[0080] For the compound with structure of Formula (lid), in one embodiment L^3a is unsubstituted heterocycloalkylene, and L^3b is -C(O)-, -S(0)₂-, or -C(0)0-. In one embodiment, L^3a is azetidine-diyl; see e.g, Cmpd 20 and the like. In one embodiment, L^3a is piperidine-diyl; see e.g, Cmpd 24 and the like.

[0081] Further to any embodiment wherein L³ is -L^3a-L^3b-, in one embodiment L^3b is -C(O)-, -S(0)₂-, or -C(0)0-. In one embodiment, L^3b is -C(O)-. In one embodiment, L^3b is -S(0)₂-. In one embodiment, L^3b is -C(0)0-.

[0082] Further to any embodiment wherein L³ is -L^3a-L^3b-, in one embodiment R³ is hydrogen, -NH₂, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl.

[0083] In one embodiment, R³ is substituted or unsubstituted alkyl. In one embodiment, R³ is unsubstituted alkyl, preferably C₁-C4 alkyl. In one embodiment, R³ is methyl. In one embodiment, R³ is substituted or unsubstituted aryl. In one embodiment, R³ is unsubstituted aryl, preferably phenyl. In one embodiment, R³ is substituted or unsubstituted heteroalkyl. In one embodiment, R³ is unsubstituted heteroalkyl, preferably -N(CH₃)₂. In one embodiment, R³ is -NH₂.

[0084] In one embodiment, R³ is substituted or unsubstituted cycloalkyl. In one embodiment, R³ is unsubstituted cycloalkyl, preferably cyclopentyl or cyclohexyl.

[0085] In one embodiment, L¹ is -NH-(CH₂)_n-, n is 0 to 6, preferably 1-2, L² is -C(O)-, and the compound has the structure of Formula (He) following.

[0086] In another aspect, there is provided a compound with structure of any one of Formulae (II), (Ila), (lib), (lie) or (lid), wherein R¹, R², R³, R⁴, L¹, L², L³, L^3a and L^3b are as disclosed above, wherein the compound is an inhibitor of thrombin, and wherein the compound is an inhibitor of fXa.

[0087] More particularly, the present disclosure relates to compounds of compounds (Cmpds) 1-93, and the pharmaceutically acceptable salts, solvates, acids or esters thereof. Cmpds 1-93 are listed in Table A and Table B following, with corresponding calculated and observed (mass spectrometric) molecular weights (MW, Dalton) and inhibition activity levels against thrombin and fXa. Legend: For Table A and Table B inhibition activity ("ACTIVITY") levels: a: IC₅₀ <= 0.1 μΜ; b: 0.1 μΜ <IC₅₀ < 1 μΜ; c: IC₅₀ >= 1 μΜ; THR: thrombin; FXA: coagulation factor Xa.

[0088] In one embodiment, the compound is selected from Table A; i.e., any one of Cmpds 1, 3-18, 20-27, 29, or 31-80. In one embodiment, the compound is selected from Table B, i.e., any one of Cmpds 3, 19, 28, 30, and 81-93. Table A:

MOLECULAR

ACTIVITY

CMPD WEIGHTS

IUPAC NAME NO.

CALC MEAS THR FXA

N-[(4-fluorophenyl)methyl]-3-(furan-2-yl)-

1 1 - [(2-methoxyphenyl)carbonyl]- 1 H- 1 ,2,4- 392 393 a c triazol-5 -amine

3 1 -benzoyl-N-benzyl-3 -(pyridin-2-yl)- 1 H- 355 356 a c 1 ,2,4-triazol-5-amine

4 1 - [5 -(benzylamino)-3 -(pyridin-2-yl)- 1 H- 369 370 a c 1 ,2,4-triazol- 1 -yl]-2-phenylethan- 1 -one

5 N-benzyl-l-[(2-chlorophenyl)carbonyl]-3- 390 390 a c (pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

6 N-benzyl- 1 -[(4-chlorophenyl)carbonyl] -3 - 390 390 a c (pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

1 -(5- {[(4-fluorophenyl)methyl] amino} -3-

7 (pyridin-2-yl)- 1 H- 1 ,2,4-triazol- 1 -yl)-2- 387 388 a c phenylethan- 1 -one

N-[(4-fluorophenyl)methyl] - 1 - [(2-

8 methoxyphenyl)carbonyl]-3-(pyridin-2-yl)- 403 404 a c 1 H- 1 ,2,4-triazol-5 -amine

9 1 -benzoyl-N-benzyl-3 -(pyridin-4-yl)- 1 H- 355 356 a c 1 ,2,4-triazol-5-amine

10 N-benzyl-l-[(2-chlorophenyl)carbonyl]-3- 390 390 a c (pyridin-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

11 N-benzyl- l-[(2-methoxyphenyl)carbonyl]- 385 386 a c 3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine

N-[(4-fluorophenyl)methyl] - 1 - [(2-

12 methoxyphenyl)carbonyl]-3-(pyridin-4-yl)- 403 404 a c 1 H- 1 ,2,4-triazol-5 -amine

13 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]- 386 387 a c 3-(pyrimidin-4-yl)- IH- 1 ,2,4-triazol-5 -amine

14 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]- 386 387 a c 3-(pyrimidin-5-yl)- IH- 1 ,2,4-triazol-5 -amine

15 N-benzyl- l-[(2-methoxyphenyl)carbonyl]- 386 387 a c 3-(pyrimidin-2-yl)- IH- 1 ,2,4-triazol-5 -amine 1 -(5 - { [(5-chlorothiophen-2- yl)methyl] amino } -3 -(oxan-4-yl)- 1 H- 1 ,2,4- 383 383 a c triazol- 1 -yl)-2,2-dimethylpropan- 1 -one

1 -(5 - { [(5-chlorothiophen-2- yl)methyl] amino } -3 -(oxolan-2-yl)- 1 H- 369 369 a c 1 ,2,4-triazol- 1 -yl)-2,2-dimethylpropan- 1 - one

1 -(5 - { [(5-chlorothiophen-2- yl)methyl] amino } -3 -(oxolan-3 -yl)- 1 H- 369 369 a c 1 ,2,4-triazol- 1 -yl)-2,2-dimethylpropan- 1 - one

1 - [3 -(5 - { [(5-chlorothiophen-2- yl)methy 1] amino } - 1 - [(2 - methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 488 488 a a 3-yl)azetidin-l-yl]-2,2-dimethylpropan-l- one

1 - [3 -(5 - { [(5-chlorothiophen-2- yl)methy 1] amino } - 1 - [(2 - 446 446 a b methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 3 -yl)azetidin- 1 -yljethan- 1 -one

1 - [3 -(5 - { [(5-chlorothiophen-2- yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 - 354 354 c c yl)azetidin- 1 -yl]-2,2-dimethylpropan- 1 -one

1 - [3 -(5 - { [(5-chlorothiophen-2- yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 - 312 312 c c yl)azetidin- 1 -yljethan- 1 -one

l-[4-(5- {[(5-chlorothiophen-2- yl)methy 1] amino } - 1 - [(2 - methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 516 516 a b 3 -y l)piperidin- 1 -y 1] -2 ,2 -dimethy lpropan- 1 - one

l-[4-(5- {[(5-chlorothiophen-2- yl)methy 1] amino } - 1 - [(2 - 474 474 a c methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 3 -yl)piperidin- 1 -yl] ethan- 1 -one

l-[4-(5- {[(5-chlorothiophen-2- yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 - 382 382 c c yl)piperidin- 1 -yl]-2,2-dimethylpropan- 1 - one l-[4-(5-{[(5-chlorothiophen-2- yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 - 340 340 c c yl)piperidin- 1 -yl] ethan- 1 -one

3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine 168 169 c c

3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5 -amine 154 155 c c

3 - [ 1 -(benzenesulfony l)azetidin-3 -y 1] -N- [(5 - chlorothiophen-2 -y l)methy 1] - 1 - [(2 - 544 544 a b methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 5-amine

3 - [ 1 -(benzenesulfony l)piperidin-4-yl]-N- [(5-chlorothiophen-2-yl)methyl]-l-[(2- 572 572 a b methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 5-amine

4-(5- {[(5-chlorothiophen-2- yl)methy 1] amino } - 1 - [(2 - methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 503 503 a b

3-yl)-N,N-dimethylpiperidine-l- carboxamide

4-(5- {[(5-chlorothiophen-2- yl)methy 1] amino } - 1 - [(2 - 475 475 a c methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 3 -yl)piperidine- 1 -carboxamide

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,3- dihydro-l,4-benzodioxin-5-yl)carbonyl]-3- 461 461 a c (oxan-4-yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,3- dihydro-l,4-benzodioxin-5-yl)carbonyl]-3- 447 447 a b (oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,3- dihydro-l,4-benzodioxin-5-yl)carbonyl]-3- 447 447 a c (oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4- dimethoxyphenyl)carbonyl]-3-(oxan-4-yl)- 463 463 a c 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4- dimethoxyphenyl)carbonyl]-3-(oxolan-2- 449 449 a c yl)-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4- dimethoxypheny l)carbonyl] -3 -(oxolan-3 - 449 449 a c yl)-lH-l,2,4-triazol-5-amine N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-3-(oxan-4-yl)- 433 433 a c 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-3-(oxolan-2-yl)- 419 419 a b 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-3-(oxolan-3-yl)- 419 419 a b 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-3 -[ 1 -(propane-2- 510 510 a b sulfonyl)azetidin-3 -yl] - 1 H- 1 ,2,4-triazol-5- amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-3 -[ 1 -(propane-2- 538 538 a c sulfonyl)piperidin-4-yl]-lH-l,2,4-triazol-5- amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-3 -phenyl- 1 H- 425 425 a c l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-3 - { 1 - [(piperidin- 543 543 a b 1 -yl)carbonyl]piperidin-4-yl} - 1 H- 1 ,2,4- triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-3 - { 1- 529 529 a b [(pyrrolidin-l-yl)carbonyl]piperidin-4-yl}- 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methylphenyl)carbonyl]-3 -(oxan-4-yl)- 1 H- 417 417 a c l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methylphenyl)carbonyl]-3-(pyridin-2-yl)- 410 410 a c 1 H- 1 ,2,4-triazol-5 -amine

N- [(5 -chlorothiophen-2 -y l)methy 1] - 1 - [(furan-3 -yl)carbonyl]-3 -(oxan-4-yl)- 1 H- 393 393 a c l,2,4-triazol-5-amine

N- [(5 -chlorothiophen-2 -y l)methy 1] - 1 -

[(furan-3-yl)carbonyl]-3-(oxolan-2-yl)-lH- 379 379 a b l,2,4-triazol-5-amine N- [(5 -chlorothiophen-2 -y l)methy 1] - 1 - [(furan-3 -yl)carbonyl]-3 -(oxolan-3 -yl)- 1 H- 379 379 a b l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(l- methanesulfonylazetidin-3-yl)- 1 -[(2- 482 482 a b methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(l- methanesulfonylpiperidin-4-yl)-l-[(2- 510 510 a c methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 5-amine

N- [(5 -chlorothiophen-2 -y l)methy 1] -3 -(oxan- 4-yl)- 1 - [(thiophen-3 -yl)carbonyl]- 1 H- 1 ,2,4- 409 409 a b triazol-5 -amine

N- [(5 -chlorothiophen-2 -y l)methy 1] -3 -(oxan- 299 299 c c 4-yl)- 1 H- 1 ,2,4-triazol-5 -amine

N- [(5 -chlorothiophen-2 -y l)methy 1] -3 - (oxolan-2-yl)- 1 -[(thiophen-3-yl)carbonyl]- 395 395 a b 1 H- 1 ,2,4-triazol-5 -amine

N- [(5 -chlorothiophen-2 -y l)methy 1] -3 - 285 285 c c (oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

N- [(5 -chlorothiophen-2 -y l)methy 1] -3 - (oxolan-3 -yl)- 1 -[(thiophen-3-yl)carbonyl]- 395 395 a b 1 H- 1 ,2,4-triazol-5 -amine

N- [(5 -chlorothiophen-2 -y l)methy 1] -3 - 285 285 c c (oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-[l- (cyclohexanesulfony l)azetidin-3 -y 1] - 1 - [(2 - 550 550 a a methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-[l- (cyclohexanesulfonyl)piperidin-4-yl]-l-[(2- 578 578 a c methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 5-amine

N- [(5 -chlorothiophen-2 -y l)methy 1] -3 - cyclopentyl-l-[(2- 417 417 a c methoxyphenyl)carbonyl]- 1 H- 1 ,2,4-triazol- 5-amine N-benzyl-l-[(2,3- dimethoxyphenyl)carbonyl] -3 -(pyridin-2- 415 416 a c yl)-lH-l,2,4-triazol-5-amine

N-benzyl- l-[(2-fluoro-4- methylphenyl)carbonyl]-3-(pyridin-2-yl)- 387 388 a c 1 H- 1 ,2,4-triazol-5 -amine

N-benzyl- l-[(2-fluorophenyl)carbonyl]-3- 373 374 a c (pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

N-benzyl- l-[(2-methoxyphenyl)carbonyl]- 392 393 c c 3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-benzyl- l-[(2-methoxyphenyl)carbonyl]- 386 387 a c 3-(pyridazin-3-yl)-lH-l,2,4-triazol-5-amine

N-benzyl- l-[(2-methoxyphenyl)carbonyl]- 385 386 a c 3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-benzyl-l-[(3-methoxyphenyl)carbonyl]- 385 386 a c 3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-benzyl-3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5- 258 259 c c amine

tert-butyl 3 -(5 -amino- 1 H- 1 ,2,4-triazol-3 - 239 240 c c yl)azetidine- 1 -carboxylate

tert-butyl 3 -(5 - { [(5 -chlorothiophen-2- yl)methy 1] amino } - 1 - [(2 - 504 504 a b methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 3 -y l)azetidine- 1 -carboxylate

tert-butyl 3 -(5 - { [(5 -chlorothiophen-2- yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 - 370 370 c c yl)azetidine- 1 -carboxylate

tert-butyl 4-(5 -amino- 1 H- 1 ,2,4-triazol-3 - 267 268 c c yl)piperidine- 1 -carboxylate

tert-butyl 4-(5- { [(5-chlorothiophen-2- yl)methy 1] amino } - 1 - [(2 - 532 532 a b methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 3 -yl)piperidine-l -carboxylate

tert-butyl 4-(5- { [(5-chlorothiophen-2- yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 - 398 398 c c yl)piperidine- 1 -carboxylate tert-butyl 4-[5-(benzylamino)-l-[(2-

80 methoxyphenyl)carbonyl]-lH-l,2,4-triazol- 492 492 a c 3-yl]piperidine-l-carboxylate

Table B.

1 - [(4-chlorophenyl)carbonyl]-N- [(4-

87 fluorophenyl)methyl] -3 -(pyridin-3 -yl)- 1 H- 408 408 a c l,2,4-triazol-5-amine

1 - [3 -(pyridin-3 -yl)-5- [(thiophen-2-

88 ylmethyl)amino]- 1 H- 1 ,2,4-triazol- 1 - 299 a c yl]ethan-l-one

1 - [5 -(benzylamino)-3 -(furan-2-yl)- 1 H-

89 358 359 a c 1 ,2,4-triazol- 1 -yl]-2-phenylethan- 1 -one

1 - [5 -(benzylamino)-3 -(pyridin-3 -yl)- 1 H-

90 307 308 a c 1 ,2,4-triazol- 1 -yl]propan- 1 -one

3-(furan-2-yl)-l-[(2-

91 methoxyphenyl)carbonyl]-5- 315 a c (methylsulfanyl)- 1H- 1 ,2,4-triazole

3-(furan-2-yl)-l-[(pyridin-3-yl)carbonyl]-N-

92 (thiophen-2-ylmethyl)-lH-l,2,4-triazol-5- 351 a c amine

N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-

93 385 386 a c 3 -(pyridin-3 -yl)-lH-l,2,4-triazol-5 -amine

[0089] The compounds of the present invention may have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof. [0090] Pharmaceutically acceptable salts of the compounds above, where a basic or acidic group is present in the structure, are also included within the scope of this invention. When an acidic substituent is present, such as-NHSOsH, COOH and P(0)(OH)₂, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form. Basic groups, such as amino or basic heteroaryl radicals, or pyridyl and acidic salts, such as hydrochloride, hydrobromide, acetate, maleate, palmoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.

[0091] Also, in the case of the R-COOH being present, pharmaceutically acceptable esters can be employed, e.g., methyl, ethyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations .

[0092] The term "prodrug" is used according to its plain ordinary meaning and is intended to mean compounds that require a chemical or enzymatic transformation in order to release the active parent drug in vivo prior to producing a pharmacological effect. [0093] In addition, some of the compounds of the instant invention may be metabolized. Such metabolites are also encompassed within the scope of the invention.

[0094] In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.

[0095] A given compound can be used in a variety of forms, including a pharmaceutically acceptable prodrug, metabolite, analogue, derivative, solvate or salt.

III. Biological assay

[0096] Compounds disclosed herein were assayed for inhibition of the protease activity of thrombin and fXa. The protease activities of these proteins were monitored using -nitroanilide peptide substrates which upon hydrolysis release -nitroanilide, which gives rise to color. See e.g., Lottenberg, R, Et al, 1983, Biochemica et Biophysica Acta 752:539-557). The change in color was monitored with a spectrophotometer, e.g., at 405 nm, and is directly proportional to the proteolytic activity of the enzymes. [0097] In some embodiments, compounds described herein exhibit inhibitory activity against thrombin and fXa with activities > 1 μΜ, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 μΜ, or even greater. In some embodiments, the compounds exhibit inhibitory activity against thrombin and fXa with activities between 0.1 μΜ and 1 μΜ, e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 μΜ. In some embodiments, compounds described herein exhibit inhibitory activity against thrombin and fXa with activities < 0.1 μΜ, e.g., about 1, 2, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100 nM. Ranges of values using a combination of any of the values recited herein as upper and/or lower limits are also contemplated, for example, but not limited to, 1-10 nM, 10-100 nM, 0.1-1 μΜ, 1-10 μΜ, 10-100 μΜ, 100-200 μΜ, 200-500 μΜ, or even 500-1000 μΜ. In some embodiments, the inhibitory activity is in the range of about 1-10 nM, 10-100 nM, 0.1-1 μΜ, 1-10 μΜ, 10-100 μΜ, 100-200 μΜ, 200-500 μΜ, or even 500-1000 μΜ. It is understood that for purposes of quantification, the terms "activity,"

"inhibitory activity," "biological activity," "thrombin activity," "fXa activity" and the like in the context of an inhibitory compound disclosed herein can be quantified in a variety of ways known in the art. Unless indicated otherwise, as used herein such terms refer to IC5₀. Inhibition of thrombin and fXa inhibits the blood coagulation process. Accordingly, the compounds disclosed herein are indicated in the treatment or management of thrombotic disorders or other disorders involving the blood coagulation process.

[0098] Accordingly, in another aspect there is provided a method for inhibiting thrombin and coagulation factor Xa (fXa). The method includes contacting thrombin or fXa with a compound as set forth herein, thereby inhibiting thrombin or fXa.

[0099] In one embodiment, the compound is as set forth in Table A or Table B. In one embodiment, the compound is selected from any one of Cmpds 1, 3-18, 20-27, 29, or 31-80.

IV. Methods of Treating and Preventing Disease

[0100] Clinical indications (e.g., diseases and disorders) contemplated herein include the following.

[0101] Thrombosis. Thrombotic diseases are the primary indications for thrombin and fXa inhibition, because of their location in the coagulation cascade and, in turn, the importance of the coagulation cascade in the progression of blood clotting processes. However, without wishing to be bound by any theory, it is believed the coagulation cascade in general, and thrombin and fXa in particular, are important in a variety other disease states.

[0102] It has been discovered that compounds described herein, e.g., multisubstituted aromatic compounds, exhibit inhibitory action against thrombin and fXa. This, in turn inhibits the blood coagulation process.

[0103] This inhibitory action is useful in the treatment of a variety of thrombotic disorders, such as, but not limited to, acute vascular diseases such as acute coronary syndromes; venous-, arterial- and cardiogenic thromboembolisms; the prevention of other states such as disseminated intravascular coagulation, or other conditions that involve the presence or the potential formation of a blood clot thrombus. Other indications for methods described herein include the following.

[0104] Cancer. It has long been recognized that cancer progression is accompanied by venous thrombosis, but it has not been understood how each disease is related. From several clinical trials studying the treatment of VTE, metaanalyses have shown that low molecular weight heparins (LMWHs) improve overall survival in subgroups of cancer patients. See e.g.,

Zacharski, L. R. & Lee, A. Y., 2008, Expert Opin Inves tig Drugs, 17: 1029-1037; Falanga, A. & Piccioli, A., 2005, Current Opinion in Pulmonary Medicine, 11:403-407; Smorenburg, S. M., et al, 1999, Thromb Haemost, 82: 1600-1604; Hettiarachchi, R. J., et al, 1999, Thromb Haemost, 82:947-952. This finding was substantiated in later clinical trials that measured specifically the survival of cancer patients. See e.g., Lee, A. Y.et al, 2005, J Clin Oncol, 23:2123-2129; Klerk, C. P.et al, 2005, J Clin Oncol., 23:2130-2135; Kakkar, A. K., et al, 2004, J Clin Oncol,

22: 1944-1948; Altinbas, M., et al, 2004, J Thromb Haemost, 2: 1266-1271. [0105] More recently, researchers have focused on the specific anticancer effect of DTIs. For example, it was shown that heparin significantly prolonged the survival of patients with limited small cell lung cancer. See e.g., Akl, E. A., et al, 2008, J Exp Clin Cancer Res, 27:4. Other investigators found that systemic use of argatroban reduced tumor mass and prolonged survival time in rat glioma models leading to the conclusion that argatroban should be considered as a novel therapeutic for glioma, a notoriously difficult to treat cancer type. See e.g., Hua, Y., et al, 2005, Acta Neurochir, SuppL, 95:403-406; Hua, Y., et al, 2005, J Thromb Haemost, 3: 1917- 1923. Very recently, it was demonstrated that dabigatran etexilate, a DTI recently FDA- approved (see e.g., Hughes, B., 2010, Nat Rev Drug Discov, 9:903-906) for DVT indications, inhibited both the invasion and metastasis of malignant breast tumors. See e.g., DeFeo, K.et al, 2010, Thrombosis Research, 125 (Supplement 2): S188-S188; Defeo, K., et al, 2010, Cancer Biol Ther, 10: 1001-1008. Thus, dabigatran etexilate treatment led to a 50% reduction in tumor volume at 4 weeks with no weight loss in treated mice. Dabigatran etexilate also reduced tumor cells in the blood and liver micrometastases by 50-60%. These investigators concluded that dabigatran etexilate may be beneficial in not only preventing thrombotic events in cancer patients, but also as adjunct therapy to treat malignant tumors.

[0106] Further, hirudin and the LMWH nadroparin dramatically reduced the number of lung metastases when administered prior to cancer cell inoculation. See e.g., Hu, L., et al, 2004, Blood, 104:2746-51.

[0107] The de novo thrombin inhibitor d-Arg-Oic-Pro-d-Ala-Phe(p-Me) has been found to block thrombin-stimulated invasion of prostate cancer cell line PC-3 in a concentration dependent manner. See e.g., Nieman, M. T., et al, 2008, J Thromb Haemost, 6:837-845. A reduced rate of tumor growth was observed in mice dosed with the pentapeptide through their drinking water. The mice also showed reduced fold rate in tumor size and reduced overall tumor weight compared to untreated mice. Microscopic examination of treated tumors showed reduced number of large blood vessels thus concluding that the pentapeptide interfered with tumor angiogenesis. Nieman, M. T., et al, 2010, Thromb Haemost, 104: 1044-8. [0108] In view of these and related studies, it is suggested that anticoagulants affect tumor metastasis; that is, angiogenesis, cancer cell adhesion, migration and invasion processes. See e.g., Van Noorden, C. J., et al, 2010, Thromb Res, 125 Suppl 2:S77-79.

[0109] Fibrosis. Several studies have shown the utility of anticoagulant therapy in fibrotic disorders. For example, in a rat model of CCl₄-induced chronic liver injury, the DTI SSR182289 decreased liver fibrogenesis significantly after 7 weeks of administration. Similar observations were made in other studies using the LMWHs nadroparin, tinzaparin, enoxaparin, and dalteparin sodium. See e.g., Duplantier, J. G., et al, 2004, Gut, 53: 1682-1687; Abdel-Salam, O. M., et al, 2005, Pharmacol Res, 51:59-67; Assy, N., et al, 2007, Dig Dis Sci, 52: 1187-1193; Abe, W., et al, 2007, J Hepatol, 46:286-294.

[0110] In another example, the DTI melagatran greatly reduced ischemia reperfusion injury in a kidney transplant model in the large white pig. This led to a drastically improved kidney graft survival at 3 months. See e.g., Favreau, F., et al, 2010, Am J Transplant, 10:30-39.

[0111] Recent studies have shown that in a bleomycin-induced mouse model of pulmonary fibrosis, dabigatran etexilate treatment reduced important profibrotic events in lung fibroblasts, including the production of collagen and connective tissue growth factor. See e.g., Silver, R. M., et al., 2010, Am. J. Respir. Crit. Care Med, 181:A6780; Bogatkevich, G. S., et al, 2009, Arthritis Rheum, 60:3455-3464.

[0112] The above experimental evidence points to a close relationship between thrombin and fibrosis and suggests novel therapeutic opportunities for fibrosis using thrombin inhibitors. See e.g., Calvaruso, V., et al, 2008, Gut, 57: 1722-1727; Chambers, R. C, 2008, Br J Pharmacol, 153 Suppl l:S367-378; Chambers, R. C. & Laurent, G. J., 2002, Biochem Soc Trans, 30: 194- 200; Howell, D. C, et al, 2001, Am J Pathol, 159: 1383-1395.

[0113] Alzheimer's Disease. Very recent experiments confirm higher thrombin levels in brain endothelial cells of patients with Alzheimer's disease. While 'normal' thrombin levels are connected to regulatory CNS functions, thrombin accumulation in the brain is toxic. It has also been found that the neural thrombin inhibitor Protease Nexin 1 (PN-1) is significantly reduced in the Alzheimer's disease brain, despite the fact that PN-1 mRNA levels are unchanged. These observations have led some investigators to suggest that reduction of CNS-resident thrombin will prove useful in Alzheimer's Disease (AD) treatment. See e.g., Vaughan, P. J., et al., 1994, Brain Res, 668:160-170; Yin, X., et al, 2010, Am J Pathol, 176: 1600-1606; Akiyama, FL, et al., 1992, Neurosci Lett, 146: 152-154. [0114] Multiple Sclerosis. Investigators have found that hirudin treatment in an animal model of Multiple Sclerosis (MS) shows a dramatic improvement in disease severity. See e.g., Han, M. H., et al, 2008, Nature, 451: 1076-1081. Similar results were obtained following treatment with heparin (a DTI) and dermatan sulfate, another coagulation inhibitor. See e.g., Chelmicka-Szorc, E. & Arnason, B. G., 1972, Arch Neurol, 27: 153-158; Inaba, Y., et al, 1999, Cell Immunol, 198:96-102. Other evidence shows that naturally occurring antithrombin III has antiinflammatory effects in diseases such as endotoxemia and other sepsis-related conditions. See e.g., Wiedemann, C. J. & Romisch, J., 2002, Acta Med Austriaca, 29:89-92. Naturally occurring thrombin inhibitors are presumably synthesized in situ and have protective roles in CNS inflammation. Therefore, therapeutic thrombin inhibition has been proposed as a potential MS treatment. See e.g., Luo, W., et al, 2009, In: THROMBIN, Maragoudakis, M. E.;

Tsopanoglou, N. E., Eds. Springer New York: 2009; pp 133-159.

[0115] Pain. In a rat pain model with partial lesion of the sciatic nerve, intrathecal hirudin prevented the development of neuropathic pain and curbed pain responses for 7 days. The investigators found that following injury, neuropathic pain was mediated by thrombin generation, which in turn activated PAR- 1 receptor in the spinal cord. Hirudin inhibited thrombin generation and ultimately led to pain relief. See e.g., Garcia, P. S., et al, 2010, Thromb Haemost, 103: 1 145-1151 ; Narita, M., et al, 2005, JNeurosci, 25: 10000-10009. Researchers hypothesize that thrombin and the PARs are involved not just as part of the coagulation cascade, but in inflammation, nociception and neurodevelopment. Development of a DTI to intersect an unexploited pharmacology will lead to pain therapeutics distinct from opioids and NSAIDs, whose shortcomings are well documented. See e.g., Garcia 2010, Id.

[0116] Accordingly, in another aspect, there is provided a method for treating a thrombotic disorder in a subject in need. The method includes administering to a subject in need an effective amount of a compound of Formula (II), thereby treating the thrombotic disorder. In one embodiment, the compound is any one of Cmpds 1-93.

[0117] The present disclosure contemplates methods for ameliorating wound healing and for mediating tissue repair (including but not limited to treatment of peripheral and coronary vascular disease). According to these methods, a subject having a wound or in need of tissue repair, is treated at the site of the wound or damaged tissue or treated systemically, with a compound of the present invention in the form of a free compound or a pharmaceutically- acceptable prodrug, metabolite, analogue, derivative, solvate or salt. [0118] Accordingly, in another aspect, there is provided a method for ameliorating wound healing in a subject in need. The method includes administering to a subject in need thereof a compound of Formula (II) as described herein, thereby ameliorating wound healing. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.

[0119] In another aspect, there is provided a method for mediating tissue repair in a subject in need. The method includes administering to a subject in need thereof a compound of Formula (II) as described herein, thereby mediating tissue repair. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.

[0120] In one another aspect, there is provided a method for treating a disease or disorder in a subject. The method includes administering a compound according to Formula (II) to a subject in need thereof in an amount effective to treat the disease or disorder. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.

[0121] In one embodiment, the disease or disorder is a thrombotic disorder. In one embodiment, the thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism.

[0122] In one embodiment, the disease or disorder is fibrosis. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.

[0123] In one embodiment, the disease or disorder is Alzheimer's Disease. In one

embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93. [0124] In one embodiment, the disease or disorder is multiple sclerosis. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.

[0125] In one embodiment, the disease or disorder is pain. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93. [0126] In one embodiment, the disease or disorder is cancer. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93.

[0127] In another aspect, there is provided a method for preventing a disease or disorder in a subject. The method includes administering a compound according to Formula (II) to a subject in need thereof in an amount effective to prevent the disease or disorder. In one embodiment, the disease or disorder is a thrombotic disorder. In one embodiment, the thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism. In one embodiment, the thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism. In one embodiment, the thrombotic disorder is disseminated intravascular coagulation. In one embodiment, the thrombotic disorder involves the presence or the potential formation of a blood clot thrombus. In one embodiment, the compound is selected from any one of the compounds set forth in Table A or Table B. In one embodiment, the compound is any one of Cmpds 1-93. V. Preparation and formulations

[0128] In one aspect there is provided a pharmaceutical composition including a compound according to Formula (II) and a pharmaceutically acceptable excipient.

[0129] Thus, the present disclosure has the objective of providing suitable topical, oral, and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compounds disclosed herein may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use may contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. [0130] The tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. The terms

"pharmaceutically acceptable" and the like refer in the customary sense to salts, esters, solvates, prodrugs, carriers, excipients, compounds and the like which are acceptable for administration to a subject, e.g., a human subject, as judged by a medical or veterinary practitioner. These excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coating may also be performed using techniques described in the U. S. Pat. Nos. 4,256, 108; 4,160, 452; and 4,265, 874 to form osmotic therapeutic tablets for control release.

[0131] A compound of the present invention, in the form of a free compound or a

pharmaceutically-acceptable prodrug, metabolite, analogue, derivative, solvate or salt, can be administered, for in vivo application, parenterally by injection or by gradual perfusion over time. Administration may be intravenously, intraperitoneally, intramuscularly, subcutaneously, intracavity, or transdermally. For in vitro studies the compounds may be added or dissolved in an appropriate biologically acceptable buffer and added to a cell or tissue.

[0132] Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, growth factors and inert gases and the like.

[0133] Generally, the terms "treating", "treatment" and the like are used herein to mean affecting a subject, tissue or cell to obtain a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or disorder or sign or symptom thereof, and/or may be therapeutic in terms of a partial or complete cure for a disorder and/or adverse effect attributable to it. "Treating" as used herein covers any treatment of, or prevention of a disease or disorder in a vertebrate, a mammal, particularly a human, and includes: (a) preventing the disease or disorder from occurring in a subject that may be predisposed to the disease or disorder, but has not yet been diagnosed as having it; (b) inhibiting the disease or disorder, i.e., arresting its development; or (c) relieving or ameliorating the disease or disorder, i.e., cause regression of the disease or disorder.

[0134] The invention includes various pharmaceutical compositions useful for ameliorating diseases and disorders, including thrombosis and the like. The pharmaceutical compositions according to one embodiment of the invention are prepared by formulating a compound of the present invention, in the form of a free compound or a pharmaceutically-acceptable prodrug, metabolite, analogue, derivative, solvate or salt, either alone or together with other

pharmaceutical agents, suitable for administration to a subject using carriers, excipients and additives or auxiliaries. Frequently used carriers or auxiliaries include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, vitamins, cellulose and its derivatives, animal and vegetable oils, polyethylene glycols and solvents, such as sterile water, alcohols, glycerol and polyhydric alcohols. Intravenous vehicles include fluid and nutrient replenishers.

[0135] Preservatives include antimicrobial, anti-oxidants, chelating agents and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like, as described, for instance, in REMINGTON'S PHARMACEUTICAL SCIENCES, 15th ed. Easton: Mack Publishing Co., 1405-1412, 1461-1487 (1975) and THE NATIONAL FORMULARY XIV, 14th ed. Washington: American Pharmaceutical Association (1975), the contents of which are hereby incorporated by reference and for all purposes. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art . See, e.g., Goodman and Gilman's THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).

[0136] The pharmaceutical compositions are preferably prepared and administered in dose units. Solid dose units are tablets, capsules and suppositories. For treatment of a subject, depending on activity of the compound, manner of administration, nature and severity of the disease or disorder, age and body weight of the subject, different daily doses can be used.

[0137] Under certain circumstances, however, higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else several smaller dose units and also by multiple administrations of subdivided doses at specific intervals.

[0138] The pharmaceutical compositions according to the invention may be administered locally or systemically in a therapeutically effective dose. Amounts effective for this use will, of course, depend on the severity of the disease or disorder and the weight and general state of the subject. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of the pharmaceutical composition, and animal models may be used to determine effective dosages for treatment of particular disorders. [0139] Various considerations are described, e.g., in Langer, 1990, Science 249: 1527; Gilman et al. (eds. ), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.), each of which is herein incorporated by reference in its entirety and for all purposes. Dosages for parenteral administration of active pharmaceutical agents can be converted into corresponding dosages for oral administration by multiplying parenteral dosages by appropriate conversion factors. As to general applications, the parenteral dosage in mg/m² times 1.8 = the corresponding oral dosage in milligrams ("mg"), where "m²" is the surface area of the subject (meters²). As to oncology applications, the parenteral dosage in mg/m² times 1.6 = the corresponding oral dosage in mg. An average adult weighs about 70 kg. See the MILLER-KEANE ENCYCLOPEDIA & DICTIONARY OF MEDICINE, NURSING & ALLIED HEALTH, 5th Ed., (W. B. Saunders Co. 1992), pp. 1708 and 1651. [0140] The method by which the compound of the present invention may be administered for oral use would be, for example, in a hard gelatin capsule wherein the active ingredient is mixed with an inert solid diluent, or soft gelatin capsule, wherein the active ingredient is mixed with a co-solvent mixture, such as PEG 400 containing Tween-20. A compound of the present invention may also be administered in the form of a sterile injectable aqueous or oleaginous solution or suspension. The compound of the present invention can generally be administered intravenously or as an oral dose of 0.5 to 20 mg/kg given, for example, every 3 - 12 hours.

[0141] Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0142] Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension. Such excipients may be (1) suspending agent such as sodium carboxymethyl cellulose, methyl cellulose,

hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate ; (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. [0143] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. [0144] A compound of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.

[0145] Such materials include cocoa butter and polyethylene glycols. [0146] The compounds of the present invention as used in the present 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 phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0147] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.

[0148] Dosage levels of the compounds of the present invention as used in the present invention are of the order of about 0.5 mg to about 20 mg per kilogram body weight, an average adult weighing 70 kilograms, with a preferred dosage range between about 5 mg to about 20 mg per kilogram body weight per day (from about 0.3 gms to about 1.2 gms per patient per day). The amount of the compound of the present invention that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain about 5 mg to 1 g of a compound of the present invention with an appropriate and convenient amount of carrier material that may vary from about 5 to 95 percent of the total composition. Dosage unit forms will generally contain between from about 5 mg to 500 mg of the present invention active ingredient.

[0149] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [0150] In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.

[0151] In further embodiments the invention provides compositions comprising a compound of the present invention in the form of pharmaceutically-acceptable prodrugs, metabolites, analogues, derivatives, solvates or salts, either alone or in admixture with other active pharmaceutical agents, together with a pharmaceutically acceptable diluent, adjuvant, or carrier.

[0152] While the invention has been described in detail with reference to certain preferred embodiments thereof, it will be understood that modifications and variations are within the spirit and scope of that which is described and claimed. VI. Examples

[0153] Examples herein are meant to illustrate certain embodiments and not to limit the scope thereof. Abbreviations used herein have their conventional meaning in the art, unless indicated otherwise. Specific abbreviations include the following: A = Angstrom; AC₂O = acetic anhydride; AcOH = acetic acid; aq = aqueous; Bt = benzotriazole; BOC = N-tert- butoxycarbonyl; br = broad; ?-BuOH = tert-butanol; °C = degree Celsius; d = doublet; DABCO = l,4-diazabicyclo[2.2.2]octane; DCE = 1,2-dichloroethane; DCM = dichloromethane; dd = doublet of doublets; DIEA = diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO = dimethylsulfoxide; δ = chemical shift (given in ppm, unless otherwise indicated); EDCI = l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; eq = equivalent; Et₂0 = diethyl ether; Ets = triethylamine; EtOAc = ethyl acetate; EtOH = ethanol; g = gram; h (or hr) = hour; HOBt = hydroxybenzotriazole; HPLC = high performance liquid chromatography; Hz = Hertz; IC5₀ = inhibitory concentration at 50% inhibition; J= coupling constant (given in Hz, unless otherwise indicated); LC = liquid chromatography; LHMDS = lithium hexamethyldisilazide; m = multiplet; M = molar; [M+H]⁺ = parent mass spectrum peak plus H⁺; MS = mass spectrum; ms = molecular sieves; MP = melting point; Me₂ H = dimethylamine; MeOH = methanol; mg = milligram; mL = milliliter; mM = millimolar; mmol = millimole; min = minute; μϊ_^ = microliter; μΜ = micromolar; ng = nanogram; nM = nanomolar; NMR = nuclear magnetic resonance; ppm = parts per million; q = quartet; R_f = retention factor; RT = room temperature; s = singlet; t = triplet; TFA = trifluoroacetic acid; THF =

tetrahydrofuran; TLC = thin layer chromatography. General Scheme I.

[0154] A synthetic scheme useful for synthesis of compounds described herein is disclosed in General Scheme I following, wherein the term "Ar" in General Scheme I refers to substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the terms R¹ and R² are as defined above. General Scheme I

i. R¹CHO, EtOH, 78 °C ii. NaCNBH₃, AcOH

Example 1 - Preparation of Intermediate 1

General Procedure 1

Int 1

[0155] 2-Furoyl chloride (7.9 mL, 75.2 mmol) was added to a solution of aminoguanidine sulfate (10 g, 75.2 mmol, 1 eq) in pyridine (50 mL) at 0°C. The reaction mixture was then allowed to stir at RT for 14 h before being neutralized with saturated aqueous NaHC0₃ (20 mL), extracted with ?-BuOH (3 x 100 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. The crude residue was then dissolved in water (150 mL) and stirred at 100°C for 6 h. The reaction mixture was cooled to 0°C and extracted with EtOAc (5 x 100 mL), dried over Na₂S0₄, filtered and concentrated to afford Int 1 (3.5 g, 31%) as an off-white solid. ^XH NMR complies; MS: 151 [M + H]⁺; MP: 202-204°C; TLC: 20% MeOH/NH₃ in CHC1₃: R_f: 0.40.

Example 2- Preparation of Intermediate 2

General Procedure 2

Int 1 Int 2

[0156] 4-Fluorobenzaldehyde (1.14 mL, 10.6 mmol, 2 eq) and molecular sieves (4A powder) were added to a solution of Int 1 (0.8 g, 5.29 mmol) in EtOH (20 mL) at RT and refluxed for 8 h. Then was added a catalytic quantity of AcOH, NaCNBH₃ (0.67 g, 10.6 mmol, 2 eq) at 0°C and with stirring for 15 h at RT. The solvent was distilled off, and the residue was dissolved in EtOAc (100 mL) and filtered through a Celite® pad to remove inorganic materials. The filtrate was washed with saturated aqueous NaHC0₃ (2 x 10 mL), brine (20 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. The resultant compound was purified by column

chromatography over silica gel (100-200 mesh) by using a solvent gradient of 0-10% MeOH- CHC1₃ as the eluent to afford Int 2 (350 mg, 25%). MS: 259 [M + H]⁺; TLC: 10% MeOH in CHC1₃: R_f: 0.25.

Example 3 - Preparation of Compound 1

General Procedure 3

Int 2 Cmpd 1 [0157] 2-Methoxybenzoyl chloride (52 μΐ_^, 0.35 mmol, 1.2 eq) was added to a solution of Int 2 (75 mg, 0.29 mmol) in triethylamine (3 mL) at RT and stirred for 5 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL). The organic layer washed with water (10 mL), saturated aqueous NaHCC (10 mL), brine (10 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. The crude compound was purified by column

chromatography over silica gel (100-200 mesh) by using a gradient mixture of 0-30% EtOAc - hexane as the eluent to afford Cmpd 1 (20 mg, 17%). ¾ NMR complies; MS: 393 [M + H]⁺; MP: 150-152°C; TLC: 50% EtOAc in hexane: R_f: 0.60.

Example 4 - Preparation of Compound 2

Int 2 Cmpd 2

[0158] General Procedure 3 was followed to obtain Cmpd 2 (20 mg, 17%). ^XH NMR complies; MS: 397 [M + H]⁺; MP: 199-201°C; TLC: 50% EtOAc in hexane: R_f: 0.60.

General Scheme II.

[0159] A synthetic scheme useful for synthesis of compounds described herein is disclosed in General Scheme II following, wherein the term "Ar" in General Scheme II refers to substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the terms "R¹" and "R²" are as defined above.

General Scheme II

i. R CHO, EtOH, 78 °C ii. NaCNBH₃, AcOH

Example 5 - Preparation of Intermediate 3

General Procedure 4

Int 3

[0160] A solution of 2-picolinic acid (15 g, 112 mmol) in water (45 mL) was added slowly portion-wise to a previously stirred mixture of aminoguanidine sulfate (15.2 g, 124 mmol, 1.1 eq) in concentrated H2SO4 (6.1 mL, 1 13 mmol), and the reaction mixture was stirred at 140°C for 72 h. The reaction mixture was diluted with water (50 mL) and neutralized with saturated aqueous K2CO₃ (30 mL), and the resultant solid was filtered. The residue was washed with water (2 x 30 mL), Et₂0 (2 x 30 mL) and dried under vacuum to afford Int 3 (8.5 g, 46%) as an off-white solid. 1H NMR complies; MS: 162 [M + H]⁺; MP: 218-220°C; TLC: 20% MeOH/NH₃

Example 6 - Preparation of Intermediate 4

Int 3 Int 4

[0161] General Procedure 2 was followed to afford Int 4 (2.8 g, 60%). 1H NMR complies; MS: 252 [M + H]⁺; MP: 226-228°C; TLC: 10% MeOH in CHC1₃: R_f: 0.30.

Example 7 - Preparation of Compound 3

Int 4 Cmpd 3

[0162] General Procedure 3 was followed to afford Cmpd 3 (50 mg, 35%). H NMR complies; MS: 356 [M + H]⁺; MP: 136-138°C; TLC: 50% EtOAc in hexane: R_f: 0.50. Example 8 - Preparation of Compound 4

General Procedure 5

Int 4 Cmpd 4

[0163] Phenylacetic acid (60 μΐ_^, 0.48 mmol, 1.2 eq) was added to a solution containing Int 4 (100 mg, 0.4 mmol), EDCI (93 mg, 0.60 mmol, 1.5 eq) and HOBt (162 mg, 1.2 mmol, 3 eq) in DMF (4 mL) and the resulting mixture was stirred for 16 h at RT. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL). The organic layer washed with water (10 mL), saturated aqueous aHC03 (10 mL), brine (10 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. The crude compound was purified by column chromatography over silica gel (100-200 mesh) by using a gradient mixture of 0-30% EtOAc-hexane as the eluent to afford Cmpd 4 (40 mg, 27%). ¾ NMR complies; MS: 370 [M + H]⁺; MP: 106-108°C; TLC: 50% EtOAc in hexane: R_f: 0.60.

Example 9 - Preparation of Compound 5

Int 4 Cmpd 5

[0164] General Procedure 3 was followed to afford Cmpd 5 (53 mg, 34%). ¾ NMR complies; MS: 390 [M + H]⁺; MP: 182-186°C; TLC: 50% EtOAc in hexane: R_f: 0.60. Example 10 - Preparation of Compound 6

[0165] General Procedure 3 was followed to afford Cmpd 6 (30 mg, 19%). ¾ NMR complies; MS: 390 [M + H]⁺; MP: 150-152°C; TLC: 50% EtOAc in hexane: R_f: 0.60.

Example 11 - Preparation of Intermediate 5

Int 3 Int 5

[0166] General Procedure 2 was followed to afford Int 5 (1.6 g, 48%). ^XH NMR complies; MS: 270 [M + H]⁺; MP: 219-220°C; TLC: 10% MeOH in CHC1₃: R_f: 0.25.

Example 12 - Preparation of Compound 7

Int 5 Cmpd Ό 7

[0167] General Procedure 5 was followed to afford Cmpd 7 (30 mg, 19%). ¾ NMR complies; MS: 388 [M + H]⁺; MP: 135-137°C; TLC: 50% EtOAc in hexane: R_f: 0.60. Example 13 - Preparation of Compound 8

Int 5 Cmpd 8

[0168] General Procedure 3 was followed to afford Cmpd 8 (35 mg, 23%). ¾ NMR complies; MS: 404 [M + H]⁺; MP: 161- 163°C; TLC: 50% EtOAc in hexane: R_f: 0.60.

Example 14 - Preparation of Intermediate 6

Int 6

[0169] General Procedure 4 was followed to afford Int 6 (12 g, 67%). ¾ NMR complies; MS: 162 [M + H]⁺; TLC: 20% MeOH in CHC1₃: R_f: 0.40.

Example 15 - Preparation of Intermediate 7

Int 6 Int 7

[0170] General Procedure 2 was followed to afford Int 7 (2.2 g, 48%). ^XH NMR complies; MS: 252 [M + H]⁺; MP: 193-196°C; TLC: 10% MeOH in CHC1₃: R_f: 0.30. Example 16 - Preparation of Compound 9

Int 7 Cmpd 9

[0171] General Procedure 3 was followed to afford Cmpd 9 (68 mg, 48%). ¾ NMR complies; MS: 356 [M + H]⁺; MP: 187-188°C; TLC: 50% EtOAc in hexane: R_f: 0.50.

Example 17 - Preparation of Compound 10

Int 7 Cmpd 10

[0172] General Procedure 3 was followed to afford Cmpd 10 (17 mg, 11%). ^XH NMR complies; MS: 390 [M + H]⁺; MP: 166-169°C; TLC: 50% EtOAc in hexane: R_f: 0.60.

Example 18 - Preparation of Compound 11

Int 7 Cmpd 11

[0173] General Procedure 3 was followed to afford Cmpd 11 (25 mg, 16%). ^XH NMR complies; MS: 386 [M + H]⁺; MP: 154-156°C; TLC: 50% EtOAc in hexane: R_f: 0.60. Example 19 - Preparation of Intermediate 8

Int 6 Int 8

[0174] General Procedure 2 was followed to afford Int 8 (1.4 g, 42%). ^XH NMR complies; MS: 270 [M + H]⁺; TLC: 10% MeOH in CHC1₃: R_f: 0.25. Example 20 - Preparation of Compound 12

Int 8 Cmpd 12

[0175] General Procedure 3 was followed to afford Cmpd 12 (28 mg, 18%). ^XH NMR complies; MS: 404 [M + H]⁺; MP: 171-172°C; TLC: 50% EtOAc in hexane: R_f: 0.60.

General Scheme III.

[0176] A synthetic scheme useful for synthesis of compounds described herein is disclosed in General Scheme III following, wherein the term "Ar" in General Scheme III refers to substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the terms "R¹" and "R²" are as defined above.

General Scheme III

i. R¹CHO, EtOH, 78 °C ii. NaCNBH₃, AcOH

Example 21 - Preparation of Intermediate 9

General Procedure 6

Int 9

[0177] Thionyl chloride (3.55 mL, 48.4 mmol, 3 eq) was added drop-wise to a solution of pyrimidine-4-carboxylic acid (2 g, 16.1 mmol) in EtOH (15 mL) and the resulting mixture was heated to reflux for 14 h. The mixture was then cooled to RT and made alkaline with saturated aqueous NaHCC to pH 8. The basic solution was then extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂S0₄, filtered and concentrated in vacuo to afford Int 9 (1.7g, 77%). ¾ NMR: complies; MS: 153 [M + H]⁺; TLC: 40% hexane in EtOAc: R_f: 0.40.

Example 22 - Preparation of Intermediate 10

Int 9 Int 10 [0178] Int 9 (1.6 g, 10.5 mmol) was added drop-wise to a vigorously stirring mixture of aminoguanidine sulfate (10.3 g, 42.1 mmol, 4 eq) in freshly prepared NaOMe (using 968 mg, 42.1 mmol of Na in 28 mL of dry MeOH) at 0°C. The resulting mixture was heated to reflux for 20 h. The mixture was then cooled to RT, carefully poured over ice cold water (20 mL) and concentrated in vacuo. The crude residue was purified over neutral alumina using 4-10%

MeOH-CHCls as the eluent to give Int 10 (500mg, 26%). MS: 163 [M + H]⁺; TLC: 20% MeOH in CHC1₃: R_f: 0.20.

Example 23 - Preparation of Intermediate 11

Int 10 Int 11

[0179] General Procedure 2 was followed to afford Int 11 (210 mg, 34%). ^XH NMR:

complies; TLC: EtOAc: R_f: 0.30.

Example 24 - Preparation of Compound 13

General Procedure 8

Int 11 Cmpd 13 [0180] 2-Methoxybenzoyl chloride (72 μί, 0.54 mmol, 2 eq) was added to a solution of Int 11 (70 mg, 0.27 mmol) in Et₃N (0.18 mL, 1.35 mmol) and DCM (3 mL) at 0°C. The resulting mixture was allowed to stir at RT for 2 h. The reaction mixture was then diluted with water (5 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with saturated aqueous aHC0₃ (10 mL), water (2 x 5 mL), brine (15 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. The crude material was purified by column chromatography over silica gel (100-200 mesh) using a gradient mixture of 0-70% EtOAc-hexane as the eluent to afford Cmpd 13 (45 mg, 29%). 'H NMR: complies; MS: 387 [M + H]⁺; MP: 192-195°C; TLC: 40% hexane in EtOAc: R_f: 0.30.

Example 25 - Preparation of Intermediate 12

Int 12

[0181] General Procedure 6 was followed to afford Int 12 (950 mg, 86%). ¾ NMR:

complies; TLC: 40% EtOAc in hexane: R_f: 0.50.

Example 26 - Preparation of Intermediate 13

H2

M U

Int 12 Int 13

[0182] General Procedure 7 was followed to afford Int 13 (500 mg, 45%). ^XH

complies; TLC: 20% MeOH in CHC1₃: R_f: 0.20.

Example 27 - Preparation of Intermediate 14

Int 13 Int 14

[0183] General Procedure 2 was followed to afford Int 14 (160 mg, 20%). ^XH NMR:

complies; MS: 253 [M + H]⁺; TLC: EtOAc: R_f: 0.30. Example 28 - Preparation of Compound 14

Int 14 Cmpd 14

[0184] General Procedure 8 was followed to afford Cmpd 14 (30 mg, 16%). ^XH NMR:

complies; MS: 387 [M + H]⁺; MP: 154-157°C; TLC: 40% EtOAc in hexane: R_f: 0.20.

General Scheme IV.

[0185] A synthetic scheme useful for synthesis of compounds described herein is disclosed in General Scheme IV following, wherein the term "Ar" in General Scheme IV refers to substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, and the terms "R¹" and "R²" are as defined above. General Scheme IV

i. R¹CHO, EtOH, 78 °C ii. NaCNBH₃, AcOH

Example 29 - Preparation of Intermediate 15

General Procedure 9

Int 15

[0186] Oxalyl chloride (2.36 niL, 24.2 mmol, 1.5 eq) and a catalytic quantity of DMF were added to a solution of pyrimidine-2-carboxylic acid (2 g, 16.1 mmol) in dry DCM (30 mL) at 0°C. The resulting mixture was allowed to warm to RT and stirred for 3 h. The volatiles were removed in vacuo and the residue was thoroughly dried to afford pyrimidine-2-carboxylic acid chloride (2.1 g, 14.8 mmol) as a black solid. The crude material was added portion-wise to a solution of aminoguanidine sulfate (5.5 g, 22.2 mmol, 1.5 eq) in pyridine (20 mL) at 0°C. The resulting mixture was allowed to warm to RT and stir for 14 h. The mixture was then neutralized with saturated aqueous aHC0₃, extracted with ?-BuOH (5 x 50 mL), dried over Na₂S0₄, filtered and concentrated in vacuo. The crude material was dissolved in water (45 mL) and the resulting solution was heated to 100°C for 24 h. The reaction mixture was then cooled to RT, extracted with ?-BuOH (5 x 30 mL), dried over Na₂S0₄, filtered and concentrated in vacuo to afford Int 15 (650 mg, 25 %) as off-white solid. TLC: 30% MeOH in CHC1₃: R_f: 0.20.

Example 30 - Preparation of Intermediate 16

Int 15 Int 16

[0187] General Procedure 2 was followed to afford Int 16 (120 mg, 17%). H NMR:

complies; MS: 253 [M + H]⁺; TLC: EtOAc: R_f: 0.30. xample 31 - Preparation of Compound 15

Int 16 Cmpd 15

[0188] General Procedure 8 was followed to afford Cmpd 15 (120 mg, 17%). ¾ NMR: complies; MS: 387 [M + H]⁺; MP: 203-205°C; TLC: 40% EtOAc in hexane: R_f: 0.40. [0189] The contents of all references, patents, and published applications cited herein are hereby incorporated by reference in their entirety and for all purposes.

[0190] While the invention has been described in detail with reference to certain preferred embodiments thereof, it will be understood that modifications and variations are within the spirit and scope of that which is described and claimed.

Claims

WHAT IS CLAIMED IS:

1. A compound with structure of Formula (II)

or pharmaceutically acceptable salt, ester, solvate, or prodrug thereof;

wherein

R¹ and R² are independently hydrogen, substituted or unsubstituted alkyl,

substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;

R³ is hydrogen, -NH₂, substituted or unsubstituted alkyl, substituted or

unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl;

R⁴ is unsubstituted alkyl;

L¹ and L² are each independently a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -SO₂-, -NHCO₂-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene;

L³ is a bond, -NH-, -NR⁴-, -CONH-, -CSNH-, -C(O)-, -C(0)0-, -NHCONH-, -NHCSNH-,-NHS0₂-, -0-, -S-, -S(O)-, -S0₂-, -NHC0₂-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, or -L^3a-L^3b-;

L^3a is substituted or unsubstituted heterocycloalkylene; and

L^3b is -C(O)-, -S(0)₂-, or -C(0)0;

wherein

said compound inhibits both thrombin and coagulation factor Xa (fXa).

2. The compound according to claim I, said compound having IC5₀ > 1.0 μΜ for thrombin inhibition. 3. The compound according to claim I, said compound having IC₅₀ > 1.0 μΜ for fXa inhibition. 4. The compound according to claim 1, said compound having IC5₀ > 0.1 μΜ and < 1.0 μΜ for thrombin inhibition. 5. The compound according to claim I, said compound having IC5₀ > 0.1 μΜ and < 1.0 μΜ for fXa inhibition. 6. The compound according to claim I, said compound having IC5₀ < 0.1 μΜ for thrombin inhibition. 7. The compound according to claim I, said compound having IC₅₀ < 0.1 μΜ for fXa inhibition. 8 . The compound according to claim 1 , having the structure of Formula (Ila),

L¹ is -NH-(CH₂)_n-; and

n is 0 to 6.

The compound according to claim 1 , having the structure of Formula (lib),

wherein

L¹ is -S-(CH₂)_n-; and

n is 0 to 6. 10. The compound according to claim 1 , having the structure of Formula (lie),

The compound according to claim 1 , having the structure of Formula (Ild),

The compound according to claim 1 , having the structure of Formula (He),

wherein

L¹ is -NH-(CH₂)_n-; and

n is 0 to 6. 13. The compound according to claim 1, wherein said compound is selected from: Cmpd Structure

1 N-[(4-fluorophenyl)methyl]-3-(furan-2-yl)-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4 ria

3 l-benzoyl-N-benzyl-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

4 l-[5-(benzylammo)-3-(pyridm-2-yl)-lH-l,2,4-triazol-l-yl]-2-phenylethan-l-one

5 N-benzyl- 1 -[(2-chlorophenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

6 N-benzyl- 1 -[(4-chlorophenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

7 1 -(5 - { [(4-fluorophenyl)methyl] amino } -3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol- 1 -yl)-2-phenylethan- 1 -one

8 N-[(4-fluorophenyl)methyl]- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

9 l-benzoyl-N-benzyl-3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine

10 N-benzyl- 1 -[(2-chlorophenyl)carbonyl]-3 -(pyridin-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

11 N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine

12 N-[(4-fluorophenyl)methyl]- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyridin-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

13 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyrimidin-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

14 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl] -3 -(pyrimidin-5 -yl)- 1 H- 1 ,2,4-triazol-5 -amine

15 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyrimidin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

l-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-(oxan-4-yl)-lH-l,2,4-triazol-l-yl)-2,2-dimethylpropan-

16

1-one

1 -(5- { [(5-chlorothiophen-2-yl)methyl]amino } -3-(oxolan-2-yl)- 1H- 1 ,2,4-triazol- 1 -yl)-2,2-

17

dimethylpropan- 1 -one

1 -(5 - { [(5-chlorothiophen-2-yl)methyl] amino } -3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol- 1 -yl)-2,2-

18

dimethylpropan- 1 -one

1 -[3 -(5- { [(5-chlorothiophen-2-yl)methyl]amino } - 1 -[(2-methoxyphenyl)carbonyl]- 1H- 1 ,2,4-triazol -3 -

20

yl)azetidin- 1 -yl]-2,2-dimethylpropan- 1 -one

l-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3-

21

yl)azetidin- 1 -yljethan- 1 -one

l-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-lH-l,2,4-triazol-3-yl)azetidin-l-yl]-2,2-

22

dimethylpropan- 1 -one

23 l-[3-(5-{[(5 -chlorothiophen-2-yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 -yl)azetidin- 1 -yljethan- 1 -one l-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3-

24

yl)piperidin- 1 -yl]-2,2-dimethylpropan- 1 -one

l-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3-

25

yl)piperidin- 1 -yljethan- 1 -one

l-[4-(5-{[(5 -chlorothiophen-2-yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 -yl)piperidin- 1 -yl] -2,2-

26

dimethylpropan- 1 -one

27 1 -[4-(5 - { [(5 -chlorothiophen-2-yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 -yl)piperidin- 1 -yljethan- 1 -one

29 3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5 -amine

31 3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

3 -[ 1 -(benzenesulfonyl)azetidin-3 -yl] -N-[(5 -chlorothiophen-2-yl)methyl] - 1 -[(2-

32

methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

3-[l-(benzenesulfonyl)piperidin-4-yl]-N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-

33

methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

4-(5- { [(5-chlorothiophen-2-yl)methyl]amino } - 1 -[(2-methoxyphenyl)carbonyl]-l H- 1 ,2,4-triazol-3 -yl)-

34

N,N-dimethylpiperidine- 1 -carboxamide

4-(5- { [(5-chlorothiophen-2-yl)methyl]amino } - 1 -[(2-methoxyphenyl)carbonyl]- 1 H- 1 ,2,4-triazol-3 -

35

yl)piperidine- 1 -carboxamide

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,3-dihydro-l,4-benzodioxin-5-yl)carbonyl]-3-(oxan-4-yl)-lH-

36

1 ,2,4-triazol-5-amine N- [(5 -chlorothiophen-2 -y l)methyl] - 1 - [(2 , 3 -dft^

l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,3-dihydro-l,4-benzodioxin-5-yl)carbonyl]-3-(oxolan-3-yl)-lH- l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4-dimethoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol- 5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4-dimethoxyphenyl)carbonyl]-3-(oxolan-2-yl)-lH-l,2,4-triazol- 5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4-dimethoxyphenyl)carbonyl]-3-(oxolan-3-yl)-lH-l,2,4-triazol- 5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5- amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-(oxolan-2-yl)-lH-l,2,4-triazol-5- amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-(oxolan-3-yl)-lH-l,2,4-triazol-5- amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-[l-(propane-2-sulfonyl)azetidin-3- yl]-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-[l-(propane-2-sulfonyl)piperidin- 4-yl]- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-phenyl-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-{ l-[(piperidin-l- yl)carbonyl]piperidin-4-yl } - 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-{ l-[(pyrrolidin-l- yl)carbonyl]piperidin-4-yl } - 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]- 1 -[(2-methylphenyl)carbonyl]-3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5- amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methylphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5- amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(furan-3-yl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol -5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(furan-3-yl)carbonyl]-3-(oxolan-2-yl)-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(furan-3-yl)carbonyl]-3-(oxolan-3-yl)-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(l-methanesulfonylazetidin-3-yl)-l-[(2-methoxyphenyl)carbonyl]- lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(l-methanesulfonylpiperidin-4-yl)-l-[(2- methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3 -(oxan-4-yl)- 1 -[(thiophen-3 -yl)carbonyl]- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(oxolan-2-yl)-l-[(thiophen-3-yl)carbonyl]-lH-l,2,4-triazol-5- amine

N-[(5 -chlorothiophen-2-yl)methyl] -3 -(oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(oxolan-3-yl)-l-[(thiophen-3-yl)carbonyl]-lH-l,2,4-triazol-5- amine

N-[(5 -chlorothiophen-2-yl)methyl] -3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-3-[l-(cyclohexanesulfonyl)azetidin-3-yl]-l-[(2- methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-[l-(cyclohexanesulfonyl)piperidin-4-yl]-l-[(2- methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine N-[(5-chlorothiophen-2-yl)methyl]-3-cyclopen1yl-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-

65

amine

66 N-benzyl-l-[(2,3-dimethoxyphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amme

67 N-benzyl-l-[(2-fluoro-4-methylphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

68 N-benzyl- 1 -[(2-fluorophenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

69 N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

70 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyridazin-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

71 N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

72 N-benzyl- 1 -[(3 -methoxyphenyl)carbonyl] -3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5 -amine

73 N-benzyl-3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

74 tert-butyl 3 -(5-amino- 1H- 1 ,2,4-triazol-3 -yl)azetidine- 1 -carboxylate

tert-butyl 3 -(5 - { [(5-chlorothiophen-2-yl)methyl] amino } - 1 -[(2-methoxyphenyl)carbonyl] - 1 H- 1 ,2,4-

75

triazol-3 -yl)azetidine- 1 -carboxylate

76 tert-butyl 3 -(5- {[(5-chlorothiophen-2-yl)methyl]amino } - 1H- 1 ,2,4-triazol-3 -yl)azetidine- 1 -carboxylate

77 tert-butyl 4-(5-amino- 1H- 1 ,2,4-triazol-3 -yl)piperidine- 1 -carboxylate

tert-butyl 4-(5 - { [(5-chlorothiophen-2-yl)methyl] amino } - 1 -[(2-methoxyphenyl)carbonyl] - 1 H- 1 ,2,4-

78

triazol-3 -yl)piperidine- 1 -carboxylate

79 tert-butyl 4-(5 - { [(5-chlorothiophen-2-yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 -yl)piperidine- 1 -carboxylate tert-butyl 4-[5-(benzylamino)-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3-yl]piperidine-l-

80

carboxylate.

14. A method for inhibiting thrombin or coagulation factor Xa (fXa), said method comprising contacting thrombin or coagulation factor Xa with a compound as set forth in claim I, thereby inhibiting said thrombin or said fXa.

15. The method according to claim 14, wherein said compound is selected from:

Cmpd Structure

1 N-[(4-fluorophenyl)methyl]-3-(furan-2-yl)-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

3 l-benzoyl-N-benzyl-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

4 l-[5-(benzylamino)-3-(pyridin-2-yl)-lH-l,2,4-triazol-l-yl]-2-phenylethan-l-one

9 l-benzoyl-N-benzyl-3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine

14 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl] -3 -(pyrimidin-5 -yl)- 1 H- 1 ,2,4-triazol-5 -amine N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyrimidin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

l-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-3-(oxan-4-yl)-lH-l,2,4-triazol-l-yl)-2,2-dimethylpropan- 1-one

1 -(5- { [(5-chlorothiophen-2-yl)methyl]amino } -3-(oxolan-2-yl)- 1H- 1 ,2,4-triazol- 1 -yl)-2,2- dimethylpropan- 1 -one

1 -(5 - { [(5-chlorothiophen-2-yl)methyl] amino } -3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol- 1 -yl)-2,2- dimethylpropan- 1 -one

l-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3- yl)azetidin-l-yl]-2,2-dimethylpropan-l-one

l-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3- yl)azetidin- 1 -yljethan- 1 -one

l-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-lH-l,2,4-triazol-3-yl)azetidin-l-yl]-2,2- dimethylpropan- 1 -one

l-[3-(5-{[(5 -chlorothiophen-2-yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 -yl)azetidin- 1 -yljethan- 1 -one l-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3- yl)piperidin- 1 -yl]-2,2-dimethylpropan- 1 -one

l-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3- yl)piperidin- 1 -yljethan- 1 -one

l-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-lH-l,2,4-triazol-3-yl)piperidin-l-yl]-2,2- dimethylpropan- 1 -one

1 -[4-(5 - { [(5 -chlorothiophen-2-yl)methyl] amino } - 1 H- 1 ,2,4-triazol-3 -yl)piperidin- 1 -yljethan- 1 -one

3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5 -amine

3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

3 -[ 1 -(benzenesulfonyl)azetidin-3 -yl] -N-[(5 -chlorothiophen-2-yl)methyl] - 1 -[(2- methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

3-[l-(benzenesulfonyl)piperidin-4-yl]-N-[(5-chlorothiophen-2-yl)methyl]-l-[(2- methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

4-(5- { [(5-chlorothiophen-2-yl)methyl]amino } - 1 -[(2-methoxyphenyl)carbonyl]-l H- 1 ,2,4-triazol-3 -yl)- N,N-dimethylpiperidine- 1 -carboxamide

4-(5- { [(5-chlorothiophen-2-yl)methyl]amino } - 1 -[(2-methoxyphenyl)carbonyl]- 1 H- 1 ,2,4-triazol-3 - yl)piperidine- 1 -carboxamide

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,3-dihydro-l,4-benzodioxin-5-yl)carbonyl]-3-(oxan-4-yl)-lH- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,3-dihydro-l,4-benzodioxin-5-yl)carbonyl]-3-(oxolan-2-yl)-lH- l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-(oxolan-3-yl)-lH-l,2,4-triazol-5- amine N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-[l-(propane-2-sidfonyl)azetidin-3- yl]- 1 H- 1 ,2,4-triazol-5-amine

N- [(5 -chlorothiophen-2 -yl)methyl] - 1 - [(2 -meto

4-yl]- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(furan-3-yl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-[(5 -chlorothiophen-2 -yl)methyl] -3 -(oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-[(5 -chlorothiophen-2 -yl)methyl] -3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-[(5-chlorothiophen-2-yl)methyl]-3-[l-(cyclohexanesulfonyl)piperidin-4-yl]-l-[(2- methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-cyclopentyl-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5- amine

N-benzyl-l-[(2,3-dimethoxyphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

N-benzyl-l-[(2-fluoro-4-methylphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

N-benzyl- 1 -[(2-fluorophenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyridazin-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

N-benzyl- 1 -[(3 -methoxyphenyl)carbonyl] -3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-benzyl-3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

tert-butyl 3 -(5-amino- 1H- 1 ,2,4-triazol-3 -yl)azetidine- 1 -carboxylate

tert-butyl 3 -(5 - { [(5-chlorothiophen-2-yl)methyl] amino } - 1 -[(2-methoxyphenyl)carbonyl] - 1 H- 1 ,2,4- triazol-3 -yl)azetidine- 1 -carboxylate

tert-butyl 3 -(5- {[(5-chlorothiophen-2-yl)methyl]amino } - 1H- 1 ,2,4-triazol-3 -yl)azetidine- 1 -carboxylate tert-butyl 4-(5-amino- 1H- 1 ,2,4-triazol-3 -yl)piperidine- 1 -carboxylate tert-butyl 4-(5 - { [(5-chlorothiophen-2-yl)methyl] amino } - 1 -[(2-methoxyphenyl)carbonyl] - 1 H- 1 ,2,4-

78

triazol-3 -yl)piperidine- 1 -carboxylate

80

carboxylate

2 l-[(2-chlorophenyl)carbonyl]-N-[(4-fluorophenyl)methyl]-3-(furan-2-yl)-lH-l,2,4-triazol-5-amine

19 l-[(2-methoxyphenyl)carbonyl]-3-(pyridin-2-yl)-N-(thiophen-2-ylmethyl)-lH-l,2,4-triazol-5-amine

28 3 -(5 - { [(4-fluorophenyl)methyl] sulfanyl } - 1 -[(2-methoxyphenyl)carbonyl] - 1 H- 1 ,2,4-triazol-3 -yl)pyridine

30 3 -(oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

81 1 -(5-[(4-chlorophenyl)methyl] amino-3 -(pyridin-3 -yl)- 1 H- 1 ,2,4-triazol- 1 -yl)ethan- 1 -one

82 1 -(5-[(4-chlorophenyl)methyl] amino-3 -(pyridin-3 -yl)- 1 H- 1 ,2,4-triazol- 1 -yl)propan-l -one

83 1 -(5-[(4-fluorophenyl)methyl]amino-3 -(furan-2-yl)- 1 H- 1 ,2,4-triazol- 1 -yl)-2-methylpropan- 1 -one

84 1 -(5-[(4-fluorophenyl)methyl]amino-3 -(pyridin-3 -yl)- 1 H- 1 ,2,4-triazol- 1 -yl)-2-phenylethan- 1 -one

85 1 -(5-[(4-fluorophenyl)methyl]amino-3 -(pyridin-3 -yl)- 1 H- 1 ,2,4-triazol-l -yl)butan- 1 -one

86 1 -(5-[(4-fluorophenyl)methyl]amino-3 -(pyridin-3 -yl)- 1 H- 1 ,2,4-triazol- 1 -yl)ethan- 1 -one

87 l-[(4-chlorophenyl)carbonyl]-N-[(4-fluorophenyl)methyl]-3-(pyridin-3-yl)-lH-l,2,4-triazol-5-amine

88 1 -[3 -(pyridin-3 -yl)-5-[(thiophen-2-ylmethyl)amino]- 1H- 1 ,2,4-triazol- 1 -yljethan- 1 -one

89 1 -[5-(benzylamino)-3-(furan-2-yl)- 1 H- 1 ,2,4-triazol- 1 -yl]-2-phenylethan- 1 -one

90 1 -[5-(benzylamino)-3 -(pyridin-3 -yl)- 1 H- 1 ,2,4-triazol- 1 -yl]propan- 1 -one

91 3-(furan-2-yl)-l-[(2-methoxyphenyl)carbonyl]-5-(methylsulfanyl)-lH-l,2,4-triazole

92 3-(furan-2-yl)-l-[(pyridin-3-yl)carbonyl]-N-(thiophen-2-ylmethyl)-lH-l,2,4-triazol-5-amine

93 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl] -3 -(pyridin-3 -yl)- 1 H- 1 ,2,4-triazol-5 -amine .

16. A method for treating a thrombotic disorder, said method comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, thereby treating said thrombotic disorder.

17. The method according to claim 16, wherein said compound is selected

N-[(4-fluorophenyl)methyl]- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyridin-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyrimidin-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

N-benzyl- 1 -[(2-methoxyphenyl)carbonyl] -3 -(pyrimidin-5 -yl)- 1 H- 1 ,2,4-triazol-5 -amine

N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyrimidin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

l-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-l-[(2-methoxyphenyl)carbonyl]-lH-l,2,4-triazol-3- yl)azetidin- 1 -yl]-2,2-dimethylpropan- 1 -one

3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5 -amine

3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5- amine N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-methoxyphenyl)carbonyl]-3-(oxolan-2-yl)-lH-l,2,4-triazol-5- amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-benzyl-3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

tert-butyl 3 -(5-amino- 1H- 1 ,2,4-triazol-3 -yl)azetidine- 1 -carboxylate tert-butyl 3 -(5 - { [(5-chlorothiophen-2-yl)methyl] amino } - 1 -[(2-methoxyphenyl)carbonyl] - 1 H- 1 ,2,4-

75

triazol-3 -yl)azetidine- 1 -carboxylate

77 tert-butyl 4-(5-amino- 1H- 1 ,2,4-triazol-3 -yl)piperidine- 1 -carboxylate

78

triazol-3 -yl)piperidine- 1 -carboxylate

80

carboxylate

30 3 -(oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

85 1 -(5-[(4-fluorophenyl)methyl]amino-3 -(pyridin-3 -yl)- 1 H- 1 ,2,4-triazol- 1 -yl)butan- 1 -one

18. A method for ameliorating wound healing, said method comprising administering to a subject in need thereof an effective amount of a compound according to claim 1 , thereby ameliorating wound healing.

19. The method according to claim 18, wherein said compound is selected from:

Cmpd Structure

3 l-benzoyl-N-benzyl-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

8 N-[(4-fluorophenyl)methyl]- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine l-benzoyl-N-benzyl-3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine

N-benzyl- 1 -[(2-chlorophenyl)carbonyl]-3 -(pyridin-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine

3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5 -amine

3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4-dimethoxyphenyl)carbonyl]-3-(oxolan-2-yl)-lH-l,2,4-triazol- 5-amine N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4-dimethoxyphenyl)carbonyl]-3-(oxolan-3-yl)-lH-l,2,4 riazol- 5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine 72 N-benzyl- 1 -[(3 -methoxyphenyl)carbonyl] -3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5 -amine

73 N-benzyl-3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

74 tert-butyl 3 -(5-amino- 1H- 1 ,2,4-triazol-3 -yl)azetidine- 1 -carboxylate

75

triazol-3 -yl)azetidine- 1 -carboxylate

77 tert-butyl 4-(5-amino- 1H- 1 ,2,4-triazol-3 -yl)piperidine- 1 -carboxylate

78

triazol-3 -yl)piperidine- 1 -carboxylate

80

carboxylate

30 3 -(oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

20. A method for mediating tissue repair, said method comprising administering to a subject in need thereof an effective amount of a compound according to claim I, thereby mediating tissue repair.

21. The method according to claim 20, wherein said compound is selected

Cmpd Structure

3 l-benzoyl-N-benzyl-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

5 N-benzyl- 1 -[(2-chlorophenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine N-benzyl- 1 -[(4-chlorophenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

1 -(5 - { [(4-fluorophenyl)methyl] amino } -3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol- 1 -yl)-2-phenylethan- 1 -one

N-[(4-fluorophenyl)methyl]- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyridin-2-yl)- 1 H- 1 ,2,4-triazol-5-amine l-benzoyl-N-benzyl-3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine

3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5 -amine

3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4-dimethoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol- 5-amine N-[(5-chlorothiophen-2-yl)methyl]-l-[(2,4-dimethoxyphenyl)carbonyl]-3-(oxolan-2-yl)-lH-l,2,4 riazol- 5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine 70 N-benzyl- 1 -[(2-methoxyphenyl)carbonyl]-3 -(pyridazin-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

71 N-benzyl-l-[(2-methoxyphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amme

73 N-benzyl-3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

74 tert-butyl 3 -(5-amino- 1H- 1 ,2,4-triazol-3 -yl)azetidine- 1 -carboxylate

75

triazol-3 -yl)azetidine- 1 -carboxylate

77 tert-butyl 4-(5-amino- 1H- 1 ,2,4-triazol-3 -yl)piperidine- 1 -carboxylate

78

triazol-3 -yl)piperidine- 1 -carboxylate

80

carboxylate

30 3 -(oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

22. The method according to claim 20, said mediating tissue repair comprising treatment of peripheral vascular or coronary vascular disease.

23. A method for treating a disease or disorder in a subject, said method comprising administering a compound according to claim 1 to a subject in need thereof in an amount effective to treat the disease or disorder.

24. The method according to claim 23, wherein said compound is selected from: Cmpd Structure

3 l-benzoyl-N-benzyl-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amine

4 l-[5-(benzylammo)-3-(pyridm-2-yl)-lH-l,2,4-triazol-l-yl]-2-phenylethan-l-one

9 l-benzoyl-N-benzyl-3-(pyridin-4-yl)-lH-l,2,4-triazol-5-amine

16

1-one

17

dimethylpropan- 1 -one

18

dimethylpropan- 1 -one

20

yl)azetidin- 1 -yl]-2,2-dimethylpropan- 1 -one

21

yl)azetidin- 1 -yljethan- 1 -one

22

dimethylpropan- 1 -one

24

yl)piperidin- 1 -yl]-2,2-dimethylpropan- 1 -one

25

yl)piperidin- 1 -yljethan- 1 -one

l-[4-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-lH-l,2,4-triazol-3-yl)piperidin-l-yl]-2,2-

26

dimethylpropan- 1 -one

29 3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5 -amine

31 3 -(oxolan-3 -yl)- 1 H- 1 ,2,4-triazol-5-amine

32

methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

3-[l-(benzenesulfonyl)piperidin-4-yl]-N-[(5-chlorothiophen-2-yl)methyl]-l-[(2-

33

methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine

34

N,N-dimethylpiperidine- 1 -carboxamide

35

yl)piperidine- 1 -carboxamide

36

l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-(oxan-4-yl)-lH-l,2,4-triazol-5-amine

N-[(5-chlorothiophen-2-yl)methyl]-3-[l-(cyclohexanesulfonyl)piperidin-4-yl]-l-[(2- methoxyphenyl)carbonyl]-lH-l,2,4-triazol-5-amine N-[(5-chlorothiophen-2-yl)methyl]-3-cyclopentyl-l-[(2-methoxyp

65

amine

67 N-benzyl-l-[(2-fluoro-4-methylphenyl)carbonyl]-3-(pyridin-2-yl)-lH-l,2,4-triazol-5-amme

73 N-benzyl-3 -(oxan-4-yl)- 1 H- 1 ,2,4-triazol-5-amine

74 tert-butyl 3 -(5-amino- 1H- 1 ,2,4-triazol-3 -yl)azetidine- 1 -carboxylate

75

triazol-3 -yl)azetidine- 1 -carboxylate

77 tert-butyl 4-(5-amino- 1H- 1 ,2,4-triazol-3 -yl)piperidine- 1 -carboxylate

78

triazol-3 -yl)piperidine- 1 -carboxylate

80

carboxylate

30 3 -(oxolan-2-yl)- 1 H- 1 ,2,4-triazol-5-amine

25. The method according to claim 23, wherein said disease or disorder is a thrombotic disorder.

26. The method according to claim 25, wherein thrombotic disorder is acute coronary syndrome, venous thromboembolism, arterial thromboembolism or cardiogenic thromboembolism.

27. The method according to claim 23, wherein said disease or disorder is fibrosis.

28. The method according to claim 23, wherein said disease or disorder is Alzheimer's Disease.

29. The method according to claim 23, wherein said disease or disorder is multiple sclerosis.

30. The method according to claim 23, wherein said disease or disorder is pain.

31. The method according to claim 23, wherein said disease or disorder is cancer.

32. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.