Thrombin inhibitors, formulations, and uses thereof

Abstract

To provide thrombin-inhibiting compounds that are useful for the treatment and prevention of thrombin-related diseases and disorders.SOLUTION: The present invention provides compounds according to structure I, or pharmaceutically acceptable salts, solvates, or cocrystals thereof (where R1 is selected from the group consisting of hydrogen and pivaloyl).SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present disclosure generally relates to serine protease inhibitors, formulations, and their uses. The disclosure more particularly relates to compounds, formulations, and methods for thrombin inhibition.

[0002] Cross-reference to Priority Applications and Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 697,817, filed on Jul. 13, 2018, entitled "THROMBIN INHIBITORS, FORMLATIONS, AND USES THEREOF", which is currently co-pending, and the entire disclosure of which is incorporated herein by reference for all purposes.

Background Art

[0003] Serine proteases are a large family of enzymes with diverse biological functions, and their common feature lies in the presence of a serine residue at the active site and its important function. Their central function is the catalytic cleavage of peptide bond substrates via three residues, Ser, His, and Asp, within the active site (Kraut, 1977 J. Annual Review of Biochemistry, 46:331-358).

[0004] Thrombin (fIIa, the active form of prothrombin) is a serine protease involved in the blood coagulation cascade, a mammalian system that addresses vascular damage caused by bleeding events. The cascade includes the intrinsic and extrinsic pathways and involves the activation of at least 13 factors and various cofactors as well as other regulatory proteins that are interrelated. It exists. When vascular injury occurs, plasma factor VII interacts with exposed tissue factor (TF). and a series of complex events are initiated by the resulting TF-fVIIa complex. Factor Xa is produced immediately "downstream" of the TF-fVIIa complex and is amplified several-fold via the intrinsic pathway. Subsequently, FXa acts as a catalyst for thrombin (fIIa) formation, and thrombin activates platelets by cleavage of protease-activated receptors and strengthens the clot by generating fibrin from fibrinogen. As a result, a fibrinolytic clot is formed and hemostasis occurs. Fibrinolysis, which converts the polymeric clot into fibrin monomers, results in lysis and restores the system to a pre-thrombotic state. The cascade is in a complex equilibrium of factors and cofactors and is tightly regulated. In disease states, undesirable upregulation or downregulation of certain factors can lead to conditions such as bleeding or thrombosis. Anticoagulants have historically been used in patients at risk of thromboembolic complications such as angina, stroke, and heart attacks. Warfarin is a vitamin K antagonist that inhibits, among others, factors II, VII, IX, and X. Warfarin inhibits fibrin formation but has significant drug interactions and can cause side effects that are not easily reversible due to its very long half-life (more than 2 days). Furthermore, since vitamin K is a cofactor distributed unevenly within the coagulation cascade, antagonistic effects occur and multiple coagulation factors are inhibited simultaneously, potentially leading to serious bleeding complications.

[0005] In disease states, undesirable upregulation or downregulation of certain factors can lead to conditions such as bleeding or thrombosis. Anticoagulants have historically been used in patients at risk of thromboembolic complications such as angina, stroke, and heart attacks. Warfarin is a vitamin K antagonist that inhibits, among others, factors II, VII, IX, and X. Warfarin inhibits fibrin formation but has significant drug interactions and can cause side effects that are not easily reversible due to its very long half-life (more than 2 days). Furthermore, since vitamin K is a cofactor distributed unevenly within the coagulation cascade, antagonistic effects occur and multiple coagulation factors are inhibited simultaneously, potentially leading to serious bleeding complications. Warfarin inhibits fibrin formation but has significant drug interactions and can cause side effects that are not easily reversible due to its very long half-life (more than 2 days). Furthermore, since vitamin K is a cofactor distributed unevenly within the coagulation cascade, antagonistic effects occur and multiple coagulation factors are inhibited simultaneously, potentially leading to serious bleeding complications. effects occur and multiple coagulation factors are inhibited simultaneously, potentially leading to serious bleeding complications. There is a risk of leading to.

[0006] Heparin is an endogenous inhibitor of antithrombin III, which is an inhibitor of many factors in the coagulation cascade. Since it is a natural polysaccharide that activates II(AT III), it has attracted great attention. Parenteral administration is required for heparin-derived therapeutic agents, and warfarin, which is orally available, has the cumbersome requirement of heavy monitoring, so the discovery and development of orally available drugs with a wide therapeutic range in terms of safety and efficacy are being promoted.

[0007] Thrombin has become popular as a drug discovery target because of its position in the coagulation cascade. Thrombin is a central protein in the coagulation process and is activated and amplified upon vascular injury. Thrombin generation promotes cascades in various factors of the coagulation cascade and ultimately attaches fibrin, which is the framework for the clot. This clot stops the bleeding event associated with vascular injury. Thrombin and related proteins ultimately dissolve the clot via "fibrinolysis" and restore the system to its pre-injury state. In the "normal" state of injury, this generation of thrombin and attachment of the clot are desirable. In disease states, clot attachment is undesirable. Common thrombotic events are the clinical consequences of clot attachment and accumulation in arteries, veins or the heart. When the accumulated clot structure is finally released into the vascular system, the clot will move to the brain and / or lungs, which can lead to stroke, myocardial infarction (heart attack), pulmonary embolism, paralysis and inevitable death. Compounds that inhibit thrombin have been shown in the literature to be useful as anticoagulants in vitro and in vivo, and such compounds can meet the large unmet medical needs of patients in the clinic.

[0008] A complete discussion of thrombin and its role in the coagulation process can be found in various references Wieland, H.A., et al., 2003, Curr Opin Investig Drugs, 4:264 - 71; Gross, P.L. & Weitz, J.I., 2008, Arterioscler Thromb Va sc Biol, 28:380 - 6; Hirsh, J., et al., 2005, Bl ood, 105:453 - 63; Prezelj, A., et al., 2007, Cu rr Pharm Des, 13:287 - 312, all of which are hereby incorporated by reference herein for all purposes. Without wishing to be bound by any theory, the use of direct thrombin inhibitors (DTIs) such as hirudin - based anticoagulants has sufficient precedent, so there is strong interest in the discovery and development of new DTIs.

SUMMARY OF THE INVENTION

[0009] The present invention encompasses compounds according to Structure I:

Chemical formula

[0010] Embodiments of the present invention include prodrugs of the compounds according to claim 1 according to General Structure II:

Chemical formula

[0011] A further embodiment of the present invention includes the compound according to claim 1, wherein R 1 may be pivaloyl as in Compound 1: [Chemical formula] [Chemical formula] .

[0012] In some embodiments, the compound may be in crystalline form.

[0013] In some embodiments where R 1 is pivaloyl as in Compound 1, the crystalline form is , 9.9°, 12.3°, 12.6°, 14.7°, 15.0°, 16.7°, 17.0 °, 17.7°, 18.4°, 18.7°, 19.7°, 20.3°, 22.1°, 22 .5°, 23.2°, and 24.7° and may have a powder x-ray diffraction pattern including at least 5 2θ values selected from the group consisting of, and each of the at least 5 2θ values may be within an error range of ±0.3 °. In some embodiments, the crystalline form is 4.9°, 9.7 °, 14.4°, 16.0°, 16.5°, 17.0°, 18.2°, 18.5°, 19 .2°, 19.7°, 20.2°, 22.8°, 23.3°, 24.0°, 24.5°, .2°, 19.7°, 20.2°, 22.8°, 23.3°, 24.0°, 24.5°, and 24.8° and may have a powder x-ray diffraction pattern including at least 5 2θ values selected from the group consisting of, and each of the at least 5 2θ values may be within an error range of ±0.3° ​ obtained. In some embodiments, the crystalline form has a powder x-ray diffraction pattern comprising at least five 2θ values selected from the group consisting of 8.6°, 9.5°, 11.8°, 12 .4°, 12.9°, 14.2°, 15.2°, 15.5°, 16.5°, 17.2°, 18.8°, 19.1°, 20.1°, 20.9°, and 22.9°, and each of the at least five 2θ values can be within an error range of ±0.3°.

[0014] Embodiments of the invention also include compounds according to Structure I, wherein, like Compound 2, R 1 can be hydrogen:

Chemical formula

[0015] In some embodiments, the compound according to Structure I can be in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt can have a counterion including potassium, calcium , L-arginine, L-lysine, meglumine, and / or tris(hydroxymethyl ) aminomethane. In some embodiments, the counterion can be tris(hydroxymethyl)aminomethane. In some embodiments, the counter ion can be tris(hydroxymethyl)aminomethane and R can be pivaloyl 1 . In some embodiments where the counterion can be tris(hydroxymethyl)aminomethane and R can be pivaloyl 1 , the compound can have 6.8°, 10.0°, 13. 0°, 15.1°, 16.0°, 16.5°, 18.0°, 18.4°, 19.8°, 2 0°, etc. 0.5°, 20.8°, 21.2°, 21.5°, 22.8°, 23.3°, 25.9° having a powder x-ray diffraction pattern comprising at least 5 two-theta values selected from the group consisting of and may be in crystalline form, each of the at least 5 two-theta values being within an error range of ±0.3° obtained.

[0016] In some embodiments, the compound or prodrug can be one of the following compounds: : 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pi razol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid ; 2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]acetic acid; 4-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]butanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]-2,2-difluoropropanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]propenamide; 1-(2-amino-2-methylpropyl)-3-(5-{[(5-chlorothiophen-2 -yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3- yl)-1,2-dihydropyridin-2-one; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3 -hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2- oxo-1,2-dihydropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylbutanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydr opyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(f uran-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydr opyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-chloro-1-oxo-1lambda4-thiophen-2-yl) methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl )-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid; (2S,3S,4S,5R,6S)-6-({3-[3-(5-{[(5-chlorothiophen -2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyr azole-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propano (R)-3,4,5-trihydroxyoxane-2-carboxylic acid; ethyl 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}- 1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo- 1,2-dihydropyridin-1-yl]propanoate; prop-2-en-1-yl 3-[3-(5-{[(5-chlorothiophen-2-yl )methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3- yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate; 2-(a cetyl-oxy)ethyl; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]propanoate; 1-(acetyloxy)ethyl 3-[3-(5-{[(5-chlorothiophen-2-yl yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3 -yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate; ({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1- (2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1, 2-dihydropyridin-1-yl]propanoyl}oxy)methyl 2,2-dimethylprop anoate; (3,5,6-trimethylpyrazin-2-yl)methyl 3-[3-(5-{[(5-ch loro-thiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl) -1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl] Propanoate; ({3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1- (2,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1, 2-Dihydropyridin-1-yl]propanoate}oxy)methyl=(2S)-2-{ ((tert-Butoxy)carbonyl]amino}-3-methylbutanoate; 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl](2H4)propanoic acid; 3-{3-[5-({[5-Chloro(3,4-2H2)thiophen-2-yl](2H2 )methyl}amino)-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3- yl]-2-oxo-1,2-dihydropyridin-1-yl}propanoic acid; and 3-[3-(5-{[(5-Chlorothiophen-2-yl)(2H2)methyl]amino} -1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo -1,2-dihydropyridin-1-yl]propanoic acid.

[0017] Embodiments of the present invention also include one of the aforementioned compounds or prodrugs or more, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and one or more pharmaceutical acceptable excipients.

[0018] Embodiments of the present invention also include a method for treating and / or preventing a target disease or disorder comprising one or more of the aforementioned compounds or prodrugs, or the above administering the described pharmaceutical composition to a subject in need thereof in an amount effective to treat or prevent said disease or disorder is included, including a method.

[0019] In some embodiments of the method, the disease or disorder is a thrombotic disease or disorder and / or may be accompanied by the potential formation of a thrombus that is a blood clot or a thrombus that is a blood clot. In some embodiments, the thrombotic disease or disorder may include acute coronary syndrome, thromboembolism, and / or thrombosis. In some embodiments, thromboembolism may include venous thromboembolism, arterial thromboembolism, and / or cardiogenic thromboembolism. In some embodiments venous thromboembolism may include deep vein thrombosis and / or pulmonary embolism. In some embodiments deep vein thrombosis and / or pulmonary embolism may occur after a medical procedure. In some embodiments, the thrombotic disease or disorder may be accompanied by coagulation failure or disseminated intravascular coagulation. In some embodiments, the subject may be at risk of undergoing percutaneous coronary intervention (PCI). In some embodiments, the thrombotic disease or disorder may be accompanied by the potential formation of a thrombus that is a blood clot or a thrombus that is a blood clot, and may further be accompanied by stroke and / or one or more transient ischemic attacks (TIAs). In some embodiments, the thrombotic disease or disorder accompanied by the potential formation of a thrombus that is a blood clot or a thrombus that is a blood clot may further be accompanied by stroke, and the subject may have non-valvular atrial fibrillation.

[0020] In some embodiments, the thrombotic disease or disorder may be accompanied by the potential formation of a thrombus that is a blood clot or a thrombus that is a blood clot, and may further be accompanied by pulmonary hypertension. In some embodiments Alternatively, pulmonary hypertension can be caused by one or more left heart disorders and / or chronic thromboembolic disease. In some embodiments, pulmonary hypertension can be associated with one or more pulmonary diseases including pulmonary fibrosis (idiopathic or otherwise), and / or hypoxia.

[0021] In some embodiments, the disease or disorder can include fibrosis, Alzheimer's disease, multiple sclerosis, pain, cancer, inflammation, and / or type I diabetes mellitus. In some embodiments the disease or disorder can be associated with recurrent cardiac events after myocardial infarction.

[0022] In some embodiments, venous thromboembolism can be associated with the formation of a thrombus within a vein associated with one or more acquired or genetic risk factors, and / or embolism of a peripheral vein caused by a detached thrombus. In some embodiments, one or more risk factors can include a history of venous thromboembolism.

[0023] In some embodiments, cardiogenic thromboembolism can be due to the formation of a thrombus within the heart associated with arrhythmia, valvular heart disease, prosthetic heart valves or heart disease, and / or embolism of a peripheral artery caused by a detached thrombus. In some embodiments, the detached thrombus can be in the brain (ischemic stroke). In some embodiments, the detached thrombus can cause a transient ischemic attack (TIA). In some embodiments, cardiogenic thromboembolism can be due to non-valvular atrial fibrillation.

[0024] In some embodiments, the thrombosis can be arterial thrombosis. In some embodiments arterial thrombosis can occur in one or more underlying atherosclerotic processes of an artery It can be caused. In some embodiments, one or more fundamental atherosclerotic artery processes narrow or occlude the artery, causing myocardial ischemia (angina pectoris, acute coronary syndrome), causing myocardial infarction, narrowing or occluding the peripheral artery (ischemic peripheral artery disease ), and / or the artery can be narrowed or occluded after a vascular procedure (reocclusion or restenosis after percutaneous coronary intervention or reocclusion or restenosis after percutaneous transluminal angioplasty of the peripheral artery ).

[0025] In some embodiments, treatment or prevention may include adjuvant therapy. In some embodiments, the subject may have had a myocardial infarction, and the adjuvant therapy may be performed along with thrombolytic therapy. In some embodiments, the subject may have unstable angina, thrombosis, and / or heparin-induced thrombocytopenia, and the adjuvant therapy can be combined with antiplatelet therapy. In some embodiments, the subject may have non-valvular atrial fibrillation, and the adjuvant therapy can be performed together with one or more other therapies. In some embodiments, the subject may have at least one of coronary artery disease and heart failure, and the adjuvant therapy can be combined with antiplatelet therapy.

[0026] In some embodiments, the subject may further have valvular or non-valvular atrial fibrillation. In some embodiments, the subject may have valvular or non-valvular atrial fibrillation and may have undergone percutaneous coronary intervention with a stent, and the adjuvant therapy can be combined with antiplatelet therapy.

[0027] Embodiments of the invention also relate to Compound 1 (wherein R 1It includes tablets containing a pharmaceutical composition containing pivaloyl). It includes tablets containing a pharmaceutical composition.

[0028] In some embodiments, Compound 1 can exist as an amorphous solid in an amorphous solid dispersion. In some embodiments, the amorphous solid dispersion can be 50% by weight of the tablet. In some embodiments, the amorphous solid dispersion contains a first polymer. In some embodiments, the first polymer can be a vinyl pyrrolidone-vinyl acetate copolymer. In some embodiments, Compound 1 and the first polymer are present in a weight ratio of 1: 3.

[0029] In some embodiments, the tablet can contain at least one disintegrant. In some embodiments, the disintegrant contains crospovidone. In some embodiments, the tablet can contain at least one filler. In some embodiments, the filler contains microcrystalline cellulose or mannitol. In some embodiments, the tablet can contain at least one lubricant or glidant. In some embodiments, the lubricant or glidant contains magnesium stearate or talc.

[0030] In some embodiments, the tablet can contain an outer layer or film. In some embodiments, the outer layer or film contains at least a second polymer. In some embodiments, the second polymer can prevent dissolution of the tablet at a pH of less than 5.5. In some embodiments, the second polymer can be Eudragit (registered trademark) L30 D-55. The rum contains 57% of Eudragit® L30 D-55, 14.6 of Plas acryl® HTP20, and 28.4% of water. In some embodiments, the second polymer is a methacrylic acid-ethyl acrylate copolymer.

[0031] In some embodiments, the tablet comprises an outer layer of the second polymer, and the tablet without the outer layer may be 50 wt% amorphous solid dispersion, 10 wt% crospovidone, 2 wt% magnesium stearate, 19 wt% microcrystalline cellulose, 18 wt% man nitol, and 1 wt% talc. In some embodiments, the second poly mer may be Eudragit® L30 D-55. In some embodiments, the tablet without the outer layer has a total mass of 180 mg ± 9 mg. In some embodiments, the tablet without the outer layer may have a total mass of 1000 mg ± 50 mg.

[0032] Embodiments of the present invention also include tablets comprising a pharmaceutical composition 1 comprising a prodrug having the general structure II (wherein R is hydrogen or pivaloyl 2 and R is substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl ).

[0033] Embodiments of the present invention also include a process for manufacturing the aforementioned tablets, the process comprising: (1) generating an amorphous solid dispersion of Compound 1; (2) granulating the amorphous solid dispersion of step (1) with the raw materials inside the granules in a dry state; (3) blending the granules of step (2) with the raw materials outside the granules to form a final mixture; (4)​ Compressing the final mixture into tablets; and (5) filling the tablets of step (4) may include coating with a film or layer. In some embodiments, the process comprises: (1) generating an amorphous solid dispersion of Compound 1 using spray drying dispersion (SDD) technology; (2) mixing the amorphous solid dispersion of step (1) with an intragranular raw material comprising at least one disintegrant and at least one lubricant; (3) dry granulating the mixture of step (2), wherein the granulation process comprises forming a compressed ribbon using a roller compactor, and the compressed ribbon is subsequently milled into granules, dry granulating; (4) blending the granules of step (3) with an extragranular raw material from which lumps have been removed and comprising a disintegrant and a lubricant; (5) compressing the blend of step (4) into tablets; and (6) further optionally coating the tablets of step (5) with a film or layer.

[0034] The following detailed description, together with the accompanying drawings, provides a better understanding of the nature and advantages of the present invention.

[0035] Those skilled in the art will understand that the drawings described below are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

[0036] Various embodiments according to the present disclosure are described with reference to the drawings.

Brief Description of the Drawings

[0037]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0038] In the following description, various embodiments are described. For the purpose of the description, specific configurations and details are shown. However, it will also be apparent to those skilled in the art that the embodiments can be practiced without specific details. Further, known features may be omitted or simplified so that the described embodiments are not obscured. To provide a complete understanding of the embodiments, specific configurations and details are shown. However, it will also be apparent to those skilled in the art that the embodiments can be practiced without specific details. Further, known features may be omitted or simplified so that the described embodiments are not obscured. To provide a complete understanding of the embodiments, specific configurations and details are shown. However, it will also be apparent to those skilled in the art that the embodiments can be practiced without specific details. Further, known features may be omitted or simplified so that the described embodiments are not obscured. To provide a complete understanding of the embodiments, specific configurations and details are shown. However, it will also be apparent to those skilled in the art that the embodiments can be practiced without specific details. Further, known features may be omitted or simplified so that the described embodiments are not obscured.

[0039] The techniques described herein and the techniques suggested include various aspects of the present invention.

[0040] I. Definitions Unless otherwise specified, terms are to be understood according to the conventional usage by those skilled in the relevant art. shall be

[0041] The abbreviations used herein have the conventional meanings in the chemical and biological fields. The chemical structures and chemical formulas shown herein are constructed according to the standard rules of chemical valence known in the chemical field. shall be

[0042] When a substituent is specified by the conventional chemical formula described from left to right, the substituent also includes a chemically identical substituent obtained by describing its structure from right to left. For example, -CH2O- is equivalent to -OCH2-. When a substituent is specified by the conventional chemical formula described from left to right, the substituent also includes a chemically identical substituent obtained by describing its structure from right to left. For example, -CH2O- is equivalent to -OCH2-. When a substituent is specified by the conventional chemical formula described from left to right, the substituent also includes a chemically identical substituent obtained by describing its structure from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0043] As used herein, the term "bonded" means a stable covalent bond, certain preferred attachment points will be apparent to those skilled in the art.

[0044] The term "halogen" or "halo" includes fluorine, chlorine, bromine, and iodine. In addition, terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl and mean that. For example, the term "haloalkyl" includes, but is not limited to, fluoromethyl, difluoro methyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like.

[0045] The term "alkyl", by itself or as part of another substituent, unless otherwise indicated, may be fully saturated, monounsaturated or polyunsaturated, and has the specified number of carbon atoms (i.e., C1-C 10 means 1 to 10 carbons), straight-chain (i.e., non branched-chain) or branched-chain, or combinations thereof. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and their homologs and isomers such as n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 1,1-dimethylethyl (tert-butyl), etc. Unsaturated alkyl groups are groups having one or more double or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl , 2-isopentenyl, ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers, but are not limited thereto. In addition, "alkyl" and higher homologs and isomers, but are not limited thereto. In addition, "alkyl" and ​​​The term "alkyl" can refer to linear saturated, branched saturated, linear unsaturated, or branched unsaturated aliphatic hydrocarbon groups, etc. Typically, an alkyl group has 1 to 24 carbon atoms, and an alkyl group having 10 or fewer carbon atoms is preferred in the compounds disclosed herein. The term "lower alkyl" generally refers to a short-chain alkyl group having 8 or fewer carbon atoms.

[0046] The term "alkylene", by itself or as part of another substituent, unless otherwise indicated, refers to a divalent radical derived from a branched or unbranched saturated or unsaturated alkyl as defined above, and includes, but is not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH=CHCH2-, etc. Typically, an alkylene group has 1 to 24 carbon atoms, and an alkylene group having 10 or fewer carbon atoms is preferred in the compounds disclosed herein. The term "lower alkylene" generally refers to a short-chain alkylene group having 8 or fewer carbon atoms.

[0047] The term "heteroalkyl", by itself or in combination with another term, unless otherwise indicated, refers to a linear or branched, or combinations thereof, consisting of at least 1 carbon atom and at least 1 heteroatom selected from the group consisting of O, N, Si, P, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, Si, P, and S may be located at any internal position of the chain. The heteroalkyl group may be fully saturated, monounsaturated or polyunsaturated. Thus, the term "heteroalkyl" The term "heteroalkyl" can refer to a saturated or unsaturated straight-chain or branched-chain, etc. Examples include -CH2 -O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, - CH2-S-CH2-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-C H3, -CH2-CH=N-OCH3, -CN, etc., but are not limited thereto . Up to two heteroatoms may be consecutive, for example, as in -CH2-NH-OCH3 .

[0048] Similarly, the term "heteroalkylene" by itself or as part of another substituent, unless otherwise indicated, means a divalent radical derived from the heteroalkyl defined above , and non-limiting examples include -CH2-CH2-S-CH2-CH2- and -CH2 -S-CH2-CH2-NH-CH2-. Further, for alkylene linking groups and heteroalkylene linking groups, the orientation of the linking group is not suggested by the orientation in which the formula of the linking group is described. For example, the formula -CO2CH2- represents both -C(=O)OCH2- and -CH2OC( =O)-. The terms "cycloalkyl", "cycloalkylene", "heterocycloalkyl", and "hetero cycloalkylene" by themselves or in combination with other terms, unless otherwise indicated, each mean the cyclic form of "alkyl", "alkylene", "heteroalkyl", and " heteroalkylene", respectively. "Cycloalkyl" groups, "cycloalkylene " groups, "heterocycloalkyl" groups, and "heterocycloalkylene" groups include, for example, not only monocyclic rings having 3

[0049] ~8 members, but also bicyclic rings having 4~16 members and tricyclic rings having 5~24 members ​​​​ including a tricyclic ring and the like. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclooctyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 2-piperidinyl, 3-piperidinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 2-piperazinyl, and the like. "Cycloalkylene" and "heterocycloalkylene" each mean a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively, either alone or as part of another substituent.

[0050] The term "alkoxy" refers to an alkyl group as defined above, in which a specified number of carbon atoms are bonded via an oxygen bridge. Examples include methoxy, ethoxy, and the like. The term "alkyleneoxy" refers to a divalent alkoxy group, unless otherwise indicated. Examples of alkyleneoxy groups include -OCH2-, -OCH2CH2-, -OCH=CHCH2-, and the like.

[0051] The term "alkylamino" refers to one or two alkyl or heteroalkyl groups as defined above, in which a specified number of carbon atoms are bonded via an amine bridge. Examples include dimethylamino, ethylamino, and the like. The two alkyl groups and / or heteroalkyl groups, together with the nitrogen to which they are bonded, form a ring system. ​​​​​​​​can be formed, and this ring system has 1 to C 16 alkyl, aryl C0 to C 16 alkyl or, regardless of the presence or absence of a substituent of C0 to C 16 alkylaryl, contains 3 to 8 carbon atoms The term "alkyleneamino" refers to a divalent alkyl amino group, unless otherwise indicated. Examples of alkyleneamino groups include -NHCH2-, -NHCH2CH2 -, -N(CH3)CH2CH2-, and the like.

[0052] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated alkyl group. The double bond can occur at any stable point along the chain, and the carbon-carbon double bond can have either a cis or trans configuration. For example, this definition includes, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl , 1,5-octadienyl, 1,4,7-nonatrienyl, and the like. "Cycloalkenyl" means the cyclic form of an alken yl group, either alone or as part of another substituent. Examples of cycloalkenyl include cyclopentenyl, cyclo hexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenyl cyclopentyl, l-pentenyl-3-cyclohexenyl, and the like. Similarly, " heteroalkenyl" refers to a heteroalkyl having one or more double bonds, where heteroalkyl is as defined above, and "heterocycloalkenyl" refers to the cyclic form of the heteroalkenyl group defined above. where heteroalkyl is as defined above, and "heterocycloalkenyl" refers to the cyclic form of the heteroalkenyl group defined above. ined heteroalkenyl group.

[0053] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated having one or more triple bonds and refers to an alkyl group. The term "cycloalkynyl" refers to a cycloalkyl as defined above having one or more triple bonds. The term "heterocycloalkynyl" refers to a heterocycloalkyl having one or more triple bonds.

[0054] The term "acyl", unless otherwise indicated, refers to an alkyl group of the formula -C(O)R (or shown as -C(=O)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.

[0055] The term "aryl", unless otherwise indicated, means a polyvalent unsaturated aromatic hydrocarbon substituent that can be monocyclic or polycyclic (preferably 1 to 3 rings), and the rings can be fused (i.e., fused-ring aryl) or covalently linked, and each ring contains 4 to 20 atoms, preferably 5 to 10 atoms. Fused-ring aryl refers to a fused polycyclic ring in which at least one of the fused rings is an aryl ring, and each ring contains 4 to 20 atoms, preferably 5 to 10 atoms. The term "heteroaryl" refers to an aryl group (or ring) as defined above containing 1 to 4 heteroatoms selected from N, O, and S, and the nitrogen and sulfur atoms can be optionally oxidized and the nitrogen atom(s) can be optionally quaternized. Accordingly, the term "heteroaryl" refers to a fused-ring heteroaryl group (i.e., fused It includes a condensed polycycle in which at least one of the rings is an aromatic heterocycle. 5,6-membered condensation Ring heteroarylene refers to two condensed rings where one ring is 5-membered, the other ring is 6-membered, and at least one of the rings is a heteroaryl ring. Similarly, 6,6-membered condensed ring he teroarylene refers to two condensed rings where one ring is 6-membered, the other ring is 6-membered, and at least one ring is a heteroaryl ring. 6,5-membered condensed ring heteroaryle ne refers to two condensed rings where one ring is 6-membered, the other ring is 5-membered, and at least one ring is heteroary l ring. Non-limiting examples of aryl groups and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 2-pyrrolyl , 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazo lyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thia zolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3 -thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimi dyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-qui nolyl, 6-quinolyl, 2,3-dihydro-1,4-benzodioxin, etc. . Those skilled in the art will recognize that in a particular ring system, one or more heteroatoms of the heteroaryl system can be optionally substituted (e.g., 1-pyrazole).

[0056] "Arylene" and "heteroarylene", alone or as part of another substituent, each mean a divalent radical derived from aryl and heteroaryl, respectively. Thus the term "aryl" refers to any ring position capable of forming a stable covalent bond covalently bonded at, unsubstituted, mono-substituted, di-substituted, or tri-substituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups, and certain preferred bonding points will be apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl).

[0057] Briefly stated, the term "aryl", when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl rings and heteroaryl rings as defined above. Thus, terms such as "arylalkyl" are intended to include radicals in which an alkylene group links an aryl group to another part of the molecule (e.g., benzyl, phenethyl, pyridylmethyl, etc.). The alkylene groups included in the term "arylalkyl" are those in which a carbon atom (e.g., a methylene group) is substituted by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.), or a sulfur atom substituted alkylene groups. The term "amide", unless otherwise indicated, generally refers to the group -C(O)NR-, wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0058] ​ is selected. The term "amide" alone does not imply a particular bond orientation.

[0059] The term "carboxy", unless otherwise indicated, generally refers to the group -C(O)O- or -CO2-. The term "carboxy" alone does not imply a particular bond orientation .

[0060] The term "oxo", as used herein, means oxygen double-bonded to a carbon atom.

[0061] Each of the above terms (e.g., "alkyl", "heteroalkyl", "aryl", "heteroaryl", etc.) includes both substituted and unsubstituted forms of the specified radical. .

[0062] The group of substituents for a substituted radical includes, but is not limited to, -OR', =O, =NR', = N-OR', -NR''''R'''''',' -SR', -halogen, -SiR'R''R '''', -OC(O)R', -C(O)R', -CO2R', -CONR''''R'' '''', -OC(O)NR''''R'''''',' -NR'C(O)R'', -NR'- C(O)NR''''R'''''',' -NR'C(O)2R'', -NR'-C(NR' '''''R'''''')=NR'', -S(O)R', -S(O)2R', -S(O)2NR ''''R'''''',' -NR'SO2R'', -CN, -NO2, trihalomethyl, C1 ~ 16 alkyl, aryl C1~ 16 alkyl, C0~ 16 alkyloxy C0~ 16 alkyl, a ryl C0~ 16 alkyloxy C0~ 16 alkyl, C0~16 Alkylthio C0~ 16 alkyl, aryl C0~ 16 Alkylthio C0~ 16 alkyl, C0~ 16 Alkylamino C0~ 16 alkyl , aryl C0~ 16 Alkylamino C0~ 16 alkyl, di(aryl C1~ 16 alkyl)a mino C0~ 16 alkyl, C1~ 16 Alkylcarbonyl C0~ 16 alkyl, aryl C1~ 16 a lkylcarbonyl C0~ 16 alkyl, C1~ 16 Alkylcarboxy C0~ 16 alkyl, ari -l C1~ 16 Alkylcarboxy C0~ 16 alkyl, C1~ 16 Alkylamide C0~ 16 alki l, aryl C1~ 16 Alkylamide C0~ 16 alkyl, -C0~ 16 alkyl COOR’, -C0~ 16 alkyl CONR’’’’R’’’’’ generally selected from the group consisting of, wherein , R’, R’’, R’’’, R’’’’ and R’’’’’ are hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalky l, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and also substituted or unsubstituted heteroaryl independently selected from, optionally, R’’’’ and R’’’’’ together with the nitrogen to which they are attached form a ring system, and this ring system is one C1~ 16 alkyl, aryl C0~C16 Alkyl, or C0-C 16 Alkyl a With or without a reel substituent, contains 3 to 8 carbon atoms. Substituted alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, heteroal kyl groups, heteroalkenyl groups, heterocycloalkyl groups, and heterocycloalkenyl groups may have any number of substituents from 0 to (2n + 1), where n is the total number of carbon atoms in such a radical . Substituted aryl groups and heteroaryl groups may have any number of substituents from 0 to the total number of valence atoms on the ring system. Two substituents may optionally combine to form an alkylene group or a heteroalkylene group. In one embodiment, the ring-forming substituent is attached to adjacent members of the basic structure. For example, two ring-forming substituents attached to adjacent members of a cyclic basic structure form a fused ring structure (e.g., 2-amino-3 -ethylbenzene can cyclize to form a 7-(2,3-dihydroindole) group). In another embodiment, the ring-forming substituent is attached to a single member of the basic structure . For example, two ring-forming substituents attached to a single member of a cyclic basic structure form a spi rocyclic structure (e.g., 2-(hydroxymethyl)-2-methyl-cyclohexane can cyclize to form a 2-oxaspiro[3.5]nonane group). In yet another embodiment, the ring-forming substituent is attached to non-adjacent members of the basic structure. For example , two ring-forming substituents attached to non-adjacent members of a cyclic basic structure form a bridged cyclic structure (e.g., 1-aminocyclooctane can cyclize to form 9-aza-[3.3.1] bicyclononane). In a further embodiment, the ring-forming substituent is attached to non-adjacent members of the basic structure. For example , two ring-forming substituents attached to non-adjacent members of a cyclic basic structure form a bridged cyclic structure (e.g., 1-aminocyclooctane can cyclize to form 9-aza-[3.3.1] bicyclononane).

[0063] The term "about" as used in a numerical context, unless otherwise expressly indicated, refers to a range of + / - 10% of that numerical value.

[0064] II. Compounds The present disclosure relates to substituted acylated pyrazole-pyridone compounds. These compounds exhibit biological activities such as inhibitory activity against thrombin, a serine protease.

[0065] Embodiments of the invention include compounds having the following structure I:

Chemical formula

Chemical formula

[0066] In some embodiments, R 1 is pivaloyl, and as a result, the compound is 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]a mino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2- oxo-1,2-dihydropyridin-1-yl]propanoic acid, shown below as Compound 1:

Chemical formula

[0067] In some embodiments, Compound 1 exists in a crystalline form. In one embodiment, the crystalline form, as shown in Figure 1 as Crystal Form 1, has 9.9°, 12.3°, 12.6°, 14.7°, 15.0°, 16.7°, 17.0°, 17.7°, 18.4°, 18.7 °, 19.7°, 20.3°, 22.1°, 22.5°, 23.2°, and 24.7° or selected from the group consisting of, each within an error range of ±0.3°, 1, 2, 3, 4, 5, or more 2θ values, having a powder x-ray diffraction pattern. In another embodiment the crystalline form, as shown in Figure 2 as crystalline form 2, is 4.9°, 9.7°, 1 4.4°, 16.0°, 16.5°, 17.0°, 18.2°, 18.5°, 19.2° , 19.7°, 20.2°, 22.8°, 23.3°, 24.0°, 24.5°, and 2 4.8° selected from the group consisting of, each within an error range of ±0.3°, 1, 2 , 3, 4, 5, or more 2θ values, having a powder x-ray diffraction pattern. In another embodiment, the crystalline form, as shown in Figure 3 as crystalline form 3, is 8.6°, 9 .5°, 11.8°, 12.4°, 12.9°, 14.2°, 15.2°, 15.5°, 16.5°, 17.2°, 18.8°, 19.1°, 20.1°, 20.9°, and 22 .9° selected from the group consisting of, each within an error range of ±0.3°, 1, 2, 3, 4, 5, or more 2θ values, having a powder x-ray diffraction pattern.

[0068] In some embodiments, R 1 is hydrogen, and as a result, compound 2 is as follows 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino} -1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl] propanoic acid:

Chemical formula

[0069] Additional embodiments include salt forms of the compounds encompassed by Structure I that include Compound 1. In these embodiments, the compound exists in a charged state with a counterion. In some embodiments, the counterion can be selected from the group consisting of sodium, potassium, calcium, L-arginine, L -lysine, meglumine, and tris(hydroxymethyl)aminomethane. It can be selected.

[0070] In some embodiments, when Compound 1 is in a salt form having tris(hydroxymethyl) aminomethane as a counterion, the substance is in a crystalline form. In some embodiments wherein Compound 1 is in a salt form having tris(hydroxymethyl)aminomethane as a counterion The crystalline form of Compound 1 has a powder x-ray diffraction pattern that includes a selection of 1, 2, 3, 4, 5, or more 2θ values selected from the group consisting of 6.8°, 10.0°, 13.0°, 15.1°, 16.0°, 16.5°, 18.0°, 18.4°, 19. 8°, 20.5°, 20.8°, 21.2°, 21.5°, 22.8°, 23.3°, and 25.9°, each within an error range of ±0.3°, as shown in Figure 4 as Crystal Form 4. It has.

[0071] Certain embodiments of the present invention relate to certain prodrugs of Structure I and have the general formula of Structure II: In the formula, R

Chemical formula

[0072] In the formula, R 1 is selected from the list consisting of hydrogen and pivaloyl, R​2 is selected from the list of substituted or un substituted alkyl and substituted or unsubstituted heteroalkyl. Further In embodiments, R 2 is selected from the list consisting of the following structures:

Chemical Formula

[0073] In some embodiments, the prodrug of Structure I can be formulated as its pharmaceutically acceptable salts, solvates, and co-crystals.

[0074] Further compounds disclosed herein include the following compounds listed in Table A below:

Table 1

[0075] The compounds disclosed herein can also exist as mixtures with one or more additional compounds and / or as mixtures containing isotope-labeled compounds and radio-labeled compounds. For example, Goding, 1986, MONOCLONAL ANTIBODIES PRINCI PLES AND PRACTICE; Academic Press, p. 104 for reference is desired. Such isomers can be isolated by standard separation techniques, such as fractional crystallization, chiral chromatography, etc. For example, see Eliel, E.L . & Wilen S.H., 1993, STEREOCHEMISTRY IN OR GANIC COMPOUNDS; John Wiley & Sons, New Yo rk. In some embodiments, such mixtures include Compound 1, Compound 2, or both Compound 1 and Compound 2, where such mixtures optionally further include isotopically labeled and radiolabeled compounds, e.g., isotopically labeled and radiolabeled forms of Compound 1, Compound 2, or both.

[0076] The compounds disclosed herein may also contain unnatural proportions of atomic isotopes among one or more of the atoms that make up such compounds. For example, the compounds can be deuterated and / or labeled with carbon-13 ( C) and / or also, for example, tritium ( 13 H 3 ) or carbon-14 ( C) etc., and those skilled in the art 14 will recognize that these isotopes can be present within the scope of the present invention. All isotopic forms of the compounds disclosed herein, whether radioactive or not, are included within the contemplated scope. Exemplary deuterated compounds according to the present invention include Compound Numbers 22, 23, and 24 in Table A, which represent exemplary positions at which the compounds according to the present invention can be deuterated, and those skilled in the art and those understanding chemical principles will know which compounds can be deuterated and at which positions (but not limited to, the compounds in Table A will know which compounds can be deuterated and at which positions (not limited to, the compounds in Table A recognize whether it can be deuterated (including the positions shown in article numbers 22, 23, and 24). would

[0077] In some embodiments, the metabolites of the compounds disclosed herein are useful in the methods disclosed herein.

[0078] Certain compounds disclosed herein may exist in solvated forms, including hydrated forms, as well as in unsolvated forms. Generally, solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the intended compounds. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the compounds and methods contemplated herein and are intended to be within the scope disclosed herein.

[0079] III. Assay The compounds described herein can be assayed by a variety of methods known in the art and described herein for various chemical properties and various biological activities. For example, these parameters include inhibition of thrombin, solubility and stability, as well as pharmacokinetic properties.

[0080] Human thrombin generation assay The human thrombin generation assay (TGA; having the same initials and not to be confused with "thermogravimetric analysis", which is used separately. One of ordinary skill in the art will recognize which meaning is intended based on the context of the surrounding technical information) was generated as follows. In a 96-well plate, 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.137, and 0.0 ​​​​​​​​​​4 μL of a solution of the test compound in 46 μM in DMSO was added to a continuous well filled with 68 μL of the "TGA working solution". For the description of this solution and other related solutions, see below Please refer to the following. The plate was incubated at room temperature for 10 minutes, and then 8 μL of warm "substrate solution" was added to each well to make the substrate Z-GGR-AMC (Z- Gly-Gly-Arg-7-amino-4-methylcoumarin·HCl) at a concentration of 500 μM in each well. The acquisition of fluorescence intensity data (Ex / Em 380 / 460 nm) was immediately started using a Cytation™ or Synergy™ H1 96-well plate reader. The reader was set to shake in an 8-shaped pattern for 4 seconds and then incubate the plate at 37 °C for a 90-minute data acquisition period. The test compound was measured in parallel with wells of the substrate in DMSO at various concentrations (2.50, 0.833, 0.2 78, 0.093 mM) in buffer to generate a standard fluorescence curve, as well as blanks and controls. The data values were automatically calculated, including the ET P EC value, which is the concentration of the compound that reduces the potential AUC of endogenous thrombin by 50%.

[0081] 50

[0081] The various solutions were prepared as follows. The HEPES / NaCl assay buffer was made by combining 7.5 mL of 5 M NaCl, 1.19 g of 4-(2-hydroxyethyl)piperazine- 1-ethanesulfonic acid (HEPES), and 230 mL of water. The "Innovin master solution" was prepared by dissolving 20 μL of Siemens Dade Innovin recombinant tissue in 450 μL of the above HEPES / NaCl assay buffer. The factors and thromboplastin were prepared by combining them with 50 μL of 0.5 mM phospholipid-TGT obtained from DiaPharma®. The solution was then vortexed for several seconds. Next, the "substrate master solution" was prepared by adding 3.2 mL of DMSO to 100 mg of Z-GGR-AMC (Z-Gly-Gly-Arg-7-amino-4-methylcoumarin·HCl) in a polystyrene tube and vortexing. This solution was stored at -20 °C. The "TGA working solution" was prepared by adding 6.2 mL of human plasma, 50 μL of Innovin master solution, and 80 μL of phospholipid to 2.6 mL of HEPES / NaCl assay buffer. The "substrate working solution" was prepared by adding 200 μL of the above "substrate master solution" to a pre-warmed (37 °C) mixture of 1.46 mL of HEPES / NaCl assay buffer and 340 μL of 1 M CaCl2 immediately before adding to the assay plate. For further description of this assay, see Robert, S. et al. ‘Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs?’ 2009, Pharmacol Res 59:160-6 as well as Hemker, H.C. et al. ‘Calibrated automated thrombin generation measurement in clot’ by combining with 50 μL of 0.5 mM phospholipid-TGT obtained from DiaPharma®. The solution was then vortexed for several seconds. Next, the "substrate master solution" was prepared in a polystyrene tube by adding 3.2 mL of DMSO to 100 mg of Z-GGR-AMC (Z-Gly-Gly-Arg-7-amino-4- methylcoumarin·HCl) and vortexing. This solution was stored at -20 °C. The "TGA working solution" was prepared by adding 6.2 mL of human plasma, 50 μL of Innovin master solution, and 80 μL of phospholipid to 2.6 mL of HEPES / NaCl assay buffer. The "substrate working solution" was prepared by adding 200 μL of the above "substrate master solution " to a pre-warmed (37 °C) mixture of 1.46 mL of HEPES / NaCl assay buffer and 340 μL of 1 M CaCl2 immediately before adding to the assay plate. For further description of this assay, see Robert, S. et al. ‘Is

[0082] thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs ?’ 2009, Pharmacol Res 59:160-6 as well as Hemker, H.C. et al. ‘Calibrated automated thrombin generation measurement in clot ’ 2009, Thromb Haemost 102:177-84 For further description of this assay, see Robert, S. et al. ‘Is ting plasma.’ 2003, Pathophysiol Haemost See Thromb 33:4-15, 2003.

[0083] Plasma stability in mice and rats The plasma stability results for mice (CD-1) and rats (SD) were generated as follows Eight μL of a solution of each test compound at 1 mM in DMSO was placed in two wells of a Nunc™ 96-well plate, together with a positive control of propantheline bromide. This was called the “dilution plate”. To one well, 392 μL of HyClone™ water was added and mixed with a pipette. To the other well, 392 μL of mouse plasma or rat plasma stabilized with sodium citrate purchased from Innovative Research was added and mixed with a pipette. To reduce evaporation of the solvent, the dilution plate was covered and heated in an incubator at 37 °C. At each of the time points listed below, the plate was removed from the incubator and 50 μL of the test compound / water or test compound / plasma solution was transferred to the corresponding well in a “quench plate” (a 96-well Costar® plate) containing 150 μL of a quench solution containing an internal standard (20 μM diclofenac in acetonitrile). The dilution plate was then returned to the incubator. This process was carried out at 0, 5, 10, 20, 40, 80, and 160 minutes from the initial mixing of the test compound with water or plasma in the dilution plate. After quenching at the 160-minute time point, the quench plate was then centrifuged at 4 °C and 1000 × g for 10 minutes. Then, 100 μL of the supernatant from each well was transferred to a “read plate” filled with 100 μL of HyClone™ water. This process was carried out at the time points of 0, 5, 10, 20, 40, 80, and 160 minutes from the initial mixing of the test compound with water or plasma in the dilution plate. After quenching at the 160-minute time point, the quench plate was then centrifuged at 4 °C and 1000 × g for 10 minutes. Then, 100 μL of the supernatant from each well was transferred to a “read plate” filled with 100 μL of HyClone™ water. Transferred to the corresponding unique wells in a "plate" (96-well Costar® plate). Subsequently, the plate was sealed and analyzed by UHPLC by injecting 10 μL of the sample into a Phenomenex® Kinetex column pre-equilibrated with loading buffer (95:5 water: acetonitrile). The parameters were as follows. Mobile phase A: water, 0.025% formic acid. Mobile phase B: acetonitrile, 0.025% formic acid. Flow rate: 0.5 mL / min. LC gradient: 0.0 - 0.5 min: hold at 5% B; 0.5 - 2.5 min: 5% - 95% B; 2.5 - 3.0 min: hold at 95% B; 3.0 - 3.05 min: 95% - 5% B; 3.0 - 4.0 min: hold at 5% B. Absorbance was monitored at 254 nm and 280 nm. The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". and transferred to the corresponding unique wells in a "plate" (96-well Costar® plate). Subsequently, the plate was sealed and 10 μL of the sample was used to inject into a Phenomenex® Kinetex column pre-equilibrated with loading buffer (95:5 water: acetonitrile) for UHPLC analysis. The parameters were as follows. Mobile phase A: water, 0.025% formic acid. Mobile phase B: acetonitrile, 0.025% formic acid. Flow rate: 0.5 mL / min. LC gradient: 0.0 - 0.5 min: hold at 5% B; 0.5 - 2.5 min: 5% - 95% B; 2.5 - 3.0 min: hold at 95% B; 3.0 - 3.05 min: 95% - 5% B; 3.0 - 4.0 min: hold at 5% B. Absorbance was monitored at 254 nm and 280 nm. The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". buffer (95:5 water: acetonitrile). The parameters were as follows. Mobile phase A: water, 0.025% formic acid. Mobile phase B: acetonitrile, 0.025% formic acid. Flow rate: 0.5 mL / min. LC gradient: 0.0 - 0.5 min: hold at 5% B; 0.5 - 2.5 min: 5% - 95% B; 2.5 - 3.0 min: hold at 95% B; 3.0 - 3.05 min: 95% - 5% B; 3.0 - 4.0 min: hold at 5% B. Absorbance was monitored at 254 nm and 280 nm. The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". trademark) Kinetex column pre-equilibrated with loading buffer (95:5 water: acetonitrile). The parameters were as follows. Mobile phase A: water, 0.025% formic acid. Mobile phase B: acetonitrile, 0.025% formic acid. Flow rate: 0.5 mL / min. LC gradient: 0.0 - 0.5 min: hold at 5% B; 0.5 - 2.5 min: 5% - 95% B; 2.5 - 3.0 min: hold at 95% B; 3.0 - 3.05 min: 95% - 5% B; 3.0 - 4.0 min: hold at 5% B. Absorbance was monitored at 254 nm and 280 nm. The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". Mobile phase A: water, 0.025% formic acid. Mobile phase B: acetonitrile, 0.025% formic acid. Flow rate: 0.5 mL / min. LC gradient: 0.0 - 0.5 min: hold at 5% B; 0.5 - 2.5 min: 5% - 95% B; 2.5 - 3.0 min: hold at 95% B; 3.0 - 3.05 min: 95% - 5% B; 3.0 - 4.0 min: hold at 5% B. Absorbance was monitored at 254 nm and 280 nm. The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". Flow rate: 0.5 mL / min. LC gradient: 0.0 - 0.5 min: hold at 5% B; 0.5 - 2.5 min: 5% - 95% B; 2.5 - 3.0 min: hold at 95% B; 3.0 - 3.05 min: 95% - 5% B; 3.0 - 4.0 min: hold at 5% B. Absorbance was monitored at 254 nm and 280 nm. The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". LC gradient: 0.0 - 0.5 min: hold at 5% B; 0.5 - 2.5 min: 5% - 95% B; 2.5 - 3.0 min: hold at 95% B; 3.0 - 3.05 min: 95% - 5% B; 3.0 - 4.0 min: hold at 5% B. Absorbance was monitored at 254 nm and 280 nm. The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". Absorbance was monitored at 254 nm and 280 nm. The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". The compound concentration was assumed to vary linearly with the integrated peak area obtained from the wavelength at which the compound exhibited stronger absorbance. The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". The time of the half-life (t1 / 2) was calculated using chi-square analysis by fitting the peak area to an exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". 1 / exponential decay model of compound concentration as a function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". function of time. If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". If less than half of the half-life time had elapsed by the last time point of 160 minutes, the error in the extracted half-life value could be large. Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". Therefore, the half-life time calculated under these circumstances is reported in this document as "≥300 minutes". minutes".

[0084] Mouse and Rat Liver Microsomal Stability The results of mouse (CD-1) and rat (SD) liver microsomal stability were generated as follows. In a 96-well Nunc® plate, 1.5 μL of a 200 μM solution of the test compound in DMSO was placed in the wells. Subsequently, this plate (the "reactant plate") was placed in the wells. Subsequently, this plate (the "reactant plate") 1.5 μL of a 200 μM solution of the test compound in DMSO was placed in the wells. Subsequently, this plate (the "reactant plate") The “-plate”) was warmed to 37 °C in an oven. In the second 96-well Nunc™ plate ( “quench plate”), six wells were filled with 180 μL of an internal standard quench solution composed of 100 nM diclofenac in acetonitrile. These six wells corresponded to six time points for data acquisition: 0, 0.5, 5, 15, 30, and 60 minutes. The “assay buffer” was prepared by combining 6.96 g of dipotassium phosphate, 1.36 g of monopotassium phosphate, and 0.30 g of magnesium chloride hexahydrate, and then diluting to a final volume of 500 mL with water and adjusting the pH to 7.4 if necessary. The assay buffer was warmed to 37 °C and 12 mL was added to a 10 mg vial of NADPH. Then, 300 μL of a 20 mg / mL liver microsome suspension was added to obtain a 0.5 mg / mL liver microsome suspension. Next, 300 μL of this liver microsome suspension was added to the test compound solution in the reaction plate and mixed well with a pipette tip. At each time point, 30 μL of this mixture was transferred to the corresponding well in the quench plate. Between each time point, the reaction plate was sealed and incubated at 37 °C in an incubator. When the last time point was complete, the quench plate was centrifuged at 4 °C, 1000 × g for 10 minutes. Then, 50 μL of the supernatant from each well was transferred to the appropriate well in a 96-well Costar® plate (the “analysis plate”) filled with 150 μL of 50:50 acetonitrile:HyClone™ water. The analysis plate was then sealed with a press-to-seal plate seal and analyzed by an appropriate LCMS method with a 10 μL injection. The extracted AUC data were then automatically plotted to calculate the intrinsic clearance in units of μL / min / mg. This experiment ​​​​​​​​ The assays were performed with positive and negative controls. One skilled in the art would recognize that, due to the parameters of this procedure, the lower limit of quantitation of this assay is 5 μL / min / mg. Thus, a particular compound is classified if its clearance is ≤ 5 μL / min / mg.

[0085] Mouse Pharmacokinetics Mouse pharmacokinetic data were generated as follows. Male CD-1 mice weighing 18 - 25 g were administered the compound either by single intravenous (IV) bolus injection via the tail vein or by single oral (PO) gavage. The nominal doses were 1 mg / kg and 5 mg / kg for IV and PO administration, respectively. The IV dose was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor® (Solutol®) HS15, and 80% sterile water (v / v / v). The PO dose was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 90% Kolliphor® (Solutol®) HS15 and 10% absolute ethanol (v / v).

[0086] Animals were housed in standard holding cages with free access to food and water, except for those used for PO administration which were fasted overnight prior to dosing. At each time point before and after dosing (5 minutes (IV only), 15 minutes, 30 minutes, 60 minutes, 120 minutes, 4 hours, 8 hours, 12 hours, and 24 hours), two animals were sacrificed and blood samples were collected three times by cardiac puncture. By centrifugation, Plasma was obtained and stored frozen until analyzed by LC-MS / MS using an AB Sciex (trademark) QTrap (registered trademark) 5500 connected to a Shimadzu Nexera X2 equipped with a Luna (registered trademark) Omega 1.6μm Polar C18 100Å 50×2.1mm obtained from Phenomenex (registered trademark). Samples were compared to a standard curve of the test compound at concentrations ranging from 10,000 to 0.3 ng / mL. and attached to a Shimadzu Nexera X2 equipped with a Luna (registered trademark) Omega 1.6μm Polar C18 100Å 50×2.1mm obtained from Phenomenex (registered trademark). Samples were compared to a standard curve of the test compound at concentrations ranging from 10,000 to 0.3 ng / mL. Plasma was obtained and stored frozen until analyzed by LC-MS / MS using an AB Sciex (trademark) QTrap (registered trademark) 5500 connected to a Shimadzu Nexera X2 equipped with a Luna (registered trademark) Omega 1.6μm Polar C18 100Å 50×2.1mm obtained from Phenomenex (registered trademark). Samples were compared to a standard curve of the test compound at concentrations ranging from 10,000 to 0.3 ng / mL. Plasma was obtained and stored frozen until analyzed by LC-MS / MS using an AB Sciex (trademark) QTrap (registered trademark) 5500 connected to a Shimadzu Nexera X2 equipped with a Luna (registered trademark) Omega 1.6μm Polar C18 100Å 50×2.1mm obtained from Phenomenex (registered trademark).

[0087] Pharmacokinetic parameters are calculated from mean concentration values using non-compartmental analysis as described below and are apparent to those skilled in the art. The concentration at time zero for IV (C0) was established by extrapolation of a log-linear regression using equal weighting of the first three sample time points. The area under the curve (AUC) values were calculated using linear trapezoidal integration. Pharmacokinetic parameters are calculated from mean concentration values using non-compartmental analysis as described below and are apparent to those skilled in the art. The concentration at time zero for IV (C0) was established by extrapolation of a log-linear regression using equal weighting of the first three sample time points. The area under the curve (AUC) values were calculated using linear trapezoidal integration. Pharmacokinetic parameters are calculated from mean concentration values using non-compartmental analysis as described below and are apparent to those skilled in the art. The concentration at time zero for IV (C0) was established by extrapolation of a log-linear regression using equal weighting of the first three sample time points. The area under the curve (AUC) values were calculated using linear trapezoidal integration. Pharmacokinetic parameters are calculated from mean concentration values using non-compartmental analysis as described below and are apparent to those skilled in the art. The concentration at time zero for IV (C0) was established by extrapolation of a log-linear regression using equal weighting of the first three sample time points. The area under the curve (AUC) values were calculated using linear trapezoidal integration.

[0088] Rat Pharmacokinetics Rat pharmacokinetic data were generated as follows. The compound was administered intravenously (IV) via the tail vein or orally (PO) via gavage to Sprague-Dawley rats weighing nominally 250 - 275 g in which a jugular vein catheter (JVC) had been surgically implanted. The nominal doses were 1 mg / kg for IV and 5 mg / kg for PO. The dose for IV administration was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor (registered trademark) (Solutol (registered trademark)) HS15, and 80% sterile water (v / v / v). The dose for PO administration was formulated either as Option A or Option B. Rat pharmacokinetic data were generated as follows. The compound was administered intravenously (IV) via the tail vein or orally (PO) via gavage to Sprague-Dawley rats weighing nominally 250 - 275 g in which a jugular vein catheter (JVC) had been surgically implanted. The nominal doses were 1 mg / kg for IV and 5 mg / kg for PO. The dose for IV administration was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor (registered trademark) (Solutol (registered trademark)) HS15, and 80% sterile water (v / v / v). The dose for PO administration was formulated either as Option A or Option B. Rat pharmacokinetic data were generated as follows. The compound was administered intravenously (IV) via the tail vein or orally (PO) via gavage to Sprague-Dawley rats weighing nominally 250 - 275 g in which a jugular vein catheter (JVC) had been surgically implanted. The nominal doses were 1 mg / kg for IV and 5 mg / kg for PO. The dose for IV administration was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor (registered trademark) (Solutol (registered trademark)) HS15, and 80% sterile water (v / v / v). The dose for PO administration was formulated either as Option A or Option B. Rat pharmacokinetic data were generated as follows. The compound was administered intravenously (IV) via the tail vein or orally (PO) via gavage to Sprague-Dawley rats weighing nominally 250 - 275 g in which a jugular vein catheter (JVC) had been surgically implanted. The nominal doses were 1 mg / kg for IV and 5 mg / kg for PO. The dose for IV administration was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor (registered trademark) (Solutol (registered trademark)) HS15, and 80% sterile water (v / v / v). The dose for PO administration was formulated either as Option A or Option B. Rat pharmacokinetic data were generated as follows. The compound was administered intravenously (IV) via the tail vein or orally (PO) via gavage to Sprague-Dawley rats weighing nominally 250 - 275 g in which a jugular vein catheter (JVC) had been surgically implanted. The nominal doses were 1 mg / kg for IV and 5 mg / kg for PO. The dose for IV administration was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor (registered trademark) (Solutol (registered trademark)) HS15, and 80% sterile water (v / v / v). The dose for PO administration was formulated either as Option A or Option B. Rat pharmacokinetic data were generated as follows. The compound was administered intravenously (IV) via the tail vein or orally (PO) via gavage to Sprague-Dawley rats weighing nominally 250 - 275 g in which a jugular vein catheter (JVC) had been surgically implanted. The nominal doses were 1 mg / kg for IV and 5 mg / kg for PO. The dose for IV administration was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor (registered trademark) (Solutol (registered trademark)) HS15, and 80% sterile water (v / v / v). The dose for PO administration was formulated either as Option A or Option B. Rat pharmacokinetic data were generated as follows. The compound was administered intravenously (IV) via the tail vein or orally (PO) via gavage to Sprague-Dawley rats weighing nominally 250 - 275 g in which a jugular vein catheter (JVC) had been surgically implanted. The nominal doses were 1 mg / kg for IV and 5 mg / kg for PO. The dose for IV administration was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor (registered trademark) (Solutol (registered trademark)) HS15, and 80% sterile water (v / v / v). The dose for PO administration was formulated either as Option A or Option B. Rat pharmacokinetic data were generated as follows. The compound was administered intravenously (IV) via the tail vein or orally (PO) via gavage to Sprague-Dawley rats weighing nominally 250 - 275 g in which a jugular vein catheter (JVC) had been surgically implanted. The nominal doses were 1 mg / kg for IV and 5 mg / kg for PO. The dose for IV administration was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 5% N,N-dimethylacetamide (DMA), 15% Kolliphor (registered trademark) (Solutol (registered trademark)) HS15, and 80% sterile water (v / v / v). The dose for PO administration was formulated either as Option A or Option B. Done. Option A was formulated by dissolving the test compound at a dose concentration of 0.25 mg / mL in a mixture of 90% Kolliphor® (Solutol®) HS15 and 10% pure ethanol (v / v). Option B was formulated by dissolving the test compound in a mixture of 20% Labrasol® and 80% phosphate buffer at pH 6.8 (v / v). Animals were housed in standard holding cages with free access to food and water, except for those used for PO administration which were fasted overnight prior to dosing. One to three rats were used per experiment. Samples were manually collected via the JVC immediately prior to dosing, as well as at 5, 15, 30, 60, 120 minutes, 4, 8, 12, and 24 hours. Alternatively, samples were automatically collected by transferring the animals to a BASi Culex® automated blood collection system during the experimental period. Plasma was obtained by centrifugation and stored frozen until analyzed by LC-MS / MS using an AB Sciex® QTrap® 5500 connected to a Shimadzu Nexera X2 equipped with a Luna® Omega 1.6μm Polar C18 100Å 50×2.1mm obtained from Phenomenex®. Samples were compared to a standard curve of the test compound at concentrations ranging from 10,000 to 0.3 ng / mL. Pharmacokinetic parameters were calculated from mean concentration values using non-compartmental analysis as described below and apparent to those skilled in the art. The concentration at time zero for IV (C0)

[0089]

[0090] ​​​​​​​​​​​​​​was established by extrapolation of a log-linear regression using equal weighting at the first three sample time points The area under the curve (AUC) value was calculated using linear trapezoidal integration.

[0091] Inhibition of platelet activation in CD-1 mouse plasma Assays for inhibition of platelet activation in mouse plasma were performed according to the following procedure First, the test compound and positive control were serially diluted 3-fold with DMSO to concentrations in the range of 1500 - 0 .08 μM. Then, 2 μL of each sample solution was placed into the corresponding wells of a 96-well plate (the "assay plate") containing 88 μL of platelet-rich plasma (PRP) mix as described below. Next, 10 μL of a 10 nM solution of mouse thrombin in assay buffer (described below) was added to each well of the assay plate. Next the plate was shaken at 300 RPM for 2 minutes on a Titramax shaker from Lab-Line Instruments Inc. Then, 10 μL of Chrono-L ume® solution was added to each well. The plate was shaken again at 300 RPM for 3 minutes . Luminescence data was recorded with a plate reader. Each sample was measured in duplicate against blanks with and without mouse thrombin to record background and maximum signal measurements. IC 50 data was automatically calculated from the luminescence counts measured by means recognized by those skilled in the art. The various solutions included in this procedure are as described below. Assay buffer was prepared by placing 7.5 mL of 5 M NaCl and 1.19 g of HEPES in a 500 mL flask and making up to volume with water. The assay buffer was adjusted to pH 7.4 with NaOH. Mouse thrombin solution was prepared by dissolving mouse thrombin in assay buffer to a concentration of 10 nM. Chrono-L 50 ume® solution was prepared by dissolving Chrono-Lume® in DMSO to a concentration of 1 mM. The luminescence counts were measured using a plate reader. The IC 50 data was automatically calculated from the luminescence counts measured by means recognized by those skilled in the art.

[0092] The various solutions included in this procedure are as follows. Assay buffer was prepared by placing 7.5 mL of 5 M NaCl and 1.19 g of HEPES in a 500 mL flask S powder, 0.5 mL of 1 M MgCl2, 1.5 mL of 1 M KCl and 235 mL of water was prepared by combining. The pH of the solution was adjusted to 7.4 using 10 N NaOH , and then the final volume was made up to 250 mL using water. A 20 mM solution of H-Gly-Pro-Arg-Pro-OH (GPRP) in this assay buffer was prepared from commercially available powder . The PRP mix was prepared by first placing 600 μL of CD-1 mouse whole blood into 1. 8 mL of sodium citrate vacutainer and centrifuging at 100 × g for 10 minutes at room temperature in an Eppendorf 5810 R centrifuge. The plasma layer was then extracted into a storage vial together with as much buffy coat as possible. In many cases, extracts from multiple animals were pooled. To make the final mixture, 2.3 mL of these blood plasma extracts were combined with 7.2 mL of the above assay buffer and 0.5 mL of 20 mM GPRP solution . In this final PRP mixture, the platelet count was approximately 200 × 10 / mL 6 -1 . The mouse thrombin solution was prepared by mixing mouse thrombin obtained from Haematologica l Technologies, Inc. in the above assay buffer to produce a 10 0 nM solution .

[0093] Biological activity The following presentation of biological data is meant to illustrate various aspects of the embodiments and is not intended to limit the present disclosure.

[0094] Table B below shows the ETP EC 50 values of selected compounds in a human thrombin generation assay ​​​is shown. "ND" indicates a compound for which data was not available at the time of filing. [Table 2]

[0095] The following Table C shows the plasma stability and hepatic microsomal clearance of the selected compounds in mice and rats. [Table 3]

[0096] The following Table D shows various pharmacokinetic data of the selected compounds in CD-1 mice. [Table 4]

[0097] The following Table E shows various pharmacokinetic data of the selected compounds in SD rats . [Table 5]

[0098] The following Table F shows the EC 50 of the selected compounds for the inhibition of platelet activation in CD-1 mice. [Table 6]

[0099] IV. Methods for Treating and Preventing Diseases Thrombotic diseases are the first sign of thrombin inhibition. This is because thrombin is located in the coagulation cascade and the coagulation cascade is important in the progression of the blood coagulation process. However, while not wishing to be bound by any theory, generally the coagulation cascade Thrombin, in particular, is thought to be important in a variety of other disease states. 。

[0100] In general, terms such as "treating," "treatment," etc. are used in this specification to mean affecting a subject, tissue, or cell in order to obtain a desired pharmacological and / or physiological effect. The effect can be prophylactic in that it completely or partially prevents a disease or disorder or its symptoms or signs, and / or therapeutic in that it effects a partial or complete cure of a disorder and / or a deleterious effect attributable to the disorder (e.g., pulmonary embolism after a medical procedure). As used herein, "treating" includes any treatment or prevention of a disease or disorder in a vertebrate, mammalian animal, particularly a human, and includes (a) preventing the onset of a disease or disorder in a subject who may be predisposed to the disease or disorder but has not yet been diagnosed as having it; (b) inhibiting, i.e., arresting, the development of a disease or disorder; or (c) relieving or alleviating, i.e., causing regression of, a disease or disorder. The compounds described herein, for example, 3-[3-(5-{[(5-chlorothiophen -2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyraz ol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid and the compounds illustrated in Table A have been found to exhibit an inhibitory effect against thrombin (activated blood coagulation factor II; EC 3. 4.21.5). As a result, this will inhibit the blood coagulation process. 。 。

[0101] The compounds described herein, for example, 3-[3-(5-{[(5-chlorothiophen -2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyraz ol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid and the compounds illustrated in Table A have been found to exhibit an inhibitory effect against thrombin (activated blood coagulation factor II; EC 3. 4.21.5). As a result, this will inhibit the blood coagulation process. 。

[0102] This inhibitory effect is useful in the treatment of various thrombotic disorders, such as, but not limited to, acute coronary syndrome and other acute vascular diseases; the treatment of venous, arterial and cardiogenic thromboembolism; the prevention of other situations such as disseminated intravascular coagulation, or other conditions associated with the presence or potential formation of a thrombus which is a blood clot. Other indications for the methods described herein are as follows.

[0103] Known thrombin inhibitors have been reported to be useful in the treatment and prevention of acute coronary syndrome (ACS) (Clemens, A. et al. WIPO Patent Application No. WO / 200 8 / 009638). ACS is a group of symptoms caused by myocardial ischemia. The drug can be used as a prevention of myocardial infarction or for a certain period after an event (e.g., after myocardial infarction, M I; i.e., long-term therapy, secondary prevention). Without wishing to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful in the treatment and prevention of acute coronary syndrome.

[0104] Non-valvular atrial fibrillation is a persistent cardiac disorder often associated with heart disease. Known thrombin inhibitors such as ximelagatran have been reported to be useful in the prevention of stroke in patients with non-valvular atrial fibrillation (Diener H.-C. Cerebro vasc Dis 2006;21:279-293).

[0105] The selective thrombin inhibitor ximelagatran has been tested in two Phase III clinical trials ((S PORTIF III and SPORTIF V) for the prevention of cardiac thromboembolic events in patients with non-valvular atrial fibrillation, comparing ximelagatran with warfarin The investigators in the SPORTIF III clinical trial compared coagulation monitoring with Fixed-dose ximelagatran without cross-linking reduces the risk of developing high-risk patients with atrial fibrillation It protects against thromboembolism as effectively as well-controlled warfarin and Combining the results from SPORTIF III and V, Ximelagatran was shown to reduce the incidence of all strokes (ischemic or hemorrhagic), systemic embolic events, It was associated with a 16% relative risk reduction in the combined outcome measure of major bleeding and death . (Olsson,SB,2003,Lancet,362(9397):1691 -1698;Hirsh,J.,2005 et al.Blood,105(2):4 53-463; Clemens, A. et al. WIPO Patent Application No. WO / 2008 / Without wishing to be further bound by any theory, Thrombosis We believe that inhibition of AF may be useful in preventing stroke in individuals with atrial fibrillation in general. It is appropriate to

[0106] A transient ischemic attack (TIA) is a temporary neurological impairment that typically lasts no more than an hour. is an acute episode of cerebrovascular disease resulting from focal ischemia of the brain, spinal cord, or retina, with acute tissue infarction In people who have a TIA, the incidence of subsequent strokes is The short-term risk of stroke after a TIA is 11% in the first 5 years and 24-29% in the next 5 years. Given the high risk of developing thromboembolism, many physicians recommend that antithrombotic therapy be initiated as soon as intracranial hemorrhage is ruled out. Stroke prevention drugs typically recommended for cardioembolic TIA The following are some of the reasons for this: Patients with atrial fibrillation after TIA should be treated with long-term anticoagulation with warfarin ( When oral anticoagulants cannot be taken, aspirin (325 mg / day); acute myocardial infarction (MI) due to left ventricular thrombus requires oral anticoagulation with warfarin; for ischemic coronary artery disease (CAD) aspirin up to 162 mg / day is used in combination; in dilated cardiomyopathy, oral anticoagulation with warfarin or antiplatelet therapy; in rheumatic mitral valve disease, oral anticoagulation with warfarin For patients with cardiac source TIA and ischemic stroke caused by atrial fibrillation, vitamin K antagonists (VKAs) are extremely effective in preventing recurrent ischemic stroke, but due to significant constraints, they are not used sufficiently. Antiplatelet therapy is less effective than VKAs. The direct thrombin inhibitor dabigatran etexilate showed greater efficacy than warfarin in trials. In 2010, other new anticoagulants were evaluated, including the factor Xa oral inhibitors rivaroxaban, apixaban, and edoxaban, the factor Xa parenteral inhibitor idraparinux, and the new VKA, tecarfarin. (Hankey, G.J.; Eikelboom, J.W., 2010, ‘Antithrombotic Drugs for Patients with Ischaemic Stroke and Transient Ischaemic Attack to Prevent Recurrent Major Vascular Events.’ The Lancet Neurology, 9(3):273 - 284. ) (Hankey,G.J.;Eikelboom,J.W.,2010,‘Antith rombotic Drugs for Patients with Ischaem ic Stroke and Transient Ischaemic Attack to Prevent Recurrent Major Vascular Eve nts.’ The Lancet Neurology,9(3):273 - 284. )

[0107] Known thrombin inhibitors are associated with acquired risk factors (long - term bed rest, surgery, trauma, malignancy, pregnancy and the postpartum state) or genetic risk factors (deficiency of natural coagulation inhibitors). It is useful for the treatment of venous thromboembolism caused by the formation of thrombi in veins (venous thrombosis). This has been reported (Marsic, L.P. et al. WIPO Patent Application No. WO / 2 003 / 048155). Without wishing to be further bound by any theory, thrombin inhibition is generally considered to be useful for the treatment of venous thromboembolism caused by the formation of thrombi in veins associated with acquired or genetic risk factors, and / or the embolism of peripheral veins caused by detached thrombi. It is reasonable to consider that it may be useful for the treatment of venous thromboembolism. An example of an acquired risk factor may be a history of venous thromboembolism.

[0108] Known thrombin inhibitors are useful for the treatment of cardiogenic thromboembolism caused by the formation of thrombi in the heart associated with arrhythmia, heart failure, artificial heart valves or heart diseases, and the embolism of peripheral arteries most commonly caused by detached thrombi in the brain (ischemic stroke). See Marsic, L.P. et al. WIPO Patent Application No. WO / 200 3 / 048155. Without wishing to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of cardiogenic thromboembolism.

[0109] Known thrombin inhibitors narrow or occlude arteries, cause myocardial ischemia (angina pectoris, acute coronary syndrome) or myocardial infarction, narrow or occlude peripheral arteries (ischemic peripheral arterial diseases), narrow or occlude arteries after vascular procedures (reocclusion or restenosis after percutaneous coronary angioplasty, reocclusion or restenosis after percutaneous transluminal angioplasty of peripheral arteries), and are useful for the treatment of arterial thrombosis caused by the underlying atherosclerotic process in arteries. ​​​​​​​​has been reported. Marsic, L.P. et al. See WIPO Patent Application No. WO / 20 03 / 048155. Without wishing to be bound by any theory, it is considered plausible that thrombin inhibition may generally be useful in the treatment of arterial thrombosis.

[0110] Known thrombin inhibitors have been reported to be useful in the prevention of recurrent cardiac events after myocardial infarction. The selective thrombin inhibitor ximelagatran has been tested in a Phase II clinical trial called ESTEEM, and the efficacy and safety of ximelagatran, a direct oral thrombin inhibitor, were measured in patients with subacute myocardial injury. The results of the ESTEEM trial support the concept that long-term treatment with direct oral thrombin inhibitors reduces arterial thrombotic events. Oral ximelagatran in combination with acetylsalicylic acid was more effective than acetylsalicylic acid alone in reducing the frequency of major cardiovascular events during 6 months of treatment in patients with subacute myocardial infarction. (Hirsh, J., 2005, et al. Blood, 105(2):453 - 463.). Without wishing to be bound by any theory, it is considered plausible that thrombin inhibition may generally be useful in the prevention of recurrent cardiac events after myocardial infarction.

[0111] Known thrombin inhibitors have been reported to be useful in the postoperative prevention of deep vein thrombosis. The selective thrombin inhibitor ximelagatran has been found to be effective in the prevention of venous thromboembolism after medical procedures such as total hip or knee arthroplasty. (Fr ​​​​​​​ancis, C.W. et al., 2002, Ann Intern Med, 137 : 648 - 55; Heit, J.A., 2001, et al. Arch Intern Med, 161: 2215 - 21; Eriksson BI et al., 2003 , Thromb Haemost, 89: 288 - 96). Although we do not wish to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the postoperative prevention of deep vein thrombosis. Although we do not wish to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the postoperative prevention of deep vein thrombosis. Although we do not wish to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the postoperative prevention of deep vein thrombosis.

[0112] Known thrombin inhibitors such as dabigatran have been reported to be useful for the long - term treatment of pulmonary embolism. (Robertson L, Kesteven P, McCasl in JE. Cochrane Database Syst Rev. 2015 De c 4; 12). Although we do not wish to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary embolism. Although we do not wish to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary embolism.

[0113] Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension. Dabigatran, a selective thrombin inhibitor, has been published as a drug useful for the treatment of pulmonary arterial hypertension (PAH). Furthermore, dabigatran has been found to be useful for the treatment of (i) pulmonary hypertension caused by left - heart impairment, (ii) pulmonary hypertension associated with lung diseases such as pulmonary fibrosis, especially idiopathic pulmonary fibrosis, and / or hypoxia, and (iii) pulmonary hypertension caused by chronic thromboembolic diseases. (Feuring, M. WIPO Patent Application No. WO / 2010 Although we do not wish to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Although we do not wish to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. Although we do not wish to be further bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. / 020600). Although we do not wish to be further bound by any theory, it is reasonable to consider that throm bin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. It is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension. It is.

[0114] Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension caused by left heart disorders (Feuring, M. WIPO Patent Application No. WO / 2010 / 0 20600). Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension caused by left heart disorders. inhibition may generally be useful for the treatment of pulmonary arterial hypertension caused by left heart disorders. It is reasonable.

[0115] Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary arterial hypertension associated with any lung disease, particularly idiopathic pulmonary fibrosis and / or hypoxemia (Feuring, M. WIPO Patent Application No. WO / 2010 / 020600). Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary arterial hypertension associated with lung diseases. inhibition may generally be useful for the treatment of pulmonary arterial hypertension associated with lung diseases. inhibition may generally be useful for the treatment of pulmonary arterial hypertension associated with lung diseases. It is reasonable.

[0116] Known thrombin inhibitors have been reported to be useful for the treatment of pulmonary hypertension caused by chronic thromboembolic diseases (Feuring, M. WIPO Patent Application No. WO / 2010 / 0 20600). Without wishing to be bound by any theory, it is reasonable to consider that thrombin inhibition may generally be useful for the treatment of pulmonary hypertension caused by chronic thromboembolic diseases. inhibition may generally be useful for the treatment of pulmonary hypertension caused by chronic thromboembolic diseases. It is reasonable.

[0117] Known thrombin inhibitors are used in many conditions where activation of thrombosis causes coagulation failure with extensive thrombosis in the vascular system (e.g., complications during pregnancy, metastatic malignant diseases, extensive thrombosis in the vascular system (e.g., complications during pregnancy, metastatic malignant diseases, extensive It has been reported to be useful for the treatment of disseminated intravascular coagulation in septic shock after extensive injury (see Marsic, L.P. et al., WIPO Patent Application No. WO / 2003 / 0 48155). Without wishing to be bound by any further theory, it is considered appropriate that thrombin inhibition may generally be useful for the treatment of disseminated intravascular coagulation.

[0118] Known thrombin inhibitors have been reported to be useful for the prevention of coagulation in patients undergoing percutaneous coronary intervention. Percutaneous coronary intervention (PCI) requires invasive anticoagulant therapy and has historically been achieved with unfractionated heparin. However, heparin is contraindicated in many patients, particularly in patients with heparin-induced thrombocytopenia ( HIT). In such cases, the intravascular destruction and hypercoagulable state characterizing HIT mean that the patient is at risk of thrombosis during PCI. (Lewis, B.E. et al., 2002, Catheterization and cardiovascular interventions, 57(2):177 - 184; Kokolis, S et al., 2004, Progress in ca rdiovascular diseases, 46(6):506 - 523.) In the clinical setting, bivalirudin, which has already been claimed as a thrombin inhibitor and also as a useful anticoagulant, has also been published as a secondary treatment agent for percutaneous intervention cardiac catheterization. (Reilly et al., WIPO Patent Application No. WO / 2010 / 020602). Without wishing to be bound by any further theory, thrombin inhibition may generally (see Reilly et al., WIPO Patent Application No. WO / 2010 / 020602). Without wishing to be bound by any further theory, thrombin inhibition may generally It is considered that it may be useful for the prevention of coagulation in patients undergoing percutaneous coronary intervention is appropriate.

[0119] Known thrombin inhibitors have been reported to be useful as adjuvant therapies in combination with thrombolytic therapy in recent myocardial infarction, in combination with aspirin in patients with unstable angina who are planned to undergo percutaneous transluminal angioplasty, and in the treatment of patients with thrombosis and heparin-induced thrombocytopenia (Marsic, L.P. et al. WIPO Patent Application No. WO / 2003 / 048155). Without wishing to be further bound by any theory it is considered appropriate that thrombin inhibition may generally be useful as an adjuvant therapy with other antithrombotic therapies and. It has long been recognized that venous thrombosis is associated with cancer progression, but it is not known how the respective diseases are related to each other. Meta-analyses from several clinical trials studying the treatment of VTE have shown that low molecular weight heparin (LMWH) improves the overall survival of a subpopulation of cancer patients

[0120] . For example, see Zacharski, L.R. & Lee, A.Y. , 2008, Expert Opin Investig Drugs, 17:1029 -1037; Falanga, A. & Piccioli, A., 2005, Curr ent Opinion in Pulmonary Medicine, 11:403- 407; Smorenburg, S.M., et al., 1999, Thromb H aemost, 82:1600-1604; Hettiarachchi, R.J., e t al., 1999, Thromb Haemost, 82:947-952 Please refer to ​​ is desired. This finding has been demonstrated in late-stage clinical trials that specifically measured the survival of cancer patients . For example, Lee, A.Y. et al., 2005, J Clin Oncol, 23 : 2123-2129; Klerk, C.P. et al., J Clin Oncol 2005, 23: 2130-2135; Kakkar, A.K., et al., 20 04, J Clin Oncol, 22: 1944-1948; Altinbas, M. , et al., 2004, J Thromb Haemost, 2: 1266-127 1. See reference

[0121] More recently, researchers have focused on the specific anti-cancer effects of DTI. For example, he parin has been shown to significantly extend the survival of patients with limited-stage small cell lung cancer. For example, A kl, E.A., et al., 2008, J Exp Clin Cancer Re s, 27: 4. See reference. Other researchers have found that in a rat glioma model, systemic use of argatroban reduced the tumor mass and extended the survival period. Therefore it was concluded that argatroban should be considered a novel therapeutic agent for glioma, a cancer type known for its difficult treatment . For example, Hua, Y., et al., 20 05, Acta Neurochir, Suppl 2005, 95: 403-406; Hua, Y., et al., 2005, J Thromb Haemost, 3: 19 17-1923. See reference. Very recently, dabigatran etexilate, a DTI recently approved by the FDA for the indication of DVT (for example, Hughes, B., 2010 ; see Nat Rev Drug Discov, 9: 903-906), has been shown to have an effect on malignant breast tumors . ​ Both invasion and metastasis were demonstrated to be suppressed. For example, DeFeo, K. et a l., 2010, Thrombosis Research, 125 (Suppleme nt 2): S188 - S188; Defeo, K., et al., 2010, Can cer Biol Ther, 10: 1001 - 1008. Thus, in dabigatran etexilate - treated mice, tumor volume decreased by 50% in 4 weeks without weight loss. Dabigatran etexilate also reduced tumor cells in blood and liver micrometastases by 50 - 60%. These researchers concluded that dabigatran etex ilate may be beneficial not only in preventing thrombotic events in cancer patients but also as an adjuvant therapy for treating malignant tumors.

[0122] In further studies, the applicability of anticoagulants for the treatment of patients with coronary artery disease and / or peripheral artery disease was investigated. In the COMPASS trial, an improvement in cardiovascular outcomes was observed in patients treated with rivaroxaban in combination with antiplatelet therapy. For example, see Eikelboom, J. W., et al. 2017, N Engl J Med, 377: 1319 - 30. Furthermore, in the COMMANDER trial, the usefulness of rivaroxaban for improving cardiovascular outcomes in patients with coronary artery disease, including patients with heart failure, particularly those with heart failure with reduced ejection fraction (HF - rEF), was investigated. For example, see Zannad, F., et al., 2015 European Journal of Heart Failure, 17: 735 - 42. see Therefore, anticoagulants may be useful in adjuvant therapy in a subject having at least one of coronary artery disease and heart failure and the adjuvant therapy may further include antiplatelet therapy .

[0123] The European Society of Cardiology recommends the use of an anticoagulant in combination with antiplatelet therapy in patients with valvular or non-valvular atrial fibrillation and a history of at least one acute coronary syndrome event . For example, see Kirchhof, P., et al., 2016, European Heart Journal, 37:2893-2962 . Therefore, anticoagulants may be useful in adjuvant therapy in a subject having atrial fibrillation and at least one of coronary artery disease and heart failure and the adjuvant therapy may further include antiplatelet therapy . The European Society of Cardiology also recommends the use of an anticoagulant in combination with antiplatelet therapy in subjects with valvular or non-valvular atrial fibrillation undergoing elective percutaneous coronary intervention (PCI) with stent . For example, see Kirchhof, P., et al., 2016, European Heart Journal, 37:2893-2962 . Therefore, anticoagulants may be useful in adjuvant therapy in a subject with valvular or non-valvular atrial fibrillation undergoing percutaneous coronary intervention with stent and the adjuvant therapy may further include antiplatelet therapy . chhof, P., et al., 2016, European Heart Journal, 37:2893-2962 . Therefore, anticoagulants may be useful in adjuvant therapy in a subject with valvular or non-valvular atrial fibrillation undergoing percutaneous coronary intervention with stent and the adjuvant therapy may further include antiplatelet therapy .

[0124] Furthermore, hirudin and LMWH nadroparin dramatically reduced the number of lung metastases when administered prior to cancer cell inoculation . For example, see Hu, L., et al., 2004, Blood ​Please see od, 104:2746-51.

[0125] A novel thrombin inhibitor, d-Arg-Oic-Pro-d-Ala-Phe(p -Me) concentration-dependently blocked thrombin-stimulated invasion of prostate cancer cell line PC-3. For example, Nieman, MT, et al., 2008, J See Thromb Haemost, 6:837-845. A slowing of tumor growth rate was observed in mice given methadone via drinking water. The mice also showed a fold increase in tumor size compared to untreated mice. The treated tumors also showed a reduction in IL-1 expression and overall tumor weight. The pentapeptide was shown to inhibit tumor angiogenesis by reducing the number of large blood vessels. It was concluded that this prevented the omb Haemostasis,104:1044-8.

[0126] Considering these and related studies, anticoagulants may play a role in preventing tumor metastasis, i.e., angiogenesis. , suggesting that it may affect cancer cell adhesion, migration and invasion processes. Noorden,CJ,et al.,2010,Thromb Res,125 See Suppl 2:S77-79.

[0127] Several studies have shown the benefit of anticoagulant therapy in fibrotic disorders. For example, in a rat model of CCl4-induced chronic liver injury, the DTI SSR1822 89 significantly reduced liver fibrosis after 7 weeks of treatment. Similar observations have also been made in other studies using tinzaparin, enoxaparin, and dalteparin sodium. For example, see Duplantier, J.G., et al., 20 04, 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. Thus, thrombin inhibitors as anticoagulants may be useful in the treatment of fibrinolytic diseases.

[0128] In another example, melagatran, a DTI, significantly reduced ischemia-reperfusion injury in a renal transplantation model in large Yorkshire pigs. As a result, kidney graft engraftment at 3 months was dramatically improved. For example, see Favreau, F., et al., 2010, Am J Transplant, 10:30-39.

[0129] In a recent study, in a mouse model of bleomycin-induced pulmonary fibrosis, treatment with dabigatran etexilate reduced important fibrosis-promoting events in pulmonary fibroblasts, including the production of collagen and connective tissue growth factor. For example, see Silver, R.M., et al., 2010, Am.J.Respir.Crit.Car e Med., 181:A6780; Bogatkevich, G.S., et al. , 2009, Arthritis Rheum, 60:3455-3464.

[0130] The above experimental evidence points to a close relationship between thrombin and fibrosis, suggesting new treatment possibilities for fibrosis using thrombin inhibitors. For example, Calva ruso, V., et al., 2008, Gut, 57:1722-1727; Cha mbers, R.C., 2008, Br J Pharmacol, 153 Suppl 1:S367-378; Chambers, R.C. & Laurent, G.J., 2002, Biochem Soc Trans, 30:194-200; Howell , D.C., et al., 2001, Am J Pathol, 159:1383-1 395. See also

[0131] In very recent experiments, it has been confirmed that thrombin levels are higher in the brain endothelial cells of Alzheimer's disease patients. Since "normal" thrombin levels are related to regulatory CNS function, the accumulation of thrombin in the brain is toxic. Also, in the brains of Alzheimer's disease patients, protease nexin 1 (PN-1), a nervous system thrombin inhibitor, has been found to be significantly reduced despite the fact that the mRNA levels of PN-1 remain unchanged. These observations have led some researchers to suggest that a decrease in constitutive thrombin in the CNS may be useful for the treatment of Alzheimer's disease (AD). For example, see Vaughan, P.J., et al., 1994, Brain Re s, 668:160-170; Yin, X., et al., 2010, Am J Pa thol, 176:1600-1606; Akiyama, H., et al., 199 2, Neurosci Lett, 146:152-154. ​​​​​​​

[0132] Researchers have found that hirudin treatment in an animal model of multiple sclerosis (MS) shows a dramatic improvement in disease severity. For example, see Han, M. H., et al., 2008, Nature, 451: 1076 - 1081. Similar results were also obtained after treatment with heparin (DTI) and another anticoagulant, dermatan sulfate. For example, see Chelmicka - Szorc, E. & Arnason, B. G., 1972, Arch Neurol, 27: 153 - 158; Inaba, Y., et al., 1999, Cell Immunol, 198: 96 - 102. Other evidence also shows that naturally occurring antithrombin III has an anti - inflammatory effect in diseases such as endotoxemia and other sepsis - related conditions. For example, see Wiedermann, C. J. & Romisch, J., 2002, Acta Med Austriaca, 29: 89 - 92. The naturally occurring thrombin inhibitor is probably synthesized in situ and has a protective role in CNS inflammation. Therefore, therapeutic thrombin inhibition has been proposed as a candidate for MS treatment. For example, see Luo, W., et al., 2009, In: THROMBIN, Maragoudakis, M. E.; Tspanoglou, N. E., Eds. Springer New York: 2009; pp 133 - 159. For example, see Han, M. H., et al., 200 8, Nature, 451: 1076 - 1081. See also heparin (DTI) and treatment with another anticoagulant, dermatan sulfate, gave similar results. For example , see Chelmicka - Szorc, E. & Arnason, B. G., 1972, A rch Neurol, 27: 153 - 158; Inaba, Y., et al., 19 99, Cell Immunol, 198: 96 - 102. Naturally occurring antithrombin III has an anti - inflammatory effect in diseases such as endotoxemia and other sepsis - related conditions. For example , see Wiedermann, C. J . & Romisch, J., 2002, Acta Med Austriaca, 29 : 89 - 92. The naturally occurring thrombin inhibitor is probably synthesized in si tu and has a protective role in CNS inflammation. Therefore, therapeutic throm bin inhibition has been proposed as a candidate for MS treatment. For example, see Luo, W., et al . 2009, In: THROMBIN, Maragoudakis, M. E.; Tso panoglou, N. E., Eds. Springer New York: 2009 ; pp 133 - 159.

[0133] In a rat pain model with a partially damaged sciatic nerve, intrathecal hirudin prevented the development of neuropathic pain and suppressed the pain response for 7 days. The researchers found that after injury, neuropathic pain ​Pain is mediated by thrombin generation, and thrombin activates the PAR-1 receptor in the spinal cord It has been found that. Hirudin inhibits thrombin generation and ultimately results in pain relief For example, see Garcia, P.S., et al., 2010, Thromb Hae most, 103:1145-1151; Narita, M., et al., 2005 , J Neurosci, 25:10000-10009. The researchers hypothesize that thrombin and PAR are involved not only as part of the coagulation cascade, but also in inflammation, pain sensation and neurogenesis. The development of DTI that delves into unexploited pharmacology will lead to pain therapeutics different from opioids and NSAIDs, whose drawbacks have been reported in detail See, for example, Garcia 2010 (ibid). Known thrombin inhibitors are used in inflammation (Kirk, I. WIPO Patent Application No. WO / 200 0 / 041716), type I diabetes mellitus (Korsgren, O.; Nillson, B . WIPO Patent Application No. WO / 2003 / 061682), cancer (Kakkar, A.K . et al., 2004, J Clin Oncol, 2, (10):1944-8; Hua, Y. et al., 2005, Acta Neurochir Suppl, 9 5:403-6; Nieman, M.T. et al., 2008, J Thromb Haemost, 6:837-845; Van Ryn, J.; Clemens, A.W IPO Patent Application No. WO / 2010 / 020601), fibrosis (Duplantier, J.G. et al., 2004, Gut, 53:1682-1687; Seijo, S . et al., 2007, J Hepatol, 46:286-294; Assy, N . et al., 2007, J Hepatol, 46:286-294; Assy, N . et al., 2007, J Hepatol, 46:286-294; Assy, N . et al., 2007, Dig Dis Sci, 52: 1187 - 1193; Bo gatkevich, G. S. et al., 2009, Arthritis Rheu m, 60: 3455 - 3464), and pain (Garcia, P. S. et al., 2 010, Thromb Haemost, 103: 1145 - 1151; Narita, M. et al., 2005, J Neurosci, 25: 10000 - 10009) have been reported to be useful for the treatment of. A meta - analysis of clinical trials studying the use of anticoagulants in cancer patients showed that low - molecular - weight heparin (LMWH), a selective thrombin inhibitor improved the overall survival of a sub - population of cancer patients. This finding was verified in late - stage clinical trials that specifically measured the survival of cancer patients, specifically the FAMOUS clinical trial . Without wishing to be further bound by any theory, it is considered reasonable that thrombin inhibition may generally be useful for the treatment of inflammation, diabetes mellitus, cancer, fibrosis, or pain .

[0134] V. Pharmaceutical Compositions In another aspect, a pharmaceutical composition is provided that comprises a compound disclosed herein and a pharmaceutically acceptable excipient . The compound is a compound of Structure I disclosed herein, or a compound shown as Compound 1 or Compound 2 herein, or a pharmaceutically acceptable salt or solvate thereof .

[0135] The term "pharmaceutically acceptable salt" refers to a salt of an active compound prepared using relatively non - toxic acids or bases depending on the specific substituents found on the compounds described herein . means comprising. This treatment of the active compound with a relatively non-toxic acid or base results in the formation of the ionic forms of the active compound and the counterion.

[0136] When the compounds disclosed herein contain relatively acidic functional groups such as -NHSO3H, -COOH, and -P(O)(OH)2 etc., the neutral form of such compounds can be obtained by contacting the neutral form, either as such or in a suitable inert solvent, with a sufficient amount of the desired base to obtain a base addition salt. Examples of pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amines, or magnesium , or similar salts.

[0137] In certain embodiments, the compound is Compound I and the counterion is selected from the group consisting of sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane.

[0138] Certain specific compounds disclosed herein contain both basic and acidic functional groups such that the compound can be converted into either a base addition salt or an acid addition salt. The neutral form of the compound is preferably regenerated by contacting the salt with a base or an acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from the various salt forms in terms of certain physical properties such as solubility in polar solvents.

[0139] In addition, some of the compounds disclosed herein can form solvates with water or common organic solvents. Such solvates are within the scope of the methods contemplated herein It is included within the enclosure.

[0140] Furthermore, some embodiments include co-crystals comprising the compounds disclosed herein. Co-crystals are a defined stoichiometric ratio of two or more distinct chemical substances known as co-formers, which cannot be otherwise classified as salts or solvates, and can be understood as any single material of a crystalline form. One of ordinary skill in the art will recognize, in accordance with the present invention, which co-formers can be used to form co-crystals with the presently claimed compounds. For example, the U.S. Food and Drug Administration (FDA)'s Select Committee on GRAS Substances (SCOGS) maintains a database of substances generally recognized as safe (GRAS), and many common co-formers can be used in accordance with the present invention to form co-crystals with the presently claimed compounds. As of July 2019, the SCOGS list includes the GRAS substances listed in Table G below. One of ordinary skill in the art will recognize that the FDA may update, revise, or change the name of this list over time, and that additional compounds may be generally recognized as safe, and that such compounds can likewise be used in accordance with the present invention. Co-formers can include, for example, one or more counterions such as sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane. Accordingly, the present invention encompasses co-crystals with compounds on the list of GRAS substances administered by the FDA, or compounds listed in Table G, or other compounds generally regarded as safe, and / or one or more counterions, such as sodium, potassium, calcium, L-arginine, L-lysine, me glumine, and tris(hydroxymethyl)aminomethane. As of July 2019, the SCOGS list includes the GRAS substances listed in Table G below. One of ordinary skill in the art will recognize that the FDA may update, revise, or change the name of this list over time, and that additional compounds may be generally recognized as safe, and that such compounds can likewise be used in accordance with the present invention. Co-formers can include, for example, one or more counterions such as sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane. Accordingly, the present invention encompasses co-crystals with compounds on the list of GRAS substances administered by the FDA, or compounds listed in Table G, or other compounds generally regarded as safe, and / or one or more counterions, such as sodium, potassium, calcium, L-arginine, L-lysine, me glumine, and tris(hydroxymethyl)aminomethane. Co-formers can include, for example, one or more counterions such as sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane. Accordingly, the present invention encompasses co-crystals with compounds on the list of GRAS substances administered by the FDA, or compounds listed in Table G, or other compounds generally regarded as safe, and / or one or more counterions, such as sodium, potassium, calcium, L-arginine, L-lysine, me glumine, and tris(hydroxymethyl)aminomethane. Accordingly, the present invention encompasses co-crystals with compounds on the list of GRAS substances administered by the FDA, or compounds listed in Table G, or other compounds generally regarded as safe, and / or one or more counterions, such as sodium, potassium, calcium, L-arginine, L-lysine, me glumine, and tris(hydroxymethyl)aminomethane. It may contain glucamine, tris(hydroxymethyl)aminomethane, etc. Table G. GRAS substances Acetic acid Acetylated adipic acid crosslinked starch Acetylated glycerol crosslinked starch Acetylated phosphate crosslinked starch Acetylated oxypropanol crosslinked starch Acid-modified starch Aconitic acid Adipic acid Agar Allyl isothiocyanate Ammonium aluminum sulfate Calcium aluminum silicate Aluminum hydroxide Aluminum oleate (for packaging) Aluminum palmitate (for packaging) Potassium aluminum sulfate Sodium aluminum sulfate Aluminum sulfate Ammonium alginate Ammonium bicarbonate Ammonium carbonate Ammonium chloride Ammonium citrate Ammonium hydroxide Dibasic ammonium phosphate (Report 32) Dibasic ammonium phosphate (Report 34) Monobasic ammonium phosphate (Report 32) Monobasic ammonium phosphate (Report 34) Ammonium sulfate Arrowroot starch L-Ascorbic acid Ascorbyl palmitate (palmitoyl L-ascorbic acid) Beeswax (yellow or white) Bentonite Benzoic acid Biotin Bleached starch Brown algae Butylated Hydroxyanisole (BHA) Butylated Hydroxytoluene (BHT) Caffeine Calcium Acetate Calcium Alginate Calcium Carbonate Calcium Caseinate Calcium Chloride Calcium Citrate Calcium Gluconate Calcium Glycerophosphate Calcium Glycerophosphate (Packaging) Calcium Hexametaphosphate Calcium Hydroxide Calcium Hypophosphite Calcium Iodate L-Ascorbic Acid Calcium Calcium Lactate L(+)-Calcium Lactate Calcium Oxide D- or DL-Calcium Pantothenate Calcium Dibasic Phosphate Calcium Monobasic Phosphate Calcium Tribasic Phosphate Calcium Phytate Calcium Propionate Calcium Pyrophosphate Calcium Silicate Calcium Sorbate Calcium Stearate Caprylic Acid Caramel Carbon Dioxide Carbonyl Iron Carbonyl Iron (Packaging) Carboxymethyl Cellulose (Packaging) Carnauba Wax Carob Bean Gum Carotene (Beta-Carotene) Carrageenan Casein Casein Hydrolyzed by Enzyme Treatment Cellulose Cellulose acetate (for packaging) Microcrystalline cellulose Cholic acid Choline bitartrate Choline chloride Citric acid Clay (kaolin) (for packaging) Cinnamon bud extract Cinnamon bud oil Cinnamon bud oleoresin Cinnamon leaf oil Cinnamon stem oil Palm oil (for packaging) Copper(II) gluconate Copper(II) sulfate Corn silk Corn sugar (dextrose) Corn syrup Corn starch Cuprous iodide Deoxycholic acid Dextran Dextrin Corn dextrin (for packaging) Diacetyl Diatomaceous earth (filter aid) Dietary iron Dilauryl thiodipropionate Glycerol-crosslinked starch Oxopropanol-crosslinked starch Phosphate-crosslinked starch Electrolytic iron Electrolytic iron (for packaging) Erythorbic acid (D-isoascorbic acid) Ethyl acrylate, monomer (for packaging) Ethyl acrylate, polymer (for packaging) Ethyl cellulose (for packaging) Ethyl formate Ferric ammonium citrate Ferric chloride (for packaging) Ferric citrate Ferric oxide Ferric oxide (for packaging) Ferric phosphate Ferric pyrophosphate Sodium ferric pyrophosphate Ferric sulfate (packaged) Ferrous ascorbate Iron carbonate Ferrous citrate Ferrous fumarate Iron gluconate Iron lactate Ferrous sulfate Ferrous sulfate (packaged) Hydrogenated fish oil (packaged) Formic acid (packaged) Garlic and garlic oil Gelatin L-Glutamic acid L-Glutamic acid hydrochloride Glycerin and glycerides Glycolic acid Licorice Ammoniated glycyrrhizin Guar gum Gum arabic Gatti gum Guayac gum Tragacanth gum Helium gas High amylose corn starch Hydrochloric acid Hydrogen peroxide Hardened soybean oil Hydrogenated tallow (packaged) p-Hydroxybenzyl isothiocyanate Hydroxypropyl glycerol cross-linked starch Hydroxypropyl phosphate cross-linked starch Hydroxypropyl starch Hydroxypropyl oxidized starch Hydroxypropyl methylcellulose Indilli seed Inositol Invert sugar Report on Bioavailability and Utilization of Iron availability and Utilization of Iron) Report on Clinical Research Protocols to Elucidate The Possible Hazards of Increased Iron port on Clinical Research Protocols to E lucidate The Possible Hazards of Increas ed Iron Fortifiers for Serial Products Iron Caprylate (Packaging) Iron Linoleate (Packaging) Iron Naphthenate Iron Oxide (Packaging) Iron Peptonate Iron Polyvinylpyrrolidone Iron Tartrate (Packaging) Elemental Iron (Packaging) Isopropyl Citrate Beeswax (Packaging) D(-)-Lactic Acid Lactic Acid L(+)-Lactic Acid Lard (Packaging) Lard Oil (Packaging) Lecithin Lecithin Bleached with Hydrogen Peroxide Licorice Root Linoleic Acid Magnesium Carbonate Magnesium Chloride Magnesium Gluconate Magnesium Glycerophosphate (Packaging) Magnesium Hydroxide Magnesium Oxide Magnesium Dibasic Phosphate Magnesium Tribasic Phosphate Magnesium Silicate Magnesium Stearate Magnesium Sulfate Malic Acid L-Malic Acid Manganese Glycerophosphate Manganese Chloride Manganese Citrate Manganese Gluconate Manganese Hypophosphite Manganese oxide Manganese sulfate Mannitol Methyl acrylate, monomer (packaging) Methyl acrylate, polymer (packaging) Methyl paraben Methyl cellulose Myro-dextrin Ammonium L-glutamate Potassium L-glutamate Sodium L-glutamate Phosphorylated dextrin Mustard and mustard oil (brown and yellow) Niacin (nicotinic acid) Niacinamide (nicotinamide) Nickel (element) Nutmeg and mace Henna oil Oleic acid (packaging) Ox bile extract D-Pantothenyl alcohol Papain Peanut oil (packaging) Amidated pectin High-ester pectin Low-acid pectin Pectin ate Pectic acid Perlite (filter aid) Phosphate monoesterified phosphate cross-linked dextrin Phosphoric acid Potassium L(+)-tartrate Potassium alginate Potassium bicarbonate Potassium carbonate Potassium chloride Potassium citrate Potassium gluconate Potassium glycerophosphate Potassium hydroxide Potassium hypophosphite Potassium iodate Potassium iodide Potassium metabisulfite Potassium dibasic phosphate Potassium monobasic phosphate Potassium tribasic phosphate Potassium polymetaphosphate Potassium pyrophosphate Potassium silicate Potassium sorbate Potassium tripolyphosphate Potato starch α-Starch Propionic acid Propyl gallate Propyl paraben Propylene glycol Propylene glycol alginate Propylene glycol monostearate Acid-hydrolyzed protein Enzyme-hydrolyzed protein Pulp (for packaging) Pyridoxine Pyridoxine hydrochloride Red seaweed Reduced iron Reduced iron (for packaging) Rennet Riboflavin Riboflavin-5'-phosphate Rice starch Silica aerogel Silicon dioxide Sodium acetate Sodium acid pyrophosphate Sodium alginate Sodium aluminate (for packaging) Sodium aluminosilicate Sodium aluminum acid phosphate Sodium aluminum basic phosphate Sodium benzoate Sodium bicarbonate Sodium bisulfite Sodium calcium aluminosilicate Sodium carbonate Sodium carboxymethyl cellulose Sodium caseinate Sodium chloride Sodium citrate Sodium diacetate Sodium erythorbate (Sodium D - isoascorbate) Sodium ferric EDTA Ferric pyrophosphate, soluble Sodium formate (for packaging) Sodium gluconate Sodium hexametaphosphate Sodium metabisulfite (for packaging) Sodium hydroxide Sodium hydroxide - gelatinized starch Sodium hypophosphite Sodium L - ascorbate Sodium disulfite Sodium metaphosphate Sodium oleate (for packaging) Sodium palmitate (for packaging) Sodium D - or DL - pantothenate Sodium dibasic phosphate Sodium monobasic phosphate Sodium tribasic phosphate Sodium phosphoaluminate (for packaging) Sodium potassium L( + ) - tartrate Sodium propionate Sodium tetrabasic pyrophosphate Sodium sesquicarbonate Sodium silicate Sodium sorbate Sodium sulfite Sodium L( + ) - tartrate Sodium tetrametaphosphate Sodium tetraphosphate Sodium thiosulfate Sodium trimetaphosphate Sodium tripolyphosphate Sorbic acid Sorbitol Sorbose (for packaging) Isolate of soy protein Soy sauce Stannous chloride Starch acetate Octenyl succinic anhydride modified starch aluminum salt Octenyl succinic anhydride modified starch sodium salt Succinic anhydride modified starch sodium salt Sodium hypochlorite oxidized starch Starter distillate Stearic acid (packaging) Stearyl citrate Starcuria gum (karaya gum) Succinic acid Succinylated glycerol cross-linked starch Sucrose Sulfamic acid (packaging) Sulfur dioxide Sulfuric acid Talc (basic magnesium silicate) Tall oil (packaging) Tallow (packaging) Tannic acid (hydrolyzable gallotannin) Tapioca starch L(+)-Tartaric acid Taurocholic acid Thiamine hydrochloride Thiamine mononitrate Thiodipropionic acid α-Tocopherol acetate Tocopherol Tricalcium silicate Triethyl citrate Urea Vitamin A Vitamin A acetate Vitamin A palmitate Vitamin B12 (cyanocobalamin) Vitamin D2 (ergocalciferol) Vitamin D3 (cholecalciferol) Waxy corn starch Wheat starch Autolyzed yeast Zinc acetate Zinc carbonate Zinc chloride Zinc gluconate Zinc Dithionite (Packaging) Zinc Oxide Zinc Sulfate

[0141] A. Formulations The compounds disclosed herein can be formulated and administered in a wide variety of oral, parenteral, and topical dosage forms. Preferred embodiments of the methods described herein involve oral administration of one or more of the compounds described herein. The compounds described herein can further be administered by injection (e.g., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal). Also, the compounds described herein can be administered by inhalation, e.g., by nasal administration. Further, the compounds disclosed herein can also be administered transdermally. Also, it is contemplated that the compounds disclosed herein can be administered using multiple routes of administration (e.g., intramuscular, oral, etc.). The compounds are administered in the form of solids or liquids, as required, using the desired method of administration. In the case of oral administration, the compounds can be administered as solids or liquids in various embodiments. In some embodiments where administered as an injection, the compounds can be delivered as a liquid or a liquid suspension. In some oral embodiments, the compounds disclosed herein can be administered as solids, more specifically, in the form of tablets, lozenges, troches, powders, granules, or capsules. In some other oral embodiments, the compounds disclosed herein can be administered as liquids, more specifically, as solutions, aqueous or oily suspensions, capsules

[0142]

[0143] ​​​​​​​​​​​​​, can be administered as an emulsion, syrup or elixir. For oral use The composition is refined as a medicine and contains one or more agents selected from the group consisting of a sweetening agent, a flavoring agent, a coloring agent and a preservative in order to produce a palatable preparation. Thus , a pharmaceutically acceptable carrier or excipient and one or more compounds disclosed herein are also provided with a pharmaceutical composition.

[0144] In the case of a powder, the carrier is a micronized solid and is a mixture with the micronized active ingredient In the case of tablets, the active ingredient is mixed with a carrier having the necessary binding action in a suitable ratio and compressed into the desired shape and size. Suitable carriers are magnesium carbonate, magnesium stearate , talc, sugar, lactose, pectin, dextrin, starch, gelatin, trag acanth, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose , mannitol, low melting wax, cocoa butter and the like. The term "preparation" is intended to include a formulation of an active compound using a capsule material which is a carrier providing a capsule, in which case the active ingredient is surrounded by the carrier regardless of the presence or absence of other carriers and is thus associated with the carrier. Similarly, cachets and lozenges are also included.

[0145] In some embodiments, the tablet contains the active ingredient as a mixture with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. These excipients are, for example, (1) inert diluents such as calcium carbonate , lactose, calcium phosphate, carboxymethylcellulose, or sodium phosphate (2) corn starch, alginic acid, and crosp Granulating agents such as polymers such as Kollidon® CL, also known as beads and disintegrants; (3) binders such as starch, gelatin or gum arabic; and (4 ) may be lubricants such as magnesium stearate, stearic acid or talc. These tablets may not be coated, or may be coated with a film or layer by known techniques to delay disintegration and absorption in the digestive tract and thereby provide a sustained action over a long period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be utilized. Another example is Eudragit® L30 D-55, which is a polymer containing copolymerized methacrylates and preventing dissolution at pH less than 5.5. In some embodiments, the tablets contain the active ingredient as an amorphous solid. This can be achieved by producing an amorphous solid dispersion containing the active ingredient and at least one polymer. In some embodiments, the polymer is Kollidon® VA64, which is a vinylpyrrolidone-vinyl acetate copolymer. One of ordinary skill in the art will recognize that a specific weight ratio of the active ingredient to the polymer is required to maintain the active ingredient in an amorphous state. This weight ratio of the active ingredient to the polymer can range from 1:1 to 1:10 or more. In some embodiments, the weight ratio of the active ingredient:polymer is 1:3. One of ordinary skill in the art will also recognize that various techniques are available for producing amorphous solid dispersions, including hot melt extrusion and spray drying dispersion (SDD) methods.

[0146] ​​​​​​​​​​​​

[0147] In certain embodiments, it may be desirable to adjust the particle size distribution. Many techniques, including micronization techniques, can be employed to achieve the desired particle size distribution in a particular embodiment of a given formulation.

[0148] Also included are solid form preparations that are intended to be converted to a liquid form preparation for oral administration immediately prior to use. Such liquid forms include solutions, suspensions, and emulsions. These solutions can be water or a water / propylene glycol mixture. These preparations can contain, in addition to the active ingredient, one or more colorants, flavorants, stabilizers, buffers, artificial and natural sweeteners, surfactants, dispersants, thickeners, solubilizers, and the like.

[0149] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorants, stabilizers, and thickeners as needed. Aqueous suspensions suitable for oral use can be made by dispersing the micronized active ingredient in water together with viscous materials such as natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.

[0150] When parenteral application is required or desired, particularly suitable mixtures for the compounds disclosed herein are sterile solutions for injection, preferably oily or aqueous solutions, and suspensions, emulsions, or implants including suppositories. In particular, carriers for parenteral administration include aqueous dextrose solutions, physiological saline, pure water, ethanol, glycerol, propylene glycol , peanut oil, sesame oil, polyoxyethylene-block polymer, polyethylene glycol, etc. are included. The ampoule is a convenient unit dosage form. The compounds disclosed in this specification can also be incorporated into liposomes, or can be administered via a transdermal pump or patch. Suitable pharmaceutical mixtures for use in the pharmaceutical compositions and methods disclosed in this specification include, for example, those described in PHARMACEUTICAL SCIENCES (17 th ed., Mack Pub.Co., Easton, PA) and WO 96 / 05409, and any teachings are incorporated herein by reference. th E d., Mack Pub.Co., Easton, PA) and WO 96 / 05409, and any teachings are incorporated herein by reference. In some embodiments, preparations for parenteral administration include sterile aqueous or

[0151] 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, alcohol / aqueous solutions, emulsions or suspensions including physiological saline and buffered media. Parenteral vehicles include sodium chloride solution, glucose plus Ringer's solution, dextrose and sodium chloride; body fluids and nutrient replenishers, electrolytes replenishers (such as those based on glucose plus Ringer's solution), and lactated Ringer's intravenous vehicle including, for example. Preservatives and other additives, such as antibacterial agents, antioxidants, chelating agents, growth factors, and inert gases, etc. may also be present.

[0152]

[0152] Some compounds may have limited solubility in water, and therefore, surfactants or other suitable co-solvents may be required in the composition. Such co-solvents include, for example, Resorbate 20, 60, and 80; Pluronic F-68, F-84, and P- 103; Cyclodextrin; and polyoxyl 35 castor oil are included. Such co-solvents are typically utilized in an amount between about 0.01% and about 2% by weight.

[0153] To reduce variability when dispensing the formulation, to reduce physical separation of the components of the formulation suspension or emulsion, and / or to improve the formulation in another way, higher viscosity than simple aqueous solutions may be desirable. Such viscous binders include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxy propylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically utilized in an amount between about 0.01% and about 2% by weight.

[0154] An aqueous suspension usually contains the active material as a mixture with excipients suitable for the manufacture of an aqueous suspension. Such excipients are (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum, and gum arabic; (2) (a) natural phosphatides such as lecithin; (b) condensation products of alkylene oxides and fatty acids, for example, polyoxyethylene stearate; (c) condensation products of ethylene oxide and long-chain aliphatic alcohols, for example, heptadecaethylene oxide cetyl alcohol; (d) condensation products of ethylene oxide and fatty acids and long-chain aliphatic amines, for example, polyoxyethylene dioleylamine; and (3) inorganic salts such as sodium chloride, calcium chloride, and magnesium chloride. Such excipients are typically utilized in an amount between about 0.1% and about 5% by weight. long-chain aliphatic amines, such as polyoxyethylene dioleylamine; and (3) A condensation product of a partial ester derived from hexitol, for example, polyoxyethylene sorbitol monooleate, or (e) a condensation product of a partial ester derived from ethylene oxide, a fatty acid, and anhydrohexitol, for example, polyoxyethylene sorbitan monooleate, which may be a dispersant or a wetting agent. ethylene sorbitol, or preservatives include bactericides, antioxidants, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include, for example, those described in Remington’s Pharmaceutical Sciences, 15th ed. Easton: Mack Publishing

[0155] Co., 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th ed. Washington: A merican Pharmaceutical Association (1975) as described in; aqueous solutions containing non-toxic excipients such as salts, preservatives, buffers, etc., and the content of this document is incorporated herein by reference. The pH and exact concentrations of the various components of the pharmaceutical composition are adjusted according to conventional methods in the art. For example, see Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7 ed.). The compounds disclosed herein can also be administered in the form of suppositories for rectal administration of drugs. These compositions mix the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, so that the drug dissolves in the rectum and releases the drug. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to conventional methods in the art. For example, see Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7 th ed.).

[0156] The compounds disclosed herein can also be administered in the form of suppositories for rectal administration of drugs. These compositions mix the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, so that the drug dissolves in the rectum and releases the drug. These compositions mix the drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, so that the drug dissolves in the rectum and releases the drug. by being liquid at rectal temperature to dissolve and release the drug in the rectum. It can be prepared by. Such materials include cocoa butter and polyethylene glycol. -ol.

[0157] When preparing suppositories, low melting point waxes such as mixtures of fatty acid glycerides or the aforementioned cocoa First, melt the cocoa butter and disperse the active ingredient uniformly by stirring or the like. Then, pour the melted homogeneous mixture into a mold of a convenient size, cool it, and solidify it.

[0158] For topical use, creams, ointments, gels, solutions, or suspensions containing the compounds disclosed herein are employed.

[0159] The compounds disclosed herein used in the methods disclosed herein can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine, or phosphatidylcholine.

[0160] For in vivo use, the compounds disclosed herein can be administered parenterally by injection or by time - dependent step - wise perfusion. Administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavitary, or transdermal. In in vitro tests, the compounds can be added or dissolved in a biologically acceptable appropriate buffer and added to cells or tissues.

[0161] Pharmaceutical preparations are preferably in unit dosage form. In such form, the preparation is further divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a packaged preparation, and the package can be a packaged tablet, capsule, and vial or ampoule. ​ accommodates a separate quantity of a preparation such as a powder incorporated. Also, the unit dosage form may be a capsule, a tablet, a cachet, or a lozenge per se, or may be in the form of a package of an appropriate number of any of these .

[0162] The amount of the active ingredient in the unit dosage preparation may vary or be adjusted according to the specific use and the potency of the active ingredient, from 0. 1 mg to 10,000 mg, more typically 1.0 mg to 1000 mg, and most typically 10 m g to 500 mg. The composition may also contain other therapeutically compatible agents, if desired.

[0163] The pharmaceutical composition is preferably prepared and administered in dosage units. To treat a subject, different daily dosages may be used depending on the activity of the compound, the mode of administration, the nature and severity of the disease or disorder, and the age and weight of the subject. Typically, the dosage used in vitro can provide useful guidance on the amount beneficial for in situ administration of the pharmaceutical composition, and the dosage effective for treating a specific disorder can be determined using an animal model. However, in certain circumstances, a higher or lower daily dosage may be appropriate. Administration of the daily dosage can be effected by either a single administration in the form of an individual dosage unit or a smaller number of dosage units, or multiple administrations at specific intervals of subdivided dosages.

[0164] For various considerations, see, for example, Langer, 1990, Science, 249: 1527; Goodman and Gilman’s (eds.), 1990 (ibid.)

[0165] described therein, each of which is hereby incorporated by reference herein for all purposes. The dosage for parenteral administration of the active pharmaceutical can be converted to the corresponding dosage for oral administration by multiplying the parenteral dosage by an appropriate conversion factor. For general use, the dosage obtained from in vivo animal studies can be converted to a human equivalent dose (HED) by applying an appropriate animal conversion factor to the mg / kg ratio of the given in vivo animal. The average body weight of an adult human is about 60 kg. For example, see GUIDANCE FOR INDUSTRY:Estimating the Maximum Safe Starting Dose in Initial Clinical Trial s for Therapeutics in Adult Healthy Volu nteers (FDA Guidance; July 2005). Starting Dose in Initial Clinical Trial s for Therapeutics in Adult Healthy Volu nteers (FDA Guidance; July 2005).

[0166] B. Effective Dosage The pharmaceutical compositions provided herein include compositions in which the active ingredient is contained in a therapeutically effective amount, i.e., an amount sufficient to achieve the intended purpose. The actual amount effective for a particular use is determined, inter alia, according to the condition to be treated. The dosage and frequency of administration (single or multiple administrations) of the compound can vary depending on various factors including the route of administration; the physique, age, sex, health status, weight, body mass index, and diet of the recipient; the nature and degree of symptoms of the disease for which the treatment is being

[0167] made (e.g., a disease responsive to thrombin inhibition); the presence of other diseases or other health-related problems; the type of combination therapy; and complications due to any disease or treatment regimen. The dosage may also vary depending on other treatment regimens or other health-related problems; the type of combination therapy; and complications due to any disease or treatment regimen. The dosage may also vary depending on other treatment regimens Alternatively, a therapeutic agent can also be used together with the methods and compounds disclosed herein.

[0168] For any of the compounds described herein, a therapeutically effective amount is first determined by various techniques known in the art, such as biochemical characterization of thrombin inhibition, cell culture assays, etc. The target concentration is, for example, the concentration of an active compound ( plural possible) capable of reducing enzyme activity when measured using the methods described.

[0169] A therapeutically effective amount for use in humans can be determined from animal models. For example, human dosages can be derived to achieve concentrations known to be effective in animals. Dosages in humans can be adjusted by monitoring enzyme inhibition and increasing or decreasing the dosage up or down as described above.

[0170] Dosages can vary depending on the requirements of the patient and the compound employed. The dosage administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time in the context of the methods disclosed herein. The magnitude of the dosage is also determined by the presence, nature, and extent of any adverse side effects. Generally, treatment is initiated at a low dosage less than the optimal dosage of the compound. Thereafter, the dosage is increased gradually until the optimal effect is reached under the circumstances. In some embodiments of the methods disclosed herein, the dosage range is from 0.001% to 10% w / v. In some embodiments, the dosage range is from 0.1% to 5% w / v.

[0171] The dosage and dosing interval can be adjusted individually so that the level of the compound administered is effective for the clinical indication being treated. This provides a treatment regimen appropriate to the severity of the individual's disease state.

[0172] A prophylactic or therapeutically effective treatment regimen that treats the clinical symptoms exhibited by a particular patient without causing substantial toxicity and is fully effective to treat the clinical symptoms exhibited by a particular patient can be planned using the teachings provided herein. In formulating such a regimen, factors such as the potency of the compound, relative bioavailability, the weight of the patient, the presence and severity of adverse side effects, the preferred route of administration, and the toxicity profile of the selected agent are considered, and the active compound is carefully selected.

[0173] Accordingly, in some embodiments, the dosage levels of the compounds disclosed herein used in the methods of the invention are, for example, from about 0.1 mg to about 1 mg, about 1 mg to about 10 mg, about 0.5 mg to about 20 mg per kg of body weight, and when the average adult body weight is 60 kilograms, the preferred dosage range is from about 0.1 mg to about 2 0 mg per kg of body weight per day (from about 6.0 mg to about 1.2 g per day per patient). The amount of the compounds disclosed herein that can be combined with a carrier material to make a single dosage can vary depending upon the host being treated and the particular route of administration. For example, a formulation intended for oral administration to humans can contain from about 5 μg to 1 g of the compounds disclosed herein, along with a suitable and convenient amount of carrier material that can vary between 5 and 95 percent of the total composition. Unit dosage forms generally contain from about 0.1 mg to 500 mg of the compounds disclosed herein. ​

[0174] However, the specific dosage level for any particular patient will depend on 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 being treated. It will be understood that this is determined accordingly.

[0175] C. Toxicity The ratio of toxicity to therapeutic effect for a particular compound is the therapeutic index and can be expressed as the ratio of LD 50 (the amount of the compound that is lethal to 5 0% of a population) to ED 50 (the amount of the compound that is effective in 50% of a population). Compounds showing a high therapeutic index are preferred. Therapeutic index data obtained from in vitro assays, cell culture assays and / or animal studies can be used to derive the range of dosage levels for use in humans. The dosage of such compounds preferably falls within the plasma concentration range that results in little or no toxicity at the ED The dosage 50 The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. For example, see Fingl et al.,In:THE PHARMACOLOGICAL BA SIS OF THERAPEUTICS,Ch.1,p.1,1975. The exact formulation, route of administration, and dosage will be selected by the individual practitioner taking into account the patient's condition and the specific method in which the compound is to be used. In the case of in vitro formulations, the exact formulation and dosage will be selected by the individual practitioner taking into account the patient's condition and the specific method in which the compound is to be used.

[0176] Although the present invention has been described in detail, it is to be recognized that modifications, variations, and equivalent embodiments are possible without departing from the scope of the invention as defined in the appended claims. It will be recognized that modifications, variations, and equivalent embodiments are possible without departing from the scope of the invention as defined in the appended claims. Furthermore, it is to be recognized that all examples in this disclosure are provided as non-limiting examples. It should be recognized that all examples in this disclosure are provided as non-limiting examples.

Examples

[0177] The following non-limiting examples are provided to further illustrate embodiments of the invention disclosed herein and are not intended to limit the scope of the disclosure. The techniques disclosed in the following examples represent techniques that have been found to function well in the practice of the invention and, as such, the techniques may be considered to constitute examples of their implementation. However, one of ordinary skill in the art will recognize that, in light of this disclosure, many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtain equivalent or similar results. The following non-limiting examples are provided to further illustrate embodiments of the invention disclosed herein and are not intended to limit the scope of the disclosure. The techniques disclosed in the following examples represent techniques that have been found to function well in the practice of the invention and, as such, the techniques may be considered to constitute examples of their implementation. However, one of ordinary skill in the art will recognize that, in light of this disclosure, many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtain equivalent or similar results. The techniques disclosed in the following examples represent techniques that have been found to function well in the practice of the invention and, as such, the techniques may be considered to constitute examples of their implementation. It should be recognized by those skilled in the art that the techniques may be considered to constitute examples of their implementation. However, one of ordinary skill in the art will recognize that, in light of this disclosure, many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtain equivalent or similar results. However, one of ordinary skill in the art will recognize that, in light of this disclosure, many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtain equivalent or similar results. It should be recognized that many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtain equivalent or similar results. It should be recognized that many modifications can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtain equivalent or similar results.

[0178] Example 1 General Synthesis of Pyrazole-Pyridone Compounds The general synthetic scheme 1 illustrated below provides a general method for synthesizing acylated pyrazole-pyridone compounds disclosed herein. In the following general scheme I, the terms "R", "R", and "R" each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted or unsubstituted heterocycloalkyl. -pyridone compounds. In the following general scheme I, the terms "R", "R", and "R" each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted or unsubstituted heterocycloalkyl. x ", "R", "R", and "R" each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted or unsubstituted heterocycloalkyl. y ", "R", "R", and "R" each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted or unsubstituted heterocycloalkyl. z ", "R", "R", and "R" each independently represent hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted or unsubstituted heterocycloalkyl. alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted or unsubstituted heterocycloalkyl. alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted or unsubstituted heterocycloalkyl. Kill, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or other groups obvious to those skilled in the art.

Chemical formula

[0179] Step A-1 - Synthesis of exemplary intermediate A1 A solution of 2-hydroxy nicotinic acid (50. 0 g, 0.359 mol, 1.0 equivalent) in dichloromethane (500 mL, 10V) at 0 °C was added dropwise with thionyl chloride (133.6 mL, 1.79 8 mol, 5.0 equivalents, 2.67V). After 30 minutes, tetrahydrofuran (500 mL, 10V) was added, and the reaction mixture was stirred at ambient temperature for 14 - 15 hours. The reaction mixture was cooled to 0 °C and methanol (150 mL, 3V) was added dropwise, and the mixture was stirred at room temperature for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain a solid, which was then neutralized with an aqueous sodium bicarbonate solution (pH 7 - 8) and concentrated again to obtain a solid product. The solid was dissolved in methanol , filtered, and the filtrate was concentrated to obtain the desired product, exemplary intermediate A1, methyl-2- oxo-1,2-dihydropyridine-3-carboxylate (yield 45.0 g, yield 81 .8%). m / z 153.99 [M+H]+ 1H NMR (DMSO-d6, 400 MHz) δ 8.051 - 074 (1H, q), 7.661 - 7.682 ( 1H, q), 6.259 - 6.292 (1H, m), 3.734 (3H, s) p pm. pm.

[0180] Step A-2 - Synthesis of intermediate A2 A solution of acetonitrile (8.18 mL, 0. A cold (-78°C) solution of n-BuLi(hexa 2.5 M in ethanol; 62.68 mL, 0.156 mol, 1.2 eq, 3.13 V) for 60 min. After the addition, the reaction was stirred for an additional 60 minutes and then methyl 2-oxo- 1,2-Dihydropyridine-3-carboxylate (Intermediate A1, 20.0 g, 130 m mol, 1.0 equiv) was added in portions to the reaction mixture and kept at -78°C for 3 hours. The mixture was quenched with water and washed with ethyl acetate. The aqueous layer was evaporated to give the crude product, which was then dissolved in methanol. The solid was filtered off with suction and dried under high vacuum. Intermediate A2 was obtained (yield: 11.5 g, 54%).

[0181] Step A-3—Synthesis of Intermediate A3 in isopropanol (600 mL, 30 V) and acetic acid (22.2 mL, 1.11 V) To a solution of intermediate A2 (20.0 g, 0.123 mol, 1.0 equiv.) was added hydrazine monohydrate (7.40 mL, 0.148 mol, 1.2 eq, 0.37 V) was added dropwise and the reaction was heated to 85° C. After cooling, the reaction mixture was concentrated to give the crude product, which was then dissolved in neutral silica gel. The mixture was purified by column chromatography using gel (60-120 mesh). The desired product was eluted with a gradient of 10-25% methanol / dichloromethane. Intermediate A3 (yield: 13.25 g, 61%) was obtained. m / z 177.06 [M+H ]+ 1H NMR (DMSO-d6, 400 MHz) δ 11.831 (1H, s ), 7.857-7.879 (1H, q), 7.383-7.403 (1H, q) , 6.303-6.336 (1H, m), 6.048 (1H, s) 4.633 ( (2H, s) ppm.

[0182] Step A-4 - Synthesis of Exemplary Intermediate A4 To a solution of Intermediate A3 (10.0 g, 0.0568 mol) in dimethylformamide (100 mL, 10V) at 10 - 15 °C, acetic acid (11.2 mL, 1.12V) was added dropwise, followed by the addition of 5-chlorothiophene-2-carbaldehyde (9.15 g, 0.0624 mol, 1 .1 eq) in portions. The reaction mixture was stirred at room temperature for 30 - 45 minutes. Sodium cyanoborohydride (5.35 g, 0.0851 mol, 1.5 eq) was added portionwise over 45 minutes and the reaction mixture was stirred for 2 hours. After completion of the reaction, with stirring, the mixture was poured into ice-cold water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography using neutral silica gel and eluted with 10 - 12% methanol / dichloromethane as the mobile phase to give the pure desired product, Exemplary Intermediate A4, 3-(5-{[(5-chloro thiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1,2-dihydro pyridin-2-one (yield 7.3 g, yield 42.7%). m / z [M + H] + 307.10 1H NMR (DMSO-d6, 400 MHz) δ 12.034 ( 1H, s), 11.815 (1H, s), 7.869 - 7.882 (1H, q) , 7.404 - 7.415 (1H, d), 6.922 - 6.931 (1H, d), , 6.862 - 6.871 (1H, d), 6.314 - 6.331 (1H, d), , 6.117 (1H, s), 5.867 - 5.898 (1H, t), 4.348 - 4 307.10 1H NMR (DMSO-d6, 400MHz) δ 12.034 ( 1H, s), 11.815 (1H, s), 7.869 - 7.882 (1H, q) , 7.404 - 7.415 (1H, d), 6.922 - 6.931 (1H, d), , 6.862 - 6.871 (1H, d), 6.314 - 6.331 (1H, d), , 6.117 (1H, s), 5.867 - 5.898 (1H, t), 4.348 - 4 6.117 (1H, s), 5.867 - 5.898 (1H, t), 4.348 - 4 .363 (2H, d) ppm. Those skilled in the art will recognize that various borohydride reagents can be used in this step to achieve similar results.

[0183] Step A-5 - Synthesis of Exemplary Intermediate A5 To a cold (0 °C) solution of the above exemplary Intermediate A4 in triethylamine (2.98 mL, 0.0215 mol, 3.0 eq) and dichloromethane (40 mL) was added pivaloyl chloride (0.776 g, 0.00647 mol, 0.9 eq) dropwise over 30 minutes. The reaction mixture was stirred for 2 - 3 hours by maintaining the temperature below 10 °C. After completion, while stirring, the reaction mixture was diluted with ice-cold water and the product was extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using neutral silica gel and eluted with 5 - 8% methanol / dichloromethane to give the pure desired product, 3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrrolo [3,2-b]pyridin-3-yl)-1,2-dihydropyridin-2-one (yield 0.76 g, yield 43 .6%). m / z [M+H]+ 391.24 1H NMR (DMSO-d6, 400 MHz) δ 11.250 (1H, s), 8.086 - 8.109 (1H, q), 7.731 - 7.761 (1H, t), 7.484 (1H, s), 6.9 74 - 6.984 (1H, d), 6.934 - 6.944 (1H, d), 6.31 7 - 6.350 (1H, t), 6.213 (1H, s), 4.471 - 4.486 q), 7.731 - 7.761 (1H, t), 7.484 (1H, s), 6.9 74 - 6.984 (1H, d), 6.934 - 6.944 (1H, d), 6.31 7 - 6.350 (1H, t), 6.213 (1H, s), 4.471 - 4.486 (2H, d), 1.47 (9H, s) ppm. Those skilled in the art will recognize that the pyrazole center can be acylated using various methods and reagents, such as forming an active ester. and the like.

[0184] Step A-6 - Synthesis of Exemplary Compound A6 Exemplary intermediate A5 (0.200 g, 5.1×10 -6 mol) was dissolved in dimethylformamide (5 mL, 25 V) and stirred. Then, cesium carbonate (0.400 g, 1. 2×10 -3 mol) was added and stirred for 10 - 15 minutes. Then, 2-bromoethyl methyl ether (0.075 g, 8.1×10-6 mol, 1.5 eq) was added, and the reaction mixture was stirred at room temperature until completion as determined by TLC tracking. Then, the reaction product was diluted with excess water, extracted with ethyl acetate, and purified by column chromatography to obtain A6 of the exemplary compound also listed as compound 7 in Table A above, 3-(5-{ [(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylprop anoyl)-1H-pyrazol-3-yl)-1-(2-methoxyethyl)-1,2-dih dropyridin-2-one (yield 0.030 g, yield 13.2%). 1H NMR ( DMSO-d6, 400 MHz) δ 8.094 - 8.071 (dd, J = 7.2 , 2.0 Hz, 1H), 7.757 (m, 2H), 6.984 (d, J = 4 Hz, 1H), 6.945 (d, J = 3.6, 1H), 6.358 (t, J = 7.0 Hz, 1H), 6.215 (s, 1H), 4.479 (d, J = 7 Hz, 1H), 4.479 (d, J = 7 Hz, 1H), 4.479 (d, J = 7 .0 Hz, 2H), 4.138 (t, J = 5.2, 2H), 3.598 (t, J = 5.2 Hz, 2H), 3.243 (s, 3H), 1.471 (s, 9H ) ppm. Those skilled in the art will recognize that in certain similar reactions, potassium carbonate may be preferred over cesium carbonate depending on the details of the reagents involved.

[0185] Example 2 Specific synthesis of Compound 1 The specific synthesis scheme I illustrated below provides the specific synthesis of 3-[3-(5-{[(5- chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl )-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl propanoic acid of Compound 1. [Chemical formula]

[0186] Step 1 - Synthesis of Intermediate 1 Trimethyl orthoformate (286.06 g, 2.696 mol, 1.5 eq) was added to a mixture of 2-hydroxynicotinic acid (250 g, 1.797 mo l) in methanol (3750 mL, 15 V) at 25 - 30 °C. After stirring the mixture for 15 minutes, concentrated H2SO4 (52 .87 g, 0.539 mol, 0.3 eq) was added at 25 - 30 °C. Then, the mixture was refluxed at 65 - 70 °C for 2 hours. After replacing the reflux condenser with a distillation apparatus, then the product was distilled for 4 hours to a constant volume to remove unreacted trimethyl orthoformate. After cooling to 25 - 30 °C , then the reaction mixture was added to NaHCO3 (20 in MeOH (500 mL) It was slowly added to a mixture of 0 g, 2.381 mol, 1.32 equivalents to adjust the pH to about 7.0, and then stirred at the same temperature for 15 minutes. The resulting product was passed through Celite® and filtered, and washed with MeOH (250 mL, 1 V). Next, while maintaining the temperature of the product below 55 °C, the filtrate was distilled under reduced pressure until the internal volume decreased to about 2 volumes. Then , the product was diluted with toluene (1250 mL, 5 V) and distilled again until it reached about 2 volumes. This process is called "solvent chasing" using toluene. This process was repeated until the MeOH content of the product was less than 3%. Finally, the product was cooled to 25 - 30 °C, diluted with toluene (750 mL, 3 V), filtered, washed with toluene (500 mL, 2 V), and then dried under vacuum at 65 - 70 °C to obtain unpurified intermediate 1 (yield 315 g, yield 76%). [1H NMR (DMSO-d6 , 400 MHz) δ 12.107 (s, 1H), 8.056 (dd, J = 6 .8, 2.0 Hz, 1H), 7.663 (dd, J = 6.4, 2.4 Hz, 1H), 6.269 (t, 6.8 Hz, 1H), 3.776 (s, 3H)].

[0187] Step 2 - Synthesis of Intermediate 2 A solution of n-butyllithium (549 mL, 2.5 M in hexane, 1.37 mol, 2. 1 equivalents) was added dropwise to a solution of acetonitrile (71.3 mL, 1.37 mol, 2.1 equivalents) in tetrahydrofuran (4500 mL, 45 V) at -70 to -80 °C. Then, the resulting product was stirred at -70 to -80 °C for 1 hour. Then, intermediate 1 (100 g, 0 .653 mol) was added. After stirring the entire mixture at -70 to -80 °C for an additional 3 hours, the resulting product was quenched with DM H2O (1500 mL, 15 V) at -70 to 0 °C and stirred at 0 to 5 °C for 10 - 15 minutes, and then diluted with ethyl acetate (2000 mL, 20 V). Subsequently, the mixture was warmed to 25 - 30 °C, stirred for 15 minutes, and then the organic layer was separated. Next, the aqueous layer was cooled to 10 - 15 °C, and its pH was adjusted to 2 - 3 with 6N HCl aqueous solution. The slurry was stirred at 10 - 15 °C for 30 minutes, then filtered, washed with DM H2O (400 mL, 4 V), and dried under vacuum at 50 - 55 °C for 6 hours to obtain Intermediate 2 (yield 40.2 g, yield 38 %). [1H NMR (DMSO-d6, 400 MHz) δ 8.185 (d d, J = 7.6, 2.4 Hz, 1H), 7.808 (dd, J = 6.0, 2 .0 Hz, 1H), 6.441 (t, J = 6.8 Hz, 1H), 3.716 (s, 2H)].

[0188] Step 3 - Synthesis of Intermediate 3 Acetic acid (45.6 mL, 1.14 V) was added to a mixture of Intermediate 2 (40 g, 0.2466 mol) in isopropanol (400 mL, 10 V) at 25 - 30 °C. The resulting product was stirred at the same temperature for 10 - 15 minutes. Then, hydrazine hydrate (14.81 g, 0 .296 mol, 1.2 equivalents) was added to the reaction mixture, and then heated to 80 - 85 °C and stirred for about 3 hours, whereby Intermediate 2 became less than 1 area % by HPLC analysis. The obtained product was cooled to 25 - 30 °C, filtered, washed with isopropanol (2 × 40 mL), and finally dried under vacuum at 50 - 55 °C to obtain Intermediate 3 (yield 36.0 g, yield 83.3 %). (%) was obtained. [1H NMR (DMSO-d6, 400 MHz) δ 11.784 ( s, 2H), 7.867 (dd, J = 7.2, 1.6 Hz, 1H), 7.39 1 (dd, J = 6.4, 2.0 Hz, 1H), 6.319 (t, J = 6.8 Hz, 1H), 6.047 (s, 1H), 4.622 (s, 1H)].

[0189] Step 4 - Synthesis of Intermediate 4 5-Chlorothiophene-2-carbaldehyde (31.81 g, 0.2185 mol, 1 .1 eq) was added to a mixture of Intermediate 3 (35.0 g , 0.1986 mol) in DMF (350 mL, 10V) at 25 - 30 °C, and then stirred for 15 minutes. Then, acetic acid (4 1.75 g, 0.695 mol, 1.1 eq) was added. The mixture was stirred for about 2 hours until the content of Intermediate 3 was less than 1 area% by HPLC analysis. Then, the resulting product was slowly added to DM H2O (1750 mL, 50V) at 25 - 30 °C, filtered, washed with DM H2O (350 mL, 10V), and dried in vacuo at 50 - 55 °C to obtain Intermediate 4 ( Yield 55.0 g, yield 90.9%).

[0190] Step 5 - Synthesis of Intermediate 5 Sodium borohydride (7.7 g, 0.2035 mol, 2 eq) was slowly added to a suspension of Intermediate 4 (31.0 g, 0.1017 mol, 1 eq) in dichloromethane (310 mL, 10V) and ethanol (310 mL, 10V) at 0 - 5 °C. Then, the resulting mixture was warmed to 25 - 30 °C and stirred for 30 minutes. Then, additional sodium borohydride (7.7 g, 0.20 mol, 2 eq and 3.85 g, 0.1018 mo l) was added. ​l equivalent) was added in two portions with a 30-minute interval. Then, the mixture was stirred at 25 - 3 0 °C for 1 hour, and the subsequent content of Intermediate 4 was less than 1 area% by HPLC analysis and then the mixture was cooled to 10 - 20 °C and the pH was adjusted to 7 - 8 using 1N HCl aqueous solution (355 mL, 11.45V). Then, the product was stirred at 25 - 30 °C for 1 hour, filtered, washed with DM H2O (155 mL, 5V), and dried under reduced pressure at 60 - 65 °C for 10 hours to obtain Intermediate 5. Using this procedure, one of ordinary skill in the art can expect a chemical yield close to 100% in this step using the techniques and methods described herein, or techniques and methods that are functionally equivalent and recognized by one of ordinary skill in the art . [1H NMR (DMSO-d6, 400 MHz) δ 11.8 67 (s, 2H), 7.859 (d, J = 5.6 Hz, 1H), 7.406 (d, J = 4.8 Hz, 1H), 6.890 (dd, J = 22.8, 3.6 Hz, 2H), 6.323 (t, J = 6.8 Hz, 1H), 6.106 (s, 1H), 5.860 (t, J = 6 Hz, 1H), 4.353 (d, J = 6 Hz, 2H)].

[0191] Step 6 - Synthesis of Intermediate 6 HATU (46.47 g, 0.122 mol, 1.5 equivalents) was added to a solution of pivalic acid (16.64 g, 0.163 mol, 2 equivalents) in DMF (250 mL, 1 0 V) at 25 - 30 °C. Then, the mixture was stirred at 25 - 30 °C for 30 minutes, and then Intermediate 5 (25. 0 g, 0.0815 mol, 1 equivalent) was added portionwise and stirred for an additional 5 minutes. Then , DIPEA (42.58 mL, 0.245 mol, 3 equiv.) was added dropwise at 25-30°C. The reaction mixture was stirred at 25-30° C. for an additional hour. The reaction mixture was then cooled to 15° C. and diluted with DMSO. 20 (250 mL, 10 V) and then cooled to room temperature while maintaining the product temperature below 25 °C. The pH of the mixture was then adjusted to 5.8-6.3 with 1% citric acid. The mixture was stirred at 25-30 °C for 30 min, filtered, and washed with DMHO (250 mL, 10 V). The mixture was washed and dried under reduced pressure at 55-60°C for 10 hours to give intermediate 6. Those skilled in the art will be able to easily implement the techniques and methods described herein, or as recognized by those skilled in the art. Using techniques and methods understood to be functionally equivalent, an average of 59% efficiency was achieved in this step. A high optical yield can be expected. [1H NMR (400 MHz, DMSO-d6) δ 11.92 - 11.86 (m, 1H), 8.09 (dd, J = 7.0, 2 .1 Hz, 1H), 7.73 (t, J = 6.2 Hz, 1H), 7.48 (d d, J = 6.4, 2.2 Hz, 1H), 7.00 - 6.90 (m, 2H), 6.33 (t, J = 6.7 Hz, 1H), 6.21 (s, 1H), 4.47 (d, J = 6.1 Hz, 2H), 1.47 (s, 9H)].

[0192] Step 7 - Synthesis of Compound 1 Cesium carbonate (333.4 g, 1.023 mol, 4.0 equiv.) was added to D of intermediate 6 (100 g, 0.256 mol, 1.0 equiv) in MF (500 mL, 5 V) Slowly add to the suspension. The mixture is stirred for 10 min. DMF (250 mL, 2.5 V) A solution of 3-chloropropionic acid (41.64 g, 0.384 mol, 1.5 eq) therein was added dropwise at 25 - 30 °C. The resulting product was stirred for 1 hour, then filtered and washed twice with DMF (100 mL, 1V). Then, while maintaining the temperature of the product at 20 - 30 °C, the filtrate was slowly added to DM H2O (4000 mL, 40V) and stirred for 10 minutes. Using a 2N aqueous HCl solution at 20 - 30 °C, the pH was adjusted to 4.5 - 5.0. Next, the reaction product was stirred for 30 minutes, filtered, and washed twice with 200 mL of DM H2O to obtain Compound 1. Using this procedure, one of ordinary skill in the art can use the techniques and methods described herein, or techniques and methods that are understood to be functionally equivalent as recognized by one of ordinary skill in the art, to expect an average chemical yield of 19%. [1H NMR (DMSO-d6, 300 MHz) δ 12.43 (s, 1H), 8.06 (m, 1H), 7.8 , 300 MHz) δ 12.43 (s, 1H), 8.06 (m, 1H), 7.81 (m, 1H), 7.74 (m, 1H), 6.95 (dd, J = 12.0, 3.0 Hz, 2H), 6.35 (t, J = 6.0 Hz, 1H), 5.74 ( s, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.13 (t, J = 7.5 Hz, 2H), 2.69 (t. J = 6.0 Hz, 2H), 1.45 ( s, 9H)]. s, 9H)].

[0193] To purify the final product, ethyl acetate (400 mL, 4V) was added to the wet crude product (216 g) and stirred at 25 - 30 °C for 1 hour. After removing the aqueous layer, then, the organic layer was treated with charcoal (8.0 g) at 25 - 30 °C for 30 minutes. Then, diatomaceous earth ​Filtered through (12g), and then the earthen floor was washed with ethyl acetate (120 mL). While keeping the temperature of the product below 40 °C, ethyl acetate was distilled off from the filtrate until the internal volume reached approximately 150 mL (1.5V). Next, the product was cooled to 25 - 30 °C, stirred for 30 minutes, and then pure intermediate 5 (0.1% w / w) was added as a seed crystal. The slurry was cooled to 0 - 5 °C and stirred for 1 hour. Then, the slurry was filtered and washed twice with pre-cooled (0 - 5 °C) ethyl acetate (20 mL, 0.2V). Next, the product was dried under vacuum at 25 - 30 °C.

[0194]

[0195] To a solution of compound 1 (67 g) in dichloromethane (670 mL, 10V) at 25 - 30 °C, n - heptane (670 mL, 10V) was added dropwise to further purify the product. Then, the slurry was stirred at 25 - 30 °C for 30 minutes, filtered, and washed with n - heptane (134 mL). Next, the solid was dried under vacuum at 25 - 30 °C. By this synthesis, a crystalline solid was obtained having a powder x - ray diffraction pattern including selections of 1, 2, 3, 4, 5, or 2θ values, each within the error range of ±0.3°, selected from the list consisting of 9.9°, 12.3°, 12.6°, 14.7°, 15.0°, 16.7°, 17.0°, 17.7°, 18.4°, 18.7°, 19.7°, 20.3°, 22.1°, 22.5°, 23.2°, and 24.7° as shown in Figure 1 in crystalline form 1. The solid was analyzed with a Bruker D8Advance X - ray Powder Diffractometer (tube: Cu:Kα (λ = 1.54179 Å)). Generator: 40 kV; 40 mA, and scanning range: 3 to 40 degrees). One of ordinary skill in the art would recognize that variations in XRPD plots can occur from various sources. Accordingly, for all XRPD plots shown herein, there are certain embodiments where the error range for each peak is ±0.0°, ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, ±0.6°, ±0.7°, ±0.8 °, ±0.9°, or ±1.0°.

[0196] Example 3 Specific Synthesis of Compound 2 The specific synthetic scheme II illustrated below provides the synthesis of 3-[3-(5-{[(5 -chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-2 -oxo-1,2-dihydropyridin-1-yl]propanoic acid of Compound 2.

Chemical Structure

[0197] In its unique step, Compound 1 (1 g, 2.16 mmol) was dissolved in methanol (1 0 mL, 10 V), and reagent grade water (2 mL, 2 V). Then, while maintaining the mixture at 15 - 25 °C, NaOH (431.97 mg, 10.80 mmol, 5 equivalents) was added all at once. The mixture was then stirred at 15 - 25 °C for 1 hour. Then, ice water (10 mL, 10 V) was added to the mixture, and then 6N HCl (11 mL, 11 V) was used to adjust its pH to 5 - 6. The resulting solid was filtered and washed with water (10 mL, 10 V) to recover Compound 2 (yield 0.5 g, 1.32 mmol, 61.10%). [1H NMR 400 MHz, DMSO-d6) δ 7.839 (m, 1H), 7.704 (m, 1H), 6.860 (dd, 2H), 6.334 (t, 1H ), 6.107 (s, 1H), 4.331 (s, 2H), 4.141 (t, 2 H), 2.695 (t, 2H)]

[0198] Example 4 Polymorph Some embodiments are crystalline solids of Compound 1 that can exist as several polymorphs . As an example, the solid material has the polymorph illustrated in FIG. 1. To convert a certain amount of Compound 1 into the polymorph of FIG. 1, the following procedure was carried out. Compound 1 was dissolved in a THF / EA (4V / 10V) mixture at 30° C. and filtered. Then, the solution was cooled to 5° C. and seeded with seed crystals obtained from the synthetic process of the specific synthetic scheme I above. Then, after stirring the mixture at 5° C. for 3 hours , 15V of n-heptane was added at 5° C. over 10 hours. Thereafter, an additional 21 V of n-heptane was added at 5° C. for 5 hours, and then the mixture was stirred at 5° C. for an additional 22 - 24 hours, after which the solid was recovered. When examined by XRPD, the spectrum obtained showed peaks including 9.9°, 12.3°, 12.6°, 14.7°, 15.0°, 16.7°, 17.0°, 17.7°, 18.4 °, 18.7°, 19.7°, 20.3°, 22.1°, 22.5°, 23.2°, and 24.7° that were each within an error range of ±0.3° as shown in FIG. 1 for Crystal Form 1. The XRPD data was obtained using a Bruker D8Advanc e X-ray Powder Diffractometer (tube: Cu: Kα (λ = 1.54179 Å), generator: 40 kV; 40 mA, scan range: 3 - 40 degrees, sample rotation speed: 15 rpm, and scan speed: 10 degrees / min). Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were also performed. The TGA data was obtained using a TA Instruments Q500 Thermogravimetric Analyzer (heating rate: 10° C. / min, nitrogen flow rate: 50 mL / min). The DSC data was obtained using a TA Instruments Q200 Differential Scanning Calorimeter (heating rate: 10° C. / min, nitrogen flow rate: 50 mL / min). Report the differential scanning calorimetry (DSC) data in Table H below.

[0199] In another embodiment, Compound 1, as shown in Figure 2 as crystalline form 2, respectively is within an error range of ±0.3°, 4.9°, 9.7°, 14.4°, 16.0°, 16 .5°, 17.0°, 18.2°, 18.5°, 19.2°, 19.7°, 20.2°, 22.8°, 23.3°, 24.0°, 24.5°, and 24.8° and has an XR PD spectrum, and is a crystalline solid. In this embodiment, Compound 1 (35 mg ) was mixed with isopropyl alcohol (0.5 mL) and slurried by shielding from light at room temperature and 500 rpm for 2 days. The solid was then separated in an Eppendorf 5418 centrifuge at 14,000 rpm for 10 minutes and then dried under vacuum at room temperature for 3 days. The sample was then confirmed by XRPD, TGA, and DSC. The XRPD data was obtained using a Bruker D8Advance X-ray Powder Diffractome ter (tube: Cu:Kα (λ = 1.54179 Å), generator: 40 kV; 40 mA, scan range: 3 - 40 degrees, sample rotation speed 15 rpm, and scan speed: 10 degrees / min). Report the TGA and DSC data in Table H below.

[0200] In another embodiment, Compound 1, as shown in Figure 3 as crystalline form 3, has an XRPD spectrum with peaks at at least ±0.3° and 8.6°, 9.5°, 11.8°, 12.4°, 12.9°, 1 4.2°, 15.2°, 15.5°, 16.5°, 17.2°, 18.8°, 19.1° , 20.1°, 20.9°, and 22.9°. It was a crystalline solid. In this embodiment, 15.6 mg of Compound 1 was mixed with a 1:1 ethanol :water mixture (0.3 mL) and slurried at 40 °C and 500 rpm for 1 day. The solid was then separated by an Eppendorf 5418 centrifuge at 14000 r pm for 10 minutes and then dried under vacuum at room temperature for 3 days. The sample was then confirmed by XRPD, TGA, and DSC. The XRPD data was obtained on a Bruker D8A dvance X-ray Powder Diffractometer ( tube: Cu:Kα (λ = 1.54179 Å), generator: 40 kV; 40 mA, scan range: 3 ~40 degrees, sample rotation speed 15 rpm, and scan speed: 10 degrees / min). The TGA and DSC da ta are reported in Table H below.

[0201] Example 5 Salt Synthesis Some embodiments include Compound 1 as a salt with a suitable counterion. In some embodiments the counterion is tris(hydroxymethyl)aminomethane, hereinafter referred to as "Tris". To form the Tris salt of Compound 1, 320 mg of Compound 1 was placed in a glass vial and dissolved in 10.7 mL of acetone. The vial was then sonicated for a short time to obtain a hazy suspension. The suspension was then centrifuged at 10,000 rpm for 5 minutes in a Xiangyi H1650 centrifuge, and 1.67 mL of supernatant was separated from the remaining pellet and volume. To this 1.67 mL portion of the supernatant, 0. 059 mL of Tris (2N aqueous solution) was added to form a 1:1.1 molar ratio of Compound 1:Tri s. The mixture was then stirred at room temperature for 24 hours. The resulting suspension was then E Centrifuged at 10,000 rpm for 10 minutes using a ppendorf Centrifuge 5418 to separate the solid material, which was then dried overnight at 40 °C in a Boxun DZF-6050 Vacuum Oven. The solid was then analyzed using a Bruker D8Advance X-ray Powder Diffractometer (tube: Cu:Kα (λ = 1.54179 Å), generator: 40 kV; 40 mA, scanning range: 3 - 4 0 degrees, sample rotation speed: 15 rpm, and scanning speed: 10 degrees / min). Figure 4 shows the obtained XR PD spectrum. In this embodiment, Compound 1 is shown in Figure 4 as crystalline form 4, with 2θ values of 6.8°, 10.0°, 13.0°, 15.1°, 16.0°, 16.5°, 18.0°, 18.4°, 19.8°, 20.5°, 20.8°, 21.2°, 21.5 °, 22.8°, 23.3°, and 25.9°, each selected from the list and within an error range of ±0.3° for 1, 2, 3, 4, 5, or more 2θ values, and exists in crystalline form with a powder X-ray diffraction pattern including such selections. The TGA and DSC data are reported in Table H below. One skilled in the art would recognize that similar salts can be made by a similar process that uses an appropriate amount of another counterion to produce a 1:1.1 molar ratio of Compound 1:counterion in the mixture. Examples of alternative counterions include sodium, potassium, calcium, L-arginine, L-lysine, and meglumine. The resulting salts can be recovered by means similar to those described above.

[0202]

Table 7

[0203] Thermogravimetric analysis (TGA) data was obtained using a TA Q5000IR with samples weighing 0.5 - 5.0 mg and heating the platinum open pans from room temperature to 250 °C at a rate of 10 °C / min for measurement.

[0204] Differential scanning calorimetry (DSC) data was obtained using a TA Q2000 with samples weighing 0.5 - 1.0 mg and heating the crimped aluminum pans with small holes in the lids from room temperature to 250 °C at a rate of 10 °C / min for measurement.

[0205] Example 6 Metabolites of Compound 1 Certain metabolites of Compound 1 were detected from various in vivo and in vitro tests. These compounds include those listed in Table I below. Compound 1 0, 13, and 14 are proposed metabolites. [Table 8]

[0206] The metabolites of Compound 1 have various uses as would be recognized by those skilled in the art. Certain metabolites such as Compound 10 have biological activity (see Table B above). The metabolites of Compound 1 may also be useful as pharmacokinetic indicators of Compound 1 in biological assays and in organisms including human patients.

[0207] Example 7 Pharmaceutical Composition Example 7a - Amorphous Solid Dispersion of Compound 1 An amorphous solid dispersion of Compound 1, an amorphous solid, with the polymer Kollidon® VA64, a vinyl pyrrolidone - vinyl acetate copolymer, is contained in the pharmaceutical composition. ​​​​​A substance was prepared. The amorphous solid dispersion contains Compound 1 and Kollidon® VA64 in a weight ratio of 1:3, using THF as the solvent, and the following process pa rameters: nozzle temperature = 40 °C; process temperature = 80 °C, nozzle gas flow rate = 4.0 kg / h, chamber gas flow rate = 35.0 kg / h, spray rate = 32 g / min, and was prepared by spray drying dispersion (SDD) technology as recognized by those skilled in the art. Subsequently, the material was dried in a convection oven at 5 0 °C for 48 hours and then further dried at 60 °C for 18 hours. Those skilled in the art will recognize that Compound 1 and Kollidon® VA64 can be used in various weight ratios to achieve the desired amorphous state of Compound 1 in the amorphous solid dispersion. One skilled in the art will recognize that the embodiments of the present invention may include various pharmaceutically acceptable excipients known to those skilled in the art. For example, these excipients may include disintegrants such as croscarmellose sodium, fillers such as microcrystalline cellulose and mannitol, and lubricants or glidants such as magnesium stearate and / or talc.

[0208] Example 7b - Tableting of Compound 1 as an Amorphous Solid Dispersion Compound 1, which is the amorphous solid dispersion described in Example 7a above, was formulated into tablets. One skilled in the art will recognize that the embodiments of the present invention may include various pharmaceutically acceptable excipients known to those skilled in the art. For example, these excipients may include disintegrants such as croscarmellose sodium, fillers such as microcrystalline cellulose and mannitol, and lubricants or glidants such as magnesium stearate and / or talc. In this example, the following components were included in the weight ratios listed below, compared to the total mass of the tablets, to prepare the tablets.

Table 9

[0209] In one preparation, the tablets had a total mass of 180 mg ± 9 mg. In another preparation In this case, the tablets had a total mass of 1000 mg ± 50 mg.

[0210] In a further embodiment, the tablets are coated with an outer film or layer called an enteric coating. This layer contains a polymer and / or other materials and can provide additional properties such as resistance to dissolution in an environment with a pH of less than 5.5. In some embodiments, the polymer is a copolymer containing copolymerized methacrylates. In this example, the polymer of this outer film or layer was Eudragit® L30 D-55. In this example, the polymer of this outer film or layer was Eudragit® L30 D-55. In this example, the polymer of this outer film or layer was Eudragit® L30 D-55.

[0211] Manufacturing process of the tablets of Example 7c - Example 7b The process used to manufacture the tablets of Example 7b disclosed above is provided herein. First, an amorphous solid dispersion of Compound 1 was produced using the spray drying dispersion technique with Compound 1 and Kollidon® VA64 in a weight ratio of 1:3 as described in Example 7a above. The process used to manufacture the tablets of Example 7b disclosed above is provided herein. First, an amorphous solid dispersion of Compound 1 was produced using the spray drying dispersion technique with Compound 1 and Kollidon® VA64 in a weight ratio of 1:3 as described in Example 7a above. The process used to manufacture the tablets of Example 7b disclosed above is provided herein. First, an amorphous solid dispersion of Compound 1 was produced using the spray drying dispersion technique with Compound 1 and Kollidon® VA64 in a weight ratio of 1:3 as described in Example 7a above. Next, this amorphous solid dispersion was mixed with the raw materials inside the granules. In one embodiment of the present invention, these materials may include at least one disintegrant and at least one lubricant. In some

[0212] embodiments, the raw materials inside the granules further include at least one filler. In this example, the disintegrant included crospovidone (Kollidon® CL), the lubricant was magnesium stearate, and the raw materials inside the granules further included microcrystalline cellulose (Avicel® PH101) and mannitol (Partek® M100). Those skilled in the art will understand that these components inside the granules are passed through a mesh screen (Avicel® PH101) and mannitol (Partek® M100). Those skilled in the art will understand that these components inside the granules are passed through a mesh screen (Avicel® PH101) and mannitol (Partek® M100). Those skilled in the art will understand that these components inside the granules are passed through a mesh screen (Avicel® PH101) and mannitol (Partek® M100). Those skilled in the art will understand that these components inside the granules are passed through a mesh screen (Avicel® PH101) and mannitol (Partek® M100). Those skilled in the art will understand that these components inside the granules are passed through a mesh screen It will be recognized that the lumps can be removed using. In this example, the lumps of filler, disintegrant, and amorphous solid dispersion were removed, and after blending for 10 minutes, the lubricant that had been lumps-removed was added to the mixture and blended for an additional 3 minutes.

[0213] Next, the blended mixture of this intragranular material and amorphous solid dispersion was compressed and then , it can be pulverized. In this example, a roller compactor was used to apply a force of 5 kN and the product was made into ribbons using a 1,000 μm screen at 20 rpm. Next, these compressed ribbons were further pulverized into granules by a method recognized by those skilled in the art.

[0214] In one embodiment, the above mixing is carried out under dry conditions, and the granulation carried out is dry granulation. In this example, dry mixing and dry granulation were used.

[0215] Next, the dry granules of the above steps were further mixed with extra-granular raw materials. In one embodiment of the present invention, these materials include at least one disintegrant and at least one lubricant and / or flow promoter and at least one filler. In this example, the disintegrant includes crospovidone (Kollidon® CL), and the lubricant and / or flow promoter includes magnesium stearate and talc, and the extra-granular raw materials further include microcrystalline cellulose and mannitol (Partek® M100). Those skilled in the art will recognize that these extra-granular components can have lumps removed using a mesh screen. In this example, the filler(s) and disintegrant with lumps removed and (Optional) was first blended with granules for 10 minutes, and then lumps were removed to obtain a lubricant (optional) and / or a flow promoter (optional) was added to the mixture and blended for an additional 3 minutes to obtain a final mixture .

[0216] Next, this final mixture was compressed into tablets of a desired shape and size having the characteristics shown in Table J .

[0217] In some preparations, the mass of the tablets was 180 mg ± 9 mg, while in other preparations, the tablets had a mass of 1000 mg ± 50 mg. Those skilled in the art will recognize that compression step parameters such as the press speed and compression force can vary depending on the desired shape, size, mass, and other characteristics of the selected embodiment for the tablets.

[0218] In this example, the component distribution between the inner and outer parts of the granules as a weight percentage of the total weight of the tablets was as described in Table K below.

Table 10

[0219] Finally, the compressed tablets were coated with a film or layer. In some embodiments , this outer layer contains a polymer and confers additional properties to the tablets, such as preventing dissolution at a pH below 5.5. In some embodiments, the polymer contains polymerized methacrylic acid-ethyl acrylate. In this example, this polymer was Eudragit® L30 D-55. Further, this polymer was 57% Eudragit® L30 D-44, 14.6% Plusacryl HTP20 . ​ and used in a mixture that is 28.4% water. One of ordinary skill in the art would recognize that the final water composition due to evaporation of water can be sufficiently reduced by evaporation techniques. One of ordinary skill in the art would recognize that various techniques are available for coating the tablets with this outer layer. In some embodiments, pan coating techniques are employed. would recognize that various techniques are available for coating the tablets with this outer layer. In some embodiments, pan coating techniques are employed.

[0220] Embodiments of the present disclosure can be described in view of the following clauses.

[0221] 1. Structure I: [Chemical formula] A compound according to, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof (wherein R 1 is selected from the group consisting of hydrogen and pivaloyl).

[0222] 2. General Structure II: [Chemical formula] A prodrug of the compound according to clause 1, or a pharmaceutically acceptable salt, solvate of the compound, or a co-crystal thereof (wherein R 1 is selected from the group consisting of hydrogen and pivaloyl, R 2 is selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl ).

[0223] 3. The prodrug according to clause 2, wherein R 2 is selected from the following groups: [Chemical formula] .

[0224] 4. A compound as described in clause 1, wherein R 1 is pivaloyl:

Chemical formula

[0225] 5. A compound as described in clause 1 or 4, wherein the compound is in crystalline form.

[0226] 6. A compound as described in clause 5, wherein the crystalline form has a powder X-ray diffraction pattern comprising at least 5 2θ values selected from the group consisting of 9.9°, 12.3°, 12.6°, 14.7°, 15.0°, 1 6.7°, 17.0°, 17.7°, 18.4°, 18.7°, 19.7°, 20.3° , 22.1°, 22.5°, 23.2°, and 24.7°, and each of the at least 5 2θ values is within an error range of ±0.3°.

[0227] 7. A compound as described in clause 5, wherein the crystalline form has a powder X-ray diffraction pattern comprising at least 5 2θ values selected from the group consisting of 4.9°, 9.7°, 14.4°, 16.0°, 16.5°, 17 .0°, 18.2°, 18.5°, 19.2°, 19.7°, 20.2°, 22.8°, 23.3°, 24.0°, 24.5°, and 24.8°, and each of the at least 5 2θ values is within an error range of ±0.3°.

[0228] 8. A compound as described in clause 5, wherein the crystalline form has a powder X-ray diffraction pattern comprising at least 5 2θ values selected from the group consisting of 8.6°, 9.5°, 11.8°, 12.4°, 12.9°, 14 .2°, 15.2°, 15.5°, 16.5°, 17.2°, 18.8°, 19.1°, 20.1°, 20.9°, and 22.9°, and each of the at least 5 2θ values is within an error range of ± ​​The compound according to item 5, which is within an error range of 0.3°.

[0229] 9. A compound as in Compound 2, where R 1 is hydrogen, as described in any one of items 1 or 4 - 8 of the compound:

Chemical formula

[0230] 10. The compound according to any one of items 1 or 4 - 9, where the compound is in the form of a pharmaceutically acceptable salt. of the compound described in item 1 or 4 - 9.

[0231] 11. The compound according to item 10, where the pharmaceutically acceptable salt has a counter ion selected from the group consisting of sodium, potassium, calcium, L - arginine, L - lysine, meglumine, and tris(hydroxymethyl)aminomethane. of the compound described in item 10.

[0232] 12. The compound according to item 11, where the counter ion is tris(hydroxymethyl)aminomethane. of the compound described in item 11.

[0233] 13. A compound as in item 1 or 4 - 12, where R 1 is pivaloyl. .

[0234] 14. The compound according to item 13, which is in a crystalline form having a powder X - ray diffraction pattern including at least five 2θ values selected from the group consisting of 6.8°, 10.0°, 13.0°, 15.1°, 16.0°, 16.5°, 18.0°, 18.4°, 19.8°, 20.5°, 20.8°, 21.2 °, 21.5°, 22.8°, 23.3°, 25.9°, and each of the at least five 2θ values is within an error range of ±0.3°. of the compound described in item 13.

[0235] A compound or prodrug according to any one of the preceding claims, selected from the group consisting of: Prodrug: 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1H-pi razol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid ; 2-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]acetic acid; 4-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]butanoic acid; 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]-2,2-difluoropropanoic acid; 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]propeneamide; 1-(2-Amino-2-methylpropyl)-3-(5-{[(5-chlorothiophen-2 -yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3- 1,2-Dihydropyridin-2-one; 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(3 -Hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2- Oxo-1,2-dihydropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylbutanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-di Hydropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(ph Lan-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihyd ropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-Chloro-1-oxo-1λ4-thiophen-2-yl) Methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-i L)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid; (2S,3S,4S,5R,6S)-6-({3-[3-(5-{[(5-Chlorothiop ene-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pi razol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoi l}oxy)-3,4,5-trihydroxyoxane-2-carboxylic acid; Ethyl 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}- 1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo- 1,2-dihydropyridin-1-yl]propanoate; Prop-2-en-1-yl = 3-[3-(5-{[(5-chlorothiophen-2-yl )methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3- yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate; 2-(a cetyl)ethyl; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]propanoate; 1-(acetyloxy)ethyl = 3-[3-(5-{[(5-chlorothiophen-2-yl yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3 -yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate; ({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1- (2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1, 2-dihydropyridin-1-yl]propanoyl}oxy)methyl = 2,2-dimethylp ropanoate; (3,5,6-trimethylpyrazin-2-yl)methyl = 3-[3-(5-{[(5-ch lorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl) -1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl] propanoate; ({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1- (2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1, 2-dihydropyridin-1-yl]propanoyl}oxy)methyl = (2S)-2-{ (tert-Butoxy)carbonyl]amino}-3-methylbutanoate; 3-[3-(5-{[(5-Chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl](2H4)propanoic acid; 3-{3-[5-({[5-Chloro(3,4-2H2)thiophen-2-yl](2H2 )methyl}amino)-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3- yl]-2-oxo-1,2-dihydropyridin-1-yl}propanoic acid; and 3-[3-(5-{[(5-Chlorothiophen-2-yl)(2H2)methyl]amino} -1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo -1,2-dihydropyridin-1-yl]propanoic acid.

[0236] 16. A pharmaceutical composition comprising a compound or prodrug according to any one of clauses 1 to 15, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and a pharmaceutically acceptable excipient. 17. A method for treating and / or preventing a target disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or prodrug according to any one of clauses 1 to 15, or a pharmaceutical composition according to clause 16, to treat or prevent the disease or disorder. 18. The method according to clause 17, wherein the disease or disorder is a thrombotic disease or disorder and / or involves the potential formation of a thrombus or blood clot with a thrombus or blood clot having a blood clot.

[0237] 17. A method for treating and / or preventing a target disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound or prodrug according to any one of clauses 1 to 15, or a pharmaceutical composition according to clause 16, to treat or prevent the disease or disorder. 18. The method according to clause 17, wherein the disease or disorder is a thrombotic disease or disorder and / or involves the potential formation of a thrombus or blood clot with a thrombus or blood clot having a blood clot. 19. The method according to clause 18, wherein the compound or prodrug, or the pharmaceutical composition, is administered orally, parenterally, topically, or by inhalation. 20. The method according to clause 18, wherein the compound or prodrug, or the pharmaceutical composition, is administered in a dose of from about 0.01 mg / kg to about 100 mg / kg of body weight of the subject per day.

[0238] 18. The method according to clause 17, wherein the disease or disorder is a thrombotic disease or disorder and / or involves the potential formation of a thrombus or blood clot with a thrombus or blood clot having a blood clot. 19. The method according to clause 18, wherein the compound or prodrug, or the pharmaceutical composition, is administered orally, parenterally, topically, or by inhalation.

[0239] 19. The method according to clause 18, wherein the thrombotic disease or disorder comprises acute coronary syndrome, thromboembolism, and / or thrombosis. The method according to clause 18, which includes

[0240] 20. The method according to clause 19, wherein the thromboembolism comprises venous thromboembolism, arterial thromboembolism, and / or cardiogenic thromboembolism. The method according to clause 19, which includes

[0241] 21. The method according to clause 20, wherein the venous thromboembolism comprises deep vein thrombosis and / or pulmonary embolism. The method according to clause 20, which includes

[0242] 22. The method according to clause 21, wherein the deep vein thrombosis and / or pulmonary embolism occur after a medical treatment. The method according to clause 21, which includes

[0243] 23. The method according to any one of clauses 18 to 22, wherein the thrombotic disease or disorder is associated with coagulation failure or disseminated intravascular coagulation. The method according to any one of clauses 18 to 22, which includes

[0244] 24. The method according to clause 23, wherein the subject is undergoing percutaneous coronary intervention (PCI). The method according to clause 23, which includes

[0245] 25. The method according to any one of clauses 18 to 24, wherein the thrombotic disease or disorder is associated with the presence of a thrombus that is a blood clot or the potential formation of a thrombus that is a blood clot, and further associated with stroke and / or one or more transient ischemic attacks (TIAs). The method according to any one of clauses 18 to 24, which includes The method according to any one of clauses 18 to 24, which includes

[0246] 26. The method according to clause 25, wherein the thrombotic disease or disorder associated with the presence of a thrombus that is a blood clot or the potential formation of a thrombus that is a blood clot is further associated with stroke, and the subject has non-valvular atrial fibrillation. The method according to clause 25, which includes The method according to clause 25, which includes

[0247] 27. The thrombotic disease or disorder associated with the potential formation of a thrombus that is a blood clot or a thrombus that is a blood clot or the disorder further involves pulmonary hypertension, and is the method according to any one of Items 18 to 26.

[0248] 28. The method according to Item 27, wherein the pulmonary hypertension is caused by one or more left heart disorders and / or chronic thromboembolic diseases.

[0249] 29. The method according to Item 27, wherein the pulmonary hypertension is associated with one or more pulmonary diseases including pulmonary fibrosis (idiopathic or otherwise) and / or hypoxemia.

[0250] 30. The method according to any one of Items 17 to 29, wherein the disease or disorder includes fibrosis, Alzheimer's disease, multiple sclerosis, pain, cancer, inflammation, and / or type I diabetes mellitus.

[0251] 31. The method according to any one of Items 17 to 30, wherein the disease or disorder is accompanied by recurrent cardiac events after myocardial infarction.

[0252] 32. The method according to any one of Items 20 to 31, wherein the venous thromboembolism is related to the formation of thrombus in the vein associated with one or more acquired or genetic risk factors, and / or peripheral venous embolism caused by a detached thrombus.

[0253] 33. The method according to Item 32, wherein the one or more risk factors include a history of venous thromboembolism.

[0254] 34. The method according to any one of Items 20 to 33, wherein the cardiogenic thromboembolism is caused by the formation of thrombus in the heart associated with arrhythmia, valvular heart disease, artificial heart valve or heart disease, and / or peripheral arterial embolism caused by a detached thrombus.

[0255] 35. The method according to clause 34, wherein the separated thrombus is in the brain (ischemic stroke).

[0256] 36. The method according to clause 35, wherein the separated thrombus causes a transient ischemic attack (TIA). as described.

[0257] 37. The method according to any one of clauses 34 to 36, wherein the cardiogenic thromboembolism is caused by non-valvular atrial fibrillation. as described in any one of the above clauses.

[0258] 38. The method according to any one of clauses 19 to 37, wherein the thrombosis is arterial thrombosis. .

[0259] 39. The method according to clause 38, wherein the arterial thrombosis is caused by one or more underlying atherosclerotic processes of the artery. as described in clause 38.

[0260] 40. The method according to clause 39, wherein one or more underlying atherosclerotic processes of the artery narrow or occlude the artery, cause myocardial ischemia (angina pectoris, acute coronary syndrome), cause myocardial infarction, narrow or occlude the peripheral artery (ischemic peripheral artery disease), and / or narrow or occlude the artery after a vascular procedure (reocclusion or restenosis after percutaneous coronary angioplasty, reocclusion or restenosis after percutaneous transluminal angioplasty of the peripheral artery). as described in clause 39. as described in clause 39. as described in clause 39. as described in clause 39.

[0261] 41. The method according to any one of clauses 17 to 40, wherein the treatment or prevention includes adjuvant therapy. as described in any one of the above clauses.

[0262] 42. The method according to clause 41, wherein the subject has myocardial infarction and the adjuvant therapy is performed together with thrombolytic therapy. as described in clause 41.

[0263] 43. The subject has unstable angina, thrombosis, and / or heparin-induced thrombocytopenia. The method according to clause 41 or 42, having and the adjuvant therapy being combined with an antiplatelet therapy. Method.

[0264] 44. The method according to any one of clauses 41 to 43, wherein the subject has non-valvular atrial fibrillation and the adjuvant therapy is performed together with one or more other therapies.

[0265] 45. The method according to any one of clauses 41 to 45, wherein the subject has at least one of coronary artery disease and heart failure and the adjuvant therapy is combined with an antiplatelet therapy.

[0266] 46. The method according to clause 45, wherein the subject further has valvular or non-valvular atrial fibrillation.

[0267] 47. The method according to any one of clauses 41 to 46, wherein the subject has valvular or non-valvular atrial fibrillation and has undergone percutaneous coronary intervention with a stent, and the adjuvant therapy is combined with an antiplatelet therapy.

[0268] 48. A tablet comprising a pharmaceutical composition comprising compound 1 according to clause 4.

[0269] 49. The tablet according to clause 48, wherein compound 1 is present as an amorphous solid in an amorphous solid dispersion.

[0270] 50. The tablet according to clause 49, wherein the amorphous solid dispersion comprises a first polymer.

[0271] 51. The tablet according to clause 50, wherein the first polymer is a vinyl pyrrolidone-vinyl acetate copolymer.

[0272] 52. The tablet according to clause 51, wherein compound 1 and the first polymer are present in a weight ratio of 1:3. The above-mentioned tablet.

[0273] 53. The tablet according to any one of clauses 48 to 52, further comprising at least one disintegrant. Tablet.

[0274] 54. The tablet according to clause 53, wherein the disintegrant comprises crospovidone.

[0275] 55. The tablet according to any one of clauses 48 to 54, further comprising at least one filler. Tablet.

[0276] 56. The tablet according to clause 55, wherein the filler comprises microcrystalline cellulose or mannitol. Tablet.

[0277] 57. The tablet according to any one of clauses 48 to 56, further comprising at least one lubricant or glidant. Tablet.

[0278] 58. The tablet according to clause 57, wherein the lubricant or glidant comprises magnesium stearate or talc. Tablet.

[0279] 59. The tablet according to any one of clauses 48 to 58, further comprising an outer layer or film. Tablet.

[0280] 60. The tablet according to clause 59, wherein the outer layer or film comprises at least a second polymer. Tablet.

[0281] 61. The tablet according to clause 60, wherein the second polymer prevents dissolution of the tablet at a pH of less than 5.5. Tablet.

[0282] 62. The tablet according to clause 60 or 61, wherein the second polymer comprises Eudragit® L30 D-55. Tablet.

[0283] 63. The outer layer or film contains 57% Eudragit® L30 D-55, 14.6% Plasacryl® HTP20, and 28.4% water, and is the tablet according to any one of items 59 to 62.

[0284] 64. The second polymer contains a methacrylic acid-ethyl acrylate copolymer, and is the tablet according to any one of items 59 to 63.

[0285] 65. The amorphous solid dispersion is contained at 50% by weight of the tablet, and is the tablet according to any one of items 48 to 64.

[0286] 66. Further including an outer layer of the second polymer, the tablet without the outer layer contains 50% by weight of the amorphous solid dispersion, 10% by weight of crospovidone, 2% by weight of magnesium stearate, 19% by weight of microcrystalline cellulose, 18% by weight of mannitol, and 1% by weight of talc, and is the tablet according to any one of items 48 to 65.

[0287] 67. The second polymer contains Eudragit® L30 D-55 and is the tablet according to item 66.

[0288] 68. The tablet without the outer layer has a total mass of 180 mg ± 9 mg, and is the tablet according to item 66 or 67.

[0289] 69. The tablet without the outer layer has a total mass of 1000 mg ± 50 mg and is the tablet according to item 66 or 67.

[0290] 70. A tablet containing a pharmaceutical composition containing the prodrug having the general structure II according to item 2. ​

[0291] 71. A process for manufacturing tablets having the pharmaceutical composition according to any one of Items 48 to 69 which comprises: (1) generating an amorphous solid dispersion of Compound 1; (2) granulating the amorphous solid dispersion of step (1) together with the raw materials inside the granules in a dry state; ; (3) blending the granules of step (2) with the raw materials outside the granules to form a final mixture; ; (4) compressing the final mixture of step (3) into tablets; and (5) coating the tablets of step (4) with a film or layer, the said process.

[0292] 72. The process is (1) generating an amorphous solid dispersion of Compound 1 using spray-dried dispersion (SDD) technology; ; (2) mixing the amorphous solid dispersion of step (1) with the raw materials inside the granules containing at least one disintegrant and at least one lubricant; ; (3) dry granulating the mixture of step (2), wherein the granulating process includes forming a compressed ribbon using a roller compactor, and the compressed ribbon is then crushed into granules, the said dry granulating; ; (4) blending the granules of step (3) with the raw materials outside the granules that have been deblocked and contain a disintegrant and a lubricant; ; (5) compressing the blend of step (4) into tablets; and (6) further coating the tablets of step (5) with a film or layer, the process according to Item 71.

[0293] The various methods and techniques described above provide several ways for implementing the present invention. Of course, it should be understood that not all of the described objectives or advantages may be achieved in accordance with any particular embodiment described herein. Thus, for example, one skilled in the art may recognize that one or a group of advantages taught or suggested herein may be achieved or optimized in a manner that does not necessarily achieve all of the other objectives or advantages taught or suggested herein. Various alternatives are mentioned herein. Some preferred embodiments specifically include one, another, or some of the features, while other embodiments specifically do not include one, another, or some of the features, and still other embodiments understandably reduce certain features by including one, another, or some of the advantageous features. Of course, it should be understood that not all of the described objectives or advantages may be achieved in accordance with any particular embodiment described herein. Thus, for example, one skilled in the art may recognize that one or a group of advantages taught or suggested herein may be achieved or optimized in a manner that does not necessarily achieve all of the other objectives or advantages taught or suggested herein. Various alternatives are mentioned herein. Some preferred embodiments specifically include one, another, or some of the features, while other embodiments specifically do not include one, another, or some of the features, and still other embodiments understandably reduce certain features by including one, another, or some of the advantageous features. Of course, it should be understood that not all of the described objectives or advantages may be achieved in accordance with any particular embodiment described herein. Thus, for example, one skilled in the art may recognize that one or a group of advantages taught or suggested herein may be achieved or optimized in a manner that does not necessarily achieve all of the other objectives or advantages taught or suggested herein.

[0294] Furthermore, one skilled in the art will recognize the availability of various features from the various embodiments. Similarly, one skilled in the art will be able to implement the methods in accordance with the principles described herein by employing various combinations of the various elements, features, and steps discussed above, as well as other known equivalents of such elements, features, or steps. Of the various elements, features, and steps, some are specifically included and others are specifically excluded in different embodiments. Of the various elements, features, and steps, some are specifically included and others are specifically excluded in different embodiments. Of the various elements, features, and steps, some are specifically included and others are specifically excluded in different embodiments.

[0295] This application is disclosed in the context of certain specific embodiments and examples, but one skilled in the art will understand that embodiments of the invention extend beyond the specifically disclosed embodiments to include other alternative embodiments and / or uses and their modifications and equivalents.

[0296] In embodiments of the present invention, many variations and alternative elements are disclosed. Further variations and alternative elements will be apparent to those skilled in the art. Various embodiments of the present invention may specifically include or exclude any of these variations or elements.

[0297] In some embodiments, the numbers representing properties such as component amounts, molecular weights, and reaction conditions, used to describe and claim certain embodiments of the present application, may, in some cases, be modified by the term "about." Therefore, in some embodiments, the numerical parameters shown in the descriptions and the appended claims are approximate values and may vary depending on the desired properties to be obtained in a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the reported significant digits and by applying ordinary rounding techniques. The numerical ranges and parameters indicating broad ranges of some embodiments of the present application are approximate values, but the values shown in specific examples are reported as accurately as practicable. The numerical values presented in some embodiments of the present invention may contain certain errors necessarily resulting from the standard deviations recognized in each test measurement.

[0298] Conjunctions such as the phrase "at least one of A, B, and C" or "at least one of A, B, and C" generally present that an item, term, etc. can be either A or B or C, or any non-empty subset of the set of A and B and C, unless specifically stated otherwise or clearly contradicting the context. ​​​is understood differently in the context in which it is used. For example, an exemplary example of a set having three components, the connectives "at least one of A, B, and C" and "at least one of A, B, and C" refer to any of the following sets: {A}, {B}, {C}, {A, B}, {A, C}, {B, C}, {A, B, C}. Thus, such connectives are generally not intended to imply that a particular embodiment requires the presence of at least one A, at least one B, and at least one C, respectively. No.

[0299] Any examples provided herein, or the use of exemplary language (e.g., "such as"), are merely intended to better clarify embodiments of the invention and, unless otherwise claimed, do not limit the scope of the invention. No language in this specification shall be construed as indicating that any unclaimed element is essential to the practice of the invention.

[0300] In some embodiments, the terms "a," "an," and "the" and similar indicatives used in the context of describing particular embodiments of the present application (especially in connection with some of the following claims) can be construed to include both the singular and the plural. The description of a range of values herein is merely intended to serve as a concise way of specifying each individual value falling within that range. Unless otherwise specified herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein It can be implemented in any suitable order, as long as it is not clearly inconsistent with the context. Any examples provided with respect to certain embodiments of this specification, or the use of exemplary language (e.g., "such as") are merely intended to clarify the present application better and do not impose limitations on the scope of the present application, unless specifically claimed. No language in this specification should be construed as indicating that any unclaimed element is essential for the implementation of the present application.

[0301] The classification of alternative elements or embodiments of the invention disclosed herein is not to be construed as a limitation. The components of each group can be referred to and claimed individually, or in any combination with other components of that group or other elements described herein. One or more components of a group may be included in the group or removed from the group for reasons of convenience and / or patentability. In the event of either such inclusion or removal, this specification is considered to contain the group as modified to meet the description of all Markush groups used in the appended claims.

[0302] Preferred embodiments of the present application are described herein. Modifications to those preferred embodiments will be apparent to those skilled in the art upon reading the foregoing description. Those skilled in the art can adopt such modifications as needed and are intended to be able to implement the present application in a manner different from that specifically described herein. Therefore, many embodiments of the present application are within the scope of the appended claims as permitted by the applicable law. This invention includes all modifications and equivalents of the subject matter enumerated in the above, as well as all possible variations thereof. Any combination of the above-mentioned elements in any combination is contemplated unless otherwise specified herein or in the text. Unless expressly inconsistent with the present context, all such disclosures are incorporated herein by reference.

[0303] All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference in their entirety. Documents are individually and specifically indicated to be incorporated by reference and to be included in their entirety for all purposes. The subject matter is incorporated herein by reference as if fully set forth herein, except that any prosecution history relating thereto that is inconsistent with or in conflict with this document Any of these, or the broadest scope of any patent claim now or hereafter related to this document. Any of these that may have a limiting effect on the Any use of statements, definitions and / or terms relating to any of the above and those related to this document In the event of any discrepancy or inconsistency between the statements, definitions, and / or The use of the term shall prevail.

[0304] Finally, the embodiments of the present application disclosed herein are illustrative of the principles of embodiments of the present invention. It should be understood that other variations that may be employed are within the scope of this application. As such, by way of example and not by way of limitation, alternative configurations of the embodiments of the present application are The present application is not intended to be a limiting example of the present invention, but may be practiced in accordance with the teachings herein. and is not intended to be strictly limited to the description.

Claims

1. Structure I: 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, or cocrystal thereof. (In the formula, R 1 is selected from the group consisting of hydrogen and pivaloyl.

2. General structure II: 【Chemistry 2】 A prodrug of the compound according to claim 1, or a pharma- ceutically acceptable salt thereof, a solvent Solutes or cocrystals (In the formula, R 1 is selected from the group consisting of hydrogen and pivaloyl; R 2 consists of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl (selected from the group consisting of:

3. R 2 The prodrug of claim 2, wherein is selected from the following groups: 【Chemistry 3】 。

4. As in compound 1, R 1 is pivaloyl. 【Chemistry 4】 。

5. The compound of claim 4 , wherein the compound is in a crystalline form.

6. The crystalline forms are 9.9°, 12.3°, 12.6°, 14.7°, 15.0°, 16. ７°、１７．０°、１７．７°、１８．４°、１８．７°、１９．７°、２０．３°、２ At least one angle selected from the group consisting of 2.1°, 22.5°, 23.2°, and 24.7° and a powder x-ray diffraction pattern including at least five 2θ values, The compound according to claim 5, each of which is within an error range of ±0.3°.

7. The crystal form is 4.9°, 9.7°, 14.4°, 16.0°, 16.5°, 17.0°, °、１８．２°、１８．５°、１９．２°、１９．７°、２０．２°、２２．８°、２３ At least one angle selected from the group consisting of 24.3°, 24.0°, 24.5°, and 24.8° A powder x-ray diffraction pattern comprising at least five 2θ values, The compound according to claim 5, which is within an error range of ±0.3°.

8. The crystal form is 8.6°, 9.5°, 11.8°, 12.4°, 12.9°, 14.2°, °、１５．２°、１５．５°、１６．５°、１７．２°、１８．８°、１９．１°、２０ At least five 2θ values ​​selected from the group consisting of .1°, 20.9°, and 22.9° and each of said at least five 2θ values ​​is within ±0.

6. The compound according to claim 5, which is within an error range of 3°.

9. As in compound 2, R 1 is hydrogen; 【Chemistry 5】 。

10. The compound of claim 1 , wherein the compound is in the form of a pharma- ceutically acceptable salt.

11. The pharma- ceutically acceptable salts include sodium, potassium, calcium, L-arginine, From the group consisting of L-lysine, meglumine, and tris(hydroxymethyl)aminomethane The compound of claim 10 having a selected counterion.

12. 12. The method of claim 11, wherein the counterion is tris(hydroxymethyl)aminomethane. Compound.

13. R 1 The compound of claim 12, wherein is pivaloyl.

14. The compound has angles of 6.8°, 10.0°, 13.0°, 15.1°, 16.0°, 16. ５°、１８．０°、１８．４°、１９．８°、２０．５°、２０．８°、２１．２°、２ At least 5 degrees selected from the group consisting of 1.5°, 22.8°, 23.3°, and 25.9° a crystalline form having a powder x-ray diffraction pattern containing at least five 2θ values; 14. The compound of claim 13, wherein each of the theta values ​​is within an error range of ±0.3°.

15. A compound or proteolytic agent according to any one of the preceding claims, selected from the group consisting of: drag: 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyridin 3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid ； 2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]acetic acid; 4-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]butanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]-2,2-difluoropropanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]propenamide; 1-(2-amino-2-methylpropyl)-3-(5-{[(5-chlorothiophene-2 -yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazole-3- yl)-1,2-dihydropyridin-2-one; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3 -Hydroxy-2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2- oxo-1,2-dihydropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-dimethylbutanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2-di Hydropyridin-1-yl]propanoic acid; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(phenyl) Ran-3-carbonyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydrido lopyridine-1-yl]propanoic acid; 3-[3-(5-{[(5-chloro-1-oxo-1 lambda 4-thiophen-2-yl) methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl 1,2-dihydropyridin-1-yl]-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid; (2S,3S,4S,5R,6S)-6-({3-[3-(5-{[(5-chlorothio 1-(2,2-dimethylpropanoyl)-1H-phenyl-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-phenyl 3-(2-oxo-1,2-dihydropyridin-1-yl)propanoyl {oxy}-3,4,5-trihydroxyoxane-2-carboxylic acid; Ethyl = 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}- 1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo- 1,2-dihydropyridin-1-yl]propanoate; Prop-2-en-1-yl = 3-[3-(5-{[(5-chlorothiophen-2-yl ) methyl]amino}-1-(2,2-dimethylpropanoyl)-1H-pyrazole-3- 2-(ayl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate; Cetyloxy)ethyl; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- Dihydropyridin-1-yl]propanoate; 1-(acetyloxy)ethyl = 3-[3-(5-{[(5-chlorothiophene-2-yl {1-(2,2-dimethylpropanoyl)-1H-pyrazole-3} -yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoate; ({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1- (2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1, 2-dihydropyridin-1-yl]propanoyl}oxy)methyl = 2,2-dimethylprop Lopanoate; (3,5,6-trimethylpyrazin-2-yl)methyl = 3-[3-(5-{[(5- thiophene-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl -1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl] Propanoate; ({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1- (2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1, 2-dihydropyridin-1-yl]propanoyl}oxy)methyl=(2S)-2-{[ (tert-butoxy)carbonyl]amino}-3-methylbutanoate; 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2 ,2-Dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl](2H4)propanoic acid; 3-{3-[5-({[5-chloro(3,4-2H2)thiophen-2-yl](2H2 ) methyl}amino)-1-(2,2-dimethylpropanoyl)-1H-pyrazole-3- yl]-2-oxo-1,2-dihydropyridin-1-yl}propanoic acid; and 3-[3-(5-{[(5-chlorothiophen-2-yl)(2H2)methyl]amino} -1-(2,2-dimethylpropanoyl)-1H-pyrazol-3-yl)-2-oxo -1,2-dihydropyridin-1-yl]propanoic acid.

16. The compound or prodrug according to any one of claims 1 to 15, or a pharmaceutical composition thereof. and a pharma- ceutically acceptable salt, solvate, or cocrystal thereof, and a pharma- ceutically acceptable excipient. Pharmaceutical compositions.

17. A method for treating and / or preventing a disease or disorder in a subject, comprising the steps of:

17. A compound or prodrug according to any one of claims 5 to 16, or a medicament according to claim 16. The composition is administered to a subject in need thereof, and is effective to treat or prevent said disease or disorder. The method comprises administering to said subject a therapeutically effective amount of

18. The disease or disorder is a thrombotic disease or disorder and / or a blood clot.

20. The method of claim 17, involving the potential formation of a thrombus, which is a plug or clot.

19. The thrombotic disease or disorder includes acute coronary syndrome, thromboembolism, and / or thrombosis. The method according to claim 18.

20. The thromboembolism is venous thromboembolism, arterial thromboembolism, and / or cardiogenic thromboembolism.

20. The method of claim 19, comprising:

21. 21. The method of claim 20, wherein the venous thromboembolism includes deep vein thrombosis and / or pulmonary embolism. Method of posting.

22. 22. The method of claim 21 , wherein the deep vein thrombosis and / or pulmonary embolism occurs following a medical procedure. The method described.

23. 1 , wherein the thrombotic disease or disorder involves coagulation dysfunction or disseminated intravascular coagulation.

8. The method according to claim 8.

24. 24. The method of claim 23, wherein the subject is undergoing percutaneous coronary intervention (PCI). The method described.

25. The thrombotic disease or disorder may be a thrombus that is a blood clot or a potential formation of a thrombus that is a blood clot. and further comprising a stroke and / or one or more transient ischemic attacks (TIA).

18. The method according to claim 18.

26. Thrombotic diseases or disorders involving the potential formation of said blood clots, thrombi, or blood clots, thrombi 26. The method of claim 25, wherein the harm further involves stroke and the subject has non-valvular atrial fibrillation. How to.

27. Thrombotic diseases or disorders involving the potential formation of said blood clots, thrombi, or blood clots, thrombi 20. The method of claim 18, wherein the harm is further associated with pulmonary hypertension.

28. The pulmonary hypertension is caused by one or more of left ventricular disorders and / or chronic thromboembolic diseases. The method according to claim 27.

29. The pulmonary hypertension is one comprising pulmonary fibrosis (idiopathic or otherwise) and / or hypoxia.

28. The method of claim 27, which is associated with the above lung diseases.

30. The disease or disorder is selected from the group consisting of fibrosis, Alzheimer's disease, multiple sclerosis, pain, cancer, inflammation, and the like.

18. The method of claim 17, comprising administering to a patient suffering from type 1 diabetes mellitus or type 2 diabetes mellitus.

31. 18. The method of claim 17, wherein the disease or disorder involves recurrent cardiac events following myocardial infarction. method.

32. The venous thromboembolism is associated with one or more acquired or inherited risk factors. Regarding the formation of thrombi and / or embolism of peripheral veins caused by detached thrombi 21. The method of claim 20,

33. 33. The method of claim 32, wherein the one or more risk factors comprises a history of venous thromboembolism.

34. The cardiogenic thromboembolism is associated with cardiac arrhythmia, cardiac valvular insufficiency, an artificial cardiac valve, or cardiac disease. The formation of thrombi in the heart and / or peripheral arterial embolism caused by detached thrombi 21. The method of claim 20, resulting from thrombosis.

35. 35. The method of claim 34, wherein the detached thrombus is in the brain (ischemic stroke).

36. 36. The method of claim 35, wherein the detached thrombus causes a transient ischemic attack (TIA). method.

37. 35. The method of claim 34, wherein the cardiogenic thromboembolism results from non-valvular atrial fibrillation.

38. 20. The method of claim 19, wherein the thrombosis is arterial thrombosis.

39. The arterial thrombosis is due to one or more underlying atherosclerotic processes in the artery. The method of claim 38 .

40. One or more underlying atherosclerotic processes in the artery cause the artery to narrow or This causes myocardial ischemia (angina pectoris, acute coronary syndrome), myocardial infarction, and eventually Peripheral arteries are narrowed or occluded (ischemic peripheral arterial disease) and / or arterial hyperplasia occurs after vascular procedures. (reocclusion or restenosis after transluminal coronary angioplasty, peripheral 40. The method of claim 39, wherein the vascular endovascular treatment is a vascular endovascular treatment for a vascular endovascular disease.

41. 18. The method of claim 17, wherein the treatment or prevention comprises adjunctive therapy.

42. 4. The method of claim 1, wherein the subject has a myocardial infarction and the adjunctive therapy is administered in conjunction with thrombolytic therapy.

42. The method according to claim 41.

43. the subject has unstable angina, thrombosis, and / or heparin-induced thrombocytopenia; 42. The method of claim 41, wherein the adjunctive therapy is combined with antiplatelet therapy.

44. the subject has non-valvular atrial fibrillation and the adjunctive therapy is administered in combination with one or more other therapies 42. The method of claim 41, wherein

45. the subject has at least one of coronary artery disease and heart failure, and the adjunctive therapy is an antihypertensive 42. The method of claim 41 in combination with platelet therapy.

46. 46. ​​The method of claim 45, wherein the subject further has valvular or non-valvular atrial fibrillation. Law.

47. The subject has valvular or non-valvular atrial fibrillation and is receiving percutaneous coronary intervention with a stent. and the adjunctive therapy is combined with antiplatelet therapy.

42. The method according to claim 41.

48. A tablet comprising a pharmaceutical composition comprising compound 1 according to claim 4.

49. 49. The tablet of claim 48, wherein compound 1 is present as an amorphous solid in an amorphous solid dispersion. Agent.

50. 50. The tablet of claim 49, wherein the solid amorphous dispersion comprises a first polymer.

51. The first polymer is a vinylpyrrolidone-vinyl acetate copolymer. Item 51. The tablet according to item 50.

52. 52. The method of claim 51 , wherein compound 1 and the first polymer are present in a weight ratio of 1:

3. tablet.

53. 50. The tablet of claim 49, further comprising at least one disintegrant.

54. 54. The tablet of claim 53, wherein the disintegrant comprises crospovidone.

55. 50. The tablet of claim 49, further comprising at least one filler.

56. 56. The tablet of claim 55, wherein the filler comprises microcrystalline cellulose or mannitol. Agent.

57. 50. The tablet of claim 49, further comprising at least one lubricant or glidant.

58. The lubricant or glidant comprises magnesium stearate or talc. Item 58. The tablet according to item 57.

59. 49. The tablet of claim 48, further comprising an outer layer or film.

60. 60. The method of claim 59, wherein the outer layer or film comprises at least a second polymer. Tablets.

61. 61. The method of claim 60, wherein the second polymer prevents dissolution of the tablet at a pH below 5.

5. Tablets.

62. The second polymer comprises Eudragit® L30 D-55. Item 60. The tablet according to item 60.

63. The outer layer or film is 57% Eudragit® L30 D- 55, 14.6 Plasacryl® HTP20, and 28.4% water. The tablet of claim 60.

64. The second polymer comprises a methacrylic acid-ethyl acrylate copolymer.

60. The tablet according to claim 60.

65. 50. The tablet of claim 49, wherein the amorphous solid dispersion comprises 50% by weight of the tablet. 。

66. The tablet further comprises an outer layer of a second polymer, the tablet not comprising said outer layer comprising 50% by weight of The amorphous solid dispersion, 10% by weight of crospovidone, 2% by weight of magnesium stearate % by weight of cellulose, 19% by weight of microcrystalline cellulose, 18% by weight of mannitol, and 1% by weight of talc. The tablet of claim 52,

67. The second polymer comprises Eudragit® L30 D-55. Item 67. The tablet according to item 66.

68. 67. The tablet of claim 66, wherein the tablet without the outer layer has a total mass of 180 mg ± 9 mg. Tablets as described.

69. 7. The tablet, excluding the outer layer, has a total mass of 1000 mg±50 mg.

7. The tablet according to claim 6.

70. A tablet comprising a pharmaceutical composition comprising a prodrug having the general structure II of claim 2.

71. A process for producing a tablet having the pharmaceutical composition according to any one of claims 48 to 69. And, (1) forming an amorphous solid dispersion of Compound 1; (2) granulating the amorphous solid dispersion of step (1) in a dry state with intragranular raw materials; To do so; (3) blending the granules of step (2) with extragranular ingredients to form a final mixture. and; (4) compressing the final blend of step (3) into tablets; and (5) coating the tablets of step (4) with a film or layer. The process described below.

72. The process comprising: (1) Producing an amorphous solid dispersion of Compound 1 using spray-dried dispersion (SDD) technology and; (2) disintegrating the amorphous solid dispersion of step (1) with at least one disintegrant and at least mixing with intragranular ingredients containing another lubricant; (3) dry granulating the mixture of step (2), the granulation process comprising: forming a compressed ribbon using a roller compactor, said compressed ribbon comprising: said dry granulating being then milled into granules; (4) The granules of step (3) are mixed with a de-lumped extragranular ingredient mixture, including a disintegrant and a lubricant. Blending with materials; (5) compressing the blend of step (4) into a tablet; and (6) further comprising coating the tablet of step (5) with a film or layer.

72. The process of claim 71.

Images