Thrombin inhibitors, formulations and uses thereof

Abstract

Disclosed herein are acylated pyrazole-pyridinone compounds of Formula (II) that inhibit thrombin and pharmaceutical compositions, including tablets, containing the acylated pyrazole-pyridinone compounds. These compounds are useful for the treatment and prevention of thrombin-related diseases and disorders. Also included are processes for making tablets containing the acylated pyrazole-pyridinones.

Description

TECHNICAL FIELD

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

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application No. 62 / 697,817 (THROMBIN INHIBITORS, FORMULATIONS, AND USES THEREOF), filed July 13, 2018, which is currently co-pending with the present application and is incorporated by reference in its entirety for all purposes. BACKGROUND

[0004] Serine proteases are a large family of enzymes with diverse biological functions, which share the commonality of the presence of an active site serine residue and a key function. Their important function is to catalyze the cleavage of peptide bond substrates through the Ser, His, Asp triad within the active site (Kraut, 1977 J. Annual Review of Biochemistry, 46:331-358).

[0005] Thrombin (flla, the active form of prothrombin) is a serine protease involved in the coagulation cascade, a system in mammalian systems that deals with vascular damage caused by bleeding events. The cascade includes the extrinsic and intrinsic pathways, involving the activation of at least 13 interconnected factors and a variety of cofactors and other regulatory proteins. Upon vascular damage, plasma factor VII interacts with exposed tissue factor (TF), and the resulting TF-fVIIa complex initiates a series of complex events. Factor Xa is produced directly “downstream” from the TF-fVIIa complex and amplifies the cascade through the intrinsic pathway. FXa then acts as a catalyst to form thrombin (flla), which in turn activates platelets by cleaving protease-activated receptors and enhances clotting by producing fibrin from fibrinogen. The result is a fibrinolytic clot, which stops the bleeding. Dissolution of the polymer clot by fibrinolysis into fibrin monomers results in lysis and returns the system to the pre-coagulation state. The cascade is a complex balance of factors and cofactors, and is tightly regulated.

[0006] In disease states, undesired up- or down-regulation of any of the factors leads to conditions such as bleeding or thrombosis. Historically, anticoagulants have been used in patients at risk of suffering from thrombotic complications such as angina, stroke, and heart attack. Warfarin is a vitamin K antagonist and inhibits factors II, VII, IX, and X, among others. It does inhibit fibrin generation, but it has serious drug-drug interactions and its very long half-life (>2 days) can cause side effects that are not easily reversed. In addition, because vitamin K is an ubiquitous cofactor within the coagulation cascade, antagonism simultaneously inhibits many coagulation factors and thus can lead to significant bleeding complications.

[0007] Much attention has been focused on heparin, a naturally occurring polysaccharide that activates antithrombin III (AT III), an endogenous inhibitor of many factors in the coagulation cascade. The need for parenteral administration of heparin-derived therapeutics and the inconvenience of close supervision of orally available warfarin have driven the discovery and development of orally available drugs with a wide therapeutic window in terms of safety and efficacy.

[0008] The position of thrombin in the coagulation cascade has made it a popular target for drug discovery. Thrombin is a central protein in the coagulation process that is activated and amplified after vascular injury. Thrombin generation sets off a cascade of various factors in the coagulation cascade that ultimately deposits fibrin, the framework of the clot. The clot causes the bleeding event that accompanies vascular injury to stop. Thrombin and related proteins ultimately cause the clot to be dissolved by "fibrinolysis" that returns the system to the pre-injury state. In the "normal" state of wounding, this thrombin generation and clot deposition is desirable. In the disease state, clot deposition is undesirable. A general thrombotic event is the clinical result of clot deposition and accumulation within an artery, vein, or heart. The structure of the accumulated clot eventually breaks loose into the vascular system and can cause the clot to travel to the brain and / or lungs, resulting in stroke, myocardial infarction (heart attack), pulmonary embolism, paralysis, and 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 a significant unmet medical need for clinical patients.

[0009] A thorough discussion of thrombin and its role in the coagulation process can be found in numerous references, including the following, which are incorporated herein by reference in their entirety for all purposes: Wieland, H. A. et al., 2003, Curr Opin Investig Drugs, 4:264-71; Gross, P. L. and Weitz, J. I., 2008, Arterioscler Thromb Vase Biol, 28:380-6; Hirsh, J. et al., 2005, Blood, 105:453-63; Prezelj, A. et al., 2007, Curr Pharm Des, 13:287-312. Without wishing to be bound by any theory, it is believed that there is a strong precedent for the use of thrombin inhibitors (DTIs), e.g., with hirudin-based anticoagulants, and thus a strong interest in discovering and developing novel DTIs. SUMMARY

[0010] The present invention encompasses compounds according to structure I:

[0011]

[0012] and pharmaceutically acceptable salts, solvates, and co-crystals thereof, and uses thereof, wherein R 1 may be hydrogen or pivaloyl.

[0013] Embodiments of the present invention include prodrugs of the compounds according to claim 1 according to general structure II:

[0014]

[0015] and pharmaceutically acceptable salts, solvates, and co-crystals thereof, wherein R 1 may be hydrogen and pivaloyl; and wherein R 2 may be substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl. In some embodiments, R 2 may include the following groups:

[0016]

[0017] Other embodiments of the present invention include the compounds according to claim 1, wherein R 1 may be pivaloyl, as in compound 1:

[0018]

[0019] In some embodiments, the compounds can be in crystalline form.

[0020] In some embodiments, wherein R 1is neopentyl, such as in compound 1, the crystalline form can have an x-ray powder diffraction pattern comprising at least five 2 theta values selected from the group 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°, wherein each of the at least five 2 theta values can be within an error range of ±0.3°. In some embodiments, the crystalline form can have an x-ray powder diffraction pattern comprising at least five 2 theta 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°, wherein each of the at least five 2 theta values can be within an error range of ±0.3°. In some embodiments, the crystalline form can have an x-ray powder diffraction pattern comprising at least five 2 theta 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°, wherein each of the at least five 2 theta values can be within an error range of ±0.3°.

[0021] Embodiments of the application also encompass compounds according to structure I, wherein R 1 may be hydrogen, such as in compound 2:

[0022]

[0023] 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 counterion can be tris(hydroxymethyl)aminomethane and R 1 may be neopentyl. In some embodiments, wherein the counterion can be tris(hydroxymethyl)aminomethane and R 1may be pivaloyl, the compound can be in a crystalline form having an x-ray powder diffraction pattern comprising at least five 2 theta 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°, wherein each of the at least five 2 theta values can be within an error range of ± 0.3°.

[0024] In some embodiments, the compound or prodrug can be one of the following compounds:

[0025] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0026] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]propanoic acid;

[0027] 2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetic acid;

[0028] 4-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]butanoic acid;

[0029] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2,2-difluoropropanoic acid;

[0030] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]acrylamide;

[0031] 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;

[0032] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropionyl)- 1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0033] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylbutanoyl)-1H-pyrazol-3- yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0034] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3-yl)- 2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0035] 3-[3-(5-{[(5-chloro-1-oxo-1 lambda4-thiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)- 1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0036] (2S,3S,4S,5R,6S)-6-({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethyl- propionyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoyl}oxy)-3,4,5-trihydroxy- oxane-2-carboxylic acid;

[0037] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H-pyrazol-3- yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid ethyl ester;

[0038] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H-pyrazol-3- yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid prop-2-en-1-yl ester; 2-(acetyloxy)ethyl ester;

[0039] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H-pyrazol-3- yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid ester;

[0040] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H-pyrazol-3- yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid 1-(acetyloxy)ethyl ester;

[0041] 2,2-dimethylpropanoic 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]propanoyl}oxy)methyl ester;

[0042] 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 (3,5,6-trimethylpyrazin-2- yl)methyl ester;

[0043] (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoic 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]propanoyl}oxy)methyl ester;

[0044] 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;

[0045] 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

[0046] 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.

[0047] Embodiments of the present application also encompass pharmaceutical compositions comprising one or more of any of the foregoing compounds or prodrugs, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and one or more pharmaceutically acceptable excipients.

[0048] Embodiments of the present application also encompass methods for treating and / or preventing a disease or disorder in a subject, the methods comprising administering one or more of any of the foregoing compounds or prodrugs, or a pharmaceutical composition as described above, to a subject in need thereof in an amount effective to treat or prevent the disease or disorder.

[0049] In some embodiments of the methods, the disease or condition can be a thrombotic disease or condition and / or involve a blood clot thrombus or potential formation of a blood clot thrombus. In some embodiments, the thrombotic disease or condition can include acute coronary syndrome, thromboembolism, and / or thrombosis. In some embodiments, the thromboembolism includes venous thromboembolism, arterial thromboembolism, and / or cardioembolism. In some embodiments, the venous thromboembolism includes deep vein thrombosis and / or pulmonary embolism. In some embodiments, the deep vein thrombosis and / or pulmonary embolism occurs following a medical procedure. In some embodiments, the thrombotic disease or condition can involve dysfunctional coagulation or disseminated intravascular coagulation. In some embodiments, the subject can be undergoing percutaneous coronary intervention (PCI). In some embodiments, the thrombotic disease or condition can involve a blood clot thrombus or potential formation of a blood clot thrombus and can further involve stroke and / or one or more transient ischemic attacks (TIAs). In some embodiments, the thrombotic disease or condition involving a blood clot thrombus or potential formation of a blood clot thrombus can further involve stroke and the subject can have non-valvular atrial fibrillation.

[0050] In some embodiments, the thrombotic disease or condition can involve a blood clot thrombus or potential formation of a blood clot thrombus and can further involve pulmonary arterial hypertension. In some embodiments, the pulmonary arterial hypertension can be caused by one or more left-sided heart conditions and / or chronic thromboembolic disease. In some embodiments, the pulmonary arterial hypertension can be associated with one or more pulmonary diseases, including pulmonary fibrosis (idiopathic or otherwise), and / or hypoxia.

[0051] In some embodiments, the disease or condition can include fibrosis, Alzheimer’s disease, multiple sclerosis, pain, cancer, inflammation, and / or Type I diabetes. In some embodiments, the disease or condition can involve recurrent cardiac events following myocardial infarction.

[0052] In some embodiments, the venous thromboembolism can be associated with thrombosis within a vein and / or peripheral venous embolism caused by a detached thrombus associated with the same one or more acquired or genetic risk factors. In some embodiments, the one or more risk factors can include a prior venous thromboembolism.

[0053] In some embodiments, the cardiogenic thromboembolism can be due to thrombus formation within the heart associated with cardiac arrhythmia, heart valve defects, prosthetic heart valves, or heart disease and / or peripheral arterial embolization 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 transient ischemic attack (TIA). In some embodiments, the cardiogenic thromboembolism can be due to non-valvular atrial fibrillation.

[0054] In some embodiments, the thrombosis can be arterial thrombosis. In some embodiments, the arterial thrombosis can be due to one or more underlying atherosclerotic processes in the artery. In some embodiments, the one or more underlying atherosclerotic processes in the artery can cause occlusion or closure of the artery, cause myocardial ischemia (angina pectoris, acute coronary syndrome), cause myocardial infarction, cause occlusion or closure of peripheral arteries (ischemic peripheral arterial disease), and / or cause occlusion or closure of the artery after surgery on the blood vessel (reocclusion or restenosis after percutaneous transluminal coronary angioplasty, reocclusion or restenosis after percutaneous transluminal peripheral angioplasty).

[0055] In some embodiments, the treatment or prevention can include adjunct therapy. In some embodiments, the subject can have myocardial infarction and the adjunct therapy can be combined with thrombolytic therapy. In some embodiments, the subject can have unstable angina, thrombosis, and / or heparin-induced thrombocytopenia and the adjunct therapy can be combined with antiplatelet therapy. In some embodiments, the subject can have non-valvular atrial fibrillation and the adjunct therapy can be combined with one or more other therapies. In some embodiments, the subject can have at least one of coronary artery disease and heart failure and wherein the adjunct therapy can be combined with antiplatelet therapy.

[0056] In some embodiments, the subject can also have valvular or non-valvular atrial fibrillation. In some embodiments, the subject can have valvular or non-valvular atrial fibrillation and can be undergoing percutaneous coronary intervention with a stent and the adjunct therapy can be combined with antiplatelet therapy.

[0057] Embodiments of the application also encompass a tablet comprising a pharmaceutical composition comprising Compound 1, wherein R 1 is pivaloyl.

[0058] In some embodiments, Compound 1 can exist as an amorphous solid in an amorphous solid dispersion. In some embodiments, the amorphous solid dispersion can comprise 50% by weight of the tablet. In some embodiments, the amorphous solid dispersion comprises a first polymer. In some embodiments, the first polymer can be vinylpyrrolidone-vinyl acetate copolymer. In some embodiments, Compound 1 and the first polymer are present in a weight ratio of 1 :3.

[0059] In some embodiments, the tablet can comprise at least one disintegrant. In some embodiments, the disintegrant comprises crospovidone. In some embodiments, the tablet can comprise at least one filler. In some embodiments, the filler comprises microcrystalline cellulose or mannitol. In some embodiments, the tablet can comprise at least one lubricant or glidant. In some embodiments, the lubricant or glidant comprises magnesium stearate or talc.

[0060] In some embodiments, the tablet can comprise an outer layer or film. In some embodiments, the outer layer or film comprises at least one second polymer. In some embodiments, the second polymer can prevent the tablet from dissolving below pH 5.5. In some embodiments, the second polymer can be L 30D-55. In some embodiments, the outer layer or film comprises 57% of L 30D-55, 14.6% of HTP20, and 28.4% of water. In some embodiments, the second polymer is methacrylic acid-ethyl acrylate copolymer.

[0061] In some embodiments, the tablet comprises an outer layer of a second polymer, and wherein a tablet without the outer layer can be 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. In some embodiments, the second polymer can be L 30D-55. In some embodiments, the total mass of the tablet without the outer layer is 180 mg ± 9 mg. In some embodiments, the total mass of the tablet without the outer layer can be 1000 mg ± 50 mg.

[0062] Embodiments of the present application also encompass a tablet comprising a pharmaceutical composition comprising a prodrug having the general structure II, wherein R 1 may be hydrogen or pivaloyl, and wherein R 2 may be substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl.

[0063] Embodiments of the present application also encompass a process of manufacturing the foregoing tablet, wherein the process can comprise: (1) producing an amorphous solid dispersion of Compound 1; (2) granulating the amorphous solid dispersion of step (1) with intragranular ingredients under dry conditions; (3) blending the granules of step (2) with extragranular ingredients to form a final mixture; (4) compressing the final mixture of step (3) into a tablet; and (5) coating the tablet of step (4) with a film or layer. In some embodiments, the process can further comprise: (1) producing an amorphous solid dispersion of Compound 1 using spray-dried dispersion (SDD) technology; (2) mixing the amorphous solid dispersion of step (1) with intragranular ingredients comprising at least one disintegrant and at least one lubricant; (3) dry granulating the mixture of step (2), wherein the granulation process comprises using a roller compactor to produce a compacted ribbon, wherein the compacted ribbon is subsequently milled into granules; (4) blending the granules of step (3) with deagglomerated extragranular ingredients comprising a disintegrant and a lubricant; (5) compressing the blend of step (4) into a tablet; and (6) coating the tablet of step (5) with a film or layer.

[0064] The following detailed description together with the accompanying drawings will provide a better understanding of the nature and advantages of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0065] Those skilled in the art will understand that the drawings described below are for purposes of illustration only. The drawings are not intended to limit the scope of the present teachings in any way.

[0066] Various embodiments according to the present disclosure will be described with reference to the drawings, in which:

[0067] Figure 1 An XRPD spectrum of crystalline Form 1 of Compound 1 is shown.

[0068] Figure 2 An XRPD spectrum of crystalline Form 2 of Compound 1 is shown.

[0069] Figure 3 An XRPD spectrum of crystalline Form 3 of Compound 1 is shown.

[0070] Figure 4 An XRPD spectrum of crystalline Form 4 of Compound 1 as a salt with tris(hydroxymethyl)aminomethane is shown. DETAILED DESCRIPTION

[0071] In the following description, various embodiments will be described. For the purpose of explanation, specific configurations and details will be set forth in order to provide a thorough understanding of the embodiments. However, it will also be apparent to one skilled in the art that the embodiments can be practiced without the specific details. Furthermore, well-known features will not be described in detail in order to not unnecessarily obscure the described embodiments.

[0072] The technology described and claimed herein includes various aspects of the present application.

[0073] I. DEFINITIONS

[0074] The terms are to be understood in accordance with their conventional meanings in the relevant technical field, unless otherwise specified.

[0075] Abbreviations used herein have their conventional meanings within the chemical and biological arts. Chemical structures and formulas shown herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0076] Where a substituent group is specified by its conventional chemical formula (written from left to right), it equally encompasses the chemically identical substituent obtained by writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0077] As used herein, the term "linkage" denotes a stable covalent bond, certain preferred linkages will be apparent to those of ordinary skill in the art.

[0078] The term "halogen" or "halo" includes fluorine, chlorine, bromine and iodine. Additionally, terms such as "haloalkyl" are meant to include mono and polyhaloalkyl groups. For example, the term "haloalkyl" includes, but is not limited to, fluoroalkyl, di-fluoroalkyl, tri-fluoroalkyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0079] The term "alkyl," by itself or as part of another substituent means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched-chain hydrocarbon, or combinations thereof, which can be fully saturated, mono-unsaturated, or poly-unsaturated, having the indicated number of carbon atoms (i.e., C1-C 10saturated alkyl groups include, but are not limited to, groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like, including homologs and isomers such as n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 1,1-dimethylethyl (tert-butyl), and the like. Unsaturated alkyl is an alkyl group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, 2-propenyl, crotyl, 2- isopentenyl, ethynyl, 1-propynyl, and 3-propynyl, 3-butynyl, and higher homologs and isomers. Thus, the term "alkyl" can refer to straight-chain saturated, branched- chain saturated, straight-chain unsaturated, or branched-chain unsaturated aliphatic hydrocarbon groups, and the like. Typically, alkyl groups will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. "Lower alkyl" is a shorter chain alkyl group, typically having eight or fewer carbon atoms.

[0080] The term "alkylene," by itself or as part of another substituent, means, unless otherwise specified, a divalent group derived from a branched or straight-chain, saturated or unsaturated alkyl group as defined above, such as, but not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH=CHCH2-, and the like. Typically, alkylene groups will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the compounds disclosed herein. "Lower alkylene" is a shorter chain alkylene group, typically having eight or fewer carbon atoms.

[0081] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise specified, a straight-chain or branched-chain, or combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, Si, P, and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom O, N, Si, P, and S can be placed at any interior position of the chain. Heteroalkyl groups can be fully saturated, monounsaturated, or polyunsaturated. Thus, the term "heteroalkyl" can refer to saturated or unsaturated straight-chain or branched-chain, and the like. Examples include, but are not limited to: -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-CH3, -CH2-CH=N-OCH3, -CN, and the like. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3.

[0082] Similarly, the term "heteroalkylene" by itself or as part of another substituent means, unless otherwise specified, a divalent radical derived from a heteroalkyl group, as defined above. Non-limiting examples of heteroalkylene groups include -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2- and the like. Additionally, for alkylene and heteroalkylene linking groups, no orientation of a linking group is implied by the direction in which the formula of the linking group is written. For example, the chemical formula -CO2CH2- represents both -C(=O)OCH2- and -CH2OC(=O)-.

[0083] The terms "cycloalkyl," "cycloalkylene," "heterocycloalkyl," and "heterocycloalkylene" by themselves or in combination with other terms, mean cyclic versions of "alkyl," "alkylene," "heteroalkyl," and "heteroalkylene," respectively. "Cycloalkyl," "cycloalkylene," "heterocycloalkyl," and "heterocycloalkylene" groups include, for example, mono-, bi-, tri-, and the like, rings having from 3 to 8 ring members, and double-bonded ring members are counted as ring members. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclooctyl, and the like. Examples of heterocycloalkyl groups include, but are not limited to, 1-(1,2,5,6-tetrahydropyridinyl), 2-piperidinyl, 3-piperidinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 2-piperazinyl, and the like. "Cycloalkylene" and "heterocycloalkylene" mean, by themselves or as part of another substituent, divalent radicals derived from cycloalkyl and heterocycloalkyl, respectively.

[0084] The term "alkoxy" denotes an alkyl group as defined above attached to the rest of the molecule by an oxygen bridge. Examples include methoxy, ethoxy, and the like. Unless otherwise specified, the term "alkyleneoxy" denotes a divalent alkyl group. Examples of alkyleneoxy groups include -OCH2-, OCH2CH2-, -OCH=CHCH2-, and the like.

[0085] The term "alkylamino" denotes one or two alkyl or heteroalkyl groups as defined above attached to the rest of the molecule by an amine bridge. Examples include dimethylamino, ethylamino, and the like. The two alkyl and / or heteroalkyl groups can form, together with the nitrogen to which they are attached, a ring system containing 3 to 8 carbon atoms, with or without one C1-C4 alkyl group as a substituent. Unless otherwise specified, the term "alkyleneamino" denotes a divalent alkylamino group. Examples of alkyleneamino groups include -NHCH2-, -NHCH2CH2-, -N(CH3)CH2CH2-, and the like. 16 alkyl, aryl Co-C 16 alkyl or Co-C 16 alkyl aryl substituent. Unless otherwise specified, the term "alkyleneamino" denotes a divalent alkylamino group. Examples of alkyleneamino groups include -NHCH2-, -NHCH2CH2-, -N(CH3)CH2CH2-, and the like.

[0086] The term "alkenyl" refers to straight-chain or branched-chain unsaturated alkyl groups. The double bond can occur in any stable position along the chain, and the carbon-carbon double bond can have the cis- or trans-configuration. For example, this definition shall include, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, 1,5-octadienyl, 1,4,7-nonatrienyl, and the like. "Cycloalkenyl" alone or as part of another substituent means a cyclic version of an alkenyl group. Examples of cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, ethylcyclohexenyl, butenylcyclopentyl, 1-pentenyl-3-cyclohexenyl, and the like. Similarly, "heteroalkenyl" refers to a heteroalkyl group having one or more double bonds, where heteroalkyl is as defined above, and "heterocycloalkenyl" refers to a cyclic version of a heteroalkenyl group as defined above.

[0087] The term "alkynyl" refers to straight-chain or branched-chain unsaturated alkyl groups having one or more triple bonds. The term "cycloalkynyl" refers to a cyclic version of a cycloalkyl group as defined above additionally having one or more triple bonds. The term "heterocycloalkynyl" refers to a heterocycloalkyl group additionally having one or more triple bonds.

[0088] Unless otherwise indicated, the term "acyl" refers to an alkyl group of the formula -C(O)R (alternatively depicted 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.

[0089] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic hydrocarbon substituent which can be a single ring or multiple rings (preferably 1 to 3 rings) which are fused together (i.e., fused rings) or linked covalently, wherein each ring in the system contains from 4 to 20 atoms, and preferably 5 to 10 atoms. A fused ring aryl is meant to include multiple rings fused together wherein at least one of the fused rings is an aromatic ring and wherein each ring contains 4 to 20 atoms, and preferably 5 to 10 atoms. The term "heteroaryl" means an aryl group (or ring) as defined above containing from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and one or more of the nitrogen atoms are optionally quaternized. The term "heteroaryl" therefore includes fused ring heteroaryls (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene is meant to include two rings fused together wherein one ring has 5 members and the other ring has 6 members, wherein at least one of the rings is a heteroaromatic ring. Similarly, a 6,6-fused ring heteroarylene is meant to include two rings fused together wherein one ring has 6 members and the other ring has 6 members, wherein at least one of the rings is a heteroaromatic ring. And a 6,5-fused ring heteroarylene is meant to include two rings fused together wherein one ring has 6 members and the other ring has 5 members, wherein at least one of the rings is a heteroaromatic ring. Non-limiting examples of aryl 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-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl, 6-quinolyl, 2,3-dihydro-1,4- benzodioxinyl, and the like. Those skilled in the art will appreciate that in certain ring systems one or more of the heteroatoms of the heteroaryl system can optionally be substituted (e.g., 1-pyrazole).

[0090] "Arylene" and "heteroarylene" mean, alone or as part of another substituent, divalent radicals derived from aryl and heteroaryl, respectively. Thus, the term "aryl" can mean an unsubstituted, mono-substituted, di-substituted, or tri-substituted monocyclic, polycyclic covalently linked aryl and heteroaromatic group covalently linked at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art (e.g., 3-indolyl, 4-imidazolyl).

[0091] For simplicity, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthoxy, arylalkyl) includes aryl and heteroaryl rings as defined above. Therefore, the term "arylalkyl" and the like are intended to include those groups (e.g., benzyl, phenethyl, pyridylmethyl, etc.) in which an alkylene group connects an aryl group to another part of the molecule. The alkylene group covered by the term "arylalkyl" includes alkylene groups in which a carbon atom (e.g., methylene) has been substituted with, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.) or a sulfur atom.

[0092] Unless otherwise stated, the term "amide" generally refers to the group -C(O)NR-, where R is selected from 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. The term "amide" alone does not imply a particular linkage orientation.

[0093] Unless otherwise stated, the term "carboxyl" generally refers to the group -C(O)O- or -CO2-. The term "carboxyl" alone does not imply a specific linkage orientation.

[0094] As used in this article, the term "oxo-group" refers to oxygen that is double-bonded to a carbon atom.

[0095] Each of the above terms (e.g., "alkyl", "heteroalkyl", "aryl", "heteroaryl", etc.) includes both substituted and unsubstituted forms of the indicated group.

[0096] The substituents in the substituent groups are generally selected from the group consisting of (but 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, C 1-16 Alkyl, aryl C 1-16 Alkyl, CO- 16 Alkoxy C 0-16 Alkyl, aryl C 0-16 Alkoxy C 0-16 Alkyl, C 0-16 Alkyl thiocto-C0- 16 Alkyl, aryl C 0-16 Alkyl thio C0-16 alkyl, C 0-16 alkylamino C 0-16 alkyl, aryl C 0-16 alkylamino C 0-16 alkyl, di(aryl C 1-16 alkyl)amino C 0-16 alkyl, C1- 16 alkylcarbonyl C 0-16 alkyl, aryl C 1-16 alkylcarbonyl C 0-16 alkyl, C 1-16 alkylcarboxy C 0-16 alkyl, aryl C 1-16 alkylcarboxy C 0-16 alkyl, C 1-16 alkylamido C 0-16 alkyl, aryl C 1-16 alkylamido C 0-16 alkyl, -C 0-16 alkyl COOR’, -C 0-16 alkyl CONR””R””’, wherein R’, R”, R’”, R””, and R”’” are independently selected from 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, optionally wherein R”” and R”’” together with the nitrogen to which they are attached form a ring system containing 3 to 8 carbon atoms, with or without one C 1-16 alkyl, aryl C0-C 16 alkyl or C0-C 16Alkyl aryl substituents. Substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, heterocycloalkyl, and heterocycloalkenyl groups can have from 0 to (2n + 1) substituents of any number, where n is the total number of carbon atoms in the group. Substituted aryl and heteroaryl groups can have from 0 to the total number of valences on the ring system, any number of substituents. Two substituents can optionally be joined forming an alkylene or heteroalkylene. In one embodiment, ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure result in a fused ring structure (e.g., 2-amino-3-ethylbenzene can cyclize to form a 7-(2,3-dihydroindolyl) group). In another embodiment, ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure result in a spirocyclic structure (e.g., 2-(hydroxymethyl)-2-methyl-cyclohexane cyclizes to form a 2-oxaspiro[3.5]nonane group). In another embodiment, ring-forming substituents are attached to non-adjacent members of the base structure. For example, two ring-forming substituents attached to non-adjacent members of a cyclic base structure result in a bridged cyclic structure (e.g., 1-aminocyclooctane can cyclize to form a 9-aza-[3.3.1]bicyclononane).

[0097] The term "about," as used herein in the context of a value, refers to a range of + / - 10% of that value, unless otherwise explicitly stated.

[0098] II. Compounds

[0099] The present disclosure relates to substituted acylated pyrazole-pyridinone compounds. These compounds exhibit biological activity, for example, inhibitory activity against thrombin, a serine protease.

[0100] Embodiments of the present invention encompass compounds having the following Structure I:

[0101]

[0102] or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, wherein R 1 is selected from the group consisting of hydrogen and pivaloyl, which describes the formula -C(0)C(CH3)3 as depicted below:

[0103]

[0104] In some embodiments, R 1 is pivaloyl, resulting in 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, as shown below as Compound 1:

[0105]

[0106] In some embodiments, Compound 1 exists in a crystalline form. In one embodiment, the crystalline form has a selected x-ray powder diffraction pattern comprising one, two, three, four, five or more 2-theta values selected from the group 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°, each within an error range of ±0.3°, as shown in Crystalline Form 1 in Table 1. Figure 1 In another embodiment, the crystalline form has a selected x-ray powder diffraction pattern comprising one, two, three, four, five or more 2-theta 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°, each within an error range of ±0.3°, as shown in Crystalline Form 2 in Table 1. Figure 2 In another embodiment, the crystalline form has a selected x-ray powder diffraction pattern comprising one, two, three, four, five or more 2-theta 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°, each within an error range of ±0.3°, as shown in Crystalline Form 3 in Table 1. Figure 3 In another embodiment, the crystalline form has a selected x-ray powder diffraction pattern comprising one, two, three, four, five or more 2-theta 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°, each within an error range of ±0.3°, as shown in Crystalline Form 3 in Table 1.

[0107] In some embodiments, R 1 is hydrogen, resulting in 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid, as shown below as Compound 2:

[0108]

[0109] Other embodiments include salt forms of the compounds encompassed by Structure I, including 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.

[0110] In some embodiments, when Compound 1 is in the form of a salt having tris(hydroxymethyl)aminomethane as a counterion, the material is in crystalline form. In some embodiments, the crystalline form of Compound 1 in the form of a salt having tris(hydroxymethyl)aminomethane as a counterion has a selected x-ray powder diffraction pattern comprising one, two, three, four, five or more 2 theta 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 measured by powder x-ray diffraction, e.g., as shown in FIG. 1. Figure 4

[0111] Certain embodiments of the present application relate to certain prodrugs of Structure I, which have the general structure of Structure II:

[0112]

[0113] wherein R 1 is selected from hydrogen and pivaloyl, and R 2 is selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl. In further embodiments, R 2 is selected from the list of the following structures:

[0114]

[0115] In some embodiments, the prodrugs of Structure I can be formulated as their pharmaceutically acceptable salts, solvates, and co-crystals.

[0116] Other compounds disclosed herein include the following compounds listed in Table A below:

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] ​The compounds disclosed herein may also exist as mixtures with one or more other compounds and / or as mixtures including isotopically labeled and radiolabeled compounds. See, for example, Goding, 1986, *Monoclonal Lantibodies Principles and Practice*; Academic Press, p. 104. Such isomers can be separated by standard analytical techniques, including, for example, fractional crystallization, chiral chromatography, etc. See, for example, Eliel, EL and Wilen S.H., 1993, *Stereochememistry in Organic Components*; John Wiley & Sons, New York. In some embodiments, such mixtures comprise compound 1, compound 2, or both compound 1 and compound 2, wherein such mixtures may optionally also include isotopically labeled and radiolabeled compounds, such as isotopically and radiolabeled forms like compound 1, compound 2, or both.

[0126] The disclosed compounds may also contain atomic isotopes in non-natural proportions at one or more atoms constituting the compound. For example, the compounds may be deuterated and / or made with carbon-13 (… 13 C) labeled, and / or labeled with a radioactive isotope such as tritium ( 3 H) or carbon-14 ( 14 C) Radiolabeling; those skilled in the art will understand which isotopes may be present within the scope of this invention. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the intended scope. Exemplary deuterated compounds according to the invention include compound numbers 22, 23, and 24 in Table A; these compounds represent exemplary positions where compounds according to the invention can be deuterated, and those skilled in the art, with an understanding of the chemical principles, will understand which compounds can be deuterated and at which positions, including but not limited to the positions shown in compound numbers 22, 23, and 24 in Table A.

[0127] In some embodiments, metabolites of the compounds disclosed herein may be used in the methods disclosed herein.

[0128] Some of the compounds disclosed herein may exist in both soluble and soluble forms, including hydrated forms. Generally, soluble forms are equivalent to soluble forms and are covered within the scope of the intended compounds. Some of the compounds of this invention may exist in polymorphic or amorphous forms. Generally, all physical forms are equivalent to the compounds and methods contemplated herein and are intended to be within the scope of the disclosure herein.

[0129] III. Measurement

[0130] The compounds described herein can be determined using a variety of methods known in the art and applicable to a wide range of chemical properties and biological activities. These parameters include, for example, thrombin inhibition, solubility and stability, and pharmacokinetic properties.

[0131] Human thrombin generation assay

[0132] Results of the Human Thrombin Generation Assay (TGA); do not confuse this with “thermogravimetric analysis,” which is used elsewhere and uses the same acronym. Those skilled in the art will understand the intended meaning based on the context of the surrounding technical information generated below. In a 96-well plate, 4 μL of solutions of the test compound in DMSO at concentrations of 100, 33.3, 11.1, 3.7, 1.23, 0.41, 0.137, and 0.046 μM were added to sequential wells filled with 68 μL of “TGA Working Solution.” See the description of this solution and other related solutions below. The plate was incubated at room temperature for 10 minutes, followed by the addition of 8 μL of warm “Substrate Solution” to each well, resulting in a 500 μM concentration of substrate Z-GGR-AMC (Z-Gly-Gly-Arg-7-amino-4-methylcoumarin·HCl) in each well. Immediately use with Cytation. TM or Synergy TM The H1 96-well microplate reader was used to begin collecting fluorescence intensity data (Ex / Em 380 / 460nm). After a 4-second double-track vibration, the plate was incubated at 37°C for a 90-minute data collection period. Parallel wells containing DMSO substrate at different concentrations (2.50, 0.833, 0.278, 0.093 mM) in buffer were used to measure the test compounds and generate standard fluorescence curves. Data values, including AUC, were automatically calculated. 50 This value represents the concentration of a compound that reduces the potential AUC of endogenous thrombin by 50%.

[0133] Various solutions were prepared as follows. The HEPES / NaCl assay buffer was prepared by combining 7.5 mL of 5M NaCl, 1.19 g of 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), and 230 mL of water. The assay buffer was prepared by combining 20 μL of Siemens DadeInnovin recombinant tissue factor and thrombin with 50 μL of [a specific solution / container ... The 0.5 mM phospholipid-TGT was combined in 450 μL of the above HEPES / NaCl assay buffer to make the "Innovin master solution". This solution was then vortexed for a few seconds. Next, a "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) and vortexing in a polystyrene tube. This solution was stored at -20 °C. A "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. A "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 prior to its addition to the assay plate.

[0134] 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, and Hemker, H.C. et al. 'Calibrated automated thrombin generation measurement in clotting plasma.' 2003, Pathophysiol Haemost Thromb 33: 4-15.

[0135] Mouse and rat plasma stability

[0136] The results for mouse (CD-1) and rat (SD) plasma stability were generated as follows. Along with a positive control of bromocriptine, 8 μL of each test compound at 1 mM in DMSO was placed in two wells of a Nunc TM 96-well plate (referred to as the "dilution plate"). To one well, 392 μL of HyClone TMWater and mixed by pipette. To another well was added 392 μL of mouse or rat plasma stabilized with sodium citrate purchased from Innovative Research and mixed by pipette. The dilution plate was kept covered to reduce solvent evaporation and heated in an incubator at 37°C. At each time point listed below, the plate was removed from the incubator and 50 μL of test compound / water or test compound / plasma solution was transferred to the corresponding unique well in a "quench plate" (96 well plate) containing 150 μL of a quench solution containing an internal standard (20 uM diclofenac in acetonitrile). The dilution plate was then returned to the incubator. This process was performed at 0, 5, 10, 20, 40, 80, and 160 minutes after the original mixing of 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 1000 x g for 10 minutes at 4°C. 100 μL of supernatant from each well was then transferred to the corresponding unique well in a "read plate" (96 well TM plate) filled with 100 μL HyClone Water. The plate was then sealed and analyzed via UHPLC using a 10 μL injection through a Kinetex column pre-equilibrated with loading buffer (95:5 water:acetonitrile). Flow phase A: water, 0.025% formic acid. Flow phase B: acetonitrile, 0.025% formic acid. Flow rate: 0.5 mL / min. LC gradient: 0.0-0.5 minutes: hold at 5% B; 0.5-2.5 minutes: 5%-95% B; 2.5-3.0 minutes: hold at 95% B; 3.0-3.05 minutes: 95%-5% B; 3.0-4.0 minutes: hold at 5% B. Absorbance was monitored at 254 nm and 280 nm and compound concentration was assumed to vary linearly with integrated peak area obtained from the wavelength at which the compound showed stronger absorbance. Half-life (t 1 / 2 ) times were calculated by using a chi-squared analysis to fit peak area to an exponential decay model of compound concentration versus time. If half-life was not reached by the last time point of 160 minutes, then the error in the extracted half-life value can be large. Therefore, in this document, half-lives calculated in this case are reported as "≥ 300 minutes."

[0137] Mouse and rat liver microsome stability

[0138] Mouse (CD-1) and rat (SD) liver microsome stability results were generated as follows. In a 96 well Nunc TM plate, 1.5 μL of a 200 μM solution of test compound in DMSO was placed in one well. This plate ("reaction plate") was then warmed to 37°C in an oven. In a second 96 well NuncTM In the plate ("quench plate"), six wells are filled with 180 μL of internal standard quench solution consisting of 100 nM diclofenac in acetonitrile. These six wells correspond to the six time points for data collection: 0, 0.5, 5, 15, 30, and 60 minutes. "Assay buffer" is prepared by combining 6.96 g of dibasic potassium phosphate, 1.36 g of monobasic potassium phosphate, and 0.30 g of magnesium chloride hexahydrate, followed by dilution in water to a final concentration of 500 mL and adjustment to pH 7.4 as needed. The assay buffer is warmed to 37 °C, and 12 mL is added to a 10 mg vial of NADPH. Then 300 μL of a 20 mg / mL suspension of liver microsomes is added to give 0.5 mg / mL of liver microsomal suspension. Then 300 μL of this liver microsomal suspension is 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 is transferred to the corresponding well of the quench plate. Between time points, the reaction plate is kept sealed and warm in an incubator at 37 °C. When the last time point has been completed, the quench plate is centrifuged at 1000 x g for 10 minutes at 4 °C. Then 50 μL of supernatant from each well is transferred to the corresponding unique well of a 96-well plate ("analysis plate") that is filled with 150 μL of 50:50 acetonitrile:HyClone water. The analysis plate is then sealed with precut plate seals, and then analyzed via the appropriate LCMS method at 10 μL injection. The extracted AUC data are then plotted to calculate the intrinsic clearance (μL / min / mg). This experiment is run with positive and negative controls. Due to the parameters of this procedure, one skilled in the art will understand that the lower measurable limit of this assay is 5 μL / min / mg; therefore, the clearance of certain compounds is noted as ≤ 5 μL / min / mg. TM

[0139] Mouse pharmacokinetics

[0140] Mouse pharmacokinetics data are generated as follows. Compounds are administered intravenously (IV) via tail vein as a single dose or orally (PO) via gavage as a single dose to male CD-1 mice weighing between 18 and 25 g. The nominal doses for IV and PO administration are 1 mg / kg and 5 mg / kg, respectively. IV doses are prepared by dissolving the test compound in a mixture of 5% N,N-dimethylacetamide (DMA), 15% 1-methyl-2-pyrrolidinone (NMP), and 80% sterile water (v / v / v) at a dose concentration of 0.25 mg / mL. PO doses are prepared by dissolving the test compound in a mixture of 90% HS15 and 10% pure ethanol (v / v) at a dose concentration of 0.25 mg / mL. PO doses are prepared by dissolving the test compound in a mixture of 90% HS15 and 10% pure ethanol (v / v) at a dose concentration of 0.25 mg / mL. PO doses are prepared by dissolving the test compound in a mixture of 90% HS15 and 10% pure ethanol (v / v) at a dose concentration of 0.25 mg / mL.​

[0141] Animals were housed in standard home cages with ad libitum access to food and water, except for animals used for PO dosing which were fasted overnight prior to dosing. At pre-dose and each time point post-dose (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 in triplicate via cardiac puncture. Plasma was obtained by centrifuge and stored frozen until analyzed by LC-MS / MS using an AB Sciex Omega 1.6 pm Polar C18 Shimadzu Nexera X2 coupled to an AB Sciex TM 5500. Samples were compared to a standard curve of test compound at concentrations ranging from 10,000 to 0.3 ng / mL.

[0142] Pharmacokinetic parameters were calculated using non-compartmental analysis by averaging the concentration values as described below and as would be apparent to one of ordinary skill in the art. The concentration at time zero (C0) for IV was established by extrapolation of a log-linear regression using equal weighting of the first three sampling time points. Area under the curve (AUC) values were calculated using linear trapezoidal integration.

[0143] Rat Pharmacokinetics

[0144] Rat pharmacokinetic data were generated as follows. Compounds were administered intravenously (IV) via tail vein or orally (PO) via gavage to Sprague-Dawley rats equipped with surgically implanted jugular vein catheters (JVC) with a nominal weight of 250 to 275 g. The nominal dose for IV and PO was 1 mg / kg and 5 mg / kg, respectively. IV dosing was prepared by dissolving test compound in a mixture of 5% N,N-dimethylacetamide (DMA), 15% HS15, and 80% sterile water (v / v / v) at a dose concentration of 0.25 mg / mL. PO dosing was prepared as Option A or Option B. Option A was prepared by dissolving test compound in a mixture of 90% HS15 and 10% pure ethanol (v / v) at a dose concentration of 0.25 mg / mL. Option B was prepared by dissolving test compound in a mixture of 20% HS15 and 80% phosphate buffer (v / v) at a dose concentration of 0.25 mg / mL.

[0145] ​​​​Animals were housed in standard home cages with ad libitum access to food and water, except for animals used for PO dosing which were fasted overnight prior to dosing. One to three rats were used per experiment. Samples were collected via their JVCs just prior to dosing and at 5 minute, 15 minute, 30 minute, 60 minute, 120 minute, 4 hour, 8 hour, 12 hour, and 24 hour time points. Alternatively, animals were transferred to BASi an automated blood sampling system to collect samples automatically. Plasma was obtained by centrifuge and stored frozen until analyzed by LC-MS / MS using an AB Sciex 5500 coupled to a Shimadzu Nexera X2 equipped with a 50 x 2.1 mm Omega 1.6 pm Polar C18 column. Samples were compared to a standard curve of test compound at concentrations ranging from 10,000 to 0.3 ng / mL. TM

[0146] As described below and as will be apparent to one of ordinary skill in the art, pharmacokinetic parameters were calculated using non-compartmental analysis by averaging the concentration values. The concentration at time zero (C0) for IV was established by extrapolation of a log-linear regression using equal weighting of the first three sampling time points. Area under the curve (AUC) values were calculated using linear trapezoidal integration.

[0147] Inhibition of platelet activation in CD-1 mouse plasma

[0148] The assay for inhibition of platelet activation in mouse plasma was performed by the following procedure. Test compounds and positive controls were first diluted in DMSO in a three-fold serial dilution to yield a concentration range from 1500 to 0.08 mM for each. Two pL of each sample solution was then placed in the corresponding well of a 96-well plate ("assay plate") containing 88 pL of a platelet-rich plasma (PRP) mixture described below. Ten pL of a 10 nM solution of mouse thrombin in assay buffer (described below) was then added to each well of the assay plate. The plate was then shaken on a Lab-Line Instruments Inc. titration plate shaker at 300 RPM for 2 minutes. Ten pL of a 1 mM solution of ADP in assay buffer was then added to each well. The plate was again shaken at 300 RPM for 3 minutes. Luminescence data was recorded from a microplate reader. Each sample was measured in duplicate and against a blank with and without mouse thrombin to record background and maximum signal measurements. IC data was automatically calculated from the luminescence counts measured according to methods known to those skilled in the art. 50 Data.​

[0149] The various solutions involved in this procedure are described below. The assay buffer was prepared by combining 7.5 mL of 5 M NaCl with 1.19 g of HEPES powder, 0.5 mL of 1 M MgCl2, 1.5 mL of 1 M KCl, and 235 mL of water in a 500 mL flask. The pH of the solution was adjusted to 7.4 using 10 N NaOH, followed by adjusting its final volume 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 obtained powder. The PRP mixture was prepared by first centrifuging 600 μL of CD-1 mouse whole blood at room temperature in a 1.8 mL sodium citrate vacuum container in an Eppendorf 5810R centrifuge at 100 x g for 10 minutes. The plasma layer was then extracted into a storage vial along with as much of the buffy coat layer as possible. Extracts from multiple animals were usually pooled together. To make the final mixture, 2.3 mL of these plasma extracts were combined with 7.2 mL of the above assay buffer and 0.5 mL of the 20 mM GPRP solution. In this final PRP mixture, the platelet count was approximately 200 x 10 6 mL -1 A mouse thrombin solution was prepared by mixing mouse thrombin obtained from Haematological Technologies, Inc. in the above assay buffer to yield a 100 nM solution.

[0150] Biological Activity

[0151] The biological data presented below are intended to illustrate various aspects of the embodiments and are not intended to limit the disclosure.

[0152] Table B below shows the ETP EC 50 values for selected compounds in a human thrombin generation assay; "ND" indicates that no data were available for the compound at the time of filing the application.

[0153] Table B.

[0154]

[0155] Table C below shows mouse and rat plasma stability and liver microsomal clearance for selected compounds.

[0156] Table C.

[0157]

[0158] Table D below shows various pharmacokinetic data for selected compounds in CD-1 mice.

[0159] Table D.

[0160]

[0161] The following Table E shows various pharmacokinetic data for selected compounds in SD rats.

[0162] Table E.

[0163]

[0164] The following Table F shows EC50values for selected compounds against inhibition of platelet activation in CD-1 mice. 50 .

[0165] Table F.

[0166]

[0167] IV. Methods of treating and preventing disease

[0168] Thrombotic diseases are a primary indication for inhibition of thrombin, because of the position of thrombin in the coagulation cascade and the importance of the coagulation cascade in the progression of the coagulation process. However, without wishing to be bound by any theory, it is believed that the coagulation cascade in general and thrombin in particular are important in a variety of other disease states.

[0169] In general, the terms "treatment," "treating," and the like, as used herein, mean affecting a subject, tissue or cell to obtain a desired pharmacologic and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or can be therapeutic in terms of a partial or complete cure for a disease and / or adverse effect attributable to the disease (e.g., pulmonary embolism after surgery). "Treatment," as used herein, covers any treatment of a disease or condition in a vertebrate, mammal, particularly in a human, and includes: (a) preventing the disease or condition from occurring in a subject which can be predisposed to the disease or condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition, i.e., arresting its development; or (c) relieving or ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0170] It has been found that the presently described compounds, for example 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, and the compounds depicted in Table A, exhibit inhibitory effects against thrombin (activated coagulation factor II; EC 3.4.21.5). This in turn inhibits the coagulation process.

[0171] This inhibitory effect can be used to treat a variety of thrombotic conditions, such as, but not limited to, acute vascular disorders such as acute coronary syndrome; venous, arterial and cardiogenic thromboembolism; prophylaxis in other conditions such as disseminated intravascular coagulation, or other conditions involving the presence or potential formation of blood clot thrombi. Other indications for the methods described herein include the following.

[0172] It has been reported that known thrombin inhibitors can be used to treat and prevent acute coronary syndrome (ACS) (Clemens, A. et al. WIPO Patent Application WO / 2008 / 009638). ACS is a group of symptoms caused by myocardial ischemia. The drug can be used to prevent myocardial infarction or at some time after the event has occurred (e.g., post-myocardial infarction, post-MI; i.e., chronic therapy, secondary prevention). Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be used to treat and prevent acute coronary syndrome.

[0173] Non-valvular atrial fibrillation is a persistent cardiac disturbance, often associated with heart disease. It has been reported that known thrombin inhibitors such as ximelagatran can be used for stroke prevention in patients with non-valvular atrial fibrillation (Diener H.-C. Cerebrovasc Dis 2006; 21 :279-293).

[0174] The selective thrombin inhibitor ximelagatran was studied in two phase III clinical trials (SPORTIF III and SPORTIF V) that compared ximelagatran and warfarin for the prevention of cardiac embolic events in patients with non-valvular atrial fibrillation. The investigators of the SPORTIF III clinical trial found that ximelagatran, administered at a fixed dose without coagulation monitoring, was at least as effective as well-controlled warfarin in protecting high-risk atrial fibrillation patients from thromboembolism and was associated with a reduction in bleeding. When the results of SPORTIF III and V were combined, ximelagatran was associated with a 16% relative risk reduction in the combined outcome measure of all strokes (ischemic or hemorrhagic), systemic embolism events, major bleeding, and death. (Olsson, S. B., 2003, Lancet, 362(9397): 1691-1698; Hirsh, J., 2005 et al. Blood, 105(2):453-463; Clemens, A. et al. WIPO Patent Application WO / 2008 / 009638). Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be used to prevent stroke in individuals with atrial fibrillation.

[0175] Transient ischemic attack (TIA) is an acute episode of transient neurologic dysfunction, usually lasting less than one hour; caused by focal cerebral, spinal cord, or retinal ischemia; and not associated with acute tissue infarction. In people with TIA, the subsequent stroke rate is as high as 11% in the next 7 days and 24-29% in the next 5 years. Given the high risk of short-term stroke after TIA, many physicians believe that antithrombotic therapy should be initiated as soon as intracranial hemorrhage is ruled out. Stroke prophylaxis drugs commonly recommended for cardioembolic TIA are as follows: long-term oral anticoagulation with warfarin for patients with atrial fibrillation after TIA (oral aspirin 325 mg daily for patients who cannot take oral anticoagulants); oral anticoagulation with warfarin in acute myocardial infarction (MI) with left ventricular thrombus; for ischemic coronary artery disease [CAD], oral aspirin 75-162 mg daily; in dilated cardiomyopathy, oral anticoagulation with warfarin or antiplatelet therapy; in rheumatic mitral valve disease, oral anticoagulation with warfarin. For patients with TIA and cardiac ischemic stroke due to atrial fibrillation, vitamin K antagonists (VKAs) are very effective in preventing recurrent ischemic stroke, but have significant limitations and are therefore underutilized. Antiplatelet therapy is far less effective than VKAs. In trials, the direct thrombin inhibitor dabigatran etexilate has shown efficacy superior to warfarin. Other new anticoagulants, including oral factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), parenteral factor Xa inhibitor (idrabiotaparinux), and a new VKA (tecarfarin), were evaluated in 2010. (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.)

[0176] It is reported that known thrombin inhibitors can be used to treat venous thromboembolism due to intravenous thrombosis associated with acquired (prolonged bed rest, surgery, injury, malignancy, pregnancy, and postpartum states) or inherited (deficiency in natural clotting inhibitors) risk factors (Marsic, L.P. et al. WIPO Patent Application WO / 2003 / 048155). Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be used to treat venous thromboembolism due to intravenous thrombosis associated with acquired or inherited risk factors and / or peripheral venous embolism caused by detached thrombus. One example of an acquired risk factor is a previous venous thromboembolism.

[0177] It is reported that known thrombin inhibitors can be used to treat cardiogenic thromboembolism, most commonly in the brain (ischemic stroke), due to intracardiac thrombosis associated with cardiac arrhythmias, heart valve defects, artificial heart valves, or heart disease, peripheral arterial embolism caused by detached thrombus. See Marsic, L.P. et al. WIPO Patent Application WO / 2003 / 048155. Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be used to treat cardiogenic thromboembolism.

[0178] It is reported that known thrombin inhibitors can be used to treat arterial thrombosis due to underlying atherosclerotic processes in the arteries that cause the arteries to occlude or close off and cause myocardial ischemia (angina pectoris, acute coronary syndrome) or myocardial infarction, occlude or close off peripheral arteries (ischemic peripheral arterial disease), and occlude or close off arteries after surgery on the blood vessels (reocclusion or restenosis after intracoronary angioplasty, reocclusion or restenosis after percutaneous transluminal angioplasty). See Marsic, L.P. et al. WIPO Patent Application WO / 2003 / 048155. Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be used to treat arterial thrombosis.

[0179] Known thrombin inhibitors have been reported to be useful in preventing recurrent cardiac events after myocardial infarction. The selective thrombin inhibitor simelagatran was studied in a phase II clinical trial, ESTEEM, which measured the efficacy and safety of oral direct thrombin inhibitor simelagatran in patients with recent myocardial damage. The results of the ESTEEM trial support the notion that long-term treatment with oral direct thrombin inhibitors can reduce arterial thrombotic events. Oral simelagatran in combination with acetylsalicylic acid was more effective than acetylsalicylic acid alone in reducing the frequency of major cardiovascular events within 6 months of treatment in patients with recent myocardial infarction. (Hirsh, J., 2005, et al. Blood, 105(2):453-463.) Without wishing to be bound by any theory further, it is believed that thrombin inhibition in general can be useful in preventing recurrent cardiac events after myocardial infarction.

[0180] Known thrombin inhibitors have been reported to be useful in the prevention of deep vein thrombosis after surgery. The selective thrombin inhibitor simelagatran was found to be effective in preventing venous thromboembolism after medical procedures such as total hip or knee replacement (Francis, 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). Without wishing to be bound by any theory further, it is believed that thrombin inhibition in general can be useful in the prevention of deep vein thrombosis after surgery.

[0181] Known thrombin inhibitors, such as dabigatran, have been reported to be useful in the long-term treatment of pulmonary embolism. (Robertson L, Kesteven P, McCaslin JE. Cochrane Database Syst Rev. 2015 Dec 4; 12). Without wishing to be bound by any theory further, it is believed that thrombin inhibition in general can be useful in the treatment of pulmonary embolism.

[0182] It has been reported that known thrombin inhibitors can be useful in the treatment of pulmonary arterial hypertension. Dabigatran is a selective thrombin inhibitor that has been disclosed as a drug useful in the treatment of pulmonary arterial hypertension (PAH). In addition, it has been found that dabigatran is useful in the treatment of: (i) pulmonary arterial hypertension due to left heart disorders; (ii) pulmonary arterial hypertension associated with lung diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or hypoxia; (iii) pulmonary arterial hypertension due to chronic thromboembolic disease. (Feuring, M. WIPO Patent Application WO / 2010 / 020600). Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be useful in the treatment of pulmonary arterial hypertension.

[0183] It has been reported that known thrombin inhibitors can be useful in the treatment of pulmonary arterial hypertension due to left heart disorders (Feuring, M. WIPO Patent Application WO / 2010 / 020600). Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be useful in the treatment of pulmonary arterial hypertension due to left heart disorders.

[0184] It has been reported that known thrombin inhibitors can be useful in the treatment of pulmonary arterial hypertension associated with lung diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis, and / or hypoxia (Feuring, M. WIPO Patent Application WO / 2010 / 020600). Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be useful in the treatment of pulmonary arterial hypertension associated with lung diseases.

[0185] It has been reported that known thrombin inhibitors can be useful in the treatment of pulmonary arterial hypertension due to chronic thromboembolic disease (Feuring, M. WIPO Patent Application WO / 2010 / 020600). Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be useful in the treatment of pulmonary arterial hypertension due to chronic thromboembolic disease.

[0186] It has been reported that known thrombin inhibitors can be useful in the treatment of disseminated intravascular coagulation in a variety of settings (e.g., in pregnancy complications, in metastatic malignancies, after severe trauma, in bacterial sepsis) when thrombin activation leads to dysfunctional coagulation with extensive thrombus formation within the vasculature. See Marsic, L.P. et al. WIPO Patent Application WO / 2003 / 048155. Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be useful in the treatment of disseminated intravascular coagulation.

[0187] It is reported that known thrombin inhibitors can be used to prevent coagulation in patients undergoing percutaneous coronary intervention. Percutaneous coronary intervention (PCI) requires aggressive anticoagulation therapy, which historically has been achieved using unfractionated heparin. However, in many patients, heparin is contraindicated, particularly in patients with heparin-induced thrombocytopenia (HIT). In such cases, intravascular damage and hypercoagulable state characteristic of HIT means 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 cardiovascular diseases, 46(6):506-523.) Dabigatran has been clinically considered as a thrombin inhibitor and available anticoagulant, and has also been published as a secondary drug for percutaneous interventional cardiac catheterization. (Reilly et al. WIPO Patent Application WO / 2010 / 020602.) Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be useful to prevent coagulation in patients undergoing percutaneous coronary intervention.

[0188] It is reported that known thrombin inhibitors can be used in conjunction with thrombolytic therapy in recent myocardial infarction, with aspirin in patients with unstable angina undergoing percutaneous transluminal angioplasty, and in the treatment of patients with thrombosis and heparin-induced thrombocytopenia (Marsic, L. P. et al. WIPO Patent Application WO / 2003 / 048155). Without wishing to be further bound by any theory, it is believed that thrombin inhibition in general can be useful as an adjunct therapy to other anti-thrombotic therapies.

[0189] It has long been recognized that cancer progression is associated with venous thromboembolism, but how each disease is related has not been understood. Through several clinical trials investigating VTE treatment, meta-analyses have shown that low molecular weight heparin (LMWH) improves overall survival in subsets of cancer patients. See, e.g., Zacharski, L. R. and Lee, A. Y., 2008, Expert Opin Investig Drugs, 17: 1029-1037; Falanga, A. and Piccioli, A., 2005, Current Opinion in Pulmonary Medicine, 11 :403-407; Smorenburg, S. M. et al., 1999, Thromb Haemost, 82: 1600-1604; Hettiarachchi, R. J. et al., 1999, Thromb Haemost, 82: 947-952. This finding was later confirmed in clinical trials specifically measuring survival in cancer patients. See, e.g., 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., 2004, J Clin Oncol, 22: 1944-1948; Altinbas, M. et al., 2004, J Thromb Haemost, 2: 1266-1271.

[0190] Recently, researchers have focused on the specific anticancer effects of DTIs. For example, results showed that heparin significantly prolonged survival in patients with limited-stage small-cell lung cancer. See, e.g., Akl, E. A. et al., 2008, J Exp Clin Cancer Res, 27:4. Other researchers found that systemic use of argatroban reduced tumor mass and prolonged survival time in a rat glioma model, concluding that argatroban should be considered as a novel therapeutic agent for glioma, a well-known type of cancer that is difficult to treat. See, e.g., Hua, Y. et al., 2005, Acta Neurochir, Suppl 2005, 95:403-406; Hua, Y. et al., 2005, J Thromb Haemost, 3:1917-1923. Recently, it was demonstrated that dabigatran etexilate, an FDA recently approved DTI for DVT indications (see, e.g., Hughes, B., 2010, Nat Rev Drug Discov, 9:903-906), inhibited invasion and metastasis of malignant breast tumors. See, e.g., DeFeo, K. et al., 2010, Thrombosis Research, 125(Suppl 2):S188-S188; Defeo, K. et al., 2010, Cancer Biol Ther, 10:1001-1008. Thus, dabigatran etexilate treatment resulted in a 50% reduction in tumor volume and no weight loss in treated mice over 4 weeks. Dabigatran etexilate also reduced tumor cells in blood and liver micrometastases by 50-60%. These researchers concluded that dabigatran etexilate can have benefits not only in preventing thrombotic events in cancer patients, but also as an adjunct therapy for treating malignant tumors.

[0191] Other studies investigated the suitability of anticoagulants in treating patients with coronary artery disease and / or peripheral artery disease. In the COMPASS trial, patients treated with rivaroxaban in combination with antiplatelet platelet therapy improved cardiovascular outcomes. See, e.g., Eikelboom, J. W. et al. 2017, N Engl J Med, 377:1319-30. In addition, the COMMANDER trial investigated the utility of rivaroxaban in improving cardiovascular outcomes in patients with coronary artery disease, including patients exhibiting heart failure, particularly heart failure with reduced ejection fraction (HF-rEF). See, e.g., Zannad, F. et al., 2015 European Journal of Heart Failure, 17:735-42. Thus, it is suggested that anticoagulants can be used in an adjunct therapy for subjects having at least one of coronary artery disease and heart failure, and wherein the adjunct therapy further comprises antiplatelet therapy.

[0192] The European Society of Cardiology recommends the use of an anticoagulant in combination with antiplatelet therapy for patients with valvular or non-valvular atrial fibrillation and at least one previous acute coronary syndrome event. See, e.g., Kirchhof, P. et al., 2016, European Heart Journal, 37: 2893-2962. Thus, it is recommended that an anticoagulant can be used in an adjunct therapy for a subject with atrial fibrillation and at least one of coronary artery disease and heart failure, and wherein the adjunct therapy further comprises antiplatelet therapy. The European Society of Cardiology recommends the use of an anticoagulant in combination with antiplatelet therapy for subjects with valvular or non-valvular atrial fibrillation and undergoing elective percutaneous coronary intervention (PCI) with stents. See, e.g., Kirchhof, P. et al., 2016, European Heart Journal, 37: 2893-2962. Thus, it is recommended that an anticoagulant can be used in an adjunct therapy for a subject with valvular or non-valvular atrial fibrillation and undergoing percutaneous coronary intervention with stents, and wherein the adjunct therapy further comprises antiplatelet therapy.

[0193] Furthermore, hirudin and LMWH, nadroparin, substantially reduced the number of lung metastases when administered prior to cancer cell inoculation. See, e.g., Hu, L. et al., 2004, Blood, 104: 2746-51.

[0194] It has been found that the rethrombin inhibitor d-Arg-Oic-Pro-d-Ala-Phe(p-Me) blocks the invasion of the prostate cancer cell line PC-3 stimulated by thrombin in a concentration-dependent manner. See, e.g., Nieman, M. T. et al., 2008, J Thromb Haemost, 6: 837-845. In mice that were administered the pentapeptide through drinking water, a reduced rate of tumor growth was observed. These mice also showed a reduced rate of tumor size doubling and a reduced overall tumor weight compared to untreated mice. Microscopic examination of the treated tumors showed a reduced number of large blood vessels, from which it was concluded that the pentapeptide interferes with tumor angiogenesis. Nieman, M. T. et al., 2010, Thromb Haemost, 104: 1044-8.

[0195] In view of these and related studies, it is suggested that anticoagulants affect tumor metastasis, i.e., the processes of angiogenesis, cancer cell adhesion, migration, and invasion. See, e.g., Van Noorden, C. J. et al., 2010, Thromb Res, 125 Suppl 2: S77-79.

[0196] Several studies have demonstrated the utility of anticoagulation therapy in fibrotic disorders. For example, in a rat model of CCl4-induced chronic liver injury, DTI SSR182289 significantly reduced liver fibrogenesis after 7 weeks of administration. Similar observations were made in other studies using LMWH nadroparin, tinzaparin, enoxaparin, and dalteparin. See, e.g., Duplantier, J. G. et al., 2004, Gut, 53: 1682-1687; Abdel-Salam, O. M. et al., 2005, Pharmacol Res, 51 :59-67; Assy, N. et al., 2007, Dig Dis Sci, 52: 1187-1193; Abe, W. et al., 2007, J Hepatol, 46:286-294. Thus, thrombin inhibitors as anticoagulants can be useful in the treatment of fibrinolytic diseases.

[0197] In another example, DTI melagatran greatly reduced ischemia-reperfusion injury in a kidney transplant model in large white pigs. This resulted in a greatly improved kidney transplant survival for 3 months. See, e.g., Favreau, F. et al., 2010, Am J Transplant, 10:30-39.

[0198] Recent studies have shown that in a mouse model of bleomycin-induced pulmonary fibrosis, dabigatran etexilate treatment reduced important pro-fibrotic events in lung fibroblasts, including collagen and connective tissue growth factor production. See, e.g., Silver, R. M. et al., 2010, Am. J. Respir. Crit. Care Med., 181 :A6780; Bogatkevich, G. S., et al., 2009, Arthritis Rheum, 60:3455-3464.

[0199] The above experimental evidence points to a close relationship between thrombin and fibrosis and suggests a new therapeutic opportunity for the treatment of fibrosis using thrombin inhibitors. See, e.g., Calvaruso, V. et al., 2008, Gut, 57: 1722-1727; Chambers, R. C., 2008, Br J Pharmacol, 153 Suppl 1 :S367-378; Chambers, R. C. and Laurent, G. J., 2002, Biochem Soc Trans, 30:194-200; Howell, D. C. et al., 2001, Am J Pathol, 159: 1383-1395.

[0200] Recent experiments have determined that levels of thrombin are higher in the brain endothelial cells of Alzheimer's patients. While "normal" levels of thrombin are associated with modulating CNS function, accumulation of thrombin in the brain is toxic. It has also been found that neurothrombin inhibitor protease nexin 1 (PN-1) is significantly reduced in Alzheimer's brains, despite no change in PN-1 mRNA levels. These observations have led some researchers to suggest that reducing CNS resident thrombin would prove useful in Alzheimer's disease (AD) therapy. See, e.g., Vaughan, P.J. et al., 1994, Brain Res, 668: 160-170; Yin, X. et al., 2010, Am J Pathol, 176: 1600-1606; Akiyama, H. et al., 1992, Neurosci Lett, 146: 152-154.

[0201] Researchers have found that leech therapy in an animal model of multiple sclerosis (MS) showed a marked improvement in disease severity. See, e.g., Han, M.H. et al., 2008, Nature, 451: 1076-1081. Similar results were obtained following treatment with heparin (DTI) and dermatan sulfate (another clotting inhibitor). See, e.g., Chelmicka-Szorc, E. and Arnason, B.G., 1972, Arch Neurol, 27: 153-158; Inaba, Y. et al., 1999, Cell Immunol, 198: 96-102. Other evidence suggests that naturally occurring anti-thrombin III has anti-inflammatory effects in diseases such as endotoxemia and other sepsis-related conditions. See, e.g., Wiedermann, C.J. and Romisch, J., 2002, Acta Med Austriaca, 29: 89-92. Naturally occurring thrombin inhibitors are likely synthesized in situ and have a protective role in CNS inflammation. Thus, therapeutic thrombin inhibition has been proposed as a potential MS therapy. See, e.g., Luo, W. et al., 2009, In: THROMBIN, Maragoudakis, M.E.; Tsopanoglou, N.E., Eds Springer New York: 2009; pp. 133-159.

[0202] In a rat model of pain with partial injury of the sciatic nerve, intrathecal hirudin prevented the development of neuropathic pain and inhibited the pain response for up to 7 days. Researchers found that neuropathic pain is mediated by thrombin generation after injury, which in turn activates PAR-1 receptors in the spinal cord. Hirudin inhibits thrombin generation and ultimately leads to pain reduction. See, e.g., Garcia, P.S., et al., 2010, Thromb Haemost, 103: 1145-1151; Narita, M., et al., 2005, J Neurosci, 25: 10000-10009. Researchers hypothesize that thrombin and PARs are involved not only as part of the coagulation cascade, but also in inflammation, nociception, and neural development. DTI development with no cross- utilization of pharmacology would lead to a pain treatment agent different from opioids and NSAIDs, which have well-documented drawbacks. See, e.g., Garcia 2010, supra. Known thrombin inhibitors have been reported to be useful in treating inflammation (Kirk, I. WO Patent Application WO / 2000 / 041716), Type I diabetes (Korsgren, O.; Nilsson, B. WO Patent Application 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, 95:403-6; Nieman, M.T., et al., 2008, J Thromb Haemost, 6:837-845; Van Ryn, J.; Clemens, A. WO Patent Application 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, Dig Dis Sci, 52: 1187-1193; Bogatkevich, G.S., et al., 2009, Arthritis Rheum, 60:3455-3464), and pain (Garcia, P.S., et al., 2010, Thromb Haemost, 103: 1145-1151; Narita, M., et al., 2005, J Neurosci, 25: 10000-10009). A meta-analysis of clinical trials investigating the use of anticoagulants in cancer patients showed that the selective thrombin inhibitor low molecular weight heparin (LMWH) improved overall survival in a subset of cancer patients. This finding was confirmed in later clinical trials specifically measuring survival in cancer patients, particularly in the landmark CLOUDBREAK trial.Without wishing to be bound by any theory, it is believed that thrombin inhibition can be generally useful in the treatment of inflammation, diabetes, cancer, fibrosis, or pain.

[0203] V. Pharmaceutical Compositions

[0204] In another aspect, a pharmaceutical composition is provided, comprising a compound disclosed herein and a pharmaceutically acceptable excipient. The compound is a compound of Structure I disclosed herein, or a compound as shown herein as Compound 1 or Compound 2, or a pharmaceutically acceptable salt or solvate thereof.

[0205] The term "pharmaceutically acceptable salt" is meant to include salts of the active compounds which are relatively non-toxic to the subjects in which they are administered and which possess the desired pharmacological activity of the active compound. Such salts include acid addition salts.

[0206] When the compounds disclosed herein contain relatively acidic functionalities, for example, -NHSO3H, -COOH and -P(O)(OH)2, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base to provide the salt. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.

[0207] In certain embodiments, the compound is Compound I, and the counterion is selected from sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane.

[0208] Certain specific compounds disclosed herein contain both basic and acidic functionalities, allowing the compounds to be converted into either base or acid addition salts. Neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the free base or acid. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0209] Additionally, some of the compounds disclosed herein can form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the methods contemplated herein.

[0210] Further, some embodiments include co-crystals comprising the compounds disclosed herein. Co-crystals can be understood as any single substance in crystalline form that comprises two or more different chemical substances (referred to as co-formers) that are present in a defined stoichiometric ratio, which cannot be classified as a salt or a solvate. Those skilled in the art will understand which co-formers can be used to form co-crystals with the presently claimed compounds according to the present application. For example, the Select Committee on GRAS Substances (SCOGS) of the U.S. Food and Drug Administration (FDA) maintains a database of many common co-formers in its Generally Recognized as Safe (GRAS) substances, which can be used according to the present application 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. Those skilled in the art will understand that the FDA can update, revise, or rename this list over time, and that other compounds can generally be considered safe and can also be used according to the present application. Co-formers can include one or more counterions, such as, for example, sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane, among others. Accordingly, the present application encompasses co-crystals formed with compounds from the FDA-maintained list of GRAS substances, or with the compounds listed in Table G, or with other compounds that are generally considered safe and / or can include one or more counterions (such as, for example, sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane, among others).

[0211] Table G.

[0212] GRAS substances

[0213] acetic acid

[0214] acetylated distarch hexahydrophthalate

[0215] acetylated distarch glycerol

[0216] acetylated distarch phosphate

[0217] acetylated distarch oxypropyl alcohol

[0218] acid modified starch

[0219] aconitic acid

[0220] adipic acid

[0221] agar

[0222] allyl isothiocyanate

[0223] aluminum ammonium sulfate

[0224] aluminum calcium silicate

[0225] aluminum hydroxide

[0226] Aluminum oleate (packaging)

[0227] Aluminum palmitate (packaging)

[0228] Potassium aluminum sulfate

[0229] Sodium aluminum sulfate

[0230] Aluminum sulfate

[0231] Ammonium alginate

[0232] ammonium bicarbonate

[0233] ammonium carbonate

[0234] ammonium chloride

[0235] Ammonium citrate

[0236] ammonium hydroxide

[0237] Diammonium hydrogen phosphate (Report 32)

[0238] Diammonium hydrogen phosphate (Report 34)

[0239] Ammonium dihydrogen phosphate (Report 32)

[0240] Ammonium dihydrogen phosphate (Report 34)

[0241] ammonium sulfate

[0242] Kudzu starch

[0243] L-Ascorbic Acid

[0244] Palmitate ascorbate (palmitoyl L-ascorbic acid)

[0245] Beeswax (yellow or white)

[0246] Bentonite

[0247] benzoic acid

[0248] Biotin

[0249] Bleached starch

[0250] Brown algae

[0251] Butylated hydroxyanisole (BHA)

[0252] Butylated hydroxytoluene (BHT)

[0253] caffeine

[0254] Calcium acetate

[0255] Calcium alginate

[0256] Calcium carbonate

[0257] Calcium caseinate

[0258] Calcium chloride

[0259] Calcium citrate

[0260] Calcium gluconate

[0261] Calcium glycerophosphate

[0262] Calcium glycerophosphate (packaged)

[0263] Calcium hexametaphosphate

[0264] Calcium hydroxide

[0265] Calcium hypophosphite

[0266] Calcium iodate

[0267] Calcium L-ascorbate

[0268] Calcium lactate

[0269] Calcium L(+)-lactate

[0270] Calcium oxide

[0271] Calcium D- or DL-pantothenate

[0272] Calcium phosphate, dibasic

[0273] Calcium phosphate, monobasic

[0274] Calcium phosphate, tribasic

[0275] Calcium phytate

[0276] Calcium propionate

[0277] Calcium pyrophosphate

[0278] Calcium silicate

[0279] Calcium sorbate

[0280] Calcium stearate

[0281] Caprylic acid

[0282] Caramel

[0283] Carbon dioxide

[0284] Carbonyl iron

[0285] Carbonyl iron (packaged)

[0286] Carboxymethylcellulose (packaged)

[0287] Carnauba wax

[0288] Carob gum

[0289] Carotene (beta-carotene)

[0290] carrageenan

[0291] casein

[0292] enzymatically hydrolyzed casein

[0293] cellulose

[0294] cellulose acetate (packaging)

[0295] microcrystalline cellulose

[0296] cholic acid

[0297] hydrochlo-ride

[0298] choline chloride

[0299] citric acid

[0300] clay (kaolin) (packaging)

[0301] clove bud extract

[0302] clove bud oil

[0303] clove bud oleoresin

[0304] clove leaf oil

[0305] clove stem oil

[0306] coconut oil (packaging)

[0307] copper gluconate (cupric)

[0308] copper sulfate (cupric)

[0309] corn silk

[0310] corn sugar (dextrose)

[0311] corn syrup

[0312] corn starch

[0313] cuprous iodide

[0314] deoxycholic acid

[0315] dextran

[0316] dextrin

[0317] dextrin (packaging)

[0318] diacetyl

[0319] diatomaceous earth (filter aid)

[0320] dietary iron

[0321] dilauryl thiodipropionate

[0322] dual starch glycerol

[0323] dual starch oxypropyl alcohol

[0324] dual starch phosphate

[0325] electrolytic iron

[0326] electrolytic iron (packaged)

[0327] erythorbic acid (d-erythorbic acid)

[0328] ethyl acrylate, monomer (packaged)

[0329] ethyl acrylate, polymer (packaged)

[0330] ethyl cellulose (packaged)

[0331] ethyl formate

[0332] ferric ammonium citrate

[0333] ferric chloride (packaged)

[0334] ferric citrate

[0335] ferric oxide

[0336] ferric oxide (packaged)

[0337] ferric phosphate

[0338] ferric pyrophosphate

[0339] ferric sodium pyrophosphate

[0340] ferric sulfate (packaged)

[0341] ferrous ascorbate

[0342] ferrous carbonate

[0343] ferrous citrate

[0344] ferrous fumarate

[0345] ferrous gluconate

[0346] ferrous lactate

[0347] ferrous sulfate

[0348] ferrous sulfate (packaged)

[0349] fish oil, hydrogenated (packaged)

[0350] formic acid (packaged)

[0351] garlic and garlic oil

[0352] gelatin

[0353] L-glutamic acid

[0354] L-glutamic acid hydrochloride

[0355] glycerin and glycerides

[0356] glycolic acid

[0357] glycyrrhizin

[0358] glycyrrhizinates

[0359] guar gum

[0360] gum arabic

[0361] gum ghatti

[0362] gum rosin

[0363] gum tragacanth

[0364] helium

[0365] high amylose corn starch

[0366] hydrochloric acid

[0367] hydrogen peroxide

[0368] hydrogenated soybean oil

[0369] hydrogenated tallow (packaged)

[0370] p-hydroxybenzyl isothiocyanate

[0371] hydroxypropyl bis starch glycerol

[0372] hydroxypropyl bis starch phosphate

[0373] hydroxypropyl starch

[0374] oxidized hydroxypropyl starch

[0375] hydroxypropyl methylcellulose

[0376] indian coriander seed

[0377] inositol

[0378] invert sugar

[0379] iron - iron bioavailability and utilization report

[0380] iron - report on clinical study protocol to elucidate possible hazards of iron increase

[0381] iron enrichment of cereal products

[0382] iron octoate (packaged)

[0383] iron linoleate (packaged)

[0384] iron naphthenate

[0385] iron oxide (packaging)

[0386] iron proteinate

[0387] iron polyvinylpyrrolidone

[0388] iron fatty acid (packaging)

[0389] elemental iron (packaging)

[0390] isopropyl citrate

[0391] japan wax (packaging)

[0392] D(-)-lactic acid

[0393] lactic acid

[0394] L(+)-lactic acid

[0395] lard (packaging)

[0396] pork fat (packaging)

[0397] lecithin

[0398] hydrogen peroxide bleached lecithin

[0399] liquorice

[0400] linoleic acid

[0401] magnesium carbonate

[0402] magnesium chloride

[0403] magnesium gluconate

[0404] magnesium glycerophosphate (packaging)

[0405] magnesium hydroxide

[0406] magnesium oxide

[0407] magnesium phosphate

[0408] magnesium phosphate

[0409] magnesium silicate

[0410] magnesium stearate

[0411] magnesium sulfate

[0412] malic acid

[0413] L-malic acid

[0414] manganese glycerophosphate

[0415] manganese chloride

[0416] Manganese citrate

[0417] Manganese gluconate

[0418] Manganese hypophosphite

[0419] Manganese oxide

[0420] Manganese sulfate

[0421] Mannitol

[0422] Methyl acrylate, monomer (packaged)

[0423] Methyl acrylate, polymer (packaged)

[0424] Methyl paraben

[0425] Methylcellulose

[0426] Milo starch

[0427] Monammonium L-glutamate

[0428] Monopotassium L-glutamate

[0429] Monosodium L-glutamate

[0430] Monostarch phosphate

[0431] Mustard and mustard oil (brown and yellow)

[0432] Niacin (nicotinic acid)

[0433] Niacinamide (nicotinamide)

[0434] Nickel (element)

[0435] Nutmeg and mace

[0436] Oil of bitter orange

[0437] Oleic acid (packaged)

[0438] Ox gall extract

[0439] D-Pantothenyl alcohol

[0440] Papain

[0441] Peanut oil (packaged)

[0442] Pectin amidated

[0443] Pectin high ester

[0444] Pectin low acid

[0445] Pectin ester

[0446] pectic acid

[0447] perlite (filter aid)

[0448] phosphated distarch phosphate

[0449] phosphoric acid

[0450] potassium L(+)-tartrate

[0451] potassium alginate

[0452] potassium bicarbonate

[0453] potassium carbonate

[0454] potassium chloride

[0455] potassium citrate

[0456] potassium gluconate

[0457] potassium glycerophosphate

[0458] potassium hydroxide

[0459] potassium hypophosphite

[0460] potassium iodate

[0461] potassium iodide

[0462] potassium metabisulfite

[0463] dipotassium hydrogen phosphate

[0464] monopotassium hydrogen phosphate

[0465] tripotassium phosphate

[0466] potassium polymetaphosphate

[0467] potassium pyrophosphate

[0468] potassium silicate

[0469] potassium sorbate

[0470] potassium tripolyphosphate

[0471] potato starch

[0472] pregelatinized starch

[0473] propionic acid

[0474] propyl gallate

[0475] propyl paraben

[0476] propylene glycol

[0477] propylene glycol alginate

[0478] propylene glycol monostearate

[0479] acid hydrolyzed proteins

[0480] enzyme hydrolyzed proteins

[0481] pulp (packaging)

[0482] pyridoxine

[0483] pyridoxine hydrochloride

[0484] red algae

[0485] reduced iron

[0486] reduced iron (packaging)

[0487] rennet

[0488] riboflavin

[0489] riboflavin-5'-phosphate

[0490] rice starch

[0491] silica aerogel

[0492] silicon dioxide

[0493] sodium acetate

[0494] sodium acid pyrophosphate

[0495] sodium alginate

[0496] sodium aluminate (packaging)

[0497] sodium aluminosilicate

[0498] sodium aluminum phosphate, acidic

[0499] sodium aluminum phosphate, basic

[0500] sodium benzoate

[0501] sodium bicarbonate

[0502] sodium bisulfite

[0503] sodium calcium aluminosilicate

[0504] sodium carbonate

[0505] sodium carboxymethylcellulose

[0506] sodium caseinate

[0507] sodium chloride

[0508] sodium citrate

[0509] sodium diacetate

[0510] sodium erythorbate (sodium D-erythorbate)

[0511] EDTA iron sodium

[0512] Sodium ferric pyrophosphate

[0513] Sodium formate (packaged)

[0514] Sodium gluconate

[0515] Sodium hexametaphosphate

[0516] Sodium dithionite (packaged)

[0517] Sodium hydroxide

[0518] Sodium hydroxide pregelatinized starch

[0519] Sodium hypophosphite

[0520] Sodium L-ascorbate

[0521] Sodium metabisulfite

[0522] Sodium metaphosphate

[0523] Sodium oleate (packaged)

[0524] Sodium palmitate (packaged)

[0525] Sodium D- or DL-pantothenate

[0526] Sodium hydrogen phosphate

[0527] Sodium dihydrogen phosphate

[0528] Trisodium phosphate

[0529] Sodium aluminate phosphate (packaged)

[0530] L(+)-Sodium potassium tartrate

[0531] Sodium propionate

[0532] Tetrasodium pyrophosphate

[0533] Sodium sesquicarbonate

[0534] Sodium silicate

[0535] Sodium sorbate

[0536] Sodium sulfite

[0537] L(+)-Sodium tartrate

[0538] Sodium tetramethphosphate

[0539] Sodium tetraphosphate

[0540] Sodium thiosulfate

[0541] Sodium tripolyphosphate

[0542] Sodium tripolyphosphate

[0543] Sorbic acid

[0544] Sorbitol

[0545] Sorbitol (packaging)

[0546] Soy protein isolate

[0547] Soy sauce

[0548] Stannous chloride

[0549] Starch acetate

[0550] Starch aluminum octenyl succinate

[0551] Starch sodium octenyl succinate

[0552] Starch sodium succinate

[0553] Starch sodium succinate oxides

[0554] Starters distillate

[0555] Stearic acid (packaging)

[0556] Stearyl citrate

[0557] Styrax (gum) (storax)

[0558] Succinic acid

[0559] Succinyl bis-starch glycerol

[0560] Sucrose

[0561] Sulfamic acid (packaging)

[0562] Sulfur dioxide

[0563] Sulfuric acid

[0564] Talc (magnesium silicate, basic)

[0565] Tall oil (packaging)

[0566] Tallow (packaging)

[0567] Tannic acid (hydrolysable gallotannins)

[0568] Tapioca starch

[0569] L(+)-Tartaric acid

[0570] Taurocholic acid

[0571] Thiamine hydrochloride

[0572] Thiamine mononitrate

[0573] Thiobispropionic acid

[0574] Alpha-tocopherol acetate

[0575] Tocopherol

[0576] Tricalcium silicate

[0577] Triethyl citrate

[0578] Urea

[0579] Vitamin A

[0580] Vitamin A acetate

[0581] Vitamin A palmitate

[0582] Vitamin B12 (Cyanocobalamin)

[0583] Vitamin D2 (ergocalciferol)

[0584] Vitamin D3 (cholecalciferol)

[0585] Waxy maize starch

[0586] Wheat starch

[0587] Yeast autolysate

[0588] Zinc acetate

[0589] Zinc carbonate

[0590] Zinc chloride

[0591] Zinc gluconate

[0592] Zinc sulfite (packaging)

[0593] Zinc oxide

[0594] Zinc sulfate

[0595] A. Formulations

[0596] The compounds disclosed herein can be prepared and administered in a wide variety of oral dosage forms, parenteral dosage forms, and topical dosage forms. Preferred embodiments of the methods described herein include oral administration of one or more of the compounds described herein. The compounds described herein can additionally 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., intranasally. In addition, the compounds disclosed herein can be transdermally administered. It is also contemplated that multiple routes of administration (e.g., intramuscular, oral, etc.) can be used to administer the compounds disclosed herein.

[0597] The compounds are suitably administered in solid or liquid form as appropriate for the method of administration desired. For oral administration, in various embodiments, the compounds can be administered as solids or liquids. For some embodiments administered in the form of an injection, the compounds can be delivered as a liquid or a liquid suspension.

[0598] In some oral embodiments, the compounds disclosed herein can be administered as solids, more specifically as tablets, troches, lozenges, 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, emulsions, syrups, or elixirs. Compositions intended for oral use can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Thus, there are also provided pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more of the compounds disclosed herein.

[0599] In a powder, the carrier is a finely divided solid, with the active component mixed in. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, mannitol, low melting wax, cocoa butter, and the like. The term "formulation" is intended to embrace formulations with the active compound in association with encapsulating material as a carrier, providing a capsule in which the active component is sealed from the environment. Similarly, sachets and lozenges are included.

[0600] In some embodiments, tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch, alginic acid, and polyvinylpyrrolidone; (3) binding agents, and humectants, such as starch, gelatin or acacia; and (4) lubricating agents such as magnesium stearate, stearic acid, glycolly stearate sodium starch glycolate or talc. Tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Also known as crospovidone) ; (3) binders such as starch, gelatin or acacia; and (4) lubricants such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over an extended period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. L 30D-55, which is a copolymer of methacrylate that dissolves below pH 5.5.

[0601] In some embodiments, the tablet contains the active ingredient as an amorphous solid. This can be achieved by creating an amorphous solid dispersion containing the active ingredient and at least one polymer. In some embodiments, the polymer is VA64, which is a vinylpyrrolidone-vinyl acetate copolymer. Those skilled in the art will understand that a certain weight ratio of active ingredient to polymer is necessary to maintain the active ingredient in an amorphous state. The active ingredient: polymer weight ratio can range from 1 : 1 to 1 : 10 or more. In some embodiments, the active ingredient: polymer weight ratio is 1 : 3. Those skilled in the art will also understand that there are a variety of techniques that can be used to create amorphous solid dispersions, including holt melt extrusion and spray-dried dispersion (SDD) methods.

[0602] In certain embodiments, it can be desirable to control the particle size distribution. In certain embodiments of a given formulation, a variety of techniques can be employed, including micronization techniques, to produce the desired particle size distribution.

[0603] Also included are solid form preparations that are intended to be converted to liquid form preparations for oral administration at the point of use. Such liquid forms include solutions, suspensions, and emulsions. These solutions can be aqueous or water / propylene glycol mixtures. These preparations can contain, in addition to the active ingredient, one or more coloring, flavoring, stabilizing, buffering, artificial and natural sweetening agents, surface active or dispersing agents, suspending agents, thickening agents, emulsifying agents, etc.

[0604] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0605] Particularly suitable additional agents for the compounds disclosed herein when parenteral application is required or desired are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants, including suppositories. Specifically, carriers for parenteral administration include aqueous vehicles, saline, buffered saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, polyethylene glycol, and the like. Ampoules are suitable unit-dosage forms. The compounds disclosed herein can also be incorporated into a liposome or administered by a transdermal pump or patch. Pharmaceutical admixtures suitable for use in the pharmaceutical compositions and methods disclosed herein include, for example, those described in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO96 / 05409, the teachings of both of which are incorporated herein by reference.

[0606] In some embodiments, formulations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions. Examples of nonaqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous vehicles include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's intravenous vehicles (including body fluids and nutrients, electrolyte supplements such as those based on Ringer's dextrose), and the like. Preservatives and other additives such as antimicrobials, antioxidants, chelating agents, growth factors, and inert gases can also be present.

[0607] Some compounds can have limited solubility in water and, therefore, a surfactant or other appropriate cosolvent can be required in the composition. Such cosolvents include polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrins, and polyoxyl 35 castor oil. Such cosolvents are generally used at levels of about 0.01% to about 2% by weight.

[0608] Viscosity greater than that of simple aqueous solutions can be desirable to reduce variability in dispensing the formulation, to reduce physical separation and / or otherwise to improve the formulation of the components of a suspension or emulsion formulation. Such viscous binders include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are generally used at levels of about 0.01% to about 2% by weight.

[0609] Aqueous suspensions typically contain the active material(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; (2) dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of an alkylene oxide with erythroholyl alcohol (e.g., a seventeen-carbon oxyethylene alcohol), a condensation product of an alkylene oxide with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or a condensation product of an alkylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate).

[0610] Preservatives include antimicrobial, antioxidant, chelating agents, and inert gases. Other pharmaceutically acceptable carriers include aqueous solutions, nontoxic excipients, including salts, preservatives, buffers and the like, as described, for example, in Remington's Pharmaceutical Sciences, 15th Edition Easton: Mack Publishing Co., 1405-1412, 1461-1487 (1975) and The National Formulary XIV., 14th Edition Washington: American Pharmaceutical Association (1975), the contents of which are incorporated herein by reference. The pH and exact concentration of the various components in the pharmaceutical compositions are adjusted according to routine skills in the art. See, e.g., Goodman and Gilman (eds.), 1990, THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th Ed.).

[0611] The compounds disclosed herein can be administered in a form of a suppository for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

[0612] For preparing suppositories, a low melting wax such as a fatty acid glyceride or an ester of a saturated straight chain algebraic alcohol, or an anhydrous citrate, is first melted and the active ingredient(s) is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0613] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing a compound disclosed herein are employed.

[0614] The compounds disclosed herein as used in the methods disclosed herein can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0615] For in vivo applications, the compounds disclosed herein can be administered parenterally by injection or gradual infusion over time. Administration can be intravenous, intraperitoneal, intramuscular, subcutaneous, intracavitary, or transdermal. For in vitro studies, the compounds can be added or dissolved in an appropriate biologically acceptable buffer and added to cells or tissues.

[0616] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0617] The quantity of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and the potency of the active component. If desired, the compositions can also contain other compatible therapeutic agents.

[0618] The pharmaceutical compositions are preferably prepared and administered in a dosage unit form. For treatment of subjects, different daily dosages can be used depending on the activity of the compound, the mode of administration, the nature and severity of the disease or condition, the age and weight of the subject. In general, dosages used in vitro can provide useful guidance in amounts employed in situ for administration of the pharmaceutical compositions, and animal models can be used to determine effective dosages for treatment of particular conditions.

[0619] However, in certain instances, higher or lower daily dosages can be appropriate. The administration of the daily dose can be carried out in single dose administrations or in several smaller dose administrations and subdivided doses administered at specific intervals.

[0620] Various considerations are described, e.g., in Langer, 1990, Science, 249: 1527; Goodman and Gilman’s (eds.), 1990, supra, each of which is incorporated herein by reference for all purposes. Parenteral dosages of active agents can be converted to the corresponding oral dosages by multiplying the parenteral dosage by the appropriate conversion factor. For general applications, dosages from animal in vivo studies can be adjusted to human equivalent dosages (HED) by applying an appropriate animal-to-human conversion factor to the mg / kg ratio for a given in vivo animal. The average adult human body weight is approximately 60 kg. See, e.g., GUIDANCE FOR INDUSTRY: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers (FDA Guidance; July 2005).

[0621] B. Effective Dosage

[0622] The pharmaceutical compositions provided herein include compositions that contain an active ingredient in a therapeutically effective amount (i.e., in an amount that is effective to achieve its intended purpose). The actual effective amount for a particular application will depend, inter alia, on the condition being treated.

[0623] The dosage and frequency of administration of the compounds (single or multiple doses) can vary depending on various factors, including: the route of administration; the size, age, sex, health, body weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated (e.g., a disease responsive to inhibition of thrombin); the presence of other diseases or other health-related problems; the class of concurrent therapy; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

[0624] For any compound described herein, a therapeutically effective amount can be determined first by a variety of techniques known in the art, e.g., biochemical characterization of thrombin inhibition, cell culture assays, and the like. Target concentrations will be those concentrations of active compound that are capable of reducing enzyme activity as measured, e.g., using the methods described.

[0625] Therapeutically effective amounts for humans can be determined from animal models. For example, dosages can be formulated to achieve concentrations that have been found to be effective in animals. Dosages for humans can be adjusted by monitoring enzyme inhibition and adjusting the dosage up or down, as described above.

[0626] Doses can vary according to the requirements of the patient and the compound being used. In the context of the methods disclosed herein, the dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Generally, therapy is initiated with smaller dosages that are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments of the methods disclosed herein, the dosage ranges from 0.001% w / v to 10% w / v. In some embodiments, the dosage ranges from 0.1% w / v to 5% w / v.

[0627] The amount and spacing of doses can be adjusted to provide levels of the administered compound that are effective for the particular clinical indication being addressed. This will provide a treatment regimen that is commensurate with the severity of the individual's disease state.

[0628] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that is most appropriate for the particular circumstances. This planning should include a consideration of factors such as the potency and relative bioavailability of the active compound, 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 patient's condition.

[0629] Thus, in some embodiments, the dosage level of the compounds disclosed herein employed in the methods of the present application is, for example, from about 0.1 mg to about 1 mg, from about 1 mg to about 10 mg, from about 0.5 mg to about 20 mg per kilogram of body weight, and preferably the dosage level ranges from about 0.1 mg to about 20 mg per kilogram of body weight per day (from about 6.0 mg to about 1.2 g per patient per day) in an average-sized adult human. The amount of a compound disclosed herein that can be combined with the carrier materials to produce a single dose will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended to be administered orally to a human adult can contain from about 5 μg to 1 g of a compound disclosed herein compounded with an appropriate and convenient amount of carrier material to make a dosage unit form. Dosage unit forms would generally contain between from about 0.1 mg to 500 mg of a compound disclosed herein.

[0630] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease being treated.

[0631] C. Toxicity

[0632] The ratio between the toxicity and the therapeutic effect of a particular compound is its therapeutic index, and can be expressed as the LD 50 The ratio between the amount of a compound lethal to 50% of the population (LD 50 The ratio between the amount of a compound lethal to 50% of the population (LD 50 The ratio between the amount of a compound lethal to 50% of the population (LD x The ratio between the amount of a compound lethal to 50% of the population (LD y The ratio between the amount of a compound lethal to 50% of the population (LD z In the detailed description of the application, modifications, variations, and equivalents that fall within the scope of the application as defined by the appended claims are possible. Furthermore, it is to be understood that all examples in this disclosure are provided as non-limiting examples.

[0633] In the detailed description of the application, modifications, variations, and equivalents that fall within the scope of the application as defined by the appended claims are possible. Furthermore, it is to be understood that all examples in this disclosure are provided as non-limiting examples.

[0634] Examples

[0635] The following non-limiting examples are provided to further illustrate embodiments of the application disclosed herein, without limiting the scope of the disclosure. It will be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that have been found to work in practice, and, therefore, can be considered to be preferred modes of practicing the application. However, it will be apparent on the basis of the disclosure provided herein that numerous changes can be made and still fall within the spirit and scope of the application, and, accordingly, modifications can be made by those skilled in the art without departing from the spirit and scope of the application.

[0636] Example 1

[0637] General synthesis of pyrazole-pyridinone compounds

[0638] The general synthetic scheme 1 depicted below provides a general synthesis of acylated pyrazole-pyridinone compounds as disclosed therein. In the following general scheme I, the terms "R x "R y "R zindependently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heterocycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or other groups apparent to those skilled in the art.

[0639] General Synthetic Scheme I

[0640]

[0641] Step A-1 - Synthesis of exemplary Int-A1

[0642] To a solution of 2-hydroxybenzoic acid (50.0 g, 0.359 moles, 1.0 eq) in dichloromethane (500 mL, 10 V) was added dropwise thionyl chloride (133.6 mL, 1.798 moles, 5.0 eq, 2.67 V) at 0 °C. After 30 minutes, tetrahydrofuran (500 mL, 10 V) was added and the reaction was stirred at ambient temperature for 14-15 hours. The reaction mixture was cooled to 0 °C, to which was added dropwise methanol (150 mL, 3 V) and the mixture was stirred at room temperature for another 30 minutes. The reaction mixture was concentrated under reduced pressure to give a solid, which was then neutralized with aqueous sodium bicarbonate solution (pH 7-8), concentrated again to give a solid product. The solid was dissolved in methanol, filtered, and the filtrate was concentrated to give the desired product, exemplary Int-A1, methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (45.0 g, 81.8% yield) 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) ppm.

[0643] Step A-2 - Synthesis of Int-A2

[0644] To a cold (-78 °C) solution of acetonitrile (8.18 mL, 0.156 mole, 1.2 eq, 0.41 V) in tetrahydrofuran (300 mL, 15 V) was added dropwise n-BuLi (2.5 M in hexanes; 62.68 mL, 0.156 mole, 1.2 eq, 3.13 V) over a period of 60 minutes. After the addition was complete, the reaction was stirred for an additional 60 minutes, then 2-oxo-1,2-dihydropyridine-3-carboxylic acid methyl ester (Int-A1, 20.0 g, 130 mmol, 1.0 eq) was added portionwise to the reaction mixture and kept at -78 °C for 3 hours. The reaction was quenched with water and washed with ethyl acetate. The aqueous layer was evaporated to obtain the crude product which was suspended in methanol and stirred at room temperature for 30 minutes. The solid was filtered by suction and dried under high vacuum to obtain Int-A2 (11.5 g, 54% yield).

[0645] Step A-3 - Synthesis of Int-A3

[0646] To a solution of Int-A2 (20.0 g, 0.123 mole, 1.0 eq) in isopropanol (600 mL, 30 V) and acetic acid (22.2 mL, 1.11 V) was added hydrazine monohydrate (7.40 mL, 0.148 mole, 1.2 eq, 0.37 V) dropwise and the reaction was heated at 85 °C for 4-5 hours. After cooling, the reaction mixture was concentrated to obtain the crude product which was purified by column chromatography using neutral silica gel (60-120 mesh) eluting with 10-25% methanol in dichloromethane as a gradient to obtain the desired product Int-A3 (13.25 g, 61% yield) 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.

[0647] Step A-4 - Synthesis of exemplary Int-A4

[0648] To a solution of Int-A3 (10.0 g, 0.0568 mol) in dimethylformamide (100 mL, 10 V) was added acetic acid (11.2 mL, 1.12 V) drop wise at 10-15 °C followed by portion wise addition of 5-chlorothiophene-2-carboxaldehyde (9.15 g, 0.0624 moles, 1.1 eq). The reaction was stirred at room temperature for 30-45 min. Sodium cyanoborohydride (5.35 g, 0.0851 moles, 1.5 eq) was added in portions over a period of 45 min and the reaction was stirred for 2 h. After completion of the reaction, the mixture was poured into ice cold water under stirring and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get the crude product which was purified by column chromatography using neutral silica gel and the product was eluted with 10-12% methanol in dichloromethane as mobile phase to get the pure desired product, i.e. exemplary Int-A4, 3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-1,2- dihydropyridin-2-one (7.3 g, 42.7% yield) 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), 4.348-4.363 (2H, d) ppm. It will be appreciated by persons skilled in the art that various borohydride reagents can be used in this step to obtain similar results.

[0649] Step A-5 - Synthesis of exemplary Int-A5

[0650] To a cold (0 °C) solution of above exemplary Int-A4 in triethylamine (2.98 mL, 0.0215 mole, 3.0 eq) and dichloromethane (40 mL) was added pivaloyl chloride (0.776 g, 0.00647 mole, 0.9 eq) drop wise over a period of 30 minutes. The reaction was stirred for 2-3 hours by keeping the temperature below 10 °C. On completion, the reaction was diluted with ice cold water under stirring and the product was extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude obtained was purified by column chromatography using neutral silica gel eluting with 5-8% methanol in dichloromethane to provide pure desired product along with exemplary Int-A5, 3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropanoyl)-1H- pyrazol-3-yl)-1,2-dihydropyridin-2-one (0.76 g, 43.6% yield) 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), 6.974-6.984 (1H, d), 6.934-6.944 (1H, d), 6.317-6.350 (1H, t), 6.213 (1H, s), 4.471-4.486 (2H, d), 1.47 (9H, s) ppm. It will be appreciated by persons skilled in the art that the pyrazole center can be acylated using a variety of methods and reagents, for example to produce a reactive ester.

[0651] Step A-6 - Synthesis of exemplary compound A6

[0652] Exemplary Int-A5 (0.200 g, 5.1 x 10 -6 mol) was dissolved in dimethylformamide (5 mL, 25V) and stirred. Cesium carbonate (0.400 g, 1.2 x 10 -3mol) and stirred for 10 to 15 minutes. Next, 2-bromoethyl methyl ether (0.075 g, 8.1 x 10"6mol, 1.5 eq) was added and the reaction was further stirred at room temperature until completion of the reaction was determined by TLC monitoring. The reaction mass was then diluted in excess water and extracted with ethyl acetate, followed by purification by column chromatography to obtain exemplary compound A6, 3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2- dimethylpropanoyl)-1H-pyrazol-3-yl)-1-(2-methoxyethyl)-1,2-dihydropyridin-2-one (also listed as compound 7 in Table A above) (0.030 g, 13.2% yield)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 = 7.0 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 appreciate that in certain analogous reactions, potassium carbonate can be better than cesium carbonate depending on the details of the reagents involved.

[0653] Example 2

[0654] Specific synthesis of compound 1

[0655] The specific synthesis scheme I depicted below provides a specific synthesis of compound 1, 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.

[0656] Specific synthesis scheme I

[0657]

[0658] Step 1 - Synthesis of Int-1

[0659] Trimethyl orthoformate (286.06 g, 2.696 mol, 1.5 equivalents) was added to a mixture of 2-hydroxynicotinic acid (250 g, 1.797 mol) and methanol (3750 mL, 15V) at 25-30°C. The mixture was stirred for 15 minutes, and then concentrated H₂SO₄ (52.87 g, 0.539 mol, 0.3 equivalents) was added at 25-30°C. The mixture was then refluxed at 65-70°C for 2 hours. After replacing the reflux condenser with a distillation apparatus, the material was distilled for 4 hours to a constant volume to remove unreacted trimethyl orthoformate. After cooling to 25-30°C, the reaction mixture was slowly added to a mixture of NaHCO₃ (200 g, 2.381 mol, 1.32 equivalents) and MeOH (500 mL) to bring the pH to 7.0, and then stirred at the same temperature for 15 minutes. The resulting material was then subjected to… The sample was filtered and washed with MeOH (250 mL, 1 V). Next, the filtrate was distilled under vacuum until the internal volume was reduced to approximately 2 volumes by maintaining the material temperature below 55 °C. The material was then diluted with toluene (1250 mL, 5 V) and distilled again to approximately 2 volumes; this process is referred to as “solvent chasing” using toluene. This process was repeated until the MeOH content of the material was less than 3%. Finally, the material was cooled to 25 °C–30 °C, diluted with toluene (750 mL, 3 V), filtered, washed with toluene (500 mL, 2 V), and then dried under vacuum at 65 °C–70 °C to give unpurified Int-1 (315 g, 76% yield). [1H NMR (DMSO-d6, 400MHz) δ 12.107 (s, 1H), 8.056 (dd, J = 6.8, 2.0Hz, 1H), 7.663 (dd, J = 6.4, 2.4Hz, 1H), 6.269 (t, 6.8Hz, 1H), 3.776 (s, 3H)].

[0660] Step 2 – Synthesis of Int-2

[0661] A solution of n-butyllithium (549 mL, 2.5 M in hexanes, 1.37 mol, 2.1 eq) was added dropwise to a solution of acetonitrile (71.3 mL, 1.37 mol, 2.1 eq) in tetrahydrofuran (4500 mL, 45 V) at -70 °C to -80 °C. The resulting mass was then stirred at -70 °C to -80 °C for 1 h. Int-1 (100 g, 0.653 mol) was then added. The total mixture was stirred at -70 °C to -80 °C for another 3 h, then the mass was quenched with DM H2O (1500 mL, 15 V) at -70 °C to 0 °C, stirred for 10-15 min at 0 °C-5 °C, and diluted with ethyl acetate (2000 mL, 20 V). The mixture was then warmed to 25 °C-30 °C and stirred for 15 min, then the organic layer was separated. The aqueous layer was then cooled to 10 °C-15 °C, and its pH was adjusted to 2-3 with 6 N aqueous HC1. The slurry was stirred at 10 °C-15 °C for 30 min, then filtered, washed with DM H2O (400 mL, 4 V), and dried at 50 °C-55 °C under vacuum for 6 h to give Int-2 (40.2 g, 38% yield). [1H NMR (DMSO-d6, 400 MHz) δ 8.185 (dd, 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)].

[0662] Step 3 - Synthesis of Int-3

[0663] Acetic acid (45.6 mL, 1.14 V) was added to a mixture of Int-2 (40 g, 0.2466 mol) in isopropyl alcohol (400 mL, 10 V) at 25 °C-30 °C. The resulting mass was stirred at the same temperature for 10-15 min. Hydrazine hydrate (14.81 g, 0.296 mol, 1.2 eq) was then added to the reaction mixture, which was then heated to 80 °C-85 °C and stirred for about 3 h, whereupon Int-2 was less than 1% by area by HPLC analysis. The resulting mass was cooled to 25 °C-30 °C, filtered, washed with isopropyl alcohol (2 x 40 mL), and finally dried at 50 °C-55 °C under vacuum to give Int-3 (36.0 g, 83.3% yield). [1H NMR (DMSO-d6, 400 MHz) δ 11.784 (s, 2H), 7.867 (dd, J = 7.2, 1.6 Hz, 1H), 7.391 (dd, J = 6.4, 2.0 Hz, 1H), 6.319 (t, J = 6.8 Hz, 1H), 6.047 (s, 1H), 4.622 (s, 1H)].

[0664] Step 4 - Synthesis of Int-4

[0665] At 25-30°C, 31.81 g (0.2185 mol, 1.1 equivalents) of 5-chlorothiophene-2-carboxaldehyde was added to a mixture of Int-3 (35.0 g, 0.1986 mol) and DMF (350 mL, 10 V), followed by stirring for 15 minutes. Acetic acid (41.75 g, 0.695 mol, 1.1 equivalents) was then added. The mixture was stirred for approximately 2 hours until the Int-3 content, based on area, was less than 1% as determined by HPLC. The resulting product was then slowly added to DM H2O (1750 mL, 50 V) at 25-30°C, filtered, washed with DMH2O (350 mL, 10 V), and dried under vacuum at 50-55°C to obtain Int-4 (55.0 g, 90.9% yield).

[0666] Step 5 – Synthesis of Int-5

[0667] Sodium borohydride (7.7 g, 0.2035 mol, 2 equivalents) was slowly added to a suspension of Int-4 (31.0 g, 0.1017 mol, 1 equivalent) in dichloromethane (310 mL, 10 V) and ethanol (310 mL, 10 V) at 0-5 °C. The resulting mixture was then heated to 25-30 °C and stirred for 30 minutes. Then, additional sodium borohydride (7.7 g, 0.20 mol, 2 equivalents and 3.85 g, 0.1018 mol, 1 equivalent) was added in two portions, 30 minutes apart. The mixture was then stirred at 25-30 °C for 1 hour, and HPLC analysis showed that the Int-4 content was less than 1% by area. The mixture was then cooled to 10-20 °C, and the pH was adjusted to 7-8 using 1N HCl aqueous solution (355 mL, 11.45 V). The material was then stirred at 25°C-30°C for 1 hour, filtered, washed with DM H2O (155 mL, 5V), and dried under reduced pressure at 60°C-65°C for 10 hours until Int-5 was obtained. Using this procedure, as understood by those skilled in the art, employing the techniques and methods described herein, or those understood to be functionally equivalent, a chemical yield close to 100% is expected for this step. [1HNMR(DMSO-d6,400MHz)δ11.867(s,2H),7.859(d,J=5.6Hz,1H),7.406(d,J=4.8Hz,1H),6.890(dd, J=22.8,3.6Hz,2H),6.323(t,J=6.8Hz,1H),6.106(s,1H),5.860(t,J=6Hz,1H),4.353(d,J=6Hz,2H)].

[0668] Step 6 - Synthesis of Int-6

[0669] HATU (46.47 g, 0.122 mol, 1.5 eq) was added to a solution of pivalic acid (16.64 g, 0.163 mol, 2 eq) in DMF (250 mL, 10 V) at 25-30 °C. The mixture was then stirred at 25-30 °C for 30 min, then Int-5 (25.0 g, 0.0815 mol, 1 eq) was added portionwise and stirred for an additional 5 min. DIPEA (42.58 mL, 0.245 mol, 3 eq) was then added dropwise at 25-30 °C and stirred at 25-30 °C for an additional 1 h. The reaction mass was then cooled to 15 °C, diluted with DM H2O (250 mL, 10 V), then the pH was adjusted to 5.8-6.3 with 1% aqueous citric acid while maintaining the mass temperature below 25 °C. The resulting mass was then stirred at 25-30 °C for 30 min, filtered, washed with DM H2O (250 mL, 10 V), and dried at 55-60 °C under reduced pressure for 10 h to afford Int-6. Using this procedure, an average chemical yield of 59% for this step is expected by one of skill in the art using techniques and methods as described herein, or techniques and methods understood to be functionally equivalent. [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 (dd, 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)].

[0670] Step 7 - Synthesis of Compound 1

[0671] Cesium carbonate (333.4 g, 1.023 mol, 4.0 eq) was added slowly to a suspension of Int-6 (100 g, 0.256 mol, 1.0 eq) in DMF (500 mL, 5 V) at 25-30 °C. The mixture was stirred for 10 minutes. A solution of 3-chloropropanoic acid (41.64 g, 0.384 mol, 1.5 eq) in DMF (250 mL, 2.5 V) was added dropwise at 25-30 °C. The resulting material was stirred for one hour, then filtered and washed twice with DMF (100 mL, 1 V). The filtrate was then added slowly to DM H2O (4000 mL, 40 V) while maintaining the temperature of the material at 20-30 °C and stirring for 10 minutes. The pH was adjusted to 4.5 to 5.0 using 2N aqueous HC1 at 20-30 °C. The reaction material was then stirred for 30 minutes, filtered, and washed twice with 200 mL DM H2O to give Compound 1. Using this procedure, an average chemical yield of 19% can be expected by one of skill in the art using techniques and methods described herein, or understood to be functionally equivalent, as understood by one of skill in the art.

[0672] For purification of the final product, ethyl acetate (400 mL, 4 V) was added to the crude wet product (216 g) and stirred at 25-30 °C for 1 hour. After removal of the aqueous layer, the organic layer was then treated with charcoal (8.0 g) at 25-30 °C for 30 minutes. It was then filtered through celite (12 g) followed by washing the bed with ethyl acetate (120 mL). Ethyl acetate was distilled off from the filtrate until the internal volume reached approximately 150 mL (1.5 V) while maintaining the temperature of the material below 40 °C. The material was then cooled to 25-30 °C, stirred for 30 minutes, then seeded with pure int-5 (0.1% w / w). The slurry was cooled to 0-5 °C and stirred for 1 hour. The slurry was then filtered and washed twice with pre-chilled (0-5 °C) ethyl acetate (20 mL, 0.2 V). The material was then dried under vacuum at 25-30 °C.

[0673] The product was further purified by adding n-heptane (670 mL, 10 V) dropwise to a solution of compound 1 (67 g) in dichloromethane (670 mL, 10 V) at 25-30 °C. The slurry was then stirred at 25-30 °C for 30 minutes, filtered and washed with n-heptane (134 mL). The solid was then dried under vacuum at 25-30 °C.

[0674] This synthesis produced a crystalline solid having an x-ray powder diffraction pattern comprising a selection of one, two, three, four, five, or 2 theta values 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°, each within an error range of ±0.3°, as shown in FIG. 1. Figure 1 The solid was analyzed on a Bruker D8 Advance X-ray powder diffractometer (Tube: Cu:Kα Generator: 40 kV; 40 mA, and scan range: 3-40 degrees). Those skilled in the art will appreciate that the variance of the XRPD pattern can come from multiple sources. Thus, for all XRPD patterns in the present disclosure, 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°.

[0675] Example 3

[0676] Specific synthesis of compound 2

[0677] The specific synthesis scheme II depicted below provides for the synthesis of compound 2, 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]propanoic acid.

[0678] Specific synthesis scheme II

[0679]

[0680] In its individual steps, compound 1 (1 g, 2.16 mmol) was dissolved in methanol (10 mL, 10V) and reagent grade water (2 mL, 2V). Next, NaOH (431.97 mg, 10.80 mmol, 5 eq) was added in portions while the mixture was at 15-25 °C. The mixture was then stirred at 15-25 °C for 1 hour. Ice water (10 mL, 10V) was then added to the mixture, which was subsequently adjusted to pH 5-6 using 6N HC1 (11 mL, 11V). The resulting solid was filtered and washed with water (10 mL, 10V) to collect compound 2 (0.5 g, 1.32 mmol, 61.10% yield). [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, 2H), 2.695 (t, 2H)].

[0681] Example 4

[0682] Polymorphs

[0683] Some embodiments are crystalline solids of compound 1, which can exist in a variety of polymorphic forms. In one example, the solid material has a polymorph as depicted in Figure 1 To convert an amount of compound 1 to the polymorph of Figure 1 , the following procedure was performed. Compound 1 was dissolved in a THF / EA (4V / 10V) mixture at 30 °C and filtered. The solution was then cooled to 5 °C and seeded with seed crystals produced using the synthetic method described above in Specific Synthesis Scheme I. The mixture was then stirred at 5 °C for three hours, followed by the addition of 15V of n-heptane over 10 hours at 5 °C. Thereafter, an additional 21V of n-heptane was added over 5 hours at 5 °C, followed by an additional 22-24 hours of stirring at 5 °C, after which the solid was collected. Upon examination by XRPD, the resulting spectrum showed peaks including those at 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°, each within ±0.3° of error, as shown in Figure 1 Form 1. On a Bruker D8 Advance X-ray powder diffractometer (tube: Cu: K XRPD data were taken on a Bruker D8 Advance X-ray powder diffractometer (tube: Cu:Kα, 40 kV; 40 mA, scan range: 3-40 degrees, sample rotation: 15 rpm, and scan rate: 10 degrees / minute). Thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) data are recorded in Table H below.

[0684] In another embodiment, Compound 1 is a crystalline solid having an XRPD spectrum showing peaks at 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°, each within ± 0.3° error, as set forth in Table 1 below. Figure 2 In this embodiment, Compound 1 (35 mg) was mixed with isopropanol (0.5 mL) and slurry at room temperature and 500 rpm for 2 days protected from light. The solid was then separated via an Eppendorf 5418 centrifuge at 14000 rpm for 10 minutes, followed by drying under vacuum at room temperature for three days. The sample was then examined by XRPD, TGA, and DSC. XRPD, TGA, and DSC data were taken on a Bruker D8 Advance X-ray powder diffractometer (tube: Cu:Kα, 40 kV; 40 mA, scan range: 3-40 degrees, sample rotation: 15 rpm, and scan rate: 10 degrees / minute). TGA and DSC data are recorded in Table H below. XRPD data were taken on a Bruker D8 Advance X-ray powder diffractometer (tube: Cu:Kα, 40 kV; 40 mA, scan range: 3-40 degrees, sample rotation: 15 rpm, and scan rate: 10 degrees / minute). TGA and DSC data are recorded in Table H below.

[0685] In another embodiment, Compound 1 is a crystalline solid having an XRPD spectrum showing peaks at 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° (within at least ± 0.3°), as set forth in Table 2 below. Figure 3 In this embodiment, Compound 1 (15.6 mg) was mixed with a 1 : 1 ethanol: water mixture (0.3 mL) and slurry at 40 °C and 500 rpm for one day. The solid was then separated via an Eppendorf 5418 centrifuge at 14000 rpm for 10 minutes, followed by drying under vacuum at room temperature for three days. The sample was then examined by XRPD, TGA, and DSC. XRPD, TGA, and DSC data were taken on a Bruker D8 Advance X-ray powder diffractometer (tube: Cu:Kα, 40 kV; 40 mA, scan range: 3-40 degrees, sample rotation: 15 rpm, and scan rate: 10 degrees / minute). TGA and DSC data are recorded in Table H below. XRPD data were taken on a Bruker D8 Advance X-ray powder diffractometer (tube: Cu:Kα, 40 kV; 40 mA, scan range: 3-40 degrees, sample rotation: 15 rpm, and scan rate: 10 degrees / minute). TGA and DSC data are recorded in Table H below. XRPD data were taken on a Bruker D8 Advance X-ray powder diffractometer (tube: Cu:Kα, 40 kV; 40 mA, scan range: 3-40 degrees, sample rotation: 15 rpm, and scan rate: 10 degrees / minute). TGA and DSC data are recorded in Table H below.

[0686] Example 5

[0687] Salt synthesis

[0688] Some embodiments involve compound 1 in the form of a salt with a suitable counterion. In some embodiments, this counterion is tris(hydroxymethyl)aminomethane, hereinafter referred to as "Tris". To produce the Tris salt of compound 1, 320 mg of compound 1 is placed in a glass vial and dissolved in 10.7 mL of acetone. The vial is then sonicated for a few minutes to produce a hazy suspension. The suspension is then centrifuged at 10,000 rpm for 5 minutes in a Xiangyi H1650 centrifuge, and 1.67 mL of supernatant is separated from the remaining clumps and volume. To this 1.67 mL supernatant fraction, 0.059 mL of Tris (a 2N aqueous solution) is added to produce a 1:1.1 molar ratio of compound 1:Tris. The mixture is then stirred at room temperature for 24 hours. The resulting suspension was then centrifuged at 10,000 rpm for 10 minutes in an Eppendorf 5418 centrifuge to separate the solids. The solids were then dried overnight at 40°C in a Boxun DZF-6050 vacuum oven. The powder was then analyzed using a Bruker D8 Advance X-ray powder diffractometer (tube: Cu:Kα). The generator (40kV; 40mA, scanning range: 3-40 degrees, sample rotation speed: 15rpm, and scanning rate: 10 degrees / minute) was used to analyze solids. Figure 4 The resulting XRPD spectrum is shown. In this embodiment, compound 1 exists in a crystalline form having an X-ray powder diffraction pattern comprising one, two, three, four, five, or more 2θ values ​​selected from a list 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°. Figure 4 The image is shown in crystal form 4. TGA and DSC data are recorded in Table H below.

[0689] Those skilled in the art will understand that similar salts can be prepared by using 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 collected in the same manner as described above.

[0690] Table H.

[0691]

[0692] Thermogravimetric analysis (TGA) data were measured on a TA Q5000 IR using samples with a mass of 0.5 to 5.0 mg in an open platinum pan heated at a rate of 10 °C / min from room temperature to 250 °C.

[0693] Differential scanning calorimetry (DSC) data were measured on a TA Q2000 using samples with a mass of 0.5 to 1.0 mg in a crimped aluminum pan with a pinhole lid heated at a rate of 10 °C / min from room temperature to 250 °C.

[0694] Example 6

[0695] Metabolites of compound 1

[0696] Certain metabolites of Compound 1 have been detected from various in vivo and in vitro studies. These compounds include the compounds listed in Table I below. Compounds 10, 13, and 14 are proposed metabolites.

[0697]

[0698]

[0699] As will be appreciated by those skilled in the art, metabolites of Compound 1 have a variety of uses. Certain metabolites, such as Compound 10, are biologically active (see Table B above). Metabolites of Compound 1 can also be used as pharmacokinetic indicators of Compound 1 in biological assays and organisms, including human patients.

[0700] Example 7

[0701] Pharmaceutical compositions

[0702] Example 7a - Amorphous Solid Dispersion of Compound 1

[0703] Pharmaceutical compositions were prepared containing Compound 1 in an amorphous solid form in an amorphous solid dispersion with a polymer Compound 1 in an amorphous solid form in an amorphous solid dispersion of VA64 (i.e., vinylpyrrolidone-vinyl acetate copolymer). The amorphous solid dispersion contained Compound 1 and VA64 in a 1 :3 weight ratio. VA64 and prepared using the spray-dried dispersion (SDD) technique using THF as the solvent and utilizing the following process parameters: 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. This material was then dried in a convection oven at 50 °C for 48 hours, followed by an additional 18 hours at 60 °C. Those skilled in the art will appreciate that Compound 1 can be used with various weight ratios of VA64 to achieve the desired amorphous state of Compound 1 in an amorphous solid dispersion.

[0704] Example 7b - Tablet formulation of Compound 1 as an amorphous solid dispersion

[0705] Compound 1 as an amorphous solid dispersion as described in Example 7a above was formulated into tablets. Those skilled in the art will appreciate that embodiments of the present application can include a variety of pharmaceutically acceptable excipients, which will be known to those skilled in the art. For example, these excipients can include a disintegrant such as crospovidone, a filler such as microcrystalline cellulose and mannitol, and a lubricant or glidant such as magnesium stearate and / or talc. In this example, tablets were prepared to include the following ingredients in the weight ratios listed below, compared to the total mass of the tablet.

[0706] Table J.

[0707]

[0708] In one formulation, the total mass of the tablet is 180 mg ± 9 mg. In another formulation, the total mass of the tablet is 1000 mg ± 50 mg.

[0709] In further embodiments, the tablet is coated with an outer film or layer known as an enteric coating. This layer, which includes a polymer and / or other materials, can provide additional properties, such as resistance to dissolution in environments below pH 5.5. In some embodiments, the polymer is a copolymer including co-polymerized methacrylic acid esters. In this embodiment, the polymer of this outer film or layer is L 30D-55.

[0710] Example 7c - Method of preparing tablets of Example 7b

[0711] Provided herein is a method for preparing tablets of Example 7b as disclosed above. First, as described in embodiment 7a above, an amorphous solid dispersion of Compound 1 was produced using a 1 :3 weight ratio of Compound 1 to VA64 using the spray-dried dispersion (SDD) technique.

[0712] Next, the amorphous solid dispersion is mixed with the in-particle raw material. In one embodiment of the invention, these materials may comprise at least one disintegrant and at least one lubricant. In some embodiments, the in-particle raw material further comprises at least one filler. In this embodiment, the disintegrant includes crospovidone (Copovichone). CL), and the lubricant is magnesium stearate, and the granular material also contains microcrystalline cellulose (CL). pH 101) and mannitol ( (M 100). Those skilled in the art will understand that the components within these particles can be deagglomerated using a mesh screen. In this embodiment, the filler, disintegrant, and amorphous solid dispersion are deagglomerated and mixed for ten minutes, followed by the addition of the deagglomerated lubricant to the mixture and further mixing for three minutes.

[0713] The mixture of this granular material and amorphous solid dispersion can then be compacted and subsequently ground. In this embodiment, a roller compactor applying a 5 kN force is used, and the material is ground into strips using a 1,000 μm sieve at 20 rpm. These compacted strips are then further ground into granules using methods understood by those skilled in the art.

[0714] In one embodiment, the above mixing is carried out under dry conditions, and the granulation is dry granulation. In this embodiment, dry mixing and dry granulation are used.

[0715] Next, the dried granules from the above steps are further mixed with the off-particle raw materials. In one embodiment of the invention, these materials comprise at least one disintegrant, at least one lubricant and / or flow aid, and at least one filler. In this embodiment, the disintegrant includes cropovidone (…). CL), and the lubricant and / or flow aid includes magnesium stearate and talc, and the extra-particulate raw materials additionally include microcrystalline cellulose and mannitol (CL). (M 100). Those skilled in the art will understand that these extra-particle components can be de-agglomerated using a mesh screen. In this embodiment, one or more de-agglomerating fillers and disintegrants are first mixed with the particles for ten minutes, and then one or more de-agglomerating lubricants and / or flow aids are added to the mixture and mixed for another three minutes to produce the final mixture.

[0716] The final mixture is then compressed into tablets of the desired shape and size with the properties shown in Table J.

[0717] In some formulations, the tablet mass is 180 mg ± 9 mg, while in others it is 1000 mg ± 50 mg. Those skilled in the art will understand that the parameters of the compression step (such as pressing speed and compression force) vary depending on the desired shape, size, mass, and other characteristics of the tablet in the chosen embodiment.

[0718] In this example, the distribution of ingredients between the intra- and extra-granular portions is depicted in the following table K as a percentage of the total weight of the tablet.

[0719] Table K.

[0720]

[0721] Finally, the compressed tablet is coated with a film or layer. In some embodiments, this outer layer contains a polymer and imparts other properties on the tablet, such as protection from dissolution at a pH below 5.5. In some embodiments, the polymer contains a polymerized methacrylic acid-ethyl acrylate. In this example, this polymer is Eudragit® L 30D-55. In addition, this polymer is used as a 57% solution in ethanol. Those skilled in the art will appreciate that the evaporation technique can well reduce the final water composition due to evaporation of the water. Those skilled in the art will appreciate that there are a variety of techniques available to coat tablets with this outer layer. In some embodiments, a pan coating technique is employed. L 30D-55. In addition, this polymer is used as a 57% solution in ethanol. Those skilled in the art will appreciate that the evaporation technique can well reduce the final water composition due to evaporation of the water. Those skilled in the art will appreciate that there are a variety of techniques available to coat tablets with this outer layer. In some embodiments, a pan coating technique is employed. L 30D-44, 14.6% plasacryl HTP20, and 28.4% water. Those skilled in the art will appreciate that the evaporation technique can well reduce the final water composition due to evaporation of the water. Those skilled in the art will appreciate that there are a variety of techniques available to coat tablets with this outer layer. In some embodiments, a pan coating technique is employed.

[0722] Various embodiments of the present disclosure can be described in view of the following clauses:

[0723] 1. A compound according to structure I:

[0724]

[0725] or a pharmaceutically acceptable salt, solvate, or co-crystal thereof,

[0726] wherein R 1 is selected from the group consisting of hydrogen and pivaloyl.

[0727] 2. A prodrug according to the compound of clause 1 according to general structure II:

[0728]

[0729] or a pharmaceutically acceptable salt, solvate, or co-crystal thereof;

[0730] wherein R 1 is selected from the group consisting of hydrogen and pivaloyl; and

[0731] wherein R 2 is selected from the group consisting of substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

[0732] 3. The prodrug of clause 2, wherein R 2 is selected from the group:

[0733]

[0734] 4. The compound of clause 1, wherein R 1 is pivaloyl, as in compound 1:

[0735]

[0736] 5. The compound of clause 1 or 4, wherein the compound is in crystalline form.

[0737] 6. The compound of clause 5, wherein the crystalline form has an x-ray powder diffraction pattern comprising at least five 2 theta values selected from the group 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°, wherein each of the at least five 2 theta values is within an error range of ±0.3°.

[0738] 7. The compound of clause 5, wherein the crystalline form has an x-ray powder diffraction pattern comprising at least five 2 theta 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°, wherein each of the at least five 2 theta values is within an error range of ±0.3°.

[0739] 8. The compound of clause 5, wherein the crystalline form has an x-ray powder diffraction pattern comprising at least five 2 theta 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°, wherein each of the at least five 2 theta values is within an error range of ±0.3°.

[0740] 9. The compound of any one of clauses 1 or 4-8, wherein R 1 is hydrogen, as in compound 2:

[0741]

[0742] 10. The compound of any one of clauses 1 or 4-9, wherein the compound is in the form of a pharmaceutically acceptable salt.

[0743] 11. The compound of clause 10, wherein the pharmaceutically acceptable salt has a counterion selected from the group consisting of sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane.

[0744] 12. The compound of clause 11, wherein the counterion is tris(hydroxymethyl)aminomethane.

[0745] 13. The compound of any one of clauses 1 or 4-12, wherein R 1 is pivaloyl.

[0746] 14. The compound of clause 13, wherein the compound is in a crystalline form having an x-ray powder diffraction pattern comprising at least five 2-theta 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°, wherein each of the at least five 2-theta values is within an error range of ±0.3°.

[0747] 15. The compound or prodrug of any one of the preceding clauses, selected from the group consisting of:

[0748] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0749] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1H-pyrazol-3-yl)-2-oxo-1,2- dihydropyridin-1-yl]propanoic acid;

[0750] 2-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]acetic acid;

[0751] 4-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]butanoic acid;

[0752] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]-2,2-difluoropropanoic acid;

[0753] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]acrylamide;

[0754] 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;

[0755] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(3-hydroxy-2,2-dimethylpropionyl)- 1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0756] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylbutanoyl)-1H-pyrazol- 3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0757] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(furan-3-carbonyl)-1H-pyrazol-3- yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0758] 3-[3-(5-{[(5-chloro-1-oxo-1 lambda4-thiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)- 1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid;

[0759] (2S,3S,4S,5R,6S)-6-({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2- dimethylpropionyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoyl}oxy)-3,4,5- trihydroxyoxane-2-carboxylic acid;

[0760] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H-pyrazol- 3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid ethyl ester;

[0761] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propionic acid prop-2-en-1-yl ester; 2-(acetyloxy)ethyl;

[0762] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propionic acid;

[0763] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propionic acid 1-(acetyloxy)ethyl ester;

[0764] 2,2-dimethylpropionic acid ({3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2- dimethylpropionyl)-1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propionyl}oxy)methyl ester;

[0765] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propionic acid (3,5,6-trimethylpyrazin-2- yl)methyl ester;

[0766] (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoic acid ({3-[3-(5-{[(5- chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H-pyrazol-3-yl)-2- oxo-1,2-dihydropyridin-1-yl]propionyl}oxy)methyl ester;

[0767] 3-[3-(5-{[(5-chlorothiophen-2-yl)methyl]amino}-1-(2,2-dimethylpropionyl)-1H- pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl](2H4)propionic acid;

[0768] 3-{3-[5-({[5-chloro(3,4-2H2)thiophen-2-yl](2H2)methyl}amino)-1-(2,2- dimethylpropionyl)-1H-pyrazol-3-yl]-2-oxo-1,2-dihydropyridin-1-yl}propionic acid; and

[0769] 3-[3-(5-{[(5-chlorothiophen-2-yl)(2H2)methyl]amino}-1-(2,2-dimethylpropionyl)- 1H-pyrazol-3-yl)-2-oxo-1,2-dihydropyridin-1-yl]propanoic acid.

[0770] 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.

[0771] 17. A method for treating and / or preventing a disease or condition in a subject, the method comprising administering a compound or prodrug according to any one of clauses 1 to 15, or a pharmaceutical composition according to clause 16, to a subject in need thereof in an amount effective to treat or prevent the disease or condition.

[0772] 18. The method according to clause 17, wherein the disease or condition is a thrombotic disease or condition and / or involves a blood clot thrombus or potential formation of a blood clot thrombus.

[0773] 19. The method according to clause 18, wherein the thrombotic disease or condition comprises acute coronary syndrome, thromboembolism, and / or thrombosis.

[0774] 20. The method according to clause 19, wherein the thromboembolism comprises venous thromboembolism, arterial thromboembolism, and / or cardiogenic thromboembolism.

[0775] 21. The method according to clause 20, wherein the venous thromboembolism comprises deep vein thrombosis and / or pulmonary embolism.

[0776] 22. The method according to clause 21, wherein the deep vein thrombosis and / or pulmonary embolism occurs following a medical procedure.

[0777] 23. The method according to any one of clauses 18-22, wherein the thrombotic disease or condition involves dysfunctional coagulation or disseminated intravascular coagulation.

[0778] 24. The method according to clause 23, wherein the subject is undergoing percutaneous coronary intervention (PCI).

[0779] 25. The method according to any one of clauses 18-24, wherein the thrombotic disease or condition involves a blood clot thrombus or potential formation of a blood clot thrombus, and further involves stroke and / or one or more transient ischemic attacks (TIAs).

[0780] 26. The method of clause 25, wherein the thrombotic disease or condition involving a blood clot thrombus or potential formation of a blood clot thrombus further involves stroke, and wherein the subject has non-valvular atrial fibrillation.

[0781] 27. The method of any one of clauses 18-26, wherein the thrombotic disease or condition involving a blood clot thrombus or potential formation of a blood clot thrombus further involves pulmonary arterial hypertension.

[0782] 28. The method of clause 27, wherein the pulmonary arterial hypertension is caused by one or more left heart conditions and / or chronic thromboembolic disease.

[0783] 29. The method of clause 27, wherein the pulmonary arterial hypertension is associated with one or more pulmonary diseases, including pulmonary fibrosis (idiopathic or otherwise), and / or hypoxia.

[0784] 30. The method of any one of clauses 17-29, wherein the disease or condition comprises fibrosis, Alzheimer’s disease, multiple sclerosis, pain, cancer, inflammation, and / or Type I diabetes.

[0785] 31. The method of any one of clauses 17-30, wherein the disease or condition involves recurrent cardiac events following myocardial infarction.

[0786] 32. The method of any one of clauses 20-31, wherein the venous thromboembolism is associated with thrombosis within a vein associated with one or more acquired or genetic risk factors and / or peripheral venous embolism caused by a detached thrombus.

[0787] 33. The method of clause 32, wherein the one or more risk factors comprise a prior venous thromboembolism.

[0788] 34. The method of any one of clauses 20-33, wherein the cardiogenic thromboembolism is due to thrombosis within the heart associated with cardiac arrhythmia, heart valve defects, artificial heart valves, or heart disease and / or peripheral arterial embolism caused by a detached thrombus.

[0789] 35. The method of clause 34, wherein the detached thrombus is in the brain (ischemic stroke).

[0790] 36. The method of clause 35, wherein the detached thrombus causes a transient ischemic attack (TIA).

[0791] 37. The method of any one of clauses 34-36, wherein the cardiogenic thromboembolism is due to non-valvular atrial fibrillation.

[0792] 38. The method of any one of clauses 19-37, wherein the thrombosis is arterial thrombosis.

[0793] 39. The method of clause 38, wherein the arterial thrombosis is due to one or more underlying atherosclerotic processes in an artery.

[0794] 40. The method of clause 39, wherein the one or more underlying atherosclerotic processes in an artery occlude or occlude the artery, cause myocardial ischemia (angina pectoris, acute coronary syndrome), cause myocardial infarction, occlude or occlude peripheral arteries (ischemic peripheral arterial disease), and / or occlude or occlude the artery after a procedure on the blood vessel (reocclusion or restenosis after percutaneous transluminal coronary angioplasty, reocclusion or restenosis after percutaneous transluminal peripheral angioplasty).

[0795] 41. The method of any one of clauses 17-40, wherein the treatment or prevention comprises adjunctive therapy.

[0796] 42. The method of clause 41, wherein the subject has a myocardial infarction and the adjunctive therapy is combined with thrombolytic therapy.

[0797] 43. The method of clause 41 or 42, wherein the subject has unstable angina, thrombosis, and / or heparin-induced thrombocytopenia and the adjunctive therapy is combined with antiplatelet therapy.

[0798] 44. The method of any one of clauses 41-43, wherein the subject has non-valvular atrial fibrillation and the adjunctive therapy is combined with one or more other therapies.

[0799] 45. The method of any one of clauses 41-45, wherein the subject has at least one of coronary artery disease and heart failure, and wherein the adjunctive therapy is combined with antiplatelet therapy.

[0800] 46. The method of clause 45, wherein the subject also has valvular or non-valvular atrial fibrillation.

[0801] 47. The method of any one of clauses 41-46, wherein the subject has valvular or non-valvular atrial fibrillation and is undergoing percutaneous coronary intervention with a stent, and wherein the adjunctive therapy is combined with antiplatelet therapy.

[0802] 48. A tablet comprising a pharmaceutical composition comprising Compound 1 according to clause 4.

[0803] 49. The tablet according to Clause 48, wherein Compound 1 is present as an amorphous solid in an amorphous solid dispersion.

[0804] 50. The tablet according to Clause 49, wherein the amorphous solid dispersion comprises a first polymer.

[0805] 51. The tablet according to Clause 50, wherein the first polymer is vinylpyrrolidone-vinyl acetate copolymer.

[0806] 52. The tablet according to Clause 51, wherein Compound 1 and the first polymer are present in a weight ratio of 1:3.

[0807] 53. The tablet according to any one of Clauses 48-52, further comprising at least one disintegrant.

[0808] 54. The tablet according to Clause 53, wherein the disintegrant comprises crospovidone.

[0809] 55. The tablet according to any one of Clauses 48-54, further comprising at least one filler.

[0810] 56. The tablet according to Clause 55, wherein the filler comprises microcrystalline cellulose or mannitol.

[0811] 57. The tablet according to any one of Clauses 48-56, further comprising at least one lubricant or glidant.

[0812] 58. The tablet according to Clause 57, wherein the lubricant or glidant comprises magnesium stearate or talc.

[0813] 59. The tablet according to any one of Clauses 48-58, further comprising an outer layer or film.

[0814] 60. The tablet according to Clause 59, wherein the outer layer or film comprises at least one second polymer.

[0815] 61. The tablet according to Clause 60, wherein the second polymer prevents dissolution of the tablet below pH 5.5.

[0816] 62. The tablet according to Clause 60 or 61, wherein the second polymer comprises L 30D-55.

[0817] 63. The tablet according to any one of Clauses 59-62, wherein the outer layer or film comprises 57% of L 30D-55, 14.6% of HTP20, and 28.4% of water.

[0818] 64. The tablet according to any one of clauses 59-63, wherein the second polymer comprises a methacrylic acid-ethyl acrylate copolymer.

[0819] 65. The tablet according to any one of clauses 48-64, wherein the amorphous solid dispersion comprises 50% by weight of the tablet.

[0820] 66. The tablet according to any one of clauses 48-65, further comprising an outer layer of a second polymer, and wherein the tablet without the outer layer is 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.

[0821] 67. The tablet according to clause 66, wherein the second polymer comprises L 30D-55.

[0822] 68. The tablet according to clause 66 or 67, wherein the total mass of the tablet without the outer layer is 180 mg ± 9 mg.

[0823] 69. The tablet according to clause 66 or 67, wherein the total mass of the tablet without the outer layer is 1000 mg ± 50 mg.

[0824] 70. A tablet comprising a pharmaceutical composition comprising a prodrug having the general structure II according to clause 2.

[0825] 71. A process of manufacturing a tablet having a pharmaceutical composition as described in any one of clauses 48-69, the process comprising:

[0826] (1) producing an amorphous solid dispersion of Compound 1;

[0827] (2) granulating the amorphous solid dispersion of step (1) with intra-granular ingredients under dry conditions;

[0828] (3) blending the granules of step (2) with extra-granular ingredients to form a final mixture;

[0829] (4) compressing the final mixture of step (3) into a tablet; and

[0830] (5) coating the tablet of step (4) with a film or layer.

[0831] 72. The process of clause 71, further comprising:

[0832] (1) producing an amorphous solid dispersion of Compound 1 using spray-dried dispersion (SDD) technology;

[0833] (2) mixing the amorphous solid dispersion of step (1) with intra-granular ingredients comprising at least one disintegrant and at least one lubricant;

[0834] (3) dry granulating the mixture of step (2), wherein the granulation process comprises using a roller compactor to produce a compacted ribbon, wherein the compacted ribbon is subsequently milled into granules;

[0835] (4) blending the granules of step (3) with de-agglomerated extra-granular ingredients comprising a disintegrant and a lubricant;

[0836] (5) compressing the blend of step (4) into tablets; and

[0837] (6) coating the tablets of step (5) with a film or layer.

[0838] The various methods and techniques described above provide a number of ways to carry out the application. Of course, it is to be understood that not necessarily all objects or advantages described can be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods described can have a plurality of equivalents, and in

[0839] Furthermore, to one skilled in the art, the various features of the embodiments disclosed can be readily adapted to other embodiments and the teachings provided herein can be applied in a manner not specifically described herein. The instant disclosure is generally drawn to methods and compositions for the treatment of cancer. The following written description is provided to enable a person skilled in the art to make and use the disclosure. Various modifications to the embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein can be applied to other embodiments and applications without departing from the spirit and scope of the disclosure. Thus, the present disclosure is not intended to be limited to the embodiments described herein but is to be accorded the widest scope consistent with the claims.

[0840] While this application has been disclosed in the context of certain embodiments and examples, the skilled artisan will appreciate that embodiments of the application extend beyond the specifically disclosed embodiments to other alternative embodiments and / or uses of the application and modifications and equivalents thereof.

[0841] Numerous variations and alternatives have been disclosed in embodiments of the present invention. Other variations and alternatives 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.

[0842] In some embodiments, figures representing quantities of components, molecular weight characteristics, reaction conditions, etc., used to describe and claim certain embodiments of this application should in some cases be understood to be modified by the term "about". Therefore, in some embodiments, the numerical parameters set forth in the written description and appended claims are approximate values, which may vary depending on the desired characteristics sought to be obtained in a particular embodiment. In some embodiments, numerical parameters should be interpreted according to the number of significant figures reported and by applying conventional rounding. Although the numerical ranges and parameters set forth in the broad description of some embodiments of this application are approximate values, the values ​​set forth in the specific embodiments are reported as accurately as possible. The values ​​presented in some embodiments of the invention may contain some errors necessarily caused by the standard deviation found in their respective test measurements.

[0843] Unless otherwise specified or clearly contradicted by the context, connective language such as phrases of the form "at least one of A, B, and C" or "at least one of A, B, and C" is otherwise understood, in conjunction with the context, to generally refer to an item, term, etc., that can be A or B or C, or any non-empty subset of the set of A, B, and C. For example, in an illustrative instance of a set with three members, the connective phrases "at least one of A, B, and C" and "at least one of A, B, and C" refer to any one of the following sets: {A}, {B}, {C}, {A, B}, {A, C}, {B, C}, {A, B, C}. Therefore, such connective language is generally not intended to imply that some implementation requires the presence of at least one of A, at least one of B, and at least one of C.

[0844] The use of any and all instances or exemplary language (e.g., “such”) provided herein is intended only to better illustrate embodiments of the invention and, unless otherwise required, does not limit the scope of the invention. The language in this specification should not be construed as indicating any non-claimed element as necessary for practicing the invention.

[0845] In some embodiments, the terms “a,” “an,” and “the,” as well as similar references (particularly in the context of certain claims below) used in the context of describing particular embodiments of this application, may be interpreted to cover both the singular and the plural. Expressions of numerical ranges herein are intended only as a simplified method of individually referring to each individual numerical value falling within that range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually referenced herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context. The use of any and all instances or exemplary language (e.g., “such”) provided with respect to certain embodiments herein is intended only to better illustrate the application and, unless otherwise required, does not limit the scope of the application. The language in the specification should not be construed as indicating any unclaimed essential elements for implementing this application.

[0846] The groups of alternative elements or embodiments of the invention disclosed herein should not be construed as limiting. Each group member may be mentioned and claimed individually or in any combination with other members of the group or other elements present herein. For convenience and / or patentability, one or more members of a group may be included in or removed from the group. When any such inclusion or removal occurs, the specification herein is regarded as containing the changed group and thus conforming to the written description of the Markush group as used in the appended claims.

[0847] This document describes preferred embodiments of the present application. Variations of those preferred embodiments will become apparent to those skilled in the art upon reading the foregoing description. It is anticipated that those skilled in the art will appropriately employ such variations and may practice the present application in ways not specifically described herein. Therefore, where permitted by applicable law, many embodiments of the present application include all modifications and equivalents of the subject matter referenced in the appended claims. Furthermore, unless otherwise indicated herein or clearly contradicted by the context, the present application covers any combination of the foregoing elements in all its possible variations.

[0848] All references cited herein, including publications, patent applications, and patents, are hereby incorporated by reference to the same extent as if each reference were individually and specifically incorporated by reference and were specifically stated to be incorporated by reference for all purposes in its entirety. For example, the description, definitions and / or use of terms referred to in any of the incorporated-by-reference references, if any, are hereby expressly incorporated by reference for purposes of the present document, except in the event of any inconsistency, which in such case shall prevail only to the extent of such inconsistency. In the event that any conflict is deemed to exist between the content of a reference and the disclosure of the present document, the content of this document shall control.

[0849] In closing, it is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the present application. Other modifications that can be employed are within the scope of the application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the application can be utilized in accordance with the teachings herein. Accordingly, the present embodiments are not limited to that precisely as shown and described.

Claims

1. A compound based on compound I: Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, wherein the compound is in crystalline form, and wherein the crystalline form has an X-ray powder diffraction pattern comprising the following 2θ values: a) 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°; b) 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°; or c) 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 2θ values ​​is within an error range of ±0.3°.

3. The compound according to claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt.

4. The compound of claim 3, wherein the pharmaceutically acceptable salt has an antiion selected from the group consisting of: sodium, potassium, calcium, L-arginine, L-lysine, meglumine, and tris(hydroxymethyl)aminomethane.

5. The compound according to claim 4, wherein the counterion is tris(hydroxymethyl)aminomethane.

6. The compound according to claim 5, wherein the compound is in crystalline form having an X-ray powder diffraction pattern having 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°, wherein each of the 2θ values ​​is within an error range of ±0.3°.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

8. Use of the compound according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and / or preventing a disease or condition in a subject, wherein the disease or condition is responsive to inhibition of thrombin.

9. The use according to claim 8, wherein the disease or condition is a thrombotic disease or condition and / or involves the potential formation of a blood clot thrombus or blood clot thrombus.

10. The use according to claim 9, wherein the thrombotic disease or condition includes acute coronary syndrome, thromboembolism, and / or thrombosis.

11. The use according to claim 10, wherein the thromboembolism is venous thromboembolism, arterial thromboembolism, and / or cardiogenic thromboembolism.

12. The use according to claim 11, wherein the venous thromboembolism is deep vein thrombosis and / or pulmonary embolism.

13. The use according to claim 12, wherein the deep vein thrombosis and / or pulmonary embolism occurs after the medical procedure.

14. The use according to claim 9, wherein the thrombotic disease or condition involves dysfunctional coagulation or disseminated intravascular coagulation.

15. The use according to claim 14, wherein the subject is undergoing percutaneous coronary intervention (PCI).

16. The use according to claim 9, wherein the thrombotic disease or condition involves the potential formation of a blood clot thrombus or blood clot thrombus, and further involves stroke and / or one or more transient ischemic attacks (TIAs).

17. The use according to claim 16, wherein the thrombotic disease or condition involving the potential formation of a blood clot thrombus or blood clot thrombus further involves stroke, and wherein the subject suffers from nonvalvular atrial fibrillation.

18. The use according to claim 9, wherein the thrombotic disease or condition involving the potential formation of blood clots or thrombi further involves pulmonary hypertension.

19. The use according to claim 18, wherein the pulmonary hypertension is caused by one or more left ventricular diseases and / or chronic thromboembolic diseases.

20. The use according to claim 18, wherein the pulmonary hypertension is associated with one or more lung diseases and / or involves pulmonary fibrosis and / or hypoxia.

21. The use according to claim 8, wherein the disease or condition is fibrosis, Alzheimer's disease, multiple sclerosis, pain, cancer, inflammation, and / or type 1 diabetes.

22. The use according to claim 8, wherein the disease or condition relates to recurrent cardiac events following myocardial infarction.

23. The use according to claim 11, wherein the venous thromboembolism is associated with intravenous thrombosis and / or peripheral venous thrombosis caused by detached thrombi, which are related to the same or more acquired or hereditary risk factors.

24. The use according to claim 23, wherein one or more risk factors are prior venous thromboembolism.

25. The use according to claim 11, wherein the cardiogenic thromboembolism is caused by intracardiac thrombosis associated with arrhythmia, valvular defects, prosthetic heart valves or heart disease and / or peripheral arterial embolism caused by detached thrombi.

26. The use according to claim 25, wherein the separated thrombus is in the brain.

27. The use according to claim 26, wherein the detached thrombus causes a transient ischemic attack (TIA).

28. The use according to claim 25, wherein the cardiogenic thromboembolism is caused by non-valvular atrial fibrillation.

29. The use according to claim 10, wherein the thrombosis is arterial thrombosis.

30. The use according to claim 29, wherein the arterial thrombosis is caused by one or more potential atherosclerotic processes in the artery.

31. The use according to claim 30, wherein one or more potential atherosclerotic processes in the artery cause arterial obstruction or occlusion, resulting in myocardial ischemia, myocardial infarction, peripheral arterial obstruction or occlusion, and / or obstruction or occlusion of the artery after surgery on the vascular vessel.

32. The use according to claim 8, wherein the treatment or prevention is an adjunctive therapy.

33. The use according to claim 32, wherein the subject suffers from myocardial infarction, and the adjunctive therapy is combined with thrombolytic therapy.

34. The use according to claim 32, wherein the subject suffers from unstable angina, thrombosis and / or heparin-induced thrombocytopenia, and the adjunctive therapy is combined with antiplatelet therapy.

35. The use according to claim 32, wherein the subject suffers from nonvalvular atrial fibrillation, and the adjunctive therapy is combined with one or more other therapies.

36. The use according to claim 32, wherein the subject suffers from at least one of coronary artery disease and heart failure, and wherein the adjunctive therapy is combined with antiplatelet therapy.

37. The use according to claim 36, wherein the subject also suffers from valvular or nonvalvular atrial fibrillation.

38. The use according to claim 32, wherein the subject has valvular or nonvalvular atrial fibrillation and is undergoing percutaneous coronary intervention using a stent, and wherein the adjuvant therapy is combined with antiplatelet therapy.

39. A tablet comprising a pharmaceutical composition containing compound 1 according to claim 1.

40. The tablet according to claim 39, wherein compound 1 exists as an amorphous solid in the amorphous solid dispersion.

41. The tablet of claim 40, wherein the amorphous solid dispersion comprises a first polymer, wherein the first polymer comprises a vinylpyrrolidone-vinyl acetate copolymer.

42. The tablet of claim 41, wherein compound 1 and the first polymer are present in a weight ratio of 1:

3.

43. The tablet of claim 40, wherein the tablet further comprises at least one disintegrant.

44. The tablet of claim 43, wherein the disintegrant comprises cropovidone.

45. The tablet of claim 40, wherein the tablet further comprises at least one filler.

46. ​​The tablet of claim 45, wherein the filler comprises microcrystalline cellulose or mannitol.

47. The tablet of claim 40, wherein the tablet further comprises at least one lubricant or flow aid.

48. The tablet of claim 47, wherein the lubricant or flow aid comprises magnesium stearate or talc.

49. The tablet of claim 39, wherein the tablet further comprises an outer layer or film.

50. The tablet of claim 49, wherein the outer layer or film comprises at least one second polymer, wherein the second polymer comprises L 30D-55 and / or methacrylate-ethyl acrylate copolymer.

51. The tablet of claim 50, wherein the second polymer prevents the tablet from dissolving below pH 5.

5.

52. The tablet of claim 50, wherein the outer layer or film comprises 57% L 30D-55, 14.6% HTP20 and 28.4% water.

53. The tablet of claim 40, wherein the amorphous solid dispersion comprises 50% by weight of the tablet.

54. The tablet of claim 42, further comprising an outer layer of a second polymer, and wherein a tablet without said outer layer is 50% by weight of the amorphous solid dispersion, 10% by weight of cropovidone, 2% by weight of magnesium stearate, 19% by weight of microcrystalline cellulose, 18% by weight of mannitol and 1% by weight of talc, and wherein said second polymer comprises L 30D-55.

55. The tablet of claim 54, wherein the total mass of the tablet without the outer layer is 180 mg ± 9 mg.

56. The tablet of claim 54, wherein the total mass of the tablet without the outer layer is 1000 mg ± 50 mg.

57. A process for manufacturing a tablet having a pharmaceutical composition as described in any one of claims 39-56, the process comprising: (1) An amorphous solid dispersion of compound 1 is produced; (2) Granulate the amorphous solid dispersion of step (1) using the granulated raw material under dry conditions; (3) The particles from step (2) are blended with the off-particle raw materials to form a final mixture; (4) Compress the final mixture from step (3) into tablets; and (5) Coat the tablets from step (4) with a film or layer.

58. The process of claim 57, further comprising: (1) An amorphous solid dispersion of compound 1 was produced using spray-dried dispersion (SDD) technology; (2) The amorphous solid dispersion of step (1) is mixed with an intragranular raw material containing at least one disintegrant and at least one lubricant; (3) Dry granulation of the mixture from step (2), wherein the granulation process includes using a roller press to produce a compacted belt, wherein the compacted belt is then ground into granules. (4) The particles from step (3) are blended with a disintegrating off-particle raw material containing a disintegrant and a lubricant; (5) Compress the blend from step (4) into tablets; and (6) Coat the tablets from step (5) with a film or layer.

Images