Treatment

Abstract

Provided are methods for the parenteral use of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof, and methods for the sequential use of parenteral and oral formulations of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof.

Description

[Background technology]

[0001] Cardiovascular disease (CVD) is the leading cause of death at the global level. Among CVD, coronary artery disease (CAD) is the single most common cause of death, which accounts for one in four deaths in the United States. The main cause of CAD is atherosclerosis, an inflammatory disease characterized by localized thickening of the arterial intima, which contains lipids, connective tissue, and various cell types. The deposition of atherosclerotic plaques progressively narrows the lumen of the coronary artery, leading to clinical symptoms such as angina pectoris. Highly inflammatory and unstable plaques (vulnerable plaques) may eventually rupture, leading to potentially fatal events such as myocardial infarction (MI). In either case, the clinical event is triggered by impeding the delivery of oxygen to the myocardium through impaired or blocked coronary blood flow.

[0002] Although there have been considerable advances in medical therapies to prevent or treat CAD, because the disease is often detected at a late stage and difficult to reverse, a large proportion of patients remain symptomatic or develop complications, requiring invasive mechanical interventions such as PCI or coronary artery bypass grafting (CABG). Despite widespread implementation of primary PCI and improvements in “visit-to-balloon” times, the corresponding improvements in mortality have plateaued in recent years. Of note, a significant proportion of patients undergoing PCI, primarily to treat ACS, fail to achieve complete myocardial or microcirculatory reperfusion despite resolution of epicardial coronary artery occlusion. This is sometimes manifested angiographically as slow / no reflow, but microvascular occlusion (MVO) may have a deleterious effect on microcirculatory perfusion even in the case of normal epicardial flow, with approximately 40–60% of patients reported to have ST-segment elevation myocardial infarction (STEMI) after PCI.

[0003] MVO can be assessed immediately after PCI using several invasive techniques, including angiographic assessment of myocardial blush index (MBG) and assessment of coronary physiology based on parameters such as the index of microcirculatory resistance (IMR). Cardiac magnetic resonance (CMR) imaging, considered the "gold standard" for the diagnosis of MVO, can be performed in the days following PCI. Regardless of the method used, the presence of MVO is associated with worse clinical outcomes, including mortality and hospitalization for heart failure associated with suboptimal cardiac function and recovery in the days and months following the PCI procedure. Although several treatment options have been explored, including the use of vasodilators and antiplatelet agents, there is limited clinical efficacy data from these interventions and currently no treatments have been demonstrated to be beneficial in preventing or treating MVO in the setting of PCI. Thus, there is an unmet need for safe and effective agents that improve cardiac recovery and clinical outcomes after PCI through the prevention and treatment of MVO. Summary of the Invention

[0004] Described herein is the first clinical trial evaluating a 5-HT2A modulator on microvascular occlusion and the first clinical trial evaluating intravenous (IV) administration of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1).

[0005] The administration methods described herein provide new options for individuals undergoing PCI, including fixed sequence administration of Compound 1, which provides continuous therapeutic exposure during the PCI procedure and the subsequent recovery period.

[0006] Provided herein is a method of treating or preventing microvascular obstruction in an individual in need thereof, comprising parenterally administering to the individual a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0007] In some embodiments, the method further comprises orally administering to the individual a formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a second period of time, wherein the parenterally administered formulation is administered for the first period of time.

[0008] Also provided is a method for administering 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, to an individual in need thereof, comprising parenterally administering a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, to the individual for a first period of time; and subsequently orally administering a formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, to the individual for a second period of time.

[0009] Also provided is a method for preserving vascular integrity in an individual in need thereof, comprising parenterally administering to the individual 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate formulation thereof, for a first period of time; and subsequently orally administering to the individual Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate formulation thereof, for a second period of time.

[0010] Also provided is a method for preventing major adverse cardiovascular events (MACE) by preventing and / or treating microvascular occlusion (MVO) in an individual undergoing percutaneous coronary intervention (PCI), comprising parenterally administering to the individual a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a first period of time; and subsequently orally administering to the individual a formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a second period of time.

[0011] Also provided is a method for administering 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, to an individual in need thereof, comprising the steps of intravenously administering to the individual a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. and administering to the individual by injection a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0012] In some embodiments, the method further comprises orally administering to the individual a formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a second period of time, wherein the parenterally administered formulation is administered for the first period of time.

[0013] Also provided is a kit comprising a parenteral formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof; an oral formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof; and instructions indicating that the pharmaceutical agents are for sequential use to prevent microvascular occlusion (MVO), preserve vascular integrity, and / or prevent major adverse cardiovascular events (MACE) by preventing and / or treating microvascular occlusion (MVO) in an individual undergoing percutaneous coronary intervention (PCI).

[0014] Also provided is a pharmaceutical formulation for parenteral administration comprising a sterile solution comprising about 5 mg / mL to about 25 mg / mL (adjusted free base concentration) of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0015] Also provided is a method of safely administering 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, to an individual in need thereof, comprising the steps of: discontinuing administration of a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer, or a proton pump inhibitor to the individual; not co-administering a reduced dose of a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer, or a proton pump inhibitor to the individual; or administering a reduced dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, to the individual when co-administered with a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer, or a proton pump inhibitor; or administering a lower dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a lower dose of a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer, or a proton pump inhibitor to the individual.

[0016] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is a pharma- ceutically acceptable salt of Compound 1.

[0017] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an HCl salt of Compound 1.

[0018] These and other aspects of the present invention will become apparent upon reference to the following detailed description, and to this end, various references are provided herein which describe in more detail certain background information, procedures, compounds, and / or compositions, each of which is incorporated herein by reference in its entirety. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description As used herein, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0020] Compound 1: As used herein, "Compound 1" refers to 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide, including its crystalline forms. As a non-limiting example, Compound 1 may exist in the crystalline forms disclosed in U.S. Pat. No. 8,980,891, which is incorporated herein by reference in its entirety, and which have the following peaks in the PXRD spectrum using CuKα radiation: o The peaks may be characterized by one or more of the following 2θ values: 5.0998, 18.7064, 19.1157, 19.3029, and 23.6567, where the reported peaks may vary by about ±0.2 degrees 2θ.

[0021] Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, and its active metabolites (M1 and M2) have high affinity for human 5-HT2A and inhibit the 5-HT 2B and 5-HT 2C It has no measurable affinity for the receptor. M1 refers to N-(4-(2-(2-hydroxyethylamino)ethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide. M2 refers to N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide. Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, inhibits serotonin-mediated vasoconstriction and inhibits serotonin-mediated amplification of platelet aggregation.

[0022] Acute coronary syndrome: As used herein, "acute coronary syndrome" or "ACS" refers to three types of coronary artery disease associated with the sudden rupture of plaque inside the coronary artery, including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). The location of the blockage, the length of time blood flow is blocked, and the amount of damage caused determine the type of acute coronary syndrome. Myocardial infarction is the leading cause of death and disability worldwide. In the United States alone, ACS requires more than one million hospitalizations, of which more than half are acute myocardial infarction (AMI), including roughly two-thirds NSTEMI, and the remainder STEMI.

[0023] Percutaneous Coronary Intervention: As used herein, the term "percutaneous coronary intervention" or "PCI" means coronary angioplasty, which is a therapeutic procedure to treat stenosed (narrowed) coronary arteries of the heart found in coronary heart disease.

[0024] Global Registry of Acute Coronary Events Score: As used herein, the term "Global Registry of Acute Coronary Events (GRACE) score", "Global Registry of Acute Coronary Events score", "GRACE risk score", or "GRACE score" refers to a method of identifying individuals at high risk. Using the GRACE risk score, eight factors (age, heart rate, systolic blood pressure, renal function, congestive heart failure, ST-segment deviation, cardiac arrest, and elevated biomarkers) independently predict risk of heart attack and / or death.

[0025] Sequential therapy: As used herein, "sequential therapy" refers to the use of parenteral administration (e.g., intravenous injection) in the early stage of treatment, followed by oral administration after clinical symptoms are stabilized and improved. Intravenous infusion is used for the purpose of timely treatment of individuals who cannot administer orally, but it will inevitably result in corresponding adverse reactions, such as infusion reactions, vascular irritation, and phlebitis, causing pain to individuals. Sequential therapy can shorten the time of intravenous administration and reduce the incidence of infusion-related adverse reactions, thereby significantly shortening the hospitalization time of individuals, saving the expenses of individuals and medical institutions, saving limited economic resources, and reducing the associated social labor losses caused by the hospitalization of individuals.

[0026] Parenteral: As used herein, "parenteral" drug administration refers to any parenteral means of administration, but is generally understood to refer to direct injection into the body by passing through the skin and mucous membranes. Common parenteral routes are intramuscular (IM), subcutaneous (SC), and intravenous (IV).

[0027] Treat, Treating, or Treatment: As used herein, the terms "treat," "treating," or "treatment" refer to administering a therapy to an individual (i.e., a human) who has already developed at least one symptom of a disease or condition or who has previously developed at least one symptom of a disease or condition. For example, "treating" can include alleviating, relieving, or ameliorating a symptom of a disease or condition, preventing further symptoms, improving the underlying cause of a symptom, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition. For example, the term "treating" in reference to a disorder refers to a reduction in the severity of one or more symptoms associated with a particular disorder. Thus, treating a disorder does not necessarily mean a reduction in the severity of all symptoms associated with the disorder, nor does it necessarily mean a complete reduction in the severity of one or more symptoms associated with the disorder.

[0028] Prevent, preventive, or prophylaxis: As used herein, the terms "prevent", "preventing", or "prevention" refer to the prevention of the occurrence or onset of one or more symptoms associated with a particular disorder, and not necessarily the complete prevention of the disorder. For example, the terms "prevent", "preventing", and "prevention" refer to the administration of a prophylactic or preventive-based therapy to an individual who may eventually develop at least one symptom of a disease or condition, but has not yet done so. Such individuals may be identified from risk factors known to correlate with subsequent disease development. Alternatively, prophylactic therapy may be administered as a preventative measure, even if no risk factors are identified in advance. Delaying the onset of at least one symptom may also be considered a prophylactic or preventative method.

[0029] Dose: As used herein, "dose" refers to a measured amount of active agent that an individual should take at one time. In certain embodiments where the active agent is not the free base of Compound 1, the amount is the molar equivalent to the amount of the corresponding free base of Compound 1. For example, drugs are often packaged in the form of a pharma- ceutically acceptable salt, such as the HCl salt of Compound 1, and dosage amounts for potency refer to the mass of the molar equivalent of the corresponding free base of Compound 1.

[0030] Tolerate: As used herein, if administration of a dose to an individual does not result in unacceptable adverse events or a combination of unacceptable adverse events, the individual is said to "tolerate" that dose of a compound.Those skilled in the art will recognize that tolerability is a subjective measure, and what may be tolerable to one individual may not be tolerable to a different individual.For example, one individual may not be able to tolerate headache, whereas a second individual may find that headache is tolerable but nausea is intolerable, whereas a third individual may tolerate either headache alone or nausea alone, but the individual cannot tolerate the combination of headache and nausea (even if the severity of each is less than when experienced alone).

[0031] Adverse Event: As used herein, an "adverse event" is an untoward medical occurrence associated with treatment with Compound 1, or a pharma-ceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the adverse event is selected from dizziness, headache, and nausea.

[0032] When the phrase "pharmaceutically acceptable salts, solvates, and hydrates" or "pharmaceutically acceptable salts, solvates, or hydrates" is used in reference to Compound 1, it is understood to include pharmaceutically acceptable solvates and / or hydrates of Compound 1, pharmaceutically acceptable salts of Compound 1, and pharmaceutically acceptable solvates and / or hydrates of pharmaceutically acceptable salts of Compound 1. When the phrase "pharmaceutically acceptable solvates and hydrates" or "pharmaceutically acceptable solvates or hydrates" is used in reference to Compound 1, which is a salt, it is also understood to include pharmaceutically acceptable solvates and / or hydrates of such salts.

[0033] It will be clear to those skilled in the art that the dosage forms described herein may contain as active ingredient either Compound 1 or a pharma- ceutically acceptable salt, or as solvates or hydrates thereof. Furthermore, various hydrates and solvates of Compound 1 and its salts may find use as intermediates in the preparation of pharmaceutical compositions. The typical procedures for making and identifying suitable hydrates and solvates are well known to those skilled in the art other than those described herein. For example, see pages 202-209 of KJ Guillory, "Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids," in Polymorphism in Pharmaceutical Solids, edited by Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999. Accordingly, one aspect of the present disclosure relates to methods of formulating and / or administering Compound 1 and / or hydrates and solvates of its pharma- ceutically acceptable salts, which can be isolated and characterized by methods known in the art, such as thermogravimetric analysis (TGA), TGA-mass spectrometry, TGA-infrared spectroscopy, X-ray powder diffraction (XRPD), Karl Fischer titration, high-resolution X-ray diffraction, and the like.

[0034] As used herein, the term "greater than" is used interchangeably with the symbol >, and the term less than is used interchangeably with the symbol <. Similarly, the term greater than or equal to is interchangeable with the symbol ≧, and the term less than or equal to is interchangeable with the symbol ≦.

[0035] When integers are used in the methods disclosed herein, the term "about" can be inserted before the integer.

[0036] Throughout this specification, unless the context otherwise requires, the word "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not to the exclusion of any other step or element or integer or group of elements or integers.

[0037] Throughout this specification, unless otherwise indicated or the context otherwise requires, a reference to a single step, composition, group of steps, or group of compositions shall be interpreted as encompassing one and more (i.e., one or more) of that step, composition, group of steps, or group of compositions.

[0038] Each embodiment described in this specification is intended to apply mutatis mutandis to each and every other embodiment unless otherwise stated.

[0039] Those skilled in the art will recognize that the invention(s) described herein can accept variations and modifications other than those specifically described. It is to be understood that the invention(s) include all such variations and modifications. The invention(s) also includes all steps, features, compositions, and compounds referred to or shown in this specification, individually or collectively, unless otherwise specified, and includes any and all combinations of said steps or features or any two or more.

[0040] The invention(s) is not limited in scope by the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods are within the scope(s) of the invention as expressly described herein. For example, a dosage of Compound 1 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof disclosed herein may have an AUC and / or C of 80-125% as measured by the methods disclosed in FDA's Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), March 2003, Rev. 1, www.fda.gov / cder / guidance / index.htm. max The dosage amounts of Compound 1 disclosed herein may be replaced with dosage amounts of other salts or crystal forms, formulations, and dosing regimens that are bioequivalent to the dosage amounts of Compound 1 or pharma- ceutically acceptable salts, solvates, or hydrates thereof, including forms having the formula: For example, the dosage amounts of Compound 1 disclosed herein may be replaced with dosage amounts of other salts or crystal forms, formulations, or dosing regimens that are bioequivalent to the dosage amounts of Compound 1.

[0041] It is recognized that certain features of the invention(s) described for clarity in the context of separate embodiments can also be provided in combination in a single embodiment. For example, a method describing formulating Compound 1 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, and another method of the invention describing administering Compound 1 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof, can be combined into a single method describing formulating and administering Compound 1 or a pharma- ceutically acceptable salt, solvate, or hydrate thereof.

[0042] How to use Provided is a method for administering 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, to an individual in need thereof, comprising: parenterally administering to the individual a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a first period of time; and then orally administering to the individual a formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a second period of time. The method includes:

[0043] Also provided is a method for preventing microvascular obstruction in an individual in need thereof, comprising: parenterally administering to the individual a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a first period of time; and then orally administering to the individual a formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a second period of time. The method includes:

[0044] Also provided is a method for preserving vascular integrity in an individual in need thereof, comprising: parenterally administering to the individual a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a first period of time; and then orally administering to the individual a formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a second period of time. The method includes:

[0045] Also provided is a method for preventing major adverse cardiovascular events (MACE) by preventing and / or treating microvascular occlusion (MVO) in an individual with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), comprising: parenterally administering to the individual a formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a first period of time; and then orally administering to the individual a formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for a second period of time. The method includes:

[0046] In some embodiments, an individual's response to a parenteral formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is used to determine the dosing of an oral formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, a parenteral formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered to the individual, and if a measure of efficacy is observed, an oral formulation of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered to the individual. In some embodiments, the measure of efficacy is serotonin levels. In some embodiments, the measure of efficacy is troponin levels.

[0047] In some embodiments, the individual is undergoing PCI for ACS.

[0048] In some embodiments, the ACS is non-ST elevation myocardial infarction (NSTEMI).

[0049] In some embodiments, the individual has ACS.

[0050] In some embodiments, the individual has stable angina.

[0051] In some embodiments, the individual has unstable angina.

[0052] In some embodiments, the individual presents with STEMI.

[0053] In some embodiments, the individual presents with NSTEMI.

[0054] In some embodiments, the individual presents with a high risk of NSTEMI.

[0055] In some embodiments, the individual has a high-risk GRACE score. In some embodiments, the individual has a GRACE score greater than 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150. In some embodiments, the individual has a GRACE score greater than 140.

[0056] In some embodiments, the individual has an elevated risk of developing MACE. In some embodiments, MACE is selected from non-fatal myocardial infarction, coronary intervention, and cardiac death. In some embodiments, MACE is selected from cardiac death, myocardial reinfarction, myocardial revascularization from clinical findings, and hospitalization with a discharge diagnosis of heart failure or coronary artery disease.

[0057] In some embodiments, the individual has an elevated risk of developing MVO.

[0058] In some embodiments, the individual has an elevated risk of mortality six months post-PCI.

[0059] In some embodiments, the individual is undergoing PCI. In some embodiments, the individual is undergoing PCI for stable angina.

[0060] In some embodiments, the individual is undergoing PCI for unstable angina.

[0061] In some embodiments, the individual is undergoing PCI for a STEMI.

[0062] In some embodiments, the individual is undergoing PCI for NSTEMI.

[0063] In some embodiments, the individual is undergoing PCI for high-risk NSTEMI.

[0064] In some embodiments, the individual is undergoing primary PCI.

[0065] In some embodiments, the individual is undergoing elective PCI.

[0066] In some embodiments, the individual has received a saphenous vein graft.

[0067] In some embodiments, the individual is undergoing a stent procedure.

[0068] In some embodiments, the individual is undergoing a coronary stent procedure.

[0069] In some embodiments, the individual has undergone angioplasty with a stent.

[0070] In some embodiments, the individual has coronary artery disease (CAD).

[0071] In some embodiments, the individual has complex coronary artery disease.

[0072] In some embodiments, the individual has an acute coronary syndrome.

[0073] In some embodiments, the individual has non-obstructive coronary artery disease (NOCA).

[0074] In some embodiments, the individual has angina and NOCA.

[0075] In some embodiments, the individual has non-obstructive coronary artery disease (NCAD).

[0076] In some embodiments, the individual has acute coronary syndrome with non-obstructed coronary arteries (ACS-NOCA).

[0077] In some embodiments, the individual has troponin positive non-obstructed coronary arteries (TP-NOCA).

[0078] In some embodiments, the individual has myocardial infarction with non-occluded coronary arteries (MINOCA).

[0079] In some embodiments, the individual has peripheral arterial disease (PAD).

[0080] In some embodiments, the individual has saphenous vein thrombosis.

[0081] In some embodiments, the individual has great saphenous vein thrombosis.

[0082] In some embodiments, the individual is undergoing a stent graft procedure.

[0083] In some embodiments, the microvascular occlusion is a saphenous vein graft (SVG) occlusion.

[0084] In some embodiments, the individual is undergoing an interventional procedure for coronary artery disease.

[0085] In some embodiments, the individual is undergoing an interventional procedure for peripheral arterial disease.

[0086] In some embodiments, the methods provided herein prevent or reduce platelet aggregation following PCI.

[0087] In some embodiments, the methods provided herein are useful for preventing or treating vasoconstriction following PCI.

[0088] In some embodiments, the methods provided herein are useful for preventing or treating microvascular occlusion of coronary arteries following PCI.

[0089] In some embodiments, the methods provided herein are useful for preventing or treating MVO.

[0090] In some embodiments, the methods provided herein are useful for preventing or treating MVO in the setting of PCI.

[0091] In some embodiments, the methods provided herein are useful for preventing or treating MVO in the setting of PCI for ACS.

[0092] In some embodiments, the methods provided herein are useful for reducing the incidence of MVO about 2-30 days after PCI.

[0093] In some embodiments, the methods provided herein are useful for preventing or treating myocardial damage following PCI.

[0094] In some embodiments, the methods provided herein are useful for improving cardiac function after PCI.

[0095] In some embodiments, the methods provided herein are useful for cardiac recovery after PCI.

[0096] In some embodiments, the methods provided herein are useful for improving LV functional parameters. In some embodiments, the methods provided herein are useful for improving LV ejection fraction (LVEF). In some embodiments, the methods provided herein are useful for improving LV end diastolic volume (LVEDV). In some embodiments, the methods provided herein are useful for improving LV end systolic volume (LVESV).

[0097] In some embodiments, the methods provided herein are useful for improving cardiac recovery after PCI.

[0098] In some embodiments, the methods provided herein are useful for improving clinical outcomes following PCI.

[0099] In some embodiments, the methods provided herein are useful for improving myocardial perfusion following PCI.

[0100] In some embodiments, the methods provided herein are useful for preventing or treating damaged vasculature following PCI.

[0101] In some embodiments, the methods provided herein are useful for reducing the adverse effects of microcirculation as the endothelium heals after PCI.

[0102] In some embodiments, the methods described herein are useful for reducing the incidence of MACE. In some embodiments, MACE is a composite of cardiac death, myocardial reinfarction, clinically-based myocardial revascularization, and hospitalization with a discharge diagnosis of heart failure or coronary artery disease during the 90 days (or 3 months) after PCI. In some embodiments, the methods described herein are useful for preventing or reducing the risk of myocardial infarction, heart failure, and / or death.

[0103] In some embodiments, the ACS is ST-segment elevation myocardial infarction (STEMI).

[0104] In some embodiments, the parenteral formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered immediately before PCI. In some embodiments, the parenteral formulation is administered within 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes or within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes of PCI. In some embodiments, the parenteral formulation of Compound 1, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof, is administered during PCI.

[0105] In some embodiments, the parenteral formulation is administered by injection.

[0106] In some embodiments, parenteral administration includes injection and infusion administration.

[0107] In some embodiments, oral administration includes an oral loading dose and an oral maintenance dose.

[0108] In some embodiments, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered by injection.

[0109] In some embodiments, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered by infusion.

[0110] In some embodiments, the parenteral formulation is administered over about 5 minutes or less, 4 minutes or less, 3 minutes or less, 2 minutes or less, or 1 minute or less.

[0111] In some embodiments, about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, or 160 mg of Compound 1 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof is administered to an individual via an oral formulation.

[0112] In some embodiments, the parenteral formulation is administered once.

[0113] In some embodiments, the first period of time is 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minutes, or about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minutes, or less than about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minutes. In some embodiments, the first period of time is about 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or less than about 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or less than 10 minutes. In some embodiments, the first period of time is about 5 minutes, or less than about 5 minutes.

[0114] In some embodiments, about 20 mg of the parenteral formulation is administered over about 2 minutes, or at least about 2 minutes. In some embodiments, about 30 mg of the parenteral formulation is administered over about 5 minutes, or at least about 5 minutes. In some embodiments, about 40 mg of the parenteral formulation is administered over about 5 minutes, or at least about 5 minutes. In some embodiments, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 mg or less of the parenteral formulation is administered per minute.

[0115] In some embodiments, the parenteral formulation is administered as a single dose. In some embodiments, the parenteral formulation is administered as a bolus. In some embodiments, the parenteral formulation is administered as a single bolus. In some embodiments, the parenteral formulation is administered as a single IV bolus. In some embodiments, the parenteral formulation is administered with an infusion pump. In some embodiments, the parenteral formulation is administered as an IV injection. In some embodiments, the parenteral formulation is administered as a single IV injection. In some embodiments, a combination of parenteral formulations is administered to maintain a target plasma concentration, such as a target Cmin. For example, in some embodiments, the parenteral formulation is administered as a bolus followed by an infusion. In some embodiments, the parenteral formulation is administered as an IV bolus followed by an IV infusion. In some embodiments, the parenteral formulation is administered as an infusion followed by a bolus. In some embodiments, the parenteral formulation is administered as an IV infusion followed by an IV bolus. In some embodiments, the parenteral formulation is administered after a loading dose. In some embodiments, the parenteral formulation(s) is administered after an oral loading dose. In some embodiments, the oral loading dose is followed by an oral maintenance dose.

[0116] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered as an IV bolus, followed by an IV infusion, followed by an oral dosage form. In some embodiments, the IV infusion is initiated 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, or 6 hours after administration of the IV bolus. In some embodiments, the oral dosage form is administered at or about 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, or 8 hours after administration of the IV bolus. In some embodiments, the oral dosage form is administered 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, or more away from administration of an IV infusion. or 8 hours later, or about 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, or 8 hours later. In some embodiments, an IV bolus is administered, followed by an IV infusion about 1 hour after the start of the IV bolus, followed by an oral administration about 5 hours after the start of the IV bolus.

[0117] In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered as an IV infusion, then as an IV bolus, then as an oral dosage form. In some embodiments, compound 1, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof, is administered as an IV infusion, then as an IV bolus, then as an oral loading dose, then as an oral maintenance dose. In some embodiments, compound 1, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof, is administered as an IV infusion, then as an oral loading dose, then as an oral maintenance dose. In some embodiments, compound 1, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof, is administered as an IV bolus, then as an oral loading dose, then as an oral maintenance dose.

[0118] In some embodiments, the parenteral formulation is administered over about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 minutes or less. In some embodiments, the parenteral formulation is administered over about 5 minutes or less. In some embodiments, the parenteral formulation is administered as a bolus at a rate not exceeding 3, 2.75, 2.5, 2.25, or 2 mL of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, per minute.

[0119] In some embodiments, the oral formulation of compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered after PCI. In some embodiments, the first oral formulation of compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered on the day of the PCI procedure. In some embodiments, the first oral formulation of compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours after the PCI procedure. In some embodiments, the first oral formulation of compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered about 4 hours after the PCI procedure. In some embodiments, the first oral formulation of compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours after the administration of the parenteral dose. In some embodiments, the first oral formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered about 4 hours after administration of the parenteral dose. In some embodiments, the first oral formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered the day after the PCI procedure. In some embodiments, the first oral formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered within one week of the PCI procedure.

[0120] In some embodiments, the target plasma concentration after administration of the parenteral formulation is 5-200 ng / mL, or about 5-200 ng / mL. In some embodiments, the target plasma concentration after administration of the parenteral formulation is 60-100 ng / mL, or about 60-100 ng / mL. In some embodiments, the target plasma concentration after administration of the parenteral formulation is 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or more. or 200 ng / mL, or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, or 200 ng / mL. In some embodiments, the target plasma concentration is Cmin. In some embodiments, the target plasma concentration is a measure of Compound 1 and its metabolites. In some embodiments, the target plasma concentration is a measure of Compound 1, M1, and M2.

[0121] In some embodiments, the oral formulation is administered once daily (QD). In some embodiments, the oral formulation is administered twice daily (BID). In some embodiments, the oral formulation is administered three times daily (TID).

[0122] In some embodiments, the second period of time is at least, or at least about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some embodiments, the second period of time is at least 1 week.

[0123] In some embodiments, the second period of time is at least 1 month (or 30 days). In some embodiments, the second period of time is at least 3 months (or 90 days). In some embodiments, the second period of time is at least 6 months (or 180 days). In some embodiments, the second period of time is at least 1 year.

[0124] In some embodiments, the incidence of MVO is measured using cardiac magnetic resonance (CMR) imaging.

[0125] In some embodiments, the incidence of MVO is measured using angiographic assessment of myocardial glow index (MBG).

[0126] In some embodiments, the incidence of MVO is measured using an assessment of coronary artery physiology based on the index of microcirculatory resistance (IMR).

[0127] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is a pharma- ceutically acceptable salt of Compound 1, or a hydrate or solvate thereof.

[0128] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is a pharma- ceutically acceptable salt of Compound 1.

[0129] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an HCl salt of Compound 1. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is a hydrate of Compound 1. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is a solvate of Compound 1.

[0130] Parenteral Administration Parenteral dosage forms can be prepared by dissolving compound in suitable liquid vehicle, sterilizing this solution by filtration, then filling and sealing suitable vials or ampoules.These are only a few examples of many suitable methods known in the art for preparing dosage forms.Suitable pharmaceutically acceptable carriers are known in the art other than those described herein.For example, see Remington, The Science and Practice of Pharmacy, 20th edition, 2000, Lippincott Williams&Wilkins (editors: Gennaro et al.).

[0131] Thus, also provided is a pharmaceutical formulation for parenteral administration comprising a sterile solution. In some embodiments, the solution is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / mL or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / mL. , 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / mL (adjusted free base concentration) of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the solution comprises 4 mg / mL, or about 4 mg / mL (adjusted free base concentration) of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the solution comprises 8 mg / mL or about 8 mg / mL (adjusted free base concentration) of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the solution comprises 25 mg / mL or about 25 mg / mL (adjusted free base concentration) of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the solution is diluted prior to administration. In some embodiments, the solution is diluted with saline prior to administration.In some embodiments, the solution when administered is at or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / mL. , 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / mL (adjusted free base concentration) of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the solution as administered contains less than, or less than about, 25 mg / mL (adjusted free base concentration) of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the solution when administered contains less than or about 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 mg / mL of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof (adjusted free base concentration).

[0132] The formulation typically includes a buffer. Suitable buffers that can be used in the compositions of the present invention include, for example, histidine buffer, acetate buffer, citrate buffer, tartrate buffer, lactate buffer, succinate buffer, and phosphate buffer. The pH of the buffer will typically be between about 2 and about 10, for example, about pH 2, 3, 4, 5, 6, 7, 8, 9, or 10. The pH of the buffer will preferably be about 4 to about 8. In some embodiments, the pH of the solution is buffered to a pH of 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5, or about 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, or 4.5. In some embodiments, the pH of the solution is buffered to a pH of 3-4, or about 3-4. In some embodiments, the pH of the solution is buffered to a pH of 3.5, or about 3.5. In some embodiments, a citrate buffer is used, such as a 10 mM citrate buffer. In some embodiments, an acetate buffer is used. In some embodiments, the aqueous buffer is present in the formulation at a concentration of 0.5-5 mg / mL or about 0.5-5 mg / mL per compound with an adjusted free base concentration of 25 mg / mL. In some embodiments, the aqueous buffer is present in the formulation at a concentration of, or about, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5 mg / mL per compound at an adjusted free base concentration of 25 mg / mL.

[0133] In some embodiments, the pharmaceutical formulation for parenteral administration comprises: Aqueous 10 mM citrate buffer; 3-Methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, at a concentration of 25 mg / mL (adjusted free base concentration); and isotonicity adjusting agent Includes.

[0134] In some embodiments, the tonicity adjusting agent is an ionic or non-ionic tonicity adjusting agent, such as glycerin, sugars (including glucose, mannitol, sorbitol, trehalose, dextrose, lactose, etc.), sodium chloride, or sodium sulfate. In some embodiments, the tonicity adjusting agent comprises dextrose. In some embodiments, the tonicity adjusting agent comprises saline.

[0135] In some embodiments, the isotonicity adjusting agent is present in the formulation in an amount of about 0.1% to about 30% by weight of the composition, for example, about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2.5%, 5%, 10%, 15%, 20%, 25%, or 30% by weight of the formulation. The formulation may be hypotonic, isotonic, or hypertonic, and typically has an osmolality of about 200 to about 350 mOsmol / kg. For example, the composition may have an osmolality of, or about, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, or 350 mOsmol / kg. In some embodiments, the composition has an osmolality of, or about, 300 mOsmol / kg. One skilled in the art will understand that the amount of tonicity adjusting agent used may vary depending on the particular selection of tonicity adjusting agent and other components in the composition. In some embodiments, the isotonicity adjusting agent is at a concentration of, or about, 200, 225, 250, 275, 200, 325, or 350 mM. In some embodiments, the isotonicity adjusting agent is at a concentration of, or about, 289 mM. In some embodiments, the parenteral formulation is isotonic. In some embodiments, the isotonicity adjusting agent is present in the formulation at a concentration of, or about, 10-50 mg / mL per compound at an adjusted free base concentration of 25 mg / mL. In some embodiments, the isotonicity adjusting agent is present in the formulation at a concentration of at or about 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg / mL per compound at an adjusted free base concentration of 25 mg / mL.

[0136] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered parenterally in an amount equivalent to between about 10 mg and about 100 mg of Compound 1 free base.

[0137] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered parenterally in an amount equivalent to between about 10 mg and about 75 mg of Compound 1 free base.

[0138] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered parenterally in an amount equivalent to between about 10 mg and about 40 mg of Compound 1 free base.

[0139] In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 10 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 15 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 20 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 25 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 30 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 35 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 40 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 45 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 50 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 55 mg of compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 60 mg of Compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 65 mg of Compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 70 mg of Compound 1 free base.In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 75 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 80 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 85 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 90 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is parenterally administered in an amount equivalent to about 95 mg of compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered parenterally in an amount equivalent to about 100 mg of Compound 1 free base.

[0140] In some embodiments, the total daily dose of parenterally administered Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is 10-100 mg, or about 10-100 mg. In some embodiments, the total daily dose of parenterally administered Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg.

[0141] In some embodiments, the total daily dose of parenterally and orally administered Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is at or about 200-500 mg. In some embodiments, the total daily dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, administered parenterally and orally, is at or about 200, 220, 225, 240, 250, 260, 275, 280, 300, 320, 325, 340, 350, 360, 375, 380, 400, 420, 425, 440, 450, 460, 475, 480, or 500 mg.

[0142] In some embodiments, about 10-20 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered by IV; about 40 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered by infusion; or about 100-150 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered orally TID. In some embodiments, about 10-20 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered by IV; about 40 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered by infusion; about 200 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered as an oral loading dose; and about 100-150 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered orally TID as a maintenance dose.

[0143] Oral route In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered orally.

[0144] Thus, the compounds provided herein can be in the form of pharmaceutical formulations and unit dosages thereof together with conventional adjuvants, carriers, or diluents, and such forms can be used as solids, such as tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, gels, or capsules filled therewith (all for oral use). Such pharmaceutical compositions and unit dosage forms thereof can contain conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms can contain any suitable effective amount of active ingredient consistent with the intended daily dosage range to be used. In some embodiments, the capsule is a gelatin capsule. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the oral formulation is a powder in a capsule.

[0145] For oral administration, pharmaceutical composition can be in the form of tablet, capsule, suspension or liquid.Pharmaceutical composition is prepared in the form of dosage unit containing specific amount of active ingredient.The example of such dosage unit is capsule, tablet, powder, granule or suspension, which has conventional additives such as lactose, mannitol, cornstarch or potato starch; binder such as crystalline cellulose, cellulose derivative, gum arabic, cornstarch or gelatin; disintegrant such as cornstarch, potato starch or sodium carboxymethylcellulose; and lubricant such as talc or magnesium stearate.

[0146] In some embodiments, the oral formulation of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an immediate release dosage form comprising Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0147] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is formulated as a capsule suitable for oral administration. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is formulated as a tablet suitable for oral administration.

[0148] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to between about 10 mg and about 250 mg of Compound 1 free base.

[0149] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to between about 20 mg and about 250 mg of Compound 1 free base.

[0150] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to between about 10 mg and about 200 mg of Compound 1 free base.

[0151] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to between about 10 mg and about 80 mg of Compound 1 free base.

[0152] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to between about 10 mg and about 60 mg of Compound 1 free base.

[0153] In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 10 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 15 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 20 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 25 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 30 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 40 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 50 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 60 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 70 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 75 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 80 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 90 mg of compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 100 mg of Compound 1 free base.In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 110 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 120 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 130 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 140 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 150 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 160 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 170 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 180 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 190 mg of compound 1 free base. In some embodiments, compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 200 mg of compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 210 mg of Compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 220 mg of Compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 230 mg of Compound 1 free base.In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 240 mg of Compound 1 free base. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered in an amount equivalent to about 250 mg of Compound 1 free base.

[0154] In some embodiments, an oral loading dose of 75, 80, 85, 90, 95, 100, 105, 110, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg or about 75, 80, 85, 90, 95, 100, 105, 110, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, or 250 mg is administered. 0, 95, 100, 105, 110, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 2356, 240, 245, or 250 mg of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered to the individual.

[0155] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered once daily (QD). In some embodiments, the QD dose is a maintenance dose.

[0156] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered twice daily (BID). In some embodiments, the BID dose is a maintenance dose.

[0157] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered three times a day (TID). In some embodiments, the TID dose is a maintenance dose.

[0158] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is administered orally TID in an amount equivalent to between about 10 mg and about 80 mg of Compound 1 free base (for a total of between about 30 mg and about 240 mg of Compound 1 free base daily).

[0159] In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered TID in an amount equivalent to between about 10 mg and about 60 mg of Compound 1 free base (for a total of between about 30 mg and about 180 mg of Compound 1 free base daily).

[0160] In some embodiments, the oral formulation is administered orally for at least, or for at least about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0161] In some embodiments, an oral maintenance dose of 75, 80, 85, 90, 95, 100, 105, 110, 120, 125, 130, 135, 140, 145, or 150 mg or about 75, 80, 85, 90, 95, 100, 105, 110, 120, 125, 130, 135, 140, 145, or 150 mg of compound 1, or its pharma- ceutically acceptable salt, hydrate, or solvate, is administered to an individual.In some embodiments, the oral maintenance dose is administered TID.

[0162] In some embodiments, the total daily dose of orally administered Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is at or about 100-400 mg. In some embodiments, the total daily dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, administered orally is at or about 100, 120, 125, 140, 150, 160, 175, 180, 200, 220, 225, 240, 250, 260, 275, 280, 300, 320, 325, 340, 350, 360, 375, 380, or 400 mg.

[0163] Coadministration In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is co-administered with at least one antiplatelet agent. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is co-administered with dual antiplatelet therapy (DAPT). In some embodiments, the individual has already been administered at least one antiplatelet agent prior to administration of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, as described herein. In some embodiments, the individual is administered a loading dose of at least one antiplatelet agent prior to PCI. In some embodiments, the individual is administered a loading dose of at least one antiplatelet agent prior to PCI. In some embodiments, Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is co-administered with aspirin and an oral P2Y12 inhibitor. In some embodiments, the antiplatelet agent is aspirin. In some embodiments, the antiplatelet agent is a P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor is an oral P2Y12 inhibitor. In some embodiments, the P2Y12 inhibitor is selected from clopidogrel, ticlopidine, ticagrelor, prasugrel, and cangrelor. In some embodiments, the DAPT comprises aspirin. In some embodiments, the DAPT comprises clopidogrel. In some embodiments, the DAPT is aspirin and clopidogrel. In some embodiments, compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is co-administered with clopidogrel, but not with prasugrel or ticagrelor. In some embodiments, compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is co-administered with heparin.

[0164] In some embodiments, the individual is not co-administered with Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer. In some embodiments, the individual is already administered at least one CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer prior to administration of Compound 1, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof, as described herein. In some embodiments, administration of the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is discontinued when the individual is administered Compound 1, or a pharma-ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the individual is co-administered with a lower dose of a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer when co-administered with Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the individual is co-administered with a lower dose of a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer when co-administered with Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the individual is co-administered with a lower dose of a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer and a lower dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. In some embodiments, the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is a strong CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer. In some embodiments, the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is selected from ketoconazole, itraconazole, clarithromycin, erythromycin, rifampicin, and verapamil. In some embodiments, the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is a CYP3A4 inhibitor or inducer.In some embodiments, the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is a CYP3A5 inhibitor or inducer. In some embodiments, the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is a P-glycoprotein inhibitor or inducer. In some embodiments, the individual is co-administered intra-arterial verapamil for radial artery PCI.

[0165] Listings of inhibitors, inducers, and substrates can be found, for example, at https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers, and other sites.

[0166] In some embodiments, the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is a CYP3A4 / 5 inhibitor. In some embodiments, the CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer is itraconazole, fluconazole, and / or rifampin.

[0167] In some embodiments, the reduced or smaller dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25% of the normal daily dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, or is about 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, or 25%.

[0168] In some embodiments, the CYP3A4 / 5 inhibitor is itraconazole, ketoconazole, azamulin, troleandomycin, or verapamil. In some embodiments, the CYP3A4 / 5 inducer is rifampicin. In some embodiments, the CYP3A4 / 5 substrate is midazolam or triazolam. In some embodiments, the strong inhibitor of CYP3A4 is boceprevir, cobicistat, danoprevir, ritonavir, elvitegravir, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, paritaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir, telaprevir, tipranavir, telithromycin, troleandomycin, and / or voriconazole. In some embodiments, the strong inhibitor of CYP3A4 is clarithromycin, idelalisib, nefazodone, or nelfinavir. In some embodiments, the mild inhibitor of CYP3A4 is aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, or verapamil. In some embodiments, the weak inhibitor of CYP3A4 is chlorzoxazone, cilostazol, cimetidine, clotrimazole, fosaprepitant, istradefylline, ivacaftor, lomitapide, ranitidine, ranolazine, or ticagrelor. In some embodiments, the CYP3A4 / 5 inhibitor is ketoconazole. In some embodiments, the CYP3A4 / 5 inhibitor is itraconazole. In some embodiments, the CYP3A4 / 5 inhibitor is fluconazole.

[0169] In some embodiments, the P-glycoprotein substrate is digoxin, fexofenadine, loperamide, quinidine, talinolol, or vinblastine. In some embodiments, the P-glycoprotein inhibitor is cyclosporine, elacidar (GF120918), ketoconazole, quinidine, reserpine, ritonavir, tacrolimus, valspodar (PSC833), verapamil, or zosuquidar (LY335979). In some embodiments, the P-glycoprotein substrate is dabigatran etexilate, digoxin, or fexofenadine. In some embodiments, the P-glycoprotein inhibitor is amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir, ritonavir, propafenone, quinidine, ranolazine, saquinavir, telaprevir, tipranavir, and / or verapamil. In some embodiments, the P-glycoprotein inhibitor is itraconazole. In some embodiments, the proton pump inhibitor is esomeprazole, ilaprazole, lansoprazole, omeprazole, pantoprazole, pantoprazole sodium, pantoprazole magnesium, rabeprazole, or dexlansoprazole. In some embodiments, the proton pump inhibitor is esomeprazole.

[0170] Some embodiments include a method of making a pharmaceutical composition for fixed dose combination therapy comprising mixing at least one compound according to any of the compound embodiments disclosed herein with at least one known pharmaceutical agent and a pharma- ceutical acceptable carrier as described herein.

[0171] Further embodiments include those disclosed in the examples below, which should not be construed as limiting in any way. EXAMPLES

[0172] Example 1 - Clinical Trial 1 A phase 1, randomized, double-blind, placebo-controlled, single-ascending dose study was conducted to evaluate the tolerability, PK, and PD of the HCl salt of compound 1 at doses ranging from 1 to 320 mg (adjusted free base concentration) administered orally as a single dose to a total of 91 healthy subjects.

[0173] Compound 1 was rapidly absorbed at all doses, and measures of plasma exposure increased more than proportionally with dose. The active metabolites M1 and M2 had longer half-lives than the parent compound, and as dose escalation increased, the half-life of Compound 1 increased, exposure increased, and the ratio of metabolite to parent decreased.

[0174] PD assessment consisted of measuring platelet aggregation before and after dosing using an in vitro assay with ADP with and without 5-HT. The degree of inhibition of platelet aggregation induced by thrombin receptor activating peptide (TRAP) was similar between groups. However, Compound 1 inhibited the amplification of 5-HT-mediated platelet aggregation at doses above 1 mg.

[0175] Data on 5-HT-mediated platelet aggregation from doses of the HCl salt of Compound 1 ranging from 5 to 320 mg (adjusted free base concentrations) showed maximal inhibition at 1 to 2 hours and suggested a trend for longer duration of inhibition at higher doses, although the degree of variability complicates interpretation.

[0176] Example 2 - Clinical Trial 2 A phase 1, randomized, double-blind, placebo-controlled, multiple-ascending dose study was conducted to evaluate the safety, tolerability, PD, and steady-state PK of 5 to 80 mg (adjusted free base concentration) of the HCl salt of compound 1 administered orally TID for 7 days in a total of 50 healthy subjects.

[0177] Compound 1 was rapidly absorbed at all doses, with equivalent AUC and Cmax values ​​on day 1 similar to those in the study in Example 1. On days 1 and 7, exposure as measured by AUC was dose-proportional at 5 and 10 mg, but greater than dose-proportional at 40, 60, and 80 mg. When comparing days 1 and 7, Cmax and AUC accumulation ratio values ​​were less than 2 at all doses, indicating no accumulation after 7 days of TID administration. Half-lives were similar at all doses and days.

[0178] Exposure to the active metabolites M1 and M2 increased and the metabolite to parent ratio decreased as the dose of Compound 1 increased. The accumulation ratios, as measured by AUCtau values, were approximately 2 for M1 and M2 at 60 and 80 mg, suggesting a two-fold accumulation of these metabolites following dosing TID for 7 days.

[0179] Administration of the HCl salt of Compound 1 inhibited 5-HT-mediated amplification of platelet aggregation ex vivo, with inhibition being substantially maximal after days 1, 4, and 7 of dosing at both the 60 mg and 80 mg doses.

[0180] Example 3 - Parenteral Formulation An example of a parenteral formulation of Compound 1 is shown in Table 1:

[0181] [Table 1]

[0182] Example 4 - Oral Formulation An example of an oral formulation of Compound 1 is shown in Table 2:

[0183] [Table 2]

[0184] Example 5 - Clinical Trial 3 A Phase 1, randomized, blinded, sponsor-open, placebo-controlled, single ascending dose (SAD) study was conducted to evaluate the safety, tolerability, PK, and PD of a single IV dose of Compound 1 and two active metabolites (M1 and M2) in healthy adult subjects. Five dose cohorts (each cohort consisted of six Compound 1 subjects and two placebo subjects) were evaluated.

[0185] Subjects received a single dose of Compound 1 or placebo. Each cohort included a sentinel group with two subjects (one active, one placebo) who were dosed at least 24 hours before the remaining six subjects (five active, one placebo). The remaining subjects were dosed after review of all available safety and tolerability data from the sentinel subjects. Safety, tolerability, and PK data were reviewed after completion of each dose cohort and before escalation to the next dose cohort. PD data were reviewed before dosing in subsequent cohorts. Dose selection for subsequent cohorts was based on data from the previous cohort(s). Following administration of Compound 1 or placebo, subjects were held for 72 hours to monitor safety and to collect PK / PD samples. Cardiac dynamic electrocardiogram (ECG) sampling was taken pre-dose and throughout the 24 hours post-dose in each cohort. The clinic contacted subjects on day 11 (± 1 day) to determine if any adverse events (AEs) occurred since discharge.

[0186] IV doses of placebo (n=35), 1 mg Compound 1 (n=6), 5 mg Compound 1 (n=6), 10 mg Compound 1 (n=5), 20 mg Compound 1 (n=6), 30 mg Compound 1 (n=6), or 40 mg Compound 1 (n=6) were administered. Compound 1 doses of 1 mg, 5 mg, 10 mg, and 20 mg were administered by slow bolus infusion over 2 minutes, and compound 1 doses of 30 mg and 40 mg were administered over 5 minutes. The PD effects of single doses were investigated immediately after administration and 4 hours after administration.

[0187] No subjects discontinued treatment. The most common treatment-emergent adverse events occurred near the site of venipuncture. Nosebleeds occurred in 1 subject in the compound 1 group and 1 subject in the placebo group. Nosebleeds occurred in 1 subject in the compound 1 group and 1 subject in the placebo group. None of the bleeding-related TEAEs were above the BARC type 1 bleeding criteria.

[0188] The mean Cmax observed at the 40 mg dose was 1840 ng / mL. The mean terminal elimination half-life ranged from 1 to 2 hours and was dose-dependent. The mean plasma exposure to active metabolites was less than 15%, with the mean plasma exposure of Compound 1 being 2%. Near-maximal inhibition of 5-HT-mediated amplification of platelet aggregation was observed with Compound 1 at doses of 20 mg and above.

[0189] Example 6 - Clinical Trial 4 A phase 2b, multicenter, randomized, double-blind, placebo-controlled study is being conducted to evaluate the safety, tolerability, and effect of Compound 1 or a pharmacologic acceptable salt thereof on the prevention and treatment of MVO in subjects undergoing PCI for ACS (STEMI within 24 hours of diagnosis, or NSTEMI). Prior to the PCI procedure on day 1, subjects receive a single intravenous (IV) dose of test treatment (Compound 1 HCl salt or placebo) in addition to local standard treatment.

[0190] The injection solution is a final sterile solution composed of 25 mg / mL (adjusted free base concentration) of the active pharmaceutical ingredient (API, Compound 1 HCl) in aqueous 10 mM citrate buffer with dextrose as an isotonicity adjuster. A similar injection solution was used in nonclinical toxicology studies (10 mM citrate buffer and 289 mM dextrose in sterile water for injection).

[0191] After the PCI procedure, subjects will begin administering an oral formulation of Compound 1 (powder in capsule, excipient-free) three times a day (TID) for the following 30 days after the PCI procedure. On days 2 and 30, subjects will undergo cardiac magnetic resonance imaging (CMR) (via late gadolinium-enhanced CMR) to assess MVO. Echocardiograms (ECHO) to assess LV function will be performed on days 2, 30, and 90.

[0192] Subjects must meet the following inclusion criteria to be eligible for enrollment in the study: Patients with STEMI or NSTEMI undergoing PCI within 24 hours of diagnosis of ACS; and PCI target lesions must be deemed suitable for stenting as confirmed by diagnostic angiography. Acceptable lesions must not be in the left main artery or have chronic total occlusion or in-stent restenosis.

[0193] The primary endpoint was the incidence of MVO assessed by CMR at 2 days post-PCI with Compound 1 versus placebo.

[0194] Secondary endpoints may include: Incidence of MVO as assessed by CMR at 30 days post-PCI with Compound 1 versus placebo. LV function based on the following parameters assessed by ECHO at 2, 30, and 90 days post-PCI with Compound 1 versus placebo: ·LV ejection fraction (LVEF) LV end-diastolic volume (LVEDV) LV end-systolic volume (LVESV) ·LV mass · Safety and tolerability of Compound 1.

[0195] Exploratory endpoints may include: Incidence of MACE (defined as a composite of cardiac death, myocardial reinfarction, clinically-driven myocardial revascularization, and hospitalization with a discharge diagnosis of heart failure or coronary artery disease) during the 90 days following PCI with Compound 1 versus placebo Change in the following angiographic measures from pre-PCI to post-PCI (immediately after PCI) with Compound 1 versus placebo: Corrected Thrombolysis Frame Count (cTFC) in Myocardial Infarction ·Thrombolysis in Myocardial Infarction (TFG) Thrombolytic Myocardial Perfusion Grade (TMPG) in Myocardial Infarction Myocardial response and LV function at 2 and 30 days post-PCI with Compound 1 versus placebo, based on the following parameters assessed by CMR: Infarct size (percentage of LV mass) Myocardial hemorrhage Myocardial edema Myocardial Salvage Index LVEF ·LVEDV LVESV Example 7 - Clinical Trial 5 A phase 2, multicenter, randomized, double-blind, placebo-controlled study will be conducted to evaluate the safety, tolerability, and PK of IV administration of Compound 1 and its efficacy on microvascular occlusion (MVO) in subjects undergoing percutaneous coronary intervention (PCI). The study will be conducted in two phases (Phase A and Phase B), with each phase including a screening period of up to 14 days, a single-dose randomized study treatment (HCl salt of Compound 1 or placebo) on day 1, and 7 days (± 2 days) of telephone follow-up after administration of study treatment, for a total study duration of 6-24 days.

[0196] Test treatment is administered after baseline angiographic measures, microcirculatory resistance index (IMR), and additional coronary physiology index assessment, and blood sample collection (to assess peripheral serotonin concentration). Each subject receives a single intravenous (IV) dose of test treatment. IMR and additional coronary physiology index assessment are repeated after administration of test treatment and before the start of PCI procedure to obtain pre-PCI values. Immediately after PCI completion, the following assessments are performed to obtain post-PCI values; IMR and additional coronary physiology index assessment, angiographic measures assessment, and blood sample collection (obtained from coronary ostium and coronary artery distal to lesion for assessment of coronary serotonin concentration, and venous blood sample for peripheral serotonin concentration).

[0197] Phase A is a single-dose ascending study planned to consist of two cohorts. After treatment of each cohort in Phase A, a safety / tolerability assessment will be performed by a Data Safety Monitoring Board (DSMB) to determine whether Phase A can be dose escalated to the next dose level or progressed to Phase B. In Phase A, one more dose cohort may be investigated if deemed appropriate based on review of the data from the previous cohort.

[0198] Phase B will begin after the final safety review of Phase A has been performed. Phase B is a parallel treatment arm study planned to consist of a placebo arm and two active treatment arms (dose of Compound 1 will be selected based on safety and tolerability data from Phase A). In Phase B, enrollment will consist of 25% or less elective PCI subjects, and randomization will be stratified by site and subject type (elective PCI or PCI for non-ST elevation myocardial infarction [NSTEMI] / unstable angina [UA]).

[0199] Subjects should be treated with aspirin and an oral P2Y12 inhibitor (i.e., dual antiplatelet therapy [DAPT]) according to the institution's standard procedures; however, subjects in Phase A may only be treated with clopidogrel as the P2Y12 inhibitor DAPT component, and may not be treated with prasugrel or ticagrelor until after the subject has completed participation in the study.

[0200] The test treatment is an IV formulation containing the HCl salt of Compound 1 provided as a strength (free base concentration) of 25 mg / mL. Subjects assigned to the active treatment will receive one single dose in an IV bolus of 5 mL total (diluted in saline) administered in the forearm over a duration of at least 5 minutes.

[0201] The dose to be administered to cohort 1 in Phase A is 20 mg (to be administered over a period of 5 minutes or more). The dose to be administered to cohort 2 is planned to be 40 mg. In Phase A, one more dose cohort may be investigated if deemed appropriate based on review of the data from the previous cohort. It is planned that a selected dose from Phase A will be investigated in Phase B of the study. The planned doses in Phase A and Phase B may be adjusted depending on the safety and tolerability results of the previous cohort(s).

[0202] The primary endpoint was the change in IMR from baseline to post-PCI with Compound 1 versus placebo.

[0203] Secondary endpoints may include: Change from baseline to post-PCI with Compound 1 versus placebo in the following assessments: Coronary artery physiological function index (coronary flow reserve [CFR], fractional flow reserve [FFR]) Angiographic measures (corrected Thrombolysis in Myocardial Infarction frame count [cTFC], TFG, Myocardial Perfusion Grade [TMPG] of Thrombolysis in Myocardial Infarction) Myocardial damage markers (creatine kinase [CK], creatine kinase myocardial type [CK-MB], cTn) NOTE: Post-PCI measures for CK, CK-MB, and cTn are taken 4-6 hours after completion of the PCI procedure, not immediately after the procedure. The incidence of procedural myocardial injury with Compound 1 versus placebo, defined as an increase in cTn values ​​greater than the 99th percentile upper reference limit (URL) in subjects with normal baseline values ​​(≤99th percentile URL) or an increase in cTn greater than 20% of baseline values ​​in subjects with elevated cTn levels (cTn levels greater than the 99th percentile URL). Concentrations of compound 1 and its active metabolites M1 and M2 pre-PCI and at selected time points post-PCI up to hospital discharge Safety and tolerability of compound 1 Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the study: Patients with stable angina eligible for elective PCI or patients with NSTEMI and UA undergoing PCI at least 12 hours after diagnosis of NSTEMI / UA. NSTEMI / UA patients should be consistently hemodynamically stable up to the time of PCI and have a Thrombolysis in Myocardial Infarction (TIMI) flow classification (TFG) of 3 on diagnostic angiography. ·Target lesions for PCI must be those deemed suitable for stenting as confirmed by diagnostic angiography. Lesions must be located in coronary arteries with a diameter of 2.75 mm or greater. Lesions must also be 18 mm or greater in length and require the use of one or more stents, which must total 20 mm or greater in length. Acceptable lesions must not be in the left main artery or in venous or arterial grafts, or have chronic total occlusions or in-stent restenosis. Two or more consecutive lesions may be treated in the same artery as long as they are treated in the same session and at least one of the lesions meets the inclusion criteria. 30 to 75 years old (inclusive) Body mass index: 18.0-40.0 kg / m2 (inclusive) Subjects will be excluded from the study if they meet any of the following major exclusion criteria: Planned or anticipated use of rotational atherectomy / ablation or shockwave therapy during the PCI procedure History of any of the following: stroke, head injury, seizures, intracranial hemorrhage, or intracranial aneurysm Transient ischemic attack within 6 months prior to screening History of major trauma, major surgery, and / or clinically significant bleeding within 6 months prior to screening NSTEMI / UA with increasing (not stable or decreasing) cardiac troponin (cTn) levels as demonstrated by the two most recent measures after diagnosis of NSTEMI / UA and before randomization Any ST-segment elevation myocardial infarction (STEMI) within 10 days of screening, or any STEMI within the target vessel territory within the past 6 months of screening (e.g., patients with NSTEMI due to diagonal lesions cannot be included if there is a history of anterior STEMI due to left anterior descending artery [LAD] lesion occurring within the past 6 months) Known history of heart failure Vasculitis within 6 months prior to screening Known contraindications or allergies to: heparin (e.g., history of heparin-induced thrombocytopenia [HIT]), any antiplatelet agents (i.e., aspirin, P2Y12 inhibitors), or adenosine Actively being treated with strong cytochrome P450 (CYP) 3A4 or P-glycoprotein inhibitors or inducers (examples include but are not limited to ketoconazole, itraconazole, clarithromycin, erythromycin, rifampicin, and verapamil). Intra-arterial use of verapamil is permitted in subjects undergoing radial artery PCI. Use of medications affecting the serotonin system within 14 days of check-in (e.g., selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], atypical [second-generation] antipsychotics with 5-HT2A pharmacology, or any other serotonergic agent with 5-HT2A pharmacology [e.g., triazolopyridine antidepressants, trazodone]) Treatment with cangrelor or glycoprotein IIb / IIIa inhibitors within 24 hours of check-in The need for chronic oral anticoagulants (e.g., warfarin or direct oral anticoagulants [DOACs], which include direct oral thrombin inhibitors) for any condition (e.g., atrial fibrillation, deep vein thrombosis, or prosthetic heart valve procedure) within one week of check-in For Phase A subjects only: Use of prasugrel or ticagrelor within 14 days of check-in Example 8 - Clinical Trial 6 A Phase 1, open-label, parallel-cohort, fixed-sequence study will be conducted to evaluate food effects and drug-drug interactions (DDIs) with Compound 1 in healthy adult subjects. Approximately 66 healthy adult subjects will be assigned to one of three cohorts (22 subjects each).

[0204] The PK profiles of Compounds 1, M1, and M2 will be evaluated in each cohort for up to 3-5 days following administration of each Compound 1 within the corresponding treatment period. Cohorts and treatments are defined below: Cohort 1 (food effects and esomeprazole (ESO) DDI): Subjects are randomized (1:1) into one of two treatment sequences: A1:B:C (Sequence 1) or B:A1:C (Sequence 2). During treatment period 3, all subjects receive treatment C. Subjects remain at the study center for a domiciled period of approximately 13 days. Blood samples are collected for up to 3 days after each administration of Compound 1 for PK analysis of Compounds 1, M1, and M2. Treatments are defined as follows: Procedure A1 (reference):A single 120 mg dose of Compound 1 (6 x 20 mg capsules) is administered under fasted conditions. PK sampling continues for up to 3 days post-dose.

[0205] Procedure B (Testing): A single 120 mg dose of Compound 1 (6 x 20 mg capsules) will be administered approximately 30 minutes after consumption of an FDA recommended high fat / high calorie breakfast. PK sampling will continue for up to 3 days post-dose.

[0206] Procedure C (Testing): In treatment period 3, 40 mg of ESO (1 x 40 mg capsule) is administered qAM with a regular meal for 8 days (days 7-13), except for day 10, when ESO is administered in the fasted state. On day 10, a single 120 mg dose of Compound 1 (6 x 20 mg capsules) is administered in the fasted state approximately 1 hour after ESO administration. Blood sampling for PK continues for up to 3 days after dosing.

[0207] Study treatments and diet: All treatments are administered in the morning. Treatment A1 is administered after an overnight fast (i.e., no food or drink except water [except 1 hour before and after dosing]) of at least 10 hours duration. Treatment B is administered approximately 30 minutes after ingestion of an FDA recommended high fat / high calorie breakfast. Food is withheld for up to 4 hours after administration of Compound 1 for Treatment A1, Treatment B, and Treatment C. For Treatment C, ESO is administered 1 hour before the usual breakfast on days 7-9 and 11-13. On day 10, ESO is administered in the fasted state at least 1 hour prior to administration of Compound 1. Cohort 2 (Itraconazole (ITZ) / Fluconazole (FLU) DDI): Subjects will be assigned a fixed treatment sequence A2:D:E (Sequence 1). Subjects will remain at the study center for a stay of approximately 24 days. Blood samples will be collected for up to 5 days after each dose of Compound 1 for PK analysis of Compound 1, M1, and M2, and for itraconazole (ITZ) or fluconazole (FLU) as appropriate. Treatments are defined below: Procedure A2 (reference):During treatment period 1, a single 40 mg dose of Compound 1 (2×20 mg capsules) will be administered in the fasted state on day 1. Blood sampling for PK will continue for up to 3 days post-dose.

[0208] Procedure D (Testing): During treatment period 2, FLU is administered once daily (qAM) with breakfast (except day 7) as a loading dose of 400 mg on day 4, followed by 200 mg on days 5-12. On day 7, a single 40 mg dose of Compound 1 is administered in the fasted state 2 hours after administration of FLU. Blood collection for PK continues for up to 5 days after administration of Compound 1. No treatment is administered on days 13-15.

[0209] Procedure E (Test): During treatment period 3, 200 mg of ITZ (20 mL of 10 mg / mL oral solution) is administered once every morning (qAM) for 9 days (days 16-24) in a fasted state. On the fourth day (day 19) of ITZ treatment, a single 40 mg dose of Compound 1 (2 x 20 mg capsules) is administered in a fasted state approximately 2 hours after ITZ administration. Blood sampling for PK continues until day 24 (5 days after Compound 1 administration).

[0210] Study treatments and diet: All treatments are administered in the morning. Treatments A2 (Compound 1) and E (ITZ) are administered after an overnight fast (i.e., no food or drink except water [except 1 hour before and after dosing]) of at least 10 hours duration. For Treatment D, FLU is administered with a regular breakfast except on Day 7, on which Compound 1 and FLU are administered in the fasted state. All treatments are administered within ±1 hour of the dosing time set on Day 1 of Treatment Period 1. Fasting continues for at least 4 hours after each administration of Compound 1 and at least 1 hour after each administration of FLU and ITZ. Cohort 3 (rifampin (RIF) DDI): Subjects will be assigned a fixed sequence: A1:F. Subjects will remain at the study center for a stay of approximately 20 days. Blood samples will be collected for up to 5 days after each dose of Compound 1 for PK analysis of Compound 1, M1, and M2, and for rifampin (RIF) if needed. Treatments are defined below: Procedure A1 (reference): In treatment period 1, a single 120 mg dose of Compound 1 (6×20 mg capsules) is administered in the fasted state on day 1. PK sampling continues for up to 3 days post-dose.

[0211] Procedure F (Test): In treatment period 2, RIF 600 mg (2 x 300 capsules) is administered qAM for 10 days (days 4-13) in the fasted state. On day 15, 2 days after the last RIF dose, a single 120 mg dose of Compound 1 (6 x 20 mg capsules) is administered in the fasted state. Plasma collection for PK determination continues until day 20 (5 days after Compound 1 administration).

[0212] Study treatments and diet: All treatments are administered in the morning after at least a 10 hour overnight fast (i.e., no food or drink except water [except 1 hour before and after dosing]). Compound 1 and RIF are administered within ±1 hour of the scheduled dosing time on Day 1. Fasting continues for at least 4 hours after Compound 1 administration and at least 1 hour after each RIF administration. All cohorts: Cardiac dynamic electrocardiogram (ECG) imaging will be obtained at scheduled times.

[0213] The clinic will attempt to contact all subjects (including those who terminated the study early) 7 (± 2) days after discharge using its standard procedures to determine if any adverse events (AEs) occurred since discharge or early termination. Study drug, dose, and mode of administration: Compound 1 is in a 20 mg immediate release capsule formulation, consisting of a size 2 hard gelatin capsule containing Compound 1 HCl drug substance with no excipients.

[0214] Cohort 1 will receive a single oral dose of 120 mg of Compound 1 (6×20 mg capsules) administered with approximately 240 mL of water in the fasted or fed state.

[0215] In cohort 2, 40 mg of Compound 1 (2×20 mg capsules) will be administered as a single oral dose with approximately 240 mL of water in the fasted state.

[0216] In cohort 3, 120 mg of Compound 1 (6×20 mg capsules) will be administered as a single oral dose with approximately 240 mL of water in the fasted state. Treatment duration: The total study duration will be up to 48, 59, and 55 days (± 1 day) for subjects in cohorts 1, 2, and 3, respectively. The study includes a screening period (up to 28 days), a stay treatment period of 13 days (cohort 1), 24 days (cohort 2), and 20 days (cohort 3), and a follow-up call after discharge of 7 (± 2) days.

[0217] Interacting / reference therapy, dosage, and mode of administration: Cohort 1 In treatment period 3, 40 mg of ESO (1 x 40 mg capsule) is administered qAM for 7 consecutive days in a fed state (normal diet) with approximately 240 mL of water, except on day 10, when it is administered in a fasted state. The reference therapy is Compound 1 (120 mg, 6 x 20 mg capsules) administered in a fasted state with approximately 240 mL of water on day 10.

[0218] Cohort 2 In treatment period 2, a loading dose of 400 mg FLU (2 x 200 mg tablets) followed by 200 mg (1 x 200 mg tablet) is administered qAM under fed conditions (normal chow) with approximately 240 mL of water for 9 consecutive days, except on day 7, which is administered in the fasted state. The reference therapy is Compound 1 (40 mg, 2 x 20 mg capsules), administered on day 7 with approximately 240 mL of water in the fasted state.

[0219] Cohort 2In treatment period 3, 200 mg of ITZ (20 mL of 10 mg / mL oral solution) is administered qAM for 9 consecutive days in a fasted state with approximately 240 mL of water. The reference therapy is Compound 1 (40 mg, 2 x 20 mg capsules) administered on day 19 in a fasted state with approximately 240 mL of water.

[0220] Cohort 3 In treatment period 2, 600 mg of RIF (2 x 300 mg capsules) is administered qAM for 10 consecutive days in a fasted state with approximately 240 mL of water. The reference therapy is Compound 1 (120 mg, 6 x 20 mg capsules) administered on day 12 in a fasted state with approximately 240 mL of water. Primary endpoints may include: The following plasma PK parameters are calculated for Compounds 1, M1, and M2 after multiple doses in the presence and absence of food, ITZ, FLU, ESO, and RIF: - Area under the concentration-time curve from time 0 to the last measurable concentration (AUC t ) - Area under the concentration-time curve from time 0 to infinity (AUC 0-∞ ) - Maximum plasma concentration (C max ) - Time to peak plasma concentration (t max ) Secondary endpoints may include: Incidence of any treatment-emergent adverse event (TEAE) Laboratory tests (blood chemistry, hematology, coagulation, and urinalysis), vital signs, ECG, and physical exam Further plasma PK parameters for Compounds 1, M1, and M2: - Apparent total body clearance (CL / F) after oral administration, parent only - Apparent volume of distribution after oral administration (Vd / F), parent only - Elimination half-life (t 1 / 2 ) - Mean residence time (MRT) from time zero to the time of the last quantifiable sample 0-t), Parents only - Mean residence time (MRT) extrapolated from time zero to infinity 0-∞ ), Parents only AUC and C max The ratio of metabolites to parents is also calculated for Exploratory endpoints may include: Plasma concentrations / PK of ESO, ITZ, FLU, and RIF, as appropriate - Area under the concentration-time curve from time 0 to the last measurable concentration (AUC t ) - Area under the concentration-time curve from time 0 to infinity (AUC 0-∞ ) - Maximum plasma concentration (C max ) - Time to peak plasma concentration (t max ) - C trough , RIF only Calculate the following urinary PK parameters for Compounds 1, M1, and M2, as appropriate: - The amount of unchanged drug excreted during the urine collection interval from t1 to t2 (Aet1-t2) (Fe) - Renal clearance (CL R )-Compound 1 only Safety assessments will include monitoring of adverse events (AEs), vital signs, clinical laboratory values, ECGs, and physical examinations.

[0221] Other uses of the disclosed methods will become apparent to those of skill in the art based upon, inter alia, a review of this patent document.

Claims

1. 1. A method of treating or preventing microvascular obstruction in an individual in need thereof, comprising:

2. A method comprising parenterally administering to an individual a parenteral formulation containing a first therapeutically effective amount of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, wherein the individual is undergoing percutaneous coronary intervention (PCI).

20. A medicament comprising Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for use in

2. a) a parenteral formulation is parenterally administered during a first time period; b) following the parenteral administration, during a second period of time, an oral formulation containing a second therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is orally administered; The method of claim 1 A pharmaceutical for use in

3. 1. A method for preserving vascular integrity in an individual in need thereof, comprising: a) parenterally administering to the individual for a first period of time a parenteral formulation containing a first therapeutically effective amount of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof; and b) orally administering to the individual, for a second period of time following the parenteral administration, an oral formulation containing a second therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof. A method comprising:

20. A medicament comprising Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, for use in

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the individual is undergoing PCI for acute coronary syndrome (ACS).

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the parenteral formulation is administered immediately prior to PCI.

6. The pharmaceutical composition of any one of claims 1 to 5, wherein the parenteral formulation is a sterile solution comprising compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, at an adjusted free base concentration of about 1 mg / mL to about 50 mg / mL.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the first therapeutically effective amount is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, or about 75 mg.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the parenteral formulation is administered intravenously.

9. The method according to any one of claims 1 to 7, wherein the parenteral formulation is administered by injection.

10. The method of any one of claims 2 to 9, wherein orally administering comprises administering an oral loading dose and an oral maintenance dose.

11. The method of any one of claims 1 to 10, wherein the parenteral formulation is administered over a period of about 5 minutes or less, about 4 minutes or less, about 3 minutes or less, about 2 minutes or less, or about 1 minute or less.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the oral formulation is administered after PCI.

13. The pharmaceutical composition of any one of claims 2 to 12, wherein the second therapeutically effective amount is about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, or about 160 mg.

14. The method according to any one of claims 2 to 13, wherein the oral formulation is administered three times a day.

15. The pharmaceutical composition according to any one of claims 2 to 14, wherein the second period is at least one week.

16. The method according to any one of claims 1 to 15, wherein compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, is an HCl salt of compound 1.

17. The pharmaceutical of any one of claims 1 to 16, wherein the method results in a reduction in the incidence of major adverse cardiac events (MACE).

18. A parenteral formulation comprising: a) a first therapeutically effective amount of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof; b) an oral formulation containing a second therapeutically effective amount of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof; and c) Instructions indicating that the parenteral and oral formulations are for sequential use to prevent microvascular obstruction (MVO), preserve vascular integrity, and / or prevent major adverse cardiovascular events (MACE) by preventing and / or treating MVO in an individual undergoing percutaneous coronary intervention (PCI). Including the kit.

19. A pharmaceutical formulation for parenteral administration comprising a sterile solution comprising 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, in an adjusted free base concentration of about 1 mg / mL to about 25 mg / mL.

20. For the safe administration of 3-methoxy-N-[3-(2-methylpyrazol-3-yl)-4-(2-morpholin-4-ylethoxy)phenyl]benzamide (Compound 1), or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, to an individual in need thereof, discontinuing administration of a CYP3A4, CYP3A5, and / or P-glycoprotein inhibitor or inducer, or a proton pump inhibitor to the individual; not co-administering to the individual inhibitors or inducers of CYP3A4, CYP3A5, and / or P-glycoprotein, or proton pump inhibitors; co-administering to the individual a reduced dose of an inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein, or a proton pump inhibitor; or administering to an individual a reduced dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, when co-administered with an inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein, or a proton pump inhibitor; or administering to the individual a lower dose of Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, and a lower dose of an inhibitor or inducer of CYP3A4, CYP3A5, and / or P-glycoprotein, or a proton pump inhibitor; A pharmaceutical comprising Compound 1, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, wherein the pharmaceutical comprises Compound 1 or a pharma- ceutically acceptable salt, hydrate, or solvate thereof,