Polymorphic forms of (r)-4-(1-((3-(difluoromethyl)-1-methyl-1h-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-n-(isoxazol-3-yl)piperidine-1-carboxamide

Abstract

To provide compositions and methods useful for the treatment of cardiac disorders including systolic dysfunction, dilated cardiomyopathy (DCM), heart failure with reserved ejection fraction (HFrEF), and conditions associated with left and / or right ventricular systolic dysfunction or reduced systolic reserve.SOLUTION: Novel polymorphs of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491) are provided. The synthesis and characterization of the polymorphs, as well as methods for treating systolic dysfunction, DCM, HFrEF, and other forms of heart disease, are also provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 874,855, filed July 16, 2019, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Heart failure (HF) is a global epidemic, affecting approximately 26 million people worldwide. It is the world's fastest-growing cardiovascular condition, with substantial morbidity, mortality, and costs to healthcare systems (Ponikowski et al., ESC Heart Fail. (2014) 1(1):4-25; Savarese and Lund, Card Fail Rev. (2017) 3(1):7-11). HF is the most common cause of hospitalization among patients aged 65 years and older (Ponikowski, supra; Savarese and Lund, supra; and Shah et al., J Am Coll Cardiol. (2017) 70(20):2476-86). The 5-year mortality rate after hospitalization for HF is approximately 42%, comparable to that of many cancers (Benjamin et al., Circulation (2019) 139:e56-e528).

[0003] Heart failure is a clinical syndrome in which a patient's heart cannot provide enough blood flow to the body to meet its metabolic needs. For patients with heart failure, the heart has difficulty pumping enough blood to support other organs in the body. Others may have stiffening and contraction of the heart muscle itself, which blocks or reduces blood flow to the heart. These two conditions result in improper blood circulation to the body and congestion in the lungs. Heart failure can affect the right or left side of the heart, or both sides simultaneously. It can be either an acute (short-term) or chronic (ongoing) condition. Heart failure can be referred to as congestive heart failure when fluid builds up in various parts of the body. Symptoms of heart failure include, but are not limited to, excessive fatigue, sudden weight gain, loss of appetite, persistent cough, irregular pulse, chest discomfort, angina, palpitations, edema (e.g., swelling of the lungs, arms, legs, ankles, face, hands, or abdomen), shortness of breath (dyspnea), bulging neck veins, and decreased exercise tolerance or capacity.

[0004] The volume of blood pumped by the heart is generally determined by (a) myocardial contractility (i.e., how well the heart compresses or performs its contractile function) and (b) cardiac chamber filling (i.e., how well the heart relaxes and fills with blood or performs its diastolic function). The ejection fraction is used to assess the pumping function of the heart; it indicates the percentage of blood pumped out of the left ventricle (the main pumping chamber) per beat. A normal or preserved ejection fraction is 50% or greater. When the contractile function of the heart is impaired and the heart shows a substantial reduction in ejection fraction, the condition is known as heart failure with reduced ejection fraction (HFrEF). When the ejection fraction is <HFrEF at 40% is classic HFrEF, whereas HFrEF with an ejection fraction of 41–49% is classified as heart failure with a moderate ejection fraction (HFmrEF) under the 2013 American College of Cardiology Foundation / American Heart Association guidelines (Yancy et al., Circulation (2013) 128:e240–327) and the 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized With Heart Failure (Hollenberg et al., J Am Coll Cardiol (2019) 74:1966–2011). There are many causes of a weak myocardium (low ejection fraction), including ischemia / infarction, hypertension, heart valve defects, genetic mutations, infection, and toxin / drug exposure.

[0005] Diastolic dysfunction may contribute to morbidity in patients with HFrEF. When the heart pumps normally but becomes too stiff to adequately fill with blood, this condition is known as heart failure with preserved ejection fraction (HFpEF). Historically, HFpEF was referred to as diastolic heart failure; however, recent research suggests a more complex and heterogeneous pathophysiology. Patients with HFpEF exhibit subtle or mild abnormalities in systolic performance, which become more dramatic during exercise. Abnormal ventricular diastolic and systolic reserve, chronotropic incompetence, stiffening of ventricular tissue, atrial dysfunction, pulmonary hypertension, impaired vasodilatory function, and endothelial dysfunction have all been implicated. Often, these abnormalities are only apparent when the circulatory system is under stress.

[0006] In the United States alone, there are approximately 2.6 million patients with HFrEF, representing approximately 40% of the U.S. HF population (Bloom et al., Nat Rev Dis Primers. (2017) 3:17058). HFrEF can arise from ischemic origins (primarily due to coronary artery disease) or non-ischemic origins (due to myocardial disease from non-coronary causes). Coronary artery disease (coronary heart disease) is a condition in which the coronary arteries are narrowed. If severe, this narrowing can cause inadequate blood supply to the myocardium, potentially leading to the death of myocardial cells (infarction). Non-ischemic HFrEF is sometimes referred to as dilated cardiomyopathy (DCM). Regardless of the nomenclature, dilation (enlargement) of the heart chambers can be seen in both non-ischemic and ischemic HFrEF patients. Hereinafter, DCM refers to non-ischemic HFrEF. When no identifiable cause can be found, DCM may be assigned a clinical diagnosis of genetic or "idiopathic" DCM. Mutations in over 30 genes, including sarcomere genes, disrupt a diverse set of myocardial proteins and cause the DCM phenotype. Some of the genetic links to DCM are described in Hershberger et al., Nature Reviews (2013) 10(9):531-47, and Rosenbaum et al., Nat Rev Cardiol. (2020) 17(5):286-97.

[0007] Contemporary medical therapy for HFrEF focuses on counteracting the effects of neurohormonal activation with modulators of the renin-angiotensin-aldosterone system, beta-adrenergic blockers, diuretics, and modulators of the vasoactive peptide BNP (brain natriuretic peptide). While these drugs attenuate some of the maladaptive consequences and improve clinical outcomes, they do nothing to address the underlying pathways responsible for myocardial dysfunction.

[0008] Several inotropic agents are used in clinical practice to enhance cardiac contractility by increasing intracellular calcium or cyclic adenosine monophosphate, mechanisms that increase myocardial oxygen demand. Chronic trials with these drugs have shown increased mortality due to arrhythmias and ischemia, so their use is limited to short-term or targeted therapy in patients with refractory or end-stage heart failure, with the aim of palliation of symptoms. However, these drugs improve hemodynamics and symptoms, suggesting the potential for clinical benefit for agents that enhance contractility without arrhythmia or ischemic disadvantages.

[0009] There are currently no approved therapies to treat heart failure by directly targeting the systolic apparatus. New, safe, and effective treatments for systolic heart failure are urgently needed.

[0010] Non-ischemic HFrEF is sometimes referred to as dilated cardiomyopathy (DCM). Despite the nomenclature, dilated (enlarged) ventricles are present in both non-ischemic and ischemic HFrEF patients. Dilated cardiomyopathy (DCM) encompasses a group of myocardial disorders that result in left ventricular dilation and systolic dysfunction (abnormal contraction). DCM can be subdivided into ischemic (disease resulting from coronary artery disease) and non-ischemic (primary myocardial disease). Hereinafter, DCM refers to non-ischemic HFrEF. If no identifiable cause (other than genetic) can be found, DCM may be assigned a clinical diagnosis of "idiopathic" DCM. Idiopathic DCM can be further subdivided depending on whether a genetic cause can be identified. Mutations in more than 30 genes, including sarcomere genes, disrupt a diverse array of myocardial proteins, resulting in the DCM phenotype. Some of the genetic links to DCM are described in Hershberger et al., Nature Reviews (2013) 10(9):531-47. Epidemiological data indicate that idiopathic DCM affects approximately 1 in 2,500 people in the general population.

[0011] Mutations in sarcomere genes that cause DCM are highly penetrant, yet there is considerable variability in clinical severity and clinical course. Some genotypes are associated with a more aggressive course, but there is considerable variability between and even within families with the same mutation. While many patients with DCM report few or no symptoms over time, DCM is a progressive disease with a significant cumulative burden of morbidity and mortality. DCM is characterized by a more spherical than normal shape, a dilated left ventricle, and reduced systolic function. Patients typically present with symptoms of heart failure: dyspnea, orthopnea, exercise intolerance, fatigue, abdominal discomfort, and loss of appetite. Signs may include sinus tachycardia, gallop rhythm, mitral regurgitation murmur, rumbles, jugular vein distention, hepatomegaly, peripheral edema, and cold extremities. As with many other disorders, symptoms tend to worsen with age. Patients' lives are interrupted by hospitalization for decompensated heart failure and increased risk of sudden death due to arrhythmias and death from pump failure.

[0012] Diagnosis depends on the patient's medical history and physical examination. Plasma biomarkers such as B-type natriuretic peptide (BNP) or its N-terminal proprotein (NT-proBNP) can be helpful in diagnosing and managing DCM, particularly in distinguishing between heart failure and coexisting pulmonary disease. Coronary angiography can identify whether heart failure is of ischemic etiology. Endocardial biopsy can distinguish DCM from disease processes that may require alternative management strategies, such as myocarditis, storage diseases, sarcoidosis, or hemochromatosis.

[0013] Pharmacological therapy remains the mainstay for patients with DCM and heart failure. Beta-blockers, ACE inhibitors or ARBs, mineralocorticoid receptor blockers, and loop diuretics remain standard options for treating heart failure symptoms and reducing the risk of cardiovascular death and heart failure hospitalization. In patients with left ventricular ejection fractions less than 30%, implantable cardioverter-defibrillators (ICDs) can reduce sudden arrhythmia-related death. Additionally, cardiac resynchronization therapy (CRT) has been shown to improve heart failure-free survival in select patients. Despite these interventions, morbidity and mortality from heart failure remain high, and heart failure hospitalization remains the most common reason for hospitalization in the elderly. The present disclosure provides therapeutic agents and methods that address the unmet need for improved treatment of systolic dysfunction, DCM, HFrEF, and related cardiac disorders. Summary of the Invention

[0014] In one embodiment, the present invention provides polymorphs of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491). Four polymorphs are detailed herein, including Forms A, B, C, and D.

[0015] In another aspect, the present invention provides compositions and pharmaceutical compositions containing a polymorph of I-491, or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable excipient.

[0016] The present disclosure also provides methods for treating systolic dysfunction. In another aspect, the present invention provides methods for treating dilated cardiomyopathy. In certain aspects of the present disclosure, the present invention provides methods for treating HFrEF. These methods comprise administering to a subject in need thereof an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0017] Details of certain embodiments of the invention are set forth below in the Detailed Description of the Invention. Other features, objects, and advantages of the invention will be apparent from the definition, examples, drawings, and claims. [Brief explanation of the drawings]

[0018] [Figure 1A] Figure 1 shows the high-resolution synchrotron X-ray powder diffraction pattern (ESRF, λ = 1.000 Å) of Form A recorded at room temperature.

[0019] [Figure 1B] 1 shows an X-ray powder diffraction pattern of Form A recorded at room temperature.

[0020] [Figure 2] 1 shows the DSC and TGA thermograms of Form A.

[0021] [Figure 3] The molecular structure of Form A is shown in Ortep representation with atom labels and a thermal ellipsoid (30% probability) with regions of disorder indicated by dotted lines.

[0022] [Figure 4] A representation of the molecular packing of Form A below the minor axis is shown, showing the scheme of disorder (dotted line).

[0023] [Figure 5] 1 shows a simulated powder diffraction pattern from the crystal structure of Form A at copper wavelengths.

[0024] [Figure 6A] Figure 1 shows the high-resolution synchrotron X-ray powder diffraction pattern (ESRF, λ = 0.800 Å) of Form B recorded at room temperature.

[0025] [Figure 6B] 1 shows an X-ray powder diffraction pattern of Form B recorded at room temperature.

[0026] [Figure 7] 1 shows the DSC and TGA thermograms of Form B.

[0027] [Figure 8] The molecular structure of Form B is shown in Ortep representation with atom labels and thermal ellipsoids (30% probability). There are four independent molecules with regions of disorder indicated by dotted lines.

[0028] [Figure 9] The crystal structure of Form B is displayed by looking at the molecular packing below the disordered (011) plane, shown by the dotted line.

[0029] [Figure 10] A simulated powder diffraction pattern from the crystalline structure at copper wavelengths for Form B is shown. There is theoretically only one reflection in the 9°-10° angular region, whereas there are effectively three reflections in the 7°-8° angular region.

[0030] [Figure 11] 1 shows the DSC and TGA thermograms of Form C.

[0031] [Figure 12A] The molecular structure of Form C is shown in Ortep representation with atom labels and a thermal ellipsoid (50% probability) with regions of disorder indicated by dotted lines.

[0032] [Figure 12B] 1 shows the crystal structure of monoclinic form C displaying molecular packing below the short axis with regions of disorder indicated by dotted lines.

[0033] [Figure 13A] 1 shows a simulated powder diffraction pattern from the crystalline structure of Form C at copper wavelengths.

[0034] [Figure 13B] 1 shows an X-ray powder diffraction pattern of Form C recorded at room temperature.

[0035] [Figure 14] The molecular structure of Form D is shown in Ortep representation with atom labels and thermal ellipsoids (50% probability) with regions of disorder indicated by dotted lines.

[0036] [Figure 15] 1 shows the crystal structure of triclinic form D displaying molecular packing below the minor axis with regions of disorder indicated by dotted lines.

[0037] [Figure 16] 1 shows a simulated powder diffraction pattern from the crystalline structure of Form D at copper wavelengths. DETAILED DESCRIPTION OF THE INVENTION

[0038] The crystalline polymorphic form of a particular drug is often an important determinant of a drug's ease of manufacture, stability, solubility, storage stability, ease of formulation, and in vivo pharmacology. Polymorphic forms arise when materials of the same composition crystallize in different lattice arrangements, resulting in different thermodynamic properties and thermodynamic stabilities specific to a particular polymorphic form. When two or more polymorphic substances can be produced, it is desirable to prepare each polymorph in pure form and determine the properties of each polymorph. A preferred polymorph may be selected based on desired characteristics, properties, and stability. In certain embodiments, ease of manufacture or stability may be considered particularly important, and in certain cases, the most stable polymorph may be preferred, while in other cases, the polymorph that is easiest to manufacture (e.g., least hazardous, least expensive, highest yield) may be considered preferred. In other situations, different polymorphs may be preferred for greater solubility and / or better pharmacokinetics. For example, because there is a constant demand for improved drug formulations with better bioavailability or better stability, there is a constant need for new or purer polymorphic forms of existing drug molecules. [ka] Various crystalline polymorphs of , help meet these and other needs.

[0039] A series of polymorphs of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491) and pharmaceutically acceptable salts thereof have been found to increase contractile force by enhancing the release of phosphate from myosin without prolonging systole or shortening diastole. Therefore, the compounds can improve contractile function in patients with DCM or HFrEF and help them overcome the debilitating exertional dyspnea and fatigue often associated with the disease. The compounds can also be used to treat other cardiac disorders characterized by reduced cardiac output.

[0040] Form B was identified as the most stable polymorph (compared to Forms A, C, and D) and as such was selected as the lead polymorph for development. The more stable a polymorph, the less likely it is to convert to another form over time during storage, whether as the active pharmaceutical ingredient alone or in a formulated drug product. Changes in polymorphic form upon storage or during processing can lead to changes in solubility, dissolution rate, or bioavailability; therefore, it is important to identify stable polymorphs for use as drug candidates in the early stages of development.

[0041] definition As used herein, the term "about" is used to describe a range (e.g., of temperature, mass, weight) and is given its ordinary meaning in the art, typically referring to the error associated with the measurement or procedure for collecting the reading. Generally, when referring to temperature, the term "about" provides a deviation of ±0-2°C.

[0042] The term "salt" as used herein refers to an acid or base salt of the compound of the present invention. Pharmaceutically acceptable salts can be derived, for example, from mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium ions. It is understood that pharmaceutically acceptable salts are non-toxic. Further information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985 (incorporated herein by reference).

[0043] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0044] The term "room temperature" refers to a temperature in the range of 19-26°C.

[0045] The term "solvate" refers to a form of a compound that is associated with a solvent, usually through solvation. This physical association may involve hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further encompass both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. In certain embodiments, the solvate is a distinct polymorph. In some embodiments, the solvate is not a distinct polymorph, i.e., a polymorph defined by a distinct crystal structure may contain residual solvent molecules.

[0046] The terms "amorphous" or "amorphous form" refer to a solid form ("solid form") that substantially lacks three-dimensional order. In certain embodiments, a solid amorphous form is a solid form that is substantially non-crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of the amorphous form comprises, for example, a broadband scattering band with a peak at 2θ between 20 and 70° (inclusive) using CuKα radiation. In certain embodiments, the XRPD pattern of the amorphous form further comprises one or more peaks attributable to a crystalline structure. In certain embodiments, the maximum intensity of any one of the one or more peaks attributable to a crystalline structure observed at 2θ between 20 and 70° (inclusive) is 300 times or less, 100 times or less, 30 times or less, 10 times or less, or 3 times or less than the maximum intensity of the broadband scattering band. In certain embodiments, the XRPD pattern of the amorphous form does not comprise a peak attributable to a crystalline structure.

[0047] The term "polymorph" or "polymorphic form" refers to a crystalline form of a compound (or its salt, hydrate, or solvate) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, melting points, densities, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to predominate. Various polymorphs of a compound can be produced by crystallization under different conditions.

[0048] The term "crystalline" refers to a solid phase in which the material has a regular, ordered internal structure at the molecular level, giving rise to a characteristic X-ray diffraction pattern of defined peaks. Such materials, when heated sufficiently, will also exhibit the properties of a liquid, but the change from solid to liquid is typically characterized by a first-order (melting point) phase change. The terms "crystalline" or "crystalline form" refer to a solid form that exhibits substantial three-dimensional order. In certain embodiments, a solid crystalline form is a solid form that is not substantially amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks.

[0049] The compounds of the present invention have asymmetric carbon atoms (optical centers) and double bonds; racemates, diastereomers, geometric isomers, positional isomers, and individual isomers (e.g., separate enantiomers) are all intended to be within the scope of the present invention. The stereochemical depictions showing the compounds of the present invention refer to compounds in which one of the isomers is present and the other isomer is substantially free. "Substantially free" of another isomer means that the two isomers are present in a ratio of at least 70 / 30, more preferably 80 / 20, 90 / 10, or 95 / 5 or greater at the depicted stereochemical center. In some embodiments, one of the isomers will be present in an amount of at least 99%.

[0050] When a polymorphic form is described, it refers to the identified polymorph described herein that is substantially free of any other polymorph. "Substantially free" of another polymorph indicates that the molar ratio of the two polymorphs is at least 70 / 30, more preferably 80 / 20, 90 / 10, 95 / 5, 99 / 1, or greater. In some embodiments, one of the polymorphs will be present in an amount of at least 99%.

[0051] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as a range from the amount found in nature to an amount that is 100% composed of the atom in question. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 Radioactive isotopes such as C, or deuterium ( 2 H) or carbon-13 ( 13 The compounds of the present invention may include non-radioactive isotopes such as C). Such isotopic variations may provide additional utility to the compounds described elsewhere in this application. Isotopic variations of the compounds of the present invention may find additional utility, including, but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variations of the compounds of the present invention may alter pharmacokinetic and pharmacodynamic properties, which may contribute to enhanced safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. When specifically referred to as C1-C4 deuteroalkyl, the term refers to an alkyl group having the indicated number of carbon atoms and hydrogen atoms substituted with deuterium from 1 to the number per deuterium form, where the deuterium substitution is greater than the natural abundance of deuterium, typically 50%, 60%, 70%, 80%, 90%, 95% or more. Examples of C1-C4 deuterated alkyls are CD3, CH2CD3, CD2CD3, CH2CH2CH2D, etc.

[0052] As used herein, the term "pharmaceutically acceptable" refers to a material that is compatible with the compounds of the present invention and with any other ingredients with which the compound is formulated. Furthermore, a pharmaceutically acceptable material is not harmful to the recipient of the material. The term "pharmaceutically acceptable salt" refers to those salts that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference).

[0053] Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from appropriate bases include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, etc. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 Alkyl)4 - Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts also include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0054] The term "pharmaceutical composition" as used herein refers to a product comprising a compound of the present invention, excipients as defined herein, and any other ingredients in specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in specified amounts.

[0055] The term "excipient" as used herein refers to a substance that assists in the administration of an active agent to a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will recognize that other excipients may also be useful in the present invention.

[0056] In some embodiments, treatment may be performed after the onset or observation of one or more signs or symptoms of disease.As used herein, the terms " treat ", " treating " and " treatment " refer to any indicator of success in treating or improving the pathology, injury, disease state or symptom associated with systolic dysfunction, DCM, HFrEF or other cardiac disorders, including any objective or subjective parameter such as alleviating, alleviating, or reducing symptoms; making pathology, injury, symptom or sign more tolerable for patients; reducing the frequency or duration of pathology, injury, symptom or sign; or in some cases, preventing the onset of pathology, injury, symptom or sign.Treatment or improvement can be based on any objective or subjective parameter, including, for example, the results of physical examination.

[0057] A "subject" to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young, middle-aged, or elderly adult)) or a non-human animal. A "patient" refers to a human subject in need of treatment for a disease.

[0058] The terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing into or into a subject a polymorphic form of I-491 described herein or a composition thereof.

[0059] The terms "condition," "disease," and "disorder" are used interchangeably.

[0060] The "effective amount" of the polymorphic forms described herein refers to an amount sufficient to elicit a desired biological response, i.e., to treat a symptom. As will be understood by those skilled in the art, the effective amount of the polymorphic forms of I-491 described herein may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the polymorphic form, the symptom to be treated, the mode of administration, and the age and health of the subject. In certain embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is the amount of the polymorphic forms of I-491 described herein in a single administration. In certain embodiments, the effective amount is the amount of the polymorphic forms of I-491 described herein combined in multiple administrations.

[0061] A "therapeutically effective amount" of a polymorphic form of I-491 described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a polymorphic form refers to an amount of a therapeutic agent that, alone or in combination with another therapeutic agent, provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the signs, symptoms, or causes of a condition, and / or enhances the therapeutic effect of another therapeutic agent.

[0062] compound In one embodiment, provided herein is I-491: [ka] Polymorphic forms of I-491 are detailed herein, including Form A, Form B, Form C, and Form D.

[0063] Polymorphs of I-491 can be prepared by the methods generally outlined in the Examples. Those skilled in the art will recognize that the compounds of the present invention and their polymorphs can be prepared using other synthetic methods instead of the transformations provided in the Examples.

[0064] Form A In certain embodiments, the present disclosure provides a polymorph of I-491 characterized as Form A. Generally, Form A is obtained by irradiation with Cu-Kα and has an X-ray powder diffraction pattern having at least three peaks expressed in degrees 2-theta ±0.2 degrees selected from the following degrees: 10.98, 15.78, 16.08, 20.44, 23.78, and 26.58. In some embodiments, Form A is characterized by at least one of: (a) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα and expressed in degrees 2-theta ± 0.2° and having two or more peaks selected from the following degrees: 6.62, 10.98, 13.26, 14.48, 15.02, 15.48, 15.78, 16.08, 16.32, 17.72, 19.26, 19.86, 19.94, 20.44, 21.68, 21.90, 22.04, 22.60, 23.78, 26.16, 26.36, 26.58, 27.24, and 28.04; or (b) a DSC thermogram exhibiting an endotherm between about 181 and 200°C.

[0065] In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu—Kα having peaks expressed in degrees two-theta ±0.2 degrees selected from the following degrees: 6.62, 10.98, 13.26, 14.48, 15.02, 15.48, 15.78, 16.08, 16.32, 17.72, 19.26, 19.86, 19.94, 20.44, 21.68, 21.90, 22.04, 22.60, 23.78, 26.16, 26.36, 26.58, 27.24, and 28.04. In some embodiments, Form A is characterized by 4 or more peaks, 8 or more peaks, 16 or more peaks, or 20 or more peaks expressed in degrees 2 theta ±0.2 degrees selected from the following degrees: 6.62, 10.98, 13.26, 14.48, 15.02, 15.48, 15.78, 16.08, 16.32, 17.72, 19.26, 19.86, 19.94, 20.44, 21.68, 21.90, 22.04, 22.60, 23.78, 26.16, 26.36, 26.58, 27.24, and 28.04.

[0066] In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ± 0.2 degrees at each of the following frequencies: 10.98, 15.78, 16.08, 20.44, 23.78, and 26.58. In some embodiments, Form A is characterized by four or more peaks, alternatively two or more peaks, expressed in degrees 2-theta ± 0.2 degrees at each of the following frequencies: 10.98, 15.78, 16.08, 20.44, 23.78, and 26.58. In some embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ± 0.2 degrees at each of the following frequencies: 10.98, 15.78, 20.44, and 26.58.

[0067] In some embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ± 0.2 degrees at each of the following frequencies: 6.62, 10.98, 16.08, 23.78, and 26.58. In certain embodiments, Form A is characterized by two or more peaks, alternatively four or more peaks expressed in degrees 2-theta ± 0.2 degrees, selected from the following frequencies: 6.62, 10.98, 16.08, 23.78, and 26.58.

[0068] In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ± 0.2 degrees at each of 15.78, 16.08, and 23.78 degrees. In some embodiments, Form A is characterized by two or more peaks expressed in degrees 2-theta ± 0.2 degrees selected from 15.78, 16.08, and 23.78 degrees.

[0069] In some embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ± 0.2 degrees at each of 6.62, 15.78, 16.08, and 26.58 degrees. In some embodiments, Form A is characterized by two or more peaks expressed in degrees 2-theta ± 0.2 degrees selected from 6.62, 15.78, 16.08, and 26.58 degrees.

[0070] In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ± 0.2 degrees at each of the following frequencies: 6.62, 17.72, 23.78, and 26.58. In some embodiments, Form A is characterized by two or more peaks expressed in degrees 2-theta ± 0.2 degrees selected from the following frequencies: 6.62, 17.72, 23.78, and 26.58.

[0071] In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern essentially the same as that depicted in Figure 1A. In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern essentially the same as that depicted in Figure 1B. In certain embodiments, Form A is characterized by an X-ray powder diffraction pattern essentially the same as that depicted in Figure 5.

[0072] In certain embodiments, Form A is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks, expressed in degrees 2-theta ±0.05 degrees, at each of the following frequencies: 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80. In some embodiments, there are no peaks, expressed in degrees 2-theta ±0.05 degrees, at each of the following frequencies: 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80. In certain embodiments, at least two of the ranges consisting of 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 are free of peaks expressed in degrees 2-theta ±0.05°. In certain embodiments, at least four of the ranges consisting of 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 are free of peaks expressed in degrees 2-theta ±0.05°. In some embodiments, only weak peaks expressed in degrees 2-theta ±0.05° are present in each of the ranges 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80. In certain embodiments, only weak intensity peaks, expressed in degrees 2-theta ±0.05°, are present in at least two of the ranges consisting of 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80. In certain embodiments, only weak intensity peaks, expressed in degrees 2-theta ±0.05°, are present in at least four of the ranges consisting of 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80.

[0073] In some embodiments, there are only peaks in each of the following ranges: 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 that are no more than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In particular embodiments, there are only peaks in at least two of the ranges: 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 that are no more than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In certain embodiments, at least four of the ranges consisting of 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 have only peaks that are no more than 1 / 10 of the height of the most intense peak (in the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In some embodiments, at each of the ranges 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 have only peaks that are no more than 1 / 20 of the height of the most intense peak (in the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In certain embodiments, at least two of the ranges consisting of 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 contain only peaks that are no more than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In certain embodiments, at least four of the ranges consisting of 0 to 6.00, 8.00 to 8.90, 11.40 to 12.60, 16.80 to 17.20, and 24.40 to 24.80 contain only peaks that are no more than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°.

[0074] In some embodiments, Form A is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking a peak expressed in degrees 2-theta ±0.05° between 24.40 and 24.80. In certain embodiments, there is no peak expressed in degrees 2-theta ±0.05° between 24.40 and 24.80. In certain embodiments, there is only a weakly intense peak expressed in degrees 2-theta ±0.05° between 24.40 and 24.80. In certain embodiments, there is only a peak expressed in degrees 2-theta ±0.05° that is no more than 1 / 10 the height of the most intense peak (within the same diffraction pattern) between 24.40 and 24.80. In certain embodiments, there are only peaks between 24.40 and 24.80 degrees that are 1 / 20 or less in height than the most intense peak (within the same diffraction pattern) expressed in degrees 2 theta ±0.05°.

[0075] In certain embodiments, Form A is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks, expressed in degrees 2-theta ±0.05°, at each of the following frequencies: 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80. In some embodiments, no peaks are present at frequencies 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80. In certain embodiments, no peaks, expressed in degrees 2-theta ±0.05°, are present in at least two ranges selected from frequencies 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80. In some embodiments, only weakly intense peaks, expressed in degrees 2-theta ±0.05°, are present at frequencies 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80. In certain embodiments, only weakly intense peaks, expressed in degrees 2-theta ±0.05°, are present in at least two of the ranges selected from 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80. In some embodiments, only peaks that are 1 / 20 or less in height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05° are present in the ranges 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80. In certain embodiments, only peaks that are 1 / 20 or less in height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05° are present in at least two of the ranges selected from 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80. In some embodiments, there are only peaks present in the ranges 0-6.00, 11.40-12.60, and 24.40-24.80 that are no more than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In particular embodiments, there are only peaks present in at least two of the ranges selected from 0-6.00, 11.40-12.60, and 24.40-24.80 that are no more than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°.

[0076] In some embodiments, Form A is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking a peak expressed in degrees 2-theta ±0.05° between 11.40 and 12.60. In certain embodiments, there is no peak expressed in degrees 2-theta ±0.05° between 11.40 and 12.60. In certain embodiments, there is only a weakly intense peak expressed in degrees 2-theta ±0.05° between 11.40 and 12.60. In certain embodiments, there is only a peak expressed in degrees 2-theta ±0.05° that is no more than 1 / 20th the height of the most intense peak (within the same diffraction pattern) between 11.40 and 12.60. In certain embodiments, there are only peaks present that are 1 / 10 or less in height than the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05° between 11.40 and 12.60 degrees.

[0077] In some embodiments, Form A is characterized by a DSC thermogram substantially the same as that shown in Figure 2. In some embodiments, Form A is characterized by a DSC thermogram exhibiting an endotherm at about 181-200°C. In particular embodiments, Form A is characterized by an onset of melting at about 181°C. In some embodiments, Form A is characterized by a melting point of 191°C ± 2°C.

[0078] In certain embodiments, Form A is characterized by the structure represented in Figure 3. In certain embodiments, Form A is characterized by the structure represented in Figure 4. In some embodiments, Form A has a triclinic crystal system and a space group of P1. In certain embodiments, Form A has unit cell dimensions of a=6.403 Å, b=11.343 Å, c=13.507 Å, α=81.91°, β=85.73°, and γ=85.18°.

[0079] In certain embodiments of the present disclosure, Form A is substantially free of other forms of tert-butyl-(R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)piperidine-1-carboxylate. In particular, Form A is substantially free of Form D of tert-butyl-(R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)piperidine-1-carboxylate. In some embodiments, Form A is substantially free of amorphous tert-butyl-(R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)piperidine-1-carboxylate.

[0080] In another embodiment, provided herein are compositions comprising Form A. In some embodiments, the compositions comprise 75% or more Form A by weight. In some embodiments, the compositions comprise 85% or more Form A by weight. In some embodiments, the compositions comprise 90% or more Form A by weight. In some embodiments, the compositions comprise 95% or more Form A by weight. In some embodiments, the compositions comprise 98% or more Form A by weight. In some embodiments, the compositions comprise 99% or more Form A by weight. In some embodiments, the compositions comprise 99.5% or more Form A by weight. In some embodiments, the compositions comprise 99.9% or more Form A by weight. In another embodiment, provided herein are compositions wherein the molar ratio of the amount of Form A to the total amount of other polymorphic forms is equal to or greater than 80:20. In another embodiment, the molar ratio of the amount of Form A to the total amount of other forms is equal to or greater than 90:10. In another embodiment, the molar ratio of the amount of Form A to the total amount of other forms is equal to or greater than 95:5. In another embodiment, the molar ratio of the amount of Form A to the total amount of other forms is equal to or greater than 97:3. In another embodiment, the molar ratio of the amount of Form A to the total amount of other forms is equal to or greater than 98:2. In another embodiment, the molar ratio of the amount of Form A to the total amount of other forms is equal to or greater than 99:1. In another embodiment, the molar ratio of the amount of Form A to the total amount of other forms is equal to or greater than 99.5:0.5.

[0081] In another embodiment, provided herein is a composition wherein the molar ratio of the amount of Form A to the amount of polymorphic Form D is equal to or greater than 80:20. In another embodiment, the molar ratio of the amount of Form A to the amount of Form D is equal to or greater than 90:10. In another embodiment, the molar ratio of the amount of Form A to the amount of Form D is equal to or greater than 95:5. In another embodiment, the molar ratio of the amount of Form A to the amount of Form D is equal to or greater than 97:3. In another embodiment, the molar ratio of the amount of Form A to the amount of Form D is equal to or greater than 98:2. In another embodiment, the molar ratio of the amount of Form A to the amount of Form D is equal to or greater than 99:1. In another embodiment, the molar ratio of the amount of Form A to the amount of Form D is equal to or greater than 99.5:0.5.

[0082] Also provided herein are compositions comprising Form A that are substantially free of solvent. In some embodiments, Form A is a solvate. In certain embodiments, the composition has less than 6% solvent by weight. In some embodiments, the composition has less than 3% solvent by weight. In certain embodiments, the composition has less than 2% solvent by weight. In some embodiments, the composition has less than 0.5% solvent by weight. In certain embodiments, the solvent is methanol. In some embodiments, the solvent is ethanol. In certain embodiments, the solvent is acetone. In other embodiments, the solvent is acetonitrile.

[0083] Form B In certain embodiments, the present disclosure provides a polymorph of I-491 characterized as Form B. Generally, Form B can be obtained by irradiation with Cu-Kα and has an X-ray powder diffraction pattern having at least three peaks expressed in degrees 2-theta ±0.2 degrees selected from the following frequencies: 15.42, 16.28, 19.02, 20.70, and 26.88. In some embodiments, Form B is characterized by at least one of: (a) an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ± 0.2°, and having two or more peaks selected from the following degrees: 7.32, 7.88, 10.20, 10.88, 13.40, 14.68, 15.24, 15.42, 16.28, 17.70, 18.48, 19.02, 20.18, 20.70, 21.56, 21.98, 22.94, 23.16, 23.86, 24.24, 24.78, 25.38, 26.40, 26.88, and 28.74; or (b) a DSC thermogram exhibiting an endotherm at about 170-185°C.

[0084] In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern, obtained by irradiation with Cu-Kα, having peaks selected from the following frequencies, each of which is expressed in degrees 2-theta ±0.2 degrees, and which are 7.32, 7.88, 10.20, 10.88, 13.40, 14.68, 15.24, 15.42, 16.28, 17.70, 18.48, 19.02, 20.18, 20.70, 21.56, 21.98, 22.94, 23.16, 23.86, 24.24, 24.78, 25.38, 26.40, 26.88, and 28.74. In some embodiments, Form B is characterized by 4 or more peaks, 8 or more peaks, 16 or more peaks, or 20 or more peaks, expressed in degrees 2-theta ±0.2 degrees, selected from the following: 7.32, 7.88, 10.20, 10.88, 13.40, 14.68, 15.24, 15.42, 16.28, 17.70, 18.48, 19.02, 20.18, 20.70, 21.56, 21.98, 22.94, 23.16, 23.86, 24.24, 24.78, 25.38, 26.40, 26.88, and 28.74 degrees.

[0085] In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ±0.2° at 7.88, 10.20, 20.70, and 26.88, respectively. In some embodiments, Form B is characterized by three peaks or two peaks expressed in degrees 2-theta ±0.2° at 7.88, 10.20, 20.70, and 26.88, respectively.

[0086] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ±0.2° at 7.32, 7.88, 10.20, and 18.48, respectively. In particular embodiments, Form B is characterized by two or more peaks, alternatively three or more peaks selected from 7.32, 7.88, 10.20, and 18.48.

[0087] In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ± 0.2 degrees, respectively, at 7.32, 16.28, and 26.88 degrees 2-theta ± 0.2 degrees. In some embodiments, Form B is characterized by two or more peaks expressed in degrees 2-theta ± 0.2 degrees selected from 7.32, 16.28, and 26.88 degrees.

[0088] In some embodiments, Form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in degrees 2-theta ± 0.2 degrees at 7.88, 15.42, 17.70, and 21.56, respectively. In some embodiments, Form B is characterized by two or more peaks expressed in degrees 2-theta ± 0.2 degrees selected from 7.88, 15.42, 17.70, and 21.56.

[0089] In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern essentially the same as that depicted in Figure 6A. In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern essentially the same as that depicted in Figure 6B. In certain embodiments, Form B is characterized by an X-ray powder diffraction pattern essentially the same as that depicted in Figure 10.

[0090] In certain embodiments, Form B is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking a peak expressed in degrees 2-theta ±0.05° at each of the ranges 0 to 6.80 and 8.15 to 9.00. In certain embodiments, there is no peak expressed in degrees 2-theta ±0.05° in at least one of the ranges consisting of 0 to 6.80 and 8.15 to 9.00. In some embodiments, only a weakly intense peak expressed in degrees 2-theta ±0.05° is present in each of the ranges 0 to 6.80 and 8.15 to 9.00. In certain embodiments, there is only a weakly intense peak expressed in degrees 2-theta ±0.05° in at least one of the ranges consisting of 0 to 6.80 and 8.15 to 9.00. In some embodiments, in each of the ranges 0 to 6.80 and 8.15 to 9.00, there are only peaks that are no more than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In particular embodiments, in at least one of the ranges 0 to 6.80 and 8.15 to 9.00, there are only peaks that are no more than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In some embodiments, in each of the ranges 0 to 6.80 and 8.15 to 9.00, there are only peaks that are no more than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In certain embodiments, at least one of the ranges consisting of 0 to 6.80 and 8.15 to 9.00 has only peaks that are 1 / 10 or less in height than the most intense peak (within the same diffraction pattern) expressed in degrees 2 theta ±0.05°.

[0091] In some embodiments, Form B is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking peaks expressed in degrees 2-theta ±0.05° from 0 to 6.80. In certain embodiments, no peaks expressed in degrees 2-theta ±0.05° are present from 0 to 6.80. In certain embodiments, only weakly intense peaks expressed in degrees 2-theta ±0.05° are present from 0 to 6.80. In certain embodiments, only peaks that are no greater than 1 / 20th the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05° are present from 0 to 6.80. In certain embodiments, only peaks that are no greater than 1 / 10th the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05° are present from 0 to 6.80.

[0092] In certain embodiments, Form B is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα lacking a peak expressed in degrees 2-theta ±0.05° at each of the 8.15-9.00 power increments. In some embodiments, no peak expressed in degrees 2-theta ±0.05° is present at each of the 8.15-9.00 power increments. In some embodiments, only weakly intense peaks expressed in degrees 2-theta ±0.05° are present at each of the 8.15-9.00 power increments. In some embodiments, only peaks are present at each of the 8.15-9.00 power increments that are no more than 1 / 20th the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°. In some embodiments, only peaks are present at each of the 8.15-9.00 power increments that are no more than 1 / 10th the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ±0.05°.

[0093] In some embodiments, Form B is characterized by a DSC thermogram substantially the same as that shown in Figure 7. In some embodiments, Form B is characterized by a DSC thermogram exhibiting an endotherm at about 170-185°C. In particular embodiments, Form B is characterized by an onset of melting at about 170°C. In some embodiments, Form B is characterized by a melting point of 178°C ± 2°C. In some embodiments, Form B is characterized by a DSC thermogram exhibiting a second endotherm at about 185-200°C. In some embodiments, Form B is characterized by a second melting point of 192.7°C ± 2°C.

[0094] In certain embodiments, Form B is characterized by the structure represented in Figure 8. In certain embodiments, Form B is characterized by the structure represented in Figure 9. In some embodiments, Form B has a triclinic crystal system and a space group of P1. In certain embodiments, Form B has unit cell dimensions of a=11.926 Å, b=13.239 Å, c=13.511 Å, α=65.40°, β=80.08°, and γ=89.18°.

[0095] In certain embodiments of the present disclosure, Form B is substantially free of other forms of tert-butyl-(R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)piperidine-1-carboxylate. In particular, Form B is substantially free of Form A and / or Form D of tert-butyl-(R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)piperidine-1-carboxylate. In some embodiments, Form B is substantially free of amorphous tert-butyl-(R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)piperidine-1-carboxylate.

[0096] In another embodiment, provided herein are compositions comprising Form B. In some embodiments, the compositions comprise 99.5% or more by weight of Form B. In another embodiment, provided herein are compositions wherein the molar ratio of the amount of Form B to the total amount of other polymorphic forms is equal to or greater than 80:20. In another embodiment, the molar ratio of the amount of Form B to the total amount of other forms is equal to or greater than 90:10. In another embodiment, the molar ratio of the amount of Form B to the total amount of other forms is equal to or greater than 95:5. In another embodiment, the molar ratio of the amount of Form B to the total amount of other forms is equal to or greater than 97:3. In another embodiment, the molar ratio of the amount of Form B to the total amount of other forms is equal to or greater than 98:2. In another embodiment, the molar ratio of the amount of Form B to the total amount of other forms is equal to or greater than 99:1. In another embodiment, the molar ratio of the amount of Form B to the total amount of the other forms is equal to or greater than 99.5:0.5.

[0097] Also provided herein are compositions comprising Form B that are substantially free of solvent. In certain embodiments, the composition has less than 6% by weight of solvent. In some embodiments, the composition has less than 3% by weight of solvent. In certain embodiments, the composition has less than 1% by weight of solvent. In some embodiments, the composition has less than 0.7% by weight of solvent. In certain embodiments, the solvent is a mixture of water and methanol. In some embodiments, the solvent is a mixture of water and ethanol. In other embodiments, the solvent is a mixture of water and acetonitrile. In other embodiments, the solvent is water.

[0098] Form C Also provided herein is Form C of I-491. Generally, Form C is obtained by irradiation with Cu-Kα and has an X-ray powder diffraction pattern having at least three peaks expressed in degrees 2-theta ±0.2 degrees selected from the following frequencies: 11.78, 15.14, 19.08, 20.54, and 21.02.

[0099] In certain embodiments, Form C is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 13A. In certain embodiments, Form C is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 13B.

[0100] In some embodiments, Form C is characterized by a DSC thermogram exhibiting an endotherm at about 175-189°C. In some embodiments, Form C is characterized by a melting point of 185.9°C ± 2°C. In some embodiments, Form C is characterized by a DSC thermogram exhibiting a second endotherm at about 193-201°C. In some embodiments, Form C is characterized by a second melting point of 190°C ± 2°C.

[0101] In some embodiments, Form C is characterized by the structure represented in Figure 12A. In other embodiments, Form C is characterized by the structure represented in Figure 12B. In some embodiments, Form C has a monoclinic crystal system and a space group of P21. In particular embodiments, Form C has unit cell dimensions of a(Å)=14.47, b(Å)=17.28, c(Å)=16.11, α(°)=90.00, β(°)=109.85, and γ(°)=90.00.

[0102] Form D Also provided herein is I-491 Form D. Generally, I-491 Form D is obtained by irradiation with Cu-Kα and has an X-ray powder diffraction pattern having at least three peaks expressed in degrees 2-theta ±0.2 degrees selected from the following frequencies: 11.42, 14.72, 19.52, 19.82, and 20.44.

[0103] In some embodiments, Form D is characterized by the structure represented in Figure 14. In other embodiments, Form D is characterized by the structure represented in Figure 15. In some embodiments, Form D is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 16. In some embodiments, Form D has a triclinic crystal system and a space group of P1. In particular embodiments, Form D has unit cell dimensions of a(Å)=9.78, b(Å)=13.86, c(Å)=16.11, α(°)=65.39, β(°)=84.54, and γ(°)=72.42.

[0104] Pharmaceutical Composition In another aspect, provided herein are pharmaceutical compositions containing a polymorph of I-491, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, which are useful for treating cardiac disorders associated with systolic dysfunction, including dilated cardiomyopathy and HFrEF, in humans and other subjects.

[0105] Pharmaceutical compositions for administering the polymorphs provided herein, or pharmaceutically acceptable salts thereof, may conveniently be administered in unit dosage form and may be prepared by any method known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the carrier containing one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition generally contains the active agent in an amount sufficient to increase myocardial contractility (i.e., improve systolic dysfunction in DCM or HFrEF) and improve or not worsen left ventricular relaxation during diastole. Such improvement in relaxation can alleviate symptoms in other etiologies of diastolic dysfunction, such as dilated cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). It can also improve the effects of diastolic dysfunction that result in coronary flow impairment and can improve coronary flow impairment as an adjunct agent in angina pectoris and ischemic heart disease. It may also provide benefit to beneficial left ventricular remodeling in DCM and other causes of left ventricular dysfunction due to chronic volume or pressure overload, for example, from ischemic heart disease or myocardial infarction, valvular heart disease, or systemic hypertension.

[0106] In another embodiment, provided herein is a pharmaceutical composition comprising polymorph Form A. In another embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. Provided herein is a pharmaceutical composition, wherein the molar ratio of the amount of polymorph Form A to the total amount of other forms is equal to or greater than 80:20. In another embodiment, the molar ratio of the amount of polymorph Form A to the total amount of other forms is equal to or greater than 90:10. In another embodiment, the molar ratio of the amount of polymorph Form A to the total amount of other forms is equal to or greater than 95:5. In another embodiment, the molar ratio of the amount of polymorph Form A to the total amount of other forms is equal to or greater than 97:3. In another embodiment, the molar ratio of the amount of polymorph Form A to the total amount of other forms is equal to or greater than 98:2. In another embodiment, the molar ratio of the amount of polymorph Form A to the total amount of other forms is equal to or greater than 99:1.

[0107] In some embodiments, the pharmaceutical composition comprising the Form A polymorph further comprises an additional agent. Exemplary, non-limiting additional agents include agents that slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); agents that improve cardiac function by stimulating cardiac contraction (e.g., a positive inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or agents that reduce cardiac preload (e.g., a diuretic such as furosemide) or afterload (a vasodilator of any class, including, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator). In certain embodiments, the additional agent in the pharmaceutical composition is a cardiovascular drug.

[0108] In another embodiment, provided herein is a pharmaceutical composition comprising Form B polymorph. In another embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In another embodiment, provided herein is a pharmaceutical composition, wherein the molar ratio of the amount of Form B polymorph to the total amount of other forms is equal to or greater than 80:20. In another embodiment, the molar ratio of the amount of Form B polymorph to the total amount of other forms is equal to or greater than 90:10. In another embodiment, the molar ratio of the amount of Form B polymorph to the total amount of other forms is equal to or greater than 95:5. In another embodiment, the molar ratio of the amount of Form B polymorph to the total amount of other forms is equal to or greater than 97:3. In another embodiment, the molar ratio of the amount of Form B polymorph to the total amount of other forms is equal to or greater than 98:2. In another embodiment, the molar ratio of the amount of Form B polymorph to the total amount of other forms is equal to or greater than 99:1.

[0109] In some embodiments, the pharmaceutical composition comprising the Form B polymorph further comprises an additional agent. Exemplary, non-limiting additional agents include agents that slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); agents that improve cardiac function by stimulating cardiac contraction (e.g., positive inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone; and / or agents that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (vasodilators of any class, including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). In certain embodiments, the additional agent in the pharmaceutical composition is a cardiovascular drug.

[0110] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, liquids, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets.Compositions intended for oral use may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a pharmaceutically elegant and palatable formulation.Tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated, or they may be enterically coated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated to form osmotic therapeutic tablets for controlled release.

[0111] The preparation for oral use can also be provided as a hard gelatin capsule, in which active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, in which active ingredient is mixed with water or oil medium such as peanut oil, liquid paraffin or olive oil.In addition, emulsion can be made with non-water-miscible ingredients such as oil, and stabilized with surfactant such as mono-diglyceride, PEG ester etc.

[0112] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions, such as suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as naturally occurring phosphatides, for example, lecithin; condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0113] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickening agents, such as beeswax, mineral paraffin, or cetyl alcohol. Sweeteners and flavoring agents, such as those mentioned above, may also be added to provide a palatable oral preparation. These compositions may be preserved by adding an antioxidant, such as ascorbic acid.

[0114] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water are prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, and one or more preservatives.Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be added.

[0115] The pharmaceutical compositions provided herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as acacia gum or tragacanth gum, naturally occurring phosphatides, such as soybean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0116] Syrups and elixirs may be formulated with sweeteners such as glycerol, polyethylene glycol, sorbitol or sucrose. Such preparations may also contain anti-inflammatory agents, preservatives, and flavoring and coloring agents. Oral liquid preparations may be prepared in combination with, for example, cyclodextrin, PEG and surfactants.

[0117] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable preparations may also be used as a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0118] The polymorphs provided herein or their pharmaceutically acceptable salts may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with suitable non-irritating ingredients that are solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter and polyethylene glycol. In addition, the compounds can be administered via ocular delivery by means of solutions or ointments. Furthermore, transdermal delivery of the target compounds can be achieved by means of iontophoresis patches and the like. For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds provided herein or their pharmaceutically acceptable salts are utilized. As used herein, topical application also includes the use of mouthwashes and gargles.

[0119] The polymorphs of the present invention may also be coupled to carriers that are polymers suitable for targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the polymorphs provided herein, or pharmaceutically acceptable salts thereof, may be coupled to carriers that are biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles such as valves, stents, tubes, prostheses, etc.

[0120] Pharmaceutical Compositions Comprising Form A In certain embodiments of the present disclosure, provided herein are pharmaceutical compositions comprising Form A and a diluent. In some embodiments, the pharmaceutical composition further comprises a disintegrant. In certain embodiments, the pharmaceutical composition further comprises a binder. In some embodiments, the pharmaceutical composition further comprises a lubricant.

[0121] In some embodiments, the pharmaceutical composition comprises Form A and a diluent selected from the group consisting of calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and combinations of any of the above diluents. In some embodiments, the pharmaceutical composition further comprises a disintegrant selected from the group consisting of agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures of any of the above disintegrants. In certain embodiments, the pharmaceutical composition further comprises a binder selected from the group consisting of starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, breadwort gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and mixtures of any of the foregoing binders. In certain embodiments, the pharmaceutical composition further comprises a lubricant selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl betaine, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures of any of the foregoing lubricants.

[0122] Pharmaceutical Compositions Comprising Form B In certain embodiments of the present disclosure, provided herein are pharmaceutical compositions comprising Form B and a diluent. In some embodiments, the pharmaceutical composition further comprises a disintegrant. In certain embodiments, the pharmaceutical composition further comprises a binder. In some embodiments, the pharmaceutical composition further comprises a lubricant.

[0123] In some embodiments, the pharmaceutical composition comprises Form B and a diluent selected from the group consisting of calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures of any of the above diluents. In some embodiments, the pharmaceutical composition further comprises a disintegrant selected from the group consisting of agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures of any of the above disintegrants. In certain embodiments, the pharmaceutical composition further comprises a binder selected from the group consisting of starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, breadwort gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and mixtures of any of the foregoing binders. In certain embodiments, the pharmaceutical composition further comprises a lubricant selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl betaine, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures of any of the foregoing lubricants.

[0124] In some embodiments, the pharmaceutical composition comprises Form B, at least one diluent, at least one disintegrant, at least one binder, and / or at least one lubricant. In certain embodiments, Form B comprises about 1-55% by weight of the composition. In certain embodiments, Form B comprises about 1-20% by weight of the composition. In certain embodiments, the one or more diluents comprise about 30-95% by weight of the composition. In certain embodiments, the one or more diluents comprise about 40-95% by weight of the composition. In certain embodiments, the one or more diluents comprise about 75-95% by weight of the composition. In certain embodiments, the one or more disintegrants comprise about 0-10% by weight of the composition. In certain embodiments, the one or more disintegrants comprise about 0-5% by weight of the composition. In certain embodiments, the one or more binders comprise about 0-10% by weight of the composition. In certain embodiments, the one or more binders comprise about 0-5% by weight of the composition. In certain embodiments, the one or more lubricants comprise about 0-10% by weight of the composition. In certain embodiments, the one or more lubricants comprise about 0-5% by weight of the composition.

[0125] In certain embodiments of the disclosure, provided herein are pharmaceutical compositions comprising Form B, lactose, cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate. In some embodiments, the pharmaceutical compositions comprise Form B, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate.

[0126] Treatment for heart problems Mutations that lead to DCM cause significant perturbations in myosin mechanics. These mutations exert their effects through different mechanisms depending on their location in the myosin gene. Without wishing to be bound by any particular theory, it is believed that the compounds provided herein, or pharmaceutically acceptable salts thereof, may bind directly to mutant sarcomeric proteins, either in cis (by affecting the same specific function) or in trans (by altering a complementary function), correcting their abnormal function. Therefore, the compounds may provide therapeutic benefit to DCM patients by counteracting the reduced contractility and / or impaired relaxation associated with the disease. In addition, these compounds that increase contractile function are believed to hold promise for the treatment of a wide range of disorders whose symptoms and / or clinical outcomes result from systolic dysfunction (left- or right-sided heart failure) or reduced contractile reserve (e.g., HFpEF).

[0127] Accordingly, the present invention provides methods for treating systolic dysfunction. Additionally, methods for treating DCM are provided. Provided herein are methods for treating HFrEF. The disclosure also provides methods for treating cardiac disorders having one or more pathophysiological characteristics associated with DCM, such as dilated cardiomyopathy (DCM) or disorders with systolic dysfunction or reduced contractile reserve. The methods comprise administering to a subject in need thereof an effective amount of a polymorph or composition provided herein.

[0128] In particular, the present invention provides a method for treating systolic dysfunction by administering an effective amount of polymorphic Form B of I-491 to a subject in need thereof. Also provided is a method for treating DCM by administering an effective amount of polymorphic Form B of I-491 to a subject in need thereof. Also provided herein is a method for treating HFrEF by administering an effective amount of polymorphic Form B of I-491 to a subject in need thereof. The disclosure also provides a method for treating a cardiac disorder having one or more pathophysiological characteristics associated with dilated cardiomyopathy (DCM) or a disorder with systolic dysfunction or reduced contractile reserve by administering an effective amount of polymorphic Form B of I-491 to a subject in need thereof.

[0129] Also provided herein are methods for treating systolic dysfunction by administering an effective amount of polymorphic Form A of I-491 to a subject in need thereof, methods for treating DCM by administering an effective amount of polymorphic Form A of I-491 to a subject in need thereof, and methods for treating HFrEF by administering an effective amount of polymorphic Form A of I-491 to a subject in need thereof. The disclosure also provides methods for treating cardiac disorders having one or more pathophysiological characteristics associated with DCM, such as dilated cardiomyopathy (DCM) or disorders with systolic dysfunction or reduced contractile reserve, by administering an effective amount of polymorphic Form A of I-491 to a subject in need thereof.

[0130] The compounds of the present invention and their polymorphs or pharmaceutically acceptable salts may not only alleviate symptoms but also alter the natural course of DCM and other diseases. The mechanism of clinical benefit for DCM patients may extend to patients with other forms of cardiac disease that share similar pathophysiology, with or without demonstrable genetic influence. For example, effective treatment of DCM by improving ventricular contraction may also be effective in a broad population characterized by systolic dysfunction. The compounds of the present invention and their polymorphs or pharmaceutically acceptable salts may specifically target the underlying cause of the symptoms or act on other downstream pathways. Thus, the compounds of the present invention and their polymorphs or pharmaceutically acceptable salts may benefit patients suffering from heart failure with reduced ejection fraction (HFrEF), HFpEF, chronic congestive heart failure, acute heart failure, right-sided (or right ventricular) heart failure, cardiogenic shock, and inotropic support following cardiac surgery. The compounds and polymorphs of the present invention, or pharmaceutically acceptable salts thereof, may improve cardiac function in the following patient segments: idiopathic dilated cardiomyopathy, genetically determined or familial dilated cardiomyopathy, ischemic or post-infarction cardiomyopathy, viral cardiomyopathy or myocarditis, toxic cardiomyopathy (e.g., after anthracycline anti-cancer therapy), metabolic cardiomyopathy (in combination with enzyme replacement therapy), diastolic heart failure (with reduced contractile reserve), right heart failure due to pulmonary hypertension, and ventricular dysfunction due to cardiovascular bypass surgery. The compounds and polymorphs of the present invention, or pharmaceutically acceptable salts thereof, may also promote beneficial reverse ventricular remodeling in left ventricular dysfunction due to ischemia or volume or pressure overload, such as myocardial infarction, chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension. The compounds and polymorphs may improve symptoms of dyspnea and reduce the risk of pulmonary edema and respiratory failure by reducing left ventricular filling pressure. By reducing or eliminating functional mitral regurgitation and / or lowering left atrial pressure, it may reduce the risk of paroxysmal or permanent atrial fibrillation, which may also reduce the associated risk of arterial thromboembolic complications (including, but not limited to, cerebral arterial embolic stroke).The compounds and polymorphs, or pharmaceutically acceptable salts thereof, may reduce the severity of the chronic ischemic condition associated with DCM, thereby reducing the risk of sudden cardiac death (SCD) or its equivalent in patients with implanted cardioverter-defibrillators (frequent and / or repeated ICD discharges) and / or the need for potentially toxic antiarrhythmic medications. The compounds and polymorphs, or pharmaceutically acceptable salts thereof, may be useful in reducing or eliminating the need for concomitant medications with their associated toxicities, drug-drug interactions, and / or potentially side effects. The compounds and polymorphs, or pharmaceutically acceptable salts thereof, may reduce interstitial myocardial fibrosis and / or slow, halt, or reverse the progression of left ventricular stiffness and diastolic dysfunction.

[0131] The present disclosure provides methods of treating systolic dysfunction in a patient in need thereof. In some embodiments, the patient is suffering from heart failure (including, but not limited to, heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), congestive heart failure, and diastolic heart failure (heart failure with reduced contractile reserve)); cardiomyopathies (including, but not limited to, ischemic cardiomyopathy, dilated cardiomyopathy, post-infarction cardiomyopathy, viral cardiomyopathy, toxic cardiomyopathy (including, but not limited to, after anthracycline anticancer drug therapy), metabolic cardiomyopathy (including, but not limited to, in combination with enzyme replacement therapy), infiltrative cardiomyopathy (including, but not limited to, amyloidosis), and diabetic cardiomyopathy. The patient is suffering from a syndrome or disorder selected from the group consisting of: cardiomyopathy; cardiogenic shock; conditions benefiting from inotropic support after cardiac surgery (e.g., ventricular dysfunction due to bypass cardiovascular surgery); myocarditis (including, but not limited to, viral); atherosclerosis; secondary hyperaldosteronism; myocardial infarction; valvular disease (including, but not limited to, mitral regurgitation and aortic stenosis); systemic hypertension; pulmonary hypertension (i.e., pulmonary arterial hypertension); adverse vascular remodeling; pulmonary edema; and respiratory failure. In certain embodiments, the syndrome or disorder may be chronic and / or stable. In some embodiments, the patient has heart failure and has been diagnosed with any one of NYHA classes II to IV. In certain embodiments, the patient has symptomatic heart failure. In some embodiments, the patient has acute heart failure.

[0132] In some embodiments, the patient with HFrEF also exhibits mitral regurgitation. In some embodiments, the HFrEF is ischemic HFrEF. In some embodiments, the HFrEF is dilated cardiomyopathy (DCM); optionally, the patient has a genetic predisposition to DCM or genetic DCM (which may be caused by a pathogenic or potentially pathogenic variant in a gene associated with cardiac function, including, but not limited to, a MYH7 or Titin mutation).

[0133] Depending on the disease to be treated and the condition of the subject, the compounds and polymorphs provided herein, or pharmaceutically acceptable salts thereof, may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intrapleural injection or infusion, subcutaneous injection, or implantation), by implantation (e.g., as when the compound or polymorph is associated with a stent device), by inhalation spray, via nasal, vaginal, rectal, sublingual, or topical routes of administration, and may be formulated, alone or together, into appropriate dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each route of administration.

[0134] It will be understood, however, that the specific dose level and frequency of administration for any particular patient may vary and will depend upon a variety of factors, including the activity of the particular compound or polymorph employed, the metabolic stability and duration of action of that compound or polymorph, the age, weight, genetic characteristics, health, sex, and diet of the subject, as well as the mode or time of administration, rate of excretion, drug combination, and the severity of the individual symptoms of the subject being treated.

[0135] The compounds, polymorphs, and compositions provided herein may be used in combination with other drugs used in the treatment, prevention, suppression, or amelioration of diseases or conditions for which the compounds, polymorphs, and compositions provided herein are useful. Such other drugs may be administered simultaneously or sequentially with the compounds, polymorphs, or compositions provided herein by a route and in an amount commonly used therefor. When the compounds, polymorphs, or compositions provided herein are used contemporaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds, polymorphs, or compositions provided herein are preferred. Thus, pharmaceutical compositions provided herein include those containing one or more other active ingredients or therapeutic agents in addition to the compounds, polymorphs, or compositions provided herein. Suitable additional active agents include, for example: therapeutic agents that slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); therapeutic agents that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and therapeutic agents that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (vasodilators of any class, including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). The compounds, polymorphs, or pharmaceutically acceptable salts thereof may be used in combination with beta-blockers (a class of drugs with known side effects due to negative inotropic effects) to provide unique tolerability for target dose titration of the beta-blocker. The compounds, polymorphs, or pharmaceutically acceptable salts thereof may be used in combination with myocardial relaxants to treat diastolic heart failure (or HFpEF, a disorder associated with diastolic dysfunction and reduced contractile reserve).The weight ratio of the compound or polymorph provided herein to the second active ingredient may be varied and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used.

[0136] Example In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described herein are provided to illustrate the compounds, polymorphs, pharmaceutical compositions, and methods provided herein, and should not be construed in any way as limiting the scope thereof.

[0137] Example 1. Preparation of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491) I-491 was synthesized as described in US Pat. No. 9,925,177.

[0138] Example 2. Polymorph evaporation experiments Solutions of I-491 were prepared in various solvents at room temperature. Once the mixtures reached complete dissolution, as judged by visual observation, the solutions were evaporated to dryness from open vials at room temperature. The solids were analyzed by XRPD.

[0139] Table 1 [Table 1]

[0140] Example 3. Polymorph Slurry Experiments Selected solvents were pre-saturated by slurrying with I-491 at the selected temperature. A small amount of I-491 (20 mg / mL) was then added, and the suspension was slurried at the indicated temperature for 2 weeks. Solids were collected by vacuum filtration and analyzed by XRPD and TGA. The results are reported in Tables 2 and 3.

[0141] In the first series of experiments (Table 2), conducted using various amounts of water, a non-hydrated form designated Form B was isolated. In the second series of experiments (Table 3), Form B was isolated by slurrying in various solvents without water at room temperature. At 50°C, a mixture of Forms A and / or B plus Form C was obtained.

[0142] Table 2 [Table 2]

[0143] Table 3 [Table 3]

[0144] Example 4. Relative Stability and Interconversion of Polymorphs The relative stabilities of Form A+εD and Form B were evaluated by interconversion slurry experiments in acetonitrile and water mixtures at different temperatures. The solvent was pre-saturated by slurrying with Form A+εD at the selected temperature. A 1:1 (w / w) mixture of Form A+εD and B was then added to each mother liquor sample and slurried for 18 hours at the selected temperature. The solids were collected by vacuum filtration and analyzed by XRPD, TGA, and DSC. The results are reported in Table 4. Form B was found to be more stable than Form A at temperatures ranging from room temperature to 70°C.

[0145] Table 4 [Table 4]

[0146] Example 5. Characterization of Form A A representative XRPD pattern of Form A is shown in Figure 1B (acquisition parameters: Panalytical X-pert Pro MPD PW3040 Pro; X-ray tube = Cu (1.54059 Å); voltage = 45 kV; current = 40 mA; scan range = 1.00-39.99° 2θ; collection time: 718 s; scan rate = 3.3° / min; slits = DS: fixed slit 1 / 2°; SS = null; rotation time = 1.0 s; mode = transmission).

[0147] The DSC thermogram (parameters: equilibrium at 0.00°C, ramp at 10.00°C / min to 250.00°C) shows a single endothermic event associated with the melting of the crystalline product characterized by a melting point of 191°C and an enthalpy of fusion of 75 J / g (Figure 2). A continuous small mass loss of 1.7% is observed by TGA between room temperature and 149°C (Figure 2). The DVS isotherm demonstrates that Form A is non-hygroscopic.

[0148] Synchrotron XRPD & Single Crystal Powder samples of I-491 were sealed in 0.8 mm thin-walled borosilicate glass capillaries and then analyzed by high-resolution synchrotron XRD at the European Synchrotron Radiation Facility (Beam Line ID22, ESRF Grenoble) (Fitch, AN Mater. Sci. Forum 1996, 228-231; Experiment Register: in 952). Powder diffraction data (0.5° < 2θ < 38°) were recorded at room temperature in transmission mode using Beam Line ID31 at a wavelength of 1.0 Å (12.40 keV) and a step size of 0.003°. To eliminate any degrading effects of beam irradiation and improve counting statistics, measurements were made using an apparatus allowing horizontal translation of the capillary, so that each individual data set was obtained only from the unirradiated region of the powder (original recording). After profile normalization and background smoothing, 29 non-overlapping peaks located in the low- to medium-angle region of the resulting powder diagram were used for cell measurements. The synchrotron powder XRD pattern of I-491 shown in Figure 1A could be indexed to a triclinic unit cell whose parameters are given below (Boultif, A.; Louer, D. J. Appl. Cryst. 1991, 24, 987-993).

[0149] Crystals suitable for X-ray diffraction experiments were obtained by slow evaporation from a mixture of MeOH / EtOH. Single crystals selected by observation under a binocular microscope were mounted on the goniometer head of a Bruker Instrument APEX DUO diffractometer (Bruker AXS (2011). APEX2 suite V 2011.2-0. Madison, Wisconsin, USA). Intensity was collected at room temperature (T = 293 K) using microsource Cu-Kα radiation (ImuS, λ = 1.54178 Å). Systematic investigation of the diffraction nodes revealed that the crystals belonged to the triclinic system with a primitive Plavé lattice. The unit cell parameters at room temperature were a (Å) = 6.40, b (Å) = 11.34, c (Å) = 13.51, α (°) = 81.91, β (°) = 85.75, and γ (°) = 85.18. From the number of atoms in a molecule of Form A of I-491 and the volume of the unit cell, it was determined that the unit cell must contain two molecules of formula C16H18F3N5O4S, which corresponds to a density of 1.490 counts. The number of reflections collected was 9846, of which 5255 were unique.

[0150] Based on the statistical distribution of the intensities, a non-centrosymmetric structure is inferred.

[0151] The structure was elucidated by direct methods and F by exact least squares using SHELXTL. 2 The data was refined as described above (Sheldrick, GM, Acta Crystallogr. Sect. A 2008, A64, 112-122). All atoms except hydrogen were refined using anisotropic displacement parameters; for hydrogen atoms, a riding model was used. The final match values ​​were R1 = 0.0992 (observed reflections) and wR2 = 0.2875 (all data) with a goodness of fit of 1.694, for 5255 reflections and 542 parameters.

[0152] The compound crystallizes in space group P1 (Figure 3), and the asymmetric unit of the crystal is composed of two molecules of Form A of I-491, thus two chemical formulas are present in the unit cell (Figure 4). The asymmetric cell contains: two [C16H20F3N5O4S]. One piperidine group and both CF2 groups are disordered. Examination of the molecular structure confirms that all bond angles and lengths are within standard values.

[0153] Crystallographic data, X-ray experimental parameters, and structure refinements are shown in Table 5. Table 5.1 lists the positional parameters of all individual non-hydrogen atoms along with their equivalent isotropic displacement parameters. Both lengths and angles are listed in Tables 5.2 and 5.3. Hydrogen positions are reported in Table 5.4. Table 5.5 lists all hydrogen bonds.

[0154] Table 5 [Table 5]

[0155] Table 5.1: Atomic coordinates (x10 4 ) and the uniform isotropic displacement parameter (Å 2 x10 3 );U(eq) is the orthogonal U ij It is defined as one-third of the trace of a tensor. [Table 6] [Table 7]

[0156] Table 5.2: Bond lengths (Å) [Table 8] [Table 9] [Table 10]

[0157] Table 5.3: Bond angles (°) [Table 11] [Table 12] [Table 13] [Table 14]

[0158] Table 5.4: Hydrogen coordinates (x10 4 ) and isotropic displacement parameters (Å 2 x10 3 ) [Table 15]

[0159] Table 5.5: Hydrogen bond bond lengths (Å) and angles (°) [Table 16]

[0160] Representations of the crystal structure are shown in Figures 3 and 4. The figures were generated using the PLATON program (Spek, AL, J. Appl. Cryst. 2003, 36, 7-13).

[0161] The I-491 Form A molecule contains a sulfur atom, so it is possible to determine the absolute configuration using the resolution from the single crystal data. The Flack x parameter is calculated based on anomalous scattering (Flack, H.D.; Bernadinelli, G., Acta. Cryst. 1999, A55, 908-915). This provides the absolute structure, provided a sufficient estimated standard deviation is reached. According to theory, the expected value of the Flack x parameter is 0 for the correct case (within 3 esd) and +1 for the inverted absolute structure. Considering the C115:R;C215:R configuration, the result is 0.03(4), which is sufficient to prove the absolute configuration of I-491 Form A, despite the small esd.

[0162] A simulated diffraction pattern (Figure 5) was generated from the experimentally determined crystalline structure of Form A at room temperature. The experimental powder diffraction pattern can be compared to this theoretical pattern to demonstrate the properties of the crystalline structure. Minor differences, if any, can be explained by preferential orientation in the powder.

[0163] The crystalline structure of Form A of I-491 was determined by single-crystal X-ray diffraction, which allowed the generation of a comparable powder pattern. Although the structure was well resolved, this phase was of fairly poor quality and therefore must correspond to the dynamic form; this is confirmed by the relatively large peaks observed in the synchrotron powder pattern.

[0164] Example 6. Characterization of Form B A depiction of the XRPD pattern of Form B is shown in Figure 6B.

[0165] The DSC thermogram (parameters: equilibrium at 0.00°C, ramp at 10.00°C / min to 250.00°C) shows a first endothermic event (5.5 J / g) at 178°C associated with the solid-solid transition from Form B to Form A, followed by a second endothermic event (80 J / g) at 193°C corresponding to the melting of Form A (Figure 7).

[0166] A continuous mass loss of 0.6% between room temperature and 150° C. is observed by TGA (FIG. 7). The DVS isotherm of Form B demonstrates its non-hygroscopic nature.

[0167] Synchrotron XRPD & Single Crystal Powder samples of I-491 were sealed in 0.8 mm thin-walled borosilicate glass capillaries and then analyzed by high-resolution synchrotron XRD at the European Synchrotron Radiation Facility (beamline ID22, ESRF Grenoble) (Fitch, AN Mater. Sci. Forum 1996, 228-231; ESRF Experiment register: in 971). Powder diffraction data (0.5° < 2θ < 40°) were recorded at room temperature in transmission mode using beamline ID31 at a wavelength of 0.8 Å (15.5 keV) and a step size of 0.003°. To eliminate any degrading effects of beam irradiation and improve counting statistics, measurements were made using an apparatus allowing horizontal translation of the capillary, so that each individual data set was obtained only from the unirradiated region of the powder (original recording). After profile normalization and background smoothing, 45 non-overlapping peaks located in the low- to medium-angle region of the resulting powder diagram were used for cell measurement. The synchrotron powder XRD pattern of I-491 Form B, shown in Figure 6A, was indexed to a triclinic unit cell, the parameters of which are shown below, and finally refined to an Rwp value of 9.55% by the Pawley method using TOPAS software (TOPAS 4.2: Coelho, AA, TOPAS Academic User Manual, Brisbane, Australia, 2007; Coelho AA, J. Appl. Crystallogr. 2003, 36, 86-95).

[0168] Twin crystals grown in acetonitrile / water mixed solvent were suitable for X-ray diffraction studies.

[0169] A single crystal selected by observation under a binocular microscope was mounted on the goniometer head of a Bruker Instrument APEX DUO diffractometer (Bruker AXS (2011). APEX2 suite V 2011.2-0. Madison, Wisconsin, USA). Intensity was collected at room temperature (T = 293 K) using microsource CuKα radiation (ImuS, λ = 1.54178 Å). Systematic study of the diffraction nodes revealed that the crystal belonged to the triclinic system with a primitive Plavé lattice. The unit cell parameters at room temperature were a (Å) = 11.93, b (Å) = 13.24, c (Å) = 13.51, α (°) = 65.40, β (°) = 80.08, and γ (°) = 89.18.

[0170] From the number of atoms in a molecule of Form B of I-491 and the volume of the unit cell, it was determined that the unit cell must contain four molecules of formula C16H18F3N5O4S, which corresponds to a density of 1.516. The number of reflected beams collected was 23,771, of which 10,282 were unique.

[0171] Based on the statistical distribution of the intensities, a non-centrosymmetric structure is inferred.

[0172] The structure was elucidated by direct methods and F by exact least squares using SHELXTL. 2 The data was refined as described above (Sheldrick, GM, Acta Crystallogr. Sect. A 2008, A64, 112-122). All atoms except hydrogen were refined using anisotropic displacement parameters; for hydrogen atoms, a riding model was used. The final match values ​​were R1 = 0.0512 (observed reflections) and wR2 = 0.1445 (all data) with a goodness of fit of 1.030, for 10282 reflections and 1073 parameters.

[0173] The compound crystallizes in space group P1 (Figure 8), and the asymmetric unit of the crystal is composed of four molecules of Form B of I-491, thus four chemical formulas are present in the unit cell (Figure 9). This rather unusual property is also observed in polymorphic Forms C and D, while dynamic Form A is composed of two independent molecules. The asymmetric cell contains: four [C16H20F3N5O4S]. Several CF2 groups and one methyl are disordered in the solid state. The molecular structure is examined, confirming that all bond angles and lengths are within standard values.

[0174] Crystallographic data, X-ray experimental parameters, and structure refinements are shown in Table 6. Table 6.1 lists the positional parameters of all independent non-hydrogen atoms along with their equivalent isotropic displacement parameters. Both lengths and angles are listed in Tables 6.2 and 6.3. Hydrogen positions are reported in Table 6.4. Table 6.5 lists all hydrogen bonds.

[0175] Table 6 [Table 17]

[0176] Table 6.1: Atomic coordinates of Form B (x10 4 ) and the uniform isotropic displacement parameter (Å 2 x10 3 );U(eq) is the orthogonal U ij It is defined as one-third of the trace of a tensor. [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

[0177] Table 6.2: Bond lengths (Å) [Table 23] [Table 24] [Table 25] [Table 26] [Table 27]

[0178] Table 6.3: Bond angles (°) [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34]

[0179] Table 6.4: Hydrogen coordinates (x10 4 ) and isotropic displacement parameters (Åx10 2 ) [Table 35] [Table 36] [Table 37]

[0180] Table 6.5: Hydrogen bond bond lengths (Å) and angles (°) [Table 38] [Table 39]

[0181] Representations of the crystal structure are shown in Figures 8 and 9. The figures were generated using the PLATON program (Spek, AL, J. Appl. Cryst. 2003, 36, 7-13).

[0182] The I-491 molecule contains a sulfur atom, so it is possible to determine the absolute configuration using high-resolution data collection. The Flack x parameter is calculated based on anomalous scattering. This provides the absolute structure, provided sufficient estimated standard deviation is reached. According to theory, the expected value of the Flack x parameter is 0 for the correct case (within 3 esd) and +1 for the inverted absolute structure. The result, considering the C315:R;C215:R;C415:R;C115:R configuration, is 0.011(14), clearly demonstrating this absolute configuration of I-491 in the crystal structure of Form B.

[0183] A simulated diffraction pattern (Figure 10) was generated from the experimentally determined crystalline structure of Form B at room temperature. The experimental powder diffraction pattern can be compared to this theoretical pattern to demonstrate the characteristics of the crystalline structure. Minor differences, if any, can be explained by preferential orientation in the powder.

[0184] The crystalline structure of Form B of I-491 was determined by single crystal X-ray diffraction, which allowed the generation of a controlled powder pattern. Even though the sample used was isolated from a twinned crystal, the structure is of high quality and thus represents the precise crystalline structure of Form B.

[0185] Example 7. Characterization of Form C The solid obtained by interconversion slurry between Forms (A+εD) and B in acetonitrile / water at 80° C. was analyzed by XRPD (acquisition parameters: Type = 2Th / Th lock; Onset = 2.00°; End = 40.05°; Step = 0.03°; Step Time = 89 seconds; Temperature = 25° C. (room temperature); Start Time = 2749 seconds; 2-Theta = 2.00; and Run = Y Scale add 1000). It was found to be crystalline and corresponded to Form C plus traces of A and B.

[0186] The DSC thermogram (parameters: equilibrium at 0.00°C, ramp 10.00°C / min to 250.00°C) shows a first endothermic event (40.7 J / g) at 186°C corresponding to the melting of Form C, followed by a second endothermic event (31 J / g) at 190°C corresponding to the melting of Form A (Figure 11). A continuous mass loss of 0.9% between room temperature and 150°C is observed by TGA (Figure 11).

[0187] Single crystal Slow evaporation from a mixture of MeCN / H2O yields a small amount of crystals suitable for X-ray diffraction experiments.[3]

[0188] Another single crystal was located and selected from the same preparation by observation under a binocular microscope and attached to the goniometer head of a Bruker Instrument APEX DUO diffractometer (Bruker AXS (2011). APEX2 suite V 2011.2-0. Madison, Wisconsin, USA). Intensity was collected at low temperature (T = 113 K) using graphite-monochromated CuKα radiation (λ = 1.54178 Å). Systematic study of the diffraction nodes revealed that the second crystal belonged to the monoclinic system with a primitive Plavé lattice. The unit cell parameters of the phase designated C were a (Å) = 14.47, b (Å) = 17.28, c (Å) = 16.11, α (°) = 90.00, β (°) = 109.85, and γ (°) = 90.00.

[0189] From the number of atoms in a molecule of I-491 and the volume of the unit cell, it was determined that the unit cell must contain eight molecules of formula C16H20F3N5O4S, which corresponds to a density of 1.527. The number of reflected beams collected was 63,621, of which 13,312 were unique.

[0190] The determination of the space group was unambiguously achieved by the presence of a unique systematic extinction along the monoclinic axis.

[0191] The crystal structure of Form C was solved by direct methods using SIR software (Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M.C.; Polidori, G.; Cavalli, A., J. Appl. Crystallogr. 1994, 27, 435-436) and by exact least squares using SHELXTL. 2The data was refined as described above (Sheldrick, GM, Acta Crystallogr. Sect. A, 2008, A64, 112-122). All atoms except hydrogen were refined using anisotropic displacement parameters; for hydrogen atoms, a riding model was used. The final match values ​​were R1 = 0.0284 (observed reflections) and wR2 = 0.0847 (all data) with a goodness of fit of 1.044, for 13312 reflections and 1070 parameters.

[0192] The crystal structure of Form C (Figure 12A) shows that the compound crystallizes in space group P21. The asymmetric unit of the crystal consists of four molecules of I-491, thus presenting eight chemical formulas in the unit cell. No additional molecules, such as organics or water, are apparent. The asymmetric cell contains four (C16H20F3N5O4S) molecules. Examination of the molecular structure confirms that all bond angles and lengths are within standard ranges. Two molecules exhibit disorder in the CF2 group.

[0193] The crystallographic data, X-ray experimental parameters, and structure refinement for Form C are shown in Table 7. Table 7.1 lists the positional parameters of all independent non-hydrogen atoms along with their equivalent isotropic displacement parameters. Bond angles and lengths are listed in Tables 7.2 and 7.3. Hydrogen positions are reported in Table 7.4. Table 7.5 lists all hydrogen bonds.

[0194] Table 7 [Table 40]

[0195] Table 7.1: Atomic coordinates (x10 4 ) and the uniform isotropic displacement parameter (Å 2 x10 3 ) [Table 41] [Table 42] [Table 43] [Table 44]

[0196] Table 7.2: Bond lengths (Å) [Table 45] [Table 46] [Table 47] [Table 48] [Table 49] [Table 50] [Table 51]

[0197] Table 7.3: Bond angles (°) [Table 52] [Table 53] [Table 54] [Table 55] [Table 56] [Table 57] [Table 58] [Table 59] [Table 60] [Table 61] [Table 62] [Table 63]

[0198] Table 7.4: Hydrogen coordinates (x10 4 ) and isotropic displacement parameters (Å 2 x10 2 ) [Table 64] [Table 65] [Table 66] [Table 67]

[0199] Table 7.5: Hydrogen bond bond lengths (Å) and angles (°) [Table 68] [Table 69]

[0200] Representations of the crystal structures are shown in Figures 12A and 12B, which were generated for both structures using the PLATON program (Spek, AL, J. Appl. Cryst. 2003, 36, 7-13).

[0201] The I-491 molecule contains a sulfur atom, so high-resolution data collection (performed at low temperatures) can be used to determine the absolute configuration. The Flack x parameter is calculated based on anomalous scattering. This provides the absolute structure, provided sufficient estimated standard deviation is reached. According to theory, the expected value of the Flack x parameter is 0 for the correct (within 3 esd) case and +1 for the inverted absolute structure (Flack, H.D., Bernadinelli, G., Acta. Cryst. 1999 A55, 908-915). The result is as follows: considering the configuration C115:R; C415:R; C215:R; C315:R, the Flack parameter is 0.031(6), which unambiguously proves this absolute configuration of Form C of I-491.

[0202] A simulated diffraction pattern (Figure 13) was generated from the experimentally determined crystal structure of Form C at low temperatures. The experimental powder diffraction pattern can be compared to one of these theoretical patterns to demonstrate the properties of the crystal structure. Minor differences, if any, can be explained by preferential orientation in the powder.

[0203] The crystal structure of the I-491 Form C polymorph was determined by single crystal X-ray diffraction, which allowed the generation of a controlled powder pattern. Form C was fully characterized in this work.

[0204] Example 8. Characterization of Form D Crystals suitable for X-ray diffraction experiments were obtained by slow evaporation from a mixture of MeCN / H2O.

[0205] A single crystal selected by observation under a binocular microscope was mounted on the goniometer head of a Bruker Instrument APEX DUO diffractometer (Bruker AXS (2011). APEX2 suite V 2011.2-0. Madison, Wisconsin, USA). Intensity was collected at low temperature (T = 113 K) using graphite-monochromated CuKα radiation (λ = 1.54178 Å). A systematic study of the diffraction nodes indicates that the first crystal belongs to the triclinic system with a primitive Plavé lattice. The unit cell parameters of the phase designated D were a (Å) = 9.78, b (Å) = 13.86, c (Å) = 16.11, α (°) = 65.39, β (°) = 84.54, and γ (°) = 72.42.

[0206] From the number of atoms in a molecule of I-491 and the volume of the unit cell, it was determined that the unit cell must contain four molecules of formula C16H20F3N5O4S, which corresponds to a density of 1.522. The number of reflected beams collected was 27,364, of which 11,440 were unique.

[0207] Based on the statistical distribution of the intensities, a non-centrosymmetric structure is inferred.

[0208] The crystal structure of Form D was solved by direct methods using SIR software (Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M.C.; Polidori, G.; Cavalli, A., J. Appl. Crystallogr. 1994, 27, 435-436) and by exact least squares using SHELXTL. 2The data was refined as described above (Sheldrick, GM, Acta Crystallogr. Sect. A, 2008, A64, 112-122). All atoms except hydrogen were refined using anisotropic displacement parameters; for hydrogen atoms, a riding model was used. The final match values ​​were R1 = 0.0430 (observed reflections) and wR2 = 0.1179 (all data) with a goodness of fit of 1.071, using 11440 reflections and 1045 parameters.

[0209] The compound in the crystal structure of Form D (Figures 14 and 15) crystallizes in space group P1, and the asymmetric unit of the crystal consists of four molecules of I-491, thus four chemical formulas are present in the unit cell. No additional molecules, such as organics or water, are apparent. The asymmetric cell contains four (C16H20F3N5O4S). Examination of the molecular structure confirms that all bond angles and lengths are within standard values. The piperidine group is disordered in the solid state.

[0210] The crystallographic data, X-ray experimental parameters, and structure refinement for Form D are shown in Table 8. Table 8.1 lists the positional parameters of all independent non-hydrogen atoms along with their equivalent isotropic displacement parameters. Bond angles and lengths are listed in Tables 8.2 and 8.3. Hydrogen positions are reported in Table 8.4. Table 8.5 lists all hydrogen bonds.

[0211] Table 8 [Table 70]

[0212] Table 8.1: Atomic coordinates of Form D (x10 4 ) and the uniform isotropic displacement parameter (Å 2 x10 3 );U(eq) is the orthogonal U ij It is defined as one-third of the trace of a tensor. [Table 71] [Table 72] [Table 73] [Table 74] [Table 75] [Table 76] [Table 77]

[0213] Table 8.2: Bond lengths (Å) [Table 78] [Table 79] [Table 80] [Table 81]

[0214] Table 8.3: Bond angles (°) [Table 82] [Table 83] [Table 84] [Table 85] [Table 86] [Table 87]

[0215] Table 8.4: Hydrogen coordinates (x10 4 ) and isotropic displacement parameters (Å 2 x10 3 ) [Table 88] [Table 89] [Table 90]

[0216] Table 8.5: Hydrogen bond bond lengths (Å) and angles (°) [Table 91] [Table 92]

[0217] Representations of the crystal structures are shown in Figures 14 and 15; these figures were generated for both structures using the PLATON program (Spek, AL, J. Appl. Cryst. 2003, 36, 7-13).

[0218] The I-491 molecule contains a sulfur atom, so high-resolution data collection (performed at low temperatures) can be used to determine the absolute configuration. The Flack x parameter is calculated based on anomalous scattering. This provides the absolute structure, provided sufficient estimated standard deviations are achieved. According to theory, the expected value of the Flack x parameter is 0 for the correct (within 3 esd) case and +1 for the inverted absolute structure (Flack, H.D., Bernadinelli, G., Acta. Cryst. 1999 A55, 908-915). The result is as follows: considering the configurations C115:R;C415:R;C215:R;C315:R;C415:R, the Flack parameter is 0.003 (13), unambiguously proving this absolute configuration of I-491 form D.

[0219] A simulated diffraction pattern (Figure 16) was generated from the experimentally determined crystal structure of Form D at low temperatures. The experimental powder diffraction pattern can be compared to one of these theoretical patterns to demonstrate the properties of the crystal structure. Minor differences, if any, can be explained by preferential orientation in the powder.

[0220] The crystal structure of the Form D polymorph of I-491 was determined by single crystal X-ray diffraction, which allowed the generation of a controlled powder pattern.

[0221] Example 9. Myosin activation assay Small molecule drugs were evaluated for their ability to activate the enzymatic activity of bovine cardiac myosin using a biochemical assay that couples the release of ADP (adenosine diphosphate) from cardiac myosin to an enzyme-coupled system consisting of pyruvate kinase and lactate dehydrogenase (PK / LDH) and monitors the decrease in absorbance (at 340 nm) of NADH as a function of time. PK converts ADP to ATP (adenosine triphosphate) by converting PEP (phosphoenolpyruvate) to pyruvate. Pyruvate is then converted to lactate by LDH by converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide). The source of cardiac myosin was derived from bovine heart in the form of skinned myofibrils. Prior to testing small molecule drugs, bovine myofibrils were evaluated for their calcium responsiveness, with 50% (pCa) being the final condition for evaluating the activating effects of small molecule drugs. 50 Calcium concentrations were selected to achieve either 50% (pCa = ≈6) or <5% (pCa = 10). All enzyme activities were measured in a buffer solution (PM12 buffer) containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)) and 2 mM magnesium chloride at pH 6.8. The final assay conditions were 1 mg / mL bovine cardiac myofibrils, 0.4 mM PK / LDH, 50 μM ATP, 0.1 mg / mL BSA (bovine serum albumin), 10 ppm antifoam, 2 mM BME, 0.5 mM NADH, 1.5 mM PEP, and the desired free calcium concentration required to achieve 50% or <5% myofibril activation.

[0222] A series of diluted compounds was prepared in DMSO, and the final desired concentration of the compound was achieved in a volume of 100 μL, with the DMSO concentration fixed at 3.3% (v / v). Typically, 1 μL of the serial dilutions was added to a 384-well plate to achieve a 10-point dose-response. After adding 14 μL of a solution containing bovine cardiac muscle fibers, PK / LDH, and calcium solution (to achieve the desired activation), 15 μL of a solution containing ATP, PEP, and NADH was added to initiate the enzyme reaction. The reaction progress was monitored at ambient temperature using a PerkinElmer Envision plate reader with a clear bottom. The plate reader was set to read absorbance at 340 nm over 15 minutes in kinetic mode. Data was recorded as the slope of the absorbance response versus time. The slope of the absorbance response as a function of time was normalized to the slope of the plate containing DMSO. This normalized rate was then plotted as a function of small molecule concentration, and the data was fitted to a four-parameter fit using EXCEL XLfit. The concentrations at which the total response increased by 20 or 50% were determined as AC 20 or AC 50 Any drug that fails to achieve a corresponding percentage of activation at the highest concentration tested is reported as AC 20 or AC 50 is reported as greater than the highest concentration tested (i.e., AC 50 >50 μM).

[0223] Table 9. Myosin activation of selected compounds a [Table 93] a +++ is the myosin activation value AC 20 indicates <2 μM; ++ indicates myosin activation value AC 20 indicates that AC is 2μM~5μM; + indicates myosin activation value AC 20 indicates that the concentration is >5 μM.

[0224] Example 10. Cardiomyocyte contractile force assay Contractile force of live rat ventricular myocytes was measured by edge detection using an IonOptix contractile force system. An aliquot of cardiomyocytes in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl2, 1.5 mM CaCl2, 4 mM HEPES, 11 mM glucose) was placed in a perfusion chamber (Series 20 RC-27NE; Warner Instruments), attached to a coverslip, and then perfused with Tyrode's buffer at 37°C. Cardiomyocytes were stimulated at 1 Hz and 10 V. Only cardiomyocytes with clear striations, resting before perfusion, a cell length of 120-180 microns, a basal shortening fraction equal to 3-8% of the cell length, and a contraction velocity greater than 100 microns / second, were used for contractile force experiments. To measure compound responses, cardiomyocytes were perfused with Tyrode's buffer for 60 seconds, followed by compound for 5 minutes, and then washed with Tyrode's buffer for 140 seconds. Data were continuously recorded using Ion Optics software. Contractile force data were analyzed using Ion Wizard software (Ion Optics). For each cell, 10–20 contractile force transients were averaged and compared between basal (no compound) and compound-treated conditions. Compound activity was measured by the effect on fractional shortening (FS), where FS is the ratio of the peak contractile cell length divided by the basal cell length, normalized to 100% for untreated cells.

[0225] Table 10. Activation of cardiomyocyte contraction by selected compounds a [Table 94] a: + indicates fractional shortening activation <20% above basal; ++ indicates fractional shortening activation values ​​between 20% and 50% above basal; +++ indicates fractional shortening activation values ​​>50% above basal.

[0226] The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding; however, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Additionally, each document provided herein is incorporated by reference in its entirety to the same extent as if each document were individually incorporated by reference. In the event of a conflict between this application and the references provided herein, the present application shall control.

[0227] Equivalents and Scope In the claims, articles such as "a," "an," and "the" can mean one or more unless indicated to the contrary or otherwise clear from the context. A claim or description including "or" between a group of one or more members is considered to be sufficient if one or more, or all, of the group members are present in, utilized in, or otherwise relevant to a given product or process, unless indicated to the contrary or otherwise clear from the context. The invention encompasses embodiments in which precisely one member of a group is present in, utilized in, or otherwise relevant to a given product or process. The invention encompasses embodiments in which more than one or all, or all, of the group members are present in, utilized in, or otherwise relevant to a given product or process.

[0228] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and explanatory terms from one or more enumerated claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends on the same underlying claim. When elements are presented as a list, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element can be removed from the group. In general, when the invention, or aspects of the invention, are referred to as consisting of particular elements and / or features, it should be understood that particular embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For brevity, these embodiments have not been specifically described in this specification. Also, note that the terms "comprise" and "comprising" are intended to be open-ended, allowing for the inclusion of additional elements or steps. When ranges are specified, the endpoints are included. Furthermore, unless otherwise specified or otherwise apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can also assume any particular value or subrange within a given range in different embodiments of the invention to one-tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0229] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any one of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more claims. Because such embodiments are deemed known to those of ordinary skill in the art, such embodiments may be excluded even if not explicitly set forth herein as such. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0230] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the present application described herein is not limited to the above description, but rather is as defined in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims.

[0231] item 1. Formula (I-491): [ka] 1. A composition comprising the polymorph of formula I, wherein the polymorph is Form A.

[0232] 2. The composition of item 1, wherein the chiral purity of the polymorph is at least 99.9%.

[0233] 3. Polymorphs a. an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having two or more peaks selected from the following frequencies: 6.62, 10.98, 13.26, 14.48, 15.02, 15.48, 15.78, 16.08, 16.32, 17.72, 19.26, 19.86, 19.94, 20.44, 21.68, 21.90, 22.04, 22.60, 23.78, 26.16, 26.36, 26.58, 27.24, and 28.04; or b. DSC thermogram showing an endotherm at approximately 181-200°C; characterized by at least one of 3. The composition of any one of items 1 or 2.

[0234] 4. The composition of any one of items 1-3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at each of 10.98, 15.78, 16.08, 20.44, 23.78, and 26.58 degrees.

[0235] 5. The composition of any one of items 1-3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at each of 6.62, 10.98, 16.08, 23.78, and 26.58 degrees.

[0236] 6. The composition of any one of items 1-3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at 15.78, 16.08, and 23.78 degrees, respectively.

[0237] 7. The composition of any one of items 1-3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at each of 6.62, 15.78, 16.08, and 26.58 degrees.

[0238] 8. The composition of any one of items 1-3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at each of 6.62, 17.72, 23.78, and 26.58 degrees.

[0239] 9. The composition of any one of items 1-3, wherein the polymorph is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 1A.

[0240] 10. The composition of any one of items 1-3, wherein the polymorph is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 1B.

[0241] 11. The composition of any one of items 1 to 10, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.05°, lacking peaks at each of 0-6.00, 8.00-8.90, 11.40-12.60, 16.80-17.20, and 24.40-24.80 degrees.

[0242] 12. The composition of any one of items 1 to 10, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.05°, lacking a peak at 24.40 to 24.80 degrees.

[0243] 13. The composition of any one of items 1 to 10, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.05°, lacking peaks at each of 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80 degrees.

[0244] 14. The composition of any one of items 1 to 10, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.05°, lacking a peak between 11.40 and 12.60 degrees.

[0245] 15. The composition of any one of items 1 to 14, wherein the polymorph is characterized by an onset of melting of about 181°C.

[0246] 16. The composition of any one of items 1 to 15, wherein the polymorph is characterized by a melting point of 191°C ± 2°C.

[0247] 17. The composition of any one of paragraphs 1-16, wherein the polymorph is characterized by a DSC thermogram essentially the same as that shown in Figure 2.

[0248] 18. The composition of any one of items 1 to 17, wherein the polymorph has a triclinic crystal structure and a space group of P1.

[0249] 19. The composition of any one of items 1-18, wherein the polymorph has unit cell dimensions of a=6.403 Å, b=11.343 Å, c=13.507 Å, α=81.91°, β=85.73°, and γ=85.18°.

[0250] 20. The composition of any one of items 1 to 19, which is substantially free of other forms of I-491.

[0251] 21. The composition of any one of items 1 to 20, which is substantially free of I-491 form D.

[0252] 22. The composition of any one of items 1 to 21, which is substantially free of amorphous I-491.

[0253] 23. A composition comprising I-491 Form A, wherein the I-491 Form A is greater than or equal to 99.5% by weight.

[0254] 24. A composition comprising Form A of I-491, wherein the molar ratio of the amount of Form A of I-491 to the total amount of other forms is equal to or greater than 80:20.

[0255] 25. The composition of item 24, wherein the molar ratio of the amount of Form A of I-491 to the total amount of other forms is equal to or greater than 90:10.

[0256] 26. The composition of any one of items 24-25, wherein the molar ratio of the amount of Form A of I-491 to the total amount of other forms is equal to or greater than 95:5.

[0257] 27. The composition of any one of paragraphs 24-26, wherein the molar ratio of the amount of Form A of I-491 to the total amount of other forms is equal to or greater than 99:1.

[0258] 28. The composition of any one of paragraphs 24-27, wherein the molar ratio of the amount of Form A of I-491 to the total amount of other forms is equal to or greater than 99.5:0.5.

[0259] 29. A composition comprising I-491 Form A and I-491 Form D, wherein the molar ratio of I-491 Form A to the amount of I-491 Form D is equal to or greater than 80:20.

[0260] 30. The composition of item 29, wherein the molar ratio of I-491 to the amount of I-491 Form A to Form D is equal to or greater than 90:10.

[0261] 31. The composition of any one of items 29-30, wherein the molar ratio of I-491 to the amount of I-491 Form A to Form D is equal to or greater than 95:5.

[0262] 32. The composition of any one of paragraphs 29-31, wherein the molar ratio of I-491 to the amount of I-491 Form A to Form D is equal to or greater than 99:1.

[0263] 33. A pharmaceutical composition comprising an effective amount of the composition of any one of items 1 to 32 and a pharmaceutically acceptable carrier.

[0264] 34. Formula (I-491): [ka] which is Form B of I-491.

[0265] 35. The polymorph of item 34, wherein the chiral purity of the polymorph is at least 99.9%.

[0266] 36. an X-ray powder diffraction pattern obtained by irradiation with a Cu-Kα pattern, expressed in degrees 2-theta ±0.2°, and having two or more peaks selected from the following frequencies: 7.32, 7.88, 10.20, 10.88, 13.40, 14.68, 15.24, 15.42, 16.28, 17.70, 18.48, 19.02, 20.18, 20.70, 21.56, 21.98, 22.94, 23.16, 23.86, 24.24, 24.78, 25.38, 26.40, 26.88, and 28.74; or b. DSC thermogram showing an endotherm at approximately 170-185°C 36. The polymorph of any one of items 34 or 35, characterized by at least one of:

[0267] 37. The polymorph of any one of items 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, and having peaks at each of 15.42, 16.28, 19.02, 20.70, and 26.88 degrees.

[0268] 38. The polymorph of any one of items 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at 15.42, 20.70, and 26.88 degrees, respectively.

[0269] 39. The polymorph of any one of items 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at each of 7.88, 10.20, 20.70, and 26.88 degrees.

[0270] 40. The polymorph of any one of items 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at each of 7.32, 7.88, 10.20, and 18.48 degrees.

[0271] 41. The polymorph of any one of items 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at 7.32, 16.28, and 26.88 degrees, respectively.

[0272] 42. The polymorph of any one of items 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.2°, having peaks at each of 7.88, 15.42, 17.70, and 21.56 degrees.

[0273] 43. The polymorph of any one of items 34-42, characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 6A.

[0274] 44. The polymorph of any one of items 34-42, characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 6B.

[0275] 45. The polymorph of any one of items 34 to 44, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.05°, lacking peaks at each of 0 to 6.80 and 8.15 to 9.00 degrees.

[0276] 46. ​​The polymorph of any one of items 34 to 44, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.05° and lacking peaks between 0 and 6.80 degrees.

[0277] 47. The polymorph of any one of items 34 to 44, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, expressed in degrees 2-theta ±0.05° and lacking a peak between 8.15 and 9.00 degrees.

[0278] 48. The polymorph of any one of items 34-47, characterized by an onset of melting at about 170°C.

[0279] 49. A polymorph of any one of items 34 to 48 characterized by a melting point of 178°C ± 2°C.

[0280] 50. The polymorph of any one of items 34-49, characterized by a second endotherm at about 185-200°C.

[0281] 51. The polymorph of any one of items 34 to 50, characterized by a second melting point of 192.7°C ± 2°C.

[0282] 52. The polymorph of any one of items 34-51, characterized by a DSC thermogram essentially the same as that shown in Figure 4.

[0283] 53. The polymorph of any one of items 34 to 52, wherein the polymorph has a triclinic crystal system and a space group of P1.

[0284] 54. The polymorph of any one of items 34-53 having unit cell dimensions of a = 11.926 Å, b = 13.239 Å, c = 13.511 Å, α = 65.40°, β = 80.08°, and γ = 89.18°.

[0285] 55. A composition comprising the polymorph of any one of items 34 to 54, substantially free of other forms of I-491.

[0286] 56. A composition comprising the polymorph of any one of items 34 to 55, which is substantially free of Forms A and / or D of I-491.

[0287] 57. A composition comprising the polymorph of any one of items 34 to 56, which is substantially free of amorphous I-491.

[0288] 58. A composition comprising I-491 Form B, the composition comprising greater than or equal to 99.5% by weight of I-491 Form B.

[0289] 59. A composition comprising Form B of I-491, wherein the molar ratio of the amount of Form B of I-491 to the total amount of other forms is equal to or greater than 80:20.

[0290] 60. The composition of item 59, wherein the molar ratio of the amount of Form B of I-491 to the total amount of other forms is equal to or greater than 90:10.

[0291] 61. The composition of any one of items 59-60, wherein the molar ratio of the amount of Form B of I-491 to the total amount of other forms is equal to or greater than 95:5.

[0292] 62. The composition of any one of paragraphs 59-61, wherein the molar ratio of the amount of Form B of I-491 to the total amount of other forms is equal to or greater than 99:1.

[0293] 63. The composition of any one of items 59-62, wherein the molar ratio of the amount of Form B of I-491 to the total amount of other forms is equal to or greater than 99.5:0.5.

[0294] 64. A pharmaceutical composition comprising an effective amount of the polymorph of any one of items 34 to 54 or the composition of any one of items 55 to 63, and a pharmaceutically acceptable carrier.

[0295] 65. Form A of aI-491; and b. one or more diluents A pharmaceutical composition comprising:

[0296] 66. aI-491 form A; b. one or more diluents; and c. disintegrant 66. The pharmaceutical composition of item 65, further comprising:

[0297] 67. aI-491 form A; b. one or more diluents; c. disintegrants; and d. Binder 67. The pharmaceutical composition of item 66, further comprising:

[0298] 68. aI-491 form A; b. one or more diluents; c. disintegrants; d. binder; and e. Lubricant 68. The pharmaceutical composition of item 67, further comprising:

[0299] 69. The pharmaceutical composition of any one of items 65 to 68, wherein the one or more diluents are selected from the group consisting of calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures of any of the foregoing diluents.

[0300] 70. The pharmaceutical composition of any one of items 66 to 68, wherein the disintegrant is selected from the group consisting of agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures of any of the above disintegrants.

[0301] 71. The pharmaceutical composition of any one of items 67 to 68, wherein the binder is selected from the group consisting of starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, breadwort gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and mixtures of any of the above binders.

[0302] 72. The pharmaceutical composition of item 68, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl betaine, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures of any of the above lubricants.

[0303] 73. A pharmaceutical composition comprising I-491 Form A, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate.

[0304] 74. A method for treating a disease selected from the group consisting of systolic dysfunction, diastolic dysfunction, HFrEF, HFpEF, chronic heart failure, and acute heart failure, comprising administering to a subject in need thereof an effective amount of the polymorph of any one of items 34 to 54, or a pharmaceutically acceptable salt thereof, the composition of any one of items 1 to 32 and 55 to 63, or the pharmaceutical composition of any one of items 33, 64 to 73, and 113 to 121.

[0305] 75. The method of item 74, wherein the polymorph or pharmaceutical composition is administered in an IV formulation for the treatment of acute heart failure.

[0306] 76. A method for treating systolic dysfunction, comprising administering to a subject in need thereof an effective amount of the polymorph of any one of items 34 to 54, or a pharmaceutically acceptable salt thereof, the composition of any one of items 1 to 32 and 55 to 63, or the pharmaceutical composition of any one of items 33, 64 to 73, and 113 to 121.

[0307] 77. The method of item 76, wherein the polymorph is Form B of I-491.

[0308] 78. The method of item 76, wherein the polymorph is Form A of I-491.

[0309] 79. A method for treating HFrEF, comprising administering to a subject in need thereof an effective amount of the polymorph of any one of items 34 to 54, or a pharmaceutically acceptable salt thereof, the composition of any one of items 1 to 32 and 55 to 63, or the pharmaceutical composition of any one of items 33, 64 to 73, and 113 to 121.

[0310] 80. The method of item 79, wherein the polymorph is Form B of I-491.

[0311] 81. The method of item 79, wherein the polymorph is Form A of I-491.

[0312] 82. A method for treating dilated cardiomyopathy (DCM), comprising administering to a subject in need thereof an effective amount of the polymorph of any one of items 34 to 54, or a pharmaceutically acceptable salt thereof, the composition of any one of items 1 to 32 and 55 to 63, or the pharmaceutical composition of any one of items 33, 64 to 73, and 113 to 121.

[0313] 83. The method of item 82, wherein the polymorph is Form B of I-491.

[0314] 84. The method of item 82, wherein the polymorph is Form A of I-491.

[0315] 85. A method for treating a disease characterized by left ventricular systolic dysfunction or symptoms or reduced exercise capacity due to systolic dysfunction, comprising administering to a subject in need thereof an effective amount of the polymorph of any one of items 34 to 54, or a pharmaceutically acceptable salt thereof, the composition of any one of items 1 to 32 and 55 to 63, or the pharmaceutical composition of any one of items 33, 64 to 73, and 113 to 121, in combination with a therapy aimed at treating heart failure.

[0316] 86. The method of item 85, wherein the polymorph is Form B of I-491.

[0317] 87. The method of item 85, wherein the polymorph is Form A of I-491.

[0318] 88. The method of any one of items 74 to 87, in combination with a therapeutic agent that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor).

[0319] 89. The method of any one of items 74 to 87, in combination with a therapeutic agent that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotropic agent such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone).

[0320] 90. The method of any one of items 74 to 87, in combination with a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide).

[0321] 91. The method of any one of items 74 to 87, in combination with a therapeutic agent that reduces afterload (a vasodilator of any class, including, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

[0322] 92. The method of any one of items 74 to 87, wherein the compound is administered in combination with a beta-blocker.

[0323] 93. A polymorph of I-491, wherein the polymorph is Form A of I-491 produced in a process comprising recrystallizing I-491 in a mixture of methanol and water via slow evaporation.

[0324] 94. A polymorph of I-491, wherein the polymorph is Form B of I-491 produced by a process comprising recrystallizing I-491 in a mixture of acetonitrile and water.

[0325] 95. The polymorph of item 94, wherein the process is carried out at a temperature selected from 25°C to 70°C.

[0326] 96. The polymorph of any one of items 94-95, wherein the process is carried out at room temperature.

[0327] 97. A polymorph of I-491, wherein the polymorph is Form B of I-491, produced by a process comprising recrystallizing I-491 from a slurry of I-491 in a solvent selected from the group consisting of water, ethanol, methanol, ethyl acetate, methyl isobutyl ketone, a mixture of ethanol and water, a mixture of methanol and water, and water.

[0328] 98. The polymorph of item 97, wherein the solvent is ethanol, methanol, ethyl acetate, or methyl isobutyl ketone.

[0329] 99. The polymorph of item 98, wherein the process is carried out at a temperature selected from 20°C to 50°C.

[0330] 100. The polymorph of any one of items 98-99, wherein the process is carried out at room temperature.

[0331] 101. Formula (I-491): [ka] 1. A composition comprising a polymorph having the formula: wherein the polymorph is Form A of I-491, and Form A of I-491 is characterized by a triclinic crystal system and a P1 space group.

[0332] 102. The composition of item 101, wherein the unit cell dimensions of the polymorph are a=6.403 Å, b=11.343 Å, c=13.507 Å, α=81.91°, β=85.73°, and γ=85.18°.

[0333] 103. Formula (I-491): [ka] wherein said polymorph is Form B of I-491, and Form B of I-491 is characterized by a triclinic crystal system and a P1 space group.

[0334] 104. The polymorph of item 103 in which the unit cell dimensions of the polymorph are a = 11.926 Å, b = 13.239 Å, c = 13.511 Å, α = 65.40°, β = 80.08°, and γ = 89.18°.

[0335] 105. The composition of any one of items 1 and 101-102, wherein the composition comprises greater than or equal to 75% by weight of Form A of I-491.

[0336] 106. The composition of any one of items 1 and 101-102, wherein the composition comprises greater than or equal to 85% by weight of Form A of I-491.

[0337] 107. The composition of any one of items 1 and 101-102, wherein the composition comprises greater than or equal to 90% by weight of Form A of I-491.

[0338] 108. The composition of any one of items 1 and 101-102, wherein the composition comprises greater than or equal to 95% by weight of Form A of I-491.

[0339] 109. The composition of any one of items 1 and 101-102, wherein the composition comprises greater than or equal to 98% by weight of Form A of I-491.

[0340] 110. The composition of any one of items 1 and 101-102, wherein the composition comprises greater than or equal to 99% by weight of Form A of I-491.

[0341] 111. The composition of any one of items 1 and 101-102, wherein the composition comprises greater than or equal to 99.5% by weight of Form A of I-491.

[0342] 112. The composition of any one of items 1 and 101-102, wherein the composition comprises greater than or equal to 99.9% by weight of Form A of I-491.

[0343] 113. a. Form B of I-491; and b. one or more diluents A pharmaceutical composition comprising:

[0344] 114. a. Form B of I-491; b. one or more diluents; and c. Disintegrants 114. The pharmaceutical composition of item 113, further comprising:

[0345] 115. a. Form B of I-491; b. one or more diluents; c. disintegrants; and d. Binder 115. The pharmaceutical composition of item 114, further comprising:

[0346] 116. a. Form B of I-491; b. one or more diluents; c. disintegrants; d. binder; and e. Lubricants 116. The pharmaceutical composition of item 115, further comprising:

[0347] 117. The pharmaceutical composition of any one of items 113 to 116, wherein the one or more diluents are selected from the group consisting of calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures of any of the foregoing diluents.

[0348] 118. The pharmaceutical composition of any one of items 114 to 116, wherein the disintegrant is selected from the group consisting of agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures of any of the above disintegrants.

[0349] 119. The pharmaceutical composition of any one of items 115 to 116, wherein the binder is selected from the group consisting of starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, breadwort gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and mixtures of any of the above binders.

[0350] 120. The pharmaceutical composition of item 116, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl betaine, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures of any of the foregoing lubricants.

[0351] 121. A pharmaceutical composition comprising I-491 Form B, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate.

Claims

1. formula: 【Chemistry 1】 A polymorph of form B of compound I-491, represented by [formula], characterized by a DSC thermogram showing large endothermic activity at temperatures of 185–200°C and initiation of melting at 170°C.

2. formula: 【Chemistry 2】 A polymorph of form B of compound I-491, represented by , characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, which is represented by a frequency of 2 theta ± 0.2° and has peaks at 15.4, 16.3, 19.0, 20.7, and 26.9 degrees, respectively.

3. The polymorph according to claim 1 or 2, characterized by a DSC thermogram showing a small endothermic event below 185°C, followed by a large endothermic event at 193±2°C.

4. The polymorph according to claim 1 or 2, wherein the chiral purity of the polymorph is at least 99.5%.

5. The polymorph according to claim 1 or 2, comprising less than 6% by weight of the solvent.

6. The polymorph according to claim 1 or 2, comprising less than 1% by weight of a solvent.

7. The polymorph according to claim 1, characterized by an X-ray powder diffraction pattern obtained by irradiation with a Cu-Kα pattern, which is expressed in degrees 2 theta ± 0.2° and has peaks at each of the following degrees: 7.3, 10.2, 13.4, 14.7, 15.4, 17.7, 18.5, 21.6, 24.8, and 28.

7.

8. The polymorph according to claim 7, further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, which is expressed in degrees 2 theta ± 0.2° and has peaks at degrees 7.9, 16.3, 20.7, and 22.9, respectively.

9. The polymorph according to claim 8, further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Kα, which is expressed as a frequency of 2 theta ± 0.2° and has peaks at 19.0, 25.4, and 26.9 degrees, respectively.

10. A polymorph according to claim 1 or 2, having unit cell dimensions of a = 11.93 Å, b = 13.24 Å, c = 13.51 Å, α = 65.40°, β = 80.08°, and γ = 89.18°.

11. A pharmaceutical composition comprising a polymorph according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

12. A polymorph according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 11, for use in the treatment of a disease selected from the group consisting of systolic dysfunction, diastolic dysfunction, dilated cardiomyopathy, HFrEF, HFpEF, chronic heart failure, and acute heart failure.

13. The polymorph or pharmaceutical composition according to claim 12, wherein the disease is dilated cardiomyopathy.

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