FORMAS POLIMORFICAS DE (R)-4-(1-((3-(DIFLUOROMETIL)-1-METIL-1H-PIRAZOL-4-IL)SULFONIL)-1-FLUOROETIL)-N-(ISOXAZOL-3-IL)PIPERIDIN-1-CARBOXAMIDA

Abstract

The present invention provides novel polymorphs of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidin-1-carboxamide (I-491) that are useful for the treatment of cardiac disorders including systolic dysfunction, dilated cardiomyopathy (DCM), heart failure with reduced ejection fraction (HFrEF), and conditions associated with left and / or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the polymorphs are described, as well as methods for treating systolic dysfunction, DCM, HFrEF, and other forms of heart disease.

Description

POLYMORPHIC FORMS OF (R)-4-(1-((3-(DIFLUOROMETHYL)-1-METHYL1H-PYRAZOLE-4-IL)SULFONYL)-1-FLUOROETHYL)-N-(ISOXAZOLE-3IL)PIPERIDIN-l-CARBOXAMIDE Background of the Invention Heart failure (HF) is a global pandemic that affects approximately 26 million people worldwide. It is the fastest growing cardiovascular condition globally, with substantial morbidity, mortality and cost burden on healthcare systems (Ponikowski, 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 in patients over 65 years of age (Ponikowski, supra; Savarese and Lund, supra; and Shah, J Arn Coli Cardiol. (2017) 70(20):2476-86. The mortality rate five years after hospitalization for HF is approximately 42%, comparable to many cancers (Benjamín, Circulation (2019) 139: e56-e528). Heart failure is a clinical syndrome in which a patient's heart is unable to provide an adequate supply of blood flow to the body to meet the body's metabolic needs. For some people with heart failure, the heart has difficulty pumping enough blood to help other organs in the body. Other people may have hardening and stiffness of the heart muscle itself, which αηαηηη / ζζηζ / Ε / γίΛΐ Ref. 329557 blocks or reduces blood flow to the heart. These two conditions result in inadequate blood circulation in the body and congestion of the lungs. Heart failure can affect the right or left side of the heart, or both sides at the same time. It can be an acute (short-term) or chronic (ongoing) condition. Heart failure may be called 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, heart palpitations, edema (such as swelling of the lungs , arms, legs, ankles, face, hands or abdomen), difficulty breathing (dyspnea), bulging veins in the neck and decreased ability or tolerance to exercise. The volume of blood pumped by the heart is generally determined by: (a) the contraction of the heart muscle (i.e., how well the heart contracts or its systolic function) and (b) the filling of the cardiac chambers (i.e. , how well the heart relaxes and fills with blood or its diastolic function). Ejection fraction is used to evaluate the pumping function of the heart; represents the percentage of blood pumped from the left ventricle (the main pumping chamber) per beat. A normal or preserved ejection fraction is greater than or equal to one percent. If the systolic function of the heart is impaired such that the heart shows a substantial reduction in ejection fraction, this condition is known as heart failure with reduced ejection fraction (HFrEF). HFrEF with an ejection fraction of < 40% is classic HFrEF, while HFrEF with an ejection fraction of 41-49% is classified as heart failure with mid-range ejection fraction (HFmrEF), according to the guidelines. the 2013 American College of Cardiology Foundation / American Heart Association (Yancy, Circulation (2013) 128: e240-327) and the 2019 ACC Expert Consensus Decision Guideline on Inpatient Evaluation, Management, and Clinical Trajectory with Heart Failure (Hollenberg, J Am Coll Cardiol (2019) 74:1966-2011). There are many causes of having a weak heart muscle (low ejection fraction), including ischemia / infarction, hypertension, heart valve defects, genetic mutations, infection, and exposure to toxins / drugs. Diastolic dysfunction may contribute to morbidity in patients with HFrEF. If the heart pumps normally but is too stiff to fill properly, this condition is known as heart failure with preserved ejection fraction (HFpEF). Historically, HFpEF was called 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. Abnormalities of diastolic and systolic ventricular reserve, chronotropic incompetence, ventricular tissue stiffness, atrial dysfunction, pulmonary hypertension, impaired vasodilation, and endothelial dysfunction are implicated. Often these abnormalities are noticed only when the circulatory system is stressed. In the United States of America alone, there are approximately 2.6 million patients with HFrEF, corresponding to approximately 40% of the U.S. HF population. (Bloom, Nat Rev Dis Primers. (2017) 317058) . HFrEF can develop from an ischemic origin (mainly attributed to coronary artery disease) or a nonischemic origin (attributed to myocardial disease of non-coronary causes). Coronary artery disease (coronary heart disease) is a disease in which there is a narrowing of the passage of the coronary arteries, and when severe, the narrowing causes inadequate blood supply to the heart muscle and can lead to death of the arteries. heart muscle cells (infarction). Nonischemic HFrEF is sometimes called dilated cardiomyopathy (DCM). Despite the αηαηηη / ζζηζ / Ε / γίΛΐ nomenclature, dilated (enlarged) cardiac chambers can be found in both ischemic and nonischemic HFrEF patients. Hereinafter, DCM refers to nonischemic HFrEF. DCM can be assigned as a clinical diagnosis of genetic DCM or idiopathic DCM if no identifiable cause can be found. Mutations in more than 30 genes, including sarcomere genes, perturb a diverse set of myocardial proteins to cause a DCM phenotype. Some of the genetic links to DCM are discussed in Hershberger, Nature Reviews (2013) 10(9):531-47 and Rosenbaum, Nat Rev Cardiol. (2020) 17(5):286-97. Contemporary medical therapy for HFrEF focuses on counteracting the effects of neurohormonal activation with modulators of the reninangiotensin-aldosterone system, β-adrenergic blockers, diuretics, and modulators of the vasoactive peptide BNP (brain natriuretic peptide). Although these drugs attenuate some of the consequences of maladaptation and improve clinical outcomes, none address the underlying causal pathways of myocardial dysfunction. Various inotropic agents are used in clinical practice to increase cardiac contractility by increasing intracellular calcium or cyclic adenosine monophosphate, mechanisms that increase myocardial oxygen demand. Their use is limited to short-term or αηαηηη / ζζηζ / Ε / γίΛΐ therapy in patients with refractory or end-stage heart failure in order to relieve symptoms, since chronic studies with these drugs have shown an increase of mortality due to arrhythmias and ischemia. However, these drugs improve hemodynamics and symptoms, suggesting potential clinical benefit for agents that increase contractility without arrhythmic or ischemic risks. There are currently no approved therapies to treat heart failure that directly target the contractile system. There remains an urgent need for new safe and effective treatments for systolic heart failure. Nonischemic HFrEF is sometimes called dilated cardiomyopathy (DCM). Despite the nomenclature, dilated (enlarged) cardiac chambers can be found in both ischemic and nonischemic HFrEF patients. Dilated cardiomyopathy (DCM) comprises a group of myocardial disorders that cause dilation of the left ventricle and systolic dysfunction (contraction abnormality). DCM can be subdivided into ischemic (attributed to coronary artery disease) or non-ischemic (primary myocardial diseases). Hereinafter, DCM refers to nonischemic HFrEF. DCM may be assigned as a clinical diagnosis of idiopathic DCM if no identifiable cause (except genetics) can be found. Idiopathic DCM can be αηαηηη / ζζηζ / Ε / γίΛΐ further subdivided based on whether a genetic cause can be identified. Mutations in more than 30 genes, including sarcomere genes, perturb a diverse set of myocardial proteins to cause a DCM phenotype. Some of the genetic links to DCM are discussed in Hershberger, Nature Reviews (2013) 10(9):531-47. Epidemiologic data indicate that approximately 1 in 2,500 individuals in the general population have idiopathic DCM. Sarcomere gene mutations that cause DCM are highly penetrant, but there is great variability in clinical severity and clinical course. Some genotypes are associated with a more malignant course, but there is considerable variability between and even within families carrying the same mutation. Although many patients with DCM report minimal or no symptoms for prolonged periods, DCM is a progressive disease with a significant cumulative burden of morbidity and mortality. The hallmark of DCM is a dilated left ventricle, more spherical in shape than usual, and with decreased systolic function. Patients often present with symptoms of heart failure: dyspnea, orthopnea, exercise intolerance, fatigue, abdominal discomfort, and lack of appetite. Signs include sinus tachycardia, gallop rhythm, mitral regurgitation murmur, rales, jugular venous distention, hepatomegaly, peripheral edema, and cold extremities. As αηαηηη / ζζηζ / Ε / γίΛΐ occurs with many other disorders, symptoms tend to worsen with age. The patient's trajectory is marked by hospitalizations for decompensated heart failure and an increased risk of sudden arrhythmic death and death from pump failure. 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) may help with the diagnosis and treatment of DCM, especially to distinguish heart failure from comorbid lung disease. Coronary angiography can identify whether heart failure is due to an ischemic etiology. Endomyocardial biopsy can distinguish DCM from disease processes that may require an alternative management strategy, such as myocarditis, storage disease, sarcoidosis, or hemochromatosis. Medical therapy remains the mainstay in 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. Implantable cardioverter-defibrillators (ICDs) for αηαηηη / ζζηζ / Ε / γίΛΐ patients with left ventricular ejection fraction less than 30% may reduce sudden arrhythmic death. Additionally, cardiac resynchronization therapy (CRT) has been shown to improve heart failure-free survival in selected patients. Despite these interventions, morbidity and mortality from heart failure remain high, and hospitalization for heart failure remains the most common reason for hospitalization in older adults. The present disclosure provides therapeutic agents and methods to remedy the unmet need to improve the treatment of systolic dysfunction, DCM, HFrEF and related cardiac disorders. Brief Description of the Invention In one aspect, the invention provides polymorphs of (R)-4-(1-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3 -yl)piperidine-1carboxamide (1-491). Four polymorphs are detailed in this document, including forms A, B, C and D. In another aspect, the invention provides pharmaceutical compositions and compositions containing a polymorph of 1-491, or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable excipient. The description also provides methods for αηαηηη / ζζηζ / Ε / γίΛΐ to treat systolic dysfunction. In another aspect, the invention provides methods for treating dilated cardiomyopathy. In certain aspects of the disclosure, the invention provides methods for treating HFrEF. These methods include administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein. Details of certain aspects of the invention are set forth in the detailed description, as described below. Other features, objects and advantages of the invention will be apparent from the definitions, examples, figures and claims. Brief Description of the Figures Figure 1A shows a high-resolution synchrotron X-ray powder diffraction pattern of form A recorded at room temperature (ESRF, λ = 1,000 A). Figure IB shows a ray diffraction pattern X powder of form A recorded at room temperature. Figure 2 shows a DSC thermogram and a TGA thermogram of form A. Figure 3 shows an Ortep representation of the molecular structure of form A with atom labels and thermal ellipsoids at 30% probability and disordered regions indicated with dashed lines. Figure 4 shows a representation of the αηαηηη / ζζηζ / Ε / γίΛΐ molecular packing of form A on the short axis, showing the disorder scheme (dotted lines). Figure 5 shows a simulated powder diffraction pattern of the crystal structure of Form A at a copper wavelength. Figure 6A shows a high-resolution synchrotron X-ray powder diffraction pattern of form B recorded at room temperature (ESRF, λ = 0.800 Á). Figure 6B shows an X-ray powder diffraction pattern of form B recorded at room temperature. Figure 7 shows a DSC thermogram and a TGA thermogram of form B. Figure 8 shows the Ortep representation of the molecular structure of form B with atom labels and thermal ellipsoids at 30% probability. There are four independent molecules with disordered regions indicated by the dotted lines. Figure 9 shows a representation of the crystal structure of form B viewing the molecular clumping in the (011) plane with the disorder shown by the dashed lines. Figure 10 shows a simulated powder diffraction pattern of the crystal structure of form B at a copper wavelength. Only one theoretical reflection is present in the angular region of 9o to 10°, while 3 are actually present in the angular region of 7o to 8o. Figure 11 shows a DSC thermogram and a TGA thermogram of form C. Figure 12A shows an Ortep representation of the molecular structure of form C with atom labels and thermal ellipsoids at 50% probability and disordered regions indicated with dashed lines. Figure 12B shows the crystal structure of the monoclinic form C representing molecular packing on the short axis with disordered regions indicated with dashed lines. Figure 13A shows a simulated powder diffraction pattern of the crystal structure of form C at a copper wavelength. Figure 13B shows an X-ray powder diffraction pattern of Form C recorded at room temperature. Figure 14 shows an Ortep representation of the molecular structure of the D form with atom labels and thermal ellipsoids at 50% probability and with disordered regions indicated by the dashed lines. Figure 15 shows a crystal structure of the triclinic D form that represents molecular packing on the short axis with disordered regions indicated by the dashed lines. αηαηηη / ζζηζ / Ε / γίΛΐ Figure 16 shows a simulated powder diffraction pattern of the crystal structure of form D at a copper wavelength. Detailed description of the invention A crystalline polymorphic form of a particular drug is often an important determinant of the drug's ease of preparation, stability, solubility, storage stability, ease of formulation, and in vivo pharmacology. Polymorphic forms occur when the same composition of matter crystallizes in a different lattice arrangement, resulting in different thermodynamic properties and thermodynamic stabilities specific to a particular polymorphic form. In cases where two or more polymorphic substances can be produced, it is desirable to prepare each of the polymorphs in pure form and determine the properties of each polymorph. Based on the desired characteristics, properties and stabilities, a preferred polymorph can be selected. In certain aspects, ease of preparation or stability may be considered especially important, such that the most stable polymorph may be preferred in certain cases, while in other cases, the polymorph that is easiest to prepare (e.g., the least dangerous, least expensive, highest performance) may be considered preferred. In other situations, a different polymorph may be preferred for greater solubility and / or superior pharmacokinetics. Because improved drug formulations, with better bioavailability or better stability, for example, are constantly sought, there is a continuing need for new or purer polymorphic forms of existing drug molecules. The various crystalline polymorphs of IoFr EITHER / -\ O'N N L / -NH^H3C N 491: ' , which are described in this document, help meet these and other needs. It has been discovered that a series of polymorphs of (R)4-(1-( (3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-1fluoroethyl)-N-(isoxazol-3- il)piperidine-l-carboxamide (1-491) and pharmaceutically acceptable salts thereof increase contractility by improving phosphate release from myosin without prolonging systole or shortening diastole. As such, the compounds may improve systolic function in patients with DCM or HFrEF, helping them overcome the debilitating exertional dyspnea and fatigue that often accompany the disease. The compounds can also be used to treat other cardiac disorders characterized by decreased cardiac output. Form B was identified as the most stable polymorph (compared to form C and form D) and, as such, was selected as the primary polymorph for development. The more stable a polymorph is, the less likely it is to change over time to another form on the shelf, whether it is an active pharmaceutical ingredient alone or in a formulated pharmaceutical product. Changes in the polymorphic form during storage or during processing can lead to changes in solubility, dissolution rate or bioavailability; therefore, it is important to identify a stable polymorph for use as a drug candidate early in development. Definitions The term approximately as used herein is used to describe a range (e.g., of temperatures, of mass, of weight) and is given its ordinary meaning in the art, typically referring to the error associated with an instrument for collecting a measurement or reading. In general, the term approximately when referring to temperature provides a deviation of ±0-2°C. As used herein, the term "salt" refers to an acidic or basic salt of a compound of the invention. Pharmaceutically acceptable salts may be derived, for example, from mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid and the like), organic acids (acetic acid, propionic acid, glutamic acid, αηαηηη / ζζηζ / Ε / γίΛΐ citric acid and the like). and quaternary ammonium ions. Pharmaceutically acceptable salts are understood to be non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference. The neutral form of a compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The original form of the compound differs from the various forms of the salt in certain physical properties, such as solubility in polar solvents. The term ambient temperature refers to a temperature within the range of 19-26°C. The term solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association can include hydrogen bonds. Conventional solvents include water, methanol, ethanol, acetic acid, dimethyl sulfoxide (DMSO), tetrahydrofuran (THE), diethyl ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into a crystal lattice of the crystalline solid. Solvato encompasses both solution-phase solvates and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates. In certain respects, a solvate is a distinct polymorph. In some aspects, a solvate is not a distinct polymorph, that is, a defined polymorph with a distinct crystal structure may contain residual solvent molecules. The term amorphous or amorphous form refers to a form of a solid (solid form), which substantially lacks three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially non-crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a broad scattering band with a peak at 2Θ of, for example, between 20 and 70°, inclusive, using CuKa radiation. In certain embodiments, the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures. In certain embodiments, the maximum intensity of any one or more peaks attributed to crystal structures observed at a 2Θ angle of between 20 and 70°, inclusive, is no more than 300 times, no more than 100 times, no more than 30 times, not more than 10 times or not more than 3 times the maximum intensity of the wide scattering band. In certain embodiments, the XRPD pattern of an amorphous form does not include peaks attributed to crystalline structures. The term polymorph or polymorphic form refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystal forms generally have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. The term crystalline refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (melting point). The term crystalline or crystalline form refers to a solid form that substantially exhibits a three-dimensional αηαηηη / ζζηζ / Ε / γίΛΐ order. In certain embodiments, a crystalline form of a solid is a solid form that is substantially non-amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more clearly defined peaks. The compound of the present invention has an asymmetric carbon atom (optical center) and double bonds; Racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., separate enantiomers) are all intended to be included within the scope of the present invention. The stereochemical description shown for the compound of the present invention is intended to refer to the compound in which one of the isomers is present and substantially free of the other isomer. Substantially free of another isomer indicates at least a 70 / 30 ratio of the two isomers at the stereochemical center shown, more preferably 80 / 20, 90 / 10 or 95 / 5 or more. In some embodiments, one of the isomers will be present in an amount of at least 99%. When a polymorphic form is described, it is intended to refer to the polymorph identified as described herein, which is substantially free of any other polymorphs. Substantially free of another polymorph indicates at least a 70 / 30 molar ratio of the two polymorphs, more preferably 80 / 20, 90 / 10, 95 / 5, 99 / 1 or more. In some embodiments, one of the polymorphs will be present in an amount of at least 99%. Compounds of the present invention may also contain unnatural ratios of atomic isotopes in one or more of the atoms constituting such compounds. The unnatural ratios of an isotope can be defined as ranging from the amount found in nature to an amount that consists of 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C), or non-radioactive isotopes, such as deuterium (2H) or carbon-13 (13C). Such isotopic variations may provide additional utilities to those described elsewhere in this application. For example, isotopic variants of the compounds of the invention may find additional utility, including, but not limited to, as diagnostic and / or imaging reagents, or as cytotoxic / radiotoxic therapeutic agents. Furthermore, isotopic variants of the compounds of the invention may have altered pharmacokinetic and pharmacodynamic characteristics, which may contribute to improved safety, tolerability, or efficacy during treatment. It is intended that all isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention. When αηαηηη / ζζηζ / Ε / γίΛΐ is referred to specifically, as C1-C4 deuteroalkyl, the term refers to an alkyl group with the indicated number of carbon atoms and having hydrogen atoms replaced by deuterium in a number from one to a deuterium form, where the deuterium replacement is greater than the natural abundance of deuterium - typically 50%, 60%, 70%, 80%, 90%, 95% or more deuterium replacement. Examples of C1-C4 deuteroalkyl are CD3, CH2CD3, CD2CD3, CH2CH2CH2D and the like. As used herein, the term "pharmaceutically acceptable" refers to a substance that is compatible with a compound of the invention, as well as any other ingredients with which the compound is formulated. Furthermore, a pharmaceutically acceptable substance is not deleterious to the recipient of the substance. The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are in accordance with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19, incorporated herein by reference. αηαηηη / ζζηζ / Ε / γίΛΐ Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of non-toxic pharmaceutically acceptable acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, acid oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate. , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleal, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal αηαηηη / ζζηζ / Ε / γίΛΐ, alkaline earth metal, ammonium and N+(61-4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. As used herein, the term pharmaceutical composition refers to a product comprising a compound of the invention, an excipient as defined herein and other optional ingredients in specified amounts, as well as any product that results directly or indirectly from the combination of the specified ingredients in the specified quantities. As used herein, the term "excipient" refers to a substance that aids in the delivery of an active agent to a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colorants. One skilled in the art will recognize that other excipients may be useful in the present invention. In some embodiments, the treatment may be administered after one or more signs or symptoms of the disease have developed or been observed. As used herein, the terms treat, treating, and treatment refer to any indication of success in treating or improving a pathology, injury, condition, or symptom related to systolic dysfunction, DCM, HFrEF, or other cardiac disorders. , including any objective or subjective parameter such as despondency; remission; decrease in symptoms; that makes the pathology, injury, condition or symptom more tolerable for the patient; that reduces the frequency or duration of the pathology, injury, condition or symptom; or, in some situations, prevents the appearance of the pathology, injury, condition or symptom. Treatment or improvement can be based on any objective or subjective parameter; including, for example, the result of a physical examination. A subject for whom administration is contemplated refers to a human being (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child or adolescent) or adult subject (e.g., young adult, middle-aged adult or older adult)) or non-human animal. A patient refers to a human subject who needs treatment for a disease. The terms administering, administering or administration refer to implanting, absorbing, ingesting, injecting, inhaling or otherwise introducing a polymorphic form of 1-491 described herein, or a composition thereof, in or on a subject. The terms condition, disease, and disorder are used interchangeably. An effective amount of a polymorphic form described herein refers to an amount sufficient to elicit the desired biological response, i.e., treat the condition. As those skilled in the art will appreciate, the effective amount of a polymorphic form of 1-491 described herein may vary depending on factors such as the desired biological end point, the pharmacokinetics of the polymorphic form, the condition being treated. , the mode of administration and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is the amount of a polymorphic form of 1-491 described herein in a single dose. In certain embodiments, an effective amount is combined amounts of a polymorphic form of I491 described herein in multiple doses. A therapeutically effective amount of a polymorphic form of 1-491 described herein is an amount sufficient to provide 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 the therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of the condition. The term therapeutically effective amount may encompass an amount that improves overall therapy, reduces or prevents symptoms, signs or causes of the condition, and / or improves the therapeutic efficacy of another therapeutic agent. compounds In one aspect, polymorphs of 1-491:' (1-491) are provided herein. Polymorphic forms of 1-491 including form A, form B, form C, form D are detailed in this paper. Polymorphs of 1-491 can be prepared by methods as generally described in the examples. One skilled in the art will appreciate that the compounds and polymorphs thereof of the invention can be prepared using other synthetic methods as substitutes for the transformations provided in the examples. αηαηηη / ζζηζ / Ε / γίΛΐ Form A In certain aspects, the present disclosure provides a polymorph of 1-491 characterized as form A. In general, form A has an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα that has at least 3 peaks expressed in degrees 2-theta ± 0.2° selected between 10.98, 15.78, 16.08, 20.44, 23.78 and 26.58 degrees. In some aspects, Form A is characterized by at least one of: (a) an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having two or more peaks expressed in degrees 2-theta ± 0.2° and selected from 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, 2 2.60, 23.78, 26.16, 26.36, 26.58, 27.24 and 28.04 degrees ; or (b) a DSC thermogram showing endotherm at approximately 181-200°C. In certain aspects, Form A is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having each of the peaks expressed in degrees 2-theta ± 0.2° and selected from 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 degrees. In some aspects, 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° and selected from 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 degrees. In certain aspects, Form A is characterized by a powder 26.58 degrees. In some aspects, form A is characterized by 4 or more peaks, or 2 or more peaks expressed in degrees 2-theta ± 0.2° at each of 10.98, 15.78, 16.08, 20.44, 23.78 and 26.58 degrees. In some aspects, Form A is characterized by a powder In some aspects, Form A is characterized by a powder . In certain aspects, form A is characterized by 2 or more, or 4 or more peaks expressed in degrees 2-theta ± 0.2° selected from 6.62, 10.98, 16.08, 23.78 and 26.58 degrees. In certain aspects, Form A is characterized by a powder In αηαηηη / ζζηζ / Ε / γΐΛ some aspects, form A is characterized by 2 or more peaks expressed in degrees 2-theta ± 0.2° selected between 15.78, 16.08 and 23.78 degrees. In some aspects, Form A is characterized by a powder In some aspects, form A is characterized by 2 or more peaks expressed in degrees 2-theta ± 0.2° selected from 6.62, 15.78, 16.08 and 26.58 degrees. In certain aspects, Form A is characterized by a powder In some aspects, form A is characterized by 2 or more peaks expressed in degrees 2-theta ± 0.2° selected from 6.62, 17.72, 23.78 and 26.58 degrees. In certain aspects, Form A is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure IA. In certain aspects, Form A is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure IB. In certain aspects, Form A is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 5. αηαηηη / ζζηζ / Ε / γίΛΐ In certain aspects, Form A is further characterized by a powder 11:40 a.m. to 12:60 p.m., 4:80 p.m. to 5:20 p.m. and 12:40 p.m. to 12:80 p.m. In some aspects, there are no peaks expressed in degrees 2-theta ± 0.05° in each 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 degrees. In certain aspects, there are no peaks expressed in degrees 2-theta ± 0.05° in at least 2 of the intervals 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 aspects, there are no peaks expressed in degrees 2-theta ± 0.05° in at least 4 of the intervals 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 some aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at each 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 degrees. In certain aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° in at least 2 of the intervals 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 aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° in at least 4 of the intervals 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. αηαηηη / ζζηζ / Ε / γίΛΐ In some aspects, there are only peaks that are equal to or less than 1 / 10 the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° in each 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 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° in at least 2 of the intervals 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 aspects, there are only peaks that are equal to or less than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° in at least 4 of the intervals 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 some respects, there are only peaks that are equal to or less than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° in each 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 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° in at least 2 of the intervals 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 aspects, there are only peaks that are equal to or less than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° in at least 4 of the intervals 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 some aspects, Form A is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα without peaks expressed in degrees 2-theta ± 0.05° at 24.40 to 24.80 degrees. In certain respects, there are no peaks expressed in degrees 2-theta ± 0.05° at 24.40 to 24.80 degrees. In certain aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at 24.40 to 24.80 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in 2-theta ± 0.05° qrads at 24.40 to 24.80 qrads. In certain aspects, there are only peaks that are equal to or less than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2theta ± 0.05° at 24.40 to 24.80 degrees. In certain aspects, Form A is further characterized by an X-ray powder diffraction pattern obtained by Cu-Κα irradiation with no peaks expressed in degrees 2-theta ± 0.05° at each of 0 to 6.00, 11.40 to 12.60 and 24.40 to 24.80 degrees. In some respects, there are no peaks at 0 to 6.00, 11.40 to 12.60 and 24.40 to 24.80 degrees. In certain aspects, there are no peaks expressed in degrees 2-theta ± 0.05° in at least two of the selected intervals from 0 to 6.00, 11.40 to 12.60 and 24.40 to αηαηηη / ζζηζ / Ε / γίΛΐ 24.80 degrees. In some aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° from 0 to 6.00, 11.40 to 12.60 and 24.40 to 24.80 degrees. In certain aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° in at least two of the selected intervals from 0 to 6.00, 11.40 to 12.60 and 24.40 to 24.80 degrees. In some aspects, there are only peaks that are less than or equal to 1 / 20 the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° at 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 20 the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2theta ± 0.05° in at least two of the selected intervals from 0 to 6.00, 11.40 to 12.60 and 24.40 to 24.80 degrees. In some aspects, there are only peaks that are equal to or less than 1 / 10 the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° at 0 to 6.00, 11.40 to 12.60, and 24.40 to 24.80 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 10 the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° in at least two of the selected intervals from 0 to 6.00, 11.40 to 12.60 and 24.40 to 24.80 degrees. In some aspects, Form A is further characterized by an X-ray powder diffraction pattern obtained by αηαηηη / ζζηζ / Ε / γίΛΐ irradiation with Cu-Κα without peaks expressed in degrees 2-theta ± 0.05° at 11.40 to 12.60 degrees . In certain respects, there are no peaks expressed in degrees 2-theta ± 0.05° at 11.40 to 12.60 degrees. In certain aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at 11.40 to 12.60 degrees. In certain aspects, there are only peaks that are less than or equal to 1 / 20 the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta + 0.05° at 11.40 to 12.60 degrees. In certain aspects, there are only peaks that are less than or equal to 1 / 10 the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2theta ± 0.05° at 11.40 to 12.60 degrees. In some aspects, Form A is characterized by a DSC thermogram essentially the same as that shown in Figure 2. In some aspects, Form A is characterized by a DSC thermogram showing an endotherm at about 181-200°C. . In certain aspects, Form A is characterized by an onset of melting of about 181°C. In some aspects, Form A is characterized by a melting point of 191°C ± 2°C. In certain aspects, Form A is characterized by the structure shown in Figure 3. In certain aspects, Form A is characterized by the structure shown in Figure 4. In some aspects, Form A has a crystal system triclinics and a space group of P1. In certain aspects, form A has unit cell dimensions of a = 6.403 Á, b = 11.343 A, c = 13.507 A, a = 81.91°, β = 85.73°, and y = 85.18°. In certain aspects of the disclosure, Form A is substantially free of other forms of tert-butyl-(R)4-(1-((3-(difluoromethyl)-l-methyl-1H-pyrazol-4-yl)sulfonyl )-1fluoroethyl)piperidine-l-carboxylate. In particular, form A is substantially free of tert-butyl-(R)-4(1-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-1fluoroethyl form D. )piperidine-l-carboxylate. In some aspects, Form A is substantially free of tert-butyl-(R)-4-(1-((3(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl)-1fluoroethyl)piperidine. amorphous l-carboxylate. In another aspect, a composition comprising Form A is provided herein. In some aspects, the composition comprises greater than or equal to 75% by weight of Form A. In some aspects, the composition comprises greater than or equal to 85% by weight of Form A. In some aspects, the composition comprises greater than or equal to 90% by weight of Form A. In some aspects, the composition comprises a form A greater than or equal to 95% by weight. In some aspects, the composition comprises a form A greater than or equal to 98% by weight. In some aspects, the composition comprises a form A greater than or equal to 99% by weight. In some aspects, the composition comprises a form A greater than or equal to 99.5% by weight. In some aspects, the composition comprises a form A greater than or equal to 99.9% by weight. In another aspect, a composition is provided herein, wherein the molar ratio of the amount of form A to the sum of the amounts of other polymorphic forms is equal to or greater than 80:20. In another aspect, the molar ratio between the amount of form A and the sum of the amounts of other forms is equal to or greater than 90:10. In another aspect, the molar ratio between the amount of form A and the sum of the amounts of other forms is equal to or greater than 95:5. In another aspect, the molar ratio between the amount of form A and the sum of the amounts of other forms is equal to or greater than 97:3. In another aspect, the molar ratio between the amount of form A and the sum of the amounts of other forms is equal to or greater than 98:2. In another aspect, the molar ratio between the amount of form A and the sum of the amounts of other forms is equal to or greater than 99:1. In another aspect, the molar ratio between the amount of form A and the sum of the amounts of other forms is equal to or greater than 99.5:0.5. In another aspect, there is provided herein a composition, wherein the molar ratio of the amount of form A to polymorphic form D is equal to or greater than 80:20. In another aspect, the molar ratio of the amount of form A to form D is equal to or greater than 90:10. In another aspect, the molar ratio of the amount of form A to form D is equal to or greater than 95:5. In another aspect, the molar ratio of the amount of form A to form D is equal to or greater than 97:3. In another aspect, the molar ratio of the amount of form A to form D is equal to or greater than 98:2. In another aspect, the molar ratio of the amount of form A to form D is equal to or greater than 99:1. In another aspect, the molar ratio of the amount of form A to form D is equal to or greater than 99.5:0.5. Also provided herein is a composition comprising Form A that is essentially solvent-free. In some respects, form A is a solvate. In certain aspects, the composition has less than 6% by weight of solvent. In some aspects, the composition has less than 3% by weight of solvent. In certain aspects, the composition has less than 2% by weight of solvent. In some aspects, the composition has less than 0.5% by weight of solvent. In certain aspects, the solvent is methanol. In some aspects, the solvent is ethanol. In certain aspects, the solvent is acetone. In other aspects, the solvent is acetonitrile. Form B In certain aspects, the present disclosure provides a polymorph of 1-491 characterized as form B. In general, form B has an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα that has at least 3 peaks expressed in degrees 2-theta ± 0.2° selected between 15.42, 16.28, 19.02, 20.70 and 26.88 degrees. In some aspects, Form B is characterized by at least one of: (a) an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having two or more peaks expressed in degrees 2-theta ± 0.2° and selected from 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; or (b) a DSC thermogram showing endotherm at approximately 170-185°C. In certain aspects, form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having each of the peaks expressed in degrees 2-theta ± 0.2° and selected from 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. In some aspects, 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° and selected from 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. In certain aspects, Form B is characterized by an X-ray powder diffraction pattern obtained by Cu-Κα irradiation having peaks expressed in degrees 2theta ± 0.2° at each of 7.88, 10.20, 20.70 and 26.88 degrees. In some aspects, Form B is characterized by 3 peaks or 2 peaks expressed in degrees 2-theta ± 0.2° at each of 7.88, 10.20, 20.70, and 26.88 degrees. In some aspects, Form B is characterized by an X-ray powder diffraction pattern obtained by Cu-Κα irradiation having peaks expressed in degrees 2theta ± 0.2° at each of 7.32, 7.88, 10.20, and 18.48 degrees. In certain aspects, the B form is characterized by 2 or more, or 3 or more peaks selected between 7.32, 7.88, 10.20 and 18.48 degrees. In certain aspects, form B is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα which has peaks expressed in degrees 2theta ± 0.2° at each of 7.32, 16.28 and 26.88 degrees. In some aspects, form B is characterized by 2 or more peaks expressed in degrees 2-theta ± 0.2° selected between 7.32, 16.28 and 26.88 degrees. In some aspects, form B is characterized by an X-ray powder diffraction pattern obtained by Cu-Κα irradiation having peaks expressed in degrees 2theta ± 0.2° at each of 7.88, 15.42, 17.70, and 21.56 degrees. In some aspects, form B is characterized by 2 or more peaks expressed in degrees 2-theta ± 0.2° selected from αηαηηη / ζζηζ / Ε / γίΛΐ 7.88, 15.42, 17.70 and 21.56 degrees. In certain aspects, Form B is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 6A. In certain aspects, Form B is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 6B. In certain aspects, Form B is characterized by an X-ray powder diffraction pattern essentially the same as that shown in Figure 10. In certain aspects, Form B is further characterized by a powder . In some respects, there are no peaks expressed in degrees 2-theta ± 0.05° in each of 0 to 6.80 and 8.15 to 9.00 degrees. In certain respects, there are no peaks expressed in degrees 2-theta ± 0.05° in at least 1 of the intervals consisting of 0 to 6.80 and 8.15 to 9.00 degrees. In some respects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at each of 0 to 6.80 and 8.15 to 9.00 degrees. In certain aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° in at least 1 of the intervals consisting of 0 to 6.80 and 8.15 to 9.00. In some aspects, there are only peaks that are equal to or less than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2 αηαηηη / ζζηζ / Ε / γίΛΐ theta ± 0.05° in each of 0 to 6.80 and 8.15 to 9.00 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° at least 1 of the intervals consisting of 0 to 6.80 and 8.15 to 9.00. In some aspects, there are only peaks that are equal to or less than 1 / 10 the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° in each of 0 to 6.80 and 8.15 to 9.00 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° at least 1 of the intervals consisting of 0 to 6.80 and 8.15 to 9.00. In some aspects, Form B is further characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα without peaks expressed in degrees 2-theta ± 0.05° from 0 to 6.80 degrees. In certain respects, there are no peaks expressed in degrees 2-theta ± 0.05° from 0 to 6.80 degrees. In certain aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at 0 to 6.80 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° from 0 to 6.80 degrees. In certain aspects, there are only peaks that are equal to or less than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° from 0 to 6.80 degrees. In certain aspects, Form B is further characterized by an X-ray powder diffraction pattern obtained by Cu-Κα irradiation without peaks expressed in degrees 2-theta ± 0.05° at each of 8.15 to 9.00 degrees. In some respects, there are no peaks expressed in degrees 2-theta ± 0.05° at 8.15 to 9.00 degrees. In some aspects, there are only weak intensity peaks expressed in degrees 2-theta ± 0.05° at 8.15 to 9.00 degrees. In some aspects, there are only peaks that are equal to or less than 1 / 20 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2-theta ± 0.05° at 8.15 to 9.00 degrees. In some aspects, there are only peaks that are equal to or less than 1 / 10 of the height of the most intense peak (within the same diffraction pattern) expressed in degrees 2theta ± 0.05° at 8.15 to 9.00 degrees. In some aspects, Form B is characterized by a DSC thermogram essentially the same as that shown in Figure 7. In some aspects, Form B is characterized by a DSC thermogram showing an endotherm at approximately 170-185 ° C. . In certain aspects, Form B is characterized by an onset of melting of about 170°C. In some aspects, Form B is characterized by a melting point of 178°C ± 2°C. In some aspects, form B is characterized by a DSC thermogram showing a second endotherm at αηαηηη / ζζηζ / Ε / γίΛΐ approximately 185-200 °C. In some aspects, form B is characterized by a second melting point of 192.7 °C ± 2 °C. In certain aspects, form B is characterized by the structure shown in Figure 8. In certain aspects, form B is characterized by the structure shown in Figure 9. In some aspects, form B has a crystal system triclinics and a space group of P1. In certain aspects, form B has unit cell dimensions of a = 11.926 Á, b = 13.239 Á, c = 13.511 Á, a = 65.40°, β = 80.08° and y = 89.18°. In certain aspects of the disclosure, form B is substantially free of other forms of tert-butyl-(R)4-(1-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4-yl)sulfonyl). )-1fluoroethyl)piperidine-l-carboxylate. In particular, form B is substantially free of form A and / or form D of tert-butyl-(R)-4-(1-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4yl )sulfonyl)-1-fluoroethyl)piperidine-l-carboxylate. In some aspects, Form B is substantially free of tert-butyl-(R)-4-(1-((3-(difluoromethyl)-l-methyl-lH-pyrazol-4yl)sulfonyl)-1-fluoroethyl) piperidine. -l-carboxylate amorphous. In another aspect, there is provided herein a composition comprising form B. In some aspects, the composition comprises greater than or equal to 99.5% by weight of form B. In another aspect, there is provided herein a composition, wherein the molar ratio of the amount of αηαηηη / ζζηζ / Ε / γίΛΐ form B to the sum of the amounts of other polymorphic forms is equal to or greater than 80:20. In another aspect, the molar ratio of the amount of form B to the sum of the amounts of other forms is equal to or greater than 90:10. In another aspect, the molar ratio of the amount of form B to the sum of the amounts of other forms is equal to or greater than 95:5. In another aspect, the molar ratio of the amount of form B to the sum of the amounts of other forms is equal to or greater than 97:3. In another aspect, the molar ratio of the amount of form B to the sum of the amounts of other forms is equal to or greater than 98:2. In another aspect, the molar ratio of the amount of form B to the sum of the amounts of other forms is equal to or greater than 99:1. In another aspect, the molar ratio of the amount of form B to the sum of the amounts of other forms is equal to or greater than 99.5:0.5. Also provided herein is a composition comprising Form B that is essentially solvent-free. In certain aspects, the composition has less than 6% by weight of solvent. In some aspects, the composition has less than 3% by weight of solvent. In certain aspects, the composition has less than 1% by weight of solvent. In some aspects, the composition has less than 0.7% by weight of solvent. In certain aspects, the solvent is a mixture of water and methanol. In some aspects, the solvent is a mixture of water and ethanol. In other aspects, αηαηηη / ζζηζ / Ε / γίΛΐ the solvent is a mixture of water and acetonitrile. In other aspects, the solvent is water. Form C Also provided in this document is Form C of 1-491. In general, Form C has a powder . In certain aspects, Form C is characterized by an X-ray powder diffraction pattern essentially identical to that shown in Figure 13A. In certain aspects, Form C is characterized by an X-ray powder diffraction pattern essentially identical to that shown in Figure 13B. In some aspects, Form C is characterized by a DSC thermogram showing endotherm at approximately 175-189°C. In some aspects, form B is characterized by a melting point of 185.9 °C ± 2 °C. In some aspects, form B is characterized by a DSC thermogram showing a second endotherm at approximately 193201 °C. In some aspects, Form B is characterized by a second melting point of 190°C ± 2°C. In some aspects, form C is characterized by the structure shown in Figure 12A. In other aspects, form C is characterized by the structures shown in Figure 12B. In some aspects, form C has a monoclinic crystal system and a space group of P 21. In certain aspects, form C has unit cell dimensions of a (a) = 14.47 b (A) = 17.28 c (a) = 16.11 a (°) = 90.00 β (°) = 109.85 and (°) = 90.00. Form D Also provided in this document is Form D of 1-491. In general, the D form of 1-491 has a powder 19.82 and 20.44 degrees. In some aspects, the D-form is characterized by the structure shown in Figure 14. In other aspects, the D-form is characterized by the structures shown in Figure 15. In some aspects, the D-form is characterized by an X-ray powder diffraction pattern essentially the same as shown in Figure 16. In some aspects, form D has a triclinic crystal system and a space group of P 1. In certain aspects, form D has dimensions of unit cell of a (A) = 9.78, b (A) = 13.86, c (A) = 16.11, a (°) = 65.39, β (°) = 84.54, γ (°) = 72.42. Pharmaceutical Compositions In another aspect, provided herein is a pharmaceutical composition containing a polymorph of 1-491 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The pharmaceutical compositions are useful for treating cardiac disorders associated with systolic dysfunction, including dilated cardiomyopathy and HFrEF in humans and other subjects. Pharmaceutical compositions for administration of the polymorphs or their pharmaceutically acceptable salts provided herein may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy and drug administration. All methods include the step of associating the active ingredient with a carrier containing one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active agent is generally included in an amount sufficient to increase myocardial contractility (i.e., to improve systolic dysfunction in DCM or HFrEF) and to improve or not worsen relaxation of the left ventricle in diastole. This enhanced relaxation may alleviate symptoms of dilated cardiomyopathy and other etiologies of diastolic αηαηηη / ζζηζ / Ε / γίΛΐ dysfunction, such as heart failure with preserved ejection fraction (HFpEF). It can also improve the effects of diastolic dysfunction that causes deterioration in coronary blood flow, improving the latter as an adjuvant agent in angina pectoris and ischemic heart disease. It may also confer benefits on healthy left ventricular remodeling in DCM and other causes of left ventricular dysfunction due to ischemic heart disease or chronic volume or pressure overload, for example, myocardial infarction, valvular heart disease, or systemic hypertension. In another aspect, provided herein is a pharmaceutical composition comprising the polymorph of Form A. In another aspect, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In another aspect, provided herein is a pharmaceutical composition, wherein the molar ratio of the amount of the polymorph of form A to the sum of the amounts of other forms is equal to or greater than 80:20. In another aspect, the molar ratio between the amount of the polymorph of form A and the sum of the amounts of other forms is equal to or greater than 90:10. In another aspect, the molar ratio between the amount of the polymorph of form A and the sum of the amounts of other forms is equal to or greater than 95:5. In another aspect, the molar ratio between the amount of the polymorph of form A and the sum αηαηηη / ζζηζ / Ε / γίΛΐ of the amounts of other forms is equal to or greater than 97:3. In another aspect, the molar ratio between the amount of the polymorph of form A and the sum of the amounts of other forms is equal to or greater than 98:2. In another aspect, the molar ratio between the amount of the polymorph of form A and the sum of the amounts of other forms is equal to or greater than 99:1. In some aspects, the pharmaceutical composition comprising the polymorph of Form A further comprises an additional agent. Additional non-limiting agents include agents that slow the progression of heart failure by decreasing neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, antagonists. of aldosterone receptors, or neural endopeptidase inhibitors); agents that improve cardiac function by stimulating cardiac contractility (for example, positive inotropic agents, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or agents that reduce cardiac preload (for example, 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 αηαηηη / ζζηζ / Ε / γίΛΐ aspects, the additional agent in the pharmaceutical composition is a cardiovascular medication. In another aspect, provided herein is a pharmaceutical composition comprising the polymorph of Form B. In another aspect, the pharmaceutical composition comprises a pharmaceutically acceptable carrier. In another aspect, there is provided herein a pharmaceutical composition, in which the molar ratio of the amount of the polymorph of form B to the sum of the amounts of other forms is equal to or greater than 80:20. In another aspect, the molar ratio between the amount of the polymorph of form B and the sum of the amounts of other forms is equal to or greater than 90:10. In another aspect, the molar ratio between the amount of the polymorph of form B and the sum of the amounts of other forms is equal to or greater than 95:5. In another aspect, the molar ratio between the amount of the polymorph of form B and the sum of the amounts of other forms is equal to or greater than 97:3. In another aspect, the molar ratio between the amount of the polymorph of form B and the sum of the amounts of other forms is equal to or greater than 98:2. In another aspect, the molar ratio between the amount of the polymorph of form B and the sum of the amounts of other forms is equal to or greater than 99:1. In some aspects, the pharmaceutical composition comprising the form B polymorph further comprises an additional αηαηηη / ζζηζ / Ε / γίΛΐ agent. Additional non-limiting agents include agents that slow the progression of heart failure by decreasing neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, antagonists. of aldosterone receptors, or neural endopeptidase inhibitors); agents that improve cardiac function by stimulating cardiac contractility (eg, positive inotropic agents, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or agents that reduce cardiac preload (for example, 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 aspects, the additional agent in the pharmaceutical composition is a cardiovascular medication. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions. , mouth patch, oral gel, chewable gum, αηαηηη / ζζηζ / Ε / γίΛΐ 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 manufacture of pharmaceutical compositions and the compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be, for example, 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, for example, corn starch or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, an αηαηηη / ζζηζ / Ε / γίΛΐ retardant material such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated to form osmotic therapeutic tablets for controlled release. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed. It is mixed with water or an oil medium, for example, coconut oil, liquid paraffin or olive oil. Furthermore, emulsions can be prepared with a water-immiscible ingredient, such as oils, and stabilized with surfactants such as mono-diglycerides, PEG esters, and the like. Aqueous suspensions contain the active materials mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; The dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic alcohols. long chain αηαηηη / ζζηζ / Ε / γίΛΐ, for example, heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylenesorbitol monooleate, or condensation products of ethylene oxide, with esters partial derivatives of fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspension 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. Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by adding an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed 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, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions provided herein may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be natural gums, for example gum arabic or gum tragacanth, natural phosphatides, for example soybean, lecithin and esters or partial esters derived from fatty acids and anhydrides of hexitol, for example sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, for example, polyoxyethylenesorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be used including synthetic mono- or di-glycerides. Furthermore, fatty acids such as oleic acid find use in the preparation of injectables. The polymorphs or their pharmaceutically acceptable salts provided herein may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. In addition, the compounds can be administered via the ocular route via solutions or ointments. Furthermore, transdermal administration of the subject compounds can be accomplished by means of iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds or their pharmaceutically acceptable salts provided herein are used. As used herein, topical application also includes the use of mouthwashes and gargles. The polymorphs of this invention can also be coupled to a carrier that is a suitable polymer for targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethylaspartamide-phenol or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the polymorphs or their pharmaceutically acceptable salts provided herein can be coupled to a carrier that is a biodegradable polymer useful for achieving controlled release of a drug, such as polylactic acid, polyglycolic acid, polylactic and polyglycolic acid copolymers, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and block copolymers of cross-linked or amphipathic hydrogels. αηαηηη / ζζηζ / Ε / γίΛΐ Polymers and semipermeable polymer matrices can be formed into shaped articles, such as valves, stents, tubes, prostheses, and the like. Pharmaceutical composition comprising form A In certain aspects of the disclosure, a pharmaceutical composition is provided herein comprising Form A and a diluent. In some aspects, the pharmaceutical composition further comprises a disintegrant. In certain aspects, the pharmaceutical composition further comprises a binder. In some aspects, the pharmaceutical composition further comprises a lubricant. In some aspects, 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, corn starch, powdered sugar and mixtures of any of the above diluents. In some aspects, 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 glycolate. starch and mixtures of any of the above disintegrants. In certain aspects, the pharmaceutical composition further comprises a binder that 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. gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline 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. In certain aspects, the pharmaceutical composition further comprises a lubricant that is selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate , sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate and mixtures of any of the above lubricants. Pharmaceutical composition comprising form B In certain aspects of the disclosure, a pharmaceutical composition comprising Form B and a diluent is provided herein. In some aspects, the pharmaceutical composition further comprises a disintegrant. In certain aspects, the pharmaceutical composition further comprises a binder. In some aspects, the pharmaceutical composition further comprises a lubricant. In some aspects, 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 aspects, 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, oroscarmellose sodium, crospovidone, sodium glycolate. starch and mixtures of any of the above disintegrants. In certain aspects, the pharmaceutical composition further comprises a binder that 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. gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, carboxymethyl cellulose , methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline 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. In certain aspects, the pharmaceutical composition further comprises a lubricant that is selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate , sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate and mixtures of any of the above lubricants. In some aspects, 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 aspects, form B constitutes αηαηηη / ζζηζ / Ε / γίΛΐ about 1 to 55% of the mass of the composition. In certain aspects, form B constitutes about 1 to 20% of the mass of the composition. In certain aspects, one or more diluents constitute approximately 30-95% of the mass of the composition. In certain aspects, one or more diluents constitute about 40-95% of the mass of the composition. In certain aspects, one or more diluents They constitute approximately 75-95% of the mass of the composition. In certain aspects, one or more disintegrants constitute about 0-10% of the mass of the composition. In certain aspects, one or more disintegrants constitute about 0-5% of the mass of the composition. In certain aspects, one or more binders constitute approximately 0-10% of the mass of the composition. In certain aspects, one or more binders constitute approximately 0-5% of the mass of the composition. In certain aspects, one or more lubricants constitute about 0-10% of the mass of the composition. In certain aspects, one or more lubricants constitute about 0-5% of the mass of the composition. In certain aspects of the disclosure, there is provided herein a pharmaceutical composition comprising Form B, lactose, cellulose, croscarmellose sodium, hydroxypropylmethylcellulose and magnesium stearate. In some aspects, the pharmaceutical composition comprises, form B, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropylmethylcellulose and magnesium stearate. Methods for the treatment of cardiac disorders Mutations leading 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 or their pharmaceutically acceptable salts provided herein can directly bind mutant sarcomeric proteins and correct their aberrant function, either in cis (affecting the same specific function) or in trans (altering a complementary function). As such, they may provide a therapeutic benefit for DCM patients by counteracting the impaired and / or hypocontractile relaxation associated with this disease. In addition, these compounds that increase systolic function hold promise for the treatment of a broad spectrum of disorders in which symptoms and / or clinical outcomes are attributable to systolic dysfunction (left- or right-sided heart failure) or a reduction in reserve. systolic (eg, HFpEF). Accordingly, the invention provides an αηαηηη / ζζηζ / Ε / γίΛΐ method for treating systolic dysfunction. Methods for treating DCM are further provided. Methods for treating HFrEF are provided herein. The disclosure also provides methods for treating dilated cardiomyopathy (DCM) or a cardiac disorder that has one or more pathophysiological features associated with DCM, such as disorders with systolic dysfunction or a reduction in systolic reserve. The method includes administering to a subject in need thereof an effective amount of a polymorph or composition provided herein. In particular, the invention provides a method of treating systolic dysfunction by administering to a subject in need thereof an effective amount of 1-491 Form B polymorph. Further provided are methods of treating DCM by administering to a subject in need thereof an effective amount of 1-491 Form B polymorph. Also provided herein are methods of treating HFrEF by administering to a subject in need thereof an effective amount of 1-491 Form B polymorph. The disclosure also provides methods of treating dilated cardiomyopathy (DCM) or a cardiac disorder having one or more pathophysiological features associated with DCM, such as disorders with systolic dysfunction or a reduction in systolic reserve by administering to a subject in need thereof an amount effective form B polymorph of 1-491. Also provided herein are methods of treating systolic dysfunction by administering to a subject in need thereof an effective amount of Form A polymorph of 1-491, methods of treating DCM by administering to a subject in need thereof an effective amount of polymorph of 1-491 form A, and methods of treating HFrEF by administering to a subject in need thereof an effective amount of 1-491 form A polymorph. The disclosure also provides methods of treating dilated cardiomyopathy (DCM) or a cardiac disorder having one or more pathophysiological features associated with DCM, such as disorders with systolic dysfunction or a reduction in systolic reserve by administering to a subject in need thereof an amount effective form A polymorph of 1-491. The compounds and polymorphs thereof of the invention or their pharmaceutically acceptable salts may alter the natural history of DCM and other diseases rather than simply alleviating the symptoms. The mechanisms that confer clinical benefit to patients with DCM may extend to patients with other forms of heart disease that share similar pathophysiology, with or without demonstrable genetic influence. For example, an effective treatment for DCM, by improving ventricular contraction, may also be effective in a broader population characterized by systolic dysfunction. The compounds and polymorphs of the invention or their pharmaceutically acceptable salts may specifically target the root causes of conditions or act on other downstream pathways. Accordingly, the compounds and polymorphs of the invention or their pharmaceutically acceptable salts may also confer benefits to patients suffering from heart failure with reduced ejection fraction (HFrEF), HFpEF, chronic congestive heart failure, aqueous heart failure, right-sided heart failure. (or right ventricular) heart failure, cardiogenic shock, and inotropic support after cardiac surgery. The compounds and polymorphs of the invention or their pharmaceutically acceptable salts can potentially improve cardiac function in the following patient segments: idiopathic dilated cardiomyopathy, familial or genetically defined dilated cardiomyopathy, ischemic or post-infarction cardiomyopathy, viral cardiomyopathy or myocarditis, toxic cardiomyopathies (e.g. example, post-anthracycline cancer therapy), metabolic cardiomyopathies (along with enzyme replacement therapy), diastolic heart failure (with decreased systolic reserve), right heart failure due to pulmonary hypertension, and ventricular dysfunction due to cardiovascular bypass surgery. The compounds and polymorphs of the invention or their pharmaceutically acceptable salts may also promote healthy ventricular reverse remodeling of left ventricular dysfunction due to ischemia or volume or pressure overload; for example, myocardial infarctions, chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension. By reducing left ventricular filling pressures, the compounds and polymorphs could improve the symptom of dyspnea and reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and / or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation and thereby reduce the concomitant risk of arterial thromboembolic complications including, but not limited to, stroke. cerebral arterial embolic stroke. The compounds and polymorphs, or their pharmaceutically acceptable salts, may reduce the severity of the chronic ischemic state associated with DCM and therefore reduce the risk of sudden cardiac death (SCD) or its equivalent in patients with implantable automatic defibrillators (shocks). frequent and / or repeated ICDs) and / or the need for potentially toxic antiarrhythmic drugs. The compounds and polymorphs, or their pharmaceutically acceptable salts, could be valuable in reducing or eliminating the need for concomitant medications with their potential toxicities, drug-drug interactions and / or concomitant αηαηηη / ζζηζ / Ε / γίΛΐ side effects. The compounds and polymorphs, or their pharmaceutically acceptable salts, can reduce interstitial myocardial fibrosis and / or slow progression, arrest or reverse left ventricular stiffness and diastolic dysfunction. The present description provides a method of treating systolic dysfunction in a patient in need thereof. In some embodiments, the patient suffers from a syndrome or disorder selected from the group consisting of 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 (with decreased systolic reserve)); a cardiomyopathy (including, but not limited to, ischemic cardiomyopathy, dilated cardiomyopathy, post-infarction cardiomyopathy, viral cardiomyopathy, toxic cardiomyopathy (including, but not limited to, post-anthracycline cancer therapy), metabolic cardiomyopathy (including, but not limited to, (not limited to, along with enzyme replacement therapy), infiltrative cardiomyopathy (including, but not limited to, amyloidosis) and diabetic cardiomyopathy); cardiogenic shock; conditions that benefit from inotropic support after cardiac surgery (e.g., ventricular dysfunction due to αηαηηη / ζζηζ / Ε / γίΛΐ cardiovascular bypass surgery); myocarditis (including, but not limited to, viral); atherosclerosis; secondary aldosteronism; myocardial infarction; valve disease (including, but not limited to, mitral regurgitation and aortic stenosis); systemic hypertension; pulmonary hypertension (i.e., pulmonary arterial hypertension); detrimental 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 a diagnosis of any of NYHA classes II-IV. In certain embodiments, the patient has symptomatic heart failure. In some embodiments, the patient suffers from acute heart failure. In some modalities, the patient with HFrEF also presents with mitral regurgitation. In some embodiments, HFrEF is ischemic HFrEF. In some embodiments, 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 likely pathogenic variant of a gene related to cardiac function including, but not limited to, MYH7 or phytin mutation). Depending on the disease to be treated and the condition of the subject, the compounds and polymorphs, or their pharmaceutically acceptable salts provided herein, αηαηηη / ζζηζ / Ε / γίΛΐ may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous , ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by implantation (for example, as when the compound or polymorph is coupled to a stent device), by inhalation aerosol, nasal, vaginal, rectal administration routes, sublingual or topical and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and carriers appropriate for each route of administration. However, it will be understood that the specific dose level and dosing frequency for any particular patient may vary and will depend on a variety of factors including the activity of the specific compound or polymorph employed, metabolic stability and duration of action. of that compound or polymorph, the age, body weight, hereditary characteristics, general health, sex and diet of the subject, as well as the mode and timing of administration, the rate of excretion, the drug combination and the severity of the particular condition of the disease subject undergoing therapy. The compounds, polymorphs and compositions provided herein may be used in combination with other drugs that are used in the treatment, prevention, αηαηηη / ζζηζ / Ε / γίΛΐ suppression or amelioration of the diseases or conditions for which the compounds, polymorphs and Compositions provided herein are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound, polymorph or composition provided herein. When a compound, polymorph or composition provided herein is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound, polymorph or composition provided herein is preferred. Accordingly, pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound, polymorph or composition provided herein. Suitable additional active agents include, for example: therapies that slow the progression of heart failure by decreasing neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta blockers, aldosterone receptor antagonists or neural endopeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive αηαηηη / ζζηζ / Ε / γίΛΐ inotropic agents, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and therapies 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 or smooth muscle myosin modulators). The compounds, polymorphs or their pharmaceutically acceptable salts can be used in combination with a beta-blocker (a class of drug with known side effects due to the negative inotropic effect) to confer a unique tolerability of titration of the beta-blocker to the target doses. The compounds, polymorphs or their pharmaceutically acceptable salts can be used in combination with a lusitropic agent for the treatment of diastolic heart failure (or HFpEF, a disorder with diastolic dysfunction and reduced systolic reserve). The weight ratio of the compound or polymorph provided herein to the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Examples In order that the invention described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, polymorphs, pharmaceutical compositions and methods provided herein and should not be construed in any way as limiting their scope. Example 1. Preparation of (R)-4-(1-((3-(diflucromethyl)-1methyl-lH-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3yl)piperidin-l -carboxamide (1-491) 1-491 was synthesized as described in US Patent No. 9,925,177. Example 2. Polymorph evaporation experiments Solutions of 1-491 were prepared in various solvents at room temperature. Once the mixtures reached complete dissolution, as judged by visual observation, the solutions were allowed to evaporate to dryness from an open vial at room temperature. The solids were analyzed by XRPD. Table 1 αηαηηη / ζζηζ / Ε / γίΛΐ Solvent Polymorph obtained Acetonitrile Form A + εϋ Acetone Form A + acetone solvate Methyl ethyl ketone Form A + εϋ Dichloromethane Form A + εϋ Example 3. Polymorphic suspension experiments The selected solvent was previously saturated by slurry with 1-491 at the selected temperature. A small amount (20 mg / ml) of 1-491 was then added and the suspensions were suspended for two weeks at the indicated temperature. Solids were collected by vacuum filtration and analyzed by XRPD and TGA. The results obtained are reported in table 2 and table 3. In a first set of experiments (Table 2), which were performed using various amounts of water, a non-hydrated form designated as form B was isolated. In a second set of experiments (Table 3), form B was isolated by suspension in various solvents without water and at room temperature. At 50 °C, a mixture of forms A and / or B plus form C was obtained. Table 2 Solvent Percentage of Water Temperature Polymorph obtained Ethanol / Water 25% Room Temperature Form B Ethanol / Water 45% Room Temperature Form B Ethanol / Water 75% Room Temperature Form B Methanol / Water 25% Room Temperature Form B Methanol / Water 45% Room Temperature Form B Methanol / Water 75% Room Temperature Form B Water 100% Room Temperature Form B Table 3 Solvent Temperature Polymorph obtained Ethanol Room Temperature Form B Ethanol 50 °C Mixture of Form A + B + C Methanol Room Temperature Form B Methanol 50 °C Mixture of Form A + B + C Ethyl Acetate Room Temperature Form B Ethyl Acetate 50 ° C Mixture of Form A + B + C Methyl isobutyl ketone Room Temperature Form B Methyl isobutyl ketone 50 °C Mixture of Form B + C Example 4. Interconversion and relative stability of polymorphs The relative stability of the A + eD form and the B was evaluated by suspension interconversion experiments at different temperatures in a mixture of acetonitrile and water. The solvent was presaturated by slurry with form A + sD at the selected temperature. Next, a 1:1 (w / w) mixture of forms A + sD and B was added to each mother liquor sample and suspended for 18 hours at selected temperature. Solids were collected by vacuum filtration and analyzed by XRPD, TGA, and DSC. The results obtained were reported in Table 4. Form B was found to be αηαηηη / ζζηζ / Ε / γίΛΐ more stable compared to form A in the range of room temperature to 70 °C. Table 4. Temperature Obtained polymorph 25 °C Form B 50 °C Form B 60 °C Form B 70 °C Form B 80 °C Form C + traces of Forms A and B Example 5. Characterization of form A An XRPD plot pattern for Form A appears in Figure IB (acquisition parameters: Panalytical X-pert Pro MPD PW3040 Pro; scan speed = 1.00-39.99° 2Θ; collection time: 718 s; scan speed = 3.3° / min; slit = DS: fixed slit 1 / 2°; SS = null; revolution time = 1.0 s; mode = transmit ). The DSC thermogram (parameters: equilibrate at 0.00 °C, ramp 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 melting point of 75 J / g (figure 2). A continuous light mass loss of 1.7% is observed between room temperature and 149 °C by TGA (Figure 2). The DVS isotherm shows the non-hygroscopic character of form A. XRPD synchrotron and single crystal A powder sample of 1-491 was sealed in a 0.8 mm thin-walled borosilicate glass capillary and then analyzed by high-resolution synchrotron XRD, at the European Synchrotron Radiation Facility (beamline ID22, ESRF Grenoble ) (Fitch, A.N. Mater. Sci. Forum 1996, 228-231; Experiment record: in952). Powder diffraction data (0.5° <2θ <38°) were recorded at room temperature on the Beam Line ID31 in transmission mode with a wavelength of 1.0 Á (12.40 KeV) and a step size of 0.003° . To exclude any degradation effects due to beam exposure and improve counting statistics, measurements were performed using a device that allowed horizontal translation of the capillary, so that each individual data set was obtained only αηαηηη / ζζηζ / Ε / γίΛΐ of previously unexposed dust area (original recording) . After normalization of the profiles and background smoothing, 29 non-overlapping peaks located in the low- to mid-angle region of the resulting powder plot were used for cellular determination. The synchrotron powder next. Slow evaporation of the MeOH / EtOH mixture produces crystals suitable for X-ray diffraction studies. A single crystal selected by observation under a binocular microscope was mounted on the goniometric head of a Bruker Instrument APEX DUO diffractometer (Bruker AXS (2011 APEX2 suite V 2011.2-0. Madison, Wisconsin, USA) Intensities were collected at room temperature (T = 293 K), using a micro Cu Ka radiation source (ImuS, λ = 1.54178 Á). Systematic investigation of the diffraction nodes indicates that the crystal belongs to the triclinic system, with a primitive Bravais lattice. The room temperature unit cell parameters are: a (a) = 6.40, b (Á) = 11.34, c (A) = 13.51, a (°) = 81.91, β (°) = 85.75, and (°) = 85.18. In view of the number of atoms in the molecule of form A 1-491 and the volume of the unit cell, it was concluded that this unit cell must contain 2 molecules having the formula C16 H18 F3 N5 04 S which is equivalent to a density calculated of 1,490. The number of reflections collected was 9846, of which 5255 were unique. Based on the statistical distribution of the intensities, a non-centrosymmetric structure is deduced. The structure was solved by direct methods and refined in F2 by full least squares methods with SHELXTL (Sheldrick, G. M. Acta Crystallogr. Sect. A 2008, A64, 112-122). All non-hydrogen atoms were refined with anisotropic displacement parameters; a conduction model was used for hydrogen atoms. The final agreement values ​​are R1 = 0.0992 (observed reflections) and wR2 = 0.2875 (all data) for 5255 reflections and 542 parameters, with a goodness of fit of 1.694. The compound (figure 3) crystallizes in space group P 1, the asymmetric unit of the crystal is formed by 2 molecules of 1-491 form A, so there are 2 formulas present in the unit cell (figure 4). The asymmetric cell contains: 2 [C16 H20 F3 N5 04 S] . One piperidine group and both CF2 groups are disordered. Examination of the molecular structure confirms that all bond angles and bond lengths are within the standard range values. Crystal data, experimental parameters αηαηηη / ζζηζ / Ε / γίΛΐ equivalent isotropic displacement. Bond lengths and angles are listed in Tables 5.2 and 5.3. The hydrogen positions are reported in Table 5.4. Table 5.5 lists all hydrogen bonds. Table 5. Identification code Form A Chemical formula C16 H18 F3 N5 04 S Molecular weight 433.41 Temperature 296(2) Wavelength 1.54178 Crystal system; Triclinic space group; P 1 Unit cell dimensions a = 6.4036(8) A; a = 81.907(9)° b = 11.3434(15) A; β = 85.753(9)° c = 13.5070(15) Á; y = 85.181 (9)° Volume 966.0(2) Á3 Z, calculated density 2, 1.490 Mg / m3 Absorption coefficient 2.069 1 / mm F(000) 448 Theta interval for data collection 3.31 ° to 68.05 ° limiting indices - 7 <= h <= 7; -12 <= k <= 13; -16 <= I <= 16 Collected / single reflection 9846 / 5255 [R(int) = 0.0486] Completeness at theta max 87.8% Refinement method Full matrix least squares in F2 Data / constraints / parameters 5255 / 813 / 542 Goodness of fit in F2 1.694 final R indices [l> 2sigma (1)] R1 = 0.0992; wR2 = 0.2565 final R indices [all data] R1 = 0.1289; wR2 = 0.2875 Absolute structure parameter 0.03(4) Hole and largest difference peak 0.576 d -0.320 e / Á3 Table 5.1: Atomic coordinates (x ΙΟ4) γ parameters of αηαηηη / ζζηζ / Ε / γίΛΐ equivalent isotropic displacements (Á2 x 103) . U(eq) is defined as one third of the trace of the orthogonalized tensor Uij. 5 Label x and í Cited SISO) O Wi| Mi» w sSCSUi 5474(S) ClW; 04) mi® W WW4) w rnwi 10 'Ci^l nO •vUU mee ®L cm nsmix 3¾^¾ eco- Wi cus mu 33WÍ cm cm ww W; :HW) 15 m. WsRÓ cm iicmú íg®L 51^¾ m eme -W) TjWW? cm meco cm wco wmi <\”K um ” mu cm . Wi uWi ?4;o or “únu 11 20 cu t íVhiU wm cm •<wu^ cu 3 Wj CU4 §S50U mu) cm α§^*: a* 4» «mi cm ;WU} 4WÜ.: imu Wi ®í ® ÓW1 cm e 25 cm mu Web m'“ i 02¾ lo 1'W0s 4§W?1 73¾ ® ® 5 FW UW20i 2343(11} ti®®® W® F1® ow® 344(8) 12074(7} «3® rm 11W® 1550(30} 122® ®: 1<8) F218 73141® 20(0 Ό3® 128® ®2~ §WQi 5386(11} 86® ® ®5® BU 02020 4200(12) 3® 14} O® 5230 75Oi WíW 43® 3; 1M® 10 ÜW MmOj 7200 :8?W) W ® 5?U§® IMS® 84® g§®1® 8112® 624315} »(1® ®23 B44®® •150® 18253® 101® 04 142030 145® 11®®51 SF® OI 14385(13} -2285(8} 7552® 84® 03 D4?2O 4 IB® 7028®; 31® 15 03 SO '2: 3W® 248® w® 8384® 2357(4) w ®24 40:15} 8285® m® §0® 0102 373301) 4W® 05® (O 10320(11) 70® 5' B® g® W. 14} Λ® 144® 0120 11842(18} 1445® 7875(7} 144® 20 02® ®22í ® 253?!'8i 8453® 1(0} 0® 856013} 4yF<2® 7087® 1B® 02« 000'0 4827® «0® W1® 0220 W: 12) 4432® M?3® 1» sno i 1®2® 08® as® 7182(3} 4«®i® 3068.6(7,¾ 758® αηαηηη / ζζηζ / Ε / γίΛΐ Table 5.2: Link lengths (Angstrom) Link Length {Áj CKOC164 12W$ CIO? - CW5 1.333(13) C105> N®· 1433ΠΟ w w- 1374(10) CW? -SI® 12W0) ono^cm 1503(10) cm -ou 1310): cm-cm 1437(13) quacus 1311(0 cm-oN 1,400 αηδόνι? 1500 CHS' FUS 1.:W1) ciiocm 1.7O1H cw -c ®· 1353(14) CU!. EOS 1300 Cu2-NU3 0 (00 Cía OB 1430 (14) CO^FUT 13013) CUS ~ RB 1328 (11) C128-F13S 1,365 (16) 0203-C204 1.334 (18) 0204-C2G5 1458 (13) G205-N2G6 1308(11) C267 - N209 1,345(12) C287 - 0208 1 213(10) 0210 - 0211 1,452(14) 0211 -0212 1,311(16) C212 - C213 1,458(16) C212 - 0215 1.5 57(14} 0213-0214 1,416(16} Ο$ · O? 1:40'0 COA í wo O O 'twnm CL. 50 ÓO; O OO; O - 03 noc Ό O L$$sn§í O -O7 1^ CAO ' O A OOO ACO cu o ΟΌ OO O O orn OOO TÍO: 0'-~0 tWi OOO 120 N® - O 1 O A OI 0 i 52 HA m £F AW ΑΚϊΑί OSOW 1 03®: HMM 1 440) OÓO2 1 OIS? moco too 03-04 OCA οοο 1 WH) otoss OFU) Ν1Ό 1O® Os- CW tw® N2OW HtU 02 OH 1OU? ÓOO too 03 AÓ 1 S4§{t3) 04 ÓM 12WW AíFFí yes ts¿xJí '4? οηοηηη / 77ηζ / Ε / γι αηαηηη / ζζηζ / Ε / γΐΛ §118-01$1049 S118-3123141W; 32^-C22'024® ¡W> SO-G2201410 Table 5.3: Bond angles (°) Unstressed Angle Γ) 9^3-0104-00 106400^ CW3 - 0102-M01 9'04-0135 -HiSS 131 -¾) C1G5-NÍ01-QW 134 5¡ ?) CW-N106-C1ÜS 121 4¡6j GW-NW-CW 11 *4:7; OWí 0109-0'14 : 16 4=6' CW7 O10L· C3W C110-C111-C112 112..1(8) C110-N109-C310 37.3(14) C111-092-9311 26.2(12) G112-CT13- C114 114.0(8) 0112-C115-Cl 17 114.5(8) C112-C115-S118 112.1(7) 0113-0112-0111 112.9(8) 0113 - 0112 - C115 115.5(8) 0113 - 0112 - C 311 96.0(14 ) C114-N109-C110 114.7(7) C114-N109-C3W 122.5(12) C115 - C112-C111 116.3(8) C115-C112-C311 110.9(13) C117-C115-S118 115.0(7) C121 - 0125 - C126 131.2(9) C121-S118-C115 106.7(5) C122-C121-S118 123.4(7) C122-Ν123-C125 128.0(9) C122- N123-N124 111.4(9) 0125 - 0121 -C122 107.5(9) C125-C121-S118 129.1(8) C125-N124-Ν123 106.5(7) C126-F128-F130 53.9(9) 0126 - F130 - F128 51. 8(9) 0203 - 0204 - 0205 100.8(10) C203 - 0202 - N2Q1 105.2(8) C205 - Ν201- 0202 107.5(7) C205 - N2Q5 - 0207 124.9(7) C207 - N2GS - 0210 124.0(8) C20 7 - Ν209 - C214 115.2 (7) 0210- Ν2δ9 - C214 120.8(8) C211 -0212 - C213 119.7(10) 0211 - 0212 - 0215 122.5(10) 0212-0211-0210 123.0(10) C212 - C215 - S218 1 07.2(8) C213- C212-0215 ​​112.7(11) C213-C214-N2Q5 118.6(8) C214 -0213 - 0212 119.4(10) C217-0215-0212 120.7(10) 0217 - C215 - S218 109.7(8) C221-C2 22-N223 106.5( 7) 0221 - 0225 - 0226 123.8(10) C221 -S218 - 0215 105..914) 0222-022* -0225 C222 - 0221 - S218 C222 - Ν223 · 0229 C225 - 0221 - S218 0225 - 1224 - Ν223 0226- - F227 - F230 0226 - F230 - F227 0310 -0311 - 0112 F116 - C115 - 0112 F116-C115 -C117 F116 - C115 - SUS i- $27 - d2b - C ab F127-C126-F130 F127-F130-C126 F127 - F130 - F128 F128 - C126 0125 FT28 - 0126 - F127 F128- 0126 - F130 F130 -C126 - 0125 F130-F127-C126 F216 - C215 - C212 F216-C215-C217 F216 - C215 - S218 F227- 0226 - 0225 F227 - 0226 - F228 F227 - 0226 - F230 F228 - C225 - 0225 F22S - 0226 - F230 F228 - F230 - 0226 F228 - F230 - F227 F230- 0226 - C225 F230 - F228 - 0226 104.3(8) 122.4(6) 129.2(9) 133.3(7) 104.9(7) 60.3(11) 59.3(12) 122(2) 107.3( / ) 104.5(9) 10i.9(8) 108.7(11) 46.7(13) 65.1(11) 112.0(16) 110.4(9) 116.0(11) 74.3(15) 107.1(14) 68.2(11) 109.5(8) 108.5(11) 98.9(6) 110.5(11) 111.6(12} 60.4(18) 104.8(11) 54.5(17} S2 7(12) 118.3(17) 105.8(16} 62.8(12) αηαηηη / ζζηζ / Ε / γίΛΐ iiiAO NIDSYlOS’NlSS UY# 117.2Ϊ6· H3 / 3íU w$U‘CW 114.^7) >O-ÜW-Ú3H ?SS.5t1§? hlS-UPS·^ w.i®i n^-c^-cw woí ^4-Ci2$C1¿« 1^48) W24-m23'W$ UO 5i'S; Ον»-β$84 w.3{m OVS2S5-O® tU^7) »®-c^ 121.708) U5.«7) ^-€2ia-C2U m'?Y »-^Y2S 1177® 04 Y®, m inw 04-03 032 in.3Y 04-030® ns..^ SO 0W3 -G» e,§) w-auw mw) OWYWYIOS: GiOSlOCW WYi swsm-c® iOTdiSj 725 SUS CUS γ.ιγ oo-swo® Í(S) 0123-SIO 09 utlpl 020200 U4 3<§l 08 0® os 1W® 02®YW-.Ol yw) 021® S2:® C®5 W.í© W,9{4) W-3tlA -ÓS> i® W) Ü2SM21S'C22Í W(4) QSG-SY-OY MB αηαηηη / ζζηζ / Ε / γι Table 5.4: Hydrogen coordinates (x 104) and parameters of αηαηηη / ζζηζ / Ε / γίΛΐ isotropic displacements (Á2 x 103) Label e 3 35230 '45 '· HUA 403 ?3 0 ΗΠ8 W-δ 7W20 ?>0 H1W 41533 §1333 Ό HMD imo 53W3 §2§« 7« ΗΠΕ WWW 44043 i.OS.O HUF 1« SO3 73273 SCO 3 1 0 HÚG 10« 51343 57233 853 ΗΠΗ ws 40723 55783 853 Ttn 1351« 47223 01133 '1793 HTW 34333 050 «Ü H11K 11» 415« 08023 0.3 3333. § 7583 1173 :· 1703 <11233 5®5 WS3 15 W Ό33 10707 0 0.0 “ and 1§» •7M3 101^3 UB ho 0423 3W3 34203 §73 -33433 303 ust msc 050 0 «473 §1543 1543 H21E 20433 403 S25 so o 33043 33923 W3 20 H21S oo o 3 230 0 45723 W23 oí o smo O ;3 iW H22D Ό Ό '33 0 103 2023 H22E 103 3054 0 203 2023 *? 3043 043 203 2023 : :·» ‘ -7¾ 043 72423 73 0 85^ G 033 083 733 100450 053 023 αηαηηη / ζζηζ / Ε / γίΛΐ Table 5.5: Hydrogen bonds with bond lengths (Angstroms) and angles (degrees0) U —H..„„A Distance Distance (Η..Ά) Distance (D...A) Angle® 0.00 200 3 OdOs 15200 ««....MSI EYE 220 3 181» OM 25380 3 0:13: 182» 0 OI MW 105 C0 o rr 24» 324215 135» '240 2828»! O» oroo 2 5200 3 215· Ul 125» 0 0700 23200 2 710»! 103 09 CW-HÍ28. 0208 2.08 3 262»! m» ...OSOS s.ow 230 3.285? OR; 155.00 €203 - „ N224 o® 25» 3.421(14) 172.00 CO-H2SC..»» 0.80 23» 2.788(1® we.c-s CW’W.:-0103 3.0300 2 7200 3»7») 140». The representation of the crystalline structures is given in figures 3 and 4. The figures were generated with the PLATON program (Spek, A. L. J. Appl. Cryst. 2003, 36, 7-13). The 1-491 form A molecule contains a sulfur atom that allows the absolute configuration to be determined, taking advantage of the resolution of the individual crystal data. Flack's x parameter is calculated based on the anomalous dispersion method (Flack, H. D.; Bernadinelli, G. Acta. Cryst. 1999, A55, 908-915). The midmo provides the absolute structure, provided a sufficient estimated standard deviation is achieved. According to the theory, the expected values ​​of the Flack parameter x are 0 for the correct structure (within 3 esd.s) and +1 for the inverted absolute structure. The results considering the C115 configuration: R ; C215: R is 0.03 (4), despite the poor esds, they are sufficient to test the absolute configuration of form A of 1-491. A simulated diffraction pattern (Figure 5) is produced from the crystal structure of form A determined experimentally at room temperature. An experimental powder diffraction pattern can be compared with this theoretical pattern to demonstrate the nature of the crystal structure. Minor differences (if any) can be explained by preferential orientations in the powder. The crystal structure of 1-491 in form A was determined by X-ray diffraction on a single crystal, which allowed the generation of a reference powder standard. Even if the structure is completely resolved, this phase is of poor quality and should therefore correspond to a kinetic form; this is confirmed by the rather large peaks found in the synchrotron dust pattern. Example 6. Characterization of form B An XRPD plot pattern for Form B appears in Figure 6B. The DSC thermogram (parameters: eguilibrar at 0.00 °C, ramp from 10.00 °C / min to 250.00 °C) shows a first endothermic event at 178 °C (5.5 J / g) associated with the transition αηαηηη / ζζηζ / Ε / Solid-solid γίΛΐ of form B to form A, followed by a second endothermic event at 193 °C (80 J / g) corresponding to the melting of form A (figure 7). A continuous mass loss of 0.6% is observed between room temperature and 150 °C by TGA (Figure 7). The DVS isotherm of form B demonstrates the non-hygroscopic character of form B. XRPD synchrotron and single crystal A powder sample of 1-491 was sealed in a 0.8 mm thin-walled borosilicate glass capillary and then analyzed by high-resolution synchrotron XRD, at the European Synchrotron Radiation Facility (beamline ID22, ESRF Grenoble ) (Fitch, A. N. Mater. Sci. Forum 1996, 228-231; ESRF Experiment Record: in971). Powder diffraction data (0.5° <29 <40°) were recorded at room temperature on the Beam Line ID31 in transmission mode with a wavelength of 0.8 Á (15.5 KeV) and a step size of 0.003° . To exclude any degradation effects due to beam exposure and improve counting statistics, measurements were made using a device that allowed horizontal translation of the capillary, so that each individual data set was obtained only from the previously powdered area. not exposed (original qrabation). After normalization of the profiles and background smoothing, 45 non-overlapping αηαηηη / ζζηζ / Ε / γίΛΐ peaks located in the low- to mid-angle region of the resulting powder plot were used for cellular determination. The 1-491 form B synchrotron powder given below, and are refined by the Pawley method using the TOPAS software (TOPAS 4.2: Coelho, A. A. TOPAS Academic User Manual, Brisbane, Australia, 2007; Coelho A. A. J. Appl. Crystallogr. 2003, 36, 86-95) to a value final Rwp of 9.55%. Twinned crystals grown in acetonitrile / water mixtures were suitable for X-ray diffraction studies. A single crystal selected by observation under a binocular microscope was mounted on the goniometric head of a Bruker Instrument APEX DUO diffractometer (Bruker AXS (2011). APEX2 suite V 2011.2-0. Madison, Wisconsin, USA). Intensities were collected at room temperature (T = 293 K), with the use of a Cu Ka micro radiation source (ImuS, λ = 1.54178 Á). Systematic investigation of the diffraction nodes indicates that the crystal belongs to the triclinic system, with a primitive Bravais lattice. The room temperature unit cell parameters are: a (Á) = 11.93, b (Á) = 13.24, c (Á) = 13.51, a (°) = 65.40, β (°) = 80.08 and γ (°) = 89.18. anannn / zznz / E / YiAi In view of the number of atoms in the I491 form B molecule and the volume of the unit cell, it is concluded that this unit cell must contain 4 molecules having the formula C16 H18 F3 N5 04 S which is equivalent to a calculated density of 1.516. The number of reflections collected was 23,771, of which 10,282 were unique. Based on the statistical distribution of the intensities, a non-centrosymmetric structure is deduced. The structure was solved by direct methods and refined in F2 by full least squares methods with SHELXTL (Sheldrick, G. M. Acta Crystallogr. Sect. A 2008, A64, 112-122). All non-hydrogen atoms were refined with anisotropic displacement parameters; a conduction model was used for hydrogen atoms. The final agreement values ​​are R1 = 0.0512 (observed reflections) and wR2 = 0.1445 (all data) for 10282 reflections and 1073 parameters, with a goodness of fit of 1.030. The compound crystallizes in space group P 1 (figure 8), the asymmetric unit of the crystal is formed by 4 molecules of 1-491 form B, so 4 formulas are present in the unit cell (figure 9). This rather rare feature was also observed with the C-form and D-form polymorphs, while the kinetic A-form is made up of 2 independent molecules. The asymmetric cell contains: 4 [C16 αηαηηη / ζζηζ / Ε / γίΛΐ Η20 F3 Ν5 04 S]. Several CF2 groups and one methyl are disordered in the solid state. Examination of the molecular structure confirms that all bond angles and bond lengths are within the standard range values. Crystal data, X-ray experimental parameters, and structure refinements are given in Table 6. Table 6.1 lists the positional parameters for all independent non-hydrogen atoms along with their equivalent isotropic shift parameters. Bond lengths and angles are listed in Tables 6.2 and 6.3. The hydrogen positions are reported in Table 6.4. Table 6.5 lists all hydrogen bonds. Table 6 Identification code Form B Chemical formula C16 H19.75 F3 N5 04 S Molecular weight 435.18 Temperature 113(2) Wavelength 1.54178 Crystal system; Triclinic space group; P 1 Unit cell dimensions a = 11.9264(3) A; a = 65.3989(14)° b = 13.2395(4) A; β = 80.0842(15)° c = 13.5114(4) A ; y = 89.1777(15)° Volume 1906.89(9) A3 Z, calculated density 4, 1.516 Mg / m3 Absorption coefficient 2.097 1 / mm F(000) 903 Theta interval for data collection 3.66° to 63.25° limiting indices - 13 <= h <= 13; -14<=k<= 15; -15 <= I <= 15 Collected / single reflection 23771 / 10282 [R(int) = 0.0454] Completeness at theta max 97.8% Refinement method Full matrix least squares in F2 Data / constraints / parameters 10282 / 829 / 1073 Goodness of fit in F2 1.030 final R indices [l> 2sigma (1)] R1 = 0.0512; wR2 = 0.1329 final R indices [all data] R1 = 0.0626; wR2 = 0.1445 Absolute structure parameter 0.011(14) Hole and largest difference peak 0.444 and -0.224 e / Á3 αηαηηη / ζζηζ / Β / γι Table 6.1: Atomic coordinates (x ΙΟ4) γ parameters of equivalent isotropic displacements (Á2 x 103) for form B. U(eq) is defined as one third of the trace of the orthogonalized tensor Uij Label C103 ?! I quote W) 7489(3) 6? ?! i 0) Cl 11 554613} 385513 = 7689(2} w n 02 4489(2} 6626(2; w cm 711«) 5646(2} 50.3(9.! ?58m 3757(2) 5517(2} Wi 20 €115 5661(3} 5497(2} 6796(2} 6U(§} 0-117 65 Wí §43(0 8076} 0321 A© W(2) 6655( 2: 52 ?(§} €122 3020(3? 6472(2} 7639(3} 57.0 €125 / 3504 / 2} W§(2} 6216(2} 50 C© C126 442^3} 6806(3} 5116(3} 601 As «313} e 60(3} 76 2(1.}} 97 C203 -268(3} 6327(3) 2272(3) 67.2(1.9) G204 759(3) 6128(2) 1853(2) 59.3(8) G205 864(2) 4994(2) 2536(2} 46 :1(7) G207 2682(2} 4627(2} 1861(2) 45.4(7) C2W 2938(3) 2641(2) 2045(3) 55.0(8) 5 C2V 3879(2) 1845(2) 2230 (2) 49:8(7) C212 4781(2) 2186.1(1.9) 1187(2) 42.5(6) G213 5249(3) 3378(2) S59í3; 56.2(8) C214 4284(3} 4147(2) 657(3) 61.9(9) C215 5749(2} 1400(2) 1260(2} 42.3(6) 0217 6368(3) 1120(2) 2201(3) 60.0(8) 0221 6430(3} -520( 2) 918(2) 51.9(7) 10 0222 7019(3; -309(2) -124(2) 63.8(9) C225 6997(3} -1390(2) 1640(2) :52.4(8} C228 6710(3) -1982(3) 2870(2; 65.8(9) G229 8697(4) -1115(3) -866(3} 101.2(1.5) 0303 -6-C6(3? 13417(2) 4960(3) 63.8(9) 0304 -5195(3) 13126(3) 4440(3) 64.0(9) 15 0305 -4863(2) 12164(2) 5272(2) 45.6(7) 0307 -3072(2 ) 11808(2) 4352(2) ,43.1(7} C310 -2102(3) 10165(2) 5446(2) 58:7(9) Q3H -1392(3) 9265(2) 5259(2) 56.7( 8} C312 -274(2} 9779(2) 4478(2) 50.7(7) C313 -544(3) 10601(2) 3394(2) 53.9(8) 0314 -1201(2; 11516(2) 3563( 2) 52.2(8} 20 0315 625(2) 8963(2) 4405(2) 49.8(8) 0317 ;0!6λ3) §316(3) 5470(3) 60(1) αηαηηη / ζζηζ / Ε / γίΛΐ €32? 12512; ?W) 37W1 €322 22VO W2) O.® €325 Ιΐ® 0430 wo EYE Heard 52340 550¾¾ 73.0 4 €« 4557(31 Otó 2423(3) 55 30 €3M 4gWS) O; €423 5644(31 -237¾¾ 0X0 s:<O 3.1 €424 4334(3¾ 123.31(¾ €€54 0) €425 4737(31 JW2) -»(2) 45.40 €407 305(31 -WO 402; 43 5 (71 €410 Π54Ο 317(¾ 338(3) 31 €4H W) 0730 W) §34041 €412 1442^ 2274(2} 433:21 55.10 €4D 1755(31 WO 453® ?®1 21 1414 3í«( 3i t»Ó 44W) 32 1(1 21 €415 152(31 3(Ws -55® 54 90 €417 4« 2553(31 OOi ÍÓS2O4) €421 +00§i2j 4533(2) «O *O'7 ( C422 ? SB2<3 ? 4438(2) 127® 500 025 0730 5533(2) «W) ®.oo €425 -75® «40 -ΠΟΟ ¿€ 4 ' 31 €420 OOO 775¾¾ M4(V0 O O 51340 7WO1O SOO F12? Wi sowo «20 1'14010 F'125 WO 535¾¾ 5U® 13g.7(1O F43Q §€151'15·; €WO 726® 62 1171 F216 6536 0(1 41 1674.5(1.31 2672(10 31 3i Yes » 7227 71ΠΟ 20.00 3W7.20O 123.7(1¾ F228 ?W3(3) -14CSO 3«010 ​​1600 5315 OíOO 9575 2; 1.3). 4¾^) 32.4(1 € F328 ?8 \'2 05001 W5010 F330 §52® «or HO O® W1 «ΟΠΟ M© αηαηηη / ζζηζ / Ε / γΐΛ F42 -757(4) 7165(2) -2080(2) 163.5(15? F428 -1351« / 5777(4) -2263(2) 147.6( ί .4) NW 11243(2) 2246(2) 4686( 2} 62 / 7(7) NW6 9585(2) 2549 / 4(17} 5658.6(18) 50.5(5) NWS 7910(2) 2985.5(18) 6534.6(19) 55.0(7) 5 Ν123 2893.8(1.9) 7384..3(18) 7779.9(18) 51.9(6) Ν124 3149(2} 8320.8(1.7) 6889.4(18) 49.8(6) Ν201 -43(2) 4559(2) 3320(2} 65.3(8) Ν206 1743(2) 43118(17) 2498.4(1.6} 52.1(6) Ν209 3372(2) 3809.6(1.7) 1634.1(18} 50 2(6) Ν223 7848(3) -1006.2(19} 9(2) 68 .3 (8) Ν224 7859(2} -1670.1(19) 1077(2) 60.6(7) 10 Ν301 -5552(2} 11892.3(19} 6213(2) 59.5(7) Ν306 -3960(2) 11503.8(17) 5237.8(1.8) 47.4(6) Ν309 -2233.2(1.9) 11086.6(16) 4421.9(17) 45.4(6) Ν323 2983(2) 6756.8(17) 3085.8(18) 48.7(6) Ν324 25 65(2) 5847.0(18) 4020.9(19) 518(6} Ν401 5658(2) -504(2) -2362(2) 69.6(8) 15 Ν4δδ 3920(2) -1,814(17) -1537.5(1.7) 40(5 ) 1409 2407(2) 454.5(1.7) -6543(1.7) 47 / 8(5) Ν423 -2277(2) 5224.0(18) 10222) 55.5(7) Ν424 -2082(2} 5913(2) - 66(2) 59.9(7) 0102 12118.0(1.7) 1518.2(16) 4896.1(18) 65.8(6) 0108 8878(2)' 1525:3(1..8) 7484..1(1.8) 75.2(7) ) 0119 48.15(2} 6496.5(18) 4975.1(17) 66.5(6) 20 0120 3575(2) 4937.8(18) 6513(2) 79.6(7) 0202 -784.3(1.9) 5428.7(17) 3136. 4( 19) 71.8(7) 0208 2905(2} 5604.7(15) 1018.8(17) 63.7(6) 0219 4877(2) 491(2) 266(2) 100.8(7) 0220 4511(2) -580.8(17) 2279(2) 81.4(8) 0302 -6359.9(1.:9) 12700(16) 6010..9(1.7) 67.9(7) 25 0308 -3055.1(1.8) 126962(15) 3523.9(1.5) 57.0 (6) αηαηηη / ζζηζ / Ε / γίΛΐ 100 0319 0320 0402·. 11(2) -706.5(1.7) 6347(2) 8654.2(17) 7270.1(17) -1418(2) 27534(17) 4662.3(1.9) -2188(2) 66.5(6) 854(7) 94.3 (9) 0408 2945(2) -1305.1(1.6) 164.3(17) 70.17) 0419 1353.3(1.9) 4558.1(17) -288(2) 747í§) 0420 5 346.6(1.9) 3001.8(17) 1364 7( 1.6) 62.5(6) S118 44113(6} 5904.4(5) 6122.6(6) 53.9(18) S218 5223.3(6) •131.2(5) 1201.3(6) 58.02(18) S318 1894(6) ,8002)7 (5) 3840.3(5) 4879(17) S418 375.2(5) 3822.5(5) 236 4(5) 44.68(16) Table 6.2: Link lengths (Angstrom) 10 Link Length (A) 0103 - 0134 1.348(4) 0104-0105 1 426(4) CW5-Ni8S 1 377(4) acMW 1 353(4) 15 CW7-OWS 1W) ciw - cin 0.500 C11VC112 1 520(4) 0112.-0113 1.511(4) 0112-0115 1.538(4) 0113 - C114 1.512(4) 20 CH5-C117 1.533(5) 0115-F116 1 388(3) C115-F130 1.306(12) C115-S1 18 1,837( 4) C121 - C122 1,361(4) 101 C121-C125 1.404(4) C122-N123 1.342(4) C125 - C126 1.486(4) 0126 - F127 1.333(4) C126-F128 1.323(5) C203 - C204 1.329(5) C204 - C205 1.4 15(4) 0205 - N206 1,382(4) C207 - N209 1,359(3) C207 - 0206 1,222(3) C21C - C211 1,509(4) C211-C212 1,520(3) C212-C213 1,535(4) C212-C215 1,531(3) ) C213 - C214 1,510(4) C215-C217 1,491(4) C215-F216 1,396(3) C215-S218 1,838(3) C221 - 0222 1,376(4) C221 - C225 1,415(4) 0222 - N223 1,327(4) 0225 - 0226 1490(4) 0228 - F227 1.317(4) C22S - F228 1.337(5) C303 - 0304 1.332(5) 0304 - 0305 1.410(4) 0305 - N306 1.384(3) C3G7 - N309 1.361(3) 0307 - 0308 1. 238(3) 0310- 0311 1.533(4) 102 O3U-O312 Λ - 1. V 1 4 0312 - C313 0312- 0315 C313- 03 Ν : 5A4; 0313-0317 US O C323O327 ¿0 * 0323 - 5328 UWU) 0323-5333 4 3 C¿G3 - C4Q4 ¿4.5 b 0434-0405 1.410 0405 U?U: 0407-mss 1 3Z0U1 013 / -0453 ' Όλ; 0410-0411 UUO: 0411-0412 U13U ¢412-0413 1,401 ¢412-0413 Í54UÍ 0413-0414 14$4{81 0413-041? 0415 - Rt§ 1 Ul’ CU- 3413 tOU U21 -U 1.3SU1 C421-C425 1;4W) 0422-0423 1;33U1 0423-0423 UWl 0423 - 5427 ÚW? 0423-5433 131118) 5327 - 5330 1§?0 αηαηηη / ζζηζ / Ε / γΐΛ 103 1.293(4) UW) w-w i.Wi »cw U»(4i HW*CV4 WS(4j HOS-CW tW) Niq -n· tW) 124-005 ^1-0236 IW) N2Q1 - 0202 iwq €207 1378( 3] USE--1211 í.4?S(3i WW4 W7(3] · C22§ 1473(8) K232-N224 tS3B 1.315(4] O - €305 ÍWi N3&: -0302 14S1Á H3«-£W 13 / 5 / 3] H^-C3W 14470] N309 - 0314 1.471(3) N323 - C329 1.441(4) N323 - N324 1.353(3) N324 - C325 1.327(4) N401-C405 1.307(4) N401 -0402 1.4 13( 3) N406 - C407 1.378(3) N40§ - 0410 1.451(4) N409 - 0414 1.450(4) N423 - 0429 1.460(4) N423 - N424 1.348(3) N424 - C425 1.333(4) O102-C1 03 1.325( 4) αηαηηη / ζζηζ / Ε / γίΛΐ 104 0202 - 0203 1.332(4) 0302 - 0303 1320(4) 0402 - C403 1312(4) S118-C121 1.747(3) SI18 -0119 1410(2) S118 - 0120 1414(2) S218-C221 173 5(3) S218 -O219 1422(3) S218-O220 1433(2) S318- 0321 1726(3) S318-O319 1.412(2) S318 - 0320 1428(2) S418 - 0421 1.741(3) S418-O419 1412(2) S4 18 - 0420 14231(19} Table 6.3: Bond angles (°) Atoms Angle O αηαηηη / 77η7 / Ε / γι 0103-0104-C105 0103 0102 - NW1 C105 - NW1 - 0102 0105 - N106 - CIO? CW7-N109-C11Q C107-M109-C114 C1W-C111 -0112 C1W-NW9-C114 0111-CH2-C115 0112 - 0113 -C114 0112 - 0115 -S118 0113 - 0112 - 0111 104.0(3) 108.8(2) 106.3(2) 123.2(2) 117.3(2) 126.6(2) 110.7(3) 112.8(2) 1116(3) 111.7(2) 109.2(2) 109.4(3) 105 0113-0112-0115 113.4(2) C117-C115-C112 117.3(3) CT17 - C115-S118 109.5(2) C121-0125-0126 128.6(3) 0121-S118-C1Í5 104.25(15) 012 2-0121-C12S 105.4(2) 520 3 - 0204 - Cz05 103.3(2) C203 - 0202 - N201 108.0(2) C204 - 0203 - 0202 112.0(3) 0205 - N201 0202 104.7(2) C207 - N206 - C205 123.5(2) 0207 - N2Q9 - 0 210 122.3(2) 0207 - N20S - C214 115.0(2) C210-0211 -0212 110.7(2) C211 - 0212 - 0213 108.5(2) 0211-0212-0215 ​​115.20(19) C212-C215 - S218 106.47(18) 021 4-C213-0212 109.2 (2) 0214-N203-C210 112.8(2) 0215-0212-0213 111.1(2) 0217 - C215 - 0212 117.2(2) 0217-0215-S218 111.00(18) 0221 -C225 - 0226 128 .4(3) 0221 -S218-C215 105.78(13) 0222 - 0221 - 0225 104.5(3) 0222 - C221 - S218 125.1(2) 0222 - N223 - C22S 127.2(31 αηαηηη / ζζηζ / Ε / γι 106 C222 - Ν223 - Ν224 113.0(2) 0225-0221-S218 130.4(2) C225 - Ν224 - Ν223 105.2(2) C303 - 0304 - C305 104.3(3) C303 - 0302 - N3S1 108. 3(2) C305 - Ν301 - 0302 105.5(2) C307 - Ν306 - 0305 122.9(2) C307-Ν309-0310 123.1(2) 0307 - N309 - 0314 115.91(18) 0310 - N309 - 0314 116.4(2) 0311 - 0312 - 0315 0312-0311-0310 0312 - 0313 -0314 0312-0315-S318 116.0(2) 110.4(2) 109.8(3) 1137(2) C313 - 0312 - C311 108.0(2) C313-0312-0315 03-17 - 0315 - 0312 115.9(2 ) 113.5(3) C317 - 0315-S318 109.8(2) 0321 - 0325. - 0326' 129.6(3) 0321 -S318- 0315 104.53(14) C322 - 0321 - C325 103.2(2) C322 - 03 21 - S318 125.47( 19) 0322 - N323 - 0329 128.7(2) C322 - N323 - N324 112.2(2) C325 - 0321 - 8318 131.1(2) C325 - N324 N323 105.0(2) 0325 - F327 - F330 42.8(3) C326 - F330 - F327 51.0(4) 0331-03:5-03'2 150.7(11) 0331 - 0315 - 0317 38.2(12) 0331-0315-8318- 80.4(12) 107 C4uo - 0404 - 040o 103.4(3) 0403 - 0402 - N401 108.7(2) O4Q5-N401 -0402 104.6(2) 0407 - N406 - C405 123.0(2) C407 - N409 - 0410 115.9(2) C4 07-N409-C414 122.6(2) 0410 - C411 - C412 111.3(3) 0411-C412-C415 111.6(3) 0412-C413-0414 111.4(3) O412-C415-S418 107.0(2) C413-0412-Q411 108 .1(3 ) C413 - 0412- 0415 114.7(2) 0414 - Ν40θ - C4W 113.8(3) 0417-0415-C412 117.0(3) C417-O415-S418 112.6(3) 0421 - 0425 - 0426 130. 2(3) 0421-S418- 0415 107.58(14 0422 - 0421 - 0425 105.1(2) 0422 - 0421 - S418 123.6(2) C422-N423-C429 128.0(2) 0422 - N423 - N424 112.4(2) 0425 - 04 21 - S418 131.0(2) 0425 - N424 - N423 104.7(2) F116-0115 - 0112 109.1(2) F118-0115-0117 107.9(3) F116-C115-S118 102.8(2) F127 - 0126 - 0125 110.7(3) F128 - 01 26 - 0' 25 111.2(3) F128 -0125 - F127 105.0(3) F130-C115-CH2 151.1(8) F130-C115-CM7 54.2(7) F130-C115-F116 58.2(5; 108 F13Q - CU5 - S118 F216- C215 - 0212 F216 - 0215 - C217 F216 - 0215 - S21S F227 - 0226 - 0225 F227 - C226 - F22S F228-C226 - C225 F316 - 0315 - 0312 F316 - 0315 - 0317 F316- 0315 - 0331 F316-C315-S318 F327 u32o - v¿2o F328 - 0326 - C325 F328 - C326 - F327 F330-C326 - C325 F330 - C32S - F327 F330-C326-F328 F416 - 0415 - C412 F415 - 0415 - 0417 F416 - C415 - S418 F427 - C426 - C425 F427 - C426 - F428 F428 - 0426 C425 N101-C105-CW4 N101-C105-N106 N106-C105-C104 N109-C107-NW6 N109-C110- 0111 N1Q9 - CM4- 01 13 N123 - 0122-C121 99.3(3; 107.47(18) 109.0(2) 101.48(17) 109.7(3) 109.5(3) 110.2(3) 108.1(2) 108.8(2) 92.7(9) 102.3(2) 111.8(3) 110.6(3) 114.9(3) 119.9(5) 112.3(5) 109.4(2) 107.8(3) 102.1(2) 111.1(3) 107 0(4; 111.4(3) 110.5(2) 118.7(2) 130 7(2) 116.8(2) 111 4(2) 111.8(3) 107.9(2) αηαηηη / ζζηζ / Ε / γίΛΐ 109 NI 24- 0125-Cl 2 ί 114.1(2) Ν124-C125-C126 120.1(2) m24-N123-CÍ29 120.2(2) N2Ó1 - 0205 - C204 111 9(2) N231-C20S-N206 117 7(2) N236. 0205 - 2204 133..4(2) N209 - 0207 - N286 11S. 5(2) N209-C210-C211 112.5(2) N209 - 0214- 0213 111.9(2) N223-0222 -C221 106.6(3) N224-G225-C221 110.7(2) N224 - 0225 - 0226 123.8( 3) N224 - N223 - C229 1'19.6(3) N301 - C3O5 - C304 111.1(2) N301 - 0305 - N306 117.8(2) N306 - C305 - 0304 131.1(2) N309 - C307 - N306 117.2(2) N30S - C31 0 - C311 112.7(2) N30S-C314-C313 112.6(2) N323 - 0322 - C321 108.2(2) N324 - 0325 - 0321 111.4(2) 5324 - C325 - C326 118.9(2) N324 - N323 - C32 9 119.1( 2) N401 - 0405 - C404 111.9(3) Ν4δ1 - 0405 - Ν406 117.9(2) Ν4δ6 - C405 - C404 130.2(3) Ν409 - C407 - Ν406 116.2(2) Ν409 - 0410 - 0411 113.1(3) Ν409- C414 -0413 113.4(3) αηαηηη / ζζηζ / Ε / γίΛΐ 110 19 ? 5214j o®® si®-®® m 3413,! nn® sm-ma V§§41?> Q120-SU6-CU5 107 UlS? lomXf 0203-038?-« '2012! Q2YES-C20?-« !22 5-, 2; :0919-S2W-P215 1&3 31 !3> 0218- SUS · '® 0? 44 'í> CW-SW-(W 120 31!?} 0121- S2U -C2U 1« «14} 0220- S2W-O2Í ia oí· ni 0302-5303-03® Ί0 §31 ωδ§-αϋ?-Ν3 «UÜxO om<c»7-m^ '220-2! WW3} 03® - *313 - ÓSÚ 103 22;i3: 0319-5318-08^ WJWfí 03^-0318-0315 1304(141 0323 - 313 - 032 ! W8-G418 W§ ®® GW-W8-W1 10SW2J 111 Table 6.4: Hydrogen coordinates (x 104) and isotropic displacement parameters (Á x 102) Label x y z U(eq) 5 1Ϊ0Β 12404.0 262.0 6311.0 740 H1® 105895 6681- 72350 70.0' H10D .94 / 10 3098.0 50410 61.0 H11A 7268.0 2146.0 616 0.0 81.0 H11B 6358.0 10 2264.0 73790 810 H11C 7160.0 LM fn Κόης A 4021.0 7833 0 Aá ISA Π 8 / .0 37 A O 1 i La H11É 55220 Μ11Ρ 77^4 Π 4103.0 6488.0 .u 68.0 79 Π Π 1 * Γ f f ¿HcU 15 H11G 6834J 520.0 4954.0 í ¿..V 720 H 11H 6096.0 OI ^53111 770 H111 8254.0 4020 4911.0 770 H110 70280 6357.0 6929.0 12103 hhK üu4u.O 7148.0 M35.0 1210 20 Η111 58830 6722.0 5673.0 121.0 Í12A 1732.0 6 717.0 9302.0 114.0 -128 2784.0 5724.0 8139.0 69.0 Μ19Γ 778ΠΠ 112 RááA A i i i ή Π ί Ζ ν 1 tíJv.w / ί UiAv H12D 4372.0 8534.0 Η12Ε 2248 0 7053.0 υοΠΏ Α 7Α9Α Α QtíU .U 4533.0 8948.0 TOGA A 83.0 114.0 Rl A n¿Uu “ZríA.U / vZu.U Q í.. V H20G 1293.0: 6627.0 1:24010 '711 H20D 1:6991 3640.0 Η21Α 25201 2569.0 30391 1503,..0 621 66.0 Η21Β 2394.0 243 6.0 2750 0 66.0 Η21Ο 3555.0 1083.0 ο Π 4 Π 40Α 4 Π ΊΟΆ7Α 2 ^43 0 00 í ?í A 601 RÁ A ΠζΙΜ 4ζθ4.Ο 104 / .ν Η21Ε 43901 2205.0 join RíRÁá Π Α4ΠΑ A 583.0 ORÓ Π w.V. W 51.0 R7 A n¿ i r OuvH’.U 4*tvw.U tótB 5839.0; 3618.0 1 *40^3 λ U 1801 0 í .U 671 H2ÍB 45831 4914.0 4561 741 B21J 3966.0 4150.0 26.0 74.0 οηοηηη / 77ηζ / Ε / γι 113 H21J 6663.0 1808.0 2193 LO 90.0 Η21Κ 7004.0 666.0 2123 LO 90.0 H21L 5844.0 703.0 2901 .0 90.0 Η22Α 8634.0 -514.0 -158a 4 Λ 1 521 Η228 6863.0 232.0 -806 .0 77.0 H22C 8557.0 -1835.0 -882 .0 1521 H92D 586^ 0 -2060 0 W 0 70 0 ¡¿-ί—.Lz w i Η22Ε 9465.0 -1068.0 -715 .0 152.( Η30Β -6518.0 14052.0 4621 ...0 77.0 H30C -4848.0 13484.0 3682 LO 77.0 H30D -3954 ..0 10861.0 580F LO 57.0 Η31Α -2866.0 9829.0 5877 LO 70.0 Η31Β -1730.,0 10449.0 589C ).,.0 70.0 H31C -1237..0 8708.0 5976 10 68 .0 H31D -1827..0 8879.0 4943 LO 68.0 Η31Ε 68.0 10238.0 4794 -.0 61.0 H31F -1002.0 10218.0 3093 LO 65.0 αηαηηη / ζζηζ / Ε / γίΛΐ 114 H31G Η31Η Η3Ή 173.0 -700.0 -1421.0 10923.0 11953.0 12023.0 2855.0 3776.0 2856.0 65.0 63.0 63.0 H31J 1218..0 8824.0 5779.0 90.0 5 1684..0 7919.0 5340.0: 90.0 H31L 401.0 7778.0 5992.0 90.0 Η 32 A 4189.0 7390.0 1730.0 99.0 Η32Β 2423.0 8296.0 2288 .0 59.0 10 H32C 4037..0 6060.0 2272.0 99.0 H32D 4674..0 6678.0 2835.0 99.0 Η33Α 2076.0 81S9.0 4517.0 90.0 Η33Β ©63.0 7369.0 4921.0 90.0 15 H33C 1279.0 7931.0 5690.0 90.0 Η40Β 6155..0 -2984.0 -1008.0 Αο η ΐνυ, υ H40C H40D 4294..0 3910..0 -2506.0 439.0 -250.0 -2133.0 83.0 59.0 20 Η41Α 2187..0 468.0 845.0 108Χ Η41Β 1393..0 -466.0 7 94.0 108Χ αηαηηη / ζζηζ / Ε / γι 115 H41C 337.0 1007.0 981.0 119.0 H41D 169.0 838.0 -93.0 119.0 Η41Ε 1709.0 2482.0 3i Ο Π Π -118..0 ΟΑΐβ η 7Π Π i ν.υ Π ΪΓ H41G Η41Η 1222.0 3094.0 2115.0 1640.0 ¿UuO\w -1921.0 -2140.0 95.0 99.0 Η4Ή 3311.0 1895.0 -1128.0 99.0 H41J -1091.0 2161.0 -739.0 164.0 Η41Κ -1560.0 3148.0 -423.0 164.0 H41L -1188.0 2039.0 503.0 164.0 Η 42Α -3935.0 5259.0 1625.0 112.0 Η42Β -1509.0 3873.0 1994.0 60.0 H42C -3139.0 6210.0 1645.0 112.0 H42D 69.0 5899.0 -1870.0 80.0 Η42Ε -3138.0 4951.0 2537.0 112.0 116 Table 6.5: Hydrogen bonds with bond lengths (Á) and angles (°) D - H ..Á Distance {0Ή) Distance {H„Adj Distants (D,..A) Angle (DO,A> -FIG OJs 2.30 3.130 400 x:w -o «O 0.00 2:20 3.S47S O .® H3OOO O® 2.30 3dS4{$> 033 MOLD .. O: o® 2:20 33WÍW WM .. «24 ISO 200 3430 OSO CW-HWC. «5 0.00 230 BSS) W.SO « OIA. OI® O® 2.20 oo EYE Cí 12 O W ...O12S too® 202 OW ISO 02 OS ..:®2í Λ 2.SO 33345 140 WL , SS2 0.00 SAO jOO w.® CU 4 - HW . 0.90 240 2. OS 038 04 -OL .. Oí o® 230 3 03- 038 0-0 τα a®® 2.30 3.OS ICO o? o® .3128 ®O 7.40 2M:; o.® OOs SIS aso » ISO W W HO. Μ3 roo 2.» 3 Ό5? WO 23^1« . W aso tos OQ'X 1« Ο Ό O So 05 1ÓS ISO CO‘KO. . 0283 «o OW 2310 W® CW-sSB O® 030 so SCO 138.® so 2 02 2.O;3 OS Me ®o «o 2:30 soo -OF co «o «O «W 03 'OC w· aso SO 2SO oo CW-WW . or about 204 3.42^4! 131® αοηό. o® om «O: SsO 130 OS-OC .. w aso SO TOS OS C® o . On? too 2:03 3SO O® AS. ss iw 2:40 3 50 133.® 04 bear 2 40 1031 W® >®® 830 -’S S'·^ 2.733:4! O ® §30 3'24^4) f» \ \ \ .?Or so í: x ώ XX 3 OS os C3U-H3W . Mr oo .iC.^v'i.ííOV WO W3® 117 3.4» OKI 23» »50 »35 w? 23» Míw 53» 331413) 13138 33» 2:4» 33134) 3833 C4U -H» , <w 33» 3.153(4) «7 53 .. tói ws »55 GU» 2 4» ÚFá »50 5413 2 5 » 3 11555 αηαηηη / ζζηζ / Ε / γίΛΐ The representation of the crystalline structures is given in figures 8 and 9. The figures were generated with the PLATON program (Spek, A. L. J. Appl. Cryst. 2003 36, 7-13). The 1-491 molecule contains a sulfur atom that allows the absolute configuration to be determined, making use of a high-resolution data collection. The Flack parameter x is calculated based on the anomalous dispersion method. It gives the absolute structure, provided a sufficient estimated standard deviation is achieved. According to the theory, the expected values ​​of the Flack parameter x are 0 for the correct structure (within 3 esd.s) and +1 for the inverted absolute structure. The results considering the C315 configuration: R; 0215: R; 0415: R; 0115: R is 0.011(14), which unambiguously demonstrated this absolute configuration for 1-491 in the crystal structure of form B. A simulated diffraction pattern (Figure 10) is produced from the crystal structure of form B determined experimentally at room temperature. Can 118 compare an experimental powder diffraction pattern with this theoretical pattern to demonstrate the nature of the crystal structure. Minor differences (if any) can be explained by preferential orientations in the powder. The crystal structure of 1-491 form B was determined by single crystal X-ray diffraction, allowing the generation of a reference powder standard. Even if the sample used was isolated from twinned crystals, the structure is of high quality; and therefore represents the definitive crystal structure of form B. Example 7. Characterization of form C The solid obtained from the interconversion suspension between forms (A+sD) and B at 80 °C in acetonitrile / water was analyzed by XRPD (acquisition parameters: type = 2Th / Th blocked; start = 2.00°; end = 40.05 °; step = 0.03°; step time = 89, s; temperature = 25 °C (ambient); start time = 2749 s; 2-Theta = 2.00; and operations = Scale AND sum 1000). It was found to be crystalline and corresponded to forming C+ traces of A and B. The DSC thermogram (parameters: equilibrate at 0.00 °C, ramp from 10.00 °C / min to 250.00 °C) shows a first endothermic event at 186 °C (40.7 J / g) corresponding to the melting of form C, followed of a second endothermic event at 190 °C (31 J / g) corresponding to the fusion of form A (figure 11). A continuous mass loss of 0.9% is observed between the 119 room temperature and 150 °C by TGA (figure 11). Individual Crystal Slow evaporation of the MeCN / H2O mixture produced few crystals suitable for X-ray diffraction studies. [3] A second single crystal was found in the same preparation and selected by observation with a binocular microscope that was mounted on the goniometric head of a Bruker Instrument APEX DUO diffractometer (Bruker AXS (2011). APEX2 suite V 2011.2-0. Madison, Wisconsin, USA). Intensities were also collected at low temperature (T = 113 K), using graphite monochromatic Cu Ka radiation (λ = 1.54178 Á). Systematic investigation of the diffraction nodes indicates that the second crystal belongs to the monoclinic system, with a primitive Bravais grating. The parameters of the unit cell of the phase called C are: a (A) = 14.47 b (Á) = 17.28 c (a) = 16.11 a (°) = 90.00 β (°) = 109.85 v (°) = 90.00. In view of the number of atoms in the I491 molecule and the volume of the unit cell, it is concluded that this unit cell must contain 8 molecules of the formula C16 H20 F3 N5 04 S which is equivalent to a calculated density of 1.527. The number of reflections collected was 63,621, of which 13,312 were unique. Space group determination was achieved from αηαηηη / ζζηζ / Β / γι 120 unequivocally due to the presence of a unique systematic extinction along the monoclinic axis. The crystal structure of form 0 was solved by direct methods using the SIR software (Alternare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Cavalli, A. J. Appl . Crystallogr. 1994, 27, 435-436) and refined in F2 by complete least squares methods with SHELXTL (Sheldrick, G. M. Acta Crystallogr. Sect. A 2008, A64, 112-122). All non-hydrogen atoms were refined with anisotropic displacement parameters; a conduction model was used for hydrogen atoms. The final agreement values ​​are R1 = 0.0284 (observed reflections) and wR2 = 0.0847 (all data) for 13312 reflections and 1070 parameters, with a goodness of fit of 1.044. The compound in the crystal structure of form C (Figure 12A) crystallizes in space group P 21, the asymmetric unit of the crystal is formed by 4 molecules of 1-491, so 8 formulas are present in the unit cell. No additional molecule such as organic or water is found. The asymmetric cell contains: 4(C16 H20 F3 N5 04 S). Examination of the molecular structure confirms that all bond angles and bond lengths are within the standard range values. Two molecules showed disordered CF2 clusters. Crystal data, experimental parameters 121 Bond lengths and angles are listed in Table 7.2 and Table 7.3. The hydrogen positions are indicated in Table 7.4. Table 7.5 lists all hydrogen bonds. Table 7 Identification code Form C Chemical formula C16 H20 F3 N5 04 S Molecular weight 435.43 Temperature 113(2) Wavelength 1.54178 Crystal system; Monoclinic space group; P 21 Unit cell dimensions a = 14.4653(2) A; a = 90.00° b = 17.2765(2) A; β = 109.8534(5)° c = 16.1121(2) A; y = 90.00° Volume 3787.25(8) Á3 Z, calculated density 8, 1.527 Mg / m3 Absorption coefficient 2.112 1 / mm F(000) 1808 Theta interval for data collection 2.92° to 67.38° limiting indices - 17 <= h <= 17; - 20 <= k <= 20; - 17 <= | <= 18 Collected / Single Reflection 63621 / 13312 [R(int) = 0.0315] Completeness at theta max 99.2% Refinement Method Full Matrix Least Squares at F2 Data / Constraints / Parameters 13312 / 780 / 1070 Goodness of Fit at F2 1.044 122 final R indices [l > 2sigma (1)] R1 = 0.0284; wR2 = 0.0840 final R indices [all data] R1 = 0.0290; wR2 = 0.0847 Absolute structure parameter 0.031(6) Hole and largest difference peak 0.393 y-0.312 e / Á3 αηαηηη / ζζηζ / Β / γι Table 7.1: Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Á2 x 103) Label χ y z Lí(ssq) €103 ®282 10 2} w.010 054.8(11) 24 1® -••0 a ^41^10) 233 2® ú 22.8(3) or wnw 443 a® € 17.40} ctw 570 1· W €1 Á 17 7¡31 ms / o 5441.20· 35305(1.1} 21 3(3; CUt W 4 5145.7(10) 4254.7(1.1) 21$· 25425(10 MM 4553 €1.0} 18 3(3} 23001 2; 83113(1· 3738 €9 11 21 4i 31 €1U smog· »•1 1} 31.7· €115 3500 ¿i 5350.90.0 18.2· €117 4184.3(1 0 4g040 ai 5174 80 21 244(3} €121 502010 02.4· «·ι· i? 8· 5833 200 € 2(3} €135 8030 700 7172.8(11) 18 ?· €125 04 00 50.9(1 .1 i 8848 80 1} 2¿ 1(31 §W4(tq 5278012) 9W(t1) 27.4(4; €203 WW0 024(1 € 15717.4(12} 37 3· €224 1140(12) 8372 3(1 0 153415(0 ¿a· · €S5 W5 HUI 83>1(·} 103 +11 0 180131 123 020? 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WW) ^.or m? mm mimv mmsm mnw 3$ mu mm or mmsm mwi 3OU 532 ®p 7§.1S.4^ ¿imvi WV; F» mu o mm ím mm / w 45 15 ms wwi mrnFw 4mó(?i 35 7(2? sssm .i) 5WWJ) mm vi? mmn « sMw W8 su 1 mm mam) m.o mm mmm §W) mmx mm SMUi mmrm som W3 muim imin? §m5s m <ó mm «ó 28W 20 omim wmmw m4® mm mom w,w wmm mm 5§λ$2*1 U mmum 8375 » mm 5545 15} 7mw U'll mm ΐΟίύυδί mmirn 3411 mm m=u. mu w§?w miu wm mmi 25 mm 48701 W 83W.3il.8i m4{i αηαηηη / ζζηζ / Ε / γι 125 Ν224 4091.3(10} 8264:3(9) 8070.9(9) 23.7(3) roí -2220(9} 82527(8) 4793.8(0) 19.1(3) -1671 1=9' 8189.4(8 ) -3265.2 (9) 18.8 (3} N3C9 4086.4 (10) 8409.2 (8) -1740.2 (9} 19 5 «ν323 3177 (1} 8344.2 (8} 3707.7 (9) 19.3 (3) 04 30.2 (10} 8348.1 (9) 4430.5:9,! 23.6(3) Ν401 12579.6(10} 5732.6(10) 11014.9(10} 28.4(3) Ν406 12246.5(10} :59719(8) §529.9(9) 20.5(3) Ν40§ 11757.3(10) 5907.5(9) 7991.4(10) 23.6(3) Ν423 7350(1) 52916(9} 2527.1(9} 23.8(3) Ν424 6551.3(1.0} 5355(1} 2779.2(9} 24.7(3} 0102 -529.6(6): 8392:1(7} -948.1(7} 22.7(2) ow 419.9(8) 55519(7) 1924.9 (8) 25.1(3) 0119 3539.5(9) 6883.0(7) 61318(8} 28.1(3} 0120 4789.1(9) 6639.8(7) 5417.2(8} 27:0(3} 0202 11130.4(8) 8479.8(9} 17017.5(8} 30.7(3) 0208 10713.3(8} 7939.3(7) 14007.2(7} 211(2} 0219 7127 9(9) 7168.2(9} 9631.7(6) 324 (3) 0220 5803(1) 6847.3(8} 10419:9(8} 32.0(3) 0302 -3103.3(6) 8079.9(7) -5493.6(7} 21.1(2} 0308 -2724.0(8) 8301.4 (9} 4496.8(8) 31.1(3) 0319 2186.0(11} 7564.4(9} 766.3(9} 40.7(4} 0320 636.2(1.0) 7681.9(6) 1396.4(9) 33.9(3) O4G2 13415.6(9} 5671.7(1.1} 11779.5(9) 41.9(4} 0408 133514(9) 5710.9(9} 88410(8) 30.1(3) 0419 8068.3(12) 6505:0(9} 5282.8(10) 48.9(4} 0420 §32013) 6703.3(9) 4561(1} 52.0(5} SUS 42218(3) 6355.1(2} 59347(2} 18.75(8} S218 6278.2(3} 7397.4(2} 10036.8(2} 20.93(8) 5318 1892.6(3) 7992.5(2) 1253.8(3) 23.31(9) S4W 8873.2(3} 6207.0(2} 4814.5(3} 28.84(1} αηαηηη / ζζηζ / Ε / γι 126 Table 7.2: Link lengths (Á) Link Length (A) 00 0104 1 3UU CO- CUS ' 4'^.2 - Fim to 00-00 nwi GW? <«55 1:.2220 CTW'CA ' 3 2'4 CW A ¡2 15340 mu-mu 1.5370 01U 005 t.S^0 0113 -014 1S2S0 ¢115-0117 1 5S4U: cwfiw 1W(W iWW) CUA 022 1. W0 0121-025 1.020 0122 -03 1:3^0 025-0138 1500 0128 Ό 1500 i A · FUS '1300 CUS. w 0400 cuscas AK 0 003-0354 00 ew-€« 1 400 0355-^ O00 ®F« 1 300 1 00· assisi *osii 00?; 021 IOC? 15430 0212- C2U 1300 02125 CU5 1 00· €213*0214 15280 0213 -A 1 00: 127 css-»» W WW2 €221 < €222 a»® UVA »5 - c» 1 BB® £325 F23? i»® wB m ABA? A»-Cl» 1 348-2- w® €»»» Av? ABA A’ -0» B 2 CAA B» 1 B-2 CA - CAÍ 55B» ALCA < CBBG» i αηαηηη / ζζηζ / Ε / γΐΛ CL 3 -O» CB5-CB7 CSB-BB 5525U: iSBO W2ÍÜW CL» »Bü7> W1B®» B»»i ¢321 »325 14BB BB- IB OWi Cx* CS25 ¿τ* Λ M-W B ; WBC4G4 Bv i »»€» '4 10 04» N» ' B2 2 C<€ - W§ νΛ G4§? · 04$$ ww C4W - C4Í1 »31-W2 15W C4lB»ñ 153U2; 128 C4m 1 54U OOOM i $3m cm-OT ' AAO OS 3} C4W0 ^!Ί C421 - C422: 1 383© £421 - C425 MW) £422 -03 w?B ¢425 - 043« m ©42>© CO - 1.349(3} COO2? ©A 04© -FSM s© ©3? ©O ASO® w©ci® 1317® Ním -0102 1O©© M09-C©? ©W1 O§- ©5 W3® ®® - £114 W3® o® a® ®® - m 24 ^0© UW) NO© - (® ;3©A NOv©©© 14 W® O® 07 1 3W - 09 1O® 09 -04 1 O0! M© - 03 - 04 oo© NO© - ©25 ©213} w©m ©t$® »©Ο3δ2 W·®® ^06-C3£7 1WI o©co to® αηαηηη / ζζηζ / Ε / γίΛΐ 129 N319-C314 1 483(2) Ν323- C329 1.443(2) Ν323-Ν324 1.352)2? N324-C325 1.333(2) N401-C405 1.313(2) Ν401 -0402 1.4358(18) Ν406 - C4O7 1.378(2) N409-C410 1.467(2) N408-C414 1.480(2) Ν423 - C 429 1.455(2) Ν423 -Ν424 1.353(2) N424-C425 1.331(2) 0102 - Cl03 1.340® O202-C203 1339(2) O302-C303 1.341(2) 0402 - C4Q3 1.342(2) SW-G121 1.7373(W) S1 18 - 0119 1.4345 (13) SUS-0120 1.4407(13) S218-G221 1.7277(16) S2ÍB-Q219 1.4326(13) 3218-0220 1.4301(14) S318-C321 1.7410(18) 5318- 0318 1.4308( 15) 3318 - 0320 14385( 14) S418- 0421 1.7418(18) S4W-Ó41S 1.4338(17) S418-O420 14276(17) αηαηηη / ζζηζ / Ε / γίΛΐ 130 οηοηηη / 77ηζ / Ε / γι Table 7.3: Bond angles (°) Atoms Angle O www cías 133 WW WWW W1 WWW 0132 10512^2) www ews cw? - - 0110 WWü WWWC1M Ib ib'η ws-wi -cm m?ww Wb W2-W3 WWW CW W2-W2 1ÍWW WWT1WW wwn WWW 0115 i 14 55W w^www WWW-WS 11WW www·coa iwnw wwnwita 1112*111 WbWWnS, W W €W W OÜ5 WWW CWlbS^ WWí €122-Nia-eU§ W.Wb C122- N =25 W W Wb W-TWb bWW WW4WW1 Wü »w.w hw CWW'WW §aww om»-® w5ow awsw; b”b 185 2^13? CWNWU5 CW < iW - W W 113i cw - nao · w WWW €W W -02W WWW 131 132 ¢322 W32.3 - 03» 123 0400 C322 - - Ν334 1 325 13' C323 C321 - 23'0 00 43'03' Ote- W24 tete te 0-te-tete-Ote 123 52; te- CW3-CW3-Hte31 te? 7$ U> C4«-«3-04^ 10 47(15} W - N40? vQ® te 5303} 0-te - ú-w v.q« OteáOá! :w->HW.W4i$ (O-Ote: tete-iteW 05 2304} Q4 te -tete i - Q4 O i® Otete} C4H-0412-0415 OÜ ¢¢3 Oh •01:Mte4Í íM-WOte-WS 06 250?! 0443-0443-0411 testen WÍ3-O4ÍS -G415 ? ​​te Otete 0444-33425-04» I te O} 0417 - 0415- 0412 ? tetete te ' te i- ' 142-0. Otete 0425 -tete i3teO4ite} Ote - tete -tete «Wi 0422-0421-0425 ιδδ.^ι§>: Ote: -Otete tete 121.5^.14) OteO- teOteOO or? tete 0te2 tete M2¿ m.WW 0425 Ote 1 - tete 015304) 0425 te24 M23 WWW π?6-οο5-οο3 WWO; W5-CO5-C1F W 44 0 3; FH§-0 05-Site WWW F'0?-Otete-Otete W 350 51 W7- R25 -0124 MCW FW-FO-F527' Otete FteS-OW-OW ®«8) 133 FOOOFO WW 08-08-00. M|1(«| »(W wtwa 420 CO 025 108..35(1¾ FaS'C^'QM WCáMa a ®,® áW-W“C3« W®(® 1803(1¾ FOOOO8 imoid F3OC3OC32& oo® - 0525 4328 483..25(1¾ ®-»€Β R«-a«-C412 488^1¾ RltOOmiF wom B1S- miS <8418 00(10 u;oo« o o o momsm w WS.WW HOmOFSM ¿4 8 .n moma- m® 15 ROmOFSB 43 3® FSOÓW'W ROW$-F427 405: FWOOW 1442® F5B - (W - BSI® F5OmOC425 0.7® Feocioma i® i® 20 momo o? IMS® ®OC1OFlá M.1(10) mo ma b? 78.0(13} FO 00 05 08® FOOtOFO 3SJ® FO - OO - FO 04® R28-mOCO ®w 25 NO 70 O ® U> 134 αηαηηη / ζζηζ / Ε / γΐΛ 135 ®3«2O« 1<®Oi 1X24 - U2S 0431 11048® Μ24 005 0426 122 22061 >W4 - Wi C42§ 1 S® 8 022 003 004 01 / 0® 0? \\'4í 5 123X3® 010010010 07.017) o i $ o o® W?:W1 00 0100125 10 '3® a® oto-oro W? 4® 022 0100131 108®?) 062 0® 004 OR $0121 10 020 00 030 OR 72:14? 0228 020 O® 02; 13® 090- §20-00 Of <ísj 020 0200221 O7.W) 020 020 05 07.6® O22O2J 0221 W®€i 002 020 030 0'40 15 0X2 030 0® ' i' X ' 4' 0® 007 Ó ® \ '.'''- . Ά\ > 20000 0® o®O oooueo® 074® 00 0)0 0X1 0373® awwoMS W3® 20 000200131 ®8® 040 00'0« WO® 13®O) ©40 04 00X5 W.i® 040- Xt§ - 0431 ®s® OO O® - 3X5 10.4® 00-00-0421 ®7® W<W§'-C4O ®W1) αηαηηη / ζζηζ / Ε / γίΛΐ 136 Table 7.4: Hydrogen coordinates (x ΙΟ4) γ parameters of οηοηηη / ζζηζ / Β / γι isotropic displacements (Á x 102) Label l 9 4949.9 29.0 MUD 10.0 4082.9 4777.0 26.0 m ib 20 5 5249 9 4742 9 22 D HW 8436 9 3898.9 289 HUG do o ΒΜ9 3530 25.0 miH 1730 8757.9 3177.9 20 HIT 2182.9 »9 2467 9 20 mu 4542 .0 6149 9 4817.9 37.0 HUK 37^ 0 4473.9 WX 37 0 HUI 4554 δ 4720 57M? 37.0 5118.0 5380 9 9230 41.0 HOB 08 5694 9 7730 25.9 H12G 6266.0 5556.9 0594.0 410 H12D 6385(1$5834(15) 7022(17} 29.0 H12E 58 78.0 4724.0 S188.0 410 H208 12483.0 8108.S 17079.0 45.0 HBC 11803.0 7873.0 15473.0 37.0 HDD 9142.0 84689 14755.9 29.0 H21A 8953.0 7082.9 126210 26.0 Η218 9811.0 7626.9 12531:0 28.0 H21C 8467.0 7579.0 11177.0 25.0 H2W 8648.0 8447.0 TI 548.0 28.0 H21£ 71830 7424.0 11704.0 22.0 137 Or W® S1O uwo 23.8 ΗΌ 7^1 8 §qw 12307 0 20.0 OH ws 8:OA 3-0 23 0 Oí '3410 ?6®.O W.0 20 0 οι *0 5 ®7® 415 H21K '128 0 0342.0 W7M8 410 hs Λ 8083.0 W;0 4« ia 5401.3 S687.O «M 55.0 5322.3 700 » -O 4450 ®O 50.0 OD «IO 730 «<δ ®0 ra 04 S 330 55.0 HS® os 500 1O HS® O® A ?SO mil ®o HS® v 8182 0 ¿244 o 23.1 OA 8037.0 uoo 310 HS® ¿W.0 §380 0 ¿1005 10 HS® ÜSü ®O 5o 0 30 0 OD 07.0 §031.0 30 ®A wed 440 »w.o 4340 33.0 HS® 34410 <3.1 253 ÓG 3530 7$® 0 <3.0 W H31H 10 «a ¿®O 24.0 OI SO -2132 0 1O 04 ®§3 ®¿o WO 35 0 OH Ó W.0 ® 550 181 HM YO ®o 05 0 W Λ 430 «00 «A 3230.0 3102.0 22.0 oc 33320 7052 0 SO so H32D ®'4O íO S.3 H® os 1® 0 47M8 432 OS mt 5W.0 ¿§300 37, 0 H®G w» wo ®3O 33.0 H4® WO 340 250 αηαηηη / ζζηζ / Ε / γι 138 4 4 12623.8 OOO «® 08 1«® ®1® W® MO i» 4» <57® 356 tw® «C <X® 350 wed f®® 08 554® ®1O 288 w® w® 53815 w® 2 ® H41H iw 60A 754® W8 «i ÍSW O® $h® 3® mu «442 2 5» 070.0 A® H4® ®® 44« 810 0 4® mu «® SU® 48.8 H42A y \ o OOO »a 85.8 HO O®. 8 00.0 OOO 3® wc A® 53410 ®?o 5® Orel OOO 44850 0.8 608.8 W® 5® οηοηηη / 77ηζ / Ε / γι Table 7.5: Hydrogen bonds with bond lengths (Angstrom) and angles (degrees°) O **** H A Distance (OH) Distance (H.Á) Distance Angle (ΡΉ..Α) ^•HW;.WÍ ®®8 2 O® 2 9'« 16108 2 8580 3 147.® W1 8.3880 233-0 3 '48® 154.® O01 2.1400 2® 3® 158® 503® OS 020 a§^ G- 24« 2 '®® 115® 0Ό4-ΗΟ0 .005 085® 2 4500 2 ó® W® entino Fn§ w» 2 3808 182® 510 ®1 O.. 010 i»: 2.5500 3 58« 112 ® C04-H® ...JOS 00980 2.5100 2.873(2) 101GO C12§-H12Á....Cm 0.9508 2.4800 3.381(2) 152® 0122 - H128.... 0488 0.00 2.4600 3.248(2) 148 .00 O203-H268...N2S4 8.9500 2.3500 3.209(2) 163® 0284-K2® ...0208 0.8500 2.3000 2 791(2 / W® 139 '3210 — . 0203 0.0® 2.07 0.17 C2h -RDO 02® 7 ASO 2.4700 313® 121W a» 2.» 0214 .... CAO aw ..C® o® 2.5200 3 M2Q) 1» QU ~Η3Ο ... 0202 0.00 2.W 3)055® ÍM 1 Ω C317-H31K..O1G2 0.00 2 5100 3 4122) 15200 1 U ..... R2S 0.00 .2: 4® 31713J 142.00 0322- H32S ... CT 0.00 2.4® 3 <243® 147.00 € ® -η32δ .. „031 § 1.OG 2.5® 3.W1 123.00 W3-H408 ... R27 0.00 24700 3.» 122 JO 2®3-R0g 1424 0.00 2.4® 3 3733) .0223 2.6® 3.2732- 137.00 15 0.00 341GS 2^ 104.00 The representation of the crystal structures is given in figures 12A and 12B; The figures were generated with the PLATON program (Spek, A. L. J. Appl. Cryst. 2003 36, 7-13) for both structures. 2Q The 1-491 molecule contains a sulfur atom that allows the absolute configuration to be determined, using high-resolution data collection (performed at low temperature). The Black x parameter is calculated based on the anomalous dispersion method. Gives the absolute structure, provided an estimated standard deviation is reached 140 enough. According to the theory, the expected values ​​of Flack's 908-915). The results are as follows: Considering configuration C115: R; C415: R; C215: R; C315: R; the Flack parameter is 0.031 (6), which unambiguously demonstrated this absolute configuration for 1-491 form C. Simulated diffraction patterns were produced from the experimentally determined crystal structure of form C at low temperature (Figures 13A and 13B). An experimental powder diffraction pattern can be compared to one of these theoretical patterns to demonstrate the nature of the crystal structure. Minor differences (if any) can be explained by preferential orientations in the powder. The polymorphic crystal structures of 1-491 form C were determined by single crystal X-ray diffraction, allowing the generation of a reference powder standard. Form C was completely characterized by this work. Example 8. Characterization of form D Slow evaporation of the MeCN / H20 mixture provided crystals suitable for X-ray diffraction studies. 141 A single crystal selected by observation under a binocular microscope was mounted on the goniometric head of a Bruker Instrument APEX DUO diffractometer (Bruker AXS (2011). APEX2 suite V 2011.2-0. Madison, Wisconsin, USA). Intensities were collected at low temperature (T = 113 K), using graphite monochromatic Cu Ka radiation (A = 1.54178 a). Systematic investigation of the diffraction nodes indicates that the first crystal belongs to the triclinic system, with a primitive Bravais lattice. The unit cell parameters of the phase called D are: a (Á) = 9.78, b (Á) = 13.86, c (Á) = 16.11, a (°) = 65.39, β (°) = 84.54, and ( °) = 72.42. In view of the number of atoms in the 1-491 molecule and the volume of the unit cell, it is concluded that this unit cell must contain 4 molecules of the formula C16 H20 F3 N5 04 S which is equivalent to a calculated density of 1.522. The number of reflections collected was 27,364, of which 11,440 were unique. Based on the statistical distribution of the intensities, a non-centrosymmetric structure is deduced. The crystal structure of the D form was solved by direct methods using the 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 was refined in F2 by least squares methods 142 complete with SHELXTL (Sheldrick, G. M. Acta Crystallogr. Sect. A 2008, A64, 112-122) . All non-hydrogen atoms were refined with anisotropic displacement parameters, a conduction model was used for hydrogen atoms. The final agreement values ​​are R1 = 0.0430 (observed reflections) and wR2 = 0.1179 (all data) for 11440 reflections and 1045 parameters, with a goodness of fit of 1.071. The compound in the crystal structure of form D (figures 14 and 15) crystallizes in space group P 1, the asymmetric unit of the crystal is made up of 4 molecules of 1-491, so there are 4 formulas present in the unit cell . No additional molecule such as organic or water is found. The asymmetric cell contains: 4(C16 H20 F3 N5 04 S). Examination of the molecular structure confirms that all bond angles and bond lengths are within the standard range values. A piperidine group is disordered in the solid state. Crystal data, X-ray experimental parameters, and structure refinements for form D are given in Table 8. Table 8.1 lists the positional parameters for all independent non-hydrogen atoms along with their equivalent isotropic displacement. Bond lengths and angles are listed in Table 8.2 and Table 8.3. The positions of 143 hydrogen are indicated in table 8.4. Table 8.5 lists all hydrogen bonds. Table 8 αηαηηη / ζζηζ / Β / γι Identification code Form D Chemical formula C16 H17.75 F3 N5 04 S Molecular weight 433.16 Temperature 113(2) Wavelength 1.54178 Crystal system; Triclinic space group; P 1 Unit cell dimensions a = 9.7779(2) A; a = 65.3922(8)° b = 13.8626(2) A; β = 84.5393(9)° c = 16.1058(2) A; y = 72.4184(8)° Volume 1890.93(5) Á3 Z, calculated density 4, 1.522 Mg / m3 Absorption coefficient 2.114 1 / mm F(000) 895 Theta interval for data collection 3.02 ° to 68.04 ° limiting indices ¿ or co T T T— II II II V V V ii ii v V v v co 1--- 1--- । Collected / single reflection 27364 / 11440 [R(int) = 0.0446] Completeness at theta max 96.5% Refinement method Full matrix least squares in F2 Data / constraints / parameters 11440 / 826 / 1045 Goodness of fit in F2 1.071 final R-indexes [l > 2sigma (1)] R1 = 0.0430; wR2 = 0.1139 final R indices [all data] R1 = 0.0502; wR2 = 0.1179 Absolute structure parameter 0.003(13) Hole and largest difference peak 0.499 d -0.442 e / Á3 144 Table 8.1: Atomic coordinates (x ΙΟ4) γ parameters of equivalent isotropic displacements (Á2 x 103) for form D. U(eq) is defined as one third of the tensor trace Uij orthogonal i zated. label 1 5? 24 3A 4®(2) 5939 5.1 7: AM0A16) 24A5? cm 42») 295 A1A -20 AIS) A1A a íi WW) -»5(1A B.4(A 2112 2480(0 24 3 (5? €113 4934; 3534 g: 1 9) Ά150 A 206? €114 -A8Ó 4683A1A 32A7? 05 mam 1O 5; ? ?) -AS OCA MI (A CW 2850 901 $1 38 8A 0121 ΑΒΑ ¿A 84 4 17379:18} 28 O: 0122 21W) 6!0j 23400 2? 0125 326»: -445A l A 1815 Al .5) 25 O o 37S5(3) -104(1.8} A21A?A 32 1(6; 0122 W) WA.1A «A 0203 929(3} 8413(2) -943.0(1.8) 39Á7} 0204 1073(3) 8953.5(1.8) -34.3(1.8) 34.0(7) 0205 1945(3 ) 5939(2) 241.5(1?) 32A8) C207 1999(2) 6288.8(1.7) 1884.9(1.8) 25 AA C210 4301(2) 5034.1(1.8) 2727.3(1.8) 250(5? 0211 4894(2) 3925.3 (1.8) 3547.0(1.6) 25.6A 0212 4227(2) 4037.3(1.5) 4439.5(1.5) 267(5} 0213 2581(2) 4471.9(1.8) 4323.4(1.8) 26AA C2U 2134(2) 55 95.3(1.9) 3522.2 (1.6) 272(B> 0215 4705(2) 2968.8(1.7) 5311.3(1.5) 22.7(5} 145 C215 4705(2} 2968.8(17) 5311.3(1.5) 227(5' 627 4515(2) 1933.4(18) 5318:.:9(1.7) 268(6) 0221 6913(2) 1784.5(17) ) 6737.4(1.8) 25.315) C222 5518(3} 1978.3(18) 7509.6(1.8) 317(6; C225 7747(2) 6614(18) 7089.8(1.7} 272(8; C228 8429(2} -56.4( 15 ) 6567 2(1:7) 27 6(6) C22§ 6965(3) 803® 9194.7(1.8) 46.5(7) C303 5978(3) 2550(2) 113607(19) 47.5(9) 0304 5780(3} 2864(2) 10465.5(1.9) 418(7) C305 4676(3) 3878.1(19) 10195.4(1.7) 30.9(5) 0367 4144(2) 4267.9(18) 8632.4(1.6} 26.9(6) C3W 3503( 3) 4675.5(18) 7095.7(17} 36.6(6) C3Ú 2181(3} 5320.5(17) 6475:,8(1.6} 28.8(5) 0312 2039(2) 6567.5(1.7) 6056.3(1.5) 227 ® 0313 1977(3} 59318(17) 5849.3(16} 25.7(6} 0314 3293(3) 62314(17) 7493.4(17) 27.5(5) 0315 772(2) 7221.0(1.6) 53687(1.5) 22.8(5} 0317 -700(2) 7479.8(19} 57425(17} 26.3(6) 0321 -182(2). 89867(17} 3650:6(16) 25.1(6) 0322 -269(2) 8539.7 (18) 3037.9(1.8) 24.3(8) 0325 -1443(3) 9879.0(17) 3474.6(1.6} 26.4® 0326 -1966(31 10668.8(1.8) 3929.1(1.6) 27.4(6) 0329 -2693 (3) 8996.7(1.9) 1836.8(17) 26.8(5) 0433 11286(3} 1144.5(1.8) 16007.6(17) 23.9® 0464 10664(2) 1511.3(1.8} 151207(17} 35.6® 040 5 10310 (2) 2683.4(1.6) 148318(15) 215(5) 0407 9897(4) 3314(2) 13220(2) 537(10 0410 8567(3} 5287.7(1.9) 12386.6(1.8} 36.87} 0411 7630(5) 5983(3} Π496(3) 38.2(4) 0412 8563(5) 6111(3). W653(3) 38.2(4) 0413 9287(5) 4949(3) 10683(3) 38.2(4} 0414 10252(5} 4260(3) 11546(3) 38.2(4} οηοηηη / ζ^ηζ / Ε / γι 146 C415 7655(4) 6894(2) 9763 / 21 54M) C4U 8666(4} 6881(3) 9005(31 70.4(1 Ό! C421 5428(3) 7781(2) 84007(19} 34.6(6} C422 5739(3) 75511(19} 7633.6(17) 312(6} 0425 4557(3} 3907(2} 8046.8(18} 33.3(6) 0426 3883(3) 9619(2) 8552(2) 43.9(8 ) C42S 5060(3) 8826(2) 5968.6(18) 362 / 7} C5U 8505(8) 5062(5) 11436(4) 38 2(4 0512 7560(8} 5882(5} 10856(5) 38, 2(4 / 0513 8272(8} 4893(5} W1(4) 38.2(4} C514 8358(8} 3849(5) 11884(4) 38.2(4} F1® 2470.4(14) 1115.2(10} -276.6 (9} 33.3(4} F127 4879.7(18) -1007:7(1.3} 8257(1.1) 49.8(4) FW 4122(2} -2264.4(1.2} 1935)5(1.2} 60.3(6} F2W 3943: 6(14} 3175.7(10} 6036.0(9} 30.1(3) F228 75912(1.8} -715.3(12} 8639.6(11} 44.2(4} F227 9796.5(16) -788.9( 11} 6989:4(1 ® 38.8(4} Μ 757.2(13) §320.3(9) 4356.6(9} 25.3(3} F327 -3621(2) 11554.5(1,2) 3416.8(1, 1} 54.5(5} F328 2627.5(19} 10160:6(1.2): 4719.7(11) 46.8(4) F4« 7327.8(1.9} 7937.5(12} 9790.9(12} 40.3(5} F427 4512 (2) 10442.9(1.5} 83173(1.6} 87.2(6} F428 2514(2) 10151.0(1.4) 8268.0(15) 59.9(5} -1720(2) 5711.2(1.6) -5721.7(14) 34.1(6) -1509(2} 5017.5(1.3} -41467(1.2) 217(4} N1S9 -1273 / 2) 4227.6(14) -2561.8(13} 25.8(5) N123 3422(2) 222.4( 1.5} 2764.7(13} 27.8(5) N124 4123(2} -559.6(15) 2451.7(14) 38.4(5} N2S1 2283(3) 8686.1(18} -454.2(15) 44.0(7} αηαηηη / ζζηζ / Ε / γι 147 Η» W) ww® 11^14) >2® 12® 20202? WO »1<í. 3} 20® 1223 uu® 033.20.3) 4; 30 ® 00 w® 2100® 72®.40 A ®.3® 4338® 414®0® i 08®®®) 40®® 13® 43470? » W® 23 5® 5 1303 3402) §04900 4) 7328.04® 24 O0 1323 su»® .»01® 258® 1324 »2 077 2®2® 0 24 3® 0431 »3® 2374.80.4) »3.00 .® 2$ 8® 14® 3483.00.4) W2M® ®04) ®® $317® 4tm4w 12424,30® 55 5® Μ23 ®$4<; 0 ! 0 24 05? 10 02á ¿UC .5 '»30® 32 2® 0» WW) .2333(3) UM7® 32 008 O® 2333® ®W1 ®2® 002 ®m® 8M40® m®5®® A 8® 003 'W® 57??.O 2) -32380.1 mu Ui^t?) W.S0.4) 00073; 30 05' mu <00 3'3' m? or i W3®t® 4U® 15 «2 ;^2, U20.m 1? 4W? 020 «W® 703000,3) » 3 ’ O 33®51 mu 00 o ’ 9’ O? 0'2; ®M.M® -A» mu Ϊ4Α 1 2) 2Ú3.30.4) »30® ®J® mm Ú» W.10® 11348 70.3· ®®® W® ®M$0® »«0.0 8733.80® 3130' w CUÓI® AH 044 30® 2 0 W ti? m® » 20 > 4®4 30 3; .U €4® i®m.$0.S) W®12i '»3-0 ' 3130· G4iS 8?» 334000.7) 813® mu 430® 7159® 5''® x 0 M7® 3118 33$ 20; 100001 '04 27.33Π4; mu 3»® 270.301 ®nSH; U®® S3U 2? 847340; 44§ t ,δ$4) M®(® mu 25 7321 2 2' BU.3® ‘V? 4 < xw' ' ,; ^'Ά.'·'· <2® οηοηηη / 77ηζ / Ε / γι 148 Table 8.2: Bond lengths (Á) αηαηηη / ζζηζ / Β / γι Link Length (A) ClO3»W 1342(4) 5134 -CRIS ' C - N10S 1J» 5 ooxs 1 i oí?? ' TO; $ i ctw-an 1 314(2 / . 01)10112 1 83»· CW»113 »W) Gwom tWi Ó113O114 1.810(4) 10 ciocw ISO an$»o tWB 50-508 tW. 000122 1375(4) 0121 »125 1:410 G122 023 1W) 15 0)2300 1.408(4) 0ÓO127 1 303 i 00 0128 »55(3) C27C - 0231 1341(4} o-»: 1.420 CX5 1 «) 0O A» »?3(3} 20 CX' - 1,230 lO-O» 1820 021 - »» 1540 £212 »21 1530 0212 »213 15W) »Π»»1 1 51» 0215 EYE 14$7(3j 149 C215-S210 €2© · 02© mi' co <._© NO O® -CO ©© LO® 1 O® í 3'0 1403® 1305® 1O® ©42® cm® 1 3®4 C®4 - C®5 1411® 0203- NO 1373® 0307 - NO 1W® 010 - QO 1O® ero©;©! 1®3® in -m 1333(¾ c©Acm © . © f camcaM 015-03® cm-FO cn-m 1544® ¡mi 1528® to® 1O® 03©® CAI- 0322 :^4j €32* 0325 k Λ1 h.3} 0322 13®® 00-00 Wi® C3B-F327 ©4-3 0Ο -90 2^' ? 00-00 04© - CO -v; ó.. ®moNó: .O® ¢ 407- o® 1O® 040 00 50® Cm-OH O5S® CO-C©2 0530} 041© CO 1533® 04 50 - 04© 1®4® 150 ¢40-0:40 1W) 000' 015-15H twi «.•ΟΙ 1402(4} 0415 0418 014(4} 042 i - 023 11»W ¢42: 005 1427(3) ¢422- N40 ÚMO 028 - 005 iww 00040 1,308(4} ¢40-028 W3} ¢01 - 0012 i $300: 015- csn 1 $4¾¾} €813 -C514 1..543(8} F2200· IOS®} wv» 010: 9 0 - 00 1421(3} 00-00 1373(3} €W-€tW 1458(3} 00-0M I»} 00· a i 10(4} €123 0124 1350 €0·« 1312(3} €2000205 00 €201'0202 0« €208-0203 000 €300020 1400 000 00 14« 020« 14« 010 0® 13540 €220 025 1300 001 -« 000 €301 002 i 4800 €30000 1300 €300 030 1400 151 N3GS - Q314 1469(3} N323-C329 1.453(3) Ν323- Ν324 1.353(3) N324-C325 1.334(3) N401-C405 1.312(3) N40T-O4Q2 1.4290) mos-cw N499- 04 10 1,353(4) 1466(3) N409-C414 1,592(5) N409-0514 N423 - 0429 1,612(8) 1463(3) N423-N424 1359(3) N424-C425 O08A-C407 1312(4) 1373(5) 0088-040 7 1285 (5) 0102-0103 1343(3) 0202 - 0203 1.348(4) 0302 - 0303 1.335(3) 0402-0403 1.344(3) SH3-C121 1.734(2} SUS-0119 1437(2} S118 -0120 1 4254( 19 S218 - 0221 1.741(2} S218-0219 0218 - 0220 1.430(2} 1437(2) S318 - 0321 1731(2) S318 - 0319 S318-O320 14313(18 1440(2) 5413- 04 21 1733(3) S418 -O419 S416 -0420 1434(2} 1425(3) αηαηηη / ζζηζ / Ε / γίΛΐ 152 Table 8.3: Bond angles (°) Atoms Angle f) 0103-0124-2105 Al?» CB3 IOS 4§t t§3 us$» 5 CW5BW1 -W 10W<W €137 »108- »05 W.4W CWÜO-C» »2» »o?»i»cib IB WW cuo»m-»i2 ! 11 113 2» €117-0115-»12 IB 051® CU?·»» S» €1.7¾ B) €121 0125 -C» A2.5» 15 »»» aüib »48») »' 4 2- Al S»2>: α»α»αα »2- N WAii » »» CUS »»» i» I»»® 20 €»»»· €225 »2» BU» B2..OB C2C»Ü» C » »2»C2B 13367021 €» N2B-C2B >Zí»» CW-WBCM ' '5 58 A O»»»»» inm·» 153 te®-02» -SO» < S. VS; >' om-«12-0211 te te V 0214-0213-02» s 2 02» N2« 02» ' te 4 €2» - 0212 0211 ' te\ ' 0215-0212-0210 ' tes A 02» - 02 » - 02» 11TM) tete tete w uwi=o 0221 - 0225 - 02» »44»: WCteWWlW» C22¿ *0221 -tete tel.Wí 0222-02» -52» mww 0222-ÍW-ÍW 0223 - N223 · .'4224 112232} 0223 - te® - 1236(31 0^5--W4 -«23 »5MW tete Ote- tete teá») OteOte-te WO vite - jo tete ÍB§iB 015 W3Q1 * Ote W 31}»} «5-ÍOe -03te CW-Ote-CteO 1» te' »1 Otete-Otete 0314 tete-03»-03» »3.5« te» -te»- 03» 'te OVA 0311-0312-0315 < 0 ' 12 te» tete' ¿i» W;WW 0314 -0313-0312 twww Otete NO- OS» »3:31 (Wi €315 - 0312 - 0313 nw) €317-0315-0312 117.1(2) Ojte«H -«lg tetWW te» - tete- tete 3' Ww ii) «22 -032 te tete αηαηηη / ζζηζ / Ε / γίΛΐ 154 OS - C331 'M¿3W ®s-ó®óst S?S2: CW NSWS4 no® cb-os w WÓ 0250 24 02 10.302) CSWWi 1OS® CW-W 02 WOOíS- OW “4 2 ?<2 111.05(101 lOiWS W'fOW «3.2® OS >080 OS O w OS > 009 014 115 W w-mswsK 1U.5® WOCSb-OS 1«,§® OW 04®- 014 tw® 010'040^014 W..2 ® Ο11-0ί2*Ο« Mis® OS-OU Ό5 1 «7® OS-015-OS M7O O1¿-O«-S4« 124.4® OS-OS-OH ®7i® Ol-OSÍO 112.3(4) OS- 014-O® 10.7(3) ouwisos O4W4S-OM ?Wi O®-OS-OS W.2® 017-€4«-OS OS Ό® OS .lió® 021-O2S-OS 017® 00-010015 WS; O: 022-021 - 025 02 3® OS-O21 05 5b O 022 W 025 S81O 022-W-024 t®5®' O25-O2VÓS YES &2: 155 w&ww 803 O u 040 Μ® o$á ¢511 - CU 2 - 0415 O O ¢50 050 0513 Wi 02-000^ ®2® 5 Ο-ΟΟ O O 030050 00 111.6(3} Ό Ό \Ο 0.0® 0600 00 0. 1 ® 00-0 W1,$w FO · C OS - 05 Wj® 10 FO-CO-QO W..7® FOOIOFW OO® ΟΌ®} 2 o a® Ot- 0215017 166.51( W ñoco-seis O.®}®} nacamoo OI® F0-0®0¿5 0.7® 15 CO - 03® - F2® OO® 08-000 2 0.0® F3i$ · UO O s 06® ®oao 10174(14} FO 00 05 1O® m7* €»-FM WOlUSi ΠΟ OSOOS wtóKW 20 F4O C4OO0 oa osoaco 0.0® F4MOOO0 03 mochaos υοο foooios OJ® HOCO 028 w®> HOaaiO? co® 25 »1 03® 156 umm· NO - cws W 12OX- NWS · W - NO m NWuGtW'Cm 1 í 1.¾ O ^2- hO® η® cicu mi í$i4j -am ÑDVCW-ám '<41 Nm-CD5-N® miso Nxmcmccm muu? mJUW cma-m N223 CD2 am W.CKZÍ a® - cas - cm 1 U.C2; - C225 - cm immm cm me cm v$ Nm - mm ® Νΐ4ί$ NW<CW-0K4 wmj u§m(m «t* camón ITMÚÓj Z -i ee ; ψ U «•¡•7?··;·^ >··:'>·\;$ o sm nW} - am - aces \x~ v? m\ HHmü MCI ¢405-0484 IXmU; ¢405 -cm IMBí® MW.-W7-^e cemamom 11® lio - c-o - ow mifi αηαηηη / ζζηζ / Ε / γΐΛ 157 ws «4® C4M «oo:· C422U3U 1571® ®24 -®25-W TWW • ®3 · K5 ®0 5® N424 •N423-C® «80 ® 0030 - 340? Ws W® 0« - ®D7 - N43§ « Os® -wr-cm ® « 0® 121 791® 018S ®w?®w i 21 £42} o® 8M8-CO5 W7.mnu OfW ®n®au '« 70® 0« - Si ®eos W8«0 ow -st® o® 158 180® s® • U® 0® 103802; 0205 - Ció? - 0205 «3® BEARS <G2SU1O» 121.8® ® - S2W-C2O «40·® o» - ^.-0221 WT.2O® 02 W S216 - 0226 120.20® G2Í - SU8-C2W «80® 0220 - SU U 0221 ®818{® 03® W 1213® 0308 - 030? OU® 1218® ou§- 53 W - C3W «77® 03« SUUOiU «72(® 0U9- 5318-0320 1i§0®2i 0320· SU8-OU5 ®uo® oiu - S3W O32> 1® 0® 0 © US- .84« .04® 104.3707 041® SÚ%0421 1®.®® 0420 · $4 ® W7W7 042(0 mw® ®20 - S4«cm§ 1227707 158 Table 8.4: Hydrogen coordinates (x 104) and isotropic displacement parameters (Á2 x 103) Label x y z UH HS 43B® OTO 510 KWC 43370 37541 4724.0 4® w il® 4152.0 2® nm .WA W 351 HW -523.0 .27181 •w 351 HHC 14801 33S31 '<7.0 321 Kí® w '21441 • 1 ®í0 321 HW 10211 w 2§1 H1® ¡©δ 33021 4« 30 43 i 0 401 1371 30 miM 2S270 34541 Ό. 35 0 mi 067.0 401 •1W 301 HIS ¿2® W «1 3431 ®® 50 «IL 230® $35.0 §o H1M wo ®7 D 36031 i® H® '464 5 ®δδ δ 24® 3 321 H12C 5030 3532 33 ® 0 mi H® 28§7 i •w §« 381 H® 4S®1 35® WS ®1 H2® 38® 3441 43331 <0 833 0 44541 3331 4® Hl>® MB1 55'731 ®O 371 H2® W1 555® 3® «I® « 3 «32 0 2 ®S.O 3® H2® 3538.0 33810 3® HS® 401 33881 3437 0 3® w® 4577 0 44141 2S1 H2® 221® wii 42171 3® mie 21841 Ί1® 311 HMH M710 330 159 mu O) 0 01.0 SU 3U mu 1 USE ®o «4 40 W 2003.0 51784^ 40 mu 4752 0 13310 WO O 0 w.o §20 61.0 ÓB MÜ ww 75® 0 38® mx §064 0<S 0 6® HS ssw σ 4CO WO 41· Λ / Η22£ OU uo SU O 9 eao WÓ o Η3Χ «0 ¿4®. or WW14 O; H30D S2 or: « 0 O® US O A w 3^6 C 730 3?$ mw 4»0 -U's; WO 37.0 1320 b r ? 6316.0 35® «40 2340 Meo WO O .0 W24 O OK 4010 S4G WO FO mu. -SU W14.S 520 44® ®24 -SU SOSO,ó UU.5 43.0 H®« 40 7S0 mo O XX amo W4 43® -imo ime mo «0 HS -30® MS34 2WU 410 OS ΙΌ ®!8 1 §W6C 35.6 111O W l-U® v O ®U §3230 4W10 UPO 20 H41A WI0 63624 35 O «0 W4® 9648 3 IÍW ®O 106 0 mine O' 0 76030 840 W3 3 αηαηηη / ζζηζ / Ε / γι 160 - 83 ISO W!C 7S«® 37® 57220 WO W® 54® 3962 0 W® 9223® 53® 33510 8589® 54® «3 4085.0 8051 3779® 54® Table 8.5: Hydrogen bonds with bond lengths (Á ) and angles (degrees °) © **** H A Distance (0Ή) Distance (H..A) Distance (D„.A) Angle (O-H..A) «10D . . N4® 3 3390 2.3300 3 '084 140.® 0.88® 2..WÜ 2®§9(3} 157.® di®-O® aso xim 150.® 0133 - HW8... «24 3 09 2.4730 3.341® 153.® €W®Wé <»Q1W 0« 2.» 2®W; W.®0 EYE 2 m® 01W- hMA .. «® 3.99® 2..41^} 2 1®.® oiw®m ...wi 2.W 3.2«'® 125.® C®-H< 0402 3» 2.5600 2:W) 105.® he1VH1W....W ow 2.3900 2.758® 101;® 0113-®« 0120 asW 2 .W 3 220® 129.® 0114®®... QW 01« 2 3500 2.730® 192 00 C«2-®2SV.. W 2.W 3. «0® «5® 0 «2 ®128 W w 2 20 3 03X5: 14700 .049 10960 2W 3.366® 0203 - H2Q8, K2S4 0« 2.5500 3.33*® 141.® 0394B26C. .£» 2.4300 2®24{3) 105.® C2W.H21B...N2® ¢.9900 2.5100 2.377® W1 GO 0211 - H21C... 022® 0.9900 2.5900 3.273(3} 128.® 0212-Η21Ξ. ..0219 1.0000 2.4500 2.9 / 4(3) 112.® C213-H21G... F218 0.9900 2.3900 2.782(3) 193.® 0229-4224...0308 OJ8O0 2.3900 3.308® 155® 022 2-H22B.. .0300 0.00 2.5200 3..274B 137.® οηοηηη / 77ηζ / Ε / γι 161 C226 - H22D... F328 10090 2.52Q0 3.109(3} 117.00 C226-H22D... O22S 1W 2.3400 3.077(3) 129.00 C3» - H3G8... N324 0.9500 2.4400 3.354(3) 16 100 0304 - H30C ... 0338 0.9500 2.4200 2.812» 105.00 C310»31A ...0308 0.0900 2.3100 2.668(3) 100.00 5 0311-H31D.»316 0.9900 2.3200 2.692(3) 10100 G312»31E ...0319 1.0000 2.4900 3.040(3) 114.00 C314»31L„ 0202 0.0900 2.5000 3.304(3) 145.00 C3U »31 l·.. »08 0.0200 2.5100 2.0(3} W2.0Ü C317 - H3'U ... F22 S 0.9800 2.4900 3.342(3) 146.00 C32§ »32A... 0233 3 9830 2.4400 3.334(3) 15100 0322 »32B. ..0208 0)9530 2.4700 3.246(3} 138.00 0326 »32 0 ...008A 1.0003 2.3700 3.267(5} 140.00 C326 »32Ü . . 0320 1,0000 2.5200 3,050(3) 113.08 0404 »40C... oosa 0.9500 2.2600 2.728(4} 108.06 C4O4 - H40C.... 0068 0.9500 2.4800 2,838(4) 102.00 C404 »430 . .. 0320 2 5200 3,300(3) 139.00 0422-»428... 0108 0.00 2.4000 3,222(3) 144.00 15 C426 »420 .„0420 IOS 24600 3.1 §4(4} 133 «i The representation of the crystalline structures is given in figures 14 and 15; The figures were generated with the PLATON program (Spek, A. L. J. Appl. Cryst. 2003 36, 7-13) for both structures. The 1-491 molecule contains a sulfur atom that allows the absolute configuration to be determined, using high-resolution data collection (performed at low temperature). The Flack parameter x is calculated based on the anomalous dispersion method. Gives the absolute structure, provided an estimated standard deviation is reached 162 enough. According to the theory, the expected values ​​of Flack's 908-915). The results are as follows: Considering configuration C115: R; C215: R; C315: R; C415: R; the Flack parameter is 0.003 (13), which unambiguously demonstrated this absolute configuration for the D form of 1-491. A simulated diffraction pattern was produced from the experimentally determined crystal structure of the D form at low temperature (Figure 16). An experimental powder diffraction pattern can be compared to one of these theoretical patterns to demonstrate the nature of the crystal structure. Minor differences (if any) can be explained by preferential orientations in the powder. A 1-491 polymorphic crystal structure of form D was determined by single crystal X-ray diffraction, allowing the generation of reference powder standards. Example 9. Myosin Activation Assay The ability of small molecule agents to activate the enzymatic activity of bovine cardiac myosin was evaluated using a biochemical assay that couples the release of ADR (adenosine diphosphate) from cardiac myosin to an enzyme coupling system consisting of 163 pyruvate kinase and lactate dehydrogenase (PK / LDH) and monitoring the decrease in NADH absorbance (at 340 nm) 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 came from the heart of a bovine in the form of skinless myofibrils. Before testing the sticky molecule agents, bovine myofibrils were assessed for their responsiveness to calcium and the calcium concentration reaching 50% (pCa50 or pCa = ~6) or <5% (pCa = 10) was chosen. ) of activation of the myofibril system as an end condition to assess the activation activity of small molecule agents. All enzyme activity was measured in a buffer containing 12 mM PIPES (piperazin-N,Ν'-bis(2-ethanesulfonic acid), 2 mM magnesium chloride pH 6.8 (PM12 buffer). were 1 mg / ml bovine cardiac myofibrils, 0.4 mM PK / LDH, 50 uM ATP, 0.1 mg / ml BSA (bovine serum albumin), 10 ppm antifoam, 2 mM BME, 0.5 mM NADH, 1.5 mM PEP at the concentration of Desired free calcium required to achieve 50% or <5% myofibril activation. A series of dilutions of the compound in DMSO was created 164 such that the desired final concentration of compound would be achieved in a 100 μΐ volume with a fixed DMSO concentration of 3.3% (v / v). Typically, 1 μΐ of the dilution series was added to a 384-well plate to achieve a dose response of 10 points. After the addition of 14 μΐ of a solution containing bovine cardiac myofibrils, PK / LDH, and a calcium solution (which achieved the desired activation), the enzymatic reaction was started with the addition of 15 μΐ of a solution containing ATP, PEP and NADH. The progress of the reaction was followed in a PerkinElmer Envision plate reader at room temperature using clear bottom plates. The plate reader was set to read absorbance at 340 nm in kinetic mode for 15 minutes. Data were recorded as the slope of the absorbance response with respect to time. The slopes of the absorbance response as a function of time were normalized to slopes on the plate containing DMSO. This normalized velocity was then plotted against small molecule concentration and the data were fitted to a four-parameter fit using EXCEL XLfit. The concentration at which the total response increases by twenty or fifty percent is reported as AC20 or AC50. Any agent that did not achieve the percent activation corresponding to the highest concentration tested is reported as having an AC20 or AC50 greater than the highest concentration tested. 165 (i.e. ACso > 50 uM). Table 9. Myosin activation of selected compounds' Compound 1-491 Myosin activation Form A +++ a+++ represents an AC20 myosin activation value < 2 μΜ; ++ represents the myosin AC20 activation value from 2 μΜ to 5 μΜ; + represents the myosin activation value AC20 > 5 μΜ. Example 10. Cardiomyocyte contractility test. Contractility of ventricular myocytes from adult rats is determined by edge detection with a lonOptix contractility system. Aliquots of myocytes are placed in Tyrode buffer (137 mM NaCl, 3.7 mM KC1, 20.5 mM Mg®, 21.5 mM CaCl, 4 mM HEPES, 11 mM glucose) in a perfusion chamber (Series 20 RC-27NE; Warner Instruments), are allowed to adhere to the coverslip and then perfused with Tyrode buffer at 37 °C. Myocytes are stimulated in a row at 1Hz and 10V. Only myocytes with clear streaks, at rest before stimulation, with a cell length of 120-180 microns, a basal fractional shortening equal to 3-8% of the cell length and a contraction speed greater than 100 microns per second were used for contractility experiments. To determine the response to the compounds, myocytes are 166 perfuse first for 60 seconds with Tyrode's buffer followed by 5 minutes of the compound and a 140-second wash with Tyrode's buffer. Data is continuously recorded using lonOptix software. Contractility data are analyzed using lonwizard software (lonOptix). For each cell, 10-20 contractility transients were averaged and compared in basal (no compound) and compound-treated conditions. The activity of the compound is measured by the effects on fractional shortening (FS), where fractional shortening is the ratio of the maximum cell length in contraction divided by the basal cell length normalized to 100% for a non-cell. treated. Table 10. Activation of cardiomyocyte contraction by selected compoundsa Compound 1491 Activity at 10 uM Activity at 3.0 uM Activity at 1.0 uM Form A+++ a+ represents activation of fractional shortening <20% above baseline. ++ represents fractional shortening activation values ​​of 20% to 50% above baseline. +++ represents fractional shortening activation values ​​greater than 50% above baseline. Although the above invention has been described with 167 some detail by way of illustration and example for purposes of clarity of understanding, one skilled in the art will appreciate that certain changes and modifications may be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. Where there is a conflict between this application and a reference provided herein, this application shall prevail. Equivalents and scope In the claims articles such as one, one and the may mean one or more than one unless otherwise indicated or otherwise evident from the context. Claims or descriptions that include or among one or more members of a group are considered satisfied if one, more than one, or all members of the group are present in, used in, or otherwise relevant to a particular product or process unless otherwise indicated or otherwise apparent from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant with a given product or process. The invention includes embodiments in which more than one, or all members of the group are present in, are employed 168 in, or are otherwise relevant to a given product or process. Furthermore, the invention encompasses all variations, combinations and permutations in which one or more limitations, elements, clauses and descriptive terms of one or more of the enumerated claims are introduced into another claim. For example, any claim that depends on another claim may be modified to include one or more limitations found in any other claim that depends on the same initial claim. Where elements are present as lists, for example in Markush group format, each subgroup of the elements is also described, and any element(s) can be removed from the group. It should be understood that, in general, when the invention, or aspects of the invention, are known to comprise particular elements and / or features, certain embodiments of the invention or aspects of the invention essentially consist of or consist of these types of elements and / or characteristics. For the purposes of simplicity, these modalities have not been expressly established in haec verba in this document. It is also noted that the terms it comprises and contains are intended to be open and allow the inclusion of additional elements or stages. When intervals are given, the extremes are included. Furthermore, unless otherwise indicated or otherwise evident from the 169 context and the understanding of a person skilled in the art, the values ​​that are expressed as intervals can assume any specific value or sub-interval within the intervals established in the different embodiments of the description, to the tenth of the unit of the lower limit of the interval, unless the context clearly indicates otherwise. This application relates to various filed patents, published patent applications, journal articles, and other publications, all incorporated herein by reference. If there is a conflict between any of the incorporated references and this description, the description takes control. Furthermore, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from one or more of the claims. Since such embodiments are considered known to one skilled in the art, they may be excluded even if the exclusion is not explicitly stated herein. Any particular embodiment of the invention may be excluded from any claim, for any reason, whether or not related to the existence of the prior art. Those skilled in the art will recognize, or will be able to determine using no more than experimentation 170 routine, many equivalent to the specific modalities described in this document. The scope of the present embodiments described herein is not intended to be limited to the foregoing description, but rather is as set forth in the attached 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 present invention, as defined in the following clauses. CLAUSES 1. A composition comprising a polymorph of formula (1-491): where the polymorph is form A. 2. The composition of clause 1, wherein the polymorph has a chiral purity of at least 99.9%. 3. The composition of any of clauses 1 to 2, wherein the polymorph is characterized by at least one of: to. an 16.32, 17.72, 19.26, 19.86, 19.94, 20.44, 21.68, 21.90, 22.04, 22.60, 23.78, 171 26.16, 26.36, 26.58, 27.24 and 28.04 degrees; either b. a DSC thermogram showing an endotherm at approximately 181-200 °C. 4. The composition of any of clauses 1 to 3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα that has peaks expressed in degrees 2-theta ± 0.2° in each one of 10.98, 15.78, 16.08, 20.44, 23.78 and 26.58 degrees. 5. The composition of any of clauses 1 to 3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα that has peaks expressed in degrees 2-theta ± 0.2° in each one of 6.62, 10.98, 16.08, 23.78 and 26.58 degrees. 6. The composition of any of clauses 1 to 3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα that has peaks expressed in degrees 2-theta ± 0.2° in each one of 15.78, 16.08 and 23.78 degrees. 7. The composition of any of clauses 1 to 3, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα that has peaks expressed in degrees 2-theta + 0.2° in each one of 6.62, 15.78, 16.08 and 26.58 degrees. 8. The composition of any of clauses 1 to 3, where the polymorph is characterized by a pattern of 172 9. The composition of any of clauses 1 to 3, wherein the polymorph is characterized by an X-ray powder diffraction pattern essentially identical to that shown in Figure 1A. 10. The composition of any of clauses 1 to 3, wherein the polymorph is characterized by an X-ray powder diffraction pattern essentially identical to that shown in Figure IB. 11. The composition of any of clauses 1 to 10, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα without peaks expressed in 2-theta squares ± 0.05° in each from 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 degrees. 12. The composition of any of clauses 1 to 10, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα without peaks expressed in degrees 2-theta ± 0.05° at 24.40 a 24.80 degrees. 13. The composition of any of clauses 1 to 10, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with 173 Cu-Κα without peaks expressed in degrees 2-theta ± 0.05° in each of 0 to 6.00, 11.40 to 12.60 and 24.40 to 24.80 degrees. 14. The composition of any of clauses 1 to 10, wherein the polymorph is characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα without peaks expressed in degrees 2-theta ± 0.05° at 11.40 a 12.60 degrees. 15. The composition of any of clauses 1 to 14, wherein the polymorph is characterized by an onset of melting of approximately 181 °C. 16. The composition of any of clauses 1 to 15, wherein the polymorph is characterized by a melting point of 191 °C ± 2 °C. 17. The composition of any of clauses 1 to 16, wherein the polymorph is characterized by a DSC thermogram essentially the same as that shown in Figure 2. 18. The composition of any of clauses 1 to 17, where the polymorph has a triclinic crystal system and a space group of P1. 19. The composition of any of clauses 1 to 18, where the polymorph has unit cell dimensions of a = 6.403 Á, b = 11.343 Á, c = 13.507 Á, a = 81.91°, β = 85.73° and y = 85.18 °. 20. The composition of any of clauses 1 to 19, wherein the composition is substantially free of 174 other forms of 1-491. 21. The composition of any of clauses 1 to 20, wherein the composition is substantially free of Form D of 1-491. 22. The composition of any of clauses 1 to 21, wherein the composition is substantially free of amorphous I491. 23. A composition comprising Form A of I491, wherein the composition is greater than or equal to 99.5% by weight of Form A of 1-491. 24. A composition comprising Form A of I491, wherein the molar ratio between the amount of Form A of 1-491 and the sum of the amounts of other forms is equal to or greater than 80:20. 25. The composition of clause 24, wherein the molar ratio of the amount of form A of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 90:10. 26. The composition of any of clauses 24-25, wherein the molar ratio of the quantity of form A of 1-491 with respect to the sum of the quantities of other forms is equal to or greater than 95:5. 27. The composition of any of clauses 24-26, wherein the molar ratio of the quantity of form A of 1-491 with respect to the sum of the quantities of other 175 ways is equal to or greater than 99:1. 28. The composition of any of clauses 24-27, wherein the molar ratio of the quantity of form A of 1-491 with respect to the sum of the quantities of other forms is equal to or greater than 99.5:0.5. 29. A composition comprising Form A of I491 and Form D of 1-491, wherein the molar ratio of the amount of Form A of 1-491 to Form D of 1-491 is equal to or greater at 80:20. 30. The composition of clause 29, wherein the molar ratio of the amount of form A of 1-491 to form D of 1-491 is equal to or greater than 90:10. 31. The composition of any of clauses 29-30, wherein the molar ratio of the amount of form A of 1-491 with respect to form D of 1-491 is equal to or greater than 95:5. 32. The composition of any of clauses 29-31, wherein the molar ratio of the amount of form A of 1-491 with respect to form D of 1-491 is equal to or greater than 99:1. 33. A pharmaceutical composition comprising an effective amount of the composition of any of clauses 1 to 32 and a pharmaceutically acceptable carrier. 176 34. A polymorph of the formula (1-491): where the polymorph is the B form of 1-491. 35. The polymorph of clause 34, wherein the polymorph has a chiral purity of at least 99.9%. 36. The polymorph of any of clauses 34 to 35, characterized by at least one of: to. a powder 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; either b. a DSC thermogram showing endotherm at approximately 170-185°C. 37. The polymorph of any of clauses 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having peaks expressed in degrees 2-theta ± 0.2° in each of 15.42, 16.28 , 19.02, 20.70 and 26.88 degrees. 38. The polymorph of any of clauses 34 to 36, characterized by an X-ray diffraction pattern in 177 powder obtained by irradiation with Cu-Κα having peaks expressed in degrees 2-theta ± 0.2° at each of 15.42, 20.70 and 26.88 degrees. 39. The polymorph of any of clauses 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having peaks expressed in degrees 2-theta ± 0.2° in each of 7.88, 10.20 , 20.70 and 26.88 degrees. 40. The polymorph of any of clauses 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having peaks expressed in degrees 2-theta ± 0.2° in each of 7.32, 7.88 , 10.20 and 18.48 degrees. 41. The polymorph of any of clauses 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having peaks expressed in degrees 2-theta ± 0.2° in each of 7.32, 16.28 and 26.88 degrees. 42. The polymorph of any of clauses 34 to 36, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα having peaks expressed in degrees 2-theta ± 0.2° in each of 7.88, 15.42 , 17.70 and 21.56 degrees. 43. The polymorph of any of clauses 34 to 42, characterized by an X-ray diffraction pattern in 178 powder essentially identical to that shown in Figure 6A. 44. The polymorph of any of clauses 34 to 42, characterized by an X-ray powder diffraction pattern essentially identical to that shown in Figure 6B. 45. The polymorph of any of clauses 34 to 44, characterized by a powder 8.15 a.m. to 9.00 a.m. 46. ​​The polymorph of any of clauses 34 to 44, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα without peaks expressed in 2-theta ± 0.05° at 0 to 6.80 qrads. 47. The polymorph of any of clauses 34 to 44, characterized by an X-ray powder diffraction pattern obtained by irradiation with Cu-Κα without peaks expressed in 2-theta qrades ± 0.05° at 8.15 to 9.00 degrees. 48. The polymorph of any of clauses 34 to 47, characterized by a melting onset of approximately 170 °C. 49. The polymorph of any of clauses 34 to 48, characterized by a melting point of 178 °C ± 2 °C. 50. The polymorph of any of the clauses 34 179 to 49, characterized by a second endotherm at approximately 185-200 °C. 51. The polymorph of any of clauses 34 to 50, characterized by a second melting point of 192.7 °C ± 2 °C. 52. The polymorph of any of clauses 34 to 51, characterized by a DSC thermogram essentially identical to that shown in Figure 4. 53. The polymorph of any of clauses 34 to 52, wherein the polymorph has a triclinic crystal system and a space group of P1. 54. The polymorph of any of clauses 34 to 53, where the polymorph has unit cell dimensions of a = 11.926 Á, b = 13.239 Á, c = 13.511 Á, a = 65.40°, β = 80.08° and y = 89.18 °. 55. A composition comprising the polymorph of any of clauses 34 to 54, wherein the composition is substantially free of other forms of 1-491. 56. A composition comprising the polymorph of any of clauses 34 to 55, wherein the composition is substantially free of form A and / or D of 1-491. 57. A composition comprising the polymorph of any of clauses 34 to 56, wherein the composition is substantially free of amorphous 1-491. 58. A composition comprising form B of I 180 491, where the composition is greater than or equal to 99.5% by weight of form B of 1-491. 59. A composition comprising form B of I491, wherein the molar ratio of the amount of form B of 1-491 to the sum of the amounts of other forms is equal to or greater than 80:20. 60. The composition of clause 59, wherein the molar ratio of the amount of form B of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 90:10. 61. The composition of any of clauses 59-60, wherein the molar ratio of the quantity of form B of 1-491 with respect to the sum of the quantities of other forms is equal to or greater than 95:5. 62. The composition of any of clauses 59-61, wherein the molar ratio of the quantity of form B of 1-491 with respect to the sum of the quantities of other forms is equal to or greater than 99:1. 63. The composition of any of clauses 59-62, wherein the molar ratio of the quantity of form B of 1-491 with respect to the sum of the quantities of other forms is equal to or greater than 99.5:0.5. 64. A pharmaceutical composition comprising an effective amount of the polymorph of any of clauses 34 to 54 or a composition of any of clauses 55 to 181 αηαηηη / ζζηζ / Ε / γίΛΐ 63, and a pharmaceutically acceptable vehicle. 65. A pharmaceutical composition, comprising: a. Form A of 1-491; and b. one or more diluents. 5 6 6 . The pharmaceutical composition of clause 65, which further comprises: a. Form A of 1-491; b. one or more diluents; and c. a disintegrant. 10 67 . The pharmaceutical composition of clause 66, which further comprises: a. Form A of 1-491; b. one or more diluents; c. a disintegrant; and 15 d. a binder. 68. The pharmaceutical composition of clause 67, which further comprises: a. Form A of 1-491; b. one or more diluents; 20 c. a disintegrant; d. a binder; and e. a lubricant. 69. The pharmaceutical composition of any of clauses 65 to 68, wherein one or more diluents are selected from the group consisting of calcium carbonate, carbonate 182 sodium, 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, sugar powder and mixtures of any of the above diluents. 70. The pharmaceutical composition of any of clauses 66 to 68, 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. 71. The pharmaceutical compositions of any of clauses 67 to 68, wherein the binder is selected from the group consisting of starch (for example, corn starch and starch paste), gelatin, sugars (for example, sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, carboxymethyl cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium silicate and 183 aluminum (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. 72. The pharmaceutical composition of clause 68, wherein the lubricant is selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, benzoate sodium, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate and mixtures of any of the above lubricants. 73. A pharmaceutical composition comprising form A of 1-491, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropylmethylcellulose and magnesium stearate. 74. A method of 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 a polymorph of any of clauses 34-54, or a pharmaceutically acceptable salt thereof, a composition of any of clauses 1-32 and 55-63, or a pharmaceutical composition of any of clauses 33, 64-73 and 113- 184 121. 75. A method according to clause 74, wherein the polymorph or pharmaceutical composition is administered in an intravenous formulation for the treatment of acute heart failure. 76. A method of treating systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a polymorph of any of clauses 34-54, or a pharmaceutically acceptable salt thereof, a composition of any of clauses 1 -32 and 55-63, or a pharmaceutical composition of any of clauses 33, 64-73 and 113-121. 77. The method of clause 76, where the polymorph is the B form of 1-491. 78. The method of clause 76, where the polymorph is form A of 1-491. 79. A method of treating HFrEF, comprising administering to a subject in need thereof an effective amount of a polymorph of any of clauses 34-54, or a pharmaceutically acceptable salt thereof, a composition of any of clauses 1- 32 and 55-63, or a pharmaceutical composition of any of clauses 33, 64-73 and 113121. 80. The method of clause 79, where the polymorph is the Β form of 1-491. 185 81. The method of clause 79, where the polymorph is the Ά form of 1-491. 82. A method of treating dilated cardiomyopathy (DCM), comprising administering to a subject in need thereof an effective amount of a polymorph of any of clauses 34-54, or a pharmaceutically acceptable salt thereof, a composition of any of clauses 1-32 and 55-63, or a pharmaceutical composition of any of clauses 33, 64-73 and 113-121. 83. The method of clause 82, where the polymorph is the B form of 1-491. 84. The method of clause 82, where the polymorph is form A of 1-491. 85. A method of treating a disease characterized by left ventricular systolic dysfunction or symptoms or reduced exercise capacity due to systolic dysfunction; in conjunction with therapies for treating heart failure, comprising administering to a subject in need thereof an effective amount of a polymorph of any of clauses 34-54, or a pharmaceutically acceptable salt thereof, a composition of any of clauses 1 -32 and 55-63, or a pharmaceutical composition of any of clauses 33, 64-73 and 113121. 86. The method of clause 85, where the 186 polymorph is the B form of 1-491. 87. The method of clause 85, where the polymorph is form A of 1-491. 88. The method of any of clauses 74 to 87, combined with therapies that slow the progression of heart failure by down-regulating neurohormonal stimulation of the heart and attempting to prevent cardiac remodeling (for example, ACE inhibitors, receptor blockers (ARB), β-blockers, aldosterone receptor antagonists or neural endopeptidase inhibitors). 89. The method of any of clauses 74 to 87, combined with therapies that improve cardiac function by stimulating cardiac contractility (for example, positive inotropic agents, such as the β adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). 90. The method of any of clauses 74 to 87, combined with therapies that reduce cardiac preload (for example, diuretics, such as furosemide). 91. The method of any of clauses 74 to 87, combined with afterload-reducing therapies (vasodilators of any class, including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, inhibitors of renin, or muscle myosin modulators 187 smooth) . 92. The method of any of clauses 74 to 87, wherein such compound is administered in combination with a beta blocker. 93. A polymorph of 1-491, wherein the polymorph is Form A of 1-491, prepared by a process comprising the steps of recrystallizing 1-491 from a mixture of methanol and water by slow evaporation. 94. A polymorph of 1-491, wherein the polymorph is Form B of 1-491, prepared by a process comprising the steps of recrystallizing 1-491 from a mixture of acetonitrile and water. 95. The polymorph of clause 94, wherein the process is carried out at a temperature selected from 25 °C to 70 °C. 96. The polymorph of any of the clauses 94- 95, where the process is carried out at room temperature. 97. A polymorph of 1-491, wherein the polymorph is Form B of 1-491, prepared by a process comprising the steps of recrystallizing 1-491 from a suspension of 1-491 in a solvent selected from 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. 98. The polymorph of clause 97, where the 188 solvent is ethanol, methanol, ethyl acetate, or methyl isobutyl ketone. 99. The polymorph of clause 98, where the process is carried out at a selected temperature of 20°C to 50°C. 100. The polymorph of any of clauses 98- 99, where the process is carried out at room temperature. 101. A composition comprising a polymorph of formula (1-491): where the polymorph is the A form of 1-491, where the A form of 1-491 is characterized by a triclinic crystal system and a Pl space group. 102. The composition of clause 101, where the polymorph has unit cell dimensions of a = 6.403 Á, b = 11.343 Á, c = 13.507 a, a = 81.91°, β = 85.73° and y = 85.18°. 103. A polymorph of the formula (1-491): where the polymorph is form B of 1-491, where form B of 1-491 is characterized by a triclinic crystal system and a 189 space group of Pl. 104. The polymorph of clause 103, where the polymorph has unit cell dimensions of a = 11.926 Á, b = 13.239 k, c = 13.511 Á, a = 65.40°, β = 80.08° and y = 89.18°. 105. The composition of any of clauses 1 and 101-102, wherein the composition comprises more than or equal to 75% by weight of Form A of 1-491. 106. The composition of any of clauses 1 and 101-102, wherein the composition comprises more than or equal to 85% by weight of Form A of 1-491. 107. The composition of any of clauses 1 and 101-102, wherein the composition comprises more than or equal to 90% by weight of Form A of 1-491. 108. The composition of any of clauses 1 and 101-102, wherein the composition comprises more than or equal to 95% by weight of Form A of 1-491. 109. The composition of any of clauses 1 and 101-102, wherein the composition comprises more than or equal to 98% by weight of Form A of 1-491. 110. The composition of any of clauses 1 and 101-102, wherein the composition comprises more than or equal to 99% by weight of Form A of 1-491. 111. The composition of any of clauses 1 and 101-102, wherein the composition comprises more than or equal to 99.5% by weight of Form A of 1-491. 190 112. The composition of any of the clauses 1 and 101-102, wherein the composition comprises more than or equal to: 99.9% by weight 113 . of Form A of 1-491. A pharmaceutical composition, which 5 a. Form B of 1-491; and b. one or more diluents. 114. The pharmaceutical composition of s clause 113, which further comprises: a. Form B of 1-491; 10 b. one or more diluents; and c. a disintegrant. 115. The pharmaceutical composition of clause 114, which further comprises: a. Form B of 1-491; 15 b. one or more diluents; c. a disintegrant; and d. a binder. 116. The pharmaceutical composition of clause 115, which further includes: 20 a. Form B of 1-491; b. one or more diluents; c. a disintegrant; d. a binder; and e. a lubricant. 25 117 . The pharmaceutical composition of any of the 191 clauses 113 to 116, wherein one or more diluents is 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. 118. The pharmaceutical composition of any of clauses 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. 119. The pharmaceutical compositions of any of clauses 115 to 116, wherein the binder is selected from the group consisting of starch (for example, corn starch and starch paste), gelatin, sugars (for example, sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, carboxymethyl cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, αηαηηη / ζζηζ / Ε / γίΛΐ 192 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. 120. The pharmaceutical composition of clause 116, wherein the lubricant is selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, benzoate sodium, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate and mixtures of any of the above lubricants. 121. A pharmaceutical composition comprising form B of 1-491, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropylmethylcellulose and magnesium stearate. It is stated that in relation to this date, the best method known to the applicant to put the aforementioned invention into practice is the one that is clear from the present description of the invention. 193

Claims

Having described the invention as above, the following claims are claimed as property:

1. A composition, characterized in that it comprises a polymorph of the formula (1-491): wherein the polymorph is form A.

2. The composition according to claim 1, characterized in that the polymorph has a chiral purity of at least 99.9%.

3. The composition according to any of claims 1 to 2, characterized in that the polymorph is characterized by at least one of: a. a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having two or more peaks expressed in 2-theta ± 0.2° degrees and selected from 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 degrees; or b. A DSC thermogram showing endothermy at approximately 181-200 °C.

4. The composition according to any of claims 1 to 3, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2-theta ± 0.2° degrees at each of 10.98, 15.78, 16.08, 20.44, 23.78 and 26.58 degrees.

5. The composition according to any of claims 1 to 3, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2-theta ± 0.2° degrees at each of 6.62, 10.98, 16.08, 23.78 and 26.58 degrees.

6. The composition according to any of claims 1 to 3, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2-theta ± 0.2° degrees at each of 15.78, 16.08 and 23.78 degrees.

7. The composition according to any of claims 1 to 3, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2-theta ± 0.2° degrees at each of 6.62, 15.78, 16.08 and 26.58 degrees.

8. The composition according to any of claims 1 to 3, characterized in that the polymorph 195 is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2-theta ± 0.2° degrees at each of 6.62, 17.72, 23.78 and 26.58 degrees.

9. The composition according to any of claims 1 to 3, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern essentially identical to that shown in Figure IA.

10. The composition according to any of claims 1 to 3, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern essentially identical to that shown in Figure IB.

11. The composition according to any of claims 1 to 10, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα without peaks expressed in 2-theta ± 0.05° degrees at each 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 degrees.

12. The composition according to any of claims 1 to 10, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα without peaks expressed in degrees 2-theta ± 0.05° at 24.40 to 24.80 degrees.

13. The composition according to any of claims 1 to 10, characterized in that the polymorph 196 is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα without peaks expressed in 2-theta ± 0.05° degrees at each of 0 to 6.00, 11.40 to 12.60 and 24.40 to 24.80 degrees.

14. The composition according to any of claims 1 to 10, characterized in that the polymorph is characterized by a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα without peaks expressed in degrees 2-theta ± 0.05° to 11.40 to 12.60 degrees.

15. The composition according to any of claims 1 to 14, characterized in that the polymorph is characterized by a melting start of approximately 181 °C.

16. The composition according to any of claims 1 to 15, characterized in that the polymorph is characterized by a melting point of 191 °C ± 2 °C.

17. The composition according to any of claims 1 to 16, characterized in that the polymorph is characterized by a DSC thermogram essentially the same as that shown in Figure 2.

18. The composition according to any of claims 1 to 17, characterized in that the polymorph has a triclinic crystal system and a space group of P1.

19. The composition according to any of claims 1 to 18, characterized in that the polymorph has unit cell dimensions of a = 6.403 a, b = 11.343 A, c = 13.507 A, a = 81.91°, β = 85.73° and γ = 85.18°.

20. The composition according to any of claims 1 to 19, characterized in that it is substantially free from other forms of 1-491.

21. The composition according to any of claims 1 to 20, characterized in that it is substantially free of form D of 1-491.

22. The composition according to any of claims 1 to 21, characterized in that it is substantially free of amorphous 1-491.

23. A composition comprising form A of I491, characterized in that it is greater than or equal to 99.5% by weight of form A of I-491.

24. A composition comprising form A of I491, characterized in that the molar ratio between the amount of form A of I491 and the sum of the amounts of other forms is equal to or greater than 80:

20.

25. The composition according to claim 24, characterized in that the molar ratio of the amount of form A of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 90:

10.

26. The composition according to any of claims 24-25, characterized in that the molar ratio of the amount of form A of 1-491 to the sum of the amounts of other forms is equal to or greater than 95:

5.

27. The composition according to any of claims 24-26, characterized in that the molar ratio of the amount of form A of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 99:

1.

28. The composition according to any of claims 24-27, characterized in that the molar ratio of the amount of form A of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 99.5:0.

5.

29. A composition comprising form A of I491 and form D of 1-491, characterized in that the molar ratio of the amount of form A of 1-491 to form D of 1-491 is equal to or greater than 80:

20.

30. The composition according to claim 29, characterized in that the molar ratio of the amount of form A of 1-491 with respect to form D of 1-491 is equal to or greater than 90:

10.

31. The composition according to any of claims 29-30, characterized in that the molar ratio of the amount of form A of 1-491 to form D of 1-491 is equal to or greater than 95:

5. 199 32. The composition according to any of claims 29-31, characterized in that the molar ratio of the amount of form A of 1-491 to form D of 1-491 is equal to or greater than 99:

1.

33. A pharmaceutical composition, characterized in that it comprises an effective amount of the composition according to any one of claims 1 to 32 and a pharmaceutically acceptable vehicle.

34. A polymorph of the formula (1-491): characterized in that it is form B of 1-491.

35. The polymorph according to claim 34, characterized in that it has a chiral purity of at least 99.9%.

36. The polymorph according to any of claims 34 to 35, characterized in that it has at least one of: c. a powder X-ray diffraction pattern obtained by irradiation with a Cu-Kα pattern having two or more peaks expressed in 2-theta ± 0.2° degrees and selected from 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; 200 or d. A DSC thermogram showing endothermy at approximately 170-185 °C.

37. The polymorph according to any of claims 34 to 36, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2theta ± 0.2° degrees at each of 15.42, 16.28, 19.02, 20.70 and 26.88 degrees.

38. The polymorph according to any of claims 34 to 36, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2theta ± 0.2° degrees at each of 15.42, 20.70 and 26.88 degrees.

39. The polymorph according to any of claims 34 to 36, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2theta ± 0.2° degrees at each of 7.88, 10.20, 20.70 and 26.88 degrees.

40. The polymorph according to any of claims 34 to 36, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2theta ± 0.2° degrees at each of 7.32, 7.88, 10.20 and 18.48 degrees.

41. The polymorph according to any of claims 34 to 36, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2theta ± 0.2° degrees at each of 7.32, 16.28 and 26.88 degrees.

42. The polymorph according to any of claims 34 to 36, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα having peaks expressed in 2theta ± 0.2° degrees at each of 7.88, 15.42, 17.70 and 21.56 degrees.

43. The polymorph according to any of claims 34 to 42, characterized in that it has a powder X-ray diffraction pattern essentially identical to that shown in Figure 6A.

44. The polymorph according to any of claims 34 to 42, characterized in that it has a powder X-ray diffraction pattern essentially identical to that shown in Figure 6B.

45. The polymorph according to any of claims 34 to 44, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα without peaks expressed in 2-theta ± 0.05° degrees at each of 0 to 6.80 and 8.15 to 9.00 degrees.

46. ​​The polymorph according to any of claims 34 to 44, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα without peaks expressed in degrees 2-theta ± 0.05° to 0 to 6.80 degrees.

47. The polymorph according to any of claims 34 to 44, characterized in that it has a powder X-ray diffraction pattern obtained by irradiation with Cu-Kα without peaks expressed in degrees 2-theta ± 0.05° to 8.15 to 9.00 degrees.

48. The polymorph according to any of claims 34 to 47, characterized in that it has a melting start of approximately 170 °C.

49. The polymorph according to any of claims 34 to 48, characterized in that it has a melting point of 178 °C ± 2 °C.

50. The polymorph according to any of claims 34 to 49, characterized in that it has a second endothermy at approximately 185-200 °C.

51. The polymorph according to any of claims 34 to 50, characterized in that it has a second melting point of 192.7 °C ± 2 °C.

52. The polymorph according to any of claims 34 to 51, characterized in that it has a DSC thermogram essentially identical to that shown in figure 4.

53. The polymorph according to any of claims 34 to 52, characterized in that it has a 203 triclinic crystal system and a P1 space group.

54. The polymorph according to any of claims 34 to 53, characterized in that it has unit cell dimensions of a = 11.926 A, b = 13.239 A, c = 13.511 A, a = 65.40°, β = 80.08° and γ = 89.18°.

55. A composition comprising the polymorph according to any of claims 34 to 54, characterized in that it is substantially free of other forms of 1-491.

56. A composition comprising the polymorph according to any of claims 34 to 55, characterized in that it is substantially free of form A and / or D of 1-491.

57. A composition comprising the polymorph according to any of claims 34 to 56, characterized in that it is substantially free of amorphous 1-491.

58. A composition comprising form B of I491, characterized in that it is greater than or equal to 99.5% by weight of form B of I-491.

59. A composition comprising form B of I491, characterized in that the molar ratio of the amount of form B of I491 to the sum of the amounts of other forms is equal to or greater than 80:

20.

60. The composition according to claim 59, characterized in that the molar ratio of the amount of form B of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 90:

10.

61. The composition according to any of claims 59-60, characterized in that the molar ratio of the amount of form B of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 95:

5.

62. The composition according to any of claims 59-61, characterized in that the molar ratio of the amount of form B of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 99:

1.

63. The composition according to any of claims 59-62, characterized in that the molar ratio of the amount of form B of 1-491 with respect to the sum of the amounts of other forms is equal to or greater than 99.5:0.

5.

64. A pharmaceutical composition, characterized in that it comprises an effective amount of the polymorph according to any of claims 34 to 54 or a composition according to any of claims 55 to 63, and a pharmaceutically acceptable vehicle.

65. A pharmaceutical composition, characterized in that it comprises: a. the form Ά of 1-491; and 205 b. one or more diluents.

6. The pharmaceutical composition according to claim a, b, one, c, and 65, characterized in that it comprises form A of 1-491; or more diluents; and a disintegrant. It further comprises:

67. The pharmaceutical composition according to claim a, b, c, d, and 66, characterized in that form A of 1-491; or more diluents; disintegrant; and binder. It further comprises:

68. The pharmaceutical composition according to claim a. to 67, characterized in that form A of 1-491; further comprises: b. one or more diluents; c. a disintegrant; d. a binder; and e. a lubricant.

69. The pharmaceutical composition according to any of claims 65 to 68, characterized in that 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, dried starch, corn starch, powdered sugar, and mixtures of any of the foregoing diluents.

70. The pharmaceutical composition according to any one of claims 66 to 68, characterized in that 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 foregoing disintegrants.

71. The pharmaceutical composition according to any one of claims 67 to 68, characterized in that the binder is selected from the group consisting of starch (e.g., maize starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum®), and larch 207 arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, acid silica, polymethacrylates, waxes, water, alcohol and mixtures of any of the above binders.

72. The pharmaceutical composition according to claim 68, characterized in that the lubricant is selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures of any of the foregoing lubricants.

73. A pharmaceutical composition, characterized in that it comprises form A of 1-491, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose and magnesium stearate.

74. A polymorph according to any of claims 34-54, or a pharmaceutically acceptable salt thereof, a composition according to any of claims 1-32 and 55-63, or a pharmaceutical composition according to any of claims 33, 64-73 and 113-121, for use in the treatment of a selected disease from the group consisting of systolic dysfunction, diastolic dysfunction, HFrEF, HFpEF, chronic heart failure and acute heart failure.

75. A polymorph, a composition, or a pharmaceutical composition for use according to claim 74, wherein the polymorph or the pharmaceutical composition is administered in an intravenous formulation for the treatment of acute heart failure.

76. A polymorph according to any of claims 34-54, or a pharmaceutically acceptable salt thereof, a composition according to any of claims 1-32 and 55-63, or a pharmaceutical composition according to any of claims 33, 64-73 and 113-121, for use in the treatment of systolic dysfunction.

77. The polymorph, composition, or pharmaceutical composition for use in accordance with claim 76, wherein the polymorph is form B of 1-491.

78. The polymorph, composition, or pharmaceutical composition for use in accordance with claim 76, wherein the polymorph is form A of 1-491.

79. A polymorph according to any of claims 34-54, or a pharmaceutically acceptable salt thereof, a composition according to any of claims 1-32 and 55-63, or a pharmaceutical composition according to any of claims 33, 64-73 and 113-121, for use in the treatment of HFrEF.

80. The polymorph, composition, or pharmaceutical composition for use in accordance with claim 79, wherein the polymorph is form B of 1-491.

81. The polymorph, composition, or pharmaceutical composition for use in accordance with claim 79, wherein the polymorph is form A of 1-491.

82. A polymorph according to any of claims 34-54, or a pharmaceutically acceptable salt thereof, a composition according to any of claims 1-32 and 55-63, or a pharmaceutical composition according to any of claims 33, 64-73 and 113-121, for use in the treatment of dilated cardiomyopathy (DCM).

83. The polymorph, composition, or pharmaceutical composition for use in accordance with claim 82, wherein the polymorph is form B of 1-491.

84. The polymorph, composition, or pharmaceutical composition for use in accordance with claim 82, wherein the polymorph is form A of 1-491.

85. A polymorph according to any of claims 34-54, or a pharmaceutically acceptable salt thereof, a composition according to any of claims 1-32 and 55-63, or a pharmaceutical composition according to any of claims 33, 64-73 and 113-121, for use in the treatment of a disease characterized by left ventricular systolic dysfunction or symptoms or reduced exercise capacity due to systolic dysfunction; in conjunction with therapies intended to treat heart failure.

86. The polymorph, composition, or pharmaceutical composition for use in accordance with claim 85, wherein the polymorph is form B of 1-491.

87. The polymorph, composition, or pharmaceutical composition for use in accordance with claim 85, wherein the polymorph is form A of 1-491.

88. The polymorph, composition, or pharmaceutical composition for use according to any of claims 74 to 87, which is combined with therapies that slow the progression of heart failure by downregulating the neurohormonal stimulation of the heart and attempting to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neural endopeptidase inhibitors).

89. The polymorph, composition or pharmaceutical composition for use according to any of claims 74 to 87, which is combined with therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropic agents such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone).

90. The polymorph, composition or pharmaceutical composition for use in accordance with any of claims 74 to 87, which is combined with therapies that reduce cardiac preload (e.g., diuretics such as furosemide).

91. The polymorph, composition, or pharmaceutical composition for use according to any of claims 74 to 87, which is combined with afterload-reducing therapies (vasodilators of any class, including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators).

92. The polymorph, composition or pharmaceutical composition for use in accordance with any of claims 74 to 87, wherein the compound is administered in combination with a beta-blocker.

93. A polymorph of 1-491, characterized in that it is form A of 1-491, prepared by a process comprising the steps of recrystallizing 1-491 from a mixture of methanol and water by slow evaporation.

94. A polymorph of 1-491, characterized in that it is form B of 1-491, prepared by a process comprising the steps of recrystallizing 1-491 in a mixture of acetonitrile and water.

95. The polymorph according to claim 94, characterized in that the process is carried out at a selected temperature from 25 °C to 70 °C.

96. The polymorph according to any of claims 94-95, characterized in that the process is carried out at room temperature.

97. A polymorph of 1-491, characterized in that it is form B of 1-491, prepared by a process comprising the steps of recrystallizing 1-491 from a suspension of 1-491 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.

98. The polymorph according to claim 97, characterized in that the solvent is ethanol, methanol, ethyl acetate or methyl isobutyl ketone.

99. The polymorph according to claim 98, characterized in that the process is carried out at a selected temperature of 20 °C to 50 °C.

100. The polymorph according to any of claims 98-99, characterized in that the process is carried out at room temperature.

101. A composition comprising a polymorph of formula (1-491): characterized in that it is form A of 1-491, wherein form A of 1-491 is characterized by a triclinic crystal system and a Pl space group.

102. The composition according to claim 101, characterized in that the polymorph has unit cell dimensions of a = 6.403 Å, b = 11.343 Å, c = 13.507 Å, a = 81.91°, β = 85.73° and y = 85.18°.

103. A polymorph of formula (1-491): characterized in that it is the B form of 1-491, wherein the B form of 1-491 is characterized by a triclinic crystal system and a Pl space group.

104. The polymorph according to claim 103, characterized in that it has unit cell dimensions of a = 11.926 a, b = 13.239 a, c = 13.511 Á, a 214 = 65.40°, β = 80.08° and γ = 89.18°.

105. The composition according to any of claims 1 and 101-102, characterized in that it comprises more than or equal to 75% by weight of form A of I491.

106. The composition according to any of claims 1 and 101-102, characterized in that it comprises more than or equal to 85% by weight of form A of I491.

107. The composition according to any of claims 1 and 101-102, characterized in that it comprises more than or equal to 90% by weight of form A of I491.

108. The composition according to any of claims 1 and 101-102, characterized in that it comprises more than or equal to 95% by weight of form A of I491.

109. The composition according to any of claims 1 and 101-102, characterized in that it comprises more than or equal to 98% by weight of form A of I491.

110. The composition according to any of claims 1 and 101-102, characterized in that it comprises more than or equal to 99% by weight of form A of I-491.215 111. The composition according to any of claims 1 and 101-102, characterized in that it comprises more than or equal to 99.5% by weight of form A of I491.

112. The composition according to any of claims 1 and 101-102, characterized in that it comprises more than or equal to 99.9% by weight of form A of I491.

113. A pharmaceutical composition, characterized in that it comprises: a. form B of 1-491; and b. one or more diluents.

114. The pharmaceutical composition according to claim 113, characterized in that it further comprises: a. form B of 1-491; b. one or more diluents; and c. a disintegrant.

115. The pharmaceutical composition according to claim 114, characterized in that it further comprises: a. form B of 1-491; b. one or more diluents; c. a disintegrant; and d. a binder.

116. The pharmaceutical composition according to claim 115, characterized in that it further comprises: 216 a. form B of 1-491; b. one or more diluents; c. a disintegrant; d. a binder; and e. a lubricant.

117. The pharmaceutical composition according to any one of claims 113 to 116, characterized in that 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, dried starch, corn starch, powdered sugar, and mixtures of any of the foregoing diluents.

118. The pharmaceutical composition according to any one of claims 114 to 116, characterized in that the disintegrant is selected from the group consisting of aqar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, croscarmellose sodium, crospovidone, sodium starch glycolate, and mixtures of any one of the foregoing disintegrants.

119. The pharmaceutical composition according to any one of claims 115 to 116, characterized in that the binder is selected from the group consisting of starch (for example, maize starch and starch paste), 217 gelatin, sugars (for example, sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (for example, gum arabic, sodium alginate, Irish moss extract, panwar gum, ghatti gum, isapol husk mucilage, 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 salts of calcium, silicic acid, polymethacrylates, waxes, water, alcohol and mixtures of any of the above binders.

120. The pharmaceutical composition according to claim 116, characterized in that the lubricant is selected from a group consisting of magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures of any of the foregoing lubricants.

121. A pharmaceutical composition, characterized in that it comprises form B of 1-491, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropyl methylcellulose, and magnesium stearate. 218