Polymorphism of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

Abstract

To provide polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.SOLUTION: Provided herein are polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, compositions thereof, methods of preparation thereof, and methods of their uses. In another aspect, provided herein are methods of treating heart disease in a subject in need thereof using polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 875,350, filed July 17, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Field Provided herein are polymorphs of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, compositions thereof, methods for their preparation, and methods for their use. [Background technology]

[0003] background The cardiac sarcomere is composed of a meshwork of contractile structural proteins that regulates myocardial function. Components of the cardiac sarcomere present targets for treating various cardiac diseases and conditions, for example, by modulating systolic and diastolic function, increasing contractility or promoting complete relaxation, respectively. The force and velocity of myocardial contraction are major determinants of organ function and are modulated by the cyclic interaction of actin and myosin. Regulation of actin-myosin binding is mediated by the meshwork of myofilament regulatory proteins and intracellular Ca. 2+ The troponin complex and tropomyosin are thin filament proteins that govern the availability of actin-binding sites, while essential and regulatory light chains, as well as myosin-binding protein C, modulate the positioning and mechanical properties of myosin.

[0004] Abnormalities in cardiac sarcomeres have been identified as a driving factor in various cardiac diseases and conditions, such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Mutations in sarcomere proteins cause disease by rendering the myocardium either "hyper" or "hypo" contractile. Modulators of cardiac sarcomeres can be used to restore balance in contractility and halt or reverse the disease process.

[0005] Current agents that target cardiac sarcomeres, such as inotropes (drugs that increase cardiac contractility), have poor selectivity for cardiac tissue and have recognized adverse effects that limit their use. These adverse effects include increased cytosolic Ca in inotropically stimulated myocardium. ++ These include increased energy expenditure, exacerbated relaxation abnormalities, and cellular damage caused by potential arrhythmogenic side effects that may result from elevated cyclic AMP levels. Given the limitations of current medications, new approaches are needed to improve cardiac function in HCM and HFpEF.

[0006] There remains a significant need for drugs that can utilize novel mechanisms of action and have better outcomes in terms of symptom relief, safety, and patient mortality over both the short and long term. New drugs with improved therapeutic indices over current drugs provide a means to achieve these clinical outcomes. Drug selectivity toward cardiac sarcomeres (e.g., by targeting cardiac myosin) has been identified as a key means to achieve this improved therapeutic index. (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is a selective allosteric inhibitor of cardiac myosin that has little to no effect on smooth muscle myosin. Advantages of this compound include a broader therapeutic index, less impact on cardiac relaxation, better pharmacokinetics, and better safety, thus offering a potential treatment for cardiac diseases and conditions.

[0007] To translate a drug candidate, such as (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, into a usable pharmaceutical product, it can be important to understand whether the drug candidate has polymorphic forms and the relative stability and interconversion of these forms under conditions likely to be encountered during large-scale production, transportation, storage, and preparation prior to use. The ability to controllably produce stable polymorphs through a robust manufacturing process can be important for regulatory approval and marketing. The large-scale production process for high-purity (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide can be improved by using specific polymorphic forms. Therefore, there is a need for various novel crystalline forms of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with varying chemical and physical stability, as well as formulations and uses thereof. Summary of the Invention [Means for solving the problem]

[0008] overview In one aspect, provided herein are polymorphs of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0009] In another aspect, provided herein are methods for preparing polymorphs of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0010] In another aspect, provided herein are compositions containing a polymorph of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, as described herein.

[0011] In another aspect, provided herein is a method of treating cardiac disease using a polymorph of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide in a subject in need thereof. [Brief explanation of the drawings]

[0012] [Figure 1A] FIG. 1A shows the experimental X-ray powder diffraction (XRPD) pattern of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0013] [Figure 1B] FIG. 1B shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0014] [Figure 1C] FIG. 1C shows a dynamic vapor sorption (DVS) graph of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0015] [Figure 2A]FIG. 2A shows the experimental XRPD pattern of polymorphic Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0016] [Figure 2B] FIG. 2B shows DSC and TGA graphs of polymorphic Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0017] [Figure 3A] FIG. 3A shows an experimental XRPD pattern of a mixture of polymorphic Forms I and III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0018] [Figure 3B] FIG. 3B shows DSC and TGA graphs of a mixture of polymorphic forms I and III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0019] [Figure 4A] FIG. 4A shows the experimental XRPD pattern of polymorphic Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0020] [Figure 4B]FIG. 4B shows DSC and TGA graphs of polymorphic Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0021] [Figure 5] Figure 5 shows the experimental XRPD pattern and two modeled patterns of polymorphic Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (top to bottom: modeled at 223 K, modeled at 273 K, experimental).

[0022] [Figure 6A] FIG. 6A shows two experimental XRPD patterns of polymorphic Form VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide: (a) on top, XRPD of Form VI measured before drying; and (b) on bottom, XRPD of Form VI measured after drying (oven, vacuum, 25° C. for 24 hours).

[0023] [Figure 6B] Figures 6B and 6C show TGA graphs of polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 6B shows the weight loss of an oven-dried sample of Form VI (oven, vacuum, overnight at 25°C) over the range of 25 to 300°C. Figure 6C shows the TGA plot over the range of 25 to 300°C for a sample of Form VI that was oven-dried (oven, vacuum, overnight at 25°C) and further heated at 150°C before thermogravimetric analysis. [Figure 6C]Figures 6B and 6C show TGA graphs of polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 6B shows the weight loss of an oven-dried sample of Form VI (oven, vacuum, overnight at 25°C) over the range of 25 to 300°C. Figure 6C shows the TGA plot over the range of 25 to 300°C for a sample of Form VI that was oven-dried (oven, vacuum, overnight at 25°C) and further heated at 150°C before thermogravimetric analysis.

[0024] [Figure 6D] Figures 6D and 6E show DSC graphs of polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 6D shows the DSC plot of an oven-dried sample of Form VI (oven, vacuum, overnight at 25°C) over the range of 25 to 300°C. Figure 6E shows the DSC plot of a sample of Form VI that was oven-dried (oven, vacuum, overnight at 25°C) and further heated at 150°C before thermogravimetric analysis over the range of 25 to 300°C. [Figure 6E] Figures 6D and 6E show DSC graphs of polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 6D shows the DSC plot of an oven-dried sample of Form VI (oven, vacuum, overnight at 25°C) over the range of 25 to 300°C. Figure 6E shows the DSC plot of a sample of Form VI that was oven-dried (oven, vacuum, overnight at 25°C) and further heated at 150°C before thermogravimetric analysis over the range of 25 to 300°C. DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description definition As used in this specification and in the appended claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise.

[0026] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in conjunction with a dose, amount, or weight percent of a component of a composition or dosage form, refer to a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art as producing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent that is within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified dose, amount, or weight percent.

[0027] As used herein, the term "polymorph" or "polymorphic form" refers to a crystalline form of a compound. Different polymorphs may have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum, as a result of, for example, the arrangement or conformation of molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters, such as storage stability, compressibility, density (which is important in formulation and product manufacturing), and dissolution rate (which is an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differences in oxidation such that a dosage form composed of one polymorph discolors more quickly than one composed of another), mechanical changes (e.g., tablets crumble during storage when a kinetically favored polymorph converts to a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more susceptible to degradation at high humidity). In extreme cases, some polymorphic transitions can result in a lack of efficacy or, in other extreme cases, toxicity as a result of differences in solubility / dissolution. Furthermore, the physical properties of the crystalline form can be important in processing; for example, one polymorph may be more likely to form solvates or may be difficult to filter and wash free of impurities (e.g., particle shape and size distribution may differ between polymorphs).

[0028] As used herein, a "therapeutically effective amount" refers to an amount that produces the desired pharmacological and / or physiological effect on a condition. This effect can be prophylactic, in that it completely or partially prevents the condition or symptoms, and / or therapeutic, in that it partially or completely cures the condition and / or adverse effects that can result from the condition.

[0029] As used herein, the term "pharmaceutically acceptable carrier" and its cognates refer to adjuvants, binders, diluents, etc., known to those skilled in the art, suitable for administration to an individual (e.g., mammalian or non-mammalian). Combinations of two or more carriers are also contemplated. The pharmaceutically acceptable carriers described herein, and any additional components, should be compatible for use with the intended route of administration (e.g., oral, parenteral) for a particular dosage form, as would be recognized by one skilled in the art.

[0030] The terms "treat," "treating," and "treatment" are intended to include alleviating or abrogating a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or slowing the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. Often, the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder, or condition.

[0031] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., in reference to a mammalian subject, e.g., a human.

[0032] As used herein, the term "substantially as shown in," when referring to, for example, an XRPD pattern, a DSC graph, a TGA graph, or a GVS graph, includes patterns or graphs that are not necessarily identical to those depicted herein, but that, when examined by one of ordinary skill in the art, fall within experimental error or variation.

[0033] In some embodiments, the term "substantially pure" means that the polymorphic form contains less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 1% impurities by weight. In other embodiments, "substantially pure" refers to a material that is free of impurities. Impurities can include, for example, by-products or unreacted reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.

[0034] As used herein, the term "substantially free" means that a composition comprising a polymorphic form contains less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the indicated substance(s). polymorphism

[0035] In one aspect, a compound having the structure shown below [ka] Provided herein are polymorphs of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, which can have properties suitable for medical or pharmaceutical use, such as bioavailability and stability under certain conditions.

[0036] Polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide can offer bioavailability and stability advantages and may be suitable for use as an active agent in pharmaceutical compositions. Changes in the crystalline structure of a drug substance can affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.) of the pharmaceutical product. Such changes can affect the method of preparation or formulation of the pharmaceutical composition in various dosage or delivery forms, e.g., solid oral dosage forms, including tablets and capsules. Compared with other forms, such as non-crystalline or amorphous forms, polymorphs can provide desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Thus, polymorphs of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide can provide advantages in the manufacturing process of the active agent, in improving the stability or storage of a drug product form of the active agent, or in having suitable bioavailability and / or stability as the active agent.

[0037] It has been found that the use of certain conditions, such as different solvents and / or temperatures, produces various polymorphs of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, including polymorphic Forms I through VI described herein, which may exhibit one or more advantageous characteristics described herein. Methods for preparing the polymorphs described herein, and characterization of these polymorphs, are described in more detail below. Form I

[0038] In some embodiments, (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H- Provided herein is polymorphic Form I of pyrazole-4-carboxamide.

[0039] In some embodiments, Form I has an XRPD pattern substantially as shown in Figure 1A. The 2-theta angles and relative peak intensities that may be observed for Form I using XRPD are shown in Table 1. [Table 1]

[0040] In some embodiments, polymorph Form I has an XRPD pattern substantially as shown in FIG. 1A or presented in Table 1, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles, including the peaks with the highest intensities. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting practices, and the instrument and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for polymorph Form I, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0041] In some embodiments, polymorphic Form I is 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 14.9±0.2, 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 23.6±0.2, 24.6±0.2, 25.6±0.2, 26.6±0.2, 27.6±0.2, 28.6±0.2, 29.6±0.2, 30.6±0.2, 31.6±0.2, 32.6±0.2, 33.6±0.2, 34.6±0.2, 35.6± ±0.2, 22.8±0.2, 23.2±0.2, 23.9±0.2, 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2 and 39.8±0.2 degrees two-theta angle. In some embodiments, polymorphic Form I has an XRPD pattern comprising peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 degrees 2-theta. In some embodiments, polymorphic Form I has an XRPD pattern comprising peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees 2-theta. It should be understood that additional peaks may be observed in XRPD patterns other than those shown in FIG. 1 or presented in Table 1 due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0042] In some embodiments, Form I has a differential scanning calorimeter (DSC) graph substantially as shown in Figure IB. In some embodiments, Form I is characterized as having an endothermic onset at about 199°C, as determined by DSC. In some embodiments, Form I is characterized as having an endothermic onset at 199±2°C (e.g., 199±1.9°C, 199±1.8°C, 199±1.7°C, 199±1.6°C, 199±1.5°C, 199±1.4°C, 199±1.3°C, 192±1.2°C, 199±1, 199±0.9°C, 199±0.8°C, 199±0.7°C, 199±0.6°C, 199±0.5°C, 199±0.4°C, 199±0.3°C, 199±0.2°C, or 199±0.1°C), as determined by DSC.

[0043] In some embodiments, Form I has a TGA graph substantially as shown in Figure 1B.

[0044] In some embodiments, Form I has a DVS graph substantially as shown in Figure 1C.

[0045] In some embodiments of Form I, at least one, at least two, at least three, at least four, at least five, or all of the following (a)-(f) are true: (a) Form I has an XRPD pattern containing peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees 2-theta angles; an XRPD pattern containing peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 degrees 2-theta angles; or an XRPD pattern containing peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 14.9±0.2 degrees 2-theta angles. , having XRPD patterns containing peaks at 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0.2, 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2 and 39.8±0.2 degrees 2-theta angle; (b) Form I has an XRPD pattern substantially as shown in Figure 1A; (c) Form I has a DSC graph substantially as shown in Figure 1B; (d) Form I is characterized as having an endothermic onset at about 199°C as determined by DSC; (e) Form I has a TGA graph substantially as shown in Figure 1B; and (f) Form I has a DVS graph substantially as shown in Figure 1C. Form II

[0046] In some embodiments, provided herein is polymorphic Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0047] In some embodiments, Form II has an XRPD pattern substantially as shown in Figure 2 A. The 2 theta angles and relative peak intensities that can be observed for Form II using XRPD are shown in Table 2. [Table 2]

[0048] In some embodiments, polymorph Form II has an XRPD pattern substantially as shown in FIG. 2A or presented in Table 2, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles, including the peaks with the highest intensities. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting practices, and the instrument and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for polymorph Form II, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0049] In some embodiments, polymorph Form II is 3.7±0.2, 7.4±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2 degrees 2-theta. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees 2-theta. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees 2-theta. It should be understood that additional peaks may be observed in an XRPD pattern other than that shown in FIG. 2A or presented in Table 2 due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0050] In some embodiments, Form II has a DSC graph substantially as shown in Figure 2B. In some embodiments, Form II is characterized as having an endothermic onset at about 199°C, as determined by DSC. In some embodiments, Form II is characterized as having an endothermic onset at about 199±2°C (e.g., 199±1.9°C, 199±1.8°C, 199±1.7°C, 199±1.6°C, 199±1.5°C, 199±1.4°C, 199±1.3°C, 199±1.2°C, 199±1, 199±0.9°C, 199±0.8°C, 199±0.7°C, 199±0.6°C, 199±0.5°C, 199±0.4°C, 199±0.3°C, 199±0.2°C, or 199±0.1°C), as determined by DSC.

[0051] In some embodiments, Form II has a TGA graph substantially as shown in Figure 2B.

[0052] In some embodiments of Form II, at least one, at least two, at least three, at least four, or all of the following (a)-(e) are true: (a) Form II has an XRPD pattern containing peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees 2-theta angles; an XRPD pattern containing peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees 2-theta angles; or an XRPD pattern containing peaks at 3.7±0.2, 7.4±0.2, 9.8± having XRPD patterns containing peaks at 0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2 degrees 2-theta angle; (b) Form II has an XRPD pattern substantially as shown in Figure 2A; (c) Form II has a DSC graph substantially as shown in Figure 2B; (d) Form II is characterized as having an onset of a melting endotherm at about 199°C as determined by DSC; and (e) Form II has a TGA graph substantially as shown in Figure 2B. Form III

[0053] In some embodiments, provided herein is polymorphic Form III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0054] In some embodiments, the mixture of Forms I and III has an XRPD pattern substantially as shown in Figure 3A. The observable 2 theta angles and relative peak intensities are shown in Table 3. [Table 3]

[0055] In some embodiments, polymorphic Form III has an XRPD pattern comprising peaks at 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees 2-theta angles. In some embodiments, polymorphic Form III has an XRPD pattern comprising peaks at 9.6±0.2, 10.9±0.2, 14.5±0.2, 15.8±0.2, and 18.1±0.2 degrees 2-theta angles. In some embodiments, polymorphic Form III has an XRPD pattern comprising peaks at 9.6±0.2, 10.9±0.2, 14.5±0.2, 15.8±0.2, 18.1±0.2, and 20.2±0.2 degrees 2-theta angles. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting practices, and the instrument and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In embodiments, the peak assignments listed herein, including for polymorph Form III, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees two-theta.

[0056] In some embodiments, the mixture of polymorphic Forms I and III has a DSC graph substantially as shown in Figure 3B.

[0057] In some embodiments, the mixture of polymorphic Forms I and III has a TGA graph substantially as shown in Figure 3B. Form IV

[0058] In some embodiments, provided herein is polymorphic Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0059] In some embodiments, Form IV has an XRPD pattern substantially as shown in Figure 4A. The 2-theta angles and relative peak intensities that can be observed for Form IV using XRPD are shown in Table 4. [Table 4]

[0060] In some embodiments, polymorph Form IV has at least two, at least three, at least four, at least five, at least six, or at least two of the highest intensity lines at 2 theta angles in an XRPD pattern substantially as shown in FIG. 4A or presented in Table 4. Each of the polymorphs has an XRPD pattern exhibiting at least seven, at least eight, at least nine, or at least ten peaks. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting practices, and the instrument and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for polymorph Form IV, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees two-theta.

[0061] In some embodiments, polymorphic Form IV is 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2, 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2 and 39.8±0.2 degrees 2-theta angles. In some embodiments, polymorphic Form IV has an XRPD pattern comprising peaks at 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, and 24.8±0.2 degrees 2-theta. In some embodiments, polymorphic Form IV has an XRPD pattern comprising peaks at 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees 2-theta. It should be understood that additional peaks may be observed in an XRPD pattern other than that shown in FIG. 4A or presented in Table 4 due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0062] In some embodiments, Form IV has a DSC graph substantially as shown in Figure 4B. In some embodiments, Form IV is characterized as having an endothermic onset at about 200°C, as determined by DSC. In some embodiments, Form IV is characterized as having a melting endothermic onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C), as determined by DSC.

[0063] In some embodiments, Form IV has a TGA graph substantially as shown in Figure 4B.

[0064] In some embodiments of Form IV, at least one, at least two, at least three, at least four, or all of the following (a)-(e) are true: (a) Form IV has an XRPD pattern containing peaks at 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2 and 24.4±0.2 degrees 2-theta angle; 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2 and 24 XRPD patterns containing peaks at 2-theta angles of 0.8±0.2 degrees; or 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2 .2, 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28.0±0.2. 2, having an XRPD pattern containing peaks at 28.6±0.2, 29.0±0.2, 30.0±0.2, 30.5±0.2, 30.8±0.2, 31.0±0.2, 31.4±0.2, 33.8±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, and 39.8±0.2 degrees 2-theta angle; (b) Form IV has an XRPD pattern substantially as shown in Figure 4A; (c) Form IV has a DSC graph substantially as shown in Figure 4B; (d) Form IV is characterized as having an onset of a melting endotherm at about 200°C as determined by DSC; and (e) Form IV has a TGA graph substantially as shown in Figure 4B. Form V

[0065] In some embodiments, provided herein is polymorphic Form V of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0066] In some embodiments, Form V has an XRPD pattern substantially as shown in Figure 5. The 2-theta angles and relative peak intensities that may be observed for Form V using XRPD are shown in Table 5. [Table 5-1] [Table 5-2]

[0067] In some embodiments, polymorph Form V has an XRPD pattern substantially as shown in Figure 5 or presented in Table 5, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles, including the peaks with the highest intensities. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting practices, and the instrument and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for polymorph Form V, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0068] In some embodiments, polymorphic Form V is 5.7±0.2, 8.3±0.2, 11.5±0.2, 13.8±0.2, 15.5±0.2, 15.8±0.2, 16.3±0.2, 16.6±0.2, 17.2±0.2, 17.8±0.2, 18.5±0.2, 18.9±0.2, 19.1±0.2, 19.8±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2. 2, 21.6±0.2, 23.0±0.2, 23.1±0.2, 23.3±0.2, 24.0±0.2, 24.2±0.2, 24.3±0.2, 24.6±0.2, 24.7±0.2, 25.2±0.2, 25.6±0.2, 26.7±0.2, 27.1±0.2, 27.3±0.2, 27.5±0.2, 27.9±0.2, 28.1±0.2, 28.4±0.2, 28.9±0.2, 29 .2±0.2, 29.7±0.2, 29.8±0.2, 29.9±0.2, 30.4±0.2, 30.6±0.2, 31.1±0.2, 31.3±0.2, 31.5±0.2, 32.0±0.2, 32.9±0.2, 33.0±0.2, 33.2±0.2, 33.5±0.2, 34.4±0.2, 34.6±0.2, 34.9±0.2, 35.3±0.2, 35.7±0.2, 36.0±0.2 0.2, 36.2±0.2, 36.5±0.2, 36.6±0.2, 37.0±0.2, 37.1±0.2, 37.5±0.2, 37.8±0.2, 37.9±0.2, 38.3±0.2, 38.4±0.2, 38.7±0.2, 38.8±0.2, 39.3±0.2, 39.4±0.2, 39.6±0.2 and 39.9±0.2 degrees 2-theta angle. In some embodiments, polymorphic Form V is 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21 In some embodiments, polymorphic Form V has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees two-theta. In some embodiments, polymorphic Form V has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees two-theta. In some embodiments, polymorphic Form V has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees 2-theta. It should be understood that additional peaks may be observed in an XRPD pattern other than that shown in Figure 5 or presented in Table 5 due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0069] In some embodiments of Form V, at least one or both of the following are true: (a) Form V has an XRPD pattern containing peaks at 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees 2-theta; an XRPD pattern containing peaks at 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees 2-theta; or 5.7±0.2 , having an XRPD pattern containing peaks at 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2 and 31.1±0.2 degrees 2-theta angle; and (b) Form V has an XRPD pattern substantially as shown in FIG. Form VI

[0070] In some embodiments, provided herein is polymorphic Form VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0071] In some embodiments, Form VI has an XRPD pattern substantially as shown in Figure 6 A. The 2-theta angles and relative peak intensities that can be observed for Form VI using XRPD are shown in Table 6. [Table 6-1] [Table 6-2]

[0072] In some embodiments, polymorph Form VI has an XRPD pattern substantially as shown in FIG. 6A or presented in Table 6, exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten peaks at 2-theta angles, including the peaks with the highest intensities. It should be understood that relative intensities may vary depending on several factors, including sample preparation, mounting practices, and the instrument and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein, including for polymorph Form VI, may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[0073] In some embodiments, polymorphic Form VI may be at least one of the following: 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 21.9±0.2, 2 2.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0.2, 27.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0.2, 29.6±0.2, 2 In some embodiments, polymorphic Form VI has an XRPD pattern comprising peaks at 9.9±0.2, 30.4±0.2, 30.9±0.2, 31.6±0.2, 32.2±0.2, 32.6±0.2, 33.1±0.2, 33.3±0.2, 34.5±0.2, 35.0±0.2, 35.5±0.2, and 38.5±0.2 degrees 2-theta. In some embodiments, polymorphic Form VI has an XRPD pattern comprising peaks at 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees 2-theta. In some embodiments, polymorphic Form VI has an XRPD pattern comprising peaks at 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees 2-theta. It should be understood that additional peaks may be observed in an XRPD pattern other than that shown in Figure 6A or presented in Table 6 due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0074] In some embodiments, Form VI has a TGA graph substantially as shown in Figure 6B or a TGA graph substantially as shown in Figure 6C. In some embodiments, Form VI exhibits a weight loss of about 2% ± 0.5% between 25°C and 200°C as determined by TGA. Indicates a small amount.

[0075] In some embodiments, Form VI has a DSC graph substantially as shown in Figure 6D or a DSC graph substantially as shown in Figure 6E. In some embodiments, Form VI is characterized as having an onset of a melting endotherm at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C), as determined by DSC. In some embodiments, Form VI can be obtained at a temperature of about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C). , 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C or 200±0.1°C), and the endotherm begins at approximately 115±2°C (e.g., 115±1.9°C, 115±1.8°C, 115±1.7°C, 115±1.6°C, 115±1.5°C, 115±1.4°C, 115±1.3°C, 115±1.2°C, 115±1.3°C). Onset of fever at 5±1°C, 115±0.9°C, 115±0.8°C, 115±0.7°C, 115±0.6°C, 115±0.5°C, 115±0.4°C, 115±0.3°C, 115±0.2°C, or 115±0.1°C), or at approximately 41±2°C (e.g., 41±1.9°C, 41±1.8°C, 41±1.7°C, 41±1.6°C, and characterized as having an endothermic onset at 41±1.5°C, 41±1.4°C, 41±1.3°C, 41±1.2°C, 41±1, 41±0.9°C, 41±0.8°C, 41±0.7°C, 41±0.6°C, 41±0.5°C, 41±0.4°C, 41±0.3°C, 41±0.2°C or 41±0.1°C), or a combination thereof.

[0076] In some embodiments of Form VI, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) are true: (a) Form VI has an XRPD pattern containing peaks at 10.6 ± 0.2, 12.1 ± 0.2, 15.0 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2 degrees 2-theta; (b) Form VI has an XRPD pattern containing peaks at 5.4 ± 0.2, 5.9 ± 0.2, 8.1 ± 0.2, 9.6 ± 0.2, 10.6 ± 0.2, 12.1 ± 0.2, 14.0 ± 0.2, 15.0 ± 0.2, 16.1 ± 0.2, and 17.8 ± 0.2 degrees 2-theta. XRPD patterns including; or 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17. 8±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 21.9±0.2, 22.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0.2, 27.4±0.2 having an XRPD pattern containing peaks at 2-theta angles of .6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0.2, 29.6±0.2, 29.9±0.2, 30.4±0.2, 30.9±0.2, 31.6±0.2, 32.2±0.2, 32.6±0.2, 33.1±0.2, 33.3±0.2, 34.5±0.2, 35.0±0.2, 35.5±0.2, and 38.5±0.2 degrees; (b) Form VI has an XRPD pattern substantially as shown in Figure 6A; (c) Form VI has a TGA graph substantially as shown in Figure 6B or Figure 6C; (d) Form VI exhibits a melting point of approximately 2% ± 0.5°C between 25°C and 200°C as determined by TGA. % weight loss; (e) Form VI has a DSC graph substantially as shown in Figure 6D or Figure 6E; and (f) Form IV is characterized as having an onset of a melting endotherm at about 200°C as determined by DSC; and (g) Form VI is characterized as having an endotherm onset at about 200° C., an exotherm onset at about 115° C., or an endotherm onset at about 41° C., or any combination thereof, as determined by DSC. composition

[0077] Also provided herein are compositions containing a polymorph described herein, e.g., Form I, Form II, Form III, Form IV, Form V, Form VI, or a mixture thereof. In some embodiments, the composition contains Form I. In some embodiments, the composition contains Form II. In some embodiments, the composition contains Form III. In some embodiments, the composition contains a mixture of Forms I and III. In some embodiments, the composition contains Form IV. In some embodiments, the composition contains Form V. In some embodiments, the composition contains Form VI. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0078] In some embodiments, provided are compositions containing (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide Form I. In some embodiments, the compositions are substantially free of at least one, at least two, at least three, or all of polymorphic Forms II-VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0079] In some embodiments of compositions containing Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is Form I. In some embodiments of compositions containing Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, the amount of Form I is at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, or at least about 60% by weight of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. , at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% is present in Form I.

[0080] In some embodiments, a composition is provided containing Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms I, III, IV, V, and VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0081] In some embodiments of a composition containing Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is Form II. In some embodiments of compositions containing Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, the amount of Form II is at least about 0.1%, at least about 0.3%, by weight of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. %, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least 99.9% is in Form II.

[0082] In some embodiments, a composition is provided containing Form III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms I, II, IV, V, and VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. ... The compound is substantially free of salts of (1-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0083] In some embodiments of a composition containing Form III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is Form III. In some embodiments of compositions containing Form III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, the amount of Form III is at least about 0.1%, at least about 0.3%, by weight of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. %, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least 99.9% is in Form III.

[0084] In some embodiments, a composition is provided containing Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms I-III, V, and VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0085] In some embodiments of a composition containing Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is Form IV. (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide In some embodiments of compositions containing Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, by weight, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% is present in Form IV.

[0086] In some embodiments, compositions are provided containing Form I and Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, Form I and Form IV are present in a weight ratio of 99:1, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, or 1:99. In some embodiments, the weight ratio of Form I:Form IV is between 90:10 and 99:1. In some embodiments of compositions containing Form I and Form IV, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is Form I. In some embodiments of a composition containing Form I and Form IV, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form I.In some embodiments of compositions containing Form I and Form IV, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is Form IV. In some embodiments of a composition containing Form I and Form IV, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form IV.

[0087] In some embodiments, provided are compositions containing (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide Form V. In some embodiments, the compositions are substantially free of at least one, at least two, at least three, or all of polymorphic Forms I-IV and VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0088] In some embodiments of the composition containing Form V of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is Form V. In some embodiments of compositions containing Form V of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, the amount of Form V is at least about 0.1%, at least about 0.3%, by weight of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. %, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least 99.9% is in Form V.

[0089] In some embodiments, a composition is provided containing Form VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms I-V of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0090] (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2, In some embodiments of a composition containing Form VI of 3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition is Form VI. In some embodiments of compositions containing Form VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, the amount of Form VI is at least about 0.1%, at least about 0.3%, by weight of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. %, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or at least 99.9% is present in Form VI.

[0091] In some embodiments, tablets or capsules are provided containing one or more of the polymorphic forms described herein (e.g., Forms I, II, III, IV, V, VI, or mixtures thereof) and one or more pharmaceutically acceptable carriers. In some embodiments, tablets or capsules are provided containing substantially pure polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, tablets or capsules are provided containing substantially pure polymorphic Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, there are provided tablets or capsules containing substantially pure polymorphic Form III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, there are provided tablets or capsules containing substantially pure polymorphic Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, there is provided a tablet or capsule containing substantially pure polymorphic Form V of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers.In some embodiments, there is provided a tablet or capsule containing substantially pure polymorphic Form VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. Preparation method Form I

[0092] In some embodiments, there is provided a method for preparing polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, comprising: (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent; and (2) cooling the mixture of step (1) or removing the solvent from the mixture of step (1). In some embodiments, the solvent comprises an alcohol (e.g., methanol, ethanol, or propanol), an acetate (e.g., isopropyl acetate or ethyl acetate), an ether (e.g., methyl t-butyl ether, diethyl ether, or 2-methyltetrahydrofuran), a ketone (e.g., methyl ethyl ketone or methyl isobutyl ketone), a nitrile (e.g., acetonitrile), an amide (e.g., N,N-dimethylformamide), a non-aromatic hydrocarbon (e.g., hexane), an aromatic hydrocarbon (e.g., toluene), or water, or a mixture thereof. In some embodiments, the solvent comprises acetone, acetonitrile (ACN), dichloromethane (DCM), 1,4-dioxane, N,N-dimethylformamide (DMF), ethanol (EtOH), methanol (MeOH), 2-methyltetrahydrofuran (2-MeTHF), 2-propanol (IPA), tetrahydrofuran (THF), water, diethyl ether (EtO), methyl ethyl ketone (MEK), toluene, water, ethyl acetate, or hexane, or a mixture thereof. In some embodiments, the solvent comprises DCM. In some embodiments, step (1) comprises heating the mixture to a temperature (e.g., a temperature greater than room temperature), such as greater than about 80°C, about 75°C, about 70°C, about 65°C, about 60°C, about 55°C, about 50°C, about 45°C, about 40°C, or about 35°C. In some embodiments, step (1) is performed at room temperature. In some embodiments, step (2) comprises removing the solvent from the mixture of step (1).It is understood that Form I can also be prepared using the appropriate methods described in Example 6 below.

[0093] In some embodiments, the method for preparing polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide comprises: The present invention further includes a method for preparing an amide, which comprises: (1) reacting tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate with propanoyl propanoate, thereby producing tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate. (2) reacting tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate with trifluoroacetic acid (TFA), thereby forming (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine; and (3) reacting 1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine with 1-methyl-1H-pyrazole-4-carboxylic acid, thereby forming (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Form II

[0094] In some embodiments, (R)—N-(5-(5-ethyl-1,2,4-oxazolidinyl)methyl)-N-(5-methyl-1,2,4-oxazolidinyl)methyl)-N-(5-(5-ethyl ... A process for preparing polymorphic Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising the step of milling polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, provided is a method for preparing polymorphic Form II of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, comprising: (1) forming a mixture of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with a solvent, wherein the solvent comprises an alcohol (e.g., methanol, ethanol, or propanol); and (2) cooling the mixture of step (1). In some embodiments, the solvent comprises ethanol. In some embodiments, step (1) comprises heating the mixture to an elevated temperature, e.g., about 80°C, about 75°C, about 70°C, about 65°C, about 60°C, about 55°C, about 50°C, about 45°C, about 40°C, or about 35°C. In some embodiments, step (1) comprises heating the mixture to about 60°C. In some embodiments, an anti-solvent is added before step (2) is performed. In some embodiments, the anti-solvent is water. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature below the temperature at which step (1) is performed, e.g., to about 20°C, about 15°C, about 10°C, about 5°C, about 0°C, about −5°C, about −10°C, about −15°C, or about −20°C. It is understood that Form II can also be prepared using suitable methods described in Example 6, below. Mixture of Form I and Form III

[0095] In some embodiments, a method is provided for preparing a mixture of polymorphic Forms I and III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, comprising: (1) forming a mixture of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with a solvent, wherein the solvent comprises an ether (e.g., methyl t-butyl ether, diethyl ether, 2-methyltetrahydrofuran, or dioxane) or a non-aromatic hydrocarbon (e.g., hexane), or a mixture thereof; and (2) cooling the mixture of step (1). In some embodiments, the solvent comprises hexane or dioxane, or a mixture thereof. In some embodiments, step (1) comprises heating the mixture to an elevated temperature, e.g., about 80°C, about 75°C, about 70°C, about 65°C, about 60°C, about 55°C, about 50°C, about 45°C, about 40°C, or about 35°C. In some embodiments, step (1) is performed at about 60°C. In some embodiments, an anti-solvent is added before step (2) is performed. In some embodiments, the anti-solvent is water. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature below the temperature at which step (1) is performed, e.g., to about 20°C, about 15°C, about 10°C, about 5°C, about 0°C, about −5°C, about −10°C, about −15°C, or about −20°C. It is understood that a mixture of Forms I and III can also be prepared using a suitable method, as described in Example 6 below. Form IV

[0096] In some embodiments, the method comprises the steps of: (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent;

[0010] Methods for preparing polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide are provided, comprising: (1) a solvent comprising a nitrile (e.g., acetonitrile (ACN)) or water, or a mixture thereof; and (2) cooling the mixture of step (1). In some embodiments, the solvent comprises ACN or water, or a mixture thereof. In some embodiments, the solvent comprises ACN or a mixture of ACN and water. In some embodiments, step (1) comprises heating the mixture or solvent to an elevated temperature, e.g., about 80°C, about 75°C, about 70°C, about 65°C, about 60°C, about 55°C, about 50°C, about 45°C, about 40°C, or about 35°C. In some embodiments, step (1) comprises heating the mixture or solvent to about 80°C. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature below the temperature at which step (1) was carried out, e.g., to about 20° C., about 15° C., about 10° C., about 5° C., about 0° C., about −5° C., about −10° C., about −15° C., or about −20° C. In some embodiments, step (2) comprises cooling the mixture of step (1) to about 20° C.

[0097] In some embodiments, the method for preparing polymorphic Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide comprises: The method further comprises the step of preparing pyrazole-4-carboxamide by (1) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride to thereby produce (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. (2) reacting (R)—N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with hydroxylamine to form (R,Z)—N-(5-(N′-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; and (3) reacting R,Z)—N-(5-(N′-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with propionic acid. Form V

[0098] In some embodiments, provided is a method for preparing polymorphic Form V of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, comprising: (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an acetate ester (e.g., isopropyl acetate or ethyl acetate); and (2) cooling the mixture of step (1). In some embodiments, the solvent comprises ethyl acetate. In some embodiments, step (1) comprises mixing (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent at room temperature. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature below the temperature at which step (1) was carried out, for example, to about 15° C., about 10° C., about 5° C., about 0° C., about −5° C., about −10° C., about −15° C., or about −20° C. In some embodiments, step (2) comprises mixing the mixture of step (1) to a temperature below the temperature at which step (1) was carried out, for example, to about 15° C., about 10° C., about 5° C., about 0° C., about −5° C., about −10° C., about −15° C., or about −20° C. to about 5° C. In some embodiments, the method further comprises isolating the polymorph present in long needle morphology. In some embodiments, the method comprises: (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises ethyl acetate; (2) cooling the mixture of step (1) to about 5° C.; and (3) isolating the polymorph present in long needle morphology. Form VI

[0099] In some embodiments, provided is a method for preparing polymorphic Form VI of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, comprising: (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises a nitrile (e.g., acetonitrile (ACN)) and water; and (2) stirring the mixture of step (1). In some embodiments, the solvent comprises ACN and water. In some embodiments, the mixture prepared in step 1 is a near-saturated solution, a saturated solution, or a slurry. In some embodiments, the mixture prepared in step 1 comprises combining a solid form of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with a solvent, wherein the solid form of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide contains Form I, Form IV, Form V, or any combination thereof. In some embodiments, the solid form contains Form VI in combination with another solid form of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (e.g., Form I, IV, or V). In some embodiments, the solid form of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide comprises a combination of Form IV and Form VI. In some embodiments, step (2) comprises stirring the mixture at a temperature between about 0° C. and about 30° C., between about 0° C. and about 25° C., between about 0° C. and about 20° C., between about 0° C. and about 15° C., or between about 0° C. and about 10° C.In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature below the temperature at which step (1) was carried out, e.g., to between about 0° C. and about 20° C., between about 0° C. and about 15° C., or between about 0° C. and about 10° C. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature of about 20° C., about 15° C., about 12° C., about 10° C., about 8° C., about 5° C., about 2° C., or about 0° C. How to use

[0100] The polymorphic forms and compositions provided herein may be used to treat or prevent a disease or condition in an individual or subject.

[0101] Without being bound by theory, the provided polymorphic forms and compositions are believed to act by inhibiting myosin. This inhibition potentially reduces the number of independent myosin heads that interact with actin filaments, reducing the amount of contraction. Reducing myocardial contraction can be important for treating cardiac diseases where excessive contraction is a problem. In some embodiments, a method for treating or preventing cardiac disease in an individual or subject in need thereof is provided. In some embodiments, methods are provided for treating or preventing cardiac disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the polymorphic forms and compositions provided herein. In some embodiments, methods are provided for treating cardiac disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the polymorphic forms and compositions provided herein. In some embodiments, methods are provided for treating cardiac disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the polymorphic forms and compositions provided herein. In some embodiments, methods are provided for treating established or diagnosed cardiac disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the polymorphic forms and compositions provided herein. In some embodiments, methods are provided for preventing cardiac disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the polymorphic forms and compositions provided herein.

[0102] Also provided herein is the use of polymorphic forms and compositions provided herein in the manufacture of a medicament for treating cardiac disease in a subject. In some aspects, provided are polymorphic forms as described herein for use in a method of treating the human or animal body by therapy. In some embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in a method of treating the human or animal body by therapy. In some embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in the treatment or prevention of cardiac disease. In some embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in the treatment of cardiac disease. In some embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in the treatment of established or diagnosed cardiac disease. In other embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in the prevention of cardiac disease. Provided herein in some embodiments are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in treating diseases or conditions associated with HCM. Provided herein in some embodiments are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in treating diseases or conditions associated with secondary left ventricular wall thickening. Provided herein in some embodiments are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in ameliorating symptoms associated with heart disease. Provided herein in other embodiments are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in reducing the risk of symptoms associated with heart disease.In other embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in treating diseases or conditions associated with a small left ventricular cavity, lumen obstruction, hyperdynamic left ventricular contractions, obstruction of blood flow out of the left ventricle, cardiac hypertrophy, reduced cardiac output, impaired left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis. In certain embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in treating diseases or conditions associated with a small left ventricular cavity and lumen obstruction, hyperdynamic left ventricular contractions, myocardial ischemia, or cardiac fibrosis. In some embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in treating muscular dystrophy. In some embodiments, provided herein are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in treating glycogen storage disease. In other embodiments herein, Forms I, II, III, IV, V or VI, etc., for use in modulating cardiac sarcomeres, for example inhibiting cardiac sarcomeres. Further provided herein in other embodiments are polymorphic forms, such as Form I, II, III, IV, V, or VI, and compositions thereof, for use in enhancing cardiac myosin.

[0103] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, pig, sheep, horse, cow, or human. In some embodiments, the subject is a human. In some embodiments, the subject has established or diagnosed heart disease. In some embodiments, the subject has established or diagnosed hypertrophic cardiomyopathy (HCM). In some embodiments, the subject is at risk of developing heart disease. In some embodiments, the subject has a mutation that increases the risk of heart disease. In some embodiments, the subject has a mutation that increases the risk of hypertrophic cardiomyopathy (HCM). In some embodiments, the mutation is a sarcomere mutation. In some embodiments, the mutation is in myosin heavy chain beta (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha-1 chain (TPM1), myosin-binding protein C cardiac type (MYBPC3), cardiac troponin I (cTnI), myosin essential light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / cardiac isoform (MLC-2), cardiac alpha actin, muscle LIM protein (MLP), or protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2). In some embodiments, the mutation is in MHC-β. In some embodiments, the subject has established or diagnosed hypertrophic cardiomyopathy without a confirmed genetic etiology.

[0104] In some embodiments, the subject has a high risk of progressive symptoms. In some embodiments, the subject has a high risk of atrial fibrillation, ventricular tachyarrhythmia, stroke, and / or sudden death. In some embodiments, the subject has a reduced exercise capacity. In some embodiments, the reduced exercise capacity is compared with a control population of the same age. In some embodiments, the subject is eligible for surgical intervention or percutaneous ablation to treat heart disease.

[0105] In some embodiments, the cardiac disease is hypertrophic cardiomyopathy (HCM). In some embodiments, the cardiac disease is obstructive HCM. In some embodiments, the cardiac disease is non-obstructive HCM. In some embodiments, the HCM is associated with a sarcomere mutation. In some embodiments, the HCM is associated with a non-sarcomere mutation. In some embodiments, the cardiac disease is obstructive or non-obstructive HCM caused by a sarcomere and / or non-sarcomere mutation. In some embodiments, the sarcomere mutation is a mutation in myosin heavy chain beta (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha-1 chain (TPM1), myosin-binding protein C cardiac type (MYBPC3), cardiac troponin I (cTnI), myosin essential light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / cardiac isoform (MLC-2), cardiac alpha actin, or muscle LIM protein (MLP). In some embodiments, the sarcomeric mutation is a mutation in MHC-β. In some embodiments, the non-sarcomeric mutation is a mutation in protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).

[0106] Provided herein in some embodiments are methods for treating a disease or condition associated with HCM, comprising administering to an individual or subject in need thereof the polymorphic forms and compositions provided herein. In some embodiments, the disease or condition is Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome.

[0107] Also provided herein is the use of the polymorphic forms and compositions provided herein in the manufacture of a medicament for treating a disease or condition associated with HCM.

[0108] In some embodiments, the cardiac disease is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the cardiac disease is diastolic dysfunction. In some embodiments, the cardiac disease is cardiomyopathy. In some embodiments, the cardiac disease is primary or secondary restrictive cardiomyopathy. In some embodiments, the cardiac disease is a condition or symptom caused by coronary artery disease. In some embodiments, the cardiac disease is myocardial infarction or angina pectoris. In some embodiments, the cardiac disease is left ventricular outflow tract obstruction. In some embodiments, the cardiac disease is hypertensive heart disease. In some embodiments, the cardiac disease is congenital heart disease. In some embodiments, the cardiac disease is cardiac ischemia and / or coronary heart disease. In some embodiments, the cardiac disease is diabetic heart disease. In other embodiments, the cardiac disease is congestive heart failure. In some embodiments, the cardiac disease is right heart failure. In other embodiments, the cardiac disease is cardiorenal syndrome. In some embodiments, the cardiac disease is infiltrative cardiomyopathy. In some embodiments, the cardiac disease is or is a condition related to cardiac aging or diastolic dysfunction resulting from aging, hi some embodiments, the cardiac disease is or is a condition related to left ventricular hypertrophy and / or concentric left ventricular remodeling.

[0109] In some embodiments, methods are provided for treating a disease or condition associated with secondary left ventricular wall thickening in an individual or subject, comprising administering to an individual or subject in need thereof the polymorphic forms and compositions provided herein. In some embodiments, the disease is hypertension, valvular heart disease (aortic stenosis, mitral regurgitation), metabolic syndrome (diabetes, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, or Pompe disease.

[0110] Also provided herein is the use of the polymorphic forms and compositions provided herein in the manufacture of a medicament for treating a disease or condition associated with secondary left ventricular wall thickening.

[0111] In some embodiments, methods are provided for ameliorating symptoms associated with cardiac disease in a subject, comprising administering to an individual or subject in need thereof the polymorphic forms and compositions provided herein, wherein the symptoms are one or more selected from poor or reduced cardiac elasticity, poor or reduced diastolic left ventricular relaxation, abnormal left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or permanent atrial fibrillation, increased left atrial and pulmonary capillary wedge pressure, increased left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, a left ventricular mass, increased left ventricular wall thickening, left ventricular mid-cavity obstruction, increased systolic anterior motion of the mitral valve, left ventricular outflow tract obstruction, chest pain, dyspnea on exertion, presyncope, impaired exercise capacity, and fatigue.

[0112] In some embodiments, methods are provided for treating a disease or condition associated with a small left ventricular lumen, lumen obstruction, hyperdynamic left ventricular contractions, obstruction of blood flow out of the left ventricle, cardiac hypertrophy, reduced cardiac output, impaired left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis in an individual or subject, comprising administering to an individual or subject in need thereof the polymorphic forms and compositions provided herein.

[0113] In some embodiments, methods are provided for treating a disease or condition associated with small left ventricular lumen and lumen obstruction, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in an individual or subject, comprising administering to an individual or subject in need thereof the polymorphic forms and compositions provided herein.

[0114] Also herein, small left ventricular lumen and lumen obstruction, hyperdynamic left ventricular contractions, myocardial ischemia, Or, there is provided use of the polymorphic forms and compositions provided herein in the manufacture of a medicament for treating a disease or condition associated with cardiac fibrosis.

[0115] In some embodiments, provided are methods of treating muscular dystrophy (e.g., Duchenne muscular dystrophy) in an individual or subject, comprising administering to an individual or subject in need thereof the polymorphic forms and compositions provided herein. Also provided herein are uses of the polymorphic forms and compositions provided herein in the manufacture of a medicament for treating muscular dystrophy (e.g., Duchenne muscular dystrophy).

[0116] In some embodiments, provided herein are methods of treating glycogen storage disease in an individual or subject, comprising administering to an individual or subject in need thereof the polymorphic forms and compositions provided herein. Also provided herein are uses of the polymorphic forms and compositions provided herein in the manufacture of a medicament for treating glycogen storage disease.

[0117] Also provided are methods for modulating cardiac sarcomeres in an individual or subject, comprising administering to an individual or subject in need thereof a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, provided are methods for inhibiting cardiac sarcomeres, comprising contacting cardiac sarcomeres with at least one chemical entity as described herein, such as the polymorphic forms and compositions provided herein. Further provided herein is the use of at least one chemical entity as described herein, such as the polymorphic forms and compositions provided herein, in the manufacture of a medicament for inhibiting cardiac sarcomeres in an individual or subject.

[0118] Also provided is a method for enhancing cardiac myosin in an individual or subject, comprising administering to an individual or subject in need thereof a therapeutically effective amount of at least one chemical entity as described herein, such as the polymorphic forms and compositions provided herein. Further provided herein is the use of at least one chemical entity as described herein, such as the polymorphic forms and compositions provided herein, in the manufacture of a medicament for enhancing cardiac myosin in an individual or subject.

[0119] In some embodiments, the methods provided herein further comprise monitoring the effectiveness of treatment.Examples of indicators include, but are not limited to, one or more improvements in the following: New York Heart Association (NYHA) functional class, exercise capacity, cardiac elasticity, diastolic left ventricular relaxation, left atrial pressure, paroxysmal or permanent atrial fibrillation, left atrial and pulmonary capillary wedge pressure, left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, left ventricular wall thickness, left ventricular mid-lumen obstruction, mitral valve systolic anterior motion, left ventricular outflow tract obstruction, chest pain, exertional dyspnea, presyncope, exercise capacity abnormalities, and fatigue.These indicators can be monitored by techniques known in the art, including self-reporting, ECG, including ambulatory ECG, echocardiography, cardiac MRI, CT, biopsy, cardiopulmonary exercise testing (CPET), and actigraphy.

[0120] In some embodiments, the polymorphic forms and compositions thereof described herein reduce cardiomyocyte contractility. In some embodiments, the polymorphic forms and compositions thereof reduce cardiomyocyte contractility by more than 40%, e.g., more than 45%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90%. In some embodiments, the polymorphic forms and compositions thereof reduce cardiomyocyte contractility by 40% to 90%, e.g., 40% to 80%, 40% to 70%, 50% to 90%, 50% to 80%, or 50% to 70%. In some embodiments, the polymorphic forms and compositions thereof does not significantly alter calcium transients in cardiomyocytes. In some embodiments, the polymorphic forms and compositions thereof reduce ATPase activity in cardiomyocytes. Methods for measuring contractility, ATPase activity, and calcium transients are known in the art, for example, by calcium labeling, electrophysiological recording, and microscopic imaging. In some embodiments, the polymorphic forms and compositions thereof do not significantly inhibit or induce cytochrome P450 (CYP) proteins.

[0121] In some embodiments, the subject has a left ventricular wall that is thicker than normal before treatment.In some embodiments, the subject has a left ventricular wall thickness of more than 15 mm, for example, more than 18 mm, more than 20 mm, more than 22 mm, more than 25 mm, or more than 30 mm before treatment.In some embodiments, the left ventricular wall thickness is reduced by more than 5%, for example, more than 8%, more than 10%, more than 12%, more than 15%, more than 20%, or more than 30% after treatment.The left ventricular wall thickness can be measured by methods known in the art, for example, by echocardiography, CT scan, or cardiac MRI.

[0122] In some embodiments, the subject has abnormal cardiac fibrosis before treatment. In some embodiments, the abnormal cardiac fibrosis is reduced by more than 5%, for example, more than 8%, more than 10%, more than 12%, more than 15%, more than 20%, or more than 30% after treatment. Cardiac fibrosis can be measured by methods known in the art, for example, by biopsy or cardiac MRI.

[0123] In some embodiments, the subject has reduced exercise capacity before treatment. In some embodiments, the subject's exercise capacity increases by more than 5%, e.g., more than 8%, more than 10%, more than 12%, more than 15%, more than 20%, or more than 30% after treatment. In some embodiments, exercise capacity is measured by cardiopulmonary exercise testing (CPET). CPET measures changes in oxygen consumption (VO2 max). CPET and methods for measuring VO2 max are well known in the art (Malhotra et al., JACC:Heart Failure, 2016, 4(8):607-616; Guazzi et al., J Amer College Cardiol, 2017, 70 (13):1618-1636; Rowin et al., JACC:Cariovasc Imaging, 2017, 10(11):1374-1386). In some embodiments, VO2 max increases by more than 1 mL / kg / m after treatment. 2 greater than, e.g., 1.2 mL / kg / m 2 Ultra, 1.4mL / kg / m 2 Ultra, 1.5mL / kg / m 2 Ultra, 1.7mL / kg / m 2 Ultra, 2mL / kg / m 2 Ultra, 2.2mL / kg / m 2 Ultra, 2.5mL / kg / m 2 Ultra, 3mL / kg / m 2 Ultra, 3.2mL / kg / m 2 > or 3.5 mL / kg / m 2 Super improved.

[0124] In some embodiments, the subject has a New York Heart Association (NYHA) functional class of II, III, or IV before treatment. In some embodiments, the subject has a New York Heart Association (NYHA) functional class of III or IV before treatment. In some embodiments, the subject has a New York Heart Association (NYHA) functional class of IV before treatment. In some embodiments, the subject maintains the same NYHA functional class or has a reduced NYHA functional class after treatment.

[0125] In some embodiments, VO2 max is greater than or equal to 1 mL / kg / m after treatment. 2 greater than, e.g., 1.2 mL / kg / m 2 Ultra, 1.4mL / kg / m 2 Ultra, 1.5mL / kg / m 2 Ultra, 1.7mL / kg / m 2 > or 2 mL / kg / m 2 In some embodiments, the VO2 max is greater than or equal to 2.5 mL / kg / m after treatment, and the subject has a reduction in NYHA functional class. 2 Ultra, 3mL / kg / m 2 Ultra, 3.2mL / kg / m 2 > or 3.5 mL / kg / m 2 Super-improved, subjects maintain the same NYHA functional class or experience a decrease in NYHA functional class.

[0126] In some embodiments, the subject's daily functioning and / or activity level is improved after treatment. Improvement in daily functioning and / or activity level can be measured, for example, by journaling or actigraphy, e.g., FITBIT® or FITBIT®-like This can be measured by a monitor.

[0127] In some embodiments, the subject has one or more of reduced shortness of breath, reduced chest pain, reduced arrhythmia burden, e.g., atrial fibrillation and ventricular arrhythmias, reduced incidence of heart failure, and reduced ventricular outflow tract obstruction after treatment. Dosage

[0128] The polymorphic forms and compositions disclosed and / or described herein are administered at therapeutically effective dosages, e.g., dosages sufficient to provide treatment for a medical condition. While human dosage levels have not yet been optimized for the chemical entities described herein, generally, daily doses range from about 0.01 to 100 mg / kg body weight, in some embodiments, about 0.05 to 10.0 mg / kg body weight, and in some embodiments, about 0.10 to 1.4 mg / kg body weight. Thus, for administration to a 70 kg human, in some embodiments, the dosage range would be about 0.7 to 7000 mg per day, in some embodiments, about 3.5 to 700.0 mg per day, and in some embodiments, about 7 to 100.0 mg per day. The amount of chemical entity administered will depend, for example, on the subject and medical condition being treated, the severity of the affliction, the mode and schedule of administration, and the judgment of the attending physician. For example, an exemplary dosage range for oral administration is about 5 mg to about 500 mg per day, and an exemplary dosage for intravenous administration is about 5 mg to about 500 mg per day, each depending on pharmacokinetics.

[0129] Daily dose is the total amount administered in one day.Daily dose can be administered every day, every two days, every week, every two weeks, every month, or at various intervals, but is not limited to this.In some embodiments, daily dose is administered for a period ranging from 1 day to the life of the subject.In some embodiments, daily dose is administered once a day.In some embodiments, daily dose is administered in multiple divided doses, for example, 2, 3 or 4 divided doses.In some embodiments, daily dose is administered in 2 divided doses.

[0130] Administration of the polymorphic forms and compositions described herein can be by any accepted method of administration for therapeutic agents, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, intravaginal, rectal, or intraocular administration. In some embodiments, the polymorphic forms or compositions are administered orally or intravenously. In some embodiments, the polymorphic forms or compositions disclosed and / or described herein are administered orally.

[0131] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosol forms. The polymorphic forms disclosed and / or described herein can also be administered over time in sustained- or controlled-release dosage forms (e.g., controlled / sustained-release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patch forms) and / or can be administered in pulsed doses at predetermined rates. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise doses.

[0132] The polymorphic forms described herein can be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical compositions can contain minor amounts of nontoxic auxiliary substances, such as wetting agents, emulsifiers, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, olein, etc.). The pharmaceutical composition may also contain an aqueous solution of a compound disclosed and / or described herein, in an amount of about 0.005% to 95% by weight, or about 0.5% to 50% by weight, depending on the intended method of administration. Actual methods for preparing such dosage forms will be known or will be apparent to those skilled in the art, and can be found, for example, in Remington's See Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0133] In some embodiments, the composition takes the form of a pill or tablet, and thus the composition may contain one or more diluents (e.g., lactose, sucrose, dicalcium phosphate), lubricants (e.g., magnesium stearate), and / or binders (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) along with the polymorphic form disclosed and / or described herein. Other solid dosage forms include powders, granules, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) encapsulated in a gelatin capsule.

[0134] Pharmaceutically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, or suspending the polymorphic form disclosed and / or described herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol, etc.) to form a solution or suspension. Injectables can be prepared in any conventional form: as a liquid solution or suspension, as an emulsion, or in a solid form suitable for dissolution or suspension in liquid prior to injection. The percentage of the polymorphic form contained in such parenteral compositions will depend, for example, on the physical properties of the polymorphic form, the activity of the polymorphic form, and the needs of the subject. However, percentages of active ingredient between 0.01% and 10% in solution can be used, and may be higher if the composition is a solid that is to be subsequently diluted to another concentration. In some embodiments, the composition comprises about 0.2-2% of the polymorphic form disclosed and / or described herein in solution.

[0135] Pharmaceutical compositions of the polymorphic forms and compositions described herein can also be administered to the respiratory tract as aerosols or solutions for nebulizers, or as fine powders for insufflation, either alone or in combination with an inert carrier such as lactose.In such cases, the particles of the pharmaceutical composition can have a diameter of less than 50 microns, or in some embodiments, less than 10 microns.

[0136] Additionally, pharmaceutical compositions can include a polymorphic form as disclosed and / or described herein, as well as one or more additional drugs, pharmaceuticals, adjuvants, etc. Suitable drugs and pharmaceuticals include those described herein. kit

[0137] Also provided are articles of manufacture and kits containing any of the polymorphic forms or compositions provided herein. The articles of manufacture can include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The container can be formed from a variety of materials, such as glass or plastic. The container can hold a pharmaceutical composition provided herein. The label on the container can indicate that the pharmaceutical composition is used to prevent, treat, or suppress a condition described herein, and can also indicate instructions for use either in vivo or in vitro.

[0138] In one aspect, provided herein is a kit comprising a polymorphic form or composition described herein and instructions for use. The kit can be administered to an individual in need of treatment for a cardiac disorder. The kit may include instructions for use in treating cardiac disease in a body or subject. The kit may further include any material or device that can be used in administering the polymorphic form or composition, such as a vial, a syringe, or an IV bag. The kit may also include sterile packaging. combination

[0139] The polymorphic forms and compositions described herein can be administered alone or in combination with other therapeutic agents and / or therapeutic agents useful in the treatment of the aforementioned disorders, diseases or conditions.

[0140] The polymorphic forms and compositions described herein can be combined with one or more other therapeutic agents for treating cardiac disease, such as HCM or HFpEF. In some embodiments, the one or more therapeutic agents include a therapeutic agent that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor). In some embodiments, the one or more therapeutic agents include a therapeutic agent that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotropic agent, such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). In other embodiments, the one or more therapeutic agents include a therapeutic agent that reduces cardiac preload (e.g., a diuretic, e.g., furosemide) or a therapeutic agent that reduces afterload (a vasodilator agent of any class, including but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

[0141] The polymorphic forms and compositions described herein can be combined with one or more other therapeutic agents for treating HCM or HFpEF. In some embodiments, the polymorphic forms and / or compositions can be combined with a beta-blocker, verapamil, and / or disopyramide.

[0142] Some exemplary embodiments are provided below. 1. Polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. 2. The polymorph of embodiment 1, characterized in that it has peaks in its XRPD pattern at 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2 and 22.4±0.2 degrees 2-theta. 3. The polymorph of embodiment 1 or 2, characterized in that it has an XRPD pattern comprising peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2 and 26.1±0.2 degrees 2-theta. 4. The polymorph of any one of embodiments 1-3, characterized in that it has an XRPD pattern substantially as shown in Figure 1A. 5. The polymorph of any one of embodiments 1 to 4, characterized in that it has a DSC graph substantially as shown in Figure 1B. 6. The polymorph of any one of embodiments 1 to 5, characterized by an endothermic onset at about 199°C as determined by DSC. 7. The polymorph of any one of embodiments 1 to 6, characterized in that it has a TGA graph substantially as shown in Figure 1B. 8. Implementation, characterized in that it has a DVS graph substantially as shown in FIG. 1C. The polymorph of any one of Forms 1 to 7. 9. The polymorph of embodiment 1, characterized in that it has an XRPD pattern comprising peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees 2-theta. 10. The polymorph of embodiment 1 or 9, characterized in that it has an XRPD pattern comprising peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2 and 23.3±0.2 degrees 2-theta. 11. The polymorph of any one of embodiments 1, 9 and 10, characterized in that it has an XRPD pattern substantially as shown in Figure 2A. 12. The polymorph of any one of embodiments 1 and 9-11, characterized in that it has a DSC graph substantially as shown in Figure 2B. 13. The polymorph of any one of embodiments 9-12, characterized by an endothermic onset at about 199°C as determined by DSC. 14. The polymorph of any one of embodiments 1 and 9-13, characterized in that it has a TGA graph substantially as shown in Figure 2B. 15. The polymorph of embodiment 1, characterized in that it has an XRPD pattern comprising peaks at 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees 2-theta. 16. The polymorph of embodiment 1, characterized in that it has an XRPD pattern comprising peaks at 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees 2-theta. 17. The polymorph of embodiment 1 or 16, characterized in that it has an XRPD pattern comprising peaks at 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2 and 24.8±0.2 degrees 2-theta. 18. The polymorph of any one of embodiments 1, 16 and 17, characterized in that it has an XRPD pattern substantially as shown in Figure 4A. 19. The polymorph of any one of embodiments 1 and 16-18, characterized in that it has a DSC graph substantially as shown in Figure 4B. 20. The polymorph of any one of embodiments 1 and 16-19, characterized by an endothermic onset at about 200°C as determined by DSC. 21. The polymorph of any one of embodiments 1 and 16-20, characterized in that it has a TGA graph substantially as shown in Figure 4B. 22. The polymorph of embodiment 1, characterized in that it has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees 2-theta. 23. The polymorph of embodiment 1 or 22, characterized in that it has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees 2-theta. 24. The polymorph of any one of embodiments 1, 22 and 23, characterized in that it has an XRPD pattern comprising peaks at 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2 and 31.1±0.2 degrees two-theta. 25. The polymorph of any one of embodiments 1 and 22-24, characterized in that it has an XRPD pattern substantially as shown in FIG. 5. 26. The polymorph of embodiment 1, characterized in that it has an XRPD pattern comprising peaks at 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees 2-theta. 27. The polymorph of embodiment 1 or 26, characterized in that it has an XRPD pattern comprising peaks at 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees 2-theta. 28. The polymorph of any one of embodiments 1, 26 and 27, characterized in that it has an XRPD pattern substantially as shown in Figure 6A. 29. The polymorph of any one of embodiments 1 and 26-28, characterized in that it has a TGA graph substantially as shown in Figure 6B or Figure 6C. 30. The polymorph of any one of embodiments 1 and 26-29, characterized by an endothermic onset at about 200°C as determined by DSC. 31. The polymorph of any one of embodiments 1 and 26-30, characterized in that it has a DSC graph substantially as shown in Figure 6D or Figure 6E. 32. (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent; and (2) cooling the mixture of step (1) or removing the solvent from the mixture of step (1). 9. A method for preparing the polymorph of any one of embodiments 2 to 8, comprising: 33. The method of embodiment 32, wherein the solvent comprises dichloromethane (DCM). 34. The method of embodiment 32 or 33, wherein step (2) comprises removing the solvent. 35. A method for preparing the polymorph of any one of embodiments 9-14, comprising the step of triturating Form I in water. 36. (1) forming a mixture of Form I and ethanol; and (2) cooling the mixture of step (1); 15. A method for preparing the polymorph of any one of embodiments 9 to 14, comprising: 37. The method of embodiment 36, wherein step (1) comprises heating the mixture to about 60°C. 38. The method of embodiment 36 or 37, wherein step (2) comprises cooling the mixture of step (1) to about -5°C, about -10°C, about -15°C, or about -20°C. 39. (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises acetonitrile (ACN) or a mixture of ACN and water; and (2) cooling the mixture of step (1). 22. A method for preparing the polymorph of any one of embodiments 16 to 21, comprising: 40. The method of embodiment 39, wherein step (1) comprises heating a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 80° C. 41. The method of embodiment 39 or 40, wherein step (2) comprises cooling the mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 20° C. 42. (1)(R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazoline forming a mixture of benzoyl-4-carboxamide and a solvent, wherein the solvent comprises an acetate ester; and (2) cooling the mixture of step (1). 26. A method for preparing the polymorph of any one of embodiments 22-25, comprising: 43. The method of embodiment 42, wherein the solvent comprises ethyl acetate. 44. The method of embodiment 42 or 43, wherein step (2) comprises cooling the mixture of step (1) to about 5°C. 45. The method of any one of embodiments 42-44, further comprising the step of separating the polymorph present in long needle morphology. 46. ​​(1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises a nitrile and water; and (2) stirring the mixture of step (1); 32. A method for preparing the polymorph of any one of embodiments 26-31, comprising: 47. The method of embodiment 46, wherein the solvent comprises acetonitrile. 48. The method of embodiment 46 or 47, wherein step (2) comprises cooling the mixture of step (1) to between about 0°C and about 10°C. 49. A pharmaceutical composition comprising the polymorph of any one of embodiments 1 to 31 and a pharmaceutically acceptable excipient. 50. A method for treating cardiac disease in a subject in need thereof, comprising administering to the subject a polymorph described in any one of embodiments 1 to 31, or a pharmaceutical composition described in embodiment 49. 51. The method of embodiment 50, wherein the cardiac disease is hypertrophic cardiomyopathy (HCM). 52. The method of embodiment 51, wherein the HCM is obstructive or non-obstructive, or associated with sarcomeric and / or non-sarcomeric mutations. 53. The method of embodiment 50, wherein the cardiac disease is heart failure with preserved ejection fraction (HFpEF). 54. The method of embodiment 50, wherein the cardiac disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina pectoris, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, and infiltrative cardiomyopathy. 55. The method of embodiment 50, wherein the cardiac disease is or is associated with one or more conditions selected from the group consisting of cardiac aging, age-related diastolic dysfunction, left ventricular hypertrophy, and concentric left ventricular remodeling. 56. A method for treating a disease or condition associated with hypertrophic cardiomyopathy in a subject in need thereof, comprising administering to the subject a polymorph described in any one of embodiments 1 to 31, or a pharmaceutical composition described in embodiment 49. 57. The method of embodiment 56, wherein the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome. 58. A method for treating a disease or condition associated with secondary left ventricular wall thickening in a subject in need thereof, comprising administering to the subject a polymorph described in any one of embodiments 1 to 31, or a pharmaceutical composition described in embodiment 49. 59. The method of embodiment 58, wherein the disease or condition is selected from the group consisting of hypertension, valvular heart disease, metabolic syndrome, end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, and Pompe disease. 60. A method for treating a disease or condition associated with small left ventricular lumen and lumen obstruction, hyperdynamic left ventricular contractions, myocardial ischemia, or cardiac fibrosis in a subject in need thereof, comprising administering to the subject a polymorph of any one of embodiments 1 to 31, or a pharmaceutical composition of embodiment 49. 61. A method for treating a disease or condition selected from muscular dystrophy and glycogen storage disease in a subject in need thereof, comprising administering to the subject a polymorph described in any one of embodiments 1 to 31, or a pharmaceutical composition described in embodiment 49. 62. A method for inhibiting cardiac sarcomeres, comprising contacting the cardiac sarcomeres with a polymorph described in any one of embodiments 1 to 31, or a pharmaceutical composition described in embodiment 49. [Example]

[0143] The following examples are presented to further aid in understanding the embodiments disclosed in this application and assume understanding of conventional methods well known to those skilled in the art for these examples. The specific materials and conditions described hereinafter are intended to illustrate certain aspects of the embodiments disclosed herein and should not be construed as limiting their reasonable scope.

[0144] The following abbreviations may be used herein: [Table 1A]

[0145] The polymorphic forms of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide were characterized by various analytical techniques, including XRPD, DSC and TGA, using the procedures described below. XRPD

[0146] The Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg-Brentano geometry using a linear X-ray beam. The X-ray source was a long Cu microfocus tube operated at 40 kV and 44 mA. The source provided an incident beam profile at the sample that varied from a narrow line at high angles to a wide rectangle at low angles. A beam-tuning slit was used on the X-ray source line to ensure that the maximum beam size was less than 10 mm both along the line and perpendicular to it. Bragg-Brentano geometry is a parallel-focusing geometry controlled by passive divergence and receiving slits, which, together with the sample itself, act as the focusing component for the optics. The inherent resolution of the Bragg-Brentano geometry is determined in part by the radius of the diffractometer used and the width of the receiving slit. The Rigaku Smart-Lab typically operates to provide peak widths of 0.1° 2θ or less. The axial divergence of the X-ray beam is controlled by 5.0 degree Soller slits in both the incident and diffracted beam paths.

[0147] Powder samples were prepared in low-background silicon holders using light manual pressure to keep the sample surface flat and level with the reference plane of the sample holder. Each sample was analyzed from 2 to 40° 2θ using a continuous scan of 6° 2θ per minute with an effective step size of 0.02° 2θ. DSC

[0148] DSC analyses were performed using a TA Instruments Q2000 instrument. Instrument temperature calibration was performed using indium. The DSC cell was maintained under a nitrogen purge of approximately 50 mL per minute during each analysis. Samples were placed in standard fluted aluminum pans and heated from 25°C to 350°C at a rate of 10°C per minute. TGA

[0149] TGA was performed using a TA Instruments Q50 instrument. The balance was calibrated using a Class M weight, and temperature calibration was performed using Alumel. The nitrogen purge was approximately 40 mL / min for the balance and approximately 60 mL / min for the furnace. Each sample was placed in a pre-tared platinum pan and heated from 20°C to 350°C at a rate of 10°C / min. DVS

[0150] DVS analysis was performed on a TA Instruments Q5000 Dynamic Water Vapor Sorption Analyzer. The instrument was calibrated for humidity using standard weights and sodium bromide standards. Samples were analyzed at 25°C in 10% relative humidity (RH) increments from 5% to 95% RH (adsorption cycle) and from 95% to 5% RH (desorption cycle), with a maximum equilibration time of 60 minutes. Example 1 Preparation of Form I

[0151] Polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the scheme presented below. [ka]

[0152] Step 1: Preparation of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate: To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate (16 g, 54.9 mmol, 1.0 equiv) in dioxane (300 mL) was added propanoyl propanoate (8.4 g, 64.5 mmol, 1.2 equiv). The mixture was stirred at 105° C. for 8 h, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to give 17.5 g (97%) of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid.

[0153] Step 2: Preparation of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine: To a solution of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (17.6 g, 53.4 mmol, 1.0 equiv.) in DCM (120 mL) was added TFA (24 mL). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The mixture was then poured into ethanol (50 mL) and water (5 mL), and the pH was adjusted to 12 with sodium hydroxide solution (2N). The mixture was then extracted three times with dichloromethane (200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 11.2 g of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine as a brown oil. Step 3: Preparation of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. To a stirred solution of 1-methyl-1H-pyrazole-4-carboxylic acid (27.1 g, 214.55 mmol, 1.05 equiv) and EDCI (58.8 g, 306.50 mmol, 1.5 equiv) in DMF (540 mL) was added HOAt (41.7 g, 306.50 mmol, 1.5 equiv) and DIPEA (105.6 g, 817.34 mmol, 4 equiv) at room temperature. The mixture was stirred at room temperature for 5 minutes, and then (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (54.3 g, 204.34 mmol, 1 equiv.) was added. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was poured into water / ice at room temperature. The precipitated solid was collected by filtration and washed three times with water (1000 mL). The solid was dissolved in DCM (1500 mL). The organic phase was diluted with NH4Cl (5 The mixture was washed three times with 1000 mL of saturated aqueous solution and three times with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by trituration with EtOAc / n-hexane = 1 / 2 (600 mL) to give (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (62.0704 g, 89.14%) Form I as an off-white solid. LRMS (ES) m / z 338 [M+H]. 1 H NMR: (DMSO, 300MHz, ppm): δ 8.41 (1H, d, J=8.4 Hz), 8.16 (1H, s), 7.91-7.79 (3H, m), 7.34 (1H, d, J=7.9 Hz), 5.53 (1H, q, J=8.3 Hz), 3.84 (3H, s), 3.13-2.81 (4H, m), 2.44 (1H, dd, J=7.9, 4.7 Hz), 1.95 (1H, m), 1.33 (3H, t, J=7.5 Hz).

[0154] Polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, TGA, and DVS. Figure 1A shows the XRPD pattern of Form I. Figure 1B shows the DSC and TGA graphs of Form I. As shown in the DSC graph, an endothermic onset was observed at approximately 199 °C. As shown in the TGA graph, a weight loss of 0.2% was observed below 200 °C. Figure 1C shows the DVS graph of Form I. As shown in Figure 1C, a water uptake of 0.60% w / w was observed over a relative humidity (RH) range of 5 to 90%, as determined by DVS. Example 2 Preparation of Form II

[0155] Polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the method presented below. Method 1

[0156] 18.2 mg of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was placed in a PEEK grinding cup containing a stainless steel ball, and 10 μL of water was added. The grinding cup was placed in a Retsch mill at 100% power for 20 minutes. The solid was scraped out of the grinding cup with a spatula and analyzed by XRPD. The solid was determined to be Form II. Method 2

[0157] A 20 mL glass vial containing 19.5 mg of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was heated on a 60° C. plate with magnetic stirring. Ethanol was added to the glass vial until the solid dissolved (4 mL of ethanol was added). The vial was then removed from the plate and 16 mL of cold water (chilled in the refrigerator) was added. The vial was then placed in the refrigerator for 4 days. After 4 days, the vial was centrifuged, the liquid was decanted, and the resulting solid was air-dried and analyzed by XRPD. The solid was determined to be Form II.

[0158] Polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. Figure 2A shows the XRPD pattern of Form II. Figure 2B shows the DSC and TGA patterns of Form II. As shown in the DSC graph, an endothermic onset was observed at approximately 199°C. As shown in the TGA graph, a weight loss of approximately 0.18% was observed from the onset to 200°C. Example 3 Preparation of a mixture of Form I and Form III

[0159] In a 1-dram glass vial, 19.1 mg of polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was suspended in 1 mL of hexane. With magnetic stirring on a hot plate at 60° C., dioxane was slowly added until the solid dissolved (2.2 mL of dioxane was added). The heat was then turned off and the vial was capped. The vial was placed in a freezer (approximately −15° C.) for 2 days. After 2 days, the vial was then placed in a refrigerator for 4 days. After 4 days, the vial was centrifuged, the liquid was decanted, and the resulting solid was air-dried and analyzed by XRPD, which determined it to be a mixture of Forms I and III.

[0160] A mixture of polymorphic Forms I and III of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. FIG. 3A shows the XRPD pattern of the mixture of Forms I and III. FIG. 2B shows the DSC and TGA graphs of the mixture of Forms I and III. As shown in the DSC graph, an exotherm onset at about 107° C. and an endotherm onset at about 196° C. were observed. As shown in the TGA graph, a weight loss of about 18.89% was observed from the onset to 125° C. Example 4 Preparation of Form IV

[0161] Polymorphic form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the scheme presented below. [ka]

[0162] Step 1: Preparation of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. 2-MeTHF (71. A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (10.5 g, 0.0833 mol, 1.00 equiv) and N,N-dimethylformamide (0.054 g, 0.057 mL, 0.00074 mol, 0.0089 equiv) in 100 mL of 1-methyl-1H-pyrazole-4-carboxylic acid (10.5 g, 0.0833 mol, 1.00 equiv) (6 g, 83.3 mL, 7.93 vol) was stirred at 20±5° C. A solution of oxalyl chloride (9.98 g, 0.0786 mol, 0.945 equiv) was added over at least 45 minutes and allowed to react at 30±5° C. until ≦15% of the starting 1-methyl-1H-pyrazole-4-carboxylic acid remained. The mixture was cooled to 20±5° C. (vessel 1). A mixture of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride (15.4 g, 0.0791 mol, 0.95 equiv.) in 2-MeTHF (66.1 mL, 4.3 volumes relative to (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride) was treated with 4N sodium hydroxide solution (79 mL, 0.316 mol, 3.8 equiv.) at 20±5° C. The resulting mixture was stirred at 20±5° C. for at least 30 minutes (vessel 2). To this reaction mixture was added a solution of freshly prepared 1-methyl-1H-pyrazole-4-carboxylic acid chloride, maintaining the temperature at <30° C. After the addition was complete, the mixture was reacted at 20±5° C. until only ≦5% of the intermediate (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride remained. The mixture was then filtered. The resulting filter cake was washed with 2-MeTHF (25 mL) and then with water until the pH of the filtrate reached 8.5±1.5. The solid was then dried and isolated. 18.9 g (89.6%) of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained as a light gray solid.

[0163] Step 2: Preparation of (R,Z)—N-(5-(N′-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. A solution of (R)—N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (15.0 g, 0.0563 mol, 1.00 equiv) in NMP (77.3 g, 75.1 mL, 5.0 vol) was cooled to 5±5° C., and aqueous hydroxylamine (50% in water, 11.2 g, 0.169 mol, 3.00 equiv) was added slowly while maintaining the temperature below 15° C. The resulting mixture was stirred at 20±5°C for at least 16 hours until only ≦2% (R)—N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide remained. The reaction mixture was heated to 65±5°C and treated with isopropyl acetate (150 mL, 10 vol) while maintaining the temperature at ≧50°C. The resulting mixture was slowly cooled to 20±5°C and stirred for at least 2 hours. The mixture was then cooled to 15±5°C and stirred for at least 1 hour. The solid product was collected by filtration. The wet filter cake was washed with isopropyl acetate (2×70 mL) and the solid was dried. The material was then packaged. Obtained 14.62 g (86.7%) of (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide as an off-white solid.

[0164] Step 3: Preparation of polymorphic form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. 1A mixture of propionic acid (4.25 g, 0.057 mol, 1.10 equiv.) and 1,1'-carbonyldiimidazole (CDI) (8.87 g, 0.0547 mol, 1.05 equiv.) in acetonitrile (105.1 g, 133.7 mL) was stirred at 20 ± 5 °C until less than 20% unreacted propionic acid remained, as determined by H NMR. The activated propionic acid solution was added to (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methylpropionic acid in acetonitrile (45.0 g, 57.3 mL). To the reaction mixture was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.87 g, 0.104 mol, 2.00 equiv.). The temperature of the mixture was adjusted to 70 ± 5 °C and the mixture was stirred at 70 ± 5 °C until 2% or less of the uncyclized intermediate remained. After confirming the reaction was complete, the reaction mixture was quenched with water (48 mL). The batch temperature was adjusted to 55±5°C, and the solution was polish filtered. The resulting filtrate was concentrated to approximately 10 volumes. The mixture was adjusted to 80±5°C, and water (310 mL) was slowly charged over at least 1 hour while maintaining the temperature at ≥70°C. The mixture was adjusted to 80±5°C, and the resulting slurry was stirred at 80±5°C for at least 2 hours. The mixture was slowly cooled to 20±5°C over at least 4 hours and stirred at 20±5°C for at least 2 hours. The mixture was filtered. The resulting filter cake was washed with water (3×120 mL) and dried in a vacuum oven until an LOD≦1% was reached. The material was then packaged. A total of 16.32 g of polymorphic form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained as an off-white solid in 92.8% yield.

[0165] Polymorphic Form IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. FIG. 4A shows the XRPD pattern of Form IV. FIG. 4B shows the DSC and TGA graphs of Form IV. As shown in the DSC graph, an endothermic onset was observed at approximately 200° C. As shown in the TGA graph, a weight loss of approximately 0.003% was observed from the onset to 200° C. Example 5 Preparation of Form V

[0166] Polymorphic form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the method presented below.

[0167] (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was mixed with ethyl acetate at room temperature. The mixture was cooled to 5° C. Two polymorphic forms were produced. One present in a fibrous, fine-needle morphology was isolated and confirmed by XRPD to be polymorphic Form IV. One present in a long-needle morphology was isolated and confirmed by XRPD to be polymorphic Form V. Figure 5 shows the experimental and modeled XRPD patterns of Form V. Example 6 Preparation of Form VI

[0168] Polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the method presented below. Method 1 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2, 3-Dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (Form VI) (500 mg) was added to 60:40 acetonitrile:water (8 mL) and stirred at ambient temperature for 48 hours using a stir bar. The solid was isolated by suction filtration and analyzed by XRPD, DSC, and TGA.

[0169] Polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. Figure 6A shows the experimental XRPD pattern of Form VI. Figures 6B and 6D show the TGA and DSC graphs, respectively, of Form VI measured after oven drying (24 hours, 25°C). As shown in the TGA graph in Figure 6B, a weight loss of approximately 2.185% was observed between 25 and 65°C. As shown in the DSC graph in Figure 6D, a broad endotherm at approximately 41°C onset, a small exotherm at approximately 115°C onset, and a sharp endotherm at 200°C onset were observed.

[0170] Figures 6C and 6E show the TGA and DSC graphs, respectively, of Form VI measured after oven drying and heating (oven drying at 25°C for 24 hours; heating at 150°C). As shown in the TGA graph in Figure 6C, negligible decrease was observed up to 200°C. As shown in the DSC graph in Figure 6E, a sharp endotherm onset at 200°C was observed. Method 2

[0171] A solid of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (Form I, IV, or V) (30 mg) was slurried in 10-90% acetonitrile in water (1 mL), and the slurry was then stirred with a stir bar at 2-8° C. for 24 hours. The solid was isolated by suction filtration and identified as polymorphic Form VI by XRPD. Example 7 Polymorphism Screening

[0172] Polymorphic Form I of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was mixed with various solvents under various conditions. The resulting samples were analyzed by XRPD. The results are presented in Table 6 below. [Table 6-3] [Table 6-4] Example 8 Competitive slurry experiments between Form I and Form IV

[0173] Forms I and IV of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide were subjected to competitive slurry experiments to determine the most stable form over a temperature range (2-60° C.). Form IV was found to be more stable than Form I over the entire temperature range tested. The results of the competitive slurry experiments are presented below in Table 7. [Table 7] Example 9 Myofibril assay

[0174] To evaluate the effect of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide on the ATPase activity of full-length cardiac myosin in the context of native sarcomeres, a stripped myofibril assay was performed. Bovine cardiac myofibrils were obtained by homogenizing left ventricular tissue from bovine hearts in the presence of detergents such as Triton X-100. Such treatment removes most of the membrane and soluble cytoplasmic proteins but leaves the cardiac sarcomeric actomyosin apparatus intact. Myofibril preparations were enriched in Ca. 2+ The ability to hydrolyze ATP in a regulated manner is maintained. Ca activates the ATPase activity of such myofibrillar preparations to a defined maximal fraction (i.e., 25%, 75%) in the presence and absence of compounds. 2+ Small molecule agents were assayed at concentrations of 0.01% and 0.02%. Small molecule agents were assessed for their ability to inhibit the steady-state ATPase activity of bovine cardiac myofibrils using a pyruvate kinase and lactate dehydrogenase (PK / LDH) coupled enzyme system. This assay regenerates ADP produced by myosin to ATP by oxidizing NADH, resulting in an absorbance change at 340 nm. Prior to testing small molecule agents, bovine cardiac myofibrils were assessed for their calcium responsiveness, measuring 50% (pCa) of the myofibrillar system. 50 ) or 75%(pCa 75The calcium concentration that achieved either activation or activation was selected as the final condition for assessing the inhibitory activity of small molecule agents. All enzyme activities were measured in a buffer solution containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid) and 2 mM magnesium chloride at pH 6.8 (PM12 buffer). The final assay conditions were 1 mg / mL bovine cardiac myofibrils, 4 U / mL pyruvate kinase, 6 U / mL lactate dehydrogenase, 50 μM ATP, 0.1 mg / mL bovine serum albumin (BSA), 10 ppm ATP, and 100 ppm ATP. The mixture consisted of 100 mM antifoam, 1 mM DTT, 0.5 mM NADH, 1.5 mM PEP, 0.6 mM EGTA, and a sufficient amount of CaCl to achieve either 50% or 75% activation of myofibrillar ATPase activity. The IC of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was used. 15 (CDMF75) was 0.4 μM, and the IC of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide 50 (CDMF75) is 1.4 μM. Example 10 Myocyte assay

[0175] Adult male Sprague-Dawley rats were anesthetized, the hearts were rapidly excised, rinsed, and the ascending aorta was cannulated. Continuous retrograde perfusion was initiated through the hearts at a perfusion pressure of 60 cmH2O. Hearts were first perfused nominally with Ca. 2+ The rats were perfused with modified Krebs solution containing the following composition: 113 mM NaCl, 4.7 mM KCl, 0.6 mM KH2PO4, 0.6 mM Na2HPO4, 1.2 mM MgSO4, 12 mM Na The medium was 10 mM HCO3, 10 mM KHCO3, 30 mM taurine, 5.5 mM glucose, and 10 mM Hepes (all Sigma). The medium was not recirculated but was constantly aerated with a 95% O2 / 5% CO2 mixture. After approximately 3 minutes, the heart was perfused with modified Krebs buffer supplemented with collagenase (Worthington) and a final calcium concentration of 12.5 μM. After the heart appeared pale and soft, it was removed from the cannula. The atria and blood vessels were removed, and the ventricles were carefully dissected into smaller pieces using forceps. The tissue was homogenized by repeated pipette trituration, the collagenase reaction was stopped with 10% bovine calf serum (BCS), precipitated, and resuspended in perfusion buffer containing 5% BCS and 12.5 μM CaCl2. Myocytes were made calcium-tolerant by the stepwise addition of CaCl2 solution to a final concentration of 1.2 mM. Cells were then washed and resuspended in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl2, 11 mM glucose, 4 mM Hepes, and 1.2 mM CaCl2, pH 7.4). Cells were maintained at 37°C for 60 min before starting the experiment and used within 5 h of isolation. Cell preparations were only used if they initially passed QC criteria by demonstrating contractile responses to standard (>150% of basal) and isoproterenol (ISO, >250% of basal) treatment. Furthermore, only cells with basal contractility between 3 and 8% were used in subsequent experiments with compounds.

[0176] An aliquot of myocytes in Tyrode's buffer was placed in a perfusion chamber (Series 20 RC-27NE, Warner Instruments) equipped with a heating platform. The myocytes were allowed to adhere, the chamber was heated to 37°C, and the cells were perfused with 37°C Tyrode's buffer. Myocytes were field stimulated at 1 Hz with a platinum electrode (20% above threshold). Only cells that had clear striations and were quiescent before pacing were used for contractility experiments. To determine basal contractility, myocytes were imaged with a 40x objective. Images were digitized using a charge-coupled device camera with a variable frame rate (60-240 Hz) and displayed on a computer screen at a sampling rate of 240 Hz (IonOptix, Milton, MA). Once cell contractility was stable over time, test compounds (0.01-15 μM) were perfused into the chamber and over the myocytes for 5 minutes. Myocyte contractility and the rates of contraction and relaxation were then recorded using edge detection.

[0177] For each compound, five or more individual myocytes from two or more different myocyte preparations were tested. For each cell, 20 or more basal (defined as 1 minute before compound injection) and post-compound (defined as 5 minutes after starting compound perfusion) contractile transients were averaged and compared. These averaged transients were analyzed using IonWizard software (IonOptix) to determine changes in diastolic length and fractional shortening. Fractional shortening was calculated as ((resting length - peak contraction length) divided by resting length). The percent change in fractional shortening from baseline was calculated as ((post-drug fractional shortening / basal fractional shortening) x 100). The percent reduction in fractional shortening from baseline was calculated as (100 - percent change in fractional shortening from baseline). Maximum contraction and relaxation velocities (µm / s) were also determined. Results from individual cells were averaged, and SEM was calculated. The effect of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided below. [Table 1B] FS% = average of (post-baseline peak height percentage / pre-baseline peak height percentage) × 100 for each cell Example 11 Echocardiographic assessment of acute pharmacodynamic effects on rat cardiac contractility.

[0178] In vivo cardiac function assessment by echocardiography was performed in male Sprague-Dawley rats under isoflurane (1–3%) anesthesia. 2-D M-mode images of the left ventricle were acquired in the parasternal long-axis view before, during, and after compound administration via continuous IV infusion or oral gavage. In vivo fractional shortening was determined by M-mode image analysis using the following calculation: ((end-diastolic diameter - end-systolic diameter) / end-diastolic diameter × 100). For continuous IV infusion experiments, three predose baseline M-mode images were acquired at 1-minute intervals before compound infusion. Compounds were formulated in 50% propylene glycol (PG): 16% Captisol: 10% dimethylacetamide (DMA) and delivered at a rate of 1 mL / kg / h via a jugular vein catheter. M-mode images were acquired at 5-minute intervals during the infusion. The infusion was stopped when fractional shortening reached a maximum 60% reduction from baseline. Blood samples were taken to determine the plasma concentration of the compound. Data are expressed as an estimated IC, the concentration at which the fractional shortening was 50% of the pre-dose baseline contractility. 50 The IC values ​​obtained for (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide were reported. 50 The value is 7.2±0.20 μM (mean±standard deviation).

[0179] In oral dosing studies, three pre-dose baseline M-mode images were obtained 1 minute apart before compound administration. (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was formulated in a 0.5% hydroxypropylmethylcellulose 2910 (HPMC2910):0.1% Tween 80 suspension and delivered via oral gavage as a single dose (5 mL / kg). At selected time points over a 24-hour period, rats were lightly anesthetized for M-mode echocardiography measurements. Various dose levels were evaluated. The effect of the compound on cardiac shunt fraction at the highest dose evaluated is shown below as the percentage reduction of baseline fractional shortening (=100%). [Table 1C]

[0180] Concurrently with the echocardiographic measurements, blood samples were taken to determine the corresponding compound plasma concentrations. Estimated IC were the concentrations at which fractional shortening was 50% and 10% of the pre-dose baseline contractility, respectively. 50 and IC 10 The value was 7.9 μM (IC 50 ) and 0.8 μM (IC 10 )

[0181] All documents cited herein, including all patents, patent applications, and publications, including all documents, tables, and figures cited herein, are expressly incorporated by reference in their entirety for all purposes.

[0182] The foregoing description of the compounds, uses, and methods described herein will enable one of ordinary skill in the art to make and use the compounds, uses, and methods described herein, but one of ordinary skill in the art will understand and appreciate that there are variations, combinations, and equivalents of the specific embodiments, methods, and examples herein. Thus, the compounds, uses, and methods provided herein should not be limited by the foregoing embodiments, methods, or examples, but rather encompass all embodiments and methods that fall within the scope and spirit of the compounds, uses, and methods provided herein. The present invention provides, for example, the following. (Item 1) Polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. (Item 2) 2. The polymorph according to item 1, characterized in that it has peaks in its XRPD pattern at 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2 and 22.4±0.2 degrees 2-theta angle. (Item 3) 3. The polymorph according to item 1 or 2, characterized in that it has an XRPD pattern comprising peaks at 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2 and 26.1±0.2 degrees 2-theta angle. (Item 4) 4. The polymorph according to any one of items 1 to 3, characterized in that it has an XRPD pattern substantially as shown in FIG. 1A. (Item 5) 5. The polymorph according to any one of items 1 to 4, characterized in that it has a DSC graph substantially as shown in Figure 1B. (Item 6) 6. The polymorph according to any one of items 1 to 5, characterized by an endothermic onset at about 199°C as determined by DSC. (Item 7) 7. The polymorph according to any one of items 1 to 6, characterized in that it has a TGA graph substantially as shown in Figure 1B. (Item 8) 8. The polymorph according to any one of items 1 to 7, characterized in that it has a DVS graph substantially as shown in Figure 1C. (Item 9) 2. The polymorph according to item 1, characterized in that it has an XRPD pattern comprising peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2 and 20.4±0.2 degrees 2-theta. (Item 10) 10. The polymorph according to item 1 or 9, characterized in that it has an XRPD pattern comprising peaks at 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2 and 23.3±0.2 degrees 2-theta. (Item 11) 11. The polymorph according to any one of items 1, 9 and 10, characterized in that it has an XRPD pattern substantially as shown in Figure 2A. (Item 12) 12. The polymorph according to any one of items 1 and 9 to 11, characterized in that it has a DSC graph substantially as shown in Figure 2B. (Item 13) 13. The polymorph according to any one of items 9 to 12, characterized by an endothermic onset at about 199°C as determined by DSC. (Item 14) 14. The polymorph according to any one of items 1 and 9 to 13, characterized in that it has a TGA graph substantially as shown in Figure 2B. (Item 15) 2. The polymorph according to item 1, characterized in that it has an XRPD pattern comprising peaks at 9.6±0.2, 10.9±0.2, 15.8±0.2 and 18.1±0.2 degrees 2-theta angles. (Item 16) 2. The polymorph according to item 1, characterized in that it has an XRPD pattern comprising peaks at 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2 and 24.4±0.2 degrees 2-theta. (Item 17) 17. The polymorph according to item 1 or 16, characterized in that it has an XRPD pattern comprising peaks at 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2 and 24.8±0.2 degrees 2-theta. (Item 18) 18. The polymorph according to any one of items 1, 16 and 17, characterized in that it has an XRPD pattern substantially as shown in Figure 4A. (Item 19) 19. The polymorph according to any one of items 1 and 16 to 18, characterized in that it has a DSC graph substantially as shown in Figure 4B. (Item 20) 20. The polymorph according to any one of items 1 and 16-19, characterized by an endothermic onset at about 200°C as determined by DSC. (Item 21) 21. The polymorph according to any one of items 1 and 16 to 20, characterized in that it has a TGA graph substantially as shown in Figure 4B. (Item 22) 2. The polymorph according to item 1, characterized in that it has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2 and 24.7±0.2 degrees 2-theta angle. (Item 23) 23. The polymorph according to item 1 or 22, characterized in that it has an XRPD pattern comprising peaks at 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2 and 26.7±0.2 degrees 2-theta. (Item 24) 24. The polymorph of any one of items 1, 22 and 23, characterized in that it has an XRPD pattern comprising peaks at 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2 and 31.1±0.2 degrees two-theta angle. (Item 25) Item 1 and 2, characterized in that they have an XRPD pattern substantially as shown in FIG. 25. The polymorph according to any one of claims 22 to 24. (Item 26) 2. The polymorph according to item 1, characterized in that it has an XRPD pattern comprising peaks at 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2 and 17.8±0.2 degrees 2-theta angle. (Item 27) 27. The polymorph according to item 1 or 26, characterized in that it has an XRPD pattern comprising peaks at 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2 and 17.8±0.2 degrees 2-theta. (Item 28) 28. The polymorph according to any one of items 1, 26 and 27, characterized in that it has an XRPD pattern substantially as shown in Figure 6A. (Item 29) 29. The polymorph according to any one of items 1 and 26 to 28, characterized in that it has a TGA graph substantially as shown in Figure 6B or Figure 6C. (Item 30) 30. The polymorph according to any one of items 1 and 26-29, characterized by an endothermic onset at about 200°C as determined by DSC. (Item 31) 31. The polymorph of any one of items 1 and 26-30, characterized in that it has a DSC graph substantially as shown in Figure 6D or Figure 6E. (Item 32) (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent; and (2) cooling the mixture of step (1) or removing the solvent from the mixture of step (1). 9. A method for preparing the polymorph according to any one of items 2 to 8, comprising: (Item 33) 33. The method of claim 32, wherein the solvent comprises dichloromethane (DCM). (Item 34) Item 34. The method according to item 32 or 33, wherein step (2) comprises removing the solvent. (Item 35) 15. A method for preparing the polymorph according to any one of items 9 to 14, comprising the step of milling Form I in water. (Item 36) (1) forming a mixture of Form I and ethanol; and (2) cooling the mixture of step (1); 15. A method for preparing the polymorph according to any one of items 9 to 14, comprising: (Item 37) Item 37. The method of item 36, wherein step (1) comprises heating the mixture to about 60°C. (Item 38) Item 38. The method of claim 36 or 37, wherein step (2) comprises cooling the mixture of step (1) to about −5° C., about −10° C., about −15° C., or about −20° C. (Item 39) (1) (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4 - forming a mixture of the carboxamide with a solvent, wherein the solvent comprises acetonitrile (ACN) or a mixture of ACN and water, and (2) cooling the mixture of step (1). 22. A method for preparing the polymorph according to any one of items 16 to 21, comprising: (Item 40) Item 39. The method according to item 39, wherein step (1) comprises heating a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 80° C. (Item 41) 41. The method of claim 39 or 40, wherein step (2) comprises cooling the mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 20° C. (Item 42) (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an acetate ester; and (2) cooling the mixture of step (1). 26. A method for preparing the polymorph according to any one of items 22 to 25, comprising: (Item 43) 43. The method of claim 42, wherein the solvent comprises ethyl acetate. (Item 44) Item 44. The method according to item 42 or 43, wherein step (2) comprises cooling the mixture of step (1) to about 5°C. (Item 45) 45. The method according to any one of items 42 to 44, further comprising the step of separating said polymorph present in long needle morphology. (Item 46) (1) forming a mixture of (R)—N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises a nitrile and water; and (2) stirring the mixture of step (1); 32. A method for preparing the polymorph of any one of embodiments 26-31, comprising: (Item 47) The method of embodiment 46, wherein the solvent comprises acetonitrile. (Item 48) 48. The method of embodiment 46 or 47, wherein step (2) comprises cooling the mixture of step (1) to between about 0°C and about 10°C. (Item 49) 32. A pharmaceutical composition comprising the polymorph according to any one of items 1 to 31 and a pharmaceutically acceptable excipient. (Item 50) 50. A method of treating a cardiac disease in a subject in need thereof, comprising administering to said subject the polymorph of any one of items 1 to 31 or the pharmaceutical composition of item 49. (Item 51) 51. The method of item 50, wherein the heart disease is hypertrophic cardiomyopathy (HCM). (Item 52) 52. The method of claim 51, wherein the HCM is obstructive or non-obstructive, or is associated with sarcomeric and / or non-sarcomeric mutations. (Item 53) 51. The method of item 50, wherein the heart disease is heart failure with preserved ejection fraction (HFpEF). (Item 54) 51. The method of claim 50, wherein the cardiac disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina pectoris, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, and infiltrative cardiomyopathy. (Item 55) 48. The method of item 47, wherein the cardiac disease is or is associated with one or more conditions selected from the group consisting of cardiac aging, age-related diastolic dysfunction, left ventricular hypertrophy, and concentric left ventricular remodeling. (Item 56) 50. A method of treating a disease or condition associated with hypertrophic cardiomyopathy in a subject in need thereof, comprising administering to said subject the polymorph of any one of items 1 to 31, or the pharmaceutical composition of item 49. (Item 57) 57. The method of item 56, wherein the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome. (Item 58) 50. A method of treating a disease or condition associated with secondary left ventricular wall thickening in a subject in need thereof, comprising administering to said subject the polymorph of any one of items 1 to 31 or the pharmaceutical composition of item 49. (Item 59) 59. The method of item 58, wherein the disease or condition is selected from the group consisting of hypertension, valvular heart disease, metabolic syndrome, end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, and Pompe disease. (Item 60) 50. A method of treating a disease or condition associated with small left ventricular lumen and lumen obstruction, hyperdynamic left ventricular contractions, myocardial ischemia, or cardiac fibrosis in a subject in need thereof, comprising administering to said subject a polymorph according to any one of items 1 to 31 or a pharmaceutical composition according to item 49. (Item 61) 50. A method of treating a disease or condition selected from muscular dystrophy and glycogen storage disease in a subject in need thereof, comprising administering to said subject a polymorph according to any one of items 1 to 31 or a pharmaceutical composition according to item 49. (Item 62) 50. A method of inhibiting cardiac sarcomeres, comprising contacting said cardiac sarcomeres with the polymorph of any one of items 1 to 31, or the pharmaceutical composition of item 49.

Claims

1. A polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, said polymorph being polymorph form IV, said polymorph form IV having an XRPD pattern comprising peaks at 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, 24.8±0.2, and 28.0±0.2 degrees 2-theta.

2. The polymorphic Form IV was 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2, 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.8±0.2 2. The polymorph of claim 1, having an XRPD pattern comprising peaks at 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28.0±0.2, 28.6±0.2, 29.0±0.2, 30.0±0.2, 30.5±0.2, 30.8±0.2, 31.0±0.2, 31.4±0.2, 33.8±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, and 39.8±0.2 degrees two-theta.

3. 3. The polymorph of claim 1 or 2, wherein the polymorphic Form IV has an endothermic onset at 200±2° C. as determined by DSC.

4. 4. The polymorph of any one of claims 1 to 3, wherein the polymorphic Form IV has a weight loss of 0.003% from onset to 200°C as determined by TGA.

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