RU2846046C2 - Polymorphs (r)-n-(5-(5-ethyl-1,2,4,-oxadiazol-3-yl)-2,3-dihydro-1n-inden-1-yl)-1-methyl-1n-pyrazole-4-carboxamide - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to 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, where said polymorph is polymorphic form IV, wherein said polymorphic form IV is characterized by: a) an X-ray powder diffraction (XRPD) pattern comprising peaks at 2-theta 11.1 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 22.8 ± 0.2, 24.4 ± 0.2 degrees; and/or b) an XRPD pattern comprising peaks 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; and/or c) an XRPD pattern comprising peaks at 2-theta 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, 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, 39.8 ± 0.2 degrees; and/or d) is characterized by an XRPD pattern as shown in Fig. 4A; and/or e) a differential scanning calorimetry (DSC) graph as shown in Fig. 4B; and/or f) beginning of endotherm at 200 ± 2 °C, as determined by DSC; and/or g) a thermogravimetric analysis (TGA) graph as shown in Fig. 4b; and/or h) weight loss by 0.003 % from beginning to 200 °C, as shown in tga graph.

EFFECT: polymorphic 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, having stability.

9 cl, 7 tbl, 15 dwg, 11 ex

Description

CROSS-REFERENCE TO RELATED APPLICATION

[1] This application claims priority and benefit from co-pending U.S. Patent Application Ser. No. 62/875,350, filed July 17, 2019, the entire disclosure of which is incorporated herein by reference in its entirety.

AREA OF TECHNOLOGY

[2] This document provides 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, their compositions, methods for their preparation, and methods of using them.

LEVEL OF TECHNOLOGY

[3] The cardiac sarcomere consists of a network of contractile and structural proteins that regulate cardiac muscle function. Components of the cardiac sarcomere represent targets for the treatment of various cardiac diseases and conditions, for example by increasing contractility or facilitating full relaxation to modulate systolic and diastolic function, respectively. The force and velocity of cardiac muscle contraction are major determinants of organ function and are modulated by cyclic interactions of actin and myosin. Regulation of actin and myosin coupling is determined by a network of myofilament regulatory proteins and intracellular Ca ²⁺ levels. Troponin complex and tropomyosin are thin filament proteins that regulate the availability of actin binding sites, and the basic and regulatory light chains and myosin-binding protein C modulate the position and mechanical properties of myosin.

[4] Abnormalities in the cardiac sarcomere have been identified as the underlying cause of 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 making the heart muscle either hyper- or hypocontractile. Cardiac sarcomere modulators can be used to restore the contractility balance and halt or reverse the disease.

[5] Available agents targeting the cardiac sarcomere, such as inotropes (drugs that increase cardiac contractility), are poorly selective for cardiac tissue, resulting in known adverse effects that limit their use. These adverse effects include cellular injury caused by an increased rate of energy expenditure, exacerbation of relaxation disorders, and potential arrhythmogenic side effects that may result from increased cytosolic Ca ⁺⁺ and cyclic adenosine monophosphate AMP concentrations in inotropically stimulated myocardium. Given the limitations of available agents, new approaches are needed to improve cardiac function in HCM and HFpEF.

[6] There remains an urgent need for agents that utilize novel mechanisms of action and can result in improved outcomes in terms of symptom relief, safety, and patient mortality, both short-term and long-term. Novel agents with an improved therapeutic index compared to existing agents will provide the means to achieve these clinical outcomes. Selectivity of agents targeting the cardiac sarcomere (eg, by targeting cardiac myosin) has been identified as an important means to achieve an 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 effect on smooth muscle myosin. The advantages of this compound include a broader therapeutic index, less effect on cardiac relaxation, better pharmacokinetic parameters and better safety, so it provides a potential treatment for cardiac diseases and conditions.

[7] To transform 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 successful pharmaceutical product, it may be important to understand whether the drug candidate has polymorphic forms, as well as the relative stability and interconversion of these forms under conditions that may arise during large-scale manufacturing, transportation, storage, and preparation for use. The ability to control and produce a stable polymorph through a robust manufacturing process may be key to regulatory approval and marketing. Large-scale processes for the preparation of 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 certain polymorphic forms. Accordingly, there is a need for various new 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 different chemical and physical stabilities, as well as their compositions and applications.

BRIEF DISCLOSURE

[8] According to one aspect, the present document provides 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.

[9] According to another aspect, the present document provides 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.

[10] According to another aspect, the present document provides compositions comprising the 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 disclosed herein.

[11] According to another aspect, the present document provides methods for treating a cardiac 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.

DISCLOSURE OF GRAPHIC MATERIALS

[12] 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.

[13] Fig. 1B shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of polymorph 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.

[14] In FIG. 1C shows a dynamic vapor sorption (DVA) graph of form I polymorph (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazol-4-carboxamide.

[15] Figure 2A shows the experimental XRPD pattern of polymorph 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.

[16] In FIG. 2B shows DSC and TGA plots of polymorph II (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[17] Fig. 3A shows the 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.

[18] In FIG. 3B shows DSC and TGA plots of a mixture of polymorphs 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.

[19] Figure 4A shows the experimental XRPD pattern of polymorph 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.

[20] In FIG. 4B shows DSC and TGA plots of polymorph 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.

[21] Figure 5 shows the experimental XRPD pattern and two simulated 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 (from top to bottom: simulated at 223 K; simulated at 273 K; experimental).

[22] Figure 6A shows two experimental XRPD patterns of polymorph 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) top - XRPD of Form VI taken before drying; and (b) bottom - after drying (oven, vacuum, 24 hours, at 25°C).

[23] Figures 6B and 6C show the TGA plots of polymorph 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 (oven, vacuum, overnight, 25°C) of Form VI over the range 25-300°C. Figure 6C shows the TGA plot over the range 25-300°C for a sample of Form VI that was oven-dried (oven, vacuum, overnight, 25°C) and then heated at 150°C prior to thermogravimetric analysis.

[24] Figures 6D and 6E show the DSC plots of polymorph 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 (oven, vacuum, overnight, 25°C) of Form VI over the range 25-300°C. Figure 6E shows the DSC plot over the range 25-300°C for a sample of Form VI that was oven-dried (oven, vacuum, overnight, 25°C) and then heated at 150°C prior to thermogravimetric analysis.

DETAILED DISCLOSURE

Definitions

[25] As used in this document and in the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise.

[26] Unless otherwise specified, the terms "about" and "approximately" as used herein, when used in conjunction with doses, amounts, or weight percentages of ingredients in a composition or dosage form, mean a dose, amount, or weight percentage that is known to those skilled in the art to provide a pharmacological effect equivalent to that obtained from the stated dose, amount, or weight percentage. In particular, the terms "about" and "approximately" as used herein mean a dose, amount, or weight percentage within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the stated dose, amount, or weight percentage.

[27] As used herein, the term "polymorph" or "polymorphic form" refers to the crystalline form of a compound. Different polymorphs may have different physical properties, such as, for example, melting points, heats of fusion, solubilities, dissolution rates, and/or vibrational spectra, as a result of the arrangement or conformation of the molecules or ions in the crystal lattice. Differences in the physical properties exhibited by polymorphs may affect pharmaceutical parameters such as storage stability, compressibility, density (important in product formulation and manufacturing), and dissolution rate (important in bioavailability). Differences in stability may result from changes in chemical reactivity {eg, differential oxidation, whereby a dosage form discolors more rapidly when composed of one polymorph than when containing another polymorph), mechanical changes {eg, tablets crumble on storage as a kinetically favorable polymorph converts to a thermodynamically more stable polymorph), or both (eg, tablets of one polymorph are more susceptible to disintegration in high humidity). As a result of differences in solubility/dissolution, at the extreme, some polymorphic transitions may result in lack of efficacy or, at the other extreme, toxicity. Additionally, the physical properties of the crystalline form may be important in processing; for example, one polymorph may be more likely to form solvates or may be difficult to filter and leach out of impurities (eg, the shape and particle size distribution may differ between polymorphs).

[28] As used herein, the term "therapeutically effective amount" means an amount that produces a desired pharmacological and/or physiological effect with respect to a condition. The effect may be prophylactic in terms of complete or partial prevention of the condition or a symptom thereof and/or may be therapeutic in terms of partial or complete cure of the condition and/or an adverse effect associated with the condition.

[29] As used herein, the term "pharmaceutically acceptable carrier" and its related words refer to adjuvants, vehicles, diluents, etc., known to one of skill in the art that are suitable for administration to an individual (e.g., a mammal or non-mammal). Combinations of two or more carriers are also contemplated. The pharmaceutically acceptable carrier(s) and any additional components disclosed herein should be suitable for use in the intended route of administration (e.g., oral, parenteral) for the particular dosage form, as will be known to one of skill in the art.

[30] The terms "treat," "treating," and "treatment" mean alleviating or eliminating 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. Often, the beneficial effects that a subject obtains from a therapeutic agent do not result in a complete cure of the disease, disorder, or condition.

[31] 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 to refer to, for example, a mammalian subject, such as a human.

[32] As used herein, the term "substantially as shown in" when referring to, for example, an XRPD pattern, a DSC plot, a TGA plot, or a GSP vapor sorption gravimetric plot, includes a pattern or plot that is not necessarily identical to those depicted herein but that is within the limits of experimental error or variation when considered by one of ordinary skill in the art.

[33] 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% by weight of impurities. In other embodiments, "substantially pure" refers to a substance that does not contain impurities. Impurities may include, for example, by-products or residues from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.

[34] As used herein, the term "substantially free" means that the composition containing the 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 specified substance or substances.

Polymorphs

[35] According to one aspect, the present document provides 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, a compound characterized by the structure shown below

Polymorphs may have properties, such as bioavailability and stability under certain conditions, that are suitable for medical or pharmaceutical applications.

[36] The 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 may provide advantages in bioavailability and stability and may be suitable for use as an active agent in a pharmaceutical composition. Variations in the crystal structure of a pharmaceutical drug substance may affect the rate of dissolution (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known potency, etc.), and stability (e.g., thermal stability, shelf life (including resistance to degradation), etc.) of the pharmaceutical drug product. Such variations may affect the methods of preparing or formulating pharmaceutical compositions in different dosages or delivery forms, such as solid oral dosage forms, including tablets and capsules. Compared to other forms, such as non-crystalline or amorphous forms, polymorphs may provide desirable or advantageous 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 may provide advantages in terms of improved manufacturing process of the active agent, or stability or storage of the drug product form of the active agent, or having suitable bioavailability and/or stability as the active agent.

[37] It has been found that the use of certain conditions, such as the use of different solvents and/or temperatures, allows for the preparation of different 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 the polymorphic forms I-VI disclosed herein, which may exhibit one or more of the advantageous characteristics disclosed herein. Methods for preparing the polymorphs disclosed herein and the characterization of these polymorphs are described in more detail below.

Form I

[38] According to some embodiments, provided herein is polymorph 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.

[39] According to some embodiments, Form I is characterized by an XRPD pattern substantially as shown in Fig. 1A. The 2-theta angles and relative peak intensities that can be observed for Form I using XRPD are shown in Table 1.

[40] According to some embodiments, polymorph Form I is characterized by an XRPD pattern that exhibits 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 with the highest intensity in the XRPD pattern, substantially as shown in Fig. 1A or as presented in Table 1. It should be appreciated that the relative intensities may vary depending on a number of factors, including sample preparation, setup, and the instrument, analytical procedure, and settings used to obtain the spectrum. The relative peak intensities and peak distributions may vary within experimental error. In some embodiments, the peak distributions provided herein, including for polymorphic Form I, may vary within approximately ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[41] According to some embodiments, polymorphic Form I is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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, 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. According to some embodiments, polymorphic Form I is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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. According to some embodiments, polymorphic Form I is characterized by an XRPD pattern comprising peaks at 2-theta angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees. It should be taken into account that additional peaks may be observed in the XRPD pattern other than those shown in Fig. 1 or presented in Table 1, for example, due to the presence of impurities, solvent or other polymorphs or amorphous forms present in the test sample.

[42] In some embodiments, Form I is characterized by a differential DSC plot substantially as shown in Fig. 1B. In some embodiments, Form I is characterized by an endotherm onset at about 199°C as determined by DSC. According to some embodiments, Form I is characterized by an onset of endotherm 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 with with the help of DSC.

[43] According to some embodiments, Form I is characterized by a TGA plot substantially as shown in Fig. 1B.

[44] According to some embodiments, Form I is characterized by a DSP schedule substantially as shown in Fig. 1C.

[45] According to 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 applicable:

(a) Form I is characterized by an XRPD pattern containing peaks at 2-theta angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees; an XRPD pattern containing peaks at 2-theta angles of 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; or an XRPD pattern containing peaks at 2-theta angles of 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, 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;

(b) Form I is characterized by an XRPD pattern substantially as shown in Fig. 1A;

(c) Form I is characterized by a DSC plot substantially as shown in Fig. 1B;

(d) Form I is characterized by an endotherm onset at approximately 199°C as determined by DSC;

(e) Form I is characterized by a TGA plot substantially as shown in Fig. 1B; and

(f) Form I is characterized by a DSP graph substantially as shown in Fig. 1C.

Form II

[46] According to some embodiments, provided herein is a polymorph 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.

[47] According to some embodiments, Form II is characterized by an XRPD pattern substantially as shown in Fig. 2A. The 2-theta angles and relative peak intensities that can be observed for Form II using XRPD are shown in Table 2.

[48] According to some embodiments, polymorph Form II is characterized by an XRPD pattern that exhibits 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 with the highest intensity in the XRPD pattern, substantially as shown in Fig. 2A or as presented in Table 2. It should be appreciated that the relative intensities may vary depending on a number of factors, including sample preparation, setup, and the instrument, analytical procedure, and settings used to obtain the spectrum. The relative peak intensities and peak distributions may vary within experimental error. In some embodiments, the peak distributions provided herein, including for polymorphic Form II, may vary within approximately ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[49] According to some embodiments, polymorphic Form II is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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, 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. According to some embodiments, polymorphic Form II is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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. According to some embodiments, polymorphic form II is characterized by an XRPD pattern comprising peaks at 2-theta angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees. It should be appreciated that additional peaks may be observed in the XRPD pattern other than those shown in Fig. 2A or presented in Table 2, for example, due to the presence of impurities, solvent, or other polymorphs or amorphous forms present in the test sample.

[50] In some embodiments, Form II is characterized by a DSC plot substantially as shown in Fig. 2B. In some embodiments, Form II is characterized by an endotherm onset at about 199°C, as determined by DSC. In some embodiments, Form II is characterized by an endotherm 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 with with the help of DSC.

[51] According to some embodiments, Form II is characterized by a TGA plot substantially as shown in Fig. 2B.

[52] According to 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 applicable:

(a) Form II is characterized by an XRPD pattern containing peaks at 2-theta angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees; an XRPD pattern containing peaks at 2-theta angles of 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; or an XRPD pattern containing peaks at 2-theta angles of 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, 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;

(b) Form II is characterized by an XRPD pattern substantially as shown in Fig. 2A;

(c) Form II is characterized by a DSC plot substantially as shown in Fig. 2B;

(d) Form II is characterized by an onset of melting endotherm at approximately 199°C as determined by DSC; and

(e) Form II is characterized by a TGA plot substantially as shown in Fig. 2B.

Form III

[53] According to some embodiments, provided herein is polymorph 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.

[54] According to some embodiments, the mixture of Forms I and III is characterized by an XRPD pattern substantially as shown in Fig. 3A. The 2-theta angles and relative peak intensities that can be observed for the mixture of Forms I and III using XRPD are shown in Table 3.

[55] According to some embodiments, polymorphic Form III is characterized by an XRPD pattern comprising peaks at 2-theta angles of 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees. According to some embodiments, polymorphic Form III is characterized by an XRPD pattern comprising peaks at 2-theta angles of 9.6±0.2, 10.9±0.2, 14.5±0.2, 15.8±0.2, and 18.1±0.2 degrees. In some embodiments, polymorphic Form III is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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. It should be appreciated that the relative intensities may vary depending on a number of factors, including sample preparation, setup, and the instrument, analytical procedure and settings used to obtain the spectrum. The relative peak intensities and peak distributions may vary within experimental error. In some embodiments, the peak distributions provided herein, including for polymorphic Form III, may vary within about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees or ±0.1 degrees 2-theta.

[56] According to some embodiments, the mixture of polymorphic forms I and III is characterized by a DSC plot substantially as shown in Fig. 3B.

[57] According to some embodiments, the mixture of polymorphic forms I and III is characterized by a TGA plot substantially as shown in Fig. 3B.

Form IV

[58] According to some embodiments, provided herein is polymorph 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.

[59] According to some embodiments, Form IV is characterized by an XRPD pattern substantially as shown in Fig. 4A. The 2-theta angles and relative peak intensities that can be observed for Form IV using XRPD are shown in Table 4.

[60] According to some embodiments, polymorph Form IV is characterized by an XRPD pattern that exhibits 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 with the highest intensity in the XRPD pattern, substantially as shown in Fig. 4A or as presented in Table 4. It should be appreciated that the relative intensities may vary depending on a number of factors, including sample preparation, setup, and the instrument, analytical procedure, and settings used to obtain the spectrum. The relative peak intensities and peak distributions may vary within experimental error. In some embodiments, the peak distributions provided herein, including for polymorphic form IV, may vary within approximately ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[61] According to some embodiments, polymorphic Form IV is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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, 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, 39.8±0.2 degrees. According to some embodiments, polymorphic Form IV is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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. According to some embodiments, polymorphic form IV is characterized by an XRPD pattern comprising peaks at 2-theta angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees. It should be appreciated that additional peaks may be observed in the XRPD pattern other than those shown in Fig. 4A or presented in Table 4, for example, due to the presence of impurities, solvent, or other polymorphs or amorphous forms present in the test sample.

[62] In some embodiments, Form IV is characterized by a DSC plot substantially as shown in Fig. 4B. In some embodiments, Form IV is characterized by an endotherm onset at about 200°C, as determined by DSC. According to some embodiments, Form IV is characterized by an onset of 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 using DSC.

[63] According to some embodiments, Form IV is characterized by a TGA plot substantially as shown in Fig. 4B.

[64] According to 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 applicable:

(a) Form IV is characterized by an XRPD pattern containing peaks at 2-theta angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees; an XRPD pattern containing peaks at 2-theta angles of 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; or an XRPD pattern containing peaks at 2-theta angles of 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, 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, 39.8±0.2 degrees;

(b) Form IV is characterized by an XRPD pattern substantially as shown in Fig. 4A;

(c) Form IV is characterized by a DSC plot substantially as shown in Fig. 4B;

(d) Form IV is characterized by an onset of melting endotherm at approximately 200°C as determined by DSC; and

(e) Form IV is characterized by a TGA plot substantially as shown in Fig. 4B.

Form V

[65] According to some embodiments, provided herein is a 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.

[66] According to some embodiments, Form V is characterized by an XRPD pattern substantially as shown in Fig. 5. The 2-theta angles and relative peak intensities that can be observed for Form V using XRPD are shown in Table 5.

[67] According to some embodiments, polymorph Form V is characterized by an XRPD pattern that exhibits 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 with the highest intensity in the XRPD pattern, substantially as shown in Fig. 5 or as presented in Table 5. It should be appreciated that the relative intensities may vary depending on a number of factors, including sample preparation, setup, and the instrument, analytical procedure, and settings used to obtain the spectrum. The relative peak intensities and peak distributions may vary within experimental error. In some embodiments, the peak distributions provided herein, including for polymorphic form V, may vary within approximately ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[68] According to some embodiments, polymorphic Form V is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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, 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, 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. According to some embodiments, polymorphic Form V is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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. According to some embodiments, polymorphic Form V is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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. According to some embodiments, polymorphic Form V is characterized by an XRPD pattern comprising peaks at 2-theta angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees. It should be taken into account that additional peaks may be observed in the XRPD pattern other than those shown in Fig. 5 or presented in Table 5, for example, due to the presence of impurities, solvent or other polymorphs or amorphous forms present in the test sample.

[69] According to some embodiments of Form V, at least one or both of the following (a)-(b) are applicable:

(a) Form V is characterized by an XRPD pattern containing peaks at 2-theta angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees; an XRPD pattern containing peaks at 2-theta angles of 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; or an XRPD pattern containing peaks at 2-theta angles of 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; and

(b) Form V is characterized by an XRPD pattern substantially as shown in Fig. 5.

Form VI

[70] According to some embodiments, provided herein is polymorph 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.

[71] According to some embodiments, Form VI is characterized by an XRPD pattern substantially as shown in Fig. 6A. The 2-theta angles and relative peak intensities that can be observed for Form VI using XRPD are shown in Table 6.

[72] According to some embodiments, polymorph Form VI is characterized by an XRPD pattern 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 with the highest intensity in the XRPD pattern, substantially as shown in Fig. 6A or as presented in Table 6. It should be appreciated that the relative intensities may vary depending on a number of factors, including sample preparation, setup, and the instrument, analytical procedure, and settings used to obtain the spectrum. The relative peak intensities and peak distributions may vary within experimental error. In some embodiments, the peak distributions provided herein, including for polymorphic Form VI, may vary within approximately ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2-theta.

[73] According to some embodiments, polymorph Form VI is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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, 27.6±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. According to some embodiments, polymorphic Form VI is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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. According to some embodiments, polymorphic Form VI is characterized by an XRPD pattern comprising peaks at 2-theta angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees. It should be noted that additional peaks may be observed in the XRPD pattern other than those shown in Fig. 6A or presented in Table 6, for example, due to the presence of impurities, solvent, or other polymorphs or amorphous forms present in the test sample.

[74] According to some embodiments, Form VI is characterized by a TGA plot substantially as shown in Fig. 6B or a TGA plot substantially as shown in Fig. 6C. According to some embodiments, Form VI exhibits a weight loss of about 2%±0.5% from 25°C to 200°C, as determined by TGA.

[75] According to some embodiments, Form VI is characterized by a DSC plot substantially as shown in Fig. 6D or a DSC plot substantially as shown in Fig. 6E. According to some embodiments, Form VI is characterized by an onset of 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 using DSC. In some embodiments, Form VI is characterized by an onset of an 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), an exotherm 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, 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 the onset of the endotherm at approximately 41±2°C (e.g., 41±1.9°C, 41±1.8°C, 41±1.7°C, 41±1.6°C, 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 any combinations thereof.

[76] According to 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 applicable:

(a) Form VI is characterized by an XRPD pattern containing peaks at 2-theta angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees; an XRPD pattern containing peaks at 2-theta angles of 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; or an XRPD pattern containing peaks at 2-theta angles of 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, 27.6±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 is characterized by an XRPD pattern substantially as shown in Fig. 6A;

(c) Form VI is characterized by a TGA plot substantially as shown in Fig. 6B or Fig. 6C;

(d) Form VI is characterized by a mass loss of approximately 2%±0.5% over the temperature range 25°C to 200°C as determined by TGA;

(e) Form VI is characterized by a DSC plot substantially as shown in Fig. 6D or Fig. 6E; and

(f) Form IV is characterized by an onset of melting endotherm at approximately 200°C as determined by DSC; and

(d) Form VI is characterized by an onset of endotherm at approximately 200°C, an onset of exotherm at approximately 115°C, or an onset of endotherm at approximately 41°C, or any combination thereof, as determined by DSC.

Compositions

[77] Also provided herein are compositions comprising the polymorphs disclosed herein, such as Form I, Form II, Form III, Form IV, Form V, Form VI, or a mixture thereof. In some embodiments, the composition comprises Form I. In some embodiments, the composition comprises Form II. In some embodiments, the composition comprises Form III. In some embodiments, the composition comprises a mixture of Forms I and III. In some embodiments, the composition comprises Form IV. In some embodiments, the composition comprises Form V. In some embodiments, the composition comprises Form VI. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[78] According to some embodiments, a composition comprising 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 is provided. According to some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms II through 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 an amorphous or non-crystalline 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. In some embodiments, the composition is substantially free of a salt 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.

[79] According to some embodiments of a composition comprising 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 a composition comprising 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 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide exists in Form I.

[80] According to some embodiments, a composition comprising 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. According to 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 an amorphous or non-crystalline 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. In some embodiments, the composition is substantially free of a salt 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.

[81] According to some embodiments of a composition comprising 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 a composition comprising 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 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide exists in Form II.

[82] According to some embodiments, a composition comprising 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 is provided. According to 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 an amorphous or non-crystalline 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. In some embodiments, the composition is substantially free of a salt 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.

[83] According to some embodiments of a composition comprising 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 a composition comprising Form III (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 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide exists in Form III.

[84] According to some embodiments, a composition comprising 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 is provided. According to 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 an amorphous or non-crystalline 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. In some embodiments, the composition is substantially free of a salt 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.

[85] According to some embodiments of a composition comprising 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. In some embodiments of a composition comprising 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, 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 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide exists in Form IV.

[86] According to some embodiments, a composition comprising 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 is provided. In some embodiments, Form I and Form IV are present in a weight ratio of 99 to 1, 90 to 10, 80 to 20, 70 to 30, 60 to 40, 50 to 50, 40 to 60, 30 to 70, 20 to 80, 10 to 90, or 1 to 99. In some embodiments, the weight ratio of Form I to Form IV is from 90 to 10 to 99 to 1. In some embodiments of a composition comprising 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 comprising 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 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 (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 in Form I. In some embodiments of a composition comprising 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 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. According to some embodiments of a composition comprising 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 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazol-4-carboxamide exists in form IV.

[87] According to some embodiments, a composition comprising 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 is provided. According to some embodiments, the composition is 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 an amorphous or non-crystalline 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. In some embodiments, the composition is substantially free of a salt 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.

[88] According to some embodiments of a composition comprising 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 a composition comprising 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 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide exists in Form V.

[89] According to some embodiments, a composition comprising 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 is provided. According to some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of Polymorphic Forms I through 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 an amorphous or non-crystalline 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. In some embodiments, the composition is substantially free of a salt 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.

[90] According to some embodiments of a composition comprising 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, 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 a composition comprising 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, 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 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide exists in Form VI.

[91] According to some embodiments, there is provided a tablet or capsule comprising one or more polymorphic forms disclosed herein (e.g., Form I, II, III, IV, V, VI, or a mixture thereof) and one or more pharmaceutically acceptable carriers. According to some embodiments, there is provided a tablet or capsule comprising 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. According to some embodiments, there is provided a tablet or capsule comprising substantially pure polymorph 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. According to some embodiments, there is provided a tablet or capsule comprising substantially pure polymorph 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. According to some embodiments, there is provided a tablet or capsule comprising substantially pure polymorph 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. According to some embodiments, there is provided a tablet or capsule comprising substantially pure polymorph 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. According to some embodiments, a tablet or capsule is provided comprising substantially pure polymorph 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.

Method of obtaining

Form I

[92] According to some embodiments, a method for preparing polymorph 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 is provided, 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 includes an alcohol (e.g., methanol, ethanol, or propanol), an acetate (e.g., isopropyl acetate or ethyl acetate), an ether (e.g., methyl tert-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., NN-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-methyltetrahydrofuran), 2-propanol (IPA), tetrahydrofuran (THF), water, diethyl ether ( _Et2O ), 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 an elevated temperature (e.g., a temperature greater than room temperature), such as 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 should be appreciated that Form I can also be prepared using a suitable method as disclosed in Example 6 below.

[93] According to some embodiments, the method for preparing Polymorph 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 further comprises a method for preparing (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) reacting tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate with propanoyl propanoate, thereby forming 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) to thereby form (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine and β) 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 to thereby form (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazol-4-carboxamide.

Form II

[94] According to some embodiments, a method for preparing polymorph 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 milling polymorph 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 water. According to some embodiments, a method for producing Polymorph 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 (1) forming a mixture of Polymorph 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 a solvent, wherein the solvent comprises an alcohol (e.g., methanol, ethanol, or propanol); and (2) cooling the mixture of step (1). According to some embodiments, the solvent comprises ethanol. In some embodiments, step (1) comprises heating the mixture to an elevated temperature, such as 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, step (2) comprises adding an anti-solvent. In some embodiments, the anti-solvent is water. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature lower than the temperature at which step (1) is performed, such as cooling the mixture of step (1) 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 should be appreciated that Form II can also be prepared using a suitable method as disclosed in Example 6 below. A mixture of Forms I and III

[95] According to some embodiments, a method for producing 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 and a solvent, wherein the solvent comprises an ether (e.g., methyl tert-butyl ether, diethyl ether, 2-methyltetrahydrofuran, or dioxane) or a non-aromatic hydrocarbon (e.g., hexane), or a mixture thereof; (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, such as 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, adding an anti-solvent is performed before step (2). In some embodiments, the anti-solvent is water. According to some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature lower than the temperature at which step (1) is performed, such as cooling the mixture of step (1) 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 should be appreciated that the mixture of Forms I and III can also be prepared using a suitable method as disclosed in Example 6 below.

Form IV

[96] According to some embodiments, a method for producing Polymorph 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 is provided, 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)), 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, such as 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 lower than the temperature at which step (1) is performed, such as cooling the mixture of step (1) 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. According to some embodiments, step (2) comprises cooling the mixture from step (1) to about 20°C.

[97] According to some embodiments, a method for preparing Polymorph 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 further 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, which comprises (1) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride, thereby forming (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 thereby form (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and β) 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

[98] According to some embodiments, a method for producing Polymorph 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 is provided, 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 (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 lower than the temperature at which step (1) is performed, such as cooling the mixture of step (1) 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 cooling the mixture of step (1) to about 5°C. In some embodiments, the method further comprises separating the polymorph existing in the form of long needles. According to 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 β) separating the polymorph existing in the form of long needles.

Form VI

[99] According to some embodiments, a method for preparing Polymorph 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 is provided, 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 formed in step 1 is a near saturated solution, a saturated solution, or a slurry. According to some embodiments, the mixture obtained in step 1 comprises a combination of 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 and 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 comprises Form I, Form IV, Form V, or any combination thereof. In some embodiments, the solid form includes 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., Forms 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 includes a combination of Form IV and Form VI. In some embodiments, step (2) comprises mixing the mixture at a temperature of from about 0°C to about 30°C, from about 0°C to about 25°C, from about 0°C to about 20°C, from about 0°C to about 15°C, or from about 0°C to about 10°C. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature lower than the temperature at which step (1) is performed, such as cooling the mixture of step (1) to from about 0°C to about 20°C, from about 0°C to about 15°C, or from about 0°C to 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.

Methods of application

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

[101] Without being limited by theory, it is believed that the provided polymorphic forms and compositions act by inhibiting myosin. Such inhibition potentially reduces the number of independent myosin heads interacting with actin filaments, reducing the number of contractions. Reducing cardiac muscle contraction may be important for the treatment of cardiac diseases in which excessive contraction is a problem. In some embodiments, methods are provided for treating or preventing cardiac disease in an individual or subject comprising administering to the individual or subject in need thereof a polymorphic form or composition provided herein. 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 a polymorphic form or composition 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 a polymorphic form or composition provided herein. According to some embodiments, methods of treating an established or diagnosed cardiac disease in a subject in need thereof are provided, comprising administering to the subject a therapeutically effective amount of the polymorphic form or composition provided herein. According to some embodiments, methods of preventing cardiac disease in a subject in need thereof are provided, comprising administering to the subject a therapeutically effective amount of the polymorphic form or composition provided herein.

[102] Also provided herein is the use of a polymorphic form or composition provided herein in the manufacture of a medicament for treating a cardiac disorder in a subject. In some aspects, provided herein is a polymorphic form disclosed herein for use in a method of treating a human or animal body by therapy. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in a method of treating a human or animal body by therapy. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating or preventing a cardiac disorder. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating a cardiac disorder. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating an established or diagnosed cardiac disease. In other embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in preventing a cardiac disease. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating a disease or condition associated with HCM. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating a disease or condition associated with secondary left ventricular wall thickening. According to some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in alleviating a symptom associated with a cardiac disease. According to other embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in reducing the risk of a symptom associated with a cardiac disease. According to other embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating a disease or condition associated with a small left ventricular cavity, cavity obliteration, hyperdynamic left ventricular contraction, left ventricular outflow obstruction, cardiac hypertrophy, low cardiac stroke volume, impaired left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating a disease or condition associated with left ventricular small cavity and cavity obliteration, left ventricular hyperdynamic contraction, myocardial ischemia, or cardiac fibrosis. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating muscular dystrophies. In some embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in treating glycogen storage disease. In other embodiments, provided herein is a polymorphic form, such as Form I, II, III, IV, V, or VI, or a composition thereof, for use in modulating cardiac sarcomere, such as inhibiting cardiac sarcomere. According to further embodiments, provided herein is a polymorphic form, such as form I, II, III, IV, V, or VI, or a composition thereof, for use in potentiating cardiac myosin.

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

[104] In some embodiments, the subject is at high risk for progression of symptoms. In some embodiments, the subject is at high risk for developing atrial fibrillation, ventricular tachyarrhythmia, stroke, and/or sudden death. In some embodiments, the subject has decreased exercise capacity. In some embodiments, exercise capacity is decreased compared to an age-matched control population. In some embodiments, the subject meets criteria for surgery or percutaneous ablation to treat a cardiac disorder.

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

[106] In some embodiments, provided herein are methods of treating a disease or condition associated with HCM comprising administering to an individual or subject in need thereof a polymorphic form or composition provided herein. In some embodiments, the disease or condition is Fabry disease, Danon disease, mitochondrial cardiomyopathies, or Noonan syndrome.

[107] Also provided herein is the use of the polymorphic form or composition provided herein in the manufacture of a medicament for the treatment of a disease or condition associated with HCM.

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

[109] 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 the individual or subject in need thereof a polymorphic form or composition as provided herein. In some embodiments, the disease is hypertension, heart valve disease (aortic stenosis, mitral valve regurgitation), metabolic syndromes (diabetes mellitus, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, or Pompe disease.

[110] Also provided herein is the use of the polymorphic form or composition provided herein in the manufacture of a medicament for the treatment of a disease or condition associated with secondary left ventricular wall thickening.

[111] According to some embodiments, methods are provided for alleviating a symptom associated with cardiac disease in a subject comprising administering to an individual or subject in need thereof a polymorphic form or composition as provided herein, wherein the symptom is one or more selected from poor or decreased cardiac compliance, poor or decreased left ventricular diastolic relaxation, abnormal left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or persistent atrial fibrillation, elevated left atrial and pulmonary end capillary pressure, elevated left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular myocardial mass, increased left ventricular wall thickness, left ventricular midsegment obstruction, increased mitral anterior systolic motion, valve, left ventricular outflow tract obstruction, chest pain, dyspnea on exertion, presyncope, abnormal exercise capacity and fatigue.

[112] According to some embodiments, methods are provided for treating a disease or condition associated with a small left ventricular cavity, cavity obliteration, hyperdynamic left ventricular contraction, left ventricular outflow obstruction, cardiac hypertrophy, low cardiac stroke volume, 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 a polymorphic form or composition as provided herein.

[113] According to some embodiments, methods are provided for treating a disease or condition associated with left ventricular small cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in an individual or subject, comprising administering to the individual or subject in need thereof a polymorphic form or composition as provided herein.

[114] Also provided herein is the use of the polymorphic form or composition provided herein in the manufacture of a medicament for the treatment of a disease or condition associated with a small left ventricular cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia or cardiac fibrosis.

[115] According to some embodiments, methods of treating muscular dystrophies in an individual or subject (e.g., Duchenne muscular dystrophy) are provided, comprising administering to the individual or subject in need thereof a polymorphic form or composition as provided herein. Also provided herein is the use of a polymorphic form or composition as provided herein in the manufacture of a medicament for treating muscular dystrophies (e.g., Duchenne muscular dystrophy).

[116] According to some embodiments, methods of treating a glycogen storage disease in an individual or subject are provided, comprising administering to the individual or subject in need thereof a polymorphic form or composition as provided herein. Also provided herein is the use of a polymorphic form or composition as provided herein in the manufacture of a medicament for treating a glycogen storage disease.

[117] Also provided are methods of modulating a cardiac sarcomere in an individual or subject, the method comprising administering to the individual or subject in need thereof a therapeutically effective amount of at least one chemical compound disclosed herein. In some embodiments, provided are methods of inhibiting a cardiac sarcomere comprising contacting a cardiac sarcomere with at least one chemical compound disclosed herein, such as a polymorphic form or composition as provided herein. Further provided herein is the use of at least one chemical compound disclosed herein, such as a polymorphic form or composition as provided herein, in the manufacture of a medicament for inhibiting a cardiac sarcomere in an individual or subject.

[118] Also provided are methods for potentiating cardiac myosin in an individual or subject, the method comprising administering to the individual or subject in need thereof a therapeutically effective amount of at least one chemical compound disclosed herein, such as a polymorphic form or composition as provided herein. Additionally provided herein is the use of at least one chemical compound disclosed herein, such as a polymorphic form or composition as provided herein, in the manufacture of a medicament for potentiating cardiac myosin in an individual or subject.

[119] According to some embodiments, the methods provided herein further comprise monitoring the effectiveness of the treatment. Examples of indicators include, but are not limited to, improvement in one or more of the following: New York Heart Association (NYHA) functional classification, exercise capacity, cardiac compliance, left ventricular diastolic relaxation, left atrial pressure, paroxysmal or permanent atrial fibrillation, left atrial and pulmonary capillary tip pressures, left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular myocardial mass, left ventricular wall thickness, left ventricular midsegment obstruction, mitral anterior systolic motion, left ventricular outflow tract obstruction, chest pain, dyspnea on exertion, presyncope, abnormal exercise capacity, and fatigue. These indicators can be monitored using techniques known in the art, including self-reporting; electrocardiogram ECG, including ambulatory ECG; echocardiogram; cardiac magnetic resonance imaging MRI; computed tomography CT; biopsy; cardiopulmonary exercise testing (CPET) and actigraphy.

[120] In some embodiments, the polymorphic forms or compositions disclosed herein reduce the contractility of a cardiomyocyte. In some embodiments, the polymorphic forms or compositions reduce the contractility of a cardiomyocyte by more than 40%, such as more than 45%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the polymorphic forms or compositions reduce the contractility of a cardiomyocyte by 40%-90%, such as 40%-80%, 40%-70%, 50%-90%, 50%-80%, or 50%-70%. In some embodiments, the polymorphic forms or compositions do not significantly alter calcium transients in a cardiomyocyte. In some embodiments, the polymorphic forms or compositions reduce adenosine triphosphatase ATPase activity in a cardiomyocyte. Methods for measuring contractility, ATPase activity and calcium transients are known in the art, such as by calcium labeling, electrophysiological recording and microscopic imaging. According to some embodiments, the polymorphic forms or compositions do not significantly inhibit or induce cytochrome P450 protein (CYP).

[121] According to some embodiments, the subject has a left ventricular wall that is thicker than normal before treatment. According to some embodiments, the subject has a left ventricular wall thickness that is greater than 15 mm, such as greater than 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm, before treatment. According to some embodiments, the left ventricular wall thickness is reduced by more than 5%, such as greater than 8%, 10%, 12%, 15%, 20%, or 30%, after treatment. The left ventricular wall thickness can be measured by methods known in the art, such as by an echocardiogram, a CT scan, or a cardiac MRI.

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

[123] In some embodiments, the subject has a decreased ability to tolerate exercise prior to treatment. In some embodiments, the subject's ability to tolerate exercise is increased by more than 5%, such as more than 8%, 10%, 12%, 15%, 20%, or 30%, following treatment. In some embodiments, the ability to tolerate exercise is measured using a cardiopulmonary exercise test (CPET). CPET measures changes in oxygen consumption ( _VO2 max). Methods for measuring CPET and _maxVO2 are well known in the art (Malhotra et al., JACC: Heart Failure, 2016, 4(8): 607-616; Guazzi era/., J Amer College Cardiol, 2017, 70(13): 1618-1636; Rowin et al., JACC: Cariovasc Imaging, 2017, 10(11): 1374-1386). In some embodiments, VO ₂ max is improved by more than 1 ml/kg/m ² , e.g., greater than 1.2 ml/kg/m ² , 1.4 ml/kg/m ² , 1.5 ml/kg/m ² , 1.7 ml/kg/m ² , 2 ml/kg/m ² , 2.2 ml/kg/m ² , 2.5 ml/kg/ ^m2 , 3 ml/kg/ ^m2 , 3.2 ml/kg/ ^m2 or 3.5 ml/kg/ ^m2 , after treatment.

[124] In some embodiments, the subject is in New York Heart Association (NYHA) functional class II, III, or IV prior to treatment. In some embodiments, the subject is in New York Heart Association (NYHA) functional class III or IV prior to treatment. In some embodiments, the subject is in New York Heart Association (NYHA) functional class IV prior to treatment. In some embodiments, the subject remains in the same NYHA functional class or is in a lower NYHA functional class after treatment.

[125] In some embodiments, the _VO2 max improves by more than 1 mL/kg/ ^m2 , such as more than 1.2 mL/kg/ ^m2 , 1.4 mL/kg/ ^m2 , 1.5 mL/kg/ ^m2 , 1.7 mL/kg/ ^m2 , or 2 mL/kg/ ^m2 , and the subject has a lower NYHA functional class after treatment. In some embodiments, the _VO2 max improves by more than 2.5 mL/kg/ ^m2 , 3 mL/kg/ ^m2 , 3.2 mL/kg/ ^m2 , or 3.5 mL/kg/ ^m2 , and the subject remains in the same NYHA functional class or has a lower NYHA functional class after treatment.

[126] According to some embodiments, the subject's level of daily functioning and/or activity is improved following treatment. The improved level of daily functioning and/or activity can be measured, for example, by keeping a diary or by actigraphy, for example, by using ^FITBIT® or FITBIT® ^- like monitors.

[127] In some embodiments, the subject is characterized by one or more of decreased shortness of breath, decreased chest pain, decreased abnormal heart rhythms such as atrial fibrillation and ventricular arrhythmia, decreased incidence of heart failure, and decreased ventricular outflow tract obstruction following treatment. Dosages

[128] The polymorphic forms and compositions provided and/or disclosed herein are administered at a therapeutically effective dosage, such as a dosage sufficient to provide treatment for a disease state. Although dosage levels for humans have not yet been optimized for the chemical compounds disclosed herein, in general, the daily dosage ranges from about 0.01 to 100 mg/kg body weight; in some embodiments, from about 0.05 to 10.0 mg/kg body weight; and in some embodiments, from about 0.10 to 1.4 mg/kg body weight. Thus, for administration to a 70 kg individual, in some embodiments, the dosage range would be from about 0.7 to 7000 mg per day; in some embodiments, from about 3.5 to 700.0 mg per day; and in some embodiments, from about 7 to 100.0 mg per day. The amount of the chemical compound administered will depend, for example, on the subject and the disease state being treated, the severity of the disease, the route and schedule of administration, and the judgment of the attending physician. For example, an illustrative dosage range for oral administration is from about 5 mg to about 500 mg per day, and an illustrative dosage range for intravenous administration is from about 5 mg to about 500 mg per day, each depending on pharmacokinetic parameters.

[129] A daily dose is the total amount administered per day. A daily dose may be administered ad hoc every day, every other day, every week, every 2 weeks, every month, or at a variable interval. In some embodiments, the daily dose is administered over a period ranging from one day to the life of the subject. In some embodiments, the daily dose is administered once per day. In some embodiments, the daily dose is administered in multiple divided doses, such as 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered in two divided doses.

[130] Administration of the polymorphic forms and compositions disclosed herein can be by any accepted route of therapeutic administration, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the polymorphic form or composition is administered orally or intravenously. In some embodiments, the polymorphic form or composition provided and/or disclosed herein is administered orally.

[131] Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms such as tablet, capsule, powder, liquid, suspension, suppository and aerosol forms. The polymorphic forms provided and/or disclosed herein can also be administered in sustained or controlled release dosage forms (e.g., pill

controlled/sustained release, depot injection, osmotic pump or transdermal (including electrotransport) patch forms) for prolonged and/or pulsed administration at a predetermined rate. According to some embodiments, the compositions are provided in unit dosage forms suitable for a single administration of a precisely determined dose.

[132] The polymorphic forms disclosed herein can be administered either 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 composition may also contain minor amounts of non-toxic excipients such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). In general, depending on the intended route of administration, the pharmaceutical composition will contain from about 0.005% to 95%, or from about 0.5% to 50%, by weight of a compound provided and/or disclosed herein. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

[133] According to some embodiments, the compositions will be in the form of a pill or tablet, and thus the composition may comprise, together with the polymorph form provided and/or disclosed herein, one or more of a diluent (e.g., lactose, sucrose, calcium hydrogen phosphate), a lubricant (e.g., magnesium stearate), and/or a binder (e.g., starch, acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powder, marumerized granules, solution or suspension (e.g., in propylene carbonate, vegetable oils, or triglycerides) encapsulated in a gelatin capsule.

[134] Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing or suspending, etc., a polymorphic form as provided and/or disclosed herein and optional pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectable forms can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for solution or suspension in liquid prior to injection. The percentage of polymorphic form contained in such parenteral compositions depends on, for example, the physical nature of the polymorphic form, the activity of the polymorphic form and the needs of the subject. However, a percentage of the active ingredient from 0.01% to 10% in solution may be used, and may be higher if the composition is solid and will subsequently be diluted to a different concentration. According to some embodiments, the composition will contain from about 0.2 to 2% of the polymorphic form proposed and/or disclosed herein in solution.

[135] The pharmaceutical compositions of the polymorphic forms and compositions disclosed herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as an ultrafine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition may have diameters of less than 50 microns, or in some embodiments, less than 10 microns.

[136] In addition, the pharmaceutical compositions may include a polymorphic form as provided and/or disclosed herein and one or more additional medicinal agents, pharmaceutical agents, adjuvants, etc. Suitable medicinal and pharmaceutical agents include those disclosed herein.

Sets

[137] Also provided are articles and kits comprising any of the polymorphic forms or compositions disclosed herein. The article may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. Containers may be made from a variety of materials, such as glass or plastic. The container may contain a pharmaceutical composition disclosed herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or suppress a condition disclosed herein, and may also indicate directions for in vivo or in vitro use.

[138] In one aspect, the present document provides kits comprising a polymorphic form or composition disclosed herein and instructions for use. The kits may comprise instructions for use in the treatment of a cardiac disorder in an individual or subject in need thereof. In addition, the kit may comprise any materials or equipment that may be used in administering the polymorphic form or composition, such as vials, syringes, or IV bags. The kit may also comprise sterile packaging. Combinations

[139] The polymorphic forms and compositions disclosed herein may be administered alone or in combination with other therapies and/or therapeutic agents useful in the treatment of the above-mentioned disorders, diseases or conditions.

[140] The polymorphic forms and compositions disclosed herein may be combined with one or more other therapies to treat a cardiac disease, such as HCM or HFpEF. In some embodiments, the one or more therapies include therapies that inhibit the progression of heart failure by suppressing neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, aldosterone receptor antagonists, or neutral endopeptidase inhibitors). In some embodiments, the one or more therapies include therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). In other embodiments, the one or more therapies include therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (vasodilators of any class, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators).

[141] The polymorphic forms and compositions disclosed herein may be combined with one or more other therapies for the treatment of HCM or HFpEF. In some embodiments, the polymorphic forms and compositions may be combined with a β-blocker, verapamil, and/or disopyramide.

[142] Some illustrative embodiments are presented below.

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

2. The polymorph according to embodiment 1, characterized in that it has peaks in the XRPD pattern at 2-theta angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees.

3. The polymorph according to embodiment 1 or 2, characterized in that it is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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.

4. The polymorph according to any one of embodiments 1-3, characterized in that it is characterized by an XRPD pattern substantially as shown in Fig. 1A.

5. The polymorph according to any one of embodiments 1-4, characterized in that it has a DSC plot substantially as shown in Fig. 1B.

6. The polymorph according to any one of embodiments 1-5, characterized in that it exhibits an onset of endotherm at approximately 199°C as determined by DSC.

7. The polymorph according to any one of embodiments 1-6, characterized in that it is characterized by a TGA plot substantially as shown in Fig. 1B.

8. A polymorph according to any one of embodiments 1-7, characterized in that it has a DSP graph substantially as shown in Fig. 1C.

9. The polymorph of embodiment 1, characterized in that it is characterized by an XRPD pattern containing peaks at 2-theta angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees.

10. The polymorph of embodiment 1 or 9, characterized in that it is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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.

11. A polymorph according to any one of embodiments 1, 9 and 10, characterized in that it is characterized by an XRPD pattern substantially as shown in Fig. 2A.

12. A polymorph according to any one of embodiments 1 and 9-11, characterized in that it is characterized by a DSC plot substantially as shown in Fig. 2B.

13. The polymorph according to any one of embodiments 9-12, characterized in that it exhibits an onset of endotherm at approximately 199°C as determined by DSC.

14. The polymorph according to any one of embodiments 1 and 9-13, characterized in that it is characterized by a TGA plot substantially as shown in Fig. 2B.

15. The polymorph of embodiment 1, characterized in that it is characterized by an XRPD pattern containing peaks at 2-theta angles of 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees.

16. The polymorph of embodiment 1, characterized in that it is characterized by an XRPD pattern containing peaks at 2-theta angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees.

17. The polymorph of embodiment 1 or 16, characterized in that it is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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.

18. The polymorph according to any one of embodiments 1, 16 and 17, characterized in that it is characterized by an XRPD pattern substantially as shown in Fig. 4A.

19. The polymorph according to any one of embodiments 1 and 16-18, characterized in that it is characterized by a DSC plot substantially as shown in Fig. 4B.

20. The polymorph according to any one of embodiments 1 and 16-19, characterized in that it is characterized by an onset of endotherm at approximately 200°C as determined by DSC.

21. A polymorph according to any one of embodiments 1 and 16-20, characterized in that it is characterized by a TGA plot substantially as shown in Fig. 4B.

22. The polymorph of embodiment 1, characterized in that it is characterized by an XRPD pattern containing peaks at 2-theta angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees.

23. The polymorph according to embodiment 1 or 22, characterized in that it is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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.

24. The polymorph according to any one of embodiments 1, 22 and 23, characterized in that it is characterized in that it has an XRPD pattern comprising peaks at 2-theta angles of 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.

25. The polymorph according to any one of embodiments 1 and 22-24, characterized in that it is characterized by an XRPD pattern substantially as shown in Fig. 5.

26. The polymorph of embodiment 1, characterized in that it is characterized by an XRPD pattern containing peaks at 2-theta angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees.

27. The polymorph of embodiment 1 or 26, characterized in that it is characterized by an XRPD pattern comprising peaks at 2-theta angles of 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.

28. The polymorph according to any one of embodiments 1, 26 and 27, characterized in that it is characterized by an XRPD pattern substantially as shown in Fig. 6A.

29. The polymorph according to any one of embodiments 1 and 26-28, characterized in that it is characterized by a TGA plot substantially as shown in Fig. 6B or Fig. 6C.

30. The polymorph according to any one of embodiments 1 and 26-29, characterized in that it is characterized by an onset of endotherm at approximately 200°C as determined by DSC.

31. The polymorph according to any one of embodiments 1 and 26-30, characterized in that it is characterized by a DSC plot substantially as shown in Fig. 6D or Fig. 6E.

32. A method for producing a polymorph according to any one of embodiments 2-8, 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 from step (1) or removing the solvent from the mixture from step (1).

33. The method of embodiment 32, wherein the solvent comprises dichloromethane (DCM).

34. The method according to embodiment 32 or 33, wherein step (2) comprises removing the solvent.

35. A method for producing a polymorph according to any one of embodiments 9-14, comprising milling Form I in water.

36. A method for producing a polymorph according to any one of embodiments 9-14, comprising (1) forming a mixture of Form I and ethanol and (2) cooling the mixture from step (1).

37. The method of embodiment 36, wherein step (1) comprises heating the mixture to about 60°C.

38. The method according to embodiment 36 or 37, wherein step (2) comprises cooling the mixture from step (1) to about -5°C, about -10°C, about -15°C, or about -20°C.

39. A method for producing a polymorph according to any one of embodiments 16-21, 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 acetonitrile (ACN) or a mixture of ACN and water; and

(2) cooling the mixture from stage (1).

40. The method according to 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 a solvent to about 80°C.

41. The method according to embodiment 39 or 40, wherein step (2) comprises cooling 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 to about 20°C.

42. A method for producing a polymorph according to any one of embodiments 22-25, 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 acetate and

(2) cooling the mixture from stage (1).

43. The method of embodiment 42, wherein the solvent comprises ethyl acetate.

44. The method according to embodiment 42 or 43, wherein step (2) comprises cooling the mixture from step (1) to about 5°C.

45. The method according to any one of embodiments 42-44, further comprising separating the polymorph existing in the form of long needles.

46. A method for producing a polymorph according to any one of embodiments 26-31, 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 nitrile and water; and

(2) mixing the mixture of stage (1).

47. The method of embodiment 46, wherein the solvent comprises acetonitrile.

48. The method according to embodiment 46 or 47, wherein step (2) comprises cooling the mixture from step (1) to about 0°C to about 10°C.

49. A pharmaceutical composition comprising a polymorph according to any one of embodiments 1-31 and a pharmaceutically acceptable excipient.

50. A method of treating a cardiac disease in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1-31 or a pharmaceutical composition according to embodiment 49.

51. The method of embodiment 50, wherein the heart disease is hypertrophic cardiomyopathy (HCM).

52. The method of embodiment 51, wherein the HCM is obstructive or non-obstructive or is associated with a sarcomeric and/or non-sarcomeric mutation.

53. The method of embodiment 50, wherein the heart disease is heart failure with preserved ejection fraction (HFpEF).

54. The method according to embodiment 50, wherein the heart disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right ventricular 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 left ventricular concentric remodeling.

56. A method of treating a disease or condition associated with HCM in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1-31 or a pharmaceutical composition according to 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 cardiomyopathies, and Noonan syndrome.

58. A method of treating a disease or condition that is associated with secondary left ventricular wall thickening in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1-31 or a pharmaceutical composition according to embodiment 49.

59. The method of embodiment 58, wherein the disease or condition is selected from the group consisting of hypertension, heart valve disease, metabolic syndromes, 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 left ventricular small cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia or cardiac fibrosis in a subject in need thereof, comprising administering to the subject a polymorph according to any of embodiments 1-31 or a pharmaceutical composition according to embodiment 49.

61. A method of treating a disease or condition selected from muscular dystrophies and glycogen storage diseases in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1-31 or a pharmaceutical composition according to embodiment 49.

62. A method of inhibiting a cardiac sarcomere, comprising contacting a cardiac sarcomere with a polymorph according to any one of embodiments 1-31 or a pharmaceutical composition according to embodiment 49.

Examples

[143] The following examples are provided to further aid in understanding the embodiments disclosed herein and assume an understanding of conventional techniques well known to those of ordinary skill in the art to which the examples pertain. The specific materials and conditions disclosed herein are intended to illustrate particular aspects of the embodiments disclosed herein and are not to be construed as limiting the scope thereof.

[144] The following abbreviations may be used in this document.

[145] 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

[146] The Rigaku Smart-Lab X-ray diffraction system is designed to produce a Bragg-Brentano geometry using an X-ray beam from a line source. The X-ray source was a Cu Long Fine Focus tube operated at 40 kV and 44 mA. This source provided an incident beam profile on the sample that varied from a narrow line at high angles to a wide rectangle at low angles. Beam shaping slits were used on the line X-ray source to ensure a maximum beam size of less than 10 mm along and normal to the line. The Bragg-Brentano geometry is a parafocusing geometry controlled by passive diverging and receiving slits, with the sample itself acting as the focusing optics. The resolution inherent in the Bragg-Brentano geometry is partly dependent on the radius of the diffractometer and the width of the receiving slit used. Typically, the Rigaku Smart-Lab operates with a peak width of 0.1°2θ or less. The axial divergence of the X-ray beam was controlled by 5.0° Soller slits in the incident and diffracted beam paths.

[147] Powder samples were obtained in a low-background Si holder using light manual pressure to keep the sample surface flat and level with the sample holder support surface. Each sample was analyzed over a range of 2 to 40°2θ using a continuous scan of 6°2θ per minute with an effective step size of 0.02°2θ.

DSK

[148] DSC analyses were performed using a TA Instruments Q2000 apparatus. The apparatus was temperature calibrated using indium. The DSC cell was maintained under nitrogen purge at ~50 ml per minute during each analysis. The sample was placed in a standard rolled aluminum crucible and heated from 25°C to 350°C at a rate of 10°C per minute. TGA

[149] TGA was performed using a TA Instruments Q50 apparatus. The apparatus balance was calibrated using class M weights and the temperature calibration was performed using alumel. Nitrogen purge was ~40 ml/min on the balance and ~60 ml/min in the furnace. Each sample was placed in a pre-weighed platinum crucible and heated from 20°C to 350°C at a rate of 10°C/min. DSP

[150] DSP analyses were performed on a TA Instruments Q5000 Dynamic Vapor Sorption Analyzer. The instrument was calibrated using standard weights and a sodium bromide humidity standard. Samples were analyzed at 25°C with a maximum equilibration time of 60 minutes at 10% relative humidity (RH) with increments from 5% to 95% RH (adsorption cycle) and from 95% to 5% RH (desorption cycle).

Example 1. Obtaining Form I

[151] 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 below.

[152] 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. Propanoyl propanoate (8.4 g, 64.5 mmol, 1.2 equiv) was added 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). The mixture was stirred at 105°C for 8 h, cooled to rt, concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate EA/petroleum ether 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.

[153] 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 at room temperature overnight 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 (2 N). 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 (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazol-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) were 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 for 5 min at room temperature and then (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-amine hydrochloride (54.3 g, 204.34 mmol, 1 equiv.) was added. The resulting mixture was stirred for another 2 h at room temperature. The reaction mixture was poured into water/ice at room temperature. The precipitated solids were collected by filtration and washed with water (1000 mL) three times. The solid was dissolved in DCM (1500 mL). The organic phase was washed with NH ₄ Cl (500 mL saturated aqueous solution) three times and brine (500 mL) three times, 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 Form I (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%) as an off-white solid. Low-resolution electrospray mass spectrometry (ESM) m/z 338 [M+H]. Proton nuclear magnetic resonance ¹ H NMR: (DMSO, 300 MHz, e parts per million): δ 8.41 (1H, d, J=8.4 Hz), 8.16 (1H, s), 7.91-7.79 (3H, t), 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).

[154] Polymorph 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 DSP. Figure 1A shows the XRPD pattern of Form I. Figure 1B shows the DSC and TGA plots of Form I. As shown in the DSC plot, an endotherm was observed at approximately 199 °C. As shown in the TGA plot, a weight loss of 0.2% was observed below 200 °C. Figure 1C shows the DSP plot of Form I. As shown in Figure 1C, a moisture uptake of 0.60% w/w was observed in the relative humidity (RH) range of 5-90% as determined by DSP.

Example 2. Obtaining Form II

[155] 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 methods presented below.

Method 1

[156] 18.2 mg of polymorph Form I (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 polyaryl ether ether ketone PEEK grinding bowl with a stainless steel ball and 10 μL of water was added. The grinding bowl was placed in a Retsch mill for 20 min at 100% power. The solids were scraped out of the grinding bowl with a spatula and analyzed by XRPD. The solids were identified as Form II.

Method 2

[157] 19.5 mg of polymorph Form I (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 20 mL glass vial and heated on a hotplate at 60 °C while stirring with a magnetic stirrer. Ethanol was added to the glass vial until the solids dissolved (4 mL of ethanol was added). The vial was then removed from the hotplate and 16 mL of cold water (refrigerated) 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 solids were air dried and analyzed by XRPD. The solids were identified as Form II.

[158] Polymorph 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 plots of Form II. As shown in the DSC plot, an endotherm was observed at approximately 199 °C. As shown in the TGA plot, a mass loss of approximately 0.18% was observed from onset to 200 °C.

Example 3. Obtaining a mixture of forms I and III

[159] (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (19.1 mg) of polymorph Form I was suspended in 1 mL of hexane in a 1 dram glass vial. Dioxane was slowly added while stirring with a magnetic stirrer on a hotplate heated to 60°C until the solids dissolved (2.2 mL of dioxane was added). The vial was then capped and the heat was turned on. The vial was placed in a freezer (approximately -15°C) for 2 days. After 2 days, the vial was placed in a refrigerator for 4 days. After 4 days, the vial was centrifuged, the liquid was decanted, the resulting solid was air dried, analyzed by XRPD and determined to be a mixture of forms I and III.

[160] 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. Figure 3A shows the XRPD pattern of the mixture of Forms I and III. Figure 2B shows the DSC and TGA plots of the mixture of Forms I and III. As shown in the DSC plot, an exotherm was observed at approximately 107 °C and an endotherm was observed at approximately 196 °C. As shown in the TGA plot, a weight loss of approximately 18.89% from onset to 125 °C was observed.

Example 4. Obtaining Form IV

[161] 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 below.

[162] Step 1. Preparation of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. 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, 0.0009 equiv.) in 2-MeTHF (71.6 g, 83.3 mL, 7.93 vol.) was stirred at 20±5°C. Oxalyl chloride solution (9.98 g, 0.0786 mol, 0.945 equiv) was added over a period of at least 45 min and the reaction was allowed to proceed at 30 ± 5 °C until ≤ 15% of 1-methyl-1H-pyrazole-4-carboxylic acid starting material 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 vol relative to (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride) was treated with 4 N HCl. 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 min (vessel 2). Freshly prepared 1-methyl-1H-pyrazole-4-carboxylic acid chloride solution was added to the reaction mixture while maintaining the temperature < 30 °C. After complete addition, the mixture was allowed to react at 20 ± 5 °C until ≤ 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 was 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 were obtained as a light gray solid.

[163] 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 an aqueous solution of hydroxylamine (50% water, 11.2 g, 0.169 mol, 3.00 equiv.) was slowly added while maintaining the temperature ≤15 °C. The resulting mixture was stirred at 20 ± 5 °C for at least 16 hours until ≤ 2% of (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 ≥ 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 cake was washed with isopropyl acetate (2 x 70 mL) and the solid was dried. The material was then packaged. 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 were obtained as an off-white solid.

[164] Step 3. Preparation of polymorph 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. A 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 no more than 20% of unreacted propionic acid remained, as determined by ¹ H NMR. The activated propionic acid solution was transferred to (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (15.6 g, 0.0521 mol, 1.00 equiv.) in acetonitrile (45.0 g, 57.3 mL). The reaction mixture was heated to 50 ± 5 °C and shaken at 50 ± 5 °C until ≤ 2% of (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide remained. After confirmation of reaction completion, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.87 g, 0.104 mol, 2.00 equiv) was added to the reaction mixture. The temperature of the mixture was brought to 70 ± 5 °C and the mixture was shaken at 70 ± 5 °C until no more than 2% of the uncyclized intermediate remained. After confirmation of reaction completion, the reaction mixture was quenched with water (48 mL). The batch temperature was brought to 55 ± 5 °C and the solution was polished filtered. The resulting filtrate was concentrated to about 10 volumes. The mixture was brought to 80±5°C and water (310 ml) was slowly added over a period of at least 1 hour while maintaining the temperature ≥70°C. The mixture was brought to 80±5°C and the resulting slurry was shaken at 80±5°C for at least 2 hours. The mixture was slowly cooled to 20±5°C over a period of at least 4 hours and shaken at 20±5°C for at least 2 hours. The mixture was filtered. The resulting filter cake was washed with water (3 x 120 ml) and dried in a vacuum oven until a loss on drying weight (LOD) of ≤1% was achieved. The material was then packaged. A total of 16.32 g of polymorphic 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 was obtained as an off-white solid with a yield of 92.8%.

[165] Polymorph 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. Figure 4A shows the XRPD pattern of Form IV. Figure 4B shows the DSC and TGA plots of Form IV. As shown in the DSC plot, an endotherm was observed at approximately 200 °C. As shown in the TGA plot, a mass loss of approximately 0.003% from onset to 200 °C was observed.

Example 5. Obtaining form V

[166] 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.

[167] (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 types of polymorphic forms were formed. The type existing in fiber-like fine needle forms was isolated and confirmed to be polymorphic form IV by XRPD. The type existing in long needle forms was isolated and confirmed to be polymorphic form V by XRPD. Fig. 5 shows the experimental and simulated XRPD patterns of form V.

Example 6: Obtaining Form VI

[168] 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 methods presented below.

Method 1

To (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 acetonitrile:water 60:40 (8 mL) and stirred with a stir bar at ambient temperature for 48 h. Solids were isolated by vacuum filtration and analyzed by XRPD, DSC, and TGA.

[169] Polymorph 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 plots, respectively, of Form VI taken after oven drying (25 °C for 24 hours). As shown in the TGA plot of Figure 6B, a weight loss of approximately 2.185% was observed from 25 °C to 65 °C. As shown in the DSC plot of Figure 6D, a broad endotherm was observed to appear at approximately 41°C, a small exotherm to appear at approximately 115°C, and a narrow endotherm to appear at 200°C.

[170] Figures 6C and 6E show the TGA and DSC plots, respectively, of Form VI taken after oven drying and heating (oven drying at 25°C for 24 hours; heating at 150°C). As shown in the TGA plot of Figure 6C, a slight loss was observed up to 200°C. As shown in the DSC plot of Figure 6E, a narrow endotherm was observed at 200°C.

Method 2

[171] A slurry 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 (Forms I, IV, or V, 30 mg) solids was prepared in 10-90% acetonitrile in water (1 mL) and then the slurry was shaken with a stir bar at 2-8 °C for 24 h. The solids were isolated by vacuum filtration and identified as polymorph Form VI by XRPD.

Example 7: Screening for polymorphs

[172] Polymorph 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 different solvents under different conditions. The resulting samples were analyzed by XRPD. The results are presented in Table 6 below.

AS (from English - antisolvent) = antisolvent; NC (from English - by crystallization) = no crystallization; RH = relative humidity; r.t. = room temperature.

Example 8. Experiments on competitive suspension formation between Form I and Form IV

[173] Competitive suspension experiments were performed between 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 to determine which form was more stable over a temperature range (2-60°C). Form IV was found to be more stable than Form I over the entire range of temperatures tested. The results of the competitive suspension experiments are presented in Table 7 below.

Example 9. Myofiber assays [174] To assess 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 the native sarcomere, purified myofibers were assayed. Bovine cardiac myofibers were prepared by homogenization of bovine left ventricular tissue in the presence of a detergent such as Triton X-100. This treatment removed membranes and most soluble cytoplasmic proteins but left the sarcomeric actomyosin apparatus of the heart intact. The myofiber preparations retained the ability to hydrolyze adenosine triphosphate (ATP) in a Ca ²⁺ -regulated manner. The ATPase activities of these myofiber preparations in the presence and absence of compounds were analyzed at Ca2 ⁺ concentrations activating a given fraction of the maximal velocity (i.e., 25%, 75%). Small molecules were assessed for their ability to inhibit the steady-state ATPase activity of bovine cardiac myofibers using the pyruvate kinase-lactate dehydrogenase (PK/LDH)-associated enzyme system. In this assay, myosin-derived adenosine diphosphate ADP is converted to ATP by oxidation of reduced nicotinamide adenine dinucleotide NADH, causing a change in absorbance at 340 nm. Before testing the low molecular weight agents, bovine cardiac myofibrils were assessed for their sensitivity to calcium, and a calcium concentration that reached 50% (pCa ₅₀ ) or 75% (pCa ₇₅ ) of the myofibril system activation was chosen as the endpoint for assessing the inhibitory activity of the low molecular weight agents. All enzyme activities were measured in a buffered solution containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), 2 mM magnesium chloride, at pH 6.8 (buffer PM 12). The final assay conditions were 1 mg/ml bovine cardiac myofibers, 4 U/ml pyruvate kinase, 6 U/ml lactate dehydrogenase, 50 μM ATP, 0.1 mg/ml BSA, 10 ppm antifoam, 1 mM dithiothreitol DTT, 0.5 mM NADH, 1.5 mM phosphoenolpyruvate PEP, 0.6 mM ethylene glycol tetraacetic acid EGTA and an amount of CaCl ₂ sufficient to achieve 50% or 75% activation of myofibril ATPase activity. IC ₁₅ (from English - inhibitory concentration) (CDMF75) 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 was 0.4 μM, and IC ₅₀ (CDMF75) 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 was 1.4 μM.

Example 10. Myocyte analysis

[175] Adult male Sprague-Dawley rats were anesthetized, the hearts were rapidly excised, and the aorta and ascending aorta were flushed and cannulated. Hearts were placed under continuous retrograde perfusion at a perfusion pressure _of 60 cm _H2O . Hearts were first perfused with a nominally Ca2 ⁺ -free modified Krebs solution of the following composition: 113 mM NaCl, 4.7 mM KCl, 0.6 mM _KH2PO4 , _0.6 mM _Na2HPO4 , 1.2 mM _MgSO4 , 12 mM _NaHCO3 , 10 mM _KHCO3 , 30 mM taurine, 5.5 mM glucose, and 10 mM Hepes (all from Sigma). This medium was not recirculated and was continuously aerated with 95% O2/5% _CO2 . After approximately 3 min, the heart was perfused with modified Krebs buffer supplemented with collagenase (Worthington) and a final concentration of 12.5 μM calcium. The heart was cannulated after it had become discolored and soft in appearance. The atria and vessels were removed and the ventricles were carefully cut into small pieces using tweezers. The tissue was homogenized by repeated pipetting, and the collagenase reaction was stopped with 10% bovine calf serum (BCS), pelleted, and resuspended in perfusion buffer containing 5% BCS and 12.5 μM _CaCl2 . Myocytes were calcium tolerized by 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 incubated for 60 min at 37°C prior to experiments and used within 5 h after isolation. Cell preparations were used only if the cells initially met the QC criteria by demonstrating a contractile response to treatment with standard (>150% of baseline) and isoproterenol (ISO;>250% of baseline). In addition, only cells with baseline contractility between 3 and 8% were used in subsequent compound experiments.

[176] Aliquots of myocytes in Tyrode's buffer were placed in perfusion chambers (20 Series RC-27NE; Warner Instruments) complete with heating platforms. Myocytes were allowed to attach, the chambers were warmed to 37°C, and the cells were perfused with Tyrode's buffer at 37°C. Myocytes were stimulated with a 1 Hz field using platinum electrodes (20% above threshold). Only cells that were clearly striated and quiescent prior to stimulation were used for contractility experiments. Myocytes were imaged through a 40× objective to determine baseline contractility. Using a variable frame rate (60–240 Hz) charge-coupled device camera, images were digitized and displayed on a computer screen at a sampling rate of 240 Hz (lonOptix Milton, MA). Once cell contraction was stable over time, test compounds (0.01-15 μM) were perfused into myocyte chambers for 5 min. Myocyte contractility and contraction and relaxation rates were then recorded using edge detection.

[177] For each compound, five or more individual myocytes from two or more different myocyte preparations were tested. For each cell, twenty or more contraction sounds were averaged and compared at baseline (defined as 1 minute before compound infusion) and after compound addition (defined as 5 minutes after the start of compound perfusion). These average sounds were analyzed using lonWizard software (lonOptix) to determine changes in diastolic length and fractional shortening. Fractional shortening was calculated as ((resting length - peak contraction length) divided by resting length). Percent change from baseline in fractional shortening was calculated as ((post-dose fractional shortening/baseline fractional shortening)*100). The percent change in fractional shortening from baseline was calculated as (100 - percent change in fractional shortening from baseline). The maximum contraction and relaxation velocity (μm/s) were also determined. The results for individual cells were averaged and the SEM (Standard Error Of Mean) 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 shown below.

Example 11. Echocardiographic evaluation of acute pharmacodynamic effect on cardiac contractility in rats

[178] In vivo cardiac function assessment by echocardiography was performed in male Sprague Dawley rats under isoflurane (1-3%) anesthesia. Two-dimensional M-mode images of the left ventricle were obtained in the parasternal long-axis view before, during, and after compound administration by 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 baseline pre-dose M-mode images were obtained at 1-minute intervals before compound infusion. Compounds were formulated in 50% propylene glycol (PG):16% captisol:10% dimethylacetamide (DMA) and infused through a jugular venous catheter at 1 ml/kg/hr. M-mode images were obtained at 5-minute intervals during the infusion. Infusion was stopped when fractional shortening reached a 60% decrease from baseline. Blood samples were collected to determine plasma compound concentrations. Data were reported as the estimated IC ₅₀ value, which is the concentration at which fractional shortening is 50% of the predose baseline contractility. The IC ₅₀ value 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 was 7.2±0.20 μM (mean ± SD).

[179] For oral administration studies, three pre-dose baseline M-mode images were obtained at 1-minute intervals prior to 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 0.5% hydroxypropyl methylcellulose 2910 (HPMC 2910):0.1% Tween 80 suspension and delivered as a single dose (5 mL/kg) via oral gavage. Rats were lightly anesthetized for M-mode echocardiographic measurements at selected time points over a 24-hour period. Different dose levels were evaluated. The effect of the compound on fractional shortening of the heart at the highest dose is presented below as a percentage reduction in fractional shortening (=100%).

[180] Blood samples were collected simultaneously with echocardiographic measurements to determine the corresponding plasma concentration of the compound. The calculated IC ₅₀ and IC ₁₀ values, which represent the concentration at which the fractional shortening is 50% and 10% of the initial pre-dose contractility, respectively, were 7.9 μM (IC ₅₀ ) and 0.8 μM (IC ₁₀ ).

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

[182] Although the foregoing written disclosure of the compounds, uses, and methods disclosed herein enables those skilled in the art to make and use the compounds, uses, and methods disclosed herein, those skilled in the art will understand and appreciate the possibility of variations, combinations, and equivalents of a particular embodiment, method, and examples herein. Therefore, the compounds, uses, and methods provided herein should not be limited to the above embodiments, methods, or examples, but rather encompass all embodiments and methods within the scope and spirit of the compounds, uses, and methods provided herein.

Claims (17)

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, wherein said polymorph is polymorph form IV, wherein said polymorph form IV is characterized by: a) an X-ray powder diffraction (XRPD) pattern containing peaks at 2-theta angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, 24.4±0.2 degrees; and/or b) an XRPD pattern containing peaks at 2-theta angles of 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; and/or c) an XRPD pattern containing peaks at 2-theta angles of 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, 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, 39.8±0.2 degrees; and/or d) an XRPD pattern as shown in Fig. 4A; and/or e) a differential scanning calorimetry (DSC) graph as shown in Fig. 4B; and/or f) onset of endotherm at 200±2°C as determined by DSC; and/or g) a thermogravimetric analysis (TGA) graph as shown in Fig. 4B; and/or h) a mass loss of 0.003% from the start to 200°C, as shown in the TGA graph. 2. 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, wherein said polymorph is polymorph form IV, wherein said polymorph form IV is characterized by an XRPD pattern containing peaks at 2-theta angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, 24.4±0.2 degrees. 3. The polymorph of claim 1, wherein polymorphic form IV is characterized by an XRPD pattern containing peaks at 2-theta angles of 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. 4. The polymorph of claim 1, wherein polymorphic form IV is characterized by an XRPD pattern containing peaks at 2-theta angles of 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, 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, 39.8±0.2 degrees. 5. The polymorph of claim 1, wherein polymorph form IV is characterized by an XRPD pattern as shown in Fig. 4A. 6. The polymorph of claim 1, wherein polymorph form IV is characterized by an endotherm onset at 200±2°C as determined by DSC. 7. The polymorph of claim 1, wherein polymorph form IV is characterized by a DSC plot as shown in Fig. 4B. 8. The polymorph of claim 1, wherein polymorphic form IV is characterized by a TGA plot as shown in Fig. 4B. 9. The polymorph of claim 1, wherein polymorph form IV is characterized by a mass loss of 0.003% from onset to 200°C, as determined by TGA.