Polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide

Abstract

Polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide, their compositions, methods of preparation, and methods of use are provided herein.

Description

Technology Field

[0001] Polymorphs of (R)-N-(5-(5-ethyl(ethyl)-1,2,4-oxadiazol-3-yl(yl))-2,3-dihydro-1H-inden-1-yl(yl))-1-methyl(ethyl)-1H-pyrazole-4-carboxamide, compositions thereof, methods of preparation thereof, and methods of use thereof are provided herein.

[0002] This application follows U.S. Provisional Patent Application No. 62 / 875,350 filed on July 17, 2019, the entire disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0003] The cardiac sarcomere consists of a network of contractile and structural proteins that regulate cardiac muscle function. The components of the cardiac sarcomere, for example, provide targets for the treatment of various heart diseases and conditions by increasing contractility or enabling full relaxation to regulate contractile and diastolic functions, respectively. The force and speed of cardiac muscle contraction are major determinants of tissue function and are regulated by the cyclic interactions of actin and myosin. The regulation of actin and myosin binding involves a network of myofilament regulatory proteins and intracellular Ca 2 + It is determined by the level of. Troponin complex and tropomyosin are thin filament proteins that govern the availability and intrinsic regulatory light chains of actin binding sites, and myosin-binding protein C regulates the position and mechanical properties of myosin.

[0004] Abnormalities within the above cardiac muscle fiber segments have been identified as inducing causes for various heart diseases and conditions, such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Mutations in the proteins of the above muscle fiber segments cause disease by causing the myocardium to contract 'over' or 'under'. Regulators of the above cardiac muscle fiber segments can be used to readjust contractility and to stop or reverse the course of the disease.

[0005] Current drugs targeting the aforementioned cardiac muscle segments, such as inotropes (drugs that increase the contractile capacity of the heart), are a poor choice for cardiac tissue and cause recognized adverse effects that limit their use. These adverse effects include cellular damage caused by the increased rate of energy consumption, exacerbation of diastolic abnormalities, and increased cellular fluid Ca within the contractileally stimulated myocardium. ++ and potential arrhythmia-inducing side effects that may arise from circulating AMP concentrations. Given the limitations of current drugs, new approaches are required to improve cardiac function in HCM and HFpEF.

[0006] There remains a great need for drugs that can develop new mechanisms of action on actin and yield superior results in terms of symptom relief, safety, and patient mortality over both the short and long term. New drugs with improved therapeutic indices compared to current drugs will provide the means to realize these clinical outcomes. The selection of drugs targeting the cardiac muscle segments (e.g., targeting cardiac myosin) has been identified as an important means to realize these improved therapeutic indices. (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is a selective allosteric inhibitor of cardiac myosin that has little or no effect on smooth muscle myosin. The benefits of these compounds include a broader therapeutic index, less impact on cardiac relaxation, superior pharmacokinetics, and superior safety, and are accordingly provided for heart diseases and conditions. The problem to be solved

[0007] To realize a drug candidate such as (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide as a commercially viable pharmaceutical product, it may be important to understand not only the polymorph forms of the drug candidate but also the relative stability and interconversion of these forms under the conditions that may be encountered in large-scale production, transport, storage, and pre-use manufacturing. The ability to control and produce stable polymorphs through robust manufacturing processes can be a critical factor for regulatory approval and market launch.

[0008] Large-scale production processes for high-purity (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide can be improved by utilizing specific polymorphic forms. Accordingly, there is a need for various new crystalline forms, formulations, and applications of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide having different chemical and physical stability. means of solving the problem

[0009] In one aspect, polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide are provided herein.

[0010] In another aspect, methods for preparing polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide are provided herein.

[0011] In another aspect, compositions containing polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide as described herein are provided herein.

[0012] In another aspect, methods for treating heart disease in the required subjects using polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide are provided herein. Brief explanation of the drawing

[0013] Figure 1a shows the experimental X-ray powder diffraction (XRPD) pattern of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 1b shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) graphs of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 1c shows the dynamic vapor adsorption (DVS) graph of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 2a shows the experimental XRPD pattern of polymorph form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 2b shows the DSC and TGA graphs of polymorph form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 3a shows the experimental XRPD pattern of a mixture of polymorph forms I and III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 3b shows the DSC and TGA graphs of a mixture of polymorph forms I and III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 4a shows the experimental XRPD pattern of polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 4b shows the DSC and TGA graphs of polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 5 shows the experimental XRPD pattern of polymorph form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the simulation patterns of both (from top to bottom: simulation at 223K; simulation at 273K; experiment). Figure 6a shows the experimental XRPD patterns of two forms VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, (a) the top is the XRPD of form VI taken before drying, and (b) the bottom is the XRPD of form VI taken after drying (oven, vacuum, 24 hours, 25°C). Figures 6b and 6c show TGA graphs of polymorph form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 6b shows the weight loss of oven-dried samples of form VI (oven, vacuum, overnight, 25°C) over the range of 25°C to 300°C. Figure 6c shows the TGA plot over the range of 25°C to 300°C for samples of form VI in which oven drying (oven, vacuum, overnight, 25°C) was performed and heating at 150°C was added prior to thermogravimetric analysis. Figures 6d and 6e show DSC graphs of polymorph form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 6d shows the DSC plot of an oven-dried sample of form VI (oven, vacuum, overnight, 25°C) over a range of 25°C to 300°C. Figure 6e shows the DSC plot over a range of 25°C to 300°C for a sample of form VI in which oven drying (oven, vacuum, overnight, 25°C) was performed and heating at 150°C was added prior to thermogravimetric analysis. Specific details for implementing the invention

[0014] definition

[0015] As used herein, singular expressions such as "one," "one," and "one" include plural expressions unless explicitly indicated otherwise in the text.

[0016] As used herein, unless otherwise specified, the expressions “about” and “approximately” mean a dose, amount, or weight percentage recognized by a person skilled in the art as providing a pharmaceutical effect equivalent to that obtained from a specified dose, amount, or weight percentage when used in relation to doses, amounts, or weight percentages of components of a composition or dosage form. Specifically, the expressions “about” and “approximately” refer to doses, amounts, or weight percentages within 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a specified dose, amount, or weight percentage when used in the text.

[0017] As used herein, the terms “polymorph” or “polymorphic form” refer to the crystalline form of a compound. Different polymorphs may have different physical properties, such as melting points, heats of fusion, solubility, dissolution rates, and / or vibrational spectra, as a result of, for example, the arrangement or stereotype of molecules or ions within a crystal lattice. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability may arise from changes in chemical reactivity (e.g., differential oxidation, which causes discoloration to occur more rapidly when the formulation consists of a single polymorph than when it consists of other polymorphs), mechanical changes (e.g., tablets crumbling during storage as a kinetically desirable polymorph transforms into a thermodynamically more stable polymorph), or both (e.g., tablets of a single polymorph are more susceptible to degradation at high humidity). As a result of differences in solubility / dissolution, in severe cases, certain polymorph variations may lead to a loss of efficacy, or in more severe cases, toxicity. Additionally, the physical properties of the crystalline form may be important in processing; for example, one polymorph may be more prone to forming solvates or more difficult to filter and wash away impurities (e.g., particle shape and size distribution may differ among the polymorphs).

[0018] As used herein, the expression "therapeutically effective amount" refers to an amount that produces a desired pharmacological and / or physiological effect on the said condition. The effect may be preventive in that it completely or partially prevents the condition or symptoms, and / or therapeutic in that it causes partial or complete healing of the said condition and / or any side effects that may be caused by the said condition.

[0019] As used herein, “pharmaceutically acceptable carrier” and similar expressions refer to adjuvants, binders, diluents, etc., known to those skilled in the art as suitable for administration to individuals (e.g., mammals or non-mammalians). Combinations of two or more carriers are also considered. Pharmacologically acceptable carrier(s) and any additional components as described herein must be compatible with use via the intended route of administration (e.g., oral, parenteral) for a particular formulation as recognized by those skilled in the art.

[0020] The expressions "treat," "treating," and "treatment" mean alleviating or eliminating one or more of a disorder, disease, or condition, or symptoms associated with said disorder, disease, or condition, or delaying the progression, spread, or worsening of one or more of said disease, disorder, or condition, or symptoms. Often, the beneficial effect on a target induced by a therapeutic agent does not result in a complete cure of said disease, disorder, or condition.

[0021] The term "object" refers to animals including, but not limited to, primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms "object" and "patient" are used interchangeably here with respect to mammalian objects, such as humans, for example.

[0022] As used herein, the expression “as substantially illustrated” includes, for example, XRPD patterns, DSC graphs, TGA graphs, or GVS graphs, patterns or graphs that, while not necessarily identical to those illustrated herein, fall within the limits of experimental error or deviation as considered by a person of ordinary skill in the art.

[0023] In some embodiments, the expression “substantially pure” means that the polymorph forms contain impurities of less than about 30 wt%, less than about 20 wt%, less than about 15 wt%, less than about 10 wt%, less than about 5 wt%, or less than about 1 wt%. In other embodiments, the expression “substantially pure” refers to a material free of impurities. Impurities may include, for example, by-products or leftover reagents from chemical reactions, contaminants, decomposition products, other polymorph forms, water, and solvents.

[0024] As used herein, the expression “substantially absent” means that the composition containing the polymorphic form contains less than 50 wt%, less than 40 wt%, less than 30 wt%, less than 20 wt%, less than 15 wt%, less than 10 wt%, less than 5 wt%, less than 4 wt%, less than 3 wt%, less than 2 wt%, or less than 1 wt%.

[0025] Polymorphs

[0026] In one aspect, polymorphs of (R)-N-(5-(5-ethyl(ethyl)-1,2,4-oxadiazol-3-yl(yl))-2,3-dihydro-1H-inden-1-yl(yl))-1-methyl(ethyl)-1H-pyrazole-4-carboxamide, a compound having the structure shown below, are provided herein.

[0027]

[0028] The above polymorphs may possess properties such as bioavailability and stability under specific conditions suitable for medical or pharmaceutical uses.

[0029] Polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide may provide advantages in bioavailability and stability and may be suitable for use as active agents in pharmaceutical compositions. Changes in the crystal structure of pharmaceutical drug substances may affect the solubility (which may affect bioavailability, etc.), manufacturability (e.g., ease of handling, ease of tableting, ability to continuously produce doses of known strength, etc.), and stability (e.g., thermal stability, storage duration (including resistance to degradation), etc.). These modifications may affect the methods of manufacturing or dispensing pharmaceutical compositions in different dosages or delivery forms, such as solid oral dosage forms including tablets and capsules. Compared to other forms, such as amorphous or non-crystalline forms, polymorphs can provide desired or suitable hygroscopicity, particle size control, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control. Accordingly, polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide can enhance the manufacturing process of the active agent or the stability or storage capability of the active agent in the form of a drug product, or provide advantages such as bioavailability and / or stability suitable for use as an active agent.

[0030] It has been found that the use of specific conditions, such as the use of different solvents and / or temperatures, produces other polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide capable of exhibiting one or more of the desirable properties described herein, including polymorph forms I to V described herein. The processes for the preparation of the polymorphs described herein and for characterizing these polymorphs are described in more detail below.

[0031] Form I

[0032] In some embodiments, polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide is provided herein.

[0033] In some embodiments, form I has substantially the X-ray powder diffraction (XRPD) pattern as illustrated in FIG. 1a. The angle 2-theta and relative peak intensities that can be observed for form I using XRPD are shown in Table 1.

[0034] Table 1

[0035]

[0036] In some embodiments, polymorph form I has an XRPD pattern that substantially displays 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 a column of peaks at an angle 2-theta having the greatest intensity within the XRPD pattern, as illustrated in FIG. 1a or provided in Table 1. It should be understood that relative intensities may vary depending on numerous factors, including sample preparation, mounting, and apparatus and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak arrangements may vary within experimental error. In some embodiments, including the case for polymorph form I, the peak arrangements listed herein may vary by about ±0.6°, ±0.4°, ±0.2°, or ±0.1° at 2-theta.

[0037] In some embodiments, polymorph form I is 3.7±0.2°, 11.2±0.2°, 12.9±0.2°, 13.5±0.2°, 14.4±0.2°, 14.9±0.2°, 16.6±0.2°, 17.8±0.2°, 18.6±0.2°, 21.6±0.2°, 22.2±0.2°, 22.4±0.2°, 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°, It has an XRPD pattern including peaks at angles of 2-theta of 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°. In some embodiments, polymorph form I has an XRPD pattern including peaks at angles 2-theta 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°. In some embodiments, polymorph form I has an XRPD pattern including peaks at angles 2-theta of 3.7±0.2°, 11.2±0.2°, 12.9±0.2°, 14.4±0.2°, and 22.4±0.2°. It should be understood that additional peaks in the XRPD pattern other than those shown in Fig. 1a or provided in Table 1 may be observed due to the presence of, for example, impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0038] In some embodiments, form I has a differential scanning calorimetry (DSC) graph substantially as shown in FIG. 1b. In some embodiments, form I is characterized by having an endotherm onset at about 199°C as determined by DSC. In some embodiments, form I is characterized by having an endothermic onset at 199±2℃ (e.g., 199±1.9℃, 199±1.8℃, 199±1.7℃, 199±1.6℃, 199±1.5℃, 199±1.4℃, 199±1.3℃, 192±1.2℃, 199±1, 199±0.9℃, 199±0.8℃, 199±0.7℃, 199±0.6℃, 199±0.5℃, 199±0.4℃, 199±0.3℃, 199±0.2℃, or 199±0.1℃) as determined by DSC.

[0039] In some embodiments, form I substantially has a temperature history analysis (TGA) graph as illustrated in FIG. 1b.

[0040] In some embodiments, form I has a dynamic vapor adsorption (DVS) graph substantially as shown in FIG. 1c.

[0041] In some embodiments of form I, at least one, at least two, at least three, at least four, at least five, or all of the following (a)-(f) apply.

[0042] (a) Form I is an XRPD pattern containing peaks at angles 2-theta of 3.7±0.2°, 11.2±0.2°, 12.9±0.2°, 14.4±0.2° and 22.4±0.2°; an XRPD pattern containing peaks at angles 2-theta 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°; or 3.7±0.2°C, 11.2±0.2°C, 12.9±0.2°C, 13.5±0.2°C, 14.4±0.2°C, 14.9±0.2°C, 16.6±0.2°C, 17.8±0.2°C, 18.6±0.2°C, 21.6±0.2°C, 22.2±0.2°C, 22.4±0.2°C, 22.8±0.2°C, 23.2±0.2°C, 23.9±0.2°C, 24.4±0.2°C, 24.7±0.2°C, 25.0±0.2°C, 25.8±0.2°C, 26.1±0.2°C, 28.6±0.2°C, 29.0±0.2°C, It has an XRPD pattern including peaks at angles of 2-theta of 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°.

[0043] (b) Form I substantially has an XRPD pattern as illustrated in FIG. 1a.

[0044] (c) Form I substantially has a DSC graph as shown in FIG. 1b.

[0045] (d) Type I is characterized by having an endothermic onset at approximately 199°C, as determined by DSC.

[0046] (e) Form I substantially has a TGA graph as shown in FIG. 1b.

[0047] (f) Form I substantially has a DVS graph as shown in Fig. 1c.

[0048] Form II

[0049] In some embodiments, polymorph form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide is provided herein.

[0050] In some embodiments, form II has substantially the XRPD pattern as illustrated in FIG. 2a. The angle 2-theta and relative peak intensities that can be observed for form II using XRPD are shown in Table 2.

[0051] Table 2

[0052]

[0053] In some embodiments, polymorph form II has an XRPD pattern that substantially displays 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 a column of peaks at an angle 2-theta having the greatest intensity within the XRPD pattern as illustrated in FIG. 2a or provided in Table 2. It should be understood that relative intensities may vary depending on numerous factors, including sample preparation, mounting, and apparatus and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak arrangements may vary within experimental error. In some embodiments, including the case for polymorph form II, the peak arrangements listed herein may vary by about ±0.6°, ±0.4°, ±0.2°, or ±0.1° at 2-theta.

[0054] In some embodiments, polymorph form II is 3.7±0.2°, 7.4±0.2°, 9.8±0.2°, 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 14.4±0.2°, 14.7±0.2°, 16.1±0.2°, 17.0±0.2°, 18.5±0.2°, 20.4±0.2°, 21.6±0.2°, 22.3±0.2°, 23.3±0.2°, 24.0±0.2°, 24.3±0.2°, 24.8±0.2°, 25.8±0.2°, 27.4±0.2°, 28.8±0.2°, The XRPD pattern includes peaks at angles 2-theta of 29.5±0.2° and 30.5±0.2°. In some embodiments, polymorph form II has an XRPD pattern including peaks at angles 2-theta 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°. In some embodiments, polymorph form II has an XRPD pattern containing peaks at angles 2-theta of 3.7±0.2°, 9.8±0.2°, 11.1±0.2°, 12.8±0.2°, and 20.4±0.2°. It should be understood that additional peaks within the XRPD pattern, other than those shown in FIG. 2a or provided in Table 2, may be observed due to the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample, for example.

[0055] In some embodiments, form II substantially has a DSC graph as shown in FIG. 2b. In some embodiments, form II is characterized by having an endothermic onset at about 199°C as determined by DSC. In some embodiments, form II is characterized by having an endothermic onset at about 199±2°C (e.g., 199±1.9°C, 199±1.8°C, 199±1.7°C, 199±1.6°C, 199±1.5°C, 199±1.4°C, 199±1.3°C, 199±1.2°C, 199±1, 199±0.9°C, 199±0.8°C, 199±0.7°C, 199±0.6°C, 199±0.5°C, 199±0.4°C, 199±0.3°C, 199±0.2°C, or 199±0.1°C) as determined by DSC.

[0056] In some embodiments, form II substantially has a TGA graph as shown in FIG. 2b.

[0057] In some embodiments of Type II, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply.

[0058] (a) Form II is an XRPD pattern containing peaks at angles 2-theta of 3.7±0.2°, 9.8±0.2°, 11.1±0.2°, 12.8±0.2°, and 20.4±0.2°; an XRPD pattern containing peaks at angles 2-theta 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°; or 3.7±0.2°C, 7.4±0.2°C, 9.8±0.2°C, 11.1±0.2°C, 12.8±0.2°C, 13.5±0.2°C, 14.4±0.2°C, 14.7±0.2°C, 16.1±0.2°C, 17.0±0.2°C, 18.5±0.2°C, 20.4±0.2°C, 21.6±0.2°C, 22.3±0.2°C, 23.3±0.2°C, 24.0±0.2°C, 24.3±0.2°C, 24.8±0.2°C, 25.8±0.2°C, 27.4±0.2°C, 28.8±0.2°C, 29.5±0.2°C, and It has an XRPD pattern containing peaks at an angle of 2-theta of 30.5±0.2 degrees.

[0059] (b) Form II substantially has an XRPD pattern as shown in FIG. 2a or FIG. 12.

[0060] (c) Form II substantially has a DSC graph as shown in FIG. 2b.

[0061] (d) Type II is characterized by having an endothermic onset at approximately 199°C, as determined by DSC.

[0062] (e) Type II substantially has a TGA graph as shown in FIG. 2b.

[0063] Form III

[0064] In some embodiments, polymorph form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide is provided herein.

[0065] In some embodiments, a mixture of polymorphic forms I and III substantially has an XRPD pattern as illustrated in FIG. 3a. The angle 2-theta and relative intensities that can be observed for a mixture of polymorphic forms I and III using XRPD are shown in Table 3.

[0066] Table 3

[0067]

[0068]

[0069] In some embodiments, polymorph form III has an XRPD pattern including peaks at angles 2-theta of 9.6±0.2°, 10.9±0.2°, 15.8±0.2°, and 18.1±0.2°. In some embodiments, polymorph form III has an XRPD pattern including peaks at angles 2-theta of 9.6±0.2°, 10.9±0.2°, 14.5±0.2°, 15.8±0.2°, and 18.1±0.2°. In some embodiments, polymorph form III has an XRPD pattern including peaks at angles 2-theta 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°. It should be understood that relative intensities may vary depending on numerous factors, including sample preparation, mounting, and instruments, as well as analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak placements may vary within experimental error. In some embodiments, including the case for polymorph form III, the peak placements listed herein may vary by 2-theta of about ±0.6°, ±0.4°, ±0.2°, or ±0.1°.

[0070] In some embodiments, a mixture of polymorph I and form III substantially has a DSC graph as shown in FIG. 3b.

[0071] In some embodiments, a mixture of polymorph I and form III substantially has a TGA graph as shown in FIG. 3b.

[0072] Form IV

[0073] In some embodiments, polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide is provided herein.

[0074] In some embodiments, form IV has substantially the XRPD pattern as illustrated in FIG. 4a. The angle 2-theta and relative intensities that can be observed for form IV using XRPD are shown in Table 4.

[0075] Table 4

[0076]

[0077]

[0078] In some embodiments, polymorph form IV substantially has an XRPD pattern displaying 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 a column of peaks at an angle 2-theta having the greatest intensity within the XRPD pattern, as illustrated in FIG. 4a or provided in Table 4. It should be understood that relative intensities may vary depending on numerous factors, including sample preparation, mounting, and apparatus and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak arrangements may vary within experimental error. In some embodiments, including the case for polymorph form IV, the peak arrangements listed herein may vary by about ±0.6°, ±0.4°, ±0.2°, or ±0.1° at 2-theta.

[0079] In some embodiments, polymorph form IV is 3.7±0.2°, 7.7±0.2°, 11.1±0.2°, 12.4±0.2°, 12.8±0.2°, 13.5±0.2°, 14.3±0.2°, 15.5±0.2°, 16.6±0.2°, 17.9±0.2°, 18.5±0.2°, 18.6±0.2°, 19.1±0.2°, 19.9±0.2°, 20.9±0.2°, 21.5±0.2°, 21.6±0.2°, 21.9±0.2°, 22.3±0.2°, 22.4±0.2°, 22.8±0.2°, 23.1±0.2°C, 23.5±0.2°C, 23.9±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.0±0.2°C, 25.3±0.2°C, 25.8±0.2°C, 26.2±0.2°C, 27.1±0.2°C, 27.4±0.2°C, 28.0±0.2°C, 28.6±0.2°C, 29.0±0.2°C, 30.0±0.2°C, 30.5±0.2°C, 30.8±0.2°C, 31.0±0.2°C, 31.4±0.2°C, 33.8±0.2°C, 35.0±0.2°C, 35.7±0.2°C, The XRPD pattern includes peaks at angles 2-theta of 36.1±0.2°, 36.7±0.2°, 37.9±0.2°, 38.1±0.2°, and 39.8±0.2°. In some embodiments, polymorph form IV has an XRPD pattern including peaks at angles 2-theta 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°. In some embodiments, polymorph form IV has an XRPD pattern including peaks at angles 2-theta of 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 22.8±0.2°, and 24.4±0.2°.It should be understood that additional peaks in the XRPD pattern other than those shown in Fig. 4a or provided in Table 4 may be observed due to the presence of, for example, impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0080] In some embodiments, form IV substantially has a DSC graph as shown in FIG. 4b. In some embodiments, form IV is characterized by having an endothermic onset at about 200°C as determined by DSC. In some embodiments, form IV is characterized by having a melt endothermic onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C) as determined by DSC.

[0081] In some embodiments, form IV substantially has a TGA graph as shown in FIG. 4b.

[0082] In some embodiments of form IV, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply.

[0083] (a) Form IV is an XRPD pattern containing peaks at angles 2-theta of 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 22.8±0.2° and 24.4±0.2°; an XRPD pattern containing peaks at angles 2-theta 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°; or 3.7±0.2°C, 7.7±0.2°C, 11.1±0.2°C, 12.4±0.2°C, 12.8±0.2°C, 13.5±0.2°C, 14.3±0.2°C, 15.5±0.2°C, 16.6±0.2°C, 17.9±0.2°C, 18.5±0.2°C, 18.6±0.2°C, 19.1±0.2°C, 19.9±0.2°C, 20.9±0.2°C, 21.5±0.2°C, 21.6±0.2°C, 21.9±0.2°C, 22.3±0.2°C, 22.4±0.2°C, 22.8±0.2°C, 23.1±0.2°C, 23.5±0.2°C, 23.9±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.0±0.2°C, 25.3±0.2°C, 25.8±0.2°C, 26.2±0.2°C, 27.1±0.2°C, 27.4±0.2°C, 28.0±0.2°C, 28.6±0.2°C, 29.0±0.2°C, 30.0±0.2°C, 30.5±0.2°C, 30.8±0.2°C, 31.0±0.2°C, 31.4±0.2°C, 33.8±0.2°C, 35.0±0.2°C, 35.7±0.2°C, 36.1±0.2°C, It has an XRPD pattern including peaks at angles of 2-theta of 36.7±0.2°, 37.9±0.2°, 38.1±0.2°, and 39.8±0.2°.

[0084] (b) Form IV substantially has an XRPD pattern as shown in Fig. 4a.

[0085] (c) Form IV substantially has a DSC graph as shown in FIG. 4b.

[0086] (d) Type IV is characterized by having a melt endothermic onset at about 200°C as determined by DSC.

[0087] (e) Form IV substantially has a TGA graph as shown in FIG. 4b.

[0088] Shape V

[0089] In some embodiments, polymorphic form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide is provided herein.

[0090] In some embodiments, form V substantially has an XRPD pattern as illustrated in FIG. 5. The angle 2-theta and relative intensities that can be observed for form V using XRPD are shown in Table 5.

[0091] Table 5

[0092]

[0093]

[0094]

[0095] In some embodiments, polymorph form V has an XRPD pattern that substantially displays 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 an angle 2-theta having the greatest intensity within the XRPD pattern, as illustrated in FIG. 5 or provided in Table 5. It should be understood that relative intensities may vary depending on numerous factors, including sample preparation, mounting, and apparatus and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak arrangements may vary within experimental error. In some embodiments, including the case for polymorph form V, the peak arrangements listed herein may vary by about ±0.6°, ±0.4°, ±0.2°, or ±0.1° at 2-theta.

[0096] In some embodiments, polymorph form V is 5.7±0.2°, 8.3±0.2°, 11.5±0.2°, 13.8±0.2°, 15.5±0.2°, 15.8±0.2°, 16.3±0.2°, 16.6±0.2°, 17.2±0.2°, 17.8±0.2°, 18.5±0.2°, 18.9±0.2°, 19.1±0.2°, 19.8±0.2°, 20.0±0.2°, 20.2±0.2°, 20.7±0.2°, 21.2±0.2°, 21.6±0.2°, 23.0±0.2°, 23.1±0.2°, 23.3±0.2°C, 24.0±0.2°C, 24.2±0.2°C, 24.3±0.2°C, 24.6±0.2°C, 24.7±0.2°C, 25.2±0.2°C, 25.6±0.2°C, 26.7±0.2°C, 27.1±0.2°C, 27.3±0.2°C, 27.5±0.2°C, 27.9±0.2°C, 28.1±0.2°C, 28.4±0.2°C, 28.9±0.2°C, 29.2±0.2°C, 29.7±0.2°C, 29.8±0.2°C, 29.9±0.2°C, 30.4±0.2°C, 30.6±0.2°C, 31.1±0.2°C, 31.3±0.2°C, 31.5±0.2°C, 32.0±0.2°C, 32.9±0.2°C, 33.0±0.2°C, 33.2±0.2°C, 33.5±0.2°C, 34.4±0.2°C, 34.6±0.2°C, 34.9±0.2°C, 35.3±0.2°C, 35.7±0.2°C, 36.0±0.2°C, 36.2±0.2°C, 36.5±0.2°C, 36.6±0.2°C, 37.0±0.2°C, 37.1±0.2°C, 37.5±0.2°C, 37.8±0.2°C, 37.9±0.2°C, The XRPD pattern includes peaks at 2-theta at 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°. In some embodiments, polymorph form V has peaks at 5.7±0.2°, 8.3±0.2°, 11.5±0.2°, 16.3±0.2°, 17.2±0.2°, 19.1±0.2°, 20.0±0.2°, 20.2±0.2°, 20.7±0.2°, 21.2±0.2°, 23.3±0.2°, and 24.The polymorph form V has an XRPD pattern including peaks at 2-theta at 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°. In some embodiments, polymorph form V has an XRPD pattern including peaks at 2-theta at 11.5±0.2°, 16.3±0.2°, 19.1±0.2°, 20.0±0.2°, 20.2±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, 25.6±0.2°, and 26.7±0.2°. In some embodiments, polymorph form V has an XRPD pattern including peaks at 2-theta at 11.5±0.2°, 16.3±0.2°, 20.0±0.2°, 21.2±0.2°, and 24.7±0.2°. It should be understood that additional peaks within the XRPD pattern other than those shown in FIG. 5 or provided in Table 5 may be observed due to the presence of impurities, solvents, or other polymorphs or amorphous forms present in the test sample, for example.

[0097] In some embodiments of form V, at least one or all of the following (a)-(b) apply.

[0098] (a) Shape V is an XRPD pattern including peaks at 2-theta at 11.5±0.2°, 16.3±0.2°, 20.0±0.2°, 21.2±0.2° and 24.7±0.2°; an XRPD pattern including peaks at 2-theta at 11.5±0.2°, 16.3±0.2°, 19.1±0.2°, 20.0±0.2°, 20.2±0.2°, 21.2±0.2°, 24.0±0.2°, 24.7±0.2°, 25.6±0.2° and 26.7±0.2°; Or it has an XRPD pattern including peaks at 2-theta at 5.7±0.2°, 8.3±0.2°, 11.5±0.2°, 16.3±0.2°, 17.2±0.2°, 19.1±0.2°, 20.0±0.2°, 20.2±0.2°, 20.7±0.2°, 21.2±0.2°, 23.3±0.2°, 24.0±0.2°, 24.7±0.2°, 25.6±0.2°, 26.7±0.2°, 28.1±0.2°, 29.2±0.2°, 29.7±0.2°, 29.9±0.2°, and 31.1±0.2°.

[0099] (b) The shape of V substantially has an XRPD pattern as shown in FIG. 5.

[0100] Form VI

[0101] In some embodiments, polymorphic form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide is provided herein.

[0102] In some embodiments, form VI substantially has an XRPD pattern as shown in FIG. 6a. The angle 2-theta and relative intensities that can be observed for form VI using XRPD are shown in Table 6.

[0103] Table 6

[0104]

[0105]

[0106] In some embodiments, polymorph form VI has an XRPD pattern that substantially displays 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 a column of peaks at an angle 2-theta having the greatest intensity within the XRPD pattern, as illustrated in FIG. 6a or provided in Table 6. It should be understood that relative intensities may vary depending on numerous factors, including sample preparation, mounting, and apparatus and analytical procedures and settings used to obtain the spectrum. Relative peak intensities and peak arrangements may vary within experimental error. In some embodiments, including the case for polymorph form VI, the peak arrangements listed herein may vary by about ±0.6°, ±0.4°, ±0.2°, or ±0.1° at 2-theta.

[0107] In some embodiments, polymorph form VI is 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°C, 19.6±0.2°C, 20.0±0.2°C, 20.3±0.2°C, 20.7±0.2°C, 21.1±0.2°C, 21.9±0.2°C, 22.6±0.2°C, 22.9±0.2°C, 23.6±0.2°C, 23.8±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.5±0.2°C, 26.4±0.2°C, 26.7±0.2°C, 27.3±0.2°C, 27.6±0.2°C, 28.2±0.2°C, 28.5±0.2°C, 29.0±0.2°C, 29.6±0.2°C, It has an XRPD pattern including peaks at 2-theta of 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°. In some embodiments, polymorph form VI has an XRPD pattern including peaks at 2-theta at 5.4±0.2°, 5.9±0.2°, 8.1±0.2°, 9.6±0.2°, 10.6±0.2°, 12.1±0.2°, 14.0±0.2°, 15.0±0.2°, 16.1±0.2°, and 17.8±0.2°. In some embodiments, polymorph form VI has an XRPD pattern including peaks at 2-theta at 10.6±0.2°, 12.1±0.2°, 15.0±0.2°, 16.1±0.2°, and 17.8±0.2°.It should be understood that additional peaks in the XRPD pattern other than those shown in Fig. 6a or provided in Table 6 may be observed due to the presence of, for example, impurities, solvents, or other polymorphs or amorphous forms present in the test sample.

[0108] In some embodiments, form VI substantially has a TGA graph as shown in FIG. 6b or a TGA graph as shown in FIG. 6c. In some embodiments, form VI exhibits a weight loss of about 2% ± 0.5% at 25°C to 200°C as determined by TGA.

[0109] In some embodiments, form VI substantially has a DSC graph as shown in FIG. 6d, or a DSC graph as shown in FIG. 6e. In some embodiments, form VI is characterized by having an endothermic onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C) as determined by DSC. In some embodiments, form VI has an endothermic onset at about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C, or 200±0.1°C), about 115±2°C (e.g., 115±1.9°C, 115±1.8°C, 115±1.7°C), Endothermic onset at 115±1.6℃, 115±1.5℃, 115±1.4℃, 115±1.3℃, 115±1.2℃, 115±1, 115±0.9℃, 115±0.8℃, 115±0.7℃, 115±0.6℃, 115±0.5℃, 115±0.4℃, 115±0.3℃, 115±0.2℃, or 115±0.1℃), or about 41±2℃ (e.g., 41±1.9℃, 41±1.8℃, 41±1.7℃, 41±1.6℃, 41±1.5℃, 41±1.4℃, 41±1.3℃, 41±1.2℃, 41±1, It is characterized by having endothermic onset at 41±0.9℃, 41±0.8℃, 41±0.7℃, 41±0.6℃, 41±0.5℃, 41±0.4℃, 41±0.3℃, 41±0.2℃, or 41±0.1℃, or any combination thereof.

[0110] In some embodiments of form VI, at least one, at least two, at least three, at least four, at least five, at least six, or all of the following (a)-(g) apply.

[0111] (a) Shape VI is an XRPD pattern including peaks at 2-theta at 10.6±0.2°, 12.1±0.2°, 15.0±0.2°, 16.1±0.2° and 17.8±0.2°; an XRPD pattern including peaks at 2-theta at 5.4±0.2°, 5.9±0.2°, 8.1±0.2°, 9.6±0.2°, 10.6±0.2°, 12.1±0.2°, 14.0±0.2°, 15.0±0.2°, 16.1±0.2° and 17.8±0.2°; or 3.0±0.2°, 5.0±0.2°, 5.4±0.2°, 5.9±0.2°, 7.2±0.2°, 8.1±0.2°, 8.9±0.2°, 9.6±0.2°, 9.9±0.2°, 10.6±0.2°, 12.1±0.2°, 13.3±0.2°, 14.0±0.2°, 14.4±0.2°, 14.7±0.2°, 15.0±0.2°, 15.4±0.2°, 16.1±0.2°, 16.5±0.2°, 17.8±0.2°, 18.9±0.2°, 19.0±0.2°, 19.2±0.2°, 19.6±0.2°C, 20.0±0.2°C, 20.3±0.2°C, 20.7±0.2°C, 21.1±0.2°C, 21.9±0.2°C, 22.6±0.2°C, 22.9±0.2°C, 23.6±0.2°C, 23.8±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.5±0.2°C, 26.4±0.2°C, 26.7±0.2°C, 27.3±0.2°C, 27.6±0.2°C, 28.2±0.2°C, 28.5±0.2°C, 29.0±0.2°C, 29.6±0.2°C, 29.9±0.2°C, It has an XRPD pattern including peaks at 2-theta of 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°.

[0112] (b) Type VI substantially has an XRPD pattern as shown in FIG. 6a.

[0113] (c) Form VI substantially has a TGA as illustrated in FIG. 6b or FIG. 6c.

[0114] (d) Form VI has a weight loss of about 2% ± 0.5% at 25°C to 20°C as determined by TGA.

[0115] (e) Form VI substantially has a DSC le Gaff as illustrated in FIG. 6d or FIG. 6e.

[0116] (f) Type IV is characterized by having endothermic melting at about 200°C as determined by DSC.

[0117] (g) Form VI is characterized by having an endothermic onset at about 200°C, an endothermic onset at about 41°C, or any combination thereof, as determined by DSC.

[0118] Compositions

[0119] Additionally, compositions containing polymorphs described herein, such as form I, form II, form III, form IV, form V, form VI, or mixtures thereof, are provided herein. In some embodiments, the composition contains form I. In some embodiments, the composition contains form II. In some embodiments, the composition contains form III. In some embodiments, the composition contains a mixture of form I and form III. In some embodiments, the composition contains form IV. In some embodiments, the composition contains form V. In some embodiments, the composition contains form VI. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0120] In some embodiments, a composition is provided containing form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of the polymorph forms II to VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the amorphous or noncrystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0121] In some embodiments of the above composition containing form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98% by weight, at least about 99% by weight, or at least about 99.9% by weight is form I. In some embodiments of the above composition containing form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.9 wt% is present in form I.

[0122] In some embodiments, a composition is provided containing form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially absent from at least one, at least two, at least three, or all of the polymorph forms I, III, IV, V, and VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the amorphous or noncrystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0123] In some embodiments of the above composition containing form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98% by weight, at least about 99% by weight, or at least about 99.9% by weight is form II. In some embodiments of the above composition containing form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt% of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, At least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.9 wt% is present in form II.

[0124] In some embodiments, a composition is provided containing form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially absent from at least one, at least two, at least three, or all of the polymorph forms I, II, IV, V, and VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the amorphous or non-crystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0125] In some embodiments of the above composition containing form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98% by weight, at least about 99% by weight, or at least about 99.9% by weight is form III. In some embodiments of the above composition containing form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.9 wt% is present in form III.

[0126] In some embodiments, a composition is provided containing form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of the polymorph forms I, III, V, and VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the amorphous or noncrystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0127] In some embodiments of the above composition containing form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98% by weight, at least about 99% by weight, or at least about 99.9% by weight is form IV. In some embodiments of the above composition containing form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.9 wt% is present in form IV.

[0128] In some embodiments, a composition is provided containing form I and form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. 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 90 to 10 to 99 to 1. In some embodiments of a composition containing form I and form IV, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.9 wt% of the total composition is form I. In some embodiments of compositions containing form I and form IV, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, and at least about 5 wt% of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.9 wt% is present in form I. In some embodiments of a composition containing form I and form IV, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.9% by weight of the total composition is form IV. In some embodiments of compositions containing Form I and Form IV, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, At least about 99% by weight, or at least about 99.9% by weight, exists in form IV.

[0129] In some embodiments, a composition is provided containing form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of the polymorph forms I, IV, and VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the amorphous or noncrystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0130] In some embodiments of the above composition containing form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98% by weight, at least about 99% by weight, or at least about 99.9% by weight is form V. In some embodiments of the above composition containing form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.9 wt% is present in form V.

[0131] In some embodiments, a composition is provided containing form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially absent from at least one, at least two, at least three, or all of the polymorph forms I to V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the amorphous or noncrystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of the salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0132] In some embodiments of the above composition containing form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98% by weight, at least about 99% by weight, or at least about 99.9% by weight is form VI. In some embodiments of the above composition containing form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 wt%, at least about 0.3 wt%, at least about 0.5 wt%, at least about 0.8 wt%, at least about 1.0 wt%, at least about 5.0 wt%, at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, at least about 80 wt%, at least about 85 wt%, at least about 90 wt%, at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt%, or at least about 99.9 wt% is present in form VI.

[0133] In some embodiments, a tablet or capsule is provided containing one or more of the polymorphic forms described herein (e.g., form I, form II, form III, form IV, form V, form VI, or a mixture thereof) and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing a substantially pure polymorphic form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing a substantially pure polymorph form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing a substantially pure polymorph form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing a substantially pure polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing a substantially pure polymorph form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers.In some embodiments, a tablet or capsule is provided containing a substantially pure polymorph form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide and one or more pharmaceutically acceptable carriers.

[0134] Manufacturing method

[0135] Form I

[0136] In some embodiments, a method for preparing polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising the steps of: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent; and (2) cooling the mixture of (1) or removing the solvent from the mixture of (1). In some embodiments, the solvent is an alcohol (e.g., methanol, ethanol, or propanol), acetate (e.g., isopropyl acetate or ethyl acetate), ether (e.g., methyl t-butyl ether, diethyl ether, or 2-methyl tetrahydrofuran), ketone (e.g., methyl ethyl ketone or methyl isobutyl ketone), nitrile (e.g., acetonitrile), amide (e.g., N,N-dimethylformamide), non-aromatic hydrocarbon (e.g., hexane), aromatic It includes hydrocarbons (e.g., toluene), water, or mixtures thereof.In some embodiments, the solvent comprises acetone, acetonitrile (ACN), dichloromethane (DCM), 1,4-dioxane, N,N-dimethylformamide (DMF), ethanol (EtOH), methanol (MeOH), 2-methyltetrahydrofuran (2-MeTHF), 2-propanol (IPA), tetrahydrofuran (THF), water, diethyl ether (Et2O), methyl ethyl ketone (MEK), toluene, water, ethyl acetate, 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 higher 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 will also be understood that Form I can be prepared using a suitable method as described in Experimental Example 6 below.

[0137] In some embodiments, the method for preparing polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide further comprises the method for preparing (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, which comprises (1) tert-butyl N-[(1R)-5-(N-dihydroxycarbamimidoyl))-2,3-dihydro-1H-indene-1-yl(yl)]carbamate propanol A step of reacting with propanoyl propanoate to form tert-butyl N-[(1R)-5-(5-ethyl(ethyl)-1,2,4-oxadiazol-3-yl(yl))-2,3-dihydro-1H-inden-1-yl(yl)] carbamate; (2) a step of reacting tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate with trifluoroacetic acid (TFA) to form (1R)-5-(5-ethyl(ethyl)-1,2,4-oxadiazol(yl)-3-yl(yl))-2,3-dihydro(dihydro)-1H-indene-1-amine; And (3) the step of reacting (1R)-5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-amine with 1-methyl(methyl)-1H-pyrazole-4-carboxylic acid to form (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0138] Form II

[0139] In some embodiments, a method for preparing form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising the step of grinding form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide in water. In some embodiments, a method for preparing polymorph form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising the step of (1) forming a mixture of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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). In 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, an anti-solvent is added before step (2) is performed. In some embodiments, the anti-solvent is water. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature 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.In addition, it will be understood that Form II can be manufactured using a suitable method as described in Experimental Example 6 below.

[0140] A mixture of Form I and Form III

[0141] In some embodiments, a method for preparing a mixture of polymorph form I and form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising the step of (1) forming a mixture of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an ether (e.g., methyl t-butyl ether, diethyl ether, 2-methyl tetrahydrofuran, or dioxane) or a non-aromatic hydrocarbon (e.g., hexane), or a mixture thereof; (2) includes a step of cooling the mixture of step (1). In some embodiments, the solvent comprises hexane, dioxane, or a mixture thereof. In some embodiments, step (1) includes a step of 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, an antisolvent is added before step (2) is performed. In some embodiments, the antisolvent is water. In some embodiments, step (2) includes 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 will also be understood that mixtures of form I and form III can be prepared using a suitable method as described in Experimental Example 6 below.

[0142] Form IV

[0143] In some embodiments, a method for preparing polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising the step of (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises nitrile (e.g., acetonitrile (ACN)), water, or a mixture thereof; and (2) cooling the mixture of step (1). In some embodiments, the solvent comprises ACN, 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. In some embodiments, step (2) comprises cooling the mixture of step (1) to about 20°C.

[0144] In some embodiments, a method for preparing polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide further comprises the step of preparing R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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, A step of forming (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (2) A step of reacting (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with hydroxylamine to form (R,Z)-N-(5-(N'-hydroxycarbamimidoyl))-2,3-dihydro-1H-indene-1-yl(yl))-1-methyl-1H-pyrazole-4-carboxamide; and (3) the step of reacting (R,Z)-N-(5-(N'-hydroxycarbamimidoy)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide with propionic acid.

[0145] Shape V

[0146] In some embodiments, a method for preparing polymorph form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising the step of (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the 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 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 polymorphs existing in long-needle forms. In some embodiments, the method comprises the step of (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises ethyl acetate; (2) cooling the mixture of step (1) to about 5°C; and (3) separating the polymorphs existing in long needle forms.

[0147] Form VI

[0148] In some embodiments, a method for preparing polymorph form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising the step of (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises nitrile (e.g., acetonitrile) and water; and (2) stirring the mixture of step (1). In some embodiments, the solvent comprises ACN and water. In some embodiments, the mixture prepared in step (1) is a nearly saturated solution, a saturated solution, or a slurry. In some embodiments, the mixture prepared in step (1) comprises solid forms of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solid form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide contains form I, form IV, form V, or any combination thereof. In some embodiments, the solid form contains form VI combined with another solid form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (e.g., form I, form IV, or form V). In some embodiments, the solid form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide contains a combination of form IV and form VI.In some embodiments, step (2) comprises stirring the mixture at a temperature of about 0°C to about 30°C, about 0°C to about 25°C, about 0°C to about 20°C, about 0°C to about 15°C, or 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 about 0°C to about 20°C, about 0°C to about 15°C, or 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.

[0149] How to use

[0150] The polymorphic forms and compositions provided herein may be used to treat or prevent diseases or conditions in an individual or object.

[0151] Without being bound by theory, the provided polymorphic forms and compositions are believed to act by inhibiting myosin. This inhibition reduces the number of independent myosin heads interacting with actin filaments, which potentially reduces the amount of contraction. Reducing the contraction of heart muscle may be important for the treatment of heart diseases in which excessive contraction is a problem. In some embodiments, methods for treating or preventing heart disease in an individual or subject are provided, comprising the step of administering the polymorphic form or composition provided herein to said individual or subject in need. In some embodiments, methods for treating or preventing heart disease in said subject in need are provided, comprising the step of administering a therapeutically effective amount of the polymorphic form or composition provided herein to said subject. In some embodiments, methods for treating heart disease in said subject in need are provided, comprising the step of administering a therapeutically effective amount of the polymorphic form or composition provided herein to said subject. In some embodiments, methods for treating established or diagnosed heart disease in a subject in need are provided, comprising the step of administering to said subject a therapeutically effective amount of a polymorphic form or composition provided herein. In some embodiments, methods for preventing heart disease in a subject in need are provided, comprising the step of administering to said subject a therapeutically effective amount of a polymorphic form or composition provided herein.

[0152] Additionally, the use of the polymorphic forms or compositions provided herein in the manufacture of medicines for the treatment of heart disease in the subject is provided herein. In some aspects, polymorphic forms or compositions as described herein are provided herein for use in methods of treating a human body or an animal body by therapy. In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof are provided herein for use in methods of treating a human body or an animal body by therapy. In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof are provided herein for use in treating or preventing heart disease. In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof are provided herein for use in treating heart disease. In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in treating established or diagnosed heart disease. In other embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in preventing heart disease. In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in treating diseases or conditions associated with HCM. In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in treating diseases or conditions associated with secondary left ventricular wall thickening.In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V, or Form VI, or combinations thereof, are provided herein for use in improving symptoms associated with heart disease. In other embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V, or Form VI, or combinations thereof, are provided herein for use in reducing the risk of symptoms associated with heart disease. In other embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V, or Form VI, or combinations thereof, are provided herein for use in treating diseases or conditions associated with a small left ventricular cavity, cavity obliteration, hyperdynamic left ventricular contraction, obstruction of blood flow from the left ventricle, cardiac hypertrophy, small cardiac stroke volume, impaired left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis. In certain embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in treating diseases or conditions associated with small left ventricular cavity and cavity occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis. In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in treating muscular dystrophy. In some embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in treating glycogen storage disease.In other embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in modulating cardiac sarcomeres, such as inhibiting cardiac sarcomeres. In yet other embodiments, polymorphic forms such as Form I, Form II, Form III, Form IV, Form V or Form VI, or combinations thereof, are provided herein for use in enhancing cardiac myosin.

[0153] In some embodiments, the subject is a mammal. In some embodiments, the subject is a mouse, rat, dog, cat, pig, sheep, horse, cattle, or human. In some embodiments, the subject is a human. In some embodiments, the subject has established or diagnosed heart disease. In some embodiments, the subject has established or diagnosed hypertrophic cardiomyopathy (HCM). In some embodiments, the subject is at risk of progression of heart disease. In some embodiments, the subject has a mutation that increases the risk of heart disease. In some embodiments, the subject has a mutation that increases the risk of hypertrophic cardiomyopathy (HCM). In some embodiments, the mutation is a 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), myosin-binding protein C cardiac type (MYBPC3), cardiac troponin I (cTnI), myosin basic light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / cardiac muscle isoform (MLC-2), cardiac muscle 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 established or diagnosed hypertrophic cardiomyopathy without an acknowledged genetic etiology.

[0154] In some embodiments, there is a high risk of progressive symptoms. In some embodiments, the subject has a high risk of atrial fibrillation, ventricular tachyarrhythmias, stroke, and / or sudden death. In some embodiments, the subject has reduced exercise capacity. In some embodiments, said reduced exercise capacity is compared to a control group of the same age. In some embodiments, the subject may be eligible for surgical treatment or percutaneous ablation to treat heart disease.

[0155] In some embodiments, the heart disease is hypertrophic cardiomyopathy (HCM). In some embodiments, the heart disease is obstructive HCM. In some embodiments, the heart disease is non-obstructive HCM. In some embodiments, the HCM is associated with a myofibril mutation. In some embodiments, the HCM is associated with a non-myofibril mutation. In some embodiments, the heart disease is obstructive or non-obstructive HCM caused by myofibril and / or non-myofibril mutations. In some embodiments, the myofibrillar segment mutation is a mutation in myosin heavy chain β (MHC-β), cardiac muscle troponin T (cTnT), tropomyosin alpha-1 chain (TPM1), myosin-binding protein C cardiac form (MYBPC3), cardiac troponin I (cTnI), myosin basic light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / cardiac muscle isoform (MLC-2), cardiac muscle alpha-actin, or muscle LIM protein (MLP). In some embodiments, the myofibrillar segment mutation is a mutation in MHC-β. In some embodiments, the non-myofibrillar segment mutation is a mutation in protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).

[0156] In some embodiments, methods for treating a disease or condition associated with HCM are provided herein and include the step of administering a polymorphic form or composition provided herein to an individual or target in need. In some embodiments, the disease or condition is Fabry's disease, Danon disease, mitochondrial cardiomyopathy, or Noonan syndrome.

[0157] In addition, the use of the polymorphic forms or compositions provided herein in the manufacture of medicines for the treatment of diseases or conditions associated with HCM is provided herein.

[0158] In some embodiments, the heart disease is heart failure with a preserved ejection fraction (HFpEF). In some embodiments, the heart disease is diastolic dysfunction. In some embodiments, the heart disease is cardiomyopathy. In some embodiments, the heart disease is primary or secondary restrictive cardiomyopathy. In some embodiments, the heart disease is a condition or symptom caused by coronary artery disease. In some embodiments, the heart disease is myocardial infarction or angina pectoris. 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 heart 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 cardiac senescence or aging-related cardiac dilatative dysfunction or a condition associated therewith.In some embodiments, the heart disease is left ventricular hypertrophy and / or concentric left ventricular remodeling or a condition related thereto.

[0159] In some embodiments, methods for treating a disease or condition associated with secondary left ventricular wall thickening in an individual or subject are provided, comprising the step of administering a polymorphic form or composition provided herein to said individual or subject in need. In some embodiments, said disease is hypertension, valvular heart diseases (aortic stenosis, mitral valve regurgitation), metabolic syndromes (diabetes mellitus, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich ataxia, Danon disease, Noonan syndrome, or Pompe disease.

[0160] In addition, the use of the polymorphic form or composition provided herein in the manufacture of medicines for the treatment of diseases or conditions associated with secondary left ventricular wall thickening is provided herein.

[0161] In some embodiments, methods for improving symptoms associated with heart disease in a subject are provided, comprising the step of administering a polymorphic form or composition provided herein to the subject or subject in need, wherein the symptoms are one or more selected from poor or reduced cardiac elasticity, poor or reduced diastolic left ventricular relaxation, abnormal left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or permanent atrial fibrillation, increased left atrial and pulmonary capillary wedge pressures, increased left ventricular diastolic pressures, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, increased left ventricular wall thickness, left ventricular mid-cavity occlusion, increased systolic anterior movement of the mitral valve, left ventricular outflow tract occlusion, chest pain, exertional dyspnea, presyncope, abnormal exercise capacity, and fatigue.

[0162] In some embodiments, methods for treating diseases or conditions associated with a small left ventricular cavity, cavity occlusion, hyperdynamic left ventricular contraction, obstruction of blood outflow from the left ventricle, cardiac hypertrophy, small cardiac output, impaired relaxation of the left ventricle, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis in an individual or subject are provided, comprising the step of administering a polymorphic form or composition provided herein to said individual or subject in need.

[0163] In some embodiments, methods for treating a disease or condition associated with small left ventricular cavity and cavity occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in an individual or subject are provided, and include the step of administering a polymorphic form or composition provided herein to said individual or subject in need.

[0164] In addition, the use of the polymorphic forms or compositions provided herein in the manufacture of medicines for the treatment of diseases or conditions associated with small left ventricular cavity and cavity occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis is provided herein.

[0165] In some embodiments, methods for treating muscular dystrophy (e.g., Duchenne muscular dystrophy) in an individual or subject are provided, comprising the step of administering the polymorphic form or composition provided herein to said individual or subject in need. Additionally, the use of the polymorphic form or composition provided herein in the manufacture of a medicine for the treatment of muscular dystrophy (e.g., Duchenne muscular dystrophy) is provided herein.

[0166] In some embodiments, methods for treating glycogen storage disease in an individual or subject are provided, comprising the step of administering a polymorphic form or composition provided herein to said individual or subject in need. Additionally, the use of a polymorphic form or composition provided herein in the manufacture of a medicine for the treatment of glycogen storage disease is provided herein.

[0167] Additionally, methods for modulating cardiac sarcomeres in an individual or subject are provided, said methods comprising the step of administering a therapeutically effective amount of at least one chemical entity as described herein to the individual or subject in need. In some embodiments, methods for inhibiting cardiac sarcomeres are provided, said cardiac sarcomeres comprising the step of bringing said cardiac sarcomeres into contact with at least one chemical entity as described herein, such as a polymorphic form or composition provided herein. Additionally, the use of at least one chemical entity as described herein, such as a polymorphic form or composition provided herein, in the manufacture of a medicine for inhibiting cardiac sarcomeres in an individual or subject is provided herein.

[0168] Additionally, methods for enhancing cardiac myosin in an individual or subject are provided, said methods comprising the step of administering a therapeutically effective amount of at least one chemical entity as described herein, such as a polymorphic form or composition provided herein, to an individual or subject in need. Additionally, in the manufacture of a medicine for enhancing cardiac myosin in an individual or subject, at least one chemical entity as described herein, such as a polymorphic form or composition provided herein, is provided herein.

[0169] In some embodiments, the methods provided herein further include a step of monitoring the effect of the treatment. Examples of indicators include, but are not limited to, one or more of the following: exercise capacity as a New York Heart Association (NYHA) functional classification, cardiac resilience, diastolic left ventricular relaxation, left atrial pressure, paroxysmal or permanent atrial fibrillation, left atrial and pulmonary capillary wedge pressures, left ventricular diastolic pressures, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, left ventricular wall thickness, left ventricular mid-sac obstruction, increased systolic anterior movement of the mitral valve, left ventricular outflow tract obstruction, chest pain, exertional dyspnea, presyncope, abnormal exercise capacity, and fatigue. These indicators may be self-reported; ECG including ambulatory ECG; echocardiography; cardiac MRI; CT; biopsy; cardiopulmonary exercise testing (CPET); And it can be monitored by techniques known in the relevant technical field, including actigraphy.

[0170] In some embodiments, the polymorphic forms or compositions described herein reduce the contractility of cardiomyocytes. In some embodiments, the polymorphic forms or compositions reduce the contractility of cardiomyocytes by more than 40%, such as in cases where it is greater than 45%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the polymorphic forms or compositions reduce the contractility of cardiomyocytes by 40%-90%, such as in cases where it is 40%-80%, 40%-70%, 50%-90%, 50%-80%, or 50%-70%. In some embodiments, the polymorphic forms or compositions do not significantly alter calcium retention within the cardiomyocytes. In some embodiments, the polymorphic forms or compositions reduce ATPase activity within the cardiomyocytes. Methods for measuring contractility, aTPase activity, and calcium retention are known in the art, for example, by calcium labeling, electrophysiological recordings, and microscopic imaging. In some embodiments, the polymorphic forms or compositions do not significantly inhibit or induce cytochrome P450 (CYP) protein.

[0171] In some embodiments, the subject has a left ventricular wall thicker than usual prior to treatment. In some embodiments, the subject has a left ventricular wall thickness greater than 15 mm, such as 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm. In some embodiments, the left ventricular wall thickness is reduced by more than 5% following treatment, such as by more than 8%, 10%, 12%, 15%, 20%, or 30%. The left ventricular wall thickness may be measured by methods known in the art, such as by echocardiography, CT scan, or cardiac MRI.

[0172] In some embodiments, the subject has abnormal cardiac fibrosis prior to treatment. In some embodiments, the abnormal cardiac fibrosis is reduced by more than 5% following treatment, such as by 8%, 10%, 12%, 15%, 20%, or more than 30%. Cardiac fibrosis may be measured by methods known in the art, such as by biopsy or cardiac MRI.

[0173] In some embodiments, the subject has reduced exercise capacity prior to treatment. In some embodiments, the subject's exercise capacity increases by more than 5% after treatment, such as by 8%, 10%, 12%, 15%, 20%, or greater than 30%. In some embodiments, the exercise capacity is measured by a cardiopulmonary exercise test (CPET). CPET measures oxygen consumption (VO2 Measures changes in (max). CPET and VO2 Methods for measuring max are well known in the field of technology (Malhotra et al. "JACC: Heart Failure" (2016, 4(8): 607-616); Guazzi et al. "J Amer College Cardiol" (2017, 70 (13): 1618-1636); Rowin et al. "JACC: Cariovasc Imaging" (2017, 10(11): 1374-1386)). In some embodiments, VO2max is improved by more than 1 ml / kg / m² after treatment, such as 1.2 ml / kg / m², 1.4 ml / kg / m², 1.5 ml / kg / m², 1.7 ml / kg / m², 2 ml / kg / m², 2.2 ml / kg / m², 2.5 ml / kg / m², 3 ml / kg / m², 3.2 ml / kg / m², or 3.5 ml / kg / m².

[0174] In some embodiments, the subject has a New York Heart Association (NYHA) functional classification II, III, or IV prior to treatment. In some embodiments, the subject has a New York Heart Association (NYHA) functional classification III or IV prior to treatment. In some embodiments, the subject has a New York Heart Association (NYHA) functional classification IV prior to treatment. In some embodiments, the subject remains at the same NYHA functional class or has a reduced NYHA functional class after treatment.

[0175] In some embodiments, VO2 max improves by 1 ml / kg / m² or more, such as 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 or more, and the subject has a reduced NYHA function grade after treatment. In some embodiments, VO2 The max improves to 2.5 ml / kg / m², 3 ml / kg / m², 3.2 ml / kg / m², or 3.5 ml / kg / m² or higher, and The subject remains at the same NYHA function grade or has a reduced NYHA function grade after treatment.

[0176] In some embodiments, the daily function and / or activity level of the subject improves after treatment. The improved daily function and / or activity level may be measured by journaling or actigraphy, such as with a FitBit or FitBit-like monitors, for example.

[0177] In some embodiments, the subject has one or more of reduced shortness of breath, reduced chest pain, reduced arrhythmia burden such as atrial fibrillation and ventricular arrhythmia, reduced incidence of renal failure, and reduced ventricular outflow occlusion after treatment.

[0178] Dosages

[0179] The polymorphic forms and compositions disclosed and / or described herein may be administered at a therapeutically effective dose, e.g., a dose sufficient to provide treatment for a diseased state. Although human dosage levels have not yet been optimized for the chemical entities described herein, the general daily dosage range is from about 0.01 mg / kg to 100 mg / kg of body weight, from about 0.05 mg / kg to 10.0 mg / kg of body weight in some embodiments, and from about 0.10 mg / kg to 1.4 mg / kg of body weight in some embodiments. Accordingly, for administration to a person weighing 70 kg, the dosage range in some embodiments may be from about 0.7 mg to 7000 mg per day, from about 3.5 mg to 700.0 mg per day in some embodiments, and from 7 mg to 100.0 mg per day in some embodiments. The amount of the chemical entity administered will depend, for example, on the target and the disease state being treated, the severity of the pain, the mode and schedule of administration, and the judgment of the prescribing physician. For example, according to each pharmacokinetic, an exemplary dosage range for oral administration is from about 5 mg to about 500 mg per day, and an exemplary intravenous dosage is from about 5 mg to about 500 mg per day.

[0180] The daily dose is the total amount administered per day. The daily dose may be administered daily, every other day, weekly, every two weeks, monthly, or at varying intervals, but not limited to. In some embodiments, the daily dose is administered from daily for a period spanning the lifespan of the subject. In some embodiments, the daily dose is administered once daily. In some embodiments, the daily dose is administered in multiple divided doses, such as two, three, or four divided doses. In some embodiments, the daily dose is administered in two divided doses.

[0181] The administration of the polymorphic forms and compositions described herein may be via any approved mode of administration for therapeutic agents, but not limited to: orally, sublingually, subcutaneously, parenterally, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonaryly, vaginally, rectally, or intraocularly. In some embodiments, the polymorphic form or composition is administered orally or intravenously. In some embodiments, the polymorphic form or composition disclosed or / or described herein is administered orally.

[0182] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol formulations such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosol forms. Additionally, the polymorphic forms disclosed and / or described herein may be administered as sustained or controlled-release formulations (e.g., controlled / sustained-release pills, depot injections, osmotic pumps, or transdermal (including electron transport) patch forms) for extended duration and / or intermittent administration at a given rate. In some embodiments, the compositions are provided in unit formulations suitable for a single administration of an accurate dose.

[0183] The polymorphic forms described herein may be administered alone or in combination with one or more conventional pharmaceutically acceptable carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may also contain minute amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and similar substances (e.g., sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95% by weight, or about 0.5% to 50% by weight of the compounds disclosed or / or described herein. The practical methods for manufacturing these formulations are known or will be obvious to those skilled in the art. For example, please refer to Remington's *Pharmaceutical Sciences* (Mack Publishing Company, Easton, Pennsylvania).

[0184] In some embodiments, the compositions will take the form of pills or tablets, and accordingly, the compositions may contain one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives) together with the polymorphic forms disclosed or / or described herein. Other solid formulations comprise powders, marume, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides) encapsulated within gelatin capsules.

[0185] Liquid pharmaceutically administerable compositions may be prepared, for example, by dissolution, dispersion, suspension, etc. within a carrier (e.g., water, saline solution, aqueous dextrose, glycerol, glycols, ethanol, or similar substances). The polymorphic forms and optional pharmaceutical additives disclosed or described herein form a solution or suspension. Injectable drugs may be prepared prior to injection as liquid solutions or suspensions, as emulsions, or in conventional forms such as solid forms suitable for dispersion or suspension in liquid. The percentage of said polymorphic form contained in these parenteral compositions depends, for example, on the physical properties of said polymorphic form, the activity of said polymorphic form, and the needs of said target. However, percentages of the active ingredient in the solution may be applied from 0.01% to 10%, and may be higher in the case of a solid that the composition will subsequently be diluted to other concentrations. In some embodiments, said composition will contain about 0.2% to 2% of the polymorphic form disclosed or / or described herein in the solution.

[0186] Additionally, the pharmaceutical compositions of the polymorphic forms and compositions described herein may be administered into the respiratory tract alone or in combination with an inert carrier such as lactose as an aerosol or solution for a nebulizer, or as an ultrafine powder for inhalation. In such cases, the particles of the pharmaceutical composition may have a diameter smaller than 50 microns, or in some embodiments, a diameter smaller than 10 microns.

[0187] Additionally, pharmaceutical compositions may include the polymorphic forms disclosed or described herein and one or more additional drugs, agents, adjuvants, and similar substances. Suitable medical and pharmaceutical drugs include those described herein.

[0188] Kits

[0189] Articles of manufacture and kits containing any of the polymorphic forms or compositions provided herein are also provided. The articles of manufacture may include a labeled container. Suitable containers include, for example, bottles, vials, and test tubes. The containers may be formed from various materials such as glass or plastic. The container may hold the pharmaceutical composition provided herein. A label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or inhibit the condition described herein, and may also indicate instructions for in vivo or in vitro use.

[0190] In one aspect, kits containing the polymorphic forms or compositions described herein and instructions for use are provided herein. The kits may include instructions for use in the treatment of heart disease in an individual or subject in need. The kits may additionally include any materials or equipment that can be used for administering the polymorphic forms or compositions, such as vials, syringes, or IV bags. Additionally, the kits may include sterile packaging.

[0191] combinations

[0192] The polymorphic forms and compositions described herein may be administered alone or in combination with other therapies and / or therapeutic agents useful for the treatment of the aforementioned disorders, diseases, or conditions.

[0193] The polymorphic forms and compositions described herein may be combined with one or more other therapies to treat heart disease such as HCM or HFpEF. In some embodiments, the one or more other therapies include therapies that attempt to delay the progression of heart failure and prevent heart remodeling by downregulating neurohormonal stimulation of the heart (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors). In some embodiments, the one or more other therapies include therapies that improve heart function by stimulating cardiac contractility (e.g., positive inotropic agents such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). In other embodiments, the one or more other therapies include therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any class of vasodilators including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators).

[0194] The polymorphic forms and compositions described herein may be combined with one or more other therapies to treat HCM or HFpEF. In some embodiments, the polymorphic forms and compositions described herein may be combined with a β-blocker, verapamil, and / or disopyramide.

[0195] Some exemplary embodiments are provided below.

[0196] 1. Polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0197] 2. The polymorph of Example 1 is characterized by having an XRPD pattern including peaks at angles 2-theta of 3.7±0.2°, 11.2±0.2°, 12.9±0.2°, 14.4±0.2°, and 22.4±0.2°.

[0198] 3. The polymorph of Example 1 or Example 2 is characterized by having an XRPD pattern including peaks at angles 2-theta 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°.

[0199] 4. Any one of the polymorphs in Examples 1 to 3 is characterized by having an XRPD pattern substantially as shown in FIG. 1a.

[0200] 5. Any one of the polymorphs in Examples 1 to 4 is characterized by having a DSC graph substantially as shown in FIG. 1b.

[0201] 6. Any one of the polymorphs in Examples 1 to 5 is characterized by having an endothermic onset at about 199°C as determined by DSC.

[0202] 7. Any one of the polymorphs in Examples 1 to 6 is characterized by having a TGA graph substantially as shown in FIG. 1b.

[0203] 8. Any one of the polymorphs in Examples 1 to 7 is characterized by having a DVS graph substantially as shown in FIG. 1c.

[0204] 9. The polymorph of Example 1 is characterized by having an XRPD pattern including peaks at angles 2-theta of 3.7±0.2°, 9.8±0.2°, 11.1±0.2°, 12.8±0.2°, and 20.4±0.2°.

[0205] 10. The polymorph of Example 1 or Example 9 is characterized by having an XRPD pattern including peaks at angles 2-theta 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°.

[0206] 11. Any one of the polymorphs in Example 1, Example 9 and Example 10 is characterized by having an XRPD pattern substantially as shown in FIG. 2a.

[0207] 12. Any one of the polymorphs in Example 1 and Examples 9 to 11 is characterized by having a DSC graph substantially as shown in FIG. 2b.

[0208] 13. Any one of the polymorphs in Examples 9 to 12 is characterized by having an endothermic onset at about 199°C as determined by DSC.

[0209] 14. Any one of the polymorphs in Example 1 and Examples 9 to 13 is characterized by having a TGA graph substantially as shown in FIG. 2b.

[0210] 15. The polymorph of Example 1 is characterized by having an XRPD pattern including peaks at angles of 2-theta of 9.6±0.2°, 10.9±0.2°, 15.8±0.2°, and 18.1±0.2°.

[0211] 16. The polymorph of Example 1 is characterized by having an XRPD pattern including peaks at angles 2-theta of 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 22.8±0.2°, and 24.4±0.2°.

[0212] 17. The polymorph of Example 1 or Example 16 is characterized by having an XRPD pattern including peaks at angles 2-theta 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°.

[0213] 18. Any one of the polymorphs in Example 1, Example 16 and Example 17 is characterized by having an XRPD pattern substantially as shown in FIG. 4a.

[0214] 19. Any one of the polymorphs in Example 1 and Examples 16 to 18 is characterized by having a DSC graph substantially as shown in FIG. 4b.

[0215] 20. Any one of the polymorphs in Example 1 and Examples 16 to 19 is characterized by having an endothermic onset at about 200°C as determined by DSC.

[0216] 21. Any one of the polymorphs in Example 1 and Examples 16 to 20 is characterized by having a TGA graph substantially as shown in FIG. 4b.

[0217] 22. The polymorph of Example 1 is characterized by having an XRPD pattern including peaks at angles 2-theta of 11.5±0.2°, 16.3±0.2°, 20.0±0.2°, 21.2±0.2°, and 24.7±0.2°.

[0218] 23. The polymorph of Example 1 or Example 22 is characterized by having an XRPD pattern including peaks at angles 2-theta 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°.

[0219] 24. In any one of the polymorphs of Example 1, Example 22 and Example 23, 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° It is characterized by having an XRPD pattern including peaks at 2-theta.

[0220] 25. Any one of the polymorphs in Example 1 and Examples 22 to 24 is characterized by having an XRPD pattern substantially as shown in FIG. 5.

[0221] 26. The polymorph of Example 1 is characterized by having an XRPD pattern including peaks at angles 2-theta of 10.6±0.2°, 12.1±0.2°, 15.0±0.2°, 16.1±0.2°, and 17.8±0.2°.

[0222] 27. The polymorph of Example 1 or Example 26 is characterized by having an XRPD pattern including peaks at angles of 2-theta 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°.

[0223] 28. Any one of the polymorphs in Example 1, Example 26 and Example 27 is characterized by having an XRPD pattern substantially as shown in FIG. 6a.

[0224] 29. Any one of the polymorphs in Example 1 and Examples 26 to 28 is characterized by having a TGA graph substantially as shown in FIG. 6b or FIG. 6c.

[0225] 30. Any one of the polymorphs in Example 1 and Examples 26 to 29 is characterized by having an endothermic onset at about 200°C as determined by DSC.

[0226] 31. Any one of the polymorphs in Example 1 and Examples 26 to 30 is characterized by having a DSC graph substantially as shown in FIG. 6d or FIG. 6e.

[0227] 32. In a method for preparing any one of the polymorphs in Examples 2 to 8,

[0228] (1) a step of forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent; and

[0229] (2) The method includes cooling the mixture of step (1) or removing the solvent from the mixture of step (1).

[0230] 33. In the method of Example 32, the solvent is characterized by containing dichloromethane (DCM).

[0231] 34. In the method of Example 32 or Example 33, the step (2) is characterized by including the step of removing the solvent.

[0232] 35. A method for preparing any one of the polymorphs in Examples 9 to 14 is characterized by including the step of grinding Form I in water.

[0233] 36. In a method for preparing any one of the polymorphs in Examples 9 to 14,

[0234] (1) A step of forming a mixture of form I and ethanol; and

[0235] (2) Includes a step of cooling the mixture of step (1) above.

[0236] 37. In the method of Example 36, step (1) is characterized by including the step of heating the mixture to about 60°C.

[0237] 38. In the method of Example 36 or Example 37, the step (2) is characterized by including the step of cooling the mixture of the step (1) to about -5°C, about -10°C, about -15°C, or about -20°C.

[0238] 39. In a method for preparing any one of the polymorphs in Examples 16 to 21,

[0239] (1) The method comprises the step of forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises acetonitrile (ACN) or a mixture of ACN and water;

[0240] (2) Includes a step of cooling the mixture of step (1) above.

[0241] 40. In the method of Example 39, step (1) is characterized by including the step of heating the mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 80°C.

[0242] 41. In the method of Example 39 or Example 40, step (2) is characterized by including the step of cooling the mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 20°C.

[0243] 42. In a method for preparing any one of the polymorphs in Examples 22 to 25,

[0244] (1) The method comprises the step of forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an acetate;

[0245] (2) Includes a step of cooling the mixture of step (1) above.

[0246] 43. In the method of Example 42, the solvent is characterized by containing ethyl acetate.

[0247] 44. In the method of Example 42 or Example 43, step (2) is characterized by including a step of cooling the mixture of step (1) to about 5°C.

[0248] 45. In any one of Examples 42 to 44, the method further comprises the step of separating the polymorphs existing in long needle forms.

[0249] 46. ​​In a method for preparing any one of the polymorphs in Examples 26 to 31,

[0250] (1) The method comprises the step of forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises nitrile and water;

[0251] (2) Includes a step of stirring the mixture of step (1) above.

[0252] 47. In the method of Example 46, the solvent is characterized by containing acetonitrile.

[0253] 48. In the method of Example 46 or Example 47, the step (2) is characterized by including the step of cooling the mixture of the step (1) to about 0°C to about 10°C.

[0254] 49. A pharmaceutical composition comprising any one of the polymorphs of Examples 1 to 31 and a pharmaceutically acceptable excipient.

[0255] 50. A method for treating heart disease in a subject requiring treatment comprises the step of administering to the subject any one of the polymorphs of Examples 1 to 31, or the pharmaceutical composition of Example 49.

[0256] 51. In the method of Example 50, the heart disease is characterized as being hypertrophic cardiomyopathy (HCM).

[0257] 52. In the method of Example 51, the HCM is characterized as being obstructive or non-obstructive associated with a myofibrillar segment and / or non-myofibrillar segment mutation.

[0258] 53. In the method of Example 50, the heart disease is characterized as heart failure with preserved ejection fraction (HFpEF).

[0259] 54. In the method of Example 50, the heart disease is characterized by being selected from the group consisting of dilated heart disease, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina pectoris, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, and infiltrative cardiomyopathy.

[0260] 55. In the method of Example 50, the heart disease is characterized by being one or more conditions selected from the group consisting of cardiac senility, cardiac dilatational dysfunction due to aging, left ventricular hypertrophy, and concentric left ventricle remodeling, or associated conditions.

[0261] 56. A method for treating a disease or condition associated with HCM in a subject in need comprises the step of administering to the subject any one of the polymorphs of Examples 1 to 31, or the pharmaceutical composition of Example 49.

[0262] 57. In the method of Example 56, the disease or condition is characterized by being selected from the group consisting of Fabry disease, Danone disease, mitochondrial cardiomyopathy and Noonan syndrome.

[0263] 58. A method for treating a disease or condition associated with secondary left ventricular wall thickening in a subject requiring treatment, characterized by including the step of administering to the subject any one of the polymorphs of Examples 1 to 31, or the pharmaceutical composition of Example 49.

[0264] 59. In the method of Example 58, the disease or condition is characterized by being selected from the group consisting of hypertension, valvular heart diseases, metabolic syndromes, end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danone's disease, Noonan syndrome, and Pompe disease.

[0265] 60. A method for treating a disease or condition associated with small left ventricular cavity and cavity occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in a subject requiring treatment, characterized by comprising the step of administering to the subject any one of the polymorphs of Examples 1 to 31, or the pharmaceutical composition of Example 49.

[0266] 61. A method for treating diseases or conditions associated with muscular dystrophy and glycogen storage disease in a subject in need, characterized by including the step of administering to the subject any one of the polymorphs of Examples 1 to 31 or the pharmaceutical composition of Example 49.

[0267] 62. A method for inhibiting cardiac muscle fiber segments in a required subject comprises the step of contacting said cardiac muscle fiber segments with any one of the polymorphs of Examples 1 to 31, or with the pharmaceutical composition of Example 49.

[0268] Experimental examples

[0269] The following experimental examples are provided to further contribute to understanding the embodiments disclosed in the present invention and to presuppose an understanding of conventional methods well known to those skilled in the art to which the experimental examples belong. The specific materials and conditions described below are intended to exemplify specific aspects of the embodiments disclosed herein and should not be construed as being limited to a reasonable scope.

[0270] The following abbreviations may be used here.

[0271]

[0272] Polymorphic forms of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide were characterized by various analytical techniques, including XRPD, DSC, and TGA, using the procedures described below.

[0273] XRPD

[0274] The Rigaku Smart-Lab X-ray diffraction system was configured for a reflected Bragg-Brentano geometry using a line source X-ray beam. The X-ray source is a Cu Long Fine Focus tube operated at 40 kV and 44 mA. The source provides an incident beam profile on the sample that varies from a narrow line at high angles to a wide square at low angles. Beam control slits are used on the line X-ray source to ensure a maximum beam size of less than 10 mm along the line and the normal to the line. The Bragg-Brentano geometry is a para-focusing geometry controlled by passive diverging and receiving slits, along with the sample itself, which functions as the focusing component of the optical body. The intrinsic resolution of the Bragg-Brentano geometry is partially governed by the diffractometer radius and the width of the receiving slit used. Typically, the above-mentioned Rigaku Smart-Lab is operated to obtain peak widths of 0.1° 2θ or less. The axial divergence of the X-ray beam is controlled by 5.0-degree Soller slits in both the incident and diffracted beam paths.

[0275] Powder samples were prepared in a low-background Si holder using slight manual pressure to keep the sample surfaces flat and parallel to the reference surface of the sample holder. Each sample was analyzed at 2° to 40° using a continuous scan of 2° at 6° per minute with an effective step size of 0.02° 2°.

[0276] DSC

[0277] DSC analyses were performed using a TA Instruments Q2000 instrument. Instrument temperature calibration was performed using indium. DSC cells were maintained under a nitrogen purge of ~50 mL / min during each analysis. The samples were placed in a standard corrugated aluminum pan and heated from 25°C to 350°C at a rate of 10°C / min.

[0278] TGA

[0279] TGA was performed using a TA Instruments Q50 instrument. Instrument equilibrium was calibrated using Class M weights, and temperature calibration was performed using an alumel. Nitrogen purging was ~40 ml / min at equilibrium and ~60 ml / min in the furnace. Each sample was placed in a pre-weighed platinum pan and heated from 20°C to 350°C at a rate of 10°C / min.

[0280] DVS

[0281] DVS analyses were performed using a TA Instruments Q5000 Dynamic Vapor Sorption analyzer. The instrument was calibrated for humidity with standard weights and sodium bromide standards. Samples were analyzed at 25°C with a maximum equilibrium time of 60 minutes in 10% relative humidity (RH) steps, with RH (adsorption cycles) from 5% to 95% and RH (desorption cycles) from 95% to 5%.

[0282] Experimental Example 1: Preparation of Form I

[0283] Polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide was prepared according to the scheme provided below.

[0284]

[0285] 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 (8.4g, 54.9 mmol, 1.0 equiv) in a solution of tert-butyl N-[(1R)-5-(N-dihydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate (16g, 54.9 mmol, 1.0 equiv) in dioxane (300 ml) 64.5 mmol (1.2 equiv) was added. The mixture was stirred at 105°C for 8 hours, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (EA / PE, 1 / 9) to obtain 17.5 g (97%) of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl]carbamate as a white solid.

[0286] Step 2: Preparation of (1R)-5-(5-ethyl(ethyl)-1,2,4-oxadiazol-3-yl(yl))-2,3-dihydro-1H-inden-1-amine: TFA (24 mL) was added 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). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The mixture was then poured into ethanol (50 mL) and water (5 mL), and the pH was adjusted to 12 with a sodium hydroxide solution (2 N). The above mixture was subsequently extracted three times with dichloromethane (200 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 11.2 g of (1R)-5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-amine as a brown oil.

[0287] Step 3: Preparation of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid. HOAt (41.7g, 306.50 mmol, 1.5 equiv) and DIPEA (105.6g, 817.34 mmol, 4 equiv) were added at room temperature to a stirred solution of 1-methyl-1H-pyrazole-4-carboxylic acid (27.1g, 214.55 mmol, 1.05 equiv) and EDCI (58.8g, 306.50 mmol, 1.5 equiv) in DMF (540 mL). The mixture was stirred at room temperature for 5 minutes, after which (1R)-5-(5-ethyl-1,2,4-oxadiazole-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 at room temperature for an additional 2 hours. The reaction mixture was poured into water / ice at room temperature. The precipitated solids were collected by filtration and washed three times with water (1000 ml). The solids were dissolved in DCM (1500 ml). The organic phase was washed three times with NH4Cl (500 mL sat. aq) and three times with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide a raw product purified by grinding in EtOAc / n-hexane=1 / 2 (600 mL) to obtain Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (62.0704 g, 89.14%) as a yellowish-white solid. LRMS(ES) m / z 338 [M+H]. 1 ¹H NMR: (DMSO, 300 MHz, ppm): δ 8.41 (1H, d, J = 8.4 ㎐), 8.16 (1H, s), 7.91-7.79 (3H, m), 7.34 (1H, d, J = 7.9 ㎐), 5.53 (1H, q, J = 8.3 ㎐), 3.84 (3H, s), 3.13-2.81(4H, m), 2.44(1H, dd, J=7.9, 4.7Hz), 1.95(1H, m), 1.33(3H, t, J=7.5Hz).

[0288] Polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, TGA, and DVS. Figure 1a shows the XRPD pattern of form I. Figure 1b shows the DSC and TGA graphs of form I. As shown in the DSC graph, an endotherm onset was observed at approximately 199°C. As shown in the TGA graph, a weight loss of 0.2% was observed below 200°C. Figure 1c shows the DVS graph of form I. As shown in Fig. 1c, moisture absorption of 0.60% w / w was observed over a relative humidity (RH) range of 5%-90% as determined by DVS.

[0289] Experimental Example 2: Preparation of Form II

[0290] Polymorph form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the methods provided below.

[0291] Method 1

[0292] 18.2 mg of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was placed in a PEEK grinding cup equipped with a PEEK stainless steel ball, and 10 µl of water was added. The grinding cup was placed on a Retsch mill at 100% power for 20 minutes. The solids were scraped from the grinding cup with a spatula and analyzed by XRPD. The solids were determined to be form II.

[0293] Method 2

[0294] 19.5 mg of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide) was placed in a 20 mL glass vial and heated on a plate at 60°C with magnetic stirring. Ethanol was added to the glass vial until the solids dissolved (4 mL of ethanol was added). The vial was then removed from the plate, and 16 mL of cold water (cooled in a refrigerator) was added. The vial was then kept in a refrigerator for 4 days. After 4 days, the vial was centrifuged, the liquid was drained, the resulting solids were air-dried, and analyzed by XRPD. The solids were determined to be form II.

[0295] Polymorph form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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 graphs of form II. As shown in the DSC graph, endothermic onset was observed at approximately 199°C. As shown in the TGA graph, a weight loss of approximately 0.18% was observed from the start to 200°C.

[0296] Experimental Example 3: Preparation of a mixture of Form I and Form III

[0297] 19.1 mg of polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was suspended in 1 mL of hexane in a 1-dram glass vial. Dioxane was slowly added on a hot plate at 60°C while magnetically stirring until the solids dissolved (2.2 mL of dioxane was added). The vial was then stopped and the heating device was turned off. The vial was placed in a freezer (approx. -15°C) for 2 days. After 2 days, the vial was placed in a refrigerator for 4 days. After 4 days, the above vial was centrifuged, the liquid was poured out, the resulting solid was air-dried, analyzed by XRPD, and determined to be a mixture of form I and form III.

[0298] A mixture of polymorph forms I and III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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 3b shows the DSC and TGA graphs of the mixture of forms I and III. As shown in the DSC graph, exothermic onset at approximately 107°C and endothermic onset at approximately 196°C were observed. As shown in the TGA graph, a weight loss of approximately 18.89% was observed from the start to 125°C.

[0299] Experimental Example 4: Preparation of Form IV

[0300] Polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide was prepared according to the scheme provided below.

[0301]

[0302] 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 (10.5g, 0.0833mol, 1.00equiv) and N,N-dimethylformamide (0.054g, 0.057ml, 0.00074mol, 0.0089equiv) in 2-MeTHF (71.6g, 83.3ml, 7.93vol) was stirred at 20±5℃. A solution of oxalyl chloride (9.98 g, 0.0786 mol, 0.945 equiv) was added over a period of at least 45 minutes and allowed to react at 30 ± 5°C until ≤15% of the starting material, 1-methyl-1H-pyrazole-4-carboxylic acid, remained. The mixture was cooled to 20 ± 5°C (Vessel 1). A mixture of (R)-1-amino(amino)-2,3-dihydro(dihydro)-1H-indene(inden)-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 a 4N sodium hydroxide solution (79 ml, 0.316 mol, 3.8 eq.) at 20 ± 5°C. The resulting mixture was stirred at 20 ± 5°C for at least 30 minutes (Vessel 2). A freshly prepared 1-methyl-1H-pyrazole-4-carboxylic acid chloride solution was added to the reaction mixture while maintaining a temperature of <30°C. After the addition was completed, the mixture was allowed to react at 20±5°C until ≤5% of the intermediate (R)-1-amino-2,3-dihydro-1H-indene-5-carbonnitrile hydrochloride remained. The mixture was subsequently filtered.The resulting filter cake was washed with 2-MeTHF (25 ml) accompanied by water until the pH of the filtrate was 8.5 ± 1.5. Afterward, the solid was dried and separated. 18.9 g (89.6%) of (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained as a pale gray solid.

[0303] Step 2: Preparation of (R,Z)-N-(5-(N'-hydroxycarbamimidoyyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. A solution of (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (15.0 g, 0.0563 mol, 1.00 equiv) in NMP (77.3 g, 75.1 ml, 5.0 vol) was cooled to 5 ± 5°C, and aqueous hydroxylamine (11.2 g, 0.169 mol, 3.00 equiv) was slowly added while maintaining a temperature of ≤15°C. The resulting mixture was stirred at 20±5°C for at least 16 hours until ≤2% (R)-N-(5-cyano-2,3-dihydro-1H-indene-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 a temperature of ≥50°C. The resulting mixture was slowly cooled to 20±5°C and stirred for at least 2 hours. Subsequently, the mixture was cooled to 15±5°C and stirred for at least 1 hour. The solid product was collected by filtration. The wet filter cake was washed with isopropyl acetate (2 x 70 ml), and the solid was dried. The material was subsequently packaged. 14.62 g (86.7%) of (R,Z)-N-(5-(N'-hydroxycarbamimidoyyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazol-4-carboxamide was obtained as a yellowish-white solid.

[0304] Step 3: Preparation of polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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) 1The mixture was stirred at 20±5°C until less than 20% of unreacted propionic acid remained, as determined by H NMR. The activated propionic acid solution was transferred to (R,Z)-N-(5-(N'-hydroxycarbamimidoyyl)-2,3-dihydro-1H-indene-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 temperature of the reaction mixture was adjusted to 50±5°C, and the mixture was stirred at 50±5°C until the (R,Z)-N-(5-(N'-hydroxycarbamimidoyyl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide remained at ≤2%. When the completion of the reaction was confirmed, 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 adjusted to 70±5°C, and the mixture was stirred at 70±5°C until less than 2% of the uncyclized intermediate remained. After confirming the completion of the reaction, the reaction mixture was rapidly cooled with water (48 ml). The batch temperature was adjusted to 55 ± 5°C, and the solution was filtered. The resulting filtrate was concentrated to approximately 10 vol. The mixture was adjusted to 80 ± 5°C, and water (310 ml) was slowly added over a period of at least 1 hour while maintaining a temperature of ≥70°C. The mixture was adjusted to 80 ± 5°C, and the resulting slurry was stirred at 80 ± 5°C for at least 2 hours. The mixture was slowly cooled to 20 ± 5°C over a period of at least 4 hours and stirred at 20 ± 5°C for at least 2 hours. The mixture was filtered. The resulting filtrate cake was washed with water (3 x 120 ml) and dried in a vacuum oven until an LOD of ≤1% was achieved. The materials were subsequently packaged. Total 16.Polymorph form IV of 32 g of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained as a yellowish-white solid with a yield of 92.8%.

[0305] Polymorph form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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 graphs of form IV. As shown in the DSC graph, endothermic onset was observed at approximately 200°C. As shown in the TGA graph, a weight loss of approximately 0.003% was observed from the start to 200°C.

[0306] Experimental Example 5: Preparation of Form V

[0307] Polymorph form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the method provided below.

[0308] (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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 polymorphs were generated. A type existing as fine-needle-like fibrous forms was isolated and identified by XRPD as polymorph form IV. A type existing as long-needle forms was isolated and identified by XRPD as polymorph form V. Figure 5 shows the experimental and simulated XRPD patterns of form V.

[0309] Experimental Example 6: Preparation of Form VI

[0310] Polymorph form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the methods provided below.

[0311] Method 1

[0312] 60:40 acetonitrile:water (8 ml) was added to (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (form VI) (500 mg) and stirred at ambient temperature for 48 hours. The solids were separated by vacuum filtration and analyzed by XRPD, DSC, and TGA.

[0313] Polymorph form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. Figure 6a shows the experimental XRPD pattern of form VI. Figures 6b and 6d show the TGA and DSC graphs of form VI taken after oven drying (at 25°C for 24 hours), respectively. As shown in the TGA graph of Figure 6b, a weight loss of approximately 2.185% was observed between 25°C and 65°C. As shown in the DSC graph of Figure 6d, a broad endothermic onset at approximately 41°C, a small exothermic onset at approximately 115°C, and a sharp endothermic onset at 200°C were observed.

[0314] Figures 6c and 6e show the TGA and DSC graphs of Form VI taken after oven drying and heating (oven drying at 25°C for 24 hours; heating at 150°C), respectively. As shown in the TGA graph of Figure 6c, negligible weight loss was observed up to 200°C. As shown in the DSC graph of Figure 6e, a sharp endothermic onset was observed at 200°C.

[0315] Method 2

[0316] A slurry was prepared from solids of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (form I, form IV, or form V) (30 mg) in 10%-90% acetonitrile in water (1 ml), and the slurry was subsequently stirred with a stirring bar at 2°C-8°C for 24 hours. The solids were separated by vacuum filtration and identified as polymorph form VI by XRPD.

[0317] Experimental Example 7: Polymorph Selection

[0318] Polymorph form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was mixed with various solvents under various conditions. The samples were analyzed by XRPD. The results are shown in Table 6 below.

[0319] Table 6

[0320]

[0321]

[0322]

[0323] AS = Semi-solvent; NC = Non-crystallization; RH = Relative humidity; RT = Room temperature

[0324] Experimental Example 8: Competitive Slurry Experiments Between Form I and Form IV

[0325] Competitive slurry experiments were performed for Forms I and IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide to determine the most stable form over a temperature range (2°C–60°C). Form IV was found to be more stable than Form I over the entire tested temperature range. The results of the competitive slurry experiments are provided in Table 7 below.

[0326] Table 7

[0327]

[0328] Experimental Example 9: Myofibrils Analysis

[0329] To evaluate the effect of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide on the ATPase activity of full-length cardiac myosin within tissues of natural myofibril segments, skinned myofibril analyses were performed. Bovine cardiac myofibrils were obtained by homogenizing bovine left ventricular heart tissue in the presence of a lavage agent such as Triton X-100. This treatment removes membranes and the majority of soluble cytoplasmic proteins, but leaves intact cardiac myofibril segment actomyosin machinery. The myofibril preparations were Ca 2+ It maintains the ability to hydrolyze ATP through a regulatory mechanism. The athiase activities of these myofibril products are activated up to a defined portion of the maximum proportion (i.e., 25%, 75%) by Ca in the presence and absence of compounds. 2+They were analyzed at various concentrations. Small molecule agents were evaluated for their ability to inhibit steady-state aTPase activity in bovine cardiac myofibrils using the pyruvate kinase and lactate dehydrogenase (PK / LDH)-coupled enzyme system. This analysis involves the oxidization of NADH to regenerate myosin-generated ADP into ATP, generating a change in uptake at 340 nm. Prior to testing the small molecule agents, the bovine cardiac myofibrils were evaluated for their calcium responsiveness, and 50% (pCa) of the myofibril system 50 ) or 75% (pCa 75 A calcium concentration that enables ) activation was selected as the final condition for evaluating the inhibitory activity of the above small molecules. All enzyme activities were measured in a buffer solution (PM 12 buffer) containing 12 mM PIPES (piperazine-N,N'-bis)(2-ethanesulfonic acid) and 2 mM magnesium chloride at pH 6.8. The final assay conditions were 1 mg / mL bovine cardiac myofibrils, 4 U / mL pyruvate kinase, 6 U / mL lactate dehydrogenase, 50 μM ATP, 0.1 mg / mL BSA (bovine serum albumin), 10 ppm antifoam, 1 mM DTT, 0.5 mM NADH, 1.5 mM PEP, 0.6 mM EGTA, and an amount of CaCl2 sufficient to achieve 50% or 75% activation of the said myofibril aTPase. IC for (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide 15 (CDMF 75) is 0.4 μM, and the IC for (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide 50(CDMF 75) is 1.4 μM.

[0330] Experimental Example 10: Muscle Cell Analyses

[0331] Adult male Sprague-Dawley rats were anesthetized, the hearts were rapidly resected and irrigated, and a cannula was inserted into the ascending aorta. Continuous retrograde perfusion was initiated on the hearts at a perfusion pressure of 60 cm H2O. The hearts were initially nominally Ca of the following composition 2 +It was perfused with a modified Krebs solution containing 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 Sigma). This medium was not recirculated and was continuously aerated with a 95% O2 / 5% CO2 mixture. After approximately 3 minutes, the heart was perfused with a modified Krebs buffer supplemented with collagenase (Worthington) and a final calcium concentration of 12.5 mM. The heart was removed from the cannulas after the heart had become white and soft. The atria and blood vessels were removed, and the ventricles were gently dissected into small pieces with forceps. The tissue was homogenized by repeated pipette grinding, and the collagenase reaction was stopped by sedimentation and resuspension in 10% calf serum (BCS) in perfusion buffer containing 5% BCS and 12.5 μM CaCl2. Muscle cells were calcium-tolerant by the sequential addition of CaCl2 solution to a final concentration of 1.2 mM. The cells were subsequently washed and resuspensioned in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl2, 11 mM glucose, 4 mM Hepes, and 1.2 mM CaCl2, pH 7.4). Cells were maintained at 37°C for 60 minutes prior to the start of the experiments and were used within 5 hours of separation. Cell products were used only if the cells passed QC criteria by demonstrating a shrinkage response up to standard (>150% base) and isoproterenol (ISO; >250% base) treatments.In addition, only cells with a basal contractility between 3% and 8% were used in subsequent experiments with compounds. In addition, only cells with a basal contractility between 3% and 8% were used in subsequent experiments with compounds.

[0332] Partial samples of muscle cells in tie rod buffer were placed in perfusion chambers (Series 20 RC-27NE; Warner Instruments) equipped with heating platforms. The muscle cells were placed to attach, the chambers were heated to 37°C, and the cells were perfused with tie rod buffer at 37°C. The muscle cells were field-stimulated at 1 Hz with platinum electrodes (upper threshold of 20%). Only cells that had clear striations and were static prior to tuning were used for contractility experiments. To determine basal contractility, the muscle cells were imaged through a 40x objective lens. Using a charge-coupled device camera with a variable frame rate (60 Hz–240 Hz), the images were digitized and displayed on a computer screen at a sampling rate of 240 Hz (IonOptix Milton, Massachusetts). Once cell contraction had stabilized over time, test compounds (0.01 mM–15 mM) were perfused into the chamber for 5 minutes. The contractility of the muscle cells and the rates of contraction and relaxation were subsequently recorded using edge detection.

[0333] Five or more individual muscle cells were tested for each compound from two or more different muscle cell preparations. For each cell, twenty or more contractile transitions were averaged and compared at baseline (defined as 1 minute prior to compound injection) and after compound addition (defined as 5 minutes after compound perfusion was initiated). These average transitions were analyzed using IonWizard software (IonOptix) to determine changes in diastolic length and fractional shortening. Fractional shortening was calculated as (resting length divided by (length at peak contraction)). The percentage change in fractional shortening from baseline was calculated as ((fractional shortening after dose administration / baseline fractional shortening) * 100). The percentage decrease in fractional shortening from baseline was calculated as (100 - percentage of fractional shortening from baseline). Maximum contraction and relaxation rates (µm / sec) were also determined. The results from individual cells were averaged, and SEM was calculated. The effect of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided below.

[0334]

[0335] % FS = Average of each cell (Post-baseline percent peak height / Pre-baseline percent peak height) x 100

[0336] Experimental Example 11: Cardiac Ultrasound Evaluation of Rapid Pharmacokinetic Effects in Rat Cardiac Contractility

[0337] Evaluation of in vivo cardiac function by echocardiography was performed on male Sprag-Daury rats under isofuran (1%–3%) anesthesia. 2-D M-mode images of the left ventricle were acquired in a parasternal long-axis view before, during, and after administration of the compounds via sequential IV infusion or oral feeding. In vivo fractional shortening was determined by M-mode image analysis using the following calculation: ((terminal diastolic diameter - terminal systolic diameter) / terminal diastolic diameter x 100). For the sequential IV infusion experiments, three pre-administration baseline M-mode images were taken at 1-minute intervals prior to the infusion of the compounds. The compounds were prepared in 50% propylene glycol (PG): 16% captisol: 10% dimethylacetamide (DMA) and infused via a neck vein catheter at a rate of 1 ml / kg / h. During the infusion, M-mode images were taken at 5-minute intervals. The infusion was stopped when fraction reduction reached 60% from baseline. Blood samples were taken to determine the plasma concentrations of the compounds. The data included the calculated IC50 at which fraction reduction reached 50% of the baseline constrictive concentration before administration. 50 The IC was reported as a value for (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. 50 The value is 7.2±0.20μM (mean±SD).

[0338] For the oral administration studies, baseline M-mode images prior to administration of the three compounds were taken at 1-minute intervals prior to compound administration. (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared in a 0.5% hydroxypropyl methylcellulose 2910 (HPMC 2910):0.1% Tween 80 suspension and delivered as a single dose (5 ml / kg) by oral ingestion. Rats were lightly anesthetized for M-mode echocardiogram measurements at selected time points over a 24-hour period. Different dose levels were evaluated. At the highest dose evaluated, the effect of the compound on cardiac fraction shortening is presented as a percentage reduction in baseline fraction shortening (=100%).

[0339]

[0340] Blood samples were taken simultaneously with cardiac ultrasound measurements to determine the plasma concentrations of the corresponding compounds. The calculated IC50 was determined at which fractional shortening resulted in concentrations of 50% and 10% of the baseline contractility before administration. 50 and IC 10 The values ​​were 7.9μM (IC) each 50 ) and 0.8μM(IC 10 )am.

[0341] All documents, including all literature, figures, and drawings mentioned herein, including patents, patent applications, and published patents, are incorporated herein by reference in their entirety for all purposes.

[0342] The foregoing descriptive descriptions of the compounds, uses, and methods described herein enable a person skilled in the art to implement and utilize the compounds, uses, and methods described herein; however, a person skilled in the art will understand and recognize the existence of variations, combinations, and equivalents to the specific embodiments, methods, and experimental examples provided herein. Accordingly, the compounds, uses, and methods provided herein should not be limited by the embodiments, methods, or experimental examples described above, but rather should be understood to encompass all embodiments and methods within the spirit and scope of the compounds, uses, and methods provided herein.

Claims

Claim 1 A pharmaceutical composition comprising a polymorph of (R)-N-(5-(5-ethyl(ethyl)-1,2,4-oxadiazol-3-yl(yl))-2,3-dihydro-1H-inden-1-yl(yl))-1-methyl(1H-pyrazole)-4-carboxamide and a pharmaceutically acceptable excipient, which is used to treat heart disease in subjects requiring care, to treat diseases or conditions associated with small left ventricular cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in subjects requiring care, or to inhibit cardiac muscle fiber segments, wherein the polymorph is polymorph form IV, and the polymorph form IV is, a) X-ray powder diffraction (XRPD) patterns including peaks at angles of 2-theta at 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 22.8±0.2°, and 24.4±0.2°; and / or b) XRPD patterns including peaks at angles of 2-theta at 3.7±0.2°, 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 21.9±0.2°, 22.8±0.2°, 23.1±0.2°, 23.5±0.2°, 24.4±0.2°, and 24.8±0.2°; and / or c) 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°C, 23.9±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.0±0.2°C, 25.3±0.2°C, 25.XRPD patterns including peaks at angles 2-theta of 8±0.2°, 26.2±0.2°, 27.1±0.2°, 27.4±0.2°, 28.0±0.2°, 28.6±0.2°, 29.0±0.2°, 30.0±0.2°, 30.5±0.2°, 30.8±0.2°, 31.0±0.2°, 31.4±0.2°, 33.8±0.2°, 35.0±0.2°, 35.7±0.2°, 36.1±0.2°, 36.7±0.2°, 37.9±0.2°, 38.1±0.2°, and 39.8±0.2°; and / or d) endotherm onset at 200±2℃ as determined by DSC; and / or e) having a weight loss of 0.003% from onset at 200℃ as determined by TGA. Claim 2 A pharmaceutical composition comprising a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, which is used to treat heart disease in subjects requiring it, to treat diseases or conditions associated with small left ventricular cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in subjects requiring it, or to inhibit cardiac myofibrosis, wherein the polymorph is polymorph form IV, and the polymorph form IV has an XRPD pattern including peaks at angle 2-theta of 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 22.8±0.2°, and 24.4±0.2°. A pharmaceutical composition characterized by the following. Claim 3 A pharmaceutical composition according to claim 2, characterized in that the polymorph form IV has an endothermic onset at 200±2℃ as determined by DSC. Claim 4 A pharmaceutical composition according to claim 1, characterized in that the composition comprises 0.5% to 50% by weight of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Claim 5 A pharmaceutical composition according to claim 1, characterized in that at least 90 weight percent of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in form IV. Claim 6 A pharmaceutical composition according to claim 1, characterized in that at least 5.0 weight% or at least 10 weight% of the total composition is polymorph form IV. Claim 7 A pharmaceutical composition according to claim 1, characterized in that the composition comprises less than 5% by weight of the amorphous or non-crystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Claim 8 A pharmaceutical composition according to claim 1, wherein the composition comprises less than 1% by weight of the amorphous or non-crystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Claim 9 A pharmaceutical composition according to claim 1, characterized in that the pharmaceutically acceptable excipient is selected from one or more of mannitol, cellulose, sodium crosscarmellose, and magnesium stearate. Claim 10 A pharmaceutical composition according to claim 1, characterized in that the composition is a tablet or capsule and contains less than 5% by weight of impurities. Claim 11 A pharmaceutical composition according to claim 1, characterized in that the composition is a tablet or capsule and contains less than 1% by weight of impurities. Claim 12 In a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, said polymorph is polymorph form I, said polymorph form I comprises: a) an XRPD pattern including peaks at angles 2-theta of 3.7±0.2°, 11.2±0.2°, 12.9±0.2°, 14.4±0.2°, and 22.4±0.2°; and / or b) an XRPD pattern including peaks at angles 2-theta 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°; and / or c) 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°, A polymorph characterized by having an XRPD pattern including peaks at angles 2-theta of 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°; and / or d) endothermic onset at 199±2°C as determined by DSC; and / or e) a weight loss of 0.2% below 200°C as determined by TGA; and / or f) a moisture absorption of 0.06% over a relative humidity (RH) range of 5%-90% as determined by DVS. Claim 13 In a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, said polymorph is polymorph form II, said polymorph form II comprises: a) an XRPD pattern including peaks at angles 2-theta of 3.7±0.2°, 9.8±0.2°, 11.1±0.2°, 12.8±0.2°, and 20.4±0.2°; and / or b) an XRPD pattern including peaks at angles 2-theta 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°; and / or c) 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 A polymorph characterized by an XRPD pattern including peaks at an angle of 2-theta of 30.5±0.2 degrees; and / or d) endothermic onset at 199±2°C as determined by DSC; and / or e) a weight loss of 0.18% from onset at 200°C as determined by TGA. Claim 14 A polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, wherein the polymorph is polymorph form III, and the polymorph form III is characterized by having an XRPD pattern including peaks at angles 2-theta of 9.6±0.2°, 10.9±0.2°, 15.8±0.2°, and 18.1±0.2°. Claim 15 In a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, said polymorph is polymorph form V, said polymorph form V comprises: a) an XRPD pattern including peaks at angles 2-theta of 11.5±0.2°, 16.3±0.2°, 20.0±0.2°, 21.2±0.2°, and 24.7±0.2°; and / or b) an XRPD pattern including peaks at angles 2-theta 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°; and / or c) an XRPD pattern including peaks at angles 2-theta 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°; and / or d) 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°C, 24.2±0.2°C, 24.3±0.2°C, 24.6±0.2°C, 24.7±0.2°C, 25.2±0.2°C, 25.6±0.2°C, 26.7±0.2°C, 27.1±0.2°C, 27.3±0.2°C, 27.5±0.2°C, 27.9±0.2°C, 28.1±0.2°C, 28.4±0.2°C, 28.9±0.2°C, 29.2±0.2°C, 29.7±0.2°C, 29.8±0.2°C, 29.9±0.2°C, 30.4±0.2°C, 30.6±0.2°C, 31.1±0.2°C, 31.3±0.2°C, 31.5±0.2°C, 32.0±0.2°C, 32.9±0.2°C, 33.0±0.2°C, 33.2±0.2°C, 33.5±0.2°C, 34.4±0.2°C, 34.6±0.2°C, 34.9±0.2°C, 35.3±0.2°C, 35.7±0.2°C, 36.0±0.2°C, A polymorph characterized by having an XRPD pattern including peaks at an angle of 2-theta of 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°. Claim 16 In a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, said polymorph is polymorph form VI, said polymorph form VI comprises: a) an XRPD pattern including peaks at angles 2-theta of 10.6±0.2°, 12.1±0.2°, 15.0±0.2°, 16.1±0.2°, and 17.8±0.2°; and / or b) an XRPD pattern including peaks at angles 2-theta 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°; and / or c) 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°C, 19.6±0.2°C, 20.0±0.2°C, 20.3±0.2°C, 20.7±0.2°C, 21.1±0.2°C, 21.9±0.2°C, 22.6±0.2°C, 22.9±0.2°C, 23.6±0.2°C, 23.8±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.5±0.2°C, 26.4±0.2°C, 26.7±0.2°C, 27.3±0.2°C, 27.6±0.2°C, 28.2±0.2°C, 28.5±0.2°C, 29.0±0.2°C, 29.6±0.2°C, 29.9±0.2°C, 30.4±0.2°C, 30.9±0.2°C, 31.6±0.2°C, 32.2±0.2°C, 32.6±0.2°C, 33.1±0.2°C, 33.3±0.2°C, 34.5±0.2°C, 35.0±0.2°C, 35.5±0.2°C, and 38.5±0.A polymorph characterized by having an XRPD pattern including peaks at an angle of 2 degrees and 2-theta; and / or d) a weight loss of 2% ± 0.5% between 25°C and 200°C as determined by TGA; and / or e) endothermic onset at 200 ± 2°C as determined by DSC; and / or f) endothermic onset at 200 ± 2°C, exothermic onset at 115 ± 2°C, endothermic onset at 41 ± 2°C, or any combination thereof as determined by DSC. Claim 17 A method for preparing a polymorph of claim 12, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-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), optionally comprising a) the solvent comprises dichloromethane (DCM); and / or b) step (2) comprises removing the solvent. Claim 18 A method for producing a polymorph of claim 13, comprising: a) grinding form I of claim 12 in water; or b) (1) forming a mixture of form I of claim 12 and ethanol; and (2) cooling the mixture of step (1), optionally i) step (1) comprising heating the mixture to 50°C to 70°C; and / or ii) step (2) comprising cooling the mixture of step (1) to -5°C to -20°C. Claim 19 A method for preparing a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, wherein the polymorph is polymorph form IV, and the polymorph form IV comprises: a) an XRPD pattern including peaks at angles 2-theta of 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 22.8±0.2°, and 24.4±0.2°; and / or b) an XRPD pattern including peaks at angles 2-theta 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°; and / or c) 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°C, 23.9±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.0±0.2°C, 25.3±0.2°C, 25.8±0.2°C, 26.2±0.2°C, 27.1±0.2°C, 27.4±0.2°C, 28.0±0.2°C, 28.6±0.2°C, 29.0±0.2°C, 30.0±0.2°C, 30.5±0.2°C, 30.8±0.2°C, 31.0±0.2°C, 31.4±0.2°C, 33.8±0.2°C, 35.0±0.2°C, 35.7±0.2°C, 36.1±0.2°C, 36.7±0.2°C, 37.9±0.2°C, 38.1±0.2°C, 39.8±0.d) an XRPD pattern including peaks at an angle of 2 degrees and 2-theta; and / or d) endothermic onset at 200±2℃ as determined by DSC; and / or e) having a weight loss of 0.003% from the start at 200°C as determined by TGA, the method comprises (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises acetonitrile (ACN) or a mixture of ACN and water, and (2) cooling the mixture of step (1), optionally, A) step (1) forms a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent A method comprising the step of heating to 60°C to 85°C; and / or B) the step (2) comprises the step of cooling the mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to 5°C to 25°C. Claim 20 A method for preparing a polymorph of claim 15, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an acetate; (2) cooling the mixture of step (1), optionally a) the solvent comprises an ethyl acetate; and / or b) step (2) cooling the mixture of step (1) to -5°C to 15°C; and / or c) further comprising a step of separating the polymorph existing in long needle forms. Claim 21 A method for preparing a polymorph of claim 16, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises nitrile and water; (2) stirring the mixture of step (1), optionally a) the solvent comprises acetonitrile; and / or b) step (2) cooling the mixture of step (1) to 0°C to 20°C. Claim 22 A pharmaceutical composition to be used to treat heart disease in a subject in need, to treat a disease or condition associated with a small left ventricular cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in a subject in need, or to inhibit cardiac muscle fiber segments, comprising a polymorph of any one of claims 12 to 16 and a pharmaceutically acceptable excipient. Claim 23 A pharmaceutical composition of any one of claims 1 to 11 or a pharmaceutical composition comprising a polymorph of claims 12 to 16 for use in treating heart disease in a subject requiring it. Claim 24 A pharmaceutical composition according to claim 23, characterized in that the heart disease is hypertrophic cardiomyopathy (HCM). Claim 25 A pharmaceutical composition according to claim 24, wherein the above HCM is obstructive or non-obstructive associated with sarcomeric and / or non-sarcomeric mutations. Claim 26 A pharmaceutical composition according to claim 23, characterized in that the heart disease is heart failure with a preserved ejection fraction (HFpEF). Claim 27 A pharmaceutical composition according to claim 23, wherein the heart disease is selected from the group consisting of diastolic dysfunction, primary or secondary restrictive cardiomyopathy, myocardial infarction and angina pectoris, left ventricular outflow tract obstruction, hypertensive heart disease, congenital heart disease, cardiac ischemia, coronary heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, and infiltrative cardiomyopathy. Claim 28 A pharmaceutical composition according to claim 23, characterized in that the heart disease is one or more conditions selected from the group consisting of cardiac senescence, cardiac dilatative dysfunction due to aging, left ventricular hypertrophy, and concentric left ventricular remodeling, or associated conditions. Claim 29 A pharmaceutical composition comprising a polymorph of any one of claims 1 to 11 or a pharmaceutical composition comprising any one of claims 12 to 16 for use in treating a disease or condition associated with a small left ventricular cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in a subject requiring treatment. Claim 30 A pharmaceutical composition comprising any one of claims 1 to 11 or any one of claims 12 to 16 for use in inhibiting cardiac muscle fiber segments. Claim 31 In a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, said polymorph is polymorph form IV, said polymorph form IV comprises: a) an XRPD pattern including peaks at angles 2-theta of 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 22.8±0.2°, and 24.4±0.2°; and / or b) an XRPD pattern including peaks at angles 2-theta 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°; and / or c) 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°C, 23.9±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.0±0.2°C, 25.3±0.2°C, 25.8±0.2°C, 26.2±0.2°C, 27.1±0.2°C, 27.4±0.2°C, 28.0±0.2°C, 28.6±0.2°C, 29.0±0.2°C, 30.0±0.2°C, 30.5±0.2°C, 30.8±0.2°C, 31.0±0.2°C, 31.4±0.2°C, 33.8±0.2°C, 35.0±0.2°C, 35.7±0.2°C, 36.1±0.2°C, XRPD patterns including peaks at angles 2-theta of 36.7±0.2°, 37.9±0.2°, 38.1±0.2°, and 39.8±0.2°; and / or d) endothermic onset at 200±2°C as determined by DSC; and / or e) 0.0 from onset at 200°C as determined by TGA.A polymorph characterized by having a weight loss of 0.03%. Claim 32 A polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazole-3-yl)-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, wherein the polymorph is polymorph form IV, and the polymorph form IV is characterized by having an XRPD pattern including peaks at angles 2-theta of 11.1±0.2°, 12.8±0.2°, 13.5±0.2°, 22.8±0.2°, and 24.4±0.2°. Claim 33 A polymorph according to claim 31 or 32, wherein polymorph form IV has an XRPD pattern comprising peaks at angles 2-theta 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°. Claim 34 In claim 31 or 32, the polymorph form IV is 3.7±0.2°, 7.7±0.2°, 11.1±0.2°, 12.4±0.2°, 12.8±0.2°, 13.5±0.2°, 14.3±0.2°, 15.5±0.2°, 16.6±0.2°, 17.9±0.2°, 18.5±0.2°, 18.6±0.2°, 19.1±0.2°, 19.9±0.2°, 20.9±0.2°, 21.5±0.2°, 21.6±0.2°, 21.9±0.2°, 22.3±0.2°, 22.4±0.2°, 22.8±0.2°C, 23.1±0.2°C, 23.5±0.2°C, 23.9±0.2°C, 24.4±0.2°C, 24.8±0.2°C, 25.0±0.2°C, 25.3±0.2°C, 25.8±0.2°C, 26.2±0.2°C, 27.1±0.2°C, 27.4±0.2°C, 28.0±0.2°C, 28.6±0.2°C, 29.0±0.2°C, 30.0±0.2°C, 30.5±0.2°C, 30.8±0.2°C, 31.0±0.2°C, 31.4±0.2°C, 33.8±0.2°C, 35.0±0.2°C, A polymorph characterized by having an XRPD pattern including peaks at angles 2-theta of 35.7±0.2°, 36.1±0.2°, 36.7±0.2°, 37.9±0.2°, 38.1±0.2°, and 39.8±0.2°. Claim 35 A polymorph according to claim 31 or 32, characterized in that polymorph form IV has an endothermic onset at 200±2℃ as determined by DSC. Claim 36 A polymorph according to claim 31 or 32, characterized in that polymorph form IV has a weight loss of 0.003% from the start at 200°C as determined by TGA. Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete Claim 48 delete Claim 49 delete Claim 50 delete Claim 51 delete Claim 52 delete Claim 53 delete Claim 54 delete Claim 55 delete Claim 56 delete Claim 57 delete Claim 58 delete Claim 59 delete Claim 60 delete Claim 61 delete Claim 62 delete

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