Polymorphs

Abstract

Provided herein are polymorphic forms of (R)-N-(5-(5-ethyl-1, 2, 4-oxadiazol-3-yl)-2, 3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazol-4-carboxamide, compositions of the polymorphic forms, methods of making the polymorphic forms, and methods of using the polymorphic forms of (R)-N-(5-(5-ethyl-1, 2, 4-oxadiazol-3-yl)-2, 3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazol-4-carboxamide.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application date: July 16, 2020; application number: 202080059660.0 (international application number: PCT / US2020 / 042387); invention name: (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide polymorph).

[0002] Cross-reference to related applications

[0003] This application claims priority to and the benefit of U.S. Provisional Application No. 62 / 875,350, filed on July 17, 2019, the entire disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] Provided herein are polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, compositions thereof, methods of making the same, and methods of using the same. Background Art

[0005] The cardiac sarcomere is composed of a network of contractile and structural proteins that regulate myocardial function. The components of the cardiac sarcomere present targets for the treatment of various cardiac diseases and conditions, for example by increasing contractility or promoting complete relaxation to modulate systolic and diastolic function, respectively. The force and speed of myocardial contraction are major determinants of organ function and are regulated by the cyclic interaction of actin and myosin. Regulation of actin and myosin binding is controlled by a network of myofilament regulatory proteins and intracellular Ca 2+ The troponin complex and tropomyosin are thin, filamentous proteins that control the availability of actin binding sites, while essential and regulatory light chains and myosin-binding protein C regulate the position and mechanical properties of myosin.

[0006] Cardiac sarcomeric abnormalities have been identified as a cause of various cardiac diseases and conditions, such as hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF). Mutations in sarcomeric proteins cause disease by causing the heart muscle to contract 'too much' or 'too little'. Sarcomeric modulators can be used to restore balance in contractility and halt or reverse the course of the disease.

[0007] Existing agents that target cardiac sarcomeres (such as inotropes, drugs that increase the heart's ability to contract) are insufficiently selective for cardiac tissue, leading to well-recognized side effects that limit their use. These side effects include cellular damage due to increased rates of energy expenditure, exacerbation of relaxation abnormalities, and potentially arrhythmic side effects due to increased cytosolic Ca++ and cyclic AMP concentrations in the contractilely stimulated myocardium. Given the limitations of existing agents, new approaches are needed to improve cardiac function in HCM and HFpEF.

[0008] There remains a great need for agents that employ novel mechanisms of action and that may provide better outcomes in terms of symptom relief, safety, and patient mortality (both short-term and long-term). New agents with improved therapeutic indexes compared to existing agents would provide a means for achieving these clinical outcomes. Selectivity of agents for cardiac sarcomeres (e.g., by targeting cardiac myosin) has been identified as an important means of achieving this improved therapeutic index. (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is a selective allosteric inhibitor of cardiac myosin that has little or no effect on smooth muscle myosin. The benefits of this compound include a wider therapeutic index, lower effects on cardiac relaxation, better pharmacokinetics, and a better safety profile, and therefore it offers potential treatments for cardiac diseases and conditions.

[0009] In order to make a drug candidate such as (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide into a viable drug product, it is important to understand whether the drug candidate has polymorphic forms and the relative stabilities and interconversions of these forms under conditions likely to be encountered during large-scale production, transportation, storage, and preparation for use. The ability to control and produce stable polymorphs through robust manufacturing processes can be important for regulatory approval and commercialization. Large-scale production processes for high-purity (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide can be improved by using specific polymorphic forms. Therefore, there is a need for various new crystalline forms of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide having different chemical and physical stabilities, as well as formulations and uses thereof. Summary of the Invention

[0010] In one aspect, provided herein are polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0011] In another aspect, provided herein are methods for preparing polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0012] In another aspect, provided herein are compositions containing a polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide as described herein.

[0013] In another aspect, provided herein are methods of using polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide to treat heart disease in a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1A Shown is the experimental X-ray powder diffraction (XRPD) pattern of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0015] Figure 1B Shown are the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0016] Figure 1C Shown is the dynamic vapor sorption (DVS) curve of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0017] Figure 2A Shown is an experimental XRPD pattern of polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0018] Figure 2B Shown are the DSC and TGA curves of polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0019] Figure 3A Shown is an experimental XRPD pattern of a mixture of polymorphic Forms I and III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0020] Figure 3B Shown are the DSC and TGA graphs of a mixture of polymorphic forms I and III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0021] Figure 4A Shown is an experimental XRPD pattern of polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0022] Figure 4B Shown are the DSC and TGA curves of polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0023] Figure 5 Shown are the experimental XRPD pattern and two simulated patterns of polymorphic Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (from top to bottom: simulated at 223 K; simulated at 273 K; experimental).

[0024] Figure 6A Shown are two experimental XRPD patterns of polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide: (a) at top, XRPD of Form VI taken before drying; and (b) at bottom, after drying (oven, vacuum, 24 hours at 25°C).

[0025] Figure 6B and 6CShown is a TGA graph of polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 6B Shown are the weight losses of oven-dried samples (oven, vacuum, overnight at 25°C) of Form VI over the range of 25-300°C. Figure 6C Shown is a TGA plot over the range of 25-300°C for a sample of Form VI that was oven dried (oven, vacuum, overnight at 25°C) and further heated at 150°C prior to thermogravimetric analysis.

[0026] Figure 6D and 6E Shown is a DSC graph of polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Figure 6D Shown is the DSC plot of an oven-dried sample (oven, vacuum, overnight at 25°C) of Form VI in the range of 25-300°C. Figure 6E Shown is a DSC trace over the range of 25-300°C for a sample of Form VI that was oven dried (oven, vacuum, overnight at 25°C) and further heated at 150°C prior to thermogravimetric analysis. Detailed Description of the Invention

[0028] definition

[0029] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0030] As used herein and unless otherwise specified, the terms "about" and "approximately" when used in conjunction with a dose, amount, or weight percentage of an ingredient of a composition or dosage form means a dose, amount, or weight percentage recognized by one skilled in the art as providing a pharmacological effect equivalent to that obtained by the specified dose, amount, or weight percentage. Specifically, when used in this context, the terms "about" and "approximately" encompass doses, amounts, or weight percentages that are within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose, amount, or weight percentage.

[0031] As used herein, the terms "polymorph" or "polymorphic form" refer to the crystalline form of a compound. Different polymorphs can have different physical properties, such as melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum, as a result of the arrangement or conformation of molecules or ions in the crystal lattice. Differences in the physical characteristics exhibited by polymorphs can affect pharmacological parameters such as storage stability, compressibility, density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, causing a dosage form containing one polymorph to change color more quickly than a dosage form containing another polymorph), mechanical changes (e.g., tablets breaking during storage due to the conversion of a kinetically favored polymorph to a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more susceptible to cracking in high humidity). In extreme cases, some polymorphic transitions can lead to insufficient efficacy or, in other extreme cases, toxicity due to differences in solubility / dissolution. Furthermore, the physical properties of the crystalline form may be important in processing; for example, one polymorph may be more likely to form solvates or may be difficult to filter and wash free of impurities (eg, the particle shape and size distribution of the polymorphs may differ).

[0032] As used herein, a "therapeutically effective amount" refers to an amount that produces the desired pharmacological and / or physiological effect on a condition. The effect can be prophylactic, in terms of completely or partially preventing the condition or its symptoms, and / or therapeutic, in terms of partially or completely curing the condition and / or adverse effects attributable to the condition.

[0033] As used herein, the term "pharmaceutically acceptable carrier" and its equivalents refer to adjuvants, binders, diluents, etc. known to those skilled in the art that are suitable for administration to a subject (e.g., a mammal or non-mammal). Combinations of two or more carriers are also contemplated. As will be appreciated by those skilled in the art, the pharmaceutically acceptable carrier and any other components described herein should be compatible with the intended route of administration (e.g., oral, parenteral) for a particular dosage form.

[0034] The terms "treat," "treating," and "treatment" are intended to include alleviating or eliminating a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or slowing the progression, spread, or worsening of a disease, disease, or condition, or one or more symptoms thereof. Typically, the beneficial effects a subject obtains from a therapeutic agent do not result in a complete cure of the disease, disorder, or condition.

[0035] The term "subject" refers to an animal, including but not limited to a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to, for example, a mammalian subject, such as a human.

[0036] As used herein, when referring to, for example, an XRPD pattern, a DSC plot, a TGA plot, or a GVS plot, the term "substantially as shown in..." includes patterns or curves that do not necessarily conform to the patterns or curves depicted herein, but are considered by those skilled in the art to be within the limits of experimental error or deviation.

[0037] In some embodiments, the term "substantially pure" means that the polymorphic form contains less than about 30% by weight, less than about 20% by weight, less than about 15% by weight, less than about 10% by weight, less than about 5% by weight, or less than about 1% by weight of impurities. In other embodiments, "substantially pure" refers to a material that is free of impurities. Impurities can include, for example, byproducts or residual reagents from chemical reactions, contaminants, degradation products, other polymorphic forms, water, and solvents.

[0038] As used herein, the term "substantially free" means that a composition comprising a polymorphic form contains less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% by weight of the indicated substance.

[0039] polymorphs

[0040] In one aspect, provided herein are polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, which are compounds having the structure shown below,

[0041]

[0042] Polymorphs may have properties, such as bioavailability and stability, that are suitable for medical or pharmaceutical use under certain conditions.

[0043] Polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide may offer advantages in bioavailability and stability and may be suitable for use as active agents in pharmaceutical compositions. Changes in the crystal structure of a pharmaceutical drug can affect the dissolution rate (which can affect bioavailability, among other things), manufacturability (e.g., ease of handling, ease of purification, ability to consistently prepare doses of known strength, and so on), and stability (e.g., thermal stability, shelf life (including resistance to degradation), and so on) of a pharmaceutical drug product. Such changes can affect methods for preparing or formulating pharmaceutical compositions in different dosage or delivery forms, such as solid oral dosage forms including tablets and capsules. Polymorphs may provide desirable or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, reproducibility, and / or process control compared to other forms, such as non-crystalline or amorphous forms. Therefore, polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide may provide the following advantages: improved manufacturing methods of active agents or stability or storage properties of active agents in pharmaceutical product forms, or have bioavailability and / or stability suitable for active agents.

[0044] It has been discovered that the use of certain conditions, such as the use of different solvents and / or temperatures, can produce different polymorphs of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, including polymorphic Forms I-VI described herein, which may exhibit one or more of the advantageous characteristics described herein. Methods for preparing the polymorphs described herein and characterizing these polymorphs are described in more detail below.

[0045] Form I

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

[0047] In some embodiments, Form I has substantially Figure 1A The 2θ angles and relative peak intensities of Form I observable using XRPD are shown in Table 1.

[0048] Table 1

[0049]

[0050]

[0051] In some embodiments, the XRPD pattern of polymorphic Form I exhibits an XRPD pattern in which the 2θ angles and the maximum intensity of 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 in the XRPD pattern are substantially the same. Figure 1A 1 degrees 2θ.

[0052] In some embodiments, polymorphic Form I has a morphology comprising 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 14.9±0.2, 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0.2 , 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2 and 39.8±0.2 degrees 2θ angle XRPD pattern. In some embodiments, polymorphic Form I has an XRPD pattern comprising peaks at 2θ angles of 3.7 ± 0.2, 11.2 ± 0.2, 12.9 ± 0.2, 13.5 ± 0.2, 14.4 ± 0.2, 18.6 ± 0.2, 22.4 ± 0.2, 24.7 ± 0.2, 25.0 ± 0.2, and 26.1 ± 0.2 degrees. In some embodiments, polymorphic Form I has an XRPD pattern comprising peaks at 2θ angles of 3.7 ± 0.2, 11.2 ± 0.2, 12.9 ± 0.2, 14.4 ± 0.2, and 22.4 ± 0.2 degrees. It should be understood that other peaks in the XRPD pattern other than those shown in Figure 1 or as provided in Table 1 may be observed, for example, due to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

[0053] In some embodiments, Form I has substantially Figure 1BIn some embodiments, Form I is characterized by an endotherm with an onset of about 199° C., as determined by DSC. In some embodiments, Form I is characterized by an endotherm with an onset of 199±2° C. (e.g., 199±1.9° C., 199±1.8° C., 199±1.7° C., 199±1.6° C., 199±1.5° C., 199±1.4° C., 199±1.3° C., 192±1.2° C., 199±1, 199±0.9° C., 199±0.8° C., 199±0.7° C., 199±0.6° C., 199±0.5° C., 199±0.4° C., 199±0.3° C., 199±0.2° C., or 199±0.1° C.), as determined by DSC.

[0054] In some embodiments, Form I has substantially Figure 1B The TGA curve is shown in .

[0055] In some embodiments, Form I has substantially Figure 1C The DVS graph shown in .

[0056] 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:

[0057] (a) Form I has an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2, and 22.4±0.2 degrees; an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 degrees; or an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, an XRPD pattern having peaks at 2θ angles of 16.6±0.2, 17.8±0.2, 18.6±0.2, 21.6±0.2, 22.2±0.2, 22.4±0.2, 22.8±0.2, 23.2±0.2, 23.9±0.2, 24.4±0.2, 24.7±0.2, 25.0±0.2, 25.8±0.2, 26.1±0.2, 28.6±0.2, 29.0±0.2, 29.4±0.2, 29.9±0.2, 30.6±0.2, 33.8±0.2, 36.1±0.2, 36.8±0.2, 37.8±0.2, and 39.8±0.2 degrees;

[0058] (b) Form I has substantially Figure 1A The XRPD pattern shown in;

[0059] (c) Form I has substantially Figure 1B The DSC curve diagram shown in;

[0060] (d) Form I is characterized by an endotherm with an onset at about 199° C. as determined by DSC;

[0061] (e) Form I has substantially Figure 1B The TGA graph shown in ; and

[0062] (f) Form I has substantially Figure 1C The DVS graph shown in .

[0063] Form II

[0064] In some embodiments, provided herein is polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0065] In some embodiments, Form II has substantially Figure 2A The 2θ angles and relative peak intensities of Form II observable using XRPD are shown in Table 2.

[0066] Table 2

[0067]

[0068] In some embodiments, the polymorphic Form II exhibits an XRPD pattern wherein the 2θ angles and the maximum intensity of 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 in the XRPD pattern are substantially the same. Figure 2A 2θ.

[0069] In some embodiments, polymorphic Form II has an XRPD pattern comprising peaks at angles 2θ of 3.7±0.2, 7.4±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2 degrees. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 2θ angles of 3.7 ± 0.2, 9.8 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, 14.7 ± 0.2, 16.1 ± 0.2, 18.5 ± 0.2, 20.4 ± 0.2, 22.3 ± 0.2, and 23.3 ± 0.2 degrees. In some embodiments, polymorph Form II has an XRPD pattern comprising peaks at 2θ angles of 3.7 ± 0.2, 9.8 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, and 20.4 ± 0.2 degrees. It is understood that peaks other than those observed may be present. Figure 2A Additional peaks in the XRPD pattern other than those shown in or as provided in Table 2 may be due to, for example, the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

[0070] In some embodiments, Form II has substantially Figure 2B In some embodiments, Form II is characterized by an endotherm with an onset of about 199° C., as determined by DSC. In some embodiments, Form II is characterized by an endotherm with an onset of 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.

[0071] In some embodiments, Form II has substantially Figure 2B The TGA curve is shown in .

[0072] In some embodiments of Form II, at least one, at least two, at least three, at least four, or all of the following (a)-(e) apply:

[0073] (a) Form II has an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees; an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees; or an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees; 0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 14.4±0.2, 14.7±0.2, 16.1±0.2, 17.0±0.2, 18.5±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.3±0.2, 24.0±0.2, 24.3±0.2, 24.8±0.2, 25.8±0.2, 27.4±0.2, 28.8±0.2, 29.5±0.2, and 30.5±0.2 degrees 2θ.

[0074] (b) Form II has substantially Figure 2A The XRPD pattern shown in;

[0075] (c) Form II has substantially Figure 2B The DSC curve diagram shown in;

[0076] (d) Form II is characterized by having a melting endotherm with an onset at about 199°C as determined by DSC; and

[0077] (e) Form II has substantially Figure 2B The TGA curve is shown in .

[0078] Form III

[0079] In some embodiments, provided herein is polymorphic Form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0080] In some embodiments, the mixture of Forms I and III has substantially Figure 3A The 2θ angles and relative peak intensities of the mixture of Forms I and III observable using XRPD are shown in Table 3.

[0081] Table 3

[0082]

[0083]

[0084] In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 15.8 ± 0.2, and 18.1 ± 0.2 degrees. In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 14.5 ± 0.2, 15.8 ± 0.2, and 18.1 ± 0.2 degrees. In some embodiments, polymorph Form III has an XRPD pattern comprising peaks at 2θ angles of 9.6 ± 0.2, 10.9 ± 0.2, 14.5 ± 0.2, 15.8 ± 0.2, 18.1 ± 0.2, and 20.2 ± 0.2 degrees. It should be understood that relative intensities can vary depending on a variety of factors, including sample preparation, installation, and the instrument and analytical procedures and settings used to obtain the spectra. Relative peak intensities and peak assignments can vary within experimental error. In some embodiments, the peak assignments recited herein (including polymorphic Form III) may vary by about ±0.6 degrees, ±0.4 degrees, ±0.2 degrees, or ±0.1 degrees 2Θ.

[0085] In some embodiments, the mixture of polymorphic forms I and III has substantially Figure 3B The DSC curve diagram shown in .

[0086] In some embodiments, the mixture of polymorphic forms I and III has substantially Figure 3B The TGA curve is shown in .

[0087] Form IV

[0088] In some embodiments, provided herein is polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0089] In some embodiments, Form IV has substantially Figure 4A The 2θ angles and relative peak intensities of Form IV observable using XRPD are shown in Table 4.

[0090] Table 4

[0091]

[0092]

[0093] In some embodiments, the XRPD pattern of polymorph Form IV exhibits an XRPD pattern in which the 2θ angles to the maximum intensity of 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 in the XRPD pattern are substantially the same as Figure 4A 4 or as provided in Table 4. It will be appreciated that relative intensities may vary depending on a variety of factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to obtain the spectra. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including polymorphic Form IV) may vary by approximately ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0094] In some embodiments, polymorph Form IV has a morphology comprising 3.7±0.2, 7.7±0.2, 11.1±0.2, 12.4±0.2, 12.8±0.2, 13.5±0.2, 14.3±0.2, 15.5±0.2, 16.6±0.2, 17.9±0.2, 18.5±0.2, 18.6±0.2, 19.1±0.2, 19.9±0.2, 20.9±0.2, 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2 0.2, 34.6±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, and 39.8±0.2 degrees. In some embodiments, polymorph Form IV has an XRPD pattern comprising peaks at 2θ angles of 3.7 ± 0.2, 11.1 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 21.9 ± 0.2, 22.8 ± 0.2, 23.1 ± 0.2, 23.5 ± 0.2, 24.4 ± 0.2, and 24.8 ± 0.2 degrees. In some embodiments, polymorph Form IV has an XRPD pattern comprising peaks at 2θ angles of 11.1 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 22.8 ± 0.2, and 24.4 ± 0.2 degrees. It is understood that peaks other than those observed may be present. Figure 4AAdditional peaks in the XRPD pattern other than those shown in or as provided in Table 4 are due, for example, to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

[0095] In some embodiments, Form IV has substantially Figure 4B In some embodiments, Form IV is characterized by an endotherm with an onset of about 200° C., as measured by DSC. In some embodiments, Form IV is characterized by a melting endotherm with an onset of about 200±2° C. (e.g., 200±1.9° C., 200±1.8° C., 200±1.7° C., 200±1.6° C., 200±1.5° C., 200±1.4° C., 200±1.3° C., 200±1.2° C., 200±1, 200±0.9° C., 200±0.8° C., 200±0.7° C., 200±0.6° C., 200±0.5° C., 200±0.4° C., 200±0.3° C., 200±0.2° C., or 200±0.1° C.), as measured by DSC.

[0096] In some embodiments, Form IV has substantially Figure 4B The TGA curve is shown in .

[0097] 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:

[0098] (a) Form IV has an XRPD pattern comprising peaks at 2θ angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees; and peaks at 2θ angles of 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, and 24. or an XRPD pattern comprising a peak at a 2θ angle of 8 ± 0.2 degrees; or a peak at a 2θ angle of 3.7 ± 0.2, 7.7 ± 0.2, 11.1 ± 0.2, 12.4 ± 0.2, 12.8 ± 0.2, 13.5 ± 0.2, 14.3 ± 0.2, 15.5 ± 0.2, 16.6 ± 0.2, 17.9 ± 0.2, 18.5 ± 0.2, 18.6 ± 0.2, 19.1 ± 0.2, 19.9 ± 0.2, 20.9 ± 0.2 , 21.5±0.2, 21.6±0.2, 21.9±0.2, 22.3±0.2, 22.4±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 23.9±0.2, 24.4±0.2, 24.8±0.2, 25.0±0.2, 25.3±0.2, 25.8±0.2, 26.2±0.2, 27.1±0.2, 27.4±0.2, 28 XRPD pattern of peaks at 2θ angles of .0±0.2, 28.6±0.2, 29.0±0.2, 30.0±0.2, 30.5±0.2, 30.8±0.2, 31.0±0.2, 31.4±0.2, 33.8±0.2, 35.0±0.2, 35.7±0.2, 36.1±0.2, 36.7±0.2, 37.9±0.2, 38.1±0.2, and 39.8±0.2 degrees;

[0099] (b) Form IV has substantially Figure 4A The XRPD pattern shown in;

[0100] (c) Form IV has substantially Figure 4B The DSC curve diagram shown in;

[0101] (d) Form IV is characterized by having a melting endotherm with an onset at about 200° C. as determined by DSC; and

[0102] (e) Form IV has substantially Figure 4B The TGA curve is shown in .

[0103] Form V

[0104] In some embodiments, provided herein is polymorphic Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0105] In some embodiments, Form V has substantially Figure 5 The 2θ angles and relative peak intensities of Form V observable using XRPD are shown in Table 5.

[0106] Table 5

[0107]

[0108]

[0109]

[0110]

[0111] In some embodiments, the XRPD pattern of polymorph Form V exhibits an XRPD pattern in which the 2θ angles and the maximum intensity of 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 in the XRPD pattern are substantially the same. Figure 5 5 or as provided in Table 5. It will be appreciated that relative intensities may vary depending on a variety of factors, including sample preparation, mounting, and the instrumentation and analytical procedures and settings used to obtain the spectra. Relative peak intensities and peak assignments may vary within experimental error. In some embodiments, the peak assignments listed herein (including polymorphic Form V) may vary by approximately ±0.6, ±0.4, ±0.2, or ±0.1 degrees 2θ.

[0112] In some embodiments, polymorph Form V has a molecular weight comprising 5.7±0.2, 8.3±0.2, 11.5±0.2, 13.8±0.2, 15.5±0.2, 15.8±0.2, 16.3±0.2, 16.6±0.2, 17.2±0.2, 17.8±0.2, 18.5±0.2, 18.9±0.2, 19.1±0.2, 19.8±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21. 2±0.2, 21.6±0.2, 23.0±0.2, 23.1±0.2, 23.3±0.2, 24.0±0.2, 24.2±0.2, 24.3±0.2, 24.6±0.2, 24.7±0.2, 25.2±0.2, 25.6±0.2, 26.7±0.2, 27.1±0.2, 27.3±0.2, 27.5±0.2, 27.9±0.2, 28.1±0.2, 28.4±0.2, 28.9 ±0.2, 29.2±0.2, 29.7±0.2, 29.8±0.2, 29.9±0.2, 30.4±0.2, 30.6±0.2, 31.1±0.2, 31.3±0.2, 31.5±0.2, 32.0±0.2, 32.9±0.2, 33.0±0.2, 33.2±0.2, 33.5±0.2, 34.4±0.2, 34.6±0.2, 34.9±0.2, 35.3±0.2, 35.7± The XRPD pattern of peaks at 2θ angles of 0.2, 36.0±0.2, 36.2±0.2, 36.5±0.2, 36.6±0.2, 37.0±0.2, 37.1±0.2, 37.5±0.2, 37.8±0.2, 37.9±0.2, 38.3±0.2, 38.4±0.2, 38.7±0.2, 38.8±0.2, 39.3±0.2, 39.4±0.2, 39.6±0.2, and 39.9±0.2 degrees. In some embodiments, polymorphic Form V has an XRPD pattern comprising peaks at angles 2θ of 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees.In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at 2θ angles of 11.5 ± 0.2, 16.3 ± 0.2, 19.1 ± 0.2, 20.0 ± 0.2, 20.2 ± 0.2, 21.2 ± 0.2, 24.0 ± 0.2, 24.7 ± 0.2, 25.6 ± 0.2, and 26.7 ± 0.2 degrees. In some embodiments, polymorph Form V has an XRPD pattern comprising peaks at 2θ angles of 11.5 ± 0.2, 16.3 ± 0.2, 20.0 ± 0.2, 21.2 ± 0.2, and 24.7 ± 0.2 degrees. It is understood that peaks other than 2θ may be observed. Figure 5 Additional peaks in the XRPD pattern other than those shown in or as provided in Table 5 are due, for example, to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

[0113] In some embodiments of Form V, at least one or both of the following (a)-(b) apply:

[0114] (a) Form V has an XRPD pattern comprising peaks at 2θ angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees; an XRPD pattern comprising peaks at 2θ angles of 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees; or an XRPD pattern comprising peaks at 2θ angles of 5.7±0.2 , 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees 2θ;

[0115] (b) Form V has substantially Figure 5 The XRPD pattern shown in .

[0116] Form VI

[0117] In some embodiments, provided herein is polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0118] In some embodiments, Form VI has substantially Figure 6A The 2θ angles and relative peak intensities of Form VI observable using XRPD are shown in Table 6.

[0119] Table 6

[0120]

[0121]

[0122]

[0123] In some embodiments, the XRPD pattern of polymorph Form VI exhibits an XRPD pattern in which the 2θ angles and the maximum intensity of 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 in the XRPD pattern are substantially the same. Figure 6A 6, 7, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 113, 114, 115, 116, 117, 118, 119, 120

[0124] In some embodiments, polymorph Form VI has a molecular weight comprising 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, 0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 21 .9±0.2, 22.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3±0.2, 27.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0.2 In some embodiments, polymorph Form VI has an XRPD pattern comprising peaks at 2θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees. In some embodiments, polymorph Form VI has an XRPD pattern comprising peaks at 2θ angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees. Figure 6A Additional peaks in the XRPD pattern other than those shown in or as provided in Table 6 are due, for example, to the presence of impurities, solvents, or other polymorphs or amorphous forms in the test sample.

[0125] In some embodiments, Form VI has substantially Figure 6B The TGA curve shown in or substantially as shown in Figure 6C In some embodiments, Form VI exhibits a weight loss of about 2% ± 0.5% between 25°C and 200°C, as determined by TGA.

[0126] In some embodiments, Form VI has substantially Figure 6D The DSC curve shown in or substantially as shown in Figure 6E In some embodiments, Form VI is characterized by having a melting endotherm with an 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 is characterized by having a temperature of about 200±2°C (e.g., 200±1.9°C, 200±1.8°C, 200±1.7°C, 200±1.6°C, 200±1.5°C, 200±1.4°C, 200±1.3°C, 200±1.2°C, 200±1, 200±0.9°C, 200±0.8°C, 200±0.7°C, 200±0.6°C, 200±0.5°C, 200±0.4°C, 200±0.3°C, 200±0.2°C or 200±0.1°C), an endotherm starting at about 115±2°C (e.g., 115±1.9°C, 115±1.8°C, 115±1.7°C, 115±1.6°C, 115±1.5°C, 115±1.4°C, 115±1.3°C) , 115±1.2°C, 115±1, 115±0.9°C, 115±0.8°C, 115±0.7°C, 115±0.6°C, 115±0.5°C, 115±0.4°C, 115±0.3°C, 115±0.2°C or 115±0.1°C or an exotherm starting at about 41±2°C (e.g., 41±1.9°C, 41±1.8°C, 41±1 .7°C, 41±1.6°C, 41±1.5°C, 41±1.4°C, 41±1.3°C, 41±1.2°C, 41±1, 41±0.9°C, 41±0.8°C, 41±0.7°C, 41±0.6°C, 41±0.5°C, 41±0.4°C, 41±0.3°C, 41±0.2°C or 41±0.1°C), or any combination thereof.

[0127] In some embodiments of Form I, 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:

[0128] (a) Form VI has an XRPD pattern comprising peaks at 2θ angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees; an XRPD pattern comprising peaks at 2θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees. or including 3.0±0.2, 5.0±0.2, 5.4±0.2, 5.9±0.2, 7.2±0.2, 8.1±0.2, 8.9±0.2, 9.6±0.2, 9.9±0.2, 10.6±0.2, 12.1±0.2, 13.3±0.2, 14.0±0.2, 14.4±0.2, 14.7±0.2, 15.0±0.2, 15.4±0.2, 16.1±0.2, 16.5±0.2, 17.8 ±0.2, 18.9±0.2, 19.0±0.2, 19.2±0.2, 19.6±0.2, 20.0±0.2, 20.3±0.2, 20.7±0.2, 21.1±0.2, 21.9±0.2, 22.6±0.2, 22.9±0.2, 23.6±0.2, 23.8±0.2, 24.4±0.2, 24.8±0.2, 25.5±0.2, 26.4±0.2, 26.7±0.2, 27.3± an XRPD pattern having peaks at 2θ angles of 0.2, 27.6±0.2, 28.2±0.2, 28.5±0.2, 29.0±0.2, 29.6±0.2, 29.9±0.2, 30.4±0.2, 30.9±0.2, 31.6±0.2, 32.2±0.2, 32.6±0.2, 33.1±0.2, 33.3±0.2, 34.5±0.2, 35.0±0.2, 35.5±0.2, and 38.5±0.2 degrees;

[0129] (b) Form VI has substantially Figure 6A The XRPD pattern shown in;

[0130] (c) Form VI has substantially Figure 6B or Figure 6C The TGA curve shown in ;

[0131] (d) Form VI has a weight loss of about 2% ± 0.5% between 25°C and 200°C as determined by TGA;

[0132] (e) Form VI has substantially Figure 6D or Figure 6E The DSC graph shown in ; and

[0133] (f) Form IV is characterized by having a melting endotherm with an onset at about 200° C. as determined by DSC; and

[0134] (g) Form VI is characterized by having an endotherm with an onset at about 200°C, an exotherm with an onset at about 115°C, or an endotherm with an onset at about 41°C, or any combination thereof, as determined by DSC.

[0135] Composition

[0136] Also provided herein are compositions containing a polymorph described herein, such as Form I, Form II, Form III, Form IV, Form V, Form VI, or mixtures thereof. In some embodiments, the composition contains Form I. In some embodiments, the composition contains Form II. In some embodiments, the composition contains Form III. In some embodiments, the composition contains a mixture of Forms I and III. In some embodiments, the composition contains Form IV. In some embodiments, the composition contains Form V. In some embodiments, the composition contains Form VI. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0137] In some embodiments, a composition is provided that contains Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms II-VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of an amorphous or non-crystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0138] In some embodiments of compositions containing Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, Form I comprises at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition. In some embodiments of the compositions containing Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1% by weight, at least about 0.3% by weight, at least about 0.5% by weight, at least about 0.8% by weight, at least about 1.0% by weight, at least about 5.0% by weight, at least about 10% by weight, at least about 20% by weight, at least about 30% by weight, at least about 40% by weight, at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 100% by weight, at least about 15 ... At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form I.

[0139] In some embodiments, a composition is provided that contains Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms I, III, IV, V, and VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0140] In some embodiments of compositions containing Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, Form II comprises at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition. In some embodiments of the compositions containing Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1% by weight, at least about 0.3% by weight, at least about 0.5% by weight, at least about 0.8% by weight, at least about 1.0% by weight, at least about 5.0% by weight, at least about 10% by weight, at least about 20% by weight, at least about 30% by weight, at least about 40% by weight, At least about 50 weight percent, at least about 60 weight percent, at least about 70 weight percent, at least about 80 weight percent, at least about 85 weight percent, at least about 90 weight percent, at least about 95 weight percent, at least about 96 weight percent, at least about 97 weight percent, at least about 98 weight percent, at least about 99 weight percent, or at least 99.9 weight percent of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is in Form II.

[0141] In some embodiments, a composition is provided that contains Form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms I, II, IV, V, and VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of amorphous or non-crystalline forms of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0142] In some embodiments of compositions containing Form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, Form III comprises at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition. In some embodiments of the compositions containing Form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1% by weight, at least about 0.3% by weight, at least about 0.5% by weight, at least about 0.8% by weight, at least about 1.0% by weight, at least about 5.0% by weight, at least about 10% by weight, at least about 20% by weight, at least about 30% by weight, at least about 40% by weight, At least about 50 weight percent, at least about 60 weight percent, at least about 70 weight percent, at least about 80 weight percent, at least about 85 weight percent, at least about 90 weight percent, at least about 95 weight percent, at least about 96 weight percent, at least about 97 weight percent, at least about 98 weight percent, at least about 99 weight percent, or at least 99.9 weight percent of the (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form III.

[0143] In some embodiments, a composition is provided that contains Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms I-III, V, and VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of an amorphous or non-crystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0144] In some embodiments of compositions containing Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, Form IV comprises at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition. In some embodiments of the composition containing Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1% by weight, at least about 0.3% by weight, at least about 0.5% by weight, at least about 0.8% by weight, at least about 1.0% by weight, at least about 5.0% by weight, at least about 10% by weight, at least about 20% by weight, at least about 30% by weight, at least about 40% by weight, At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form IV.

[0145] In some embodiments, a composition is provided containing Form I and Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, Form I and Form IV are present in a weight ratio of 99:1, 90:10, 80:20, 70:30, 60:40, 50:50, 40:60, 30:70, 20:80, 10:90, or 1:99. In some embodiments, the weight ratio of Form I to Form IV is between 90:10 and 99:1. In some embodiments of the composition containing Form I and Form IV, Form I comprises at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition. In some embodiments of the composition containing Form I and Form IV, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form I. In some embodiments of the composition containing Form I and Form IV, Form IV comprises at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition.In some embodiments of the composition containing Form I and Form IV, at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form IV.

[0146] In some embodiments, a composition is provided that contains Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Forms I-IV and VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of an amorphous or non-crystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0147] In some embodiments of compositions containing Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, Form V comprises at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition. In some embodiments of the compositions containing Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1% by weight, at least about 0.3% by weight, at least about 0.5% by weight, at least about 0.8% by weight, at least about 1.0% by weight, at least about 5.0% by weight, at least about 10% by weight, at least about 20% by weight, at least about 30% by weight, at least about 40% by weight, at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 100% by weight, at least about 15 ... At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form V.

[0148] In some embodiments, a composition is provided that contains Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of at least one, at least two, at least three, or all of polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of an amorphous or non-crystalline form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. In some embodiments, the composition is substantially free of salts of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0149] In some embodiments of compositions containing Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, Form VI comprises at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 5.0%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of the total composition. In some embodiments of the compositions containing Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, at least about 0.1 weight percent, at least about 0.3 weight percent, at least about 0.5 weight percent, at least about 0.8 weight percent, at least about 1.0 weight percent, at least about 5.0 weight percent, at least about 10 weight percent, at least about 20 weight percent, at least about 30 weight percent, at least about 40 weight percent, at least about 50 weight percent, at least about 60 weight percent, at least about 70 weight percent, at least about 80 weight percent, at least about 90 weight percent, at least about 100 weight percent, at least about 15 ... At least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least 99.9% by weight of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is present in Form VI.

[0150] In some embodiments, a tablet or capsule is provided containing one or more of the polymorphic forms described herein (e.g., Form I, II, III, IV, V, VI, or mixtures thereof) and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing substantially pure polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing substantially pure polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing substantially pure polymorphic Form III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing substantially pure polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing substantially pure polymorphic Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers. In some embodiments, a tablet or capsule is provided containing substantially pure polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and one or more pharmaceutically acceptable carriers.

[0151] Preparation method

[0152] Form I

[0153] In some embodiments, a method for preparing polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent; and (2) cooling the mixture of step (1) or removing the solvent from the mixture of step (1). In some embodiments, the solvent comprises an alcohol (e.g., methanol, ethanol, or propanol), an acetate (e.g., isopropyl acetate or ethyl acetate), an ether (e.g., methyl tert-butyl ether, diethyl ether, or 2-methyltetrahydrofuran), a ketone (e.g., methyl ethyl ketone or methyl isobutyl ketone), a nitrile (e.g., acetonitrile), an amide (e.g., N,N-dimethylformamide), a non-aromatic hydrocarbon (e.g., hexane), an aromatic hydrocarbon (e.g., toluene), or water, or a mixture thereof. In some embodiments, the solvent comprises acetone, acetonitrile (ACN), dichloromethane (DCM), 1,4-dioxane, N,N-dimethylformamide (DMF), ethanol (EtOH), methanol (MeOH), 2-methyltetrahydrofuran (2-MeTHF), 2-propanol (IPA), tetrahydrofuran (THF), water, diethyl ether (Et2O), methyl ethyl ketone (MEK), toluene, water, ethyl acetate, or hexane, or a mixture thereof. In some embodiments, the solvent comprises DCM. In some embodiments, step (1) comprises heating the mixture to an elevated temperature (e.g., a temperature above 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 be appreciated that Form I may also be prepared using a suitable method as described in Example 6 below.

[0154] In some embodiments, the method for preparing polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide further comprises preparing (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. A method for preparing 1-methyl-1H-pyrazole-4-carboxamide comprising: (1) reacting tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate with propionyl propionate to form N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate; -yl] tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate; (2) reacting tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate with trifluoroacetic acid (TFA) to form (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine; and ( 3) reacting (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine with 1-methyl-1H-pyrazole-4-carboxylic acid to form (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0155] Form II

[0156] In some embodiments, a method for preparing polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising grinding polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide in water. In some embodiments, a method for preparing polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising (1) forming a mixture of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an 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 antisolvent is added before proceeding to (2). In some embodiments, the antisolvent is water. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature lower than the temperature used to perform step (1), 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 be appreciated that Form II may also be prepared using a suitable method as described in Example 6 below.

[0157] Mixture of Forms I and III

[0158] In some embodiments, a method for preparing a mixture of polymorphic Forms I and III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising (1) forming a mixture of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an ether (e.g., methyl tert-butyl ether, diethyl ether, 2-methyltetrahydrofuran, or dioxane) or a non-aromatic hydrocarbon (e.g., hexane), or a mixture thereof; and (2) cooling the mixture of step (1). In some embodiments, the solvent comprises hexane or dioxane, or a mixture thereof. In some embodiments, step (1) comprises heating the mixture to an elevated temperature, 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 performing step (2). In some embodiments, the antisolvent is water. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature lower than the temperature used to perform step (1), such as cooling the mixture of step (1) to about 20°C, about 15°C, about 10°C, about 5°C, about 0°C, about -5°C, about -10°C, about -15°C, or about -20°C. It should be understood that a mixture of Forms I and III may also be prepared using a suitable method as described in Example 6 below.

[0159] Form IV

[0160] In some embodiments, a method for preparing polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises a nitrile (e.g., acetonitrile (ACN)) or water, or a mixture thereof; and (2) cooling the mixture of step (1). In some embodiments, the solvent comprises ACN or water, or a mixture thereof. In some embodiments, the solvent comprises ACN or a mixture of ACN and water. In some embodiments, step (1) comprises heating the mixture or solvent to an elevated temperature, such as about 80° C., about 75° C., about 70° C., about 65° C., about 60° C., about 55° C., about 50° C., about 45° C., about 40° C., or about 35° C. In some embodiments, step (1) comprises heating the mixture or solvent to about 80° C. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature lower than the temperature used to perform step (1), 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.

[0161] In some embodiments, the method of preparing polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide comprises further preparing (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide, which comprises: (1) reacting 1-methyl-1H-pyrazole-4-carboxylic acid with (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride to form (R)-N- (5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; (2) reacting (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with hydroxylamine to form (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide; and (3) reacting (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with propionic acid.

[0162] Form V

[0163] In some embodiments, a method for preparing polymorphic Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an acetate (e.g., isopropyl acetate or ethyl acetate); and (2) cooling the mixture of step (1). In some embodiments, the solvent comprises ethyl acetate. In some embodiments, step (1) comprises mixing (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide with a solvent at room temperature. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature lower than the temperature used to perform step (1), such as cooling the mixture of step (1) to about 15°C, about 10°C, about 5°C, about 0°C, about -5°C, about -10°C, about -15°C, or about -20°C. In some embodiments, step (2) comprises cooling the mixture of step (1) to about 5°C. In some embodiments, the method further comprises isolating the polymorph that exists in the form of elongated needles. In some embodiments, the method comprises: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises ethyl acetate; (2) cooling the mixture of step (1) to about 5° C.; and (3) isolating the polymorph in the form of elongated needles.

[0164] Form VI

[0165] In some embodiments, a method for preparing polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises a nitrile (e.g., acetonitrile (ACN)) and water; and (2) stirring the mixture of step (1). In some embodiments, the solvent comprises ACN and water. In some embodiments, the mixture 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 a solid form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide in combination with a solvent, wherein the solid form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide contains Form I, Form IV, Form V, or any combination thereof. In some embodiments, the solid form contains Form VI in combination with another solid form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (e.g., Form I, IV, or V). In some embodiments, the solid form of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide contains a combination of Form IV and Form VI. In some embodiments, step (2) comprises stirring the mixture at a temperature between about 0°C and about 30°C, between about 0°C and about 25°C, between about 0°C and about 20°C, between about 0°C and about 15°C, or between about 0°C and about 10°C. In some embodiments, step (2) comprises cooling the mixture of step (1) to a temperature lower than the temperature used to perform step (1), 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.

[0166] How to use

[0167] The polymorphic forms and compositions provided herein are useful for treating or preventing a disease or condition in an individual or subject.

[0168] Without being bound by theory, it is believed that the provided polymorphic forms and compositions act by inhibiting myosin. This inhibition potentially reduces the number of independent myosin heads that interact with actin filaments, thereby reducing the amount of contraction. Reducing the contraction of the myocardium may be important for treating 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 administering to an individual or subject in need thereof a polymorphic form or composition provided herein. In some embodiments, methods for treating or preventing heart disease in a subject in need thereof are provided, comprising administering to a subject a therapeutically effective amount of a polymorphic form or composition provided herein. In some embodiments, methods for treating heart disease in a subject in need thereof are provided, comprising administering to a subject a therapeutically effective amount of a polymorphic form or composition provided herein. In some embodiments, methods for treating an established or diagnosed heart disease in a subject in need thereof are provided, comprising administering to a 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 thereof are provided, comprising administering to a subject a therapeutically effective amount of a polymorphic form or composition provided herein.

[0169] Also provided herein are uses of the polymorphic forms or compositions provided herein for the manufacture of a medicament for treating a heart disease in a subject. In some aspects, polymorphic forms as described herein are provided for use in methods of treating a human or animal body by therapy. In some embodiments, polymorphic forms such as Forms I, II, III, IV, V, or VI, or compositions thereof, are provided herein for use in methods of treating a human or animal body by therapy. In some embodiments, polymorphic forms such as Forms I, II, III, IV, V, or VI, or compositions thereof, are provided herein for use in treating or preventing a heart disease. In some embodiments, polymorphic forms such as Forms I, II, III, IV, V, or VI, or compositions thereof, are provided herein for use in treating a heart disease. In some embodiments, polymorphic forms such as Forms I, II, III, IV, V, or VI, or compositions thereof, are provided herein for use in treating a confirmed or diagnosed heart disease. In other embodiments, polymorphic forms such as Forms I, II, III, IV, V, or VI, or compositions thereof, are provided herein for use in preventing a heart disease. In some embodiments, provided herein are polymorphic forms, such as Forms I, II, III, IV, V, or VI, or compositions thereof, for use in treating diseases or conditions associated with HCM. In some embodiments, provided herein are polymorphic forms, such as Forms I, II, III, IV, V, or VI, or compositions thereof, for use in treating diseases or conditions associated with secondary left ventricular wall thickening. In some embodiments, provided herein are polymorphic forms, such as Forms I, II, III, IV, V, or VI, or compositions thereof, for use in improving symptoms associated with heart disease. In some embodiments, provided herein are polymorphic forms, such as Forms I, II, III, IV, V, or VI, or compositions thereof, for use in reducing the risk of symptoms associated with heart disease. In other embodiments, polymorphic forms such as Forms I, II, III, IV, V or VI, or compositions thereof, are provided herein for use in treating diseases or conditions associated with small left ventricular cavity, cavity occlusion, hyperdynamic left ventricular contraction, obstructed blood outflow from the left ventricle, cardiac hypertrophy, small stroke volume, decreased left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis. In some embodiments, polymorphic forms such as Forms I, II, III, IV, V or VI, or compositions 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 Forms I, II, III, IV, V or VI, or compositions thereof, are provided herein for use in treating muscular dystrophy. In some embodiments, polymorphic forms such as Forms I, II, III, IV, V or VI, or compositions thereof, are provided herein for use in treating glycogen storage diseases.In some embodiments, provided herein are polymorphic forms, such as Forms I, II, III, IV, V, or VI, or compositions thereof, for use in modulating cardiac sarcomeres, such as inhibiting cardiac sarcomeres. In some embodiments, provided herein are polymorphic forms, such as Forms I, II, III, IV, V, or VI, or compositions thereof, for use in enhancing cardiac myosin.

[0170] 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 human. In some embodiments, the subject suffers from a confirmed or diagnosed heart disease. In some embodiments, the subject suffers from a confirmed or diagnosed hypertrophic cardiomyopathy (HCM). In some embodiments, the subject has a risk of developing a heart disease. In some embodiments, the subject has a mutation that increases the risk of heart disease. In some embodiments, the subject has a mutation that increases the risk of hypertrophic cardiomyopathy (HCM). In some embodiments, the mutation is a sarcomere mutation. In some embodiments, the mutation is a mutation in myosin heavy chain beta (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha-1 chain (TPM1), cardiac myosin binding protein C (MYBPC3), cardiac troponin I (cTnI), myosin essential light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / cardiac isoform (MLC-2), cardiac alpha actin, muscle LIM protein (MLP), or protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2). In some embodiments, the mutation is a mutation in MHC-β. In some embodiments, the subject has established or diagnosed hypertrophic cardiomyopathy without a proven genetic cause.

[0171] In some embodiments, the subject is at high risk for progressive symptoms. In some embodiments, the subject is at high risk for atrial fibrillation, ventricular tachycardia, stroke, and / or sudden death. In some embodiments, the subject has decreased exercise capacity. In some embodiments, the decreased exercise capacity is compared to an age-matched control group. In some embodiments, the subject is eligible for surgical intervention or percutaneous ablation for treatment of heart disease.

[0172] 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, HCM is associated with sarcomeric mutations. In some embodiments, HCM is associated with non-sarcomeric mutations. In some embodiments, the heart disease is obstructive or non-obstructive HCM caused by sarcomeric and / or non-sarcomeric mutations. In some embodiments, the sarcomeric mutation is a mutation in myosin heavy chain beta (MHC-β), cardiac troponin T (cTnT), tropomyosin alpha-1 chain (TPM1), cardiac myosin binding protein C (MYBPC3), cardiac troponin I (cTnI), myosin essential light chain (ELC), titin (TTN), myosin regulatory light chain 2 ventricular / cardiac isoform (MLC-2), cardiac alpha actin, or muscle LIM protein (MLP). In some embodiments, the sarcomeric mutation is a mutation in MHC-β. In some embodiments, the non-sarcomeric mutation is a mutation in protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2).

[0173] In some embodiments, provided herein are methods for treating a disease or condition associated with HCM, comprising administering to an individual or subject in need thereof a polymorphic form or composition provided herein. In some embodiments, the disease or condition is Fabry's disease, Danon disease, mitochondrial cardiomyopathy, or Noonan syndrome.

[0174] Also provided herein is the use of a polymorphic form or composition provided herein in the manufacture of a medicament for treating a disease or condition associated with HCM.

[0175] In some embodiments, the heart disease is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart disease is diastolic dysfunction. In some embodiments, the heart disease is 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 artery 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 a condition of diastolic dysfunction caused by or resulting from aging of the heart or a condition associated with diastolic dysfunction caused by or resulting from aging of the heart. In some embodiments, the cardiac disease is a condition or a condition associated with left ventricular hypertrophy and / or concentric left ventricular remodeling.

[0176] In some embodiments, a method for treating a disease or condition associated with secondary left ventricular wall thickening in an individual or subject is provided, comprising administering to an individual or subject in need thereof a polymorphic form or composition provided herein. In some embodiments, the disease is hypertension, valvular heart disease (aortic stenosis, mitral regurgitation), metabolic syndrome (diabetes, obesity), end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich Ataxia, Danon disease, Noonan syndrome, and Pompe disease.

[0177] Also provided herein is the use of a polymorphic form or composition provided herein for the manufacture of a medicament for treating a disease or condition associated with secondary left ventricular wall thickening.

[0178] In some embodiments, a method is provided for ameliorating a symptom associated with heart disease in a subject, comprising administering to an individual or subject in need thereof a polymorphic form or composition provided herein, wherein the symptom is one or more symptoms selected from the group consisting of poor or decreased cardiac elasticity, poor or decreased diastolic left ventricular relaxation, abnormal left atrial pressure (e.g., abnormally high left atrial pressure), paroxysmal or permanent atrial fibrillation, increased left atrial and pulmonary capillary wedge pressure, increased left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, increased left ventricular wall thickness, left ventricular mid-chamber obstruction, increased systolic forward motion of the mitral valve, left ventricular outflow tract obstruction, chest pain, exertional dyspnea, presyncope, abnormal exercise capacity, and fatigue.

[0179] In some embodiments, methods are provided for treating a disease or condition associated with a small left ventricular cavity, cavity occlusion, hyperdynamic left ventricular contraction, obstructed blood outflow from the left ventricle, cardiac hypertrophy, small stroke volume, decreased left ventricular relaxation, high left ventricular filling pressure, myocardial ischemia, or cardiac fibrosis in an individual or subject, comprising administering to the individual or subject in need thereof a polymorphic form or composition provided herein.

[0180] In some embodiments, methods are provided for treating a disease or condition associated with left ventricular microsomia and occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in an individual or subject, comprising administering to the individual or subject in need thereof a polymorphic form or composition provided herein.

[0181] Also provided herein is the use of a polymorphic form or composition provided herein for the manufacture of a medicament for treating a disease or condition associated with left ventricular microsomia and occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis.

[0182] In some embodiments, a method for treating a muscular dystrophy (e.g., Duchenne muscular dystrophy) in an individual or subject is provided, comprising administering to an individual or subject in need thereof a polymorphic form or composition provided herein. Also provided herein is the use of a polymorphic form or composition provided herein for the manufacture of a medicament for treating a muscular dystrophy (e.g., Duchenne muscular dystrophy).

[0183] In some embodiments, a method for treating a glycogen storage disease in an individual or subject is provided, comprising administering to an individual or subject in need thereof a polymorphic form or composition provided herein. Also provided herein is the use of a polymorphic form or composition provided herein for the manufacture of a medicament for treating a glycogen storage disease.

[0184] Also provided are methods for regulating cardiac myotomes in an individual or subject, the methods comprising administering to an individual or subject in need thereof a therapeutically effective amount of at least one chemical entity as described herein. In some embodiments, methods for inhibiting cardiac myotomes are provided, comprising contacting a cardiac myotome with at least one chemical entity as described herein (such as a polymorphic form or composition provided herein). Also provided herein are uses of at least one chemical entity as described herein (such as a polymorphic form or composition provided herein) for the manufacture of a medicament for inhibiting cardiac myotomes in an individual or subject.

[0185] Also provided are methods for enhancing cardiac myosin in an individual or subject, the methods comprising administering to an individual or subject in need thereof a therapeutically effective amount of at least one chemical entity as described herein, such as a polymorphic form or composition provided herein. Also provided herein are uses of at least one chemical entity as described herein, such as a polymorphic form or composition provided herein, for the manufacture of a medicament for enhancing cardiac myosin in an individual or subject.

[0186] In some embodiments, the methods provided herein further comprise monitoring the effectiveness of treatment. Examples of indicators include, but are not limited to, improvements in one or more of the following: New York Heart Association (NYHA) functional class, exercise capacity, cardiac elastance, diastolic left ventricular relaxation, left atrial pressure, paroxysmal or permanent atrial fibrillation, left atrial and pulmonary capillary wedge pressure, left ventricular diastolic pressure, syncope, ventricular relaxation during diastole, ventricular fibrosis, left ventricular hypertrophy, left ventricular mass, left ventricular wall thickness, left ventricular mid-cavity obstruction, increased systolic forward motion of the mitral valve, left ventricular outflow tract obstruction, chest pain, exertional dyspnea, presyncope, abnormal exercise capacity, and fatigue. These indicators can be monitored by techniques known in the art, including self-report; ECG, including ambulatory ECG; echocardiography; cardiac MRI; CT; biopsy; cardiopulmonary exercise testing (CPET); and actigraphy.

[0187] 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 more 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 40%-80%, 40-70%, 50%-90%, 50%-80% or 50%-70%. In some embodiments, the polymorphic forms or compositions do not significantly change the calcium transients in cardiomyocytes. In some embodiments, the polymorphic forms or compositions reduce the ATPase activity in cardiomyocytes. Methods for measuring contractility, ATPase activity and calcium transients are known in the art, for example, by calcium labeling, electrophysiological recording and microscopic imaging. In some embodiments, the polymorphic forms or compositions do not significantly inhibit or induce cytochrome P450 (CYP) proteins.

[0188] In some embodiments, prior to treatment, the subject's left ventricular wall thickness is higher than normal. In some embodiments, prior to treatment, the subject's left ventricular wall thickness is greater than 15 mm, such as greater than 18 mm, 20 mm, 22 mm, 25 mm, or 30 mm. In some embodiments, after treatment, the left ventricular wall thickness decreases by more than 5%, such as more than 8%, 10%, 12%, 15%, 20%, or 30%. Left ventricular wall thickness can be measured by methods known in the art, such as by echocardiography, CT scan, or cardiac MRI.

[0189] In some embodiments, prior to treatment, the subject has abnormal cardiac fibrosis. In some embodiments, after treatment, the abnormal cardiac fibrosis is reduced by more than 5%, such as more than 8%, 10%, 12%, 15%, 20%, or 30%. Cardiac fibrosis can be measured by methods known in the art, such as by biopsy or cardiac MRI.

[0190] In some embodiments, before treatment, the subject suffers from decreased exercise capacity. In some embodiments, after treatment, the subject's exercise capacity increases by more than 5%, such as more than 8%, 10%, 12%, 15%, 20% or 30%. In some embodiments, exercise capacity is measured by cardiopulmonary exercise testing (CPET). CPET measures changes in oxygen consumption (maximum VO2). The method for measuring CPET and maximum VO2 is well known in the art (Malhotra et al., JACC:Heart Failure, 2016, 4 (8): 607-616; Guazzi et al., J Amer College Cardiol, 2017, 70 (13): 1618-1636; Rowin et al., JACC:Cariovasc Imaging, 2017, 10 (11): 1374-1386). In some embodiments, after treatment, maximum VO2 improves by more than 1 mL / kg / m 2 , such as more than 1.2 mL / kg / m 2 , 1.4 mL / kg / m 2 1.5 mL / kg / m 2 , 1.7 mL / kg / m 2 2mL / kg / m 2 2.2 mL / kg / m 2 2.5 mL / kg / m 2 3mL / kg / m 2 3.2 mL / kg / m 2 or 3.5 mL / kg / m 2 .

[0191] In some embodiments, prior to treatment, the subject's New York Heart Association (NYHA) functional class is II, III, or IV. In some embodiments, prior to treatment, the subject's New York Heart Association (NYHA) functional class is III or IV. In some embodiments, prior to treatment, the subject's New York Heart Association (NYHA) functional class is IV. In some embodiments, after treatment, the subject maintains the same NYHA functional class or has a decreased NYHA functional class.

[0192] In some embodiments, after treatment, VO2max improves by more than 1 mL / kg / m 2 , such as more than 1.2 mL / kg / m 2 , 1.4 mL / kg / m 2 1.5 mL / kg / m 2 , 1.7 mL / kg / m 2 or 2 mL / kg / m 2, and the subject has a reduced NYHA functional class. In some embodiments, after treatment, VO2max improves by more than 2.5 mL / kg / m 2 3mL / kg / m 2 3.2 mL / kg / m 2 or 3.5 mL / kg / m 2 And the subject remains in the same NYHA functional class or has a decreased NYHA functional class.

[0193] In some embodiments, after treatment, the subject's daily function and / or activity level is improved. The improved daily function and / or activity level can be recorded, for example, by a diary or actigraphy device (such as or Class monitor) measurements.

[0194] In some embodiments, after treatment, the subject has one or more of: reduced shortness of breath, reduced chest pain, reduced arrhythmia burden (such as atrial fibrillation and ventricular arrhythmias), reduced incidence of heart failure, and reduced ventricular outflow obstruction.

[0195] dose

[0196] The polymorphic forms and compositions disclosed and / or described herein are administered in a therapeutically effective dose (e.g., a dose sufficient to provide treatment for a disease condition). Although human dosage levels for the chemical entities described herein have yet to be optimized, generally, the daily dose is in the range of about 0.01 to 100 mg per kilogram of body weight; in some embodiments, in the range of about 0.05 to 10.0 mg per kilogram of body weight, and in some embodiments, in the range of about 0.10 to 1.4 mg per kilogram of body weight. Thus, for administration to a 70 kg subject, in some embodiments, the dosage range will be about 0.7 to 7000 mg / day; in some embodiments, about 3.5 to 700.0 mg / day, and in some embodiments, about 7 to 100.0 mg / day. The amount of the chemical entity administered will depend, for example, on the subject and disease condition being treated, the severity of the ailment, the mode of administration and schedule, and the judgment of the prescribing physician. For example, an exemplary dosage range for oral administration is about 5 mg to about 500 mg / day, and an exemplary dosage range for intravenous administration is about 5 mg to about 500 mg / day, each depending on pharmacokinetics.

[0197] The daily dose is the total amount administered in one day. The daily dose may be administered daily, every other day, weekly, every two weeks, monthly, or at various intervals. In some embodiments, the administration period of the daily dose ranges from one day to the lifetime of the subject. In some embodiments, the daily dose is administered once a day. In some embodiments, the daily dose is administered in multiple divided doses, such as 2, 3, or 4 divided doses. In some embodiments, the daily dose is administered in 2 divided doses.

[0198] Administration of the polymorphic forms and compositions described herein can be carried out via any acceptable mode of administration for therapeutic agents, including but not limited to oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the polymorphic forms or compositions are administered orally or intravenously. In some embodiments, the polymorphic forms or compositions disclosed and / or described herein are administered orally.

[0199] Pharmaceutically acceptable compositions include solid, semisolid, liquid, and aerosol dosage forms, such as tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols. The polymorphic forms disclosed and / or described herein can also be administered in sustained or controlled release dosage forms (e.g., controlled / sustained release pills, reservoir injections, osmotic pumps, or transdermal (including electrotransmission) patches) for long-term, timed, and / or pulsed administration at a predetermined rate. In some embodiments, the compositions are provided in unit dosage forms suitable for single administration of precise dosages.

[0200] The polymorphic forms described herein can be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). The pharmaceutical compositions may also contain small amounts of non-toxic auxiliary substances, such as wetting agents, emulsifiers, solubilizers, pH buffers, and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate), as needed. Typically, depending on the intended mode of administration, the pharmaceutical compositions will contain from about 0.005% to 95% by weight or from about 0.5% to 50% by weight of the compounds disclosed and / or described herein. Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0201] In some embodiments, the composition will be in the form of a pill or tablet and thus, in addition to the polymorphic forms disclosed and / or described herein, the composition 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, polyvinyl pyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powders encapsulated in gelatin capsules, spherical pellets, solutions, or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides).

[0202] Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving, dispersing or suspending the polymorphic forms disclosed and / or described herein and optionally selected pharmaceutical additives in a carrier (e.g., water, saline, aqueous dextrose solution, glycerol, glycol, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, in the form of liquid solutions or suspensions, in the form of emulsions, or in the form of solids suitable for dissolving or suspending in a liquid prior to injection. The percentage of polymorphic forms contained in such parenteral compositions depends, for example, on the physical properties of the polymorphic forms, the activity of the polymorphic forms, and the requirements of the subject. However, percentages of the active ingredient in the solution of 0.01% to 10% can be used, and if the composition is a solid that will be subsequently diluted to another concentration, the percentage can be higher. In some embodiments, the composition will contain about 0.2 to 2% of the polymorphic forms disclosed and / or described herein in the solution.

[0203] The pharmaceutical compositions of the polymorphic forms and compositions described herein can also be administered to the respiratory tract in the form of an aerosol or solution for a nebulizer or in the form of a finely divided powder for insufflation, alone or in combination with an inert carrier such as lactose. In such cases, the particles of the pharmaceutical composition have a diameter of less than 50 microns or, in some embodiments, less than 10 microns.

[0204] In addition, pharmaceutical compositions may include polymorphic forms disclosed and / or described herein and one or more other drugs, agents, adjuvants, and the like. Suitable drugs and agents include those described herein.

[0205] Reagent test kit

[0206] Also provided are articles of manufacture and kits containing any of the polymorphic forms or compositions provided herein. The articles of manufacture may comprise a container with a label. Suitable containers include, for example, bottles, vials, and test tubes. The container may be formed from a variety of materials, such as glass or plastic. The container may contain the pharmaceutical composition provided herein. The label on the container may indicate that the pharmaceutical composition is used to prevent, treat, or inhibit the conditions described herein, and may also indicate instructions for in vivo or in vitro use.

[0207] In one aspect, provided herein is a kit comprising a polymorphic form or composition described herein and instructions for use. The kit may contain instructions for use in treating a cardiac disease in an individual or subject in need thereof. The kit may also contain any materials or equipment useful for administering the polymorphic form or composition, such as a vial, syringe, or IV bag. The kit may also contain a sterile package.

[0208] combination

[0209] The polymorphic forms and compositions described herein may be administered alone or in combination with other therapies and / or therapeutic agents useful in treating the aforementioned disorders, diseases, or conditions.

[0210] The polymorphic forms and compositions described herein can be combined with one or more other therapies to treat heart disease, such as HCM or HFpEF. In some embodiments, the one or more therapies include therapies that block the progression of heart failure and attempt to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors). In some embodiments, the one or more therapies include therapies that improve cardiac function by stimulating myocardial contractility (e.g., positive inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone). In other embodiments, the one or more therapies include therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (vasodilators of any class, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0211] The polymorphic forms and compositions described herein can be combined with one or more other therapies to treat HCM or HFpEF. In some embodiments, the polymorphic forms and compositions can be combined with beta-blockers, verapamil, and / or disopyramide.

[0212] Some exemplary embodiments are provided below:

[0213] 1. A polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0214] 2. The polymorph of embodiment 1, characterized by having XRPD peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2 and 22.4±0.2 degrees.

[0215] 3. The polymorph of embodiment 1 or 2, characterized by having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 degrees.

[0216] 4. A polymorph according to any one of embodiments 1 to 3, characterized in that it has substantially Figure 1A The XRPD pattern shown in .

[0217] 5. A polymorph according to any one of embodiments 1 to 4, characterized in that it has substantially Figure 1B The DSC curve diagram shown in .

[0218] 6. The polymorph of any one of embodiments 1 to 5, characterized by having an endotherm with an onset at about 199°C as determined by DSC.

[0219] 7. A polymorph according to any one of embodiments 1 to 6, characterized in that it has substantially Figure 1B The TGA curve is shown in .

[0220] 8. A polymorph according to any one of embodiments 1 to 7, characterized in that it has substantially Figure 1C The DVS graph shown in .

[0221] 9. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees.

[0222] 10. The polymorph of embodiment 1 or 9, characterized by having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees.

[0223] 11. A polymorph according to any one of embodiments 1, 9 and 10, characterized in that it has substantially Figure 2A The XRPD pattern shown in .

[0224] 12. A polymorph according to any one of embodiments 1 and 9 to 11, characterized in that it has substantially Figure 2B The DSC curve diagram shown in .

[0225] 13. The polymorph of any one of embodiments 9 to 12, characterized by having an endotherm with an onset at about 199°C as determined by DSC.

[0226] 14. A polymorph according to any one of embodiments 1 and 9 to 13, characterized in that it has substantially Figure 2B The TGA curve is shown in .

[0227] 15. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees.

[0228] 16. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees.

[0229] 17. The polymorph of embodiment 1 or 16, characterized by having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, and 24.8±0.2 degrees.

[0230] 18. A polymorph according to any one of embodiments 1, 16 and 17, characterized in that it has substantially Figure 4A The XRPD pattern shown in .

[0231] 19. A polymorph according to any one of embodiments 1 and 16 to 18, characterized in that it has substantially Figure 4B The DSC curve diagram shown in .

[0232] 20. The polymorph of any one of embodiments 1 and 16 to 19, characterized by having an endotherm with an onset at about 200°C as determined by DSC.

[0233] 21. A polymorph according to any one of embodiments 1 and 16 to 20, characterized in that it has substantially Figure 4B The TGA curve is shown in .

[0234] 22. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees.

[0235] 23. The polymorph of embodiment 1 or 22, characterized by having an XRPD pattern comprising peaks at 2θ angles of 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees.

[0236] 24. The polymorph of any one of embodiments 1, 22, and 23, characterized by having an XRPD pattern comprising peaks at 2θ angles of 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees.

[0237] 25. A polymorph according to any one of embodiments 1 and 22 to 24, characterized in that it has substantially Figure 5 The XRPD pattern shown in .

[0238] 26. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees.

[0239] 27. The polymorph of embodiment 1 or 26, characterized by having an XRPD pattern comprising peaks at 2θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees.

[0240] 28. A polymorph according to any one of embodiments 1, 26 and 27, characterized in that it has substantially Figure 6A The XRPD pattern shown in .

[0241] 29. A polymorph according to any one of embodiments 1 and 26 to 28, characterized in that it has substantially Figure 6B or Figure 6C The TGA curve is shown in .

[0242] 30. The polymorph of any one of embodiments 1 and 26 to 29, characterized by having an endotherm with an onset at about 200°C as determined by DSC.

[0243] 31. A polymorph according to any one of embodiments 1 and 26 to 30, characterized in that it has substantially Figure 6D or Figure 6E The DSC curve diagram shown in .

[0244] 32. A method for preparing a polymorph according to any one of embodiments 2 to 8, comprising:

[0245] (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent; and

[0246] (2) Cooling the mixture of step (1) or removing the solvent from the mixture of step (1).

[0247] 33. The method of embodiment 32, wherein the solvent comprises dichloromethane (DCM).

[0248] 34. The method of embodiment 32 or 33, wherein step (2) comprises removing the solvent.

[0249] 35. A process for preparing the polymorph of any one of embodiments 9 to 14, comprising grinding Form I in water.

[0250] 36. A method for preparing a polymorph according to any one of embodiments 9 to 14, comprising (1) forming a mixture of Form I and ethanol; and

[0251] (2) Cooling the mixture of step (1).

[0252] 37. The method of embodiment 36, wherein step (1) comprises heating the mixture to about 60°C.

[0253] 38. The method of embodiment 36 or 37, wherein step (2) comprises cooling the mixture of step (1) to about -5°C, about -10°C, about -15°C, or about -20°C.

[0254] 39. A method for preparing a polymorph according to any one of embodiments 16 to 21, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises acetonitrile (ACN) or a mixture of ACN and water; and

[0255] (2) Cooling the mixture of step (1).

[0256] 40. The method of embodiment 39, wherein step (1) comprises heating a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 80°C.

[0257] 41. The method of embodiment 39 or 40, wherein step (2) comprises cooling the mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 20°C.

[0258] 42. A method for preparing a polymorph according to any one of embodiments 22 to 25, comprising:

[0259] (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an acetate; and

[0260] (2) Cooling the mixture of step (1).

[0261] 43. The method of embodiment 42, wherein the solvent comprises ethyl acetate.

[0262] 44. The method of embodiment 42 or 43, wherein step (2) comprises cooling the mixture of step (1) to about 5°C.

[0263] 45. The method of any one of embodiments 42 to 44, further comprising isolating the polymorph in the form of elongated needles.

[0264] 46. ​​A method for preparing the polymorph of any one of embodiments 26 to 31, comprising:

[0265] (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises nitrile and water; and

[0266] (2) Stirring the mixture of step (1).

[0267] 47. The method of embodiment 46, wherein the solvent comprises acetonitrile.

[0268] 48. The method of embodiment 46 or 47, wherein step (2) comprises cooling the mixture of step (1) to a temperature of about 0°C to about 10°C.

[0269] 49. A pharmaceutical composition comprising the polymorph according to any one of embodiments 1 to 31 and a pharmaceutically acceptable excipient.

[0270] 50. A method for treating a cardiac disease in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0271] 51. The method of embodiment 50, wherein the heart disease is hypertrophic cardiomyopathy (HCM).

[0272] 52. The method of embodiment 51, wherein the HCM is obstructive or non-obstructive or is associated with sarcomeric and / or non-sarcomeric mutations.

[0273] 53. The method according to embodiment 50, wherein the heart disease is heart failure with preserved ejection fraction (HFpEF).

[0274] 54. The method of embodiment 50, 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.

[0275] 55. The method of embodiment 47, wherein the heart disease is or is associated with one or more conditions selected from the group consisting of cardiac aging, diastolic dysfunction due to aging, left ventricular hypertrophy, and concentric left ventricular remodeling.

[0276] 56. A method for treating a disease or condition associated with HCM in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0277] 57. The method of embodiment 56, wherein the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome.

[0278] 58. A method for treating a disease or condition associated with secondary left ventricular wall thickening in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0279] 59. The method of embodiment 58, wherein the disease or condition is selected from the group consisting of hypertension, valvular heart disease, metabolic syndrome, end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, and Pompe disease.

[0280] 60. A method for treating a disease or condition associated with left ventricular microsomia and occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0281] 61. A method for treating a disease or condition selected from muscular dystrophy and glycogen storage disease in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0282] 62. A method for inhibiting a cardiac myotome comprising contacting the cardiac myotome with the polymorph of any one of embodiments 1 to 31 or the pharmaceutical composition of embodiment 49. Example

[0283] The following examples are provided to help further understand the embodiments disclosed in this application, and it is assumed that those skilled in the art are familiar with the understanding of the conventional methods related to the embodiments. The specific materials and conditions described below are intended to illustrate specific aspects of the embodiments disclosed herein and should not be considered to limit their reasonable scope.

[0284] The following abbreviations may be used in this article:

[0285] XRPD X-ray powder diffraction DSC Differential Scanning Calorimetry TGA Thermogravimetric analysis DVS Dynamic vapor adsorption 2-MeTHF 2-Methyltetrahydrofuran equiv or eq equivalent vol volume RH relative humidity ca. about RT Room temperature MEK Methyl ethyl ketone iProAc Isopropyl acetate MIBK Methyl isobutyl ketone EtOH ethanol DMSO Dimethyl sulfoxide TBME tert-Butyl methyl ether THF Tetrahydrofuran DCM dichloromethane MeOH Methanol DMF N,N-Dimethylformamide ACN Acetonitrile NMP N-Methylpyrrolidone IPA 2-Propanol TFA Trifluoroacetic acid

[0286] The polymorphic forms of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide were characterized by various analytical techniques using the procedures described below.

[0287] XRPD

[0288] The Rigaku Smart-Lab X-ray diffraction system is configured to utilize a line-source X-ray beam that reflects Bragg-Brentano geometry. The X-ray source is a CuLong Fine Focus tube operated at 40 kV and 44 mA. This source provides an incident beam profile at the sample that changes from a narrow line at high angles to a wide rectangle at low angles. Beam-regulated slits are used on the linear X-ray source to ensure that the maximum beam size, both along the line and perpendicular to the line, is less than 10 mm. Bragg-Brentano geometry is a focused geometry controlled by passive divergence and receiving slits, in which the sample itself serves as the focusing element of the optics. The inherent resolution of the Bragg-Brentano geometry is governed by the diffractometer radius and the width of the receiving slit used. The Rigaku Smart-Lab is typically operated to achieve 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.

[0289] Powder samples were prepared in a low-background Si holder using light manual pressure to keep the sample surface flat and flush with the reference surface of the sample holder. Each sample was analyzed using a continuous scan from 2 to 40° 2θ at 6° 2θ / min with an effective step size of 0.02° 2θ.

[0290] DSC

[0291] DSC analyses were performed using a TA Instruments Q2000. Instrument temperature calibration was performed using indium. During each analysis, the DSC cell was maintained under a nitrogen purge of approximately 50 ml / min. The sample was placed in a standard, crimped, aluminum pan and heated from 25°C to 350°C at a rate of 10°C / min.

[0292] TGA

[0293] TGA was performed using a TA Instruments Q50 instrument. The instrument balance was calibrated using a Class M weight, and temperature calibration was performed using alumel. A nitrogen purge was maintained at approximately 40 ml / min at the balance and 60 ml / min at the boiler. Each sample was placed in a pre-tared platinum pan and heated from 20°C to 350°C at a rate of 10°C / min.

[0294] DVS

[0295] DVS analysis was performed using a TA Instruments Q5000 Dynamic Vapor Sorption Analyzer. The instrument was calibrated with standard weights and sodium bromide standards for humidity. Samples were analyzed at 25°C with a maximum equilibration time of 60 minutes in 10% relative humidity (RH) steps from 5% to 95% RH (sorption cycle) and from 95% to 5% RH (desorption cycle).

[0296] Example 1. Preparation of Form I

[0297] Polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the protocol provided below.

[0298]

[0299] Step 1: Preparation of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate: To a solution of tert-butyl N-[(1R)-5-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl]carbamate (16 g, 54.9 mmol, 1.0 equiv) in dioxane (300 mL) was added propionyl propionate (8.4 g, 64.5 mmol, 1.2 equiv). The mixture was stirred at 105 °C for 8 h, cooled to room temperature, concentrated under reduced pressure and purified by silica gel chromatography (EA / PE, 1 / 9) to give 17.5 g (97%) of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate as a white solid.

[0300] Step 2: Preparation of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine: To a solution of tert-butyl N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]carbamate (17.6 g, 53.4 mmol, 1.0 equiv) in DCM (120 mL) was added TFA (24 mL). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The mixture was then poured into ethanol (50 mL) and water (5 mL) and the pH was adjusted to 12 with sodium hydroxide solution (2N). The mixture was then extracted three times with dichloromethane (200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 11.2 g of (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine as a brown oil.

[0301] Step 3: Preparation of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. To a stirred solution of 1-methyl-1H-pyrazole-4-carboxylic acid (27.1 g, 214.55 mmol, 1.05 equiv) and EDCI (58.8 g, 306.50 mmol, 1.5 equiv) in DMF (540 mL) was added HOAt (41.7 g, 306.50 mmol, 1.5 equiv) and DIPEA (105.6 g, 817.34 mmol, 4 equiv) at room temperature. The mixture was stirred at room temperature for 5 minutes and then (1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine hydrochloride (54.3 g, 204.34 mmol, 1 equivalent) was added. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was poured into water / ice at room temperature. The precipitated solid was collected by filtration and washed three times with water (1000 mL). The solid was dissolved in DCM (1500 mL). The organic phase was washed three times with NH4Cl (500 mL of a saturated aqueous solution) and three times with brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by trituration with EtOAc / n-hexane = 1 / 2 (600 mL) to give Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (62.0704 g, 89.14%) as an off-white solid. LRMS (ES) m / z 338 [M+H]. 1 H NMR: (DMSO, 300MHz, ppm): δ8.41 (1H, d, J = 8.4Hz), 8.16 (1H, s), 7.91-7.79 (3H, m), 7.34 (1H, d, J = 7.9Hz), 5.53 (1 H,q,J=8.3Hz),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).

[0302] Polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, TGA, and DVS. Figure 1A The XRPD pattern of Form I is shown. Figure 1BThe DSC and TGA graphs of Form I are shown. As shown in the DSC graph, an endothermic effect was observed with an onset of approximately 199° C. As shown in the TGA graph, a weight loss of 0.2% was observed below 200° C. Figure 1C Display the DVS curve of form I. Figure 1C As shown in , a moisture uptake of 0.60% w / w was observed in the range of 5-90% relative humidity (RH), as determined by DVS.

[0303] Example 2. Preparation of Form II

[0304] Polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the method provided below.

[0305] Method 1

[0306] 18.2 mg of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was placed in a PEEK grinding cup with a 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 solid was scraped out of the grinding cup with a spatula and analyzed by XRPD. The solid was determined to be Form II.

[0307] Method 2

[0308] 19.5 mg of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was placed in a 20 mL glass vial and heated on a 60 °C plate while magnetically stirring. Ethanol was added to the glass vial until the solid dissolved (4 mL of ethanol was added). The vial was then removed from the plate and 16 mL of cold water (cooled in the freezer) was added. The vial was then placed in the freezer for 4 days. After 4 days, the vial was centrifuged, the liquid decanted, and the resulting solid was air-dried and analyzed by XRPD. The solid was determined to be Form II.

[0309] The polymorphic Form II of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. Figure 2A The XRPD pattern of Form II is shown. Figure 2BThe DSC and TGA graphs of Form II are shown. As shown in the DSC graph, an endothermic effect was observed with an onset of approximately 199° C. As shown in the TGA graph, a weight loss of approximately 0.18% was observed from the onset to 200° C.

[0310] Example 3. Preparation of a mixture of Forms I and III

[0311] In a 1 dram glass vial, 19.1 mg of polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was suspended in 1 mL of hexane. While magnetically stirring on a 60°C hot plate, dioxane was slowly added until the solid dissolved (2.2 mL of dioxane was added). The vial was then capped and heating was stopped. The vial was placed in a freezer (approximately -15°C) for 2 days. After 2 days, the vial was then placed in a freezer for 4 days. After 4 days, the vial was centrifuged, the liquid decanted, and the resulting solid was air-dried and analyzed by XRPD and determined to be a mixture of Forms I and III.

[0312] The mixture of polymorphic Forms I and III of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. Figure 3A An XRPD pattern is shown for a mixture of Forms I and III. Figure 2B The DSC and TGA graphs of the mixture of Forms I and III are shown. As shown in the DSC graph, an exotherm starting at about 107° C. and an endotherm starting at about 196° C. were observed. As shown in the TGA graph, a weight loss of about 18.89% was observed from the onset to 125° C.

[0313] Example 4. Preparation of Form IV

[0314] Polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the protocol provided below.

[0315]

[0316] Step 1: Preparation of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. A mixture of 1-methyl-1H-pyrazole-4-carboxylic acid (10.5 g, 0.0833 mol, 1.00 equiv) and N,N-dimethylformamide (0.054 g, 0.057 mL, 0.00074 mol, 0.0089 equiv) in 2-MeTHF (71.6 g, 83.3 mL, 7.93 volumes) was stirred at 20±5° C. 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 (container 1). A mixture of (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride (15.4 g, 0.0791 mol, 0.95 equiv) in 2-MeTHF (66.1 mL, 4.3 volumes relative to (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride) was treated with 4N sodium hydroxide solution (79 mL, 0.316 mol, 3.8 equiv) at 20 ± 5 ° C. The resulting mixture was stirred at 20 ± 5 ° C for at least 30 minutes (container 2). Freshly prepared 1-methyl-1H-pyrazole-4-carboxylic acid chloride solution was added to the reaction mixture while maintaining the temperature < 30 ° C. After the addition is complete, the mixture is allowed to react at 20±5°C until ≤5% of the intermediate (R)-1-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride remains. The mixture is then filtered. The resulting filter cake is washed sequentially with 2-MeTHF (25 mL) and water until the pH of the filtrate reaches 8.5±1.5. The solid is then dried and isolated. 18.9 g (89.6%) of (R)-N-(5-cyano-2,3-dihydro-1H-indene-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is obtained as a light gray solid.

[0317] Step 2: Preparation of (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. A solution of (R)-N-(5-cyano-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (15.0 g, 0.0563 mol, 1.00 equiv) in NMP (77.3 g, 75.1 mL, 5.0 volumes) was cooled to 5±5°C, and aqueous hydroxylamine solution (50% in water, 11.2 g, 0.169 mol, 3.00 equiv) was slowly added while maintaining the temperature ≤15°C. The resulting mixture was stirred at 20 ± 5 ° C for at least 16 hours until ≤ 2% of (R) -N- (5-cyano-2,3-dihydro -1H- inden-1-yl) -1-methyl -1H- pyrazole -4- carboxamide remained. The reaction mixture was heated to 65 ± 5 ° C and treated with isopropyl acetate (150 mL, 10 volumes) while maintaining the temperature ≥ 50 ° C. The resulting mixture was slowly cooled to 20 ± 5 ° C and stirred for at least 2 hours. Then, the mixture was cooled to 15 ± 5 ° C and stirred for at least 1 hour. The solid product was collected by filtration. The wet cake was washed with isopropyl acetate (2 × 70 mL) and the solid was dried. Then, the material was packaged. 14.62 g (86.7%) of (R,Z)-N-(5-(N′-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide were obtained as an off-white solid.

[0318] Step 3: Preparation of polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. A mixture of propionic acid (4.25 g, 0.057 mol, 1.10 equiv) and 1,1'-carbonyldiimidazole (CDI) (8.87 g, 0.0547 mol, 1.05 equiv) in acetonitrile (105.1 g, 133.7 mL) was stirred at 20±5° C. until no more than 20% of unreacted propionic acid remained, as determined by 1The activated propionic acid solution was transferred to acetonitrile (45.0 g, 57.3 mL) containing (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (15.6 g, 0.0521 mol, 1.00 equiv). The temperature of the reaction mixture was adjusted to 50±5°C and the mixture was stirred at 50±5°C until the remaining (R,Z)-N-(5-(N'-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was ≤2%. After confirming that the reaction is complete, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (15.87 g, 0.104 mol, 2.00 equivalents) is added to the reaction mixture. The temperature of the mixture is adjusted to 70 ± 5 ° C and the mixture is stirred at 70 ± 5 ° C until no more than 2% of the uncyclized intermediate remains. After confirming that the reaction is complete, the reaction mixture is quenched with water (48 mL). The batch temperature is adjusted to 55 ± 5 ° C and the solution is finely filtered. The resulting filtrate is concentrated to about 10 times the volume. The mixture is adjusted to 80 ± 5 ° C and slowly filled with water (310 mL) over a period of at least 1 hour while maintaining a temperature of ≥ 70 ° C. The mixture is adjusted to 80 ± 5 ° C and stirred at 80 ± 5 ° C for at least 2 hours. The mixture is 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 is filtered. The resulting filter cake was washed with water (3 x 120 mL) and dried in a vacuum oven until LOD ≤ 1% was achieved. The material was then packaged. A total of 16.32 g of polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained as an off-white solid in a yield of 92.8%.

[0319] Polymorphic Form IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. Figure 4A The XRPD pattern of Form IV is shown. Figure 4B The DSC and TGA graphs of Form IV are shown. As shown in the DSC graph, an endothermic effect was observed starting at about 200° C. As shown in the TGA graph, a weight loss of about 0.003% was observed from the onset to 200° C.

[0320] Example 5. Preparation of Form V

[0321] Polymorphic Form V of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the method provided below.

[0322] (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was mixed with ethyl acetate at room temperature. The mixture was cooled to 5°C. Two types of polymorphs were produced. The type that existed as fibrous, thin needles was isolated and confirmed by XRPD to be polymorph Form IV. The type that existed as long needles was isolated and confirmed by XRPD to be polymorph Form V. Figure 5 Experimental and simulated XRPD patterns of Form V are shown.

[0323] Example 6: Preparation of Form VI

[0324] Polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was prepared according to the method provided below.

[0325] Method 1

[0326] To (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (Form VI) (500 mg) was added acetonitrile:water (60:40) (8 mL) and stirred with a stir bar at ambient temperature for 48 hours. The solid was isolated by vacuum filtration and analyzed by XRPD, DSC, and TGA.

[0327] Polymorphic Form VI of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was analyzed by XRPD, DSC, and TGA. Figure 6A The experimental XRPD pattern of Form VI is shown. Figure 6B and 6D The TGA and DSC curves of Form VI obtained after oven drying (25°C for 24 hours) are shown respectively. Figure 6B As shown in the TGA curve of , a weight loss of about 2.185% was observed between 25 and 65 °C. Figure 6D As shown in the DSC graph of , a broad endotherm starting at about 41°C, a small exotherm starting at about 115°C, and a strong endotherm starting at 200°C were observed.

[0328] Figure 6C and 6E The TGA and DSC curves of Form VI obtained after oven drying and heating (oven drying at 25°C for 24 hours; heating at 150°C) are shown, respectively. Figure 6C As shown in the TGA curve of , only negligible loss is observed up to 200 °C. Figure 6E As shown in the DSC graph of , a strong endothermic effect starting at 200°C was observed.

[0329] Method 2

[0330] Solid (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide (Form I, IV, or V) (30 mg) was slurried in 10-90% acetonitrile / water (1 mL) and the slurry was stirred with a stir bar at 2-8° C. for 24 hours. The solid was isolated by vacuum filtration and identified as polymorphic Form VI by XRPD.

[0331] Example 7. Polymorph Screening

[0332] Polymorphic Form I of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was mixed with various solvents under various conditions. The resulting samples were analyzed by XRPD. The results are provided in Table 6 below.

[0333] Table 6

[0334]

[0335]

[0336]

[0337] AS = antisolvent; NC = not crystallized; RH = relative humidity; RT = room temperature

[0338] Example 8. Competitive slurry experiment between Form I and Form IV

[0339] Competitive slurry experiments were conducted between Forms I and IV of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide to determine the most stable form within a certain temperature range (2-60° C.). Form IV was found to be more stable than Form I over the entire temperature range tested. The results of the competitive slurry experiments are provided in Table 7 below.

[0340] Table 7

[0341]

[0342] Example 9. Myofibril Analysis

[0343] To evaluate the effect of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide on the ATPase activity of full-length cardiac myosin in the context of native sarcomeres, a peeled myofibril assay was performed. Bovine cardiac myofibrils were obtained by homogenizing bovine left ventricular tissue in the presence of a detergent such as triton X-100. This treatment removes the membrane and most soluble cytoplasmic proteins, but leaves the cardiac sarcomere actomyosin apparatus intact. The myofibril preparation retains the Ca- 2+ The ability to hydrolyze ATP is regulated. At a given fraction (i.e., 25%, 75%) of the maximum activation rate, the Ca 2+ The ATPase activity of these myofibril preparations was analyzed in the presence and absence of the compound at different concentrations. The ability of small molecule agents to inhibit the steady-state ATPase activity of bovine cardiac myofibrils was evaluated using a pyruvate kinase and lactate dehydrogenase (PK / LDH) coupled enzyme system. This assay regenerates ATP from ADP generated by myosin by oxidizing NADH, resulting in a change in absorbance at 340 nm. Prior to testing small molecule agents, the calcium response of bovine cardiac myofibrils was assessed and a concentration that achieved 50% (pCa) of the myofibril system was selected. 50 ) or 75% (pCa 75 ) activated calcium concentration as the final condition for evaluating the inhibitory activity of small molecule agents. All enzyme activities were measured in a buffer solution containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)) and 2 mM magnesium chloride (PM 12 buffer) 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 defoamer, 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 myofibril ATPase activity. IC of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide 15(CDMF75) was 0.4 μM and the IC of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was 0.4 μM. 50 (CDMF75) was 1.4 μM.

[0344] Example 10. Myocyte Analysis

[0345] Adult male Sprague-Dawley rats were anesthetized and the heart was rapidly excised, flushed, and the ascending aorta cannulated. Continuous retrograde perfusion was initiated at a perfusion pressure of 60 cm H2O. 2+ The heart was perfused with a modified Krebs solution consisting of 113 mM NaCl, 4.7 mM KCl, 0.6 mM KH2PO4, 0.6 mM Na2HPO4, 1.2 mM MgSO4, 12 mM NaHCO3, 10 mM KHCO3, 30 mM taurine, 5.5 mM glucose, and 10 mM Hepes (all from Sigma). This medium was not recirculated and was continuously aerated with 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 μM. After the heart became whitish and soft in appearance, it was removed from the cannula. The atria and blood vessels were removed, and the ventricles were gently peeled into smaller pieces using forceps. The tissue was homogenized by repeated pipetting and the collagenase reaction was stopped with 10% calf serum (BCS), sedimented, and resuspended in perfusion buffer containing 5% BCS and 12.5 μM CaCl2. Myocytes were rendered calcium tolerant by the gradual addition of CaCl2 solution to a final concentration of 1.2 mM. Next, the cells were washed and resuspended in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl2, 11 mM glucose, 4 mM Hepes, and 1.2 mM CaCl2, pH 7.4). Cells were maintained at 37°C for 60 minutes before the start of the experiment and used within 5 hours of isolation. Cell preparations were used only after cells first met QC criteria by demonstrating a contractile response to standard (>150% of basal) and isoproterenol (ISO; >250% of basal) treatment. Furthermore, in subsequent experiments with compounds, only cells with a basal contractility between 3% and 8% were used.

[0346] An aliquot of Tyrode's buffer containing myocytes was placed in a perfusion chamber with a heated platform (20RC-27NE series; Warner Instruments). Myocytes were attached, the perfusion chamber was heated to 37°C, and the cells were perfused with 37°C Tyrode's buffer. Myocytes were field stimulated at 1 Hz (20% above threshold) using platinum electrodes. Only cells with clear striations and that were quiescent before pacing were used for contractility experiments. To determine basal contractility, myocytes were imaged through a 40x objective. Images were digitized using a variable frame rate (60-240 Hz) charge-coupled device camera and displayed on a computer screen at a sampling rate of 240 Hz (IonOptix Milton, MA). After cell contraction stabilized over time, test compounds (0.01-15 μM) were perfused into the chamber above the myocytes over a period of 5 minutes. Myocyte contractility and contraction and relaxation velocities were then recorded using edge detection.

[0347] For each compound, five or more individual myocytes were tested by two or more different myocyte preparations. For each cell, 20 or more contractility transients of the basis (defined as 1 minute before compound infusion) and after compound addition (defined as 5 minutes after starting compound infusion) were averaged and compared. These average transients were analyzed using IonWizard software (IonOptix) to determine the changes in diastolic length and fractional shortening. Fractional shortening was calculated as: ((length at resting length-peak contraction) divided by resting length). Fractional shortening was calculated as the percentage change from baseline: ((fractional shortening / basal shortening after administration) × 100). Fractional shortening was calculated as the percentage reduction from baseline: (100-fractional shortening from baseline). Maximum contraction and relaxation velocity (μm / sec) were also determined. The results of individual cells were averaged and SEM was calculated. The effect of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide is provided below.

[0348]

[0349] %FS = average of (post-baseline peak height percentage / pre-baseline peak height percentage) × 100 for each cell

[0350] Example 11. Echocardiographic Assessment of Acute Pharmacodynamic Effects on Myocardial Contractility in Rats

[0351] In vivo cardiac function assessments by echocardiography were performed in male Sprague Dawley rats under isoflurane (1-3%) anesthesia. 2-DM mode images of the left ventricle were obtained in the parasternal left ventricular long axis section before, during, and after administration of the compound by continuous IV infusion or oral gavage. The in vivo fractional shortening was determined by M-mode image analysis using the following calculation: ((end-diastolic diameter-end-systolic diameter) / end-diastolic diameter×100). For the continuous IV infusion experiment, three pre-dose baseline M-mode images were obtained at 1-minute intervals before the compound was infused. The compound was formulated in 50% propylene glycol (PG): 16% Captisol: 10% dimethylacetamide (DMA) and delivered via a jugular vein catheter at a rate of 1 mL / kg / h. During the infusion, M-mode images were obtained at 5-minute intervals. The infusion was stopped when the fractional shortening reached a 60% reduction from baseline. Blood samples were obtained to determine the plasma concentration of the compound. The data are reported as the IC evaluated. 50 The IC of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was obtained. 50 The value was 7.2±0.20 μM (mean±SD).

[0352] For oral dosing studies, three pre-dose baseline M-mode images were acquired at 1-minute intervals prior to compound administration. (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide was formulated in a 0.5% hydroxypropylmethylcellulose 2910 (HPMC 2910):0.1% Tween 80 suspension and delivered as a single dose (5 mL / kg) by oral gavage. M-mode echocardiography measurements were obtained under light anesthesia at selected time points over a 24-hour period. Different dose levels were evaluated. The effect of the compound on cardiac fractional shortening at the highest dose evaluated is presented below as the percentage reduction from baseline fractional shortening (=100%).

[0353]

[0354] During the echocardiography measurements, blood samples were obtained to determine the corresponding compound plasma concentrations. 50 and IC 10 The values ​​(the concentrations that resulted in fractional shortening of 50% and 10% of the baseline contractility before administration, respectively) were 7.9 μM (IC 50 ) and 0.8μM (IC10 ).

[0355] This application specifically relates to the following implementation plans:

[0356] 1. A polymorph of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide.

[0357] 2. The polymorph of embodiment 1, characterized by having XRPD peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2 and 22.4±0.2 degrees.

[0358] 3. The polymorph of embodiment 1 or 2, characterized by having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2, and 26.1±0.2 degrees.

[0359] 4. A polymorph according to any one of embodiments 1 to 3, characterized in that it has substantially Figure 1A The XRPD pattern shown in .

[0360] 5. A polymorph according to any one of embodiments 1 to 4, characterized in that it has substantially Figure 1B The DSC curve diagram shown in .

[0361] 6. The polymorph of any one of embodiments 1 to 5, characterized by having an endotherm with an onset at about 199°C as determined by DSC.

[0362] 7. A polymorph according to any one of embodiments 1 to 6, characterized in that it has substantially Figure 1B The TGA curve is shown in .

[0363] 8. A polymorph according to any one of embodiments 1 to 7, characterized in that it has substantially Figure 1C The DVS graph shown in .

[0364] 9. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, and 20.4±0.2 degrees.

[0365] 10. The polymorph of embodiment 1 or 9, characterized by having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2, and 23.3±0.2 degrees.

[0366] 11. A polymorph according to any one of embodiments 1, 9 and 10, characterized in that it has substantially Figure 2A The XRPD pattern shown in .

[0367] 12. A polymorph according to any one of embodiments 1 and 9 to 11, characterized in that it has substantially Figure 2B The DSC curve diagram shown in .

[0368] 13. The polymorph of any one of embodiments 9 to 12, characterized by having an endotherm with an onset at about 199°C as determined by DSC.

[0369] 14. A polymorph according to any one of embodiments 1 and 9 to 13, characterized in that it has substantially Figure 2B The TGA curve is shown in .

[0370] 15. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 9.6±0.2, 10.9±0.2, 15.8±0.2, and 18.1±0.2 degrees.

[0371] 16. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 11.1±0.2, 12.8±0.2, 13.5±0.2, 22.8±0.2, and 24.4±0.2 degrees.

[0372] 17. The polymorph of embodiment 1 or 16, characterized by having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 11.1±0.2, 12.8±0.2, 13.5±0.2, 21.9±0.2, 22.8±0.2, 23.1±0.2, 23.5±0.2, 24.4±0.2, and 24.8±0.2 degrees.

[0373] 18. A polymorph according to any one of embodiments 1, 16 and 17, characterized in that it has substantially Figure 4A The XRPD pattern shown in .

[0374] 19. A polymorph according to any one of embodiments 1 and 16 to 18, characterized in that it has substantially Figure 4BThe DSC curve diagram shown in .

[0375] 20. The polymorph of any one of embodiments 1 and 16 to 19, characterized by having an endotherm with an onset at about 200°C as determined by DSC.

[0376] 21. A polymorph according to any one of embodiments 1 and 16 to 20, characterized in that it has substantially Figure 4B The TGA curve is shown in .

[0377] 22. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 11.5±0.2, 16.3±0.2, 20.0±0.2, 21.2±0.2, and 24.7±0.2 degrees.

[0378] 23. The polymorph of embodiment 1 or 22, characterized by having an XRPD pattern comprising peaks at 2θ angles of 11.5±0.2, 16.3±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 21.2±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, and 26.7±0.2 degrees.

[0379] 24. The polymorph of any one of embodiments 1, 22, and 23, characterized by having an XRPD pattern comprising peaks at 2θ angles of 5.7±0.2, 8.3±0.2, 11.5±0.2, 16.3±0.2, 17.2±0.2, 19.1±0.2, 20.0±0.2, 20.2±0.2, 20.7±0.2, 21.2±0.2, 23.3±0.2, 24.0±0.2, 24.7±0.2, 25.6±0.2, 26.7±0.2, 28.1±0.2, 29.2±0.2, 29.7±0.2, 29.9±0.2, and 31.1±0.2 degrees.

[0380] 25. A polymorph according to any one of embodiments 1 and 22 to 24, characterized in that it has substantially Figure 5 The XRPD pattern shown in .

[0381] 26. The polymorph of embodiment 1, characterized by having an XRPD pattern comprising peaks at 2θ angles of 10.6±0.2, 12.1±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees.

[0382] 27. The polymorph of embodiment 1 or 26, characterized by having an XRPD pattern comprising peaks at 2θ angles of 5.4±0.2, 5.9±0.2, 8.1±0.2, 9.6±0.2, 10.6±0.2, 12.1±0.2, 14.0±0.2, 15.0±0.2, 16.1±0.2, and 17.8±0.2 degrees.

[0383] 28. A polymorph according to any one of embodiments 1, 26 and 27, characterized in that it has substantially Figure 6A The XRPD pattern shown in .

[0384] 29. A polymorph according to any one of embodiments 1 and 26 to 28, characterized in that it has substantially Figure 6B or Figure 6C The TGA curve is shown in .

[0385] 30. The polymorph of any one of embodiments 1 and 26 to 29, characterized by having an endotherm with an onset at about 200°C as determined by DSC.

[0386] 31. A polymorph according to any one of embodiments 1 and 26 to 30, characterized in that it has substantially Figure 6D or Figure 6E The DSC curve diagram shown in .

[0387] 32. A method for preparing a polymorph according to any one of embodiments 2 to 8, comprising:

[0388] (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent; and

[0389] (2) Cooling the mixture of step (1) or removing the solvent from the mixture of step (1).

[0390] 33. The method of embodiment 32, wherein the solvent comprises dichloromethane (DCM).

[0391] 34. The method of embodiment 32 or 33, wherein step (2) comprises removing the solvent.

[0392] 35. A process for preparing the polymorph of any one of embodiments 9 to 14, comprising grinding Form I in water.

[0393] 36. A method for preparing a polymorph according to any one of embodiments 9 to 14, comprising (1) forming a mixture of Form I and ethanol; and

[0394] (2) Cooling the mixture of step (1).

[0395] 37. The method of embodiment 36, wherein step (1) comprises heating the mixture to about 60°C.

[0396] 38. The method of embodiment 36 or 37, wherein step (2) comprises cooling the mixture of step (1) to about -5°C, about -10°C, about -15°C, or about -20°C.

[0397] 39. A method for preparing a polymorph according to any one of embodiments 16 to 21, comprising: (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises acetonitrile (ACN) or a mixture of ACN and water; and

[0398] (2) Cooling the mixture of step (1).

[0399] 40. The method of embodiment 39, wherein step (1) comprises heating a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 80°C.

[0400] 41. The method of embodiment 39 or 40, wherein step (2) comprises cooling the mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and the solvent to about 20°C.

[0401] 42. A method for preparing a polymorph according to any one of embodiments 22 to 25, comprising:

[0402] (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises an acetate; and

[0403] (2) Cooling the mixture of step (1).

[0404] 43. The method of embodiment 42, wherein the solvent comprises ethyl acetate.

[0405] 44. The method of embodiment 42 or 43, wherein step (2) comprises cooling the mixture of step (1) to about 5°C.

[0406] 45. The method of any one of embodiments 42 to 44, further comprising isolating the polymorph in the form of elongated needles.

[0407] 46. ​​A method for preparing the polymorph of any one of embodiments 26 to 31, comprising:

[0408] (1) forming a mixture of (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide and a solvent, wherein the solvent comprises nitrile and water; and

[0409] (2) Stirring the mixture of step (1).

[0410] 47. The method of embodiment 46, wherein the solvent comprises acetonitrile.

[0411] 48. The method of embodiment 46 or 47, wherein step (2) comprises cooling the mixture of step (1) to a temperature of about 0°C to about 10°C.

[0412] 49. A pharmaceutical composition comprising the polymorph according to any one of embodiments 1 to 31 and a pharmaceutically acceptable excipient.

[0413] 50. A method for treating a cardiac disease in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0414] 51. The method of embodiment 50, wherein the heart disease is hypertrophic cardiomyopathy (HCM).

[0415] 52. The method of embodiment 51, wherein the HCM is obstructive or non-obstructive or is associated with sarcomeric and / or non-sarcomeric mutations.

[0416] 53. The method according to embodiment 50, wherein the heart disease is heart failure with preserved ejection fraction (HFpEF).

[0417] 54. The method of embodiment 50, 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.

[0418] 55. The method of embodiment 47, wherein the heart disease is or is associated with one or more conditions selected from the group consisting of cardiac aging, diastolic dysfunction due to aging, left ventricular hypertrophy, and concentric left ventricular remodeling.

[0419] 56. A method for treating a disease or condition associated with HCM in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0420] 57. The method of embodiment 56, wherein the disease or condition is selected from the group consisting of Fabry disease, Danon disease, mitochondrial cardiomyopathy, and Noonan syndrome.

[0421] 58. A method for treating a disease or condition associated with secondary left ventricular wall thickening in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0422] 59. The method of embodiment 58, wherein the disease or condition is selected from the group consisting of hypertension, valvular heart disease, metabolic syndrome, end-stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry disease, Friedreich's ataxia, Danon disease, Noonan syndrome, and Pompe disease.

[0423] 60. A method for treating a disease or condition associated with left ventricular microsomia and occlusion, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0424] 61. A method for treating a disease or condition selected from muscular dystrophy and glycogen storage disease in a subject in need thereof, comprising administering to the subject a polymorph according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 49.

[0425] 62. A method for inhibiting a cardiac myotome comprising contacting the cardiac myotome with the polymorph of any one of embodiments 1 to 31 or the pharmaceutical composition of embodiment 49.

[0426] All documents cited herein, including patents, patent applications, and publications (including all documents cited therein), tables, and figures, are expressly incorporated by reference in their entirety for all purposes.

[0427] Although the foregoing written description of the compounds, uses, and methods described herein allows one skilled in the art to make and use the compounds, uses, and methods described herein, one skilled in the art will understand and appreciate variations, combinations, and equivalents of the specific embodiments, methods, and embodiments presented herein. Therefore, the compounds, uses, and methods provided herein should not be limited by the above-described embodiments, methods, or embodiments, but rather encompass all embodiments and methods within the scope and spirit of the compounds, uses, and methods provided herein.

Claims

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

2. The polymorph according to claim 1, characterized in that The XRPD pattern has peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 14.4±0.2 and 22.4±0.2 degrees.

3. The polymorph according to claim 1 or 2, characterized in that Having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 11.2±0.2, 12.9±0.2, 13.5±0.2, 14.4±0.2, 18.6±0.2, 22.4±0.2, 24.7±0.2, 25.0±0.2 and 26.1±0.2 degrees.

4. The polymorph according to any one of claims 1 to 3, characterized in that Having an XRPD pattern substantially as shown in Figure 1A.

5. The polymorph according to any one of claims 1 to 4, characterized in that Having a DSC graph substantially as shown in FIG. 1B .

6. The polymorph according to any one of claims 1 to 5, characterized in that Has an endotherm with an onset at about 199°C as determined by DSC.

7. The polymorph according to any one of claims 1 to 6, characterized in that Having a TGA graph substantially as shown in FIG. 1B .

8. The polymorph according to any one of claims 1 to 7, characterized in that With a DVS graph substantially as shown in FIG. 1C .

9. The polymorph according to claim 1, characterized in that Having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2 and 20.4±0.2 degrees.

10. The polymorph according to claim 1 or 9, characterized in that Having an XRPD pattern comprising peaks at 2θ angles of 3.7±0.2, 9.8±0.2, 11.1±0.2, 12.8±0.2, 14.7±0.2, 16.1±0.2, 18.5±0.2, 20.4±0.2, 22.3±0.2 and 23.3±0.2 degrees.

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