Crystalline salt forms of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide and methods of use thereof

Abstract

Described herein, in part, are crystalline and salt forms of N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide useful for preventing and / or treating diseases or conditions associated with abnormal functioning of T-type calcium channels, such as, for example, epilepsy and epilepsy syndromes (e.g., absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy), tremors (e.g., essential tremor), and psychiatric disorders (e.g., mood disorders (e.g., major depressive disorder)).

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 449,467, filed March 2, 2023, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] T-type calcium channel is a low-voltage activated ion channel that mediates the influx of calcium into cells.The abnormal function of these ion channels is associated with several diseases or conditions, including psychiatric disorders (e.g., mood disorders), pain, tremors (e.g., essential tremor), epilepsy, or epilepsy syndromes (e.g., absence seizures and juvenile myoclonic epilepsy).Therefore, the compound that selectively regulates T-type calcium channel in mammals can be useful in treating such diseases or conditions. N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide, referred to herein as Compound 1, is a novel, selective T-type calcium channel blocker currently in clinical development. Compound 1 is disclosed, for example, in WO2021 / 007487 and has the following structure: [ka] Compound 1 is currently in clinical development for a number of indications, including, for example, essential tremor. See, e.g., U.S. Clinical Trial Identifier NCT05021978. Given the clinical importance of Compound 1, there is a need to prepare and characterize various salts of Compound 1, including crystalline forms of salts of Compound 1. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2021 / 007487 Summary of the Invention [Means for solving the problem]

[0004] Described herein are salts and crystalline forms of Compound 1, wherein the salts and / or crystalline forms are selected from the group consisting of acetate, adipate, alginate, ascorbate, aspartate, besylate, benzoate, citrate, cyclamate, edisylate, esylate salt, isethionate, fumarate, gentisate, gluconate, glucuronate, glutamate, glutarate, ketoglutarate, glycolate, hippurate, lactobionate, maleate, malate, malonate, mesylate, napadisylate, napsylate, oleate, oroate salt, oxalate, pamoate, phosphate, sebacate, succinate, and tartrate.

[0005] In certain embodiments, provided herein is a crystalline form of the edisylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 1.

[0006] In another embodiment, provided herein is a crystalline form of the esylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 2.

[0007] In another embodiment, provided herein is a crystalline form of the glutarate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 3.

[0008] In another embodiment, provided herein is a crystalline form of the napadisylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 4.

[0009] In another embodiment, provided herein is a crystalline form of the napsylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 5.

[0010] In another embodiment, provided herein is a crystalline form of the orotate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 6.

[0011] In another embodiment, provided herein is a crystalline form of the maleate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 7.

[0012] In yet another embodiment, provided herein is a crystalline form of the malonate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 8.

[0013] In another embodiment, provided herein is a crystalline form of the mesylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 9.

[0014] In another embodiment, provided herein is a crystalline form of the pamoate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 10.

[0015] In another embodiment, provided herein is a crystalline form of the adipate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 11.

[0016] In another embodiment, provided herein is a crystalline form of the besylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 12.

[0017] In another embodiment, provided herein is a crystalline form of the cyclamate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 13.

[0018] In another embodiment, provided herein is a crystalline form of the fumarate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 14.

[0019] In another embodiment, provided herein is a crystalline form of the glycolic acid salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 15.

[0020] In another embodiment, provided herein is a crystalline form of the oxalate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 16.

[0021] In another embodiment, provided herein is a crystalline form of the phosphate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 17.

[0022] In another embodiment, provided herein is a crystalline form of a sebacate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 18.

[0023] Also provided herein is a pharmaceutical composition comprising a salt or crystalline form of Compound 1 described herein and a pharmaceutically acceptable carrier.

[0024] Also provided herein are methods for treating neurological disorders, comprising administering a salt or crystal of Compound 1 described herein, or a pharmaceutical composition described herein.

[0025] Also provided herein are methods for treating a psychiatric disorder, comprising administering a salt or crystal of Compound 1 described herein, or a pharmaceutical composition described herein. [Brief explanation of the drawings]

[0026] [Figure 1] FIG. 1 shows the X-ray powder diffractogram of the crystalline salt of the edisylate salt of Compound 1 (Form 1). [Figure 2] FIG. 2 shows the X-ray powder diffractogram of the crystalline salt of the esylate salt of Compound 1 (Form 2). [Figure 3]FIG. 3 shows an X-ray powder diffractogram of the crystalline salt of the glutarate salt of Compound 1 (Form 3). [Figure 4] FIG. 4 shows the X-ray powder diffractogram of the crystalline napadisylate salt of Compound 1 (Form 4). [Figure 5] FIG. 5 shows the X-ray powder diffractogram of the crystalline salt of the napsylate salt of Compound 1 (Form 5). [Figure 6] FIG. 6 shows an X-ray powder diffractogram of the crystalline salt of Compound 1 orotate (Form 6). [Figure 7] FIG. 7 shows the X-ray powder diffractogram of the crystalline salt of the maleate salt of Compound 1 (Form 7). [Figure 8] FIG. 8 shows an X-ray powder diffractogram of the crystalline salt of the malonate salt of Compound 1 (Form 8). [Figure 9] FIG. 9 shows the X-ray powder diffractogram of the crystalline salt of Compound 1 mesylate (Form 9). [Figure 10] FIG. 10 shows an X-ray powder diffractogram of the crystalline salt of the pamoate salt of Compound 1 (Form 10). [Figure 11] FIG. 11 shows an X-ray powder diffractogram of the crystalline salt of Compound 1 adipate (Form 11). [Figure 12] FIG. 12 shows an X-ray powder diffractogram of the crystalline salt of the besylate salt of Compound 1 (Form 12). [Figure 13] FIG. 13 shows an X-ray powder diffractogram of the crystalline salt of the cyclamate salt of Compound 1 (Form 13). [Figure 14] FIG. 14 shows an X-ray powder diffractogram of the crystalline salt of the fumarate salt of Compound 1 (Form 14). [Figure 15] FIG. 15 shows an X-ray powder diffractogram of the crystalline salt of the glycolate salt of Compound 1 (Form 15). [Figure 16] FIG. 16 shows an X-ray powder diffractogram of the crystalline salt of the oxalate salt of Compound 1 (Form 16). [Figure 17]FIG. 17 shows an X-ray powder diffractogram of a crystalline salt of the phosphate salt of Compound 1 (Form 17). [Figure 18] FIG. 18 shows an X-ray powder diffractogram of the crystalline salt of the sebacate salt of Compound 1 (Form 18). [Figure 19] FIG. 19 shows the results of DSC and TGA analysis of the crystalline salt of the edisylate salt of Compound 1 (Form 1). [Figure 20] FIG. 20 shows the results of NMR analysis of the crystalline salt of the edisylate salt of Compound 1 (Form 1). [Figure 21] FIG. 21 shows the results of DSC and TGA analysis of the crystalline salt of the maleate salt of Compound 1 (Form 7). [Figure 22] FIG. 22 shows the results of NMR analysis of the crystalline salt of the maleate salt of Compound 1 (Form 7). [Figure 23] FIG. 23 shows the results of DSC and TGA analysis of the crystalline salt of the malonate salt of Compound 1 (Form 8). [Figure 24] FIG. 24 shows the results of NMR analysis of the crystalline salt of the malonate of Compound 1 (Form 8). [Figure 25] FIG. 25 shows the results of DSC and TGA analysis of the crystalline salt of Compound 1 mesylate (Form 9). [Figure 26] FIG. 26 shows the results of NMR analysis of the crystalline salt of Compound 1 mesylate (Form 9). [Figure 27] FIG. 27 shows the results of DSC and TGA analysis of the crystalline salt of the pamoate salt of Compound 1 (Form 10). [Figure 28] FIG. 28 shows the results of NMR analysis of the crystalline salt of the pamoate salt of Compound 1 (Form 10). DETAILED DESCRIPTION OF THE INVENTION

[0027] As generally described herein, the present disclosure provides salts, including crystalline salts, of Compound 1. The present disclosure also provides methods of treating neurological disorders, psychiatric disorders, generalized epilepsy syndromes with absence seizures, and essential tremor, the methods comprising administering a therapeutically effective amount of a salt of Compound 1, including a crystalline salt of Compound 1.

[0028] definition As used herein, the term "anhydrous" means that the reference crystalline form has substantially no water in the crystal lattice. In one embodiment, the reference anhydrous crystalline form has, for example, less than about 0.1 wt. %, e.g., less than about 0.09 wt. %, less than about 0.08 wt. %, less than about 0.07 wt. %, less than about 0.06 wt. %, less than about 0.05 wt. %, less than about 0.04 wt. %, less than about 0.03 wt. %, less than about 0.02 wt. %, or less than about 0.01 wt. %, as determined by Karl Fisher analysis.

[0029] As used herein, the term "amorphous" refers to existing in a non-crystalline state or form. Amorphous solids have an irregular molecular arrangement, such that they lack a discernible crystal lattice or unit cell, and consequently, no definable long-range order. Instead, at least one broad signal (e.g., at least one halo) may appear in the diffractogram. Broad signals are characteristic of amorphous solids. The solid-state order of a solid can be determined by standard techniques known in the art, such as X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids by birefringence, for example, using a polarized light microscope.

[0030] As used herein, the terms "polymorph," "crystalline form," "crystalline form," "solid state form," and "form" refer interchangeably to solids having a particular molecular packing arrangement within a crystal lattice. Crystalline forms can be identified and distinguished from one another by at least one characterization technique, including, for example, X-ray powder diffraction (XRPD), single crystal X-ray diffraction, differential scanning calorimetry (DSC), dynamic vapor sorption (DVS), and / or thermogravimetric analysis (TGA). Different polymorphs may have different physical properties, such as melting point, heat of fusion, solubility, dissolution rate, and / or vibrational spectra, as a result of differences in the arrangement or structure of the molecules in the crystal lattice. Differences in the physical properties exhibited by different polymorphs can affect parameters important to a pharmaceutical substance, such as, for example, storage stability, compressibility, and density (important in formulation and product manufacturing), and dissolution rate (an important factor for bioavailability).

[0031] Differences in the stability of different polymorphs can also result from differences in chemical reactivity (e.g., differences in susceptibility to oxidation). Thus, a dosage form composed of one polymorph may discolor more rapidly than a dosage form composed of various polymorphs of the same substance. Differences in the stability of different polymorphs can also result from differences in mechanical properties (e.g., a tablet may disintegrate upon storage as it transforms from a kinetically favored polymorph to a thermodynamically more stable polymorph), or from differences in both chemical and mechanical properties (e.g., a tablet of one polymorph is more susceptible to degradation at high humidity). In extreme cases, differences in solubility / dissolution can result in some polymorphic transformations resulting in a loss of potency or, in other extreme cases, toxicity. Additionally, the physical properties of the crystals can be important in processes. For example, different polymorphs of the same substance may exhibit differences in their tendency to form solvates or may exhibit differences in the shape and size distribution of their particles, which may affect purification (e.g., one polymorph may be more difficult to filter and wash free of impurities than another).

[0032] Polymorphs of molecules can be obtained by many methods known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, and sublimation. Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy such as IR and Raman spectroscopy, solid-state NMR, hot-stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility testing, and dissolution testing. Specifically, XRPD is a technique used to characterize the crystal structure, size, and preferred orientation of polycrystalline or powdered solid samples. It can also be used to characterize heterogeneous solid mixtures to determine the proportion of crystalline compounds present and provide structural information about unknown materials.

[0033] The term "X-ray powder diffraction pattern," as used herein, which is used interchangeably with the terms "XRPD pattern" or "X-ray powder diffractogram," refers to a graphical representation of the data collected by XRPD analysis.

[0034] As used herein, the term "peak" refers to a peak in an XRPD pattern that has an intensity that is at least about 20%, e.g., at least about 30%, at least about 40%, at least about 50%, or at least about 100% greater than the baseline noise.

[0035] As used herein with respect to peaks in an "XRPD pattern," the term "approximately" or "about" refers to an XRPD pattern in which the peak appears within 0.5 °2θ, e.g., within 0.4, 0.3, 0.2, 0.1, 0.05, or 0.01 °2θ, of a given °2θ value.

[0036] As used herein, an XRPD pattern is "substantially the same as the XRPD pattern shown in a [particular] figure" if at least about 80%, e.g., at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the peaks in the two diffractograms are identical within ±0.5° 2θ. In determining "substantial similarity," one of skill in the art will understand that variations in intensity and / or signal positions may exist in XRPD diffractograms even for the same crystalline form.

[0037] As used herein, the term "chemical purity" refers to the degree to which a form of the present disclosure is free of substances with different chemical structures. In the crystalline forms of the present disclosure, the chemical purity of a compound refers to the weight of the compound divided by the sum of the weight of the compound plus the weight of substances / impurities with different chemical structures multiplied by 100%, i.e., the critical percentage. In one embodiment, the crystalline form of the compound of the present disclosure has a chemical purity of 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 95% by weight, or at least about 99% by weight.

[0038] As used herein, the terms "crystalline" or "crystalline form" refer to a solid form of a compound, e.g., Compound 1, in which the atoms are arranged in a regular repeating pattern. In some embodiments, the term "crystalline" encompasses, without distinction, polymorphs or non-amorphous forms of a compound, e.g., Compound 1. The crystalline nature of a compound can be confirmed, for example, by examination of the compound's XRPD pattern. A compound is crystalline if the XRPD shows sharp, intense peaks in the XRPD.

[0039] As used herein, the term "solvate" refers to a crystalline compound wherein a stoichiometric or non-stoichiometric amount of a solvent or mixture of solvents is incorporated within the crystal structure.

[0040] As used herein, the term "hydrate" refers to a crystalline compound in which stoichiometric or non-stoichiometric amounts of water are incorporated into the crystal structure. Hydrates are solvates in which the solvent incorporated into the crystal structure is water.

[0041] The term "anhydrous" as used herein with respect to a compound means that there is substantially no solvent incorporated into the crystalline structure.

[0042] As used herein, the term "N-((1-(2-(tert-butylamino)-2-oxoethyl)piperidin-4-yl)methyl)-3-chloro-5-fluorobenzamide" is used interchangeably with the term "Compound 1" in reference to the compound of the following structure: [ka]

[0043] The two-theta (2θ) values ​​of the X-ray powder diffraction patterns of the crystalline forms described herein may vary slightly from instrument to instrument and are also dependent on variations in sample preparation and batch-to-batch variations. Therefore, unless otherwise defined, the XRPD patterns / assignments listed herein are not to be construed as absolute and may vary by ±0.5 degrees.

[0044] For example, with respect to the DSC peaks herein, temperatures may vary slightly from instrument to instrument and are also dependent on variations in sample preparation, batch-to-batch variations, and environmental factors. Thus, unless otherwise specified, the temperature values ​​listed herein are not to be construed as absolute values ​​and may vary by ±5°C or ±2°C.

[0045] Generally, the term "effective amount" of a compound refers to an amount sufficient to induce a desired biological response.As will be understood by those skilled in the art, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, health, and condition of the subject.The effective amount includes therapeutic and prophylactic treatment.

[0046] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effect of another therapeutic agent.

[0047] As used herein, the term "refractory" refers to a disease, disorder, or condition that does not readily succumb to or respond to a therapy or treatment, or that is not controlled by a therapy or treatment. In some embodiments, the diseases, disorders, or conditions described herein are refractory (e.g., refractory epilepsy or refractory absence seizures) and do not respond to standard therapies or treatments.

[0048] As used herein, a "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female, of any age, e.g., pediatric subjects such as infants, children, and adolescents, or adult subjects, e.g., young adults, middle-aged and elderly adults, and geriatrics), and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus or rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human" and "patient" are used interchangeably herein.

[0049] The terms "disease," "disorder," and "condition" are used interchangeably herein.

[0050] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions that occur while a subject is afflicted with the specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition or slow or delay the progression of the disease, disorder, or condition ("therapeutic treatment"), and also contemplate actions that occur before a subject begins to suffer from the specified disease, disorder, or condition.

[0051] Salt of Compound 1 Provided herein are salts, including crystalline salts, of Compound 1. Compound 1 is represented by the following structural formula: [ka]

[0052] In some embodiments, the present disclosure provides a compound selected from the group consisting of Compound 1 acetate, Compound 1 adipate, Compound 1 alginate, Compound 1 ascorbate, Compound 1 aspartate, Compound 1 besylate, Compound 1 benzoate, Compound 1 citrate, Compound 1 cyclamate, Compound 1 edisylate, Compound 1 esylate, Compound 1 isethionate, Compound 1 fumarate, Compound 1 gentisate, Compound 1 gluconate, Compound 1 glucuronate, Compound 1 glutamate, Compound 1 glutarate, Provided is a salt of Compound 1 selected from the group consisting of Compound 1 ketoglutarate, Compound 1 glycolate, Compound 1 hippurate, Compound 1 lactobionate, Compound 1 maleate, Compound 1 malate, Compound 1 malonate, Compound 1 mesylate, Compound 1 napadisylate, Compound 1 napsylate, Compound 1 oleate, Compound 1 oroate, Compound 1 oxalate, Compound 1 pamoate, Compound 1 phosphate, Compound 1 sebacate, Compound 1 succinate, and Compound 1 tartrate.

[0053] In some embodiments, the present disclosure provides a salt of Compound 1 selected from the group consisting of Compound 1 adipate, Compound 1 besylate, Compound 1 cyclamate, Compound 1 edisylate, Compound 1 esylate, Compound 1 isethionate, Compound 1 gentisate, Compound 1 glucuronate, Compound 1 glutamate, Compound 1 glutarate, Compound 1 ketoglutarate, Compound 1 glycolate, Compound 1 hippurate, Compound 1 mesylate, Compound 1 napadisylate, Compound 1 napsylate, Compound 1 oroate, and Compound 1 sebacate.

[0054] In some embodiments, the present disclosure provides an acetate salt of Compound 1.

[0055] In some embodiments, the present disclosure provides an adipic acid salt of Compound 1.

[0056] In some embodiments, the present disclosure provides an alginate salt of Compound 1.

[0057] In some embodiments, the present disclosure provides an ascorbate salt of Compound 1.

[0058] In some embodiments, the present disclosure provides an aspartate salt of Compound 1.

[0059] In some embodiments, the present disclosure provides a besylate salt of Compound 1.

[0060] In some embodiments, the present disclosure provides a benzoate salt of Compound 1.

[0061] In some embodiments, the present disclosure provides a citrate salt of Compound 1.

[0062] In some embodiments, the present disclosure provides a cyclamate salt of Compound 1.

[0063] In some embodiments, the present disclosure provides an edisylate salt of Compound 1.

[0064] In some embodiments, the present disclosure provides an esylate salt of Compound 1.

[0065] In some embodiments, the present disclosure provides an isethionate salt of Compound 1.

[0066] In some embodiments, the present disclosure provides a fumarate salt of Compound 1.

[0067] In some embodiments, the present disclosure provides a gentisate salt of Compound 1.

[0068] In some embodiments, the present disclosure provides a gluconate salt of Compound 1.

[0069] In some embodiments, the present disclosure provides a glucuronate salt of Compound 1.

[0070] In some embodiments, the present disclosure provides a glutamate salt of Compound 1.

[0071] In some embodiments, the present disclosure provides a glutarate salt of Compound 1.

[0072] In some embodiments, the present disclosure provides a ketoglutarate salt of Compound 1.

[0073] In some embodiments, the present disclosure provides a glycolic acid salt of Compound 1.

[0074] In some embodiments, the present disclosure provides a hippuric acid salt of Compound 1.

[0075] In some embodiments, the present disclosure provides a lactobionate salt of Compound 1.

[0076] In some embodiments, the present disclosure provides a maleate salt of Compound 1.

[0077] In some embodiments, the present disclosure provides a malate salt of Compound 1.

[0078] In some embodiments, the present disclosure provides a malonate salt of Compound 1.

[0079] In some embodiments, the present disclosure provides a mesylate salt of Compound 1.

[0080] In some embodiments, the present disclosure provides a napadisylate salt of Compound 1.

[0081] In some embodiments, the present disclosure provides a napsylate salt of Compound 1.

[0082] In some embodiments, the present disclosure provides an oleate salt of Compound 1.

[0083] In some embodiments, the disclosure provides an oroate of Compound 1.

[0084] In some embodiments, the present disclosure provides an oxalate salt of Compound 1.

[0085] In some embodiments, the present disclosure provides a pamoate salt of Compound 1.

[0086] In some embodiments, the present disclosure provides a phosphate salt of Compound 1.

[0087] In some embodiments, the present disclosure provides a sebacate salt of Compound 1.

[0088] In some embodiments, the present disclosure provides a succinate salt of Compound 1.

[0089] In some embodiments, the present disclosure provides a tartrate salt of Compound 1.

[0090] Crystalline salt forms of Compound 1 The present disclosure also provides crystalline forms of salts of Compound 1. In some embodiments, the salt is selected from the group consisting of adipate, besylate, cyclamate, edisylate, esylate, fumarate, glutarate, glycolate, napadisylate, napsylate, orotate, oxalate, maleate, malonate, mesylate, pamoate, phosphate, and sebacate.

[0091] Crystalline form of the edisylate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of the edisylate salt of Compound 1.

[0092] In some embodiments, the present disclosure provides crystalline Form 1 of the edisylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 1. [Table 1-1] [Table 1-2]

[0093] In some embodiments, crystalline Form 1 of the edisylate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 1. In some embodiments, the crystalline form of the edisylate salt of Compound 1 is crystalline Form 1 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following degrees 2θ (±0.2°): 11.0°, 16.4°, 17.6°, 18.6°, 19.5°, 20.2°, 20.5°, 21.1°, 21.3°, 21.8°, 21.9°, 22.6°, 23.1°, and 38.8°. In another embodiment, the crystalline form of the edisylate salt of Compound 1 is crystalline Form 1 characterized by an XRPD pattern comprising peaks at the following degrees 2θ (±0.2°): 18.6°, 19.5°, 21.1°, and 21.8°.

[0094] In some embodiments, crystalline Form 1 of the edisylate salt of Compound 1 has a melting point of about 176° C. as determined by differential scanning calorimetry (DSC).

[0095] In some embodiments, crystalline Form 1 of the edisylate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0096] In some embodiments, crystalline Form 1 of the edisylate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0097] Crystalline form of the esylate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of an esylate salt of Compound 1.

[0098] In some embodiments, the present disclosure provides a crystalline form of the esylate salt of Compound 1 (Crystalline Form 2), characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 2. [Table 2-1] [Table 2-2]

[0099] In some embodiments, the crystalline form of the esylate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 2. In some embodiments, the crystalline form of the esylate salt of Compound 1 is crystalline Form 2, characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 8.1°, 16.1°, 17.4°, 19.1°, 19.4°, 19.9°, 20.7°, and 29.1°. In another embodiment, the crystalline form of the esylate salt of Compound 1 is crystalline Form 2, characterized by an XRPD pattern including peaks at the following 2θ degrees (±0.2°): 8.1°, 17.4°, and 19.1°.

[0100] In some embodiments, the crystalline form of the esylate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0101] In some embodiments, the crystalline form of the esylate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0102] Crystalline form of the glutarate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of the glutarate salt of Compound 1.

[0103] In some embodiments, the present disclosure provides crystalline Form 3 of the glutarate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 3. [Table 3-1] [Table 3-2]

[0104] In some embodiments, crystalline Form 3 of a glutarate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 3. In some embodiments, the crystalline form of a glutarate salt of Compound 1 is crystalline Form 3 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following degrees 2θ (±0.2°): 6.9°, 12.7°, 17.8°, 18.8°, 19.1°, 19.6°, 20.3°, 20.7°, 21.7°, 24.0°, 24.5°, 25.3°, 25.4°, and 28.8°. In another embodiment, the crystalline form of the glutarate salt of Compound 1 is crystalline Form 3, characterized by an XRPD pattern comprising peaks at the following degrees 2θ (±0.2°): 12.7°, 17.8°, 19.1°, 20.3°, and 20.7°.

[0105] In some embodiments, crystalline Form 3 of the glutarate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0106] In some embodiments, crystalline Form 3 of the glutarate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0107] Crystalline Form of the Napadisylate Salt of Compound 1 In some embodiments, the present disclosure provides a crystalline form of the napadisylate salt of Compound 1.

[0108] In some embodiments, the present disclosure provides a crystalline form of the napadisylate salt of Compound 1 (Crystalline Form 4), characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 4. [Table 4-1] [Table 4-2]

[0109] In some embodiments, the crystalline form of napadisylate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 4. In some embodiments, the crystalline form of napadisylate salt of Compound 1 is crystalline Form 4, characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 7.6°, 12.4°, 15.1°, 19.6°, 21.6°, 24.4°, 24.6°, and 25.0°. In another embodiment, the crystalline form of napadisylate salt of Compound 1 is crystalline Form 4, characterized by an XRPD spectrum including peaks at the following 2θ degrees (±0.2°): 7.6°, 12.4°, 15.1°, and 19.6°.

[0110] In some embodiments, the crystalline form of the napadisylate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0111] In some embodiments, the crystalline form of the napadisylate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0112] Crystalline form of napsylate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of the napsylate salt of Compound 1.

[0113] In some embodiments, the present disclosure provides a crystalline form of the napsylate salt of Compound 1 (Crystalline Form 5), characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 5. [Table 5-1] [Table 5-2]

[0114] In some embodiments, the crystalline form of the napsylate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 5. In some embodiments, the crystalline form of the napsylate salt of Compound 1 is crystalline Form 5, characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following degrees 2θ (±0.2°): 6.0°, 13.9°, 15.3°, 16.0°, 17.5°, 17.9°, 18.2°, 18.8°, 19.6°, 20.4°, 21.2°, 21.5°, 22.5°, 23.1°, and 27.2°. In another embodiment, the crystalline form of the napsylate salt of Compound 1 is crystalline Form 5, characterized by an XRPD pattern comprising peaks at the following degrees 2θ (±0.2°): 16.0°, 18.8°, 21.5°, 22.5°, and 23.1°.

[0115] In some embodiments, the crystalline form of the napsylate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0116] In some embodiments, the crystalline form of the napsylate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0117] Crystalline form of the orotate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of an orotate salt of Compound 1.

[0118] In some embodiments, the present disclosure provides crystalline Form 6 of an orotate salt of Compound 1, wherein the crystalline Form 6 is characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 6. [Table 6-1] [Table 6-2]

[0119] In some embodiments, crystalline Form 6 of orotate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 6. In some embodiments, the crystalline form of orotate salt of Compound 1 is crystalline Form 6 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following degrees 2θ (±0.2°): 10.9°, 16.6°, 16.9°, 17.1°, 17.6°, 18.9°, 19.1°, 19.7°, 20.1°, 22.0°, 22.4°, 23.0°, 23.1°, 24.8°, 25.2°, and 28.6°. In another embodiment, the crystalline form of the orotate salt of Compound 1 is crystalline Form 6, characterized by an XRPD pattern comprising peaks at the following degrees 2θ (±0.2°): 16.6°, 17.6°, 18.9°, 19.1°, 24.8°, 25.2°, and 28.6°.

[0120] In some embodiments, crystalline Form 6 of the orotate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0121] In some embodiments, crystalline Form 6 of the orotate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0122] Crystalline form of the maleate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of the maleate salt of Compound 1.

[0123] In some embodiments, the present disclosure provides crystalline Form 7 of the maleate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 7. [Table 7-1] [Table 7-2]

[0124] In some embodiments, crystalline Form 7 of the maleate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 7. In some embodiments, the crystalline form of the maleate salt of Compound 1 is crystalline Form 7 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following degrees 2θ (±0.2°): 5.3°, 10.6°, 12.1°, 14.7°, 17.0°, 17.8°, 19.6°, 21.3°, 21.6°, 22.2°, 23.3°, 23.7°, and 25.3°. In another embodiment, the crystalline form of the maleate salt of Compound 1 is crystalline Form 7, characterized by an XRPD pattern containing peaks at the following degrees 2θ (±0.2°): 5.3°, 14.7°, 19.6°, 21.6°, and 23.7°.

[0125] In some embodiments, crystalline Form 7 of the maleate salt of Compound 1 has a melting point of about 161° C. as determined by differential scanning calorimetry (DSC).

[0126] In some embodiments, crystalline Form 7 of the maleate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0127] In some embodiments, crystalline Form 7 of the maleate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0128] Crystalline form of the malonate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of the malonate salt of Compound 1.

[0129] In some embodiments, the present disclosure provides crystalline Form 8 of the malonate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 8. [Table 8-1] [Table 8-2]

[0130] In some embodiments, crystalline Form 8 of a malonate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 8. In some embodiments, the crystalline form of a malonate salt of Compound 1 is crystalline Form 8 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 5.5°, 12.2°, 14.6°, 16.4°, 18.1°, 18.3°, 19.9°, 20.3°, 22.6°, 24.0°, 24.4°, and 26.2°. In another embodiment, the crystalline form of a malonate salt of Compound 1 is crystalline Form 8 characterized by an XRPD pattern including peaks at the following 2θ degrees (±0.2°): 5.5°, 18.1°, 19.9°, and 24.4°.

[0131] In some embodiments, crystalline Form 8 of the malonate salt of Compound 1 has a melting point of about 161° C. as determined by differential scanning calorimetry (DSC).

[0132] In some embodiments, crystalline Form 8 of the malonate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0133] In some embodiments, crystalline Form 8 of the malonate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0134] Crystalline form of the mesylate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of the mesylate salt of Compound 1.

[0135] In some embodiments, the present disclosure provides crystalline Form 9 of the mesylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 9. [Table 9]

[0136] In some embodiments, crystalline Form 9 of the mesylate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 9. In some embodiments, the crystalline form of the mesylate salt of Compound 1 is crystalline Form 9 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 8.6°, 15.3°, 17.1°, 18.3°, 19.3°, 19.9°, 21.2°, 21.8°, and 23.1°. In another embodiment, the crystalline form of the mesylate salt of Compound 1 is crystalline Form 9 characterized by an XRPD pattern including peaks at the following 2θ degrees (±0.2°): 8.6°, 17.1°, 18.3°, and 21.2°.

[0137] In some embodiments, crystalline Form 9 of the mesylate salt of Compound 1 has a melting point of about 190° C. as determined by differential scanning calorimetry (DSC).

[0138] In some embodiments, crystalline Form 9 of the mesylate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0139] In some embodiments, crystalline Form 9 of the mesylate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0140] Crystalline Form of the Pamoate Salt of Compound 1 In some embodiments, the present disclosure provides a crystalline form of the pamoate salt of Compound 1.

[0141] In some embodiments, the present disclosure provides crystalline Form 10 of the pamoate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 10. [Table 10-1] [Table 10-2]

[0142] In some embodiments, crystalline Form 10 of the pamoate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 10. In some embodiments, the crystalline form of the pamoate salt of Compound 1 is crystalline Form 10 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following degrees 2θ (±0.2°): 5.9°, 11.2°, 11.7°, 14.1°, 17.6°, 18.8°, 19.6°, 20.1°, 20.6°, 21.0°, 22.7°, and 23.7°. In another embodiment, the crystalline form of the pamoate salt of Compound 1 is crystalline form 10, characterized by an XRPD pattern comprising peaks at the following degrees 2θ (±0.2°): 5.9°, 14.1°, 18.8°, 20.1°, 21.0°, and 23.7°.

[0143] In some embodiments, crystalline Form 10 of the pamoate salt of Compound 1 has a melting point of about 225° C. as determined by differential scanning calorimetry (DSC).

[0144] In some embodiments, crystalline Form 10 of the pamoate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0145] In some embodiments, crystalline Form 10 of the pamoate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0146] Crystalline form of the adipate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of the adipic acid salt of Compound 1.

[0147] In some embodiments, the present disclosure provides crystalline Form 11 of the adipic acid salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 11. [Table 11-1] [Table 11-2]

[0148] In some embodiments, crystalline Form 11 of an adipate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 11. In some embodiments, the crystalline form of an adipate salt of Compound 1 is crystalline Form 11 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at the following degrees 2θ (±0.2°): 6.8°, 13.7°, 18.4°, 18.6°, 19.7°, 20.6°, 20.8°, 21.1°, 21.2°, 21.5°, 22.3°, 22.9°, 24.2°, 25.6°, 25.9°, and 27.5°. In another embodiment, the crystalline form of the adipate salt of Compound 1 is crystalline Form 11, characterized by an XRPD pattern including peaks at the following degrees 2θ (±0.2°): 13.7°, 18.4°, 19.7°, 20.6°, 20.8°, and 22.9°.

[0149] In some embodiments, crystalline Form 11 of the adipic acid salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0150] In some embodiments, crystalline Form 11 of the adipic acid salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0151] Crystalline form of the besylate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of the besylate salt of Compound 1.

[0152] In some embodiments, the present disclosure provides crystalline Form 12 of the besylate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 12. [Table 12-1] [Table 12-2]

[0153] In some embodiments, crystalline form 12 of a besylate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 12. In some embodiments, the crystalline form of a besylate salt of Compound 1 is crystalline form 12 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 7.1°, 15.3°, 16.3°, 17.5°, 20.4°, 21.0°, 22.9°, and 24.5°. In another embodiment, the crystalline form of a besylate salt of Compound 1 is crystalline form 12 characterized by an XRPD pattern including peaks at the following 2θ degrees (±0.2°): 7.1°, 15.3°, 17.5°, and 20.4°.

[0154] In some embodiments, crystalline Form 12 of the besylate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0155] In some embodiments, crystalline Form 12 of the besylate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0156] Crystalline form of the cyclamate salt of compound 1 In some embodiments, the present disclosure provides a crystalline form of a cyclamate salt of Compound 1.

[0157] In some embodiments, the present disclosure provides crystalline Form 13 of the cyclamate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 13. [Table 13-1] [Table 13-2]

[0158] In some embodiments, crystalline Form 13 of cyclamate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 13. In some embodiments, the crystalline form of cyclamate salt of Compound 1 is crystalline Form 13 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 5.1°, 9.3°, 10.2°, 10.3°, 10.5°, 17.4°, 18.5°, 19.0°, 20.0°, 20.4°, 20.8°, 21.4°, 21.9°, 22.4°, and 25.6°. In another embodiment, the crystalline form of the cyclamate salt of Compound 1 is crystalline Form 13, characterized by an XRPD pattern comprising peaks at the following degrees 2θ (±0.2°): 5.1°, 10.2°, 17.4°, 20.8°, and 25.6°.

[0159] In some embodiments, crystalline Form 13 of the cyclamate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0160] In some embodiments, crystalline Form 13 of the cyclamate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0161] Crystalline form of the fumarate salt of Compound 1 In some embodiments, the present disclosure provides a crystalline form of the fumarate salt of Compound 1.

[0162] In some embodiments, the present disclosure provides crystalline Form 14 of the fumarate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 14. [Table 14-1] [Table 14-2]

[0163] In some embodiments, crystalline Form 14 of a fumarate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 14. In some embodiments, the crystalline form of a fumarate salt of Compound 1 is crystalline Form 14 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 10.3°, 16.5°, 18.0°, 18.3°, 18.5°, 20.0°, 20.2°, 20.7°, 22.5°, 24.1°, 24.3°, 25.4°, and 26.5°. In another embodiment, the crystalline form is crystalline Form 14 characterized by an XRPD pattern including peaks at the following 2θ degrees (±0.2°): 18.0°, 18.5°, 20.2°, and 22.5°.

[0164] In some embodiments, crystalline Form 14 of the fumarate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0165] In some embodiments, crystalline Form 14 of the fumarate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0166] Crystalline form of the glycolate salt of Compound 1 In some embodiments, the present disclosure provides a crystalline form of the glycolic acid salt of Compound 1.

[0167] In some embodiments, the present disclosure provides crystalline Form 15 of the glycolic acid salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 15. [Table 15-1] [Table 15-2]

[0168] In some embodiments, crystalline Form 15 of the glycolic acid salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 15. In some embodiments, the crystalline form of the glycolic acid salt of Compound 1 is crystalline Form 15 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following degrees 2θ (±0.2°): 10.6°, 12.2°, 17.3°, 17.7°, 19.2°, 20.4°, 20.7°, 22.1°, 22.4°, 22.9°, 23.3°, and 24.0°. In another embodiment, the crystalline form of the glycolic acid salt of Compound 1 is crystalline form 15, characterized by an XRPD pattern comprising peaks at the following degrees 2θ (±0.2°): 10.6°, 19.2°, 20.4°, 20.7°, and 24.0°.

[0169] In some embodiments, crystalline Form 15 of the glycolic acid salt of Compound 1 is at least about 60% by weight in a single crystalline form, at least about 70% by weight in a single crystalline form, at least about 80% by weight in a single crystalline form, at least about 90% by weight in a single crystalline form, at least about 95% by weight in a single crystalline form, or at least about 99% by weight in a single crystalline form.

[0170] In some embodiments, crystalline Form 15 of the glycolic acid salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0171] Crystalline form of the oxalate salt of Compound 1 In some embodiments, the present disclosure provides a crystalline form of the oxalate salt of Compound 1.

[0172] In some embodiments, the present disclosure provides crystalline Form 16 of the oxalate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 16. [Table 16-1] [Table 16-2]

[0173] In some embodiments, crystalline Form 16 of the oxalate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 16. In some embodiments, the crystalline form of the oxalate salt of Compound 1 is crystalline Form 16 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 5.7°, 10.5°, 17.0°, 18.5°, 20.3°, 20.6°, 22.7°, and 24.8°. In another embodiment, the crystalline form of the oxalate salt of Compound 1 is crystalline Form 16 characterized by an XRPD pattern including peaks at the following 2θ degrees (±0.2°): 5.7°, 17.0°, and 24.8°.

[0174] In some embodiments, crystalline Form 16 of the oxalate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0175] In some embodiments, crystalline Form 16 of the oxalate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0176] Crystalline form of the phosphate salt of Compound 1 In some embodiments, the present disclosure provides a crystalline form of the phosphate salt of Compound 1.

[0177] In some embodiments, the present disclosure provides crystalline Form 17 of the phosphate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 17. [Table 17-1] [Table 17-2]

[0178] In some embodiments, crystalline form 17 of a phosphate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 17. In some embodiments, the crystalline form of a phosphate salt of Compound 1 is crystalline form 17 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 5.7°, 7.1°, 18.1°, 18.8°, 19.0°, 20.5°, 21.2°, 21.8°, 22.9°, 23.1°, 25.3°, and 26.2°. In another embodiment, the crystalline form of a phosphate salt of Compound 1 is crystalline form 17 characterized by an XRPD pattern including peaks at the following 2θ degrees (±0.2°): 18.1°, 18.8°, 21.2°, and 21.8°.

[0179] In some embodiments, crystalline Form 17 of the phosphate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0180] In some embodiments, crystalline Form 17 of the phosphate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0181] Crystalline form of the sebacate salt of Compound 1 In some embodiments, the present disclosure provides a crystalline form of the sebacate salt of Compound 1.

[0182] In some embodiments, the present disclosure provides crystalline Form 18 of the sebacate salt of Compound 1, characterized by an X-ray powder diffraction pattern (XRPD pattern) including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks, at diffraction angles (°2θ) selected from the group of peaks listed in Table 18. [Table 18-1] [Table 18-2]

[0183] In some embodiments, crystalline Form 18 of the sebacate salt of Compound 1 is characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 18. In some embodiments, the crystalline form of the sebacate salt of Compound 1 is crystalline Form 18 characterized by an XRPD pattern including at least one peak, e.g., at least two peaks, at least three peaks, at least four peaks, or at least five or more peaks at the following 2θ degrees (±0.2°): 8.2°, 11.9°, 16.4°, 19.6°, 19.8°, 20.5°, 21.3°, 21.6°, 22.1°, and 24.2°. In another embodiment, the crystalline form of the sebacate salt of Compound 1 is crystalline Form 18 characterized by an XRPD pattern including peaks at the following 2θ degrees (±0.2°): 16.4°, 19.8°, 20.5°, 21.6°, and 22.1°.

[0184] In some embodiments, crystalline Form 18 of the sebacate salt of Compound 1 is at least about 60% by weight in single crystalline form, at least about 70% by weight in single crystalline form, at least about 80% by weight in single crystalline form, at least about 90% by weight in single crystalline form, at least about 95% by weight in single crystalline form, or at least about 99% by weight in single crystalline form.

[0185] In some embodiments, crystalline Form 18 of the sebacate salt of Compound 1 is substantially free of amorphous forms of Compound 1.

[0186] Compositions Comprising Salts and Crystalline Forms of Compound 1 The present disclosure also provides pharmaceutical compositions comprising the salts and crystalline salt forms of Compound 1 provided by the present disclosure. The amount of the salt or crystalline salt form of Compound 1 in the provided compositions is an amount that allows Compound 1 to act as an effective T-type calcium channel blocker. For example, the amount of the salt or crystalline salt form of Compound 1 in the pharmaceutical composition is an amount that is effective for treating, for example, neurological disorders, psychiatric disorders, generalized epilepsy syndromes, or tremors, including essential tremor.

[0187] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. Generally, such methods include bringing into association a salt or crystalline salt form of Compound 1 provided by the present disclosure with the carrier and / or one or more other accessory ingredients, and then, as necessary and / or desired, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0188] Pharmaceutically acceptable carriers used in the preparation of the provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. For example, carriers such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may be present in the compositions.

[0189] Examples of diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and mixtures thereof.

[0190] Examples of granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water-insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0191] Examples of surfactants and emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters, and the like. sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monolaurate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene sorbitan monolaurate (Tween 80 ... Polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate,Examples include sodium lauryl sulfate, Pluronic® F-68, Poloxamer-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0192] Examples of binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of psyllium (isapol husks), carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabinogalactan, alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0193] Examples of preservatives include antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0194] Examples of antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0195] Examples of chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Examples of antibacterial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0196] Examples of antifungal preservatives include butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0197] Examples of alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethyl alcohol.

[0198] Examples of acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0199] Other preservatives include tocopherol, tocopheryl acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0200] Examples of buffering agents include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, hydroxyapatite, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0201] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, sodium stearyl fumarate, and mixtures thereof.

[0202] Examples of natural oils include almond oil, apricot kernel oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, borage oil, juniper tar oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter oil, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate oil, jojoba oil, kukui seed oil, lavandin oil, lavender oil, and lemon oil. These include mon oil, lily of the valley oil, macadamia nut oil, mallow oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange roughy oil, palm oil, palm kernel oil, peach kernel oil, peanut oil, poppy oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, sasquana oil, savory oil, sea buckthorn oil, sesame oil, shea butter oil, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and wheat germ oil. Examples of synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, caprylic triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0203] The pharmaceutical compositions provided herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, transmucosally, or in ophthalmic preparations. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In one embodiment, the pharmaceutical compositions provided herein are orally administered in an orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants, such as magnesium stearate, are also often added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

[0204] The amount of salt or crystalline salt form of Compound 1 combined with the carrier materials to produce a composition in a single dosage form will vary depending on the subject being treated and the mode of administration. For example, the specific dosage and treatment regimen for a subject will depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combinations, the judgment of the treating physician, and the severity of the particular disease being treated. In one embodiment, pharmaceutical compositions may be formulated so that a dosage equivalent to about 0.001 to about 100 mg / kg body weight / day of a salt or crystalline salt form of Compound 1 (e.g., about 0.5 to about 100 mg / kg of Compound 1) can be administered to a subject receiving these compositions. Alternatively, dosages equivalent to 1 mg / kg to 1000 mg / kg of Compound 1 every 4 to 120 hours are also acceptable. As used herein, "dose" refers to the amount of a salt or crystalline salt form of Compound 1 provided by the present disclosure.

[0205] In some embodiments, a salt or crystalline salt form of Compound 1 provided by the present disclosure is formulated for administration at a dose equivalent to about 2 mg to about 3000 mg of Compound 1, e.g., about 5 mg to about 350 mg, about 5 mg to about 200 mg, about 5 mg to about 100 mg, or about 20 mg to about 40 mg of Compound 1. In certain embodiments, a salt or crystalline salt form of Compound 1 is formulated for administration at a dose equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg of Compound 1.

[0206] In some embodiments, a salt or crystalline salt form of Compound 1 provided by the present disclosure is formulated for administration at a dose equivalent to about 2 mg to about 3000 mg of Compound 1 per day, e.g., about 5 mg to about 500 mg, about 5 mg to about 200 mg, or about 20 mg to about 40 mg of Compound 1 per day. In some embodiments, a salt or crystalline salt form of Compound 1 provided by the present disclosure is formulated for administration at a dose equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1 per day. In some embodiments, a salt or crystalline salt form of Compound 1 provided by the present disclosure may be administered once daily. In other embodiments, a salt or crystalline salt form of Compound 1 provided by the present disclosure may be administered twice daily. In yet other embodiments, a salt or crystalline salt form of Compound 1 provided by the present disclosure may be administered once every other day.

[0207] In some embodiments, the methods of the present disclosure include administering to a subject in need thereof a set dose of a salt or crystalline form of Compound 1 provided by the present disclosure. In some embodiments, the maximum set dose is 60 mg per day or 100 mg per day. In one embodiment, the maximum set dose is 60 mg per day.

[0208] In some embodiments, a salt or crystalline salt form of Compound 1 provided by the present disclosure may be formulated as a tablet composition with a pharmaceutically acceptable carrier. Suitable carriers for use in tablet compositions may be selected from one or more of microcrystalline cellulose, mannitol, croscarmellose sodium, and sodium stearyl fumarate. For example, in some embodiments, the carrier may be microcrystalline cellulose, which may be present in the tablet composition in an amount of about 40% w / w to about 80% w / w, e.g., about 50% w / w to about 70% w / w, or about 55% w / w to about 65% w / w. In some embodiments, the carrier may be mannitol, which may be present in the tablet composition in an amount of 20% w / w to about 45% w / w, e.g., about 20% w / w to about 30% w / w. In some embodiments, the carrier may be croscarmellose sodium, which may be present in an amount of about 1% w / w to about 5% w / w. In some embodiments, the carrier may be stearyl fumarate, which may be present in the tablet composition in an amount of, for example, from about 1% w / w to about 5% w / w.

[0209] In some embodiments, the salt or crystalline salt form of Compound 1 provided by the present disclosure may be present in the tablet composition in an amount equivalent to about 1 mg to about 150 mg of Compound 1, e.g., about 1 mg to about 100 mg, about 5 mg to about 50 mg, or about 20 mg to about 40 mg of Compound 1.

[0210] In one aspect, the pharmaceutical composition provided by the present disclosure comprises a single unit dosage form comprising a salt or crystalline salt form of Compound 1. In certain embodiments, the single unit dosage form comprises up to 200 mg of a salt or crystalline salt form of Compound 1. In some embodiments, the single unit dosage form comprises a length of up to 16 mm, e.g., from about 14 mm to about 16 mm, and / or a width of up to 7 mm, e.g., from about 5 mm to about 7 mm. In some embodiments, the single unit dosage form is bioequivalent to a reference composition of the same dosage strength administered as multiple dosage forms, such as modified release (MR) formulations comprising Compound 1 available as round, small-sized (e.g., about 6 mm in diameter), 5 mg and 20 mg tablets. In some embodiments, bioequivalence may be established by (a) a 90% confidence interval for AUC of about 80% to about 125%, and (b) a 90% confidence interval for C of about 80% to about 125%.

[0211] In some embodiments, the methods of the disclosure comprise administering to a subject in need thereof a single unit dosage form comprising a salt or crystalline salt form of Compound 1, wherein the composition is bioequivalent to a reference composition of the same dosage strength administered as multiple smaller, circular tablets.

[0212] In some embodiments, pharmaceutical compositions provided by the present disclosure may be administered to a subject once a day, or multiple times a day (e.g., twice a day, three times a day, or four times a day).

[0213] Modified-Release Dosage Forms and Compositions In some embodiments, the present disclosure also provides a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1 and an excipient that functions to modify the release rate of Compound 1. In some embodiments, the pharmaceutical composition may be a swellable core technology formulation.

[0214] The compositions of the present disclosure may include a salt or crystalline salt form of Compound 1 and a release-modifying polymer. As used herein, the term "release-modifying polymer" refers to any polymer that, when added to a composition containing a salt or crystalline salt form of Compound 1, modifies the release rate of Compound 1. The release-modifying polymer may be a hydrophilic polymer, such as a hydroxypropylmethylcellulose (HPMC) polymer, a hydrophobic polymer, such as ethylcellulose or ethocell, or a polyacrylate polymer, such as Eudragit RL100 or Eudragit RS100. In some embodiments, the release-modifying polymer is present in the composition in an amount sufficient to modify the release rate of Compound 1. In some embodiments, the composition is for oral administration.

[0215] In some embodiments, the compositions of the present disclosure comprise a modified release polymer and about 0.9% to about 40% by weight (e.g., about 0.9% to about 30% by weight, about 1% to about 25% by weight, about 2% to about 25% by weight, about 3% to about 20% by weight, about 4% to about 20% by weight, about 5% to about 20% by weight, about 5% to about 15% by weight, about 5% to about 10% by weight, or about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6% by weight, or about 10% by weight. The salt or crystalline salt form of Compound 1 may comprise about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, or about 40% by weight of a salt or crystalline salt form of Compound 1.

[0216] In some embodiments, the compositions of the present disclosure may include a modified release polymer and a salt or crystalline salt form of Compound 1 in an amount of about 1 mg to about 40 mg, e.g., about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, or about 40 mg.

[0217] In some embodiments, the composition comprises about 55 mg to about 65 mg of a release-modifying polymer (e.g., an HPMC polymer), hi some embodiments, the composition comprises about 10% to about 70% by weight, e.g., about 50% to about 60% by weight, of a release-modifying polymer (e.g., an HPMC polymer).

[0218] In some embodiments, the composition may further comprise a diluent, such as microcrystalline cellulose. In other embodiments, the composition may comprise microcrystalline cellulose in an amount of about 15 mg to about 40 mg, e.g., about 15 mg to about 25 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, or about 30 mg to about 40 mg. In some embodiments, the composition may comprise microcrystalline cellulose in an amount of about 15% to about 35% by weight, e.g., about 15% to about 20% by weight, about 20% to about 25% by weight, 25% to about 30% by weight, or 30% to about 35% by weight.

[0219] In some embodiments, the composition may further comprise a glidant, such as colloidal silicon dioxide. In some embodiments, the composition may further comprise a lubricant, such as magnesium stearate. In some embodiments, the composition may further comprise a coating.

[0220] In some embodiments, the composition may be administered to a patient once daily or twice daily. In some embodiments, the composition may be in the form of a tablet, capsule, or suspension. In one embodiment, the composition is in the form of a tablet.

[0221] Methods of Treatment Using Salts or Crystalline Salt Forms of Compound 1 The present disclosure also provides a method for treating a disease, disorder, or condition associated with T-type calcium channel function. The method comprises administering to a subject in need thereof an effective amount of a salt or crystalline salt form of Compound 1 described herein, or an effective amount of a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. The ability of Compound 1 to modulate T-type calcium channels is described, for example, at least in WO2021 / 007487, the entire contents of which are incorporated herein by reference.

[0222] In some embodiments, the disclosure provides a method of treating a neurological disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a salt or crystalline salt form of Compound 1 described herein, or an effective amount of a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the subject has a mutation in one or both of the T-type calcium channel genes CACNA1H and CACNA1G. In some embodiments, the neurological disorder is epilepsy. In some embodiments, the epilepsy is juvenile epilepsy. In some embodiments, the epilepsy is genetic epilepsy. In some embodiments, the neurological disorder is absence seizures. In some embodiments, the neurological disorder is pain (e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain, thalamic pain, or migraine). In some embodiments, the neurological disorder is tremor (e.g., essential tremor or Parkinson's tremor). In some embodiments, the neurological disorder is ataxia (e.g., spinocerebellar ataxia or spinocerebellar ataxia with CACNA1G mutation). In some embodiments, the neurological disorder is tinnitus. In certain embodiments, the neurological disorder is arousal disorder.

[0223] In some embodiments, a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, is effective for treating tremor (e.g., essential tremor). In some embodiments, a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, is effective for treating epilepsy or epileptic syndromes, for example, absence seizures, juvenile myoclonic epilepsy, status epilepticus, or genetic epilepsy. A salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, can also modulate all T-type calcium channels, for example, Cav3.1, Cav3.2, and / or Cav3.3. In some embodiments, a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, is effective for treating psychiatric disorders, for example, mood disorders, for example, major depressive disorder.

[0224] In some embodiments, the present disclosure also provides a method of treating a psychiatric disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the psychiatric disorder is a mood disorder. In some embodiments, the mood disorder is major depressive disorder.

[0225] Epilepsy and epilepsy syndromes The salt or crystalline salt form of Compound 1 described herein, or pharmaceutical compositions comprising the salt or crystalline salt form of Compound 1, can be useful for treating epilepsy and epilepsy syndrome.Epilepsy is a CNS disorder in which the activity of nerve cells in the brain is disturbed, causing seizures, which can manifest as abnormal movements, unusual behavior, sensations, and sometimes periods of loss of consciousness.The symptoms of epileptic seizures vary greatly, from a simple blank stare for a few seconds to repeated jerks of arms or legs during epileptic seizures.

[0226] Epilepsy can include generalized seizures or partial or focal seizures. All areas of the brain are involved in generalized seizures. A person experiencing a generalized seizure may scream or make some noise, stiffen for a few seconds to a minute, and then have rhythmic movements of the arms and legs. The eyes are typically open, and the person may not appear to be breathing and may actually turn blue. Consciousness gradually returns, and the person may be confused for several minutes to several hours. The main types of generalized epileptic seizures are: tonic-clonic seizures, tonic-clonic seizures, myoclonic seizures, myoclonic-tonic-clonic seizures, myoclonic-atonic seizures, atonic seizures, and absence (typical, atypical, myoclonic, lid myoclonic) seizures, as well as epileptic spasms. Partial or focal seizures involve only part of the brain, and therefore affect only part of the body. Symptoms can vary, depending on the part of the brain that has abnormal electrical activity.

[0227] Epilepsy as described herein includes generalized, partial, complex partial (e.g., seizures involving only part of the brain but with impaired consciousness), tonic-clonic, clonic, tonic, refractory seizures, status epilepticus, absence seizures, febrile seizures, or temporal lobe epilepsy.

[0228] The salt or crystalline salt form of Compound 1 described herein, or pharmaceutical compositions comprising the salt or crystalline salt form of Compound 1, can also be useful for treating epilepsy syndromes.Severe syndromes accompanied by diffuse brain dysfunction, at least partially caused by some forms of epilepsy, are also called epileptic encephalopathy.These are associated with frequent seizures that are resistant to treatment, and severe cognitive impairment, such as West syndrome.

[0229] In some embodiments, the epilepsy syndrome comprises epileptic encephalopathy, Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile spasms, West syndrome, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency. In some embodiments, the epilepsy syndrome is childhood absence epilepsy (CAE). In some embodiments, the epilepsy syndrome is juvenile absence epilepsy (JAE). In some embodiments, the epilepsy syndrome is Lennox-Gastaut syndrome. In some embodiments, the epilepsy syndrome is SLC6A1 epileptic encephalopathy. In some embodiments, the epilepsy syndrome is associated with mutations in genes encoding T-type calcium channels (e.g., CACNA1G, EEF1A2, and GABRG2 for genetic generalized epilepsy (GGE), and LGI1, TRIM3, and GABRG2 for non-acquired focal epilepsy (NAFE)). In some embodiments, the epilepsy syndrome is Doze syndrome or myoclonic-astatic epilepsy. In some embodiments, the epilepsy syndrome is epileptic encephalopathy with continuous spike and wave sleep (CSWS). In some embodiments, the epilepsy syndrome is Landau-Kleffner syndrome (LKS). In some embodiments, the epilepsy syndrome is Jeavons syndrome.

[0230] absence seizures Absence seizures are one of the most common seizure types in patients with idiopathic generalized epilepsy (IGE). Absence seizures are relatively brief, nonconvulsive seizures characterized by the sudden onset of loss of consciousness and responsiveness, usually lasting 10–30 seconds, followed by a rapid return to normal consciousness without postictal confusion. Seizures are characterized by the sudden onset and disappearance of generalized 1–6 Hz (e.g., 3 Hz) spike-wave discharges on accompanying EEG recordings. Absence seizures often occur multiple times per day, disrupting learning and psychosocial functioning and presenting a risk of injury due to the frequent episodes of loss of consciousness. Absence seizures typically begin in early childhood and resolve by the late teens. However, in a minority of patients, they persist into adulthood, often becoming drug-resistant, and may be accompanied by other seizure types, such as generalized tonic-clonic seizures. In these adult patients, absence seizures, in particular, are usually highly disabling and are associated with significant psychosocial impairment, as the accompanying periods during which the affected individual is unconscious pose a safety risk and disqualify them from obtaining a driver's license or pursuing occupations and hobbies.

[0231] Although absence seizures are generally perceived as relatively "easy" to treat, randomized controlled trials in patients with childhood absence epilepsy showed that even the most effective antiepileptic drugs, ethosuximide and valproate, completely controlled seizures in only 53% and 58% of patients, respectively, at 16 weeks and in 45% and 44% of patients, respectively, at 12 months, as assessed by video-EEG recording. Another commonly used AED, lamotrigine, controlled seizures in only 29% of patients at 16 weeks and 21% at 12 months. Furthermore, both ethosuximide and valproate are commonly associated with intolerable side effects (occurring in 24% of patients treated with either of these medications), and the latter is now generally considered contraindicated in girls and women of childbearing age. Other treatment options for absence seizures are limited; only benzodiazepines have established efficacy, and these are generally poorly tolerated due to sedative and cognitive side effects. Absence seizures that persist into adulthood are particularly difficult to treat, and patients are often treated with multiple medications, resulting in significant side effects, without achieving seizure control.

[0232] A large body of evidence indicates that low-threshold (T-type) calcium channels play a key role in the generation and maintenance of absence seizures and are a key component of the oscillatory burst firing that occurs in thalamocortical neurons during absence seizures. In some embodiments, the present disclosure provides a method for treating absence seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the absence seizures are refractory absence seizures. In some embodiments, the absence seizures are refractory to antiepileptic drugs (e.g., ethosuximide, valproic acid, or lamotrigine).

[0233] In some embodiments, the subject has epilepsy. In some embodiments, the absence seizures are atypical absence seizures. In some embodiments, the absence seizures include adult absence seizures, juvenile absence seizures, or childhood absence seizures.

[0234] In some embodiments, the methods described herein further comprise identifying a subject having absence seizures.

[0235] In some embodiments, the present disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the method reduces the number of seizures.

[0236] In some embodiments, the present disclosure provides a method for treating generalized epilepsy syndrome with absence seizures in a subject in need thereof, the method comprising administering to the subject an effective amount of a salt or crystalline salt form of Compound 1, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, as described herein.

[0237] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce the mean or total seizure duration.

[0238] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce seizure frequency, duration, or both as measured by electroencephalogram (EEG).

[0239] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce the mean seizure duration as measured by EEG.

[0240] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce cumulative seizure duration as measured by EEG.

[0241] In some embodiments, the methods of treating generalized epilepsy with absence seizures provided by the present disclosure reduce hyperventilation and the total time with 2.5-4 Hz spike-and-wave discharges following photic stimulation, as measured by EEG.

[0242] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce overall severity as measured by the Clinical Global Impression-Severity (CGI-S) or Clinical Global Impression-Improvement (CGI-I) score. The CGI-S is a 7-point scale test that assesses the severity of a patient's illness at the time of evaluation compared to a clinician's past experience with patients with the same diagnosis. The CGI-I is a 7-point scale test that assesses improvement in a patient's illness compared to baseline.

[0243] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce the number of seizures.

[0244] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce seizure density as measured by electroencephalogram (EEG).

[0245] In some embodiments, the methods of treating generalized epilepsy syndrome with absence seizures provided by the present disclosure reduce the mean seizure duration as measured by EEG.

[0246] Hereditary epilepsy In some embodiments, the present disclosure provides a method of treating epilepsy or an epilepsy syndrome in a subject in need thereof, the method comprising administering to the subject an effective amount of a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1.

[0247] In some embodiments, the epilepsy or epilepsy syndrome is a genetic epilepsy or a genetic epilepsy syndrome. In some embodiments, the epilepsy or epilepsy syndrome is a genetic generalized epilepsy. In some embodiments, the epilepsy or epilepsy syndrome comprises epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory childhood epilepsy with generalized tonic-clonic seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0248] In some embodiments, the methods described herein include administering a salt or crystalline salt form of Compound 1, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, as described herein, to a patient suffering from epilepsy or an epileptic syndrome (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, refractory generalized tonic-clonic seizures). In some embodiments, the method further includes identifying a subject with a condition, such as a pediatric epilepsy, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with an SCN3A mutation, cryptogenic childhood partial epilepsy with an SCN3A mutation, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0249] In one aspect, the disclosure provides a method for treating epilepsy or epilepsy syndromes (e.g., epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutations, generalized epilepsy with febrile convulsions, generalized tonic-clonic syndrome), comprising administering to a subject in need thereof an effective amount of a salt or crystalline salt form of Compound 1, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, as described herein. Provided are methods for treating intractable childhood epilepsy with seizures, infantile spasms, benign familial neonatal-infantile seizures, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutations, cryptogenic childhood partial epilepsy with SCN3A mutations, SCN8A epileptic encephalopathy, Rasmussen's encephalitis, malignant focal moving partial seizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, and KCNT1 epileptic encephalopathy.

[0250] A salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, may be used to treat epileptic encephalopathy in a subject in need thereof, wherein the subject is also taking one of the following drugs: ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KC Mutations in one or more of NB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0251] In some embodiments, the methods described herein include administering to a subject a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, the method comprising administering to a subject ... The method further includes identifying the subject having a mutation in one or more of KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, WWOX, CACNA1G, CACNA1H, and CACNA1I.

[0252] A salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, may be used to treat epileptic encephalopathy in a subject in need thereof, wherein the subject is taking any of the following drugs: ADSL, ALDH5A1, ALDH7A1, ALG13, ARG1, ARHGEF9, ARX, ATP1A2, ATP1A3, ATRX, BRAT1, C12orf57, CACNA1A, CACNA2D2, CARS2, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLCN4, CLN2 (TPP1), CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, F RRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD 1C, KANSL1, KCNA2, KCNB1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NED D4L, NEXMIF, NGLY1, NHLRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QAR S, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SL C2A1, SLC35A2, SLC6A1, SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24,Mutations in one or more of TCF4, TPK1, TSC1, TSC2, UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0253] In some embodiments, the methods described herein include administering to a subject a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, the salt or crystalline salt form of which is a soluble or insoluble component ... N6, CLN8, CNTNAP2, CSTB, CTSD, DDC, DEPDC5, DNAJC5, DNM1, DOCK7, DYRK1A, EEF1A2, EFHC1, EHMT1, EPM2A, FARS2, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1 , GABRB2, GABRB3, GABRG2, GAMT, GATM, GLRA1, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, HNRNPU, IER3IP1, IQSEC2, ITPA, JMJD1C, KANSL1, KCNA2, KCN B1, KCNC1, KCNH2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, LIAS, MBD5, MECP2, MEF2C, MFSD8, MOCS1, MOCS2, MTOR, NEDD4L, NEXMIF, NGLY1, NH LRC1, NPRL3, NRXN1, PACS1, PCDH19, PIGA, PIGN, PIGO, PLCB1, PNKD, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRIMA1, PRRT2, PURA, QARS, RELN, ROGDI, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN8A, SCN9A, SERPINI1, SGCE, SIK1, SLC12A5, SLC13A5, SLC19A3, SLC25A12, SLC25A22, SLC2A1, SLC35A2, SLC6A1 , SLC6A8, SLC9A6, SMC1A, SNX27, SPATA5, SPTAN1, ST3GAL5, STRADA, STX1B, STXBP1, SUOX, SYN1, SYNGAP1, SYNJ1, SZT2, TBC1D24, TCF4, TPK1, TSC1, TSC2,The method further includes identifying subjects with a mutation in one or more of UBE3A, WDR45, WWOX, ZDHHC9, ZEB2, ABAT, ARHGEF15, ATP6AP2, CACNA1H, CACNB4, CASR, CERS1, CNTN2, CPA6, DIAPH1, FASN, GABRD, GAL, GPHN, KCNA1, KCND2, KCNH5, KPNA7, LMNB2, NECAP1, PIGG, PIGQ, PIK3AP1, PRDM8, PRICKLE2, RBFOX1, RBFOX3, RYR3, SCN5A, SETD2, SLC35A3, SNAP25, SRPX2, ST3GAL3, TBL1XR1, AMT, GCSH, GLDC, FLNA, PTEN, and RANBP2.

[0254] A salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, may be used to treat epileptic encephalopathy in a subject in need thereof, wherein the subject is taking any of the following drugs: ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A , EEF1A2, EHMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, K CNH1, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, ME CP2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3.NR2F1, NRXN1, PACS1, PCDH19, PIGA Mutations in one or more of PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0255] In some embodiments, the methods described herein include administering to a patient a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, prior to administration of the salt or crystalline salt form of Compound 1 described herein, ADSL, ALDH5A1, ALDH7A1, ALG13, ARHGEF9, ARX, ASNS, ATP1A2, ATP1A3, ATP6AP2, ATRX, BRAT1, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNA7, CHRNB2, CLCN4, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CSTB, CTNNB1, CTSD(CLN10), CTSF, DDX3X, DEPDC5, DNAJC5(CLN4B), DNM1, DYRK1A, EEF1A2, E HMT1, EPM2A, FLNA, FOLR1, FOXG1, FRRS1L, GABBR2, GABRA1, GABRB2, GABRB3, GABRG2, GAMT, GATM, GLDC, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HNRNPU, IQSEC2, KANSL1, KCNA2, KCNB1, KCNC1, KCNH1 , KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7(CLN14), KDM6A, KIAA2022, LGI1, MAGI2, MBD5, MECP 2, MEF2C, MFSD8(CLN7), NALCN, NGLY1, NHLRC1(EPM2B), NPRL3.NR2F1, NRXN1, PACS1, PCDH19, PIGA The method further includes identifying subjects with a mutation in one or more of PIGO, PIGV, PLCB1, PNKP, PNPO, POLG, PPP2R5D, PPT1(CLN1), PRRT2, PURA, QARS, SATB2, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SLC13A5, SLC19A3, SLC25A22, SLC2A1, SLC6A1, SLC6A8, SLC9A6, SMC1A, SPATA5, SPTAN1, STX1B, STXBP1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1(CLN2), TSC1, TSC2, UBE3A, WDR45, WWOX, and ZEB2.

[0256] A salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, may be used to treat epileptic encephalopathy in a subject in need thereof, wherein the subject is taking any of the following drugs: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HN RNPU, IQSEC2, KCNA2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC 1, NRXN1, PCDH19, PIGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SC Mutations in one or more of N8A, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0257] In some embodiments, the methods described herein include administering a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, to a patient receiving one or more of the following: ALDH7A1, ARHGEF9, ARX, ATP13A2, ATP1A2, CACNA1A, CASK, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, CRH, CSTB, CTSD, CTSF, DCX, DEPDC5, DNAJC5, DNM1, DYNC1H1, DYRK1A, EEF1A2, EPM2A, FLNA, FOLR1, FOXG1, GABRA1, GABRB3, GABRG2, GAMT, GATM, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, IQSEC2, KCNA 2, KCNC1, KCNJ10, KCNQ2, KCNQ3, KCNT1, KCTD7, KIAA2022, LGI1, MECP2, MEF2C, MFSD8, NHLRC1, NRXN1, PCDH19, P IGA, PLCB1, PNKP, PNPO, POLG, PPT1, PRICKLE1, PRRT2, PURA, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SIK1, SLC13A 5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SLC9A6, SMC1A, SNAP25, SPTAN1, ST3GAL3, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, TBL1XR1, TCF4, TPP1, TSC1, TSC2, UBE3A, WDR45, and ZEB2.

[0258] Mood disorders In some embodiments, the present disclosure also provides a method for treating a psychiatric disorder, comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the psychiatric disorder can be a mood disorder, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, catatonic depression, seasonal affective disorder, dysthymia, dual depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. The method comprises administering to the subject an effective amount of a salt or crystalline salt form of Compound 1 described herein, or an effective amount of a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the methods described herein provide a therapeutic effect to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0259] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression also experience sleep disturbances, weight loss, and generally agitated and irritable feelings. Clinical depression affects the way an individual feels, thinks, and behaves and can lead to a variety of emotional and physical problems. Individuals with clinical depression may struggle to perform everyday activities and feel that life is not worth living.

[0260] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, difficulty sleeping, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, emotional withdrawal from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0261] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that affects women after birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased sexual desire, crying episodes, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0262] In some embodiments, the subject with PND also experiences depression or depressive symptoms during pregnancy.This depression is herein referred to as perinatal depression.In embodiments, the subject who experiences perinatal depression is at increased risk of experiencing PND.

[0263] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and positivity, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or drowsiness (hypersomnia), a feeling of heaviness in the legs, and significant social impairment as a result of hypersensitivity to perceived interpersonal rejection.

[0264] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), failure to respond to pleasurable stimuli, depressed mood that is more prominent than sadness or loss, excessive weight loss, or excessive guilt.

[0265] Psychotic major depression (PMD) or psychotic depression refers specifically to a major depressive episode of a melancholic nature in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0266] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. The individual may become silent and stuporous, immobile, or exhibit purposeless or bizarre movements.

[0267] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that fall in the fall or winter.

[0268] Dysthymia refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. These tend to be less severe but last longer (e.g., at least two years).

[0269] Dual depression refers to a significant depressed mood (dysthymia) lasting for at least two years and interrupted by periods of major depression.

[0270] Depressive personality disorder (DPD) refers to a personality disorder that has depressive traits.

[0271] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes about once a month, each lasting less than two weeks, typically less than two to three days.

[0272] Minor depressive disorder or mild depression refers to depression in which at least two symptoms are present for two weeks.

[0273] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may feel or behave unusually happy, energetic, or irritable. They often make decisions with little consideration for the consequences. The need for sleep is usually reduced. During depressive periods, individuals may cry, make little eye contact with others, and have a negative outlook on life. The risk of suicide in those with the disorder is high at over 6% over a 20-year period, while self-harm occurs in 30-40% of cases. Other mental health problems, such as anxiety disorders and substance use disorders, are commonly associated with bipolar disorder.

[0274] Depression caused by a chronic medical condition refers to depression caused by a chronic medical condition such as cancer or chronic pain, chemotherapy, or chronic stress.

[0275] Treatment-resistant depression refers to the state that individuals are treated for depression, but symptoms do not improve.For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression.In some cases, individuals with treatment-resistant depression improve their symptoms, but then relapse.Treatment-resistant depression occurs in patients with depression that is resistant to standard pharmacological treatment, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics, and non-pharmacological treatment (for example, psychotherapy, electroconvulsive therapy, vagus nerve stimulation and / or transcranial magnetic stimulation).

[0276] Postoperative depression refers to feelings of depression after a surgical procedure (e.g., as a result of having to face death). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in normally enjoyable hobbies and activities, or persistent feelings of worthlessness or despair.

[0277] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (e.g., depression) that is associated with (e.g., caused by) a women's health condition or disorder (e.g., as described herein).

[0278] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation relates to thoughts about suicide or an abnormal preoccupation with suicide. The spectrum of suicidal ideation varies widely, from fleeting thoughts to extensive thinking, detailed plans, role-playing, and abortive attempts. Symptoms include talking about suicide, obtaining the means to commit suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless in the situation, increased alcohol or drug use, doing risky or self-destructive things, and saying goodbye to people as if they will never see each other again.

[0279] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty exercising, loss of interest in enjoyable activities or hobbies, loss of concentration, loss of energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts.The presence, severity, frequency, and duration of symptoms may vary depending on each individual case.Depression symptoms and their alleviation can be confirmed by a doctor or psychologist (for example, by mental status examination).

[0280] In some embodiments, the mood disorder is selected from depression, major depressive disorder, bipolar disorder, dysthymic disorder, anxiety disorder, stress, post-traumatic stress disorder, bipolar disorder, and obsessive-compulsive disorder. In some embodiments, the mood disorder is major depressive disorder.

[0281] In some embodiments, the method includes monitoring the subject using known depression scales, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression-Improvement (CGI), and the Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the therapeutic effect can be determined by a reduction in the Hamilton Depression (HAM-D) total scale exhibited by the subject. The therapeutic effect can be evaluated over a specific treatment period. For example, the therapeutic effect can be determined by a reduction from baseline in the HAM-D total scale after administration of a composition described herein (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more after administration; or 1 day, 2 days, 14 days, 21 days, or 28 days after administration; or 1 week, 2 weeks, 3 weeks, or 4 weeks after administration; or 1 month, 2 months, 6 months, or 10 months after administration; or 1 year, 2 years, or lifetime).

[0282] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a composition described herein) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is 14 or greater and 18 or less. In some embodiments, the subject's baseline HAM-D total score is 19 or greater and 22 or less. In some embodiments, the subject's HAM-D total score before treatment with a composition described herein is 23 or greater. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total score after treatment with a composition described herein is about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8). In some embodiments, the HAM-D total score after treatment with a composition described herein is less than 10, 7, 5, or 3. In some embodiments, the reduction in HAM-D total score is from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27), to a HAM-D total score of about 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2, or 1.8) after treatment with a composition described herein. In some embodiments, the reduction in HAM-D total score after treatment with a composition described herein from baseline HAM-D total score is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, or 50).In some embodiments, the percentage reduction in the HAM-D total score after treatment with a composition described herein from the baseline HAM-D total score is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in the HAM-D total score after treatment with a composition described herein compared to the baseline HAM-D total score.

[0283] In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as measured by a reduction in the Hamilton Depression Score (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within the first or second day of treatment with a composition described herein. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 28 days, e.g., within 21 days or within 14 days, from the start of treatment with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1.

[0284] In some embodiments, the therapeutic effect is a reduction from baseline in the HAM-D total score after treatment with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the subject's HAM-D total score before treatment with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, is at least 18, at least 24, or between 14 and 18. In some embodiments, the methods of treating a depressive disorder described herein result in a reduction in the HAM-D total score of at least 10 or at least 15. In some embodiments, the subject's HAM-D total score after treatment with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, is 8 or less, e.g., 7 or less, or 6 or less.

[0285] In some embodiments, the methods for treating a depressive disorder provided herein provide a therapeutic effect (e.g., as measured by a reduction in the Clinical Global Impression-Improvement scale (CGI)). In some embodiments, the reduction in the CGI is achieved within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours, of initiating treatment with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the methods for treating a depressive disorder, e.g., major depressive disorder, provide a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is a reduction from baseline in CGI scores at the end of the treatment period (14 days after initiation of administration of a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1).

[0286] In some embodiments, the methods for treating depressive disorders provided herein provide a therapeutic effect (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS) score presented by the subject). For example, the methods provided by the present disclosure result in a reduction in the MADRS score within 14, 4, 3, 2, or 1 day, or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours after initiation of treatment with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. The MADRS is a 10-item diagnostic questionnaire (related to apparent sadness, reported sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of sensation, pessimistic thoughts, and suicidal ideation) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0287] pain The present disclosure also provides a method of treating pain, comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the pain comprises acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine. In some embodiments, the pain comprises acute pain or chronic pain. In some embodiments, the pain comprises neuropathic pain, inflammatory pain, or nociceptive pain. In some embodiments, the pain comprises central pain (e.g., thalamic pain). In some embodiments, the pain comprises migraine.

[0288] In some embodiments, the methods provided by the present disclosure further include identifying a subject with pain, e.g., acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, central pain (e.g., thalamic pain), or migraine, prior to administration of a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1.

[0289] Tremor The present disclosure also provides a method of treating tremor comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the tremor may be cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, or rubral tremor. Tremor may include, for example, genetic, degenerative, and idiopathic disorders such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases; peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy disease, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (neuroleptic tricyclics, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproic acid, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and motion-specific and position-specific tremor), dystonic tremor, Parkinson's disease tremor, cerebellar tremor, Holmes tremor (i.e., rubral tremor), palatal tremor, neuropathic tremor, toxin- or drug-induced tremor, and psychogenic tremor. In some embodiments, the tremor may be familial tremor.

[0290] In some embodiments, a subject is selected for treatment with a salt or crystalline salt form of Compound 1, or a pharmaceutical composition of a salt or crystalline salt form of Compound 1, due to a clinical diagnosis of essential tremor. In some embodiments, a subject selected for treatment with a salt or crystalline salt form of Compound 1, or a pharmaceutical composition of a salt or crystalline salt form of Compound 1, has essential tremor but does not have intention tremor.

[0291] Tremor is an involuntary, rhythmic muscle contraction and relaxation that may involve shaking or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0292] Cerebellar tremor or intention tremor is the slow and widespread tremor of limbs that occurs after purposeful movement.Cerebellar tremor is caused by the lesion or damage to the cerebellum, such as tumor, stroke or other localized lesion disease (such as multiple sclerosis) or neurodegenerative disease.

[0293] Dystonic tremor occurs in individuals with dystonia, and is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful abnormal postures or positions.Dystonic tremor can affect any muscle in the body.Dystonic tremor occurs irregularly, and can often be alleviated by complete rest or certain sensory manipulations.

[0294] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive in some cases, beginning on one side of the body and progressing slowly, typically affecting both sides. The hands are most frequently affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremors can decrease with age, but the severity may increase. Increased emotion, stress, fever, physical exhaustion, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms generally progress over time and can be visible and persistent after onset. Tremors, including essential tremor, can interfere with any or all of a person's daily activities, such as personal hygiene, cooking, eating, dressing, home improvement, and interacting with others. Tremors, including essential tremor, can interfere with career choices and the ability to perform job functions (e.g., typing on a computer or cell phone, using tools, sewing, working in a restaurant (cooking or serving), caring for others (medical or veterinary work), or jobs requiring mobility may be difficult). Tremor can also have significant emotional effects, for example, fear of discovering the tremor, fear of others' reactions, or fear of rejection.

[0295] Orthostatic tremor is characterized by rapid (greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Spasms can be felt in the thighs and legs, and patients may tremble uncontrollably when asked to stand in one position. Orthostatic tremor can occur in patients with essential tremor.

[0296] Parkinsonism tremor is caused by damage to structures in the brain that control movement. Parkinsonism tremor is typically seen as a "pill-making" movement of the hands that may also affect the jaw, lips, legs, and trunk. The onset of Parkinsonism tremor usually begins after the age of 60. The movement may begin in one leg or one side of the body and progress to involve the other side.

[0297] Rubral tremor is characterized by a coarse, slow tremor that can be present at rest, in position, and with intention. Tremor is associated with conditions that affect the red nucleus in the midbrain, such as stroke.

[0298] In some embodiments, the tremor is selected from essential tremor, Parkinson's tremor, or cerebellar tremor. In some embodiments, the tremor is essential tremor.

[0299] In some embodiments, the present disclosure also provides a method of treating essential tremor, comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the method results in a reduction in essential tremor as assessed by the Essential Tremor Rating Scale (TETRAS) score. As used herein, the term "Essential Tremor Rating Scale (TETRAS)" refers to a scale developed to quantify the severity of essential tremor and its impact on daily activities. It includes an Activities of Daily Living (ADL) component and a Performance component. The ADL component has 12 items rated from 0 to 4, and the Performance component has 9 items rated from 0 to 4.

[0300] In some embodiments, reduction in essential tremor is assessed by the Essential Tremor Rating Scale (TETRAS) Upper Extremity score.

[0301] In some embodiments, reduction in essential tremor is assessed by the TETRAS Performance subscale score or individual items of the TETRAS Performance.

[0302] In some embodiments, subjects treated by the methods provided herein have moderate essential tremor (i.e., a TETRAS score of 10-15). In some embodiments, subjects treated herein have a TETRAS score of about 10 to about 15, or a TETRAS score of about 12, prior to treatment with the methods of the present disclosure. Treatment with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, can reduce the subject's TETRAS score. In some embodiments, subjects treated with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, experience a reduction in the mean TETRAS score of about 2 to 5, e.g., about 3. In some embodiments, subjects treated with a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, experience a reduction in the mean TETRAS score of about 30% to about 50%, e.g., about 40%.

[0303] In some embodiments, the present disclosure also provides a method of treating essential tremor, comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. In some embodiments, the method reduces essential tremor as assessed by an accelerometer-based score, e.g., an accelerometer-based upper extremity score. In some embodiments, the method reduces essential tremor as assessed by a CGI score.

[0304] In some embodiments, the essential tremor is upper limb tremor.

[0305] The effectiveness of a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, for treating essential tremor can be measured by the methods described in the following references: Ferreira, JJ et al., "MDS Evidence-Based Review of Treatments for Essential Tremor." Mov. Disord. 2019 Jul; 34(7): 950-958; Elble, R. et al., "Task Force Report: Scales for Screening and Evaluating Tremor." Mov. Disord. 2013 Nov; 28(13): 1793-800; Deuschl G. et al. "Treatment of patients with essential tremor." Lancet Neurol. 2011; 10: 148-61; Reich SGet al. "Essential Tremor." Med. Clin. N. Am. 103(2019) 351-356. The disclosures of the references are incorporated herein in their entireties.

[0306] ataxia In some embodiments, the present disclosure also provides a method for treating ataxia, comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. Ataxia, including both cerebellar ataxia and spinal ataxia (e.g., posterior spinal ataxia), is generally accompanied by a loss or insufficiency of coordination. Patients with ataxia may have difficulty controlling the force, range, direction, speed, and rhythm involved in posture, balance, and limb movements. Trunk ataxia may, for example, be characterized by increased postural instability and an inability to maintain the center of gravity over the base of support. Primary or secondary symptoms of ataxia and ataxic gait and leg tremor may be accompanied by speech impairment, dysphagia, abnormal ventilation and speech, and involuntary eye movements, dystonia, pyramidal or extrapyramidal symptoms, which may substantially interfere with activities of daily living.

[0307] As mentioned above, ataxia can result from a wide range of underlying diseases and conditions in a patient, including cerebellar and neurodegenerative disorders and diseases resulting from chronic or long-term exposure to toxins. Ataxic symptoms can result from a wide range of diseases, disorders, and environmental factors, including, among other things, infectious diseases, metabolic diseases, neurodegenerative diseases, genetic diseases, vascular diseases, neoplastic diseases, demyelinating diseases, neuromuscular diseases, and diseases resulting from long-term or chronic exposure to toxins (including drugs and alcohol); in one embodiment, for example, ataxia is the result of a metabolic disease, neurodegenerative disease, vascular disease, neuromuscular disease, or disease resulting from long-term or chronic exposure to toxins. Diseases, disorders, syndromes, and conditions that may result in ataxia symptoms that may be treated according to the methods described herein include, among others, amyotrophic lateral sclerosis, benign paroxysmal positional vertigo, cerebellar ataxia type 1 (autosomal recessive), cerebellar ataxia (autosomal recessive), cerebellar ataxia (dominant pure), cerebellar cortical atrophy, cerebellar degeneration (subacute), cerebellar dysfunction, cerebellar insufficiency, cerebellar hypoplasia (endosteal sclerosis), cerebellar hypoplasia (pigment epithelial retinal degeneration), cerebellar parenchymal autosomal recessive disorder 3, cerebellar parenchymal disorder V, cerebellar agenesis (hydrocephalus), cerebral amyloid angiopathy (familial), cerebral palsy, demyelinating disorders, spinal conditions, autonomic disorders, disequilibrium syndromes, paresthesia, endocrine disorders, diseases caused by chronic exposure to toxins (e.g., alcohol, drugs, antiepileptic drugs, neuroleptic drugs), fragile X / ataxia tremens. syndrome, Friedreich's ataxia, frontal lobe dysfunction, genetic disorders, central nervous system granulomatous vasculitis, Hallervorden-Spatz syndrome, hereditary motor and sensory neuropathies, hydrocephalus (e.g., hypotonia or normal pressure), hypotonia, congenital nystagmus, ataxia and abnormal auditory brainstem response, infantile-onset spinocerebellar ataxia, Machado-Joseph disease, Meniere's disease, metabolic disorders, Miller-Fisher syndrome, Minamata disease, multiple sclerosis, muscular dystrophy, myoclonic ataxia, neurodegenerative disorders, olivopontocerebellar atrophy, paraneoplastic disorders, parkinsonism (atypical), peroneal muscular atrophy, phenytoin toxicity, posterior column ataxia with retinitis pigmentosa, post-polio syndrome, severe brain injury (e.g., head injury, brain surgery, multiple sclerosis or cerebral palsy, chronic alcohol / drug abuse, chronic exposure to toxins, viral infection,or those caused by brain tumors), spastic hemiparesis, spastic paraplegia 23, spastic paraplegia, glaucoma, precocious puberty, SPG, spinocerebellar ataxia, spinocerebellar ataxia (muscular atrophy-hearing loss), spinocerebellar ataxia (dysmorphism), spinocerebellar ataxia 11, spinocerebellar ataxia 17, spinocerebellar ataxia 20, spinocerebellar ataxia 25, spinocerebellar ataxia 29, spinocerebellar ataxia 42, spinocerebellar ataxia 3, spinocerebellar ataxia (autosomal recessive 1), spinocerebellar ataxia (autosomal recessive 3), spinocerebellar ataxia (autosomal recessive) Examples of ataxia include, but are not limited to, spinocerebellar ataxia (autosomal recessive 5), spinocerebellar ataxia (autosomal recessive with axonal neuropathy), spinocerebellar ataxia (Machado-Joseph type II), spinocerebellar ataxia (X-linked 2), spinocerebellar ataxia (X-linked 3), spinocerebellar ataxia (X-linked 4), spinocerebellar degeneration (Book type), stroke (e.g., acute or hemorrhagic), vertebral artery dissection, vertebrobasilar insufficiency, and diseases caused by vitamin deficiency. In one embodiment, the ataxia is the result of a disease selected from spinocerebellar ataxia, Friedreich's ataxia, and fragile X-associated / tremor ataxia syndrome. In another specific embodiment, the ataxia is the result of spinocerebellar ataxia or fragile X / tremor ataxia.

[0308] Tinnitus In some embodiments, the present disclosure also provides a method for treating tinnitus, comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. Tinnitus is a condition in which the affected individual perceives sound in one or both ears or in the head in the absence of external sound. Often referred to as a "ringing" in the ears, tinnitus occurs intermittently or consistently, with a perceived volume ranging from low to painfully loud. However, objective measurements of tinnitus volume in one patient may be perceived as painful, while in another, the same volume may be perceived as insignificant. The perceived volume of tinnitus may vary from patient to patient.

[0309] Sleep disorders In some embodiments, the present disclosure also provides a method of treating a sleep disorder, comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. For example, the sleep disorder can be central nervous system disorders of excessive sleepiness, narcolepsy type I, narcolepsy type II, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to a medical disorder, medication- or substance-induced hypersomnia, hypersomnia associated with a psychiatric disorder, insufficient sleep syndrome, circadian rhythm sleep-wake disorder, delayed sleep-wake phase disorder, advanced sleep-wake phase disorder, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm disorder, shift work disorder, jet lag disorder, or circadian rhythm sleep-wake disorder not otherwise specified (NOS).

[0310] Combination therapy In some embodiments, an effective amount of a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, may be administered in combination with another agent or therapy. As used herein, the term "in combination" refers to the administration of a salt or crystalline salt form of Compound 1, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1, and at least one other agent or therapy, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, whereby the subject has an effective prescription for the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and an effective prescription for at least one of the other agents or therapies, or a pharmaceutically acceptable salt thereof, and is instructed by a physician to take the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one other effective agent or therapy, or a pharmaceutically acceptable salt thereof. In some embodiments, the term "in combination" also refers to the administration of the crystalline form of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and at least one other effective agent or therapy, or a pharmaceutically acceptable salt thereof, to a subject in need thereof over the same period of time. In some embodiments, the crystalline form of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one other effective agent or therapy or a pharmaceutically acceptable salt thereof may be administered in combination to a subject in need thereof, each according to the same administration schedule or each according to a different administration schedule. For example, in some embodiments, the crystalline form of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one other effective agent or therapy or a pharmaceutically acceptable salt thereof may be administered to a subject in need thereof once a day, for example, in the morning, for the same period of time. In other embodiments, the crystalline form of the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered to a subject once a day, for example, in the morning, and at least one other effective agent or therapy or a pharmaceutically acceptable salt thereof may be administered to a subject in need thereof twice or three times a day for the same period of time.In some embodiments, the crystalline form of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one other active agent or therapy, or a pharmaceutically acceptable salt thereof, may be administered simultaneously to a subject in need thereof as part of a new pharmaceutical composition. In other embodiments, the crystalline form of the compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one other active agent or therapy, or a pharmaceutically acceptable salt thereof, may be administered simultaneously or within minutes or hours of each other as part of different pharmaceutical compositions to a subject in need thereof.

[0311] In some embodiments, the present disclosure also provides a method of treating ataxia, comprising administering to a subject in need thereof a salt or crystalline salt form of Compound 1 described herein, or a pharmaceutical composition comprising a salt or crystalline salt form of Compound 1. The subject may have a disease, disorder, or condition, or a symptom thereof, that would benefit from treatment with another agent or therapy. The disease or condition may be related to epilepsy or an epileptic syndrome (e.g., absence seizures, juvenile myoclonic epilepsy, or genetic epilepsy) or tremor (e.g., essential tremor).

[0312] Antiepileptic drugs Antiepileptic drugs include brivaracetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide, ezogabine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tiagabine, topiramate, valproic acid, vigabatrin, and zonisamide.

[0313] painkillers Analgesics are therapeutic drugs used to relieve pain.Examples of analgesics include opiates and morphine-like drugs, such as fentanyl and morphine; paracetamol; NSAIDs and COX-2 inhibitors.Considering the ability of compound 1 to treat pain through the inhibition of T-type calcium channels (for example, Cav3.1, Cav3.2 and Cav3.3), it is particularly contemplated that compound 1 can be used in combination with analgesics.

[0314] Tremor drug treatment Tremor medications include propranolol, primidone, clonazepam, diazepam, lorazepam, alprazolam, gabapentin, topiramate, Topamax, Neurontin, atenolol, klonopin, alprazolam, nebivolol, carbidopa / levodopa, clonazepam, hydrochlorothiazide / metoprolol, gabapentin enacarbil, labetalol, lactulose, lamotrigine, metoprolol, nadolol, hydrochlorothiazide, and zonisamide. [Example]

[0315] Example 1. Screening of salts of Compound 1 The purpose of this experiment was to produce various salts of Compound 1 and determine which of the resulting salts were crystalline salts. For the experiment, Compound 1 was mixed with acid under various conditions, as shown in Table 19, and the resulting products were characterized by XRPD (XRPD spectra not shown). Several samples were identified that were characterized by unique XRPD patterns, i.e., XRPD patterns that did not contain peaks from the starting material. In the case of the fumarate, glutarate, maleate, orotate, and oxalate salts of Compound 1, two distinct XRPD patterns were obtained for one salt, indicating that these salts were polymorphs. [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4]

[0316] Selected salts with unique XRPD patterns were further analyzed by proton NMR spectroscopy (spectra not shown). The results are summarized below in Table 20. Materials that were suspected to contain unreacted starting material were not analyzed. [Table 20-1] [Table 20-2]

[0317] method Typical methods used to prepare and characterize the salts listed in Table 19 are described below.

[0318] Typical cooling methods This method was used, for example, in an experiment aimed at producing the besylate salt of Compound 1. To a 1-dram glass vial was added 24.6 mg (0.064 mmol) of Compound 1 free base, 10.2 mg of benzenesulfonic acid (0.064 mmol), and 1 mL of ethyl acetate. The mixture was heated to approximately 60°C on a hot plate. Once all of the solids had dissolved, the heat was turned off and the solution was allowed to cool to room temperature. The sample was left at room temperature for 3 days, during which no crystallization occurred. The sample was then placed in a refrigerator (approximately 2°C) for 2 days, during which no crystallization occurred. The sample was then placed in a freezer (approximately -15°C) for 7 days, during which no crystallization occurred. None of the cooling experiments in the screening experiment produced any solids.

[0319] Typical evaporation method This method was used, for example, in an experiment aimed at producing the esylate salt of Compound 1. To a 1-dram glass vial, 25.0 mg (0.065 mmol) of the free base of Compound 1, 7.4 mg of ethanesulfonic acid (0.067 mmol), and 0.5 mL of acetone were added. The mixture was sonicated to obtain a solution. Aluminum foil was placed over the opening of the vial and a small hole was poked through it. The vial was left in a fume hood at ambient temperature to allow the solvent to evaporate, yielding a solid, which was subsequently analyzed by XRPD.

[0320] Typical grinding method This method was used, for example, in an experiment aimed at producing the glutarate salt of Compound 1. 25.2 mg (0.066 mmol) of the free base of Compound 1, 8.7 mg of glutaric acid (0.066 mmol), 10 μL of acetonitrile, and a steel ball were added to a PEEK grinding cup. The internal volume of the grinding cup was approximately 1.5 mL. The cup was placed on a Retsch mill, and the sample was ground at 100% power for 30 minutes. The resulting solid was analyzed by XRPD.

[0321] Typical freeze-drying method This method was used, for example, in an experiment aimed at producing the sebacate salt of the free base of Compound 1. To a 50 mL round-bottom flask, 24.9 mg (0.065 mmol) of Compound 1, 12.6 mg of sebacic acid (0.063 mmol), and 3 mL of 1,4-dioxane were added to obtain a solution. The flask was rotated in a dry ice acetone bath to freeze the solution to the sides of the flask. The flask was placed on a Labconco FreeZone 1 freeze dryer overnight to promote crystallization of the presumably amorphous freeze-dried material, resulting in a solid. The flask was placed in a 60 °C oven overnight and subsequently analyzed by XRPD.

[0322] Typical Slurry Method This method was used, for example, in an experiment aimed at producing the pamoate salt of the free base of Compound 1. To a 1-dram glass vial was added 25.1 mg (0.065 mmol) of Compound 1, 25.9 mg of pamoic acid (0.067 mmol), and 1 mL of acetonitrile. The resulting slurry was stirred at room temperature for 3 days. The vial was centrifuged, the mother liquor was decanted, and the solid was air-dried in a fume hood. After drying, the solid was analyzed by XRPD.

[0323] Typical precipitation method This method was used, for example, in an experiment aimed at producing the edisylate salt of the free base of Compound 1. A solution of 25.0 mg (0.065 mmol) of Compound 1 in 1 mL of dichloromethane was mixed with a solution of 12.0 mg of ethane-1,2-disulfonic acid (0.063 mmol in 1 mL of dichloromethane). A solid precipitated, and the resulting slurry was magnetically stirred at room temperature for 1 day. The vial was centrifuged, the mother liquor was decanted, and the solid was air-dried in a fume hood. After drying, the solid was analyzed by XRPD.

[0324] X-ray powder diffraction method (XRPD) XRPD was used to characterize salts of Compound 1 prepared as described in Table 19. The Rigaku Smart-Lab X-ray diffraction system was configured for reflection Bragg-Brentano geometry using an X-ray beam as the source. The X-ray source was a Cu Long Fine Focus tube operated at 40 kV and 44 mA. The source produced an incident beam profile at the sample that varied from a narrow, thin line at high angles to a wide rectangle at low angles. A beam-tuning slit was used on the X-ray source to achieve a maximum beam size of less than 10 mm, both along the line and perpendicular to the line. The Bragg-Brentano geometry is a parafocusing geometry controlled by passive divergence and a receiving slit, with the sample itself acting as the focusing component of the optical system. The intrinsic resolution of the Bragg-Brentano geometry is controlled in part by the radius of the diffractometer and the width of the receiving slit used. Typically, the Rigaku Smart-Lab operates to provide peak widths of 0.1° 2θ or less. The axial divergence of the X-ray beam is controlled by 5.0 degree Soller slits in both the incident and diffracted beam paths.

[0325] Powder samples were prepared in a low-background silicon holder using light manual pressure to keep the sample surface flat and level with the reference surface of the sample holder. Each sample was analyzed from 2 to 40°2θ using a continuous scan of 6°2θ per minute with an effective step size of 0.02°2θ.

[0326] Nuclear magnetic resonance (NMR) spectroscopy 1H NMR spectra were acquired on a Bruker Avance II 400 spectrometer. Samples were prepared by dissolving the material in DMSO-d6. The solutions were individually placed into 5 mm NMR tubes prior to spectral acquisition. Temperature-controlled (295 K) 1H NMR spectra acquired on the Avance II 400 utilized a 5 mm cryoprobe operating at an observation frequency of 400.18 MHz.

[0327] Tables 19 and 20 show the following salts of Compound 1 that were successfully synthesized: acetate, adipate, alginate, ascorbate, aspartate, besylate, benzoate, citrate, cyclamate, edisylate, esylate, isethionate, fumarate, gentisate, gluconate, glucuronate, glutamate, glutarate, ketoglutarate, glycolate, hippurate, lactobionate, maleate, malate, malonate, mesylate, napadisylate, napsylate, oleate, oroate, oxalate, pamoate, phosphate, sebacate, succinate, and tartrate.

[0328] Of the above salts, acetate, alginate, ascorbate, aspartate, besylate, benzoate, citrate, isethionate, gentisate, gluconate, glucuronate, glutamate, ketoglutarate, hippurate, lactobionate, malate, oleate, phosphate, sebacate, succinate, and tartrate were synthesized in amorphous form, as evidenced by their XRPD spectra. These salts are designated "NC" in Table 19.

[0329] Of the above salts, the adipate, besylate, cyclamate, edisylate, esylate, fumarate, glutarate, glycolate, maleate, malonate, mesylate, napadisylate, napsylate, oroate, oxalate, pamoate, and phosphate salts were synthesized in crystalline form, as evidenced by their XRPD spectra. These salts are designated "New," "New 1," or "New 2" in Table 19.

[0330] Example 2. Preparation and characterization of edisylate, maleate, malonate, mesylate, and pamoate crystalline salts of Compound 1. This experiment is a follow-up to the salt screening. The purpose of this experiment was to again prepare and characterize the crystalline salts of compound 1: edisylate, maleate, malonate, mesylate, and pamoate salts.

[0331] Preparation of the crystalline salt of edisylate of compound 1 Three different methods used to synthesize the crystalline salt of the edisylate salt of compound 1 are described below.

[0332] Method 1 A quantity of 103.1 mg of compound 1 was dissolved in 4 mL of dichloromethane, and 1 equivalent of ethane-1,2-disulfonic acid dihydrate (60.4 mg) was dissolved in 0.7 mL of methanol. The solutions were mixed in a glass vial to obtain a clear solution. The solution was stirred at room temperature for 1 day and remained clear. The sample was transferred to a freezer (-20°C) and stirring was continued. A solid was observed after 1 day. A quantity of 1 mL of hexane was added, and stirring was continued in the freezer for an additional 3 days. The sample was centrifuged, the mother liquor was decanted, and the solid was air-dried for XRPD analysis.

[0333] Method 2 A quantity of 102.8 mg of compound 1 was dissolved in 1 mL of dichloromethane, and 1 equivalent of ethane-1,2-disulfonic acid dihydrate (64.1 mg) was dissolved in 0.2 mL of methanol. The solutions were mixed in a glass vial to obtain a clear solution. The solution was stirred at room temperature, and solids were noted within 10 minutes. Stirring at room temperature was continued for 4 days. The sample was centrifuged, the mother liquor was decanted, and the solids were air-dried for XRPD analysis.

[0334] Method 3 The solid from Method 2 was mixed with 1 mL of acetonitrile. The resulting slurry was stirred at room temperature for 3 days. The sample was centrifuged, the mother liquor was decanted, and the solid was air-dried for XRPD analysis.

[0335] 19 shows the results of DSC and TGA analysis of the crystalline salt of the edisylate salt of Compound 1. The analysis results show that Form 1 dehydrates at about 75° C. and subsequently melts at about 176° C. The weight loss upon melting may be due to the destruction and decomposition of the salt of ethane-1,2-disulfonic acid.

[0336] Figure 20 shows the results of NMR analysis of the crystalline salt of the edisylate salt of Compound 1. The analytical results indicate that Form 1 is a dihydrate with a possible 2:1 stoichiometry of API:acid.

[0337] Preparation of the crystalline maleate salt of compound 1 A quantity of 101.3 mg of compound 1 was mixed with 1 equivalent of maleic acid (30.4 mg) and 4 mL of acetonitrile in a glass vial. The resulting slurry was stirred at room temperature and became clear within 2 minutes. A solid precipitated within 4 hours. The slurry was stirred at room temperature for 5 days. The sample was centrifuged, the mother liquor was decanted, and the solid was air-dried for XRPD analysis.

[0338] 21 shows the results of DSC and TGA analysis of the crystalline salt of the maleate salt of Compound 1. The analytical results indicate that Form 7 melts at approximately 161°C.

[0339] Figure 22 shows the results of NMR analysis of the crystalline salt of the maleate salt of Compound 1. The analytical results indicate that Form 7 has a 1:1 stoichiometry of API:acid and is unsolvated.

[0340] Preparation of the crystalline salt of malonate of compound 1 A quantity of 100.8 mg of compound 1 was mixed with 1 equivalent of malonic acid (27.5 mg) and 4 mL of acetonitrile in a glass vial. The resulting slurry was stirred at room temperature and became clear within 2 minutes. A solid precipitated within 5 minutes. The slurry was stirred at room temperature for 5 days. The sample was centrifuged, the mother liquor was decanted, and the solid was air-dried for XRPD analysis.

[0341] 23 shows the results of DSC and TGA analysis of the crystalline malonate salt of Compound 1. The analysis results indicate that Form 8 melts at approximately 161° C. The weight loss upon melting may be due to the destruction and decomposition of the malonic acid salt.

[0342] Figure 24 shows the results of NMR analysis of the crystalline salt of the malonate salt of Compound 1. The analytical results indicate that Form 8 has a 1:1 stoichiometry of API:acid and is unsolvated.

[0343] Preparation of the crystalline salt of compound 1 mesylate Three different methods used to synthesize the crystalline salt of the edisylate salt of compound 1 are described below.

[0344] Method 1 A quantity of 101.9 mg of compound 1 was added to a solution of 1 mL of methanol containing 1 equivalent of methanesulfonic acid (25.0 mg) in a glass vial. The slurry was stirred at room temperature to dissolve the solid. 1 mL aliquots of isopropyl ether were added twice daily. The solution remained clear even after the addition of 7 mL of isopropyl ether (approximately 3 days). The sample was placed in a refrigerator (5°C) for 3 days and remained clear. The sample was removed from the refrigerator and left uncapped in a fume hood to allow the solvent to evaporate. 10 mL of diethyl ether was added to the resulting oil, and the sample was sonicated, resulting in the precipitation of a white solid. The slurry was stirred at room temperature for 1 day. The sample was centrifuged, the mother liquor was decanted, and the solid was air-dried for XRPD analysis.

[0345] Method 2 A quantity of 101.4 mg of compound 1 was added to a solution of 0.5 mL of methanol containing 1 equivalent of methanesulfonic acid (25.8 mg) in a glass vial. The slurry was stirred at room temperature to dissolve the solid. 1 mL of isopropyl ether was added to the solution, and the solution remained clear after stirring overnight. 1 mL of isopropyl ether was added every 2 hours. After three aliquots (3 mL) were added, a clear oil formed. Stirring was continued for 3 days, at which point the oil remained. The solvent was evaporated by purging with dry air, yielding a white solid. The sample was heated at 60°C overnight before XRPD analysis.

[0346] Method 3 To the solid from Method 2, 1 mL of acetonitrile was added. The resulting slurry was stirred at room temperature and became clear within minutes. The sample was cooled to -15°C and remained clear. The sample was warmed to room temperature and 3 mL of tert-butyl methyl ether was added. A precipitate formed within 90 minutes. The slurry was stirred for 2 days. The sample was centrifuged, the mother liquor was decanted, and the solid was air-dried for XRPD analysis.

[0347] 25 shows the results of DSC and TGA analysis of the crystalline salt of the mesylate salt of Compound 1. The analytical results indicate that Form 9 melts at approximately 190° C.

[0348] Figure 26 shows the results of NMR analysis of the crystalline salt of the mesylate salt of Compound 1. The analytical results indicate that Form 9 has a 1:1 stoichiometry of API:acid and is unsolvated.

[0349] Synthesis of the crystalline pamoate salt of compound 1 A 102.2 mg quantity of compound 1 was mixed with 1 equivalent of pamoic acid (59.9 mg) and 4 mL of acetonitrile in a glass vial. The resulting slurry was stirred at room temperature for 6 days. The sample was centrifuged, the mother liquor was decanted, and the solid was air-dried for XRPD analysis.

[0350] 27 shows the results of DSC and TGA analysis of the crystalline salt of the pamoate salt of Compound 1. The analytical results indicate that Form 10 melts at approximately 225° C. Figure 28 shows the results of NMR analysis of the crystalline salt of the pamoate salt of Compound 1. The analytical results indicate that Form 10 has a 1:1 stoichiometry of API:acid and is unsolvated.

[0351] Characterization of the crystalline salt of compound 1 The crystalline salt of Compound 1 was characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and nuclear magnetic resonance (NMR) spectroscopy. The general methods used for each analysis are described below.

[0352] X-ray powder diffraction method (XRPD) The Rigaku Smart-Lab X-ray diffraction system is configured for reflection Bragg-Brentano geometry using an X-ray beam as the source. The X-ray source is a Cu Long Fine Focus tube operated at 40 kV and 44 ma. The source produces an incident beam profile at the sample that varies from a narrow, thin line at high angles to a wide rectangle at low angles. Beam-tuning slits are used on the X-ray source to keep the maximum beam size less than 10 mm both along the line and perpendicular to the line.

[0353] The Bragg-Brentano geometry is a parafocusing geometry controlled by passive divergence and a receiving slit, with the sample itself acting as the focusing component of the optical system. The intrinsic resolution of the Bragg-Brentano geometry is controlled in part by the radius of the diffractometer and the width of the receiving slit used. Typically, the Rigaku Smart-Lab operates to give peak widths of 0.1° 2θ or less. The axial divergence of the X-ray beam is controlled by 5.0° Soller slits in both the incident and diffracted beam paths.

[0354] Powder samples were prepared in a low-background silicon holder using light manual pressure to keep the sample surface flat and level with the reference surface of the sample holder. Each sample was analyzed from 2 to 40°2θ using a continuous scan of 6°2θ per minute with an effective step size of 0.02°2θ.

[0355] Differential scanning calorimetry (DSC) DSC analyses were performed using a TA Instruments Q2500 Discovery Series instrument. Instrument temperature calibration was performed using indium. The DSC cell was maintained under a nitrogen purge of approximately 50 mL / min during each analysis. Samples were placed in standard crimped aluminum pans and heated from approximately 25°C to 350°C at a rate of 10°C / min.

[0356] Thermogravimetric analysis (TGA) TG analysis was performed using a TA Instruments Q5500 Discovery Series instrument. The instrument's balance was calibrated using a Class M weight, and temperature calibration was performed using Alumel. The nitrogen purge was approximately 40 mL / min for the balance and approximately 60 mL / min for the furnace. Each sample was placed in a pre-tared platinum pan and heated from approximately 25 °C to 350 °C at a rate of 10 °C / min.

[0357] Nuclear magnetic resonance (NMR) spectroscopy 1H NMR spectra were acquired on a Bruker Avance II 400 spectrometer. Samples were prepared by dissolving the material in DMSO-d6. The solutions were individually placed into 5 mm NMR tubes prior to spectral acquisition. Temperature-controlled (295 K) 1H NMR spectra acquired on the Avance II 400 utilized a 5 mm cryoprobe operating at an observation frequency of 400.18 MHz.

[0358] result Table 21 below summarizes the preparation and characterization of crystalline salts of Compound 1. [Table 21]

[0359] Equality and scope In the claims, articles such as "a," "an," and "the" can mean one or more unless otherwise indicated to the contrary or clear from the context. A claim or specification including "or" between one or more elements of a group is considered to be satisfied if one, more than one, or all of the group elements are present in, employed in, or relevant to a given product or process, unless otherwise indicated to the contrary or clear from the context. The invention includes embodiments in which exactly one element of a group is present in, employed in, or relevant to a given product or process. The invention includes embodiments in which two or more, or all, group elements are present in, employed in, or relevant to a given product or process.

[0360] Furthermore, the present invention encompasses all variations, combinations, and permutations, including the introduction into another claim of one or more limitations, elements, clauses, and recited terms from one or more of the enumerated claims. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. Where elements are presented as a list, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element may be removed from the group. Generally, when the invention, or inventive aspects, are described as including certain elements and / or features, it should be understood that certain embodiments of the invention or inventive aspects consist of, or consist essentially of, such elements and / or features. For purposes of brevity, those embodiments have not been specifically described verbatim herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and permit the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can be considered to be any specific value or subrange within the stated ranges of different embodiments of the invention, to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0361] This application references various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. In addition, any particular embodiment of the present invention within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be deemed known to those of ordinary skill in the art and therefore may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0362] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above detailed description, but rather is as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims

1. Compound 1 is a salt of Compound 1, wherein Compound 1 is represented by the following structural formula: 【Chemistry 4】 The salt is selected from the group consisting of acetate, adipate, alginate, ascorbate, aspartate, besylate, benzoate, citrate, cyclamate, edisylate, esylate salt, isethionate, fumarate, gentisate, gluconate, glucuronate, glutamate, glutarate, ketoglutarate, glycolate, hippurate, lactobionate, maleate, malate, malonate, mesylate, napadisylate, napsylate, oleate, oroate salt, oxalate, pamoate, phosphate, sebacate, succinate and tartrate.

2. Compound 1 is a crystalline form of a salt of Compound 1, represented by the following structural formula: 【Transformation 5】 A crystalline form wherein the salt is selected from the group consisting of adipate, besylate, cyclamate, edisylate, esylate, fumarate, glutarate, glycolate, napadisylate, napsylate, orotate, oxalate, maleate, malonate, mesylate, pamoate, phosphate, and sebacate.

3. 3. The crystalline form of claim 2, wherein the salt is an edisylate salt.

4. 4. The crystalline form of claim 3, wherein the crystalline form is Form 1 characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 1.

5. 5. The crystalline form of claim 4, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 1.

6. The crystalline form of claim 2, wherein the salt is an esylate salt.

7. 7. The crystalline form of claim 6, wherein the crystalline form is Form 2 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 2.

8. 8. The crystalline form of claim 7, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 2.

9. 3. The crystalline form of claim 2, wherein the salt is a glutarate salt.

10. 10. The crystalline form of claim 9, wherein the crystalline form is Form 3 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 3.

11. 11. The crystalline form of claim 10, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 3.

12. 3. The crystalline form of claim 2, wherein the salt is napadisylate.

13. 13. The crystalline form of claim 12, wherein the crystalline form is Form 4 characterized by an X-ray powder diffraction pattern (XRPD pattern) comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 4.

14. 14. The crystalline form of claim 13, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 4.

15. The crystalline form of claim 2, wherein the salt is a napsylate salt.

16. 16. The crystalline form of claim 15, wherein the crystalline form is Form 5 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 5.

17. 17. The crystalline form of claim 16, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 5.

18. 3. The crystalline form of claim 2, wherein the salt is an orotate salt.

19. 19. The crystalline form of claim 18, wherein the crystalline form is Form 6 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 6.

20. 20. The crystalline form of claim 19, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 6.

21. The crystalline form of claim 2, wherein the salt is a maleate salt.

22. 22. The crystalline form of claim 21, wherein the crystalline form is Form 7 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 7.

23. 23. The crystalline form of claim 22, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 7.

24. 23. The crystalline form of claim 22, having a melting point as determined by differential scanning calorimetry (DSC) at about 161°C.

25. 3. The crystalline form of claim 2, wherein the salt is a malonate salt.

26. 26. The crystalline form of claim 25, wherein the crystalline form is Form 8 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 8.

27. 27. The crystalline form of claim 26, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 8.

28. 27. The crystalline form of claim 26, having a melting point as determined by differential scanning calorimetry (DSC) at about 161°C.

29. The crystalline form of claim 2, wherein the salt is a mesylate salt.

30. 30. The crystalline form of claim 29, wherein the crystalline form is Form 9 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 9.

31. 31. The crystalline form of claim 30, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 9.

32. 31. The crystalline form of claim 30, having a melting point as determined by differential scanning calorimetry (DSC) at about 190°C.

33. 3. The crystalline form of claim 2, wherein the salt is a pamoate salt.

34. 34. The crystalline form of claim 33, wherein the crystalline form is Form 10 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 10.

35. 35. The crystalline form of claim 34, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 10.

36. 35. The crystalline form of claim 34, having a melting point as determined by differential scanning calorimetry (DSC) of about 225°C.

37. 3. The crystalline form of claim 2, wherein the salt is an adipate salt.

38. 37. The crystalline form of claim 36, wherein the crystalline form is Form 11 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 11.

39. 39. The crystalline form of claim 38, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 11.

40. The crystalline form of claim 2, wherein the salt is a besylate salt.

41. 41. The crystalline form of claim 40, wherein the crystalline form is Form 12 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 12.

42. 42. The crystalline form of claim 41, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 12.

43. The crystalline form of claim 2, wherein the salt is a cyclamate salt.

44. 44. The crystalline form of claim 43, wherein the crystalline form is Form 13 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 13.

45. 45. The crystalline form of claim 44, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 13.

46. The crystalline form of claim 2, wherein the salt is a fumarate salt.

47. 47. The crystalline form of claim 46, wherein the crystalline form is Form 14 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 14.

48. 48. The crystalline form of claim 47, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 14.

49. 3. The crystalline form of claim 2, wherein the salt is a glycolate salt.

50. 50. The crystalline form of claim 49, wherein the crystalline form is Form 15 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 15.

51. 51. The crystalline form of claim 50, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 15.

52. The crystalline form of claim 2, wherein the salt is an oxalate salt.

53. 53. The crystalline form of claim 52, wherein the crystalline form is Form 16 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 16.

54. 54. The crystalline form of claim 53, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 16.

55. The crystalline form of claim 2, wherein the salt is a phosphate salt.

56. 56. The crystalline form of claim 55, wherein the crystalline form is Form 17 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 17.

57. 57. The crystalline form of claim 56, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 17.

58. 3. The crystalline form of claim 2, wherein the salt is a sebacate salt.

59. 59. The crystalline form of claim 58, wherein the crystalline form is Form 18 characterized by an XRPD pattern comprising at least one peak at a diffraction angle (°2θ) selected from the group of peaks listed in Table 18.

60. 60. The crystalline form of claim 59, characterized by an XRPD pattern substantially the same as the XRPD pattern shown in Figure 18.

61. 61. A pharmaceutical composition comprising the salt of claim 1 or the crystalline form of any one of claims 2 to 60, and a pharmaceutically acceptable carrier.

62. 62. The pharmaceutical composition of claim 61, further comprising a release-modifying polymer.

63. 63. The pharmaceutical composition of claim 62, wherein the release-modifying polymer is selected from the group consisting of a hydrophilic matrix polymer, a hydrophobic matrix polymer, and a polyacrylate polymer.

64. 64. The pharmaceutical composition of claim 63, wherein the hydrophilic matrix polymer is hypromellose.

65. 65. The pharmaceutical composition according to any one of claims 61 to 64, wherein the pharmaceutical composition is for oral administration.

66. 66. A method of treating a neurological disorder, comprising administering to a subject in need thereof the salt of claim 1, the crystalline form of any one of claims 2-60, or the pharmaceutical composition of any one of claims 61-65.

67. 67. The method of claim 66, wherein the neurological disorder is tremor.

68. 68. The method of claim 67, wherein the tremor is essential tremor, Parkinson's tremor, cerebellar tremor, or CACNA1G tremor.

69. 69. The method of claim 68, wherein the tremor is essential tremor.

70. 66. A method of treating a psychiatric disorder in a subject in need thereof, comprising administering to the subject a salt of claim 1, a crystalline form of any one of claims 2-60, or a pharmaceutical composition of any one of claims 61-65.

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