GABA A Salts and crystalline forms of positive allosteric modulators

Abstract

The present invention relates to salts of compound 1, crystalline forms thereof, methods of their preparation, pharmaceutical compositions thereof, and methods of their use.(1)

Description

[0001] This application is Chinese patent application No. 201980071246.9 (application date: August 30, 2019, invention title: GABA). A The application for a divisional application (for the salt and crystalline forms of sex-linked modifiers).

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Application No. 16 / 517,369, filed July 19, 2019, and U.S. Provisional Application No. 62 / 725,805, filed August 31, 2018, both of which are incorporated herein by reference in their entirety. Technical Field

[0004] This disclosure relates to salts of 3α-hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnane-20-one, their crystalline forms, and methods for preparing such salts and crystalline forms. Background Technology

[0005] 3α-Hydroxy-3β-methoxymethyl-21-(1′-imidazolyl)-5α-pregnane-20-one (Compound 1) is a synthetic neuroactive steroid. Its primary molecular target is γ-aminobutyric acid type A (GABA). A The receptor, wherein the synthesized neuroactive steroid is used as a positive sex modulator (PAM) of channel function. The structural formula of compound 1 is as follows.

[0006]

[0007] The neuroactive steroid GABA has been proven A PAM has clinical efficacy in epilepsy, postpartum depression, and major depressive disorder.

[0008] A separable, stable salt of compound 1 and a method for its preparation are required. Summary of the Invention

[0009] This disclosure provides a salt of compound 1 and a method for preparing such a salt. In some embodiments, the salt of compound 1 is crystalline. This disclosure also provides pharmaceutical compositions comprising a salt of compound 1.

[0010] In some embodiments, this disclosure provides hydrobromide, citrate, malate, maleate, methanesulfonate, phosphate, tartrate, hydrochloride, toluenesulfonate, glucuronate, ethanesulfonate, fumarate, sulfate, naphthalene-2-sulfonate, ascorbate, oxalate, naphthalene-1,5-disulfonate, malonate, aminosalicylate, benzenesulfonate, hydroxyethylsulfonate, gentianate, 1-hydroxy-2-naphthate, dichloroacetate, cyclopentarate, and ethane-1,2-disulfonate of compound 1.

[0011] In some embodiments, this disclosure provides crystalline forms of compound 1 in the form of hydrobromide, citrate, malate, maleate, methanesulfonate, phosphate, tartrate, hydrochloride, toluenesulfonate, glucuronate, ethanesulfonate, fumarate, sulfate, naphthalene-2-sulfonate, ascorbate, oxalate, naphthalene-1,5-disulfonate, malonate, aminosalicylate, benzenesulfonate, hydroxyethylsulfonate, gentianate, 1-hydroxy-2-naphthate, dichloroacetate, cyclopentarate, and ethane-1,2-disulfonate.

[0012] In some embodiments, this disclosure provides a hydrobromide salt of compound 1. In some embodiments, this disclosure provides a crystalline form of the hydrobromide salt of compound 1 (“Compound 1 HBr”). In some embodiments, this disclosure provides compound 1 HBr (Form A). In some embodiments, this disclosure provides compound 1 HBr (Form B). In some embodiments, this disclosure provides compound 1 HBr (Form C). In some embodiments, this disclosure provides compound 1 HBr (Form D). In some embodiments, this disclosure provides compound 1 HBr (Form E).

[0013] In some embodiments, this disclosure provides a citrate of compound 1. In some embodiments, this disclosure provides a crystalline form of the citrate of compound 1 (“Compound 1 citrate”). In some embodiments, this disclosure provides compound 1 citrate (Form A). In some embodiments, this disclosure provides compound 1 citrate (Form B). In some embodiments, this disclosure provides compound 1 citrate (Form C).

[0014] This disclosure also provides methods for treating diseases, disorders, or conditions, including administering a therapeutically effective amount of a salt of compound 1. This disclosure provides methods for administering a salt of compound 1. In some embodiments, the salt of compound 1 is administered orally. In some embodiments, the disease, disorder, or condition is selected from epilepsy, postpartum depression, major depressive disorder, bipolar disorder, treatment-resistant depression, and anxiety. Attached Figure Description

[0015] Figure 1 The X-ray powder diffraction (XRPD) pattern of the free base of compound 1 (Pattern A) is shown.

[0016] Figure 2 The XRPD plot of compound 1 HBr (form A) is shown.

[0017] Figure 3 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound 1 HBr (form A) are shown.

[0018] Figure 4 The dynamic vapor adsorption (DVS) isotherm plot of compound 1 HBr (form A) is shown.

[0019] Figure 5 The XRPD plot of compound 1 HBr (form B) is shown.

[0020] Figure 6 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound 1 HBr (form B) are shown.

[0021] Figure 7 The dynamic vapor adsorption (DVS) isotherm plot of compound 1 HBr (form B) is shown.

[0022] Figure 8 The XRPD plot of compound 1 HBr (form C) is shown.

[0023] Figure 9 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound 1 HBr (form C) are shown.

[0024] Figure 10 The dynamic vapor adsorption (DVS) isotherm plot of compound 1 HBr (form C) is shown.

[0025] Figure 11 The XRPD plot of compound 1 HBr (form D) is shown.

[0026] Figure 12 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound 1 HBr (form D) are shown.

[0027] Figure 13 The XRPD plot of compound 1 HBr (form E) is shown.

[0028] Figure 14 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of compound 1 HBr (form E) are shown.

[0029] Figure 15 The XRPD plot of compound 1 citrate (form A) is shown.

[0030] Figure 16 The DSC and TGA spectra of compound 1 citrate (form A) are shown.

[0031] Figure 17 The DVS isotherm plot of compound 1 citrate (form A) is shown.

[0032] Figure 18 The XRPD plot of compound 1 citrate (form B) is shown.

[0033] Figure 19 The DSC and TGA spectra of compound 1 citrate (form B) are shown.

[0034] Figure 20 The DVS isotherm plot of compound 1 citrate (form B) is shown.

[0035] Figure 21 The XRPD plot of compound 1 citrate (form C) is shown.

[0036] Figure 22 The XRPD plot of compound 1 methanesulfonate (form A) is shown.

[0037] Figure 23 The DSC and TGA spectra of compound 1 methanesulfonate (form A) are shown.

[0038] Figure 24 The DVS isotherm plot of compound 1 methanesulfonate (form A) is shown.

[0039] Figure 25A The XRPD plot of compound 1 methanesulfonate (form B) is shown.

[0040] Figure 25B The XRPD plot of compound 1 methanesulfonate (form C) is shown.

[0041] Figure 26 The XRPD plot of compound 1 methanesulfonate (form D) is shown.

[0042] Figure 27 The XRPD plot of compound 1 phosphate (form A) is shown.

[0043] Figure 28The DSC and TGA spectra of compound 1 phosphate (form A) are shown.

[0044] Figure 29 The DVS isotherm plot of compound 1 phosphate (form A) is shown.

[0045] Figure 30 The XRPD plot of compound 1L(+)-tartrate (form A) is shown.

[0046] Figure 31 The DSC and TGA spectra of compound 1L(+)-tartrate (form A) are shown.

[0047] Figure 32 The DVS isotherm plot of compound 1L(+)-tartrate (form A) is shown.

[0048] Figure 33 The XRPD plot of compound 1L(+)-tartrate (form B) is shown.

[0049] Figure 34 The DSC and TGA spectra of compound 1L(+)-tartrate (form B) are shown.

[0050] Figure 35 The DVS isotherm plot of compound 1L(+)-tartrate (form B) is shown.

[0051] Figure 36 The XRPD plot of compound 1 fumarate (form A) is shown.

[0052] Figure 37 The DSC and TGA spectra of compound 1 fumarate (form A) are shown.

[0053] Figure 38 The XRPD plot of compound 1 fumarate (form B) is shown.

[0054] Figure 39 The DSC and TGA spectra of compound 1 fumarate (form B) are shown.

[0055] Figure 40 The DVS isotherm plot of compound 1 fumarate (form B) is shown.

[0056] Figure 41 The XRPD plot of compound 1 fumarate (form C) is shown.

[0057] Figure 42 The XRPD plot of compound 1 fumarate (form D) is shown.

[0058] Figure 43 The XRPD plot of compound 1 toluenesulfonate (form A) is shown.

[0059] Figure 44 The DSC and TGA spectra of compound 1 toluenesulfonate (form A) are shown.

[0060] Figure 45 The DVS isotherm plot of compound 1 toluenesulfonate (form A) is shown.

[0061] Figure 46 The XRPD plot of compound 1 toluenesulfonate (form B) is shown.

[0062] Figure 47 The XRPD plot of compound 1 toluenesulfonate (form C) is shown.

[0063] Figure 48 The XRPD plot of compound 1 glucuronide (form A) is shown.

[0064] Figure 49 The DSC and TGA spectra of compound 1 glucuronide (form A) are shown.

[0065] Figure 50 The DVS isotherm plot of compound 1 glucuronide (form A) is shown.

[0066] Figure 51 The XRPD plot of compound 1 glucuronide (form B) is shown.

[0067] Figure 52 The XRPD plot of compound 1 ethanesulfonate (form A) is shown.

[0068] Figure 53 The DSC and TGA spectra of compound 1 ethanesulfonate (form A) are shown.

[0069] Figure 54 The DVS isotherm plot of compound 1 ethanesulfonate (form A) is shown.

[0070] Figure 55 The XRPD plot of compound 1 sulfate (form A) is shown.

[0071] Figure 56 The DSC and TGA spectra of compound 1 sulfate (form A) are shown.

[0072] Figure 57 The DVS isotherm plot of compound 1 sulfate (form A) is shown.

[0073] Figure 58The XRPD plot of compound 1 ascorbate (form A) is shown.

[0074] Figure 59 The DSC and TGA spectra of compound 1 ascorbate (form A) are shown.

[0075] Figure 60 The DVS isotherm plot of compound 1 ascorbate (form A) is shown.

[0076] Figure 61 The XRPD plot of compound 1 ascorbate (form B) is shown.

[0077] Figure 62 The XRPD plot of compound 1, naphthalene disulfonate (form A), is shown.

[0078] Figure 63 The DSC and TGA spectra of compound 1 naphthalene disulfonate (form A) are shown.

[0079] Figure 64 The DVS isotherm plot of compound 1 naphthalene disulfonate (form A) is shown.

[0080] Figure 65 The XRPD plot of compound 1 naphthalene disulfonate (form B) is shown.

[0081] Figure 66 The XRPD plot of compound 1 malonate (form A) is shown.

[0082] Figure 67 The DSC and TGA spectra of compound 1 malonate (form A) are shown.

[0083] Figure 68 The XRPD plot of compound 1, besylate (form A), is shown.

[0084] Figure 69 The DSC and TGA spectra of compound 1 benzenesulfonate (form A) are shown.

[0085] Figure 70 The DVS isotherm plot of compound 1 benzenesulfonate (form A) is shown.

[0086] Figure 71 The XRPD plot of compound 1 benzenesulfonate (form B) is shown.

[0087] Figure 72 The XRPD plot of compound 1-hydroxyethyl sulfonate (form A) is shown.

[0088] Figure 73 The DSC and TGA spectra of compound 1-hydroxyethyl sulfonate (form A) are shown.

[0089] Figure 74 The DVS isotherm plot of compound 1-hydroxyethyl sulfonate (form A) is shown.

[0090] Figure 75 The XRPD plot of compound 1-hydroxyethyl sulfonate (form B) is shown.

[0091] Figure 76 The XRPD plot of compound 1 gentianate (form A) is shown.

[0092] Figure 77 The DSC and TGA spectra of compound 1 gentianate (form A) are shown.

[0093] Figure 78 The DVS isotherm plot of compound 1 gentianate (form A) is shown.

[0094] Figure 79 The XRPD plot of compound 1 gentianate (form B) is shown.

[0095] Figure 80 The XRPD plot of compound 1 gentianate (form C) is shown.

[0096] Figure 81 The XRPD plot of compound 1, 1-hydroxy-2-naphthate (form A) is shown.

[0097] Figure 82 The DSC and TGA spectra of compound 1, 1-hydroxy-2-naphthate (form A) are shown.

[0098] Figure 83 The DVS isotherm plot of compound 1, 1-hydroxy-2-naphthate (form A) is shown.

[0099] Figure 84 The XRPD plot of compound 1, 1-hydroxy-2-naphthate (form B) is shown.

[0100] Figure 85 The XRPD plot of compound 1, 1-hydroxy-2-naphthate (form C) is shown.

[0101] Figure 86 The XRPD plot of compound 1, 1-hydroxy-2-naphthate (form D) is shown.

[0102] Figure 87 The XRPD plot of compound 1 cyclolazone (form A) is shown.

[0103] Figure 88 The DSC and TGA spectra of compound 1 cyclopeptide (form A) are shown.

[0104] Figure 89 The DVS isotherm plot of compound 1 cyclopeptide (form A) is shown.

[0105] Figure 90 The XRPD plot of compound 1, ethane-1,2-disulfonate (form A) is shown.

[0106] Figure 91 The DSC and TGA spectra of compound 1, ethane-1,2-disulfonate (form A) are shown.

[0107] Figure 92 The DVS isotherm plot of compound 1, ethane-1,2-disulfonate (form A) is shown.

[0108] Figure 93 The XRPD plot of compound 1, ethane-1,2-disulfonate (form B) is shown.

[0109] Figure 94 The XRPD plot of compound 1 dichloroacetate (form A) is shown.

[0110] Figure 95 The DSC and TGA spectra of compound 1 dichloroacetate (form A) are shown.

[0111] Figure 96 The DVS isotherm plot of compound 1 dichloroacetate (form A) is shown.

[0112] Figure 97 The XRPD plot of compound 1L-malate (form A) is shown.

[0113] Figure 98 The DSC and TGA spectra of compound 1L-malate (form A) are shown.

[0114] Figure 99 The DVS isotherm plot of compound 1L-malate (form A) is shown.

[0115] Figure 100 The XRPD plot of compound 1L-malate (form B) is shown.

[0116] Figure 101 The DSC and TGA spectra of compound 1L-malate (form B) are shown.

[0117] Figure 102The DVS isotherm plot of compound 1L-malate (form B) is shown.

[0118] Figure 103 The XRPD plot of compound 1 hydrochloride (form A) is shown.

[0119] Figure 104 The DSC and TGA spectra of compound 1 hydrochloride (form A) are shown.

[0120] Figure 105 The DVS isotherm plot of compound 1 hydrochloride (form A) is shown.

[0121] Figure 106 The XRPD plot of compound 1 hydrochloride (form B) is shown.

[0122] Figure 107 The DSC and TGA spectra of compound 1 hydrochloride (form B) are shown.

[0123] Figure 108 The DVS isotherm plot of compound 1 hydrochloride (form B) is shown.

[0124] Figure 109 The XRPD plot of compound 1 hydrochloride (form C) is shown.

[0125] Figure 110 The DSC and TGA spectra of compound 1 hydrochloride (form C) are shown.

[0126] Figure 111 The DVS isotherm plot of compound 1 hydrochloride (form C) is shown.

[0127] Figure 112 The XRPD plot of compound 1, naphthalene sulfonate (form A), is shown.

[0128] Figure 113 The DSC and TGA spectra of compound 1 naphthalene sulfonate (form A) are shown.

[0129] Figure 114 The DVS isotherm plot of compound 1 naphthalene sulfonate (form A) is shown.

[0130] Figure 115 The XRPD plot of compound 1 naphthalene sulfonate (form B) is shown.

[0131] Figure 116 The XRPD plot of compound 1 oxalate (form A) is shown.

[0132] Figure 117The DSC and TGA spectra of compound 1 oxalate (form A) are shown.

[0133] Figure 118 The DVS isotherm plot of compound 1 oxalate (form A) is shown.

[0134] Figure 119 The XRPD plot of compound 1 oxalate (form B) is shown.

[0135] Figure 120 The XRPD plot of compound 1, p-aminosalicylate (form A), is shown.

[0136] Figure 121 The DSC and TGA spectra of compound 1, p-aminosalicylate (form A), are shown.

[0137] Figure 122 The DVS isotherm plot of compound 1, p-aminosalicylate (form A), is shown.

[0138] Figure 123 The XRPD plot of compound 1, p-aminosalicylate (form B), is shown.

[0139] Figure 124 The XRPD plot of compound 1 maleate (form A) is shown. Detailed Implementation

[0140] definition

[0141] The term “about” immediately preceding a numerical value refers to a range (e.g., ±10% of the value). For example, unless the context of this disclosure otherwise indicates or is inconsistent with this interpretation, “about 50” can refer to 45 to 55, “about 25,000” can refer to 22,500 to 27,500, and so on. For example, in a series of numerical values ​​such as “about 49, about 50, about 55, ...”, the range indicated by “about 50” extends to less than half the interval between the preceding and following values, such as greater than 49.5 to less than 52.5. Furthermore, the phrase “less than about” or “greater than about” should be understood in accordance with the definition of the term “about” provided herein. Similarly, when the term “about” precedes a series of numerical values ​​or a range of values ​​(e.g., “about 10, 20, 30” or “about 10-30”), it refers to all the values ​​in that series, or the endpoints of the range, respectively.

[0142] Throughout this disclosure, various patents, patent applications, and publications (including non-patent publications) are cited. The disclosures of these patents, patent applications, and publications are incorporated herein by reference in their entirety for all purposes in order to provide a more comprehensive description of the level of art known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0143] For convenience, certain terms used in the specification, embodiments, and claims are collected herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0144] As used in this article, the term "administering" means the direct administration of compound 1 or a pharmaceutically acceptable salt thereof, or a composition containing compound 1 or a pharmaceutically acceptable salt thereof, to a patient.

[0145] As used herein, the term "aprotic solvent" refers to an organic solvent or mixture of organic solvents that is not readily deprotonated in the presence of strongly basic reactants. Non-limiting examples of aprotic solvents include ethers, dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolinone (DMI), N-methylpyrrolidone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, methyl isobutyl ketone, hexachloroacetone, and acetone. Ethyl methyl ketone, methyl ethyl ketone (MEK), ethyl acetate, isopropyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, diethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, tetrahydropyran, diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, tert-butyl methyl ether, etc.

[0146] As used herein, the term “carrier” encompasses carriers, excipients, and diluents, referring to materials, components, or media involved in carrying or transporting a drug from one organ or part of the body to another organ or part of the body, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials.

[0147] Unless otherwise stated, the term “disorder” as used in this disclosure means the term disease, symptom or condition and may be used interchangeably with the terms disease, symptom or condition.

[0148] The terms "effective amount" and "therapeutic effective amount" are used interchangeably in this disclosure and refer to the amount of a compound or its salt, solvate, or ester that, when administered to a patient, is capable of producing the desired outcome. For example, an effective amount of a salt of compound 1 is the amount required to alleviate at least one depressive symptom in a patient. The actual amount containing an "effective amount" or "therapeutic effective amount" will vary depending on a variety of factors, including, but not limited to, the severity of the disorder, the patient's size and health condition, and the route of administration. A skilled medical practitioner can readily determine the appropriate amount using methods known in the medical field.

[0149] The term "isomer" refers to compounds that have the same chemical formula but may have different stereochemical formulas, structural formulas, or special arrangements of atoms. Examples of isomers include stereoisomers, diastereomers, enantiomers, conformational isomers, rotational isomers, geometric isomers, and transisomers.

[0150] The term "peak" refers to a line with significant intensity in an XRPD diffraction pattern (or pattern) obtained from a sample using standard XRPD collection techniques. For example, a peak is a line in an XRPD diffraction pattern whose intensity is, for instance, at least approximately 10% of the intensity of the largest peak in the XRPD diffraction pattern.

[0151] The phrase “pharmaceutically acceptable” as used in this article means a compound, material, composition, and / or dosage form that, to a reasonable extent of medical judgment, is suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and has a reasonable benefit / risk ratio.

[0152] As used herein, the term "proton solvent" refers to a solvent or solvent mixture capable of being used as an acid to protonate any unreacted strongly basic reaction intermediate. Non-limiting examples of proton solvents include water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, n-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neopentanol, tert-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, etc.

[0153] As used herein, the term "salt" includes pharmaceutically acceptable salts commonly used to form free bases. The properties of the salt are not critical, provided it is pharmaceutically acceptable. The term "salt" also includes solvates of addition salts, such as hydrates, and polymorphs of addition salts. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. In salts, proton transfer occurs between the free base of compound 1 and the organic or inorganic acid. However, in some cases, proton transfer is incomplete. In such cases, the molecules of compound 1 and the "co-former" in the solid (i.e., the "co-crystal") interact through nonionic forces, such as hydrogen bonds.

[0154] A co-crystal of the co-formation and compound 1 is obtained when the acid co-formation is solid at about 23ºC (i.e., room temperature) and there is no or partial proton transfer between compound 1 and the acid co-formation. The term "salt" as used herein encompasses the co-crystal form of compound 1.

[0155] The term "substantially similar" as used in this article refers to analytical spectra, such as XRPD plots and DSC temperature plots, that are largely similar to reference spectra in terms of peak position and peak intensity.

[0156] The term "treatment" used in this article refers to the improvement of at least one symptom of a patient's disorder. Treatment can be curative, improving, or at least partially alleviating the disorder.

[0157] As used herein, the term "therapeutic effect" refers to the desired or beneficial effect provided by a method and / or composition. For example, when a method used to treat depression reduces at least one symptom of depression in a patient, the method provides a therapeutic effect.

[0158] The symbols used in this document are: “≤” to mean “not greater than” or “equal to or less than”; “<” to mean “less than”; “≥” to mean “not less than” or “equal to or greater than”; and ">” to mean “greater than”. Furthermore, when used in conjunction with purity or impurity content in this document, numbers include not only exact figures but also approximate ranges around those figures. For example, the phrase “99.0% purity” means approximately 99.0% purity.

[0159] Salt of compound 1

[0160] Compound 1 is a highly potent neuroactive steroid GABA-A positive sex modulator (PAM) similar to clinical-stage neuroactive steroids (alloenolone, ganexone, SAGE-217, alphaxolone). Compound 1 is poorly soluble at the pH found in the lower gastrointestinal tract, which may limit its oral bioavailability.

[0161] The synthesis of compound 1 is described in U.S. Publication Nos. 2004 / 034002 and 2009 / 0118248; the crystalline polymorph of the free base of compound 1 is described in U.S. Publication No. 2006 / 0074059; and pharmaceutical compositions comprising compound 1 are described in U.S. Publication No. 2009 / 0131383, the entire contents of which are incorporated herein by reference for all purposes.

[0162] This disclosure provides a salt of compound 1 and its crystalline form.

[0163] Crystalline salt of compound 1

[0164] In some embodiments, this disclosure provides crystalline forms of salts of compound 1. Polymorphism can be characterized as the ability of a compound to crystallize into different crystalline forms while maintaining the same structural formula (i.e., the covalent bonds in the compound are the same in different crystalline forms). A crystalline polymorph of a given drug product is chemically identical to any other crystalline polymorph of the drug product, containing the same atoms bonded to each other in the same manner, but its crystalline form differs, which can affect one or more physical properties, such as stability, solubility, melting point, bulk density, flow properties, etc., or pharmacological properties such as bioavailability, etc.

[0165] In some embodiments, the crystalline form is characterized by the interplanar spacing between crystal lattices as determined by X-ray powder diffraction (XRPD). XRPD diffraction patterns are typically represented by plotting peak intensities against peak positions (i.e., diffraction angles 2θ in degrees). Characteristic peaks of a given XRPD diffraction pattern can be selected based on their positions and relative intensities to conveniently distinguish the crystal structure from other crystal structures. The percentage intensity of the peak relative to the strongest peak can be expressed as I / Io. XRPD diffraction patterns described herein are obtained using copper K-α radiation.

[0166] Those skilled in the art will recognize that, for a given crystalline form of the same compound, measurements of XRPD peak positions and / or intensities will vary within error limits. The value of °2θ allows for appropriate error limits. Typically, error limits are expressed in “±”. For example, °2θ of approximately “8.716 ± 0.2” represents a range from approximately 8.716 + 0.2 (i.e., approximately 8.916) to approximately 8.716 - 0.2 (i.e., approximately 8.516). Depending on sample preparation techniques, calibration techniques applied to the instrument, variations in human operation, etc., those skilled in the art will recognize that, for XRPD, appropriate error limits can be approximately ±0.7; ±0.6; ±0.5; ±0.4; ±0.3; ±0.2; ±0.1; ±0.05; or smaller.

[0167] Further details of the methods and apparatus used for XRPD analysis are described in the Examples section.

[0168] In some implementations, the crystalline form is characterized by differential scanning calorimetry (DSC). DSC temperature spectra are typically represented by plotting a normalized heat flux in watts per gram (“W / g”) against the measured sample temperature (in degrees Celsius). DSC temperature spectra are generally used to assess extrapolated outset temperatures, peak temperatures, and heat of fusion. Peak characteristic values ​​from DSC temperature spectra are often used as characteristic peaks to distinguish the crystal structure from other crystal structures.

[0169] Those skilled in the art will recognize that, for a given crystalline form of the same compound, DSC temperature measurements will vary within error limits. The values ​​of singlet characteristic values, expressed in degrees Celsius, allow for appropriate error limits. Typically, error limits are expressed in “±”. For example, a singlet characteristic value of approximately “53.09 ± 2.0” represents a range from approximately 53.09 + 2 (i.e., approximately 55.09) to approximately 53.09 - 2 (i.e., approximately 51.09). Depending on sample preparation techniques, calibration techniques applied to the instrument, variations in human intervention, etc., those skilled in the art will recognize that appropriate error limits for singlet characteristic values ​​can be ±2.5; ±2.0; ±1.5; ±1.0; ±0.5; or less.

[0170] Further details of the methods and apparatus used for DSC temperature spectrum analysis are described in the Examples section.

[0171] hydrobromide

[0172] In some embodiments, this disclosure provides the hydrobromide salt of compound 1 (“compound 1 HBr”). In some embodiments, this disclosure provides the crystalline form of compound 1 HBr.

[0173] In one embodiment, this disclosure provides compound 1 HBr (form A). In some embodiments, compound 1 HBr (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 7.6, 15.2, 16.3, 19.8, and 22.9° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form A) exhibits an XRPD containing three or more peaks at about 7.6, 15.2, 16.3, 19.8, and 22.9° 2θ, with an error limit of ±0.2. In some embodiments, the XRPD of compound 1 HBr (form A) further includes one or more peaks at about 15.5, 19.2, 20.6, 26.1, and 31.3° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or smaller (specifically, about ±0.2). In some embodiments, compound 1 HBr (form A) exhibits an XRPD including the peaks shown in Table 1 below:

[0174] Table 1. XRPD table of compound 1 HBr (form A)

[0175]

[0176]

[0177] Some embodiments provide compound 1 HBr (form A), in which form A shows only three peaks in the range of 15.2 ± 0.2 to 16.3 ± 0.2° 2θ in the XRPD plot.

[0178] In some embodiments, compound 1 HBr (form A) exhibits similarity to... Figure 2 Basically similar to XRPD.

[0179] In some embodiments, compound 1 HBr (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 243.1°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form A) exhibits a similar... Figure 3 Basically similar DSC temperature spectra.

[0180] In some embodiments, compound 1 HBr (form A) exhibits similarity to... Figure 3The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 HBr (form A) show a weight loss of approximately 0.0 to 1.9% in the temperature range of 25 to 230°C.

[0181] In some embodiments, compound 1 HBr (form A) exhibits similarity to... Figure 4 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 HBr (form A) shows an adsorption of approximately 1.1% (by weight) of water at 80% relative humidity.

[0182] In one embodiment, this disclosure provides compound 1 HBr (form B). In some embodiments, compound 1 HBr (form B) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 3.6, 16.3, 17.7, 21.4, and 23.5° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 HBr (form B) further contains one or more peaks at about 14.4, 18.7, 24.8, 27.3, and 28.2° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form B) exhibits XRPD containing the peaks shown in Table 2 below:

[0183] Table 2. XRPD table of compound 1 HBr (form B)

[0184]

[0185]

[0186]

[0187] In some embodiments, compound 1 HBr (form B) exhibits similarity to... Figure 5 Basically similar to XRPD.

[0188] In some embodiments, compound 1 HBr (form B) exhibits an endothermic DSC temperature spectrum at approximately 121°C, with error limits of approximately ±2.5; approximately ±2.0; approximately ±1.5; approximately ±1.0; approximately ±0.5; or less (specifically, approximately ±0.2). In some embodiments, compound 1 HBr (form B) exhibits a similar... Figure 6 Basically similar DSC temperature spectra.

[0189] In some embodiments, compound 1 HBr (form B) exhibits similarity to... Figure 6 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 HBr (form B) show a weight loss of approximately 0.0% to 3.4% in the temperature range of 25 to 120°C.

[0190] In some embodiments, compound 1 HBr (form B) exhibits similarity to... Figure 7 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 HBr (form B) shows an adsorption of about 0.2% (by weight) of water at 80% relative humidity.

[0191] In some embodiments, compound 1HBr (form B) is defined by unit cell parameters substantially similar to the following: a = 9.3(4) Å; b = 10.8(4) Å; c = 25.2(11) Å; α = 90º; β = 90º; γ = 90º. o Space group P212121; Molecular / Asymmetric unit 1, wherein the crystalline form is at approximately 120 K.

[0192] In one embodiment, this disclosure provides compound 1 HBr (form C). In some embodiments, compound 1 HBr (form C) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 6.9, 13.8, 20.8, 21.6, and 27.7° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 HBr (form C) further comprises one or more peaks at about 8.8, 25.6, 27.5, 36.2, and 37.3° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form C) exhibits XRPD containing the peaks shown in Table 3 below:

[0193] Table 3. XRPD table of compound 1 HBr (form C)

[0194]

[0195] In some embodiments, compound 1 HBr (form C) exhibits similarity to... Figure 8 Basically similar to XRPD.

[0196] In some embodiments, compound 1 HBr (form C) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 141°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form C) exhibits a similar... Figure 9 Basically similar DSC temperature spectra.

[0197] In some embodiments, compound 1 HBr (form C) exhibits similarity to... Figure 9 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 HBr (in form C) show a weight loss of approximately 0.0% to 4.1% in the temperature range of 25 to 170°C.

[0198] In some embodiments, compound 1 HBr (form C) exhibits similarity to... Figure 10 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 HBr (form C) shows an adsorption of about 0.25% (by weight) of water at 80% relative humidity.

[0199] In one embodiment, this disclosure provides compound 1 HBr (form D). In some embodiments, compound 1 HBr (form D) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 14.7, 15.2, 15.6, 16.4, and 23.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 HBr (form D) further contains one or more peaks at about 18.2, 19.9, 21.3, 22.2, and 23.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form D) exhibits XRPD containing the peaks shown in Table 4 below:

[0200] Table 4. XRPD table of compound 1 HBr (form D)

[0201]

[0202]

[0203] In some embodiments, compound 1 HBr (form D) exhibits similarity to... Figure 11 Basically similar to XRPD.

[0204] In some embodiments, compound 1 HBr (form D) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 248°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form D) exhibits a similar... Figure 12 Basically similar DSC temperature spectra.

[0205] In some embodiments, compound 1 HBr (form D) exhibits similarity to... Figure 12 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 HBr (form D) show a weight loss of approximately 0.0 to 1.7% in the temperature range of 29 to 150°C.

[0206] In some embodiments, this disclosure provides compound 1 HBr (form E). In some embodiments, compound 1 HBr (form E) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 7.6, 15.2, 16.3, 22.9, and 23.2° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form E) exhibits an XRPD containing three or more peaks at about 7.6, 15.2, 16.3, 22.9, and 23.2° 2θ, with an error limit of ±0.2. In some embodiments, the XRPD of compound 1 HBr (form E) further includes one or more peaks at about 9.6, 17.4, 22.4, 23.6, and 31.2° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or smaller (specifically, about ±0.2). In some embodiments, compound 1 HBr (form E) exhibits an XRPD including the peaks shown in Table 5 below:

[0207] Table 5. XRPD table of compound 1 HBr (form E)

[0208]

[0209]

[0210] Some embodiments provide compound 1 HBr (form E), in which form E shows only two peaks in the range of 15.2 ± 0.2 to 16.3 ± 0.2° 2θ in the XRPD plot.

[0211] In some embodiments, compound 1 HBr (form E) exhibits similarity to... Figure 13 Basically similar to XRPD.

[0212] In some embodiments, compound 1 HBr (form E) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 245°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 HBr (form E) exhibits a similar... Figure 14 Basically similar DSC temperature spectra.

[0213] In some embodiments, compound 1 HBr (form E) exhibits similarity to... Figure 14 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 HBr (form E) show a weight loss of about 0.0 to 0.5% in the temperature range of 28 to 150°C.

[0214] In some embodiments, compound 1HBr (form E) is defined by unit cell parameters substantially similar to the following: a = 7.5 (10) Å; b = 15.0 (2) Å; c = 23.0 (2) Å; α = 90º; β = 90º; γ = 90º. o Space group P212121; Molecular / Asymmetric unit 1, wherein the crystalline form is at approximately 120 K.

[0215] In some embodiments, compound 1 HBr (form E) is defined by unit cell parameters substantially similar to the following: a = 23.3 (5) Å; b = 15.0 (3) Å; c = 7.5 (10) Å; α = 90º; β = 90º; γ = 90º. o Space group P212121; Molecular / Asymmetric unit 1, wherein the crystalline form is at approximately 298 K.

[0216] citrate

[0217] In some embodiments, this disclosure provides a citrate of compound 1 (“compound 1 citrate”). In some embodiments, this disclosure provides a crystalline form of compound 1 citrate.

[0218] In one embodiment, this disclosure provides citrate of compound 1 (form A). In some embodiments, citrate of compound 1 (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 5.7, 11.9, 17.1, 20.1, and 20.3° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, citrate of compound 1 (form A) exhibits an XRPD containing three or more peaks at about 5.7, 11.9, 17.1, 20.1, and 20.3° 2θ, with an error limit of ±0.2. In some embodiments, the XRPD of compound 1 citrate (form A) further includes one or more peaks at about 12.7, 13.0, 13.6, 15.3, and 16.8° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or smaller (specifically, about ±0.2). In some embodiments, compound 1 citrate (form A) exhibits an XRPD including the peaks shown in Table 6 below:

[0219] Table 6. XRPD table of compound 1 citrate (form A)

[0220]

[0221]

[0222]

[0223] In some embodiments, compound 1 citrate (form A) is shown in about: 5.7 ± 0.2; 12.5 ± 0.2 and 13.0 ± 0.2; or 5.7 ± 0.2, 12.5 ± 0.2 and 20.1 ± 0.2; or 5.7 ± 0.2; 12.5 ± 0.2 and 20.3 ± 0.2; or 5.7 ± 0.2; 12.7 ± 0.2 and 13.0 ± 0.2; or 5.7 ± 0.2; 12.7 ± 0.2 and 20.3 ± 0.2; or XRPD of peaks of 5.7±0.2, 13.0±0.2 and 20.3±0.2; or 5.7±0.2, 16.8±0.2 and 20.1±0.2; or 5.7±0.2; 20.1±0.2 and 20.3±0.2; or 12.5±0.2, 13.0±0.2 and 20.3±0.2; or 12.7±0.2, 13.0±0.2 and 20.3±0.2; or 16.8±0.2, 20.1±0.2 and 20.3±0.2° 2θ.

[0224] In some embodiments, compound 1 citrate (form A) exhibits similarity to Figure 15 Basically similar to XRPD.

[0225] In some embodiments, compound 1 citrate (form A) shows an endothermic DSC temperature spectrum at about 89.0°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 citrate (form A) shows an endothermic DSC temperature spectrum at about 89.0 ± 2.0°C. In some embodiments, compound 1 citrate (form A) shows an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 139.5°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 citrate (form A) shows an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 139.5 ± 2.0°C. In some embodiments, compound 1 HBr (form A) exhibits similarity to... Figure 16 Basically similar DSC temperature spectra.

[0226] In some embodiments, compound 1 citrate (form A) exhibits similarity to Figure 16 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 citrate (form A) show a weight loss of 0.0 to 2.6% in the temperature range of 25 to 65°C.

[0227] In some embodiments, compound 1 citrate (form A) exhibits similarity to Figure 17 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 citrate (form A) shows an adsorption of approximately 3.6% (by weight) of water at 80% relative humidity.

[0228] In some embodiments, compound 1 citrate (form A) is defined by unit cell parameters substantially similar to the following: a = 8.9 (10) Å; b = 12.2 (10) Å; c = 16.5 (10) Å; α = 73.7 (10)º; β = 76.6 (10)º; γ = 83.2 (10) o Space group P212121; Molecular / Asymmetric unit 1, wherein the crystalline form is at approximately 120.00 K.

[0229] In one embodiment, this disclosure provides citrate of compound 1 (form B). In some embodiments, citrate of compound 1 (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 5.5, 5.7, 10.9, 16.3, and 20.5° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of citrate of compound 1 (form B) further comprises one or more peaks at about 3.4, 11.8, 14.6, 17.2, and 21.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 citrate (form B) exhibits XRPD containing the peaks shown in Table 7 below:

[0230] Table 7. XRPD table of compound 1 citrate (form B)

[0231]

[0232] In some embodiments, compound 1 citrate (form B) exhibits similarity to Figure 18 Basically similar to XRPD.

[0233] In some embodiments, compound 1 citrate (form B) shows an endothermic DSC temperature spectrum containing about 77.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 citrate (form B) shows an endothermic DSC temperature spectrum containing about 121.5°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 citrate (form B) shows an endothermic DSC temperature spectrum containing about 136.6°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 citrate (form B) shows a similar temperature spectrum to... Figure 19 Basically similar DSC temperature spectra.

[0234] In some embodiments, compound 1 citrate (form B) exhibits similarity to Figure 19The TGA thermograms are essentially similar. In some embodiments, the TGA thermograms of compound 1 citrate (form B) show a weight loss of approximately 0.0 to 4.5% in the temperature range of 25 to 120°C.

[0235] In some embodiments, compound 1 citrate (form B) exhibits similarity to Figure 20 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 citrate (form B) shows an adsorption of approximately 2.8% (by weight) of water at 80% relative humidity.

[0236] In one embodiment, this disclosure provides citrate of compound 1 (form C). In some embodiments, citrate of compound 1 (form C) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 15.4, 18.7, 19.7, 20.6, and 27.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of citrate of compound 1 (form C) further comprises one or more peaks at about 13.5, 15.5, 16.2, 17.0, and 22.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 citrate (form C) exhibits XRPD containing the peaks shown in Table 8 below:

[0237] Table 8. XRPD table of compound 1 citrate (form C)

[0238]

[0239]

[0240] In some embodiments, compound 1 citrate (form C) exhibits similarity to Figure 21 Basically similar to XRPD.

[0241] Methanesulfonates

[0242] In some embodiments, this disclosure provides a methanesulfonate salt of compound 1 (“Compound 1 methanesulfonate”). In some embodiments, this disclosure provides a crystalline form of Compound 1 methanesulfonate.

[0243] In one embodiment, this disclosure provides compound 1 methanesulfonate (form A). In some embodiments, compound 1 methanesulfonate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.6, 7.1, 14.2, 19.1, and 25.9° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 citrate (form A) further comprises one or more peaks at about 7.7, 12.7, 17.8, 19.4, and 21.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 methanesulfonate (form A) exhibits XRPD containing the peaks shown in Table 9 below:

[0244] Table 9. XRPD table of compound 1 methanesulfonate (form A)

[0245]

[0246] In some embodiments, compound 1 methanesulfonate (form A) exhibits similarity to... Figure 22 Basically similar to XRPD.

[0247] In some embodiments, compound 1 methanesulfonate (form A) shows an endothermic DSC temperature spectrum containing about 170.9°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 methanesulfonate (form A) shows an endothermic (e.g., strongly endothermic) DSC temperature spectrum containing about 209.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 methanesulfonate (form A) shows a DSC temperature spectrum with... Figure 23 Basically similar DSC temperature spectra.

[0248] In some embodiments, compound 1 methanesulfonate (form A) exhibits similarity to... Figure 23 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 methanesulfonate (form A) show a weight loss of 0.0 to 0.5% in the temperature range of 25 to 150°C.

[0249] In some embodiments, compound 1 methanesulfonate (form A) exhibits similarity to... Figure 24The DVS isotherm plots are essentially similar. In some embodiments, compound 1 methanesulfonate (form A) shows an adsorption of approximately 3.4% (by weight) of water at 80% relative humidity.

[0250] In one embodiment, this disclosure provides compound 1 methanesulfonate (form B). In some embodiments, compound 1 methanesulfonate (form B) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 7.1, 14.3, 15.9, 21.4, and 22.6° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 methanesulfonate (form B) exhibits an XRPD containing the peaks shown in Table 10 below:

[0251] Table 10A. XRPD table of compound 1 methanesulfonate (form B)

[0252]

[0253] In some embodiments, compound 1 methanesulfonate (form B) exhibits similarity to... Figure 25A Basically similar to XRPD.

[0254] In some embodiments, this disclosure provides compound 1 methanesulfonate (form C). In some embodiments, compound 1 methanesulfonate (form C) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 7.5, 15.0, 19.4, 22.5, and 30.2° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 methanesulfonate (form C) exhibits an XRPD containing the peaks shown in Table 10B below:

[0255] Table 10B. XRPD table of compound 1 methanesulfonate (form C)

[0256]

[0257] In some embodiments, compound 1 methanesulfonate (form C) exhibits similarity to... Figure 25B Basically similar to XRPD.

[0258] In one embodiment, this disclosure provides compound 1 methanesulfonate (form D). In some embodiments, compound 1 methanesulfonate (form D) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 7.4, 15.0, and 22.6° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 methanesulfonate (form D) exhibits an XRPD containing the peaks shown in Table 11 below:

[0259] Table 11. XRPD table of compound 1 methanesulfonate (form D)

[0260]

[0261] In some embodiments, compound 1 methanesulfonate (form D) exhibits similarity to... Figure 26 Basically similar to XRPD.

[0262] phosphate

[0263] In some embodiments, this disclosure provides a phosphate of compound 1 (“Compound 1 phosphate”). In some embodiments, this disclosure provides a crystalline form of compound 1 phosphate.

[0264] In one embodiment, this disclosure provides phosphate of compound 1 (form A). In some embodiments, phosphate of compound 1 (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 3.3, 3.6, 5.4, 9.9, and 13.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of phosphate of compound 1 (form A) further contains one or more peaks at about 16.1, 17.9, 20.9, 23.7, and 26.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 phosphate (form A) exhibits XRPD containing the peaks shown in Table 12 below:

[0265] Table 12. XRPD table of compound 1 phosphate (form A)

[0266]

[0267] In some embodiments, compound 1 phosphate (form A) exhibits similarity to Figure 27Basically similar to XRPD.

[0268] In some embodiments, compound 1 phosphate (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 217.6°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 phosphate (form A) exhibits a similar... Figure 28 Basically similar DSC temperature spectra.

[0269] In some embodiments, compound 1 phosphate (form A) exhibits similarity to Figure 28 The TGA thermograms are essentially similar. In some embodiments, the TGA thermograms of compound 1 phosphate (form A) show a weight loss of 0.0 to 1.7% in the temperature range of 25 to 204°C.

[0270] In some embodiments, compound 1 phosphate (form A) exhibits similarity to Figure 29 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 phosphate (form A) shows approximately 2.1% (by weight) of water adsorption at 80% relative humidity.

[0271] Tartrate

[0272] In some embodiments, this disclosure provides a tartrate of compound 1 (“Compound 1 tartrate”). In some embodiments, this disclosure provides a D(-)-tartrate of compound 1 (“Compound 1 D(-)-tartrate”). In some embodiments, this disclosure provides an L(+)-tartrate of compound 1 (“Compound 1 L(+)-tartrate”).

[0273] In some embodiments, this disclosure provides a crystalline form of compound 1 tartrate. In some embodiments, this disclosure provides a crystalline form of compound 1 D(-)-tartrate. In some embodiments, this disclosure provides a crystalline form of compound 1 L(+)-tartrate.

[0274] In one embodiment, this disclosure provides compound 1 L(+)-tartrate (form A). In some embodiments, compound 1 L(+)-tartrate exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 3.6, 4.7, 13.9, 18.6, and 22.8° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 L(+)-tartrate (form A) further contains one or more peaks at about 14.6, 17.8, and 18.1° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 L(+)-tartrate (form A) exhibits XRPD containing the peaks shown in Table 13 below:

[0275] Table 13. XRPD table of compound 1 L(+)-tartrate (form A)

[0276]

[0277] In some embodiments, compound 1 L(+)-tartrate (form A) exhibits similarity to... Figure 30 Basically similar to XRPD.

[0278] In some embodiments, compound 1 L(+)-tartrate (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 207.6°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 L(+)-tartrate (form A) exhibits a similar... Figure 31 Basically similar DSC temperature spectra.

[0279] In some embodiments, compound 1 L(+)-tartrate (form A) exhibits similarity to... Figure 31 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 L(+)-tartrate (form A) show a weight loss of 0.0 to 1.2% in the temperature range of 25 to 189°C.

[0280] In some embodiments, compound 1 L(+)-tartrate (form A) exhibits similarity to... Figure 32Essentially similar DVS isotherm plots. In some embodiments, compound 1 L(+)-tartrate (form A) shows approximately 1.6% (by weight) of water adsorption at 80% relative humidity.

[0281] In one embodiment, this disclosure provides compound 1 L(+)-tartrate (form B). In some embodiments, compound 1 L(+)-tartrate (form B) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 3.6, 4.6, 12.4, 13.9, and 22.7° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 L(+)-tartrate (form B) further contains one or more peaks at about 14.8, 18.3, and 18.5° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 L(+)-tartrate (form B) exhibits XRPD containing the peaks shown in Table 14 below:

[0282] Table 14. XRPD table of compound 1 L(+)-tartrate (form B)

[0283]

[0284] In some embodiments, compound 1 L(+)-tartrate (form B) exhibits similarity to... Figure 33 Basically similar to XRPD.

[0285] In some embodiments, compound 1 L(+)-tartrate (form B) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 207.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 L(+)-tartrate (form B) exhibits a similar... Figure 34 Basically similar DSC temperature spectra.

[0286] In some embodiments, compound 1 L(+)-tartrate (form B) exhibits similarity to... Figure 34 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 L(+)-tartrate (form B) show a weight loss of 0.0 to 0.6% in the temperature range of 25 to 180°C.

[0287] In some embodiments, compound 1 L(+)-tartrate (form B) exhibits similarity to... Figure 35 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 L(+)-tartrate (form B) shows an adsorption of about 1.7% (by weight) of water at 80% relative humidity.

[0288] Fumarate

[0289] In some embodiments, this disclosure provides a fumarate of compound 1 (“Compound 1 fumarate”). In some embodiments, this disclosure provides a crystalline form of compound 1 fumarate.

[0290] In one embodiment, this disclosure provides compound 1 fumarate (form A). In some embodiments, compound 1 fumarate (form A) exhibits an XRPD containing one or more peaks at about 3.5 and 16.0° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 fumarate (form A) exhibits an XRPD containing the peaks shown in Table 15 below:

[0291] Table 15. XRPD table of compound 1 fumarate (form A)

[0292]

[0293] In some embodiments, compound 1 fumarate (form A) exhibits similarity to... Figure 36 Basically similar to XRPD.

[0294] In some embodiments, compound 1 fumarate (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 87.0°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 fumarate (form A) exhibits a similar... Figure 37 Basically similar DSC temperature spectra.

[0295] In some embodiments, compound 1 fumarate (form A) exhibits similarity to... Figure 37 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 fumarate (form A) show a weight loss of 0.0 to 0.9% in the temperature range of 25 to 75°C.

[0296] In some embodiments, this disclosure provides compound 1 fumarate (form B). In some embodiments, compound 1 fumarate (form B) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 3.6, 11.0, 16.2, and 17.5° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 fumarate (form B) exhibits an XRPD containing the peaks shown in Table 16 below:

[0297] Table 16. XRPD table of compound 1 fumarate (form B)

[0298]

[0299] In some embodiments, compound 1 fumarate (form B) exhibits similarity to... Figure 38 Basically similar to XRPD.

[0300] In some embodiments, compound 1 fumarate (form B) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 89.9°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 fumarate (form B) exhibits a similar... Figure 39 Basically similar DSC temperature spectra.

[0301] In some embodiments, compound 1 fumarate (form B) exhibits similarity to... Figure 39 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 fumarate (form B) show a weight loss of 0.0 to 1.85% in the temperature range of 25 to 150°C.

[0302] In some embodiments, compound 1 fumarate (form B) exhibits similarity to... Figure 40 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 fumarate (form B) shows an adsorption of approximately 7.2% (by weight) of water at 80% relative humidity.

[0303] In one embodiment, this disclosure provides compound 1 fumarate (form C). In some embodiments, compound 1 fumarate (form C) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 14.5, 15.4, 16.7, 17.6, and 28.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 fumarate (form C) further comprises one or more peaks at about 8.4, 19.7, 20.5, 22.9, and 38.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 fumarate (form C) exhibits XRPD containing the peaks shown in Table 17 below:

[0304] Table 17. XRPD table of compound 1 fumarate (form C)

[0305]

[0306] In some embodiments, compound 1 fumarate (form C) exhibits similarity to... Figure 41 Basically similar to XRPD.

[0307] In one embodiment, this disclosure provides compound 1 fumarate (form D). In some embodiments, compound 1 fumarate (form D) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 5.2, 12.2, 15.2, 15.5, and 19.9° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 fumarate (form D) further comprises one or more peaks at about 10.4, 13.6, 14.2, 21.2, and 22.3° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 fumarate (form D) exhibits XRPD containing the peaks shown in Table 18 below:

[0308] Table 18. XRPD table of compound 1 fumarate (form D)

[0309]

[0310] In some embodiments, compound 1 fumarate (form D) exhibits similarity to... Figure 42 Basically similar to XRPD.

[0311] Toluenesulfonate

[0312] In some embodiments, this disclosure provides a toluenesulfonate salt of compound 1 (“Compound 1 Toluenesulfonate”). In some embodiments, this disclosure provides a crystalline form of Compound 1 Toluenesulfonate.

[0313] In one embodiment, this disclosure provides compound 1 tosylate (form A). In some embodiments, compound 1 tosylate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.4, 9.8, 10.3, 12.5, and 15.3° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 tosylate (form A) further comprises one or more peaks at about 17.4, 17.9, 19.6, 23.2, and 26.0° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0314] In some embodiments, compound 1 toluenesulfonate (form A) exhibits XRPD containing the peaks shown in Table 19 below:

[0315] Table 19. XRPD table of compound 1 toluenesulfonate (form A)

[0316]

[0317] In some embodiments, compound 1 toluenesulfonate (form A) exhibits similarity to Figure 43 Basically similar to XRPD.

[0318] In some embodiments, compound 1 toluenesulfonate (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 186.2°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 toluenesulfonate (form A) exhibits a similarity to... Figure 44 Basically similar DSC temperature spectra.

[0319] In some embodiments, compound 1 toluenesulfonate (form A) exhibits similarity to Figure 44The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 toluenesulfonate (form A) show a weight loss of 0.0 to 0.9% in the temperature range of 25 to 175°C.

[0320] In some embodiments, compound 1 toluenesulfonate (form A) exhibits similarity to Figure 45 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 toluenesulfonate (form A) shows an adsorption of about 1.5% (by weight) of water at 80% relative humidity.

[0321] In one embodiment, this disclosure provides compound 1 tosylate (form B). In some embodiments, compound 1 tosylate (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 10.0, 15.2, 15.5, 17.2, and 19.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 tosylate (form B) further comprises one or more peaks at about 10.3, 16.7, 19.1, 20.1, and 20.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0322] In some embodiments, compound 1 toluenesulfonate (form B) exhibits XRPD containing the peaks shown in Table 20 below:

[0323] Table 20. XRPD table of compound 1 toluenesulfonate (form B)

[0324]

[0325]

[0326] In some embodiments, compound 1 toluenesulfonate (form B) exhibits similarity to Figure 46 Basically similar to XRPD.

[0327] In one embodiment, this disclosure provides compound 1 tosylate (form C). In some embodiments, compound 1 tosylate (form C) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 7.4, 10.2, 12.5, 18.3, and 19.7° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 tosylate (form C) further comprises one or more peaks at about 9.8, 14.7, 16.6, 17.8, and 23.2° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0328] In some embodiments, compound 1 toluenesulfonate (form C) exhibits XRPD containing the peaks shown in Table 21 below:

[0329] Table 21. XRPD table of compound 1 toluenesulfonate (form C)

[0330]

[0331]

[0332] In some embodiments, compound 1 toluenesulfonate (form C) exhibits similarity to Figure 47 Basically similar to XRPD.

[0333] glucuronide

[0334] In some embodiments, this disclosure provides a glucuronide of compound 1 (“Compound 1 glucuronide”). In some embodiments, this disclosure provides a D-glucuronide of compound 1 (“Compound 1 D-glucuronide”). In some embodiments, this disclosure provides an L-glucuronide of compound 1 (“Compound 1 L-glucuronide”).

[0335] In some embodiments, this disclosure provides a crystalline form of compound 1 glucuronide. In some embodiments, this disclosure provides a crystalline form of compound 1 D-glucuronide. In some embodiments, this disclosure provides a crystalline form of compound 1 L-glucuronide.

[0336] In one embodiment, this disclosure provides compound 1 D-glucuronide (form A). In some embodiments, compound 1 D-glucuronide (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 4.3, 12.9, 16.8, 20.2, and 20.9° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 D-glucuronide (form A) further comprises one or more peaks at about 3.3, 14.7, 17.3, 21.6, and 24.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0337] In some embodiments, compound 1 D-glucuronide (form A) exhibits XRPD containing the peaks shown in Table 22 below:

[0338] Table 22. XRPD table of compound 1 D-glucuronide (form A)

[0339]

[0340] In some embodiments, compound 1 D-glucuronide (form A) exhibits similarity to Figure 48 Basically similar to XRPD.

[0341] In some embodiments, compound 1 D-glucuronide (form A) shows an endothermic DSC temperature spectrum at about 116.2°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 D-glucuronide (form A) shows an endothermic DSC temperature spectrum at about 139.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 D-glucuronide (form A) shows a similar temperature spectrum to... Figure 49 Basically similar DSC temperature spectra.

[0342] In some embodiments, compound 1 D-glucuronide (form A) exhibits similarity to Figure 49 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 D-glucuronide (form A) show a weight loss of 0.0 to 3.0% in the temperature range of 25 to 120°C.

[0343] In some embodiments, compound 1 D-glucuronide (form A) exhibits similarity to Figure 50 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 D-glucuronide (form A) shows an adsorption of approximately 1.4% (by weight) of water at 80% relative humidity.

[0344] In one embodiment, this disclosure provides compound 1 D-glucuronide (form B). In some embodiments, compound 1 D-glucuronide (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 14.7, 16.7, 17.0, 20.0, and 20.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 D-glucuronide (form B) further comprises one or more peaks at about 8.5, 15.0, 19.5, 22.5, and 24.3° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0345] In some embodiments, compound 1 D-glucuronide (form B) exhibits XRPD containing the peaks shown in Table 23 below:

[0346] Table 23. XRPD table of compound 1 D-glucuronide (form B)

[0347]

[0348]

[0349] In some embodiments, compound 1 D-glucuronide (form B) exhibits similarity to Figure 51 Basically similar to XRPD.

[0350] ethanesulfonate

[0351] In some embodiments, this disclosure provides an ethanesulfonate of compound 1 (“Compound 1 ethanesulfonate”). In some embodiments, this disclosure provides a crystalline form of Compound 1 ethanesulfonate.

[0352] In one embodiment, this disclosure provides compound 1 ethanesulfonate (form A). In some embodiments, compound 1 ethanesulfonate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.4, 3.7, 7.6, 15.3, and 23.0° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 ethanesulfonate (form A) further comprises one or more peaks at about 23.3 and 30.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0353] In some embodiments, compound 1 ethanesulfonate (form A) exhibits XRPD containing the peaks shown in Table 24 below:

[0354] Table 24. XRPD table of compound 1 ethanesulfonate (form A)

[0355]

[0356] In some embodiments, compound 1 ethanesulfonate (form A) exhibits similarity to... Figure 52 Basically similar to XRPD.

[0357] In some embodiments, compound 1 ethanesulfonate (form A) shows an endothermic DSC temperature spectrum at about 177.9°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 ethanesulfonate (form A) shows an endothermic DSC temperature spectrum at about 207.0°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 ethanesulfonate (form A) shows a similar temperature spectrum to... Figure 53 Basically similar DSC temperature spectra.

[0358] In some embodiments, compound 1 ethanesulfonate (form A) exhibits similarity to... Figure 53 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 ethanesulfonate (form A) show a weight loss of 0.0 to 2.9% in the temperature range of 25 to 180°C.

[0359] In some embodiments, compound 1 ethanesulfonate (form A) exhibits similarity to... Figure 54The DVS isotherm plots are essentially similar. In some embodiments, compound 1 ethanesulfonate (form A) shows an adsorption of approximately 1.4% (by weight) of water at 80% relative humidity.

[0360] sulfates

[0361] In some embodiments, this disclosure provides a sulfate of compound 1 (“Compound 1 sulfate”). In some embodiments, this disclosure provides a crystalline form of Compound 1 sulfate.

[0362] In one embodiment, this disclosure provides a sulfate of compound 1 (form A). In some embodiments, the sulfate of compound 1 (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.6, 5.2, 7.8, 8.1, and 15.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of the sulfate of compound 1 (form A) further comprises one or more peaks at about 14.7, 17.4, 18.2, 18.4, and 19.7° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 sulfate (form A) exhibits XRPD containing the peaks shown in Table 25 below:

[0363] Table 25. XRPD table of sulfate of compound 1 (form A)

[0364]

[0365] In some embodiments, compound 1 sulfate (form A) exhibits similarity to... Figure 55 Basically similar to XRPD.

[0366] In some embodiments, compound 1 sulfate (form A) exhibits an endothermic DSC temperature spectrum at approximately 167.1°C, with tolerances of approximately ±2.5; approximately ±2.0; approximately ±1.5; approximately ±1.0; approximately ±0.5; or less (specifically, approximately ±0.2). In some embodiments, compound 1 sulfate (form A) exhibits a similar temperature to... Figure 56 Basically similar DSC temperature spectra.

[0367] In some embodiments, compound 1 sulfate (form A) exhibits similarity to... Figure 56The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 sulfate (form A) show a weight loss of 0.0 to 1.0% in the temperature range of 25 to 120°C.

[0368] In some embodiments, compound 1 sulfate (form A) exhibits similarity to... Figure 57 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 sulfate (form A) shows an adsorption of approximately 6.2% (by weight) of water at 80% relative humidity.

[0369] Ascorbate

[0370] In some embodiments, this disclosure provides an ascorbate salt of compound 1 (“compound 1 ascorbate”). In some embodiments, this disclosure provides a crystalline form of compound 1 ascorbate.

[0371] In one embodiment, this disclosure provides compound 1 ascorbate (form A). In some embodiments, compound 1 ascorbate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.6, 5.6, 16.6, 19.6, and 19.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 ascorbate (form A) further comprises one or more peaks at about 11.5, 11.9, 21.6, 24.1, and 24.5° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0372] In some embodiments, compound 1 ascorbate (form A) exhibits XRPD containing the peaks shown in Table 26 below:

[0373] Table 26. XRPD table of compound 1 ascorbate (form A)

[0374]

[0375] In some embodiments, compound 1 ascorbate (form A) exhibits similarity to... Figure 58 Basically similar to XRPD.

[0376] In some embodiments, compound 1 ascorbate (form A) shows an endothermic DSC temperature spectrum at about 46.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 ascorbate (form A) shows an endothermic DSC temperature spectrum at about 124.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 ascorbate (form A) shows a similar temperature spectrum to... Figure 59 Basically similar DSC temperature spectra.

[0377] In some embodiments, compound 1 ascorbate (form A) exhibits similarity to... Figure 59 The TGA thermograms are essentially similar. In some embodiments, the TGA thermograms of compound 1 ascorbate (form A) show a weight loss of 0.0 to 5.6% in the temperature range of 25 to 120°C.

[0378] In some embodiments, compound 1 ascorbate (form A) exhibits similarity to... Figure 60 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 ascorbate (form A) shows an adsorption of approximately 5.7% (by weight) of water at 80% relative humidity.

[0379] In one embodiment, this disclosure provides compound 1 ascorbate (form B). In some embodiments, compound 1 ascorbate (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 5.5, 16.6, 19.7, 20.1, and 28.3° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 ascorbate (form B) further comprises one or more peaks at about 14.7 and 23.6° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0380] In some embodiments, compound 1 ascorbate (form B) exhibits XRPD containing the peaks shown in Table 27 below:

[0381] Table 27. XRPD table of compound 1 ascorbate (form B)

[0382]

[0383] In some embodiments, compound 1 ascorbate (form B) exhibits similarity to... Figure 61 Basically similar to XRPD.

[0384] Naphthalene disulfonate

[0385] In some embodiments, this disclosure provides a naphthalene disulfonate of compound 1 (“compound 1 naphthalene disulfonate”). In some embodiments, this disclosure provides a crystalline form of compound 1 naphthalene disulfonate.

[0386] In one embodiment, this disclosure provides compound 1-naphthalene disulfonate (form A). In some embodiments, compound 1-naphthalene disulfonate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.3, 9.4, 14.2, 16.4, and 17.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1-naphthalene disulfonate (form A) further comprises one or more peaks at about 9.7, 17.3, 20.3, 24.4, and 26.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, compound 1 naphthalene disulfonate (form A) exhibits XRPD containing the peaks shown in Table 28 below:

[0387] Table 28. XRPD table of compound 1 naphthalene disulfonate (form A)

[0388]

[0389] In some embodiments, compound 1 naphthalene disulfonate (form A) exhibits similarity to... Figure 62 Basically similar to XRPD.

[0390] In some embodiments, compound 1 naphthalene disulfonate (form A) exhibits an endothermic DSC temperature spectrum at about 41.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 naphthalene disulfonate (form A) exhibits similarity to... Figure 63 Basically similar DSC temperature spectra.

[0391] In some embodiments, compound 1 naphthalene disulfonate (form A) exhibits similarity to... Figure 63The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1-naphthalene disulfonate (form A) show a weight loss of 0.0 to 0.7% in the temperature range of 25 to 120°C.

[0392] In some embodiments, compound 1 naphthalene disulfonate (form A) exhibits similarity to... Figure 64 The DVS isotherm plots are essentially similar. In some embodiments, compound 1-naphthalene disulfonate shows an adsorption of approximately 3.1% (by weight) of water at 80% relative humidity.

[0393] In some embodiments, this disclosure provides compound 1-naphthalene disulfonate (form B). In some embodiments, compound 1-naphthalene disulfonate (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 6.0, 14.2, 18.1, 19.0, and 20.3° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1-naphthalene disulfonate (form B) further comprises one or more peaks at about 12.0, 16.9, 18.4, 19.4, and 24.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0394] In some embodiments, compound 1 naphthalene disulfonate (form B) exhibits XRPD containing the peaks shown in Table 29 below:

[0395] Table 29. XRPD table of compound 1 naphthalene disulfonate (form B)

[0396]

[0397] In some embodiments, compound 1 naphthalene disulfonate (form B) exhibits similarity to... Figure 65 Basically similar to XRPD.

[0398] malonate

[0399] In some embodiments, this disclosure provides a malonate of compound 1 (“Compound 1 malonate”). In some embodiments, this disclosure provides a crystalline form of compound 1 malonate.

[0400] In one embodiment, this disclosure provides compound 1 malonate (form A). In some embodiments, compound 1 malonate (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 15.1, 18.0, 18.8, 23.4, and 23.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 malonate (form A) further includes one or more peaks at about 3.6, 13.8, 15.6, 21.4, and 27.6° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0401] In some embodiments, compound 1 malonate (form A) exhibits XRPD containing the peaks shown in Table 30 below:

[0402] Table 30. XRPD table of compound 1 malonate (form A)

[0403]

[0404] In some embodiments, compound 1 malonate (form A) exhibits similarity to... Figure 66 Basically similar to XRPD.

[0405] In some embodiments, compound 1 malonate (form A) shows an endothermic DSC temperature spectrum at about 36.9°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 malonate (form A) shows an endothermic DSC temperature spectrum at about 124.6°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 malonate (form A) shows a similar... Figure 67 Basically similar DSC temperature spectra.

[0406] In some embodiments, compound 1 malonate (form A) exhibits similarity to... Figure 67 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 malonate (form A) show a weight loss of 0.0 to 1.9% in the temperature range of 25 to 120°C.

[0407] benzenesulfonate

[0408] In some embodiments, this disclosure provides a benzenesulfonate salt of compound 1 (“Compound 1 benzenesulfonate”). In some embodiments, this disclosure provides a crystalline form of compound 1 benzenesulfonate.

[0409] In one embodiment, this disclosure provides compound 1 benzenesulfonate (form A). In some embodiments, compound 1 benzenesulfonate (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 14.7, 15.8, 22.1, 23.2, and 26.6° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 benzenesulfonate (form A) further includes one or more peaks at about 3.7, 16.2, 17.8, 19.5, and 30.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0410] In some embodiments, compound 1 benzenesulfonate (form A) exhibits XRPD containing the peaks shown in Table 31 below:

[0411] Table 31. XRPD table of compound 1 benzenesulfonate (form A)

[0412]

[0413] In some embodiments, compound 1 benzenesulfonate (form A) exhibits similarity to... Figure 68 Basically similar to XRPD.

[0414] In some embodiments, compound 1 benzenesulfonate (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 194.2°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 benzenesulfonate (form A) exhibits a similarity to... Figure 69 Basically similar DSC temperature spectra.

[0415] In some embodiments, compound 1 benzenesulfonate (form A) exhibits similarity to... Figure 69 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 benzenesulfonate (form A) show a weight loss of 0.0 to 0.3% in the temperature range of 25 to 120°C.

[0416] In some embodiments, compound 1 benzenesulfonate (form A) exhibits similarity to... Figure 70 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 benzenesulfonate (form A) shows approximately 4.0% (by weight) of water adsorption at 80% relative humidity.

[0417] In one embodiment, this disclosure provides compound 1 benzenesulfonate (form B).

[0418] In some embodiments, compound 1 benzenesulfonate (form B) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 7.3, 14.7, 22.1, 23.2, and 29.6° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 benzenesulfonate (form B) further includes one or more peaks at about 7.9, 16.2, 16.4, 17.2, and 30.4° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0419] In some embodiments, compound 1 benzenesulfonate (form B) exhibits XRPD containing the peaks shown in Table 32 below:

[0420] Table 32. XRPD table of compound 1 benzenesulfonate (form B)

[0421]

[0422] In some embodiments, compound 1 benzenesulfonate (form B) exhibits similarity to... Figure 71 Basically similar to XRPD.

[0423] Hydroxyethyl sulfonate

[0424] In some embodiments, this disclosure provides a hydroxyethyl sulfonate of compound 1 (“Compound 1 Hydroxyethyl Sulfonate”). In some embodiments, this disclosure provides a crystalline form of Compound 1 Hydroxyethyl Sulfonate.

[0425] In one embodiment, this disclosure provides compound 1-hydroxyethyl sulfonate (form A).

[0426] In some embodiments, compound 1-hydroxyethyl sulfonate (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 5.6, 16.7, 16.9, 18, and 20.9° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1-hydroxyethyl sulfonate (form A) further includes one or more peaks at about 3.7, 15.7, 16.2, 20.7, and 25.1° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0427] In some embodiments, compound 1-hydroxyethyl sulfonate (form A) exhibits XRPD containing the peaks shown in Table 33 below:

[0428] Table 33. XRPD table of compound 1-hydroxyethyl sulfonate (form A)

[0429]

[0430] In some embodiments, compound 1-hydroxyethyl sulfonate (form A) exhibits similarity to... Figure 72 Basically similar to XRPD.

[0431] In some embodiments, compound 1-hydroxyethyl sulfonate (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 153.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1-hydroxyethyl sulfonate (form A) exhibits a similarity to... Figure 73 Basically similar DSC temperature spectra.

[0432] In some embodiments, compound 1-hydroxyethyl sulfonate (form A) exhibits similarity to... Figure 73 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1-hydroxyethyl sulfonate (form A) show a weight loss of 0.0 to 0.0% in the temperature range of 25 to 120°C.

[0433] In some embodiments, compound 1-hydroxyethyl sulfonate (form A) exhibits similarity to... Figure 74 The DVS isotherm plots are essentially similar. In some embodiments, compound 1-hydroxyethyl sulfonate (form A) shows approximately 4.9% (by weight) of water adsorption at 80% relative humidity.

[0434] In one embodiment, this disclosure provides compound 1-hydroxyethyl sulfonate (form B). In some embodiments, compound 1-hydroxyethyl sulfonate (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 14.5, 15.8, 17.9, 18.1, and 18.6° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1-hydroxyethyl sulfonate (form B) further comprises one or more peaks at about 11.4, 13.1, 14.2, 15.0, and 17.0° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0435] In some embodiments, compound 1-hydroxyethyl sulfonate (form B) exhibits XRPD containing the peaks shown in Table 34 below:

[0436] Table 34. XRPD table of compound 1-hydroxyethyl sulfonate (form B)

[0437]

[0438] In some embodiments, compound 1-hydroxyethyl sulfonate (form B) exhibits similarity to... Figure 75 Basically similar to XRPD.

[0439] Gentian salts

[0440] In some embodiments, this disclosure provides a gentianate salt of compound 1 (“compound 1 gentianate”). In some embodiments, this disclosure provides a crystalline form of compound 1 gentianate.

[0441] In one embodiment, this disclosure provides gentianate of compound 1 (form A). In some embodiments, gentianate of compound 1 (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.4, 3.6, 7.0, 14.6, and 21.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of gentianate of compound 1 (form A) further comprises one or more peaks at about 16.0, 18.0, 18.5, 19.5, and 21.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0442] In some embodiments, compound 1 gentianate (form A) exhibits XRPD containing the peaks shown in Table 35 below:

[0443] Table 35. XRPD table of compound 1 gentianate (form A)

[0444]

[0445] In some embodiments, compound 1 gentianate (form A) exhibits similarity to Figure 76 Basically similar to XRPD.

[0446] In some embodiments, compound 1 gentianate (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 117.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 gentianate (form A) exhibits a similarity to... Figure 77 Basically similar DSC temperature spectra.

[0447] In some embodiments, compound 1 gentianate (form A) exhibits similarity to Figure 77 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 gentianate (form A) show a weight loss of 0.0% to 9.0% in the temperature range of 25 to 200°C.

[0448] In some embodiments, compound 1 gentianate (form A) exhibits similarity to Figure 78 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 gentianate (form A) shows an adsorption of approximately 3.1% (by weight) of water at 80% relative humidity.

[0449] In one embodiment, this disclosure provides gentianate of compound 1 (form B). In some embodiments, gentianate of compound 1 (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 5.5, 10.9, 16.4, 21.9, and 22.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of gentianate of compound 1 (form B) further comprises one or more peaks at about 9.2, 13.0, 17.2, 18.7, and 27.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0450] In some embodiments, compound 1 gentianate (form B) exhibits XRPD containing the peaks shown in Table 36 below:

[0451] Table 36. XRPD table of compound 1 gentianate (form B)

[0452]

[0453] In some embodiments, compound 1 gentianate (form B) exhibits similarity to... Figure 79 Basically similar to XRPD.

[0454] In one embodiment, this disclosure provides gentianate of compound 1 (form C). In some embodiments, gentianate of compound 1 (form C) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 5.3, 15.2, 15.9, 21.4, and 26.6° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of gentianate of compound 1 (form C) further comprises one or more peaks at about 7.6, 10.6, 13.8, 16.9, and 19.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0455] In some embodiments, compound 1 gentianate (form C) exhibits XRPD containing the peaks shown in Table 37 below:

[0456] Table 37. XRPD table of compound 1 gentianate (form C)

[0457]

[0458] In some embodiments, compound 1 gentianate (form C) exhibits similarity to... Figure 80 Basically similar to XRPD.

[0459] 1-Hydroxy-2-naphthate

[0460] In some embodiments, this disclosure provides a 1-hydroxy-2-naphthate of compound 1 (“Compound 1 1-hydroxy-2-naphthate”). In some embodiments, this disclosure provides a crystalline form of compound 1 1-hydroxy-2-naphthate.

[0461] In one embodiment, this disclosure provides compound 1, 1-hydroxy-2-naphthate (form A). In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 3.2, 6.2, 13.8, 21.2, and 21.6° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1, 1-hydroxy-2-naphthate (form A) further includes one or more peaks at about 13.4, 16.2, 19.9, 20.2, and 24.7°2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0462] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), exhibits XRPD containing the peaks shown in Table 38 below:

[0463] Table 38. XRPD table of compound 1, 1-hydroxy-2-naphthate (form A)

[0464]

[0465] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), exhibits similarity to... Figure 81 Basically similar to XRPD.

[0466] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), shows an endothermic DSC temperature spectrum at about 57.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), shows an endothermic DSC temperature spectrum at about 79.1°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), shows an endothermic DSC temperature spectrum at about 116.1°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), shows an endothermic DSC temperature spectrum at about 164.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), shows a similar... Figure 82 Basically similar DSC temperature spectra.

[0467] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), exhibits similarity to... Figure 82 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1, 1-hydroxy-2-naphthate (form A), show a weight loss of 0.0 to 3.6% in the temperature range of 25 to 120°C.

[0468] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), exhibits similarity to... Figure 83 The DVS isotherm plots are essentially similar. In some embodiments, compound 1, 1-hydroxy-2-naphthate (form A), shows approximately 4.6% (by weight) of water adsorption at 80% relative humidity.

[0469] In one embodiment, this disclosure provides compound 1, 1-hydroxy-2-naphthate (form B). In some embodiments, compound 1, 1-hydroxy-2-naphthate (form B) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 8.0, 8.6, 13.5, 13.8, and 20.6° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1, 1-hydroxy-2-naphthate (form B), further includes one or more peaks at about 14.4, 15.2, 16.1, 21.4, and 23.8°2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0470] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form B), exhibits XRPD containing the peaks shown in Table 39 below:

[0471] Table 39. XRPD table of compound 1, 1-hydroxy-2-naphthate (form B)

[0472]

[0473]

[0474] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form B), exhibits similarity to... Figure 84 Basically similar to XRPD.

[0475] In one embodiment, this disclosure provides compound 1, 1-hydroxy-2-naphthate (form C). In some embodiments, compound 1, 1-hydroxy-2-naphthate (form C) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 8.5, 13.7, 14.2, 17.3, and 21.4° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1, 1-hydroxy-2-naphthate (form C), further includes one or more peaks at about 7.7, 15.4, 20.2, 20.6, and 21.1° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0476] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form C), exhibits XRPD containing the peaks shown in Table 40 below:

[0477] Table 40. XRPD table of compound 1, 1-hydroxy-2-naphthate (form C)

[0478]

[0479] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form C), exhibits similarity to... Figure 85 Basically similar to XRPD.

[0480] In one embodiment, this disclosure provides compound 1, 1-hydroxy-2-naphthate (form D). In some embodiments, compound 1, 1-hydroxy-2-naphthate (form D) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 10.4, 12.9, 13.5, 20.4, and 20.9° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1, 1-hydroxy-2-naphthate (form D), further includes one or more peaks at about 6.3, 9.1, 11.2, 13.2, and 19.9° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0481] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form D), exhibits XRPD containing the peaks shown in Table 41 below:

[0482] Table 41. XRPD table of compound 1, 1-hydroxy-2-naphthate (form D)

[0483]

[0484] In some embodiments, compound 1, 1-hydroxy-2-naphthate (form D), exhibits similarity to... Figure 86 Basically similar to XRPD.

[0485] Cyclopyralid

[0486] In some embodiments, this disclosure provides a cyclolazone of compound 1 (“compound 1 cyclolazone”). In some embodiments, this disclosure provides a crystalline form of compound 1 cyclolazone.

[0487] In one embodiment, this disclosure provides compound 1 cyclolazone (form A). In some embodiments, compound 1 cyclolazone (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 6.6, 7.2, 18.5, 19.5, and 21.6° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 cyclolazone (form A) further comprises one or more peaks at about 14.3, 14.8, 17.2, 17.6, and 18.2° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0488] In some embodiments, compound 1 cyclopeptide (form A) exhibits XRPD containing the peaks shown in Table 42 below:

[0489] Table 42. XRPD table of compound 1 cyclopyralid (form A)

[0490]

[0491] In some embodiments, compound 1 cyclolazone (form A) exhibits similarity to Figure 87 Basically similar to XRPD.

[0492] In some embodiments, compound 1 cyclolazone (form A) shows an endothermic DSC temperature spectrum at about 60.1°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 cyclolazone (form A) shows an endothermic DSC temperature spectrum at about 168.5°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 cyclolazone (form A) shows a similar temperature spectrum to... Figure 88 Basically similar DSC temperature spectra.

[0493] In some embodiments, compound 1 cyclolazone (form A) exhibits similarity to Figure 88 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 cyclolactalate (form A) show a weight loss of 0.0 to 5.1% in the temperature range of 25 to 180°C.

[0494] In some embodiments, compound 1 cyclolazone (form A) exhibits similarity to Figure 89The DVS isotherm plots are essentially similar. In some embodiments, compound 1 cyclolactalate (form A) shows approximately 7.3% (by weight) of water adsorption at 80% relative humidity.

[0495] Ethane-1,2-disulfonate

[0496] In some embodiments, this disclosure provides ethane-1,2-disulfonate of compound 1 (“compound 1 ethane-1,2-disulfonate”). In some embodiments, this disclosure provides the crystalline form of compound 1 ethane-1,2-disulfonate.

[0497] In one embodiment, this disclosure provides compound 1 ethane-1,2-disulfonate (form A). In some embodiments, compound 1 ethane-1,2-disulfonate (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 16.2, 16.5, 17.5, 20.7, and 21.3° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 ethane-1,2-disulfonate (form A) further includes one or more peaks at about 3.7, 5.5, 13.8, 14.7, and 26.0° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0498] In some embodiments, compound 1 ethane-1,2-disulfonate (form A) exhibits XRPD containing the peaks shown in Table 43 below:

[0499] Table 43. XRPD table of compound 1 ethane-1,2-disulfonate (form A)

[0500]

[0501] In some embodiments, compound 1 ethane-1,2-disulfonate (form A) exhibits similarity to... Figure 90 Basically similar to XRPD.

[0502] In some embodiments, compound 1 ethane-1,2-disulfonate (form A) shows an endothermic DSC temperature spectrum at about 59.0°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 ethane-1,2-disulfonate (form A) shows an endothermic DSC temperature spectrum at about 154.8°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 ethane-1,2-disulfonate (form A) shows a similar temperature spectrum to... Figure 91 Basically similar DSC temperature spectra.

[0503] In some embodiments, compound 1 ethane-1,2-disulfonate (form A) exhibits similarity to... Figure 91 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 ethane-1,2-disulfonate (form A) show a weight loss of 0.0 to 0.7% in the temperature range of 25 to 120°C.

[0504] In some embodiments, compound 1 ethane-1,2-disulfonate (form A) exhibits similarity to... Figure 92 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 ethane-1,2-disulfonate (form A) shows approximately 12.9% (by weight) of water adsorption at 80% relative humidity.

[0505] In one embodiment, this disclosure provides compound 1 ethane-1,2-disulfonate (form B). In some embodiments, compound 1 ethane-1,2-disulfonate (form B) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 5.5, 16.4, 17.4, 17.6, and 20.7° 2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 ethane-1,2-disulfonate (form B) further includes one or more peaks at about 10.9, 13.7, 14.6, 21.2, and 22.1°2θ, with error limits of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0506] In some embodiments, compound 1 ethane-1,2-disulfonate (form B) exhibits XRPD containing the peaks shown in Table 44 below:

[0507] Table 44. XRPD table of compound 1 ethane-1,2-disulfonate (form B)

[0508]

[0509] In some embodiments, compound 1 ethane-1,2-disulfonate (form B) exhibits similarity to... Figure 93 Basically similar to XRPD.

[0510] dichloroacetate

[0511] In some embodiments, this disclosure provides a dichloroacetic acid salt of compound 1 (“compound 1 dichloroacetic acid”). In some embodiments, this disclosure provides a crystalline form of compound 1 dichloroacetic acid.

[0512] In one embodiment, this disclosure provides dichloroacetate of compound 1 (form A). In some embodiments, dichloroacetate of compound 1 (form A) exhibits an XRPD containing one or more peaks (specifically, three or more peaks) at about 3.4, 3.6, 16.2, 17.1, and 19.5° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of dichloroacetate of compound 1 (form A) further includes one or more peaks at about 8.1, 11.4, 12.8, 16.7, and 20.0° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0513] In some embodiments, compound 1 dichloroacetate (form A) exhibits XRPD containing the peaks shown in Table 45 below:

[0514] Table 45. XRPD table of compound 1 dichloroacetate (form A)

[0515]

[0516] In some embodiments, compound 1 dichloroacetate (form A) exhibits similarity to... Figure 94 Basically similar to XRPD.

[0517] In some embodiments, compound 1 dichloroacetate (form A) exhibits an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 117.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 dichloroacetate (form A) exhibits a similarity to... Figure 95 Basically similar DSC temperature spectra.

[0518] In some embodiments, compound 1 dichloroacetate (form A) exhibits similarity to... Figure 95 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 dichloroacetate (form A) show a weight loss of 0.0 to 3.7% in the temperature range of 25 to 150°C.

[0519] In some embodiments, compound 1 dichloroacetate (form A) exhibits similarity to... Figure 96 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 dichloroacetate (form A) shows an adsorption of approximately 1.8% (by weight) of water at 80% relative humidity.

[0520] malate

[0521] In some embodiments, this disclosure provides an olate of compound 1 (“Compound 1 olate”). In some embodiments, this disclosure provides a D-olate of compound 1 (“Compound 1 D-olate”). In some embodiments, this disclosure provides an L-olate of compound 1 (“Compound 1 L-olate”).

[0522] In some embodiments, this disclosure provides a crystalline form of compound 1 malate. In some embodiments, this disclosure provides a crystalline form of compound 1 D-malate. In some embodiments, this disclosure provides a crystalline form of compound 1 L-malate.

[0523] In one embodiment, this disclosure provides compound 1 L-malate (form A). In some embodiments, compound 1 L-malate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.2, 12.5, 14.4, 15.7, and 18.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 L-malate (form A) further comprises one or more peaks at about 3.6, 6.1, 13.2, 18.9, and 21.1° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0524] In some embodiments, compound 1 L-malate (form A) exhibits XRPD containing the peaks shown in Table 46 below:

[0525] Table 46. XRPD table of compound 1 L-malate (form A)

[0526]

[0527]

[0528] In some embodiments, compound 1 L-malate (form A) exhibits similarity to Figure 97 Basically similar to XRPD.

[0529] In some embodiments, compound 1 L-malate (form A) shows an endothermic (e.g., strongly endothermic) DSC temperature spectrum containing about 120.9°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 L-malate (form A) shows an endothermic (e.g., strongly endothermic) DSC temperature spectrum containing about 142.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 L-malate (form A) shows a DSC temperature spectrum containing about 142.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). Figure 98 Basically similar DSC temperature spectra.

[0530] In some embodiments, compound 1 L-malate (form A) exhibits similarity to Figure 98The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 L-malate (form A) show a weight loss of 0.0 to 0.7% in the temperature range of 25 to 105°C.

[0531] In some embodiments, compound 1 L-malate (form A) exhibits similarity to Figure 99 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 L-malate (form A) shows an adsorption of about 2.0% (by weight) of water at 80% relative humidity.

[0532] In one embodiment, this disclosure provides compound 1 L-malate (form B). In some embodiments, compound 1 L-malate (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 5.6, 13.4, 17.3, 20.8, and 23.2° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 L-malate (form B) further comprises one or more peaks at about 3.7, 11.2, 14.4, 14.9, and 17.8° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0533] In some embodiments, compound 1 L-malate (form B) exhibits XRPD containing the peaks shown in Table 47 below:

[0534] Table 47. XRPD table of compound 1 L-malate (form B)

[0535]

[0536] In some embodiments, compound 1 L-malate (form B) exhibits similarity to Figure 100 Basically similar to XRPD.

[0537] In some embodiments, compound 1 L-malate (form B) shows an endothermic DSC temperature spectrum containing about 108.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 L-malate (form B) shows an endothermic (e.g., strongly endothermic) DSC temperature spectrum containing about 143.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 L-malate (form B) shows a DSC temperature spectrum with... Figure 101 Basically similar DSC temperature spectra.

[0538] In some embodiments, compound 1 L-malate (form B) exhibits similarity to Figure 101 The TGA spectra are essentially similar. In some embodiments, the TGA spectra of compound 1 L-malate (form B) show a weight loss of 0.0 to 1.2% in the temperature range of 25 to 120°C.

[0539] In some embodiments, compound 1 L-malate (form B) exhibits similarity to Figure 102 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 L-malate (form B) shows an adsorption of approximately 3.5% (by weight) of water at 80% relative humidity.

[0540] hydrochloride

[0541] In some embodiments, this disclosure provides a hydrochloride salt of compound 1 (“Compound 1 hydrochloride”). In some embodiments, this disclosure provides a crystalline form of Compound 1 hydrochloride.

[0542] In one embodiment, this disclosure provides compound 1 hydrochloride (form A). In some embodiments, compound 1 hydrochloride (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.6, 5.2, 14.2, 17.4, and 17.7° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 hydrochloride (form A) further comprises one or more peaks at about 12.8, 13.4, 14.9, 18.9, and 20.4° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0543] In some embodiments, compound 1 hydrochloride (form A) exhibits XRPD containing the peaks shown in Table 48 below:

[0544] Table 48. XRPD table of compound 1 hydrochloride (form A)

[0545]

[0546] In some embodiments, compound 1 hydrochloride (form A) exhibits similarity to Figure 103 Basically similar to XRPD.

[0547] In some embodiments, compound 1 hydrochloride (form A) shows an endothermic DSC temperature spectrum at about 220.5°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 hydrochloride (form A) shows an endothermic DSC temperature spectrum at about 232.7°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 hydrochloride (form A) shows a similar... Figure 104 Basically similar DSC temperature spectra.

[0548] In some embodiments, compound 1 hydrochloride (form A) exhibits similarity to Figure 104 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 hydrochloride (form A) show a weight loss of 0.0 to 1.2% in the temperature range of 25 to 150°C.

[0549] In some embodiments, compound 1 hydrochloride (form A) exhibits similarity to Figure 105 The DVS isotherm plots are essentially similar. In some embodiments, compound 1 hydrochloride (form A) shows an adsorption of approximately 3.6% (by weight) of water at 80% relative humidity.

[0550] In one embodiment, this disclosure provides compound 1 hydrochloride (form B). In some embodiments, compound 1 hydrochloride (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.3, 7.8, 15.4, 16.6, and 23.2° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 hydrochloride (form B) further comprises one or more peaks at about 15.0, 18.8, 20.4, 23.5, and 26.5° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0551] In some embodiments, compound 1 hydrochloride (form B) exhibits XRPD containing the peaks shown in Table 49 below:

[0552] Table 49. XRPD table of compound 1 hydrochloride (form B)

[0553]

[0554] In some embodiments, compound 1 hydrochloride (form B) exhibits similarity to Figure 106 Basically similar to XRPD.

[0555] In some embodiments, compound 1 hydrochloride (form B) shows an endothermic DSC temperature spectrum containing about 87.1°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 hydrochloride (form B) shows a strongly endothermic DSC temperature spectrum containing about 207.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 hydrochloride (form B) shows a similar... Figure 107 Basically similar DSC temperature spectra.

[0556] In some embodiments, compound 1 hydrochloride (form B) exhibits similarity to Figure 107 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 hydrochloride (form B) show a weight loss of 0.0 to 0.7% in the temperature range of 25 to 120°C.

[0557] In some embodiments, compound 1 hydrochloride (form B) exhibits similarity to Figure 108The DVS isotherm plots are essentially similar. In some embodiments, compound 1 hydrochloride (form B) shows an adsorption of approximately 2.9% (by weight) of water at 80% relative humidity.

[0558] In one embodiment, this disclosure provides compound 1 hydrochloride (form C). In some embodiments, compound 1 hydrochloride (form C) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 14.6, 16.5, 18.0, 21.5, and 21.9° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 hydrochloride (form C) further comprises one or more peaks at about 3.6, 18.8, 19.9, 22.1, and 23.7° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0559] In some embodiments, compound 1 hydrochloride (form C) exhibits XRPD containing the peaks shown in Table 50 below:

[0560] Table 50. XRPD table of compound 1 hydrochloride (form C)

[0561]

[0562] In some embodiments, compound 1 hydrochloride (form C) exhibits similarity to... Figure 109 Basically similar to XRPD.

[0563] In some embodiments, compound 1 hydrochloride (form C) exhibits an endothermic DSC temperature spectrum at about 132.9°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 hydrochloride (form C) exhibits a similar temperature to... Figure 110 Basically similar DSC temperature spectra.

[0564] In some embodiments, compound 1 hydrochloride (form C) exhibits similarity to... Figure 110 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1 hydrochloride (form C) show a weight loss of 0.0 to 3.8% in the temperature range of 25 to 120°C.

[0565] In some embodiments, compound 1 hydrochloride (form C) exhibits similarity to... Figure 111The DVS isotherm plots are essentially similar. In some embodiments, compound 1 hydrochloride (form C) shows an adsorption of about 0.7% (by weight) of water at 80% relative humidity.

[0566] Naphthalenesulfonate

[0567] In some embodiments, this disclosure provides a naphthalene sulfonate of compound 1 (“compound 1 naphthalene sulfonate”). In some embodiments, this disclosure provides a crystalline form of compound 1 naphthalene sulfonate.

[0568] In one embodiment, this disclosure provides compound 1-naphthalenesulfonate (form A). In some embodiments, compound 1-naphthalenesulfonate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 3.4, 9.5, 16.6, 17.0, and 17.5° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1-naphthalenesulfonate (form A) further comprises one or more peaks at about 8.3, 8.7, 19.8, 25.0, and 25.5° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0569] In some embodiments, compound 1 naphthalene sulfonate (form A) exhibits XRPD containing the peaks shown in Table 51 below:

[0570] Table 51. XRPD table of compound 1 naphthalene sulfonate (form A)

[0571]

[0572] In some embodiments, compound 1 naphthalene sulfonate (form A) exhibits similarity to... Figure 112 Basically similar to XRPD.

[0573] In some embodiments, compound 1 naphthalenesulfonate (form A) shows an endothermic DSC temperature spectrum at about 100.1°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 naphthalenesulfonate (form A) shows an endothermic (e.g., strongly endothermic) DSC temperature spectrum at about 202.3°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 naphthalenesulfonate shows a DSC temperature spectrum with... Figure 113 Basically similar DSC temperature spectra.

[0574] In some embodiments, compound 1 naphthalene sulfonate (form A) exhibits similarity to... Figure 113 The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1-naphthalenesulfonate show a weight loss of 0.0 to 1.7% in the temperature range of 25 to 180°C.

[0575] In some embodiments, compound 1 naphthalene sulfonate (form A) exhibits similarity to... Figure 114 The DVS isotherm plots are essentially similar. In some embodiments, compound 1-naphthalenesulfonate (form A) shows approximately 3.9% (by weight) of water adsorption at 80% relative humidity.

[0576] In one embodiment, this disclosure provides compound 1-naphthalenesulfonate (form B). In some embodiments, compound 1-naphthalenesulfonate (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 9.1, 15.6, 16.1, 18.2, and 19.7° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1-naphthalenesulfonate (form B) further comprises one or more peaks at about 8.6, 12.9, 17.1, 25.8, and 26.2° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0577] In some embodiments, compound 1 naphthalene sulfonate (form B) exhibits XRPD containing the peaks shown in Table 52 below:

[0578] Table 52. XRPD table of compound 1 naphthalene sulfonate (form B)

[0579]

[0580] In some embodiments, compound 1 naphthalene sulfonate (form B) exhibits similarity to... Figure 115 Basically similar to XRPD.

[0581] oxalate

[0582] In some embodiments, this disclosure provides an oxalate of compound 1 (“compound 1 oxalate”). In some embodiments, this disclosure provides a crystalline form of compound 1 oxalate.

[0583] In one embodiment, this disclosure provides oxalate of compound 1 (form A). In some embodiments, oxalate of compound 1 (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 6.1, 18.2, 19.1, 19.8, and 24.3° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of oxalate of compound 1 (form A) further comprises one or more peaks at about 12.1, 13.9, 21.1, 21.7, and 24.7° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0584] In some embodiments, compound 1 oxalate (form A) exhibits XRPD containing the peaks shown in Table 53 below:

[0585] Table 53. XRPD table of compound 1 oxalate (form A)

[0586]

[0587] In some embodiments, compound 1 oxalate (form A) exhibits similarity to Figure 116 Basically similar to XRPD.

[0588] In some embodiments, compound 1 oxalate (form A) shows an endothermic DSC temperature spectrum containing about 163.8°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 oxalate (form A) shows an endothermic (e.g., strongly endothermic) DSC temperature spectrum containing about 198.6°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1 oxalate shows a DSC temperature spectrum with... Figure 117 Basically similar DSC temperature spectra.

[0589] In some embodiments, compound 1 oxalate (form A) exhibits similarity to Figure 117 The TGA thermograms are essentially similar. In some embodiments, the TGA thermograms of compound 1 oxalate show a weight loss of 0.0 to 0.4% in the temperature range of 25 to 150°C.

[0590] In some embodiments, compound 1 oxalate (form A) exhibits similarity to Figure 118The DVS isotherm plots are essentially similar. In some embodiments, compound 1 oxalate (form A) shows an adsorption of about 1.4% (by weight) of water at 80% relative humidity.

[0591] In one embodiment, this disclosure provides oxalate of compound 1 (form B). In some embodiments, oxalate of compound 1 (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 6.0, 6.3, 18.2, 18.8, and 20.0° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of oxalate of compound 1 (form B) further comprises one or more peaks at about 12.1, 12.5, 17.8, 20.7, and 23.5° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0592] In some embodiments, compound 1 oxalate (form B) exhibits XRPD containing the peaks shown in Table 54 below:

[0593] Table 54. XRPD table of compound 1 oxalate (form B)

[0594]

[0595] In some embodiments, compound 1 oxalate (form B) exhibits similarity to Figure 119 Basically similar to XRPD.

[0596] para-aminosalicylate

[0597] In some embodiments, this disclosure provides a para-aminosalicylate of compound 1 (“compound 1 para-aminosalicylate”). In some embodiments, this disclosure provides a crystalline form of compound 1 para-aminosalicylate.

[0598] In one embodiment, this disclosure provides compound 1, para-aminosalicylate (form A). In some embodiments, compound 1, para-aminosalicylate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 5.4, 13.8, 15.7, 20.7, and 21.2°2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1, para-aminosalicylate (form A) further comprises one or more peaks at about 12.5, 13.5, 15.3, 19.2, and 27.6°2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0599] In some embodiments, compound 1, p-aminosalicylate (form A), exhibits XRPD containing the peaks shown in Table 55 below:

[0600] Table 55. XRPD table of compound 1, p-aminosalicylic acid salt (form A)

[0601]

[0602]

[0603] In some embodiments, compound 1, p-aminosalicylate (form A), exhibits similarity to... Figure 120 Basically similar to XRPD.

[0604] In some embodiments, compound 1, para-aminosalicylate (form A), shows an endothermic DSC temperature spectrum at about 97.1°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1, para-aminosalicylate (form A), shows an endothermic DSC temperature spectrum at about 146.8°C, with error limits of about ±2.5; about ±2.0; about ±1.5; about ±1.0; about ±0.5; or less (specifically, about ±0.2). In some embodiments, compound 1, para-aminosalicylate (form A), shows a similar temperature spectrum to... Figure 121 Basically similar DSC temperature spectra.

[0605] In some embodiments, compound 1, p-aminosalicylate (form A), exhibits similarity to... Figure 121The TGA temperature spectra are essentially similar. In some embodiments, the TGA temperature spectra of compound 1, para-aminosalicylate (form A), show a weight loss of 0.0% to 4.0% in the temperature range of 25 to 120°C.

[0606] In some embodiments, compound 1, p-aminosalicylate (form A), exhibits similarity to... Figure 122 The DVS isotherm plots are essentially similar. In some embodiments, compound 1, para-aminosalicylate (form A), shows approximately 4.0% (by weight) of water adsorption at 80% relative humidity.

[0607] In one embodiment, this disclosure provides compound 1, para-aminosalicylate (form B). In some embodiments, compound 1, para-aminosalicylate (form B) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 12.3, 15.2, 17.3, 19.9, and 22.9°2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1, para-aminosalicylate (form B) further comprises one or more peaks at about 6.3, 12.5, 14.8, 16.4, and 20.7°2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0608] In some embodiments, compound 1, p-aminosalicylate (form B), exhibits XRPD containing the peaks shown in Table 56 below:

[0609] Table 56. XRPD table of compound 1, p-aminosalicylic acid salt (form B)

[0610]

[0611] In some embodiments, compound 1, p-aminosalicylate (form B), exhibits similarity to... Figure 123 Basically similar to XRPD.

[0612] Maleate

[0613] In some embodiments, this disclosure provides a maleate salt of compound 1 (“Compound 1 maleate”). In some embodiments, this disclosure provides a crystalline form of compound 1 maleate.

[0614] In one embodiment, this disclosure provides compound 1 maleate (form A). In some embodiments, compound 1 maleate (form A) exhibits an XRPD comprising one or more peaks (specifically, three or more peaks) at about 6.4, 9.5, 11.2, 13.1, 15.0, and 17.6° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2). In some embodiments, the XRPD of compound 1 maleate (form A) further comprises one or more peaks at about 11.2, 12.6, 14.0, 16.7, and 19.2° 2θ, with an error limit of about ±0.5; about ±0.4; about ±0.3; about ±0.2; about ±0.1; about ±0.05; or less (specifically, about ±0.2).

[0615] In some embodiments, compound 1 maleate (form A) exhibits XRPD containing the peaks shown in Table 57 below:

[0616] Table 57. XRPD table of compound 1 maleate (form A)

[0617]

[0618] In some embodiments, compound 1 maleate (form A) exhibits similarity to Figure 124 Basically similar to XRPD.

[0619] Method for preparing salt of compound 1

[0620] The salt of compound 1 (and its crystalline form) can be prepared, for example, by mixing the free base of compound 1 with an acid (e.g., hydrochloric acid) in a suitable solvent to provide a salt of compound 1 (as a suspension in a suitable solvent). In some embodiments, the salt of compound 1 can be prepared by slow evaporation, slow cooling, or by adding an antisolvent to the mixture of the free base of compound 1 and the acid.

[0621] In some embodiments, this disclosure provides a method for preparing a crystalline form of the salt of compound 1. In some embodiments, the salt of compound 1 is suspended in a suitable solvent for a time sufficient to provide a suspension in the crystalline form of the salt of compound 1.

[0622] In some embodiments, the salt of compound 1 is dissolved in a suitable solvent to provide a solution, and the crystalline form of the salt of compound 1 precipitates from the solution. In some other embodiments, the salt of compound 1 is dissolved by heating a mixture of the salt of compound 1 and a suitable solvent. In some other embodiments, the crystalline form of the salt of compound 1 precipitates from the solution by cooling the solution. In other embodiments, the crystalline form of the salt of compound 1 precipitates from the solution by adding an antisolvent (i.e., a solvent that reduces the solubility of the crystalline form of the salt of compound 1). In still other embodiments, the crystalline form of the salt of compound 1 precipitates from the solution by evaporating a portion of the suitable solvent from the solution. In some other embodiments, the suitable solvent includes water.

[0623] In some embodiments, the salt of compound 1 is heated to provide a melt, and the melt is cooled to provide a crystalline form of the salt of compound 1. In some embodiments, the salt of compound 1 is compressed under pressure and time sufficient to provide a crystalline form of the salt of compound 1 (e.g., 5 mPa, 5 minutes). In some embodiments, the salt of compound 1 is ground (e.g., using a mortar and pestle or a grinder) to provide a crystalline form of the salt of compound 1. In some other embodiments, the salt of compound 1 is ground in the presence of a suitable solvent to provide a crystalline form of the salt of compound 1. In some embodiments, the salt of compound 1 is subjected to relative humidity and temperature (e.g., at 45°C and 75% relative humidity) for a time sufficient to provide a crystalline form of the salt of compound 1.

[0624] In some embodiments, suitable solvents include aprotic solvents. In some embodiments, the aprotic solvent includes at least one solvent selected from the following: dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolinone (DMI), N-methylpyrrolidone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, methyl... Ethyl ketone (MEK), hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, diethoxymethane, tetrahydrofuran, toluene, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, tetrahydropyran, diisopropyl ether, dibutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, tert-butyl methyl ether. In some embodiments, the aprotic solvent is acetone. In some embodiments, the aprotic solvent is ethyl acetate. In some embodiments, the aprotic solvent is acetonitrile.

[0625] In some embodiments, suitable solvents include proton solvents. In some embodiments, the proton solvent includes at least one solvent selected from the following: water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, n-butanol, 2-butanol, isobutanol, tert-butanol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neopentanol, tert-pentanol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, and glycerol. In some embodiments, the proton solvent includes a mixture of 2-propanol and water.

[0626] In some embodiments, a suitable solvent is a single solvent. In some embodiments, the solvent is a mixture of solvents. In some embodiments, a suitable solvent is a mixture of protic and non-protic solvents.

[0627] In some embodiments, the salt of compound 1 (or the crystalline form of the salt) is separated after preparation. The separation of the salt (or the crystalline form of the salt) can be accomplished using methods such as filtration, decantation, centrifugation, or other suitable separation techniques.

[0628] In some embodiments, the separated salt (or the crystalline form of the salt) is optionally washed with a liquid such as an antisolvent, acetonitrile, methanol, ethanol, ethyl acetate, methyl ethyl ketone, acetone, tetrahydrofuran, or a combination thereof.

[0629] In some embodiments, the salt of compound 1 prepared by the above embodiments is substantially pure. For example, in some embodiments, the chemical purity of the salt of compound 1 (e.g., compound 1 hydrochloride) may include at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, or about 95% of the salt of compound 1. Chemical purity can be determined using methods known to those skilled in the art (e.g., HPLC chromatography using suitable solvents and a column detecting at a wavelength of 210 nm). In some embodiments, the basic purity is determined based on weight percentage. In some embodiments, the basic purity is determined based on the area under the curve.

[0630] In some embodiments, the salt of compound 1 prepared by the above embodiments is crystalline. In some embodiments, the crystalline salt of compound 1 prepared by the above embodiments is substantially pure. For example, in some embodiments, the polymorphic purity of the crystalline salt of compound 1 (e.g., compound 1 hydrochloride) may include at least about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% in a single crystal form (e.g., compound 1 hydrochloride (form A)). Polymorphic purity can be determined using methods known to those skilled in the art (including X-ray powder crystallography as described in Shah, B., et al., Analytical techniques for quantification of amorphous / crystalline phases in pharmaceutical solids, J.Pharm. Sci. 2006, 95(8), pages 1641-1665, etc., the entire contents of which are incorporated herein by reference).

[0631] In some embodiments, the salt of Compound 1 prepared according to the above embodiments is epimerically enriched at one or more positions compared to the epimeric purity of the free base starting material of Compound 1. For example, in some embodiments, the salt of Compound 1 may comprise at least about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, or about 20:1 of the 17-β:17α epimer of Compound 1. In some embodiments, the salt of Compound 1 may comprise at least about 8:1, about 9:1, about 10:1, about 11:1, about 12:1, about 13:1, about 14:1, about 15:1, or about 20:1 of the 3α-hydroxy:3β-hydroxy form of Compound 1. In some embodiments, the epimeric purity of the salt of Compound 1 described herein is substantially the same as the epimeric purity of the free base starting material of Compound 1.

[0632] Pharmaceutical Composition

[0633] In one aspect, this disclosure provides pharmaceutical compositions comprising a salt of compound 1. In some embodiments, the salt of compound 1 is compound 1 hydrobromide, compound 1 citrate, compound 1 L-malate, compound 1 methanesulfonate, compound 1 phosphate, compound 1 L(+)-tartrate, compound 1 hydrochloride, compound 1 toluenesulfonate, compound 1 glucuronide, or compound 1 ethanesulfonate. In some embodiments, the salt of compound 1 is compound 1 hydrobromide (form A). In some embodiments, the salt of compound 1 is compound 1 hydrobromide (form B). In some embodiments, the salt of compound 1 is compound 1 hydrobromide (form C). In some embodiments, the salt of compound 1 is compound 1 hydrobromide (form D). In some embodiments, the salt of compound 1 is compound 1 hydrobromide (form E). In some embodiments, the salt of compound 1 is compound 1 citrate (form A). In some embodiments, the salt of compound 1 is compound 1 citrate (form B). In some embodiments, the salt of compound 1 is compound 1 citrate (form C).

[0634] The composition may be administered via suitable routes, including but not limited to oral, parenteral, rectal, topical, and excipient administration. The composition may be in liquid, semi-liquid, or solid form and may be formulated in a manner suitable for each route of administration using methods known to those skilled in the art.

[0635] Oral dosage forms include, for example, solid dosage forms (such as tablets, capsules, pills, granules, etc.) and liquid dosage forms (such as oral solutions, oral suspensions, syrups, etc.).

[0636] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a salt of compound 1 or a solvate thereof and a pharmaceutically acceptable excipient.

[0637] How to use

[0638] In one aspect, the present invention provides a method for treating a disease or ailment in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a salt of compound 1.

[0639] In some implementations, the illness or condition is depression. In some implementations, the illness or condition is treatment-resistant depression. In some implementations, the illness or condition is postpartum depression. In some implementations, the illness or condition is major depressive disorder. In some implementations, the illness or condition is bipolar disorder. In some implementations, the illness or condition is epilepsy. In some implementations, the illness or condition is anxiety.

[0640] Example

[0641] The invention is further illustrated by referring to the following embodiments. However, it should be noted that these embodiments, like the above-described embodiments, are illustrative and should not be construed as limiting the scope of the invention in any way.

[0642] “EtOAc” refers to ethyl acetate. “(m)DSC” refers to (adjusted) differential scanning calorimetry. “ACN” refers to acetonitrile. “AR” refers to analytical grade. “DCM” refers to dichloromethane. “DMF” refers to dimethylformamide. “DMSO” refers to dimethyl sulfoxide. “DI” refers to distillation. “DSC” refers to differential scanning calorimetry. “DVS” refers to dynamic vapor adsorption. “eq” refers to equivalent. “EtOH” refers to ethanol. “FaSSIF” refers to intestinal fluid simulated under fasting conditions. “FeSSIF” refers to intestinal fluid simulated under feeding conditions. “1H-NMR” refers to proton nuclear magnetic resonance. “IPA” refers to isopropanol. “IPAC” refers to isopropyl acetate. “IPE” refers to diisopropyl ether. “LC” refers to low crystallinity. “MEK” refers to methyl ethyl ketone. “MeOH” refers to methanol. “MIBK” refers to methyl isobutyl ketone. “MTBE” refers to methyl tert-butyl ether. “NMR” refers to nuclear magnetic resonance. "PLM" refers to polarizing microscope. "RH" refers to relative humidity. "RRT" refers to relative retention time. "RT" refers to room temperature. "RT(min)" refers to retention time. "SGF" refers to simulated gastric juice. "TGA" refers to thermogravimetric analysis. "THF" refers to tetrahydrofuran. "UPLC" refers to ultra-high performance liquid chromatography. "XRPD" refers to X-ray powder diffraction.

[0643] In some cases, the compound 1:acid ratio in the salt of compound 1 described herein was determined by ion chromatography (IC) using the following method: 25 μL of a 10.0 μg / mL sample or standard was injected into a Dionex IonPac AG18 column at a flow rate of 1.0 mL / min, and detected using a Thermo ICS-2100 conductivity detector. The ASRS-4mm suppressor was set to 38 mA, and the column temperature was 30ºC. Chromatographic elution was performed with 15 mM KOH, and the total run time was 20 min.

[0644] X-ray powder diffraction patterns were collected on a Rigaku D / Max-2200 / PC or Bruker D8 Advance powder diffractometer. The sample was irradiated with copper K-α X-rays (λ=1.54179Å) using a generator operating at 40 kV / 40 mA. The sample was scanned in a continuous mode from 3º to 40º, with a sample rotation speed of 15 rpm and a scan rate of 10º / min.

[0645] Single-crystal X-ray analysis: Single-crystal X-ray diffraction data were obtained using a Rigaku XtaLAB Synergy-R(Cu) diffractometer (Micro-Max007HF Cu mode, CuKα: λ = 1.54184 Å, Hypix6000HE detector).

[0646] Use the following SCXRD instrument parameters:

[0647]

[0648] Suitable single crystals with good diffraction quality were isolated from the bulk crystalline sample and coated with Paratone-N (an oil-based cryoprotectant). The crystals were mounted randomly on a polyester film ring and immersed in a nitrogen stream at the temperatures specified in the examples below. Preliminary examination and data collection were performed on a Rigaku XtaLAB Synergy R (CuKα radiation, λ = 1.54184 Å) diffractometer, and analysis was performed using the CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software package.

[0649] The structure was solved using Intrinsic Phasing in the ShelXT (Sheldrick, GM Acta Cryst. 2015, A71, 3-8.) structure analysis program, and the structure was refined using the ShelXL (Version 2017 / 1; Sheldrick, GM Acta Cryst. 2015, C71, 3-8) refinement package to the F-type structures contained in OLEX2 (Dolomanov, OV, Bourhis, LJ, Gildea, RJ, Howard, JAK & Puschmann, HJ Appl. Cryst. 2009, 42, 339-341). 2 Refinement was performed using full matrix least squares. All non-hydrogen atoms underwent anisotropic refinement. The positions of hydrogen atoms bonded to carbon atoms were geometrically calculated and refined using a riding model, but hydrogen atoms bonded to nitrogen and oxygen atoms were freely refined based on a difference Fourier map.

[0650] DSC data were collected on a TA Q2000. For each sample analyzed, approximately 1 mg of sample was placed in a sealed aluminum dish with a pinhole and heated from 25ºC to 250ºC at a rate of 10ºC / min.

[0651] TGA data were collected on a TA Q5000. For each sample analyzed, approximately 4 mg of material was placed in an open platinum dish and heated from 30ºC to 300ºC or <80% by weight at a rate of 10ºC / min.

[0652] Dynamic vapor adsorption (DVS) was performed using the SMS DVS Advantage 1 system. For each sample analyzed, approximately 10 mg of material was transferred to the DVS instrument, and the weight change relative to atmospheric humidity at 25ºC was recorded using the following parameters: equilibrium dm / dt: 0.01% / min (duration: 10 min and maximum: 180 min); drying was set to 0% RH for 120 min; RH (%) measurement steps were 10%, and the RH (%) measurement step range was 0–90–0%.

[0653] Collection on a Bruker 400 MHz magnet 1 ¹H-NMR. For each sample analyzed, approximately 6 mg of material was dissolved in 0.6 mL of d6-DMSO for analysis. As is known to those skilled in the art, 1 The relative ppm shift and integral value of H-NMR resonance can vary depending on various sample factors, including, for example, the water content in d6-DMSO, the ion concentration in the sample, etc. Therefore, the following examples report... 1 H-NMR values ​​should not be considered as characteristics of their respective salts and polycrystalline forms.

[0654] UPLC data were collected by injecting 0.5 µL of sample or standard into a Waters Acquity UPLC Shield RP18 column at a flow rate of 0.8 mL / min using an Agilent 1290 UPLC (detection wavelength: 210 nm). The column was equilibrated with mobile phase A, which consisted of an aqueous solution of 0.1% H3PO4. Mobile phase B was acetonitrile (CAN). The elution program was as follows: after reequilibration, wait one minute; the total run time was 6 minutes.

[0655]

[0656] The crystalline salts described herein were characterized using a polarizing microscope. In some embodiments, the crystalline salts described herein exhibit birefringence, which indicates crystallinity.

[0657] Example 1: Preparation of hydrobromide of compound 1

[0658] The hydrobromide of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0659] Compound 1 HBr (Form A):

[0660] Compound 1 (1.2 kg) was added to ethanol (2.84 kg, 9% w / w water). Another portion of ethanol (0.95 kg, 9% w / w water) was added, and the resulting mixture was heated to an internal temperature of 55–65 °C with stirring until a solution was obtained. The resulting solution was passed through a 10 μm filter and cooled to an internal temperature below 30 °C. Acetone (940 g) was added to the solution containing 48% w / w HBr aqueous solution (523 g), maintaining the temperature below 30 °C and stirring for 1 h. Acetone (8.47 kg) was added, and the resulting slurry was cooled to 0–5 °C and stirred for 1 h. The solid was collected by filtration and washed with acetone (1.88 kg). The resulting solid was dried under vacuum at 50 °C to give the HBr salt of compound 1 (1.17 kg, 82% yield).

[0661] The obtained solid was compound 1 HBr (form A). Ion chromatography determined that the ratio of compound 1 to HBr in compound 1 HBr (form A) was 1:1.02. XPRD is as follows. Figure 2 As shown; DSC and TGA are as follows Figure 3 As shown; and DVS as Figure 4 As shown.

[0662] Compound 1 HBr (Form B):

[0663] 1 g of compound 1 HBr (form A) was suspended in 20 mL of a 0.603 water activity solution (14.5% water in acetone, v / v) to produce a suspension of 50 mg / mL. The suspension was stirred at 700 rpm and maintained at 50 °C for 26 hours. The suspension was centrifuged and the precipitate was collected. The obtained wet product was dried under vacuum at 30 °C for three days to obtain a powder with a yield of 70.82%. The ratio of compound 1 to HBr in compound 1 HBr (form B) was determined to be 1:1.01 by ion chromatography. XPRD is as follows. Figure 5 As shown; DSC and TGA are as follows Figure 6 As shown; and DVS as Figure 7 As shown.

[0664] Compound 1 HBr (form C):

[0665] 500 mg of compound 1 HBr (form A) was dissolved in 4.5 mL of DMSO to produce a clear solution, and then 31.5 mL of water (antisolvent) was added to the DMSO solution. The solution was left to stand at room temperature for 7 days. The precipitate was then separated. The obtained wet product was dried under vacuum at 30 °C for three days to obtain a powder, with a yield of 66.1%. Ion chromatography determined that the ratio of compound 1 to HBr in compound 1 HBr (form C) was 1:1.09. XPRD is as follows. Figure 8 As shown; DSC and TGA are as follows Figure 9 As shown; and DVS as Figure 10 As shown.

[0666] Compound 1 HBr (form D):

[0667] When form B is heated to 160°C, form D is observed using VT-XRPD. XRPD is as follows. Figure 11 As shown; TGA and DSC are as follows Figure 12 As shown.

[0668] Compound 1 HBr (Form E):

[0669] In a 20 mL vial equipped with a stir bar, a solution of compound 1 (1.00 g, 1.0 equivalent) in EtOH (5 mL) was stirred at 60 °C for 30 min. HBr (48% w / w aqueous solution, 0.3 mL, 1.1 equivalent) was added to the mixture, and the mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to 25 °C, and ethyl acetate antisolvent (5 mL) was added to the reaction mixture, followed by stirring for 1 h. The mixture was kept in an ice bath for 30 min, then filtered, the solid was collected, and dried under vacuum at 25 °C overnight to give compound 1 HBr (876 mg, 73.7% yield). XRPD as... Figure 13 As shown; DSC and TGA are as follows Figure 14 As shown.

[0670] General process for preparing compound 1 HBr

[0671] The following general procedure is performed to prepare compound 1 HBr.

[0672] General Process 1

[0673] In a 20 mL vial equipped with a stir bar, a solution of compound 1 (1.00 g, 1.0 equivalent) in solvent (15 mL, 15 mL / g compound 1) was stirred at 60 °C for 30 min. HBr (48% w / w aqueous solution, 0.3 mL, 1.1 equivalent) was added to the reaction mixture, and the mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to 25 °C and stirred for 1 h. The mixture was kept in an ice bath for 30 min (keeping processes 1-2 at 25 °C), then filtered, the solid was collected, and dried under vacuum at 25 °C overnight to give compound 1 HBr.

[0674] General Process 2

[0675] In a 20 mL vial equipped with a stir bar, a solution of compound 1 (1.00 g, 1.0 equivalent) in solvent (3.5 mL, 3.5 mL / g compound 1) was stirred at 60 °C for 30 min. A solution of HBr (48% w / w aqueous solution, 0.3 mL, 1.1 equivalent) in acetone (3.5 mL, 3.5 mL / g compound 1) was added to the reaction mixture, and the mixture was stirred at 60 °C for 1 h. The reaction was cooled to 25 °C and stirred for 1 h. The mixture was kept in an ice bath for 30 min, then filtered, the solid was collected, and dried under vacuum at 25 °C overnight to give compound 1 HBr.

[0676] General Process 3

[0677] In a 20 mL vial equipped with a stir bar, a solution of compound 1 (1.00 g, 1.0 equivalent) in EtOH (5 mL, 5 mL / g compound 1) was stirred at 60 °C for 30 min. HBr (48% w / w aqueous solution, 0.3 mL, 1.1 equivalent) was added to the mixture, and the mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to 25 °C, and then the antisolvent (5 mL, 5 mL / g compound 1) was added to the reaction mixture, and the mixture was stirred for 1 h. The mixture was kept in an ice bath for 30 min, then filtered, the solid was collected, and dried overnight under vacuum at 25 °C to give compound 1 HBr.

[0678] The table below summarizes the preparation of compound 1 HBr according to the general process:

[0679]

[0680]

[0681] Chemical and physical stability tests

[0682] For each salt, approximately 5 mg of the compound was added to an 8 mL glass vial with a porous aluminum foil cap and kept at 60°C, 40°C / 75% RH for 1 week. For photostability testing, the uncapped vials were stored in a photostability chamber and exposed to a total illuminance of 1.2 million lux-hours, while the samples in vials fully covered with aluminum foil served as a dark control. Visual observation was recorded, followed by purity assessment of the residual solids and XPRD data collection.

[0683] The table below shows the chemical and physical stability test results for compound 1 HBr (form A), compound 1 HBr (form B), compound 1 HBr (form C), and the free base of compound 1:

[0684]

[0685] Solubility test in simulated gastric and intestinal fluids

[0686] For each salt, approximately 4–6 mg of Compound 1 or the salt was added to three 2 mL vials. Then, 1 mL of the biorelevant medium (SGF, FaSSIF, or FeSSIF) was added to each vial. All vials were placed on a heat mixer and kept at 37°C while shaking at 700 rpm. If the compound was completely dissolved in the medium, more compound was added until the system was in suspension; if the concentration of the compound exceeded 25 mg / mL, no further substances were added. After shaking at 37°C for 24 hours, 300 μL of suspension was separated from each system for analysis. The sample was centrifuged at 12,000 rpm for 5 min and the supernatant was analyzed by UPLC after 10 dilutions with ACN:H2O (4 / 1, V / V). The final pH of the biorelevant medium was measured and recorded. The table below shows the solubility results (mg / mL) of Compound 1 HBr (form A), Compound 1 HBr (form B), Compound 1 HBr (form C), and Compound 1 free base in the biorelevant solution:

[0687]

[0688] Single-crystal X-ray analysis of compound 1 in HBr form B

[0689] Bulk single crystals of compound 1 in hydrobromide form B, used for SCXRD characterization, were crystallized from a MeOH / MEK (1:3, v / v) solvent mixture by slow evaporation.

[0690] Characterization of the salt by PLM and XRPD showed that it was compound 1 in the form of HBr B.

[0691] Using CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software, cell parameters and orientation matrices were retrieved and refined (least squared refinement) for data collection with a set angle of 45416 reflections within the range of 3.488º < θ < 75.836º. The minimum diffraction angle (θ) of the data collected at 120.00 K was 3.506º, and the maximum diffraction angle (θ) was 68.243º. The final integrity was 100%. The average I / σ of the data was 91.7, and the maximum resolution obtained was 0.83 Å.

[0692] The table below provides SCXRD data obtained using the methods described in this paper.

[0693]

[0694] Single-crystal X-ray analysis of compound 1 in the form of HBr (E)

[0695] Bulk single crystals of compound 1 in hydrobromide form E, used for SCXRD characterization, were crystallized from a MeOH / MEK (1:3, v / v) solvent mixture by slow evaporation. Characterization of the salt by PLM and XRPD confirmed that it was compound 1 in HBr form E.

[0696] Data collection at 120 K Cellular parameters and orientation matrices were retrieved and refined (least squared refined) using CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software with a set angle of 10196 reflections in the range of 3.499º < θ < 75.657º for data collection. The minimum diffraction angle (θ) of the data collected at 120.00(10) K was 3.508º, and the maximum diffraction angle (θ) was 66.553º. The final integrity was 100%. The average I / σ of the data was 19.3, and the maximum resolution obtained was 0.84 Å.

[0697] Data collection at room temperature Using CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software, with a set angle of 17551 reflections within the range of 3.483º < θ < 75.825º, cell parameters and orientation matrices were retrieved and refined (least squared refinement) for data collection. The minimum diffraction angle (θ) of the data collected at room temperature was 3.496º, and the maximum diffraction angle (θ) was 66.597º. The final integrity was 100%. The average I / σ of the data was 40.0, and the maximum resolution obtained was 0.84 Å.

[0698] The table below provides SCXRD data obtained using the methods described in this paper.

[0699]

[0700] Example 2: Preparation of citrate of compound 1

[0701] The citrate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0702] Compound 1 citrate (form A):

[0703] Compound 1 (1 kg) was added to a mixture of ethanol (2.37 kg, 9% w / w water) and isopropyl acetate (2.61 kg). A further portion of ethanol (0.39 kg, 9% w / w water) and isopropyl acetate (0.44 kg) was added. The resulting mixture was heated to 55–65 °C with stirring until a solution was obtained. The resulting solution was passed through a 10 μm filter. A solution of citric acid monohydrate (541 g) in ethanol (0.79 kg, 9% w / w water) and isopropyl acetate (0.87 kg) was added with stirring. A further portion of ethanol (0.39 kg) and isopropyl acetate (0.44 kg) was used for the quantitative transfer of citric acid into the reactor. The resulting mixture was cooled to 0–5 °C for 1 h with stirring. The obtained solid was collected by filtration, washed with isopropyl acetate (1.29 kg), and dried under vacuum at 50 °C to give compound 1 citrate (1.174 kg, 81% yield).

[0704] The obtained solid was citrate of compound 1 (form A). HPLC analysis showed that the ratio of compound 1 to citric acid in citrate of compound 1 (form A) was 1:1.02. XPRD results are as follows: Figure 15 As shown; DSC and TGA are as follows Figure 16 As shown; and DVS as Figure 17 As shown.

[0705] In deuterated DMSO, through 1 H-NMR analysis of compound 1 citrate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6): δ 0.48 - 0.88 (m, 7 H) 2.03 - 2.22 (m, 2 H) 2.46 -2.86 (m, 28 H) 3.00 - 3.17 (m, 3 H) 3.19 - 3.46 (m, 5 H) 4.74 - 5.35 (m, 2 H)7.09 (s, 1 H) 7.19 (s, 1 H) 7.86 (s, 1 H).

[0706] Compound 1 citrate (form B):

[0707] 500 mg of compound 1 citrate (form A) was dissolved in 4.0 mL of a 0.901 water activity solution (65% water, in acetone, v / v) to produce a suspension of 125 mg / mL. The suspension was stirred at 300 rpm and kept at 50 °C for 3 days. The suspension was centrifuged and the precipitate was collected. The wet crude product was dried under vacuum at 30 °C for one day to obtain a powder with a yield of 56.9%. The ratio of compound 1 to citric acid in compound 1 citrate (form B) was determined by ion chromatography to be 1:1.17. XPRD Figure 18 As shown; DSC and TGA are as follows Figure 19 As shown; and DVS as Figure 20 As shown.

[0708] In deuterated DMSO, through 1 H-NMR analysis of compound 1 citrate (form B) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6): δ 0.53 - 0.79 (m, 7 H) 0.85 - 1.76 (m, 24 H) 1.99 -2.14 (m, 3 H) 2.32 - 2.35 (m, 1 H) 2.61 - 2.74 (m, 6 H) 3.00 - 3.09 (m, 2 H)4.89 - 5.13 (m, 1 H) 6.99 (s, 1 H) 7.11 (s, 1 H) 7.74 (s, 1 H).

[0709] Compound 1 citrate (form C):

[0710] The sample of compound 1 in citrate form A was stirred at 50°C to form a suspension in acetonitrile. The resulting solid was separated by filtration.

[0711] General process for preparing compound 1 citrate

[0712] The following general procedure is performed to prepare citrate of compound 1.

[0713] General Process A

[0714] Compound 1 (1.00 g, 1.0 equivalent) and a solvent or co-solvent were added to a 20 mL vial equipped with a stir bar. The resulting mixture was heated to 60 °C for 30 minutes. At 60 °C, a solution of citric acid monohydrate (0.54 g, 1.1 equivalent) in the solvent or co-solvent (preheated to dissolve) was added to the mixture and stirred for 1 hour. The reaction was cooled to 25 °C and stirred overnight. The suspension was filtered and the wet filter cake was washed with acetone. The solid was collected and dried under vacuum at 25 °C overnight to give the citrate of compound 1.

[0715] General Process A-2

[0716] Compound 1 (1.00 g, 1.0 equivalent) and a cosolvent (10 mL, 10 mL / g compound 1) were added to a 20 mL vial equipped with a stir bar. The resulting mixture was heated to 60 °C for 30 minutes. At 60 °C, a solution of citric acid monohydrate (0.54 g, 1.1 equivalent) in the cosolvent (2 mL, 2 mL / g compound 1) was added (preheated to dissolve) and stirred for 1 hour. The reaction was cooled to 0 °C (no precipitation occurred). The mixture was dried under vacuum and the cosolvent (3 mL, 3 mL / g compound 1) was added at 60 °C. The reaction was cooled to 25 °C and stirred overnight. The suspension was filtered and the wet filter cake was washed with acetone. The solid was collected and dried under vacuum at 25 °C overnight to give compound 1 citrate.

[0717] General Process B

[0718] Compound 1 (1.00 g, 1.0 equivalent) and EtOH (3.5 mL, 3.5 mL / g Compound 1) were added to a 20 mL vial equipped with a stir bar. The resulting mixture was heated to 60 °C for 30 minutes. At 60 °C, a solution of citric acid monohydrate (0.54 g, 1.1 equivalent) in EtOH (1.5 mL, 1.5 mL / g Compound 1) was added (preheated to dissolve) and stirred for 1 hour. The reaction was cooled to 25 °C, and an antisolvent (5 mL, 5 mL / g Compound 1) was added at 25 °C. The reaction was cooled to 0 °C and then stirred for 1 hour. The mixture was stirred overnight at 25 °C. The reaction was cooled to 0 °C and then stirred for 1 hour. The suspension was filtered, and the wet cake was washed with acetone. The solid was collected and dried overnight under vacuum at 25 °C to give the citrate of Compound 1.

[0719] General Process C

[0720] Compound 1 (5.00 g, 1.0 equivalent) and EtOH / IPAc (1:1, 40 mL, 8 mL / g compound 1) were added to a four-necked 250 mL flask equipped with a mechanical stirrer (5.5 cm paddle; 100 rpm), a thermometer, and an N2 inlet. The resulting mixture was heated to 60 °C for 30 min. At 60 °C, a solution of citric acid monohydrate (2.73 g, 1.1 equivalent) in EtOH / IPAc (1:1, 10 mL, 2 mL / g compound 1) was added (preheated to dissolve) and stirred for 1 h. The reaction was cooled to 25 °C and then stirred for 1 h. The reaction was cooled to 0 °C and then stirred for 30 min. The suspension was filtered, and the wet filter cake was washed with acetone. The solid was collected and dried overnight under vacuum at 50 °C to give compound 1 citrate.

[0721] The table below summarizes the preparation of citrate of compound 1 according to these general processes:

[0722]

[0723] Chemical and physical stability tests

[0724] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the chemical and physical stability test results for Compound 1 citrate (form A), Compound 1 citrate (form B), and Compound 1 free base:

[0725]

[0726] ICH stability test of compound 1 citrate (form A):

[0727] The stability of compound 1 citrate (form A) was tested according to the ICH guidelines for accelerated stability studies. The results of the accelerated stability study are shown in the table below. At the 3-month time point, the data show that the determination, purity, and polymorphic stability of compound 1 citrate (form A) were maintained.

[0728]

[0729] Solubility test in simulated gastric and intestinal fluids

[0730] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of Compound 1 citrate (form A), Compound 1 citrate (form B), and Compound 1 free base in biologically relevant solutions:

[0731]

[0732] Single-crystal X-ray structure of compound 1 in citrate form A

[0733] The bulk single-crystal sample of compound 1 in citrate form A, used for SCXRD characterization, was crystallized from a THF solvent mixture by slow evaporation.

[0734] Characterization of the salt by PLM and XRPD showed that it was in the citrate form A of compound 1.

[0735] Using CrysAlisPro (Rigaku, V1.171.40.14e, 2018) software, cell parameters and orientation matrices were retrieved and refined (least squared refinement) for data collection using a set angle of 64393 reflections within the range of 3.7580º < θ < 75.8720º. The minimum diffraction angle (θ) of the data collected at 120.00 K was 3.785º, and the maximum diffraction angle (θ) was 66.597º. The final integrity was 99.3%. The average I / σ of the data was 81.3, and the maximum resolution obtained was 0.84 Å.

[0736] The table below provides SCXRD data obtained using the methods described in this paper.

[0737]

[0738] Example 3: Preparation of methanesulfonate of compound 1

[0739] The following exemplary methods can be used to prepare the methanesulfonate salt of compound 1 from compound 1.

[0740] Compound 1, methanesulfonate (form A) :

[0741] 200 mg of compound 1 was dissolved in 10.0 mL of EtOAc at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1 hour. Then, a solution of 1.1 equivalents of methanesulfonic acid in EtOAc (1.027 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 hours, then cooled to 25 °C and maintained at 25 °C for 20 hours. The suspension was centrifuged, the precipitate was collected, and washed with EtOAc. The obtained wet product was dried under vacuum at 35 °C for 22 hours to give 234.52 mg of powder, with a yield of 94.1%.

[0742] The obtained solid was compound 1 methanesulfonate (form A). Ion chromatography determined that the ratio of compound 1 to methanesulfonic acid in compound 1 methanesulfonate (form A) was 1:1.08. XPRD is as follows. Figure 22 As shown; DSC and TGA are as follows Figure 23 As shown; and DVS as Figure 24 As shown.

[0743] In deuterated DMSO, through 1 H-NMR analysis of compound 1 methanesulfonate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6): δ 0.54 - 0.81 (m, 7 H) 0.84 (t, J=7.44 Hz, 1 H) 1.84- 2.17 (m, 3 H) 2.31 (s, 3 H) 2.41 - 2.59 (m, 20 H) 2.65 - 2.83 (m, 1H) 3.05(s, 2 H) 3.22 - 3.48 (m, 1 H) 3.23 - 3.51 (m, 6 H) 4.96 - 5.52 (m, 1 H) 4.96- 5.52 (m, 1 H) 7.62 (s, 1 H) 7.55 - 7.64 (m, 1 H) 7.62 - 7.77 (m, 1 H) 9.01 (s, 1 H).

[0744] Compound 1 methanesulfonate (form B):

[0745] 200 mg of compound 1 was dissolved in 10.0 mL of EtOAc at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1 hour. Then, a solution of 1.1 equivalents of methanesulfonic acid in EtOAc (1.027 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 hours, then cooled to 25 °C and maintained at 25 °C for 20 hours. The suspension was centrifuged, the precipitate was collected, and washed with EtOAc. The obtained wet product was dried under vacuum at 35 °C for 22 hours to give 234.52 mg of powder, with a yield of 94.1%.

[0746] The resulting solid is compound 1 methanesulfonate (form B). XPRD as Figure 25A As shown.

[0747] Compound 1, methanesulfonate (form C):

[0748] Compound 1, methanesulfonate (form C), was prepared using ACN solvent and methanesulfonic acid. For the liquid counterion, 50 mg of compound 1 was weighed into a 2 mL vial, and then 743 μL of solvent was added to the vial. A 1.1 equivalent counterion solution (257 μL, concentration: 0.5 mol / L) of the corresponding solvent was then added to the vial. The vial was placed on a hot mixer with a stir bar and heated to 50 °C. After maintaining the temperature at 50 °C for 18 hours with stirring at 900 rpm, the vial was cooled to 25 °C. After maintaining the temperature at 25 °C for 1 hour, the solids in the suspension were separated by centrifugation and dried overnight in a vacuum oven at 30 °C.

[0749] The resulting solid is compound 1 methanesulfonate (form C). XPRD as Figure 25B As shown.

[0750] Compound 1, methanesulfonate (form D):

[0751] Approximately 5 mg of compound 1 methanesulfonate (form A) was added to an 8 mL glass vial with a porous aluminum foil cap and incubated at 60 °C, 40 °C / 75% RH for 1 week. The appearance was recorded visually, followed by purity assessment and XPRD data collection of the residual solid. The resulting solid was compound 1 methanesulfonate (form D). The dried solid was characterized by PLM and XRPD.

[0752] XPRD, for example Figure 26 As shown.

[0753] Chemical and physical stability tests

[0754] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 methanesulfonate (form A) and compound 1 free base:

[0755]

[0756] Solubility test in simulated gastric and intestinal fluids

[0757] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 methanesulfonate (form A) and compound 1 free base in biologically relevant solutions:

[0758]

[0759] Example 4: Preparation of phosphate of compound 1

[0760] The following exemplary methods can be used to prepare the phosphate of compound 1 from compound 1.

[0761] 200 mg of compound 1 was dissolved in 10.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of phosphoric acid in acetone (1.027 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C for 20 h. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 30 °C for 42 h to give 233.51 mg of powder, with a yield of 93.3%.

[0762] The obtained solid was phosphate of compound 1 (form A). Ion chromatography determined that the ratio of compound 1 to phosphoric acid in phosphate of compound 1 (form A) was 1:0.9. XPRD is as follows. Figure 27 As shown; DSC and TGA are as follows Figure 28 As shown; and DVS as Figure 29 As shown.

[0763] Chemical and physical stability tests

[0764] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 phosphate (form A) and compound 1 free base:

[0765]

[0766] Solubility test in simulated gastric and intestinal fluids

[0767] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 phosphate (form A) and compound 1 free base in biologically relevant solutions:

[0768]

[0769] Example 5: Preparation of L(+)-tartrate of compound 1

[0770] The L(+)-tartrate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0771] Compound 1L(+)-tartrate (form A) :

[0772] 200 mg of compound 1 was dissolved in 10.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, 1.1 equivalents of L(+)-tartaric acid powder (77 mg, 0.5 mmol) were added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C for 20 h. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 30 °C for 42 h to give 237.95 mg of powder, with a yield of 85.9%.

[0773] The obtained solid was compound 1 L(+)-tartrate (form A). Ion chromatography determined that the ratio of compound 1 to tartaric acid in compound 1 L(+)-tartrate (form A) was 1:1.15. XPRD is as follows. Figure 30 As shown; DSC and TGA are as follows Figure 31 As shown; and DVS as Figure 32 As shown.

[0774] In deuterated DMSO, through 1 H-NMR analysis of compound 1 L(+)-tartrate (form A) yielded the following chemical shifts: 1 H NMR (400 MHz, DMSO-d6): δ 0.49 - 0.84 (m, 7 H) 0.90 - 1.75 (m, 21 H)1.94 - 2.21 (m, 3 H) 2.35 - 2.58 (m, 14 H) 2.66 - 2.80 (m, 1 H) 3.10 (s, 2 H)3.23 - 3.34 (m, 3 H) 4.24 - 4.39 (m, 2 H) 4.80 - 5.19 (m, 2 H) 6.98 (s, 1 H)7.12 (s, 1 H) 7.67 (s, 1 H).

[0775] Compound 1L(+)-tartrate (form B) :

[0776] 200 mg of compound 1 was dissolved in 10.0 mL of EtOAc at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1 hour. Then, 1.1 equivalents of L(+)-tartaric acid powder (77 mg, 0.5 mmol) were added to the RX-0001175 solution and incubated at 60 °C for 3 hours, followed by cooling to 25 °C and maintaining at 25 °C for 20 hours. The suspension was centrifuged, the precipitate was collected, and washed with EtOAc. The obtained wet product was dried under vacuum at 35 °C for 22 hours to give 254.08 mg of powder, with a yield of 91.7%.

[0777] The obtained solid was compound 1 L(+)-tartrate (form B). Ion chromatography determined that the ratio of compound 1 to tartaric acid in compound 1 L(+)-tartrate (form B) was 1:1.19. XPRD is as follows. Figure 33 As shown; DSC and TGA are as follows Figure 34 As shown; and DVS as Figure 35 As shown.

[0778] In deuterated DMSO, through 1 H-NMR analysis of compound 1 L(+)-tartrate (form B) yielded the following chemical shifts: 1 H NMR (400 MHz, DMSO-d6): δ 0.50 - 0.82 (m, 6 H) 1.91 - 2.22 (m, 2 H) 3.03 (s, 2 H) 3.24 (s, 2 H) 3.14 - 3.53 (m, 1 H) 4.27 (s, 2 H) 4.54 - 5.21 (m, 2H) 6.71 - 7.18 (m, 2H) 7.59 (s, 1H).

[0779] Chemical and physical stability tests

[0780] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for Compound 1 L(+)-tartrate (form A), Compound 1 L(+)-tartrate (form B), and Compound 1 free base:

[0781]

[0782] Solubility test in simulated gastric and intestinal fluids

[0783] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of Compound 1 L(+)-tartrate (form A), Compound 1 L(+)-tartrate (form B), and Compound 1 free base in biologically relevant solutions:

[0784]

[0785] Example 6: Preparation of fumarate of compound 1

[0786] The fumarate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0787] Compound 1, fumarate (form A) :

[0788] 200 mg of compound 1 was dissolved in 10.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, 1.1 equivalents of fumaric acid powder (60 mg, 0.51 mmol) was added to the compound 1 solution and incubated at 60 °C for 3 h, followed by cooling to 25 °C and maintaining at 25 °C for 20 h. Then, 2 volumes of heptane were added to the acetone mixture to obtain a suspension. The suspension was centrifuged, the precipitate was collected, and then dried under vacuum at 25 °C for 42 h to obtain 75.58 mg of powder, with a yield of 29.1%.

[0789] The obtained solid was compound 1 fumarate (form A). Ion chromatography determined that the ratio of compound 1 to fumaric acid in compound 1 fumarate (form A) was 1:1.37. XPRD is as follows. Figure 36 As shown, and DSC and TGA as Figure 37 As shown.

[0790] In deuterated DMSO, through 1 H-NMR analysis of compound 1 fumarate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6): δ 0.45 - 0.80 (m, 7 H) 1.97 - 2.13 (m, 3 H) 2.47 -2.58 (m, 12 H) 2.63 - 2.78 (m, 1 H) 2.63 - 2.78 (m, 1 H) 3.04 (s, 2 H) 3.25(s, 3 H) 4.80 - 5.14 (m, 1 H) 4.80 - 5.14 (m, 1 H) 6.63 (s, 3 H) 6.91 (s, 1H) 7.05 (s, 1 H) 7.52 - 7.69 (m, 1 H).

[0791] Compound 1, fumarate (form B) :

[0792] 200 mg of compound 1 was dissolved in 10.0 mL of ethyl acetate at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1 hour. Then, 1.1 equivalents of fumaric acid powder (60 mg, 0.51 mmol) were added to the compound 1 solution. The solution was maintained at 60 °C for 3 hours, then cooled to 25 °C and maintained at 25 °C for 20 hours. During the cooling process, the clear solution became a suspension. The suspension was then centrifuged, the precipitate was collected, and dried under vacuum at 35 °C for 22 hours to give 156.78 mg of powder, with a yield of 60.4%.

[0793] The obtained solid was compound 1 fumarate (form B). Ion chromatography determined that the ratio of compound 1 to fumaric acid in compound 1 fumarate (form B) was 1:1.55. XPRD is as follows. Figure 38 As shown, DSC and TGA are as follows Figure 39 As shown; and DVS as Figure 40 As shown.

[0794] 1 H NMR (400 MHz, DMSO-d6): δ 0.43 - 0.79 (m, 8 H) 1.88 - 2.13 (m, 2 H)3.03 (s, 2 H) 3.10 - 3.39 (m, 4 H) 4.38 - 5.21 (m, 3 H) 6.61 (s, 2 H) 6.59 -6.64 (m, 1 H) 6.74 - 7.16 (m, 2 H) 7.56 (s, 1 H).

[0795] Compound 1, fumarate (form C) :

[0796] 50 mg of compound 1 and 1.1 equivalents of the counterion of fumaric acid in solid form were weighed into separate 2 mL vials, and then 1 mL of solvent ACN was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 48 hours.

[0797] The resulting solid was the fumarate of compound 1 (form C). The dried solid was characterized by PLM and XRPD.

[0798] XPRD, for example Figure 41 As shown.

[0799] Compound 1, fumarate (form D) :

[0800] Approximately 5 mg of compound 1 fumarate (form A) was added to an 8 mL glass vial with a porous aluminum foil cap and incubated at 60°C, 40°C / 75% RH for 1 week. The appearance was recorded visually, followed by purity assessment and XPRD data collection for the residual solid. The resulting solid was compound 1 fumarate (form D). The dried solid was characterized by PLM and XRPD. XPRD data are as follows: Figure 42 As shown.

[0801] Chemical and physical stability tests

[0802] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 fumarate (form A) and compound 1 free base:

[0803]

[0804] Solubility test in simulated gastric and intestinal fluids

[0805] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 fumarate (form A) and compound 1 free base in biologically relevant solutions:

[0806]

[0807] Example 7: Preparation of toluenesulfonate of compound 1

[0808] The toluenesulfonate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0809] Compound 1, toluenesulfonate (form A) :

[0810] 200 mg of compound 1 was dissolved in 10.0 mL of ACN at 60 °C while stirring at 500 rpm and maintaining the solution at 60 °C for 1 hour. Then, 1.1 equivalents of a solution of p-toluenesulfonic acid in ACN (1.027 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 hours, then cooled to 25 °C and maintained at 25 °C for 20 hours. The suspension was centrifuged, the precipitate was collected, and washed with ACN. The obtained wet product was dried under vacuum at 35 °C for 22 hours to give a powder of 141.85 g, with a yield of 49.2%.

[0811] The obtained solid was compound 1 toluenesulfonate (form A). Ion chromatography determined that the ratio of compound 1 to toluenesulfonic acid in compound 1 toluenesulfonate (form A) was 1:1.09. XPRD is as follows. Figure 43 As shown; DSC and TGA are as follows Figure 44 As shown; and DVS as Figure 45 As shown.

[0812] In deuterated DMSO, through 1 H-NMR analysis of compound 1 toluenesulfonate (form A) yielded the following chemical shifts: 1HNMR (400 MHz, DMSO-d6): δ 0.50 - 0.79 (m, 7 H) 1.98 - 2.15 (m, 3 H) 2.28 (s,4 H) 2.49 (s, 23 H) 2.60 - 2.76 (m, 1 H) 3.03 (s, 2 H) 3.21 - 3.34 (m, 5 H) 4.85 - 5.45 (m, 2 H) 7.10 (d, J=7.78 Hz, 2 H) 7.45 (s, 1 H) 7.46 - 7.73 (m, 3H) 8.99 (s, 1 H).

[0813] Compound 1, toluenesulfonate (form B) :

[0814] 50 mg of compound 1 and 1.1 equivalents of the counterion of p-toluenesulfonic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of EtOAc solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried overnight in a vacuum oven at 30°C.

[0815] The resulting solid is compound 1 toluenesulfonate (form B). XPRD as Figure 46 As shown.

[0816] Compound 1, toluenesulfonate (form C) :

[0817] Approximately 5 mg of compound 1 toluenesulfonate (form A) was added to an 8 mL glass vial with a porous aluminum foil cap and incubated at 60 °C, 40 °C / 75% RH for 1 week. The appearance was recorded visually, followed by purity assessment and XPRD data collection of the residual solid. The resulting solid was compound 1 toluenesulfonate (form C). The dried solid was characterized by PLM and XRPD.

[0818] The resulting solid is compound 1 toluenesulfonate (form C). XPRD as Figure 47 As shown.

[0819] Chemical and physical stability tests

[0820] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 toluenesulfonate (form A) and compound 1 free base:

[0821]

[0822] Solubility test in simulated gastric and intestinal fluids

[0823] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 toluenesulfonate (form A) and compound 1 free base in biologically relevant solutions:

[0824]

[0825] Example 8: Preparation of glucuronide of compound 1

[0826] The glucuronide of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0827] Compound 1, glucuronide (form A) :

[0828] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, 1.1 equivalents of D-glucuronic acid solid (248.62 mg) were added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 739.32 mg of powder, with a yield of 98.76%.

[0829] The obtained solid was compound 1 glucuronate (form A). Ion chromatography determined that the ratio of compound 1 to glucuronic acid in compound 1 glucuronate (form A) was 1:1.09. XPRD is as follows. Figure 48 As shown; DSC and TGA are as follows Figure 49 As shown; and DVS as Figure 50 As shown.

[0830] In deuterated DMSO, through 1 H-NMR analysis of compound 1 glucuronide (form A) yielded the following chemical shifts: 1HNMR (400 MHz, DMSO-d6) δ ppm 0.49 - 0.81 (m, 7 H) 0.83 - 1.73 (m, 22 H) 1.98- 2.13 (m, 2 H) 2.68 (br t, J=8.76 Hz, 1 H) 2.90 - 3.08 (m, 3 H) 3.10 - 3.20(m, 2 H) 3.57 (d, J=9.76 Hz, 1 H) 3.95 - 4.14 (m, 2 H) 4.33 (d, J=7.75 Hz, 1H) 4.78 - 5.11 (m, 4 H) 6.51 (br s, 1 H) 6.88 (s, 1 H) 7.03 (s, 1 H) 7.54 (s, 1 H).

[0831] Chemical and physical stability tests

[0832] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 glucuronide (form A) and compound 1 free base:

[0833]

[0834] Solubility test in simulated gastric and intestinal fluids

[0835] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 glucuronate (form A) and compound 1 free base in biologically relevant solutions:

[0836]

[0837] Compound 1, glucuronide (form B) :

[0838] 50 mg of compound 1 and 1.1 equivalents of the counterion of D-glucuronic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of solvent EtOAc / ACN was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0839] Characterization of dried solids using PLM and XRPD ( Figure 51 ).

[0840] Example 9: Preparation of ethanesulfonate of compound 1

[0841] The ethanesulfonate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0842] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of ethanesulfonic acid in propanol (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 546.88 mg of powder, with a yield of 84.68%.

[0843] The obtained solid was ethanesulfonate of compound 1 (form A). Ion chromatography determined that the ratio of compound 1 to ethanesulfonic acid in ethanesulfonate of compound 1 (form A) was 1:1.17. XPRD is as follows. Figure 52 As shown; DSC and TGA are as follows Figure 53 As shown; and DVS as Figure 54 As shown.

[0844] In deuterated DMSO, through 1 H-NMR analysis of compound 1 ethanesulfonate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6) δ ppm 0.52 - 0.81 (m, 7 H) 0.83 - 1.78 (m, 25 H) 1.99- 2.17 (m, 3 H) 2.39 (q, J=7.42 Hz, 2 H) 2.69 - 2.80 (m, 1 H) 3.05 (s, 2 H)3.43 (br s, 4 H) 5.11 - 5.46 (m, 2 H) 7.54 - 7.77 (m, 2 H) 9.02 (s, 1 H).

[0845] Chemical and physical stability tests

[0846] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 ethanesulfonate (form A) and compound 1 free base:

[0847]

[0848] Solubility test in simulated gastric and intestinal fluids

[0849] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 ethanesulfonate (form A) and compound 1 free base in biologically relevant solutions:

[0850]

[0851] Example 10: Preparation of the sulfate of compound 1

[0852] The sulfate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0853] 200 mg of compound 1 was dissolved in 10.0 mL of ACN at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1 hour. Then, a solution of 1.1 equivalents of sulfuric acid in ACN (1.027 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 hours, then cooled to 25 °C and maintained at 25 °C for 20 hours. The suspension was centrifuged, the precipitate was collected, and washed with ACN. The obtained wet product was dried under vacuum at 35 °C for 22 hours to give 177.38 mg of powder, with a yield of 70.9%.

[0854] The obtained solid was sulfate of compound 1 (form A). Ion chromatography determined that the ratio of compound 1 to sulfuric acid in sulfate 1 (form A) was 1:1.03. XPRD is as follows. Figure 55 As shown; DSC and TGA are as follows Figure 56 As shown; and DVS as Figure 57 As shown.

[0855] Chemical and physical stability tests

[0856] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for the sulfate (form A) of compound 1 and the free base of compound 1:

[0857]

[0858] Solubility test in simulated gastric and intestinal fluids

[0859] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 sulfate (form A) and compound 1 free base in biologically relevant solutions:

[0860]

[0861] Example 11: Preparation of ascorbate of compound 1

[0862] The ascorbate salt of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0863] Compound 1 Ascorbate (Form A):

[0864] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, 1.1 equivalents of ascorbic acid powder (226 mg) were added to the compound 1 solution and incubated at 60 °C for 3 h, followed by cooling to 25 °C and maintaining at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 264.1 mg of powder, with a yield of 36.3%.

[0865] The obtained solid was compound 1 ascorbate (form A). Ion chromatography determined that the ratio of compound 1 to ascorbic acid in compound 1 ascorbate (form A) was 1:0.98. XPRD is as follows. Figure 58 As shown; DSC and TGA are as follows Figure 59 As shown; and DVS as Figure 60 As shown.

[0866] In deuterated DMSO, through 1 ¹H-NMR analysis of compound 1 ascorbate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6) δ ppm 0.51 - 0.81 (m, 7 H) 0.83 - 1.76 (m, 22 H) 1.98- 2.14 (m, 4 H) 2.33 (br s, 1 H) 2.64 - 2.72 (m, 1 H) 3.04 (s, 2 H) 3.25 (s,3 H) 3.41 - 3.45 (m, 3 H) 3.73 (br t, J=7.65 Hz, 1 H) 4.71 (d, J=1.51 Hz, 1H) 4.87 - 5.11 (m, 3 H) 6.98 (s, 1 H) 7.10 (s, 1 H) 7.71 (s, 1 H).

[0867] Chemical and physical stability tests

[0868] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 ascorbate (form A) and compound 1 free base:

[0869]

[0870] Solubility test in simulated gastric and intestinal fluids

[0871] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 ascorbate (form A) and compound 1 free base in biologically relevant solutions:

[0872]

[0873] Compound 1 ascorbate (form B) :

[0874] 50 mg of compound 1 and 1.1 equivalents of the counterion of ascorbic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of ACN solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 21 hours with constant stirring at 500 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0875] The dry solids were characterized by PLM and XRPD.

[0876] Example 12: Preparation of naphthalene disulfonate of compound 1

[0877] The following exemplary methods can be used to prepare the naphthalene disulfonate of compound 1 from compound 1.

[0878] Compound 1, naphthalene disulfonate (form A)

[0879] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of naphthalene-1,5-disulfonic acid tetrahydrate in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 675.62 mg of a pale pink powder, with a yield of 69.38%.

[0880] The obtained solid was compound 1 naphthalene disulfonate (form A). Ion chromatography determined that the ratio of compound 1 to naphthalene-1,5-disulfonic acid in compound 1 naphthalene disulfonate (form A) was 1:0.7. XPRD results are as follows: Figure 62 As shown; DSC and TGA are as follows Figure 63 As shown; and DVS as Figure 64 As shown.

[0881] In deuterated DMSO, through 1 H-NMR analysis of compound 1-naphthalene disulfonate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6) δ ppm 0.51 - 0.81 (m, 7 H) 0.85 - 1.76 (m, 21 H) 2.00- 2.15 (m, 2 H) 2.34 (s, 1 H) 2.64 - 2.78 (m, 1 H) 3.05 (s, 2 H) 3.25 (s, 4H) 5.16 - 5.38 (m, 2 H) 7.37 - 7.45 (m, 1 H) 7.62 (s, 1 H) 7.68 (s, 1 H) 7.93 (d, J=6.88 Hz, 1 H) 8.86 (d, J=8.63 Hz, 1 H) 9.01 (s, 1 H).

[0882] Chemical and physical stability tests

[0883] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for Compound 1 naphthalene disulfonate (form A) and Compound 1 free base:

[0884]

[0885] Solubility test in simulated gastric and intestinal fluids

[0886] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of Compound 1 naphthalene disulfonate (form A) and Compound 1 free base in biologically relevant solutions:

[0887]

[0888] Compound 1: Naphthalene disulfonate (form B):

[0889] 50 mg of compound 1 and 1.1 equivalents of the counterion of solid naphthalene-1,5-disulfonic acid tetrahydrate were weighed into separate 2 mL vials. Then, 1 mL of solvent IPA / water (95 / 5, v / v) was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 21 hours with constant stirring at 500 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0890] Characterization of dried solids using PLM and XRPD ( Figure 65 ).

[0891] Example 13: Preparation of malonate of compound 1

[0892] The malonate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0893] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of malonic acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The resulting wet product was dried under vacuum at 25 °C for 72 h.

[0894] The obtained solid was compound 1 malonate (form A). Ion chromatography determined that the ratio of compound 1 to malonic acid in compound 1 malonate (form A) was 1:1.28. XPRD is as follows. Figure 66 As shown; and DSC and TGA as shown Figure 67 As shown.

[0895] In deuterated DMSO, through 1 H-NMR analysis of compound 1 malonate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6) δ ppm 0.50 - 0.79 (m, 7 H) 0.84 - 1.75 (m, 20 H) 1.91 (s, 1 H) 2.00 - 2.12 (m, 2 H) 2.65 - 2.73 (m, 1 H) 3.04 (s, 2 H) 3.13 (s, 3H) 4.92 - 5.15 (m, 2 H) 7.03 - 7.20 (m, 2 H) 7.91 (s, 1 H).

[0896] Chemical and physical stability tests

[0897] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for Compound 1 malonate (form A) and Compound 1 free base:

[0898]

[0899] Solubility test in simulated gastric and intestinal fluids

[0900] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of Compound 1 malonate (form A) and Compound 1 free base in biologically relevant solutions:

[0901]

[0902] Example 14: Preparation of benzenesulfonate of compound 1

[0903] The benzenesulfonate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0904] Compound 1, benzenesulfonate (form A)

[0905] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of benzenesulfonic acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 654.68 mg of powder, with a yield of 92.56%.

[0906] The obtained solid was compound 1 benzenesulfonate (form A). Ion chromatography determined that the ratio of compound 1 to benzenesulfonic acid in compound 1 benzenesulfonate (form A) was 1:0.94. XPRD is as follows. Figure 68 As shown; DSC and TGA are as follows Figure 69 As shown; and DVS as Figure 70 As shown.

[0907] In deuterated DMSO, through 1 H-NMR analysis of compound 1 benzenesulfonate (form A) yielded the following chemical shifts: 1HNMR (400 MHz, DMSO-d6) δ ppm 0.53 - 0.80 (m, 7 H) 0.83 - 1.78 (m, 21 H) 1.99- 2.15 (m, 3 H) 2.29 - 2.36 (m, 1 H) 2.56 (br s, 1 H) 2.66 - 2.77 (m, 1 H)3.05 (s, 2 H) 3.25 (s, 4 H) 4.03 (br s, 1 H) 5.15 - 5.39 (m, 2 H) 7.27 - 7.36 (m, 3 H) 7.55 - 7.70 (m, 4 H) 8.97 (s, 1 H).

[0908] Chemical and physical stability tests

[0909] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 benzenesulfonate (form A) and compound 1 free base:

[0910]

[0911] Solubility test in simulated gastric and intestinal fluids

[0912] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 benzenesulfonate (form A) and compound 1 free base in biologically relevant solutions:

[0913]

[0914] Compound 1, benzenesulfonate (form B)

[0915] 50 mg of compound 1 and 1.1 equivalents of the counterion of benzenesulfonic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of ACN solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 21 hours with constant stirring at 500 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0916] Dry solids obtained by PLM and XRPD characterization Figure 71 ).

[0917] Example 15: Preparation of hydroxyethyl sulfonate of compound 1

[0918] The hydroxyethyl sulfonate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0919] Compound 1-hydroxyethyl sulfonate (form A)

[0920] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of 2-hydroxyethanesulfonic acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 493.12 mg of powder, with a yield of 74.64%.

[0921] The obtained solid was compound 1-hydroxyethyl sulfonate (form A). Ion chromatography determined that the ratio of compound 1 to 2-hydroxyethanesulfonic acid in compound 1-hydroxyethyl sulfonate (form A) was 1:1.09. XPRD is as follows. Figure 72 As shown; DSC and TGA are as follows Figure 73 As shown; and DVS as Figure 74 As shown.

[0922] In deuterated DMSO, through 1 H-NMR analysis of compound 1-hydroxyethyl sulfonate (form A) yielded the following chemical shifts: 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.53 - 0.81 (m, 7 H) 0.84 - 1.78 (m, 22 H)2.01 - 2.15 (m, 3 H) 2.34 (br s, 1 H) 2.61 (t, J=6.82 Hz, 2 H) 2.66 - 2.78(m, 1 H) 3.05 (s, 2 H) 3.25 (s, 3 H) 3.63 (t, J=6.75 Hz, 2 H) 5.14 - 5.38 (m, 2 H) 7.58 - 7.69 (m, 2 H) 8.99 (s, 1 H).

[0923] Chemical and physical stability tests

[0924] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for Compound 1 hydroxyethyl sulfonate (form A) and Compound 1 free base:

[0925]

[0926] Solubility test in simulated gastric and intestinal fluids

[0927] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 hydroxyethyl sulfonate (form A) and compound 1 free base in biologically relevant solutions:

[0928]

[0929] Compound 1-hydroxyethyl sulfonate (form B)

[0930] Weigh 50 mg of compound 1 into a 2 mL vial, then add 743 μL of solvent IPA / water (95 / 5, v / v). Next, add 1.1 equivalents of the counterion of 2-hydroxyethanesulfonic acid (257 μL, concentration: 0.5 mol / L). Place the vial on a heat mixer with a stir bar and heat to 50°C. After maintaining the temperature at 50°C for 21 hours with constant stirring at 500 rpm, cool the vial to 25°C. After maintaining the temperature at 25°C for 1 hour, the vial shows a clear solution. Evaporate the solvent in a vacuum oven at 30°C.

[0931] Dry solids obtained by PLM and XRPD characterization Figure 75 ).

[0932] Example 16: Preparation of gentianate salt of compound 1

[0933] The gentianate salt of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0934] Compound 1, gentianate (form A)

[0935] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of gentianic acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 281.5 mg of powder, with a yield of 31.39%.

[0936] The obtained solid was gentianate of compound 1 (form A). Ion chromatography determined that the ratio of compound 1 to gentianic acid in gentianate of compound 1 (form A) was 1:1.03. XPRD is as follows. Figure 76 As shown; DSC and TGA are as follows Figure 77 As shown; and DVS as Figure 78 As shown.

[0937] In deuterated DMSO, through 1 H-NMR analysis of compound 1 gentianate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6) δ ppm 0.53 - 0.80 (m, 7 H) 0.85 - 1.72 (m, 20 H) 2.00- 2.13 (m, 5 H) 2.66 - 2.74 (m, 1 H) 3.04 (s, 2 H) 4.02 (br s, 1 H) 4.90 -5.12 (m, 2 H) 6.71 (d, J=8.76 Hz, 1 H) 6.88 (dd, J=8.82, 3.06 Hz, 1 H) 7.03(s, 1 H) 7.13 - 7.17 (m, 2 H) 7.78 - 7.86 (m, 1 H) 7.81 (s, 1H) 9.01 (br s,1 H).

[0938] Chemical and physical stability tests

[0939] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 gentianate (form A) and compound 1 free base:

[0940]

[0941] Compound 1, gentianate (form B)

[0942] 50 mg of compound 1 and 1.1 equivalents of the counterion of gentianic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of EtOAc solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0943] Characterization of dried solids using PLM and XRPD ( Figure 79 ).

[0944] Compound 1, gentianate (form C)

[0945] 50 mg of compound 1 and 1.1 equivalents of gentianic acid counterions in solid form were weighed into separate 2 mL vials. Then, 1 mL of IPA / water (95 / 5, v / v) solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0946] Characterization of dried solids using PLM and XRPD ( Figure 80 ).

[0947] Solubility test in simulated gastric and intestinal fluids

[0948] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 gentianate (form A) and compound 1 free base in biologically relevant solutions:

[0949]

[0950] Example 17: Preparation of 1-hydroxy-2-naphthate of compound 1

[0951] The 1-hydroxy-2-naphthate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0952] Compound 1, 1-hydroxy-2-naphthate (form A)

[0953] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of 1-hydroxy-2-naphthyl acid salt in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 675.36 mg of powder, with a yield of 68.15%.

[0954] The obtained solid was compound 1, 1-hydroxy-2-naphthate (form A). Ion chromatography determined that the ratio of compound 1 to 1-hydroxy-2-naphthic acid in compound 1, 1-hydroxy-2-naphthate (form A) was 1:1.15. XPRD is as follows. Figure 81 As shown; DSC and TGA are as follows Figure 82 As shown; and DVS as Figure 83 As shown.

[0955] In deuterated DMSO, through 1 H-NMR analysis of compound 1, 1-hydroxy-2-naphthate (form A), yielded the following chemical shifts: 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.49 - 0.79 (m, 7 H) 0.82 - 1.76 (m, 22H) 1.96 - 2.16 (m, 4 H) 2.63 - 2.76 (m, 1 H) 2.95 - 3.11 (m, 2 H) 4.98 - 5.22(m, 2 H) 7.19 - 7.32 (m, 3 H) 7.46 - 7.62 (m, 2 H) 7.72 - 7.86 (m, 2 H) 8.16- 8.29 (m, 2 H).

[0956] Chemical and physical stability tests

[0957] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of chemical and physical stability tests for Compound 1 1-hydroxy-2-naphthate (Form A) and Compound 1 free base:

[0958]

[0959] Solubility test in simulated gastric and intestinal fluids

[0960] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of Compound 1 1-hydroxy-2-naphthate (form A) and the free base of Compound 1 in biologically relevant solutions:

[0961]

[0962] Compound 1, 1-hydroxy-2-naphthate (form B)

[0963] 50 mg of compound 1 and 1.1 equivalents of the counterion of 1-hydroxy-2-naphthic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of EtOAc solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0964] Characterization of dried solids using PLM and XRPD ( Figure 84 ).

[0965] Compound 1, 1-hydroxy-2-naphthate (form C)

[0966] 50 mg of compound 1 and 1.1 equivalents of the counterion of 1-hydroxy-2-naphthic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of ACN solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50 °C. After maintaining the temperature at 50 °C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25 °C. After maintaining the temperature at 25 °C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30 °C for 18 hours.

[0967] Characterization of dried solids using PLM and XRPD ( Figure 85 ).

[0968] Compound 1, 1-hydroxy-2-naphthate (form D)

[0969] 50 mg of compound 1 and 1.1 equivalents of the counterion of 1-hydroxy-2-naphthic acid in solid form were weighed into separate 2 mL vials. Then, 1 mL of solvent IPA / water (95 / 5, v / v) was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0970] Characterization of dried solids using PLM and XRPD ( Figure 86 ).

[0971] Example 18: Preparation of the cyclopeptide salt of compound 1

[0972] The following exemplary methods can be used to prepare the cyclopeptide salt of compound 1 from compound 1.

[0973] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of cyclolatac acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 715.81 mg of powder, with a yield of 74.48%.

[0974] The obtained solid was compound 1 cyclolazone (form A). Ion chromatography determined that the ratio of compound 1 to cyclolazone acid in compound 1 cyclolazone (form A) was 1:1.00. XPRD is as follows. Figure 87 As shown; DSC and TGA are as follows Figure 88 As shown; and DVS as Figure 89 As shown.

[0975] In deuterated DMSO, through 1 H-NMR analysis of compound 1 cyclopyridine (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6) δ ppm 0.49 - 0.80 (m, 7 H) 0.84 - 1.77 (m, 30 H) 1.83- 2.14 (m, 5 H) 2.65 - 2.74 (m, 1 H) 2.90 - 3.09 (m, 3 H) 3.35 - 3.60 (m, 2H) 4.03 (br s, 1 H) 4.87 - 5.16 (m, 2 H) 6.97 - 7.18 (m, 2 H) 7.54 - 7.91 (m,3 H).

[0976] Chemical and physical stability tests

[0977] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 cyclopyralid (form A) and compound 1 free base:

[0978]

[0979] Solubility test in simulated gastric and intestinal fluids

[0980] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 cyclolactamate (form A) and compound 1 free base in biologically relevant solutions:

[0981]

[0982] Example 19: Preparation of ethane-1,2-disulfonate of compound 1

[0983] The following exemplary methods can be used to prepare ethane-1,2-disulfonate of compound 1 from compound 1.

[0984] Compound 1: Ethane-1,2-disulfonate (Form A)

[0985] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of ethane-1,2-disulfonic acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 704.45 mg of powder, with a yield of 71.61%.

[0986] The obtained solid was compound 1, ethane-1,2-disulfonate (form A). Ion chromatography determined that the ratio of compound 1 to ethane-1,2-disulfonate (form A) was 1:2.4. XPRD is as follows: Figure 90 As shown; DSC and TGA are as follows Figure 91 As shown; and DVS as Figure 92 As shown.

[0987] In deuterated DMSO, through 1 H-NMR analysis of compound 1 ethane-1,2-disulfonate (form A) yielded the following chemical shifts: 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.52 - 0.79 (m, 7 H) 0.82 - 1.77 (m, 22H) 1.97 - 2.15 (m, 2 H) 2.58 - 2.78 (m, 4 H) 3.03 (s, 2 H) 3.23 (s, 4 H) 5.13- 5.40 (m, 2 H) 7.56 - 7.71 (m, 2 H) 9.00 (s, 1 H).

[0988] Chemical and physical stability tests

[0989] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of chemical and physical stability tests for compound 1 ethane-1,2-disulfonate (form A) and the free base of compound 1:

[0990]

[0991] Compound 1: Ethane-1,2-disulfonate (Form B)

[0992] 50 mg of compound 1 and 1.1 equivalent solid equivalents of the counterion of ethane-1,2-disulfonic acid were weighed into separate 2 mL vials. Then, 1 mL of solvent EtOAc / IPA / water (95 / 5, v / v) was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[0993] Characterization of dried solids using PLM and XRPD ( Figure 93 ).

[0994] Solubility test in simulated gastric and intestinal fluids

[0995] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 ethane-1,2-disulfonate (form A) and free base of compound 1 in biologically relevant solutions:

[0996]

[0997] Example 20: Preparation of dichloroacetate of compound 1

[0998] The dichloroacetate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[0999] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of dichloroacetic acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 559.98 mg of powder, with a yield of 83.41%.

[1000] The obtained solid was compound 1 dichloroacetate (form A). Ion chromatography determined that the ratio of compound 1 to dichloroacetic acid in compound 1 dichloroacetate (form A) was 1:1.14. XPRD is as follows. Figure 94 As shown; DSC and TGA are as follows Figure 95 As shown; and DVS as Figure 96 As shown.

[1001] In deuterated DMSO, through 1 H-NMR analysis of compound 1 dichloroacetic acid (form A) yielded the following chemical shifts:1 HNMR (400 MHz, DMSO-d6) δ ppm 0.46 - 0.79 (m, 7 H) 0.82 - 1.75 (m, 21 H) 1.96- 2.15 (m, 2 H) 2.62 - 2.75 (m, 1 H) 3.02 (s, 2 H) 4.98 - 5.27 (m, 3 H) 6.30 (s, 1 H) 7.31 (d, J=12.80 Hz, 2 H) 8.32 (s, 1 H).

[1002] Chemical and physical stability tests

[1003] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 dichloroacetate (form A) and compound 1 free base:

[1004]

[1005] Solubility test in simulated gastric and intestinal fluids

[1006] Solubility tests were performed in simulated gastric and intestinal fluids using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 dichloroacetate (form A) and compound 1 free base in biologically relevant solutions:

[1007]

[1008] Example 21: Preparation of L-malate of compound 1

[1009] The L-malate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[1010] Compound 1 L-malate (Form A) :

[1011] 200 mg of compound 1 was dissolved in 10.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of L-malic acid in acetone (1.027 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C for 20 h. The organic solvent was removed by evaporation under nitrogen. The obtained wet product was dried under vacuum at 25 °C for 42 h to give 230.93 mg of powder, with a yield of 85.9%.

[1012] The obtained solid was compound 1 L-malate (form A). Ion chromatography determined that the ratio of compound 1 to malic acid in compound 1 L-malate (form A) was 1:1.35. XPRD is as follows. Figure 97 As shown; DSC and TGA are as follows Figure 98 As shown; and DVS as Figure 99 As shown.

[1013] In deuterated DMSO, through 1 H-NMR analysis of compound 1 L-malate (form A) yielded the following chemical shifts: 1 H NMR (400 MHz, DMSO-d6): δ 0.57 - 0.86 (m, 4 H) 0.70 - 0.86 (m, 4 H) 0.89 -1.79 (m, 21 H) 2.00 - 2.21 (m, 3 H) 2.33 - 2.78 (m, 13 H) 3.10 (s, 2 H) 3.31 (s, 3 H) 4.28 (dd, J=7.32, 5.44 Hz, 1 H) 4.85 - 5.19 (m, 2 H) 7.00 (s, 1 H)7.13 (s, 1 H) 7.53 - 7.84 (m, 1 H).

[1014] Compound 1 L-malate (form B) :

[1015] 10 g of compound 1 was suspended in 350 mL of acetone at 60 °C with stirring at 200 rpm and maintained at 60 °C for 0.5 h. Then, a solution of 1.1 equivalents of L-malic acid in acetone (50 mL, 0.5 mol / L) was added to the suspension of compound 1, and the mixture was incubated at 60 °C for 3 h. The mixture was then cooled to 25 °C and kept open at 25 °C for 72 h in a vial. The suspension was centrifuged, the precipitate was collected, and dried under vacuum at 30 °C for 24 h to give 4.44 g of powder, with a yield of 33.86%.

[1016] The obtained solid was compound 1 L-malate (form B). Ion chromatography determined that the ratio of compound 1 to malic acid in compound 1 L-malate (form B) was 1:1.26. XPRD is as follows. Figure 100 As shown; DSC and TGA are as follows Figure 101 As shown; and DVS as Figure 102 As shown.

[1017] In deuterated DMSO, through 1 H-NMR analysis of compound 1 L-malate (form B) yielded the following chemical shifts: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.45 - 0.79 (m, 7 H) 0.83 - 1.73 (m, 20 H)1.98 - 2.12 (m, 2 H) 2.43 (dd, J=15.69, 7.40 Hz, 1 H) 2.56 - 2.72 (m, 2 H)3.04 (s, 2 H) 4.22 (dd, J=7.28, 5.52 Hz, 1 H) 4.86 - 5.10 (m, 2 H) 6.94 (s, 1H) 7.07 (s, 1 H) 7.65 (s, 1 H).

[1018] Chemical and physical stability tests

[1019] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of chemical and physical stability tests for Compound 1 L-malate (Form A), Compound 1 L-malate (Form B), and Compound 1 free base:

[1020]

[1021] Solubility test in simulated gastric and intestinal fluids

[1022] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of Compound 1 L-malate (Form A), Compound 1 L-malate (Form B), and Compound 1 free base in biologically relevant solutions:

[1023]

[1024] Example 22: Preparation of the hydrochloride salt of compound 1

[1025] The following exemplary methods can be used to prepare the hydrochloride salt of compound 1 from compound 1.

[1026] Compound 1 hydrochloride (form A) :

[1027] 200 mg of compound 1 was dissolved in 10.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of hydrochloric acid in acetone (1.027 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C for 20 h. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 42 h to give 168.15 mg of powder, with a yield of 76.9%.

[1028] The obtained solid was compound 1 hydrochloride (form A). Ion chromatography determined that the ratio of compound 1 to hydrochloric acid in compound 1 hydrochloride (form A) was 1:0.94. XPRD is as follows. Figure 103 As shown; DSC and TGA are as follows Figure 104 As shown; and DVS as Figure 105 As shown.

[1029] Compound 1 hydrochloride (form B) :

[1030] 500 mg of hydrochloride (form A) was dissolved in 4.0 mL of ethanol at 50 °C. The solution was filtered, and then 6.25 times its volume of heptane was added dropwise to the solution to form a suspension. The suspension was stirred at a constant speed of 500 rpm and kept at 50 °C for 24 hours. The suspension was then centrifuged, the precipitate was collected, and dried under vacuum at 30 °C for 24 hours to obtain 365 mg of powder, with a yield of 73.0%.

[1031] The obtained solid was compound 1 hydrochloride (form B). Ion chromatography determined that the ratio of compound 1 to hydrochloric acid in compound 1 hydrochloride (form B) was 1:0.96. XPRD is as follows. Figure 106 As shown; DSC and TGA are as follows Figure 107 As shown; and DVS as Figure 108 As shown.

[1032] Compound 1 hydrochloride (form C) :

[1033] 300 mg of hydrochloride (form A) was suspended in 6.0 mL of a 0.901 water activity solution at 50°C with stirring at 700 rpm to produce a clear solution. Then, 200 mg of hydrochloride was added to form a suspension. The suspension was maintained at a constant stirring speed of 700 rpm and kept at 50°C for 1 week. The suspension was then centrifuged, the precipitate was collected, and dried at 30°C for 24 hours to obtain 400 mg of powder, with a yield of 80.0%.

[1034] The obtained solid was compound 1 hydrochloride (form C). Ion chromatography determined that the ratio of compound 1 to hydrochloric acid in compound 1 hydrochloride (form C) was 1:0.97. XPRD is as follows. Figure 109 As shown; DSC and TGA are as follows Figure 110 As shown; and DVS as Figure 111 As shown.

[1035] Chemical and physical stability tests

[1036] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the chemical and physical stability test results for Compound 1 hydrochloride (Form A), Compound 1 hydrochloride (Form B), Compound 1 hydrochloride (Form C), and Compound 1 free base:

[1037]

[1038]

[1039] Solubility test in simulated gastric and intestinal fluids

[1040] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of Compound 1 hydrochloride (form A), Compound 1 hydrochloride (form B), Compound 1 hydrochloride (form C), and Compound 1 free base in biologically relevant solutions:

[1041]

[1042] Example 22: Preparation of naphthalene sulfonate of compound 1

[1043] The naphthalene sulfonate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[1044] Compound 1, naphthalenesulfonate (form A) :

[1045] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of naphthalene-2-sulfonic acid hydrate in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 690.41 mg of powder, with a yield of 89.17%.

[1046] The obtained solid was compound 1 naphthalene sulfonate (form A). Ion chromatography determined that the ratio of compound 1 to naphthalene-2-sulfonic acid in compound 1 naphthalene sulfonate (form A) was 1:1.04. XPRD is as follows. Figure 112 As shown; DSC and TGA are as follows Figure 113 As shown; and DVS as Figure 114 As shown.

[1047] In deuterated DMSO, through 1 H-NMR analysis of compound 1-naphthalenesulfonate (form A) yielded the following chemical shifts: 1 HNMR (400 MHz, DMSO-d6) δ ppm 0.51 - 0.80 (m, 8 H) 0.82 - 1.77 (m, 25 H) 2.33(br d, J=1.75 Hz, 2 H) 2.54 - 2.78 (m, 3 H) 3.05 (s, 3 H) 3.20 - 3.30 (m, 6H) 4.04 (br s, 1 H) 5.15 - 5.36 (m, 2 H) 7.49 - 7.73 (m, 5 H) 7.83 - 8.01 (m, 3 H) 8.14 (s, 1 H) 8.94 (s, 1 H).

[1048] Chemical and physical stability tests

[1049] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 naphthalene sulfonate (form A) and compound 1 free base:

[1050]

[1051] Solubility test in simulated gastric and intestinal fluids

[1052] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 naphthalenesulfonate (form A) and compound 1 free base in biologically relevant solutions:

[1053]

[1054] Compound 1 naphthalenesulfonate (form B):

[1055] 50 mg of compound 1 and 1.1 equivalent solid ions of naphthalene-2-sulfonic acid hydrate were weighed into separate 2 mL vials, and then 1 mL of solvent EtOAc / ACN was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50 °C. After maintaining the temperature at 50 °C for 21 hours with constant stirring at 500 rpm, the vials were cooled to 25 °C. After maintaining the temperature at 25 °C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30 °C for 18 hours.

[1056] Characterization of dried solids using PLM and XRPD ( Figure 115 ).

[1057] Example 23: Preparation of oxalate of compound 1

[1058] The oxalate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[1059] Compound 1, oxalate (form A)

[1060] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of oxalic acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 595.76 mg of powder, with a yield of 96.32%.

[1061] The obtained solid was oxalate of compound 1 (form A). Ion chromatography determined that the ratio of compound 1 to oxalic acid in oxalate of compound 1 (form A) was 1:0.91. XPRD is as follows: Figure 116 As shown; DSC and TGA are as follows Figure 117 As shown; and DVS as Figure 118 As shown.

[1062] Chemical and physical stability tests

[1063] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of the chemical and physical stability tests for compound 1 oxalate (form A) and compound 1 free base:

[1064]

[1065] Solubility test in simulated gastric and intestinal fluids

[1066] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 oxalate (form A) and compound 1 free base in biologically relevant solutions:

[1067]

[1068] Compound 1 oxalate (form B):

[1069] 50 mg of compound 1 and 1.1 equivalents of the counterion of oxalic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of EtOAc solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 21 hours with constant stirring at 500 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[1070] Characterization of dried solids using PLM and XRPD ( Figure 119 ).

[1071] Example 24: Preparation of p-aminosalicylic acid salt of compound 1

[1072] The para-aminosalicylate of compound 1 can be prepared from compound 1 using the following exemplary methods.

[1073] Compound 1, para-aminosalicylate (form A):

[1074] 500 mg of compound 1 was dissolved in 16.0 mL of acetone at 60 °C with stirring at 500 rpm and maintained at 60 °C for 1.5 h. Then, a solution of 1.1 equivalents of 4-aminosalicylic acid in acetone (2.565 mL, 0.5 mol / L) was added to the compound 1 solution, and the mixture was incubated at 60 °C for 3 h, then cooled to 25 °C and maintained at 25 °C overnight. The suspension was centrifuged, the precipitate was collected, and washed with acetone. The obtained wet product was dried under vacuum at 25 °C for 72 h to give 583.32 mg of powder, with a yield of 83.37%.

[1075] The obtained solid was compound 1, para-aminosalicylate (form A). Ion chromatography determined that the ratio of compound 1 to 4-aminosalicylic acid in compound 1, para-aminosalicylate (form A) was 1:1.03. XPRD is as follows. Figure 120 As shown; DSC and TGA are as follows Figure 121 As shown; and DVS as Figure 122 As shown.

[1076] In deuterated DMSO, through 1H-NMR analysis of compound 1, p-aminosalicylate (form A), yielded the following chemical shifts: 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.51 - 0.80 (m, 7 H) 0.83 - 1.74 (m, 22 H)1.97 - 2.15 (m, 3 H) 2.34 (s, 1 H) 2.68 (br t, J=8.69 Hz, 1 H) 2.99 - 3.09(m, 2 H) 3.25 (s, 4 H) 4.83 - 5.10 (m, 2 H) 5.88 - 6.11 (m, 3 H) 6.76 (t, J=8.19 Hz, 1 H) 6.90 (s, 1 H) 7.04 (s, 1 H) 7.42 (d, J=8.63 Hz, 1H) 7.57 (s, 1H).

[1077] Chemical and physical stability tests

[1078] Chemical and physical stability tests were performed using the process shown in Example 1. The table below shows the results of chemical and physical stability tests on compound 1 for aminosalicylate (form A) and the free base of compound 1:

[1079]

[1080] Solubility test in simulated gastric and intestinal fluids

[1081] Solubility tests in simulated gastric and intestinal fluids were performed using the procedure shown in Example 1. The table below shows the solubility results (mg / mL) of compound 1 para-aminosalicylate (form A) and the free base of compound 1 in biorelevant solutions:

[1082]

[1083] Compound 1, para-aminosalicylate (form B):

[1084] 50 mg of compound 1 and 1.1 equivalents of the counterion of 4-aminosalicylic acid in solid form were weighed into separate 2 mL vials, and then 1 mL of solvent EtOAc / ACN was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 21 hours with constant stirring at 500 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried in a vacuum oven at 30°C for 18 hours.

[1085] Characterization of dried solids using PLM and XRPD ( Figure 123 ).

[1086] Example 25: Preparation of maleate of compound 1

[1087] The maleate salt of compound 1 can be prepared from compound 1 using the following exemplary methods.

[1088] Compound 1 maleate (form A):

[1089] 50 mg of compound 1 and 1.1 equivalents of maleic acid counterions in solid form were weighed into separate 2 mL vials, and then 1 mL of acetone solvent was added to each vial. The vials were placed on a hot mixer with a stir bar and heated to 50°C. After maintaining the temperature at 50°C for 18 hours with constant stirring at 900 rpm, the vials were cooled to 25°C. After maintaining the temperature at 25°C for 1 hour, the solids in the suspension were separated by centrifugation and dried overnight in a vacuum oven at 30°C.

[1090] Dry solids obtained by PLM and XRPD characterization Figure 124 ).

[1091] Example 26: Attempt to prepare a salt of compound 1

[1092] The following acids form non-crystalline salts under certain conditions:

[1093]

[1094] Although various conditions were tried (shown below), the acids in the table below did not provide a separable salt of compound 1.

[1095]

[1096] Experimental conditions: For each of the twenty acids listed in the table above, four solvents (acetone, EtOAc, ACN, and IPA / water (95 / 5, V / V)) were used according to the following procedure to determine whether a separable salt of compound 1 was provided by a specific solvent-acid combination.

[1097] Approximately 50 mg of Compound 1 and 1.1 molar equivalents of acid were placed in a 2 mL vial. Approximately 1 mL of solvent was added to the vial. The vial was placed on a hot mixer with a stir bar and heated to 50 °C. After stirring at 50 °C (500 rpm) for 21 hours, the vial was cooled to 25 °C and maintained at 25 °C for 1 hour, and the formation of a solid in the vial was monitored. After stirring for approximately one hour, no solid was produced in any experiment. For each experiment, the solvent was evaporated in a vacuum oven at 30 °C. Under these conditions, none of the acids listed in the table above produced a separable salt of Compound 1.

[1098] Example 27. Properties of the salt of compound 1

[1099] The bulk density, packing density, Karl quotient, and Hausner ratio of compound 1 citrate (form A); compound 1 phosphate (form A); compound 1 tartrate (form A); compound 1 HBr (form A); and compound 1 free base (form A) were determined. The results are shown in the table below.

[1100]

[1101] In the tested forms, the physical properties of compound 1 citrate (form A) are best suited for the preparation of solid drug dosage forms (e.g., tablets) and for the economical storage of active pharmaceutical ingredients (APIs) (i.e., because of its high bulk density).

[1102] Compressibility is an important property of APIs, and generally, APIs with higher compressibility are easier to compress into tablets compared to APIs with lower compressibility. The Karl index is an indicator of powder compressibility; a low Karl index indicates good compressibility, while a high Karl index indicates poor compressibility. Compound 1 citrate (form A) has a significantly lower Karl index compared to the other tested polymorphs, indicating the best compressibility among the tested forms.

[1103] API flowability is crucial in many pharmaceutical operations, such as mixing with excipients, tableting, capsule filling, and scaling up production. The Hausner ratio is a measure of powder flowability. A high Hausner ratio indicates poor powder flowability, while a low Hausner ratio indicates good flowability. The Hausner ratio of Compound 1 citrate (form A) is significantly lower than that of the polymorphs tested, indicating that the tested form has the best flowability.

[1104] Manufacturability of citrate (Form A): Compound 1 citrate (Form A) exhibits excellent manufacturability and has been prepared on a kilogram scale (Example 2). Large-scale synthesis utilizes pharmaceutically acceptable solvents and does not require seed crystals of compound 1 citrate (Form A).

[1105] Stability of citrate (form A): Compound 1 citrate (form A) is stable for at least 3 months under high temperature and high humidity conditions (see Example 2), which is ideal for APIs.

[1106] Manufacturability of HBr (Form A): Compound 1 HBr (Form A) exhibits excellent manufacturability and has been prepared on a kilogram scale (Example 1). Large-scale synthesis utilizes pharmaceutically acceptable solvents and does not require seed crystals of compound 1 HBr (Form A).

[1107] By incorporating references

[1108] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated herein in their entirety for all purposes. However, no reference, article, publication, patent, patent publication, or patent application cited herein is referenced or should be construed as an acknowledgment or implication of any kind that they constitute valid prior art or form part of common general knowledge in any country of the world.

[1109] Implementation Plan

[1110] 1. A crystalline form A of the citrate of compound 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern with three or more peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, 17.1 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ using copper K-α radiation.

[1111] 2. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, and 17.1 ± 0.2°2θ.

[1112] 3. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, and 20.1 ± 0.2°2θ.

[1113] 4. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, and 20.3 ± 0.2°2θ.

[1114] 5. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 17.1 ± 0.2, and 20.1 ± 0.2°2θ.

[1115] 6. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 17.1 ± 0.2, and 20.3 ± 0.2°2θ.

[1116] 7. The crystalline form A of citrate of embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ.

[1117] 8. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 11.9 ± 0.2, 17.1 ± 0.2, and 20.1 ± 0.2°2θ.

[1118] 9. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 11.9 ± 0.2, 17.1 ± 0.2, and 20.3 ± 0.2°2θ.

[1119] 10. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 11.9 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ.

[1120] 11. The crystalline form A of citrate according to embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern containing peaks at approximately 17.1 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ using copper K-α radiation.

[1121] 12. The crystalline form A of citrate of embodiment 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern containing four or more peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, 17.1 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ using copper K-α radiation.

[1122] 13. The crystalline form A of citrate of embodiment 12, wherein the form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, 17.1 ± 0.2, and 20.1 ± 0.2°2θ.

[1123] 14. The crystalline form A of citrate of embodiment 12, wherein the form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, 17.1 ± 0.2, and 20.3 ± 0.2°2θ.

[1124] 15. The crystalline form A of citrate of embodiment 12, wherein the form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ.

[1125] 16. The crystalline form A of citrate of embodiment 12, wherein the form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 17.1 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ.

[1126] 17. The crystalline form A of citrate of embodiment 12, wherein the form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 11.9 ± 0.2, 17.1 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ.

[1127] 18. The crystalline form A of citrate of embodiment 12, wherein form A shows an X-ray powder diffraction (XRPD) pattern containing peaks at approximately 5.7 ± 0.2, 11.9 ± 0.2, 17.1 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2°2θ using copper K-α radiation.

[1128] 19. The crystalline form A of the citrate in any of the foregoing embodiments further comprises one or more peaks, such as two or more peaks, such as three or more peaks, such as four or more peaks, such as five peaks, at about 12.7±0.2, 13.0±0.2, 13.6±0.2, 15.3±0.2 and 16.8±0.2°2θ, using copper K-α radiation.

[1129] 20. The crystalline form A of citrate of any one of embodiments 1-18, further comprising an additional peak at about 12.7 ± 0.2°2θ using copper K-α radiation.

[1130] 21. The crystalline form A of citrate of any one of embodiments 1-18 and 20, further comprising an additional peak at about 13.0 ± 0.2°2θ using copper K-α irradiation.

[1131] 22. The crystalline form A of citrate of any one of embodiments 1-18, 20 and 21, further comprising an additional peak at about 13.6 ± 0.2°2θ using copper K-α irradiation.

[1132] 23. The crystalline form A of citrate of any one of embodiments 1-18 and 20-22, further comprising an additional peak at about 15.3 ± 0.2°2θ using copper K-α irradiation.

[1133] 24. The crystalline form A of citrate of any one of embodiments 1-18 and 20-23, further comprising an additional peak at about 16.8 ± 0.2°2θ using copper K-α radiation.

[1134] 25. The crystalline form A of the citrate in any of the foregoing embodiments, wherein the XRPD pattern is substantially as shown in the figure. Figure 15 Observed in the middle.

[1135] 26. The crystalline form A of the citrate of any of the foregoing embodiments, wherein said form A has unit cell parameters at 120 K that are substantially similar to the following:

[1136] a = 8.9 Å

[1137] b = 12.2 Å

[1138] c = 16.5 Å

[1139] α = 73.7º

[1140] β = 76.6º

[1141] γ = 83.2º

[1142] Space group P1,

[1143] Molecules / Asymmetric Units 2.

[1144] 27. The crystalline form A of the citrate of embodiment 26, wherein form A has the following unit cell parameters at 120 K:

[1145] a = 8.9 ± 0.5 Å

[1146] b = 12.2 ± 0.5 Å

[1147] c = 16.5 ± 0.5 Å

[1148] α = 73.7 ± 2º

[1149] β = 76.6 ± 2º

[1150] γ = 83.2 ± 2º

[1151] Space group P1,

[1152] Molecules / Asymmetric Units 2.

[1153] 28. The crystalline form A of the citrate of embodiment 27, wherein form A has the following unit cell parameters at 120 K:

[1154] a = 8.9 ± 0.3 Å

[1155] b = 12.2 ± 0.3 Å

[1156] c = 16.5 ± 0.3 Å

[1157] α = 73.7 ± 1º

[1158] β = 76.6 ± 1º

[1159] γ = 83.2 ± 1º

[1160] Space group P1,

[1161] Molecules / Asymmetric Units 2.

[1162] 29. The crystalline form A of the citrate of embodiment 28, wherein form A has the following unit cell parameters at 120 K:

[1163] a = 8.9 ± 0.2 Å

[1164] b = 12.2 ± 0.2 Å

[1165] c = 16.5 ± 0.2 Å

[1166] α = 73.7 ± 0.5 º

[1167] β = 76.6 ± 0.5 º

[1168] γ = 83.2 ± 0.5 º

[1169] Space group P1,

[1170] Molecules / Asymmetric Units 2.

[1171] 30. The crystalline form A of citrate of any of the foregoing embodiments, wherein the form A displays a differential scanning calorimeter having a peak at about 89.0 ± 2.0 ºC or about 139.5 ± 2.0 ºC.

[1172] 31. The crystalline form A of citrate of any of the foregoing embodiments, wherein the form A exhibits a differential scanning calorimetry temperature spectrum having a peak at about 89.0 ± 2.0 ºC.

[1173] 32. The crystalline form A of citrate of any of the foregoing embodiments, wherein form A exhibits a differential scanning calorimetry temperature spectrum having a peak at about 139.5 ± 2.0 ºC.

[1174] 33. A pharmaceutical composition comprising a citrate of any of the foregoing embodiments and a pharmaceutically acceptable carrier.

[1175] 34. The pharmaceutical composition of embodiment 33, wherein the composition is a tablet.

[1176] 35. Hydrobromide of compound 1.

[1177] 36. The hydrobromide of embodiment 35, wherein at least about 80% by weight of the salt is crystalline.

[1178] 37. The hydrobromide of embodiment 35, wherein at least about 80% by weight of the salt is in single crystal form.

[1179] 38. The hydrobromide of embodiment 35, wherein at least about 95% by weight of the salt is crystalline.

[1180] 39. The hydrobromide of embodiment 35, wherein at least about 95% by weight of the salt is in single-crystal form.

[1181] 40. The hydrobromide of any one of embodiments 36-39, wherein the crystalline form is form A.

[1182] 41. The hydrobromide of embodiment 40, wherein the form A shows an X-ray powder diffraction pattern with three or more peaks at about 7.6 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 19.8 ± 0.2 and 22.9 ± 0.2°2θ.

[1183] 42. The hydrobromide of embodiment 41, wherein the X-ray powder diffraction pattern further includes one or more peaks at approximately 15.5 ± 0.2, 19.2 ± 0.2, 20.6 ± 0.2, 26.1 ± 0.2, and 31.3 ± 0.2°2θ.

[1184] 43. The hydrobromide of embodiment 40, wherein form A exhibits the same characteristics as... Figure 2 Essentially similar X-ray powder diffraction patterns.

[1185] 44. The hydrobromide of any one of embodiments 40-43, wherein the form A shows a differential scanning calorimetry temperature spectrum having a peak at about 243.1 ± 2.0 °C.

[1186] 45. The hydrobromide of any one of embodiments 40-43, wherein form A exhibits the same characteristics as... Figure 3 Essentially similar differential scanning calorimetry temperature spectra.

[1187] 46. ​​The hydrobromide of any one of embodiments 40-43, wherein form A exhibits the same characteristics as... Figure 3Essentially similar thermogravimetric analysis temperature spectra.

[1188] 47. The hydrobromide of any one of embodiments 36-39, wherein the crystalline form is form E.

[1189] 48. The hydrobromide of embodiment 47, wherein the form E shows an X-ray powder diffraction pattern containing three or more peaks at about 7.6 ± 0.2, 15.2 ± 0.2, 16.3 ± 0.2, 22.9 ± 0.2 and 23.2 ± 0.2°2θ.

[1190] 49. The hydrobromide of embodiment 48, wherein the X-ray powder diffraction pattern further includes one or more peaks at approximately 9.6 ± 0.2, 17.4 ± 0.2, 22.4 ± 0.2, 23.6 ± 0.2, and 31.2 ± 0.2°2θ.

[1191] 50. The hydrobromide of embodiment 47, wherein form E exhibits the same characteristics as... Figure 13 Essentially similar X-ray powder diffraction patterns.

[1192] 51. The hydrobromide of any one of embodiments 47-50, wherein the form E displays a differential scanning calorimetry temperature spectrum having a peak at about 245.0 ± 2.0 °C.

[1193] 52. The hydrobromide of any one of embodiments 47-50, wherein said form E exhibits the same characteristics as... Figure 14 Essentially similar differential scanning calorimetry temperature spectra.

[1194] 53. The hydrobromide of any one of embodiments 47-50, wherein said form E exhibits the same characteristics as... Figure 14 Essentially similar thermogravimetric analysis temperature spectra.

[1195] 54. Citrate of compound 1.

[1196] 55. The hydrobromide of embodiment 54, wherein at least about 80% by weight of the salt is crystalline.

[1197] 56. The hydrobromide of embodiment 54, wherein at least about 80% by weight of the salt is in single-crystal form.

[1198] 57. The hydrobromide of embodiment 54, wherein at least about 95% by weight of the salt is crystalline.

[1199] 58. The hydrobromide of embodiment 54, wherein at least about 95% by weight of the salt is in crystalline form.

[1200] 59. The citrate of any one of embodiments 55-58, wherein the crystalline form is form A.

[1201] 60. The citrate of embodiment 59, wherein the form A shows an X-ray powder diffraction pattern containing three or more peaks at about 5.7 ± 0.2, 11.9 ± 0.2, 17.1 ± 0.2, 20.1 ± 0.2 and 20.3 ± 0.2°2θ.

[1202] 61. The citrate of embodiment 60, wherein the X-ray powder diffraction pattern further includes one or more peaks at approximately 12.7 ± 0.2, 13.0 ± 0.2, 13.6 ± 0.2, 15.3 ± 0.2, and 16.8 ± 0.2°2θ.

[1203] 62. The citrate of embodiment 59, wherein form A exhibits the same characteristics as... Figure 15 Essentially similar X-ray powder diffraction patterns.

[1204] 63. The citrate of any one of embodiments 59-62, wherein the form A displays a differential scanning calorimeter having a peak at about 89.0 ± 2.0ºC or about 139.5 ± 2.0ºC.

[1205] 64. The citrate of any one of embodiments 59-63, wherein form A exhibits the same characteristics as... Figure 16 Essentially similar differential scanning calorimetry temperature spectra.

[1206] 65. The citrate of any one of embodiments 59-63, wherein form A exhibits the same characteristics as... Figure 16 Essentially similar thermogravimetric analysis temperature spectra.

[1207] 66. L-malate of compound 1.

[1208] 67. The L-malate of embodiment 66, wherein at least about 80% by weight of the salt is crystalline.

[1209] 68. The L-malate of embodiment 66, wherein at least about 80% by weight of the salt is in single-crystal form.

[1210] 69. The L-malate of embodiment 66, wherein at least about 95% by weight of the salt is crystalline.

[1211] 70. The L-malate of embodiment 66, wherein at least about 95% by weight of the salt is in single-crystal form.

[1212] 71. The L-malate of any one of embodiments 67-70, wherein the crystalline form is form A.

[1213] 72. The L-malate of embodiment 71, wherein the form A shows an X-ray powder diffraction pattern with three or more peaks at about 3.2±0.2, 12.5±0.2, 14.4±0.2, 15.7±0.2 and 18.4±0.2°2θ.

[1214] 73. The L-malate of embodiment 72, wherein the X-ray powder diffraction pattern further includes one or more peaks at approximately 3.6 ± 0.2, 6.1 ± 0.2, 13.2 ± 0.2, 18.9 ± 0.2, and 21.1 ± 0.2°2θ.

[1215] 74. The L-malate of embodiment 73, wherein form A exhibits the same characteristics as... Figure 97 Essentially similar X-ray powder diffraction patterns.

[1216] 75. The L-malate of any one of embodiments 71-74, wherein the form A displays a differential scanning calorimeter having a peak at about 120.9 ± 2.0 ºC or about 142.3 ± 2.0 ºC.

[1217] 76. The L-malate of any one of embodiments 71-75, wherein said form A exhibits the same characteristics as... Figure 98 Essentially similar differential scanning calorimetry temperature spectra.

[1218] 77. The L-malate of any one of embodiments 71-76, wherein said form A exhibits the same characteristics as... Figure 98 Essentially similar thermogravimetric analysis temperature spectra.

[1219] 78. The methanesulfonate of compound 1.

[1220] 79. The methanesulfonate of embodiment 78, wherein at least about 80% by weight of the salt is crystalline.

[1221] 80. The methanesulfonate of embodiment 78, wherein at least about 80% by weight of the salt is in single-crystal form.

[1222] 81. The methanesulfonate of embodiment 78, wherein at least about 95% by weight of the salt is crystalline.

[1223] 82. The methanesulfonate of embodiment 78, wherein at least about 95% by weight of the salt is in single-crystal form.

[1224] 83. The methanesulfonate of any one of embodiments 79-82, wherein the crystalline form is form A.

[1225] 84. The methanesulfonate of embodiment 83, wherein the form A shows an X-ray powder diffraction pattern with three or more peaks at about 3.6 ± 0.2, 7.1 ± 0.2, 14.2 ± 0.2, 19.1 ± 0.2 and 25.9 ± 0.2°2θ.

[1226] 85. The methanesulfonate of embodiment 84, wherein the X-ray powder diffraction pattern further includes one or more peaks at approximately 7.7 ± 0.2, 12.7 ± 0.2, 17.8 ± 0.2, 19.4 ± 0.2, and 21.4 ± 0.2°2θ.

[1227] 86. The methanesulfonate of embodiment 83, wherein form A exhibits the same characteristics as... Figure 22 Essentially similar X-ray powder diffraction patterns.

[1228] 87. A methanesulfonate of any one of embodiments 83-86, wherein the form A displays a differential scanning calorimeter having a peak at about 170.9 ± 2.0ºC or about 209.7 ± 2.0ºC.

[1229] 88. A methanesulfonate salt of any one of embodiments 83-87, wherein said form A exhibits the same characteristics as... Figure 23 Essentially similar differential scanning calorimetry temperature spectra.

[1230] 89. A methanesulfonate salt of any one of embodiments 83-88, wherein said form A exhibits the same characteristics as... Figure 23 Essentially similar thermogravimetric analysis temperature spectra.

[1231] 90. L(+)-tartrate of compound 1.

[1232] 91. The L(+)-tartrate of embodiment 90, wherein at least about 80% by weight of the salt is crystalline.

[1233] 92. The L(+)-tartrate of embodiment 90, wherein at least about 80% by weight of the salt is in single crystal form.

[1234] 93. The L(+)-tartrate of embodiment 90, wherein at least about 95% by weight of the salt is crystalline.

[1235] 94. The L(+)-tartrate of embodiment 90, wherein at least about 95% by weight of the salt is in single crystal form.

[1236] 95. The L(+)-tartrate of any one of embodiments 91-94, wherein the crystalline form is form A.

[1237] 96. The L(+)-tartrate of embodiment 95, wherein the form A shows an X-ray powder diffraction pattern containing three or more peaks at about 3.6±0.2, 4.7±0.2, 13.9±0.2, 18.6±0.2 and 22.8±0.2°2θ.

[1238] 97. The L(+)-tartrate of embodiment 96, wherein the X-ray powder diffraction pattern further includes one or more peaks at approximately 14.6 ± 0.2, 17.8 ± 0.2, and 18.1 ± 0.2°2θ.

[1239] 98. The L(+)-tartrate of embodiment 95, wherein form A exhibits the same characteristics as... Figure 30 Essentially similar X-ray powder diffraction patterns.

[1240] 99. The L(+)-tartrate of any one of embodiments 95-98, wherein the form A displays a differential scanning calorimetry temperature spectrum having a peak at about 207.6 ± 2.0ºC.

[1241] 100. The L(+)-tartrate of any one of embodiments 95-99, wherein form A exhibits the same characteristics as... Figure 31 Essentially similar differential scanning calorimetry temperature spectra.

[1242] 101. The L(+)-tartrate of any one of embodiments 95-100, wherein said form A exhibits the same characteristics as... Figure 31 Essentially similar thermogravimetric analysis temperature spectra.

[1243] 102. The L(+)-tartrate of any one of embodiments 91-94, wherein the crystalline form is form B.

[1244] 103. The L(+)-tartrate of embodiment 102, wherein the form B shows an X-ray powder diffraction pattern with three or more peaks at about 3.6±0.2, 4.6±0.2, 12.4±0.2, 13.9±0.2 and 22.7±0.2°2θ.

[1245] 104. The L(+)-tartrate of embodiment 103, wherein the X-ray powder diffraction pattern further includes three or more peaks at approximately 14.8 ± 0.2, 18.3 ± 0.2, and 18.5 ± 0.2°2θ.

[1246] 105. The L(+)-tartrate of embodiment 103, wherein form B exhibits the same characteristics as... Figure 33 Essentially similar X-ray powder diffraction patterns.

[1247] 106. The L(+)-tartrate of any one of embodiments 102-105, wherein the form B displays a differential scanning calorimeter with a peak at about 207.3 ± 2.0 °C.

[1248] 107. The L(+)-tartrate of any one of embodiments 102-106, wherein form B exhibits a similarity to... Figure 34 Essentially similar differential scanning calorimetry temperature spectra.

[1249] 108. The L(+)-tartrate of any one of embodiments 102-107, wherein form B exhibits a similarity to... Figure 34 Essentially similar thermogravimetric analysis temperature spectra.

[1250] 109. Phosphate of compound 1.

[1251] 110. The phosphate of embodiment 109, wherein at least about 80% by weight of the salt is crystalline.

[1252] 111. The phosphate of embodiment 109, wherein at least about 80% by weight of the salt is in single crystal form.

[1253] 112. The phosphate of embodiment 109, wherein at least about 95% by weight of the salt is crystalline.

[1254] 113. The phosphate of embodiment 109, wherein at least about 95% by weight of the salt is in single crystal form.

[1255] 114. The phosphate of any one of embodiments 110-113, wherein the crystalline form is form A.

[1256] 115. The phosphate of embodiment 114, wherein the form A shows an X-ray powder diffraction pattern with three or more peaks at about 3.3 ± 0.2, 3.6 ± 0.2, 5.4 ± 0.2, 9.9 ± 0.2 and 13.1 ± 0.2°2θ.

[1257] 116. The phosphate of embodiment 115, wherein the X-ray powder diffraction pattern further includes one or more peaks at approximately 16.1 ± 0.2, 17.9 ± 0.2, 20.9 ± 0.2, 23.7 ± 0.2, and 26.4 ± 0.2°2θ.

[1258] 117. The phosphate of embodiment 114, wherein form A exhibits the same characteristics as... Figure 27 Essentially similar X-ray powder diffraction patterns.

[1259] 118. The phosphate of any one of embodiments 114-117, wherein the form A shows a differential scanning calorimetry temperature spectrum having a peak at about 217.6 ± 2.0ºC.

[1260] 119. The phosphate of any one of embodiments 114-118, wherein said form A exhibits the same characteristics as... Figure 28 Essentially similar differential scanning calorimetry temperature spectra.

[1261] 120. The L(+)-tartrate of any one of embodiments 114-119, wherein said form A exhibits the same characteristics as... Figure 28 Essentially similar thermogravimetric analysis temperature spectra.

[1262] 121. A pharmaceutical composition comprising a salt of any one of embodiments 35-120 and a pharmaceutically acceptable carrier.

[1263] 122. The pharmaceutical composition of embodiment 121, wherein the composition is a tablet.

[1264] 123. A method of treating depression, comprising administering to a patient in need a therapeutically effective amount of a salt of any one of embodiments 1-32 and 35-120 or a composition of any one of embodiments 33, 34, 121 and 122.

[1265] 124. The method of implementation scheme 123, wherein the depression is selected from major depressive disorder, postpartum depression and treatment-resistant depression.

[1266] 125. A method for treating a disease or condition selected from epilepsy, bipolar disorder, and anxiety, comprising administering to a patient in need an effective amount of a salt of any one of embodiments 1-32 and 35-120 or a composition of any one of embodiments 33, 34, 121, and 122.

Claims

1. The crystalline form A of the citrate salt of compound 1.

2. The crystalline form A of citrate according to claim 1, wherein form A shows an X-ray powder diffraction (XRPD) pattern using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 12.5 ± 0.2, and 13.0 ± 0.2° 2θ.

3. The crystalline form A of citrate according to claim 1, wherein form A shows an XRPD plot using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 12.5 ± 0.2, and 20.1 ± 0.2° 2θ.

4. The crystalline form A of citrate according to claim 1, wherein form A shows an XRPD plot using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 12.5 ± 0.2, and 20.3 ± 0.2° 2θ.

5. The crystalline form A of citrate according to claim 1, wherein form A shows an XRPD plot using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 12.7 ± 0.2, and 13.0 ± 0.2° 2θ.

6. The crystalline form A of citrate according to claim 1, wherein form A shows an XRPD plot using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 12.7 ± 0.2, and 20.3 ± 0.2° 2θ.

7. The crystalline form A of citrate according to claim 1, wherein form A shows an XRPD plot using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 13.0 ± 0.2, and 20.3 ± 0.2° 2θ.

8. The crystalline form A of citrate according to claim 1, wherein form A shows an XRPD plot using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 16.8 ± 0.2, and 20.1 ± 0.2° 2θ.

9. The crystalline form A of citrate according to claim 1, wherein form A shows an XRPD plot using copper K-α radiation containing peaks at approximately 5.7 ± 0.2, 20.1 ± 0.2, and 20.3 ± 0.2° 2θ.

10. The crystalline form A of citrate according to claim 1, wherein form A shows an XRPD plot using copper K-α radiation containing peaks at approximately 12.5 ± 0.2, 13.0 ± 0.2, and 20.3 ± 0.2° 2θ.

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