Novel crystalline forms of pyrimidine compounds, pharmaceutical compositions containing same, and methods of use thereof

Abstract

The present disclosure relates to solid forms of pyrimidine compounds, pharmaceutical compositions containing them, and methods of using same. For example, the present disclosure relates to a crystalline polymorph of the compound of Formula 1, or a pharmaceutically acceptable salt, solvate, or solvated salt thereof. [Formula 1] JPEG2025535889000034.jpg2852 [Formula 1]

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Patent Application No. 63 / 382,463, filed November 4, 2022, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0002] The present disclosure relates to novel solid forms, such as crystalline forms, of pyrimidine compounds, pharmaceutical compositions containing them, and therapeutic uses thereof.

[0003] More specifically, the present disclosure relates to amorphous and crystalline forms of the compound of Formula 1, e.g., anhydrates, hydrates, solvates, salts, salt solvates, methods for making same, pharmaceutical compositions containing same, and therapeutic uses thereof. [Background technology]

[0004] FLT3-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed by hematopoietic stem cells and is normally expressed in hematopoietic progenitor cells, which play important roles in normal stem cells and the immune system. Abnormal overexpression and mutation of FLT3 are frequently observed in patients with leukemia. Acute myelogenous leukemia (AML) is a disorder of pluripotent hematopoietic stem cells characterized by abnormal proliferation and differentiation of blast cells in the bone marrow and peripheral blood. In recent years, FLT3 has been considered one of the most important targets for the treatment of AML.

[0005] In embodiments, the compound of Formula 1 has the compound name 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine and has antiproliferative activity, such as anticancer activity, by targeting FMS-like tyrosine kinases, and can selectively and effectively treat drug resistance caused by tyrosine kinase mutations. [ka] [Formula 1] Summary of the Invention [Problem to be solved by the invention]

[0006] One aspect is to provide a crystalline form of the compound of Formula 1.

[0007] One aspect is to provide an amorphous form of the compound of Formula 1.

[0008] Another aspect is to provide pharmaceutical compositions comprising a crystalline or amorphous form of the compound of Formula 1.

[0009] Another aspect is to provide a method of treating cancer, such as leukemia, which in certain embodiments may be acute myeloid leukemia, acute lymphocytic leukemia, or chronic myeloid leukemia. [Means for solving the problem]

[0010] One embodiment provides a crystalline form of the compound of Formula 1: [ka] [Formula 1]

[0011] Compounds of Formula 1 and methods of use thereof are disclosed in U.S. Patent Application Publication Nos. US 2020 / 0031806, US 2022 / 0110913, US 2022 / 0354842, and PCT Application Publication Nos. WO2020022600, WO2020171646, WO2020171649, WO2020262974, WO2021066443, and WO / 2022 / 098083, which are incorporated by reference herein in their entireties.

[0012] In embodiments, the present disclosure provides a solid form of Formula 1: [ka] [Formula 1]

[0013] or pharmaceutically acceptable salts and / or solvates thereof, pharmaceutical compositions comprising solid forms thereof, and therapeutic uses thereof.

[0014] In embodiments, the solid form is an amorphous form of the compound of Formula 1.

[0015] In embodiments, the solid form is an anhydrate of the compound of Formula 1.

[0016] In embodiments, the solid form is a crystalline form of the compound of Formula 1.

[0017] In embodiments, the crystalline form is a solvate of the compound of Formula 1.

[0018] In embodiments, the crystalline form is a crystalline form of a hydrate of the compound of Formula 1. For example, in embodiments, the hydrate of the compound of Formula 1 is a monohydrate or a trihydrate. In embodiments, the hydrate is a monohydrate. In embodiments, the hydrate is a trihydrate.

[0019] In embodiments, the crystalline form is a crystalline form of an alcohol solvate (e.g., an alcohol monosolvate) of the compound of Formula 1. For example, in embodiments, the solvate of the compound of Formula 1 is an ethanol solvate (e.g., an ethanol monosolvate), which has a crystal structure containing one solvent molecule per compound of Formula 1 molecule.

[0020] In embodiments, the crystalline form is a pharmaceutically acceptable salt of the compound of Formula 1 or a pharmaceutically acceptable salt solvate of the compound of Formula 1. In embodiments, the crystalline form of the pharmaceutically acceptable salt or salt solvate of the compound of Formula 1 is selected from the group consisting of hydrochloride, sulfate, fumarate, succinate, maleate, and solvates thereof.

[0021] In embodiments, the crystalline form is a pharmaceutically acceptable salt of the compound of Formula 1. In embodiments, the crystalline form of the pharmaceutically acceptable salt of the compound of Formula 1 is selected from the group consisting of hydrochloride, sulfate, fumarate, succinate, and maleate.

[0022] In embodiments, the crystalline form is a pharmaceutically acceptable salt solvate of the compound of Formula 1. In embodiments, the pharmaceutically acceptable salt solvate of the compound of Formula 1 is an ethanol solvate of the dihydrochloride salt of the compound of Formula 1.

[0023] In certain examples, the crystalline form of the compound of Formula 1 may be a hydrate, solvate, or anhydrous crystalline form.

[0024] As used in this disclosure, the verb "comprise" in its forms and conjugations as used in the specification and claims is used in its open-ended sense, meaning that what precedes it is included, but not excluding items not specifically mentioned. The present invention may suitably "comprise," "consist," or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0025] Further, it should be noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as a basis for prescribing the use of exclusionary terminology, such as "single," "only," and the like, in connection with the recitation of claim elements or the use of "negative" limitations.

[0026] As used in this disclosure, the term "crystal form" or "crystalline form" refers to a crystalline solid form comprising a compound, which may include, but is not limited to, a crystalline polymorph, solvate, hydrate, co-crystal or other molecular complex, or crystalline polymorph thereof, and may refer to a particular single-component or multi-component crystalline form.

[0027] As used in this disclosure, the terms "polymorph" and "polymorphic form" refer to two or more crystalline forms containing the same molecule, molecules, or ions. Different polymorphs may have different physical properties, such as melting point, solubility, or vibrational spectra, due to different arrangements or structures of the molecules and ions within the crystalline grid.

[0028] As used in this disclosure, the term "solvate" refers to a crystalline form of a material containing a solvent. The solvent may be a pharmaceutically acceptable solvent. For example, the solvent may be a linear or branched C1-C4 alcohol, ethylene glycol, propylene glycol, or acetic acid. The alcohol may be, for example, methanol, ethanol, isopropanol, or butanol. The solvent may preferably be ethanol, which is more suitable for use in the human body. Alternatively, the solvent may be water.

[0029] The term "hydrate" as used in this disclosure refers to a solvate in which the solvent is water. "Polymorphic solvates" refers to the existence of two or more crystalline forms for a particular solvate composition. "Polymorphic hydrates" refers to the existence of two or more crystalline forms for a particular hydrate composition. When a solvent is added to dissolve at least a portion of the compound, the solvent may be in an amount sufficient to dissolve at least a portion of the compound of Formula 1.

[0030] As used in this disclosure, the terms "amorphous" or "amorphous form" refer to a state of a material, composition, or product in which the material, composition, or product is not substantially crystalline as determined by X-ray diffraction.

[0031] As used in this disclosure, "substantially" or "substantial" refers to the complete or nearly complete extent or degree of an action, property, characteristic, state, structure, item, or result. For example, a "substantially" enclosed object means that the object is completely enclosed or nearly completely enclosed. To give another example, an XRPD pattern that is "substantially" similar to another XRPD pattern would mean that one of ordinary skill in the art would understand that the two patterns are the same material in the same form. The exact degree of deviation from absolute perfection may, in some cases, depend on the specific circumstances. Generally, however, the proximity to perfection will be such that the same overall result would be obtained as if absolute and total perfection were achieved. The use of "substantially" is equally applicable when used in the negative to refer to the complete or nearly complete absence of an action, property, characteristic, state, structure, item, or result. For example, a composition that is "substantially" free of other active agents is either completely devoid of other active agents or completely devoid of other active agents, and the effect is the same as if the other active agents were completely absent. In other words, a composition that is substantially free of a component or element, or other active agent, may still contain such, so long as there is no measurable effect thereof.

[0032] The term "treatment" refers to one or more of alleviating, ameliorating, delaying, reducing, ameliorating, or managing at least one symptom of a condition in a subject. The term "treatment" can also refer to one or more of preventing or delaying the onset (i.e., the period before clinical presentation of a symptom) or reducing the risk of developing or worsening a symptom.

[0033] An "effective amount" means the amount of a formulation according to the invention that, when administered to a patient for treating a condition, disorder, or symptom, is sufficient to effect such treatment. An "effective amount" will vary depending on the active ingredient, the condition, disorder, or symptom being treated and its severity, and the age, weight, physical condition, and responsiveness of the mammal being treated.

[0034] The term "therapeutically effective" as applied to a dose or amount refers to the amount of a compound or pharmaceutical preparation that is sufficient to result in a desired clinical benefit following administration to a patient in need thereof.

[0035] As used in this disclosure, a "subject" may be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. In embodiments, the subject is a human. In embodiments, the subject may be a subject who has cancer or is suspected of being at risk of having cancer.

[0036] Pharmaceutically acceptable salts include salts obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form salts such as hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with the appropriate inorganic or organic acid via any of a number of known methods.

[0037] In embodiments, a crystalline form of a compound of Formula 1 (e.g., as disclosed herein), or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, may comprise at least about 99.9%, at least about 99.8%, at least about 99.7%, at least about 99.6%, at least about 99.5%, at least about 99%, at least about 98%, at least about 97%, at least about 96%, at least about 95%, at least about 94%, at least about 93%, at least about 92%, at least about 91%, at least about 90%, at least about 85%, at least about 80%, at least about 75%, at least about 70%, at least about 65%, at least about 60%, at least about 55%, or at least about 50% of a single crystalline form (e.g., as disclosed herein). Polymorphic purity can be measured using methods known to those skilled in the art, such as, for example, X-ray powder crystallography.

[0038] In embodiments, a crystalline form of a compound of Formula 1 (e.g., as disclosed herein), or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, has a purity of about 99.9% or greater, about 99.8% or greater, about 99.7% or greater, about 99.6% or greater, about 99.5% or greater, about 99% or greater, about 98% or greater, about 97% or greater, about 96% or greater, about 95% or greater, about 94% or greater, about 93% or greater, about 92% or greater, about 91% or greater, about 90% or greater, about 85% or greater, or about 80% or greater. In embodiments, the crystalline form has a purity in the range of about 80% to about 99%. In embodiments, the crystalline form has a purity in the range of about 80% to about 99.5%, or about 90% to about 99.9%, or about 95% to about 100%, including all values ​​and subranges therebetween. In embodiments, purity is measured by HPLC.

[0039] In embodiments, a crystalline form of a compound of Formula 1 (e.g., as disclosed herein), or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, has a purity of about 99.9% by weight or greater, about 99.8% by weight or greater, about 99.7% by weight or greater, about 99.6% by weight or greater, about 99.5% by weight or greater, about 99% by weight or greater, about 98% by weight or greater, about 97% by weight or greater, about 96% by weight or greater, about 95% by weight or greater, about 94% by weight or greater, about 93% by weight or greater, about 92% by weight or greater, about 91% by weight or greater, about 90% by weight or greater, about 85% by weight or greater, or about 80% by weight or greater. In embodiments, the crystalline form has a purity of a single crystalline form ranging from about 80% by weight to about 99% by weight. In embodiments, purity is measured using methods known to those of skill in the art, such as HPLC.

[0040] In embodiments, the crystalline form of the compound of Formula 1 (e.g., as disclosed herein) or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof is at least about 95% pure by weight and contains about 5% or less impurities by weight. In some embodiments, the crystalline form of the compound of Formula 1 (e.g., as disclosed herein) or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof is about 95.0% to 100% pure by weight and contains 0% to about 5% impurities by weight. In some embodiments, the crystalline form of the compound of Formula 1 (e.g., as disclosed herein) or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof is about 98% to 100% pure by weight and contains 0% to about 2% impurities by weight. In some embodiments, the crystalline form of the compound of Formula 1 (e.g., as disclosed herein) or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof is about 98%, about 98.5%, about 99%, about 99.5%, or 100% pure by weight, containing about 2%, about 1.5%, about 1%, about 0.5%, or 0% by weight of impurities, respectively. In some embodiments, the crystalline form of the compound of Formula 1 (e.g., as disclosed herein) or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof is about 99.5%, about 99.9%, or about 99.95% pure by weight, containing about 0.5%, about 0.1%, or about 0.05% by weight of impurities, respectively.

[0041] In some embodiments, purity or impurities are measured using methods known to those skilled in the art, such as, for example, high performance liquid chromatography (HPLC).

[0042] In certain examples, the crystalline form may be a crystalline form of a hydrate of the compound of Formula 1. The hydrate of the compound of Formula 1 may be a monohydrate, a dihydrate, or a trihydrate.

[0043] In certain examples, the crystalline form may be a monohydrate, dihydrate, or trihydrate crystalline form of the compound of Formula 1, or preferably a monohydrate or trihydrate crystalline form.

[0044] Monohydrate crystalline form of the compound of formula 1 In certain examples, the crystalline form may be a crystalline form of a monohydrate of the compound of Formula 1.

[0045] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% monohydrate of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% monohydrate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% monohydrate of the compound of Formula 1.

[0046] The monohydrate crystalline form may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.0°±0.2°, 10.1°±0.2°, and 16.9°±0.2°.

[0047] The monohydrate crystalline form may further comprise at least one peak at a diffraction angle 2θ selected from 7.8°±0.2° and 16.8°±0.2°.

[0048] The monohydrate crystalline form may further comprise at least one peak at a diffraction angle 2θ selected from 11.0°±0.2°, 11.7°±0.2°, and 17.9°±0.2°.

[0049] The monohydrate crystalline form may further comprise at least one peak at a diffraction angle 2θ selected from 15.7°±0.2, 18.7°±0.2, 23.6°±0.2, and 24.3°±0.2°.

[0050] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0051] The X-ray powder diffraction (XRPD) of the monohydrate crystalline form may have a pattern containing 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I: I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0052] For example, the XRPD relative intensity (I / I) of the monohydrate crystalline form exhibiting peaks may be 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0053] In certain examples, when the monohydrate crystalline form is irradiated with a Cu-Kα light source, the monohydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.0°±0.2°, 7.8°±0.2°, 10.1°±0.2°, 16.8°±0.2°, and 16.9°±0.2°.

[0054] In certain examples, when the monohydrate crystalline form is irradiated with a Cu-Kα light source, the monohydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 11.0°±0.2°, 11.7°±0.2°, and 17.9°±0.2°.

[0055] In certain examples, when the monohydrate crystalline form is irradiated with a Cu-Kα light source, the monohydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 15.7°±0.2°, 18.7°±0.2°, 23.6°±0.2°, and 24.3°±0.2°.

[0056] The monohydrate crystalline form may have an X-ray powder diffraction (XRPD) pattern comprising different combinations of peaks at diffraction angles 2θ selected from 5.0°±0.2°, 7.8°±0.2°, 10.1°±0.2°, 11.0°±0.2°, 11.7°±0.2°, 15.7°±0.2°, 16.8°±0.2°, 16.9°±0.2°, 17.9°±0.2°, 18.7°±0.2°, 23.6°±0.2°, and 24.3°±0.2°, when the crystalline form is irradiated with a Cu-Kα light source.

[0057] The monohydrate crystalline form may have a peak at the diffraction angle (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0058] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0059] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks from Table 1.

[0060] The monohydrate crystalline form may exhibit the differential scanning calorimetry (DSC) profile of the crystalline form shown in FIG.

[0061] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0062] In certain examples, the monohydrate crystalline form may have an endothermic onset temperature of 74.9°C and exhibit heat absorption peaks at endothermic temperatures of 89.0°C and 161.6°C in differential scanning calorimetry (DSC).

[0063] Trihydrate crystalline form of the compound of formula 1 In certain examples, the crystalline form may be a trihydrate crystalline form of the compound of Formula 1.

[0064] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the trihydrate of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the trihydrate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the trihydrate of the compound of Formula 1.

[0065] The trihydrate crystalline form may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.3°±0.2°, and 17.2°±0.2°.

[0066] The trihydrate crystalline form may further comprise at least one peak at a diffraction angle 2θ selected from 11.1°±0.2° and 20.8°±0.2°.

[0067] The trihydrate crystalline form may further comprise at least one peak at a diffraction angle 2θ selected from 19.2°±0.2°, 19.6°±0.2°, 21.3°±0.2°, 22.9°±0.2°, 23.9°±0.2°, and 25.5°±0.2°.

[0068] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0069] The X-ray powder diffraction (XRPD) of the trihydrate crystalline form may have a pattern containing 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ, with relative intensities (I / Io: I is the intensity of each peak and Io is the intensity of the highest peak) of 10% or greater.

[0070] For example, the XRPD relative intensity (I / Io) of the trihydrate crystalline form exhibiting these peaks may be 10% or greater, 14% or greater, 15% or greater, 20% or greater, or 22% or greater.

[0071] In certain examples, when the trihydrate crystalline form is irradiated with a Cu-Kα light source, the trihydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.3°±0.2°, 11.1°±0.2°, 17.2°±0.2°, and 20.8°±0.2°.

[0072] In certain examples, when the trihydrate crystalline form is irradiated with a Cu-Kα light source, the trihydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern further comprising peaks at 19.2°±0.2°, 19.6°±0.2°, 21.3°±0.2°, 22.9°±0.2°, 23.9°±0.2°, and 25.5°±0.2°.

[0073] The trihydrate crystalline form may have an X-ray powder diffraction (XRPD) pattern comprising different combinations of peaks at diffraction angles 2θ selected from 8.2°±0.2°, 9.3°±0.2°, 11.1°±0.2°, 17.2°±0.2°, 19.2°±0.2°, 19.6°±0.2°, 20.8°±0.2°, 21.3°±0.2°, 22.9°±0.2°, 23.9°±0.2°, and 25.5°±0.2°, when the crystalline form is irradiated with a Cu-Kα light source.

[0074] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0075] The trihydrate crystalline form may have peaks at the X-ray powder diffraction (XRPD) diffraction angles (2θ±0.2) identified in FIG.

[0076] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 2.

[0077] The trihydrate crystalline form may exhibit differential scanning calorimetry (DSC) analysis of the crystalline form as identified in FIG.

[0078] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0079] In certain examples, the trihydrate crystalline form may have an endothermic onset temperature of 44.9°C and exhibit heat absorption peaks at endothermic temperatures of 68.7°C and 108.3°C in differential scanning calorimetry (DSC).

[0080] Ethanol monosolvate crystalline form of the compound of formula 1 In certain examples, the crystalline form may be that of a solvate of the compound of Formula 1. The solvate of the compound of Formula 1 may be an alcohol solvate, or preferably an ethanol solvate.

[0081] In certain examples, the crystalline form may be that of an alcohol solvate of the compound of Formula 1. In certain examples, the crystalline form may be that of an alcohol monosolvate of the compound of Formula 1. A monosolvate has a crystal structure containing one solvent molecule per compound of Formula 1 molecule.

[0082] In certain examples, the crystalline form may be a crystalline form of an ethanol solvate of the compound of Formula 1. In certain examples, the crystalline form may be a crystalline form of an ethanol monosolvate of the compound of Formula 1.

[0083] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% ethanol monosolvate of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% ethanol monosolvate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% ethanol monosolvate of the compound of Formula 1.

[0084] The ethanol monosolvate crystalline form may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.6°±0.2°, 17.2°±0.2°, and 21.4±0.2°.

[0085] The ethanol monosolvate crystalline form may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, and 21.4°±0.2°.

[0086] The crystalline form of the ethanol monosolvate may further comprise at least one peak at a diffraction angle 2θ selected from 17.5°±0.2 and 18.9°±0.2°.

[0087] The crystalline form of the ethanol monosolvate may further comprise at least one peak at a diffraction angle 2θ selected from 7.8°±0.2°, 19.2°±0.2°, 24.0°±0.2°, and 25.7°±0.2°.

[0088] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0089] The X-ray powder diffraction (XRPD) of the ethanol monosolvate crystalline form may have a pattern containing 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I: I is the intensity of each peak and I is the intensity of the highest peak) of 10% or greater.

[0090] For example, the XRPD relative intensity (I / I) of the crystalline form of the ethanol monosolvate exhibiting peaks may be 10% or greater, 20% or greater, 30% or greater, 40% or greater, 60% or greater, or 65% or greater.

[0091] In certain examples, the crystalline form of the ethanol monosolvate irradiated with a Cu-Kα light source has a characteristic X-ray powder diffraction (XRPD) pattern that includes peaks at diffraction angles 2θ of 8.6°±0.2°, 17.2°±0.2°, and 21.4±0.2°.

[0092] In certain examples, the crystalline form of the ethanol monosolvate irradiated with a Cu-Kα light source has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.9°±0.2°, and 21.4°±0.2°.

[0093] In certain examples, the crystalline form of the ethanol monosolvate illuminated with a Cu-Kα light source has a characteristic X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 7.8°±0.2°, 19.2°±0.2°, 24.0°±0.2°, and 25.7°±0.2°.

[0094] The crystalline form of the ethanol monosolvate illuminated with a Cu-Kα light source may have an X-ray powder diffraction (XRPD) pattern comprising different combinations of peaks at diffraction angles 2θ selected from 7.8°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.9°±0.2°, 19.2°±0.2°, 21.4°±0.2°, 24.0°±0.2°, and 25.7°±0.2°.

[0095] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0096] The crystalline form of the ethanol monosolvate may comprise the peaks at the diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) identified in FIG.

[0097] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 3.

[0098] The ethanol monosolvate crystalline form may exhibit the differential scanning calorimetry (DSC) analysis of the crystalline form identified in FIG.

[0099] In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG.

[0100] In certain examples, the crystalline form of the ethanol monosolvate may have an endothermic onset temperature of 99.8°C and exhibit a heat absorption peak in differential scanning calorimetry (DSC) at an endothermic temperature of 113.4°C.

[0101] Anhydrous Crystalline Form I of the Compound of Formula 1 In certain examples, the crystalline form may be a crystalline form of the anhydrate of the compound of Formula 1.

[0102] In certain examples, the crystalline form may be anhydrous crystalline Form I of the compound of Formula 1.

[0103] In embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than 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%, or about 99.0% Anhydrous Form I of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% Anhydrous Form I of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% Anhydrous Form I of the compound of Formula 1.

[0104] Anhydrous crystalline Form I may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, and 18.1±0.2°.

[0105] Anhydrous crystalline Form I may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.5°±0.2°, and 18.1°±0.2°.

[0106] Anhydrous crystalline Form I may further comprise at least one peak at a diffraction angle 2θ selected from 6.5°±0.2° and 25.7°±0.2°.

[0107] Anhydrous crystalline Form I may further comprise at least one peak at a diffraction angle 2θ selected from 11.2°±0.2°, 15.1°±0.2°, 20.2°±0.2°, 21.8°±0.2°, and 22.5°±0.2°.

[0108] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0109] The X-ray powder diffraction (XRPD) spectrum of anhydrous crystalline Form I may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I: I is the intensity of each peak, I is the intensity of the highest peak) of 10% or greater.

[0110] For example, the XRPD relative intensity (I / Io) of the peaks exhibited by anhydrous crystalline Form I may be 10% or greater, 20% or greater, 30% or greater, 40% or greater, 60% or greater, or 65% or greater.

[0111] In certain examples, when anhydrous crystalline Form I is irradiated with a Cu-Kα light source, the anhydrous crystalline Form I has a characteristic X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles of 5.2°±0.2°, 10.4°±0.2°, and 18.1±0.2°.

[0112] In certain examples, when anhydrous crystalline Form I is irradiated with a Cu-Kα light source, the anhydrous crystalline Form I has a characteristic X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.5°±0.2°, and 18.1°±0.2°.

[0113] In certain examples, when anhydrous crystalline Form I is irradiated with a Cu-Kα light source, the anhydrous crystalline Form I has a characteristic X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 6.5°±0.2°, 11.2°±0.2°, 15.1°±0.2°, 20.2°±0.2°, 21.8°±0.2°, 22.5°±0.2°, and 25.7°±0.2°.

[0114] When anhydrous crystalline Form I is irradiated with a Cu-Kα light source, the anhydrous crystalline Form I may have an X-ray powder diffraction (XRPD) pattern comprising different combinations of peaks at diffraction angles 2θ selected from 5.2°±0.2°, 6.5°±0.2°, 10.4°±0.2°, 11.2°±0.2°, 15.1°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.1°±0.2°, 20.2°±0.2°, 21.8°±0.2°, 22.5°±0.2°, and 25.7°±0.2°.

[0115] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0116] Anhydrous crystalline Form I may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum identified in FIG.

[0117] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 4.

[0118] Anhydrous crystalline Form I may be such that it exhibits a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0119] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0120] In certain examples, anhydrous crystalline Form I may be such that it has an endothermic onset temperature of 152.4°C and exhibits a heat absorption peak in differential scanning calorimetry (DSC) at an endothermic temperature of 159.5°C.

[0121] Anhydrous Crystalline Form II of the Compound of Formula 1 In certain examples, the crystalline form may be that of anhydrous crystalline Form II of the compound of Formula 1.

[0122] Anhydrous crystalline Form II may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, and 9.7±0.2°.

[0123] Anhydrous crystalline Form II may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, 9.7°±0.2°, 17.7°±0.2°, and 19.0°±0.2°.

[0124] Anhydrous crystalline Form II may further comprise at least one peak at a diffraction angle 2θ selected from 11.8°±0.2°, 14.3°±0.2°, and 23.0°±0.2°.

[0125] Anhydrous crystalline Form II may further comprise at least one peak at a diffraction angle 2θ selected from 8.1°±0.2°, 15.0°±0.2°, 21.4°±0.2°, and 25.9°±0.2°.

[0126] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0127] The X-ray powder diffraction (XRPD) of anhydrous crystalline Form II may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I: I is the intensity of each peak and I is the intensity of the highest peak) of 10% or greater.

[0128] For example, the XRPD relative intensity (I / Io) of the peaks exhibited by anhydrous crystalline Form II may be 10% or greater, 20% or greater, 30% or greater, 40% or greater, 60% or greater, or 65% or greater.

[0129] In certain examples, when anhydrous crystalline Form II is irradiated with a Cu-Kα light source, the anhydrous crystalline Form II has a characteristic X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, and 9.7±0.2°.

[0130] In certain examples, when anhydrous crystalline Form II is irradiated with a Cu-Kα light source, the anhydrous crystalline Form II has a characteristic X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, 9.7°±0.2°, 17.7°±0.2°, and 19.0°±0.2°.

[0131] In certain examples, when anhydrous crystalline Form II is irradiated with a Cu-Kα light source, the anhydrous crystalline Form II has a characteristic X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 8.1°±0.2°, 11.8°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 25.9°±0.2°.

[0132] When anhydrous crystalline Form II is irradiated with a Cu-Kα light source, the anhydrous crystalline Form II may have an X-ray powder diffraction (XRPD) having different combinations of peaks at diffraction angles 2θ selected from 4.9°±0.2°, 5.9°±0.2°, 8.1°±0.2°, 9.7°±0.2°, 11.8°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 17.7°±0.2°, 19.0°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 25.9°±0.2°.

[0133] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0134] Anhydrous crystalline Form II may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) shown in FIG.

[0135] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 5.

[0136] Anhydrous crystalline Form II may be such that it exhibits a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0137] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0138] In certain examples, anhydrous crystalline Form II may be such that it has an endothermic onset temperature of 139.8°C and exhibits a heat absorption peak at an endothermic temperature of 149.4°C in differential scanning calorimetry (DSC).

[0139] Dihydrochloride Form I of the Compound of Formula 1 In embodiments, the crystalline form may be a crystalline form of the dihydrochloride salt of the compound of Formula 1.

[0140] In embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than 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%, or about 99.0% dihydrochloride Form I of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% dihydrochloride Form I of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% dihydrochloride Form I of the compound of Formula 1.

[0141] Dihydrochloride salt crystalline Form I of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.4°±0.2°, and 19.1°±0.2°.

[0142] The XRPD pattern of the dihydrochloride salt crystalline Form I of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 14.6°±0.2° and 26.2°±0.2°.

[0143] The XRPD pattern of the dihydrochloride salt crystalline Form I of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 10.8°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 18.5°±0.2°, 23.4°±0.2°, 25.8°±0.2°, and 27.1°±0.2°.

[0144] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0145] The X-ray powder diffraction (XRPD) of the dihydrochloride salt crystalline Form I of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0146] For example, dihydrochloride salt crystalline Form I of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0147] In embodiments, when the dihydrochloride salt crystalline Form I of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.4°±0.2°, and 19.1°±0.2°.

[0148] In embodiments, when dihydrochloride salt crystalline Form I of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.4°±0.2°, 14.6°±0.2°, 19.1°±0.2°, and 26.2°±0.2°.

[0149] In embodiments, when dihydrochloride salt crystalline Form I of the compound of Formula 1 is irradiated with a Cu-Kα light source, the dihydrochloride salt crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 10.8°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 18.5°±0.2°, 23.4°±0.2°, 25.8°±0.2°, and 27.1°±0.2°.

[0150] The dihydrochloride salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0151] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0152] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 6.

[0153] The dihydrochloride salt crystalline form may be such that it exhibits a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0154] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0155] In embodiments, the dihydrochloride salt crystalline form may be such that, in differential scanning calorimetry (DSC), it exhibits an endothermic absorption peak having an onset of about 105°C and a peak maximum of about 139°C, as well as an additional endothermic absorption peak having an onset of about 187°C and a peak maximum of about 202°C.

[0156] In embodiments, the dihydrochloride salt crystalline Form I is an ethanol solvate.

[0157] Dihydrochloride Form II of the Compound of Formula 1 In embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than 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%, or about 99.0% dihydrochloride Form II of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% dihydrochloride Form II of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may be comprised of greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% dihydrochloride Form II of the compound of Formula 1.

[0158] Dihydrochloride salt crystalline Form II of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 10.5°±0.2°, 15.2°±0.2°, and 23.1°±0.2°.

[0159] The XRPD pattern of the dihydrochloride salt crystalline Form II of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 22.3°±0.2° and 27.2°±0.2°.

[0160] The XRPD pattern of the dihydrochloride salt crystalline Form II of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 12.3°±0.2°, 17.8°±0.2°, 19.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 25.1°±0.2°, and 26.3°±0.2°.

[0161] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0162] The X-ray powder diffraction (XRPD) of the dihydrochloride salt crystalline Form II of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0163] For example, dihydrochloride salt crystalline Form II of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0164] In embodiments, when the dihydrochloride salt crystalline Form II of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 10.5°±0.2°, 15.2°±0.2°, and 23.1°±0.2°.

[0165] In embodiments, when the dihydrochloride salt crystalline Form II of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 10.5°±0.2°, 15.2°±0.2°, 22.3°±0.2°, 23.1°±0.2°, and 27.2°±0.2°.

[0166] In embodiments, when dihydrochloride salt crystalline Form II of the compound of Formula 1 is irradiated with a Cu-Kα light source, the dihydrochloride salt crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 12.3°±0.2°, 17.8°±0.2°, 19.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 25.1°±0.2°, and 26.3°±0.2°.

[0167] The dihydrochloride salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0168] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0169] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 7.

[0170] The dihydrochloride salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0171] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0172] In embodiments, the dihydrochloride salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) with an onset of about 213°C and a peak maximum of about 239°C.

[0173] Monohydrochloride Form I of the Compound of Formula 1 In embodiments, the crystalline form may be a crystalline form of the monohydrochloride salt of the compound of Formula 1.

[0174] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the monohydrochloride salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the monohydrochloride salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the monohydrochloride salt of the compound of Formula 1.

[0175] The monohydrochloride salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 17.1°±0.2°, 18.6°±0.2°, and 23.5°±0.2°.

[0176] The XRPD pattern of the monohydrochloride salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 19.0°±0.2° and 20.9°±0.2°.

[0177] The XRPD pattern of the monohydrochloride salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 4.9°±0.2°, 5.4°±0.2°, 8.0°±0.2°, 9.3°±0.2°, 14.2°±0.2°, 14.6°±0.2°, and 26.0°±0.2°.

[0178] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0179] The X-ray powder diffraction (XRPD) of the monohydrochloride salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0180] For example, a monohydrochloride salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0181] In embodiments, when the monohydrochloride salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 17.1°±0.2°, 18.6°±0.2°, and 23.5°±0.2°.

[0182] In embodiments, when the monohydrochloride salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 17.1°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 20.9°±0.2°, and 23.5°±0.2°.

[0183] In n embodiments, when the monohydrochloride salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the monohydrochloride salt crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 4.9°±0.2°, 5.4°±0.2°, 8.0°±0.2°, 9.3°±0.2°, 14.2°±0.2°, 14.6°±0.2°, and 26.0°±0.2°.

[0184] The monohydrochloride salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0185] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0186] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 8.

[0187] The monohydrochloride salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0188] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0189] In embodiments, the monohydrochloride salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) with an onset of about 105°C and a peak maximum of about 121°C.

[0190] Disulfate Crystalline Form of the Compound of Formula 1 In embodiments, the crystalline form may be a crystalline form of the disulfate salt of the compound of Formula 1.

[0191] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the disulfate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the disulfate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the disulfate salt of the compound of Formula 1.

[0192] The disulfate salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.4°±0.2°, and 24.3°±0.2°.

[0193] The XRPD pattern of the disulfate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 11.1°±0.2° and 15.2°±0.2°.

[0194] The XRPD pattern of the disulfate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 17.0°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 26.5°±0.2°, and 27.8°±0.2°.

[0195] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0196] The X-ray powder diffraction (XRPD) of the disulfate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0197] For example, a disulfate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0198] In embodiments, when the disulfate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.4°±0.2°, and 24.3°±0.2°.

[0199] In embodiments, when the disulfate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 15.2°±0.2°, and 24.3°±0.2°.

[0200] In embodiments, when the disulfate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the disulfate salt crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 17.0°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 26.5°±0.2°, and 27.8°±0.2°.

[0201] The disulfate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0202] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0203] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 9.

[0204] The disulfate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0205] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0206] In embodiments, the disulfate salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) having an onset of about 79°C and a peak maximum of about 107°C.

[0207] Monosulfate crystalline form of the compound of formula 1 In embodiments, the crystalline form may be the crystalline form of the monosulfate salt of the compound of Formula 1.

[0208] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the monosulfate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the monosulfate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the monosulfate salt of the compound of Formula 1.

[0209] The monosulfate salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.4°±0.2°, and 24.3°±0.2°.

[0210] The XRPD pattern of the monosulfate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 11.1°±0.2° and 15.2°±0.2°.

[0211] The XRPD pattern of the monosulfate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 17.0°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 26.5°±0.2°, and 27.8°±0.2°.

[0212] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0213] The X-ray powder diffraction (XRPD) of the monosulfate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0214] For example, the monosulfate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0215] In embodiments, when the monosulfate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.4°±0.2°, and 24.3°±0.2°.

[0216] In embodiments, when the monosulfate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 15.2°±0.2°, and 24.3°±0.2°.

[0217] In embodiments, when the monosulfate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the monosulfate salt crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 17.0°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 26.5°±0.2°, and 27.8°±0.2°.

[0218] The monosulfate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0219] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0220] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 10.

[0221] The monosulfate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0222] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0223] In embodiments, the monosulfate salt crystalline form may exhibit, in differential scanning calorimetry (DSC), an endothermic absorption peak having an onset of about 244°C and a peak maximum of about 274°C, as well as an additional endothermic absorption peak having an onset of about 187°C and a peak maximum of about 202°C.

[0224] Monosulfate crystalline form of the compound of formula 1 In embodiments, the monosulfate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0225] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0226] The monosulfate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0227] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0228] In embodiments, the monosulfate salt crystalline form may exhibit, in differential scanning calorimetry (DSC), an endothermic absorption peak having an onset of about 244°C and a peak maximum of about 274°C, as well as an additional endothermic absorption peak having an onset of about 187°C and a peak maximum of about 202°C.

[0229] Difumarate salt crystalline form of the compound of formula 1 In embodiments, the crystalline form may be the crystalline form of the difumaric acid salt of the compound of Formula 1.

[0230] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the difumarate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the difumarate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the difumarate salt of the compound of Formula 1.

[0231] The difumarate salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 22.9°±0.2°, 28.9°±0.2°, and 29.4°±0.2°.

[0232] The XRPD pattern of the difumarate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 5.5°±0.2°, 8.5°±0.2°.

[0233] The XRPD pattern of the difumarate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 5.7°±0.2°, 14.5°±0.2°, 19.1°±0.2°, 21.1°±0.2°, 22.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2°.

[0234] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0235] The X-ray powder diffraction (XRPD) of the difumarate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0236] For example, a difumarate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0237] In embodiments, when the difumarate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 22.9°±0.2°, 28.9°±0.2°, and 29.4°±0.2°.

[0238] In embodiments, when the difumarate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.5°±0.2°, 8.5°±0.2°, 22.9°±0.2°, 28.9°±0.2°, and 29.4°±0.2°.

[0239] In embodiments, when the difumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the difumarate crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 5.7°±0.2°, 14.5°±0.2°, 19.1°±0.2°, 21.1°±0.2°, 22.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2°.

[0240] The difumarate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0241] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0242] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 11.

[0243] The difumarate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0244] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0245] In embodiments, the difumarate salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) with an onset of about 149°C and a peak maximum of about 160°C.

[0246] Hemi-fumarate salt crystalline form of the compound of formula 1 In embodiments, the crystalline form may be a crystalline form of the hemifumaric acid salt of the compound of Formula 1.

[0247] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the hemifumarate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the hemifumarate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the hemifumarate salt of the compound of Formula 1.

[0248] The hemi-fumarate crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.8°±0.2°, 12.6°±0.2°, and 17.1°±0.2°.

[0249] The XRPD pattern of the hemifumarate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 10.2°±0.2° and 23.4°±0.2°.

[0250] The XRPD pattern of the hemifumarate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 8.3°±0.2°, 13.8°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 23.1°±0.2°, and 25.6°±0.2°.

[0251] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0252] The X-ray powder diffraction (XRPD) of the hemifumarate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0253] For example, the hemifumarate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0254] In embodiments, when the hemifumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.8°±0.2°, 12.6°±0.2°, and 17.1°±0.2°.

[0255] In embodiments, when the hemifumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.8°±0.2°, 10.2°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 23.4°±0.2°.

[0256] In embodiments, when the hemifumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the hemifumarate crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 8.3°±0.2°, 13.8°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 23.1°±0.2°, and 25.6°±0.2°.

[0257] The hemifumarate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0258] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0259] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 12.

[0260] The hemifumarate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0261] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0262] In embodiments, the hemifumarate salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) with an onset of about 266°C and a peak maximum of about 269°C.

[0263] Monosuccinate salt crystalline form of the compound of formula 1 In embodiments, the crystalline form may be a crystalline form of the monosuccinate salt of the compound of Formula 1.

[0264] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the monosuccinate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the monosuccinate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the monosuccinate salt of the compound of Formula 1.

[0265] The monosuccinate salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 16.9°±0.2°, 18.5°±0.2°, and 23.6°±0.2°.

[0266] The XRPD pattern of the monosuccinate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 6.9°±0.2° and 23.3°±0.2°.

[0267] The XRPD pattern of the monosuccinate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 8.4°±0.2°, 13.9°±0.2°, 19.3°±0.2°, 21.0°±0.2°, 24.1°±0.2°, and 24.8°±0.2°.

[0268] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0269] The X-ray powder diffraction (XRPD) of the monosuccinate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0270] For example, a monosuccinate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0271] In embodiments, when the monosuccinate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 16.9°±0.2°, 18.5°±0.2°, and 23.6°±0.2°.

[0272] In embodiments, when the monosuccinate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 16.9°±0.2°, 18.5°±0.2°, 23.3°±0.2°, and 23.6°±0.2°.

[0273] In embodiments, when the monosuccinate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the monosuccinate salt crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 8.4°±0.2°, 13.9°±0.2°, 19.3°±0.2°, 21.0°±0.2°, 24.1°±0.2°, and 24.8°±0.2°.

[0274] The monosuccinate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0275] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0276] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 13.

[0277] The monosuccinate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0278] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0279] In embodiments, the monosuccinate salt crystalline form may exhibit, in differential scanning calorimetry (DSC), an endothermic absorption peak having an onset of about 95°C and a peak maximum of about 116°C, as well as an additional endothermic absorption peak having an onset of about 218°C and a peak maximum of about 220°C.

[0280] A hemisuccinate salt crystalline form of the compound of formula 1. In embodiments, the crystalline form may be a crystalline form of the hemisuccinate salt of the compound of Formula 1.

[0281] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the hemisuccinate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the hemisuccinate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the hemisuccinate salt of the compound of Formula 1.

[0282] The hemisuccinate salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 17.0°±0.2°, and 23.6°±0.2°.

[0283] The XRPD pattern of the hemisuccinate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 8.4°±0.2° and 12.6°±0.2°.

[0284] The XRPD pattern of the hemisuccinate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 10.2±0.2°, 13.9±0.2°, 18.5±0.2°, 19.3±0.2°, 23.3±0.2°, 24.8±0.2°, and 25.5±0.2°.

[0285] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0286] The X-ray powder diffraction (XRPD) of the hemisuccinate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0287] For example, a hemisuccinate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0288] In embodiments, when the hemisuccinate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 17.0°±0.2°, and 23.6°±0.2°.

[0289] In embodiments, when the hemisuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 8.4±0.2°, 12.6±0.2°, 17.0°±0.2°, and 23.6°±0.2°.

[0290] In embodiments, when the hemisuccinate salt crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the hemisuccinate salt crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 10.2±0.2°, 13.9±0.2°, 18.5±0.2°, 19.3±0.2°, 23.3±0.2°, 24.8±0.2°, and 25.5±0.2°.

[0291] The hemisuccinate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0292] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0293] In some embodiments, the hemisuccinate salt form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 14.

[0294] The hemisuccinate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0295] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0296] In embodiments, the hemisuccinate salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) having an onset of about 227°C and a peak maximum of about 229°C.

[0297] Dimaleate Crystalline Form of the Compound of Formula 1 In embodiments, the crystalline form may be a crystalline form of the dimaleate salt of the compound of Formula 1.

[0298] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the dimaleate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the dimaleate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the dimaleate salt of the compound of Formula 1.

[0299] The dimaleate salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 11.4°±0.2°, 12.2°±0.2°, and 27.4°±0.2°.

[0300] The XRPD pattern of the dimaleate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 7.1°±0.2° and 27.8°±0.2°.

[0301] The XRPD pattern of the dimaleate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 9.4±0.2°, 14.8±0.2°, 16.6±0.2°, 19.2±0.2°, 20.7±0.2°, 21.1±0.2°, and 24.1±0.2°.

[0302] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0303] The X-ray powder diffraction (XRPD) of the dimaleate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0304] For example, the dimaleate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0305] In embodiments, when the dimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 11.4°±0.2°, 12.2°±0.2°, and 27.4°±0.2°.

[0306] In embodiments, when the dimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 7.1°±0.2°, 11.4±0.2°, 12.2±0.2°, 27.4°±0.2°, and 27.8°±0.2°.

[0307] In embodiments, when the dimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the dimanate crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 9.4±0.2°, 14.8±0.2°, 16.6±0.2°, 19.2±0.2°, 20.7±0.2°, 21.1±0.2°, and 24.1±0.2°.

[0308] The dimaleate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0309] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0310] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 15.

[0311] The dimaleate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0312] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0313] In embodiments, the dimaleate salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) having an onset of about 104°C and a peak maximum of about 121°C.

[0314] Sesquimaleate Crystalline Form of the Compound of Formula 1 In embodiments, the crystalline form may be a crystalline form of the sesquimaleate salt of the compound of Formula 1.

[0315] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the sesquimaleate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the sesquimaleate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the sesquimaleate salt of the compound of Formula 1.

[0316] The sesquimaleate salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 13.8°±0.2°, 17.1°±0.2°, and 18.5°±0.2°.

[0317] The XRPD pattern of the sesquimaleate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 8.9°±0.2° and 16.1°±0.2°.

[0318] The XRPD pattern of the sesquimaleate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 14.2°±0.2°, 19.6°±0.2°, 20.3°±0.2°, 20.9°±0.2°, 22.5°±0.2°, 26.2°±0.2°, and 26.6°±0.2°.

[0319] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0320] The X-ray powder diffraction (XRPD) of the sesquimaleate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0321] For example, the sesquimaleate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0322] In embodiments, when the sesquimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 13.8°±0.2°, 17.1°±0.2°, and 18.5°±0.2°.

[0323] In embodiments, when the sesquimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.9°±0.2°, 13.8°±0.2°, 16.1°±0.2°, 17.1°±0.2°, and 18.5°±0.2°.

[0324] In embodiments, when the sesquimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the sesquimaleate crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 14.2°±0.2°, 19.6°±0.2°, 20.3°±0.2°, 20.9°±0.2°, 22.5°±0.2°, 26.2°±0.2°, and 26.6°±0.2°.

[0325] The sesquimaleate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0326] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0327] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 16.

[0328] The sesquimaleate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0329] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0330] In embodiments, the sesquimaleate salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) having an onset of about 122°C and a peak maximum of about 136°C.

[0331] Monomaleate Crystalline Form of the Compound of Formula 1 In embodiments, the crystalline form may be a crystalline form of the monomaleate salt of the compound of Formula 1.

[0332] In embodiments, the crystalline form of the compound of Formula 1 may comprise greater than 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%, or about 99.0% of the mono-maleate salt of the compound of Formula 1. In other embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of the mono-maleate salt of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of the mono-maleate salt of the compound of Formula 1.

[0333] The monomaleate salt crystalline form of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 11.9°±0.2°, and 24.0°±0.2°.

[0334] The XRPD pattern of the monomaleate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 9.6°±0.2° and 15.7°±0.2°.

[0335] The XRPD pattern of the monomaleate salt crystalline form of the compound of Formula 1 may further comprise at least one peak at a diffraction angle 2θ selected from 5.9°±0.2°, 16.0°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 23.7°±0.2°, and 28.9°±0.2°.

[0336] The peaks at diffraction angles 2θ can form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056 Å).

[0337] The X-ray powder diffraction (XRPD) of the monomaleate salt crystalline form of the compound of Formula 1 may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ with relative intensities (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 5% or greater.

[0338] For example, the monomaleate salt crystalline form of the compound of Formula 1 may have an XRPD pattern exhibiting peaks with a relative intensity (I / I) of 5% or greater, 10% or greater, 15% or greater, 19% or greater, 20% or greater, 40% or greater, or 45% or greater.

[0339] In embodiments, when the monomaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 11.9°±0.2°, and 24.0°±0.2°.

[0340] In embodiments, when the monomaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 9.6°±0.2°, 11.9°±0.2°, 15.7°±0.2°, and 24.0°±0.2°.

[0341] In embodiments, when the monomaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the monomaleate crystalline form has an X-ray powder diffraction (XRPD) pattern further comprising at least one peak at a diffraction angle 2θ selected from 5.9°±0.2°, 16.0°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 23.7°±0.2°, and 28.9°±0.2°.

[0342] The monomaleate salt crystalline form may have peaks at diffraction angles (2θ±0.2) in the X-ray powder diffraction (XRPD) spectrum shown in FIG.

[0343] In embodiments, the crystalline form has an XRPD pattern substantially similar to that of FIG.

[0344] In some embodiments, the crystalline form exhibits an XRPD pattern comprising 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks in Table 17.

[0345] The monomaleate salt crystalline form may exhibit a differential scanning calorimetry (DSC) profile of the crystalline form as shown in FIG.

[0346] In embodiments, the crystalline form has a DSC thermogram substantially similar to that of FIG.

[0347] In embodiments, the monomaleate salt crystalline form may exhibit an endothermic absorption peak in differential scanning calorimetry (DSC) having an onset of about 203°C and a peak maximum of about 207°C.

[0348] Another aspect provides a pharmaceutical composition comprising the crystalline form.

[0349] In certain examples, pharmaceutical compositions can be characterized by comprising at least one crystalline form of the compound of Formula 1 and at least one pharmaceutically acceptable carrier or diluent.

[0350] In certain examples, the crystalline form of the pharmaceutical composition may be substantially pure.

[0351] Examples of pharmaceutically acceptable carriers that may be included in pharmaceutical compositions include, but are not limited to, cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents, and the like.

[0352] Examples of diluents that may be included in the pharmaceutical composition include, but are not limited to, lactose, mannitol, sugars, microcrystalline cellulose and cellulose derivatives, and dried cornstarch.

[0353] The pharmaceutical compositions may be formulated by methods known in the art and prepared in a variety of oral dosage forms, such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc., or parenteral dosage forms, such as intramuscular, intravenous, or subcutaneous injections.

[0354] When the pharmaceutical composition is prepared in the form of an injection, examples of carriers or diluents include, but are not limited to, water, physiological saline, aqueous glucose solution, aqueous pseudo-sugar solution, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, or emulsifying agents.

[0355] As an active ingredient contained in a pharmaceutical composition, the crystalline form of the compound of Formula 1 may be administered orally or parenterally in an effective amount for treating or preventing a disease in a subject or patient, depending on the purpose. When administered orally, the amount of the pharmaceutical composition administered may be, for example, 0.01 mg to 1000 mg, 0.01 mg to 500 mg, 0.1 mg to 300 mg, or 0.1 mg to 100 mg per kg of body weight per day. Furthermore, when administered parenterally, the amount of the pharmaceutical composition administered may be, for example, 0.01 mg to 100 mg, or 0.1 mg to 50 mg per kg of body weight per day. The composition may be administered all at once, or may be divided into several doses and administered over several sessions. The dosage for a subject or patient should be determined taking into consideration various factors including the patient's weight, age, sex, health, diet, administration time, administration mode, and severity of the disease, and of course, the dosage may be appropriately adjusted by a specialist, and the dosages mentioned above are not intended to limit the scope of the present invention in any way.

[0356] The compositions may be administered orally or parenterally one to four times daily, or according to an on / off schedule. In some cases, lower doses than the above ranges may be appropriate, or higher doses may be used without causing adverse side effects, and in the case of higher doses, lower doses may be administered in a series of doses throughout the day.

[0357] The pharmaceutical compositions provide a method for preventing or treating cancer, for example, by inhibiting FLT3 kinase activity, including leukemia.

[0358] The solid form of the compound of Formula 1 may effectively regulate one or more kinases involved in intracellular signal transduction and intracellular complex biological mechanisms. For example, the compound may act on receptor tyrosine kinases (RTKs) to effectively regulate the intracellular delivery of extracellular stimuli. In one embodiment, the compound may effectively regulate FMS-like tyrosine kinase 3 (FLT3), which is frequently abnormally overexpressed or mutated in leukemia patients, and spleen tyrosine kinase (SYK), which acts on the signaling pathway of endothelial growth factor receptor (VEGFR), which is involved in the regulation of angiogenesis and other immune receptors such as B cell receptors and mast cells. The solid form of the present disclosure, according to one embodiment, effectively suppresses the mutation or overexpression of FLT3 and simultaneously suppresses the overexpression or overactivation of VEGFR, thereby blocking the supply of nutrients and oxygen to tumors and suppressing SYK. Therefore, the compound may be useful for treating acute myeloid leukemia (AML) that exhibits resistance to FLT3 inhibitors. As used in this disclosure, the term "overall survival (OV)" refers to the time from randomization to death in a clinical trial. FLT3-ITD-positive acute myeloid leukemia (AML) is a disease with very low OV. SYK is overexpressed and activated in hematological malignancies, and highly activated SYK is usually found in FLT3-ITD-positive acute myeloid leukemia (AML) with very low OV. Therefore, SYK should be considered as an important factor along with FLT3 as a therapeutic target for AML disease.

[0359] The solid form of the present disclosure, according to one embodiment, exhibits effective selective inhibitory activity against SYK as well as FLT3, thereby significantly improving the therapeutic efficacy of acute myeloid leukemia (AML) and increasing the OV time.

[0360] The solid forms and pharmaceutical compositions of the present disclosure have applications in any number of ways. For example, in some embodiments, the solid forms and pharmaceutical compositions are useful in methods for modulating FLT3 kinase activity. In embodiments, the modulation of FLT3 kinase activity is in mammalian cells. In several embodiments, modulating FLT3 kinase activity can be for the treatment of conditions or diseases described in the present disclosure, including in a subject (e.g., a mammalian subject) in need thereof, and in diseases or conditions in which inhibition of FLT3 kinase activity provides a therapeutic benefit to a subject with the disease or condition.

[0361] In one embodiment, the modulation of FLT3 kinase activity comprises binding to FLT3 kinase, hi another embodiment, the modulation of FLT3 kinase activity comprises inhibiting FLT3 kinase.

[0362] In embodiments, the present disclosure provides a method of inhibiting FLT3 kinase activity in a subject in need thereof, comprising administering an effective amount of a solid form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, or a pharmaceutical composition comprising a solid form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof, including crystalline and amorphous forms disclosed herein (e.g., amorphous form, monohydrate form, trihydrate form, ethanol monosolvate form, anhydrous Form I, anhydrous Form II, dihydrochloride Form I, dihydrochloride Form II, monohydrochloride form, disulfate form, monosulfate form, difumarate form, hemifumarate form, monosuccinate form, hemisuccinate form, dimaleate form, sesquimaleate form, or monomaleate form disclosed herein).

[0363] In one embodiment, the present disclosure provides a means for inhibiting FLT3 kinase activity. In another embodiment, the present disclosure provides a salt means for inhibiting FLT3 kinase activity. In another embodiment, the present disclosure provides a crystalline means for inhibiting FLT3 kinase activity. In another embodiment, the present disclosure provides an amorphous means for inhibiting FLT3 kinase activity.

[0364] The solid forms, such as the crystalline and amorphous forms disclosed herein, exhibit excellent FLT3 inhibitory activity and, therefore, in certain embodiments, may be effectively used in the treatment of cell proliferative disorders caused by abnormal FLT3 activity, such as cancer, e.g., leukemia.

[0365] In embodiments of the present disclosure, methods of treating a condition associated with cell proliferation in a patient in need thereof are provided. In one embodiment, the present invention provides a method of treating cancer or a tumor, e.g., a solid tumor.

[0366] The cancers in question include leukemias such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), hairy cell leukemia, and chronic neutrophilic leukemia (CNL).

[0367] In one embodiment, the cancer may be leukemia.

[0368] In one embodiment, the leukemia may be comprised of AML, ALL, or CML.

[0369] In some embodiments, the leukemia is AML. In some embodiments, the AML is AML with FLT3 mutation. In one specific embodiment, the AML is AML with mutant FLT3 polynucleotide positive, AML with FLT3 internal tandem duplication (ITD) positive, and / or AML with FLT3 point mutation.

[0370] In some embodiments, the cancer or leukemia comprises cancer cells having a mutation in the FLT3 gene. In some embodiments, the FLT3 gene has an internal tandem duplication (ITD) mutation. In some embodiments, the FLT3 gene has at least one FLT3 mutation selected from F691L, D835Y, D835F, D835I, D835H, D835V, and D835A.

[0371] In some embodiments, the cancer or leukemia comprises cancer cells having a mutation in the TKD of the amino acid sequence of FLT3 (FLT3-TKD). In some embodiments, the FLT3-TKD mutation may further comprise an ITD. In some embodiments, the cancer cells comprise a mutation selected from FLT3(D835Y), FLT3(F691L), FLT3(F691L / D835Y), FLT3(ITD / D835Y), FLT3(ITD / F691L), and combinations thereof.

[0372] The FLT3-TKD mutation may comprise one or more amino acid mutations at positions 823 to 861 of the FLT3 amino acid sequence. The TKD mutation may comprise at least one amino acid mutation selected from the group consisting of amino acids at positions 835, 836, and 842 of the FLT3 amino acid sequence. For example, the TKD mutation may comprise an amino acid mutation at position 835 of the FLT3 amino acid sequence. For example, the TKD mutation may comprise a substitution of aspartic acid with valine, tyrosine, histidine, glutamic acid, or asparagine at position 835 of the FLT3 amino acid sequence. For example, the TKD mutation may comprise a substitution of isoleucine with leucine or aspartic acid at position 836 of the FLT3 amino acid sequence. For example, the TKD mutation may comprise a substitution of tyrosine with cysteine ​​or histidine at position 842 of the FLT3 amino acid sequence. For example, the mutation may be FLT3(D835Y).

[0373] The FLT3-TKD mutation may have a mutation of at least one amino acid selected from the group consisting of amino acids at positions 621, 627, 676, 691, and 697 of the FLT3 amino acid sequence. For example, the TKD mutation may have a substitution of phenylalanine for leucine at position 691 of the FLT3 amino acid sequence. For example, the mutation may be FLT3(F691L).

[0374] The TKD mutation may further include an ITD, for example, the mutation may be FLT3(ITD / D835Y) or FLT3(ITD / F691L).

[0375] In embodiments, the present disclosure provides methods of treating cancer patients resistant to conventional therapeutic agents.

[0376] In embodiments, the present disclosure provides methods of treating cancers containing drug-resistant point mutants of FLT3 (D835Y, F691L, or F691L / D835Y) due to acquired D835Y and F691L point mutations in FLT3-TKD.

[0377] In one embodiment, the FLT3-TKD mutation may include any selected from FLT3(D835V), FLT3(D835Y), FLT3(D835H), FLT3(D835E), FLT3(D835N), FLT3(F691L), FLT3(F691L / D835YLT), ITD / D835Y, FLT3(ITD / F691L), and combinations thereof.

[0378] In some embodiments of any one of the methods disclosed herein, a compound of the invention or a composition of the invention is administered in combination with another therapeutically active agent. In some embodiments, the other therapeutically active agent is administered together with, sequentially with, or separately from the compound of the invention or the composition of the invention. In some embodiments, the other therapeutically active agent is administered in the same or a separate dosage regimen as the compound of the invention or the composition of the invention.

[0379] Another embodiment is a process for preparing the monohydrate crystalline form from a compound of Formula 1, comprising: [Formula 1] [ka] [Formula 1] (a) dissolving a compound of Formula 1 in acetone; (b) heating and stirring the solution (a); (c) cooling, filtering, and drying the stirred solution (b) to obtain a solid.

[0380] In certain embodiments, (a) may further comprise adding a small amount of water dropwise and dissolving the compound in acetone followed by mixing. The water may be added at room temperature.

[0381] In (b), the mixture (a) may be heated to about 40° C. to about 60° C. The mixture may be stirred for about 10 hours to about 30 hours.

[0382] The cooling in (c) may be performed to room temperature. (c) may further include washing, if necessary. The washing liquid may be, for example, the solvent in (a), i.e., acetone. The drying in (c) may be performed using a warm airflow at about 40°C to about 60°C.

[0383] Another embodiment is a process for preparing the trihydrate crystalline form of the compound of Formula 1, comprising: [ka] [Formula 1] (a) dissolving a compound of Formula 1 in ethyl acetate; (b) stirring the solution (a) at room temperature; (c) filtering and drying the stirred solution (b) to obtain a solid.

[0384] In certain embodiments, (b) may involve stirring solution (a) at about 20°C to about 25°C.

[0385] (c) may further include washing as necessary. The washing liquid may be, for example, the solvent of (a), i.e., ethyl acetate. Drying in (c) may be performed using a warm airflow at about 40°C to about 60°C.

[0386] Another embodiment is a process for preparing a solvate crystalline form of a compound of Formula 1, comprising: [ka] [Formula 1] (a) dissolving a compound of Formula 1 in a pharmaceutically acceptable solvate, for example, a C1-C3 alcohol; (b) cooling and stirring the solution (a); (c) filtering and drying the stirred solution (b) to obtain a solid.

[0387] In certain embodiments, the dissolving in (a) may be carried out at reflux temperature. In certain embodiments, the dissolving in (a) may be carried out in ethanol.

[0388] In certain embodiments, the cooling in (b) may be cooling to room temperature. In certain embodiments, the stirring in (b) may be performed for about 1 day to about 4 days.

[0389] In a specific embodiment, (c) may further include washing as needed. The washing liquid may be, for example, the solvent of (a), i.e., ethanol. Drying in (c) may be performed with a warm airflow at about 40°C to about 60°C.

[0390] Another embodiment is a process for preparing anhydrous crystalline Form I of the compound of Formula 1, comprising: [ka] [Formula 1] (a) dissolving a compound of Formula 1 in ethanol; (b) heating and stirring the solution (a); (c) cooling, filtering, and drying the stirred solution (b) to obtain a solid.

[0391] In certain embodiments, (a) may further comprise adding a small amount of water dropwise and dissolving the compound in ethanol followed by mixing. The water may be added at room temperature.

[0392] In (b), the mixture (a) may be heated to about 40° C. to about 60° C. The mixture may be stirred for about 10 hours to about 30 hours.

[0393] The cooling in (c) may be cooling to room temperature. (c) may further include washing, if necessary. The washing liquid may be, for example, the solvent in (a), i.e., ethanol. The drying in (c) may be performed using a warm airflow at about 40°C to about 60°C.

[0394] Another embodiment is a process for preparing anhydrous crystalline Form II of the compound of Formula 1, comprising: [ka] [Formula 1] (a) dissolving a compound of Formula 1 in isopropanol; (b) stirring the solution (a) at room temperature; (c) filtering and drying the stirred solution (b) to obtain a solid.

[0395] In certain embodiments, (b) can be stirring mixture (a) at a temperature of about 20°C to about 25°C.

[0396] (c) may further include washing as necessary. The washing liquid may be, for example, the solvent of (a), i.e., isopropanol. Drying in (c) may be performed using a warm airflow at about 40°C to about 60°C.

[0397] Reference Example Another embodiment provides an amorphous form of the compound of Formula 1: [ka] [Formula 1]

[0398] In certain examples, when the amorphous form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the amorphous form has a characteristic X-ray powder diffraction (XRPD) pattern that does not exhibit peaks with a relative intensity (I / I:I is the intensity of each peak and I is the intensity of the highest peak) of 10% or more.

[0399] In certain examples, the amorphous form may exhibit a heat absorption peak with an onset of 80.7°C and an endpoint of 91.4°C when measured by differential scanning calorimetry (DSC) at a linear heating rate of 10°C / min.

[0400] Another aspect is to provide a pharmaceutical composition comprising an amorphous form of the compound of Formula 1.

[0401] In certain examples, pharmaceutical compositions can be characterized by comprising at least one amorphous form of the compound of Formula 1 and at least one pharmaceutically acceptable carrier or diluent.

[0402] In certain embodiments, the cancer may be leukemia.

[0403] In particular examples, the leukemia may be acute myeloid leukemia, acute lymphocytic leukemia, or chronic myeloid leukemia.

[0404] In certain examples, the amorphous form of the pharmaceutical composition may be substantially pure.

[0405] Carriers or diluents that may be included in the pharmaceutical compositions, formulations of the pharmaceutical compositions, dosages, and therapeutic methods using the pharmaceutical compositions are as described above.

[0406] Another embodiment is a method of preparing an amorphous form of a compound of Formula 1, comprising: [ka] [Formula 1] (d) reacting the hydrochloride salt of the compound of formula 1 in a basic reaction solution; (e) filtering the solution after the reaction (d); (f) drying the solution after the filtering (e) to obtain a solid.

[0407] In certain examples, (d) may be carried out at room temperature with stirring. (d) may be carried out with stirring for about 5 hours to about 20 hours, for example, about 5 hours to about 15 hours. In (d), the hydrochloride salt of the compound of Formula 1 may be prepared by dissolving the compound of Formula 1 in ethanol and reacting the solution with hydrochloric acid.

[0408] (e) The method may further include washing as necessary. The washing liquid may be water.

[0409] The drying in (f) may be carried out by a warm air current at a temperature of about 40°C to about 60°C.

[0410] Unless otherwise specified, those skilled in the art will understand that peak values ​​from X-ray powder diffraction studies reported in this disclosure are typically subject to experimental error that may be observed in the art. Specifically, peaks are interpreted as occurring within ±0.5° of the values ​​reported in this disclosure. More specifically, peaks are interpreted as occurring within ±0.2° of the values ​​reported in this disclosure.

[0411] As used in this disclosure, the term "room temperature" refers to the range of 20±5°C.

[0412] As used in this disclosure, the term "reflux" means that the boiling point or a slightly higher temperature is used.

[0413] As used in this disclosure, the term "substantially pure" means at least 95% pure, or preferably 99% pure, where 95% pure means that 5% or less of the compound of Formula 1 is present in any other form (other crystalline forms, amorphous forms, etc.), and 99% pure means that 1% or less of the compound of Formula 1 is present in any other form.

[0414] Numerical values ​​described in this disclosure are considered to include the meaning of "approximately," even if not specified. As used in this disclosure, the term "approximately" means including values ​​within 5%, or preferably within 1% to 2% of a given value or range. For example, about 10% means 9.5% to 10.5%, or preferably 9.8% to 10.2%. As another example, about 100°C means 95°C to 105°C, or preferably 98°C to 102°C.

[0415] Words such as "have," "may have," "include," "contains," and the like indicate the presence of a feature (e.g., a number or component such as a material) but do not exclude the presence of other features. [Effects of the Invention]

[0416] The crystalline form (hydrate, solvate, or anhydrous form) of the compound of formula 1 according to one embodiment is excellent in terms of physicochemical properties required for pharmaceutically purposes, i.e., non-hygroscopicity to water, chemical stability, solubility, etc., and a pharmaceutical composition containing the same for preventing or treating cancer can be prepared more efficiently.

[0417] Furthermore, the crystalline forms (hydrates, solvates, or anhydrates) of the compound of Formula 1 also have superior physical and chemical properties compared to the amorphous form.

[0418] Furthermore, the crystalline forms of the hydrates according to certain examples are excellent in production reproducibility, purity, crystallinity, stability of the crystalline form, chemical stability, and non-hygroscopicity, and the crystalline form of the monohydrate according to certain examples has particularly excellent non-hygroscopicity. Thus, the crystalline forms according to certain embodiments may be stably maintained for long periods of time without the need for special storage facilities or special storage conditions, and the efficiency and stability of pharmaceutical manufacturing, distribution, storage, and preservation may be increased. [Brief explanation of the drawings]

[0419] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of the amorphous form of the compound (5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (hereinafter referred to as the compound of Formula 1). [Figure 2] FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of the monohydrate crystalline form of the compound of Formula 1. [Figure 3] FIG. 3 shows the X-ray powder diffraction (XRPD) pattern of the trihydrate crystalline form of the compound of Formula 1. [Figure 4] FIG. 4 shows the X-ray powder diffraction (XRPD) pattern of the ethanol monosolvate of the compound of formula 1. [Figure 5] FIG. 5 shows the X-ray powder diffraction (XRPD) pattern of anhydrous crystalline Form I of the compound of Formula 1. [Figure 6] FIG. 6 shows the X-ray powder diffraction (XRPD) pattern of anhydrous crystalline Form II of the compound of Formula 1. [Figure 7] FIG. 7 shows the differential scanning calorimetry (DSC) results of the amorphous form of the compound of Formula 1. [Figure 8]FIG. 8 shows the results of differential scanning calorimetry (DSC) of the monohydrate crystalline form of the compound of Formula 1. [Figure 9] FIG. 9 shows the results of differential scanning calorimetry (DSC) of the trihydrate crystalline form of the compound of Formula 1. [Figure 10] FIG. 10 shows the results of differential scanning calorimetry (DSC) of the ethanol monosolvate of the compound of formula 1. [Figure 11] FIG. 11 shows the results of differential scanning calorimetry (DSC) of anhydrous crystalline Form I of the compound of Formula 1. [Figure 12] FIG. 12 shows the results of differential scanning calorimetry (DSC) of anhydrous crystalline Form II of the compound of Formula 1. [Figure 13] FIG. 13 shows the X-ray powder diffraction (XRPD) pattern of the dihydrochloride salt crystalline Form I of the compound of Formula 1. [Figure 14] FIG. 14 shows the X-ray powder diffraction (XRPD) pattern of the dihydrochloride salt crystalline Form II of the compound of Formula 1. [Figure 15] FIG. 15 shows the X-ray powder diffraction (XRPD) pattern of the monohydrochloride salt crystalline form of the compound of Formula 1. [Figure 16] FIG. 16 shows the X-ray powder diffraction (XRPD) pattern of the disulfate salt crystalline form of the compound of Formula 1. [Figure 17] FIG. 17 shows the X-ray powder diffraction (XRPD) pattern of the monosulfate salt crystalline form of the compound of Formula 1. [Figure 18] FIG. 18 shows the X-ray powder diffraction (XRPD) pattern of the difumarate salt crystalline form of the compound of Formula 1. [Figure 19] FIG. 19 shows the X-ray powder diffraction (XRPD) pattern of the hemifumarate salt crystalline form of the compound of Formula 1. [Figure 20] FIG. 20 shows the X-ray powder diffraction (XRPD) pattern of the monosuccinate salt crystalline form of the compound of Formula 1. [Figure 21] FIG. 21 shows the X-ray powder diffraction (XRPD) pattern of the hemisuccinate salt crystalline form of the compound of Formula 1. [Figure 22] FIG. 22 shows the X-ray powder diffraction (XRPD) pattern of the dimaleate salt crystalline form of the compound of Formula 1. [Figure 23] FIG. 23 shows the X-ray powder diffraction (XRPD) pattern of the sesquimaleate salt crystalline form of the compound of Formula 1. [Figure 24] FIG. 24 shows the X-ray powder diffraction (XRPD) pattern of the monomaleate salt crystalline form of the compound of Formula 1. [Figure 25] FIG. 25 shows the results of differential scanning calorimetry (DSC) of the dihydrochloride salt crystalline Form I of the compound of Formula 1. [Figure 26] FIG. 26 shows the results of differential scanning calorimetry (DSC) of the dihydrochloride salt crystalline Form II of the compound of Formula 1. [Figure 27] FIG. 27 shows the results of differential scanning calorimetry (DSC) of the monohydrochloride salt crystalline form of the compound of Formula 1. [Figure 28] FIG. 28 shows the results of differential scanning calorimetry (DSC) of the disulfate salt crystalline form of the compound of Formula 1. [Figure 29] FIG. 29 shows the results of differential scanning calorimetry (DSC) of the monosulfate salt crystalline form of the compound of Formula 1. [Figure 30] FIG. 30 shows the results of differential scanning calorimetry (DSC) of the difumarate salt crystalline form of the compound of Formula 1. [Figure 31] FIG. 31 shows the results of differential scanning calorimetry (DSC) of the hemifumarate salt crystalline form of the compound of Formula 1. [Figure 32] FIG. 32 shows the results of differential scanning calorimetry (DSC) of the monosuccinate salt crystalline form of the compound of Formula 1. [Figure 33] FIG. 33 shows the results of differential scanning calorimetry (DSC) of the hemisuccinate salt crystalline form of the compound of Formula 1. [Figure 34] FIG. 34 shows the results of differential scanning calorimetry (DSC) of the dimaleate salt crystalline form of the compound of Formula 1. [Figure 35] FIG. 35 shows the results of differential scanning calorimetry (DSC) of the sesquimaleate salt crystalline form of the compound of Formula 1. [Figure 36] FIG. 36 shows the results of differential scanning calorimetry (DSC) of the monomaleate salt crystalline form of the compound of Formula 1. DETAILED DESCRIPTION OF THE INVENTION

[0420] The present disclosure will now be described in more detail.

[0421] Unless otherwise defined, all technical terms used in this disclosure have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Furthermore, although preferred methods or samples are described in this disclosure, similar or equivalent methods or samples are also incorporated into the scope of this disclosure. The contents of all publications cited as references in this specification are incorporated by reference in their entirety into this disclosure.

[0422] Compound of Formula 1

[0423] The compound shown in formula 1 Provided is 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine. [ka] [Formula 1]

[0424] The compound of Formula 1 may be prepared by the methods described in Korean Patent Application Publication No. 10-1954370 and International Patent Application Publication No. 2020-022600, which are incorporated herein by reference in their entireties.

[0425] Test example: analytical equipment and measurement method

[0426] 1. X-ray powder diffraction (XRPD) X-ray powder diffraction (XRPD) analysis was performed on a D8 Advance (Bruker ASX, Germany) analyzer with a diffraction angle 2θ of 3° to 40°. For sample quantities <100 mg, approximately 5 mg to 10 mg of sample was gently pressed onto a glass slide mounted on a sample holder. For sample quantities >100 mg, approximately 100 mg of sample was gently pressed onto a plastic sample holder so that the sample surface was smooth and just above the height of the sample holder.

[0427] Measurements were performed as follows: Anode material (Ka): Cu-Kα (1.54056Å) Scan range: 3°~40° Generator settings: 100mA, 40.0kV Scan speed: 1 second / step Diverter slit: 0.3° Anti-scatter slit: 0.3° Temperature: 20℃ Step size: 0.02 degrees 2θ Rotation:Use Goniometer radius: 435mm

[0428] 2. Differential Scanning Calorimetry (DSC) Differential scanning calorimetry (DSC) analysis was performed using a STA-1000 (Scinco, Korea) analyzer at 30°C to 350°C. 5 mg to 10 mg of sample was added onto an aluminum DSC pan during weighing, and the sample was heated from 30°C to 350°C at a scanning rate of 10°C / min, and the heat flow reaction generated by heating was monitored.

[0429] 3. Dynamic Vapor Sorption (DVS) DVS analysis was performed using a DVS Advantage (Surface Measurement Systems, UK) analyzer at 25°C and 0% to 90% relative humidity. A 10 mg sample was placed in a wire mesh vapor sorption balance pan and mounted on a DVS advantage dynamic vapor sorption balance (Surface Measurement Systems). The sample was subjected to a ramping profile of 10% to 90% relative humidity (RH), maintaining the sample at each step until the weight stabilized (99.5% weight change completed in one step). After the sorption cycle was completed, the sample was dried in the same manner, always applying a 0% lower RH after each step. The weight change during the sorption / desorption cycle (repeated three times) was recorded to determine the sample's hygroscopicity.

[0430] 4. High-Performance Liquid Chromatography (HPLC) High-performance liquid chromatography (HPLC) analysis was performed using an Agilent 1100 / 1200 series HPLC system (Agilent, USA) to analyze purity and content for stability tests, etc. The analytical conditions were as follows:

[0431] Purity and content analysis conditions: Flupyrimidine compound of formula 1 Column: Hydrosphere C18 (YMC), 5 μm (150 mm × 4.6 mm) Column temperature: 30℃ Detector: UV absorption photometer Detection wavelength: 254 nm Flow rate: 1.0mL / min Analysis time: 35 minutes Eluent: NaClO4-NaH2PO4-phosphate buffer (pH 2.5±0.1) / CH3CN=65 / 35(v / v%)

[0432] 5. Moisture Measurement Water content measurements were performed using a Karl Fischer water titrator 795KFT Titrino (Metrohm, Switzerland).

[0433] The present disclosure will be described in more detail below through examples. However, these examples are intended to illustrate the present disclosure, and the scope of the present disclosure is not limited thereto.

[0434] A mixture containing the compound of Formula 1 was prepared according to the methods disclosed in Korean Patent Application Publication No. 10-1954370 and International Patent Application Publication No. 2020-022600, both of which are incorporated herein by reference.

[0435] [Example 1] Preparation of amorphous form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0436] 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (compound of formula 1) (86 g) was dissolved in ethanol (86 mL). Hydrochloric acid (40 ml, 2.5 equivalents) was slowly added dropwise at room temperature, and the mixture was stirred for about 3.5 hours. The resulting solid was filtered to give 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine. The resulting hydrochloride salt was slowly added to an aqueous sodium bicarbonate solution (about 1.2 M, 2.2 L) and the mixture was stirred at room temperature for about 13 hours. The resulting solid was collected by filtration and washed with water. The resulting solid was dried in a warm air stream at 50° C. to give 72 g (84%) of the target compound.

[0437] Moisture content (Karl Fischer water titrant): approx. 2.3%

[0438] Characteristic analysis The XRPD results for the amorphous form are shown in FIG.

[0439] FIG. 1 shows the results of an X-ray powder diffraction (XRPD) analysis of the amorphous form of the compound 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (hereinafter referred to as the compound of Formula 1).

[0440] As shown in FIG. 1, when the amorphous form of the compound of Formula 1 was irradiated with a Cu-Kα light source, the amorphous form did not exhibit any peaks with a relative intensity (I / I0: I is the intensity of each peak, and I0 is the intensity of the highest peak) of 10% or more in the X-ray powder diffraction (XRPD) pattern.

[0441] FIG. 7 shows the differential scanning calorimetry (DSC) results of the amorphous form of the compound of Formula 1.

[0442] The DCS (10°C / min) results for the amorphous form show a thermal absorption peak with an onset of 80.7°C and a trough point of 91.4°C, the absorption peak at 91.4°C indicating the melting point.

[0443] The amorphous form exhibited a water content of about 2.3% in a Karl Fischer water titrator.

[0444] For the amorphous form of DVS, hygroscopicity was measured to be approximately 5% in the range of 0% to 90% relative humidity.

[0445] [Example 2] Preparation of the monohydrate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0446] 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (240 g) was dissolved in acetone (2.4 L) and water (0.6 L) was added dropwise at room temperature. The mixture was heated to 50° C. and stirred for about 19 hours. After cooling to room temperature, the solution was filtered to collect the solid, which was then washed with 80% acetone. The resulting solid was dried in a warm air stream at 50° C. to give 195 g (78%) of the target compound.

[0447] Moisture content (Karl Fischer water titrant): approx. 3.5%

[0448] Characteristic analysis The XRPD results for the monohydrate crystalline form prepared in Example 1 are shown in Table 1 and FIG.

[0449] Peaks with a relative intensity (I / I0) of 5% or greater in the XRPD spectrum of the monohydrate crystalline form are shown in Table 1 below. [Table 1]

[0450] Table 1 and Figure 2 show the results of XRPD analysis of the monohydrate crystalline form of the compound of Formula 1. As shown in Table 1 and Figure 2, the monohydrate crystalline form of the compound of Formula 1 exhibited an X-ray powder diffraction (XRPD) spectrum containing peaks with an I / I of 10% or greater at diffraction angles of 5.0°±0.2°, 7.8°±0.2°, 10.1°±0.2°, 11.0°±0.2°, 11.7°±0.2°, 16.8°±0.2°, 16.9°±0.2°, and 17.9°±0.2°.

[0451] Furthermore, as shown in Table 1 and Figure 2, the monohydrate crystalline form of the compound of Formula 1 exhibited an X-ray powder diffraction spectroscopy (XRPD) spectrum that further contained peaks with I / I of 5% or greater and less than 10% at diffraction angles of 15.7°±0.2°, 18.7°±0.2°, 23.6°±0.2°, and 24.3°±0.2°.

[0452] FIG. 8 shows the differential scanning calorimetry (DSC) analysis of the monohydrate crystalline form of the compound of Formula 1.

[0453] DSC (10° C. / min) results for the crystalline form showed a thermal absorption peak with an onset of 74.9° C. and a trough of 89.0° C., as well as a thermal absorption peak at about 161.6° C. In the DSC results, the absorption peak at about 89.0° C. indicates the dehydration point of the monohydrate crystalline form, and the absorption peak at about 161.6° C. indicates the melting point.

[0454] The crystalline form showed a water content of about 3.5% in a Karl Fischer water titrator (theoretical water content 3.5%).

[0455] DVS (10°C / min) analysis of the crystalline form shows the occurrence of moisture absorption in the 0%-20% relative humidity range, but the moisture absorption level is very low in the 30% or higher relative humidity range. The crystalline form is sufficiently stable under accelerated conditions (e.g., 40°C temperature and 75% relative humidity) and stress conditions (e.g., 60°C temperature).

[0456] [Example 3] Preparation of the trihydrate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0457] 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (5 g) was dissolved in ethyl acetate (50 mL). The mixture was stirred at 20-25°C for approximately 7 hours. The resulting solid was collected by filtration and washed with ethyl acetate. The resulting solid was dried in a warm air stream at 50°C to give 4.3 g (86%) of the target compound.

[0458] Moisture content (Karl Fischer water titrator): approx. 10.8%

[0459] Characteristic analysis The XRPD results for the trihydrate crystalline form prepared in Example 2 are shown in Table 2 and FIG.

[0460] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the trihydrate crystalline form are shown in Table 2 below. [Table 2]

[0461] Table 2 and Figure 3 show the XRPD analysis of the trihydrate crystalline form of the compound of Formula 1.

[0462] As shown in Table 2 and Figure 3, the trihydrate crystalline form of the compound of Formula 1 exhibited an X-ray powder diffraction (XRPD) spectrum containing peaks with an I / I of 15% or greater at diffraction angles of 8.2° ± 0.2°, 9.3° ± 0.2°, 11.1° ± 0.2°, 17.2° ± 0.2°, 19.2° ± 0.2°, 20.8° ± 0.2°, 21.3° ± 0.2°, 22.9° ± 0.2°, 23.9° ± 0.2°, and 25.5° ± 0.2°.

[0463] FIG. 9 shows the differential scanning calorimetry (DSC) analysis of the trihydrate crystalline form of the compound of Formula 1.

[0464] DSC (10° C. / min) results for the crystalline form showed a thermal absorption peak with an onset of 44.9° C. and a trough of 68.7° C., as well as a thermal absorption peak at about 108.3° C. In the DSC results, the absorption peak at about 68.7° C. indicates the dehydration point of the trihydrate crystalline form, and the absorption peak at about 108.3° C. indicates the melting point.

[0465] The crystalline form showed a water content of about 10.8% (theoretical water content 9.7%) in a Karl Fischer water titrator.

[0466] The crystalline form of DVS was measured to have a hygroscopicity of approximately 12% in the 0% to 90% relative humidity range. The crystalline form was sufficiently stable under accelerated conditions (e.g., 40°C and 75% relative humidity) and stress conditions (e.g., 60°C).

[0467] [Example 4] Preparation of the crystalline form of the ethanol monosolvate of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0468] 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (1 g) was added to ethanol (10 mL) and dissolved by refluxing. The solution was cooled to room temperature and stirred for about 3 days. The resulting solid was collected by filtration and washed with ethanol. The resulting solid was dried in a warm air stream at 50°C to give 0.6 g (60%) of the target compound.

[0469] Moisture content (Karl Fischer water titrant): approx. 0.2%

[0470] Characteristic analysis The XRPD results for the ethanol monosolvate crystalline form prepared in Example 3 are shown in Table 3 and FIG.

[0471] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the ethanol monosolvate crystalline form are shown in Table 3. [Table 3]

[0472] Table 3 and Figure 4 show the results of XRPD analysis of the crystalline form of the ethanol monosolvate of the compound of Formula 1. As shown in Table 3 and Figure 4, the crystalline form of the ethanol monosolvate of the compound of Formula 1 exhibited an X-ray powder diffraction (XRPD) spectrum containing peaks with an I / I of 40% or greater at diffraction angles of 7.8°±0.2°, 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.9°±0.2°, 19.2°±0.2°, 21.4°±0.2°, 24.0°±0.2°, and 25.7°±0.2°.

[0473] FIG. 10 shows the differential scanning calorimetry (DSC) analysis of the ethanol monosolvate crystalline form of the compound of Formula 1.

[0474] DSC (10° C. / min) results of the crystalline form showed a thermal absorption peak with an onset of 99.8° C. and a trough of 113° C. In the DSC results, the absorption peak at about 99.8° C. indicates the dehydration point of the ethanol monosolvate, and the absorption peak at about 113.4° C. indicates the melting point.

[0475] The crystalline form showed a water content of about 0.2% in a Karl Fischer water titrator.

[0476] For the crystalline form of DVS, hygroscopicity was measured to be approximately 0.3% in the range of 0% to 90% relative humidity. The crystalline form was sufficiently stable under accelerated conditions (e.g., 40°C and 75% relative humidity) and stress conditions (e.g., 60°C).

[0477] [Example 5] Preparation of anhydrous crystalline form I of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine.

[0478] 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (1 g) was dissolved in ethanol (8 L) and water (2 mL) was added dropwise at room temperature. The mixture was heated to 50°C and stirred for about 30 minutes. The solution was cooled to a temperature of 20-25°C and stirred for 5 hours. The resulting solid was filtered and washed with 80% ethanol. The resulting solid was dried in a warm air stream at 50°C to give 0.8 g (81%) of the target compound.

[0479] Moisture content (Karl Fischer water titrant): approx. 0.2%

[0480] Characteristic analysis The XRPD results for the anhydrous crystalline Form I prepared in Example 4 are shown in Table 4 and Figure 5. Peaks with a relative intensity (I / I) of 10% or greater in the XRPD spectrum of the anhydrous crystalline Form I are shown in Table 4 below. [Table 4]

[0481] Table 4 and Figure 5 show the XRPD analysis results for the anhydrous crystalline Form I of the compound 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (hereinafter referred to as the compound of Formula 1). As shown in Table 4 and Figure 5, anhydrous crystalline Form I of the compound of Formula 1 exhibited an X-ray powder diffraction (XRPD) spectrum containing peaks with an I / I of 15% or greater at diffraction angles of 5.2°±0.2°, 6.5°±0.2°, 10.4°±0.2°, 11.2°±0.2°, 15.1°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.1°±0.2°, and 25.7°±0.2°.

[0482] FIG. 11 shows the differential scanning calorimetry (DSC) analysis of anhydrous crystalline Form I of the compound of Formula 1.

[0483] DSC (10° C. / min) results for the crystalline form showed a thermal absorption peak with an onset of about 152.4° C. and a trough point of about 159.5° C. The absorption peak at about 159.5° C. indicates the melting point.

[0484] The crystalline form showed a water content of about 0.2% in a Karl Fischer water titrator.

[0485] The hygroscopicity of the crystalline form of DVS was measured to be approximately 3.5% in the range of 0% to 90% relative humidity. The crystalline form was sufficiently stable under accelerated conditions (e.g., 40°C and 75% relative humidity) and stress conditions (e.g., 60°C).

[0486] [Example 6] Preparation of anhydrous crystalline form II of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0487] 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (2 g) was dissolved in isopropanol (14 mL). The mixture was stirred at 20-25 °C for about 3 days. The resulting solid was filtered and washed with isopropanol. The resulting solid was dried in a warm air stream at 50 °C to give 1.7 g (85%) of the target compound.

[0488] Moisture content (Karl Fischer water titrant): approx. 0.5%

[0489] Characteristic analysis The XRPD results for the anhydrous crystalline Form II prepared in Example 5 are shown in Table 5 and Figure 6. Peaks with a relative intensity (I / I) of 10% or greater in the XRPD spectrum of the anhydrous crystalline Form II are shown in Table 5 below. [Table 5]

[0490] Table 5 and Figure 6 show the results of XRPD analysis of anhydrous crystalline Form II of the compound of Formula 1. As shown in Table 5 and Figure 6, anhydrous crystalline Form II of the compound of Formula 1 exhibited an X-ray powder diffraction (XRPD) spectrum containing peaks with an I / I of 20% or greater at diffraction angles of 4.9°±0.2°, 5.9°±0.2°, 8.1°±0.2°, 9.7°±0.2°, 11.8°±0.2°, 13.3°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 17.7°±0.2°, 19.0°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 25.9°±0.2°.

[0491] FIG. 12 shows the differential scanning calorimetry (DSC) analysis of anhydrous crystalline Form II of the compound of Formula 1.

[0492] DSC (10° C. / min) results for the crystalline form showed a thermal absorption peak with an onset of about 139.8° C. and a trough point of about 149.4° C. The absorption peak at about 149.4° C. indicates the melting point.

[0493] The crystalline form showed a water content of about 0.5% in a Karl Fischer water titrator.

[0494] For the crystalline form of DVS, hygroscopicity was measured to be approximately 0.5% in the range of 0% to 90% relative humidity. The crystalline form was sufficiently stable under accelerated conditions (e.g., 40°C and 75% relative humidity) and stress conditions (e.g., 60°C).

[0495] [Example 7] Preparation of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine dihydrochloride salt crystalline form I

[0496] 3.8 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine-dihydrochloride was placed in a flask, and then 38 mL of 80% aqueous ethanol was added. The reaction mixture was refluxed for 1 hour and then cooled to room temperature (20-25°C). The mixture was stirred at room temperature overnight (20-25°C). The resulting solid was filtered and then washed with 8 mL of 80% aqueous ethanol. The wet solid was dried in an oven at 50°C overnight.

[0497] Moisture content (Karl Fischer water titrant): approx. 3.4%

[0498] Characteristic analysis The XRPD results for dihydrochloride salt crystalline Form I prepared in Example 7 are shown in Table 6 and FIG.

[0499] Peaks in the XRPD spectrum of dihydrochloride salt crystalline Form I having a relative intensity (I / I0) of 10% or greater are shown in the table below. [Table 6]

[0500] Dihydrochloride salt crystalline Form I was determined to be an ethanol solvate. Figure 25 shows the differential scanning calorimetry (DSC) analysis of dihydrochloride salt crystalline Form I of the compound of Formula 1.

[0501] DSC (10°C / min) results for the crystalline form showed an endothermic absorption peak with an onset of 105°C and a peak maximum of 139°C, as well as an additional endothermic absorption peak with an onset of 187°C and a peak maximum of 202°C.

[0502] [Example 8] Preparation of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine dihydrochloride crystalline form II 3 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine dihydrochloride was placed in a flask, and then 30 mL of ethanol was added. The reaction mixture was refluxed for 1 hour and then cooled to room temperature (20-25 °C). The mixture was stirred at room temperature (20-25 °C) for 6 hours. The resulting solid was filtered and then washed with 6 mL of ethanol. The wet solid was dried in an oven at 50 °C overnight.

[0503] Moisture content (Karl Fischer water titrant): approx. 0.5%.

[0504] Characteristic analysis The XRPD results for the dihydrochloride salt crystalline Form II prepared in Example 8 are shown in Table 7 and FIG.

[0505] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of dihydrochloride salt crystalline Form II are shown in the table below. [Table 7]

[0506] 26 shows the differential scanning calorimetry (DSC) analysis results for the dihydrochloride salt crystalline Form II of the compound of Formula 1. The DSC (10°C / min) results for the dihydrochloride salt crystalline Form II of the compound of Formula 1 showed an endothermic absorption peak with an onset of 213°C and a peak maximum of 239°C.

[0507] [Example 9] Preparation of the Monohydrochloride Crystalline Form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0508] 5 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine was placed in a flask, and then 50 mL of acetone was added. 0.97 mL of HCl was added to the mixture. The reaction mixture was stirred overnight at room temperature (20-25 °C). The resulting solid was filtered and then washed with 10 mL of acetone. The wet solid was dried overnight in an oven at 50 °C.

[0509] Moisture content (Karl Fischer water titrator): approx. 3.7%.

[0510] Characteristic analysis The XRPD results for the monohydrochloride salt crystalline form prepared in Example 9 are shown in Table 8 and FIG.

[0511] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the monohydrochloride salt crystalline form are shown in the table below. [Table 8]

[0512] 27 shows the differential scanning calorimetry (DSC) analysis results for the monohydrochloride salt crystalline form of the compound of Formula 1. The DSC (10° C. / min) results for the monohydrochloride salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 105° C. and a peak maximum of 121° C.

[0513] [Example 10] Preparation of the disulfate salt crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0514] 10 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (amorphous) was dissolved in 100 mL of acetone, and 2.6 mL of sulfuric acid was added. The suspension was stirred overnight at room temperature (20-25 °C). The resulting suspension was filtered and washed with 10 mL of acetone. The wet solid was dried overnight in an oven at 50 °C. 11.6 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine disulfate was obtained.

[0515] Moisture content (Karl Fischer water titrator): approx. 5.4%

[0516] Characteristic analysis The XRPD results for the disulfate salt crystalline form prepared in Example 10 are shown in Table 9 and FIG.

[0517] Peaks with a relative intensity (I / Io) of 10% or greater in the XRPD spectrum of the disulfate salt crystalline form are shown in the table below. [Table 9]

[0518] 28 shows the differential scanning calorimetry (DSC) analysis results for the disulfate salt crystalline form of the compound of Formula 1. DSC (10° C. / min) results for the disulfate salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 79° C. and a peak maximum of 107° C.

[0519] [Example 11] Preparation of the Monosulfate Crystalline Form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0520] 5 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (amorphous) was placed in a flask, and then 50 mL of acetone was added. 0.59 mL of sulfuric acid was added to the mixture. The reaction mixture was stirred overnight at room temperature (20-25 °C). The resulting solid was filtered and then washed with 10 mL of acetone. The wet solid was dried overnight in an oven at 50 °C.

[0521] Moisture content (Karl Fischer water titrant): approx. 6.8%

[0522] Characteristic analysis The XRPD results for the monosulfate salt crystalline form prepared in Example 11 are shown in Table 10 and FIG.

[0523] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the monosulfate salt crystalline form are shown in the table below. [Table 10]

[0524] 29 shows the differential scanning calorimetry (DSC) analysis results for the monosulfate salt crystalline form of the compound of Formula 1. The DSC (10° C. / min) results for the monosulfate salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 244° C. and a peak maximum of 274° C.

[0525] [Example 12] Preparation of the difumarate salt crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0526] 5 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (amorphous) was placed in a flask, and then 50 mL of ethyl acetate was added. 2.9 g of fumaric acid was added to the mixture. The reaction mixture was stirred at room temperature (20-25 °C) for 7 hours. The resulting solid was filtered and then washed with 10 mL of ethyl acetate. The wet solid was dried in an oven at 50 °C overnight.

[0527] Moisture content (Karl Fischer water titrant): approx. 1.5%

[0528] Characteristic analysis The XRPD results for the difumarate salt crystalline form prepared in Example 12 are shown in Table 11 and FIG.

[0529] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the difumarate salt crystalline form are shown in the table below. [Table 11]

[0530] 30 shows the differential scanning calorimetry (DSC) analysis results for the difumaric acid salt crystalline form of the compound of Formula 1. The DSC (10° C. / min) results for the difumaric acid salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 149° C. and a peak maximum of 160° C.

[0531] [Example 13] Preparation of the hemifumarate salt crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0532] 3 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine hemifumarate was placed in a flask, and then 30 mL of 80% aqueous ethanol was added. The mixture was refluxed (dissolving and precipitating a solid). The reaction mixture was cooled to room temperature and then stirred at room temperature (20-25 °C) for 5 hours. The resulting solid was filtered and then washed with 6 mL of 80% aqueous ethanol. The wet solid was dried overnight in an oven at 50 °C.

[0533] Moisture content (Karl Fischer water titrator): approx. 0.1%.

[0534] Characteristic analysis The XRPD results for the hemifumarate salt crystalline form prepared in Example 13 are shown in Table 12 and FIG.

[0535] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the hemifumarate salt crystalline form are shown in the table below. [Table 12]

[0536] 31 shows the differential scanning calorimetry (DSC) analysis results for the hemifumarate salt crystalline form of the compound of Formula 1. DSC (10° C. / min) results for the hemifumarate salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 266° C. and a peak maximum of 269° C.

[0537] [Example 14] Preparation of the Monosuccinate Crystalline Form of 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0538] 5 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine (amorphous) was charged into a flask, and then 50 mL of acetone was added. 2.59 g of succinic acid was added to the mixture (a solid precipitated immediately). The reaction mixture was stirred at room temperature (20-25 °C) for 7 hours. The resulting solid was filtered and then washed with 10 mL of acetone. The wet solid was dried overnight in an oven at 50 °C.

[0539] Moisture content (Karl Fischer water titrant): approx. 1.8%.

[0540] Characteristic analysis The XRPD results for the monosuccinate salt crystalline form prepared in Example 14 are shown in Table 13 and FIG.

[0541] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the monosuccinate salt crystalline form are shown in the table below. [Table 13]

[0542] 32 shows the differential scanning calorimetry (DSC) analysis results for the monosuccinate salt crystalline form of the compound of Formula 1. The DSC (10° C. / min) results for the monosuccinate salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 95° C. and a maximum peak of 116° C., as well as an additional endothermic absorption peak with an onset of 218° C. and a maximum peak of 220° C.

[0543] [Example 15] Preparation of the hemisuccinate salt crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0544] 2 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine monosuccinate was placed in a flask, and then 20 mL of 80% aqueous ethanol was added. The mixture was refluxed (did not dissolve). The mixture was cooled to room temperature (20-25 °C). The mixture was stirred at room temperature overnight. The resulting solid was filtered and then washed with 4 mL of ethanol. The wet solid was dried in an oven at 50 °C overnight.

[0545] Moisture content (Karl Fischer water titrator): approx. 0.3%.

[0546] Characteristic analysis The XRPD results for the hemisuccinate salt crystalline form prepared in Example 15 are shown in Table 14 and FIG.

[0547] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the hemisuccinate salt crystalline form are shown in the table below. [Table 14]

[0548] 33 shows the differential scanning calorimetry (DSC) analysis results for the hemisuccinate salt crystalline form of the compound of Formula 1. DSC (10° C. / min) results for the monosuccinate salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 227° C. and a peak maximum of 229° C.

[0549] [Example 16] Preparation of the dimaleate salt crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0550] 5 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine was placed in a flask, and then 50 mL of ethanol was added. 2.61 g of maleic acid was added to the mixture, which was then stirred overnight (no precipitation), and the solution was concentrated under reduced pressure, and 25 mL of ethanol was added. The mixture was stirred at room temperature overnight (no precipitation). The mixture was concentrated under reduced pressure. 50 mL of acetone was added to the residue and stirred for 8 hours. The resulting solid was filtered and then washed with 10 mL of acetone. The wet solid was dried in an oven at 50 °C overnight. Water content (Karl Fischer water titrator): approximately 3.4%.

[0551] Characteristic analysis The XRPD results for the dimaleate salt crystalline form prepared in Example 16 are shown in Table 15 and FIG.

[0552] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the dimaleate salt crystalline form are shown in the table below. [Table 15]

[0553] 34 shows the differential scanning calorimetry (DSC) analysis results for the dimaleate salt crystalline form of the compound of Formula 1. DSC (10° C. / min) results for the dimaleate salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 104° C. and a peak maximum of 121° C.

[0554] [Example 17] Preparation of the Sesquimaleic Acid Crystalline Form of 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0555] 0.65 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine dimate was charged into a flask, and then 6.5 mL of ethanol was added. The mixture was refluxed (dissolving and precipitating a solid). The reaction mixture was cooled to room temperature (20-25 °C) and then stirred for 4 hours. The resulting solid was filtered and then washed with 1.3 mL of ethanol. The wet solid was dried overnight in an oven at 50 °C.

[0556] Moisture content (Karl Fischer water titrant): approx. 3.0%

[0557] Characteristic analysis The XRPD results for the sesquimaleate salt crystalline form prepared in Example 17 are shown in Table 16 and FIG.

[0558] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the sesquimaleate salt crystalline form are shown in the table below. [Table 16]

[0559] 35 shows the differential scanning calorimetry (DSC) analysis results for the sesquimaleate salt crystalline form of the compound of Formula 1. DSC (10° C. / min) results for the sesquimaleate salt crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 122° C. and a peak maximum of 136° C.

[0560] [Example 18] Preparation of the Monomaleate Crystalline Form of 5-Chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine

[0561] 1 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(6-methyl-1H-indol-3-yl)pyrimidin-2-amine monomerate was placed in a flask, and then 10 mL of ethanol was added. The reaction mixture was refluxed for 1 hour and then cooled to room temperature (20-25 °C). The mixture was stirred at room temperature (20-25 °C) for 4 hours. The resulting solid was filtered and then washed with 2 mL of ethanol. The wet solid was dried in an oven at 50 °C overnight.

[0562] Moisture content (Karl Fischer water titrator): approx. 0.2%.

[0563] Characteristic analysis The XRPD results for the monomaleate salt crystalline form prepared in Example 18 are shown in Table 17 and FIG.

[0564] Peaks with a relative intensity (I / I0) of 10% or greater in the XRPD spectrum of the monomaleic acid crystalline form are shown in the table below. [Table 17]

[0565] Figure 36 shows the differential scanning calorimetry (DSC) analysis results for the monomaleate crystalline form of the compound of Formula 1. The DSC (10°C / min) results for the monomaleate crystalline form of the compound of Formula 1 showed an endothermic absorption peak with an onset of 203°C and a peak maximum of 207°C. It will be understood by those skilled in the art that various modifications can be made therein without departing from the spirit and scope of the present disclosure. Accordingly, the exemplary examples disclosed herein should be considered in an illustrative manner, and not in a limiting manner. The scope of the present disclosure is defined by the appended claims, rather than the foregoing description, and all variations within the range of equivalents thereof should be construed as being within the present disclosure.

[0566] [Embodiment] [Embodiment 1] Crystalline forms of the compound of formula 1. [ka] [Formula 1]

[0567] [Embodiment 2] The crystalline form of embodiment 1, wherein the crystalline form is a crystalline form of a hydrate of the compound of formula 1.

[0568] [Embodiment 3] 3. The crystalline form of embodiment 2, wherein the crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.0°±0.2°, 7.8°±0.2°, 10.1°±0.2°, 16.8°±0.2°, and 16.9°±0.2° when illuminated with a Cu-Kα light source.

[0569] [Embodiment 4] 4. The crystalline form of embodiment 3, wherein the crystalline form has a characteristic XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 11.0°±0.2°, 11.7°±0.2°, and 17.9°±0.2° when illuminated with a Cu-Kα light source.

[0570] [Embodiment 5] 5. The crystalline form of embodiment 4, wherein the crystalline form has a characteristic XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 15.7°±0.2°, 18.7°±0.2°, 23.6°±0.2°, and 24.3°±0.2° when illuminated with a Cu-Kα light source.

[0571] [Embodiment 6] 3. The crystalline form of embodiment 2, wherein the crystalline form has a characteristic XRPD pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.3°±0.2°, 11.1°±0.2°, 17.2°±0.2°, and 20.8°±0.2° when illuminated with a Cu-Kα light source.

[0572] [Embodiment 7] 7. The crystalline form of embodiment 6, wherein the crystalline form has a characteristic XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 19.2°±0.2°, 19.6°±0.2°, 21.3°±0.2°, 22.9°±0.2°, 23.9°±0.2°, and 25.5°±0.2° when illuminated with a Cu-Kα light source.

[0573] [Embodiment 8] The crystalline form of embodiment 2 or 3, wherein the hydrate is a monohydrate.

[0574] [Embodiment 9] The crystalline form of embodiment 2 or 6, wherein the hydrate is a trihydrate.

[0575] [Embodiment 10] The crystalline form of embodiment 1, wherein the crystalline form is a crystalline form of an ethanol monosolvate of the compound of formula 1.

[0576] [Embodiment 11] 11. The crystalline form of embodiment 10, wherein the crystalline form of the ethanol monosolvate has a characteristic XRPD pattern comprising peaks at diffraction angles 2θ of 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.9°±0.2°, and 21.4°±0.2° when illuminated with a Cu-Kα light source.

[0577] [Embodiment 12] 12. The crystalline form of embodiment 11, wherein the crystalline form of the ethanol monosolvate has a characteristic XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 7.8°±0.2°, 19.2°±0.2°, 24.0°±0.2°, and 25.7°±0.2° when illuminated with a Cu-Kα light source.

[0578] [Embodiment 13] The crystalline form of embodiment 1, wherein the crystalline form is anhydrous crystalline Form I of the compound of formula 1.

[0579] [Embodiment 14] 14. The crystalline form of embodiment 13, wherein the anhydrous crystalline Form I has a characteristic XRPD pattern comprising peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.5°±0.2°, and 18.1°±0.2° when irradiated with a Cu-Kα light source.

[0580] [Embodiment 15] 15. The crystalline form of embodiment 14, wherein the anhydrous crystalline Form I has a characteristic XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 6.5°±0.2°, 11.2°±0.2°, 15.1°±0.2°, 20.2°±0.2°, 21.8°±0.2°, 22.5°±0.2°, and 25.7°±0.2° when illuminated with a Cu-Kα light source.

[0581] [Embodiment 16] The crystalline form of embodiment 1, wherein the crystalline form is anhydrous crystalline Form II of the compound of formula 1.

[0582] [Embodiment 17] 17. The crystalline form of embodiment 16, wherein the anhydrous crystalline Form II has a characteristic XRPD pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, 9.7°±0.2°, 17.7°±0.2°, and 19.0°±0.2° when illuminated with a Cu-Kα light source.

[0583] [Embodiment 18] 18. The crystalline form of embodiment 17, wherein the anhydrous crystalline Form II has a characteristic XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 8.1°±0.2°, 11.8°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 25.9°±0.2° when illuminated with a Cu-Kα light source.

[0584] [Embodiment 19] 2. The crystalline form of embodiment 1, wherein the crystalline form exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to the pattern shown in any one of Figures 2-6.

[0585] [Embodiment 20] Amorphous form of Formula 1 [ka] (Formula 1) or a solvate thereof.

[0586] [Embodiment 21] 21. The amorphous form of embodiment 20, exhibiting an X-ray powder diffraction pattern substantially similar to the pattern shown in FIG.

[0587] [Embodiment 22] 21. The amorphous form of embodiment 20, which exhibits a differential scanning calorimetry (DSC) thermogram substantially similar to that of FIG.

[0588] [Embodiment 23] A means for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0589] [Embodiment 24] A means for binding to FMS-like tyrosine kinase 3 (FLT3).

[0590] [Embodiment 25] The means of embodiment 23 or 24, wherein said means is in crystalline form.

[0591] [Embodiment 26] The means of embodiment 23 or 24, wherein the means is in amorphous form.

[0592] [Embodiment 27] The means of embodiment 25, wherein said crystalline form comprises a hydrate of the compound of formula 1.

[0593] [Embodiment 28] The means of embodiment 27, wherein said hydrate is a monohydrate, dihydrate, or trihydrate of the compound of Formula 1.

[0594] [Embodiment 29] The method of embodiment 25, wherein said crystalline form comprises an ethanol monosolvate of the compound of formula 1.

[0595] [Embodiment 30] 26. The method of embodiment 25, wherein the crystalline form comprises an anhydrate of the compound of Formula 1.

[0596] [Embodiment 31] A pharmaceutical composition comprising at least one crystalline form of the compound of formula 1 as described in embodiment 1 and at least one pharmaceutically acceptable carrier or diluent.

[0597] [Embodiment 32] A pharmaceutical composition comprising at least one amorphous form of the compound of formula 1 as described in embodiment 20 and at least one pharmaceutically acceptable carrier or diluent.

[0598] [Embodiment 33] A pharmaceutical composition comprising at least one crystalline form of the compound of formula 1 according to any one of embodiments 2 to 19, and at least one pharmaceutically acceptable carrier or diluent.

[0599] [Embodiment 34] A pharmaceutical composition comprising at least one amorphous form of the compound of formula 1 according to any one of embodiments 20 to 22 and at least one pharmaceutically acceptable carrier or diluent.

[0600] [Embodiment 35] A pharmaceutical composition comprising a means for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0601] [Embodiment 36] A pharmaceutical composition comprising a means for binding to FMS-like tyrosine kinase 3 (FLT3).

[0602] [Embodiment 37] The pharmaceutical composition of embodiment 35 or 36, wherein the means is in a crystalline form.

[0603] [Embodiment 38] The pharmaceutical composition according to embodiment 35 or 36, wherein said means is in amorphous form.

[0604] [Embodiment 39] A pharmaceutical composition according to embodiment 37, comprising a crystalline form of the compound of formula 1 according to any one of embodiments 2 to 19 and at least one pharmaceutically acceptable carrier or diluent.

[0605] [Embodiment 40] The pharmaceutical composition according to embodiment 38, comprising an amorphous form of the compound of formula 1 according to any one of embodiments 20 to 22 and at least one pharmaceutically acceptable carrier or diluent.

[0606] [Embodiment 41] The pharmaceutical composition of any one of embodiments 31-40, wherein the crystalline or amorphous form is at least about 70% pure in the pharmaceutical composition.

[0607] [Embodiment 42] 42. The pharmaceutical composition of embodiment 41, comprising: A pharmaceutical composition, wherein the crystalline or amorphous form is at least about 80% pure in the pharmaceutical composition.

[0608] [Embodiment 43] 41. A pharmaceutical composition according to any one of embodiments 31 to 40, A pharmaceutical composition, wherein the crystalline or amorphous form is at least about 90% pure in the pharmaceutical composition.

[0609] [Embodiment 44] 41. A pharmaceutical composition according to any one of embodiments 31 to 40, A pharmaceutical composition, wherein the crystalline or amorphous form is at least about 95% pure in the pharmaceutical composition.

[0610] [Embodiment 45] 41. A pharmaceutical composition according to any one of embodiments 31 to 40, The pharmaceutical composition, wherein the crystalline or amorphous form is at least about 99% pure in the pharmaceutical composition.

[0611] [Embodiment 46] The pharmaceutical composition of any one of embodiments 31-40, wherein the amorphous form is at least about 70% pure in the pharmaceutical composition.

[0612] [Embodiment 47] The pharmaceutical composition of embodiment 41, wherein the amorphous form is at least about 80% pure in the pharmaceutical composition.

[0613] [Embodiment 48] 41. A pharmaceutical composition according to any one of embodiments 31 to 40, The pharmaceutical composition, wherein the amorphous form is at least about 90% pure in the pharmaceutical composition.

[0614] [Embodiment 49] The pharmaceutical composition of any one of embodiments 31-40, wherein the amorphous form is at least about 95% pure in the pharmaceutical composition.

[0615] [Embodiment 50] The pharmaceutical composition of any one of embodiments 31-40, wherein the amorphous form is at least about 99% pure in the pharmaceutical composition.

Claims

1. A crystalline form of the compound of formula 1, 【Chemistry 1】 [Formula 1] or a pharmaceutically acceptable salt, solvate, or solvated salt thereof.

2. 2. The crystalline form of claim 1, wherein the crystalline form is a hydrate of the compound of formula 1.

3. 3. The crystalline form of claim 1 or 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.0°±0.2°, 10.1°±0.2°, and 16.9°±0.2° when illuminated with a Cu-Kα light source.

4. 4. The crystalline form of any one of claims 1 to 3, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.0°±0.2°, 7.8°±0.2°, 10.1°±0.2°, 16.8°±0.2°, and 16.9°±0.2° when illuminated with a Cu-Kα light source.

5. 5. The crystalline form of claim 4, wherein the crystalline form has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 11.0°±0.2°, 11.7°±0.2°, and 17.9°±0.2° when illuminated with a Cu-Kα light source.

6. 6. The crystalline form of claim 5, wherein the crystalline form has an XRPD pattern when illuminated with a Cu-Kα light source, further comprising at least one peak at a diffraction angle 2θ selected from 15.7°±0.2°, 18.7°±0.2°, 23.6°±0.2°, and 24.3°±0.2°.

7. 7. The crystalline form of any one of claims 1 to 6, wherein the crystalline form has an XRPD pattern substantially similar to Figure 2.

8. 8. The crystalline form of any one of claims 1 to 7, having a DSC thermogram substantially similar to Figure 8.

9. 3. The crystalline form of claim 2, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.3°±0.2°, and 17.2°±0.2° when illuminated with a Cu-Kα light source.

10. 10. The crystalline form of claim 2 or 9, wherein the crystalline form has an XRPD pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.3°±0.2°, 11.1°±0.2°, 17.2°±0.2°, and 20.8°±0.2° when illuminated with a Cu—Kα light source.

11. 11. The crystalline form of claim 10, wherein the crystalline form has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 19.2°±0.2°, 19.6°±0.2°, 21.3°±0.2°, 22.9°±0.2°, 23.9°±0.2°, and 25.5°±0.2° when illuminated with a Cu-Kα light source.

12. 12. The crystalline form of any one of claims 9 to 11, wherein the crystalline form has an XRPD pattern substantially similar to Figure 3.

13. 13. The crystalline form of any one of claims 9 to 12, having a DSC thermogram substantially similar to that in Figure 9.

14. The crystalline form of any one of claims 1 to 8, wherein the hydrate is a monohydrate.

15. The crystalline form of claims 1-2 or 9-13, wherein the hydrate is a trihydrate.

16. 2. The crystalline form of claim 1, wherein the crystalline form is an ethanol mono-solvate of the compound of Formula 1.

17. 17. The crystalline form of claim 16, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.6°±0.2°, 17.2°±0.2°, and 21.4±0.2° when illuminated with a Cu-Kα light source.

18. 18. The crystalline form of claim 17, wherein the crystalline form has an XRPD pattern comprising peaks at diffraction angles 2θ of 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.9°±0.2°, and 21.4°±0.2° when illuminated with a Cu—Kα light source.

19. 19. The crystalline form of claim 18, wherein the crystalline form of ethanol monosolvate has an XRPD pattern when illuminated with a Cu-Kα light source, further comprising at least one peak at a diffraction angle 2θ selected from 7.8°±0.2°, 19.2°±0.2°, 24.0°±0.2°, and 25.7°±0.2°.

20. 20. The crystalline form of any one of claims 16-19, wherein the crystalline form has an XRPD pattern substantially similar to Figure 4.

21. 21. The crystalline form of any one of claims 16 to 20, having a DSC thermogram substantially similar to Figure 10.

22. 2. The crystalline form of claim 1, wherein the crystalline form is an anhydrous crystalline form of the compound of formula 1.

23. 23. The crystalline form of claim 22, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, and 18.1±0.2° when illuminated with a Cu-Kα light source.

24. 24. The crystalline form of claim 23, wherein the anhydrous crystalline Form I has an XRPD pattern comprising peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.5°±0.2°, and 18.1°±0.2° when illuminated with a Cu-Kα light source.

25. 25. The crystalline form of claim 24, wherein the anhydrous crystalline form has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 6.5°±0.2°, 11.2°±0.2°, 15.1°±0.2°, 20.2°±0.2°, 21.8°±0.2°, 22.5°±0.2°, and 25.7°±0.2° when illuminated with a Cu—Kα light source.

26. 26. The crystalline form of any one of claims 22-25, wherein the crystalline form has an XRPD pattern substantially similar to Figure 5.

27. 27. The crystalline form of any one of claims 22 to 26, having a DSC thermogram substantially similar to Figure 10.

28. 2. The crystalline form of claim 1, which is the anhydrous crystalline form II of the compound of formula 1.

29. 29. The crystalline form of claim 22 or 28, wherein the crystalline form has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, and 9.7±0.2° when illuminated with a Cu-Kα light source.

30. 30. The crystalline form of claim 29, wherein the anhydrous crystalline form has an XRPD pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, 9.7°±0.2°, 17.7°±0.2°, and 19.0°±0.2° when illuminated with a Cu—Kα light source.

31. 31. The crystalline form of claim 30, wherein the anhydrous crystalline form has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 8.1°±0.2°, 11.8°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 25.9°±0.2° when illuminated with a Cu—Kα light source.

32. 32. The crystalline form of any one of claims 28-31, wherein the crystalline form has an XRPD pattern substantially similar to Figure 6.

33. 33. The crystalline form of any one of claims 28-32, wherein the crystalline form has a DSC thermogram substantially similar to Figure 11.

34. Amorphous Form of Formula 1 【Chemistry 2】 (Formula 1), or a solvate thereof.

35. 35. The amorphous form of claim 34, which exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to the pattern shown in Figure 1.

36. 35. The amorphous form of claim 34, exhibiting a differential scanning calorimetry (DSC) thermogram substantially similar to that of Figure 7.

37. 2. The crystalline form of claim 1, which is a pharmaceutically acceptable salt of the compound of formula 1 or a pharmaceutically acceptable salt solvate of the compound of formula 1.

38. 38. The crystalline form of claim 37, which is a crystalline form of a pharmaceutically acceptable salt of the compound of formula 1 selected from the group consisting of hydrochloride, sulfate, fumarate, succinate, maleate, and solvates thereof.

39. 39. The crystalline form of claim 37 or 38, which is a dihydrochloride salt crystalline form of the compound of formula 1 or a solvate thereof.

40. 40. The crystalline form of claim 39, wherein the dihydrochloride salt crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.4°±0.2°, and 19.1°±0.2° when illuminated with a Cu-Kα light source.

41. 41. The crystalline form of claim 40, wherein the dihydrochloride salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.4°±0.2°, 14.6°±0.2°, 19.1°±0.2°, and 26.2°±0.2° when illuminated with a Cu-Kα light source.

42. 42. The crystalline form of claim 40 or 41, wherein the dihydrochloride salt crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 10.8°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 18.5°±0.2°, 23.4°±0.2°, 25.8°±0.2°, and 27.1°±0.2° when illuminated with a Cu-Kα light source.

43. 43. The crystalline form of any one of claims 39-42, wherein the crystalline form has an XRPD pattern substantially similar to Figure 13.

44. 44. The crystalline form of any one of claims 39-43, wherein the crystalline form has a DSC thermogram substantially similar to Figure 25.

45. 45. The crystalline form of any one of claims 39 to 44, which is an ethanol solvate of the dihydrochloride salt crystalline form of the compound of formula 1.

46. 40. The crystalline form of claim 39, wherein the dihydrochloride salt crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 10.5°±0.2°, 15.2°±0.2°, and 23.1°±0.2° when illuminated with a Cu-Kα light source.

47. 47. The crystalline form of claim 46, wherein the dihydrochloride salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 10.5°±0.2°, 15.2°±0.2°, 22.3°±0.2°, 23.1°±0.2°, and 27.2°±0.2° when illuminated with a Cu-Kα light source.

48. 48. The crystalline form of claim 46 or 47, wherein the dihydrochloride salt crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 12.3°±0.2°, 17.8°±0.2°, 19.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 25.1°±0.2°, and 26.3°±0.2°.

49. 14. The crystalline form of any one of claims 46-48, wherein the crystalline form has an XRPD pattern substantially similar to Figure 14.

50. 50. The crystalline form of any one of claims 46-49, wherein the crystalline form has a DSC thermogram substantially similar to Figure 26.

51. 39. The crystalline form of claim 37 or 38, which is a monohydrochloride salt crystalline form of the compound of formula 1.

52. 52. The crystalline form of claim 51, wherein the monohydrochloride salt crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 17.1°±0.2°, 18.6°±0.2°, and 23.5°±0.2° when illuminated with a Cu-Kα light source.

53. 53. The crystalline form of claim 52, wherein the monohydrochloride salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 17.1°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 20.9°±0.2°, and 23.5°±0.2° when illuminated with a Cu-Kα light source.

54. 54. The crystalline form of any one of claims 51-53, wherein the monohydrochloride salt crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 4.9°±0.2°, 5.4°±0.2°, 8.0°±0.2°, 9.3°±0.2°, 14.2°±0.2°, 14.6°±0.2°, and 26.0°±0.2°.

55. 55. The crystalline form of any one of claims 51-54, wherein the crystalline form has an XRPD pattern substantially similar to Figure 15.

56. 56. The crystalline form of any one of claims 51 to 55, having a DSC thermogram substantially similar to Figure 27.

57. 39. The crystalline form of claim 37 or 38, which is a disulfate salt crystalline form of the compound of formula 1.

58. 58. The crystalline form of claim 57, wherein the disulfate salt crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.4°±0.2°, and 24.3°±0.2° when illuminated with a Cu-Kα light source.

59. 59. The crystalline form of claim 58, wherein the disulfate salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 15.2°±0.2°, and 24.3°±0.2° when illuminated with a Cu-Kα light source.

60. 60. The crystalline form of claim 58 or 59, wherein the disulfate salt crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 17.0°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 26.5°±0.2°, and 27.8°±0.2° when illuminated with a Cu-Kα light source.

61. 61. The crystalline form of any one of claims 57-60, wherein the crystalline form has an XRPD pattern substantially similar to Figure 16.

62. 62. The crystalline form of any one of claims 57-61, having a DSC thermogram substantially similar to Figure 28.

63. 39. The crystalline form of claim 37 or 38, which is a monosulfate salt crystalline form of the compound of formula 1.

64. 64. The crystalline form of claim 63, wherein the monosulfate salt crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.4°±0.2°, and 24.3°±0.2° when illuminated with a Cu-Kα light source.

65. 65. The crystalline form of claim 64, wherein the monosulfate salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 15.2°±0.2°, and 24.3°±0.2° when illuminated with a Cu-Kα light source.

66. 66. The crystalline form of claim 64 or 65, wherein the monosulfate salt crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 17.0°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 26.5°±0.2°, and 27.8°±0.2° when illuminated with a Cu-Kα light source.

67. 67. The crystalline form of any one of claims 63-66, wherein the crystalline form has an XRPD pattern substantially similar to Figure 17.

68. 68. The crystalline form of any one of claims 63 to 67, having a DSC thermogram substantially similar to Figure 29.

69. 39. The crystalline form of claim 37 or 38, which is a difumarate salt crystalline form of the compound of formula 1.

70. 70. The crystalline form of claim 69, wherein the difumarate salt crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 22.9°±0.2°, 28.9°±0.2°, and 29.4°±0.2° when illuminated with a Cu-Kα light source.

71. 71. The crystalline form of claim 70, wherein the difumarate salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 5.5°±0.2°, 8.5°±0.2°, 22.9°±0.2°, 28.9°±0.2°, and 29.4°±0.2° when illuminated with a Cu-Kα light source.

72. 72. The crystalline form of claim 70 or 71, wherein the difumarate salt crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 5.7°±0.2°, 14.5°±0.2°, 19.1°±0.2°, 21.1°±0.2°, 22.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2° when illuminated with a Cu-Kα light source.

73. 73. The crystalline form of any one of claims 69-72, wherein the crystalline form has an XRPD pattern substantially similar to Figure 18.

74. 74. The crystalline form of any one of claims 69 to 73, having a DSC thermogram substantially similar to Figure 30.

75. 39. The crystalline form of claim 37 or 38, which is a hemifumarate salt crystalline form of the compound of formula 1.

76. 76. The crystalline form of claim 75, wherein the hemi-fumarate crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.8°±0.2°, 12.6°±0.2°, and 17.1°±0.2° when illuminated with a Cu-Kα light source.

77. 77. The crystalline form of claim 76, wherein the hemisulfate salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 6.8°±0.2°, 10.2°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 23.4°±0.2° when illuminated with a Cu-Kα light source.

78. 77. The crystalline form of claim 75 or 76, wherein the hemimalate crystalline form of the compound of Formula 1 has an XRPD pattern, when illuminated with a Cu-Kα light source, further comprising at least one peak at a diffraction angle 2θ selected from 8.3°±0.2°, 13.8°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 23.1°±0.2°, and 25.6°±0.2°.

79. 79. The crystalline form of any one of claims 75-78, wherein the crystalline form has an XRPD pattern substantially similar to Figure 19.

80. 80. The crystalline form of any one of claims 75 to 79, having a DSC thermogram substantially similar to Figure 31.

81. 39. The crystalline form of claim 37 or 38, which is a monosuccinate salt crystalline form of the compound of formula 1.

82. 82. The crystalline form of claim 81, wherein the monosuccinate salt crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 16.9°±0.2°, 18.5°±0.2°, and 23.6°±0.2° when illuminated with a Cu-Kα light source.

83. 83. The crystalline form of claim 82, wherein the monosuccinate salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 16.9°±0.2°, 18.5°±0.2°, 23.3°±0.2°, and 23.6°±0.2° when illuminated with a Cu-Kα light source.

84. 84. The crystalline form of claim 82 or 83, wherein the monosuccinate salt crystalline form of the compound of Formula 1 has an XRPD pattern, when illuminated with a Cu-Kα light source, further comprising at least one peak at a diffraction angle 2θ selected from 8.4°±0.2°, 13.9°±0.2°, 19.3°±0.2°, 21.0°±0.2°, 24.1°±0.2°, and 24.8°±0.2°.

85. 85. The crystalline form of any one of claims 81-84, wherein the crystalline form has an XRPD pattern substantially similar to Figure 20.

86. 86. The crystalline form of any one of claims 81-85, having a DSC thermogram substantially similar to Figure 32.

87. 39. The crystalline form of claim 37 or 38, which is a hemisuccinate salt crystalline form of the compound of formula 1.

88. 88. The crystalline form of claim 87, wherein the hemisuccinate salt crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 17.0°±0.2°, and 23.6°±0.2° when illuminated with a Cu-Kα light source.

89. 90. The crystalline form of claim 88, wherein the hemisuccinate salt crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 8.4±0.2°, 12.6±0.2°, 17.0°±0.2°, and 23.6°±0.2° when illuminated with a Cu—Kα light source.

90. 90. The crystalline form of claim 88 or 89, wherein the hemisuccinate salt crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 10.2±0.2°, 13.9±0.2°, 18.5±0.2°, 19.3±0.2°, 23.3±0.2°, 24.8±0.2°, and 25.5±0.2° when illuminated with a Cu—Kα light source.

91. 91. The crystalline form of any one of claims 87-90, wherein the crystalline form has an XRPD pattern substantially similar to Figure 21.

92. 92. The crystalline form of any one of claims 87-91, having a DSC thermogram substantially similar to Figure 33.

93. 39. The crystalline form of claim 37 or 38, which is a dimaleate salt crystalline form of the compound of formula 1.

94. 94. The crystalline form of claim 93, wherein the dimaleate crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 11.4°±0.2°, 12.2°±0.2°, and 27.4°±0.2° when illuminated with a Cu-Kα light source.

95. 95. The crystalline form of claim 94, wherein the dimaleate crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 7.1°±0.2°, 11.4±0.2°, 12.2±0.2°, 27.4°±0.2°, and 27.8°±0.2° when illuminated with a Cu-Kα light source.

96. 96. The crystalline form of claim 94 or 95, wherein the dimaleate crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 9.4±0.2°, 14.8±0.2°, 16.6±0.2°, 19.2±0.2°, 20.7±0.2°, 21.1±0.2°, and 24.1±0.2° when illuminated with a Cu-Kα light source.

97. 97. The crystalline form of any one of claims 93-96, wherein the crystalline form has an XRPD pattern substantially similar to Figure 22.

98. 98. The crystalline form of any one of claims 93 to 97, having a DSC thermogram substantially similar to Figure 34.

99. 39. The crystalline form of claim 37 or 38, which is a sesquimaleate salt crystalline form of the compound of formula 1.

100. 100. The crystalline form of claim 99, wherein the sesquimaleate crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 13.8°±0.2°, 17.1°±0.2°, and 18.5°±0.2° when illuminated with a Cu-Kα light source.

101. 101. The crystalline form of claim 100, wherein the sesquimaleate crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 8.9°±0.2°, 13.8°±0.2°, 16.1°±0.2°, 17.1°±0.2°, and 18.5°±0.2° when illuminated with a Cu-Kα light source.

102. 103. The crystalline form of claim 101 or 102, wherein the sesquimaleate crystalline form of the compound of Formula 1 has an XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 14.2°±0.2°, 19.6°±0.2°, 20.3°±0.2°, 20.9°±0.2°, 22.5°±0.2°, 26.2°±0.2°, and 26.6°±0.2° when illuminated with a Cu-Kα light source.

103. 103. The crystalline form of any one of claims 99-102, wherein the crystalline form has an XRPD pattern substantially similar to Figure 23.

104. 104. The crystalline form of any one of claims 99-103, wherein the crystalline form has a DSC thermogram substantially similar to Figure 35.

105. 39. The crystalline form of claim 37 or 38, which is a monomaleate salt crystalline form of the compound of formula 1.

106. 106. The crystalline form of claim 105, wherein the monomaleate crystalline form of the compound of Formula 1 has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 11.9°±0.2°, and 24.0°±0.2° when illuminated with a Cu-Kα light source.

107. 107. The crystalline form of claim 106, wherein the monomaleate crystalline form of the compound of Formula 1 has an XRPD pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 9.6°±0.2°, 11.9°±0.2°, 15.7°±0.2°, and 24.0°±0.2° when illuminated with a Cu-Kα light source.

108. 108. The crystalline form of claim 107, wherein the monomaleate crystalline form of the compound of Formula 1 has an XRPD pattern, when illuminated with a Cu-Kα light source, further comprising at least one peak at a diffraction angle 2θ selected from 5.9°±0.2°, 16.0°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 23.7°±0.2°, and 28.9°±0.2°.

109. 109. The crystalline form of any one of claims 105-108, wherein the crystalline form has an XRPD pattern substantially similar to Figure 24.

110. 110. The crystalline form of any one of claims 105 to 109, having a DSC thermogram substantially similar to Figure 36.

111. A means for inhibiting FMS-like tyrosine kinase 3 (FLT3).

112. A means for binding to FMS-like tyrosine kinase 3 (FLT3).

113. 113. The means of claim 111 or 112, in crystalline form.

114. 113. The means of claim 111 or 112, in amorphous form.

115. 114. The means of claim 113, wherein the crystalline form comprises a hydrate of the compound of formula 1.

116. 116. The method of claim 115, wherein the hydrate is a monohydrate, dihydrate, or trihydrate of the compound of formula 1.

117. 114. The means of claim 113, wherein the crystalline form comprises an ethanol monosolvate of the compound of formula 1.

118. 114. The means of claim 113, wherein the crystalline form comprises an anhydrate of the compound of formula 1.

119. 110. A pharmaceutical composition comprising at least one crystalline form of a compound of formula 1 according to any one of claims 1 to 33 or 37 to 110, and at least one pharmaceutically acceptable carrier or diluent.

120. A pharmaceutical composition comprising at least one amorphous form of the compound of formula 1 according to any one of claims 34 to 36 and at least one pharmaceutically acceptable carrier or diluent.

121. A pharmaceutical composition comprising a means for inhibiting FMS-like tyrosine kinase 3 (FLT3).

122. A pharmaceutical composition comprising a means for binding to FMS-like tyrosine kinase 3 (FLT3).

123. 123. The pharmaceutical composition of claim 121 or 122, wherein the means is in a crystalline form.

124. 123. The pharmaceutical composition of claim 121 or 122, wherein the means is in amorphous form.

125. 125. The pharmaceutical composition of any one of claims 119-124, wherein the crystalline or amorphous form is at least about 70% pure in the pharmaceutical composition.

126. 126. The pharmaceutical composition of claim 125, wherein the crystalline or amorphous form is at least about 80% pure in the pharmaceutical composition.

127. 125. The pharmaceutical composition of any one of claims 119-124, wherein the crystalline or amorphous form is at least about 90% pure in the pharmaceutical composition.

128. 125. The pharmaceutical composition of any one of claims 119-124, wherein the crystalline or amorphous form is at least about 95% pure in the pharmaceutical composition.

129. 125. The pharmaceutical composition of any one of claims 119-124, wherein the crystalline or amorphous form is at least about 99% pure in the pharmaceutical composition.

130. 125. The pharmaceutical composition of any one of claims 120-124, wherein the amorphous form is at least about 70% pure in the pharmaceutical composition.

131. 126. The pharmaceutical composition of claim 125, wherein the amorphous form is at least about 80% pure in the pharmaceutical composition.

132. 125. The pharmaceutical composition of any one of claims 120-124, wherein the amorphous form is at least about 90% pure in the pharmaceutical composition.

133. 125. The pharmaceutical composition of any one of claims 120-124, wherein the amorphous form is at least about 95% pure in the pharmaceutical composition.

134. 125. The pharmaceutical composition of any one of claims 120-124, wherein the amorphous form is at least about 99% pure in the pharmaceutical composition.

135. 11. A method of treating cancer in a subject in need thereof, comprising administering a crystalline form of any one of claims 1-33 or 37-110, an amorphous form of any one of claims 34-36.

136. 136. The method of claim 135, wherein the cancer is leukemia.

137. 137. The method of claim 136, wherein the leukemia comprises acute myeloid leukemia, acute lymphocytic leukemia, or chronic myeloid leukemia.

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