Novel crystalline forms of pyrimidine compounds and pharmaceutical compositions comprising same and methods of using same

Abstract

The present disclosure relates to solid forms of pyrimidine compounds, pharmaceutical compositions including the same, and methods of use thereof. For example, the present disclosure relates to a crystalline polymorph of a compound of Formula 1, or a pharmaceutically acceptable salt, solvate, or solvate salt thereof. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Application No. 63 / 382,463, filed on November 4, 2022, the content of which is hereby incorporated by reference in its entirety for all purposes. Technical Field

[0003] The present disclosure relates to novel solid forms, such as crystalline forms of pyrimidine compounds, pharmaceutical compositions comprising the same, and their therapeutic uses.

[0004] More specifically, the present disclosure relates to amorphous forms and crystalline forms of compounds of Formula 1, such as anhydrates, hydrates, solvates, salts, salt solvates, methods for their preparation, pharmaceutical compositions comprising the same, and their therapeutic uses. Background Art

[0005] FMS - like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase expressed by hematopoietic cells, usually in hematopoietic progenitor cells, and it plays an important role in the normal development of stem cells and the immune system. Abnormal overexpression and mutations of FLT3 are frequently observed in leukemia patients. Acute myeloid leukemia (AML) is a pluripotent hematopoietic stem cell disease characterized by abnormal proliferation and differentiation of blast cells in the bone marrow and peripheral blood. From the perspective of AML treatment, FLT3 has recently been regarded as one of the most important targets.

[0006] In an embodiment, the compound of Formula 1, having 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, has antiproliferative activity, such as anticancer activity by targeting FMS - like tyrosine kinase, and is capable of selectively and effectively treating drug resistance caused by tyrosine kinase mutations.

[0007] [Formula 1]

[0008] Summary of the Invention

[0009] Technical Problem

[0010] One aspect is to provide a crystalline form of the compound of Formula 1.

[0011] One aspect is to provide an amorphous form of the compound of Formula 1.

[0012] Another aspect is to provide a pharmaceutical composition comprising a crystalline form or an amorphous form of the compound of Formula 1.

[0013] On the other hand, there is provided a method for treating cancers, such as leukemia. In a specific embodiment, the leukemia can be acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myeloid leukemia.

[0014] Solution to the problem

[0015] On the one hand, there is provided a crystal form of a compound of formula 1:

[0016] [Formula 1]

[0017]

[0018] The compound of formula 1 and its use methods are disclosed in U.S. Publication Nos. U.S.2020 / 0031806, U.S.2022 / 0110913, U.S.2022 / 0354842, and PCT Application Publications WO2020022600, WO2020171646, WO2020171649, WO2020262974, WO2021066443, and WO / 2022 / 098083, which patents are incorporated herein by reference in their entirety.

[0019] In an embodiment, the present disclosure relates to a solid form of formula 1

[0020]

[0021] or a pharmaceutically acceptable salt and / or solvate thereof, a pharmaceutical composition comprising said solid form, and its therapeutic use.

[0022] In an embodiment, the solid form is an amorphous form of the compound of formula 1.

[0023] In an embodiment, the solid form is an anhydrate of the compound of formula 1.

[0024] In an embodiment, the solid form is a crystal form of the compound of formula 1.

[0025] In an embodiment, the crystal form is a solvate of the compound of formula 1.

[0026] In an embodiment, the crystal form is a crystal form of a hydrate of the compound of formula 1. For example, in an embodiment, the hydrate of the compound of formula 1 is a monohydrate or a trihydrate. In an embodiment, the hydrate is a monohydrate. In an embodiment, the hydrate is a trihydrate.

[0027] In an embodiment, the crystal form is a crystal form of an alcohol solvate (e.g., an alcohol monosolvate) of the compound of formula 1. For example, in an embodiment, the solvate of the compound of formula 1 is an ethanol solvate (e.g., an ethanol monosolvate), wherein the monosolvate has a crystal structure that contains one solvent molecule per molecule of the compound of formula 1.

[0028] In an embodiment, the crystalline form is a pharmaceutically acceptable salt of the compound of Formula 1 or a solvate of a pharmaceutically acceptable salt of the compound of Formula 1. In an embodiment, the crystalline forms of the pharmaceutically acceptable salts or salt solvates of the compound of Formula 1 are selected from the group consisting of: hydrochloride, sulfate, fumarate, succinate, maleate, and solvates thereof.

[0029] In an embodiment, the crystalline form is a pharmaceutically acceptable salt of the compound of Formula 1. In an embodiment, the crystalline forms of the pharmaceutically acceptable salts of the compound of Formula 1 are selected from the group consisting of: hydrochloride, sulfate, fumarate, succinate, and maleate.

[0030] In an embodiment, the crystalline form is a solvate of a pharmaceutically acceptable salt of the compound of Formula 1. In an embodiment, the solvate of the pharmaceutically acceptable salt of the compound of Formula 1 is an ethanol solvate of the dihydrochloride salt of the compound of Formula 1.

[0031] In a specific example, the crystalline form of the compound of Formula 1 can be a crystalline form of a hydrate, solvate, or anhydrate.

[0032] As used herein, the verb “comprise” as used in this specification and the claims and their conjugates is used in its non-limiting sense to mean including the item following the word, but not excluding items not specifically mentioned. The present invention may suitably “comprise” the steps, elements, and / or reagents described in the claims, “consist of” the steps, elements, and / or reagents, or “consist essentially of” the steps, elements, and / or reagents.

[0033] It should be further noted that the claims may be drafted to exclude any optional elements. Accordingly, this statement is intended to serve as a basis for the use of exclusive terms such as “solely,” “only,” etc. or the use of “negative” limitations in connection with the recited claim elements.

[0034] As used herein, the term “crystal form” or “crystalline form” refers to a crystalline solid form of a chemical compound, which may include crystalline polymorphs, solvates, hydrates, co-crystals, or other molecular complexes or crystalline polymorphs thereof, and may refer to the crystal form of a specific single component or multi-component, but is not limited thereto.

[0035] As used herein, the terms “polymorph” and “polymorphic form” refer to two or more crystal forms that include the same one or more molecules or ions. Due to different arrangements or conformations of the molecules and ions in the crystal lattice, different polymorphs may have different physical properties, such as melting point, solubility, or vibrational spectra.

[0036] As used herein, the term "solvate" refers to a crystalline form of a material that contains a solvent. The solvent can be a pharmaceutically acceptable solvent. For example, the solvent can be a C1 to C4 straight or branched chain alcohol, ethylene glycol, propylene glycol, or acetic acid. The alcohol can be, for example, methanol, ethanol, isopropanol, or butanol. The solvent can preferably be ethanol, which is more suitable for use in the human body. Alternatively, the solvent can be water.

[0037] As used herein, the term "hydrate" refers to a solvate in which the solvent is water. "Crystalline polymorphs of a solvate" means that more than one crystalline form is present in a particular solvate composition. "Crystalline polymorphs of a hydrate" means that more than one crystalline form is present in a particular hydrate composition. A solvent is added to dissolve at least a portion of the compound, and can be an amount sufficient to dissolve at least a portion of the compound of formula 1.

[0038] As used herein, the term "amorphous" or "amorphous form" refers to a state in which a material, composition, or product is substantially non-crystalline when measured by X-ray diffraction.

[0039] As used herein, "substantially" or "essentially" refers to the degree or extent of completeness or near-completeness of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed will mean that the object is completely enclosed or nearly completely enclosed. In another example, an XRPD pattern that is "substantially" similar to another XRPD pattern will mean that one of ordinary skill in the art will understand that the two patterns have the same substance in the same form. In some cases, the exact permitted degree of deviation from absolute completeness can depend on the specific context. However, generally speaking, the proximity of completion will be such that the overall result is the same as if absolute and total completion had been achieved. When used in a negative sense to refer to the complete or nearly complete absence of an action, characteristic, property, state, structure, item, or result, the use of "substantially" applies equally. For example, a composition that is "substantially free" of other active agents will be completely lacking in other active agents, or nearly completely lacking in other active agents, such that the effect will be the same as if it were completely lacking in other active agents. In other words, a composition that is "substantially free" of a component or element or another active agent can still contain such items, as long as they have no measurable effect.

[0040] The term "treatment" means alleviating, reducing, delaying, decreasing, improving, or managing at least one symptom of a disorder in a subject. The term "treatment" can also mean blocking, delaying the onset (i.e., the period before the clinical manifestation of the disorder), or reducing the risk of occurrence or worsening of a disorder.

[0041] "Effective amount" means an amount of a formulation according to the invention sufficient to effect such treatment when administered to a patient for treating a condition, disorder or disease state. The "effective amount" will vary depending on the active ingredient, the condition, disorder or disease state to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.

[0042] The term "therapeutically effective" as applied to a dose or amount refers to an amount of a compound or pharmaceutical formulation sufficient to produce a desired clinical benefit after administration to a patient in need thereof.

[0043] As used herein, "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. In an embodiment, the subject is a human. In an embodiment, the subject may be suspected of having cancer or at risk of having cancer.

[0044] Pharmaceutically acceptable salts include salts obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as salts of 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 the compound with a suitable inorganic or organic acid via any of a variety of known methods.

[0045] In an embodiment, a crystalline form of a compound of formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof or a salt solvate thereof (e.g., as disclosed herein) can 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 determined using methods known to those skilled in the art, including, for example, X-ray powder crystallography.

[0046] In an embodiment, the purity of the crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein) is about 99.9% or higher, about 99.8% or higher, about 99.7% or higher, about 99.6% or higher, about 99.5% or higher, about 99% or higher, about 98% or higher, about 97% or higher, about 96% or higher, about 95% or higher, about 94% or higher, about 93% or higher, about 92% or higher, about 91% or higher, about 90% or higher, about 85% or higher, or about 80% or higher. In an embodiment, the purity of the crystalline form ranges from about 80% to about 99%. In an embodiment, the purity of the crystalline form ranges from about 80% to about 99.5%, or from about 90% to about 99.9%, or from about 95% to about 100%, including all values and sub-ranges therebetween. In an embodiment, the purity is determined by HPLC.

[0047] In an embodiment, the crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein) is about 99.9% pure by weight or higher, about 99.8% pure by weight or higher, about 99.7% pure by weight or higher, about 99.6% pure by weight or higher, about 99.5% pure by weight or higher, about 99% pure by weight or higher, about 98% pure by weight or higher, about 97% pure by weight or higher, about 96% pure by weight or higher, about 95% pure by weight or higher, about 94% pure by weight or higher, about 93% pure by weight or higher, about 92% pure by weight or higher, about 91% pure by weight or higher, about 90% pure by weight or higher, about 85% pure by weight or higher, or about 80% pure by weight or higher. In an embodiment, the purity of the crystalline form ranges from about 80% pure by weight to about 99% pure by weight of a single crystalline form. In an embodiment, the purity is determined using methods known to those skilled in the art (e.g., HPLC).

[0048] In an embodiment, the crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein) is at least about 95% pure by weight and contains no more than about 5% by weight of impurities. In some embodiments, the crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein) is from about 95.0% to 100% pure by weight and contains from 0% to about 5% by weight of impurities. In some embodiments, the crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein) is from about 98% to 100% pure by weight and contains from 0% to about 2% by weight of impurities. In some embodiments, the crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein) is about 98%, about 98.5%, about 99%, about 99.5% or 100% pure by weight and each contains about 2%, about 1.5%, about 1%, about 0.5% or 0% by weight of impurities. In some embodiments, the crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof (e.g., as disclosed herein) is about 99.5%, about 99.9% or about 99.95% pure by weight and each contains about 0.5%, about 0.1% or about 0.05% by weight of impurities.

[0049] In some embodiments, purity or impurities are determined using methods known to those skilled in the art, including, for example, high performance liquid chromatography (HPLC).

[0050] In a specific example, the crystalline form can be a crystalline form of a hydrate of the compound of Formula 1. The hydrate of the compound of Formula 1 can be a monohydrate, a dihydrate or a trihydrate.

[0051] In a specific example, the crystalline form can be a crystalline form of a monohydrate, a dihydrate or a trihydrate of the compound of Formula 1, or can preferably be a crystalline form of a monohydrate or a trihydrate.

[0052] Crystalline form of the monohydrate of the compound of Formula 1.

[0053] In a specific example, the crystalline form can be a crystalline form of a monohydrate of the compound of Formula 1.

[0054] In an embodiment, 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 monohydrate of the compound of Formula 1. In another embodiment, 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 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% of the monohydrate of the compound of Formula 1.

[0055] The X-ray powder diffraction (XRPD) pattern of the monohydrate crystalline form may include peaks at diffraction angles 2θ of 5.0° ± 0.2°, 10.1° ± 0.2°, and 16.9° ± 0.2°.

[0056] The monohydrate crystalline form may further include at least one peak at a diffraction angle 2θ selected from 7.8° ± 0.2° and 16.8° ± 0.2°.

[0057] The monohydrate crystalline form may further include at least one peak at a diffraction angle 2θ selected from 11.0° ± 0.2°, 11.7° ± 0.2°, and 17.9° ± 0.2°.

[0058] The monohydrate crystalline form may further include 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°.

[0059] When irradiating the crystalline form with a Cu-Kα light source the peaks at diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0060] The X-ray powder diffraction (XRPD) pattern of the monohydrate crystalline form may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angle 2θ, the relative intensity of which (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) is 5% or more.

[0061] For example, the XRPD relative intensity (I / I0) of the peaks exhibited by the monohydrate crystalline form may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0062] In a specific example, when irradiating a monohydrate crystal form with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the monohydrate crystal form includes 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°.

[0063] In a specific example, when irradiating a monohydrate crystal form with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the monohydrate crystal form further includes at least one peak at a diffraction angle 2θ selected from 11.0° ± 0.2°, 11.7° ± 0.2°, and 17.9° ± 0.2°.

[0064] In a specific example, when irradiating a monohydrate crystal form with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the monohydrate crystal form further includes 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°.

[0065] When irradiating a crystal form with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the monohydrate crystal form may include 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°.

[0066] The monohydrate crystal form may include peaks at the diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 2

[0067] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 2 .

[0068] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks in Table 1.

[0069] The monohydrate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 8 .

[0070] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 8 .

[0071] In a specific example, in differential scanning calorimetry (DSC), the monohydrate crystal form can have a heat absorption onset temperature of 74.9 °C and exhibit heat absorption peaks at heat absorption temperatures of 89.0 °C and 161.6 °C.

[0072] The trihydrate crystal form of the compound of Formula 1.

[0073] In a specific example, the crystal form can be the trihydrate crystal form of the compound of Formula 1.

[0074] In an embodiment, the crystal form of the compound of Formula 1 can 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 another embodiment, the crystal form of the compound of Formula 1 can 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 crystal form of the compound of Formula 1 can 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.

[0075] The X-ray powder diffraction (XRPD) pattern of the trihydrate crystal form can include peaks at diffraction angles 2θ of 8.2° ± 0.2°, 9.3° ± 0.2° and 17.2° ± 0.2°.

[0076] The trihydrate crystal form can further include at least one peak at a diffraction angle 2θ selected from 11.1° ± 0.2° and 20.8° ± 0.2°.

[0077] The trihydrate crystal form can further include 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°.

[0078] When irradiating the crystal form with a Cu-Kα light source The peaks at diffraction angle 2θ can form an X-ray powder diffraction (XRPD) pattern.

[0079] The X-ray powder diffraction (XRPD) pattern of the trihydrate crystal form can include 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 peaks at diffraction angle 2θ, and their relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) is 10% or more.

[0080] For example, the relative intensity (I / I0) of the peaks exhibited by the trihydrate crystal form can be 10% or more, 14% or more, 15% or more, 20% or more, or 22% or more.

[0081] In a specific example, when irradiating the trihydrate crystal form with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the trihydrate crystal form includes 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°.

[0082] In a specific example, when irradiating the trihydrate crystal form with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the trihydrate crystal form further includes 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°.

[0083] When irradiating the crystal form with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the trihydrate crystal form can include 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°.

[0084] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 3 .

[0085] The trihydrate crystal form can include peaks at the diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) identified in Figure 3 .

[0086] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks in Table 2.

[0087] The trihydrate crystal form can exhibit the analysis results of the differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 9 .

[0088] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 9 .

[0089] In a specific example, in differential scanning calorimetry (DSC), the trihydrate crystal form can have a heat absorption onset temperature of 44.9 °C and show heat absorption peaks at heat absorption temperatures of 68.7 °C and 108.3 °C.

[0090] The ethanol monosolvate crystal form of the compound of formula 1.

[0091] In a specific example, the crystal form can be a crystal form of a solvate of the compound of formula 1. The solvate of the compound of formula 1 can be an alcohol solvate, or preferably an ethanol solvate.

[0092] In a specific example, the crystal form can be a crystal form of an alcohol solvate of the compound of formula 1. In a specific example, the crystal form can be a crystal form of an alcohol monosolvate of the compound of formula 1. The monosolvate has a crystal structure that contains one solvent molecule per molecule of the compound of formula 1.

[0093] In a specific example, the crystal form can be a crystal form of an ethanol solvate of the compound of formula 1. In a specific example, the crystal form can be a crystal form of an ethanol monosolvate of the compound of formula 1.

[0094] In an embodiment, the crystal form of the compound of formula 1 can 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 ethanol monosolvate of the compound of formula 1. In another embodiment, the crystal form of the compound of formula 1 can comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of the ethanol monosolvate of the compound of formula 1. In some embodiments, the crystal form of the compound of formula 1 can comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of the ethanol monosolvate of the compound of formula 1.

[0095] The X-ray powder diffraction (XRPD) pattern of the crystal form of the ethanol monosolvate can include peaks at diffraction angles 2θ of 8.6° ± 0.2°, 17.2° ± 0.2° and 21.4 ± 0.2°.

[0096] The X-ray powder diffraction (XRPD) pattern of the crystal form of the ethanol monosolvate can include peaks at diffraction angles 2θ of 8.6° ± 0.2°, 13.0° ± 0.2°, 17.2° ± 0.2° and 21.4° ± 0.2°.

[0097] The crystal form of the ethanol monosolvate can further include at least one peak at a diffraction angle 2θ selected from 17.5° ± 0.2 and 18.9° ± 0.2°.

[0098] The crystal form of the ethanol monosolvate may further include 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°.

[0099] When irradiating the crystal form with a Cu-Kα light source the peaks at the diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0100] The X-ray powder diffraction (XRPD) pattern of the crystal form of the ethanol monosolvate may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at the diffraction angle 2θ, and the relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) is 10% or more.

[0101] For example, the XRPD relative intensity (I / I0) of the peaks exhibited by the crystal form of the ethanol monosolvate may be 10% or more, 20% or more, 30% or more, 40% or more, 60% or more, or 65% or more.

[0102] In a specific example, when irradiating the crystal form of the ethanol monosolvate with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the crystal form of the ethanol monosolvate includes peaks at the diffraction angles 2θ of 8.6° ± 0.2°, 17.2° ± 0.2°, and 21.4 ± 0.2°.

[0103] In a specific example, when irradiating the crystal form of the ethanol monosolvate with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the crystal form of the ethanol monosolvate includes peaks at the 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°.

[0104] In a specific example, when irradiating the crystal form of the ethanol monosolvate with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the crystal form of the ethanol monosolvate further includes 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°.

[0105] When irradiating the crystal form of ethanol monosolvate with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form of ethanol monosolvate may include 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°.

[0106] In the examples, the XRPD pattern of the crystal form is substantially similar to Figure 4 .

[0107] The crystal form of ethanol monosolvate may include peaks at diffraction angles (2θ ± 0.2) of X-ray powder diffraction (XRPD) identified in Figure 4 .

[0108] In some examples, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks in Table 3.

[0109] The crystal form of ethanol monosolvate may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 10 .

[0110] In the examples, the DSC thermogram of the crystal form is substantially similar to Figure 10 .

[0111] In a specific example, in differential scanning calorimetry (DSC), the crystal form of ethanol monosolvate may have a heat absorption onset temperature of 99.8 °C and exhibit a heat absorption peak at a heat absorption temperature of 113.4 °C.

[0112] The anhydrous crystal form I of the compound of formula 1.

[0113] In a specific example, the crystal form may be the crystal form of the anhydrous form of the compound of formula 1.

[0114] In a specific example, the crystal form may be the anhydrous crystal form I of the compound of formula 1.

[0115] In an embodiment, 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 anhydrous Form I of the compound of Formula 1. In another embodiment, 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 anhydrous Form I 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 anhydrous Form I of the compound of Formula 1.

[0116] The X-ray powder diffraction (XRPD) pattern of the anhydrous crystalline Form I may include peaks at diffraction angles 2θ of 5.2° ± 0.2°, 10.4° ± 0.2° and 18.1 ± 0.2°.

[0117] The X-ray powder diffraction (XRPD) pattern of the anhydrous crystalline Form I may include 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°.

[0118] The anhydrous crystalline Form I may further include at least one peak at a diffraction angle 2θ selected from 6.5° ± 0.2° and 25.7° ± 0.2°.

[0119] The anhydrous crystalline Form I may further include 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°.

[0120] When irradiating the crystalline form with a Cu-Kα light source the peaks at the diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0121] The pattern of the X-ray powder diffraction (XRPD) spectrum of the anhydrous crystalline Form I may include 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 peaks at the diffraction angle 2θ, and the relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) is 10% or more.

[0122] For example, the XRPD relative intensity (I / I0) of the peaks exhibited by the anhydrous crystalline Form I may be 10% or more, 20% or more, 30% or more, 40% or more, 60% or more or 65% or more.

[0123] In a specific example, when anhydrous form I is irradiated with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of anhydrous form I includes peaks at diffraction angles of 5.2° ± 0.2°, 10.4° ± 0.2°, and 18.1 ± 0.2°.

[0124] In a specific example, when anhydrous form I is irradiated with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of anhydrous form I includes 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°.

[0125] In a specific example, when anhydrous form I is irradiated with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of anhydrous form I further includes 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°.

[0126] When anhydrous form I is irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of anhydrous form I may include 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°.

[0127] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 5 .

[0128] Anhydrous form I may include peaks at the diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 5 .

[0129] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks in Table 4.

[0130] Anhydrous form I may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 11 .

[0131] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 11 .

[0132] In a specific example, in differential scanning calorimetry (DSC), the anhydrous form I can have an onset temperature of heat absorption at 152.4 °C and exhibit a heat absorption peak at a heat absorption temperature of 159.5 °C.

[0133] The anhydrous form II of the compound of formula 1.

[0134] In a specific example, the crystal form can be the crystal form of the anhydrous form II of the compound of formula 1.

[0135] The X-ray powder diffraction (XRPD) pattern of the anhydrous form II can include peaks at diffraction angles 2θ of 4.9° ± 0.2°, 5.9° ± 0.2°, and 9.7 ± 0.2°.

[0136] The X-ray powder diffraction (XRPD) pattern of the anhydrous form II can include 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°.

[0137] The anhydrous form II can further include at least one peak at a diffraction angle 2θ selected from 11.8° ± 0.2°, 14.3° ± 0.2°, and 23.0° ± 0.2°.

[0138] The anhydrous form II can further include 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°.

[0139] When irradiating the crystal form with a Cu-Kα light source The peaks at the diffraction angle 2θ can form an X-ray powder diffraction (XRPD) pattern.

[0140] The X-ray powder diffraction (XRPD) pattern of the anhydrous form II can include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at the diffraction angle 2θ, and their relative intensities (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) are 10% or more.

[0141] For example, the XRPD relative intensities (I / I0) of the peaks exhibited by the anhydrous form II can be 10% or more, 20% or more, 30% or more, 40% or more, 60% or more, or 65% or more.

[0142] In a specific example, when anhydrous form II is irradiated with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of anhydrous form II includes peaks at diffraction angles 2θ of 4.9° ± 0.2°, 5.9° ± 0.2°, and 9.7 ± 0.2°.

[0143] In a specific example, when anhydrous form II is irradiated with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of anhydrous form II includes 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°.

[0144] In a specific example, when anhydrous form II is irradiated with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of anhydrous form II further includes 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°.

[0145] When anhydrous form II is irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of anhydrous form II may include 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°.

[0146] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 6 .

[0147] Anhydrous form II may include peaks at diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) identified in Figure 6 .

[0148] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks in Table 5.

[0149] Anhydrous form II may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 12 .

[0150] In an embodiment, the DSC thermogram of the crystal form is substantially similar toFigure 12 。

[0151] In a specific example, in differential scanning calorimetry (DSC), the anhydrous form II can have a heat absorption onset temperature of 139.8 °C and exhibit a heat absorption peak at a heat absorption temperature of 149.4 °C.

[0152] The dihydrochloride form I of the compound of formula 1.

[0153] In an embodiment, the crystal form can be a crystal form of the dihydrochloride of the compound of formula 1.

[0154] In an embodiment, the crystal form of the compound of formula 1 can 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 dihydrochloride form I of the compound of formula 1. In another embodiment, the crystal form of the compound of formula 1 can comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of the dihydrochloride form I of the compound of formula 1. In some embodiments, the crystal form of the compound of formula 1 can comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of the dihydrochloride form I of the compound of formula 1.

[0155] The X-ray powder diffraction (XRPD) pattern of the dihydrochloride crystal form I of the compound of formula 1 can include peaks at diffraction angles 2θ of 8.2° ± 0.2°, 9.4° ± 0.2° and 19.1° ± 0.2°.

[0156] The XRPD pattern of the dihydrochloride crystal form I of the compound of formula 1 can further include at least one peak at a diffraction angle 2θ selected from 14.6° ± 0.2° and 26.2° ± 0.2°.

[0157] The XRPD pattern of the dihydrochloride crystal form I of the compound of formula 1 can further include 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°.

[0158] When irradiating the crystal form with a Cu-Kα light source the peaks at the diffraction angle 2θ can form an X-ray powder diffraction (XRPD) pattern.

[0159] The X-ray powder diffraction (XRPD) pattern of the dihydrochloride salt crystal form I of the compound of formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 peaks at diffraction angle 2θ, with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 5% or more.

[0160] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the dihydrochloride salt crystal form I of the compound of formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more or 45% or more.

[0161] In an embodiment, when irradiating the dihydrochloride salt crystal form I of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 8.2° ± 0.2°, 9.4° ± 0.2° and 19.1° ± 0.2°.

[0162] In an embodiment, when irradiating the dihydrochloride salt crystal form I of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0163] In an embodiment, when irradiating the dihydrochloride salt crystal form I of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the dihydrochloride salt crystal form further includes 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°.

[0164] The dihydrochloride salt crystal form may include peaks at the diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 13

[0165] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 13 .

[0166] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks of Table 6.

[0167] The dihydrochloride salt crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 25 .

[0168] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 25 .

[0169] In an embodiment, in differential scanning calorimetry (DSC), the dihydrochloride crystal form may exhibit an endothermic heat absorption peak starting at about 105 °C and having a peak maximum at about 139 °C, and an additional endothermic absorption peak starting at about 187 °C and having a peak maximum at about 202 °C.

[0170] In an embodiment, dihydrochloride crystal form I is an ethanol solvate.

[0171] Dihydrochloride form II of the compound of formula 1.

[0172] In an embodiment, the crystal 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 dihydrochloride form II of the compound of formula 1. In another embodiment, the crystal form of the compound of formula 1 may comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of dihydrochloride form II of the compound of formula 1. In some embodiments, the crystal 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 dihydrochloride form II of the compound of formula 1.

[0173] The X-ray powder diffraction (XRPD) pattern of dihydrochloride crystal form II of the compound of formula 1 may include peaks at diffraction angles 2θ of 10.5° ± 0.2°, 15.2° ± 0.2° and 23.1° ± 0.2°.

[0174] The XRPD pattern of dihydrochloride crystal form II of the compound of formula 1 may further include at least one peak at a diffraction angle 2θ selected from 22.3° ± 0.2° and 27.2° ± 0.2°.

[0175] The XRPD pattern of dihydrochloride crystal form II of the compound of formula 1 may further include 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°.

[0176] When irradiating the crystal form with a Cu-Kα light source the peaks at the diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0177] The X-ray powder diffraction (XRPD) pattern of the dihydrochloride salt polymorph II of the compound of formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at a diffraction angle 2θ, with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 5% or more.

[0178] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the dihydrochloride salt polymorph II of the compound of formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0179] In an embodiment, when irradiating the dihydrochloride salt polymorph II of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the polymorph includes peaks at diffraction angles 2θ of 10.5° ± 0.2°, 15.2° ± 0.2°, and 23.1° ± 0.2°.

[0180] In an embodiment, when irradiating the dihydrochloride salt polymorph II of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the polymorph includes 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°.

[0181] In an embodiment, when irradiating the dihydrochloride salt polymorph II of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the dihydrochloride salt polymorph further includes 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°.

[0182] The dihydrochloride salt polymorph may include peaks at the diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 14

[0183] In an embodiment, the XRPD pattern of the polymorph is substantially similar to Figure 14 .

[0184] In some embodiments, the XRPD pattern exhibited by the polymorph contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks of Table 7.

[0185] The dihydrochloride salt polymorph may exhibit the analysis results of differential scanning calorimetry (DSC) of the polymorph, as identified in Figure 26 .

[0186] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 26 .

[0187] In an embodiment, in differential scanning calorimetry (DSC), the dihydrochloride crystal form can exhibit an endothermic heat absorption peak starting at about 213 °C and having a peak maximum at about 239 °C.

[0188] Monohydrochloride form I of the compound of formula 1.

[0189] In an embodiment, the crystal form can be a crystal form of the monohydrochloride of the compound of formula 1.

[0190] In an embodiment, the crystal form of the compound of formula 1 can 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 of the compound of formula 1. In another embodiment, the crystal form of the compound of formula 1 can comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of the monohydrochloride of the compound of formula 1. In some embodiments, the crystal form of the compound of formula 1 can comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of the monohydrochloride of the compound of formula 1.

[0191] The X-ray powder diffraction (XRPD) pattern of the monohydrochloride crystal form of the compound of formula 1 can include peaks at diffraction angles 2θ of 17.1° ± 0.2°, 18.6° ± 0.2° and 23.5° ± 0.2°.

[0192] The XRPD pattern of the monohydrochloride crystal form of the compound of formula 1 can further include at least one peak at a diffraction angle 2θ selected from 19.0° ± 0.2° and 20.9° ± 0.2°.

[0193] The XRPD pattern of the monohydrochloride crystal form of the compound of formula 1 can further include 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°.

[0194] When irradiating the crystal form with a Cu-Kα light source the peaks at diffraction angle 2θ can form an X-ray powder diffraction (XRPD) pattern.

[0195] The X-ray powder diffraction (XRPD) pattern of the monohydrochloride crystal form of the compound of Formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at a diffraction angle 2θ, with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 5% or more.

[0196] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the monohydrochloride crystal form of the compound of Formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0197] In an embodiment, when irradiating the monohydrochloride crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 17.1° ± 0.2°, 18.6° ± 0.2°, and 23.5° ± 0.2°.

[0198] In an embodiment, when irradiating the monohydrochloride crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0199] In an embodiment, when irradiating the monohydrochloride crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the monohydrochloride crystal form further includes 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°.

[0200] The monohydrochloride crystal form may include peaks at a diffraction angle (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 15

[0201] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 15 .

[0202] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks of Table 8.

[0203] The monohydrochloride crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 27 .

[0204] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 27 .

[0205] In an embodiment, in differential scanning calorimetry (DSC), the monohydrochloride crystal form may exhibit an endothermic heat absorption peak starting at about 105 °C and having a peak maximum at about 121 °C.

[0206] The disulfate crystal form of the compound of formula 1.

[0207] In an embodiment, the crystal form may be the crystal form of the disulfate of the compound of formula 1.

[0208] In an embodiment, the crystal 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 of the compound of formula 1. In another embodiment, the crystal 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 of the compound of formula 1. In some embodiments, the crystal 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 of the compound of formula 1.

[0209] The X-ray powder diffraction (XRPD) pattern of the disulfate crystal form of the compound of formula 1 may include 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 disulfate crystal form of the compound of formula 1 may further include 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 disulfate crystal form in the form of the compound of formula 1 may further include 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] When irradiating the crystal form with a Cu-Kα light source the peaks at the diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0213] The X-ray powder diffraction (XRPD) pattern of the disulfate crystal form of the compound of formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 peaks at a diffraction angle 2θ, with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 5% or more.

[0214] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the disulfate crystal form of the compound of formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more or 45% or more.

[0215] In an embodiment, when the disulfate crystal form of the compound of formula 1 is irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 8.8° ± 0.2°, 11.4° ± 0.2° and 24.3° ± 0.2°.

[0216] In an embodiment, when the disulfate crystal form of the compound of formula 1 is irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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 an embodiment, when the disulfate crystal form of the compound of formula 1 is irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the disulfate crystal form further includes 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 disulfate crystal form may include peaks at a diffraction angle (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 16 .

[0219] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 16 .

[0220] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks in Table 9.

[0221] The disulfate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 28 .

[0222] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 28 .

[0223] In an embodiment, in differential scanning calorimetry (DSC), the disulfate crystal form can exhibit an endothermic heat absorption peak starting at about 79 °C and having a peak maximum at about 107 °C.

[0224] The monosulfate crystal form of the compound of Formula 1.

[0225] In an embodiment, the crystal form can be the crystal form of the monosulfate of the compound of Formula 1.

[0226] In an embodiment, the crystal form of the compound of Formula 1 can 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 of the compound of Formula 1. In another embodiment, the crystal form of the compound of Formula 1 can comprise greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of the monosulfate of the compound of Formula 1. In some embodiments, the crystal form of the compound of Formula 1 can comprise greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of the monosulfate of the compound of Formula 1.

[0227] The X-ray powder diffraction (XRPD) pattern of the monosulfate crystal form of the compound of Formula 1 includes peaks at diffraction angles 2θ of 8.8° ± 0.2°, 11.4° ± 0.2° and 24.3° ± 0.2°.

[0228] The XRPD pattern of the monosulfate crystal form of the compound of Formula 1 can further include at least one peak at a diffraction angle 2θ selected from 11.1° ± 0.2° and 15.2° ± 0.2°.

[0229] The XRPD pattern of the monosulfate crystal form in the form of the compound of Formula 1 can further include 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°.

[0230] When irradiating the crystal form with a Cu-Kα light source the peaks at the diffraction angle 2θ can form an X-ray powder diffraction (XRPD) pattern.

[0231] The X-ray powder diffraction (XRPD) pattern of the monosulfate crystal form of the compound of formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 peaks at a diffraction angle 2θ, with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 5% or more.

[0232] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the monosulfate crystal form of the compound of formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more or 45% or more.

[0233] In an embodiment, when irradiating the monosulfate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 8.8° ± 0.2°, 11.4° ± 0.2° and 24.3° ± 0.2°.

[0234] In an embodiment, when irradiating the monosulfate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0235] In an embodiment, when irradiating the monosulfate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the monosulfate crystal form further includes 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°.

[0236] The monosulfate crystal form may include peaks at a diffraction angle (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 17 .

[0237] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 17 .

[0238] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks in Table 10.

[0239] The monosulfate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 29 .

[0240] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 29 .

[0241] In an embodiment, in differential scanning calorimetry (DSC), the monosulfate crystal form may exhibit an endothermic heat absorption peak starting at about 244 °C and having a peak maximum at about 274 °C, and an additional endothermic absorption peak starting at about 187 °C and having a peak maximum at about 202 °C.

[0242] The monosulfate crystal form of the compound of Formula 1.

[0243] In an embodiment, the monosulfate crystal form may include peaks at diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 17 .

[0244] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 17 .

[0245] The monosulfate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 29 .

[0246] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 29 .

[0247] In an embodiment, in differential scanning calorimetry (DSC), the monosulfate crystal form may exhibit an endothermic heat absorption peak starting at about 244 °C and having a peak maximum at about 274 °C, and an additional endothermic absorption peak starting at about 187 °C and having a peak maximum at about 202 °C.

[0248] The difumarate crystal form of the compound of Formula 1.

[0249] In an embodiment, the crystal form may be the crystal form of the difumarate of the compound of Formula 1.

[0250] In an embodiment, the crystal 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 of the compound of Formula 1. In another embodiment, the crystal 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 of the compound of Formula 1. In some embodiments, the crystal 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 of the compound of Formula 1.

[0251] The X-ray powder diffraction (XRPD) pattern of the difumarate crystal form of the compound of Formula 1 may include peaks at diffraction angles 2θ of 22.9° ± 0.2°, 28.9° ± 0.2°, and 29.4° ± 0.2°.

[0252] The XRPD pattern of the difumarate crystal form of the compound of Formula 1 may further include at least one peak at a diffraction angle 2θ selected from 5.5° ± 0.2°, 8.5° ± 0.2°.

[0253] The XRPD pattern of the difumarate crystal form of the compound of Formula 1 may further include 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°.

[0254] When irradiating the crystal form with a Cu-Kα light source the peaks at diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0255] The X-ray powder diffraction (XRPD) pattern of the difumarate crystal form of the compound of Formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angle 2θ, the relative intensity of which (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) is 5% or more.

[0256] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the difumarate crystal form of the compound of Formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0257] In an embodiment, when irradiating the difumarate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 22.9° ± 0.2°, 28.9° ± 0.2°, and 29.4° ± 0.2°.

[0258] In an embodiment, when irradiating the difumarate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0259] In an embodiment, when irradiating the difumarate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the difumarate crystal form further comprises at least one peak at diffraction angles 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°.

[0260] The difumarate crystal form may comprise peaks at diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 18 ..

[0261] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 18 .

[0262] In some embodiments, the XRPD pattern exhibited by the crystal form comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks in Table 11.

[0263] The difumarate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 30 ..

[0264] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 30 .

[0265] In an embodiment, in differential scanning calorimetry (DSC), the difumarate crystal form may exhibit an endothermic heat absorption peak starting at about 149 °C and having a peak maximum at about 160 °C.

[0266] The hemifumarate crystal form of the compound of formula 1.

[0267] In an embodiment, the crystal form may be a crystal form of the hemifumarate of the compound of formula 1.

[0268] In an embodiment, the crystal 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 of the compound of formula 1. In another embodiment, the crystal 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 of the compound of formula 1. In some embodiments, the crystal 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 of the compound of formula 1.

[0269] The X-ray powder diffraction (XRPD) pattern of the hemifumarate crystal form of the compound of formula 1 may include peaks at diffraction angles 2θ of 6.8° ± 0.2°, 12.6° ± 0.2°, and 17.1° ± 0.2°.

[0270] The XRPD pattern of the hemifumarate crystal form of the compound of formula 1 may further include at least one peak at a diffraction angle 2θ selected from 10.2° ± 0.2° and 23.4° ± 0.2°.

[0271] The XRPD pattern of the hemifumarate crystal form of the compound of formula 1 may further include 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°.

[0272] When irradiating the crystal form with a Cu-Kα light source the peaks at diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0273] The X-ray powder diffraction (XRPD) pattern of the hemifumarate crystal form of the compound of formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angle 2θ, with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 5% or more.

[0274] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the hemifumarate crystal form of the compound of formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0275] In an embodiment, when irradiating the hemifumarate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 6.8° ± 0.2°, 12.6° ± 0.2°, and 17.1° ± 0.2°.

[0276] In an embodiment, when irradiating the hemifumarate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0277] In an embodiment, when irradiating the hemifumarate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the hemifumarate crystal form further includes 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°.

[0278] The hemifumarate crystal form may include peaks at the diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 19 .

[0279] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 19 .

[0280] In some embodiments, the XRPD pattern exhibited by the crystal form includes 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peaks in Table 12.

[0281] The hemifumarate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 31 .

[0282] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 31 .

[0283] In an embodiment, in differential scanning calorimetry (DSC), the hemifumarate crystal form may exhibit an endothermic heat absorption peak starting at about 266 °C and having a peak maximum at about 269 °C.

[0284] The monosuccinate crystal form of the compound of formula 1.

[0285] In an embodiment, the crystal form may be the crystal form of the monosuccinate of the compound of formula 1.

[0286] In an embodiment, the crystal form of the compound of formula 1 may contain 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 of the compound of formula 1. In another embodiment, the crystal form of the compound of formula 1 may contain greater than about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91% or 90% of the monosuccinate of the compound of formula 1. In some embodiments, the crystal form of the compound of formula 1 may contain greater than about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45% or 40% of the monosuccinate of the compound of formula 1.

[0287] The X-ray powder diffraction (XRPD) pattern of the monosuccinate crystal form of the compound of Formula 1 may include peaks at diffraction angles 2θ of 16.9° ± 0.2°, 18.5° ± 0.2°, and 23.6° ± 0.2°.

[0288] The XRPD pattern of the monosuccinate crystal form of the compound of Formula 1 may further include at least one peak at a diffraction angle 2θ selected from 6.9° ± 0.2° and 23.3° ± 0.2°.

[0289] The XRPD pattern of the monosuccinate crystal form of the compound of Formula 1 may further include 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°.

[0290] When irradiating the crystal form with a Cu-Kα light source the peaks at the diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0291] The X-ray powder diffraction (XRPD) pattern of the monosuccinate crystal form of the compound of Formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at the diffraction angle 2θ, and their relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) is 5% or more.

[0292] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the monosuccinate crystal form of the compound of Formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0293] In an embodiment, when irradiating the monosuccinate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 16.9° ± 0.2°, 18.5° ± 0.2°, and 23.6° ± 0.2°.

[0294] In an embodiment, when irradiating the monosuccinate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0295] In an embodiment, when irradiating the monosuccinate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the monosuccinate crystal form further comprises 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°.

[0296] The monosuccinate crystal form may comprise a peak at a diffraction angle (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 20 .

[0297] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 20 .

[0298] In some embodiments, the XRPD pattern exhibited by the crystal form comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks of Table 13.

[0299] The monosuccinate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 32 .

[0300] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 32 .

[0301] In an embodiment, in differential scanning calorimetry (DSC), the monosuccinate crystal form may exhibit an endothermic heat absorption peak starting at about 95 °C and having a peak maximum at about 116 °C, and an additional endothermic absorption peak starting at about 218 °C and having a peak maximum at about 220 °C.

[0302] The hemisuccinate crystal form of the compound of formula 1.

[0303] In an embodiment, the crystal form may be a crystal form of the hemisuccinate of the compound of formula 1.

[0304] In an embodiment, 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 of the compound of Formula 1. In another embodiment, 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 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 of the compound of Formula 1.

[0305] The X-ray powder diffraction (XRPD) pattern of the hemisuccinate crystalline form of the compound of Formula 1 may include peaks at diffraction angles 2θ of 6.9° ± 0.2°, 17.0° ± 0.2°, and 23.6° ± 0.2°.

[0306] The XRPD pattern of the hemisuccinate crystalline form of the compound of Formula 1 may further include at least one peak at a diffraction angle 2θ selected from 8.4° ± 0.2° and 12.6° ± 0.2°.

[0307] The XRPD pattern of the hemisuccinate crystalline form of the compound of Formula 1 may further include 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°.

[0308] When irradiating the crystalline form with a Cu-Kα light source the peaks at diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0309] The X-ray powder diffraction (XRPD) pattern of the hemisuccinate crystalline form of the compound of Formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angle 2θ, the relative intensity of which (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) is 5% or more.

[0310] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the hemisuccinate crystalline form of the compound of Formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0311] In an embodiment, when irradiating the hemisuccinate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 6.9° ± 0.2°, 17.0° ± 0.2°, and 23.6° ± 0.2°.

[0312] In an embodiment, when irradiating the hemisuccinate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0313] In an embodiment, when irradiating the hemisuccinate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the hemisuccinate crystal form further includes 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°.

[0314] The hemisuccinate crystal form may include peaks at diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 21 .

[0315] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 21 .

[0316] In some embodiments, the XRPD pattern exhibited by the hemisuccinate form includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks in Table 14.

[0317] The hemisuccinate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 33 .

[0318] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 33 .

[0319] In an embodiment, in differential scanning calorimetry (DSC), the hemisuccinate crystal form may exhibit an endothermic heat absorption peak with an onset of about 227 °C and a peak maximum of about 229 °C.

[0320] The dimaleate crystal form of the compound of Formula 1.

[0321] In an embodiment, the crystal form may be the crystal form of the dimaleate of the compound of Formula 1.

[0322] In an embodiment, 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 of the compound of Formula 1. In another embodiment, 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 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 of the compound of Formula 1.

[0323] The X-ray powder diffraction (XRPD) pattern of the dimaleate crystalline form of the compound of Formula 1 may include peaks at diffraction angles 2θ of 11.4° ± 0.2°, 12.2° ± 0.2°, and 27.4° ± 0.2°.

[0324] The XRPD pattern of the dimaleate crystalline form of the compound of Formula 1 may further include at least one peak at a diffraction angle 2θ selected from 7.1° ± 0.2° and 27.8° ± 0.2°.

[0325] The XRPD pattern of the dimaleate crystalline form of the compound of Formula 1 may further include 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°.

[0326] When irradiating the crystalline form with a Cu-Kα light source the peaks at diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0327] The X-ray powder diffraction (XRPD) pattern of the dimaleate crystalline form of the compound of Formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angle 2θ, with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 5% or more.

[0328] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the dimaleate crystalline form of the compound of Formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0329] In an embodiment, when irradiating the dimaleate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 11.4° ± 0.2°, 12.2° ± 0.2°, and 27.4° ± 0.2°.

[0330] In an embodiment, when irradiating the dimaleate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0331] In an embodiment, when irradiating the dimaleate crystal form of the compound of Formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the dimaleate crystal form further includes 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°.

[0332] The dimaleate crystal form may include peaks at diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 22

[0333] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 22 .

[0334] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks of Table 15.

[0335] The dimaleate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 34 .

[0336] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 34 .

[0337] In an embodiment, in differential scanning calorimetry (DSC), the dimaleate crystal form may exhibit an endothermic heat absorption peak starting at about 104 °C and having a peak maximum at about 121 °C.

[0338] The sesquimaleate crystal form of the compound of Formula 1.

[0339] In an embodiment, the crystal form may be the crystal form of the sesquimaleate of the compound of Formula 1.

[0340] In an embodiment, 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 sesquisuccinate of the compound of formula 1. In another embodiment, 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 sesquisuccinate 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 sesquisuccinate of the compound of formula 1.

[0341] The X-ray powder diffraction (XRPD) pattern of the sesquisuccinate crystalline form of the compound of formula 1 may include peaks at diffraction angles 2θ of 13.8° ± 0.2°, 17.1° ± 0.2°, and 18.5° ± 0.2°.

[0342] The XRPD pattern of the sesquisuccinate crystalline form of the compound of formula 1 may further include at least one peak at a diffraction angle 2θ selected from 8.9° ± 0.2° and 16.1° ± 0.2°.

[0343] The XRPD pattern of the sesquisuccinate crystalline form of the compound of formula 1 may further include 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°.

[0344] When irradiating the crystalline form with a Cu-Kα light source the peaks at diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0345] The X-ray powder diffraction (XRPD) pattern of the sesquisuccinate crystalline form of the compound of formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angle 2θ, the relative intensity of which (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) is 5% or more.

[0346] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the sesquisuccinate crystalline form of the compound of formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more, or 45% or more.

[0347] In an embodiment, when irradiating the sesquimaleate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 13.8° ± 0.2°, 17.1° ± 0.2°, and 18.5° ± 0.2°.

[0348] In an embodiment, when irradiating the sesquimaleate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0349] In an embodiment, when irradiating the sesquimaleate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the sesquimaleate crystal form further includes 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°.

[0350] The sesquimaleate crystal form may include peaks at diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 23 .

[0351] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 23 .

[0352] In some embodiments, the XRPD pattern exhibited by the crystal form contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks of Table 16.

[0353] The sesquimaleate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 35 .

[0354] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 35 .

[0355] In an embodiment, in differential scanning calorimetry (DSC), the sesquimaleate crystal form may exhibit an endothermic heat absorption peak starting at about 122 °C and having a peak maximum of about 136 °C.

[0356] The monomaleate crystal form of the compound of formula 1.

[0357] In an embodiment, the crystal form may be the crystal form of the monomaleate of the compound of formula 1.

[0358] In an embodiment, 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 monomaleate of the compound of Formula 1. In another embodiment, 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 monomaleate 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 monomaleate of the compound of Formula 1.

[0359] The X-ray powder diffraction (XRPD) pattern of the monomaleate crystalline form of the compound of Formula 1 may include peaks at diffraction angles 2θ of 6.9° ± 0.2°, 11.9° ± 0.2° and 24.0° ± 0.2°.

[0360] The XRPD pattern of the monomaleate crystalline form of the compound of Formula 1 may further include at least one peak at a diffraction angle 2θ selected from 9.6° ± 0.2° and 15.7° ± 0.2°.

[0361] The XRPD pattern of the monomaleate crystalline form of the compound of Formula 1 may further include 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°.

[0362] When irradiating the crystalline form with a Cu-Kα light source the peaks at the diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern.

[0363] The X-ray powder diffraction (XRPD) pattern of the monomaleate crystalline form of the compound of Formula 1 may include 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 peaks at the diffraction angle 2θ, the relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of which is 5% or more.

[0364] For example, the relative intensity (I / I0) of the peaks exhibited by the XRPD pattern of the monomaleate crystalline form of the compound of Formula 1 may be 5% or more, 10% or more, 15% or more, 19% or more, 20% or more, 40% or more or 45% or more.

[0365] In an embodiment, when irradiating the monomaleate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes peaks at diffraction angles 2θ of 6.9° ± 0.2°, 11.9° ± 0.2°, and 24.0° ± 0.2°.

[0366] In an embodiment, when irradiating the monomaleate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0367] In an embodiment, when irradiating the monomaleate crystal form of the compound of formula 1 with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the monomaleate crystal form further includes 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°.

[0368] The monomaleate crystal form may include peaks at the diffraction angles (2θ ± 0.2) of the X-ray powder diffraction (XRPD) spectrum identified in Figure 24 .

[0369] In an embodiment, the XRPD pattern of the crystal form is substantially similar to Figure 24 .

[0370] In some embodiments, the XRPD pattern exhibited by the crystal form includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 peaks of Table 17.

[0371] The monomaleate crystal form may exhibit the analysis results of differential scanning calorimetry (DSC) of the crystal form, as identified in Figure 36 .

[0372] In an embodiment, the DSC thermogram of the crystal form is substantially similar to Figure 36 .

[0373] In an embodiment, in differential scanning calorimetry (DSC), the monomaleate crystal form may exhibit an endothermic heat absorption peak starting at about 203 °C and having a peak maximum at about 207 °C.

[0374] On the other hand, a pharmaceutical composition is provided, which comprises the crystal form.

[0375] In a specific example, the pharmaceutical composition may be characterized by comprising at least one crystalline form of the compound of Formula 1 and at least one pharmaceutically acceptable carrier or diluent.

[0376] In a specific example, the crystalline form of the pharmaceutical composition may be substantially pure.

[0377] Examples of pharmaceutically acceptable carriers that may be included in the pharmaceutical composition include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspensions, emulsifiers, diluents, etc., but are not limited thereto.

[0378] Examples of diluents that may be included in the pharmaceutical composition include lactose, mannitol, sugars, microcrystalline cellulose and cellulose derivatives, and dry corn starch, but are not limited thereto.

[0379] The pharmaceutical composition can be formulated according to methods in the relevant art and can be prepared in various forms for oral administration, such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or in forms for parenteral administration, such as intramuscular, intravenous or subcutaneous injection.

[0380] When the pharmaceutical composition is prepared in injectable form, examples of carriers or diluents may include water, saline, aqueous glucose solution, aqueous sugar solution, alcohols, glycols, ethers (such as polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerol esters, surfactants, suspensions, emulsifiers, etc., but are not limited thereto.

[0381] As the active ingredient contained in the pharmaceutical composition, the effective amount of the crystalline form of the compound of Formula 1 for treating or preventing a disease in a subject or patient is administered orally or parenterally according to the purpose, and when administered orally, the amount of the pharmaceutical composition administered can be within a certain range such that the amount of the active ingredient administered can 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 1 kg body weight per day. In addition, when administered parenterally, the amount of the pharmaceutical composition administered can be within a certain range such that the amount of the active ingredient administered can be, for example, 0.01 mg to 100 mg or 0.1 mg to 50 mg per 1 kg body weight per day. The composition can be administered all at once or divided into several doses and administered in batches. The dose to be administered to the subject or patient should be determined according to various factors including the patient's body weight, age, gender, health, diet, time of administration, mode of administration, and severity of the disease, and it should be understood that the dose can be appropriately adjusted by an expert, and the above doses are not intended to limit the scope of the present invention in any way.

[0382] The composition can be administered 1 to 4 times a day by oral or parenteral routes or according to a dosing / withdrawal schedule. In some cases, doses below the above range may be appropriate, or higher doses may be used without causing harmful side effects, and in the case of higher doses, small doses can be administered in a series within a day.

[0383] The pharmaceutical composition provides a method for preventing or treating cancer. For example, the composition provides a method for preventing or treating cancer including leukemia by inhibiting FLT3 kinase activity.

[0384] The solid form of the compound of Formula 1 can effectively control one or more kinases involved in intracellular signal transduction and intracellular complex biological mechanisms. For example, the compound can act on receptor tyrosine kinases (RTKs) to effectively control the intracellular delivery of extracellular stimuli. In one embodiment, the compound can effectively control fms-like tyrosine kinase 3 (FLT3), which is often abnormally overexpressed or mutated in patients with leukemia, and spleen tyrosine kinase (SYK) acting on the signaling pathway of vascular endothelial growth factor receptor (VEGFR), which is involved in controlling the angiogenesis process, and other immune receptors such as B cell receptors and mast cells. The solid form of the present disclosure according to the embodiment effectively inhibits the mutation or overexpression of FLT3, and at the same time the overexpression or overactivation of VEGFR, thereby blocking the supply of nutrients and oxygen to the tumor and inhibiting SYK. Therefore, the compound can be used to treat acute myeloid leukemia (AML) that shows resistance to FLT3 inhibitors. As used herein, the term "overall survival (OV)" refers to the time period from random assignment to death in a clinical trial. FLT3-ITD positive acute myeloid leukemia (AML) is a disease with extremely low OV. SYK is overexpressed and activated in hematological malignancies, and highly activated SYK is usually seen in FLT3-ITD positive acute myeloid leukemia (AML) with extremely low OV. Therefore, as a target for treating AML disease, SYK needs to be regarded as an important factor together with FLT3.

[0385] The solid form of the present disclosure according to the embodiment shows effective selective inhibitory activity against SYK as well as FLT3, thereby greatly improving the treatment efficiency of acute myeloid leukemia (AML) and increasing the OV time.

[0386] The solid forms and pharmaceutical compositions of the present disclosure can be used in any number of methods. For example, in some embodiments, the solid forms and pharmaceutical compositions can be used in methods for modulating FLT3 kinase activity. In an embodiment, modulating FLT3 kinase activity is in mammalian cells. In an embodiment, modulating FLT3 kinase activity can be in a subject in need (e.g., a mammalian subject) and for treating the conditions or diseases described herein, including those diseases or conditions where inhibition of FLT3 kinase activity provides a therapeutic benefit to a subject suffering from the disease or condition.

[0387] In one embodiment, modulating FLT3 kinase activity is binding to the FLT3 kinase. In other embodiments, modulating FLT3 kinase activity is inhibiting the FLT3 kinase.

[0388] In an embodiment, the present disclosure provides a method for inhibiting FLT3 kinase activity in a subject in need, the method comprising administering an effective amount of a solid form of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, or a pharmaceutical composition comprising a solid form of a compound of Formula 1 or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt solvate thereof, including the crystalline and amorphous forms disclosed herein (e.g., the amorphous form, monohydrate form, trihydrate form, ethanol-monosolvate form, anhydrate Form I, anhydrate 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 as disclosed herein).

[0389] In one embodiment, the present disclosure provides a formulation for inhibiting FLT3 kinase activity. In another embodiment, the present disclosure provides a salt formulation for inhibiting FKT3 kinase activity. In another embodiment, the present disclosure provides a crystalline formulation for inhibiting FLT3 kinase activity. In another embodiment, the present disclosure provides an amorphous formulation for inhibiting FLT3 kinase activity.

[0390] The solid forms disclosed herein, such as crystalline and amorphous forms, exhibit excellent FLT3 inhibitory activity and, thus, in specific embodiments, can be effectively used to treat cell proliferative diseases caused by abnormal FLT3 activity, such as cancer, e.g., leukemia.

[0391] In an embodiment of the present disclosure, a method for treating a condition associated with cell proliferation in a patient in need is provided. In one embodiment, the present invention provides a method for treating cancer or a tumor, e.g., a solid tumor.

[0392] Cancer can include leukemia, such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), hairy cell leukemia, and chronic neutrophilic leukemia (CNL), etc.

[0393] In one embodiment, the cancer can be leukemia.

[0394] In one embodiment, the leukemia can include AML, ALL, or CML.

[0395] In an embodiment, the leukemia is AML. In an embodiment, the AML is AML with an FLT3 mutation. In a specific embodiment, the AML is mutant FLT3 polynucleotide-positive AML, FLT3 internal tandem duplication (ITD)-positive AML, and / or AML with an FLT3 point mutation.

[0396] In an embodiment, the cancer or leukemia comprises cancer cells having a mutation in the FLT3 gene. In an embodiment, the FLT3 gene has an internal tandem duplication (ITD) mutation. In an embodiment, the FLT3 gene has at least one FLT3 mutation selected from F691L, D835Y, D835F, D835I, D835H, D835V, and D835A.

[0397] In an embodiment, the cancer or leukemia comprises cancer cells having a mutation in the TKD (FLT3-TKD) having the amino acid sequence of FLT3. In an embodiment, the FLT3-TKD mutation can further comprise an ITD. In an embodiment, the cancer cells comprise a mutation selected from FLT3 (D835Y), FLT3 (F691L), FLT3 (F691L / D835Y), FLT3 (ITD / D835Y), FLT3 (ITD / F691L), and combinations thereof.

[0398] The FLT3-TKD mutation can comprise one amino acid mutation or multiple amino acid mutations at positions 823 to 861 of the FLT3 amino acid sequence. The TKD mutation can comprise a mutation of at least one amino acid selected from the group consisting of the amino acids at positions 835, 836, and 842 of the FLT3 amino acid sequence. For example, the TKD mutation can comprise a mutation of the amino acid at position 835 of the FLT3 amino acid sequence. For example, the TKD mutation can include a substitution of aspartic acid by valine, tyrosine, histidine, glutamic acid, or asparagine at position 835 of the FLT3 amino acid sequence. For example, the TKD mutation can include a substitution of isoleucine by leucine or aspartic acid at position 836 of the FLT3 amino acid sequence. For example, the TKD mutation can include a substitution of tyrosine by cysteine or histidine at position 842 of the FLT3 amino acid sequence. For example, the mutation can be FLT3(D835Y).

[0399] The FLT3-TKD mutation can have a mutation of at least one amino acid selected from the group consisting of the amino acids at positions 621, 627, 676, 691, and 697 of the FLT3 amino acid sequence. For example, the TKD mutation can have a substitution of phenylalanine by leucine at position 691 of the FLT3 amino acid sequence. For example, the mutation can be FLT3(F691L).

[0400] The TKD mutation can further include ITD. For example, the mutation can be FLT3(ITD / D835Y) or FLT3(ITD / F691L).

[0401] In an embodiment, the present disclosure provides a method for treating a cancer patient resistant to conventional therapeutic agents.

[0402] In an embodiment, the present disclosure provides a method for treating cancer, the cancer comprising a drug-resistant point mutant (D835Y, F691L, or F691L / D835Y) of FLT3 due to acquired D835Y and F691L point mutations in FLT3-TKD.

[0403] In one embodiment, the FLT3-TKD mutation is FLT3(D835V), FLT3(D835Y), FLT3(D835H), FLT3(D835E), FLT3(D835N), FLT3(F691L), FLT3(F691L / D835YLT), ITD / D835Y, FLT3(ITD / F691L), etc., and can include any one selected from the combinations thereof.

[0404] In some embodiments of any of the methods as disclosed herein, the compounds of the present invention or the compositions of the present invention are administered in combination with another therapeutic active agent. In some embodiments, the another therapeutic active agent is administered together with, sequentially, or separately from the compounds of the present invention or the compositions of the present invention. In some embodiments, the another therapeutic active agent is administered with the compounds of the present invention or the compositions of the present invention in the same or separate dosing regimens.

[0405] On the other hand, a method for preparing a monohydrate crystal form of a compound of formula 1 is provided:

[0406] [Formula 1]

[0407] The method comprises:

[0408] (a) Dissolving the compound of formula 1 in acetone;

[0409] (b) Heating and stirring solution (a); and

[0410] (c) Cooling, filtering and drying the stirred solution (b) to obtain a solid.

[0411] In a specific example, (a) may further comprise dropwise adding a small amount of water and mixing after dissolving the compound in acetone. The water may be added at room temperature.

[0412] (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.

[0413] The cooling in (c) may be cooling to room temperature. (c) may further comprise washing as needed. The washing liquid may be, for example, the solvent of (a), i.e., acetone. The drying in (c) may be carried out by a warm air flow of about 40 °C to about 60 °C.

[0414] On the other hand, a method for preparing a trihydrate crystal form of a compound of formula 1 is provided:

[0415] [Formula 1]

[0416] The method comprises:

[0417] (a) Dissolving the compound of formula 1 in ethyl acetate;

[0418] (b) Stirring solution (a) at room temperature; and

[0419] (c) Filtering and drying the stirred solution (b) to obtain a solid.

[0420] In a specific example, (b) may stir solution (a) at about 20 °C to about 25 °C.

[0421] (c) may further include washing as needed. The washing liquid may be, for example, the solvent of (a), i.e., ethyl acetate. Drying in (c) may be carried out by a warm air stream at about 40 °C to about 60 °C.

[0422] On the other hand, a method for preparing a crystalline form of a solvate of a compound of formula 1 is provided:

[0423] [Formula 1]

[0424] The method includes:

[0425] (a) Dissolving the compound of formula 1 in a pharmaceutically acceptable solvate, such as a C1 - C3 alcohol.

[0426] (b) Cooling and stirring the solution (a); and

[0427] (c) Filtering and drying the stirred solution (b) to obtain a solid.

[0428] In a specific example, the dissolution in (a) can be carried out at the reflux temperature. In a specific example, the dissolution in (a) can be carried out in ethanol.

[0429] In a specific example, the cooling in (b) can be cooling to room temperature. In a specific example, the stirring in (b) can be carried out for about 1 day to about 4 days.

[0430] In a specific example, (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 carried out by a warm air stream at about 40 °C to about 60 °C.

[0431] On the other hand, a method for preparing crystalline form I of the anhydrate of a compound of formula 1 is provided:

[0432] [Formula 1]

[0433] The method includes:

[0434] (a) Dissolving the compound of formula 1 in ethanol;

[0435] (b) Heating and stirring the solution (a); and

[0436] (c) Cooling, filtering and drying the stirred solution (b) to obtain a solid.

[0437] In a specific example, (a) may further include dropwise adding a small amount of water and mixing after dissolving the compound in ethanol. The water can be added at room temperature.

[0438] (b) The mixture (a) can be heated to about 40 °C to about 60 °C. The mixture can be stirred for about 10 hours to about 30 hours.

[0439] The cooling in (c) can be to room temperature. (c) can further include washing as needed. The washing liquid can be, for example, the solvent of (a), namely ethanol. The drying in (c) can be carried out by a warm air stream at about 40 °C to about 60 °C.

[0440] On the other hand, a method for preparing the anhydrous crystal form II of the compound of formula 1 is provided:

[0441] [Formula 1]

[0442] The method includes:

[0443] (a) Dissolving the compound of formula 1 in isopropanol;

[0444] (b) Stirring the solution (a) at room temperature; and

[0445] (c) Filtering and drying the stirred solution (b) to obtain a solid.

[0446] In a specific example, in (b), the mixture (a) can be stirred at a temperature of about 20 °C to about 25 °C.

[0447] (c) can further include washing as needed. The washing liquid can be, for example, the solvent of (a), namely isopropanol. The drying in (c) can be carried out by a warm air stream at about 40 °C to about 60 °C.

[0448] Reference Example

[0449] On the other hand, an amorphous form of the compound of formula 1 is provided:

[0450] [Formula 1]

[0451]

[0452] In a specific example, when irradiating the amorphous form of the compound of formula 1 with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the amorphous form does not exhibit peaks with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 10% or more.

[0453] In a specific example, when recording the results in differential scanning calorimetry (DSC) at a linear heating rate of 10 °C / minute, the amorphous form can show a heat absorption peak with a starting point of 80.7 °C and an ending point of 91.4 °C.

[0454] On the other hand, a pharmaceutical composition is provided, which includes the amorphous form of the compound of formula 1.

[0455] In a specific example, the pharmaceutical composition may be characterized by comprising at least one amorphous form of the compound of Formula 1 and at least one pharmaceutically acceptable carrier or diluent.

[0456] In a specific example, the cancer may be leukemia.

[0457] In a specific example, the leukemia may be acute myeloid leukemia, acute lymphoblastic leukemia or chronic myeloid leukemia.

[0458] In a specific example, the amorphous form of the pharmaceutical composition may be substantially pure.

[0459] The carrier or diluent that may be included in the pharmaceutical composition, the formulation of the pharmaceutical composition, the dosage and the method of treatment using the pharmaceutical composition are as described above.

[0460] On the other hand, a method for preparing an amorphous form of the compound of Formula 1 is provided:

[0461] [Formula 1]

[0462] The method comprises:

[0463] (d) Reacting the hydrochloride salt of the compound of Formula 1 in an alkaline reaction solution;

[0464] (e) Filtering the solution after reaction (d); and

[0465] (f) Drying the solution after filtering (e) to obtain a solid.

[0466] In a specific example, (d) may be carried out with stirring at room temperature. (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.

[0467] (e) may further include washing as needed. The washing liquid may be water.

[0468] The drying in (f) may be carried out by a warm air flow at a temperature of about 40 °C to about 60 °C.

[0469] Unless otherwise specified, those skilled in the art will understand that the peaks reported in the X-ray powder diffraction studies in the present disclosure are generally related to the experimental errors that can be observed in situ. Specifically, the peaks are interpreted as being within ±0.5° of the values reported herein. More specifically, the peaks are interpreted as being within ±0.2° of the values reported herein.

[0470] As used herein, the term "room temperature" refers to a range of 20 ± 5 °C.

[0471] As used herein, the term "reflux" means using a boiling point or slightly higher temperature.

[0472] As used herein, the term "substantially pure" means at least 95% pure or preferably 99% pure, and when 95% pure, 5% or less of the compound of formula 1 is present in any other form (other crystal forms, amorphous forms, etc.), and when 99% pure, 1% or less of the compound of formula 1 is present in any other form.

[0473] The numerical values described herein are considered to include the meaning of "about" even if not specified. As used herein, the term "about" means a value included within 5%, or preferably 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.

[0474] Expressions such as "has", "may have", "includes", or "may include" indicate the presence of a feature (e.g., a quantity or a component, such as a composition), and do not exclude the presence of other features.

[0475] Advantageous effects of the invention

[0476] The crystal form (hydrate, solvate or anhydrate) of the compound of formula 1 according to one aspect is excellent in terms of physicochemical properties required in pharmacy, that is, non-hygroscopicity to water, chemical stability, solubility, etc., and a pharmaceutical composition containing the same can be prepared more effectively for preventing or treating cancer.

[0477] In addition, the crystal form (hydrate, solvate or anhydrate) of the compound of formula 1 is also excellent in physicochemical properties compared to the amorphous form.

[0478] Furthermore, the crystal form of the hydrate according to a specific example is excellent in terms of reproducibility of preparation, purity, crystallinity, stability of the crystal form, chemical stability and non-hygroscopicity, and the crystal form of the monohydrate according to a specific example has particularly excellent non-hygroscopicity.

[0479] Therefore, the crystal form according to a specific example can be stably maintained for a long time without the need for special storage facilities or special storage conditions, and can improve the efficiency and stability of production, distribution, storage and preservation of pharmaceutical products. Description of the drawings

[0480] Figure 1The 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 "Compound of Formula 1") is shown.

[0481] Figure 2 The X-ray powder diffraction (XRPD) pattern of the monohydrate crystal form of the Compound of Formula 1 is shown.

[0482] Figure 3 The X-ray powder diffraction (XRPD) pattern of the trihydrate crystal form of the Compound of Formula 1 is shown.

[0483] Figure 4 The X-ray powder diffraction (XRPD) pattern of the ethanol monosolvate of the Compound of Formula 1 is shown.

[0484] Figure 5 The X-ray powder diffraction (XRPD) pattern of the anhydrous crystal form I of the Compound of Formula 1 is shown.

[0485] Figure 6 The X-ray powder diffraction (XRPD) pattern of the anhydrous crystal form II of the Compound of Formula 1 is shown.

[0486] Figure 7 The results of differential scanning calorimetry (DSC) of the amorphous form of the Compound of Formula 1 are shown.

[0487] Figure 8 The results of differential scanning calorimetry (DSC) of the monohydrate crystal form of the Compound of Formula 1 are shown.

[0488] Figure 9 The results of differential scanning calorimetry (DSC) of the trihydrate crystal form of the Compound of Formula 1 are shown.

[0489] Figure 10 The results of differential scanning calorimetry (DSC) of the ethanol monosolvate of the Compound of Formula 1 are shown.

[0490] Figure 11 The results of differential scanning calorimetry (DSC) of the anhydrous crystal form I of the Compound of Formula 1 are shown.

[0491] Figure 12 The results of differential scanning calorimetry (DSC) of the anhydrous crystal form II of the Compound of Formula 1 are shown.

[0492] Figure 13 The X-ray powder diffraction (XRPD) pattern of the dihydrochloride crystal form I of the Compound of Formula 1 is shown.

[0493] Figure 14 The X-ray powder diffraction (XRPD) pattern of crystalline form II of the dihydrochloride salt of the compound of formula 1 is shown.

[0494] Figure 15 The X-ray powder diffraction (XRPD) pattern of the monohydrochloride salt crystalline form of the compound of formula 1 is shown.

[0495] Figure 16 The X-ray powder diffraction (XRPD) pattern of the disulfate salt crystalline form of the compound of formula 1 is shown.

[0496] Figure 17 The X-ray powder diffraction (XRPD) pattern of the monosulfate salt crystalline form of the compound of formula 1 is shown.

[0497] Figure 18 The X-ray powder diffraction (XRPD) pattern of the difumarate salt crystalline form of the compound of formula 1 is shown.

[0498] Figure 19 The X-ray powder diffraction (XRPD) pattern of the hemifumarate salt crystalline form of the compound of formula 1 is shown.

[0499] Figure 20 The X-ray powder diffraction (XRPD) pattern of the monosuccinate salt crystalline form of the compound of formula 1 is shown.

[0500] Figure 21 The X-ray powder diffraction (XRPD) pattern of the hemisuccinate salt crystalline form of the compound of formula 1 is shown.

[0501] Figure 22 The X-ray powder diffraction (XRPD) pattern of the dimaleate salt crystalline form of the compound of formula 1 is shown.

[0502] Figure 23 The X-ray powder diffraction (XRPD) pattern of the sesquimaleate salt crystalline form of the compound of formula 1 is shown.

[0503] Figure 24 The X-ray powder diffraction (XRPD) pattern of the monomaleate salt crystalline form of the compound of formula 1 is shown.

[0504] Figure 25 The results of differential scanning calorimetry (DSC) of crystalline form I of the dihydrochloride salt of the compound of formula 1 are shown.

[0505] Figure 26 The results of differential scanning calorimetry (DSC) of crystalline form II of the dihydrochloride salt of the compound of formula 1 are shown.

[0506] Figure 27 The results of differential scanning calorimetry (DSC) of the monohydrochloride salt crystalline form of the compound of formula 1 are shown.

[0507] Figure 28 The results of differential scanning calorimetry (DSC) of the disulfate crystal form of the compound of formula 1 are shown.

[0508] Figure 29 The results of differential scanning calorimetry (DSC) of the monosulfate crystal form of the compound of formula 1 are shown.

[0509] Figure 30 The results of differential scanning calorimetry (DSC) of the difumarate crystal form of the compound of formula 1 are shown.

[0510] Figure 31 The results of differential scanning calorimetry (DSC) of the hemifumarate crystal form of the compound of formula 1 are shown.

[0511] Figure 32 The results of differential scanning calorimetry (DSC) of the monosuccinate crystal form of the compound of formula 1 are shown.

[0512] Figure 33 The results of differential scanning calorimetry (DSC) of the hemisuccinate crystal form of the compound of formula 1 are shown.

[0513] Figure 34 The results of differential scanning calorimetry (DSC) of the dimaleate crystal form of the compound of formula 1 are shown.

[0514] Figure 35 The results of differential scanning calorimetry (DSC) of the sesquimaleate crystal form of the compound of formula 1 are shown.

[0515] Figure 36 The results of differential scanning calorimetry (DSC) of the monomaleate crystal form of the compound of formula 1 are shown. Detailed Description

[0516] In the following, the present disclosure will be described in more detail.

[0517] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In addition, although preferred methods or samples are described herein, similar or equivalent methods or samples are also incorporated within the scope of the present disclosure. The content of all publications cited as references in this specification is incorporated by reference in its entirety into the present disclosure.

[0518] Compound of formula 1

[0519] There is provided 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 represented by formula 1:

[0520] [Formula 1]

[0521]

[0522] The compound of Formula 1 can be prepared by the methods described in Korean Patent Publication No. 10-1954370 and the international publication of International Application No. 2020-022600, and these documents are incorporated herein by reference in their entirety.

[0523] Test Examples: Analytical Devices and Measuring Methods

[0524] 1. X-ray Powder Diffraction (XRPD)

[0525] X-ray powder diffraction (XRPD) analysis was performed at a diffraction angle 2θ of 3° to 40° using a D8 Advance (Bruker ASX, Germany) analyzer. When the amount of the sample was < 100 mg, about 5 mg to 10 mg of the sample was gently pressed onto a glass slide mounted on a sample holder. When the amount of the sample was > 100 mg, about 100 mg of the sample was gently pressed onto a plastic sample holder such that the sample surface was smooth and just above the level of the sample holder.

[0526] The measurement was carried out as follows:

[0527] Anode material (Ka): Cu-Kα

[0528] Scanning range: 3° to 40°

[0529] Generator settings: 100 mA, 40.0 kV

[0530] Scanning speed: 1 second / step

[0531] Divergence slit: 0.3°

[0532] Anti-scattering slit: 0.3°

[0533] Temperature: 20 °C

[0534] Step size: 0.02 angle 2θ

[0535] Rotation: Used

[0536] Goniometer radius: 435 mm

[0537] 2. Differential Scanning Calorimetry (DSC)

[0538] Differential scanning calorimetry (DSC) analysis was performed using a STA-1000 analyzer (Scinco, Korea) at 30 °C to 350 °C. When weighing, 5 mg to 10 mg of the sample was added to an aluminum DSC pan, 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.

[0539] 3. Dynamic vapor sorption (DVS)

[0540] DVS analysis was performed using a DVS Advantage analyzer (Surface Measurement System, United Kingdom) at 25 °C and a relative humidity of 0% to 90%. 10 mg of the sample was placed in a wire mesh vapor sorption balance pan and mounted on a DVS Advantage dynamic vapor sorption balance (Surface Measurement System). The sample was applied to a temperature rise curve with a relative humidity (RH) of 10% to 90%, and the sample was increased by 10% while maintaining the sample at each step until a stable weight was reached (99.5% of the weight change was completed in one step). After the adsorption cycle was completed, the sample was dried in the same manner, and the relative humidity was reduced by 0% after each step. The weight change during the adsorption / desorption cycle was recorded (repeated 3 times) to measure the hygroscopicity of the sample.

[0541] 4. High performance liquid chromatography (HPLC)

[0542] High performance liquid chromatography (HPLC) analysis was performed using an Agilent 1100 / 1200 series HPLC system analyzer (Agilent, United States) to analyze purity and content, such as stability testing, and the analysis conditions were as follows.

[0543] Purity and content analysis conditions: Furanopyrimidine compound of formula 1

[0544] Column: Hydrosphere C18 (YMC), 5 μm (150 mm × 4.6 mm)

[0545] Column temperature: 30 °C

[0546] Detector: Ultraviolet absorption photometer

[0547] Detection wavelength: 254 nm

[0548] Flow rate: 1.0 mL / min

[0549] Analysis time: 35 minutes

[0550] Eluent: NaClO4 - NaH2PO4 - phosphate buffer solution (pH 2.5 ± 0.1) / CH3CN = 65 / 35 (v / v%)

[0551] 5. Measurement of moisture

[0552] The measurement of moisture was carried out by using a Karl Fischer titrator 795 KFT Titrino (Metrohm, Switzerland).

[0553] Hereinafter, the present disclosure will be described in more detail by way of examples. However, these examples are intended to illustrate the present disclosure, and the scope of the present disclosure is not limited thereto.

[0554] According to the methods disclosed in Korean Patent Publication No. 10 - 1954370 and the international publication of International Application No. 2020 - 022600, a mixture comprising the compound of Formula 1 was prepared.

[0555] Example 1: Preparation of the 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.

[0556] 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 stirred for about 3.5 hours. The resulting solid was filtered to obtain 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 hydrochloride. The resulting hydrochloride was slowly added to an aqueous sodium bicarbonate solution (about 1.2 M, 2.2 L), and stirred at room temperature for about 13 hours. The resulting solid was obtained by filtration and washed with water. The resulting solid was dried with a warm air stream at 50 °C to obtain 72 g (84%) of the compound of interest.

[0557] Moisture content (Karl Fischer titrator): about 2.3%

[0558] Characterization analysis

[0559] The XRPD results of the amorphous form are shown in Figure 1 .

[0560] Figure 1Shows the results of 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 "Compound of Formula 1").

[0561] As Figure 1 shown, when the amorphous form of the Compound of Formula 1 was irradiated with a Cu-Kα light source, in the X-ray powder diffraction (XRPD) pattern, the amorphous form did not exhibit peaks with a relative intensity (I / I0: I is the intensity of each peak; I0 is the intensity of the highest peak) of 10% or more.

[0562] Figure 7 Shows the results of differential scanning calorimetry (DSC) of the amorphous form of the Compound of Formula 1.

[0563] The DSC (10 °C / min) results of the amorphous form showed an endothermic peak with a starting point of 80.7 °C and a bottom point of 91.4 °C, and the absorption peak at 91.4 °C indicates the melting point.

[0564] In a Karl Fischer titrator, the amorphous form showed a water content of approximately 2.3%.

[0565] In the DVS of the amorphous form, in the region of relative humidity from 0% to 90%, the measured hygroscopicity was approximately 5%.

[0566] Example 2: Preparation of the monohydrate crystal 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.

[0567] 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 obtained solid was dried with a warm air stream at 50 °C to obtain 195 g (78%) of the compound of interest.

[0568] Water content (Karl Fischer titrator): approximately 3.5%

[0569] Characterization analysis

[0570] The XRPD results of the monohydrate crystal form prepared in Example 1 are shown in Table 1 andFigure 2 In

[0571] In the XRPD spectrum of the monohydrate crystal form, the peaks with a relative intensity (I / I0) of 5% or more are shown in Table 1 below.

[0572] [Table 1]

[0573]

[0574] Table 1 and Figure 2 show the XRPD analysis results of the monohydrate crystal form of the compound of formula 1. As shown in Table 1 and Figure 2 as shown, the X-ray powder diffraction (XRPD) spectrum shown by the monohydrate crystal form of the compound of formula 1 includes peaks with I / I0 of 10% or more 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°.

[0575] In addition, as shown in Table 1 and Figure 2 as shown, the X-ray powder diffraction spectroscopy (XRPD) spectrum shown by the monohydrate crystal form of the compound of formula 1 further includes peaks with I / I0 of 5% or more 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°.

[0576] Figure 8 show the analysis results of differential scanning calorimetry (DSC) of the monohydrate crystal form of the compound of formula 1.

[0577] The DSC (10 °C / min) results of the crystal form show an endothermic peak with a starting point of 74.9 °C and a bottom point of 89.0 °C and an 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 crystal form, and the absorption peak at about 161.6 °C indicates the melting point.

[0578] In a Karl Fischer titrator, the crystal form shows a water content of about 3.5% (the theoretical water content is 3.5%).

[0579] The DVS (10 °C / min) analysis results of the crystal form show that there is moisture absorption in the region of relative humidity from 0% to 20%, but in the region of relative humidity of 30% or more, the level of moisture absorption is very low. The crystal form is sufficiently stable under accelerated conditions (e.g., a temperature of 40 °C and a relative humidity of 75%) and stress conditions (e.g., a temperature of 60 °C).

[0580] Example 3: Preparation of the trihydrate crystal 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

[0581] Dissolve 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) in ethyl acetate (50 mL). Stir the mixed solution at a temperature of 20 °C to 25 °C for about 7 hours. Obtain the resulting solid by filtration and wash it with ethyl acetate. Dry the obtained solid with a warm air stream at 50 °C to obtain 4.3 g (86%) of the compound of interest.

[0582] Moisture content (Karl Fischer titrator): about 10.8%

[0583] Characterization analysis

[0584] The XRPD results of the trihydrate crystal form prepared in Example 2 are shown in Table 2 and Figure 3 in.

[0585] In the XRPD spectrum of the trihydrate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in Table 2 below.

[0586] [Table 2]

[0587]

[0588] Table 2 and Figure 3 show the XRPD analysis results of the trihydrate crystal form of the compound of formula 1.

[0589] As shown in Table 2 and Figure 3 in, the X-ray powder diffraction (XRPD) spectrum shown by the trihydrate crystal form of the compound of formula 1 includes peaks with I / I0 of 15% or more 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°.

[0590] Figure 9 show the analysis results of differential scanning calorimetry (DSC) of the trihydrate crystal form of the compound of formula 1.

[0591] The DSC (10 °C / min) results of the crystal form showed an endothermic peak with a starting point at 44.9 °C and a bottom point at 68.7 °C, as well as an absorption peak at approximately 108.3 °C. In the DSC results, the absorption peak at approximately 68.7 °C indicates the dehydration point of the trihydrate crystal form, and the absorption peak at approximately 108.3 °C indicates the melting point.

[0592] In a Karl Fischer titrator, the crystal form showed a water content of approximately 10.8% (the theoretical water content is 9.7%).

[0593] In the DVS of the crystal form, in the region of relative humidity from 0% to 90%, the measured hygroscopicity was approximately 12%. The crystal form was sufficiently stable under accelerated conditions (e.g., a temperature of 40 °C and a relative humidity of 75%) and stress conditions (e.g., a temperature of 60 °C).

[0594] Example 4: Preparation of a crystal 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.

[0595] 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 placed in ethanol (10 mL) and dissolved by refluxing. The solution was cooled to room temperature and stirred for about 3 days. The resulting solid was obtained by filtration and washed with ethanol. The obtained solid was dried with a warm air stream at 50 °C to obtain 0.6 g (60%) of the compound of interest.

[0596] Water content (Karl Fischer titrator): approximately 0.2%

[0597] Characterization analysis

[0598] The XRPD results of the crystal form of the ethanol monosolvate prepared in Example 3 are shown in Table 3 and Figure 4 in.

[0599] In the XRPD spectrum of the crystal form of the ethanol monosolvate, the peaks with a relative intensity (I / I0) of 10% or more are shown in Table 3.

[0600] [Table 3]

[0601]

[0602]

[0603] Table 3 and Figure 4 show the XRPD analysis results of the crystal form of the ethanol monosolvate of the compound of formula 1. As shown in Table 3 andFigure 4 As shown in Figure 4 , the X-ray powder diffraction (XRPD) spectrum of the crystalline form of the ethanol monosolvate of the compound of formula 1 includes peaks with I / I0 of 40% or more 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°.

[0604] Figure 10 The differential scanning calorimetry (DSC) analysis results of the crystalline form of the ethanol monosolvate of the compound of formula 1 are shown.

[0605] The DSC (10 °C / min) results of the crystalline form show an endothermic peak with a start point of 99.8 °C and a bottom point 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.

[0606] In a Karl Fischer titrator, the crystalline form shows a water content of about 0.2%.

[0607] In the DVS of the crystalline form, in the region of relative humidity from 0% to 90%, the measured hygroscopicity is as low as about 0.3%. The crystalline form is sufficiently stable under accelerated conditions (e.g., a temperature of 40 °C and a relative humidity of 75%) and stress conditions (e.g., a temperature of 60 °C).

[0608] Example 5: Preparation of the 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.

[0609] Dissolve 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) in ethanol (8 L), and add water (2 mL) dropwise at room temperature. Heat the mixture to 50 °C and stir for about 30 minutes. Cool the solution to a temperature of 20 °C to 25 °C and stir for 5 hours. Obtain the resulting solid by filtration and wash it with 80% ethanol. Dry the obtained solid with a warm air stream at 50 °C to obtain 0.8 g (81%) of the compound of interest.

[0610] Water content (Karl Fischer titrator): about 0.2%

[0611] Characterization analysis

[0612] The XRPD results of the anhydrous form I prepared in Example 4 are shown in Table 4 and Figure 5 . In the XRPD spectrum of the anhydrous form I, the peaks with a relative intensity (I / I0) of 10% or more are shown in Table 4 below.

[0613] [Table 4]

[0614]

[0615] Table 4 and Figure 5 show the XRPD analysis results of the anhydrous 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 "Compound of Formula 1"). As shown in Table 4 and Figure 5 , the X-ray powder diffraction (XRPD) spectrum shown by the anhydrous form I of the Compound of Formula 1 includes peaks with I / I0 of 15% or more 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°.

[0616] Figure 11 show the analysis results of differential scanning calorimetry (DSC) of the anhydrous form I of the Compound of Formula 1;

[0617] The DSC (10 °C / min) results of the crystal form show an endothermic peak with a starting point of about 152.4 °C and a bottom point of about 159.5 °C. The absorption peak at about 159.5 °C indicates the melting point.

[0618] In a Karl Fischer titrator, the crystal form shows a water content of about 0.2%.

[0619] In the DVS of the crystal form, in the region of relative humidity from 0% to 90%, the measured hygroscopicity is about 3.5%. The crystal form is sufficiently stable under accelerated conditions (e.g., a temperature of 40 °C and a relative humidity of 75%) and stress conditions (e.g., a temperature of 60 °C).

[0620] Example 6: Preparation of the anhydrous 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.

[0621] 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 a temperature of 20 °C to 25 °C for about 3 days. The resulting solid was obtained by filtration and washed with isopropanol. The obtained solid was dried with a warm air stream at 50 °C to obtain 1.7 g (85%) of the compound of interest.

[0622] Water content (Karl Fischer titrator): about 0.5%

[0623] Characterization analysis

[0624] The XRPD results of the anhydrous form II prepared in Example 5 are shown in Table 5 and Figure 6 In the XRPD spectrum of the anhydrous form II, the peaks with a relative intensity (I / I0) of 10% or more are shown in Table 5 below.

[0625] [Table 5]

[0626]

[0627] Table 5 and Figure 6 show the XRPD analysis results of the anhydrous form II of the compound of formula 1. As shown in Table 5 and Figure 6 The X-ray powder diffraction (XRPD) spectrum shown by the anhydrous form II of the compound of formula 1 includes peaks with I / I0 of 20% or more 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°.

[0628] Figure 12 show the differential scanning calorimetry (DSC) analysis results of the anhydrous form II of the compound of formula 1.

[0629] The DSC (10 °C / min) results of the crystal form showed an endothermic peak with a starting point of about 139.8 °C and a bottom point of about 149.4 °C. The absorption peak at about 149.4 °C indicates the melting point.

[0630] In the Karl Fischer titrator, the crystal form showed a water content of about 0.5%.

[0631] In the DVS of the crystal form, in the region of relative humidity from 0% to 90%, the measured hygroscopicity is as low as about 0.5%. The crystal form is sufficiently stable under accelerated conditions (e.g., a temperature of 40 °C and a relative humidity of 75%) and stress conditions (e.g., a temperature of 60 °C).

[0632] Example 7: Preparation of the dihydrochloride crystal 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.

[0633] 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 charged into a flask, and then 38 mL of an 80% aqueous ethanol solution was added. The reaction mixture was refluxed for 1 hour and then cooled to room temperature (20 - 25 °C). The mixture was stirred overnight at room temperature (20 - 25 °C). The resulting solid was filtered and then washed with 8 mL of an 80% aqueous ethanol solution. The wet solid was dried overnight in an oven at 50 °C.

[0634] Moisture content (Karl Fischer titrator): about 3.4%

[0635] Characterization analysis

[0636] The XRPD results of the dihydrochloride crystal form I prepared in Example 7 are shown in Table 6 and Figure 13 in.

[0637] In the XRPD spectrum of the dihydrochloride crystal form I, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0638] [Table 6]

[0639]

[0640]

[0641] The dihydrochloride crystal form I was identified as an ethanol solvate. Figure 25 The differential scanning calorimetry (DSC) analysis results of the dihydrochloride crystal form I of the compound of formula 1 are shown.

[0642] The DSC (10 °C / min) results of the crystal form showed an endothermic heat absorption peak with an onset of 105 °C and a peak maximum of 139 °C, and an additional endothermic absorption peak with an onset of 187 °C and a peak maximum of 202 °C.

[0643] Example 8: Preparation of Crystal Form II of Dihydrochloride 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

[0644] Charge 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 into a flask, and then add 30 mL of ethanol. Reflux the reaction mixture for 1 hour, and then cool to room temperature (20 - 25 °C). Stir the mixture at room temperature (20 - 25 °C) for 6 hours. Filter the resulting solid, and then wash it with 6 mL of ethanol. Dry the wet solid in an oven at 50 °C overnight.

[0645] Moisture content (Karl Fischer titrator): about 0.5%.

[0646] Characterization analysis

[0647] The XRPD results of the dihydrochloride crystal form II prepared in Example 8 are shown in Table 7 and Figure 14 in.

[0648] In the XRPD spectrum of the dihydrochloride crystal form II, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0649] [Table 7]

[0650]

[0651]

[0652] Figure 26 The differential scanning calorimetry (DSC) analysis results of the dihydrochloride crystal form II of the compound of Formula 1 are shown. The DSC (10 °C / min) results of the dihydrochloride crystal form II of the compound of Formula 1 show an endothermic heat absorption peak with an onset at 213 °C and a peak maximum at 239 °C.

[0653] Example 9: Preparation of Crystal Form of Monohydrochloride 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

[0654] 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 charged into a flask, and then 50 mL of acetone was added. 0.97 mL of concentrated 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 in an oven at 50 °C overnight.

[0655] Moisture content (Karl Fischer titrator): about 3.7%.

[0656] Characterization analysis

[0657] The XRPD results of the monohydrochloride crystal form prepared in Example 9 are shown in Table 8 and Figure 15 in.

[0658] In the XRPD spectrum of the monohydrochloride crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0659] [Table 8]

[0660]

[0661] Figure 27 The differential scanning calorimetry (DSC) analysis results of the monohydrochloride crystal form of the compound of formula 1 are shown. The DSC (10 °C / min) results of the monohydrochloride crystal form of the compound of formula 1 show an endothermic heat absorption peak with an onset of 105 °C and a peak maximum of 121 °C.

[0662] Example 10: Preparation of the disulfate crystal 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.

[0663] 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 in an oven at 50 °C overnight. 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.

[0664] Moisture content (Karl Fischer titrator): approximately 5.4%

[0665] Characterization analysis

[0666] The XRPD results of the disulfate crystal form prepared in Example 10 are shown in Table 9 and Figure 16 in

[0667] In the XRPD spectrum of the disulfate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table

[0668] [Table 9]

[0669]

[0670] Figure 28 The differential scanning calorimetry (DSC) analysis results of the disulfate crystal form of the compound of Formula 1 are shown. The DSC (10 °C / min) results of the disulfate crystal form of the compound of Formula 1 show an endothermic heat absorption peak with an onset of 79 °C and a peak maximum of 107 °C

[0671] Example 11: Preparation of the monosulfate crystal 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

[0672] 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. 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 in an oven at 50 °C overnight

[0673] Moisture content (Karl Fischer titrator): approximately 6.8%

[0674] Characterization analysis

[0675] The XRPD results of the monosulfate crystal form prepared in Example 11 are shown in Table 10 and Figure 17 in

[0676] In the XRPD spectrum of the monosulfate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table

[0677] [Table 10]

[0678]

[0679] Figure 29 The differential scanning calorimetry (DSC) analysis results of the monosulfate crystal form of the compound of formula 1 are shown. The DSC (10 °C / min) results of the monosulfate crystal form of the compound of formula 1 show an endothermic heat absorption peak with an onset at 244 °C and a peak maximum at 274 °C.

[0680] Example 12: Preparation of the difumarate crystal 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.

[0681] 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 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 overnight in an oven at 50 °C.

[0682] Moisture content (Karl Fischer titrator): about 1.5%

[0683] Characterization analysis

[0684] The XRPD results of the difumarate crystal form prepared in Example 12 are shown in Table 11 and Figure 18 in.

[0685] In the XRPD spectrum of the difumarate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0686] [Table 11]

[0687]

[0688] Figure 30 The differential scanning calorimetry (DSC) analysis results of the difumarate crystal form of the compound of formula 1 are shown. The DSC (10 °C / min) results of the difumarate crystal form of the compound of formula 1 show an endothermic heat absorption peak with an onset at 149 °C and a peak maximum at 160 °C.

[0689] Example 13: Preparation of the hemifumarate crystal 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.

[0690] 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 charged into a flask, and then 30 mL of 80% aqueous ethanol solution was added. The mixture was refluxed (dissolving and precipitating the solid). The reaction mixture was cooled to room temperature and then stirred at room temperature for 5 hours (20 - 25 °C). The resulting solid was filtered and then washed with 6 mL of 80% aqueous ethanol solution. The wet solid was dried overnight in an oven at 50 °C.

[0691] Water content (Karl Fischer titrator): about 0.1%.

[0692] Characterization analysis

[0693] The XRPD results of the hemifumarate crystal form prepared in Example 13 are shown in Table 12 and Figure 19 in.

[0694] In the XRPD spectrum of the hemifumarate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0695] [Table 12]

[0696]

[0697] Figure 31 The differential scanning calorimetry (DSC) analysis results of the hemifumarate crystal form of the compound of formula 1 are shown. The DSC (10 °C / min) results of the hemifumarate crystal form of the compound of formula 1 show an endothermic heat absorption peak with an onset at 266 °C and a peak maximum at 269 °C.

[0698] Example 14: Preparation of the monosuccinate crystal 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.

[0699] 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 (immediately precipitating the solid). 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.

[0700] Water content (Karl Fischer titrator): about 1.8%.

[0701] Characterization analysis

[0702] The XRPD results of the monosuccinate crystal form prepared in Example 14 are shown in Table 13 and Figure 20 below.

[0703] In the XRPD spectrum of the monosuccinate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0704] [Table 13]

[0705]

[0706] Figure 32 The differential scanning calorimetry (DSC) analysis results of the monosuccinate crystal form of the compound of formula 1 are shown. The DSC (10 °C / min) results of the monosuccinate crystal form of the compound of formula 1 show an endothermic heat absorption peak with an onset of 95 °C and a peak maximum of 116 °C, and an additional endothermic absorption peak with an onset of 218 °C and a peak maximum of 220 °C.

[0707] Example 15: Preparation of the hemisuccinate crystal 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.

[0708] 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 charged into a flask, and then 20 mL of an 80% aqueous ethanol solution was added. The mixture was refluxed (undissolved). The mixture was cooled to room temperature (20 - 25 °C). The mixture was stirred overnight at room temperature. The resulting solid was filtered and then washed with 4 mL of ethanol. The wet solid was dried overnight in an oven at 50 °C.

[0709] Moisture content (Karl Fischer titrator): about 0.3%.

[0710] Characterization analysis

[0711] The XRPD results of the hemisuccinate crystal form prepared in Example 15 are shown in Table 14 and Figure 21 below.

[0712] In the XRPD spectrum of the hemisuccinate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0713] [Table 14]

[0714]

[0715] Figure 33 The analysis results of differential scanning calorimetry (DSC) of the hemisuccinate crystal form of the compound of formula 1 are shown. The DSC (10 °C / min) results of the monosuccinate crystal form of the compound of formula 1 show an endothermic heat absorption peak starting at 227 °C and having a peak maximum at 229 °C.

[0716] Example 16: Preparation of the dimaleate crystal 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.

[0717] 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 charged into a flask, and then 50 mL of ethanol was added. 2.61 g of maleic acid was added to the mixture, and then the mixture was stirred overnight (no precipitation). The solution was concentrated under reduced pressure, and 25 mL of ethanol was added. The mixture was stirred overnight at room temperature (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. Moisture content (Karl Fischer titrator): approximately 3.4%.

[0718] Characterization analysis.

[0719] The XRPD results of the dimaleate crystal form prepared in Example 16 are shown in Table 15 and Figure 22 and

[0720] In the XRPD spectrum of the dimaleate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0721] [Table 15]

[0722]

[0723] Figure 34 The analysis results of differential scanning calorimetry (DSC) of the dimaleate crystal form of the compound of formula 1 are shown. The DSC (10 °C / min) results of the dimaleate crystal form of the compound of formula 1 show an endothermic heat absorption peak starting at 104 °C and having a peak maximum at 121 °C.

[0724] Example 17: Preparation of sesquisemicarbamate crystal 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.

[0725] Charge 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 dimaleate into a flask, and then add 6.5 mL of ethanol. Reflux the mixture (dissolve and precipitate the solid). Cool the reaction mixture to room temperature (20 - 25 °C), and then stir for 4 hours. Filter the resulting solid, and then wash it with 1.3 mL of ethanol. Dry the wet solid in an oven at 50 °C overnight.

[0726] Moisture content (Karl Fischer titrator): approximately 3.0%

[0727] Characterization analysis

[0728] The XRPD results of the sesquisemicarbamate crystal form prepared in Example 17 are shown in Table 16 and Figure 23 in.

[0729] In the XRPD spectrum of the sesquisemicarbamate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0730] [Table 16]

[0731]

[0732] Figure 35 The differential scanning calorimetry (DSC) analysis results of the sesquisemicarbamate crystal form of the compound of Formula 1 are shown. The DSC (10 °C / min) results of the sesquisemicarbamate crystal form of the compound of Formula 1 show an endothermic heat absorption peak with an onset at 122 °C and a peak maximum at 136 °C.

[0733] Example 18: Preparation of monomaleate crystal 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.

[0734] 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 monomaleate was charged into 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.

[0735] Water content (Karl Fischer titrator): about 0.2%.

[0736] Characterization analysis

[0737] The XRPD results of the monomaleate crystal form prepared in Example 18 are shown in Table 17 and Figure 24 in.

[0738] In the XRPD spectrum of the monomaleate crystal form, the peaks with a relative intensity (I / I0) of 10% or more are shown in the following table.

[0739] [Table 17]

[0740]

[0741] Figure 36 The differential scanning calorimetry (DSC) analysis results of the monomaleate crystal form of the compound of Formula 1 are shown. The DSC (10 °C / min) results of the monomaleate crystal form of the compound of Formula 1 show an endothermic heat absorption peak with an onset at 203 °C and a peak maximum at 207 °C. Those skilled in the art will understand that various changes can be made without departing from the spirit and scope of the present disclosure. Therefore, the exemplary examples disclosed herein should be considered from an illustrative rather than a restrictive aspect. The scope of the present disclosure is defined by the claims rather than the foregoing description, and all differences within the scope of their equivalents should be construed as being included in the present disclosure.

[0742] Examples

[0743] Example 1. A crystal form of a compound of Formula 1:

[0744] [Formula 1]

[0745]

[0746] Example 2. The crystal form according to Example 1, wherein the crystal form is a crystal form of a hydrate of the compound of Formula 1.

[0747] Example 3. The crystal form according to Example 2, wherein when irradiated with a Cu-Kα light source, the characteristic X-ray powder diffraction (XRPD) pattern of the crystal form includes 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°.

[0748] Example 4. The crystal form according to Example 3, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the crystal form further includes at least one peak at a diffraction angle 2θ selected from 11.0° ± 0.2°, 11.7° ± 0.2°, and 17.9° ± 0.2°.

[0749] Example 5. The crystal form according to Example 4, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the crystal form further includes 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°.

[0750] Example 6. The crystal form according to Example 2, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the crystal form includes 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.

[0751] Example 7. The crystal form according to Example 6, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the crystal form further includes 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°.

[0752] Example 8. The crystal form according to Example 2 or 3, wherein the hydrate is a monohydrate.

[0753] Example 9. The crystal form according to Example 2 or 6, wherein the hydrate is a trihydrate.

[0754] Example 10. The crystal form according to Example 1, wherein the crystal form is a crystal form of an ethanol monosolvate of the compound of Formula 1.

[0755] Example 11. The crystalline form according to Example 10, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the crystalline form of the ethanol monosolvate includes 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°.

[0756] Example 12. The crystalline form according to Example 11, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the crystalline form of the ethanol monosolvate further includes 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°.

[0757] Example 13. The crystalline form according to Example 1, wherein the crystalline form is the anhydrous form I of the compound of Formula 1.

[0758] Example 14. The crystalline form according to Example 13, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the anhydrous form I includes 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°.

[0759] Example 15. The crystalline form according to Example 14, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the anhydrous form I further includes 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°.

[0760] Example 16. The crystalline form according to Example 1, wherein the crystalline form is the anhydrous form II of the compound of Formula 1.

[0761] Example 17. The crystalline form according to Example 16, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the anhydrous form II includes 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.

[0762] Example 18. The crystalline form according to Example 17, wherein when irradiated with a Cu-Kα light source, the characteristic XRPD pattern of the anhydrous crystalline form II further includes 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°.

[0763] Example 19. The crystalline form according to Example 1, wherein the crystalline form exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to Figures 2-6 the pattern shown in any one of the figures in

[0764] Example 20. An amorphous form of Formula 1

[0765] or a solvate thereof.

[0766] Example 21. The amorphous form according to Example 20, wherein the amorphous form exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to Figure 1 the pattern shown in

[0767] Example 22. The amorphous form according to Example 20, wherein the amorphous form exhibits a differential scanning calorimetry (DSC) thermogram substantially similar to Figure 7 .

[0768] Example 23. A preparation for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0769] Example 24. A preparation for binding to FMS-like tyrosine kinase 3 (FLT3).

[0770] Example 25. The preparation according to Example 23 or 24, wherein the preparation is in crystalline form.

[0771] Example 26. The preparation according to Example 23 or 24, wherein the preparation is in amorphous form.

[0772] Example 27. The preparation according to Example 25, wherein the crystalline form includes a hydrate of the compound of Formula 1.

[0773] Example 28. The preparation according to Example 27, wherein the hydrate is a monohydrate, dihydrate, or trihydrate of the compound of Formula 1.

[0774] Example 29. The preparation according to Example 25, wherein the crystalline form includes an ethanol monosolvate of the compound of Formula 1.

[0775] Example 30. The preparation according to Example 25, wherein the crystal form comprises the anhydrate of the compound of formula 1.

[0776] Example 31. A pharmaceutical composition comprising at least one crystal form of the compound of formula 1 according to Example 1; and at least one pharmaceutically acceptable carrier or diluent.

[0777] Example 32. A pharmaceutical composition comprising at least one amorphous form of the compound of formula 1 according to Example 20; and at least one pharmaceutically acceptable carrier or diluent.

[0778] Example 33. A pharmaceutical composition comprising at least one crystal form of the compound of formula 1 according to any one of Examples 2 to 19 and at least one pharmaceutically acceptable carrier or diluent.

[0779] Example 34. A pharmaceutical composition comprising at least one amorphous form of the compound of formula 1 according to any one of Examples 20 to 22, and at least one pharmaceutically acceptable carrier or diluent.

[0780] Example 35. A pharmaceutical composition comprising a preparation for inhibiting FMS-like tyrosine kinase 3 (FLT3).

[0781] Example 36. A pharmaceutical composition comprising a preparation for binding to FMS-like tyrosine kinase 3 (FLT3).

[0782] Example 37. The pharmaceutical composition according to Example 35 or 36, wherein the preparation is in crystal form.

[0783] Example 38. The pharmaceutical composition according to Example 35 or 36, wherein the preparation is in amorphous form.

[0784] Example 39. The pharmaceutical composition according to Example 37, wherein the composition comprises a crystal form of the compound of formula 1 according to any one of Examples 2 to 19 and at least one pharmaceutically acceptable carrier or diluent.

[0785] Example 40. The pharmaceutical composition according to Example 38, wherein the composition comprises an amorphous form of the compound of formula 1 according to any one of Examples 20 to 22, and at least one pharmaceutically acceptable carrier or diluent.

[0786] Example 41. The pharmaceutical composition according to any one of Examples 31 to 40, wherein the crystal form or amorphous form is at least about 70% pure in the pharmaceutical composition.

[0787] Example 42. The pharmaceutical composition according to Example 41, wherein

[0788] the crystalline or amorphous form is at least about 80% pure in the pharmaceutical composition.

[0789] Example 43. The pharmaceutical composition according to any one of Examples 31 to 40, wherein

[0790] the crystalline or amorphous form is at least about 90% pure in the pharmaceutical composition.

[0791] Example 44. The pharmaceutical composition according to any one of Examples 31 to 40, wherein

[0792] the crystalline or amorphous form is at least about 95% pure in the pharmaceutical composition.

[0793] Example 45. The pharmaceutical composition according to any one of Examples 31 to 40, wherein

[0794] the crystalline or amorphous form is at least about 99% pure in the pharmaceutical composition.

[0795] Example 46. The pharmaceutical composition according to any one of Examples 31 to 40, wherein the amorphous form is at least about 70% pure in the pharmaceutical composition.

[0796] Example 47. The pharmaceutical composition according to Example 41, wherein the amorphous form is at least about 80% pure in the pharmaceutical composition.

[0797] Example 48. The pharmaceutical composition according to any one of Examples 31 to 40, wherein

[0798] the amorphous form is at least about 90% pure in the pharmaceutical composition.

[0799] Example 49. The pharmaceutical composition according to any one of Examples 31 to 40, wherein the amorphous form is at least about 95% pure in the pharmaceutical composition.

[0800] Example 50. The pharmaceutical composition according to any one of Examples 31 to 40, wherein the amorphous form is at least about 99% pure in the pharmaceutical composition.

Claims

1. A crystalline form of a compound of Formula 1: [Formula 1] or a pharmaceutically acceptable salt, solvate, or solvate salt thereof.

2. The crystalline form according to claim 1, wherein the crystalline form is a hydrate of the compound of Formula 1.

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

4. The crystalline form according to any one of claims 1 to 3, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the crystalline form comprises 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°.

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

6. The crystalline form according to claim 5, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the crystalline form further comprises 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. The crystalline form according to any one of claims 1 to 6, wherein the XRPD pattern of the crystalline form is substantially similar to Figure 2.

8. The crystalline form according to any one of claims 1 to 7, the DSC thermogram of the crystalline form is substantially similar to Figure 8.

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

10. The crystalline form according to claim 2 or 9, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the crystalline form comprises 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°.

11. The crystalline form according to claim 10, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the crystalline form further comprises 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°.

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

13. The crystalline form according to any one of claims 9 to 12, the DSC thermogram of the crystalline form is substantially similar to Figure 9.

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

15. The crystalline form according to any one of claims 1 to 2 or 9 to 13, wherein the hydrate is a trihydrate.

16. The crystalline form according to claim 1, wherein the crystalline form is an ethanol monosolvate of the compound of formula 1.

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

18. The crystalline form according to claim 17, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the crystalline form comprises 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°.

19. The crystalline form according to claim 18, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the crystalline form of the ethanol monosolvate further comprises 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. The crystalline form according to any one of claims 16 to 19, wherein the XRPD pattern of the crystalline form is substantially similar to Figure 4.

21. The crystalline form according to any one of claims 16 to 20, the DSC thermogram of the crystalline form is substantially similar to Figure 10.

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

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

24. The crystalline form according to claim 23, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of anhydrous crystalline form I comprises 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°.

25. The crystalline form according to claim 24, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the anhydrous crystalline form further comprises 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°.

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

27. The crystalline form according to any one of claims 22 to 26, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 10.

28. The crystalline form according to claim 1, wherein it is the anhydrous form II of the compound of formula 1.

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

30. The crystalline form according to claim 29, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the anhydrous form comprises 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°.

31. The crystalline form according to claim 30, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the anhydrous form further comprises 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°.

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

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

34. An amorphous form of formula 1 or a solvate thereof.

35. The amorphous form according to claim 34, wherein the X-ray powder diffraction (XRPD) pattern exhibited by the amorphous form is substantially similar to the pattern shown in Figure 1.

36. The amorphous form according to claim 34, wherein the differential scanning calorimetry (DSC) thermogram exhibited by the amorphous form is substantially similar to Figure 7.

37. The crystalline form according to claim 1, wherein 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.

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

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

40. The crystalline form according to claim 39, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the dihydrochloride crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 8.2° ± 0.2°, 9.4° ± 0.2°, and 19.1° ± 0.2°.

41. The crystalline form according to claim 40, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the dihydrochloride crystalline form of the compound of formula 1 comprises 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°.

42. The crystalline form according to claim 40 or 41, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the dihydrochloride crystalline form of the compound of formula 1 further comprises 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°.

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

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

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

46. The crystalline form according to claim 39, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the dihydrochloride crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 10.5° ± 0.2°, 15.2° ± 0.2° and 23.1° ± 0.2°.

47. The crystalline form according to claim 46, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the dihydrochloride crystalline form of the compound of formula 1 comprises 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°.

48. The crystalline form according to claim 46 or 47, wherein the XRPD pattern of the dihydrochloride crystalline form of the compound of formula 1 further comprises 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. The crystalline form according to any one of claims 46 to 48, wherein the XRPD pattern of the crystalline form is substantially similar to Figure 14.

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

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

52. The crystalline form according to claim 51, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the monohydrochloride crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 17.1° ± 0.2°, 18.6° ± 0.2°, and 23.5° ± 0.2°.

53. The crystalline form according to claim 52, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the monohydrochloride crystalline form of the compound of formula 1 comprises 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°.

54. The crystalline form according to any one of claims 51 to 53, wherein the XRPD pattern of the monohydrochloride crystalline form of the compound of formula 1 further comprises 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. The crystalline form according to any one of claims 51 to 54, wherein the XRPD pattern of the crystalline form is substantially similar to Figure 15.

56. The crystalline form according to any one of claims 51 to 55, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 27.

57. The crystalline form according to claim 37 or 38, which is the disulfate crystalline form of the compound of formula 1.

58. The crystalline form according to claim 57, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the disulfate crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 8.8° ± 0.2°, 11.4° ± 0.2°, and 24.3° ± 0.2°.

59. The crystalline form according to claim 58, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the disulfate crystalline form of the compound of formula 1 comprises 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°.

60. The crystalline form according to claim 58 or 59, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the disulfate crystalline form of the compound of formula 1 further comprises 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°.

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

62. The crystalline form according to any one of claims 57 to 61, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 28.

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

64. The crystalline form according to claim 63, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the monosulfate crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 8.8° ± 0.2°, 11.4° ± 0.2°, and 24.3° ± 0.2°.

65. The crystalline form according to claim 64, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the monosulfate crystalline form of the compound of formula 1 comprises 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°.

66. The crystalline form according to claim 64 or 65, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the monosulfate crystalline form of the compound of formula 1 further comprises 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°.

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

68. The crystalline form according to any one of claims 63 to 67, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 29.

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

70. The crystalline form according to claim 69, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the difumarate crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 22.9° ± 0.2°, 28.9° ± 0.2°, and 29.4° ± 0.2°.

71. The crystalline form according to claim 70, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the difumarate crystalline form of the compound of formula 1 comprises 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°.

72. The crystalline form according to claim 70 or 71, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the difumarate crystalline form of the compound of formula 1 further comprises 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°.

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

74. The crystalline form according to any one of claims 69 to 73, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 30.

75. The crystalline form according to claim 37 or 38, which is the hemifumarate crystalline form of the compound of formula 1.

76. The crystalline form according to claim 75, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the hemifumarate crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 6.8° ± 0.2°, 12.6° ± 0.2°, and 17.1° ± 0.2°.

77. The crystalline form according to claim 76, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the hemifumarate crystalline form of the compound of formula 1 comprises 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°.

78. The crystalline form according to claim 75 or 76, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the hemifumarate crystalline form of the compound of formula 1 further comprises 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. The crystalline form according to any one of claims 75 to 78, wherein the XRPD pattern of the crystalline form is substantially similar to Figure 19.

80. The crystalline form according to any one of claims 75 to 79, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 31.

81. The crystalline form according to claim 37 or 38, which is the monosuccinate crystalline form of the compound of formula 1.

82. The crystalline form according to claim 81, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the monosuccinate crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 16.9° ± 0.2°, 18.5° ± 0.2°, and 23.6° ± 0.2°.

83. The crystalline form according to claim 82, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the monosuccinate crystalline form of the compound of formula 1 comprises 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°.

84. The crystalline form according to claim 82 or 83, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the monosuccinate crystalline form of the compound of formula 1 further comprises 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. The crystalline form according to any one of claims 81 to 84, wherein the XRPD pattern of the crystalline form is substantially similar to Figure 20.

86. The crystalline form according to any one of claims 81 to 85, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 32.

87. The crystalline form according to claim 37 or 38, which is the hemisuccinate crystalline form of the compound of formula 1.

88. The crystalline form according to claim 87, wherein when irradiated with a Cu-Kα light source, the X-ray powder diffraction (XRPD) pattern of the hemisuccinate crystalline form of the compound of formula 1 comprises peaks at diffraction angles 2θ of 6.9° ± 0.2°, 17.0° ± 0.2°, and 23.6° ± 0.2°.

89. The crystalline form according to claim 88, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the hemisuccinate crystalline form of the compound of formula 1 comprises 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°.

90. The crystalline form according to claim 88 or 89, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the hemisuccinate crystalline form of the compound of formula 1 further comprises 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°.

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

92. The crystalline form according to any one of claims 87 to 91, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 33.

93. The crystalline form according to claim 37 or 38, which is the dimaleate crystalline form of the compound of formula 1.

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

95. The crystalline form according to claim 94, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the dimaleate crystalline form of the compound of formula 1 comprises 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°.

96. The crystalline form according to claim 94 or 95, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the dimaleate crystalline form of the compound of formula 1 further comprises at least one peak at diffraction angles 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°.

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

98. The crystalline form according to any one of claims 93 to 97, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 34.

99. The crystalline form according to claim 37 or 38, which is the sesquimaleate crystalline form of the compound of formula 1.

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

101. The crystalline form according to claim 100, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the sesquimaleate crystalline form of the compound of formula 1 comprises 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°.

102. The crystalline form according to claim 101 or 102, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the sesquimaleate crystalline form of the compound of formula 1 further comprises at least one peak at diffraction angles 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°.

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

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

105. The crystalline form according to claim 37 or 38, which is the monomaleate crystalline form of the compound of formula 1.

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

107. The crystalline form according to claim 106, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the monomaleate crystalline form of the compound of formula 1 comprises 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°.

108. The crystalline form according to claim 107, wherein when irradiated with a Cu-Kα light source, the XRPD pattern of the monomaleate crystalline form of the compound of formula 1 further comprises 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. The crystalline form according to any one of claims 105 to 108, wherein the XRPD pattern of the crystalline form is substantially similar to Figure 24.

110. The crystalline form according to any one of claims 105 to 109, wherein the DSC thermogram of the crystalline form is substantially similar to Figure 36.

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

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

113. The preparation according to claim 111 or 112, wherein the preparation is in crystalline form.

114. The preparation according to claim 111 or 112, wherein the preparation is in amorphous form.

115. The preparation according to claim 113, wherein the crystalline form comprises a hydrate of the compound of formula 1.

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

117. The preparation according to claim 113, wherein the crystalline form comprises an ethanol monosolvate of the compound of formula 1.

118. The preparation according to claim 113, wherein the crystalline form comprises an anhydrate of the compound of formula 1.

119. A pharmaceutical composition comprising at least one crystalline form of the 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 preparation for inhibiting FMS-like tyrosine kinase 3 (FLT3).

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

123. The pharmaceutical composition according to claim 121 or 122, wherein the preparation is in crystalline form.

124. The pharmaceutical composition according to claim 121 or 122, wherein the preparation is in amorphous form.

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

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

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

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

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

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

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

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

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

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

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

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

137. The method according to claim 136, wherein the leukemia is acute myeloid leukemia, acute lymphoblastic leukemia or chronic myeloid leukemia.

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