EP4612142A1

EP4612142A1 - Novel crystalline form of a pyrimidine compound and pharmaceutical compositions comprising the same and methods of use thereof

Info

Publication number: EP4612142A1
Application number: EP23886402.9A
Authority: EP
Inventors: Jong Ouk Baek; Hee Sook Oh; Hee Cheol Kim
Original assignee: Hanmi Pharmaceutical Co Ltd
Current assignee: Hanmi Pharmaceutical Co Ltd
Priority date: 2022-11-04
Filing date: 2023-11-03
Publication date: 2025-09-10
Also published as: AU2023372170A1; JP2025535889A; WO2024096708A1; CN120379987A; KR20250088750A

Abstract

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

Description

NOVEL CRYSTALLINE FORM OF A PYRIMIDINE COMPOUND AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME AND METHODS OF USE THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

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

TECHNICAL FIELD

The present disclosure relates to novel solid forms e.g., crystalline forms of a pyrimidine compound, pharmaceutical compositions including the same, and therapeutic uses thereof.

More specifically, the disclosure relates to amorphous forms and crystalline forms e.g., anhydrate, hydrates, solvates, salts, salt solvates, of a compound of Formula 1, a method of manufacturing the same, pharmaceutical compositions including the same, and therapeutic uses thereof.

FMS-like tyrosine kinase 3 (FLT3), is a receptor tyrosine kinase expressed by hemocytoblasts, typically in hematopoietic precursor cells that plays an important role in the normal development of stem cells and the immune system. Abnormal overexpression and mutation of FLT3 are often observed in leukemia patients. Acute myelogenous leukemia (AML) is a disease of multipotent hematopoietic stem cells characterized by abnormal proliferation and differentiation of blasts in bone marrow and peripheral blood. FLT3 has recently been regarded to be one of the most important targets from the therapeutic perspective of AML.

In embodiments, the compound of Formula 1, which has the compound name of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole- 3-yl)pyrimidine-2-amine, has an anti-proliferative activity such as anti-cancer activity by targeting FMS-like tyrosine kinases, and being able to selectively and effectively treat drug resistance caused by tyrosine kinase mutation.

[Formula 1]

An aspect is to provide a crystalline form of the compound of Formula 1.

An aspect is to provide an amorphous form of the compound of Formula 1.

Another aspect is to provide a pharmaceutical composition including the crystalline form or amorphous form of the compound of Formula 1.

Another aspect is to provide methods of treating cancer, such as leukemia. In a particular embodiment, the leukemia may be acute myelogenous leukemia, acute lymphocytic leukemia, or chronic bone marrow leukemia.

An aspect provides a crystalline form of the compound of Formula 1:

[Formula 1]

.

The compound of Formula 1 and its method of use is 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 are incorporated by reference in their entirety herein.

In embodiments, the present disclosure relates to solid forms of Formula 1

[Formula 1]

or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical compositions comprising the solid forms, and therapeutic uses thereof.

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

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

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

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

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

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

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

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

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

In a specific example, a crystalline form of the compound of Formula 1 may be a crystalline form of a hydrate, a solvate, or an anhydrate.

As used herein, the verb "comprise" as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably "comprise", "consist of", or "consist essentially of", the steps, elements, and/or reagents described in the claims.

It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely", "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.

As used herein, the term "crystal form" or "crystalline form" refers to a crystalline solid form including a chemical compound, may include a crystalline polymorph, a solvate, a hydrate, a co-crystal or other molecular complexes, or a crystalline polymorph thereof, and may refer to a crystalline form of a specific single component or multi-components, but is not limited thereto.

As used herein, the terms "polymorphs" and "polymorphic forms" refer to two or more crystal forms including the same molecule, molecules, or ions. Different polymorphs may have different physical properties, for example, melting points, solubility, or vibration spectrums due to different arrangements or conformations of molecules and ions in the crystal grid.

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

The term "hydrate", as used herein, refers to a solvate of which the solvent is water. "Crystalline polymorphs of a solvate" indicates the presence of more than one crystalline form for a specific solvate composition. "Crystalline polymorphs of a hydrate" indicates the presence of more than one crystalline form for a specific hydrate composition. The solvent is added to dissolve at least a portion of the compound, and may be an amount sufficient to dissolve at least a portion of the compound of Formula 1.

As used herein, the term "amorphous" or "amorphous form" refers to a state of a material, composition, or product that when measured with X-ray diffraction, the material, composition, or product is not substantially crystalline.

As used herein, "substantially" or "substantial" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, an object that is "substantially" enclosed would mean that the object is either completely enclosed or nearly completely enclosed. In another example, an XRPD pattern that is "substantially" similar to another XRPD pattern would mean that the one skilled in the art would understand the two patterns to be of the same substance in the same form. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of "substantially" is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free of" other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents. In other words, a composition that is "substantially free of" an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof.

The term "treating" means one or more of relieving, alleviating, delaying, reducing, improving, or managing at least one symptom of a condition in a subject. The term "treating" may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.

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

The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.

As used herein, a "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like. In embodiments, the subject is human. In embodiments, the subject can be suspected of having or at risk for having a cancer.

Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, 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 may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

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

In embodiments, the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof (e.g., as disclosed herein) has a purity of 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 embodiments, the crystalline form has a purity in the range of about 80% to about 99%. In embodiments, the crystalline form has a purity in the range of about 80% to about 99.5%, or about 90% to about 99.9%, or about 95% to about 100%, including all values and subranges therebetween. In embodiments, the purity is determined by HPLC.

In embodiments, the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or 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 embodiments, the crystalline form has a purity in the range of about 80% pure by weight to about 99% pure by weight of a single crystalline form. In embodiments, the purity is determined using methods known to those skilled in the art e.g., HPLC.

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

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

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

In a specific example, the crystalline form may be a crystalline form of a monohydrate, a dihydrate, or a trihydrate of the compound of Formula 1, or may preferably be a crystalline form of a monohydrate or a trihydrate.

Monohydrate crystalline form of the compound of Formula 1.

In a specific example, the crystalline form may be a crystalline form of a monohydrate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a monohydrate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a monohydrate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a monohydrate of the compound of Formula 1.

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

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°.

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°.

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°.

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

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

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

In a specific example, when the monohydrate crystalline form is irradiated with a Cu-Kα light source, the monohydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern including 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°.

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

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

When the crystalline form is irradiated with a Cu-Kα light source, the monohydrate crystalline form may have an X-ray powder diffraction (XRPD) pattern including 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°.

The monohydrate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 2.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 2.

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

The monohydrate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 8.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 8.

In a specific example, the monohydrate crystalline form may have a heat absorption initiation temperature of 74.9 °C and show heat absorption peaks at heat absorption temperatures of 89.0 °C and 161.6 °C in differential scanning calorimetry (DSC).

Trihydrate crystalline form of the compound of Formula 1.

In a specific example, the crystalline form may be a trihydrate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a trihydrate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a trihydrate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a trihydrate of the compound of Formula 1.

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

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

The trihydrate crystalline form may 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°.

The peak at the diffraction angle 2θ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-Kα light source (1.54056Å).

X-ray powder diffraction (XRPD) of the trihydrate crystalline form may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 10 % or more.

For example, XRPD relative intensity (I/I0) of the trihydrate crystalline form exhibiting the peaks may be 10 % or more, 14 % or more, 15 % or more, 20 % or more, or 22 % or more.

In a specific example, when the trihydrate crystalline form is irradiated with a Cu-Kα light source, the trihydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern including 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°.

In a specific example, when the trihydrate crystalline form is irradiated with a Cu-Kα light source, the trihydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern further including a peak 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°.

When the crystalline form is irradiated with a Cu-Kα light source, the trihydrate crystalline form may have an X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 3.

The trihydrate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) identified in FIG. 3.

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

The trihydrate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 9.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 9.

In a specific example, the trihydrate crystalline form may have a heat absorption initiation temperature of 44.9 °C, and show heat absorption peaks at heat absorption temperatures of 68.7 °C and 108.3 °C in differential scanning calorimetry (DSC).

Ethanol mono-solvate crystalline form of the compound of Formula 1.

In a specific example, the crystalline form may be a crystalline form of a solvate of the compound of Formula 1. The solvate of the compound of Formula 1 may be an alcohol solvate, or preferably an ethanol solvate.

In a specific example, the crystalline form may be a crystalline form of an alcohol solvate of the compound of Formula 1. In a specific example, the crystalline form may be a crystalline form of an alcohol mono-solvate of the compound of Formula 1. The mono-solvate has a crystal structure containing one solvent molecule per a compound molecule of Formula 1.

In a specific example, the crystalline form may be a crystalline form of an ethanol solvate of the compound of Formula 1. In a specific example, the crystalline form may be a crystalline form of an ethanol mono-solvate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a ethanol mono-solvate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a ethanol mono-solvate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a ethanol mono-solvate of the compound of Formula 1.

The crystalline form of the ethanol mono-solvate may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 8.6°±0.2°, 17.2°±0.2°, and 21.4±0.2°.

The crystalline form of the ethanol mono-solvate may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, and 21.4°±0.2°.

The crystalline form of the ethanol mono-solvate may further include at least one peak at a diffraction angle 2θ selected from 17.5°±0.2 and 18.9°±0.2°.

The crystalline form of the ethanol mono-solvate 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°.

X-ray powder diffraction (XRPD) of the crystalline form of the ethanol mono-solvate may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at a diffraction angle 2θ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 10 % or more.

For example, XRPD relative intensity (I/I0) of the crystalline form of the ethanol mono-solvate exhibiting the peaks may be 10 % or more, 20 % or more, 30 % or more, 40 % or more, 60 % or more, or 65 % or more.

In a specific example, when the crystalline form of the ethanol mono-solvate irradiated with a Cu-Kα light source, the crystalline form of the ethanol mono-solvate has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 8.6°±0.2°, 17.2°±0.2°, and 21.4±0.2°.

In a specific example, when the crystalline form of the ethanol mono-solvate irradiated with a Cu-Kα light source, the crystalline form of the ethanol mono-solvate has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.9°±0.2°, and 21.4°±0.2°.

In a specific example, when the crystalline form of the ethanol mono-solvate irradiated with a Cu-Kα light source, the crystalline form of the ethanol mono-solvate has a characteristic X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2θ selected from 7.8°±0.2°, 19.2°±0.2°, 24.0°±0.2°, and 25.7°±0.2°.

When the crystalline form of the ethanol mono-solvate irradiated with a Cu-Kα light source, the crystalline form of the ethanol mono-solvate may have an X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 4.

The crystalline form of the ethanol mono-solvate may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) identified in FIG. 4.

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

The crystalline form of the ethanol mono-solvate may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 10.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 10.

In a specific example, the crystalline form of the ethanol mono-solvate may have a heat absorption initiation temperature of 99.8 °C, and show a heat absorption peak at a heat absorption temperature of 113.4 °C in differential scanning calorimetry (DSC).

Anhydrate crystalline form I of the compound of Formula 1.

In a specific example, the crystalline form may be a crystalline form of an anhydrate of the compound of Formula 1.

In a specific example, the crystalline form may be an anhydrate crystalline form I of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 an anhydrate form I of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a anhydrate form I of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of an anhydrate form I of the compound of Formula 1.

The anhydrate crystalline form I may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, and 18.1±0.2°.

The anhydrate crystalline form I may have an X-ray powder diffraction (XRPD) pattern including 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°.

The anhydrate 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°.

The anhydrate 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°.

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

X-ray powder diffraction (XRPD) spectrum of the anhydrate crystalline form I may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 10 % or more.

For example, XRPD relative intensity (I/I0) of the anhydrate crystalline form I exhibiting the peak may be 10 % or more, 20 % or more, 30 % or more, 40 % or more, 60 % or more, or 65 % or more.

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

In a specific example, when the anhydrate crystalline form I is irradiated with a Cu-Kα light source, the anhydrate crystalline form I has a characteristic X-ray powder diffraction (XRPD) pattern including 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°.

In a specific example, when the anhydrate crystalline form I is irradiated with a Cu-Kα light source, the anhydrate crystalline form I has a characteristic X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2θ selected from 6.5°±0.2°, 11.2°±0.2°, 15.1°±0.2°, 20.2°±0.2°, 21.8°±0.2°, 22.5°±0.2°, and 25.7°±0.2°.

When the anhydrate crystalline form I is irradiated with a Cu-Kα light source, the anhydrate crystalline form I may have an X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 5.

The anhydrate crystalline form I may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 5.

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

The anhydrate crystalline form I may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 11.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 11.

In a specific example, the anhydrate crystalline form I may have a heat absorption initiation temperature of 152.4 °C, and show a heat absorption peak at a heat absorption temperature of 159.5 °C in differential scanning calorimetry (DSC).

Anhydrate crystalline form II of the compound of Formula 1.

In a specific example, the crystalline form may be a crystalline form of an anhydrate crystalline form II of the compound of Formula 1.

The anhydrate crystalline form II may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, and 9.7±0.2°.

The anhydrate crystalline form II may have an X-ray powder diffraction (XRPD) pattern including 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°.

The anhydrate crystalline form II may 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°.

The anhydrate crystalline form II may 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°.

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

X-ray powder diffraction (XRPD) of the anhydrate crystalline form II may have a pattern including 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 peaks at diffraction angles 2θ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 10 % or more.

For example, XRPD relative intensity (I/I0) of the anhydrate crystalline form II exhibiting the peaks may be 10 % or more, 20 % or more, 30 % or more, 40 % or more, 60 % or more, or 65 % or more.

n a specific example, when the anhydrate crystalline form II is irradiated with a Cu-Kα light source, the anhydrate crystalline form II has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, and 9.7±0.2°.

In a specific example, when the anhydrate crystalline form II is irradiated with a Cu-Kα light source, the anhydrate crystalline form II has a characteristic X-ray powder diffraction (XRPD) pattern including 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°.

In a specific example, when the anhydrate crystalline form II is irradiated with a Cu-Kα light source, the anhydrate crystalline form II has a characteristic X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2θ selected from 8.1°±0.2°, 11.8°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 25.9°±0.2°.

When the anhydrate crystalline form II is irradiated with a Cu-Kα light source, the anhydrate crystalline form II may have an X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 6.

The anhydrate crystalline form II may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) identified in FIG. 6.

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

The anhydrate crystalline form II may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 12.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 12.

In a specific example, the anhydrate crystalline form II may have a heat absorption initiation temperature of 139.8 °C, and show a heat absorption peak at a heat absorption temperature of 149.4 °C in differential scanning calorimetry (DSC).

Dihydrochloride Form I of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a dihydrochloride of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a dihydrochloride form I of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a dihydrochloride form I of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a dihydrochloride form I of the compound of Formula 1.

The dihydrochloride crystalline form I of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 8.2°±0.2°, 9.4°±0.2°, and 19.1°±0.2°.

The XRPD pattern of the dihydrochloride crystalline form I of the compound of Formula 1 may further include at least one peak at a diffraction angle 2θ selected from 14.6 °±0.2° and 26.2°±0.2°.

The XRPD pattern of the dihydrochloride crystalline form I of the compound of Formula 1 form may 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°.

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

For example, the dihydrochloride crystalline form I of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the dihydrochloride crystalline form I of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the dihydrochloride crystalline form I of the compound of Formula 1 is irradiated with a Cu-Kα light source, the dihydrochloride crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The dihydrochloride crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 13.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 13.

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

The dihydrochloride crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 25.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 25.

In embodiments, the dihydrochloride crystalline form may exhibit an endothermic heat absorption peak with an onset of about 105 °C and a peak maximum of about 139 °C in differential scanning calorimetry (DSC), and an additional endothermic absorption peak with an onset of about 187 °C and a peak maximum of about 202 °C.

In embodiments, the dihydrochloride crystalline form I is an ethanol solvate.

Dihydrochloride Form II of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a dihydrochloride form II of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a dihydrochloride form II of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a dihydrochloride form II of the compound of Formula 1.

The dihydrochloride crystalline form II of the compound of Formula 1 may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2θ of 10.5°±0.2°, 15.2°±0.2°, and 23.1°±0.2°.

The XRPD pattern of the dihydrochloride crystalline 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°.

The XRPD pattern of the dihydrochloride crystalline form II of the compound of Formula 1 form 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°.

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

For example, the dihydrochloride crystalline form II of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the dihydrochloride crystalline form II of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the dihydrochloride crystalline form II of the compound of Formula 1 is irradiated with a Cu-Kα light source, the dihydrochloride crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The dihydrochloride crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 14.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 14.

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

The dihydrochloride crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 26.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 26.

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

Monohydrochloride Form I of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a monohydrochloride of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a monohydrochloride of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a monohydrochloride of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a monohydrochloride of the compound of Formula 1.

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

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

The XRPD pattern of the monohydrochloride crystalline form of the compound of Formula 1 form may 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°.

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

For example, the monohydrochloride crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the monohydrochloride crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

n embodiments, when the monohydrochloride crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the monohydrochloride crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2θ selected from 4.9°±.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°.

The monohydrochloride crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 15.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 15.

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

The monohydrochloride crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 27.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 27.

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

Disulfate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a disulfate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a disulfate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a disulfate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a disulfate of the compound of Formula 1.

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

The XRPD pattern of the disulfate crystalline 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°.

The XRPD pattern of the disulfate crystalline form of the compound of Formula 1 form 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°.

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

For example, the disulfate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the disulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the disulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the disulfate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The disulfate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 16.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 16.

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

The disulfate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 28.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 28.

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

Monosulfate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a monosulfate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a monosulfate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a monosulfate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a monosulfate of the compound of Formula 1.

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

The XRPD pattern of the monosulfate crystalline 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°.

The XRPD pattern of the monosulfate crystalline form of the compound of Formula 1 form 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°.

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

For example, the monosulfate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the monosulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the monosulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the monosulfate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The monosulfate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 17.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 17.

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

The monosulfate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 29.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 29.

In embodiments, the monosulfate crystalline form may exhibit an endothermic heat absorption peak with an onset of about 244 °C and a peak maximum of about 274 °C in differential scanning calorimetry (DSC), and an additional endothermic absorption peak with an onset of about 187 °C and a peak maximum of about 202 °C.

Monosulfate crystalline form of the compound of Formula 1.

In embodiments, the monosulfate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 17.

Difumarate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a difumarate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a difumarate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a difumarate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a difumarate of the compound of Formula 1.

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

The XRPD pattern of the difumarate crystalline 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°.

The XRPD pattern of the difumarate crystalline form of the compound of Formula 1 form 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°.

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

For example, the difumarate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the difumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the difumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the difumarate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The difumarate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 18.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 18.

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

The difumarate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 30.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 30.

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

Hemifumarate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a hemifumarate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a hemifumarate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a hemifumarate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a hemifumarate of the compound of Formula 1.

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

The XRPD pattern of the hemifumarate 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° and 23.4°±0.2°.

The XRPD pattern of the hemifumarate crystalline form of the compound of Formula 1 form 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°.

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

For example, the hemifumarate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the hemifumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the hemifumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the hemifumarate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The hemifumarate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 19.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 19.

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

The hemifumarate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 31.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 31.

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

Monosuccinate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a monosuccinate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a monosuccinate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a monosuccinate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a monosuccinate of the compound of Formula 1.

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

The XRPD pattern of the monosuccinate crystalline 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°.

The XRPD pattern of the monosuccinate crystalline form of the compound of Formula 1 form 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°.

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

For example, the monosuccinate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the monosuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the monosuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the monosuccinate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The monosuccinate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 20.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 20.

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

The monosuccinate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 32.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 32.

In embodiments, the monosuccinate crystalline form may exhibit an endothermic heat absorption peak with an onset of about 95 °C and a peak maximum of about 116 °C, and an additional endothermic absorption peak with an onset of about 218 °C and a peak maximum of about 220 °C in differential scanning calorimetry (DSC).

Hemisuccinate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a hemisuccinate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a hemisuccinate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a hemisuccinate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a hemisuccinate of the compound of Formula 1.

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

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°

The XRPD pattern of the hemisuccinate crystalline form of the compound of Formula 1 form 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°.

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

For example, the hemisuccinate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the hemisuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the hemisuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the hemisuccinate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The hemisuccinate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 21.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 21.

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

The hemisuccinate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 33.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 33.

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

Dimaleate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a dimaleate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a dimaleate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a dimaleate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a dimaleate of the compound of Formula 1.

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

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°.

The XRPD pattern of the dimaleate crystalline form of the compound of Formula 1 form 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°.

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

For example, the dimaleate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the dimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the dimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the dimaleate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The dimaleate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 22.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 22.

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

The dimaleate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 34.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 34.

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

Sesquimaleate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a sesquimaleate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a sesquimaleate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a sesquimaleate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a sesquimaleate of the compound of Formula 1.

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

The XRPD pattern of the sesquimaleate 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°

The XRPD pattern of the sesquimaleate crystalline form of the compound of Formula 1 form 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°.

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

For example, the sesquimaleate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the sesquimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the sesquimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the sesquimaleate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The sesquimaleate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 23.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 23.

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

The sesquimaleate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 35.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 35.

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

Monomaleate crystalline form of the compound of Formula 1.

In embodiments, the crystalline form may be a crystalline form of a monomaleate of the compound of Formula 1.

In embodiments, the crystalline form of the compound of Formula 1 may comprise of over 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 a monomaleate of the compound of Formula 1. In another embodiment, the crystalline form of the compound of Formula 1 may comprise over about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of a monomaleate of the compound of Formula 1. In some embodiments, the crystalline form of the compound of Formula 1 may comprise over about 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of a monomaleate of the compound of Formula 1.

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

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°

The XRPD pattern of the monomaleate crystalline form of the compound of Formula 1 form 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°.

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

For example, the monomaleate crystalline form of the compound of Formula 1 may have a XRPD pattern exhibiting peaks with a relative intensity (I/I0) of 5 % or more, 10 % or more, 15 % or more, 19 % or more, 20 % or more, 40 % or more, or 45 % or more.

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

In embodiments, when the monomaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including 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°.

In embodiments, when the monomaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-Kα light source, the monomaleate crystalline form has a X-ray powder diffraction (XRPD) pattern further including 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°.

The monomaleate crystalline form may include a peak at a diffraction angle (2θ±0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 24.

In embodiments, the crystalline form has an XRPD pattern that is substantially similar to FIG. 24.

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

The monomaleate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 36.

In embodiments, the crystalline form has a DSC thermogram substantially similar to FIG. 36.

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

Another aspect provides a pharmaceutical composition including the crystalline form.

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

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

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, and the like, but are not limited thereto.

Examples of the diluent that may be included in the pharmaceutical composition include lactose, mannitol, sugar, microcrystalline cellulose and cellulose derivatives, and dry corn starch, but are not limited thereto.

The pharmaceutical composition may be formulated according to a method in the related art, and may be manufactured in various forms for oral administration such as tablets, pills, powders, capsules, syrups, emulsions, micro-emulsions, or in forms for parenteral administration such as intramuscular, intravenous, or subcutaneous injections.

When the pharmaceutical composition is prepared in a form of an injection, examples of the carrier or diluent may include water, saline, a glucose aqueous solution, an aqueous saccharide solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactants, suspensions, emulsifiers, and the like, but are not limited thereto.

As an active ingredient contained in the pharmaceutical composition, the crystalline form of the compound of Formula 1 may be administered orally or parenterally according to the purpose, in an effective amount for treatment or prevention of a disease in the subject or patient, and when administered orally, an amount of the administered pharmaceutical composition may be in a range so that an amount of the administered active ingredient may be, for example, 0.01 mg to 1000 mg, 0.01 mg to 500 mg, 0.1 mg to 300 mg, or 0.1 mg to 100 mg, per one day per 1 kg of body weight. Furthermore, when administered parenterally, an amount of the administered pharmaceutical composition may be in a range so that an amount of the administered active ingredient may be, for example, 0.01 mg to 100 mg, or 0.1 mg to 50 mg per one day per 1 kg of body weight. The composition may be administered all at once or in parts allocated into several dosages. A dose to a subject or a patient should be determined in light of various factors including a patient's weight, age, gender, health, diet, administration time, administration manner, and severity of the disease, and it should be understood that a dose may be properly adjusted by an expert, and the dose described above is not intended to limit the scope of the invention in any way.

The composition may be administered through oral or parenteral routes 1 to 4 times a day, or according to an on/off schedule. In some cases, a lower dose than the above-mentioned range may be appropriate, or a higher dose may be used without causing harmful side effects, and in the case of a higher dose, small doses may be administered in a series of administrations throughout a day.

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

The solid forms of the compound of Formula 1 may effectively control one or more kinases involved in intracellular signal transduction and intracellular complex biomechanisms. For example, the compound may act on receptor tyrosine kinase (RTK) to effectively control the intracellular delivery of extracellular stimuli. In an embodiment, the compound may effectively control fms-like tyrosine kinase 3 (FLT3) which is frequently abnormally overexpressed or mutated in patients with leukemia, and spleen tyrosine kinase (SYK) which acts on the signaling pathways of endothelial growth factor receptor (VEGFR), which are involved in controlling in the angiogenesis process, and other immunoreceptors such as B cell receptors and mast cells. The solid forms of the disclosure according to an embodiment effectively suppresses the mutation or overexpression of FLT3, and at the same time, the overexpression or overactivation of VEGFR, thereby blocking the supply of nutrition and oxygen to the tumor and suppressing SYK. Accordingly, the compound may be useful for the treatment of acute myelogenous leukemia (AML), which shows resistance to FLT3 inhibitors. The term "overall survival (OV)" used herein refers to the period of time from random allocation to death in clinical trials. FLT3-ITD positive acute myeloid leukemia (AML) is a disease with very low OV. SYK is overexpressed and activated in hematological malignant tumor, and highly activated SYK is usually found in FLT3-ITD-positive acute myeloid leukemia (AML), which has a very low OV. Therefore, as a target for the treatment of AML disease, SYK needs to be considered as an important factor together with FLT3.

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

The solid forms and the pharmaceutical compositions of the present disclosure find use in any number of methods. For example, in some embodiments the solid forms and the pharmaceutical compositions are useful in methods for modulating a FLT3 kinase activity. In embodiments, modulating FLT3 kinase activity is in a mammalian cell. In embodiments, modulating FLT3 kinase activity can be in a subject in need thereof (e.g., a mammalian subject) and for treatment of a condition or disease described herein, including diseases or conditions wherein inhibition of FLT3 kinase activity provides therapeutic benefit to a subject having the disease or condition.

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

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

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

The solid forms, such as crystalline and amorphous forms disclosed herein exhibit excellent FLT3 inhibitory activity and thus in particular embodiments, may be effectively used for the treatment of cell proliferative diseases caused by abnormal FLT3 activity such as cancer, for example, leukemia.

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

The cancer may include leukemia, such as acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute promyelocytic leukemia (APL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), or the like.

In one embodiment, the cancer may be leukemia.

In an embodiment, the leukemia may include AML, ALL, or CML.

In embodiments, the leukemia is AML. In embodiments, the AML is AML with a FLT3 mutation. In one specific embodiment, the AML is mutant FLT3 polynucleotide-positive AML, FLT3 internal tandem duplication (ITD)-positive AML, and/or AML with FLT3 point mutations.

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

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

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

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

The TKD mutation may further include ITD. For example, the mutation may be FLT3(ITD/D835Y) or FLT3(ITD/F691L).

In embodiments, the present disclosure provides methods of treating cancer patients with resistance to traditional therapeutic agents.

In embodiments, the present disclosure provides method of treating cancer comprising drug-resistant point mutants (D835Y, F691L, or F691L/D835Y) of FLT3 due to acquired D835Y and F691L point mutations in FLT3-TKD.

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), and the like, and may include any one selected from a combination thereof.

In some embodiments of any one of the methods as disclosed herein, the compound of the invention or the composition of the invention is administered in combination with another therapeutically active agent. In some embodiment, the other therapeutically active agent is administered together, sequentially, or separately with the compound of the invention or the composition of the invention. In some embodiment, the other therapeutically active agent is administered on a same or separate dosing regiment with the compound of the invention or the composition of the invention.

Another aspect provides a method of preparing a monohydrate crystalline form of the compound of Formula 1:

[Formula 1]

, the method including:

(a) dissolving the compound of Formula 1 in acetone;

(b) heating and stirring the solution (a); and

(c) cooling, filtering, and drying the stirred solution (b) to obtain a solid.

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

(b) may be heating the mixture (a) to about 40 °C to about 60 °C. The mixture may be stirred for about 10 hours to about 30 hours.

Cooling in (c) may be cooling to room temperature. (c) may further include washing as needed. The washing liquid may be, for example, the solvent of (a), that is, acetone. Drying in (c) may be carried out by warm airflow of about 40 °C to about 60 °C.

Another aspect provides a method of preparing a trihydrate crystalline form of the compound of Formula 1:

[Formula 1]

, the method including:

(a) dissolving the compound of Formula 1 in ethyl acetate;

(b) stirring the solution (a) at room temperature; and

(c) filtering and drying the stirred solution (b) to obtain a solid.

In a specific example, (b) may be stirring the solution (a) at about 20 °C to about 25 °C.

(c) may further include washing as needed. The washing liquid may be, for example, the solvent of (a), that is, ethyl acetate. Drying in (c) may be carried out by warm airflow of about 40 °C to about 60 °C.

Another aspect provides a method of preparing a crystalline form of a solvate of the compound of Formula 1:

[Formula 1]

, the method including:

(a) dissolving the compound of Formula 1 in a pharmaceutically acceptable solvate, for example, C₁ to C₃ alcohol.

(b) cooling and stirring the solution (a); and

(c) filtering and drying the stirred solution (b) to obtain a solid.

In a specific example, dissolution in (a) may be carried out at a reflux temperature. In a specific example, dissolution in (a) may be carried out in ethanol.

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

In a specific example, (c) may further include washing as needed. The washing liquid may be, for example, the solvent of (a), that is, ethanol. Drying in (c) may be carried out by warm airflow of about 40 °C to about 60 °C.

Another aspect provides a method of preparing an anhydrate crystalline form I of the compound of Formula 1:

[Formula 1]

, the method including:

(a) dissolving the compound of Formula 1 in ethanol;

(b) heating and stirring the solution (a); and

(c) cooling, filtering, and drying the stirred solution (b) to obtain a solid.

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

Cooling in (c) may be cooling to room temperature. (c) may further include washing as needed. The washing liquid may be, for example, the solvent of (a), that is, ethanol. Drying in (c) may be carried out by warm airflow of about 40 °C to about 60 °C.

Another aspect provides a method of preparing an anhydrate crystalline form II of the compound of Formula 1:

[Formula 1]

, the method including:

(a) dissolving the compound of Formula 1 in isopropanol;

(b) stirring the solution (a) at room temperature; and

(c) filtering and drying the stirred solution (b) to obtain a solid.

In a specific example, (b) may be stirring the mixture (a) at a temperature of about 20 °C to about 25 °C.

(c) may further include washing as needed. The washing liquid may be, for example, the solvent of (a), that is, isopropanol. Drying in (c) may be carried out by warm airflow of about 40 °C to about 60 °C.

Reference example

Another aspect provides an amorphous form of the compound of Formula 1:

[Formula 1]

.

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

In a specific example, the amorphous form may show heat absorption peaks of an initiation point of 80.7 °C and a termination point of 91.4 °C when the results are recorded at a linear heating rate of 10 °C/min in differential scanning calorimetry (DSC).

Another aspect is to provide a pharmaceutical composition including the amorphous form of the compound of Formula 1.

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

In a specific example, the cancer may be leukemia.

In a specific example, the leukemia may be acute myelogenous leukemia, acute lymphocytic leukemia, or chronic bone marrow leukemia.

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

A carrier or diluent that may be included in the pharmaceutical composition, formulation of the pharmaceutical composition, a dose, and a treatment method using the pharmaceutical composition are as described above.

Another aspect provides a method of preparing an amorphous form of the compound of Formula 1:

[Formula 1]

, the method including:

(d) reacting a hydrochloride of the compound of Formula 1 in a base reaction solution;

(e) filtering the solution after the reaction (d); and

(f) drying the solution after the filtration (e), to obtain a solid.

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), hydrochloride of the compound of Formula 1 may have been prepared by dissolving the compound of Formula 1 in ethanol and reacting the solution with hydrochloric acid.

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

Drying in (f) may be carried out by warm airflow of a temperature of about 40 °C to about 60 °C.

Unless otherwise specified, those skilled in the art will understand that the peak values from the X-ray powder diffraction study reported in the present disclosure are typically related to experimental errors that can be observed in the field. Specifically, a peak is construed as being located in ± 0.5 ° of the value reported herein. More specifically, a peak is construed as being located in ± 0.2 ° of the value reported herein.

The term "room temperature" as used herein refers to a range of 20±5 °C.

The term "reflux", as used herein, means that a boiling point or a slightly higher temperature is used.

The term "substantially pure", as used herein, means being at least 95 % pure, or preferably 99 % pure, and when 95 % pure, 5 % or less of the compound of Formula 1 exists as any other form (other crystalline form, amorphous form, etc.), and when 99% pure, 1% or less of the compound of Formula 1 exists in any other form.

The numerical values described herein are considered to include the meaning of "about", even when not specified. The term "about", as used herein, means to include values within 5 % of the given value or range, or preferably within 1 % to 2 %. 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.

The expressions, such as "have", "may have", "include", or "may include", indicate the presence of a characteristic (e.g., number or a component such as an ingredient), and does not exclude the presence of other characteristics.

The crystalline form (a hydrate, a solvate, or an anhydrate) of the compound of Formula 1 according to an aspect is excellent in terms of pharmaceutically required physical-chemical properties, i.e., non-hygroscopicity to water, chemical stability, solubility, and the like, and a pharmaceutical composition for preventing or treating cancer including the same may be prepared more efficiently.

In addition, the crystalline form (a hydrate, a solvate, or an anhydrate) of the compound of Formula 1 is also excellent in physical-chemical properties as compared to the amorphous form.

Furthermore, the crystalline form of the hydrate according to a specific example is excellent in reproducibility of manufacture, purity, crystallinity, stability of the crystalline form, chemical stability, and non-hygroscopicity, and the crystalline form of the monohydrate according to a specific example has particularly excellent non-hygroscopicity.

Accordingly, the crystalline form according to a specific example may be stably maintained for a long period of time without requiring a special storage facility or special storage conditions, and efficiency and stability of production, distribution, storage, and preservation of pharmaceutical products may be increased.

FIG. 1 shows a X-ray powder diffraction (XRPD) pattern of an amorphous form of a compound 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (hereinafter, referred to as "the compound of Formula 1").

FIG. 2 shows a X-ray powder diffraction (XRPD) pattern of a monohydrate crystalline form of the compound of Formula 1.

FIG. 3 shows a X-ray powder diffraction (XRPD) pattern of a trihydrate crystalline form of the compound of Formula 1.

FIG. 4 shows a X-ray powder diffraction (XRPD) pattern of an ethanol mono-solvate of the compound of Formula 1.

FIG. 5 shows a X-ray powder diffraction (XRPD) pattern of an anhydrate crystalline form I of the compound of Formula 1.

FIG. 6 shows a X-ray powder diffraction (XRPD) pattern of an anhydrate crystalline form II of the compound of Formula 1.

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

FIG. 8 shows results of differential scanning calorimetry (DSC) of the monohydrate crystalline form of the compound of Formula 1.

FIG. 9 shows results of differential scanning calorimetry (DSC) of the trihydrate crystalline form of the compound of Formula 1.

FIG. 10 shows results of differential scanning calorimetry (DSC) of the ethanol mono-solvate of the compound of Formula 1.

FIG. 11 shows results of differential scanning calorimetry (DSC) of the anhydrate crystalline form I of the compound of Formula 1.

FIG. 12 shows results of differential scanning calorimetry (DSC) of the anhydrate crystalline form II of the compound of Formula 1.

FIG. 13 shows a X-ray powder diffraction (XRPD) pattern of a dihydrochloride crystalline form I of the compound of Formula 1.

FIG. 14 shows a X-ray powder diffraction (XRPD) pattern of a dihydrochloride crystalline form II of the compound of Formula 1.

FIG. 15 shows a X-ray powder diffraction (XRPD) pattern of an monohydrochloride crystalline form of the compound of Formula 1.

FIG. 16 shows a X-ray powder diffraction (XRPD) pattern of a disulfate crystalline form of the compound of Formula 1.

FIG. 17 shows a X-ray powder diffraction (XRPD) pattern of a monosulfate crystalline form of the compound of Formula 1.

FIG. 18 shows a X-ray powder diffraction (XRPD) pattern of a difumarate crystalline form of the compound of Formula 1.

FIG. 19 shows a X-ray powder diffraction (XRPD) pattern of a hemifumarate crystalline form of the compound of Formula 1.

FIG. 20 shows a X-ray powder diffraction (XRPD) pattern of a monosuccinate crystalline form of the compound of Formula 1.

FIG. 21 shows a X-ray powder diffraction (XRPD) pattern of a hemisuccinate crystalline form of the compound of Formula 1.

FIG. 22 shows a X-ray powder diffraction (XRPD) pattern of a dimaleate crystalline form of the compound of Formula 1.

FIG. 23 shows a X-ray powder diffraction (XRPD) pattern of a sesquimaleate crystalline form of the compound of Formula 1.

FIG. 24 shows a X-ray powder diffraction (XRPD) pattern of a monomaleate crystalline form of the compound of Formula 1.

FIG. 25 shows results of differential scanning calorimetry (DSC) of a dihydrochloride crystalline form I of the compound of Formula 1.

FIG. 26 shows results of differential scanning calorimetry (DSC) of a dihydrochloride crystalline form II of the compound of Formula 1.

FIG. 27 shows results of differential scanning calorimetry (DSC) of an monohydrochloride crystalline form of the compound of Formula 1.

FIG. 28 shows results of differential scanning calorimetry (DSC) of a disulfate crystalline form of the compound of Formula 1.

FIG. 29 shows results of differential scanning calorimetry (DSC) of a monosulfate crystalline form of the compound of Formula 1.

FIG. 30 shows results of differential scanning calorimetry (DSC) of a difumarate crystalline form of the compound of Formula 1.

FIG. 31 shows results of differential scanning calorimetry (DSC) of a hemifumarate crystalline form of the compound of Formula 1.

FIG. 32 shows results of differential scanning calorimetry (DSC) of a monosuccinate crystalline form of the compound of Formula 1.

FIG. 33 shows results of differential scanning calorimetry (DSC) of an hemisuccinate crystalline form of the compound of Formula 1.

FIG. 34 shows results of differential scanning calorimetry (DSC) of a dimaleate crystalline form of the compound of Formula 1.

FIG. 35 shows results of differential scanning calorimetry (DSC) of a sesquimaleate crystalline form of the compound of Formula 1.

FIG. 36 shows results of differential scanning calorimetry (DSC) of a monomaleate crystalline form of the compound of Formula 1.

Hereinafter, the present disclosure will be described in more detail.

Unless defined otherwise, all technical terms used herein have the same meanings as those generally understood by one of ordinary skill in the art to which the present disclosure belongs. Furthermore, although preferred methods or samples are described herein, those similar or equivalent thereto are also incorporated in the scope of the present disclosure. Contents of all publications cited as references in this specification are incorporated to the disclosure in their entirety as references.

Compound of Formula 1

Provided is a compound 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine represented by Formula 1:

[Formula 1]

.

The compound of Formula 1 may be prepared by a method described in Korean Patent Publication No.10-1954370 and International Publication of International Application No.2020-022600, and these documents are incorporated herein as references in their entirety.

Test example: Analytical devices and methods of measurement

1. X-ray Powder Diffraction (XRPD)

X-ray powder diffraction (XRPD) analysis was performed in a D8 Advance (Bruker ASX, Germany) analyzer at a diffraction angle 2θ of 3° to 40°. When an amount of a sample was < 100 mg, about 5 mg to 10 mg of samples were gently pressed on a glass slide that was fitted to a sample holder. When an amount of a sample was > 100 mg, about 100 mg of samples were gently pressed on a plastic sample holder, so that a sample surface was smooth and right above the level of the sample holder.

A measurement was carried out as follows:

Anode material (Ka): Cu-Kα (1.54056 Å)

Scan range: 3° to 40°

Generator settings: 100 mA, 40.0 kV

Scan speed: 1 sec/step

Diver slit : 0.3°

Anti-scatter slit: 0.3°

Temperature: 20 °C

Step size: 0.02 deg 2θ

Rotating: use

Goniometer radius: 435 mm

2. Differential Scanning Calorimetry (DSC)

Differential scanning calorimetry (DSC) analysis was performed by an STA-1000 (Scinco, Korea) analyzer at 30 °C to 350 °C. 5 mg to 10 mg of a sample was added on an aluminum DSC pan while being weighed, 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.

3. Dynamic Vapor Sorption (DVS)

DVS analysis was performed by using a DVS Advantage (Surface Measurement System, United Kingdom) analyzer at 25 °C and a relative humidity of 0 % to 90 %. 10 mg of samples were placed in a wire mesh vapor sorption balance pan and mounted on a DVS Advantage Dynamic Vapor Sorption balance (Surface Measurement Systems, Ltd). The samples were applied to a ramping profile with relative humidity (RH) of 10 % to 90 % with a 10% increase of the sample while maintaining the sample in each step, until a stable weight is achieved (99.5 % of weight change is completed in a step). After completion of a sorption cycle, the samples were dried in the same manner, always applying a 0 % lower relative humidity after each step. Weight changes during sorption / desorption cycles (repeated 3 times) were recorded to measure hygroscopicity of the sample.

4. High-Performance Liquid Chromatography (HPLC)

High-performance liquid chromatography (HPLC) analysis was performed by using an Agilent 1100/1200 Series HPLC Systems (Agilent, USA) analyzer to analyze purity and contents such as a stability test, and analysis conditions were as follows.

Purity and content analysis conditions: Furopyrimidine compound of Formula 1

Column: Hydrosphere C18 (YMC), 5 μm (150 mm Х 4.6 mm)

Column temperature: 30 °C

Detector: ultraviolet absorption photometer

Detection wavelength: 254 nm

Flow velocity: 1.0 mL/min

Analysis time: 35 minutes

Eluent: NaClO₄-NaH₂PO₄ -phosphoric acid buffer solution (pH 2.5±0.1)/CH₃CN = 65/35 (v/v%)

5. Measurement of moisture

Measurement of moisture was carried out by using a Karl Fischer water titrator 795KFT Titrino (Metrohm, Switzerland).

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

According to a method disclosed in Korean Patent Publication No.10-1954370 and International Publication of International Application No.2020-022600 cited herein, a mixture including the compound of Formula 1 was prepared.

Example 1: Preparation of an amorphous form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (compound of Formula 1) (86 g) was dissolved in ethanol (86 mL). Hydrochloric acid (40 ml, 2.5 eq) 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-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine hydrochloride. The obtained hydrochloride was slowly added to a sodium bicarbonate aqueous 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 warm airflow of 50 °C to obtain 72 g (84 %) of the compound of interest.

Moisture content (Karl Fischer water titrator): about 2.3 %

Characterization analysis

XRPD results of the amorphous form are shown in FIG. 1.

FIG. 1 shows results of X-ray powder diffraction (XRPD) analysis of an amorphous form of a compound 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (hereinafter, referred to as "compound of Formula 1").

As shown in FIG. 1, when the amorphous form of the compound of Formula 1 was irradiated with a Cu-Kα light source, the amorphous form did not exhibit a peak having relative intensity (I/I₀: I is intensity of each peak; I₀is intensity of the highest peak) of 10 % or more in an X-ray powder diffraction (XRPD) pattern.

DCS (10 °C/min) results of the amorphous form showed heat absorption peaks of an initiation point of 80.7 °C and a bottom point of 91.4 °C, and the absorption peak at 91.4 °C indicates a melting point.

The amorphous form showed a moisture content of about 2.3 % in a Karl Fischer water titrator.

In DVS of the amorphous form, hygroscopicity was measured to be about 5 % in a region where relative humidity was 0 % to 90 %.

Example 2: Preparation of a monohydrate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-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 a solid, which was then washed with 80 % acetone. The obtained solid was dried with warm airflow of 50 °C to obtain 195 g (78 %) of the compound of interest.

Moisture content (Karl Fischer water titrator): about 3.5 %

Characterization analysis

XRPD results of the monohydrate crystalline form prepared in Example 1 are shown in Table 1 and FIG. 2.

In the XRPD spectrum of the monohydrate crystalline form, peaks having relative intensity (I/I0) of 5 % or more are shown in Table 1 below.

2θ(±0.2)	d	I/I₀(%)	2 θ(±0.2)	d	I/I₀(%)
5.0	17.6	56	16.9	5.2	45.5
7.8	11.3	19	17.9	4.9	16
7.1	12.5	5.6	18.7	4.8	7.6
10.1	8.7	100	20.6	4.3	5.6
11.0	8.0	10.1	23.6	3.8	7.9
11.7	7.6	16.8	24.3	3.7	7.5
15.7	5.6	8.7	27.0	3.3	6.1
16.8	5.3	28.5
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀(%): Relative intensity (I/I₀: I is intensity of each peak; I₀is intensity of the highest peak.)

Table 1 and FIG. 2 show XRPD analysis results of the monohydrate crystalline form of the compound of Formula 1.As shown in Table 1 and FIG. 2, the monohydrate crystalline form of the compound of Formula 1 showed an X-ray powder diffraction (XRPD) spectrum including peaks having 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°.

Furthermore, as shown in Table 1 and FIG. 2, the monohydrate crystalline form of the compound of Formula 1 showed an X-ray powder diffraction spectroscopy (XRPD) spectrum further including peaks having 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°.

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

DSC (10 °C/min) results of the crystalline form showed heat absorption peaks of an initiation point of 74.9 °C and a bottom point of 89.0 °C, and an absorption peak of about 161.6 °C. In the DSC results, an absorption peak of about 89.0 °C indicates a dehydration point of the monohydrate crystalline form, and an absorption peak of about 161.6 °C indicates a melting point.

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

DVS (10 °C/min) analysis results of the crystalline form show an occurrence of moisture absorption in a region where relative humidity is 0 % to 20 %, but in a region where relative humidity is 30 % or more, the level of moisture absorption is very low. The crystalline form was sufficiently stable under an accelerated condition (e.g., a temperature of 40 °C and relative humidity of 75 %) and a stress condition (e.g., a temperature of 60 °C).

Example 3: Preparation of a trihydrate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (5 g) was dissolved in ethyl acetate (50 mL). The mixed solution was stirred at a temperature of 20 °C to 25 °C for about 7 hours. The resulting solid was obtained by filtration and washed with ethyl acetate. The obtained solid was dried with warm airflow of 50 °C to obtain 4.3 g (86 %) of the compound of interest.

Moisture content (Karl Fischer water titrator): about 10.8 %

Characterization analysis

XRPD results of the trihydrate crystalline form prepared in Example 2 are shown in Table 2 and FIG. 3.

In the XRPD spectrum of the trihydrate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table 2 below.

2θ(±0.2)	d	I/I₀(%)	2θ (±0.2)	d	I/I₀(%)
8.2	10.8	100	20.8	4.3	20
9.3	9.5	30.7	21.3	4.2	17.3
11.1	8.0	21.9	22.5	4.0	10.2
14.2	6.2	10.1	22.9	3.9	15.8
15.9	5.6	11.3	23.1	3.9	11
16.2	5.5	12.9	23.9	3.7	17
17.2	5.2	22	24.6	3.6	11.3
17.4	5.1	10.5	25.5	3.5	17.5
18.4	4.8	13.7	26.5	3.4	10.6
19.2	4.6	19.3	27.4	3.2	10.4
19.6	4.5	14.5
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀(%): Relative intensity (I/I₀: I is intensity of each peak; I₀is intensity of the highest peak.)

Table 2 and FIG. 3 show XRPD analysis results of the trihydrate crystalline form of the compound of Formula 1.

As shown in Table 2 and FIG. 3, the trihydrate crystalline form of the compound of Formula 1 showed an X-ray powder diffraction (XRPD) spectrum including peaks having 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°.

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

DSC (10 °C/min) results of the crystalline form showed heat absorption peaks of an initiation point of 44.9 °C and a bottom point of 68.7 °C, and an absorption peak of about 108.3 °C. In the DSC results, an absorption peak of about 68.7 °C indicates a dehydration point of the trihydrate crystalline form, and an absorption peak of about 108.3 °C indicates a melting point.

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

In DVS of the crystalline form, hygroscopicity was measured to be about 12 % in a region where relative humidity was 0 % to 90 %. The crystalline form was sufficiently stable under an accelerated condition (e.g., a temperature of 40 °C and relative humidity of 75 %) and a stress condition (e.g., a temperature of 60 °C).

Example 4: Preparation of a crystalline form of an ethanol mono-solvate of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (1 g) was placed in ethanol (10 mL) and dissolved by reflux. 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 warm airflow of 50 °C to obtain 0.6 g (60 %) of the compound of interest.

Moisture content (Karl Fischer water titrator): about 0.2 %

Characterization analysis

XRPD results of the crystalline form of the ethanol mono-solvate prepared in Example 3 are shown in Table 3 and FIG. 4.

In the XRPD spectrum of the crystalline form of the ethanol mono-solvate, peaks having relative intensity (I/I0) of 10 % or more are shown in Table 3.

2θ(±0.2)	d	I/I₀(%)	2θ (±0.2)	d	I/I₀(%)
6.7	13.2	18.5	20.9	4.3	31
7.8	11.3	45.6	21.4	4.2	69
8.6	10.3	65.1	22.1	4.0	18.5
11.0	8.0	33.9	22.9	3.9	21.2
12.8	6.9	18.8	23.2	3.8	24.8
13.0	6.8	73.5	23.6	3.8	22
15.7	5.7	13.3	24.0	3.7	57.5
16.5	5.4	11.8	25.7	3.5	42.8
16.8	5.3	34.7	26.1	3.4	10.2
17.2	5.1	100	27.0	3.3	13.7
17.5	5.1	60.0	27.5	3.2	10.8
18.9	4.7	61.9	28.1	3.2	11.5
19.2	4.6	46	29.0	3.1	10.2
19.6	4.5	27.2	29.4	3.0	13.3
20.1	4.4	39.9	32.2	2.8	14.5
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀(%): Relative intensity (I/I₀: I is intensity of each peak; I₀is intensity of the highest peak.)

Table 3 and FIG. 4 show XRPD analysis results of the crystalline form of an ethanol mono-solvate of the compound of Formula 1.As shown in Table 3 and FIG. 4, the crystalline form of the ethanol mono-solvate of the compound of Formula 1 showed an X-ray powder diffraction (XRPD) spectrum including peaks having 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°.

FIG. 10 shows analysis results of differential scanning calorimetry (DSC) of the crystalline form of the ethanol mono-solvate of the compound of Formula 1.

DSC (10 °C/min) results of the crystalline form showed heat absorption peaks of an initiation point of 99.8 °C and a bottom point of 113. °C. In the DSC results, an absorption peak of about 99.8 °C indicates a dehydration point of the ethanol mono-solvate, and an absorption peak of about 113.4 °C indicates a melting point.

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

In DVS of the crystalline form, hygroscopicity was measured to be as low as about 0.3 % in a region where relative humidity was 0 % to 90 %. The crystalline form was sufficiently stable under an accelerated condition (e.g., a temperature of 40 °C and relative humidity of 75 %) and a stress condition (e.g., a temperature of 60 °C).

Example 5: Preparation of an anhydrate crystalline form I of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (1 g) was dissolved in ethanol (8 L), and water (2 mL) was added dropwise at room temperature. The mixture was heated to 50 °C and stirred for about 30 minutes. The solution was cooled to a temperature of 20 °C to 25 °C and stirred for 5 hours. The resulting solid was obtained by filtration and washed with 80% ethanol. The obtained solid was dried with warm airflow of 50 °C to obtain 0.8 g (81 %) of the compound of interest.

Moisture content (Karl Fischer water titrator): about 0.2 %

Characterization analysis

XRPD results of the anhydrate crystalline form I prepared in Example 4 are shown in Table 4 and FIG. 5. In the XRPD spectrum of the anhydrate crystalline form I, peaks having relative intensity (I/I0) of 10 % or more are shown in Table 4 below.

2θ(±0.2)	d	I/I₀(%)	2θ (±0.2)	d	I/I₀(%)
5.2	17.1	100	17.5	5.1	26.9
6.5	13.5	19.2	18.1	4.9	29.5
10.4	8.5	87.3	20.2	4.4	12.8
11.2	7.9	16.6	21.8	4.1	12.4
15.1	5.9	14.1	22.5	4.0	13.4
16.5	5.4	24.2	22.9	3.9	11.3
17.2	5.2	22.5	25.7	3.5	19.8
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀(%): Relative intensity (I/I₀: I is intensity of each peak; I₀is intensity of the highest peak.)

Table 4 and FIG. 5 show XRPD analysis results of the anhydrate crystalline form I of the compound 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (hereinafter, referred to as "compound of Formula 1").As shown in Table 4 and FIG. 5, the anhydrate crystalline form I of the compound of Formula 1 showed an X-ray powder diffraction (XRPD) spectrum including peaks having 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°.

FIG. 11 shows analysis results of differential scanning calorimetry (DSC) of the anhydrate crystalline form I of the compound of Formula 1;.

DSC (10 °C/min) results of the crystalline form showed heat absorption peaks of an initiation point of about 152.4 °C and a bottom point of about 159.5 °C. An absorption peak of about 159.5 °C indicates a melting point.

In DVS of the crystalline form, hygroscopicity was measured to be about 3.5 % in a region where relative humidity was 0 % to 90 %. The crystalline form was sufficiently stable under an accelerated condition (e.g., a temperature of 40 °C and relative humidity of 75 %) and a stress condition (e.g., a temperature of 60 °C).

Example 6: Preparation of an anhydrate crystalline form II of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-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 warm airflow of 50 °C to obtain 1.7 g (85 %) of the compound of interest.

Moisture content (Karl Fischer water titrator): about 0.5 %

Characterization analysis

XRPD results of the anhydrate crystalline form II prepared in Example 5 are shown in Table 5 and FIG. 6. In the XRPD spectrum of the anhydrate crystalline form II, peaks having relative intensity (I/I0) of 10 % or more are shown in Table 5 below.

2θ(±0.2)	d	I/I₀(%)	2θ (±0.2)	d	I/I₀(%)
4.9	18.1	99.5	17.7	5.0	83.8
5.9	14.9	86.5	19.0	4.7	55.8
6.4	13.8	11.4	19.6	4.5	15.1
8.1	10.9	20.5	21.1	4.2	17.4
9.7	9.1	100	21.4	4.1	22.1
10.7	8.3	10.1	22.3	4.0	16.4
11.8	7.5	41.7	23.0	3.9	27.7
13.3	6.6	15.1	24.8	3.6	15.3
14.3	6.2	25.2	25.9	3.4	24.7
15.0	5.9	21.4	28.5	3.1	11.9
16.3	5.4	17.8	32.7	2.7	10.1
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀(%): Relative intensity (I/I₀: I is intensity of each peak; I₀is intensity of the highest peak.)

Table 5 and FIG. 6 show XRPD analysis results of the anhydrate crystalline form II of the compound of Formula 1.As shown in Table 5 and FIG. 6, the anhydrate crystalline form II of the compound of Formula 1 showed an X-ray powder diffraction (XRPD) spectrum including peaks having 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°.

FIG. 12 shows analysis results of differential scanning calorimetry (DSC) of the anhydrate crystalline form II of the compound of Formula 1.

DSC (10 °C/min) results of the crystalline form showed heat absorption peaks of an initiation point of about 139.8 °C and a bottom point of about 149.4 °C. An absorption peak of about 149.4 °C indicates a melting point.

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

In DVS of the crystalline form, hygroscopicity was measured to be as low as about 0.5 % in a region where relative humidity was 0 % to 90 %. The crystalline form was sufficiently stable under an accelerated condition (e.g., a temperature of 40 °C and relative humidity of 75 %) and a stress condition (e.g., a temperature of 60 °C).

Example 7: Preparation of a dihydrochloride crystalline form I of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

3.8 g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine · dihydrochloride was charged into a flask, and then 38mL of 80% aq. ethanol was added. The reaction mixture was refluxed for 1hr, and then was cooled to room temperature (20~25℃). The mixture was stirred for overnight at room temperature (20~25℃). The resulting solid was filtered and then washed with 8mL of 80% aq. ethanol. The wet solid was dried under oven at 50℃ for overnight.

Moisture content (Karl Fischer water titrator): about 3.4 %

Characterization analysis

XRPD results of the dihydrochloride crystalline form I prepared in Example 7 are shown in Table 6 and FIG. 13.

In the XRPD spectrum of the dihydrochloride crystalline form I, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
5.4	16.5	26.1	21.2	4.2	13.0
8.2	10.8	98.0	21.4	4.1	21.6
9.4	9.4	82.8	21.8	4.1	19.9
10.1	8.7	24.3	22.4	4.0	19.0
10.5	8.4	16.8	23.0	3.9	14.4
10.8	8.2	33.3	23.4	3.8	59.2
11.2	7.9	23.8	24.6	3.6	24.7
12.7	6.9	15.0	24.8	3.6	23.4
13.3	6.7	12.8	25.2	3.5	19.9
14.6	6.1	64.2	25.5	3.5	24.3
15.5	5.7	50.5	25.8	3.4	47.5
15.8	5.6	19.0	26.2	3.4	75.1
16.2	5.5	12.2	27.1	3.3	34.6
16.5	5.4	31.1	28.0	3.2	16.5
17.1	5.2	26.0	29.3	3.0	11.7
17.6	5.0	54.8	31.0	2.9	19.9
18.5	4.8	51.9	33.2	2.7	22.3
19.1	4.7	100	34.5	2.6	16.1
19.9	4.5	11.0	38.4	2.3	11.2
20.5	4.3	17.0
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

The dihydrochloride crystalline form I was confirmed to be an ethanol solvate. FIG. 25 shows analysis results of differential scanning calorimetry (DSC) of the dihydrochloride crystalline form I of the compound of Formula 1.

DSC (10 °C/min) results of the crystalline 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.

Example 8: Preparation of a dihydrochloride crystalline form II of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

3g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine · dihydrochloride was charged into a flask, and then 30mL of ethanol was added. The reaction mixture was refluxed for 1hr, and then was cooled to room temperature (20~25℃). The mixture was stirred for 6hr at room temperature (20~25℃). The resulting solid was filtered and then washed with 6mL of ethanol. The wet solid was dried under oven at 50℃ for overnight.

Moisture content (Karl Fischer water titrator): about 0.5 %.

Characterization analysis

XRPD results of the dihydrochloride crystalline form II prepared in Example 8 are shown in Table 7 and FIG. 14.

In the XRPD spectrum of the dihydrochloride crystalline form II, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
8.3	10.6	22.7	21.9	4.1	14.4
8.6	10.3	22.1	22.3	4.0	54.6
10.5	8.4	100	22.7	3.9	35.9
11.9	7.4	19.7	23.1	3.8	60.9
12.3	7.2	36.5	23.5	3.8	16.8
12.6	7.0	17.0	23.9	3.7	34.8
13.6	6.5	28.9	25.1	3.5	32.9
14.5	6.1	17.0	25.7	3.5	27.6
15.0	5.9	27.0	26.3	3.4	41.8
15.2	5.8	64.2	26.7	3.3	23.6
16.2	5.5	13.4	27.2	3.3	42.7
16.7	5.3	13.4	27.9	3.2	14.7
17.8	5.0	42.3	28.1	3.2	14.7
18.1	4.9	28.2	29.4	3.0	16.1
18.8	4.7	29.1	30.1	3.0	13.6
19.1	4.6	19.3	30.8	2.9	12.7
19.8	4.5	41.6	31.2	2.9	14.6
20.3	4.4	27.6	32.7	2.7	16.8
20.8	4.3	22.7	36.2	2.5	10.8
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

FIG. 26 shows analysis results of differential scanning calorimetry (DSC) of the dihydrochloride crystalline form II of the compound of Formula 1.DSC (10 °C/min) results of the dihydrochloride crystalline form II of the compound of Formula 1 showed an endothermic heat absorption peak with an onset of 213 °C and a peak maximum of 239 °C.

Example 9: Preparation of a monohydrochloride crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine was charged into a flask, and then 50mL of acetone was added. 0.97 mL of conc. HCl was added to the mixture. The reaction mixture was stirred for overnight at room temperature (20~25℃). The resulting solid was filtered and then washed with 10mL of acetone. The wet solid was dried under oven at 50℃ for overnight.

Moisture content (Karl Fischer water titrator): about 3.7 %.

Characterization analysis

XRPD results of the monohydrochloride crystalline form prepared in Example 9 are shown in Table 8 and FIG. 15.

In the XRPD spectrum of the monohydrochloride crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
4.9	18.0	58.2	17.1	5.2	81.5
5.4	16.4	71.2	18.6	4.8	100
8.0	11.1	45.7	19.0	4.7	70.7
9.3	9.5	48.4	20.9	4.3	74.5
14.2	6.3	64.7	23.5	3.8	86.4
14.6	6.1	59.2	26.0	3.4	71.2
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

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

Example 10: Preparation of a disulfate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

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

Moisture content (Karl Fischer water titrator): about 5.4 %

Characterization analysis

XRPD results of the disulfate crystalline form prepared in Example 10 are shown in Table 9 and FIG. 16.

In the XRPD spectrum of the disulfate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
6.5	13.5	15.3	21.3	4.2	37.8
8.8	10.0	76.5	22.3	4.0	55.8
11.1	8.0	60.1	23.2	3.8	27.1
11.4	7.7	100	23.7	3.8	31.4
12.3	7.2	14.1	24.3	3.7	70.4
12.9	6.8	19.8	24.5	3.6	58.5
14.1	6.3	21.9	25.4	3.5	23.7
14.3	6.2	21.4	26.1	3.4	20.0
14.8	6.0	28.5	26.5	3.4	48.3
15.2	5.8	63.3	27.8	3.2	51.5
17.0	5.2	46.9	28.4	3.1	16.9
17.3	5.1	40.1	28.8	3.1	21.4
18.3	4.8	31.2	29.1	3.1	21.9
18.9	4.7	24.8	29.7	3.0	17.1
19.2	4.6	36.9	33.0	2.7	13.0
20.2	4.4	36.4	33.4	2.7	11.2
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

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

Example 11: Preparation of a monosulfate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (amorphous) was charged into a flask, and then 50mL of acetone was added. 0.59 mL of sulfuric acid was added to the mixture. The reaction mixture was stirred for overnight at room temperature (20~25℃). The resulting solid was filtered and then washed with 10mL of acetone. The wet solid was dried under oven at 50℃ for overnight.

Moisture content (Karl Fischer water titrator): about 6.8 %

Characterization analysis

XRPD results of the monosulfate crystalline form prepared in Example 11 are shown in Table 10 and FIG. 17.

In the XRPD spectrum of the monosulfate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

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

Example 12: Preparation of a difumarate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine (amorphous) was charged into a flask, and then 50mL of ethyl acetate was added. 2.9g of fumaric acid was added to the mixture. The reaction mixture was stirred for 7hr at room temperature (20~25℃). The resulting solid was filtered and then washed with 10mL of ethyl acetate. The wet solid was dried under oven at 50℃ for overnight.

Moisture content (Karl Fischer water titrator): about 1.5 %

Characterization analysis

XRPD results of the difumarate crystalline form prepared in Example 12 are shown in Table 11 and FIG. 18.

In the XRPD spectrum of the difumarate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
5.5	16.0	30.7	16.6	5.3	11.4
5.7	15.4	19.0	19.1	4.6	24.0
6.8	12.9	11.9	19.8	4.5	12.9
8.0	11.1	10.8	21.1	4.2	21.5
8.5	10.3	29.0	22.0	4.0	16.1
9.7	9.1	10.0	22.5	3.9	16.9
11.7	7.5	10.6	22.9	3.9	44.5
13.3	6.7	14.4	25.1	3.5	17.4
13.8	6.4	10.9	26.0	3.4	10.5
14.5	6.1	23.1	28.9	3.1	100
15.0	5.9	12.4	29.4	3.0	32.4
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

FIG. 30 shows analysis results of differential scanning calorimetry (DSC) of the difumarate crystalline form of the compound of Formula 1.DSC (10 °C/min) results of the difumarate crystalline form of the compound of Formula 1 showed an endothermic heat absorption peak with an onset of 149 °C and a peak maximum of 160 °C.

Example 13: Preparation of a hemifumarate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

3g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine hemifumarate was charged into a flask, and then 30mL of 80% aq. ethanol was added. The mixture was refluxed (dissolved and precipitated solid). The reaction mixture was cooled to room temperature and then was stirred for 5hr at room temperature (20~25℃). The resulting solid was filtered and then washed with 6mL of 80% aq. ethanol. The wet solid was dried under oven at 50℃ for overnight.

Moisture content (Karl Fischer water titrator): about 0.1 %.

Characterization analysis

XRPD results of the hemifumarate crystalline form prepared in Example 13 are shown in Table 12 and FIG. 19.

In the XRPD spectrum of the hemifumarate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
5.1	17.4	17.7	19.2	4.6	28.6
6.8	12.9	56.6	21.6	4.1	13.8
8.3	10.6	35.1	22.7	3.9	10.9
10.2	8.7	41.4	23.1	3.8	32.4
12.6	7.0	43.4	23.4	3.8	42.3
13.8	6.4	33.2	23.9	3.7	11.4
15.3	5.8	21.4	24.7	3.6	19.5
16.0	5.6	10.4	25.4	3.5	11.9
16.2	5.5	10.9	25.6	3.5	37.9
16.4	5.4	20.7	26.9	3.3	16.4
17.1	5.2	100	28.5	3.1	10.1
18.4	4.8	30.7	29.0	3.1	10.3
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

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

Example 14: Preparation of a monosuccinate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

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

Moisture content (Karl Fischer water titrator): about 1.8 %.

Characterization analysis

XRPD results of the monosuccinate crystalline form prepared in Example 14 are shown in Table 13 and FIG. 20.

In the XRPD spectrum of the monosuccinate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
5.1	17.4	22.2	21.0	4.2	44.5
6.9	12.8	71.5	21.7	4.1	41.5
8.4	10.5	47.6	22.6	3.9	41.7
8.7	10.1	17.1	23.3	3.8	62.2
9.2	9.6	14.0	23.6	3.8	100
10.2	8.7	27.2	24.1	3.7	43.5
12.6	7.0	40.4	24.8	3.6	43.3
13.9	6.4	51.2	25.5	3.5	30.5
15.3	5.8	23.8	25.9	3.4	28.3
15.9	5.6	29.3	28.5	3.1	24.0
16.3	5.4	30.7	29.2	3.0	28.0
16.9	5.2	79.5	29.8	3.0	18.7
18.5	4.8	79.7	31.3	2.9	16.9
19.3	4.6	56.7	32.8	2.7	21.9
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

FIG. 32 shows analysis results of differential scanning calorimetry (DSC) of the monosuccinate crystalline form of the compound of Formula 1. DSC (10 °C/min) results of the monosuccinate crystalline form of the compound of Formula 1 showed 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.

Example 15: Preparation of a hemisuccinate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

2g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine·monosuccinate was charged into a flask, and then 20mL of 80% aq. ethanol was added. The mixture was refluxed (not dissolved). The mixture was cooled to room temperature (20~25℃). The mixture was stirred for overnight at room temperature. The resulting solid was filtered and then washed with 4mL of ethanol. The wet solid was dried under oven at 50℃ for overnight.

Moisture content (Karl Fischer water titrator): about 0.3 %.

Characterization analysis

XRPD results of the hemisuccinate crystalline form prepared in Example 15 are shown in Table 14 and FIG. 21.

In the XRPD spectrum of the hemisuccinate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
5.1	17.4	28.3	23.1	3.9	23.5
6.9	12.8	84.9	23.3	3.8	55.7
8.4	10.5	61.8	23.6	3.8	100
10.2	8.7	34.8	24.1	3.7	28.5
12.6	7.0	56.3	24.8	3.6	34.1
13.9	6.4	49.3	25.3	3.5	15.2
15.3	5.8	24.6	25.5	3.5	32.5
15.9	5.6	19.3	26.0	3.4	18.5
16.3	5.4	17.9	26.8	3.3	11.9
16.5	5.4	24.6	27.7	3.2	13.3
17.0	5.2	97	27.9	3.2	11.8
18.5	4.8	55.4	28.5	3.1	19.9
18.8	4.7	15.8	29.2	3.1	22.9
19.3	4.6	48.8	29.8	3.0	12.5
20.1	4.4	10.2	30.8	2.9	12.2
21.1	4.2	21.3	31.3	2.9	11.8
21.7	4.1	21.6	32.8	2.7	18.5
22.6	3.9	28.6
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

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

Example 16: Preparation of a dimaleate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

5g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine was charged into a flask, and then 50mL of ethanol was added. 2.61g of Maleic acid was added to the mixture, and then was stirred for overnight (Non-precipitation), The solution was concentrated under reduced pressure, and 25mL ethanol was added. The mixture was stirred for overnight at room temperature (Non-precipitation). The mixture was concentrated under reduced pressure. 50mL of acetone was added to the residue and stirred for 8hr. The resulting solid was filtered and then washed with 10mL of acetone. The wet solid was dried under oven at 50°C for overnight.Moisture content (Karl Fischer water titrator): about 3.4 %.

Characterization analysis.

XRPD results of the dimaleate crystalline form prepared in Example 16 are shown in Table 15 and FIG. 22.

In the XRPD spectrum of the dimaleate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
5.7	15.6	16.9	21.1	4.2	41.6
7.1	12.4	47.3	22.1	4.0	28.1
8.9	9.9	34.3	22.6	3.9	31.1
9.4	9.4	47.3	22.9	3.9	27.0
11.4	7.8	100	23.5	3.8	25.4
12.2	7.3	56.6	24.1	3.7	44.1
14.0	6.3	40.6	24.4	3.6	34.3
14.8	6.0	43.8	25.0	3.6	32.9
15.1	5.9	32.4	25.9	3.4	24.2
15.8	5.6	23.3	27.4	3.2	74.2
16.6	5.4	47.0	27.8	3.2	47.5
18.6	4.8	37.9	30.1	3.0	21.7
19.2	4.6	41.1	30.6	2.9	18.5
20.0	4.4	18.7	33.0	2.7	14.4
20.7	4.3	42.2
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

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

Example 17: Preparation of a sesquimaleate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

0.65g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine·dimaleate was charged into a flask, and then 6.5mL of ethanol was added. The mixture was refluxed (dissolved and precipitated solid). The reaction mixture was cooled to room temperature (20~25℃) and then was stirred for 4hr. The resulting solid was filtered and then washed with 1.3mL of ethanol. The wet solid was dried under oven at 50℃ for overnight.

Moisture content (Karl Fischer water titrator): about 3.0 %

Characterization analysis

XRPD results of the sesquimaleate crystalline form prepared in Example 17 are shown in Table 16 and FIG. 23.

In the XRPD spectrum of the sesquimaleate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
6.7	13.2	23.4	20.1	4.4	23.4
8.9	9.9	42.9	20.3	4.4	25.9
10.1	8.8	22.7	20.9	4.2	30.9
11.8	7.5	12.4	21.5	4.1	16.8
13.8	6.4	57.0	22.0	4.0	21.4
14.2	6.2	29.4	22.5	4.0	42.0
14.5	6.1	23.3	22.7	3.9	22.2
14.9	5.9	22.7	23.2	3.8	12.5
15.8	5.6	22.7	23.5	3.8	13.5
16.1	5.5	51.3	23.8	3.7	16.2
16.4	5.4	14.5	24.4	3.6	10.2
16.7	5.3	12.0	24.8	3.6	16.6
17.1	5.2	58.0	26.2	3.4	35.5
17.4	5.1	10.0	26.6	3.3	26.9
17.9	5.0	14.0	27.7	3.2	20.3
18.5	4.8	100	28.3	3.2	12.1
18.9	4.7	17.6	29.1	3.1	19.1
19.2	4.6	19.5	32.5	2.8	12.5
19.6	4.5	33.5
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

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

Example 18: Preparation of a monomaleate crystalline form of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine.

1g of 5-chloro-N-(3-cyclopropyl-5-(((3R,5S)-3,5-dimethylpiperazine-1-yl)methyl)phenyl)-4-(6-methyl-1H-indole-3-yl)pyrimidine-2-amine·monomaleate was charged into a flask, and then 10mL of ethanol was added. The reaction mixture was refluxed for 1hr, and then was cooled to room temperature (20~25°C). The mixture was stirred for 4hr at room temperature (20~25°C). The resulting solid was filtered and then washed with 2mL of ethanol. The wet solid was dried under oven at 50°C for overnight.

Moisture content (Karl Fischer water titrator): about 0.2%.

Characterization analysis

XRPD results of the monomaleate crystalline form prepared in Example 18 are shown in Table 17 and FIG. 24.

In the XRPD spectrum of the monomaleate crystalline form, peaks having relative intensity (I/I0) of 10 % or more are shown in Table below.

2θ(±0.2)	d	I/I₀(%)	2θ(±0.2)	d	I/I₀(%)
5.9	15.0	25.3	19.4	4.6	24.2
6.9	12.9	100	19.9	4.5	24.2
9.6	9.2	30.7	20.8	4.3	18.4
11.4	7.7	12.5	20.9	4.2	16.7
11.9	7.5	46.0	21.8	4.1	15.9
13.9	6.4	10.5	23.7	3.8	23.5
14.6	6.1	10.6	24.0	3.7	45.7
15.7	5.6	32.4	25.1	3.5	17.7
16.0	5.5	20.1	25.8	3.5	14.9
17.0	5.2	11.9	28.1	3.2	17.2
17.2	5.1	14.1	28.9	3.1	19.0
18.9	4.7	20.8
2θ: Diffraction angle, d: Distance between crystal faces, I/I₀ (%): Relative intensity (I/I₀: I is intensity of each peak; I₀ is intensity of the highest peak.)

FIG. 36 shows analysis results of differential scanning calorimetry (DSC) of the monomaleate crystalline form of the compound of Formula 1.DSC (10 °C/min) results of the monomaleate crystalline form of the compound of Formula 1 showed an endothermic heat absorption peak with an onset of 203 °C and a peak maximum of 207°C.It will be understood by those skilled in the art that various changes may be made therein without departing from the spirit and scope of the present disclosure. Therefore, exemplary examples disclosed herein should be considered in an illustrative aspect rather than a restrictive aspect. The scope of the present disclosure is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present disclosure.

EMBODIMENTS

Embodiment 1. A crystalline form of the compound of Formula 1:

[Formula 1]

.

Embodiment 2. The crystalline form of embodiment 1, wherein the crystalline form is a crystalline form of a hydrate of the compound of Formula 1.

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

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

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

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

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

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

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

Embodiment 10. The crystalline form of embodiment 1, wherein the crystalline form is a crystalline form of an ethanol mono-solvate of the compound of Formula 1.

Embodiment 11. The crystalline form of embodiment 10, wherein the crystalline form of an ethanol mono-solvate has a characteristic XRPD pattern including peaks at diffraction angles 2θ of 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.9°±0.2°, and 21.4°±0.2°, when irradiated with a Cu-Kα light source.

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

Embodiment 13. The crystalline form of embodiment 1, wherein the crystalline form is an anhydrate crystalline form I of the compound of Formula 1.

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

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

Embodiment 16. The crystalline form of embodiment 1, wherein the crystalline form is an anhydrate crystalline form II of the compound of Formula 1.

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

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

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

Embodiment 20. An amorphous form of Formula 1

(Formula 1), or a solvate thereof.

Embodiment 21. An amorphous form of embodiment 20, wherein the amorphous form exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to the pattern shown in FIG. 1.

Embodiment 22. An amorphous form of embodiment 20, wherein the amorphous form exhibits a differential scanning calorimetry (DSC) thermogram substantially similar to FIG. 7.

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

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

Embodiment 25. The means of embodiments 23 or 24, wherein the means are in a crystalline form.

Embodiment 26. The means of embodiments 23 or 24, wherein the means are in an amorphous form.

Embodiment 27. The means of embodiment 25, wherein the crystalline form includes a hydrate of the compound of Formula 1.

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

Embodiment 29. The means of embodiment 25, wherein the crystalline form includes an ethanol mono-solvate of the compound of Formula 1.

Embodiment 30. The means of embodiment 25, wherein the crystalline form includes an anhydrate of the compound of Formula 1.

Embodiment 31. A pharmaceutical composition comprising at least one crystalline form of the compound of Formula 1 according to embodiment 1; and at least one pharmaceutically acceptable carrier or diluent.

Embodiment 32. A pharmaceutical composition comprising at least one amorphous form of the compound of Formula 1 according to embodiment 20; and at least one pharmaceutically acceptable carrier or diluent.

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

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

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

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

Embodiment 37. The pharmaceutical composition of embodiment 35 or 36, wherein the means are in a crystalline form.

Embodiment 38. The pharmaceutical composition of embodiment 35 or 36, wherein the means are in an amorphous form.

Embodiment 39. A pharmaceutical composition of embodiment 37, wherein the composition comprises a crystalline form of the compound of Formula 1 is according to any one of embodiments 2-19 and at least one pharmaceutically acceptable carrier or diluent.

Embodiment 40. A pharmaceutical composition of embodiment 38, wherein the composition comprises an amorphous form of the compound of Formula 1 according to any one of embodiments 20-22, and at least one pharmaceutically acceptable carrier or diluent.

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

Embodiment 42. The pharmaceutical composition of embodiment 41, wherein a

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

Embodiment 43. The pharmaceutical composition of any one of embodiments 31-40, wherein a

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

Embodiment 44. The pharmaceutical composition of any one of embodiments 31-40, wherein a

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

Embodiment 45. The pharmaceutical composition of any one of embodiments 31-40, wherein a

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

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

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

Embodiment 48. The pharmaceutical composition of any one of embodiments 31-40, wherein a

an amorphous form is at least about 90% pure in the pharmaceutical composition.

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

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

Claims

A crystalline form of the compound of Formula 1:

[Formula 1]

or a pharmaceutically acceptable salt, solvate, or solvate salt thereof.
The crystalline form of claim 1, wherein the crystalline form is a hydrate of the compound of Formula 1.
The crystalline form of claim 1 or 2, wherein the crystalline form has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.0°±0.2°, 10.1°±0.2°, and 16.9°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 1-3, wherein the crystalline form has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.0°±0.2°, 7.8°±0.2°, 10.1°±0.2°, 16.8°±0.2°, and 16.9°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 4, wherein the crystalline form has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 11.0°±0.2°, 11.7°±0.2°, and 17.9°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 5, wherein the crystalline form has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 15.7°±0.2°, 18.7°±0.2°, 23.6°±0.2°, and 24.3°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 1-6, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 2.
The crystalline form of any one of claims 1-7, that has a DSC thermogram substantially similar to FIG. 8.
The crystalline form of claim 2, wherein the crystalline form has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.3°±0.2°, and 17.2°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 2 or 9, wherein the crystalline form has a XRPD pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.3°±0.2°, 11.1°±0.2°, 17.2°±0.2°, and 20.8°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 10, wherein the crystalline form has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 19.2°±0.2°, 19.6°±0.2°, 21.3°±0.2°, 22.9°±0.2°, 23.9°±0.2°, and 25.5°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 9-11, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 3.
The crystalline form of any one of claims 9-12, that has a DSC thermogram substantially similar to FIG. 9.
The crystalline form any one of claims 1-8, wherein the hydrate is a monohydrate.
The crystalline form of claim 1-2 or 9-13, wherein the hydrate is a trihydrate.
The crystalline form of claim 1, wherein the crystalline form is an ethanol mono-solvate of the compound of Formula 1.
The crystalline form of claim 16, wherein the crystalline form has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.6°±0.2°, 17.2°±0.2°, and 21.4±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 17, wherein the crystalline form has a XRPD pattern comprising peaks at diffraction angles 2θ of 8.6°±0.2°, 13.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 18.9°±0.2°, and 21.4°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 18, wherein the crystalline form of an ethanol mono-solvate has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 7.8°±0.2°, 19.2°±0.2°, 24.0°±0.2°, and 25.7°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 16-19, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 4.
The crystalline form of any one of claims 16-20, that has a DSC thermogram substantially similar to FIG. 10.
The crystalline form of claim 1, wherein the crystalline form is an anhydrate crystalline form of the compound of Formula 1.
The crystalline form of claim 22, wherein the crystalline form has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, and 18.1±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 23, wherein the anhydrate crystalline form I has a XRPD pattern comprising peaks at diffraction angles 2θ of 5.2°±0.2°, 10.4°±0.2°, 16.5°±0.2°, 17.2°±0.2°, 17.5°±0.2°, and 18.1°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 24, wherein the anhydrate crystalline form has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 6.5°±0.2°, 11.2°±0.2°, 15.1°±0.2°, 20.2°±0.2°, 21.8°±0.2°, 22.5°±0.2°, and 25.7°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 22-25 wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 5.
The crystalline form of any one of claims 22-26, that has a DSC thermogram substantially similar to FIG. 10.
The crystalline form of claim 1, wherein the anhydrate crystalline form II of the compound of Formula 1.
The crystalline form of claim 22 or 28, wherein the crystalline form has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, and 9.7±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 29, wherein the anhydrate crystalline form has a XRPD pattern comprising peaks at diffraction angles 2θ of 4.9°±0.2°, 5.9°±0.2°, 9.7°±0.2°, 17.7°±0.2°, and 19.0°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 30, wherein the anhydrate crystalline form has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 8.1°±0.2°, 11.8°±0.2°, 14.3°±0.2°, 15.0°±0.2°, 21.4°±0.2°, 23.0°±0.2°, and 25.9°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 28-31 wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 6.
The crystalline form of any one of claims 28-32, that has a DSC thermogram substantially similar to FIG. 11.
An amorphous form of Formula 1

(Formula 1), or a solvate thereof.
The amorphous form of claim 34, wherein the amorphous form exhibits an X-ray powder diffraction (XRPD) pattern substantially similar to the pattern shown in FIG. 1.
The amorphous form of claim 34, wherein the amorphous form exhibits a differential scanning calorimetry (DSC) thermogram substantially similar to FIG. 7.
The crystalline form of claim 1, wherein the crystalline form is a pharmaceutically acceptable salt of a compound of Formula 1, or a pharmaceutically acceptable salt solvate of a compound of Formula 1.
The crystalline form of claim 37, which is a crystalline form of a pharmaceutically acceptable salt of the compound of Formula 1 selected from the group consisting of a hydrochloride salt, a sulfate salt, a fumarate salt, a succinate salt, a maleate salt and a solvate thereof.
The crystalline form of claim 37 or 38, which is a dihydrochloride crystalline form of the compound of Formula 1 or a solvate thereof.
The crystalline form of claim 39, wherein the dihydrochloride crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.4°±0.2°, and 19.1°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 40, wherein the dihydrochloride crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 8.2°±0.2°, 9.4°±0.2°, 14.6 °±0.2°, 19.1°±0.2°, and 26.2°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 40 or 41, wherein the dihydrochloride crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 10.8°±0.2°, 15.5°±0.2°, 17.6°±0.2°, 18.5°±0.2°, 23.4°±0.2°, 25.8°±0.2°, and 27.1°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 39-42 wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 13.
The crystalline form of any one of claims 39-43, that has a DSC thermogram substantially similar to FIG. 25.
The crystalline form of any one of claims 39-44, which is an ethanol solvate of the dihydrochloride crystalline form of the compound of Formula 1.
The crystalline form of claim 39, wherein the dihydrochloride crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 10.5°±0.2°, 15.2°±0.2°, and 23.1°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of claim 46, wherein the dihydrochloride crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 10.5°±0.2°, 15.2°±0.2°, 22.3°±0.2°, 23.1°±0.2°, and 27.2°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 46 or 47, wherein the dihydrochloride crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 12.3°±0.2°, 17.8°±0.2°, 19.8°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 25.1°±0.2°, and 26.3°±0.2°.
The crystalline form of any one of claims 46-48 wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 14.
The crystalline form of any one of claims 46-49, that has a DSC thermogram substantially similar to FIG. 26.
The crystalline form of claim 37 or 38, which is a monohydrochloride crystalline form of the compound of Formula 1.
The crystalline form of claim 51, wherein the monohydrochloride crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 17.1°±0.2°, 18.6°±0.2°, and 23.5°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 52, wherein the monohydrochloride crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 17.1°±0.2°, 18.6°±0.2°, 19.0°±0.2°, 20.9°±0.2°, and 23.5°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 51-53, wherein the monohydrochloride crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 4.9°±0.2°, 5.4°±0.2°, 8.0°±0.2°, 9.3°±0.2°, 14.2°±0.2°, 14.6°±0.2°, and 26.0°±0.2°.
The crystalline form of any one of claims 51-54, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 15.
The crystalline form of any one of claims 51-55, that has a DSC thermogram substantially similar to FIG. 27.
The crystalline form of claim 37 or 38, which is a disulfate crystalline form of the compound of Formula 1.
The crystalline form of claim 57, wherein the disulfate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.4°±0.2°, and 24.3°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 58, wherein the disulfate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 15.2°±0.2°, and 24.3°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 58 or 59 wherein the disulfate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 17.0°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 26.5°±0.2°, and 27.8°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 57-60, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 16.
The crystalline form of any one of claims 57-61, that has a DSC thermogram substantially similar to FIG. 28.
The crystalline form of claim 37 or 38, which is a monosulfate crystalline form of the compound of Formula 1.
The crystalline form of claim 63, wherein the monosulfate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.4°±0.2°, and 24.3°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 64, wherein the monosulfate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 8.8°±0.2°, 11.1°±0.2°, 11.4°±0.2°, 15.2°±0.2°, and 24.3°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 64 or 65, wherein the monosulfate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 17.0°±0.2°, 17.3°±0.2°, 21.3°±0.2°, 22.3°±0.2°, 24.5°±0.2°, 26.5°±0.2°, and 27.8°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 63-66, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 17.
The crystalline form of any one of claims 63-67, that has a DSC thermogram substantially similar to FIG. 29.
The crystalline form of claim 37 or 38, which is a difumarate crystalline form of the compound of Formula 1.
The crystalline form of claim 69, wherein the difumarate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 22.9°±0.2°, 28.9°±0.2°, and 29.4°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 70, wherein the difumarate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 5.5°±0.2°, 8.5°±0.2°, 22.9°±0.2°, 28.9°±0.2°, and 29.4°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 70 or 71, wherein the difumarate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 5.7°±0.2°, 14.5°±0.2°, 19.1°±0.2°, 21.1°±0.2°, 22.0°±0.2°, 22.5°±0.2°, and 25.1°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 69-72, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 18.
The crystalline form of any one of claims 69-73, that has a DSC thermogram substantially similar to FIG. 30.
The crystalline form of claim 37 or 38, which is a hemifumarate crystalline form of the compound of Formula 1.
The crystalline form of claim 75, wherein the hemifumarate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.8°±0.2°, 12.6°±0.2°, and 17.1°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 76, wherein the hemifumarate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 6.8°±0.2°, 10.2°±0.2°, 12.6°±0.2°, 17.1°±0.2°, and 23.4°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 75 or 76, wherein the hemifumarate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 8.3°±0.2°, 13.8°±0.2°, 18.4°±0.2°, 19.2°±0.2°, 23.1°±0.2°, and 25.6°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 75-78, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 19.
The crystalline form of any one of claims 75-79, that has a DSC thermogram substantially similar to FIG. 31.
The crystalline form of claim 37 or 38, which is a monosuccinate crystalline form of the compound of Formula 1.
The crystalline form of claim 81, wherein the monosuccinate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 16.9°±0.2°, 18.5°±0.2°, and 23.6°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 82, wherein the monosuccinate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 16.9°±0.2°, 18.5°±0.2°, 23.3°±0.2°, and 23.6°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 82 or 83, wherein the monosuccinate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 8.4°±0.2°, 13.9°±0.2°, 19.3°±0.2°, 21.0°±0.2°, 24.1°±0.2°, and 24.8°±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 81-84, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 20.
The crystalline form of any one of claims 81-85, that has a DSC thermogram substantially similar to FIG. 32.
The crystalline form of claim 37 or 38, which is a hemisuccinate crystalline form of the compound of Formula 1.
The crystalline form of claim 87, wherein the hemisuccinate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 17.0°±0.2°, and 23.6°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 88, wherein the hemisuccinate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 8.4 ±0.2°, 12.6±0.2°, 17.0°±0.2°, and 23.6°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 88 or 89, wherein the hemisuccinate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 10.2±0.2°, 13.9±0.2°, 18.5±0.2°, 19.3±0.2°, 23.3±0.2°, 24.8±0.2°, and 25.5±0.2°, when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 87-90, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 21.
The crystalline form of any one of claims 87-91, that has a DSC thermogram substantially similar to FIG. 33.
The crystalline form of claim 37 or 38, which is a dimaleate crystalline form of the compound of Formula 1.
The crystalline form of claim 93, wherein the dimaleate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 11.4°±0.2°, 12.2°±0.2°, and 27.4°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 94, wherein the dimaleate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 7.1°±0.2°, 11.4 ±0.2°, 12.2±0.2°, 27.4°±0.2°, and 27.8°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 94 or 95, wherein the dimaleate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 9.4±0.2°, 14.8±0.2°, 16.6±0.2°, 19.2±0.2°, 20.7±0.2°, 21.1±0.2°, and 24.1±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 93-96, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 22.
The crystalline form of any one of claims 93-97, that has a DSC thermogram substantially similar to FIG. 34.
The crystalline form of claim 37 or 38, which is a sesquimaleate crystalline form of the compound of Formula 1.
The crystalline form of claim 99, wherein the sesquimaleate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 13.8°±0.2°, 17.1°±0.2°, and 18.5°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 100, wherein the sesquimaleate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 8.9°±0.2°, 13.8°±0.2°, 16.1°±0.2°, 17.1°±0.2°, and 18.5°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 101 or 102, wherein the sesquimaleate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 14.2°±0.2°, 19.6°±0.2°, 20.3°±0.2°, 20.9°±0.2°, 22.5°±0.2°, 26.2°±0.2°, and 26.6°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 99-102, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 23.
The crystalline form of any one of claims 99-103, that has a DSC thermogram substantially similar to FIG. 35.
The crystalline form of claim 37 or 38, which is a monomaleate crystalline form of the compound of Formula 1.
The crystalline form of claim 105, wherein the monomaleate crystalline form of the compound of Formula 1 has a X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 11.9°±0.2°, and 24.0°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 106, wherein the monomaleate crystalline form of the compound of Formula 1 has a XRPD pattern comprising peaks at diffraction angles 2θ of 6.9°±0.2°, 9.6°±0.2°, 11.9°±0.2°, 15.7°±0.2°, and 24.0°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of claim 107, wherein the monomaleate crystalline form of the compound of Formula 1 has a XRPD pattern further comprising at least one peak at a diffraction angle 2θ selected from 5.9°±0.2°, 16.0°±0.2°, 18.9°±0.2°, 19.4°±0.2°, 19.9°±0.2°, 23.7°±0.2°, and 28.9°±0.2° when irradiated with a Cu-Kα light source.
The crystalline form of any one of claims 105-108, wherein the crystalline form has an XRPD pattern that is substantially similar to FIG. 24.
The crystalline form of any one of claims 105-109, that has a DSC thermogram substantially similar to FIG. 36.
A means for inhibiting FMS-like tyrosine kinase 3 (FLT3).
A means for binding to FMS-like tyrosine kinase 3 (FLT3).
The means of claims 111 or 112, wherein the means are in a crystalline form.
The means of claims 111 or 112, wherein the means are in an amorphous form.
The means of claim 113, wherein the crystalline form includes a hydrate of the compound of Formula 1.
The means of claim 115, wherein the hydrate is a monohydrate, a dihydrate, or a trihydrate of the compound of Formula 1.
The means of claim 113, wherein the crystalline form includes an ethanol mono-solvate of the compound of Formula 1.
The means of claim 113, wherein the crystalline form includes an anhydrate of the compound of Formula 1.
A pharmaceutical composition comprising at least one crystalline form of the compound of Formula 1 according to any one of claims 1-33, or 37-110; and at least one pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition comprising at least one amorphous form of the compound of Formula 1 according to any one of claims 34-36; and at least one pharmaceutically acceptable carrier or diluent.
A pharmaceutical composition comprising a means for inhibiting FMS-like tyrosine kinase 3 (FLT3).
A pharmaceutical composition comprising a means for binding to FMS-like tyrosine kinase 3 (FLT3).
The pharmaceutical composition of claim 121 or 122, wherein the means are in a crystalline form.
The pharmaceutical composition of claim 121 or 122, wherein the means are in an amorphous form.
The pharmaceutical composition of any one of claims 119-124, wherein the crystalline form or amorphous form is at least about 70% pure in the pharmaceutical composition.
The pharmaceutical composition of claim 125, wherein the crystalline form or amorphous form is at least about 80% pure in the pharmaceutical composition.
The pharmaceutical composition of any one of claims 119-124, wherein the crystalline form or amorphous form is at least about 90% pure in the pharmaceutical composition.
The pharmaceutical composition of any one of claims 119-124, wherein the crystalline form or amorphous form is at least about 95% pure in the pharmaceutical composition.
The pharmaceutical composition of any one of claims 119-124, wherein the crystalline form or amorphous form is at least about 99% pure in the pharmaceutical composition.
The pharmaceutical composition of any one of claims 120-124, wherein the amorphous form is at least about 70% pure in the pharmaceutical composition.
The pharmaceutical composition of claim 125, wherein the amorphous form is at least about 80% pure in the pharmaceutical composition.
The pharmaceutical composition of any one of claims 120-124, wherein the amorphous form is at least about 90% pure in the pharmaceutical composition.
The pharmaceutical composition of any one of claims 120-124, wherein the amorphous form is at least about 95% pure in the pharmaceutical composition.
The pharmaceutical composition of any one of claims 120-124, wherein the amorphous form is at least about 99% pure in the pharmaceutical composition.
A method for treating cancer in a subject in need thereof, comprising administering a crystalline form of any one of claims 1-33 or 37-110, an amorphous form of any one of claims 34-36.
The method of claim 135, wherein the cancer is leukemia.
The method of claim 136, wherein the leukemia is acute myelogenous leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia.