WO2024096708A1 - Nouvelle forme cristalline d'un composé de pyrimidine et compositions pharmaceutiques la comprenant et leurs procédés d'utilisation - Google Patents

Nouvelle forme cristalline d'un composé de pyrimidine et compositions pharmaceutiques la comprenant et leurs procédés d'utilisation Download PDF

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WO2024096708A1
WO2024096708A1 PCT/KR2023/017598 KR2023017598W WO2024096708A1 WO 2024096708 A1 WO2024096708 A1 WO 2024096708A1 KR 2023017598 W KR2023017598 W KR 2023017598W WO 2024096708 A1 WO2024096708 A1 WO 2024096708A1
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crystalline form
formula
compound
peaks
xrpd
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PCT/KR2023/017598
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Jong Ouk Baek
Hee Sook Oh
Hee Cheol Kim
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Hanmi Pharm. Co., Ltd.
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Publication of WO2024096708A1 publication Critical patent/WO2024096708A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • 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.
  • 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 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.
  • FLT3 Abnormal overexpression and mutation of FLT3 are often observed in leukemia patients.
  • AML Acute myelogenous leukemia
  • FLT3 has recently been regarded to be one of the most important targets from the therapeutic perspective of AML.
  • 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.
  • 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.
  • 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.
  • the leukemia may be acute myelogenous leukemia, acute lymphocytic leukemia, or chronic bone marrow leukemia.
  • the present disclosure relates to solid forms of Formula 1
  • compositions comprising the solid forms, and therapeutic uses thereof.
  • the solid form is an amorphous form of the compound of Formula 1.
  • the solid form is an anhydrate of the compound of Formula 1.
  • the solid form is a crystalline form of the compound of Formula 1.
  • the crystalline form is a solvate of the compound of Formula 1.
  • the crystalline form is a crystalline form of a hydrate of the compound of Formula 1.
  • the hydrate of the compound of Formula 1 is a monohydrate or a trihydrate.
  • the hydrate is a monohydrate.
  • the hydrate is a trihydrate.
  • the crystalline form is a crystalline form of an alcohol solvate (e.g., an alcohol mono-solvate) of the compound of Formula 1.
  • 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.
  • 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.
  • 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.
  • the crystalline form is a pharmaceutically acceptable salt of the compound of Formula 1.
  • 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.
  • the crystalline form is a pharmaceutically acceptable salt solvate of the compound of Formula 1.
  • 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.
  • a crystalline form of the compound of Formula 1 may be a crystalline form of a hydrate, a solvate, or an anhydrate.
  • 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.
  • 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.
  • 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.
  • solvate refers to a crystalline form of a material containing a solvent.
  • the solvent may be a pharmaceutically acceptable solvent.
  • 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.
  • the solvent may be water.
  • hydrate refers to a solvate of which the solvent is water.
  • Crystalstalline polymorphs of a solvate indicates the presence of more than one crystalline form for a specific solvate composition.
  • Crystalstalline 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.
  • 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.
  • substantially or substantially refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • terapéuticaally 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.
  • a "subject" can be a human, non-human primate, mammal, rat, mouse, cow, horse, pig, sheep, goat, dog, cat and the like.
  • the subject is human.
  • 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.
  • 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.
  • the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof may comprise at least about 99.9%, at least about 99.8%, at least about 99.7%, at least about 99.6%, at least about 99.5%, at least about 99%, at least about 98%, at least about 97%, at least about 96%, at least about 95%, at least about 94%, at least about 93%, at least about 92%, at least about 91%, at least about 90%, at least about 85%, at least about 80%, at least about 75%, at least about 70%, at least about 65%, at least about 60%, at least about 55%, or at least about 50% of a single crystalline form (e.g., as disclosed herein).
  • Polymorphic purity may be determined using methods known to those skilled in the art (including, e.g., X-ray powder crystallography).
  • the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof 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.
  • the crystalline form has a purity in the range of about 80% to about 99%.
  • 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.
  • the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof 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.
  • 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
  • the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof 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.
  • the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof is about 98% to 100% pure by weight, and comprises 0% to about 2% of an impurity by weight.
  • the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof is about 98%, about 98.5%, about 99%, about 99.5%, or 100% pure by weight, and comprises about 2%, about 1.5%, about 1%, about 0.5%, or 0%, respectively, of an impurity by weight.
  • the crystalline form of the compound of Formula 1, or a pharmaceutically acceptable salt thereof, solvate thereof, or salt solvate thereof is about 99.5%, about 99.9%, or about 99.95% pure by weight, and comprises about 0.5%, about 0.1%, or about 0.05%, respectively, of an impurity by weight.
  • the purity or the impurity are determined using methods known to those skilled in the art, including for example, high-performance liquid chromatography (HPLC).
  • HPLC high-performance liquid chromatography
  • 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.
  • 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.
  • the crystalline form may be a crystalline form of a monohydrate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 5.0° ⁇ 0.2°, 10.1° ⁇ 0.2°, and 16.9° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the monohydrate crystalline form may further include at least one peak at a diffraction angle 2 ⁇ 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 2 ⁇ 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 2 ⁇ 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 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the monohydrate crystalline form when the monohydrate crystalline form is irradiated with a Cu-K ⁇ light source, the monohydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 5.0° ⁇ 0.2°, 7.8° ⁇ 0.2°, 10.1° ⁇ 0.2°, 16.8° ⁇ 0.2°, and 16.9° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the monohydrate crystalline form when the monohydrate crystalline form is irradiated with a Cu-K ⁇ 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 2 ⁇ selected from 11.0° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 17.9° ⁇ 0.2°.
  • XRPD characteristic X-ray powder diffraction
  • the monohydrate crystalline form when the monohydrate crystalline form is irradiated with a Cu-K ⁇ 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 2 ⁇ selected from 15.7° ⁇ 0.2°, 18.7° ⁇ 0.2°, 23.6° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • XRPD characteristic X-ray powder diffraction
  • the monohydrate crystalline form may have an X-ray powder diffraction (XRPD) pattern including different combinations of peaks at diffraction angles 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the monohydrate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 2.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 2.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 8.
  • 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).
  • DSC differential scanning calorimetry
  • Trihydrate crystalline form of the compound of Formula 1 Trihydrate crystalline form of the compound of Formula 1.
  • the crystalline form may be a trihydrate crystalline form of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 8.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, and 17.2° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the trihydrate crystalline form may further include at least one peak at a diffraction angle 2 ⁇ 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 2 ⁇ 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 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 10 % or more.
  • 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.
  • the trihydrate crystalline form when the trihydrate crystalline form is irradiated with a Cu-K ⁇ light source, the trihydrate crystalline form has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.2° ⁇ 0.2°, 9.3° ⁇ 0.2°, 11.1° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 20.8° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the trihydrate crystalline form when the trihydrate crystalline form is irradiated with a Cu-K ⁇ 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°.
  • XRPD characteristic X-ray powder diffraction
  • the trihydrate crystalline form may have an X-ray powder diffraction (XRPD) pattern including different combinations of peaks at diffraction angles 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • 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 (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) identified in FIG. 3.
  • XRPD X-ray powder diffraction
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 9.
  • 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).
  • DSC differential scanning calorimetry
  • 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.
  • the crystalline form may be a crystalline form of an alcohol solvate of the compound of Formula 1.
  • 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.
  • the crystalline form may be a crystalline form of an ethanol solvate of the compound of Formula 1.
  • the crystalline form may be a crystalline form of an ethanol mono-solvate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 8.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 21.4 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form of the ethanol mono-solvate may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.6° ⁇ 0.2°, 13.0° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form of the ethanol mono-solvate may further include at least one peak at a diffraction angle 2 ⁇ 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 2 ⁇ selected from 7.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • the peak at the diffraction angle 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 10 % or more.
  • 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.
  • the crystalline form of the ethanol mono-solvate when the crystalline form of the ethanol mono-solvate irradiated with a Cu-K ⁇ light source, the crystalline form of the ethanol mono-solvate has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.6° ⁇ 0.2°, 17.2° ⁇ 0.2°, and 21.4 ⁇ 0.2°.
  • XRPD characteristic X-ray powder diffraction
  • the crystalline form of the ethanol mono-solvate when the crystalline form of the ethanol mono-solvate irradiated with a Cu-K ⁇ light source, the crystalline form of the ethanol mono-solvate has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ 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°.
  • XRPD characteristic X-ray powder diffraction
  • the crystalline form of the ethanol mono-solvate when the crystalline form of the ethanol mono-solvate irradiated with a Cu-K ⁇ 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 2 ⁇ selected from 7.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • XRPD characteristic X-ray powder diffraction
  • 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 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • 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 (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) identified in FIG. 4.
  • XRPD X-ray powder diffraction
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 10.
  • 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).
  • the crystalline form may be a crystalline form of an anhydrate of the compound of Formula 1.
  • the crystalline form may be an anhydrate crystalline form I of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 5.2° ⁇ 0.2°, 10.4° ⁇ 0.2°, and 18.1 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the anhydrate crystalline form I may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the anhydrate crystalline form I may further include at least one peak at a diffraction angle 2 ⁇ 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 2 ⁇ 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 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 10 % or more.
  • 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.
  • the anhydrate crystalline form I when the anhydrate crystalline form I is irradiated with a Cu-K ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the anhydrate crystalline form I when the anhydrate crystalline form I is irradiated with a Cu-K ⁇ light source, the anhydrate crystalline form I has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the anhydrate crystalline form I when the anhydrate crystalline form I is irradiated with a Cu-K ⁇ 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 2 ⁇ 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°.
  • XRPD characteristic X-ray powder diffraction
  • the anhydrate crystalline form I When the anhydrate crystalline form I is irradiated with a Cu-K ⁇ light source, the anhydrate crystalline form I may have an X-ray powder diffraction (XRPD) pattern including different combinations of peaks at diffraction angles 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • 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 (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 5.
  • XRPD X-ray powder diffraction
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 11.
  • 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).
  • 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 2 ⁇ of 4.9° ⁇ 0.2°, 5.9° ⁇ 0.2°, and 9.7 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the anhydrate crystalline form II may have an X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 4.9° ⁇ 0.2°, 5.9° ⁇ 0.2°, 9.7° ⁇ 0.2°, 17.7° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the anhydrate crystalline form II may further include at least one peak at a diffraction angle 2 ⁇ 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 2 ⁇ 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 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 10 % or more.
  • 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.
  • the anhydrate crystalline form II when the anhydrate crystalline form II is irradiated with a Cu-K ⁇ light source, the anhydrate crystalline form II has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 4.9° ⁇ 0.2°, 5.9° ⁇ 0.2°, and 9.7 ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the anhydrate crystalline form II when the anhydrate crystalline form II is irradiated with a Cu-K ⁇ light source, the anhydrate crystalline form II has a characteristic X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 4.9° ⁇ 0.2°, 5.9° ⁇ 0.2°, 9.7° ⁇ 0.2°, 17.7° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the anhydrate crystalline form II when the anhydrate crystalline form II is irradiated with a Cu-K ⁇ 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 2 ⁇ 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°.
  • XRPD characteristic X-ray powder diffraction
  • the anhydrate crystalline form II When the anhydrate crystalline form II is irradiated with a Cu-K ⁇ light source, the anhydrate crystalline form II may have an X-ray powder diffraction (XRPD) pattern including different combinations of peaks at diffraction angles 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • 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 (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) identified in FIG. 6.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 12.
  • 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).
  • the crystalline form may be a crystalline form of a dihydrochloride of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 8.2° ⁇ 0.2°, 9.4° ⁇ 0.2°, and 19.1° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the dihydrochloride crystalline form I of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.2° ⁇ 0.2°, 9.4° ⁇ 0.2°, and 19.1° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the dihydrochloride crystalline form I of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.2° ⁇ 0.2°, 9.4° ⁇ 0.2°, 14.6 ° ⁇ 0.2°, 19.1° ⁇ 0.2°, and 26.2° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the dihydrochloride crystalline form I of the compound of Formula 1 when the dihydrochloride crystalline form I of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the dihydrochloride crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the dihydrochloride crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 13.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 13.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 25.
  • 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.
  • DSC differential scanning calorimetry
  • the dihydrochloride crystalline form I is an ethanol solvate.
  • 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.
  • 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.
  • 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 2 ⁇ of 10.5° ⁇ 0.2°, 15.2° ⁇ 0.2°, and 23.1° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the dihydrochloride crystalline form II of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 10.5° ⁇ 0.2°, 15.2° ⁇ 0.2°, and 23.1° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the dihydrochloride crystalline form II of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 10.5° ⁇ 0.2°,15.2° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.1° ⁇ 0.2°, and 27.2° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the dihydrochloride crystalline form II of the compound of Formula 1 when the dihydrochloride crystalline form II of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the dihydrochloride crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the dihydrochloride crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 14.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 14.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 26.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a monohydrochloride of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 17.1° ⁇ 0.2°, 18.6° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the monohydrochloride crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 17.1° ⁇ 0.2°, 18.6° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the monohydrochloride crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 17.1° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.9° ⁇ 0.2°, and 23.5° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the monohydrochloride crystalline form of the compound of Formula 1 when the monohydrochloride crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the monohydrochloride crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the monohydrochloride crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 15.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 15.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 27.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a disulfate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 8.8° ⁇ 0.2°, 11.4° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the disulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.8° ⁇ 0.2°, 11.4° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the disulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 11.4° ⁇ 0.2°, 15.2° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the disulfate crystalline form of the compound of Formula 1 when the disulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the disulfate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the disulfate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 16.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 16.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 28.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a monosulfate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 8.8° ⁇ 0.2°, 11.4° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the monosulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.8° ⁇ 0.2°, 11.4° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the monosulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.8° ⁇ 0.2°, 11.1° ⁇ 0.2°, 11.4° ⁇ 0.2°, 15.2° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the monosulfate crystalline form of the compound of Formula 1 when the monosulfate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the monosulfate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the monosulfate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 17.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 17.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 29.
  • 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.
  • DSC differential scanning calorimetry
  • the monosulfate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 17.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 17.
  • the monosulfate crystalline form may exhibit analysis results of differential scanning calorimetry (DSC) of a crystalline form as identified in FIG. 29.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 29.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a difumarate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 22.9° ⁇ 0.2°, 28.9° ⁇ 0.2°, and 29.4° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the difumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 22.9° ⁇ 0.2°, 28.9° ⁇ 0.2°, and 29.4° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the difumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 5.5° ⁇ 0.2°, 8.5° ⁇ 0.2°, 22.9° ⁇ 0.2°, 28.9° ⁇ 0.2°, and 29.4° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the difumarate crystalline form of the compound of Formula 1 when the difumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the difumarate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the difumarate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 18.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 18.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 30.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a hemifumarate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 6.8° ⁇ 0.2°, 12.6° ⁇ 0.2°, and 17.1° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the hemifumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 6.8° ⁇ 0.2°, 12.6° ⁇ 0.2°, and 17.1° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the hemifumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 6.8° ⁇ 0.2°, 10.2° ⁇ 0.2°, 12.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the hemifumarate crystalline form of the compound of Formula 1 when the hemifumarate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the hemifumarate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the hemifumarate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 19.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 19.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 31.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a monosuccinate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 16.9° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the monosuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 16.9° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the monosuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 6.9° ⁇ 0.2°, 16.9° ⁇ 0.2°, 18.5° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the monosuccinate crystalline form of the compound of Formula 1 when the monosuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the monosuccinate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the monosuccinate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 20.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 20.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 32.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a hemisuccinate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 6.9° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the hemisuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 6.9° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the hemisuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 6.9° ⁇ 0.2°, 8.4 ⁇ 0.2°, 12.6 ⁇ 0.2°, 17.0° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the hemisuccinate crystalline form of the compound of Formula 1 when the hemisuccinate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the hemisuccinate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the hemisuccinate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 21.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 21.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 33.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a dimaleate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 11.4° ⁇ 0.2°, 12.2° ⁇ 0.2°, and 27.4° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the dimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 11.4° ⁇ 0.2°, 12.2° ⁇ 0.2°, and 27.4° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the dimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 7.1° ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.2 ⁇ 0.2°, 27.4° ⁇ 0.2°, and 27.8° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the dimaleate crystalline form of the compound of Formula 1 when the dimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the dimaleate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the dimaleate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 22.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 22.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 34.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a sesquimaleate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 13.8° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 18.5° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the sesquimaleate crystalline form of the compound of Formula 1 when the sesquimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 13.8° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 18.5° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the sesquimaleate crystalline form of the compound of Formula 1 when the sesquimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 8.9° ⁇ 0.2°, 13.8° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 18.5° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the sesquimaleate crystalline form of the compound of Formula 1 when the sesquimaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the sesquimaleate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the sesquimaleate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 23.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 23.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 35.
  • 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).
  • DSC differential scanning calorimetry
  • the crystalline form may be a crystalline form of a monomaleate of the compound of Formula 1.
  • 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.
  • 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.
  • 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 2 ⁇ of 6.9° ⁇ 0.2°, 11.9° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ 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 2 ⁇ 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 peaks at the diffraction angles 2 ⁇ may form an X-ray powder diffraction (XRPD) pattern when the crystalline form is irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • 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 2 ⁇ having relative intensity (I/I0 : I is intensity of each peak; I0 is intensity of the highest peak) of 5 % or more.
  • 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.
  • the crystalline form when the monomaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 6.9° ⁇ 0.2°, 11.9° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form when the monomaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the crystalline form has a X-ray powder diffraction (XRPD) pattern including peaks at diffraction angles 2 ⁇ of 6.9° ⁇ 0.2°, 9.6° ⁇ 0.2°, 11.9° ⁇ 0.2°, 15.7° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the monomaleate crystalline form of the compound of Formula 1 when the monomaleate crystalline form of the compound of Formula 1 is irradiated with a Cu-K ⁇ light source, the monomaleate crystalline form has a X-ray powder diffraction (XRPD) pattern further including at least one peak at a diffraction angle 2 ⁇ 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°.
  • XRPD X-ray powder diffraction
  • the monomaleate crystalline form may include a peak at a diffraction angle (2 ⁇ 0.2) of X-ray powder diffraction (XRPD) spectrum identified in FIG. 24.
  • XRPD X-ray powder diffraction
  • the crystalline form has an XRPD pattern that is substantially similar to FIG. 24.
  • 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.
  • DSC differential scanning calorimetry
  • the crystalline form has a DSC thermogram substantially similar to FIG. 36.
  • 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).
  • DSC differential scanning calorimetry
  • Another aspect provides a pharmaceutical composition including the crystalline form.
  • 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.
  • 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.
  • diluent examples 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound may act on receptor tyrosine kinase (RTK) to effectively control the intracellular delivery of extracellular stimuli.
  • RTK receptor tyrosine kinase
  • 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.
  • FLT3 fms-like tyrosine kinase 3
  • SYK spleen tyrosine kinase
  • VAGFR endothelial
  • 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.
  • the compound may be useful for the treatment of acute myelogenous leukemia (AML), which shows resistance to FLT3 inhibitors.
  • AML acute myelogenous leukemia
  • OV all survival
  • 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.
  • AML acute myeloid leukemia
  • the solid forms of the disclosure 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.
  • AML acute myeloid leukemia
  • the solid forms and the pharmaceutical compositions of the present disclosure find use in any number of methods.
  • the solid forms and the pharmaceutical compositions are useful in methods for modulating a FLT3 kinase activity.
  • modulating FLT3 kinase activity is in a mammalian cell.
  • 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.
  • the modulating FLT3 kinase activity is binding to FLT3 kinase. In other embodiments, the modulating FLT3 kinase activity is inhibiting FLT3 kinase.
  • 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).
  • crystalline and amorphous forms disclosed herein e.
  • 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.
  • a method of treating a condition associated with cell proliferation in a patient in need thereof is provided.
  • 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.
  • 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.
  • the cancer may be leukemia.
  • the leukemia may include AML, ALL, or CML.
  • the leukemia is AML.
  • the AML is AML with a FLT3 mutation.
  • the AML is mutant FLT3 polynucleotide-positive AML, FLT3 internal tandem duplication (ITD)-positive AML, and/or AML with FLT3 point mutations.
  • the cancer or leukemia comprises cancer cells having a mutation in the FLT3 gene.
  • the FLT3 gene has an internal tandem duplication (ITD) mutation.
  • the FLT3 gene has at least one FLT3 mutation selected from F691L, D835Y, D835F, D835I, D835H, D835V and D835A.
  • the cancer or leukemia comprises cancer cells having a mutation in TKD of an amino acid sequence of FLT3 (FLT3-TKD).
  • the FLT3-TKD mutation may further comprise ITD.
  • 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.
  • the TKD mutation may comprise a mutation of an amino acid at position 835 of the FLT3 amino acid sequence.
  • 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.
  • the TKD mutation may include substitution of leucine or aspartic acid for isoleucine at position 836 of the FLT3 amino acid sequence.
  • the TKD mutation may include substitution of cysteine or histidine for tyrosine at position 842 of the FLT3 amino acid sequence.
  • 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.
  • the TKD mutation may have substitution of leucine for phenylalanine at position 691 of the FLT3 amino acid sequence.
  • the mutation may be FLT3(F691L).
  • the TKD mutation may further include ITD.
  • the mutation may be FLT3(ITD/D835Y) or FLT3(ITD/F691L).
  • the present disclosure provides methods of treating cancer patients with resistance to traditional therapeutic agents.
  • 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.
  • drug-resistant point mutants D835Y, F691L, or F691L/D835Y
  • 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.
  • the compound of the invention or the composition of the invention is administered in combination with another therapeutically active agent.
  • the other therapeutically active agent is administered together, sequentially, or separately with the compound of the invention or the composition of the invention.
  • 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:
  • the method including:
  • (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:
  • the method including:
  • (b) may be stirring the solution (a) at about 20 °C to about 25 °C.
  • 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:
  • the method including:
  • dissolution in (a) may be carried out at a reflux temperature. In a specific example, dissolution in (a) may be carried out in ethanol.
  • cooling in (b) may be cooling to room temperature.
  • stirring in (b) may be carried out for about 1 day to about 4 days.
  • (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:
  • the method including:
  • (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.
  • (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, 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:
  • the method including:
  • (b) may be stirring the mixture (a) at a temperature of about 20 °C to about 25 °C.
  • 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.
  • Another aspect provides an amorphous form of the compound of Formula 1:
  • the amorphous form of the compound of Formula 1 when the amorphous form of the compound of Formula 1 is irradiated with a Cu-K ⁇ 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.
  • XRPD characteristic X-ray powder diffraction
  • 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).
  • DSC differential scanning calorimetry
  • Another aspect is to provide a pharmaceutical composition including the amorphous form of the compound of Formula 1.
  • 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.
  • the cancer may be leukemia.
  • the leukemia may be acute myelogenous leukemia, acute lymphocytic leukemia, or chronic bone marrow leukemia.
  • 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:
  • the method including:
  • (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.
  • 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.
  • 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.
  • 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.
  • room temperature refers to a range of 20 ⁇ 5 °C.
  • substantially pure 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 %.
  • “about 10 %” means 9.5 % to 10.5 %, or preferably, 9.8 % to 10.2 %.
  • “about 100 °C” means 95 °C to 105 °C, or preferably, 98 °C to 102 °C.
  • 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.
  • 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.
  • 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.
  • 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").
  • XRPD X-ray powder diffraction
  • 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.
  • 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
  • X-ray powder diffraction (XRPD) analysis was performed in a D8 Advance (Bruker ASX, Germany) analyzer at a diffraction angle 2 ⁇ of 3° to 40°.
  • XRPD X-ray powder diffraction
  • Scan range: 3° to 40°
  • Anti-scatter slit 0.3°
  • Step size 0.02 deg 2 ⁇
  • DSC Differential scanning calorimetry
  • 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).
  • RH relative humidity
  • the samples were dried in the same manner, always applying a 0 % lower relative humidity after each step.
  • Weight changes during sorption / desorption cycles were recorded to measure hygroscopicity of the sample.
  • HPLC High-performance liquid chromatography
  • 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.
  • 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 %
  • 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").
  • XRPD X-ray powder diffraction
  • the amorphous form of the compound of Formula 1 when the amorphous form of the compound of Formula 1 was irradiated with a Cu-K ⁇ light source, the amorphous form did not exhibit a peak having relative intensity (I/I 0 : I is intensity of each peak; I 0 is intensity of the highest peak) of 10 % or more in an X-ray powder diffraction (XRPD) pattern.
  • FIG. 7 shows results of differential scanning calorimetry (DSC) of the amorphous form of the compound of Formula 1.
  • the amorphous form showed a moisture content of about 2.3 % in a Karl Fischer water titrator.
  • 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.
  • Moisture content (Karl Fischer water titrator): about 3.5 %
  • 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°.
  • XRPD X-ray powder diffraction
  • 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°.
  • XRPD X-ray powder diffraction spectroscopy
  • FIG. 8 shows analysis results of differential scanning calorimetry (DSC) of the monohydrate crystalline form of the compound of Formula 1.
  • 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.
  • Moisture content (Karl Fischer water titrator): about 10.8 %
  • Table 2 and FIG. 3 show XRPD analysis results of the trihydrate crystalline form of the compound of Formula 1.
  • 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°.
  • XRPD X-ray powder diffraction
  • FIG. 9 shows analysis results of differential scanning calorimetry (DSC) of the trihydrate crystalline form of the compound of Formula 1.
  • the crystalline form showed about 10.8 % of moisture content (theoretical moisture content 9.7 %) in a Karl Fischer water titrator.
  • 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.
  • Moisture content (Karl Fischer water titrator): about 0.2 %
  • 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°.
  • XRPD X-ray powder diffraction
  • 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.
  • the crystalline form showed a moisture content of about 0.2 % in a Karl Fischer water titrator.
  • 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.
  • Moisture content (Karl Fischer water titrator): about 0.2 %
  • 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.
  • 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°.
  • XRPD X-ray powder diffraction
  • FIG. 11 shows analysis results of differential scanning calorimetry (DSC) of the anhydrate crystalline form I of the compound of Formula 1;.
  • the crystalline form showed a moisture content of about 0.2 % in a Karl Fischer water titrator.
  • 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.
  • Moisture content (Karl Fischer water titrator): about 0.5 %
  • 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°.
  • XRPD X-ray powder diffraction
  • FIG. 12 shows analysis results of differential scanning calorimetry (DSC) of the anhydrate crystalline form II of the compound of Formula 1.
  • the crystalline form showed a moisture content of about 0.5 % in a Karl Fischer water titrator.
  • 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.
  • Moisture content (Karl Fischer water titrator): about 3.4 %
  • FIG. 25 shows analysis results of differential scanning calorimetry (DSC) of the dihydrochloride crystalline form I of the compound of Formula 1.
  • 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.
  • Moisture content (Karl Fischer water titrator): about 0.5 %.
  • FIG. 26 shows analysis results of differential scanning calorimetry (DSC) of the dihydrochloride crystalline form II of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 3.7 %.
  • FIG. 27 shows analysis results of differential scanning calorimetry (DSC) of the monohydrochloride crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 5.4 %
  • FIG. 28 shows analysis results of differential scanning calorimetry (DSC) of the disulfate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 6.8 %
  • FIG. 29 shows analysis results of differential scanning calorimetry (DSC) of the monosulfate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 1.5 %
  • FIG. 30 shows analysis results of differential scanning calorimetry (DSC) of the difumarate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 0.1 %.
  • FIG. 31 shows analysis results of differential scanning calorimetry (DSC) of the hemifumarate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 1.8 %.
  • FIG. 32 shows analysis results of differential scanning calorimetry (DSC) of the monosuccinate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 0.3 %.
  • FIG. 33 shows analysis results of differential scanning calorimetry (DSC) of the hemisuccinate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • FIG. 34 shows analysis results of differential scanning calorimetry (DSC) of the dimaleate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 3.0 %
  • FIG. 35 shows analysis results of differential scanning calorimetry (DSC) of the sesquimaleate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • 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.
  • Moisture content (Karl Fischer water titrator): about 0.2%.
  • FIG. 36 shows analysis results of differential scanning calorimetry (DSC) of the monomaleate crystalline form of the compound of Formula 1.
  • DSC differential scanning calorimetry
  • Embodiment 1 A crystalline form of the compound of 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 2 ⁇ 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-K ⁇ light source.
  • XRPD characteristic X-ray powder diffraction
  • 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 2 ⁇ selected from 11.0° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 17.9° ⁇ 0.2°, when irradiated with a Cu-K ⁇ 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 2 ⁇ selected from 15.7° ⁇ 0.2°, 18.7° ⁇ 0.2°, 23.6° ⁇ 0.2°, and 24.3° ⁇ 0.2°, when irradiated with a Cu-K ⁇ light source.
  • Embodiment 6 The crystalline form of embodiment 2, wherein the crystalline form has a characteristic XRPD pattern including peaks at diffraction angles 2 ⁇ 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-K ⁇ 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 2 ⁇ 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-K ⁇ 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 2 ⁇ 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-K ⁇ 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 2 ⁇ selected from 7.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 25.7° ⁇ 0.2°, when irradiated with a Cu-K ⁇ 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 2 ⁇ 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-K ⁇ 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 2 ⁇ 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-K ⁇ 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 2 ⁇ 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-K ⁇ 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 2 ⁇ 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-K ⁇ light source.
  • a characteristic XRPD pattern further including at least one peak at a diffraction angle 2 ⁇ 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-K ⁇ 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.
  • XRPD X-ray powder diffraction
  • Embodiment 20 An amorphous form of Formula 1
  • 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.
  • XRPD X-ray powder diffraction
  • Embodiment 22 An amorphous form of embodiment 20, wherein the amorphous form exhibits a differential scanning calorimetry (DSC) thermogram substantially similar to FIG. 7.
  • DSC differential scanning calorimetry
  • Embodiment 23 A means for inhibiting FMS-like tyrosine kinase 3 (FLT3).
  • FLT3 FMS-like tyrosine kinase 3
  • Embodiment 24 A means for binding to FMS-like tyrosine kinase 3 (FLT3).
  • FLT3 FMS-like tyrosine kinase 3
  • 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).
  • FLT3 FMS-like tyrosine kinase 3
  • Embodiment 36 A pharmaceutical composition comprising a means for binding to FMS-like tyrosine kinase 3 (FLT3).
  • FLT3 FMS-like tyrosine kinase 3
  • 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.

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Abstract

La présente invention concerne des formes solides de composés de pyrimidine, des compositions pharmaceutiques les comprenant et leurs procédés d'utilisation. Par exemple, l'invention concerne des polymorphes cristallins d'un composé de formule 1, ou un sel, un solvate ou un sel solvaté pharmaceutiquement acceptable de celui-ci.
PCT/KR2023/017598 2022-11-04 2023-11-03 Nouvelle forme cristalline d'un composé de pyrimidine et compositions pharmaceutiques la comprenant et leurs procédés d'utilisation WO2024096708A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110183975A1 (en) * 2008-10-07 2011-07-28 Yasuhiro Goto Novel 6-azaindole aminopyrimidine derivatives having nik inhibitory activity
WO2015154039A2 (fr) * 2014-04-04 2015-10-08 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
US20170029413A1 (en) * 2015-07-28 2017-02-02 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US20200031806A1 (en) * 2018-07-25 2020-01-30 Hanmi Pharm. Co., Ltd. Pyrimidine compounds and pharmaceutical compositions for preventing or treating cancers including the same
US20200206266A1 (en) * 2017-08-01 2020-07-02 Julius-Maximilians-Universität Würzburg Use of flt3 car-t cells and flt3 inhibitors to treat acute myeloid leukemia

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110183975A1 (en) * 2008-10-07 2011-07-28 Yasuhiro Goto Novel 6-azaindole aminopyrimidine derivatives having nik inhibitory activity
WO2015154039A2 (fr) * 2014-04-04 2015-10-08 Syros Pharmaceuticals, Inc. Inhibiteurs de la kinase cycline-dépendante 7 (cdk7)
US20170029413A1 (en) * 2015-07-28 2017-02-02 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
US20200206266A1 (en) * 2017-08-01 2020-07-02 Julius-Maximilians-Universität Würzburg Use of flt3 car-t cells and flt3 inhibitors to treat acute myeloid leukemia
US20200031806A1 (en) * 2018-07-25 2020-01-30 Hanmi Pharm. Co., Ltd. Pyrimidine compounds and pharmaceutical compositions for preventing or treating cancers including the same

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