WO2024109909A1 - 稠环化合物的固体形式及其制备方法和用途 - Google Patents

稠环化合物的固体形式及其制备方法和用途 Download PDF

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WO2024109909A1
WO2024109909A1 PCT/CN2023/133860 CN2023133860W WO2024109909A1 WO 2024109909 A1 WO2024109909 A1 WO 2024109909A1 CN 2023133860 W CN2023133860 W CN 2023133860W WO 2024109909 A1 WO2024109909 A1 WO 2024109909A1
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crystalline form
ray powder
powder diffraction
diffraction pattern
crystal
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PCT/CN2023/133860
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English (en)
French (fr)
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钟俊
高勤
刘永波
王皓
陈肖虎
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北京志健金瑞生物医药科技有限公司
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Publication of WO2024109909A1 publication Critical patent/WO2024109909A1/zh

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a solid form of a condensed ring compound and a preparation method and use thereof, and belongs to the field of chemical medicines.
  • RET Rearranged During Transfection
  • the RET proto-oncogene is located on chromosome 10q11.2, with a total DNA length of 60kb, containing 21 exons, encoding a RET protein composed of 1100 amino acids:
  • This RET protein is a tyrosine kinase receptor containing an extracellular region composed of cysteine, a transmembrane region, and an intracellular region with catalytic tyrosine kinase activity (Mol Cell Endocrinol, 2010, 322(1-2): 2-7).
  • RET is involved in cell proliferation, nerve conduction, cell migration and cell differentiation.
  • RET fusions are drivers in some cancers.
  • the RET inhibitor selpatinib (LOXO-292) has been approved for the treatment of patients with tumors carrying RET fusion proteins, but one of the biggest challenges in cancer treatment is that tumor cells become resistant to treatment after a certain stage. Once resistant, patients' treatment options are usually extremely limited, and in most cases, cancer continues to progress unchecked. It has been reported in the literature (RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies, Journal of Thoracic Oncology, 2020, Vol.
  • RET G810 solvent front mutations such as G810R, G810S, and G801C mutations, occur in patients with RET fusion non-small cell lung cancer after using the RET inhibitor selpatinib (LOXO-292), resulting in a decrease in the effect of LOXO-292 on the ATP binding site, leading to drug resistance and cancer progression. Therefore, it is necessary to develop compounds with good RET mutation inhibitory activity.
  • RET G810 solvent front mutations such as G810R, G810S, and G801C mutations
  • the PCT patent application with application number PCT/CN2020/107049 discloses a class of compounds as RET inhibitors, which have strong inhibitory effects on RET gatekeeper residue mutant RET V804M, RET solvent front residue mutant G810R and other clinically relevant RET mutants and wt-RET. These compounds can also significantly inhibit the growth of TT cell lines derived from thyroid cancer and Ba/F3 cells transformed with various RET mutants, block cellular RET autophosphorylation and its downstream pathways, and can significantly induce TT cell death. Therefore, it is necessary to further study the solid form of such compounds, especially to develop a crystalline form that is more suitable as a pharmaceutical active ingredient.
  • the present disclosure provides a solid form of a compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
  • the solid form is selected from the solid form of an anhydrate, a hydrate, an organic solvate or a cosolvate of water and an organic solvent.
  • the organic solvent is selected from one of alcohols (such as methanol, ethanol), nitriles (such as acetonitrile), halogenated alkanes (such as dichloromethane), and ethers (such as 1,4-dioxane).
  • alcohols such as methanol, ethanol
  • nitriles such as acetonitrile
  • halogenated alkanes such as dichloromethane
  • ethers such as 1,4-dioxane
  • the solid form is selected from one, two, three or more of the crystalline forms described below.
  • the present disclosure also provides a crystalline form A of the compound of formula (I), wherein the crystalline form A has an X-ray powder diffraction pattern having one or two characteristic peaks selected from the following 2 ⁇ values: 6.91° ⁇ 0.20°, 10.32° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A has one, two or all characteristic peaks selected from the following 2 ⁇ values: 6.91° ⁇ 0.20°, 10.32° ⁇ 0.20°, 25.72° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 6.91° ⁇ 0.20°, 10.32° ⁇ 0.20°, 13.88 ⁇ 0.20°, 25.72° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.46° ⁇ 0.20°, 6.91° ⁇ 0.20°, 10.32° ⁇ 0.20°, 13.88° ⁇ 0.20°, 14.84° ⁇ 0.20°, 18.33° ⁇ 0.20°, 20.32° ⁇ 0.20°, and 25.72° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.46° ⁇ 0.20°, 6.91° ⁇ 0.20°, 10.32° ⁇ 0.20°, 10.63° ⁇ 0.20°, 13.61° ⁇ 0.20°, 13.88° ⁇ 0.20°, 14.84° ⁇ 0.20°, 18.33° ⁇ 0.20°, 20.32° ⁇ 0.20°, and 25.72° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A further has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 15.86° ⁇ 0.20°, 17.00° ⁇ 0.20°, 17.18° ⁇ 0.20°, 24.51° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form A has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form A when the X-ray powder diffraction pattern of the crystalline form A has one, two, more or all characteristic peaks selected from the following 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form A has an endothermic peak at an onset temperature of about 175.03° C. and/or a peak temperature of about 180.61° C.
  • the crystalline Form A has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 1B .
  • DSC differential scanning calorimetry
  • the weight loss is about 0.45% to about 0.55% (eg, about 0.499%) when the temperature is increased from room temperature to 190°C.
  • the crystalline form A has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 1C .
  • TGA thermogravimetric analysis
  • the crystalline form A is an anhydrous crystalline form.
  • the crystalline Form A has a 1 H NMR spectrum substantially as shown in FIG. 1D .
  • the present disclosure also provides a crystalline form B of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form B has one, two or all characteristic peaks selected from the following 2 ⁇ values: 18.19° ⁇ 0.20°, 25.74° ⁇ 0.20°, 26.95° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form B has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 11.04° ⁇ 0.20°, 12.78° ⁇ 0.20°, 16.12° ⁇ 0.20°, 16.74° ⁇ 0.20°, 18.19° ⁇ 0.20°, 25.22° ⁇ 0.20°, 25.74° ⁇ 0.20°, 26.95° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form B has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.26° ⁇ 0.20°, 11.04° ⁇ 0.20°, 12.78° ⁇ 0.20°, 16.12° ⁇ 0.20°, 16.74° ⁇ 0.20°, 18.19° ⁇ 0.20°, 19.96° ⁇ 0.20°, 24.33° ⁇ 0.20°, 25.22° ⁇ 0.20°, 25.74° ⁇ 0.20°, and 26.95° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form B has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form B when the X-ray powder diffraction pattern of the crystalline form B has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form B has an X-ray powder diffraction pattern substantially as shown in FIG. 2A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form B has an endothermic peak at an onset temperature of about 186.7°C and/or a peak temperature of about 189.8°C.
  • the Form B has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 2B .
  • DSC differential scanning calorimetry
  • the weight loss is about 0.5% to about 0.6% (eg, about 0.54%) when the temperature is increased from room temperature to 150°C.
  • the crystalline Form B has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 2B .
  • TGA thermogravimetric analysis
  • the crystalline form B is an anhydrous crystalline form.
  • the crystalline Form B has a 1 H NMR spectrum substantially as shown in FIG. 2C .
  • the present disclosure also provides a crystalline form C of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form C has one, two or all characteristic peaks selected from the following 2 ⁇ values: 7.25 ⁇ 0.20°, 16.53° ⁇ 0.20°, 18.84° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form C has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 7.25° ⁇ 0.20°, 14.48° ⁇ 0.20°, 16.53° ⁇ 0.20°, 18.84° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form C has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 7.25° ⁇ 0.20°, 12.54° ⁇ 0.20°, 13.04° ⁇ 0.20°, 14.48° ⁇ 0.20°, 16.53° ⁇ 0.20°, 18.84° ⁇ 0.20°, 19.18° ⁇ 0.20°, and 25.02° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form C has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form C has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG. 3A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form C has an endothermic peak at a peak temperature of about 109.1°C, an onset temperature of about 123.4°C and/or a peak temperature of about 132.5°C.
  • the Form C has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 3B .
  • DSC differential scanning calorimetry
  • the weight loss is about 0.2% to about 0.3% (eg, about 0.27%) when the temperature is increased from room temperature to 200°C.
  • the crystalline form C has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 3B .
  • TGA thermogravimetric analysis
  • the crystalline form C is an anhydrous crystalline form.
  • the crystalline Form C has a 1 H NMR spectrum substantially as shown in FIG. 3C .
  • the present disclosure also provides a crystalline form D of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form D has one, two or all characteristic peaks selected from the following 2 ⁇ values: 11.01° ⁇ 0.20°, 25.01° ⁇ 0.20°, 26.42° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form D has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.26° ⁇ 0.20°, 11.01° ⁇ 0.20°, 15.61° ⁇ 0.20°, 18.53° ⁇ 0.20°, 22.14° ⁇ 0.20°, 25.01° ⁇ 0.20°, 26.42° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form D has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.26° ⁇ 0.20°, 9.01° ⁇ 0.20°, 11.01° ⁇ 0.20°, 15.61° ⁇ 0.20°, 18.53° ⁇ 0.20°, 22.14° ⁇ 0.20°, 25.01° ⁇ 0.20°, and 26.42° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form D has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form D when the X-ray powder diffraction pattern of the crystalline form D has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form D has an X-ray powder diffraction pattern substantially as shown in FIG. 4A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form D has an endothermic peak at a peak temperature of about 63.7°C, an onset temperature of about 181.7°C and/or a peak temperature of about 184.3°C.
  • the crystalline Form D has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 4B .
  • thermogravimetric analysis (TGA) of the crystalline form D the weight loss is about 3.3% to about 3.4% (eg, about 3.35%) when the temperature is increased from room temperature to 200°C.
  • the crystalline form D has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 4B .
  • TGA thermogravimetric analysis
  • the crystalline form D is a hydrate.
  • the crystalline Form D has a 1 H NMR spectrum substantially as shown in FIG. 4C .
  • the crystalline form D has a variable temperature XRPD pattern substantially as shown in FIG. 4D .
  • the present disclosure also provides a crystalline form E of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form E has one, two or all characteristic peaks selected from the following 2 ⁇ values: 5.98° ⁇ 0.20°, 12.73° ⁇ 0.20°, 14.53° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form E has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 5.98° ⁇ 0.20°, 10.66 ⁇ 0.20°, 11.95 ⁇ 0.20°, 12.73° ⁇ 0.20°, 14.53° ⁇ 0.20°, 17.67° ⁇ 0.20°, 22.91° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form E has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form E when the X-ray powder diffraction pattern of the crystalline form E has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG. 5A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form E has endothermic peaks at a peak temperature of about 114.9°C and a peak temperature of about 127.9°C.
  • the Form E has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 5B .
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) of the crystalline form E there is a weight loss of about 1.9% to about 2.0% (e.g., about 1.95%) when the temperature is increased from room temperature to 50°C, and there is a weight loss of about 3.0% to about 3.1% (e.g., about 3.02%) when the temperature is increased from 50°C to 150°C.
  • the crystalline Form E has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 5B .
  • TGA thermogravimetric analysis
  • the crystalline form E is a methanol solvate.
  • the crystalline Form E has a 1 H NMR spectrum substantially as shown in FIG. 5C .
  • the crystalline Form E has a variable temperature XRPD pattern substantially as shown in FIG. 5D .
  • the present disclosure also provides a crystalline form F of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form F has one, two or all characteristic peaks selected from the following 2 ⁇ values: 11.07° ⁇ 0.20°, 24.79° ⁇ 0.20°, 26.42° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form F has one, two or all characteristic peaks selected from the following 2 ⁇ values: 11.07° ⁇ 0.20°, 17.83° ⁇ 0.20°, 22.44° ⁇ 0.20°, 24.79° ⁇ 0.20°, 26.42° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form F has one, two or all characteristic peaks selected from the following 2 ⁇ values: 11.07° ⁇ 0.20°, 17.83° ⁇ 0.20°, 22.44° ⁇ 0.20°, 24.79° ⁇ 0.20° and 26.42° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form F has one, two or all characteristic peaks selected from the following 2 ⁇ values: 11.07° ⁇ 0.20°, 14.99° ⁇ 0.20°, 17.83° ⁇ 0.20°, 19.93° ⁇ 0.20°, 20.64° ⁇ 0.20°, 22.44° ⁇ 0.20°, 24.79° ⁇ 0.20°, and 26.42° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form F has one, two or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form F when the X-ray powder diffraction pattern of the crystalline form F has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG. 6A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form F has an endothermic peak at a peak temperature of about 69.9°C, an onset temperature of about 182.1°C and/or a peak temperature of about 184.5°C.
  • the Form F has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 6B .
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) of the crystalline form F there is a weight loss of about 2.2% to about 2.3% (e.g., about 2.25%) when the temperature is increased from room temperature to 100°C, and there is a weight loss of about 2.7% to about 2.8% (e.g., about 2.79%) when the temperature is increased from 100°C to 200°C.
  • TGA thermogravimetric analysis
  • the crystalline Form F has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 6B .
  • TGA thermogravimetric analysis
  • the crystalline form F is an ethanol solvate.
  • the crystalline Form F has a 1 H NMR spectrum substantially as shown in FIG. 6C .
  • the Form F has a variable temperature XRPD pattern substantially as shown in FIG. 6D .
  • the present disclosure also provides a crystalline form G of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form G has one, two or all characteristic peaks selected from the following 2 ⁇ values: 6.97° ⁇ 0.20°, 13.39° ⁇ 0.20°, 25.81° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form G has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.50° ⁇ 0.20°, 6.97° ⁇ 0.20°, 13.39° ⁇ 0.20°, 14.40° ⁇ 0.20°, 17.11° ⁇ 0.20°, 17.81° ⁇ 0.20°, 23.94° ⁇ 0.20°, and 25.81° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form G has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form G has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form G has an X-ray powder diffraction pattern substantially as shown in FIG. 7A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form G has an endothermic peak at a peak temperature of about 122.6°C, an onset temperature of about 168.5°C and/or a peak temperature of about 173.1°C.
  • the Form G has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 7B .
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) of the crystalline form G there is a weight loss of about 1.2% to about 1.4% (e.g., about 1.3%) when the temperature is increased from room temperature to 75°C, and there is a weight loss of about 2.6% to about 2.7% (e.g., about 2.69%) when the temperature is increased from 75°C to 150°C.
  • the crystalline form G has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 7B .
  • TGA thermogravimetric analysis
  • the crystalline form G is an acetonitrile solvate.
  • the crystalline Form G has a 1 H NMR spectrum substantially as shown in FIG. 7C .
  • the present disclosure also provides a crystalline form H of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form H has one, two or all characteristic peaks selected from the following 2 ⁇ values: 12.92° ⁇ 0.20°, 15.82° ⁇ 0.20°, 17.25° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form H has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 7.89° ⁇ 0.20°, 10.51° ⁇ 0.20°, 12.92° ⁇ 0.20°, 15.82° ⁇ 0.20°, 16.69° ⁇ 0.20°, 17.25° ⁇ 0.20°, 19.12° ⁇ 0.20°, and 25.39° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form H has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form H has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form H has an X-ray powder diffraction pattern substantially as shown in FIG. 8A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form H has endothermic peaks at peak temperatures of about 121.7°C, about 138.7°C, about 170.2°C, and about 184.7°C.
  • the Form H has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 8B .
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) of the crystalline form H there is a weight loss of about 1.7% to about 1.8% (e.g., about 1.73%) when the temperature is increased from room temperature to 70°C, and there is a weight loss of about 7.9% to about 8.0% (e.g., about 7.98%) when the temperature is increased from 70°C to 150°C.
  • the crystalline form H has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 8B .
  • TGA thermogravimetric analysis
  • the crystalline form H is a dichloromethane solvate.
  • the crystalline Form H has a 1 H NMR spectrum substantially as shown in FIG. 8C .
  • the crystalline Form H has a variable temperature XRPD pattern substantially as shown in FIG. 8D .
  • the present disclosure also provides a crystalline form I of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form I has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.45° ⁇ 0.20°, 13.35° ⁇ 0.20°, 17.82° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form I has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.45° ⁇ 0.20°, 13.35° ⁇ 0.20°, 17.15° ⁇ 0.20°, 17.82° ⁇ 0.20°, 22.32° ⁇ 0.20°, 23.82° ⁇ 0.20°, 25.70° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form I has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form I when the X-ray powder diffraction pattern of the crystalline form I has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form I has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .
  • the present disclosure also provides a crystalline form J of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form J has one, two or all characteristic peaks selected from the following 2 ⁇ values: 4.22° ⁇ 0.20°, 7.15° ⁇ 0.20°, 25.24° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form J has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.22° ⁇ 0.20°, 6.74° ⁇ 0.20°, 7.15° ⁇ 0.20°, 11.04° ⁇ 0.20°, 12.62° ⁇ 0.20°, 13.48° ⁇ 0.20°, 16.86 ⁇ 0.20°, 25.24° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form J has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form J when the X-ray powder diffraction pattern of the crystalline form J has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline Form J has an X-ray powder diffraction pattern substantially as shown in FIG. 10A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form J has an endothermic peak at an onset temperature of about 178.6°C and/or a peak temperature of about 182.4°C, and a peak temperature of about 188.9°C.
  • the Form J has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 10B .
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) of the crystalline form J there is a weight loss of about 1.4% to about 1.5% (e.g., about 1.41%) when the temperature is increased from room temperature to 100°C, and there is a weight loss of about 3.3% to about 3.4% (e.g., about 3.38%) when the temperature is increased from 100°C to 200°C.
  • the crystalline Form J has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 10B .
  • TGA thermogravimetric analysis
  • the crystalline form J is a 1,4-dioxane solvate.
  • the crystalline Form J has a 1 H NMR spectrum substantially as shown in FIG. 10C .
  • the Form J has a variable temperature XRPD pattern substantially as shown in FIG. 10D .
  • the present disclosure also provides a crystalline form K of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form K has one, two or all characteristic peaks selected from the following 2 ⁇ values: 4.19° ⁇ 0.20°, 6.48° ⁇ 0.20°, 6.95° ⁇ 0.20°, 19.54° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form K has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.19° ⁇ 0.20°, 5.13° ⁇ 0.20°, 6.48° ⁇ 0.20°, 6.95° ⁇ 0.20°, 9.75° ⁇ 0.20°, 11.06° ⁇ 0.20°, 17.13° ⁇ 0.20°, and 19.54° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form K has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form K when the X-ray powder diffraction pattern of the crystalline form K has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form K has an X-ray powder diffraction pattern substantially as shown in FIG. 11A .
  • the Form K has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 11B .
  • DSC differential scanning calorimetry
  • the crystalline form K has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 11B .
  • TGA thermogravimetric analysis
  • the crystalline Form K has a 1 H NMR spectrum substantially as shown in FIG. 11C .
  • the present disclosure also provides a crystalline form L of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form L has one, two or all characteristic peaks selected from the following 2 ⁇ values: 18.85° ⁇ 0.20°, 22.30° ⁇ 0.20°, 29.35° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form L has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 9.23° ⁇ 0.20°, 18.85° ⁇ 0.20°, 22.30° ⁇ 0.20°, 22.69° ⁇ 0.20°, 23.22° ⁇ 0.20°, 23.82° ⁇ 0.20°, 26.58° ⁇ 0.20°, 29.35° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form L has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form L when the X-ray powder diffraction pattern of the crystalline form L has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form L has an X-ray powder diffraction pattern substantially as shown in FIG. 12A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form L has an endothermic peak at an onset temperature of about 95.4°C and/or a peak temperature of about 100.0°C, and a peak temperature of about 154.5°C.
  • the crystalline Form L has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 12B .
  • thermogravimetric analysis (TGA) of the crystalline form L there is a weight loss of about 8.9% to about 9.0% (e.g., about 8.98%) when the temperature is increased from room temperature to 100°C, a weight loss of about 2.5% to about 2.6% (e.g., about 2.56%) when the temperature is increased from 100°C to 125°C, and a weight loss of about 1.8% to about 1.9% (e.g., about 1.81%) when the temperature is increased from 125°C to 150°C.
  • TGA thermogravimetric analysis
  • the crystalline form L has a thermogravimetric analysis (TGA) spectrum substantially as shown in FIG. 12B .
  • TGA thermogravimetric analysis
  • the crystalline form L is a methanol-water cosolvate.
  • the crystalline Form L has a 1 H NMR spectrum substantially as shown in FIG. 12C .
  • the single crystal of the crystal form L has an asymmetric unit schematic diagram of the single crystal structure as shown in FIG. 12D .
  • the single crystal of the crystal form L has the following structural parameters:
  • the present disclosure also provides a crystalline form M of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form M has one, two or all characteristic peaks selected from the following 2 ⁇ values: 4.22° ⁇ 0.20°, 18.59° ⁇ 0.20°, 25.31° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form M has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.22° ⁇ 0.20°, 9.05° ⁇ 0.20°, 10.94° ⁇ 0.20°, 15.48° ⁇ 0.20°, 18.59° ⁇ 0.20°, 21.81° ⁇ 0.20°, 25.31° ⁇ 0.20°, and 26.48° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form M has the following characteristic peaks:
  • the X-ray powder diffraction pattern of the crystalline form M when the X-ray powder diffraction pattern of the crystalline form M has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form M has an X-ray powder diffraction pattern substantially as shown in FIG. 13A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form M has an endothermic peak at a peak temperature of about 61.3°C, an onset temperature of about 181.4°C and/or a peak temperature of about 184.2°C.
  • the crystalline Form M has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 13B .
  • the weight loss is about 2.0% to about 2.1% (eg, about 2.05%) when the temperature is increased from room temperature to 200°C.
  • the crystalline form M has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 13B .
  • TGA thermogravimetric analysis
  • the crystalline form M is a hydrate.
  • the present disclosure also provides a crystalline form N of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form N has one, two or all characteristic peaks selected from the following 2 ⁇ values: 5.82° ⁇ 0.20°, 13.96° ⁇ 0.20°, 20.24° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form N has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 5.82° ⁇ 0.20°, 7.18° ⁇ 0.20°, 12.35° ⁇ 0.20°, 13.96° ⁇ 0.20°, 15.77° ⁇ 0.20°, 17.49° ⁇ 0.20°, 18.40° ⁇ 0.20°, 20.24° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form N has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form N has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form N has an X-ray powder diffraction pattern substantially as shown in FIG. 14A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form N has an endothermic peak at an onset temperature of about 118.0°C and/or a peak temperature of about 125.9°C.
  • the Form N has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 14B .
  • DSC differential scanning calorimetry
  • the weight loss is about 0.1% to about 0.2% (eg, about 0.19%) when the temperature is increased from room temperature to 200°C.
  • the crystalline Form N has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 14B .
  • TGA thermogravimetric analysis
  • the crystalline form N is an anhydrous crystalline form.
  • the crystalline Form N has a 1 H NMR spectrum substantially as shown in FIG. 14C .
  • the crystalline Form N has a variable temperature XRPD pattern substantially as shown in FIG. 14D .
  • the present disclosure also provides a crystalline form O of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form O has one, two or all characteristic peaks selected from the following 2 ⁇ values: 11.06° ⁇ 0.20°, 24.85° ⁇ 0.20°, 26.44° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form O has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.32° ⁇ 0.20°, 11.06° ⁇ 0.20°, 15.11° ⁇ 0.20°, 15.76° ⁇ 0.20°, 17.22° ⁇ 0.20°, 17.93° ⁇ 0.20°, 24.85° ⁇ 0.20°, and 26.44° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form O has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form O has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline Form O has an X-ray powder diffraction pattern substantially as shown in FIG. 15A .
  • the differential scanning calorimetry (DSC) spectrum of the crystalline form O has endothermic peaks at peak temperatures of about 174.7°C and about 187.1°C.
  • the Form O has a differential scanning calorimetry (DSC) spectrum substantially as shown in FIG. 15B .
  • DSC differential scanning calorimetry
  • thermogravimetric analysis of the crystalline form O
  • TGA thermogravimetric analysis
  • the crystalline Form O has a thermogravimetric analysis (TGA) pattern substantially as shown in FIG. 15B .
  • TGA thermogravimetric analysis
  • the crystalline form O is a methanol solvate.
  • the crystalline Form O has a 1 H NMR spectrum substantially as shown in FIG. 15C .
  • the crystalline Form O has a variable temperature XRPD pattern substantially as shown in FIG. 15D .
  • the present disclosure also provides a crystalline form P of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form P has one, two or all characteristic peaks selected from the following 2 ⁇ values: 6.36° ⁇ 0.20°, 16.15° ⁇ 0.20°, 21.05° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form P has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 6.36° ⁇ 0.20°, 11.09° ⁇ 0.20°, 16.15° ⁇ 0.20°, 17.27° ⁇ 0.20°, 21.05° ⁇ 0.20°, 26.38° ⁇ 0.20°, 26.62° ⁇ 0.20°, and 34.88° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form P has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form P when the X-ray powder diffraction pattern of the crystalline form P has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form P has an X-ray powder diffraction pattern substantially as shown in FIG. 16A .
  • the crystalline form P is a hydrate.
  • the present disclosure also provides a crystalline form Q of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form Q has one, two or all characteristic peaks selected from the following 2 ⁇ values: 18.41° ⁇ 0.20°, 25.19° ⁇ 0.20°, 26.36° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form Q has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 4.15° ⁇ 0.20°, 10.85° ⁇ 0.20°, 13.28° ⁇ 0.20°, 18.41° ⁇ 0.20°, 20.03° ⁇ 0.20°, 21.69° ⁇ 0.20°, 25.19° ⁇ 0.20°, 26.36° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form Q has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form Q when the X-ray powder diffraction pattern of the crystalline form Q has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form Q has an X-ray powder diffraction pattern substantially as shown in FIG. 17 .
  • the crystalline form Q is an anhydrous crystalline form.
  • the present disclosure also provides a crystalline form R of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form R has one, two or all characteristic peaks selected from the following 2 ⁇ values: 7.22° ⁇ 0.20°, 13.03° ⁇ 0.20°, 18.81° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form R has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 7.22° ⁇ 0.20°, 13.03° ⁇ 0.20°, 18.81° ⁇ 0.20°, 19.15 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form R has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form R when the X-ray powder diffraction pattern of the crystalline form R has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form R has an X-ray powder diffraction pattern substantially as shown in FIG. 22A .
  • the crystalline form R is an anhydrous crystalline form.
  • the present disclosure also provides a crystalline form S of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystalline form S has one, two or all characteristic peaks selected from the following 2 ⁇ values: 6.30° ⁇ 0.20°, 16.11° ⁇ 0.20°, 21.01° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form S has one, two, more or all characteristic peaks selected from the following 2 ⁇ values: 6.30° ⁇ 0.20°, 11.06° ⁇ 0.20°, 16.11° ⁇ 0.20°, 21.01° ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the crystalline form S has one, two, more or all characteristic peaks selected from the following 2 ⁇ values:
  • the X-ray powder diffraction pattern of the crystalline form S has one, two, more or all characteristic peaks selected from the above-mentioned 2 ⁇ values, it also optionally has relative intensities corresponding to the characteristic peaks.
  • the crystalline form S has an X-ray powder diffraction pattern substantially as shown in FIG. 23 .
  • the crystalline form S is a hydrate.
  • the present disclosure also provides Form T of maleate salt of the compound of formula (I), wherein the Form T has an X-ray powder diffraction pattern substantially as shown in FIG. 24A .
  • the present disclosure also provides Form U of the mesylate salt of the compound of formula (I), wherein the Form U has an X-ray powder diffraction pattern substantially as shown in FIG. 25A .
  • the X-ray powder diffraction pattern or 2 ⁇ value of the crystal form is obtained by using Cu target radiation.
  • the present disclosure also provides a method for preparing the crystalline form A, wherein the method for preparing the crystalline form A comprises dissolving the compound of formula (I) (such as its amorphous form, such as amorphous form Z) in a mixed solvent of ethyl acetate and dichloromethane, and volatilizing the resulting solution at room temperature to obtain the crystalline form A.
  • the volume ratio of ethyl acetate to dichloromethane can be 1:1 to 20:1, such as 9:1.
  • the present disclosure also provides a method for preparing the crystal form A, wherein the method for preparing the crystal form A comprises heating the crystal form G to 150° C., cooling to room temperature and exposing to air to obtain the crystal form A.
  • the present disclosure also provides a method for preparing the crystal form A, wherein the method for preparing the crystal form A comprises drying the crystal form I at room temperature to obtain the crystal form A.
  • the present disclosure also provides a method for preparing the crystal form L, wherein the method for preparing the crystal form L comprises mixing the compound of formula (I) (such as its amorphous form) and a mixed solvent of methanol and water to obtain a solution, and volatilizing the obtained solution at room temperature to obtain the crystal form L.
  • the volume ratio of methanol to water can be 1:1 to 20:1, for example 4:1.
  • the present disclosure also provides a method for preparing the crystalline form B, wherein the method for preparing the crystalline form B comprises stirring the crystalline form L in acetone to obtain the crystalline form B.
  • the mass volume ratio of the crystalline form L to acetone can be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL.
  • the stirring is performed at 50 to 70° C., for example, 60° C.
  • the present disclosure also provides a method for preparing the crystal form C, wherein the method for preparing the crystal form C comprises stirring the crystal form L in acetone at room temperature, heating to 60°C and stirring, cooling to 0-5°C and stirring, and mixing the separated solid with water and stirring to obtain the crystal form C.
  • the mass volume ratio of the crystal form L to acetone can be 20 mg: (0.1-1 mL), for example, 20 mg: 0.5 mL; the mass volume ratio of the crystal form L to water can be 20 mg: (0.1-1 mL), for example, 20 mg: 0.5 mL.
  • the stirring of the crystalline form L in acetone is first carried out at 50 to 70° C., for example, 60° C., and then at 0-5° C.
  • the separated solid is stirred in water again, it is stirred at room temperature.
  • the crystal form L is stirred in a mixed solvent of acetone and water, wherein the volume ratio of acetone to water can be (1-2):1, for example, 1.5:1.
  • the wet sample of Form P is dried in air to obtain Form C.
  • the present disclosure also provides a method for preparing the crystal form D, wherein the method for preparing the crystal form D comprises stirring the crystal form L at room temperature in acetone, heating to 60°C and stirring, cooling to 0-5°C and stirring, and stirring the separated solid in a mixed solvent of acetone and water to obtain the crystal form D.
  • the mass volume ratio of the crystal form L to acetone can be 20 mg: (0.1-1 mL), for example, 20 mg: 0.5 mL; the mass volume ratio of the crystal form L to the mixed solvent of acetone and water can be 20 mg: (0.1-1 mL), for example, 20 mg: 0.5 mL.
  • the volume ratio of acetone to water can be (5-7): 1, for example, 1.5: 1.
  • the stirring of the crystal form L in acetone is first performed at 50 to 70° C., for example, 60° C., and then at 0-5° C.
  • the separated solid is stirred in a mixed solvent of acetone and water, it is stirred at room temperature.
  • the crystal form L is stirred in a mixed solvent of acetone and water, wherein the volume ratio of acetone to water can be (3-6):1, for example 4:1.
  • the present disclosure also provides a method for preparing the crystalline form E, wherein the method for preparing the crystalline form E comprises stirring the crystalline form L in methanol to obtain the crystalline form E.
  • the stirring is performed at room temperature.
  • the mass volume ratio of the crystalline form L to methanol can be 20 mg: (0.1-1 mL), for example 20 mg: 0.5 mL.
  • the present disclosure also provides a method for preparing the crystalline form F, wherein the method for preparing the crystalline form F comprises stirring the compound of formula (I) (such as its amorphous form) in a mixed solvent of acetone and ethanol to obtain the crystalline form F.
  • the volume ratio of acetone to ethanol can be 1:1.
  • the present disclosure also provides a method for preparing the crystal form G, wherein the method for preparing the crystal form G comprises stirring the crystal form L in acetone, and stirring the separated solid in acetonitrile to obtain the crystal form G.
  • the mass volume ratio of the crystal form L to acetone can be 20 mg: (0.1-1 mL), for example, 20 mg: 0.5 mL; the mass volume ratio of the crystal form L to acetonitrile can be 20 mg: (0.1-1 mL), for example, 20 mg: 0.5 mL.
  • the present disclosure also provides a method for preparing the crystal form H, wherein the method for preparing the crystal form H comprises stirring the crystal form L in acetone at room temperature, heating to 60° C. and stirring, cooling to 0-5° C. and stirring, and subjecting the separated solid to gas-solid infiltration in a dichloromethane atmosphere to obtain the crystal form H.
  • the mass volume ratio of the crystal form L to acetone can be 20 mg: (0.1-1 mL), for example 20 mg: 0.5 mL.
  • the present disclosure also provides a method for preparing the crystalline form I, wherein the method for preparing the crystalline form I comprises dissolving the compound of formula (I) (such as its amorphous form) in N-methylpyrrolidone, then adding an anti-solvent such as acetonitrile, and standing at room temperature to precipitate a solid to obtain the crystalline form I.
  • the mass volume ratio of the compound of formula (I) to N-methylpyrrolidone can be 20 mg: (1.0-1.5 mL).
  • the mass volume ratio of the compound of formula (I) to N-methylpyrrolidone can be 20 mg: (3-5 mL), for example 20 mg: 4 mL.
  • the present disclosure also provides a method for preparing the crystal form J, wherein the method for preparing the crystal form J comprises stirring the crystal form L in acetone at room temperature, heating to 60°C and stirring, cooling to 0-5°C and stirring, mixing the separated solid with 1,4-dioxane, stirring at 50°C, and stirring at room temperature to obtain the crystal form J.
  • the mass volume ratio of the crystal form L to acetone can be 20 mg: (0.1-1 mL), for example, 20 mg: 0.5 mL.
  • the mass volume ratio of the crystal form L to 1,4-dioxane can be 20 mg: (0.1-1 mL), for example, 20 mg: 0.5 mL.
  • the present disclosure also provides a method for preparing the crystal form M, wherein the method for preparing the crystal form M comprises heating the crystal form D to 150° C., then cooling to room temperature and exposing to air for about 10 minutes to obtain the crystal form M.
  • the present disclosure also provides a method for preparing the crystal form M, wherein the method for preparing the crystal form M comprises heating the crystal form F to 160° C., cooling to room temperature and exposing to air to obtain the crystal form M.
  • the present disclosure also provides a method for preparing the crystal form M, wherein the method for preparing the crystal form M comprises heating the crystal form O sample to 175° C. to obtain the crystal form M.
  • the present disclosure also provides a method for preparing the crystal form M, wherein the method for preparing the crystal form M comprises placing the crystal form Q under room temperature and humidity conditions to obtain the crystal form M.
  • the present disclosure also provides a method for preparing the crystal form N, wherein the method for preparing the crystal form N comprises heating the crystal form E to 100° C., then cooling the temperature to room temperature and exposing the temperature to air to obtain the crystal form N.
  • the present disclosure also provides a method for preparing the crystalline form O, wherein the method for preparing the crystalline form O comprises dissolving the compound of formula (I) (such as its amorphous form, such as amorphous form Z) in a mixed solvent of methanol and water, and volatilizing at room temperature to obtain the crystalline form O.
  • the volume ratio of methanol to water can be (3-5):1, for example 4:1.
  • the present disclosure also provides a method for preparing the crystal form P, wherein the method for preparing the crystal form P comprises stirring the crystal form L in acetone at room temperature, heating to 60° C. and stirring, cooling to 0-5° C. and stirring, and slurrying the separated solid in a mixed solvent of MEK, THF and H 2 O to obtain the crystal form P.
  • the volume ratio of MEK, THF and H 2 O may be 1:0.1:2.
  • the present disclosure also provides a method for preparing the crystal form Q, wherein the method for preparing the crystal form Q comprises purging the crystal form D under N2 protection for 20 minutes, heating the sample to 150°C and cooling it to 30°C to obtain the crystal form Q.
  • the present disclosure also provides a method for preparing the crystal form R, wherein the method for preparing the crystal form R comprises mixing a compound of formula (I) (such as an amorphous substance, such as amorphous substance Z) and a mixed solvent of dichloromethane and acetone, concentrating to dryness under reduced pressure after dissolving, adding acetone, heating to dissolve, adding water, cooling naturally to room temperature, stirring, and filtering to obtain the crystal form R.
  • a compound of formula (I) such as an amorphous substance, such as amorphous substance Z
  • a mixed solvent of dichloromethane and acetone concentrating to dryness under reduced pressure after dissolving, adding acetone, heating to dissolve, adding water, cooling naturally to room temperature, stirring, and filtering to obtain the crystal form R.
  • the volume ratio of dichloromethane to acetone may be 3:1 to 9:1, for example, 6:1; preferably, the volume ratio of acetone added after concentrating to dryness under reduced pressure to acetone in the mixed solvent of dichloromethane and acetone may be 1:1 to 1:1.5, for example, 4:5; preferably, the volume ratio of water added after heating to dissolve to acetone added after concentrating to dryness under reduced pressure may be 0.5:1 to 1:1, for example, 0.75:1.
  • the mass volume ratio of the compound of formula (I) to the mixed solvent of dichloromethane and acetone can be 1 mg: (0.3-0.5) mL, for example, 1 mg: 0.35 mL.
  • the present disclosure also provides a method for preparing the crystalline form S, wherein the method for preparing the crystalline form S comprises mixing the compound of formula (I) (such as an amorphous substance, such as amorphous substance Z) with 1,4-dioxane, dissolving, adding water, precipitating solids, filtering, and drying to obtain the crystalline form S.
  • the volume ratio of 1,4-dioxane to water is 1:2 to 1:3, for example, 1:2.2.
  • the mass volume ratio of the compound of formula (I) to 1,4-dioxane can be 1 mg: (0.08 to 0.15) mL, for example, 1 mg: 0.11 mL.
  • the present disclosure also provides a method for preparing the crystal form T, wherein the method for preparing the crystal form T comprises mixing a compound of formula (I) (such as an amorphous substance, such as amorphous substance Z) with chloroform to obtain a solution 1; mixing maleic acid with ethanol to obtain a solution 2; mixing solution 2 with solution 1, adding methyl tert-butyl ether, stirring, centrifuging, and drying to obtain crystal form T.
  • a compound of formula (I) such as an amorphous substance, such as amorphous substance Z
  • the mass volume ratio of the compound of formula (I) to chloroform can be 1g:(12-20)mL, for example, 1g:(14-15)mL.
  • the mass volume ratio of the compound of formula (I) to maleic acid can be (9-10):1.
  • the mass volume ratio of the compound of formula (I) to ethanol can be 1g:(1-4)mL, for example, 1g:2mL.
  • the volume ratio of solution 2 to solution 1 can be 1:(1.2-1.3).
  • the volume ratio of chloroform to the total amount of methyl tert-butyl ether can be (11-12):1.
  • the present disclosure also provides a method for preparing the crystalline form U, wherein the method for preparing the crystalline form U comprises mixing a compound of formula (I) (such as an amorphous substance, such as amorphous substance Z) with chloroform to obtain a solution 1; mixing methanesulfonic acid with chloroform to obtain a solution 2; mixing solution 2 with solution 1, stirring, and drying to obtain crystalline form U.
  • a compound of formula (I) such as an amorphous substance, such as amorphous substance Z
  • the mass volume ratio of the compound of formula (I) to the chloroform in solution 1 can be 1 g: (12-20) mL, for example, 1 g: (14-15) mL.
  • the mass ratio of the compound of formula (I) to methanesulfonic acid can be (9-10): 1.
  • the mass volume ratio of the compound of formula (I) to the chloroform in solution 2 can be 1 g: (1-4) mL, for example, 1 g: 2 mL.
  • the volume ratio of solution 2 to solution 1 can be 1: (1.3-1.4).
  • the present disclosure also provides a mixture, wherein the mixture comprises at least one selected from the solid forms of the compound of formula (I) or its pharmaceutically acceptable salt, for example, one, two, three or more, preferably one, two, three or more selected from the crystalline forms A to U (i.e., crystalline forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U).
  • the mixture comprises at least one selected from the solid forms of the compound of formula (I) or its pharmaceutically acceptable salt, for example, one, two, three or more, preferably one, two, three or more selected from the crystalline forms A to U (i.e., crystalline forms A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U).
  • the mixture comprises Form A and one, two, three or more selected from Forms B to U, preferably Form A and one, two, three or more selected from Forms B to U.
  • the weight percentage content of Form A is 80% or more, for example 90% or more, preferably 95% or more, for example 98% or more, further preferably 99% or more, such as 99.5% or more, 99.8% or more or 99.9% or more.
  • the present disclosure also provides a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one solid form selected from the compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably comprises one, two, three or more selected from crystalline forms A to U; or, the pharmaceutical composition comprises the mixture.
  • the pharmaceutical composition comprises the mixture as described above.
  • the pharmaceutical composition may further include a pharmaceutically acceptable excipient.
  • the pharmaceutical composition further contains at least one, such as one, two, three or more additional therapeutic agents.
  • the present disclosure also provides the use of the solid form of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the use is selected from at least one of the following, for example, one, two, three or more:
  • IBS irritable bowel syndrome
  • the present disclosure also provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cells with at least one selected from the solid forms, preferably at least one selected from forms A to U, for example, comprising form A and one, two, three or more selected from forms B to U.
  • the present disclosure also provides a method for treating a RET kinase-mediated disease, comprising administering to a patient at least one selected from the solid forms, preferably at least one selected from Forms A to U, for example, comprising Form A and one, two, three or more selected from Forms B to U.
  • the present disclosure also provides a method for treating a RET-related disease or condition in a patient in need of treatment, the method comprising administering to the patient at least one selected from the solid forms, preferably at least one selected from Forms A to U, for example, comprising Form A and one, two, three or more selected from Forms B to U.
  • the present disclosure also provides a method for treating cancer and/or inhibiting metastasis associated with a specific cancer in a patient in need of treatment, the method comprising administering to the patient at least one selected from the solid forms, preferably at least one selected from Forms A to U, for example, comprising Form A and one, two, three or more selected from Forms B to U.
  • the present disclosure also provides a method for treating irritable bowel syndrome (IBS) and/or pain associated with IBS in a patient in need of treatment, the method comprising administering to the patient at least one selected from the solid forms, preferably at least one selected from Forms A to U, for example comprising Form A and one, two, three or more selected from Forms B to U.
  • IBS irritable bowel syndrome
  • the present disclosure also provides a method for providing supportive care for cancer patients, including preventing or minimizing gastrointestinal diseases (e.g., diarrhea) associated with treatment (including chemotherapy treatment), the method comprising administering to the patient at least one selected from the solid forms, preferably at least one selected from Forms A to U, for example comprising Form A and one, two, three or more selected from Forms B to U.
  • gastrointestinal diseases e.g., diarrhea
  • chemotherapy treatment including chemotherapy treatment
  • the present disclosure also provides use of at least one selected from the solid forms, preferably at least one selected from crystal forms A to U, for example, comprising crystal form A and one, two, three or more selected from crystal forms B to U, in the preparation of a medicament for treating a RET kinase-mediated disease.
  • the present disclosure also provides use of at least one selected from the solid forms, preferably at least one selected from crystalline forms A to U, for example, comprising crystalline form A and one, two, three or more selected from crystalline forms B to U, in the preparation of a medicament for treating cancer and/or inhibiting metastasis associated with a specific cancer.
  • the present disclosure also provides use of at least one selected from the solid forms, preferably at least one selected from crystal forms A to U, for example, comprising crystal form A and one, two, three or more selected from crystal forms B to U, in the preparation of a medicament for treating irritable bowel syndrome (IBS) or pain associated with IBS.
  • IBS irritable bowel syndrome
  • the present disclosure also provides a use of at least one selected from the solid forms, preferably at least one selected from crystal forms A to U, for example, comprising crystal form A and one, two, three or more selected from crystal forms B to U, in the preparation of a medicament for providing supportive care to cancer patients, wherein the supportive care includes preventing or minimizing gastrointestinal disorders associated with treatment (including chemotherapy treatment), such as diarrhea.
  • the supportive care includes preventing or minimizing gastrointestinal disorders associated with treatment (including chemotherapy treatment), such as diarrhea.
  • the present disclosure also provides use of at least one selected from the solid forms, preferably at least one selected from crystal forms A to U, for example, comprising crystal form A and one, two, three or more selected from crystal forms B to U, in the preparation of a medicament for inhibiting RET kinase activity.
  • the present disclosure also provides use of at least one selected from the solid forms, preferably at least one selected from crystal forms A to U, for example, comprising crystal form A and one, two, three or more selected from crystal forms B to U, in the preparation of a medicament for treating RET-related diseases or disorders.
  • the present disclosure also provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining whether the cancer is associated with the following dysregulation: RET gene, RET kinase, or the expression or activity or level of any one thereof (e.g., RET-related cancer); (b) if it is determined that the cancer is associated with the following dysregulation: RET gene, RET kinase, or the expression or activity or level of any one thereof (e.g., RET-related cancer), administering to the patient at least one selected from the solid forms, preferably at least one selected from crystalline forms A to U, for example comprising crystalline form A and one, two, three or more selected from crystalline forms B to U.
  • the present disclosure also provides a method for reversing or preventing acquired resistance to an anticancer drug, the method comprising administering at least one selected from the solid forms, preferably at least one selected from crystalline forms A to U, for example, comprising crystalline form A and one, two, three or more selected from crystalline forms B to U, to a patient at risk of developing or having acquired resistance to other anticancer drugs.
  • the present disclosure also provides a method for delaying and/or preventing the development of anticancer drug resistance in an individual, the method comprising administering to the individual at least one selected from the solid forms, preferably at least one selected from crystalline forms A to U, for example comprising crystalline form A and one, two, three or more selected from crystalline forms B to U, and administering other anticancer drugs before, during or after the administration.
  • the present disclosure also provides a method for treating an individual who has cancer and has an increased likelihood of developing resistance to an anticancer drug, comprising concomitantly administering to the individual (a) at least one selected from the solid forms, preferably at least one selected from Forms A to U, for example comprising Form A and one, two, three or more selected from Forms B to U; and (b) other anticancer drugs.
  • the present disclosure also provides a method for treating an individual with a RET-related cancer, wherein the cancer has one or more RET inhibitor resistance mutations that increase the resistance of the cancer to a RET inhibitor that is not at least one of the compounds of Formula I or pharmaceutically acceptable salts thereof (e.g., substitutions at amino acid positions 804, 810, 904, such as V804M, V804L, V804E, G810R, G810S, G810C, G810V, S904F), comprising administering at least one selected from the solid forms, preferably at least one selected from Forms A to U, such as Form A and one, two, three or more selected from Forms B to U, before, during or after administering another other anticancer drug.
  • RET inhibitor resistance mutations that increase the resistance of the cancer to a RET inhibitor that is not at least one of the compounds of Formula I or pharmaceutically acceptable salts thereof (e.g., substitutions at amino acid positions 804, 810, 904, such as V804M,
  • the present disclosure also provides a method for treating an individual with a RET-related cancer, the method comprising administering at least one selected from the solid forms, preferably at least one selected from Forms A to U, for example, Form A and one, two, three or more selected from Forms B to U, before, during or after administering another other anti-cancer drug.
  • the present disclosure provides a method for treating cancer (e.g., RET-related cancer) in a patient in need thereof, the method comprising administering to the patient at least one selected from the solid forms, preferably at least one selected from Forms A to U, for example, comprising Form A and one, two, three or more selected from Forms B to U.
  • cancer e.g., RET-related cancer
  • the amount of the solid form is preferably a therapeutically effective amount.
  • the solid form of the fused ring compound provided by the present disclosure is not disclosed or taught by the prior art, and provides a more favorable pharmaceutically acceptable form for the compound of formula (I).
  • the solid form provided by the present disclosure, especially Form A has excellent physicochemical properties and pharmacokinetic properties, is conducive to improving the properties of the preparation and the shelf life, and brings more beneficial therapeutic effects to patients.
  • FIG. 1A is an X-ray powder diffraction (XRPD) pattern of Form A of the present disclosure.
  • FIG. 1B is a differential scanning calorimetry (DSC) diagram of Form A of the present disclosure.
  • FIG. 1C is a thermogravimetric analysis (TGA) graph of Form A of the present disclosure.
  • FIG. 1D is a 1 H NMR chart of Form A of the present disclosure.
  • FIG. 2A is an X-ray powder diffraction (XRPD) pattern of Form B of the present disclosure.
  • FIG2B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form B of the present disclosure.
  • FIG. 2C is a 1 H NMR graph of Form B of the present disclosure.
  • FIG. 3A is an X-ray powder diffraction (XRPD) pattern of Form C of the present disclosure.
  • FIG3B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form C of the present disclosure.
  • FIG. 3C is a 1 H NMR graph of Form C of the present disclosure.
  • FIG. 4A is an X-ray powder diffraction (XRPD) pattern of Form D of the present disclosure.
  • FIG4B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form D of the present disclosure.
  • FIG. 4C is a 1 H NMR chart of Form D of the present disclosure.
  • FIG. 4D is a temperature-dependent XRPD overlay of Form D of the present disclosure.
  • FIG. 5A is an X-ray powder diffraction (XRPD) pattern of Form E of the present disclosure.
  • FIG5B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form E of the present disclosure.
  • FIG. 5C is a 1 H NMR graph of Form E of the present disclosure.
  • FIG. 5D is a temperature-dependent XRPD overlay of Form E of the present disclosure.
  • FIG. 5E is a 1 H NMR graph of Form E of the present disclosure after heating.
  • FIG. 6A is an X-ray powder diffraction (XRPD) pattern of Form F of the present disclosure.
  • FIG6B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form F of the present disclosure.
  • FIG. 6C is a 1 H NMR graph of Form F of the present disclosure.
  • FIG6D is a temperature-dependent XRPD overlay of Form F of the present disclosure.
  • FIG. 6E is a 1 H NMR graph of Form F of the present disclosure after heating.
  • FIG. 7A is an X-ray powder diffraction (XRPD) pattern of Form G of the present disclosure.
  • FIG. 7B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form G of the present disclosure.
  • FIG. 7C is a 1 H NMR graph of Form G of the present disclosure.
  • FIG. 7D is a 1 H NMR graph of Form G of the present disclosure after heating.
  • FIG. 8A is an X-ray powder diffraction (XRPD) pattern of Form H of the present disclosure.
  • FIG8B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form H of the present disclosure.
  • FIG. 8C is a 1 H NMR graph of Form H of the present disclosure.
  • FIG8D is a temperature-dependent XRPD overlay of Form H of the present disclosure.
  • FIG. 9 is an X-ray powder diffraction (XRPD) pattern of Form I of the present disclosure.
  • FIG. 10A is an X-ray powder diffraction (XRPD) pattern of Form J of the present disclosure.
  • FIG. 10B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form J of the present disclosure.
  • FIG. 10C is a 1 H NMR chart of Form J of the present disclosure.
  • FIG. 10D is a temperature-dependent XRPD overlay of Form J of the present disclosure.
  • FIG. 10E is a 1 H NMR graph of Form J of the present disclosure after heating.
  • FIG. 11A is an X-ray powder diffraction (XRPD) pattern of Form K of the present disclosure.
  • FIG. 11B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form K of the present disclosure.
  • FIG. 11C is a 1 H NMR chart of Form K of the present disclosure.
  • FIG11D is an XRPD overlay of the crystalline form obtained by repeating the method of Example 12.
  • FIG. 12A is an X-ray powder diffraction (XRPD) pattern of Form L of the present disclosure.
  • FIG. 12B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form L of the present disclosure.
  • FIG. 12C is a 1 H NMR chart of Form L of the present disclosure.
  • FIG. 12D is a schematic diagram of an asymmetric unit of the single crystal structure of Form L of the present disclosure.
  • FIG. 13A is an X-ray powder diffraction (XRPD) pattern of Form M of the present disclosure.
  • FIG. 13B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form M of the present disclosure.
  • FIG. 14A is an X-ray powder diffraction (XRPD) pattern of Form N of the present disclosure.
  • FIG. 14B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form N of the present disclosure.
  • FIG. 14C is a 1 H NMR chart of Form N of the present disclosure.
  • FIG. 14D is a temperature-dependent XRPD overlay of Form N of the present disclosure.
  • FIG. 15A is an X-ray powder diffraction (XRPD) pattern of Form O of the present disclosure.
  • FIG. 15B is a differential scanning calorimetry (DSC) graph and a thermogravimetric analysis (TGA) graph of Form O of the present disclosure.
  • FIG. 15C is a 1 H NMR chart of Form O of the present disclosure.
  • FIG. 15D is a temperature-dependent XRPD overlay of Form O of the present disclosure.
  • FIG. 15E is a 1 H NMR graph of Form O of the present disclosure after heating.
  • FIG. 16A is an X-ray powder diffraction (XRPD) pattern of Form P of the present disclosure.
  • FIG. 16B is an XRPD overlay of Form P of the present disclosure before and after drying.
  • FIG. 17 is an X-ray powder diffraction (XRPD) pattern of Form Q of the present disclosure.
  • FIG. 18 is a DVS diagram of Form A in the hygroscopicity test of Test Example 1.
  • FIG. 19 is a DVS diagram of Form B in the hygroscopicity test of Test Example 1.
  • FIG. 20A is an XRPD overlay of the solid after suspension competition in Test Example 4.
  • FIG. 20B is an XRPD overlay of the solid after suspension competition in Test Example 4.
  • FIG. 21A is an X-ray powder diffraction (XRPD) pattern of amorphous form Z of the compound of formula (I) in Example 1.
  • FIG. 21B is a differential scanning calorimetry (DSC) graph of amorphous form Z of the compound of formula (I) in Example 1.
  • FIG. 21C is a thermogravimetric analysis (TGA) graph of amorphous form Z of the compound of formula (I) in Example 1.
  • FIG. 22A is an X-ray powder diffraction (XRPD) pattern of Form R of the present disclosure.
  • FIG. 22B is a DVS test diagram of crystal form R in Test Example 1.
  • FIG. 22C is an isothermal adsorption curve of Form R in Test Example 1.
  • FIG. 23 is an X-ray powder diffraction (XRPD) pattern of Form S disclosed herein.
  • FIG. 24A is an X-ray powder diffraction (XRPD) pattern of Form T of the present disclosure.
  • FIG. 24B is a 1 H NMR chart of Form T of the present disclosure.
  • FIG. 25A is an X-ray powder diffraction (XRPD) pattern of Form U of the present disclosure.
  • FIG. 25B is a 1 H NMR chart of Form U of the present disclosure.
  • TGA Thermogravimetric analysis
  • DSC differential scanning calorimetry
  • TGA and DSC images were collected on TA Discovery 5500 thermogravimetric analyzer and TA Discovery 2500 differential scanning calorimeter, respectively.
  • the test parameters are shown in the following table:
  • Dynamic moisture sorption (DVS) curves were collected on the DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected using the deliquescent point of LiCl, Mg(NO 3 ) 2 and KCl. The DVS test parameters are shown in the following table:
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the X-ray powder diffraction pattern of the crystal form is shown in Figure 1A
  • the differential scanning calorimetry (DSC) spectrum tested after preheating the sample to remove the surface adsorbed solvent is shown in Figure 1B
  • the thermogravimetric analysis (TGA) spectrum is shown in Figure 1C
  • the 1 H NMR spectrum is shown in Figure 1D.
  • Form A was purged under N2 protection for 20 min, heated to 150°C, and cooled to 30°C, but no change in the crystal form was observed. Combined with the TGA/DSC and 1 H NMR results of the sample, it was analyzed that Form A was anhydrous crystalline form.
  • the X-ray powder diffraction pattern of the crystal form is shown in FIG3A
  • the differential scanning calorimetry (DSC) spectrum and thermogravimetric analysis (TGA) spectrum tested after preheating the sample to remove the surface adsorbed solvent/water are shown in FIG3B
  • the 1 H NMR spectrum is shown in FIG3C .
  • Form C was purged under N2 protection for 20 min, heated to 100°C, and cooled to 30°C, but no crystal form change was observed. Combined with the TGA/DSC and 1 H NMR results of the sample, it was analyzed that Form C was anhydrous crystalline form.
  • the X-ray powder diffraction pattern of the crystal form is shown in FIG4A
  • the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum are shown in FIG4B
  • the 1 H NMR spectrum is shown in FIG4C.
  • the 1 H NMR results show that the crystal form D sample contains very little ( ⁇ 0.5 wt%) acetone residue.
  • variable temperature XRPD ( Figure 4D) show that when the Form D sample was purged under N2 protection for 20 minutes, the diffraction peaks were observed to change; when the sample was heated to 150°C and cooled to 30°C, the crystal form was observed to change, and the new crystal form obtained was Form Q; when the sample was heated to 150°C, cooled to room temperature and exposed to air, some diffraction peaks were observed to change, and the new crystal form obtained was Form M.
  • the DSC results showed a broad endothermic signal (peak temperature 63.7°C) before the melting peak, and the 1H NMR results showed that the sample contained only a very small amount of acetone residue (much less than the TGA weight loss), so the analysis showed that Form D was a hydrate.
  • Form E was identified by heating test, and the results are shown in Figure 5D.
  • Form E was heated to 48°C, cooled to room temperature and exposed to air, no change in the crystal form was observed; when the sample was heated to 100°C, cooled to room temperature and exposed to air, the new crystal form observed was Form N; when the sample was continued to be heated to 115°C, cooled to room temperature and exposed to air, amorphous formation was observed.
  • Figure 5E the solvent content did not change significantly compared with before heating
  • TGA/DSC results it was analyzed that the crystal form was a MeOH solvate.
  • the X-ray powder diffraction pattern of the crystal form is shown in FIG7A
  • the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum are shown in FIG7B
  • the 1 H NMR spectrum is shown in FIG7C .
  • Form G was identified by heating test, and the results showed that when the free form G sample was heated to 75°C, cooled to room temperature and exposed to air, no change in form was observed; when it was further heated to 150°C, cooled to room temperature and exposed to air, it was observed to transform into Form A. Combined with the 1 H NMR results of the sample after Form G was heated to 75°C ( Figure 7D, the solvent content did not change compared with before heating), combined with the TGA/DSC results, it was analyzed that the form was an acetonitrile solvate.
  • amorphous material Z prepared according to the method of Example 1 into a 3-mL vial, use 1.0-1.5 mL of solvent NMP (N-methylpyrrolidone) to dissolve the solid, filter the solution with a filter membrane to obtain a clear solution, take another 20-mL vial and add about 4 mL of anti-solvent ACN thereto, place the 3-mL vial containing the filtrate in the 20-mL vial, seal the 20 mL vial and let it stand at room temperature. When the solid precipitates, collect the solid to obtain Form I.
  • the X-ray powder diffraction pattern of the crystal form is shown in Figure 9. However, after drying at room temperature, Form I turns into Form A.
  • the X-ray powder diffraction pattern of the crystal form is shown in FIG11A
  • the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum are shown in FIG11B
  • the 1 H NMR spectrum is shown in FIG11C .
  • amorphous material Z prepared according to the method of Example 1 was weighed into a 20-mL vial, and a mixed solvent of methanol and water (4:1, v:v) was added to dissolve the solid. After filtering through a filter membrane, the obtained clear filtrate was sealed with a sealing film, and 5 small holes were pierced on it, and it was left to evaporate slowly at room temperature. The solid obtained by evaporation was collected to obtain a crystalline form L.
  • the X-ray powder diffraction spectrum of the crystalline form is shown in FIG12A
  • the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum are shown in FIG12B
  • TGA thermogravimetric analysis
  • the X-ray powder diffraction pattern of the crystal form is shown in FIG13A
  • the differential scanning calorimetry (DSC) pattern and the thermogravimetric analysis (TGA) pattern are shown in FIG13B .
  • the X-ray powder diffraction spectrum of the crystal form is shown in FIG14A
  • the differential scanning calorimetry (DSC) spectrum and thermogravimetric analysis (TGA) spectrum after heating at 100° C. to remove surface adsorbed water/solvent are shown in FIG14B
  • the 1 H NMR spectrum is shown in FIG14C .
  • Example 2 About 20 mg of the amorphous material Z prepared according to the method of Example 1 was weighed, dissolved in MeOH/H 2 O (4:1, v/v), and slowly evaporated at room temperature to obtain a crystalline form O.
  • the X-ray powder diffraction spectrum of the crystalline form is shown in FIG15A
  • the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum are shown in FIG15B
  • TGA thermogravimetric analysis
  • Form P was analyzed to be a hydrate.
  • Form Q is obtained by heating Form D under N 2 purge, Form Q is analyzed to be anhydrous. At the same time, Form Q is converted into hydrated Form M after being placed under room temperature and humidity conditions.
  • amorphous material Z prepared according to the method of Example 1 100 mg was weighed into a vial, 35 mL of a mixed solvent of dichloromethane and acetone (6:1, v:v) was added, and the mixture was stirred to dissolve and then concentrated to dryness under reduced pressure again, 4 mL of acetone was added, and about 3 mL of purified water was added after heating at 60° C. to dissolve, and the mixture was naturally cooled to room temperature, and stirring was continued for 2 h, and the crystal form R was filtered to obtain the crystal form R.
  • the X-ray powder diffraction pattern of the crystal form is shown in FIG22A , which is an anhydrous form.
  • the hygroscopicity of Form A and Form B was tested by DVS test between 0% RH and 95% RH at 25°C, and evaluated with reference to the 2015 edition of the Chinese Pharmacopoeia.
  • the DVS test results of Form A and Form B are shown in Figures 18 and 19, respectively.
  • the moisture absorption weight gain of Form A sample under 25°C/80%RH is about 1.1%
  • the moisture absorption weight gain of Form B sample is about 1.0%, indicating that both Form A and Form B are slightly hygroscopic.
  • the XRPD results show that the crystal form of Form A and Form B samples did not change after the DVS test.
  • Crystal form R begins to absorb water and transform into hydrate crystal form S at 50% RH, while crystal form S begins to dehydrate and transform into anhydrous crystal form R at 40% RH.
  • Form A and Form B samples place them at 60°C for 24 hours in a closed container, and place them at 25°C/60%RH and 40°C/75%RH in an open container for 2, 4 or 6 weeks.
  • the solid samples placed under different conditions were tested for crystal form changes by XRPD, and the purity was tested by HPLC to evaluate chemical stability.
  • Chromatographic column Waters XTERRA RP18, 4.6mm ⁇ 150mm, 3.5 ⁇ m or chromatographic column with equivalent performance.
  • Phase A is 10 mmol/L potassium dihydrogen phosphate solution (pH adjusted to 9.0 ⁇ 0.05 with phosphoric acid); Phase B is acetonitrile-methanol (85:15).
  • the detection wavelength was 250 nm
  • the column temperature was 40°C
  • the flow rate was 1.0 ml per minute
  • the injection volume was 10 ⁇ L.
  • Solubility media water, pH 4.5 acetate buffer, pH 6.8 phosphate buffer.
  • pH 4.5 acetate buffer Take 0.59806g of sodium acetate trihydrate and place it in a 200ml volumetric flask, dissolve it with appropriate amount of water, then add 1.6ml of glacial acetic acid, and dilute it to the scale with water.
  • pH 6.8 phosphate buffer Take 1.38501 g of potassium dihydrogen phosphate and 0.18086 g of sodium hydroxide, place them in a 200 mL volumetric flask, dissolve them in water and dilute to the scale.
  • pH 6.8 phosphate buffer sample solution Take a supersaturated solution of pH 6.8 phosphate buffer medium and filter it to obtain the solution.
  • Water sample solution Take the supersaturated solution of water medium and filter it to obtain
  • pH 4.5 acetic acid buffer sample solution Take a supersaturated solution of pH 4.5 acetic acid buffer medium, filter, accurately measure 1.0 mL of the filtrate and place it in a 10 mL volumetric flask, dilute to the scale with pH 4.5 acetic acid buffer medium, accurately measure 1.0 mL of the solution and place it in a 10 mL volumetric flask, dilute to the scale with methanol, and obtain.
  • pH 6.8 phosphate buffer sample solution Take a supersaturated solution of pH 6.8 phosphate buffer medium and filter it to obtain the solution.
  • Water sample solution Take the supersaturated solution of water medium and filter it to obtain
  • pH 4.5 acetic acid buffer sample solution Take a supersaturated solution of pH 4.5 acetic acid buffer medium, filter, accurately measure 1.0 mL of the filtrate and place it in a 10 mL volumetric flask, dilute to the scale with pH 4.5 acetic acid buffer medium, accurately measure 1.0 mL of the solution and place it in a 25 mL volumetric flask, dilute to the scale with methanol, and obtain.
  • a S peak area of the main peak in the test solution
  • DS dilution factor of the test solution
  • AR peak area of the main peak in the reference solution
  • DR dilution factor of the reference solution
  • the signal of form C may be generated by the crystal transformation of form P during the XRPD test.
  • the description with reference to the terms “embodiment”, “example”, etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present disclosure.
  • the schematic representation of the above terms does not necessarily refer to the same embodiment or example.
  • the specific features, structures, materials or characteristics described may be combined in a suitable manner in any one or more embodiments or examples.
  • the embodiments of the present disclosure have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations of the present disclosure. Those skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present disclosure without departing from the principles and purpose of the present disclosure.

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Abstract

本公开涉及稠环化合物的固体形式及其制备方法和用途，为式(I)化合物提供了更有利的药学上可接受的形态。本公开提供的固体形式具有有利的理化性质和药代动力学性质。

Description

稠环化合物的固体形式及其制备方法和用途
本申请要求享有申请人于2022年11月25日向中国国家知识产权局提交的申请号为202211494114.7，名称为“稠环化合物的固体形式及其制备方法和用途”的在先中国发明专利申请的优先权权益。上述在先申请的全文以引用的方式结合至本文。
技术领域
本公开涉及稠环化合物的固体形式及其制备方法和用途，属于化学药物领域。
背景技术
RET(Rearranged During Transfection)原癌基因最初是在1985年，通过NIH3T3(小鼠胚胎成纤维细胞系)细胞与人类淋巴瘤DNA的转染被证实(Cell,1985,42(2):581-588)。RET原癌基因定位于染色体10q11.2，其DNA全长为60kb，含有外显子21个，编码由1100个氨基酸组成的RET蛋白：这种RET蛋白是一种酪氨酸激酶受体，含有一个由半胱氨酸组成的细胞外区、一个跨膜区和一个具有催化酪氨酸激酶作用的细胞内区(Mol Cell Endocrinol,2010,322(1-2):2-7)。RET参与细胞增殖、神经传导、细胞迁移和细胞分化，通过配体/复合受体/RET多蛋白复合物的信号，激活各种下游途径，如RAS/RAF/MEK/ERK，PI3K/AKT和STAT通路，诱导细胞增生(J Clin Oncol,2012,30(2):200-202)。
关于RET融合物在一些癌症中是驱动者的发现促进了已具有RET抑制活性的多激酶抑制剂(multi-kinase inhibitor)的应用，用于治疗负载RET融合物蛋白质的肿瘤病人。RET抑制剂塞尔帕替尼(LOXO-292)已获批用于治疗负载RET融合物蛋白质的肿瘤病人，但癌症治疗的最大挑战之一是肿瘤细胞对于治疗一定阶段后出现耐药，一旦耐药，病人的治疗方式通常极为有限，且大多数例子中，癌症一直进展、不受抑制。有文献报道(RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies,Journal of Thoracic Oncology,2020,Vol.15,No 4,541-549)RET融合非小细胞肺癌患者在使用RET抑制剂塞尔帕替尼(LOXO-292)后出现RET G810溶剂前沿突变，如G810R,G810S,G801C突变，导致LOXO-292对ATP结合位点效果下降，从而出现耐药，癌症发生进展，因此，需要开发具有良好RET突变抑制活性的化合物。
申请号为PCT/CN2020/107049的PCT专利申请公开了作为RET抑制剂的一类化合物，其对RET看门残基突变体RET V804M，RET溶剂前沿残基突变体G810R和其他临床相关RET突变体以及wt-RET均有较强的抑制作用。这些化合物还能显著抑制甲状腺癌来源的TT细胞系和各种RET突变体转化的Ba/F3细胞的生长，阻断细胞RET自磷酸化及其下游通路，并能显著诱导TT细胞死亡。因此，需要进一步研究此类化合物的固体形式，特别是开发更适宜作为药物活性成分的晶体形式。
发明内容
为实现上述目的，本公开提供下式(I)化合物或其药学上可接受的盐的固体形式：
所述固体形式选自无水物、水合物、有机溶剂合物或水与有机溶剂的共溶剂合物的固体形式。
根据本公开的实施方案，所述有机溶剂选自醇类(如甲醇、乙醇)、腈类(如乙腈)、卤代烷烃类(如二氯甲烷)、醚类(如1,4-二氧六环)中的一种。
根据本公开的实施方案，所述固体形式选自下文所述的晶型中的一种、两种、三种或更多种。
本公开还提供式(I)化合物的晶型A，所述晶型A的X射线粉末衍射图具有一个或两个选自下列2θ值处的特征峰：6.91°±0.20°、10.32°±0.20°。
根据本公开的实施方案，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：6.91°±0.20°、10.32°±0.20°、25.72°±0.20°。
优选地，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：6.91°±0.20°、10.32°±0.20°、13.88±0.20°、25.72°±0.20°。
根据本公开的实施方案，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.46°±0.20°、6.91°±0.20°、10.32°±0.20°、13.88°±0.20°、14.84°±0.20°、18.33°±0.20°、20.32°±0.20°、25.72°±0.20°。
根据本公开的实施方案，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.46°±0.20°、6.91°±0.20°、10.32°±0.20°、10.63°±0.20°、13.61°±0.20°、13.88°±0.20°、14.84°±0.20°、18.33°±0.20°、20.32°±0.20°、25.72°±0.20°。
根据本公开的实施方案，所述晶型A的X射线粉末衍射图还具有选自下列2θ值处的一个、两个、更多个或全部特征峰：15.86°±0.20°、17.00°±0.20°、17.18°±0.20°、24.51°±0.20°。
根据本公开的实施方案，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：

根据本公开的实施方案，当所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有选自与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型A具有基本上如图1A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型A的示差扫描量热法(DSC)图谱在约175.03℃的起始温度和/或约180.61℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型A具有基本上如图1B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型A的热重分析(TGA)中，从室温升温至190℃有约0.45％至约0.55％(例如约0.499％)的失重。
根据本公开的实施方案，所述晶型A具有基本上如图1C所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型A为无水晶型。
根据本公开的实施方案，所述晶型A具有基本上如图1D所示的1H NMR图谱。
本公开还提供式(I)化合物的晶型B，所述晶型B的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：18.19°±0.20°、25.74°±0.20°、26.95°±0.20°。
根据本公开的实施方案，所述晶型B的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：11.04°±0.20°、12.78°±0.20°、16.12°±0.20°、16.74°±0.20°、18.19°±0.20°、25.22°±0.20°、25.74°±0.20°、26.95°±0.20°。
根据本公开的实施方案，所述晶型B的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.26°±0.20°、11.04°±0.20°、12.78°±0.20°、16.12°±0.20°、16.74°±0.20°、18.19°±0.20°、19.96°±0.20°、24.33°±0.20°、25.22°±0.20°、25.74°±0.20°、26.95°±0.20°。
根据本公开的实施方案，所述晶型B的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型B的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型B具有基本上如图2A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型B的示差扫描量热法(DSC)图谱在约186.7℃的起始温度和/或约189.8℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型B具有基本上如图2B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型B的热重分析(TGA)中，从室温升温至150℃有约0.5％至约0.6％(例如约0.54％)的失重。
根据本公开的实施方案，所述晶型B具有基本上如图2B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型B为无水晶型。
根据本公开的实施方案，所述晶型B具有基本上如图2C所示的1H NMR图谱。
本公开还提供式(I)化合物的晶型C，所述晶型C的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：7.25±0.20°、16.53°±0.20°、18.84°±0.20°。
根据本公开的实施方案，所述晶型C的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：7.25°±0.20°、14.48°±0.20°、16.53°±0.20°、18.84°±0.20°。
根据本公开的实施方案，所述晶型C的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：7.25°±0.20°、12.54°±0.20°、13.04°±0.20°、14.48°±0.20°、16.53°±0.20°、18.84°±0.20°、19.18°±0.20°、25.02°±0.20°。
根据本公开的实施方案，所述晶型C的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：

根据本公开的实施方案，当所述晶型C的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型C具有基本上如图3A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型C的示差扫描量热法(DSC)图谱在约109.1℃的峰值温度，以及约123.4℃的起始温度和/或约132.5℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型C具有基本上如图3B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型C的热重分析(TGA)中，从室温升温至200℃有约0.2％至约0.3％(例如约0.27％)的失重。
根据本公开的实施方案，所述晶型C具有基本上如图3B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型C为无水晶型。
根据本公开的实施方案，所述晶型C具有基本上如图3C所示的1H NMR图谱。
本公开还提供式(I)化合物的晶型D，所述晶型D的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.01°±0.20°、25.01°±0.20°、26.42°±0.20°。
根据本公开的实施方案，所述晶型D的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.26°±0.20°、11.01°±0.20°、15.61°±0.20°、18.53°±0.20°、22.14°±0.20°、25.01°±0.20°、26.42°±0.20°。
根据本公开的实施方案，所述晶型D的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.26°±0.20°、9.01°±0.20°、11.01°±0.20°、15.61°±0.20°、18.53°±0.20°、22.14°±0.20°、25.01°±0.20°、26.42°±0.20°。
根据本公开的实施方案，所述晶型D的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型D的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型D具有基本上如图4A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型D的示差扫描量热法(DSC)图谱在约63.7℃的峰值温度，以及约181.7℃的起始温度和/或约184.3℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型D具有基本上如图4B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型D的热重分析(TGA)中，从室温升温至200℃有约3.3％至约3.4％(例如约3.35％)的失重。
根据本公开的实施方案，所述晶型D具有基本上如图4B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型D为水合物。
根据本公开的实施方案，所述晶型D具有基本上如图4C所示的1H NMR图谱。
根据本公开的实施方案，所述晶型D具有基本上如图4D所示的变温XRPD图谱。
本公开还提供式(I)化合物的晶型E，所述晶型E的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：5.98°±0.20°、12.73°±0.20°、14.53°±0.20°。
根据本公开的实施方案，所述晶型E的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：5.98°±0.20°、10.66±0.20°、11.95±0.20°、12.73°±0.20°、14.53°±0.20°、17.67°±0.20°、22.91°±0.20°。
根据本公开的实施方案，所述晶型E的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型E的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型E具有基本上如图5A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型E的示差扫描量热法(DSC)图谱在约114.9℃的峰值温度，以及约127.9℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型E具有基本上如图5B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型E的热重分析(TGA)中，从室温升温至50℃有约1.9％至约2.0％(例如约1.95％)的失重，从50℃升温至150℃有约3.0％至约3.1％(例如约3.02％)的失重。
根据本公开的实施方案，所述晶型E具有基本上如图5B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型E为甲醇溶剂合物。
根据本公开的实施方案，所述晶型E具有基本上如图5C所示的1H NMR图谱。
根据本公开的实施方案，所述晶型E具有基本上如图5D所示的变温XRPD图谱。
本公开还提供式(I)化合物的晶型F，所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.07°±0.20°、24.79°±0.20°、26.42°±0.20°。
根据本公开的实施方案，所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.07°±0.20°、17.83°±0.20°、22.44°±0.20°、24.79°±0.20°、26.42°±0.20°。
优选地，所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.07°±0.20°、17.83°±0.20°、22.44°±0.20°、24.79°±0.20°和26.42°±0.20°。
根据本公开的实施方案，所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.07°±0.20°、14.99°±0.20°、17.83°±0.20°、19.93°±0.20°、20.64°±0.20°、22.44°±0.20°、24.79°±0.20°、26.42°±0.20°。
根据本公开的实施方案，所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：
根据本公开的实施方案，当所述晶型F的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型F具有基本上如图6A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型F的示差扫描量热法(DSC)图谱在约69.9℃的峰值温度，以及约182.1℃的起始温度和/或约184.5℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型F具有基本上如图6B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型F的热重分析(TGA)中，从室温升温至100℃有约2.2％至约2.3％(例如约2.25％)的失重，从100℃升温至200℃有约2.7％至约2.8％(例如约2.79％)的失重。
根据本公开的实施方案，所述晶型F具有基本上如图6B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型F为乙醇溶剂合物。
根据本公开的实施方案，所述晶型F具有基本上如图6C所示的1H NMR图谱。
根据本公开的实施方案，所述晶型F具有基本上如图6D所示的变温XRPD图谱。
本公开还提供式(I)化合物的晶型G，所述晶型G的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：6.97°±0.20°、13.39°±0.20°、25.81°±0.20°。
根据本公开的实施方案，所述晶型G的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.50°±0.20°、6.97°±0.20°、13.39°±0.20°、14.40°±0.20°、17.11°±0.20°、17.81°±0.20°、23.94°±0.20°、25.81°±0.20°。
根据本公开的实施方案，所述晶型G的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：

根据本公开的实施方案，当所述晶型G的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型G具有基本上如图7A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型G的示差扫描量热法(DSC)图谱在约122.6℃的峰值温度，以及约168.5℃的起始温度和/或约173.1℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型G具有基本上如图7B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型G的热重分析(TGA)中，从室温升温至75℃有约1.2％至约1.4％(例如约1.3％)的失重，从75℃升温至150℃有约2.6％至约2.7％(例如约2.69％)的失重。
根据本公开的实施方案，所述晶型G具有基本上如图7B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型G为乙腈溶剂合物。
根据本公开的实施方案，所述晶型G具有基本上如图7C所示的1H NMR图谱。
本公开还提供式(I)化合物的晶型H，所述晶型H的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：12.92°±0.20°、15.82°±0.20°、17.25°±0.20°。
根据本公开的实施方案，所述晶型H的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：7.89°±0.20°、10.51°±0.20°、12.92°±0.20°、15.82°±0.20°、16.69°±0.20°、17.25°±0.20°、19.12°±0.20°、25.39°±0.20°。
根据本公开的实施方案，所述晶型H的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型H的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型H具有基本上如图8A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型H的示差扫描量热法(DSC)图谱在约121.7℃、约138.7℃、约170.2℃和约184.7℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型H具有基本上如图8B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型H的热重分析(TGA)中，从室温升温至70℃有约1.7％至约1.8％(例如约1.73％)的失重，从70℃升温至150℃有约7.9％至约8.0％(例如约7.98％)的失重。
根据本公开的实施方案，所述晶型H具有基本上如图8B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型H为二氯甲烷溶剂合物。
根据本公开的实施方案，所述晶型H具有基本上如图8C所示的1H NMR图谱。
根据本公开的实施方案，所述晶型H具有基本上如图8D所示的变温XRPD图谱。
本公开还提供式(I)化合物的晶型I，所述晶型I的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.45°±0.20°、13.35°±0.20°、17.82°±0.20°。
根据本公开的实施方案，所述晶型I的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.45°±0.20°、13.35°±0.20°、17.15°±0.20°、17.82°±0.20°、22.32°±0.20°、23.82°±0.20°、25.70°±0.20°。
根据本公开的实施方案，所述晶型I的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型I的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型I具有基本上如图9所示的X射线粉末衍射图谱。
本公开还提供式(I)化合物的晶型J，所述晶型J的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：4.22°±0.20°、7.15°±0.20°、25.24°±0.20°。
根据本公开的实施方案，所述晶型J的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.22°±0.20°、6.74°±0.20°、7.15°±0.20°、11.04°±0.20°、12.62°±0.20°、13.48°±0.20°、16.86±0.20°、25.24°±0.20°。
根据本公开的实施方案，所述晶型J的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型J的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型J具有基本上如图10A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型J的示差扫描量热法(DSC)图谱在约178.6℃的起始温度和/或约182.4℃的峰值温度，以及约188.9℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型J具有基本上如图10B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型J的热重分析(TGA)中，从室温升温至100℃有约1.4％至约1.5％(例如约1.41％)的失重，从100℃升温至200℃有约3.3％至约3.4％(例如约3.38％)的失重。
根据本公开的实施方案，所述晶型J具有基本上如图10B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型J为1,4-二氧六环溶剂合物。
根据本公开的实施方案，所述晶型J具有基本上如图10C所示的1H NMR图谱。
根据本公开的实施方案，所述晶型J具有基本上如图10D所示的变温XRPD图谱。
本公开还提供式(I)化合物的晶型K，所述晶型K的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：4.19°±0.20°、6.48°±0.20°、6.95°±0.20°、19.54°±0.20°。
根据本公开的实施方案，所述晶型K的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.19°±0.20°、5.13°±0.20°、6.48°±0.20°、6.95°±0.20°、9.75°±0.20°、11.06°±0.20°、17.13°±0.20°、19.54°±0.20°。
根据本公开的实施方案，所述晶型K的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：

根据本公开的实施方案，当所述晶型K的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型K具有基本上如图11A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型K具有基本上如图11B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型K具有基本上如图11B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型K具有基本上如图11C所示的1H NMR图谱。
本公开还提供式(I)化合物的晶型L，所述晶型L的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：18.85°±0.20°、22.30°±0.20°、29.35°±0.20°。
根据本公开的实施方案，所述晶型L的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：9.23°±0.20°、18.85°±0.20°、22.30°±0.20°、22.69°±0.20°、23.22°±0.20°、23.82°±0.20°、26.58°±0.20°、29.35°±0.20°。
根据本公开的实施方案，所述晶型L的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型L的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型L具有基本上如图12A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型L的示差扫描量热法(DSC)图谱在约95.4℃的起始温度和/或约100.0℃的峰值温度，以及约154.5℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型L具有基本上如图12B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型L的热重分析(TGA)中，从室温升温至100℃有约8.9％至约9.0％(例如约8.98％)的失重，从100℃升温至125℃有约2.5％至约2.6％(例如约2.56％)的失重，从125℃升温至150℃有约1.8％至约1.9％(例如约1.81％)的失重。
根据本公开的实施方案，所述晶型L具有基本上如图12B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型L为甲醇-水共溶剂合物。
根据本公开的实施方案，所述晶型L具有基本上如图12C所示的1H NMR图谱。
根据本公开的实施方案，所述晶型L的单晶具有如图12D所示的单晶结构的不对称单元示意图。
根据本公开的实施方案，所述晶型L的单晶具有如下结构参数：

本公开还提供式(I)化合物的晶型M，所述晶型M的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：4.22°±0.20°、18.59°±0.20°、25.31°±0.20°。
根据本公开的实施方案，所述晶型M的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.22°±0.20°、9.05°±0.20°、10.94°±0.20°、15.48°±0.20°、18.59°±0.20°、21.81°±0.20°、25.31°±0.20°、26.48°±0.20°。
根据本公开的实施方案，所述晶型M的X射线粉末衍射图具有下列特征峰：
根据本公开的实施方案，当所述晶型M的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型M具有基本上如图13A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型M的示差扫描量热法(DSC)图谱在约61.3℃的峰值温度，以及约181.4℃的起始温度和/或约184.2℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型M具有基本上如图13B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型M的热重分析(TGA)中，从室温升温至200℃有约2.0％至约2.1％(例如约2.05％)的失重。
根据本公开的实施方案，所述晶型M具有基本上如图13B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型M为水合物。
本公开还提供式(I)化合物的晶型N，所述晶型N的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：5.82°±0.20°、13.96°±0.20°、20.24°±0.20°。
根据本公开的实施方案，所述晶型N的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：5.82°±0.20°、7.18°±0.20°、12.35°±0.20°、13.96°±0.20°、15.77°±0.20°、17.49°±0.20°、18.40°±0.20°、20.24°±0.20°。
根据本公开的实施方案，所述晶型N的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型N的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型N具有基本上如图14A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型N的示差扫描量热法(DSC)图谱在约118.0℃的起始温度和/或约125.9℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型N具有基本上如图14B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型N的热重分析(TGA)中，从室温升温至200℃有约0.1％至约0.2％(例如约0.19％)的失重。
根据本公开的实施方案，所述晶型N具有基本上如图14B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型N为无水晶型。
根据本公开的实施方案，所述晶型N具有基本上如图14C所示的1H NMR图谱。
根据本公开的实施方案，所述晶型N具有基本上如图14D所示的变温XRPD图谱。
本公开还提供式(I)化合物的晶型O，所述晶型O的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.06°±0.20°、24.85°±0.20°、26.44°±0.20°。
根据本公开的实施方案，所述晶型O的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.32°±0.20°、11.06°±0.20°、15.11°±0.20°、15.76°±0.20°、17.22°±0.20°、17.93°±0.20°、24.85°±0.20°、26.44°±0.20°。
根据本公开的实施方案，所述晶型O的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型O的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型O具有基本上如图15A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型O的示差扫描量热法(DSC)图谱在约174.7℃和约187.1℃的峰值温度具有吸热峰。
根据本公开的实施方案，所述晶型O具有基本上如图15B所示的示差扫描量热法(DSC)图谱。
根据本公开的实施方案，所述晶型O的热重分析(TGA)中，从室温升温至150℃有约4.0％至约4.1％(例如约4.03％)的失重，从150℃升温至200℃有约1.5％至约1.7％(例如约1.60％)的失重。
根据本公开的实施方案，所述晶型O具有基本上如图15B所示的热重分析(TGA)图谱。
根据本公开的实施方案，所述晶型O为甲醇溶剂合物。
根据本公开的实施方案，所述晶型O具有基本上如图15C所示的1H NMR图谱。
据本公开的实施方案，所述晶型O具有基本上如图15D所示的变温XRPD图谱。
本公开还提供式(I)化合物的晶型P，所述晶型P的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：6.36°±0.20°、16.15°±0.20°、21.05°±0.20°。
根据本公开的实施方案，所述晶型P的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：6.36°±0.20°、11.09°±0.20°、16.15°±0.20°、17.27°±0.20°、21.05°±0.20°、26.38°±0.20°、26.62°±0.20°、34.88°±0.20°。
根据本公开的实施方案，所述晶型P的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型P的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型P具有基本上如图16A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型P为水合物。
本公开还提供式(I)化合物的晶型Q，所述晶型Q的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：18.41°±0.20°、25.19°±0.20°、26.36°±0.20°。
根据本公开的实施方案，所述晶型Q的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.15°±0.20°、10.85°±0.20°、13.28°±0.20°、18.41°±0.20°、20.03°±0.20°、21.69°±0.20°、25.19°±0.20°、26.36°±0.20°。
根据本公开的实施方案，所述晶型Q的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型Q的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型Q具有基本上如图17所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型Q为无水晶型。
本公开还提供式(I)化合物的晶型R，所述晶型R的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：7.22°±0.20°、13.03°±0.20°、18.81°±0.20°。
根据本公开的实施方案，所述晶型R的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：7.22°±0.20°、13.03°±0.20°、18.81°±0.20°、19.15±0.20°。
根据本公开的实施方案，所述晶型R的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型R的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型R具有基本上如图22A所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型R为无水晶型。
本公开还提供式(I)化合物的晶型S，所述晶型S的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：6.30°±0.20°、16.11°±0.20°、21.01°±0.20°。
根据本公开的实施方案，所述晶型S的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：6.30°±0.20°、11.06°±0.20°、16.11°±0.20°、21.01°±0.20°。
根据本公开的实施方案，所述晶型S的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：
根据本公开的实施方案，当所述晶型S的X射线粉末衍射图具有选自上述2θ值处的一个、两个、更多个或全部特征峰时，其也可选地具有与所述特征峰相对应的相对强度。
根据本公开的实施方案，所述晶型S具有基本上如图23所示的X射线粉末衍射图谱。
根据本公开的实施方案，所述晶型S为水合物。
本公开还提供式(I)化合物马来酸盐的晶型T，其中所述晶型T具有基本上如图24A所示的X射线粉末衍射图谱。
本公开还提供式(I)化合物甲磺酸盐的晶型U，其中所述晶型U具有基本上如图25A所示的X射线粉末衍射图谱。
根据本发明说明书上下文，所述的晶型的X射线粉末衍射图谱或2θ值等数据均为使用Cu靶辐射得到。
本公开还提供所述晶型A的制备方法，其中所述晶型A的制备方法包括将式(I)化合物(如其无定形物，例如无定形物Z)溶解在乙酸乙酯与二氯甲烷的混合溶剂中，将所得的溶液在室温下挥发，得到晶型A。优选地，所述晶型A的制备方法中，乙酸乙酯与二氯甲烷的体积比可以为1:1至20:1，例如9:1。
本公开还提供所述晶型A的制备方法，其中所述晶型A的制备方法包括将晶型G加热至150℃，降至室温并暴露在空气中，得到晶型A。
本公开还提供所述晶型A的制备方法，其中所述晶型A的制备方法包括将晶型I在室温晾干，得到晶型A。
本公开还提供所述晶型L的制备方法，其中所述晶型L的制备方法包括将式(I)化合物(如其无定形物)和甲醇与水的混合溶剂混合，得到溶液，将所得的溶液在室温下挥发，得到晶型L。优选地，所述晶型L的制备方法中，甲醇与水的体积比可以为1:1至20:1，例如4:1。
本公开还提供所述晶型B的制备方法，其中所述晶型B的制备方法包括将晶型L在丙酮中搅拌，得到晶型B。优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL。优选地，所述搅拌在50至70℃下，例如60℃下进行。
本公开还提供所述晶型C的制备方法，其中所述晶型C的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体再与水混合搅拌，得到晶型C。优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；所述晶型L与水的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL。
优选地，所述晶型L在丙酮中的搅拌先在50至70℃下，例如60℃下进行，然后在0-5℃下进行。所述分离得到的固体再在水中搅拌时，为在室温下搅拌。
或者，将晶型L在丙酮与水的混合溶剂中搅拌，其中丙酮与水的体积比可以为(1～2):1，例如1.5:1。
或者，将晶型P的湿样在空气中晾干后，得到晶型C。
本公开还提供所述晶型D的制备方法，其中所述晶型D的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体再在丙酮与水的混合溶剂中搅拌，得到晶型D。优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；所述晶型L与丙酮与水的混合溶剂的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL。优选地，所述丙酮与水的混合溶剂中，丙酮与水的体积比可以为(5～7):1，例如1.5:1。
优选地，所述晶型L在丙酮中的搅拌先在50至70℃下，例如60℃下进行，然后在0-5℃下进行。所述分离得到的固体再在丙酮与水的混合溶剂中搅拌时，为在室温下搅拌。
或者，将晶型L在丙酮与水的混合溶剂中搅拌，其中丙酮与水的体积比可以为(3～6):1，例如4:1。
本公开还提供所述晶型E的制备方法，其中所述晶型E的制备方法包括将晶型L在甲醇中搅拌，得到晶型E。优选地，所述搅拌在室温下进行。优选地，所述晶型L与甲醇的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL。
本公开还提供所述晶型F的制备方法，其中所述晶型F的制备方法包括将式(I)化合物(如其无定形物)在丙酮与乙醇的混合溶剂中搅拌，得到晶型F。优选地，所述晶型L的制备方法中，丙酮与乙醇的体积比可以为1:1。
本公开还提供所述晶型G的制备方法，其中所述晶型G的制备方法包括将晶型L先在丙酮中搅拌，将分离得到的固体再在乙腈中搅拌，得到晶型G。优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；所述晶型L与乙腈的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL。
本公开还提供所述晶型H的制备方法，其中所述晶型H的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体再在二氯甲烷气氛中气固渗透，得到晶型H。优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL。
本公开还提供所述晶型I的制备方法，其中所述晶型I的制备方法包括将式(I)化合物(如其无定形物)溶解于N-甲基吡咯烷酮，然后加入反溶剂如乙腈，室温静置析出固体，得到晶型I。优选地，所述式(I)化合物与N-甲基吡咯烷酮的质量体积比可以为20mg:(1.0～1.5mL)。所述式(I)化合物与N-甲基吡咯烷酮的质量体积比可以为20mg:(3～5mL)，例如20mg:4mL。
本公开还提供所述晶型J的制备方法，其中所述晶型J的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体与1,4-二氧六环混合后在50℃下搅拌，再在室温下搅拌，得到晶型J。优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL。所述晶型L与1,4-二氧六环的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL。
本公开还提供所述晶型M的制备方法，其中所述晶型M的制备方法包括将晶型D加热至150℃，然后降至室温并暴露在空气中约10min后，得到晶型M。
本公开还提供所述晶型M的制备方法，其中所述晶型M的制备方法包括将晶型F加热至160℃，降至室温并暴露在空气中，得到晶型M。
本公开还提供所述晶型M的制备方法，其中所述晶型M的制备方法包括将晶型O样品加热至175℃后，得到晶型M。
本公开还提供所述晶型M的制备方法，其中所述晶型M的制备方法包括将晶型Q在室温室湿条件下放置，得到晶型M。
本公开还提供所述晶型N的制备方法，其中所述晶型N的制备方法包括将晶型E加热至100℃，然后降至室温并暴露在空气中，得到晶型N。
本公开还提供所述晶型O的制备方法，其中所述晶型O的制备方法包括将式(I)化合物(如其无定形物，如无定形物Z)溶解于甲醇与水的混合溶剂中，室温挥发，得到晶型O。优选地，所述甲醇与水的混合溶剂中，甲醇与水的体积比可以为(3～5):1，例如4:1。
本公开还提供所述晶型P的制备方法，其中所述晶型P的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体再在MEK、THF和H2O的混合溶剂中打浆，得到晶型P。优选地，MEK、THF和H2O的混合溶剂中，MEK、THF和H2O的体积比可以为1:0.1:2。
本公开还提供所述晶型Q的制备方法，其中所述晶型Q的制备方法包括将晶型D在N2保护下吹扫20min，加热样品至150℃并降温至30℃，得到晶型Q。
本公开还提供所述所述晶型R的制备方法，其中所述晶型R的制备方法包括将式(I)化合物(如无定形物，如无定形物Z)和二氯甲烷与丙酮的混合溶剂混合，溶清后减压浓缩至干，加入丙酮，加热溶清后加入水，自然冷却降至室温，搅拌，过滤得晶型R。优选地，所述二氯甲烷与丙酮的混合溶剂中，二氯甲烷与丙酮的体积比可以为3:1～9:1，例如6:1；优选地，减压浓缩至干后加入的丙酮与二氯甲烷与丙酮的混合溶剂中的丙酮的体积比可以为1:1～1:1.5，例如4:5；优选地，加热溶清后加入的水与减压浓缩至干后加入的丙酮的体积比可以为0.5:1～1:1，例如0.75:1。优选地，式(I)化合物与二氯甲烷和丙酮的混合溶剂的质量体积比可以为1mg:(0.3～0.5)mL，例如1mg:0.35mL。
本公开还提供所述所述晶型S的制备方法，其中所述晶型S的制备方法包括将式(I)化合物(如无定形物，如无定形物Z)与1,4-二氧六环混合，溶清，加入水，析出固体，过滤，干燥，得到晶型S。优选地，1,4-二氧六环与水的体积比为1:2～1:3，例如1:2.2。优选地，式(I)化合物与1,4-二氧六环的质量体积比可以为1mg:(0.08～0.15)mL，例如1mg:0.11mL。
本公开还提供所述所述晶型T的制备方法，其中所述晶型T的制备方法包括将式(I)化合物(如无定形物，如无定形物Z)与三氯甲烷混合，得到溶液1；将马来酸与乙醇混合，得到溶液2；将溶液2与溶液1混合，加入甲基叔丁基醚，搅拌，离心，干燥，得到晶型T。优选地，式(I)化合物与三氯甲烷的质量体积比可以为1g:(12～20)mL，例如1g:(14～15)mL。优选地，式(I)化合物与马来酸的质量比可以为(9～10):1。优选地，式(I)化合物与乙醇的质量体积比可以为1g:(1～4)mL，例如1g:2mL。优选地，溶液2与溶液1的体积比可以为1:(1.2～1.3)。优选地，三氯甲烷与甲基叔丁基醚总量的体积比可以为(11～12):1。
本公开还提供所述所述晶型U的制备方法，其中所述晶型U的制备方法包括将式(I)化合物(如无定形物，如无定形物Z)与三氯甲烷混合，得到溶液1；将甲磺酸与三氯甲烷混合，得到溶液2；将溶液2与溶液1混合，搅拌，干燥，得到晶型U。优选地，式(I)化合物与溶液1中的三氯甲烷的质量体积比可以为1g:(12～20)mL，例如1g:(14～15)mL。优选地，式(I)化合物与甲磺酸的质量比可以为(9～10):1。优选地，式(I)化合物与溶液2中的三氯甲烷的质量体积比可以为1g:(1～4)mL，例如1g:2mL。优选地，溶液2与溶液1的体积比可以为1:(1.3～1.4)。
本公开还提供一种混合物，其中所述混合物包含选自所述的式(I)化合物或其药学上可接受的盐的固体形式中的至少一种，例如一种、两种、三种或更多种，优选包含选自所述的晶型A至U(即晶型A、B、C、D、E、F、G、H、I、J、K、L、M、N、O、P、Q、R、S、T、U)中的一种、两种、三种或更多种。
根据本公开的实施方案，所述混合物包含晶型A和选自晶型B至U的一种、两种、三种或更多种，优选包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
根据本公开的实施方案，以所述混合物中式(I)化合物的总重量计，晶型A的重量百分比含量为80％以上，例如90％以上，优选95％以上，例如98％以上，进一步优选99％以上，如99.5％以上、99.8％以上或99.9％以上。
本领域技术人员应当理解，可以通过物理共混的方式获得上述任一种混合物。
本公开还提供一种药物组合物，其中所述药物组合物包含选自所述的式(I)化合物或其药学上可接受的盐的固体形式的至少一种，优选包含选自晶型A至U的一种、两种、三种或更多种；或者，所述药物组合物包含所述混合物。
或者作为选择，所述药物组合物包含上文所述的混合物。
根据本公开的实施方案，所述药物组合物还可以包含药学上可接受的辅料。
根据本公开的实施方案，所述药物组合物还进一步含有至少一种，例如一种、两种、三种或更多种的额外的治疗剂。
本公开还提供所述的式(I)化合物或其药学上可接受的盐的固体形式的用途，其中所述用途选自下列中的至少一种，例如一种、两种、三种或更多种：
用于体外或体内抑制细胞增殖的用途；或者，
用于治疗RET激酶介导的疾病的用途；或者，
用于抑制RET激酶活性的用途；或者，
用于治疗癌症和/或抑制与特定癌症相关的转移的用途；或者，
用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的用途；或者，
用于向癌症患者提供支持护理的用途，所述支持护理包括预防或最小化与治疗(包括化疗治疗)相关的胃肠病症，例如腹泻；或者，
用于治疗RET相关疾病或病症的用途；或者，
用于逆转或预防对抗癌药物的获得性抗性的用途；或者，
用于延迟和/或预防个体中抗癌药抗药性发展的用途；或者，
用于治疗患有癌症且对抗癌药物发展抗性的可能性增加的个体的用途。
本公开还提供一种体外或体内抑制细胞增殖的方法，所述方法包括使细胞与选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种相接触。
本公开还提供一种治疗RET激酶介导的疾病的方法，包括给予患者选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
本公开还提供了在有治疗需要的患者中治疗RET相关疾病或病症的方法，所述方法包括向所述患者施用选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
本公开还提供了在有治疗需要的患者中治疗癌症和/或抑制与特定癌症相关的转移的方法，所述方法包括向所述患者施用选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
本公开还提供了在有治疗需要的患者中治疗肠易激综合征(IBS)和/或与IBS相关的疼痛的方法，所述方法包括向所述患者施用选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
本公开还提供了为癌症患者提供支持护理的方法，包括预防或最小化与治疗(包括化疗治疗)相关的胃肠疾病(例如腹泻)，所述方法包括给予患者选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
本公开还提供选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种在制备用于治疗RET激酶介导的疾病的药物中的用途。
本公开还提供选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种在制备用于治疗癌症和/或抑制与特定癌症相关的转移的药物中的用途。
本公开还提供选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种在制备用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的药物中的用途。
本公开还提供选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种在制备用于向癌症患者提供支持护理的药物中的用途，所述支持护理包括预防或最小化与治疗(包括化疗治疗)相关的胃肠病症，例如腹泻。
本公开还提供选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种在制备用于抑制RET激酶活性的药物中的用途。
本公开还提供选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种在制备用于治疗RET相关疾病或病症的药物中的用途。
本公开还提供用于在有需要的患者中治疗癌症的方法，所述方法包括(a)确定所述癌症是否与下述的失调有关：RET基因、RET激酶、或其中任何一者的表达或活性或水平(例如，RET相关的癌症)；(b)如果确定所述癌症与下述的失调有关：RET基因、RET激酶、或其中任何一者的表达或活性或水平(例如，RET相关的癌症)，向患者施用选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
本公开还提供了用于逆转或预防对抗癌药物的获得性抗性的方法，所述方法包括将选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种给予处于对其他抗癌药物发展或具有获得性抗性的风险的患者。
本公开还提供延迟和/或预防个体中抗癌药抗药性发展的方法，所述方法包括在个体中施用选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种，在此之前、期间或之后施用其他抗癌药物。
本公开还提供了治疗患有癌症且对抗癌药物发展抗性的可能性增加的个体的方法，其包括对个体伴随施用(a)选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种；和(b)其他抗癌药物。
本公开还提供了治疗患有RET相关癌症的个体的方法，所述癌症具有一种或多种RET抑制剂抗性突变，所述RET抑制剂抗性突变增加所述癌症对不是式I所示的化合物或其药学上可接受的盐中的至少一种的RET抑制剂的抗性(例如，在氨基酸位置804,810,904处的取代，例如V804M、V804L、V804E、G810R、G810S、G810C、G810V、S904F)，其包括在给予另一种其他的抗癌药物之前、期间或之后，给予选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
本公开还提供了治疗患有RET相关癌症的个体的方法，所述方法包括在给予另一种其他的抗癌药物之前、期间或之后，给予选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
本公开提供了在有需要的患者中治疗癌症(例如RET相关癌症)的方法，所述方法包括向所述患者施用选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种。
根据本公开的实施方案，当将选自所述固体形式的至少一种，优选选自晶型A至U的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种用于治疗、给药或制备药物时，所述固体形式(如选自晶型A至U中的至少一种，例如包含晶型A和选自晶型B至U的一种、两种、三种或更多种)的用量优选为治疗有效量。
有益效果
本公开提供的稠环化合物的固体形式未被现有技术公开或教导，为式(I)化合物提供了更有利的药学上可接受的形态。本公开提供的固体形式，特别是晶型A，具有优异的理化性质和药代动力学特性，有利于改善制剂的性质和货架期的储存期，并为患者带来更有益的治疗效果。
附图说明
图1A为本公开晶型A的X-射线粉末衍射(XRPD)图。
图1B为本公开晶型A的差示扫描量热分析(DSC)图。
图1C为本公开晶型A的热失重分析(TGA)图。
图1D为本公开晶型A的1H NMR图。
图2A为本公开晶型B的X-射线粉末衍射(XRPD)图。
图2B为本公开晶型B的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图2C为本公开晶型B的1H NMR图。
图3A为本公开晶型C的X-射线粉末衍射(XRPD)图。
图3B为本公开晶型C的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图3C为本公开晶型C的1H NMR图。
图4A为本公开晶型D的X-射线粉末衍射(XRPD)图。
图4B为本公开晶型D的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图4C为本公开晶型D的1H NMR图。
图4D为本公开晶型D的变温XRPD叠图。
图5A为本公开晶型E的X-射线粉末衍射(XRPD)图。
图5B为本公开晶型E的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图5C为本公开晶型E的1H NMR图。
图5D为本公开晶型E的变温XRPD叠图。
图5E为本公开晶型E加热后的1H NMR图。
图6A为本公开晶型F的X-射线粉末衍射(XRPD)图。
图6B为本公开晶型F的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图6C为本公开晶型F的1H NMR图。
图6D为本公开晶型F的变温XRPD叠图。
图6E为本公开晶型F加热后的1H NMR图。
图7A为本公开晶型G的X-射线粉末衍射(XRPD)图。
图7B为本公开晶型G的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图7C为本公开晶型G的1H NMR图。
图7D为本公开晶型G加热后的1H NMR图。
图8A为本公开晶型H的X-射线粉末衍射(XRPD)图。
图8B为本公开晶型H的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图8C为本公开晶型H的1H NMR图。
图8D为本公开晶型H的变温XRPD叠图。
图9为本公开晶型I的X-射线粉末衍射(XRPD)图。
图10A为本公开晶型J的X-射线粉末衍射(XRPD)图。
图10B为本公开晶型J的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图10C为本公开晶型J的1H NMR图。
图10D为本公开晶型J的变温XRPD叠图。
图10E为本公开晶型J加热后的1H NMR图。
图11A为本公开晶型K的X-射线粉末衍射(XRPD)图。
图11B为本公开晶型K的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图11C为本公开晶型K的1H NMR图。
图11D为重复实施例12方法所得晶型的XRPD叠图。
图12A为本公开晶型L的X-射线粉末衍射(XRPD)图。
图12B为本公开晶型L的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图12C为本公开晶型L的1H NMR图。
图12D为本公开晶型L的单晶结构的不对称单元示意图。
图13A为本公开晶型M的X-射线粉末衍射(XRPD)图。
图13B为本公开晶型M的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图14A为本公开晶型N的X-射线粉末衍射(XRPD)图。
图14B为本公开晶型N的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图14C为本公开晶型N的1H NMR图。
图14D为本公开晶型N的变温XRPD叠图。
图15A为本公开晶型O的X-射线粉末衍射(XRPD)图。
图15B为本公开晶型O的差示扫描量热分析(DSC)图和热失重分析(TGA)图。
图15C为本公开晶型O的1H NMR图。
图15D为本公开晶型O的变温XRPD叠图。
图15E为本公开晶型O加热后的1H NMR图。
图16A为本公开晶型P的X-射线粉末衍射(XRPD)图。
图16B为本公开晶型P晾干前后的XRPD叠图。
图17为本公开晶型Q的X-射线粉末衍射(XRPD)图。
图18为测试例1的引湿性测试中晶型A的DVS图。
图19为测试例1的引湿性测试中晶型B的DVS图。
图20A为测试例4中混悬竞争后固体的XRPD叠图。
图20B为测试例4中混悬竞争后固体的XRPD叠图。
图21A为实施例1中式(I)化合物无定形物Z的X-射线粉末衍射(XRPD)图。
图21B为实施例1中式(I)化合物无定形物Z的差示扫描量热分析(DSC)图。
图21C为实施例1中式(I)化合物无定形物Z的热失重分析(TGA)图。
图22A为本公开晶型R的X-射线粉末衍射(XRPD)图。
图22B为测试例1中晶型R的DVS测试图。
图22C为测试例1中晶型R的等温吸附曲线图。
图23为本公开晶型S的X-射线粉末衍射(XRPD)图。
图24A为本公开晶型T的X-射线粉末衍射(XRPD)图。
图24B为本公开晶型T的1H NMR图。
图25A为本公开晶型U的X-射线粉末衍射(XRPD)图。
图25B为本公开晶型U的1H NMR图。
具体实施方式
下文将结合具体实施例对本公开的技术方案作更进一步的详细说明。下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
除非另有说明，以下实施例采用下文描述的仪器和检测方法。
I.检测仪器和方法
X射线粉末衍射(XRPD)
XRPD结果是在PANalytical Empyrean和X’Pert3X射线粉末衍射分析仪上采集，其扫描参数如下表所示：
热重分析(TGA)和差示扫描量热(DSC)
TGA和DSC图分别在TA Discovery 5500热重分析仪和TA Discovery 2500差示扫描量热仪上采集，其测试参数如下表所示：
动态水分吸附(DVS)
动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl、Mg(NO3)2和KCl的潮解点校正。DVS测试参数如下表所示：
氢谱液态核磁(1H Solution NMR)
氢谱液态核磁谱图在Bruker 400M核磁共振仪上采集，以DMSO-d6作为溶剂。
II.溶剂名称对应表
实施例1：式(I)化合物无定形物的制备
按照申请号为PCT/CN2020/107049的PCT专利申请的实施例9的方法，向4-(6-(6-((6-甲氧基吡啶-3-)亚甲基)3,6-二氮杂双环[3.1.1]庚烷-3-基)吡啶-3-基)-1H-吡唑[3',4':3,4]吡唑[1,5-a]吡啶-6-醇(150mg,0.3mmol)的DMF(10.0mL)溶液中加入2-碘乙烷(47mg,0.3mmol)，碳酸钾(83mg,0.6mmol)，加热至60℃反应12小时。加入水，用乙酸乙酯萃取，合并有机相，并用水洗涤，无水硫酸钠干燥，过滤，减压浓缩，柱层析分离，旋转蒸发除去溶剂得到本公开所述的式(I)化合物，为无定形物Z。无定形物Z的X-射线粉末衍射(XRPD)图如图21A所示，差示扫描量热分析(DSC)如图21B所示，热失重分析(TGA)图如图21C所示。
实施例2：无水晶型A的制备
将20mg实施例1制备得到的式(I)化合物无定形物Z加至20mL小瓶中，加入乙酸乙酯与二氯甲烷的混合溶剂(9:1,v:v)的溶剂溶解固体，经滤膜过滤后，将所得澄清滤液通过封口膜封口，并在上面扎5个小孔，放置在室温下缓慢挥发。收集挥发后所得的固体，得到晶型A。该晶型的X射线粉末衍射图谱如图1A所示，通过预先加热样品去除表面吸附溶剂之后测试的示差扫描量热法(DSC)图谱如图1B所示，热重分析(TGA)图谱如图1C所示，1H NMR图谱如图1D所示。
将晶型A样品在N2保护下吹扫20min，加热至150℃，降温至30℃均未观察到晶型变化，结合样品的TGA/DSC和1H NMR结果，分析晶型A为无水晶型。
实施例3：无水晶型B的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂丙酮，得到的悬浊液置于60℃下磁力搅拌(～750rpm)约6天，离心分离固体，得到晶型B。该晶型的X射线粉末衍射图谱如图2A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图2B所示，1H NMR图谱如图2C所示。
1H NMR结果表明，在该样品中观察到少量(0.2wt％)的丙酮残留。综合TGA中该样品分解前较少的失重(0.5wt％)，DSC中在样品熔融前未见明显吸热峰，因此分析晶型B为无水晶型。
实施例4：无水晶型C的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂丙酮，室温搅拌30min，升温至60℃搅拌30min，再冷却到0-5℃搅拌6h，离心分离固体，再加入0.5mL溶剂水，得到的悬浊液置于室温下磁力搅拌(～750rpm)约2周，离心分离固体，得到晶型C。该晶型的X射线粉末衍射图谱如图3A所示，通过预先加热样品去除表面吸附溶剂/水之后测试的示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图3B所示，1H NMR图谱如图3C所示。
将晶型C样品在N2保护下吹扫20min，加热至100℃，降温至30℃均未观察到晶型变化，结合样品的TGA/DSC和1H NMR结果，分析晶型C为无水晶型。
此外，将以上方法中的溶剂替换为丙酮与水的混合溶剂(6:4,v:v)，同样得到晶型C。
实施例5：水合物晶型D的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂丙酮，室温搅拌30min，升温60℃搅拌30min，再冷却到0-5℃搅拌6h，离心分离固体，再加入0.5mL丙酮与水的混合溶剂(86:14,v/v)，得到的悬浊液置于室温下磁力搅拌(～750rpm)约9天，离心分离固体，得到晶型D。该晶型的X射线粉末衍射图谱如图4A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图4B所示，1H NMR图谱如图4C所示。1H NMR结果显示晶型D样品中含有极少(～0.5wt％)的丙酮残留。
此外，将以上方法中的溶剂替换为丙酮与水的混合溶剂(4:1,v/v)，同样得到晶型D。
变温XRPD结果(图4D)表明，将晶型D样品在N2保护下吹扫20min，观察到衍射峰变化；当加热样品至150℃并降温至30℃，观察到晶型变化，所得新晶型为晶型Q；当加热样品至150℃后，降至室温并暴露在空气中后，观察到部分衍射峰变化，所得新晶型为晶型M。结合晶型D样品在N2吹扫和加热后发现晶型变化，DSC结果显示在熔融峰前有一较宽的吸热信号(峰值温度63.7℃)，且1H NMR结果表明样品中仅含有极少的丙酮残留(远小于TGA失重)，因此分析晶型D为水合物。
实施例6：甲醇溶剂合物晶型E的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂MeOH，得到的悬浊液置于室温下磁力搅拌过夜，离心分离固体，得到晶型E。该晶型的X射线粉末衍射图谱如图5A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图5B所示，1H NMR图谱如图5C所示。1H NMR结果显示(图5C)检测到2.5wt％的MeOH(MeOH与式(I)化合物的摩尔比为0.4:1)。
通过加热试验对晶型E进行鉴定，结果如图5D所示。当将晶型E加热至48℃，降至室温并暴露在空气中，未观察到晶型变化；当将该样品加热至100℃，降至室温并暴露在空气中，观察到的新晶型为晶型N；当继续加热该样品至115℃，降至室温并暴露在空气中，观察到无定形生成。结合晶型E的48℃加热后样品的1H NMR结果(图5E，溶剂含量与加热前相比未发生明显改变)，综合TGA/DSC结果，分析该晶型为MeOH溶剂合物。
实施例7：乙醇溶剂合物晶型F的制备
称取20mg按照实施例1的方法制备的无定形物Z至HPLC小瓶中，加入0.5mL丙酮与乙醇的混合溶剂(1:1,v:v)，得到的悬浊液置于室温下磁力搅拌(～750rpm)约4天，离心分离固体，得到晶型F。该晶型的X射线粉末衍射图谱如图6A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图6B所示，1H NMR图谱如图6C所示。
1H NMR分析检测到约2.1wt％的乙醇残留(乙醇与式(I)化合物的摩尔比为0.23:1)和约0.2wt％的丙酮残留。通过加热试验对晶型F进行鉴定，结果如图6D所示。当将晶型F加热至100℃，降至室温并暴露在空气中，未观察到晶型变化；当将该样品加热至160℃，降至室温并暴露在空气中，观察到转为晶型M。结合晶型F加热至100℃后样品的1H NMR结果(图6E，与加热前相比溶剂含量未发生明显改变)，综合TGA/DSC结果，分析该晶型为乙醇溶剂合物。
实施例8：乙腈溶剂合物晶型G的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂丙酮，室温搅拌30min，升温60℃搅拌30min，再冷却到0-5℃搅拌6h，离心分离固体，再加入0.5mL ACN，得到的悬浊液置于50℃下磁力搅拌(～750rpm)约4天，离心分离固体，得到晶型G。该晶型的X射线粉末衍射图谱如图7A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图7B所示，1H NMR图谱如图7C所示。
通过加热试验对晶型G进行鉴定，结果表明：将游离态晶型G样品加热至75℃，降至室温并暴露在空气中，未观察到晶型变化；继续加热至150℃，降至室温并暴露在空气中，观察到转为晶型A。结合晶型G加热至75℃后样品的1H NMR结果(图7D，溶剂含量与加热前相比未发生改变)，综合TGA/DSC结果，分析该晶型为乙腈溶剂合物。
实施例9：二氯甲烷溶剂合物晶型H的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂丙酮，室温搅拌30min，升温60℃搅拌30min，再冷却到0-5℃搅拌6h，离心分离固体在二氯甲烷中气固渗透～12天，得到晶型H。该晶型的X射线粉末衍射图谱如图8A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图8B所示，1H NMR图谱如图8C所示。
1H NMR结果显示检测到6.1wt％的二氯甲烷残留(二氯甲烷与式(I)化合物的摩尔比为0.38:1)。通过加热试验对游离态晶型H进行鉴定，结果如图8D所示。将游离态晶型H加热至125℃，降至室温并暴露在空气中，观察到低结晶度样品；当继续加热至140℃和172℃后，观察到无定形样品生成。综合该样品的TGA/DSC和1H NMR结果，分析该晶型为二氯甲烷溶剂合物。
实施例10：晶型I的制备
称取20mg按照实施例1的方法制备的无定形物Z至3-mL小瓶中，使用1.0～1.5mL溶剂NMP(N-甲基吡咯烷酮)溶解固体，滤膜过滤后得到澄清溶液，另取20-mL的小瓶向其中加入约4mL的反溶剂ACN，将装有滤液的3-mL小瓶敞口置于20-mL小瓶后，密封20mL的小瓶并于室温下静置。待固体析出时，收集固体，得到晶型I。该晶型的X射线粉末衍射图谱如图9所示。但是，晶型I在室温晾干后，转为晶型A。
实施例11：1,4-二氧六环溶剂合物晶型J的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂丙酮，室温搅拌30min，升温60℃搅拌30min，再冷却到0-5℃搅拌6h，离心分离固体，再加入0.5mL溶剂1,4-二氧六环，得到的悬浊液置于50℃下磁力搅拌(～750rpm)获得澄清溶液后，移至室温继续搅拌约4天，离心分离固体，得到晶型J。该晶型的X射线粉末衍射图谱如图10A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图10B所示，1H NMR图谱如图10C所示。
1H NMR检测到样品中含有3.0wt％的1,4-二氧六环(1,4-二氧六环与式(I)化合物的摩尔比为0.18:1)。通过加热试验对晶型J进行鉴定，结果如图10D所示。将晶型J样品)加热至100℃，降至室温并暴露在空气中，观察到晶型未发生变化；当继续加热至160℃后，观察到低结晶度样品生成。结合游离态晶型J加热至100℃后样品的1H NMR结果(图10E，溶剂含量与加热前相比未发生改变)，综合TGA/DSC结果，分析该晶型为1,4-二氧六环溶剂合物。
实施例12：晶型K的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂丙酮，室温搅拌30min，升温60℃搅拌30min，再冷却到0-5℃搅拌6h，离心分离固体，再加入MeOH与H2O的混合溶剂(4:1,v:v)的溶剂溶解固体，经滤膜过滤后，将所得澄清滤液通过封口膜封口，并在上面扎5个小孔，放置在室温下缓慢挥发。收集挥发所得固体，得到晶型K。该晶型的X射线粉末衍射图谱如图11A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图11B所示，1H NMR图谱如图11C所示。
1H NMR结果显示样品中含有0.9wt％的MeOH。但是，重复上述方法不能良好地制备晶型K，有时会得到晶型O或晶型L(图11D)。
实施例13：甲醇-水共溶剂合物晶型L的制备
称取约20mg按照实施例1的方法制备的无定形物Z至20-mL小瓶中，加入甲醇与水的混合溶剂(4:1,v:v)的溶剂溶解固体，经滤膜过滤后，将所得澄清滤液通过封口膜封口，并在上面扎5个小孔，放置在室温下缓慢挥发。收集挥发所得固体，得到晶型L。该晶型的X射线粉末衍射图谱如图12A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图12B所示，1H NMR图谱如图12C所示。
1H NMR结果显示样品中含有6.1wt％的甲醇残留(甲醇与式(I)化合物的摩尔比为1:1)。该样品被用于单晶结构解析，解析结果表明游离态晶型L为甲醇-水共溶剂合物(图12D)。
实施例14：水合物晶型M的制备
称取约20mg按照实施例5的方法制备的晶型D加热至150℃，然后降至室温并暴露在空气中后，得到晶型M。该晶型的X射线粉末衍射图谱如图13A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图13B所示。
实施例15：无水晶型N的制备
称取约20mg按照实施例6的方法制备的晶型E加热至100℃，然后降至室温并暴露在空气中，得到晶型N。该晶型的X射线粉末衍射图谱如图14A所示，100℃加热去除表面吸附水/溶剂后的示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图14B所示，1H NMR图谱如图14C所示。
1H NMR结果显示晶型N样品中不含有甲醇残留。如图14D的晶型E的变温XRPD叠图所示，由于晶型N可通过晶型E在N2保护下加热除去甲醇后获得的，分析晶型N为无水晶型。
实施例16：甲醇溶剂合物晶型O的制备
称取约20mg按照实施例1的方法制备的无定形物Z，在MeOH/H2O(4:1,v/v)中溶清后，置于室温条件下缓慢挥发，得到晶型O。该晶型的X射线粉末衍射图谱如图15A所示，示差扫描量热法(DSC)图谱和热重分析(TGA)图谱如图15B所示，1H NMR图谱如图15C所示。
1H NMR结果显示检测到1.8wt％的甲醇。通过加热试验对晶型O进行鉴定，结果如图15D所示。将晶型O样品加热至145℃，降至室温并暴露在空气中，观察到衍射峰偏移；当继续加热至175℃后，观察到转为游离态晶型M。结合游离态晶型O加热至145℃后样品的1H NMR结果(图15E，溶剂含量较加热前未发生明显改变)，综合TGA/DSC结果，分析该晶型为MeOH溶剂合物。
实施例17：水合物晶型P的制备
称取20mg按照实施例13的方法制备的晶型L至HPLC小瓶中，加入0.5mL溶剂丙酮，室温搅拌30min，升温60℃搅拌30min，再冷却到0-5℃搅拌6h，离心分离固体，再加入MEK、THF和H2O的混合溶剂(1:0.1:2,v:v:v)中，5℃下打浆4天后，得到晶型P。该晶型的X射线粉末衍射图谱如图16A所示。
将晶型P湿样在空气中放置约10min后，观察到其转变为晶型C。在空气中晾干后晶型P转为无水晶型C。因此，分析晶型P为水合物。
实施例18：无水晶型Q的制备
称取约20mg按照实施例5的方法制备的晶型D在N2保护下吹扫20min，加热样品至150℃并降温至30℃，得到晶型Q。该晶型的X射线粉末衍射图谱如图17所示。
根据图4D可知，由于晶型Q是在N2吹扫下加热晶型D获得的，因此分析晶型Q为无水晶型。同时，晶型Q在室温室湿条件下放置后转为水合物晶型M。
实施例18：晶型R的制备
称取100mg按照实施例1的方法制备的无定形物Z至小瓶中，加入35mL二氯甲烷与丙酮的混合溶剂(6:1,v:v)，搅拌溶清后再次减压浓缩至干，加入4mL丙酮，60℃加热溶清后加入约3mL纯净水，自然冷却降至室温，继续搅拌2h，过滤得晶型R。该晶型的X射线粉末衍射图谱如图22A所示，其为无水物。
实施例19：晶型S的制备
称取100mg按照实施例1的方法制备的无定形物Z至小瓶中，加入5mL 1,4-二氧六环，于35℃搅拌溶清，室温下加入11mL水，有固体析出，搅拌1小时后过滤，约5mL水冲洗滤饼，25℃干燥过夜，得到晶型S。该晶型的X射线粉末衍射图谱如图23所示，其为水合物。
实施例20：马来酸盐晶型T的制备
称取1g按照实施例1的方法制备的无定形物Z至小瓶中，加入14mL三氯甲烷，于35℃搅拌溶清，得到溶液1；将102.64mg马来酸溶清于2mL乙醇中，得到溶液2；室温搅拌下，将551μL溶液2加入到0.7mL溶液1中，无沉淀析出，搅拌5小时后，移至4-8℃过夜，无沉淀析出，加入0.8mL甲基叔丁基醚后得到浊液，搅拌下得到油状物，补加0.4mL甲基叔丁基醚，继续搅拌过夜，离心，25℃真空烘干，得到晶型T。该晶型的X射线粉末衍射图谱如图24A所示。如图24B所示，该晶型的1H-NMR分析中出现分解。
实施例21：甲磺酸盐晶型U的制备
称取1g按照实施例1的方法制备的无定形物Z至小瓶中，加入14mL三氯甲烷，得到溶液1；将107.35mg甲磺酸溶清于2mL三氯甲烷中，得到溶液2；室温搅拌下，将441μL溶液2加入到0.7mL溶液1中，析出少量颗粒，45分钟后溶解，搅拌5小时后得到浊液，继续搅拌一天，25℃真空烘干，得到晶型U。该晶型的X射线粉末衍射图谱如图25A所示。如图25B所示，该晶型的1H-NMR分析中出现分解。
测试例1：引湿性测试
通过25℃下0％RH～95％RH之间的DVS测试对晶型A和晶型B的引湿性进行测试，并参照2015版《中国药典》进行评估。
晶型A和晶型B的DVS试验结果分别如图18和图19所示。其中，25℃/80％RH条件下晶型A样品吸湿增重约为1.1％，晶型B样品吸湿增重约为1.0％，表明晶型A和晶型B均为略有引湿性。并且，XRPD结果显示，在DVS测试后晶型A和晶型B样品的晶型均未发生变化。
晶型R的DVS测试图谱如图22B所示，等温吸附曲线如图22C所示。结果显示，晶型R和晶型S在环境湿度影响下易存在相互转晶的情况：晶型R在50％RH开始明显吸水转晶为水合物晶型S，而晶型S在40％RH开始脱水转晶为无水晶型R。
测试例2：固态稳定性测试
分别称取适量的晶型A和晶型B的样品，在60℃条件下闭口放置24小时，25℃/60％RH及40℃/75％RH条件下敞口放置2、4或6周。将不同条件下放置后的固体样品，通过XRPD测试晶型变化，HPLC测试纯度评估化学稳定性。
稳定性测试前后的XRPD表征结果汇总于表2-1和表2-2，结果显示，晶型A和晶型B样品在测试条件下HPLC纯度未见明显降低，且晶型未发生改变。
表2-1晶型A的固态稳定性评估结果

表2-2晶型B的固态稳定性评估结果
测试例3：溶解度测试
试验I
称取约2mg的根据实施例2制备的晶型A样品，加入到HPLC小瓶中，再逐步(依次50/50/200/700μL)加入对应溶剂后振荡直至固体溶清。若溶剂加到1mL后样品仍未溶清，则不再增加溶剂。根据固体样品质量、添加溶剂的体积和观察到的溶解现象，计算得溶解度范围，其结果汇总于表3-1。
表3-1溶解度测试结果汇总

*：将室温溶解度测试后未溶清样品置于50℃条件下放置～1小时后澄清。
试验II
(1)色谱条件
色谱柱：Waters XTERRA RP18，4.6mm×150mm，3.5μm或效能相当的色谱柱。
流动相：A相为10mmol/L磷酸氢二钾溶液(用磷酸调pH值至9.0±0.05)；B相为乙腈-甲醇(85﹕15)。
检测波长为250nm，柱温为40℃；流速为每分钟1.0ml；进样体积10μL。
溶剂：二甲基亚砜-甲醇＝1：9
对照品浓度：0.1mg/mL
溶解度用介质：水、pH4.5醋酸缓冲盐、pH6.8磷酸缓冲盐。
梯度洗脱条件见表3-2
表3-2
(2)介质配制：
水：蒸馏水
pH4.5醋酸缓冲盐：取三水合醋酸钠0.59806g置200ml量瓶中，用适量水溶解，再加入冰醋酸1.6ml，用水稀释至刻度，即得。
pH6.8磷酸缓冲盐：取磷酸二氢钾1.38501g，氢氧化钠0.18086g，置同一200mL量瓶中，用水溶解并稀释至刻度，即得。
(3)溶液配制：
晶型A及晶型B样品均按以下方法制过饱和溶液：
精密量取以上各介质10.0mL，分别置不同的25mL量瓶中，加入适量的受试晶型，密封，于振荡器中在37℃的条件下振荡24h，使均成为过饱和溶液。
①晶型B样品溶液配制：
pH6.8磷缓样品溶液：取pH6.8磷缓介质过饱和溶液，滤过，即得。
水样品溶液：取水介质过饱和溶液，滤过，即得
pH4.5醋缓样品溶液：取pH4.5醋缓介质过饱和溶液，滤过，精密量取滤液1.0mL置10mL量瓶中，用pH4.5醋缓介质稀释至刻度，再精密量取该溶液1.0mL置10mL量瓶中，用甲醇稀释至刻度，即得。
②晶型A样品溶液配制：
pH6.8磷缓样品溶液：取pH6.8磷缓介质过饱和溶液，滤过，即得。
水样品溶液：取水介质过饱和溶液，滤过，即得
pH4.5醋缓样品溶液：取pH4.5醋缓介质过饱和溶液，滤过，精密量取滤液1.0mL置10mL量瓶中，用pH4.5醋缓介质稀释至刻度，再精密量取该溶液1.0mL置25mL量瓶中，用甲醇稀释至刻度，即得。
(4)样品测定：
取各介质样品溶液，照上述色谱条件，精密量取供试品溶液10μl，注入液相色谱仪，记录色谱图。按照以下公式计算各介质的饱和溶液度。
式中：WR＝对照品溶液的称样量，mg；PR＝对照品的纯度因子；
AS＝供试品溶液中主峰的峰面积；DS＝供试品溶液的稀释倍数；
AR＝对照品溶液中主峰的峰面积；DR＝对照品溶液的稀释倍数；
(5)试验数据见表3-3
表3-3
测试例4：混悬竞争实验
在室温下，按照表4进行晶型B与晶型D、M、N、P在乙醇/水的溶剂体系中，不同水活度(aw＝0、0.2、0.4、0.6、0.8、1.0的混悬竞争试验。试验中所得固体的XRPD图谱如图20A(试验1-5)或图20B(试验6)所示，结果如表22-1所示。其中，试验1-4和6的起始晶型均为B、D、M和N，试验5的起始晶型为B、D、M、N和P。
表4混悬竞争实验
结果表明，在aw＝0～0.2条件下得到无水晶型B，aw＝0.4～0.8条件下得到水合物晶型D，在aw＝1.0(纯水)中得到水合物晶型P和无水晶型C的混合物，晶型C的信号可能是由晶型P在XRPD测试过程中转晶产生。
测试例5：药代动力学实验
准备6只SPF级SD大鼠，给药前称重，根据体重，计算给药量。分别准确称取适量的晶型A和晶型B样品，加入5％DMSO的生理盐水通过涡旋或超声使充分混匀，得到1mg/mL的给药液，口服10mg/kg灌胃给药。给药前称重，根据体重，计算给药量，每个晶型各3只大鼠。通口服灌胃给药，给药后经颈静脉或其它合适方式采集如下时间点样品：0.25h，0.5h，1h，2h，4h，8h，24h，每个样品采集约0.20mL，并于2小时内离心分离血浆。检测化合物I，进行血浆药物浓度-时间曲线绘制，通过不同时间点的血药浓度数据，运用WinNonlin计算药代动力学参数。结果表明，晶型A的体内吸收显著优于晶型B。
表5药代动力学实验结果
在本说明书的描述中，参考术语“实施例”、实例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本公开的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。并且，尽管上面已经示出和描述了本公开的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本公开的限制，本领域的普通技术人员在不脱离本公开的原理和宗旨的情况下在本公开的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (12)

  1. 式(I)化合物或其药学上可接受的盐的固体形式：
    其中，所述固体形式选自无水物、水合物、有机溶剂合物或水与有机溶剂的共溶剂合物的固体形式。
  2. 如权利要求1所述的固体形式，所述固体形式选自下列晶型中的一种、两种、三种或更多种：
    晶型A，其中：
    所述晶型A的X射线粉末衍射图具有一个或两个选自下列2θ值处的特征峰：6.91°±0.20°、10.32°±0.20°；
    优选地，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：6.91°±0.20°、10.32°±0.20°、25.72°±0.20°；
    优选地，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：6.91°±0.20°、10.32°±0.20°、13.88±0.20°、25.72°±0.20°；
    优选地，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.46°±0.20°、6.91°±0.20°、10.32°±0.20°、13.88°±0.20°、14.84°±0.20°、18.33°±0.20°、20.32°±0.20°、25.72°±0.20°；
    优选地，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.46°±0.20°、6.91°±0.20°、10.32°±0.20°、10.63°±0.20°、13.61°±0.20°、13.88°±0.20°、14.84°±0.20°、18.33°±0.20°、20.32°±0.20°、25.72°±0.20°；
    优选地，所述晶型A的X射线粉末衍射图还具有选自下列2θ值处的一个、两个、更多个或全部特征峰：15.86°±0.20°、17.00°±0.20°、17.18°±0.20°、24.51°±0.20°；
    优选地，所述晶型A的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：

    优选地，所述晶型A具有基本上如图1A所示的X射线粉末衍射图谱；
    优选地，所述晶型A的示差扫描量热法(DSC)图谱在约175.03℃的起始温度和/或约180.61℃的峰值温度具有吸热峰；
    优选地，所述晶型A具有基本上如图1B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型A的热重分析(TGA)中，从室温升温至190℃有约0.45％至约0.55％的失重；
    优选地，所述晶型A具有基本上如图1C所示的热重分析(TGA)图谱；
    优选地，所述晶型A为无水晶型；
    或者，
    晶型B，其中：
    所述晶型B的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：18.19°±0.20°、25.74°±0.20°、26.95°±0.20°；
    优选地，所述晶型B的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：11.04°±0.20°、12.78°±0.20°、16.12°±0.20°、16.74°±0.20°、18.19°±0.20°、25.22°±0.20°、25.74°±0.20°、26.95°±0.20°；
    优选地，所述晶型B的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.26°±0.20°、11.04°±0.20°、12.78°±0.20°、16.12°±0.20°、16.74°±0.20°、18.19°±0.20°、19.96°±0.20°、24.33°±0.20°、25.22°±0.20°、25.74°±0.20°、26.95°±0.20°；
    优选地，所述晶型B具有基本上如图2A所示的X射线粉末衍射图谱；
    优选地，所述晶型B的示差扫描量热法(DSC)图谱在约186.7℃的起始温度和/或约189.8℃的峰值温度具有吸热峰；
    优选地，所述晶型B具有基本上如图2B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型B的热重分析(TGA)中，从室温升温至150℃有约0.5％至约0.6％(例如约0.54％)的失重；
    优选地，所述晶型B具有基本上如图2B所示的热重分析(TGA)图谱；
    优选地，所述晶型B为无水晶型。
  3. 如权利要求1所述的固体形式，所述固体形式选自下列晶型中的一种、两种、三种或更多种：
    晶型C，其中：
    所述晶型C的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：7.25±0.20°、16.53°±0.20°、18.84°±0.20°；
    优选地，所述晶型C的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：7.25°±0.20°、14.48°±0.20°、16.53°±0.20°、18.84°±0.20°；
    优选地，所述晶型C的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：7.25°±0.20°、12.54°±0.20°、13.04°±0.20°、14.48°±0.20°、16.53°±0.20°、18.84°±0.20°、19.18°±0.20°、25.02°±0.20°；
    优选地，所述晶型C具有基本上如图3A所示的X射线粉末衍射图谱；
    优选地，所述晶型C的示差扫描量热法(DSC)图谱在约109.1℃的峰值温度，以及约123.4℃的起始温度和/或约132.5℃的峰值温度具有吸热峰；
    优选地，所述晶型C具有基本上如图3B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型C的热重分析(TGA)中，从室温升温至200℃有约0.2％至约0.3％(例如约0.27％)的失重；
    优选地，所述晶型C具有基本上如图3B所示的热重分析(TGA)图谱；
    优选地，所述晶型C为无水晶型；
    或者，
    晶型D，其中：
    所述晶型D的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.01°±0.20°、25.01°±0.20°、26.42°±0.20°；
    优选地，所述晶型D的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.26°±0.20°、11.01°±0.20°、15.61°±0.20°、18.53°±0.20°、22.14°±0.20°、25.01°±0.20°、26.42°±0.20°；
    优选地，所述晶型D的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.26°±0.20°、9.01°±0.20°、11.01°±0.20°、15.61°±0.20°、18.53°±0.20°、22.14°±0.20°、25.01°±0.20°、26.42°±0.20°；
    优选地，所述晶型D具有基本上如图4A所示的X射线粉末衍射图谱；
    优选地，所述晶型D的示差扫描量热法(DSC)图谱在约63.7℃的峰值温度，以及约181.7℃的起始温度和/或约184.3℃的峰值温度具有吸热峰；
    优选地，所述晶型D具有基本上如图4B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型D的热重分析(TGA)中，从室温升温至200℃有约3.3％至约3.4％(例如约3.35％)的失重；
    优选地，所述晶型D具有基本上如图4B所示的热重分析(TGA)图谱；
    优选地，所述晶型D为水合物；
    或者，
    晶型E，其中：
    所述晶型E的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：5.98°±0.20°、12.73°±0.20°、14.53°±0.20°；
    优选地，所述晶型E的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：5.98°±0.20°、10.66±0.20°、11.95±0.20°、12.73°±0.20°、14.53°±0.20°、17.67°±0.20°、22.91°±0.20°；
    优选地，所述晶型E具有基本上如图5A所示的X射线粉末衍射图谱；
    优选地，所述晶型E的示差扫描量热法(DSC)图谱在约114.9℃的峰值温度，以及约127.9℃的峰值温度具有吸热峰；
    优选地，所述晶型E具有基本上如图5B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型E的热重分析(TGA)中，从室温升温至50℃有约1.9％至约2.0％(例如约1.95％)的失重，从50℃升温至150℃有约3.0％至约3.1％(例如约3.02％)的失重；
    优选地，所述晶型E具有基本上如图5B所示的热重分析(TGA)图谱；
    优选地，所述晶型E为甲醇溶剂合物；
    优选地，所述晶型E具有基本上如图5D所示的变温XRPD图谱。
  4. 如权利要求1所述的固体形式，所述固体形式选自下列晶型中的一种、两种、三种或更多种：
    晶型F，其中：
    所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.07°±0.20°、24.79°±0.20°、26.42°±0.20°；
    优选地，所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.07°±0.20°、17.83°±0.20°、22.44°±0.20°、24.79°±0.20°、26.42°±0.20°；
    优选地，所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.07°±0.20°、17.83°±0.20°、22.44°±0.20°、24.79°±0.20°和26.42°±0.20°；
    优选地，所述晶型F的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.07°±0.20°、14.99°±0.20°、17.83°±0.20°、19.93°±0.20°、20.64°±0.20°、22.44°±0.20°、24.79°±0.20°、26.42°±0.20°；
    优选地，所述晶型F具有基本上如图6A所示的X射线粉末衍射图谱；
    优选地，所述晶型F的示差扫描量热法(DSC)图谱在约69.9℃的峰值温度，以及约182.1℃的起始温度和/或约184.5℃的峰值温度具有吸热峰；
    优选地，所述晶型F具有基本上如图6B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型F的热重分析(TGA)中，从室温升温至100℃有约2.2％至约2.3％(例如约2.25％)的失重，从100℃升温至200℃有约2.7％至约2.8％(例如约2.79％)的失重；
    优选地，所述晶型F具有基本上如图6B所示的热重分析(TGA)图谱；
    优选地，所述晶型F为乙醇溶剂合物；
    优选地，所述晶型F具有基本上如图6D所示的变温XRPD图谱；
    或者，
    晶型G，其中：
    所述晶型G的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：6.97°±0.20°、13.39°±0.20°、25.81°±0.20°；
    优选地，所述晶型G的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.50°±0.20°、6.97°±0.20°、13.39°±0.20°、14.40°±0.20°、17.11°±0.20°、17.81°±0.20°、23.94°±0.20°、25.81°±0.20°；
    优选地，所述晶型G具有基本上如图7A所示的X射线粉末衍射图谱；
    优选地，所述晶型G的示差扫描量热法(DSC)图谱在约122.6℃的峰值温度，以及约168.5℃的起始温度和/或约173.1℃的峰值温度具有吸热峰；
    优选地，所述晶型G具有基本上如图7B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型G的热重分析(TGA)中，从室温升温至75℃有约1.2％至约1.4％(例如约1.3％)的失重，从75℃升温至150℃有约2.6％至约2.7％(例如约2.69％)的失重；
    优选地，所述晶型G具有基本上如图7B所示的热重分析(TGA)图谱；
    优选地，所述晶型G为乙腈溶剂合物；
    或者，
    晶型H，其中：
    所述晶型H的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：12.92°±0.20°、15.82°±0.20°、17.25°±0.20°；
    优选地，所述晶型H的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：7.89°±0.20°、10.51°±0.20°、12.92°±0.20°、15.82°±0.20°、16.69°±0.20°、17.25°±0.20°、19.12°±0.20°、25.39°±0.20°；
    优选地，所述晶型H具有基本上如图8A所示的X射线粉末衍射图谱；
    优选地，所述晶型H的示差扫描量热法(DSC)图谱在约121.7℃、约138.7℃、约170.2℃和约184.7℃的峰值温度具有吸热峰；
    优选地，所述晶型H具有基本上如图8B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型H的热重分析(TGA)中，从室温升温至70℃有约1.7％至约1.8％(例如约1.73％)的失重，从70℃升温至150℃有约7.9％至约8.0％(例如约7.98％)的失重；
    优选地，所述晶型H具有基本上如图8B所示的热重分析(TGA)图谱；
    优选地，所述晶型H为二氯甲烷溶剂合物；
    优选地，所述晶型H具有基本上如图8D所示的变温XRPD图谱。
  5. 如权利要求1所述的固体形式，所述固体形式选自下列晶型中的一种、两种、三种或更多种：
    晶型I，其中：
    所述晶型I的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.45°±0.20°、13.35°±0.20°、17.82°±0.20°；
    优选地，所述晶型I的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.45°±0.20°、13.35°±0.20°、17.15°±0.20°、17.82°±0.20°、22.32°±0.20°、23.82°±0.20°、25.70°±0.20°；
    优选地，所述晶型I具有基本上如图9所示的X射线粉末衍射图谱。
    或者，
    晶型J，其中：
    所述晶型J的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：4.22°±0.20°、7.15°±0.20°、25.24°±0.20°；
    优选地，所述晶型J的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.22°±0.20°、6.74°±0.20°、7.15°±0.20°、11.04°±0.20°、12.62°±0.20°、13.48°±0.20°、16.86±0.20°、25.24°±0.20°；
    优选地，所述晶型J具有基本上如图10A所示的X射线粉末衍射图谱；
    优选地，所述晶型J的示差扫描量热法(DSC)图谱在约178.6℃的起始温度和/或约182.4℃的峰值温度，以及约188.9℃的峰值温度具有吸热峰；
    优选地，所述晶型J具有基本上如图10B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型J的热重分析(TGA)中，从室温升温至100℃有约1.4％至约1.5％(例如约1.41％)的失重，从100℃升温至200℃有约3.3％至约3.4％(例如约3.38％)的失重；
    优选地，所述晶型J具有基本上如图10B所示的热重分析(TGA)图谱；
    优选地，所述晶型J为1,4-二氧六环溶剂合物；
    优选地，所述晶型J具有基本上如图10D所示的变温XRPD图谱；
    或者，
    晶型K，其中：
    所述晶型K的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：4.19°±0.20°、6.48°±0.20°、6.95°±0.20°、19.54°±0.20°；
    优选地，所述晶型K的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.19°±0.20°、5.13°±0.20°、6.48°±0.20°、6.95°±0.20°、9.75°±0.20°、11.06°±0.20°、17.13°±0.20°、19.54°±0.20°；
    优选地，所述晶型K具有基本上如图11A所示的X射线粉末衍射图谱；
    优选地，所述晶型K具有基本上如图11B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型K具有基本上如图11B所示的热重分析(TGA)图谱。
  6. 如权利要求1所述的固体形式，所述固体形式选自下列晶型中的一种、两种、三种或更多种：
    晶型L，其中：
    所述晶型L的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：18.85°±0.20°、22.30°±0.20°、29.35°±0.20°；
    优选地，所述晶型L的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：9.23°±0.20°、18.85°±0.20°、22.30°±0.20°、22.69°±0.20°、23.22°±0.20°、23.82°±0.20°、26.58°±0.20°、29.35°±0.20°；
    优选地，所述晶型L具有基本上如图12A所示的X射线粉末衍射图谱；
    优选地，所述晶型L的示差扫描量热法(DSC)图谱在约95.4℃的起始温度和/或约100.0℃的峰值温度，以及约154.5℃的峰值温度具有吸热峰；
    优选地，所述晶型L具有基本上如图12B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型L的热重分析(TGA)中，从室温升温至100℃有约8.9％至约9.0％(例如约8.98％)的失重，从100℃升温至125℃有约2.5％至约2.6％(例如约2.56％)的失重，从125℃升温至150℃有约1.8％至约1.9％(例如约1.81％)的失重；
    优选地，所述晶型L具有基本上如图12B所示的热重分析(TGA)图谱；
    优选地，所述晶型L为甲醇-水共溶剂合物；
    优选地，所述晶型L具有基本上如图12C所示的1H NMR图谱；
    优选地，所述晶型L的单晶具有如图12D所示的单晶结构的不对称单元示意图；
    优选地，所述晶型L的单晶具有如下结构参数：
    或者，
    晶型M，其中：
    所述晶型M的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：4.22°±0.20°、18.59°±0.20°、25.31°±0.20°；
    优选地，所述晶型M的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.22°±0.20°、9.05°±0.20°、10.94°±0.20°、15.48°±0.20°、18.59°±0.20°、21.81°±0.20°、25.31°±0.20°、26.48°±0.20°；
    优选地，所述晶型M具有基本上如图13A所示的X射线粉末衍射图谱；
    优选地，所述晶型M的示差扫描量热法(DSC)图谱在约61.3℃的峰值温度，以及约181.4℃的起始温度和/或约184.2℃的峰值温度具有吸热峰；
    优选地，所述晶型M具有基本上如图13B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型M的热重分析(TGA)中，从室温升温至200℃有约2.0％至约2.1％(例如约2.05％)的失重；
    优选地，所述晶型M具有基本上如图13B所示的热重分析(TGA)图谱；
    优选地，所述晶型M为水合物；
    或者，
    晶型N，其中：
    所述晶型N的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：5.82°±0.20°、13.96°±0.20°、20.24°±0.20°；
    优选地，所述晶型N的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：5.82°±0.20°、7.18°±0.20°、12.35°±0.20°、13.96°±0.20°、15.77°±0.20°、17.49°±0.20°、18.40°±0.20°、20.24°±0.20°；
    优选地，所述晶型N具有基本上如图14A所示的X射线粉末衍射图谱；
    优选地，所述晶型N的示差扫描量热法(DSC)图谱在约118.0℃的起始温度和/或约125.9℃的峰值温度具有吸热峰；
    优选地，所述晶型N具有基本上如图14B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型N的热重分析(TGA)中，从室温升温至200℃有约0.1％至约0.2％(例如约0.19％)的失重；
    优选地，所述晶型N具有基本上如图14B所示的热重分析(TGA)图谱；
    优选地，所述晶型N为无水晶型；
    优选地，所述晶型N具有基本上如图14D所示的变温XRPD图谱。
  7. 如权利要求1所述的固体形式，所述固体形式选自下列晶型中的一种、两种、三种或更多种：
    晶型O，其中：
    所述晶型O的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：11.06°±0.20°、24.85°±0.20°、26.44°±0.20°；
    优选地，所述晶型O的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.32°±0.20°、11.06°±0.20°、15.11°±0.20°、15.76°±0.20°、17.22°±0.20°、17.93°±0.20°、24.85°±0.20°、26.44°±0.20°；
    优选地，所述晶型O具有基本上如图15A所示的X射线粉末衍射图谱；
    优选地，所述晶型O的示差扫描量热法(DSC)图谱在约174.7℃和约187.1℃的峰值温度具有吸热峰；
    优选地，所述晶型O具有基本上如图15B所示的示差扫描量热法(DSC)图谱；
    优选地，所述晶型O的热重分析(TGA)中，从室温升温至150℃有约4.0％至约4.1％(例如约4.03％)的失重，从150℃升温至200℃有约1.5％至约1.7％(例如约1.60％)的失重；
    优选地，所述晶型O具有基本上如图15B所示的热重分析(TGA)图谱；
    优选地，所述晶型O为甲醇溶剂合物；
    据本公开的实施方案，所述晶型O具有基本上如图15D所示的变温XRPD图谱；
    或者，
    晶型P，其中：
    所述晶型P的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：6.36°±0.20°、16.15°±0.20°、21.05°±0.20°；
    优选地，所述晶型P的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：6.36°±0.20°、11.09°±0.20°、16.15°±0.20°、17.27°±0.20°、21.05°±0.20°、26.38°±0.20°、26.62°±0.20°、34.88°±0.20°；
    优选地，所述晶型P具有基本上如图16A所示的X射线粉末衍射图谱；
    优选地，所述晶型P为水合物；
    或者，
    晶型Q，其中：
    所述晶型Q的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：18.41°±0.20°、25.19°±0.20°、26.36°±0.20°；
    优选地，所述晶型Q的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：4.15°±0.20°、10.85°±0.20°、13.28°±0.20°、18.41°±0.20°、20.03°±0.20°、21.69°±0.20°、25.19°±0.20°、26.36°±0.20°；
    优选地，所述晶型Q具有基本上如图17所示的X射线粉末衍射图谱；
    优选地，所述晶型Q为无水晶型。
  8. 如权利要求1所述的固体形式，所述固体形式选自下列晶型中的一种、两种、三种或更多种：
    晶型R，其中：
    所述晶型R的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：7.22°±0.20°、13.03°±0.20°、18.81°±0.20°；
    优选地，所述晶型R的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：7.22°±0.20°、13.03°±0.20°、18.81°±0.20°、19.15±0.20°；
    优选地，所述晶型R具有基本上如图22A所示的X射线粉末衍射图谱；
    优选地，所述晶型R为无水晶型；
    或者，
    晶型S，其中：
    所述晶型S的X射线粉末衍射图具有选自下列2θ值处的一个、两个或全部特征峰：6.30°±0.20°、16.11°±0.20°、21.01°±0.20°；
    优选地，所述晶型S的X射线粉末衍射图具有选自下列2θ值处的一个、两个、更多个或全部特征峰：6.30°±0.20°、11.06°±0.20°、16.11°±0.20°、21.01°±0.20°；
    优选地，所述晶型S具有基本上如图23所示的X射线粉末衍射图谱；
    优选地，所述晶型S为水合物；
    或者，
    晶型T，其中所述晶型T具有基本上如图24A所示的X射线粉末衍射图谱；
    或者，
    晶型U，其中所述晶型U具有基本上如图25A所示的X射线粉末衍射图谱。
  9. 如权利要求1-8任一项所述的固体形式的制备方法，其中所述制备方法包括选自下列的一种：
    所述晶型A的制备方法包括将式(I)化合物(如其无定形物)溶解在乙酸乙酯与二氯甲烷的混合溶剂中，将所得的溶液在室温下挥发，得到晶型A；优选地，所述晶型A的制备方法中，乙酸乙酯与二氯甲烷的体积比可以为1:1至20:1，例如9:1；
    或者，所述晶型A的制备方法包括将晶型G加热至150℃，降至室温并暴露在空气中，得到晶型A；
    或者，所述晶型A的制备方法包括将晶型I在室温晾干，得到晶型A；
    所述晶型L的制备方法包括将式(I)化合物(如其无定形物)和甲醇与水的混合溶剂混合，得到溶液，将所得的溶液在室温下挥发，得到晶型L。优选地，所述晶型L的制备方法中，甲醇与水的体积比可以为1:1至20:1，例如4:1；
    所述晶型B的制备方法包括将晶型L在丙酮中搅拌，得到晶型B；优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；优选地，所述搅拌在50至70℃下，例如60℃下进行；
    所述晶型C的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体再与水混合搅拌，得到晶型C；优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；所述晶型L与水的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；
    优选地，所述晶型L在丙酮中的搅拌先在50至70℃下，例如60℃下进行，然后在0-5℃下进行；所述分离得到的固体再在水中搅拌时，为在室温下搅拌；
    或者，将晶型L在丙酮与水的混合溶剂中搅拌，其中丙酮与水的体积比可以为(1～2):1，例如(1.5):1；
    或者，将晶型P的湿样在空气中晾干后，得到晶型C；
    所述晶型D的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体再在丙酮与水的混合溶剂中搅拌；优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；所述晶型L与丙酮与水的混合溶剂的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；优选地，所述丙酮与水的混合溶剂中，丙酮与水的体积比可以为(5～7):1，例如1.5:1；
    优选地，所述晶型L在丙酮中的搅拌先在50至70℃下，例如60℃下进行，然后在0-5℃下进行；所述分离得到的固体再在丙酮与水的混合溶剂中搅拌时，为在室温下搅拌；
    或者，将晶型L在丙酮与水的混合溶剂中搅拌，其中丙酮与水的体积比可以为(3～6):1，例如4:1；
    所述晶型E的制备方法包括将晶型L在甲醇中搅拌，得到晶型E；优选地，所述搅拌在室温下进行；优选地，所述晶型L与甲醇的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；
    或者，所述晶型F的制备方法包括将式(I)化合物(如其无定形物)在丙酮与乙醇的混合溶剂中搅拌，得到晶型F；优选地，所述晶型L的制备方法中，丙酮与乙醇的体积比可以为1:1；
    所述晶型G的制备方法包括将晶型L先在丙酮中搅拌，将分离得到的固体再在乙腈中搅拌，得到晶型G；优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；所述晶型L与乙腈的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；
    所述晶型H的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体再在二氯甲烷气氛中气固渗透，得到晶型H；优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；
    所述晶型I的制备方法包括将式(I)化合物(如其无定形物)溶解于N-甲基吡咯烷酮，然后加入反溶剂如乙腈，室温静置析出固体，得到晶型I；优选地，所述式(I)化合物与N-甲基吡咯烷酮的质量体积比可以为20mg:(1.0～1.5mL)；所述式(I)化合物与N-甲基吡咯烷酮的质量体积比可以为20mg:(3～5mL)，例如20mg:4mL；
    所述晶型J的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体与1,4-二氧六环混合后在50℃下搅拌，再在室温下搅拌，得到晶型J；优选地，所述晶型L与丙酮的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；所述晶型L与1,4-二氧六环的质量体积比可以为20mg:(0.1～1mL)，例如20mg:0.5mL；
    所述晶型M的制备方法包括将晶型D加热至150℃，然后降至室温并暴露在空气中约10min后，得到晶型M；
    或者，所述晶型M的制备方法包括将晶型F加热至160℃，降至室温并暴露在空气中，得到晶型M；
    或者，所述晶型M的制备方法包括将晶型O样品加热至175℃后，得到晶型M；
    或者，所述晶型M的制备方法包括将晶型Q在室温室湿条件下放置，得到晶型M；
    所述晶型N的制备方法包括将晶型E加热至100℃，然后降至室温并暴露在空气中，得到晶型N；
    所述晶型O的制备方法包括将式(I)化合物(如其无定形物)溶解于甲醇与水的混合溶剂中，室温挥发，得到晶型O；优选地，所述甲醇与水的混合溶剂中，甲醇与水的体积比可以为(3～5):1，例如4:1；
    所述晶型P的制备方法包括将晶型L先在丙酮中室温搅拌，升温至60℃搅拌，再冷却到0-5℃搅拌，将分离得到的固体再在MEK、THF和H2O的混合溶剂中打浆，得到晶型P；优选地，MEK、THF和H2O的混合溶剂中，MEK、THF和H2O的体积比可以为1:0.1:2；
    所述晶型Q的制备方法包括将晶型D在N2保护下吹扫20min，加热样品至150℃并降温至30℃，得到晶型Q；
    所述晶型R的制备方法包括将式(I)化合物(如无定形物)和二氯甲烷与丙酮的混合溶剂混合，溶清后减压浓缩至干，加入丙酮，加热溶清后加入水，自然冷却降至室温，搅拌，过滤得晶型R；
    所述晶型S的制备方法包括将式(I)化合物(如无定形物)与1,4-二氧六环混合，溶清，加入水，析出固体，过滤，干燥，得到晶型S；
    所述晶型T的制备方法包括将式(I)化合物(如无定形物)与三氯甲烷混合，得到溶液1；将马来酸与乙醇混合，得到溶液2；将溶液2与溶液1混合，加入甲基叔丁基醚，搅拌，离心，干燥，得到晶型T；
    所述晶型U的制备方法包括将式(I)化合物(如无定形物)与三氯甲烷混合，得到溶液1；将甲磺酸与三氯甲烷混合，得到溶液2；将溶液2与溶液1混合，搅拌，干燥，得到晶型U。
  10. 一种混合物，其中所述混合物包含选自权利要求1-8任一项所述的式(I)化合物或其药学上可接受的盐的固体形式中的至少一种；
    优选地，以所述混合物中式(I)化合物的总重量计，所述晶型A的重量百分比含量为80％以上，优选95％以上，进一步优选99％以上。
  11. 一种药物组合物，其中所述药物组合物包含选自权利要求1-8任一项所述的式(I)化合物或其药学上可接受的盐的固体形式的至少一种；或者，所述药物组合物包含所述混合物；
    优选地，所述药物组合物还可以包含药学上可接受的辅料；
    更优选地，所述药物组合物还进一步含有至少一种额外的治疗剂。
  12. 权利要求1-8任一项所述的式(I)化合物或其药学上可接受的盐的固体形式、权利要求10所述的混合物或权利要求11所述的药物组合物的用途，其中所述用途选自下列中的至少一种：
    用于体外或体内抑制细胞增殖的用途；或者，
    用于治疗RET激酶介导的疾病的用途；或者，
    用于抑制RET激酶活性的用途；或者，
    用于治疗癌症和/或抑制与特定癌症相关的转移的用途；或者，
    用于治疗肠易激综合征(IBS)或与IBS相关的疼痛的用途；或者，
    用于向癌症患者提供支持护理的用途，所述支持护理包括预防或最小化与治疗(包括化疗治疗)相关的胃肠病症，例如腹泻；或者，
    用于治疗RET相关疾病或病症的用途；或者，
    用于逆转或预防对抗癌药物的获得性抗性的用途；或者，
    用于延迟和/或预防个体中抗癌药抗药性发展的用途；或者，
    用于治疗患有癌症且对抗癌药物发展抗性的可能性增加的个体的用途。
PCT/CN2023/133860 2022-11-25 2023-11-24 稠环化合物的固体形式及其制备方法和用途 WO2024109909A1 (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021023209A1 (zh) * 2019-08-05 2021-02-11 北京志健金瑞生物医药科技有限公司 含氮多环稠环类化合物，其药物组合物、制备方法和用途
WO2022166642A1 (zh) * 2021-02-08 2022-08-11 北京志健金瑞生物医药科技有限公司 含氮多环稠环类化合物，其药物组合物、制备方法和用途
WO2023280073A1 (zh) * 2021-07-09 2023-01-12 北京志健金瑞生物医药科技有限公司 含氮多环稠环类化合物的制备方法及其中间体和用途

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WO2021023209A1 (zh) * 2019-08-05 2021-02-11 北京志健金瑞生物医药科技有限公司 含氮多环稠环类化合物，其药物组合物、制备方法和用途
WO2022166642A1 (zh) * 2021-02-08 2022-08-11 北京志健金瑞生物医药科技有限公司 含氮多环稠环类化合物，其药物组合物、制备方法和用途
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