Solid forms of fused ring compounds, and methods for their preparation and use

Abstract

The present disclosure provides solid forms of fused ring compounds, and methods for their preparation and use, that are more advantageous pharmaceutically acceptable forms of the compound of formula (I). The solid forms provided by the present disclosure have advantageous physicochemical and pharmacokinetic properties.

Description

[Technical Field]

[0001] This application claims priority from an earlier Chinese invention patent application bearing application number 202211494114.7 and entitled "Solid form of fused ring compound, and its preparation method and use," filed by the applicant with the State Intellectual Property Administration of China on November 25, 2022. The above-mentioned earlier application is incorporated herein by reference in its entirety.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates to solid forms of fused ring compounds, and methods for their preparation and use, in the field of chemical medicine. [Background technology]

[0003] The RET (Rearranged During Transfection) proto-oncogene was first identified in 1985 by transfecting NIH3T3 (mouse embryonic fibroblast cell line) cells with human lymphoma DNA (Cell, 1985, 42(2): 581-588). The RET proto-oncogene is located on chromosome 10q11.2, spans 60 kb of DNA, contains 21 exons, and encodes the RET protein, which consists of 1,100 amino acids. The RET protein is a tyrosine kinase receptor and contains an extracellular domain consisting of cysteines, a transmembrane domain, and an intracellular domain with tyrosine kinase catalytic activity (Mol Cell Endocrinol, 2010, 322(1-2): 2-7). RET is involved in cell proliferation, neurotransmission, cell migration, and cell differentiation, and through the signaling of the ligand / receptor complex / RET multiprotein complex, it activates various downstream signaling pathways, such as RAS / RAF / MEK / ERK, PI3K / AKT, and STAT, thereby inducing cell proliferation (J Clin Oncol, 2012, 30(2): 200-202).

[0004] The discovery that RET fusions are drivers of cancer in some cancers has prompted the application of multikinase inhibitors that already have RET inhibitory activity and are being used to treat patients with tumors that harbor RET fusion proteins. The RET inhibitor selpercatinib (LOXO-292) has been approved for use in treating patients with tumors that harbor RET fusion proteins. However, one of the biggest challenges in cancer treatment is the development of drug resistance in tumor cells after a certain treatment course. Once drug resistance occurs, patients generally have very limited treatment options, and in most cases, the cancer continues to progress unchecked. It has been reported that patients with RET-fusion non-small cell lung cancer develop solvent front mutations of the RET G810, such as G810R, G810S, and G801C mutations, after treatment with the RET inhibitor selpercatinib (LOXO-292). These mutations reduce the effectiveness of LOXO-292 at the ATP binding site, leading to drug resistance and cancer progression (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). Therefore, the development of compounds with good RET mutation inhibitory activity is essential.

[0005] The PCT patent application, application number PCT / CN2020 / 107049, discloses compounds that exhibit relatively strong inhibitory effects against the RET gatekeeper residue mutant RET V804M, the RET solvent front residue mutant G810R, other clinically relevant RET mutants, and wild-type RET as RET inhibitors. These compounds also significantly inhibit the growth of TT cell lines derived from thyroid cancer and Ba / F3 cells transformed with various RET mutants, block the autophosphorylation of cellular RET and its downstream pathways, and significantly induce TT cell death. Therefore, further research is needed to develop solid forms of these compounds, particularly crystalline forms, that are more suitable as active pharmaceutical ingredients. Summary of the Invention

[0006] To achieve the above object, the present disclosure provides a solid form of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0007] [ka]

[0008] The solid form is selected from anhydrous, hydrated, organic solvate, or cosolvate solid forms of water and organic solvent.

[0009] According to an embodiment of the present disclosure, the organic solvent is one selected from alcohols (e.g., methanol, ethanol), nitriles (e.g., acetonitrile), halogenated alkanes (e.g., dichloromethane), and ethers (e.g., 1,4-dioxane).

[0010] According to an embodiment of the present disclosure, the solid form is one, two, three or more selected from the crystalline forms described below.

[0011] The present disclosure further provides crystalline form A of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form A has one or two characteristic peaks located at 2θ values ​​selected from 6.91°±0.20°, 10.32°±0.20°.

[0012] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form A has one, two or all characteristic peaks located at 2θ values ​​selected from 6.91°±0.20°, 10.32°±0.20°, and 25.72°±0.20°.

[0013] Preferably, the X-ray powder diffraction pattern of crystalline form A has one, two, more or all characteristic peaks located at 2θ values ​​selected from 6.91°±0.20°, 10.32°±0.20°, 13.88±0.20° and 25.72°±0.20°.

[0014] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form A has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°.

[0015] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form A has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°.

[0016] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form A further comprises one, two, more or all characteristic peaks located at 2θ values ​​selected from 15.86°±0.20°, 17.00°±0.20°, 17.18°±0.20° and 24.51°±0.20°.

[0017] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form A has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0018] [Table 1]

[0019] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form A has one, two, more or all of the characteristic peaks located at 2θ values ​​selected from the following, it optionally also has relative intensities selected from those corresponding to the characteristic peaks:

[0020] [Table 2]

[0021] According to an embodiment of the present disclosure, the crystalline form A has an X-ray powder diffraction pattern essentially as shown in FIG. 1A.

[0022] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form A has an endothermic peak with an onset temperature of about 175.03°C and / or a peak temperature of about 180.61°C.

[0023] According to an embodiment of the present disclosure, the crystalline form A has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 1B.

[0024] According to embodiments of the present disclosure, crystalline form A exhibits a weight loss of about 0.45% to about 0.55% (e.g., about 0.499%) upon heating from room temperature to 190°C in thermogravimetric analysis (TGA).

[0025] According to an embodiment of the present disclosure, the crystalline form A has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 1C.

[0026] According to an embodiment of the present disclosure, the crystalline form A is an anhydrous crystalline form.

[0027] According to an embodiment of the present disclosure, the crystalline form A is essentially as shown in FIG. 1 H NMR pattern.

[0028] The present disclosure further provides crystalline form B of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form B has one, two or all characteristic peaks located at 2θ values ​​selected from 18.19°±0.20°, 25.74°±0.20°, and 26.95°±0.20°.

[0029] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form B has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°, and 26.95°±0.20°.

[0030] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form B has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°.

[0031] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form B has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0032] [Table 3]

[0033] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of crystalline form B has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0034] According to an embodiment of the present disclosure, the crystalline form B has an X-ray powder diffraction pattern essentially as shown in FIG. 2A.

[0035] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form B has an endothermic peak with an onset temperature of about 186.7°C and / or a peak temperature of about 189.8°C.

[0036] According to an embodiment of the present disclosure, the crystalline form B has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 2B.

[0037] According to an embodiment of the present disclosure, the crystalline form B exhibits a weight loss of about 0.5% to about 0.6% (e.g., about 0.54%) when heated from room temperature to 150°C in thermogravimetric analysis (TGA).

[0038] According to an embodiment of the present disclosure, the crystalline form B has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 2B.

[0039] According to an embodiment of the present disclosure, the crystalline form B is an anhydrous crystalline form.

[0040] According to an embodiment of the present disclosure, the crystalline form B is essentially as shown in FIG. 2C 1H NMR pattern.

[0041] The present disclosure further provides crystalline form C of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form C has one, two or all characteristic peaks located at 2θ values ​​selected from 7.25°±0.20°, 16.53°±0.20°, and 18.84°±0.20°.

[0042] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form C has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 7.25°±0.20°, 14.48°±0.20°, 16.53°±0.20°, and 18.84°±0.20°.

[0043] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form C has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°.

[0044] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form C has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0045] [Table 4]

[0046] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of crystalline form C has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0047] According to an embodiment of the present disclosure, crystalline form C has an X-ray powder diffraction pattern essentially as shown in FIG. 3A.

[0048] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form C has an endothermic peak at a peak temperature of about 109.1°C and an onset temperature of about 123.4°C, and / or a peak temperature of about 132.5°C.

[0049] According to an embodiment of the present disclosure, the crystalline form C has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 3B.

[0050] According to embodiments of the present disclosure, crystalline form C exhibits a weight loss of about 0.2% to about 0.3% (e.g., about 0.27%) upon heating from room temperature to 200°C in thermogravimetric analysis (TGA).

[0051] According to an embodiment of the present disclosure, the crystalline form C has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 3B.

[0052] According to an embodiment of the present disclosure, the crystalline form C is an anhydrous crystalline form.

[0053] According to an embodiment of the present disclosure, the crystalline form C is essentially as shown in FIG. 1 H NMR pattern.

[0054] The present disclosure further provides crystalline form D of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form D has one, two or all characteristic peaks located at 2θ values ​​selected from 11.01°±0.20°, 25.01°±0.20°, and 26.42°±0.20°.

[0055] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form D has one, two, more or all characteristic peaks located at 2θ values ​​selected from 4.26°±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°.

[0056] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form D has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°.

[0057] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form D has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0058] [Table 5]

[0059] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of crystalline form D has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0060] According to an embodiment of the present disclosure, the crystalline form D has an X-ray powder diffraction pattern essentially as shown in FIG. 4A.

[0061] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of 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.

[0062] According to an embodiment of the present disclosure, the crystalline form D has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 4B.

[0063] According to embodiments of the present disclosure, crystalline form D exhibits a weight loss of about 3.3% to about 3.4% (e.g., about 3.35%) when heated from room temperature to 200°C in thermogravimetric analysis (TGA).

[0064] According to an embodiment of the present disclosure, the crystalline form D has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 4B.

[0065] According to an embodiment of the present disclosure, the crystalline form D is a hydrate.

[0066] According to an embodiment of the present disclosure, the crystalline form D is essentially as shown in FIG. 1 H NMR pattern.

[0067] According to an embodiment of the present disclosure, crystalline form D has a variable-temperature XRPD pattern essentially as shown in FIG. 4D.

[0068] The present disclosure further provides crystalline form E of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form E has one, two or all characteristic peaks located at 2θ values ​​selected from 5.98°±0.20°, 12.73°±0.20°, and 14.53°±0.20°.

[0069] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form E has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 5.98°±0.20°, 10.66±0.20°, 11.95±0.20°, 12.73°±0.20°, 14.53°±0.20°, 17.67°±0.20°, and 22.91°±0.20°.

[0070] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form E has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0071] [Table 6]

[0072] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of crystalline form E has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0073] According to an embodiment of the present disclosure, the crystalline form E has an X-ray powder diffraction pattern essentially as shown in FIG. 5A.

[0074] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form E has a peak temperature of about 114.9°C and an endothermic peak at a peak temperature of about 127.9°C.

[0075] According to an embodiment of the present disclosure, the crystalline form E has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 5B.

[0076] According to an embodiment of the present disclosure, the crystalline form E exhibits a weight loss of about 1.9% to about 2.0% (e.g., about 1.95%) when heated from room temperature to 50°C, and a weight loss of about 3.0% to about 3.1% (e.g., about 3.02%) when heated from 50°C to 150°C in thermogravimetric analysis (TGA).

[0077] According to an embodiment of the present disclosure, the crystalline form E has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 5B.

[0078] According to an embodiment of the present disclosure, the crystalline form E is a methanol solvate.

[0079] According to an embodiment of the present disclosure, the crystalline form E is essentially as shown in FIG. 5C 1 H NMR pattern.

[0080] According to an embodiment of the present disclosure, crystalline form E has a variable-temperature XRPD pattern essentially as shown in FIG. 5D.

[0081] The present disclosure further provides crystalline form F of compound of formula (I), wherein the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from 11.07°±0.20°, 24.79°±0.20°, and 26.42°±0.20°.

[0082] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from 11.07°±0.20°, 17.83°±0.20°, 22.44°±0.20°, 24.79°±0.20°, and 26.42°±0.20°.

[0083] Preferably, the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from 11.07°±0.20°, 17.83°±0.20°, 22.44°±0.20°, 24.79°±0.20° and 26.42°±0.20°.

[0084] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from 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°.

[0085] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from the following:

[0086] [Table 7]

[0087] According to embodiments of the present disclosure, when the X-ray powder diffraction pattern of crystalline form F has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0088] According to an embodiment of the present disclosure, crystalline form F has an X-ray powder diffraction pattern essentially as shown in FIG. 6A.

[0089] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form F has an endothermic peak at a peak temperature of about 69.9°C and an onset temperature of about 182.1°C and / or a peak temperature of about 184.5°C.

[0090] According to an embodiment of the present disclosure, the crystalline form F has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 6B.

[0091] According to embodiments of the present disclosure, crystalline form F exhibits a weight loss of about 2.2% to about 2.3% (e.g., about 2.25%) when heated from room temperature to 100°C, and a weight loss of about 2.7% to about 2.8% (e.g., about 2.79%) when heated from 100°C to 200°C in thermogravimetric analysis (TGA).

[0092] According to an embodiment of the present disclosure, the crystalline form F has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 6B.

[0093] According to an embodiment of the present disclosure, the crystalline form F is an ethanol solvate.

[0094] According to an embodiment of the present disclosure, the crystalline form F is essentially as shown in FIG. 6C 1 H NMR pattern.

[0095] According to an embodiment of the present disclosure, crystalline form F has a variable-temperature XRPD pattern essentially as shown in FIG. 6D.

[0096] The present disclosure further provides crystalline form G of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form G has one, two or all characteristic peaks located at 2θ values ​​selected from 6.97°±0.20°, 13.39°±0.20°, and 25.81°±0.20°.

[0097] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form G has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°.

[0098] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystalline form G has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0099] [Table 8]

[0100] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form G has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0101] According to an embodiment of the present disclosure, the crystalline form G has an X-ray powder diffraction pattern essentially as shown in FIG. 7A.

[0102] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form G has an endothermic peak at a peak temperature of about 122.6°C and an onset temperature of about 168.5°C and / or a peak temperature of about 173.1°C.

[0103] According to an embodiment of the present disclosure, the crystalline form G has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 7B.

[0104] According to an embodiment of the present disclosure, the crystalline form G exhibits a weight loss of about 1.2% to about 1.4% (e.g., about 1.3%) when heated from room temperature to 75°C, and a weight loss of about 2.6% to about 2.7% (e.g., about 2.69%) when heated from 75°C to 150°C in thermogravimetric analysis (TGA).

[0105] According to an embodiment of the present disclosure, the crystalline form G has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 7B.

[0106] According to an embodiment of the present disclosure, the crystalline form G is an acetonitrile solvate.

[0107] According to an embodiment of the present disclosure, the crystalline form G is essentially as shown in FIG. 7C 1 H NMR pattern.

[0108] The present disclosure further provides crystalline form H of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form H has one, two or all characteristic peaks located at 2θ values ​​selected from 12.92°±0.20°, 15.82°±0.20°, and 17.25°±0.20°.

[0109] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form H has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°.

[0110] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form H has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0111] [Table 9]

[0112] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of crystalline form H has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0113] According to an embodiment of the present disclosure, crystalline form H has an X-ray powder diffraction pattern essentially as shown in FIG. 8A.

[0114] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of 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.

[0115] According to an embodiment of the present disclosure, the crystalline form H has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 8B.

[0116] According to an embodiment of the present disclosure, crystalline form H exhibits a weight loss of about 1.7% to about 1.8% (e.g., about 1.73%) when heated from room temperature to 70°C, and a weight loss of about 7.9% to about 8.0% (e.g., about 7.98%) when heated from 70°C to 150°C in thermogravimetric analysis (TGA).

[0117] According to an embodiment of the present disclosure, the crystalline form H has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 8B.

[0118] According to an embodiment of the present disclosure, the crystalline form H is a dichloromethane solvate.

[0119] According to an embodiment of the present disclosure, the crystalline form H is essentially as shown in FIG. 1 H NMR pattern.

[0120] According to an embodiment of the present disclosure, crystalline form H has a variable-temperature XRPD pattern essentially as shown in FIG. 8D.

[0121] The present disclosure further provides crystalline Form I of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline Form I has one, two, more or all characteristic peaks located at 2θ values ​​selected from 4.45°±0.20°, 13.35°±0.20°, and 17.82°±0.20°.

[0122] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline Form I has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 4.45°±0.20°, 13.35°±0.20°, 17.15°±0.20°, 17.82°±0.20°, 22.32°±0.20°, 23.82°±0.20°, and 25.70°±0.20°.

[0123] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystalline form I has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0124] [Table 10]

[0125] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form I has one, two, more or all of the characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0126] According to an embodiment of the present disclosure, the crystalline form I has an X-ray powder diffraction pattern essentially as shown in FIG.

[0127] The present disclosure further provides crystalline form J of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form J has one, two or all characteristic peaks located at 2θ values ​​selected from 4.22°±0.20°, 7.15°±0.20°, and 25.24°±0.20°.

[0128] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form J has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°, and 25.24°±0.20°.

[0129] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystalline form J has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0130] [Table 11]

[0131] According to embodiments of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form J has one, two, more, or all characteristic peaks selected from the above 2θ values, it optionally also has the relative intensities corresponding to the characteristic peaks.

[0132] According to an embodiment of the present disclosure, the crystalline form J has an X-ray powder diffraction pattern essentially as shown in FIG. 10A.

[0133] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form J has an endothermic peak with 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.

[0134] According to an embodiment of the present disclosure, the crystalline form J has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 10B.

[0135] According to embodiments of the present disclosure, crystalline form J exhibits a weight loss of about 1.4% to about 1.5% (e.g., about 1.41%) when heated from room temperature to 100°C, and a weight loss of about 3.3% to about 3.4% (e.g., about 3.38%) when heated from 100°C to 200°C in thermogravimetric analysis (TGA).

[0136] According to an embodiment of the present disclosure, the crystalline form J has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 10B.

[0137] According to an embodiment of the present disclosure, the crystalline form J is a 1,4-dioxane solvate.

[0138] According to an embodiment of the present disclosure, the crystalline form J is essentially as shown in FIG. 10C 1 H NMR pattern.

[0139] According to an embodiment of the present disclosure, crystalline form J has a variable-temperature XRPD pattern essentially as shown in FIG. 10D.

[0140] The present disclosure further provides crystalline form K of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form K has one, two or all characteristic peaks located at 2θ values ​​selected from 4.19°±0.20°, 6.48°±0.20°, 6.95°±0.20°, and 19.54°±0.20°.

[0141] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form K has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°.

[0142] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystalline form K has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0143] [Table 12]

[0144] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form K has one, two, more, or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0145] According to an embodiment of the present disclosure, the crystalline form K has an X-ray powder diffraction pattern essentially as shown in FIG. 11A.

[0146] According to an embodiment of the present disclosure, the crystalline form K has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 11B.

[0147] According to an embodiment of the present disclosure, the crystalline form K has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 11B.

[0148] According to an embodiment of the present disclosure, the crystalline form K is essentially as shown in FIG. 1 H NMR pattern.

[0149] The present disclosure further provides crystalline form L of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form L has one, two or all characteristic peaks located at 2θ values ​​selected from 18.85°±0.20°, 22.30°±0.20°, and 29.35°±0.20°.

[0150] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form L has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°, and 29.35°±0.20°.

[0151] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form L has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0152] [Table 13]

[0153] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of crystalline form L has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0154] According to an embodiment of the present disclosure, crystalline form L has an X-ray powder diffraction pattern essentially as shown in FIG. 12A.

[0155] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form L has an endothermic peak with 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.

[0156] According to an embodiment of the present disclosure, the crystalline form L has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 12B.

[0157] According to an embodiment of the present disclosure, the crystalline form L exhibits a thermogravimetric analysis (TGA) weight loss of about 8.9% to about 9.0% (e.g., about 8.98%) when heated from room temperature to 100°C, a weight loss of about 2.5% to about 2.6% (e.g., about 2.56%) when heated from 100°C to 125°C, and a weight loss of about 1.8% to about 1.9% (e.g., about 1.81%) when heated from 125°C to 150°C.

[0158] According to an embodiment of the present disclosure, the crystalline form L has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 12B.

[0159] According to an embodiment of the present disclosure, the crystalline form L is a methanol-water cosolvate.

[0160] According to an embodiment of the present disclosure, the crystalline form L is essentially as shown in FIG. 12C 1 H NMR pattern.

[0161] According to an embodiment of the present disclosure, the single crystal of crystalline form L has the asymmetric unit schematic of the single crystal structure shown in Figure 12D.

[0162] According to an embodiment of the present disclosure, the crystalline form L has the following structural parameters:

[0163] [Table 14]

[0164] The present disclosure further provides crystalline form M of compound of formula (I), wherein the X-ray powder diffraction pattern of crystalline form M has one, two or all characteristic peaks located at 2θ values ​​selected from 4.22°±0.20°, 18.59°±0.20°, and 25.31°±0.20°.

[0165] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form M has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°.

[0166] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form M has the following characteristic peaks:

[0167] [Table 15]

[0168] According to embodiments of the present disclosure, when the X-ray powder diffraction pattern of crystalline form M has one, two, more, or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0169] According to an embodiment of the present disclosure, the crystalline form M has an X-ray powder diffraction pattern essentially as shown in FIG. 13A.

[0170] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of 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.

[0171] According to an embodiment of the present disclosure, the crystalline form M has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 13B.

[0172] According to embodiments of the present disclosure, crystalline Form M exhibits a weight loss of about 2.0% to about 2.1% (e.g., about 2.05%) when heated from room temperature to 200°C in thermogravimetric analysis (TGA).

[0173] According to an embodiment of the present disclosure, the crystalline form M has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 13B.

[0174] According to an embodiment of the present disclosure, the crystalline form M is a hydrate.

[0175] The present disclosure further provides crystalline form N of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form N has one, two or all characteristic peaks located at 2θ values ​​selected from 5.82°±0.20°, 13.96°±0.20°, and 20.24°±0.20°.

[0176] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form N has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°, and 20.24°±0.20°.

[0177] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystalline form N has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0178] [Table 16]

[0179] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form N has one, two, more, or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0180] According to an embodiment of the present disclosure, the crystalline form N has an X-ray powder diffraction pattern essentially as shown in FIG. 14A.

[0181] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form N has an endothermic peak with an onset temperature of about 118.0°C and / or a peak temperature of about 125.9°C.

[0182] According to an embodiment of the present disclosure, the crystalline form N has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 14B.

[0183] According to an embodiment of the present disclosure, the crystalline form N exhibits a weight loss of about 0.1% to about 0.2% (e.g., about 0.19%) when heated from room temperature to 200°C in thermogravimetric analysis (TGA).

[0184] According to an embodiment of the present disclosure, the crystalline form N has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 14B.

[0185] According to an embodiment of the present disclosure, the crystalline form N is an anhydrous crystalline form.

[0186] According to an embodiment of the present disclosure, the crystalline form N is essentially as shown in FIG. 14C 1 H NMR pattern.

[0187] According to an embodiment of the present disclosure, the crystalline form N has a variable-temperature XRPD pattern essentially as shown in FIG. 14D.

[0188] The present disclosure further provides crystalline form O of compound of formula (I), wherein the X-ray powder diffraction pattern of crystalline form O has one, two or all characteristic peaks located at 2θ values ​​selected from 11.06°±0.20°, 24.85°±0.20°, and 26.44°±0.20°.

[0189] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form O has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°.

[0190] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form O has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0191] [Table 17]

[0192] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of crystalline form O has one, two, more, or all characteristic peaks selected from the above 2θ values, it also optionally has relative intensities corresponding to the characteristic peaks.

[0193] According to an embodiment of the present disclosure, crystalline form O has an X-ray powder diffraction pattern essentially as shown in FIG. 15A.

[0194] According to an embodiment of the present disclosure, the differential scanning calorimetry (DSC) pattern of crystalline form O has endothermic peaks at peak temperatures of about 174.7°C and about 187.1°C.

[0195] According to an embodiment of the present disclosure, the crystalline form O has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 15B.

[0196] According to an embodiment of the present disclosure, the crystalline form O exhibits a weight loss of about 4.0% to about 4.1% (e.g., about 4.03%) when heated from room temperature to 150°C, and a weight loss of about 1.5% to about 1.7% (e.g., about 1.60%) when heated from 150°C to 200°C in thermogravimetric analysis (TGA).

[0197] According to an embodiment of the present disclosure, the crystalline form O has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 15B.

[0198] According to an embodiment of the present disclosure, the crystalline form O is a methanol solvate.

[0199] According to an embodiment of the present disclosure, the crystalline form O is essentially as shown in FIG. 15C 1 H NMR pattern.

[0200] According to an embodiment of the present disclosure, crystalline form O has a variable-temperature XRPD pattern essentially as shown in FIG. 15D.

[0201] The present disclosure further provides crystalline form P of compound of formula (I), wherein the X-ray powder diffraction pattern of crystalline form P has one, two or all characteristic peaks located at 2θ values ​​selected from 6.36°±0.20°, 16.15°±0.20°, and 21.05°±0.20°.

[0202] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form P has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°.

[0203] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form P has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0204] [Table 18]

[0205] According to embodiments of the present disclosure, when the X-ray powder diffraction pattern of crystalline form P has one, two, more, or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0206] According to an embodiment of the present disclosure, the crystalline form P has an X-ray powder diffraction pattern essentially as shown in FIG. 16A.

[0207] According to an embodiment of the present disclosure, the crystalline form P is a hydrate.

[0208] The present disclosure further provides crystalline form Q of compound of formula (I), wherein the X-ray powder diffraction pattern of said crystalline form Q has one, two or all characteristic peaks located at 2θ values ​​selected from 18.41°±0.20°, 25.19°±0.20°, and 26.36°±0.20°.

[0209] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form Q has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 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°, and 26.36°±0.20°.

[0210] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystalline form Q has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0211] [Table 19]

[0212] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form Q has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0213] According to an embodiment of the present disclosure, the crystalline form Q has an X-ray powder diffraction pattern essentially as shown in FIG.

[0214] According to an embodiment of the present disclosure, the crystalline form Q is an anhydrous crystalline form.

[0215] The present disclosure further provides crystalline form R of compound of formula (I), wherein the X-ray powder diffraction pattern of crystalline form R has one, two or all characteristic peaks located at 2θ values ​​selected from 7.22°±0.20°, 13.03°±0.20°, and 18.81°±0.20°.

[0216] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form R has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 7.22°±0.20°, 13.03°±0.20°, 18.81°±0.20°, and 19.15°±0.20°.

[0217] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of the crystalline form R has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0218] [Table 20]

[0219] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form R has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0220] According to an embodiment of the present disclosure, the crystalline form R has an X-ray powder diffraction pattern essentially as shown in Figure 22A.

[0221] According to an embodiment of the present disclosure, the crystalline form R is an anhydrous crystalline form.

[0222] The present disclosure further provides crystalline form S of compound of formula (I), wherein the X-ray powder diffraction pattern of crystalline form S has one, two or all characteristic peaks located at 2θ values ​​selected from 6.30°±0.20°, 16.11°±0.20°, and 21.01°±0.20°.

[0223] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form S has one, two, more, or all characteristic peaks located at 2θ values ​​selected from 6.30°±0.20°, 11.06°±0.20°, 16.11°±0.20°, and 21.01°±0.20°.

[0224] According to an embodiment of the present disclosure, the X-ray powder diffraction pattern of crystalline form S has one, two, more, or all characteristic peaks located at 2θ values ​​selected from the following:

[0225] [Table 21]

[0226] According to an embodiment of the present disclosure, when the X-ray powder diffraction pattern of the crystalline form S has one, two, more or all characteristic peaks selected from the above 2θ values, it also optionally has the relative intensities corresponding to the characteristic peaks.

[0227] According to an embodiment of the present disclosure, crystalline form S has an X-ray powder diffraction pattern essentially as shown in FIG.

[0228] According to an embodiment of the present disclosure, the crystalline form S is a hydrate.

[0229] The present disclosure further provides crystalline Form T of the maleate salt of compound of Formula (I), wherein said crystalline Form T has an X-ray powder diffraction pattern essentially as shown in Figure 24A.

[0230] The present disclosure further provides crystalline form U of the methanesulfonate salt of compound of Formula (I), wherein said crystalline form U has an X-ray powder diffraction pattern essentially as shown in Figure 25A.

[0231] In the context of this specification, any data such as X-ray powder diffraction patterns or 2θ values ​​of the above crystalline forms were obtained using Cu target radiation.

[0232] The present disclosure further provides a method for preparing crystalline form A, which comprises dissolving compound of formula (I) (e.g., its amorphous form, e.g., amorphous form Z) in a mixed solvent of ethyl acetate and dichloromethane, and volatilizing the resulting solution at room temperature to obtain crystalline form A. Preferably, in the method for preparing crystalline form A, the volume ratio of ethyl acetate to dichloromethane may be 1:1 to 20:1, for example, 9:1.

[0233] The present disclosure further provides a method for preparing the crystalline form A, which comprises heating the crystalline form G to 150°C, cooling to room temperature, and exposing to air to obtain the crystalline form A.

[0234] The present disclosure further provides a method for preparing the crystalline form A, which comprises drying the crystalline form I at room temperature to obtain the crystalline form A.

[0235] The present disclosure further provides a method for preparing crystalline form L, which comprises mixing the compound of formula (I) (e.g., its amorphous form) with a mixed solvent of methanol and water to obtain a solution, and evaporating the resulting solution at room temperature to obtain crystalline form L. Preferably, in the method for preparing crystalline form L, the volume ratio of methanol to water may be 1:1 to 20:1, for example, 4:1.

[0236] The present disclosure further provides a method for preparing crystalline form B, which comprises stirring crystalline form L in acetone to obtain crystalline form B. Preferably, the mass / volume ratio of crystalline form L to acetone is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL. Preferably, the stirring is performed at 50 to 70°C, for example, 60°C.

[0237] The present disclosure further provides a method for preparing crystalline form C, which comprises stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and then mixing the separated solid with water and stirring to obtain crystalline form C. Preferably, the mass / volume ratio of crystalline form L to acetone may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL, and the mass / volume ratio of crystalline form L to water may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL.

[0238] Preferably, the stirring of crystalline form L in acetone is first carried out at 50 to 70° C., for example, 60° C., and then at 0 to 5° C. When the separated solid is further stirred in water, it is stirred at room temperature.

[0239] Alternatively, crystalline form L may be stirred in a mixed solvent of acetone and water, in which the volume ratio of acetone to water is (1-2):1, for example, 1.5:1.

[0240] Alternatively, a wet sample of crystalline form P is dried in air to give crystalline form C.

[0241] The present disclosure further provides a method for preparing crystalline form D, which comprises stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and then stirring the separated solid in a mixed solvent of acetone and water to obtain crystalline form D. Preferably, the mass / volume ratio of crystalline form L to acetone may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL, and the mass / volume ratio of crystalline form L to the mixed solvent of acetone and water may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL. Preferably, the volume ratio of acetone to water in the mixed solvent of acetone and water may be (5-7):1, for example, 1.5:1.

[0242] Preferably, the stirring of crystalline form L in acetone is first carried out at 50 to 70° C., for example, 60° C., and then at 0 to 5° C. When the separated solid is further stirred in a mixed solvent of acetone and water, the stirring is carried out at room temperature.

[0243] Alternatively, crystalline form L may be stirred in a mixed solvent of acetone and water, in which the volume ratio of acetone to water is (3-6):1, for example, 4:1.

[0244] The present disclosure further provides a method for preparing crystalline form E, which comprises stirring crystalline form L in methanol to obtain crystalline form E. Preferably, the stirring is performed at room temperature. Preferably, the mass / volume ratio of crystalline form L to methanol may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL.

[0245] The present disclosure further provides a method for preparing crystalline form F, which comprises stirring compound of formula (I) (e.g., its amorphous form) in a mixed solvent of acetone and ethanol to obtain crystalline form F. Preferably, in the method for preparing crystalline form L, the volume ratio of acetone to ethanol may be 1:1.

[0246] The present disclosure further provides a method for preparing crystalline form G, which comprises stirring crystalline form L in acetone and further stirring the separated solid in acetonitrile to obtain crystalline form G. Preferably, the mass / volume ratio of crystalline form L to acetone may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL, and the mass / volume ratio of crystalline form L to acetonitrile may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL.

[0247] The present disclosure further provides a method for preparing crystalline form H, which comprises stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and subjecting the separated solid to gas-solid infiltration in a dichloromethane atmosphere to obtain crystalline form H. Preferably, the mass-volume ratio of crystalline form L to acetone is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL.

[0248] The present disclosure further provides a method for preparing the crystalline form I, which comprises dissolving the compound of formula (I) (e.g., its amorphous form) in N-methylpyrrolidone, adding an antisolvent such as acetonitrile, and allowing the mixture to stand at room temperature to precipitate a solid, thereby obtaining the crystalline form I. Preferably, the mass / volume ratio of the compound of formula (I) to N-methylpyrrolidone may be 20 mg:(1.0-1.5 mL). The mass / volume ratio of the compound of formula (I) to N-methylpyrrolidone may be 20 mg:(3-5 mL), for example, 20 mg:4 mL.

[0249] The present disclosure further provides a method for preparing crystalline form J, which comprises stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and then mixing the separated solid with 1,4-dioxane, followed by stirring at 50°C and further stirring at room temperature to obtain crystalline form J. Preferably, the mass-volume ratio of crystalline form L to acetone may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL. The mass-volume ratio of crystalline form L to 1,4-dioxane may be 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL.

[0250] The present disclosure further provides a method for preparing crystalline form M, which comprises heating crystalline form D to 150°C, then cooling to room temperature, and exposing to air for 10 minutes to obtain crystalline form M.

[0251] The present disclosure further provides a method for preparing crystalline form M, which comprises heating crystalline form F to 160°C, cooling to room temperature, and exposing to air to obtain crystalline form M.

[0252] The present disclosure further provides a method for preparing the crystalline form M, which comprises heating a sample of crystalline form O to 175°C to obtain crystalline form M.

[0253] The present disclosure further provides a method for preparing the crystalline form M, which comprises exposing the crystalline form Q to room temperature and humidity conditions to obtain the crystalline form M.

[0254] The present disclosure further provides a method for preparing the above-mentioned crystalline form N, which comprises heating the crystalline form E to 100°C, then cooling to room temperature, and exposing to air to obtain the crystalline form N.

[0255] The present disclosure further provides a method for preparing crystalline form O, which comprises dissolving compound of formula (I) (e.g., its amorphous form, e.g., amorphous form Z) in a mixed solvent of methanol and water, and volatilizing at room temperature to obtain crystalline form O. Preferably, the volume ratio of methanol to water in the mixed solvent of methanol and water may be (3-5):1, for example, 4:1.

[0256] The present disclosure further provides a method for preparing crystalline form P, which comprises stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and separating the solid, which is then slurried in a mixed solvent of MEK, THF, and HO to obtain crystalline form P. Preferably, the volume ratio of MEK, THF, and HO in the mixed solvent of MEK, THF, and HO may be 1:0.1:2.

[0257] The present disclosure further provides a method for preparing the above crystalline form Q, which includes purging the crystalline form D with N2 for 20 minutes, heating the sample to 150°C, and then cooling it to 30°C to obtain the crystalline form Q.

[0258] The present disclosure further provides a method for preparing crystalline form R, which includes mixing compound of Formula (I) (e.g., an amorphous substance, e.g., amorphous substance Z) in a mixed solvent of dichloromethane and acetone, dissolving and clarifying the compound, concentrating under reduced pressure until dry, adding acetone, dissolving and clarifying the compound by heating, adding water, allowing the mixture to cool to room temperature, stirring, and filtering to obtain crystalline form R. Preferably, the volume ratio of dichloromethane to acetone in the mixed solvent of dichloromethane and acetone is 3:1 to 9:1, for example, 6:1. Preferably, the volume ratio of acetone added after concentrating under reduced pressure until dry and acetone in the mixed solvent of dichloromethane and acetone is 1:1 to 1:1.5, for example, 4:5. Preferably, the volume ratio of water added after concentrating under reduced pressure until dry and acetone added after concentrating under reduced pressure until dry is 0.5:1 to 1:1, for example, 0.75:1. Preferably, the mass / volume ratio of the compound of formula (I) to the mixed solvent of dichloromethane and acetone may be 1 mg:(0.3 to 0.5) mL, for example, 1 mg:0.35 mL.

[0259] The present disclosure further provides a method for preparing crystalline form S, which comprises mixing the compound of formula (I) (e.g., an amorphous substance, e.g., amorphous substance Z) with 1,4-dioxane, dissolving and clarifying the mixture, adding water to precipitate a solid, filtering, and drying to obtain crystalline form S. Preferably, the volume ratio of 1,4-dioxane to water is 1:2 to 1:3, e.g., 1:2.2. Preferably, the mass-volume ratio of the compound of formula (I) to 1,4-dioxane may be 1 mg:(0.08 to 0.15) mL, e.g., 1 mg:0.11 mL.

[0260] The present disclosure further provides a method for preparing crystalline form T, which includes mixing the compound of Formula (I) (e.g., an amorphous substance, e.g., amorphous substance Z) with chloroform to obtain solution 1, mixing maleic acid with ethanol to obtain solution 2, mixing solution 2 with solution 1, adding methyl tert-butyl ether, stirring, centrifuging, and drying to obtain crystalline form T. Preferably, the mass / volume ratio of the compound of Formula (I) to chloroform may be 1 g:(12-20) mL, for example, 1 g:(14-15) mL. Preferably, the mass / volume ratio of the compound of Formula (I) to maleic acid may be (9-10):1. Preferably, the mass / volume ratio of the compound of Formula (I) to ethanol may be 1 g:(1-4) mL, for example, 1 g:2 mL. Preferably, the volume ratio of solution 2 to solution 1 may be 1:(1.2-1.3). Preferably, the volume ratio of the total amount of chloroform to methyl tert-butyl ether may be (11-12):1.

[0261] The present disclosure further provides a method for preparing crystalline form U, which includes mixing a compound of Formula (I) (e.g., an amorphous substance, e.g., amorphous substance Z) with chloroform to obtain solution 1, mixing methanesulfonic acid with chloroform to obtain solution 2, mixing solution 2 with solution 1, stirring, and drying to obtain crystalline form U. Preferably, the mass / volume ratio of the compound of Formula (I) to chloroform in solution 1 may be 1 g:(12-20) mL, for example, 1 g:(14-15) mL. Preferably, the mass / volume ratio of the compound of Formula (I) to methanesulfonic acid may be (9-10):1. Preferably, the mass / volume ratio of the compound of Formula (I) to chloroform in solution 2 may be 1 g:(1-4) mL, for example, 1 g:2 mL. Preferably, the volume ratio of solution 2 to solution 1 may be 1:(1.3-1.4).

[0262] The present disclosure further provides a mixture, wherein the mixture comprises at least one, for example one, two, three or more solid forms selected from the solid forms of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and preferably comprises at least one, two, three or more solid forms 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 and U).

[0263] According to an embodiment of the present disclosure, the mixture contains one, two, three or more selected from crystalline form A and crystalline forms B to U, preferably one, two, three or more selected from crystalline form A and crystalline forms B to U.

[0264] According to an embodiment of the present disclosure, based on the total weight of compound of formula (I) in the mixture, the weight percentage content of crystalline form A is 80% or more, such as 90% or more, preferably 95% or more, such as 98% or more, more preferably 99% or more, such as 99.5% or more, 99.8% or more or 99.9% or more.

[0265] Those skilled in the art will appreciate that any of the above mixtures may be obtained by physical co-mixing methods.

[0266] The present disclosure further provides a pharmaceutical composition, wherein the pharmaceutical composition comprises at least one solid form selected from the solid forms of the compound of formula (I) or a pharmaceutically acceptable salt thereof, preferably one, two, three or more selected from crystalline forms A to U, or the pharmaceutical composition comprises a mixture thereof.

[0267] Alternatively, the pharmaceutical composition comprises the mixture.

[0268] According to embodiments of the present disclosure, the pharmaceutical composition may further comprise a pharmaceutically acceptable adjuvant.

[0269] According to an embodiment of the present disclosure, the pharmaceutical composition further comprises at least one, eg, one, two, three or more, additional therapeutic agents.

[0270] The present disclosure further provides uses of a solid form of the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the use is at least one, for example one, two, three or more, selected from the following uses:

[0271] Use for inhibiting cell proliferation in vitro or in vivo; or Use for treating a RET kinase mediated disease, or Use for inhibiting RET kinase activity, or Use for treating cancer and / or inhibiting metastasis associated with certain cancers; or for treating irritable bowel syndrome (IBS) or pain associated with IBS; or Use for providing supportive care to cancer patients, where the supportive care includes preventing or minimizing gastrointestinal symptoms such as diarrhea associated with treatment (including chemotherapy treatment); or for use in treating a RET-related disease or condition; or Use for reversing or preventing acquired resistance to anticancer drugs; or Use for delaying and / or preventing the development of anti-cancer drug resistance in an individual; or Use for treating individuals who have cancer and are at increased risk of developing resistance to anti-cancer drugs.

[0272] The present disclosure further provides a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with at least one selected from the solid forms described above, preferably at least one selected from among crystalline forms A through U, such as crystalline form A and one, two, three or more selected from crystalline forms B through U.

[0273] The present disclosure further provides a method of treating a RET kinase-mediated disease, said method comprising administering to a patient at least one selected from the solid forms described above, preferably at least one selected from crystalline forms A through U, e.g., one comprising crystalline form A and one, two, three or more selected from crystalline forms B through U.

[0274] The present disclosure further provides a method of treating a RET-associated disease or condition in a patient in need thereof, said method comprising administering to said patient at least one selected from the solid forms described above, preferably at least one selected from crystalline forms A through U, for example, a solid form comprising crystalline form A and one, two, three or more selected from crystalline forms B through U.

[0275] The present disclosure further provides a method of treating cancer and / or inhibiting metastasis associated with certain cancers in a patient in need thereof, said method comprising administering to said patient at least one selected from the solid forms described above, preferably at least one selected from among crystalline forms A through U, such as crystalline form A and one, two, three or more selected from crystalline forms B through U.

[0276] The present disclosure further provides a method of treating irritable bowel syndrome (IBS) and / or IBS-associated pain in a patient in need thereof, said method comprising administering to said patient at least one solid form selected from the above, preferably at least one selected from crystalline forms A through U, such as one comprising crystalline form A and one, two, three or more selected from crystalline forms B through U.

[0277] The present disclosure further provides a method of providing supportive care to a cancer patient, including preventing or minimizing gastrointestinal disorders (e.g., diarrhea) associated with treatment (including chemotherapy treatment), said method comprising administering to the patient at least one solid form selected from the above, preferably at least one selected from among crystalline forms A through U, such as crystalline form A and one, two, three or more selected from crystalline forms B through U.

[0278] The present disclosure further provides the use of at least one solid form selected from the above, preferably at least one selected from crystalline forms A to U, such as crystalline form A and one, two, three or more selected from crystalline forms B to U, in the manufacture of a medicament for treating a RET kinase-mediated disease.

[0279] The present disclosure further provides the use of at least one solid form selected from the above, preferably at least one selected from crystalline forms A to U, such as crystalline form A and one, two, three or more selected from crystalline forms B to U, in the manufacture of a medicament for treating cancer and / or inhibiting metastasis associated with certain cancers.

[0280] The present disclosure further provides the use of at least one solid form selected from the above, preferably at least one selected from crystalline forms A to U, such as crystalline form A and one, two, three or more selected from crystalline forms B to U, in the manufacture of a medicament for treating irritable bowel syndrome (IBS) or pain associated with IBS.

[0281] The present disclosure further provides the use of at least one solid form selected from the above, preferably at least one selected from among crystalline forms A to U, such as comprising crystalline form A and one, two, three or more selected from crystalline forms B to U, in the manufacture of a medicament for providing supportive care to a cancer patient, wherein the supportive care includes preventing or minimizing gastrointestinal symptoms such as diarrhea associated with treatment (including chemotherapy treatment).

[0282] The present disclosure further provides the use of at least one solid form selected from the above, preferably at least one selected from crystalline forms A to U, such as crystalline form A and one, two, three or more selected from crystalline forms B to U, in the manufacture of a medicament for inhibiting RET kinase activity.

[0283] The present disclosure further provides the use of at least one solid form selected from the above, preferably at least one selected from crystalline forms A to U, such as crystalline form A and one, two, three or more selected from crystalline forms B to U, in the manufacture of a medicament for treating a RET-related disease or condition.

[0284] The present disclosure further provides a method for treating cancer in a patient in need thereof, the method comprising: (a) determining whether the cancer is associated with dysregulation of expression, activity or levels of the RET gene, RET kinase, or any one of them (e.g., a RET-associated cancer); and (b) if the cancer is determined to be associated with dysregulation of expression, activity or levels of the RET gene, RET kinase, or any one of them (e.g., a RET-associated cancer), administering to the patient at least one solid form selected from the above solid forms, preferably at least one selected from crystalline forms A to U, for example, one, two, three or more selected from crystalline forms A and B to U.

[0285] The present disclosure further provides a method for reversing or preventing acquired resistance to an anti-cancer drug, said method comprising administering at least one solid form selected from the above, preferably at least one selected from among crystalline forms A through U, such as comprising crystalline form A and one, two, three or more selected from crystalline forms B through U, to a patient at risk of developing or having acquired resistance to other anti-cancer drugs.

[0286] The present disclosure further provides a method for delaying and / or preventing the development of anti-cancer drug resistance in an individual, said method comprising administering to the individual at least one solid form selected from the above-mentioned solid forms, preferably at least one selected from crystalline forms A to U, such as crystalline form A and one, two, three or more selected from crystalline forms B to U, and administering before, during or after the administration of another anti-cancer drug.

[0287] The present disclosure further provides a method of treating an individual afflicted with cancer and having an increased likelihood of developing resistance to an anti-cancer agent, comprising co-administering to the individual (a) at least one solid form selected from the above, preferably at least one selected from among crystalline forms A through U, such as one comprising crystalline form A and one, two, three or more selected from crystalline forms B through U, and (b) another anti-cancer agent.

[0288] The present disclosure further provides a method of treating an individual suffering from a RET-associated cancer, comprising administering at least one selected from the above solid forms, preferably at least one selected from crystalline forms A to U, for example, one, two, three or more selected from crystalline forms A and B to U, before, during or after administration of another anti-cancer agent, wherein the cancer has one or more RET inhibitor-resistant mutations, which increase the resistance of the cancer to a RET inhibitor other than at least one of the compound of Formula I or a pharmaceutically acceptable salt thereof (e.g., substitutions at amino acid positions 804, 810, 904, e.g., V804M, V804L, V804E, G810R, G810S, G810C, G810V, S904F).

[0289] The present disclosure further provides a method of treating an individual suffering from a RET-associated cancer, said method comprising administering at least one selected from the above solid forms, preferably at least one selected from crystalline forms A through U, such as one comprising crystalline form A and one, two, three or more selected from crystalline forms B through U, before, during or after administration of another anti-cancer agent.

[0290] The present disclosure provides a method of treating cancer (e.g., a RET-associated cancer) in a patient in need thereof, said method comprising administering to said patient at least one selected from the solid forms described above, preferably at least one selected from among crystalline forms A through U, e.g., comprising crystalline form A and one, two, three or more selected from crystalline forms B through U.

[0291] According to embodiments of the present disclosure, when at least one selected from the above solid forms, preferably at least one selected from crystalline forms A to U, e.g., comprising one, two, three or more selected from crystalline form A and crystalline forms B to U, is used in treatment, administration or manufacture of a medicament, the amount of the solid form (e.g., comprising at least one from crystalline forms A to U, e.g., comprising one, two, three or more selected from crystalline form A and crystalline forms B to U) used is preferably a therapeutically effective amount. [Effects of the Invention]

[0292] The solid forms of the fused ring compounds provided by the present disclosure have not been disclosed or suggested in the prior art and provide a more advantageous pharmaceutically acceptable form for the compound of formula (I). The solid forms provided by the present disclosure, particularly crystalline form A, have excellent physicochemical and pharmacokinetic properties, which are advantageous for improving formulation properties and shelf life, resulting in more beneficial therapeutic effects for patients. [Brief explanation of the drawings]

[0293] [Figure 1A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form A of the present disclosure. [Figure 1B] 1 is a differential scanning calorimetry (DSC) pattern of crystalline form A of the present disclosure. [Figure 1C] 1 is a thermogravimetric analysis (TGA) pattern of crystalline form A of the present disclosure. [Figure 1D] 1 is a 1H NMR pattern of crystalline form A of the present disclosure. [Figure 2A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form B of the present disclosure. [Figure 2B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form B of the present disclosure. [Figure 2C] 1 is a 1H NMR pattern of crystalline form B of the present disclosure. [Figure 3A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form C of the present disclosure. [Figure 3B]1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form C of the present disclosure. [Figure 3C] 1 is a H NMR pattern of crystalline form C of the present disclosure. [Figure 4A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form D of the present disclosure. [Figure 4B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form D of the present disclosure. [Figure 4C] 1 is a 1H NMR pattern of crystalline form D of the present disclosure. [Figure 4D] 1 is a variable temperature XRPD overlay of crystalline form D of the present disclosure. [Figure 5A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form E of the present disclosure. [Figure 5B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form E of the present disclosure. [Figure 5C] 1 is a 1H NMR pattern of crystalline form E of the present disclosure. [Figure 5D] FIG. 1 is a variable temperature XRPD overlay of crystalline form E of the present disclosure. [Figure 5E] 1 is a H NMR pattern of crystalline form E of the present disclosure after heating. [Figure 6A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form F of the present disclosure. [Figure 6B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form F of the present disclosure. [Figure 6C] 1 is a H NMR pattern of crystalline form F of the present disclosure. [Figure 6D] FIG. 1 is a variable temperature XRPD overlay of crystalline form F of the present disclosure. [Figure 6E] 1 is a H NMR pattern of crystalline form F of the present disclosure after heating. [Figure 7A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form G of the present disclosure. [Figure 7B]1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form G of the present disclosure. [Figure 7C] 1 is a H NMR pattern of crystalline form G of the present disclosure. [Figure 7D] 1 is a H NMR pattern of crystalline form G of the present disclosure after heating. [Figure 8A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form H of the present disclosure. [Figure 8B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form H of the present disclosure. [Figure 8C] 1 is a 1H NMR pattern of crystalline form H of the present disclosure. [Figure 8D] FIG. 1 is a variable temperature XRPD overlay of crystalline form H of the present disclosure. [Figure 9] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline Form I of the present disclosure. [Figure 10A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form J of the present disclosure. [Figure 10B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form J of the present disclosure. [Figure 10C] 1 is a H NMR pattern of crystalline form J of the present disclosure. [Figure 10D] 1 is a variable temperature XRPD overlay of crystalline form J of the present disclosure. [Figure 10E] 1 is a H NMR pattern of crystalline form J of the present disclosure after heating. [Figure 11A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form K of the present disclosure. [Figure 11B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form K of the present disclosure. [Figure 11C] 1 is a H NMR pattern of crystalline form K of the present disclosure. [Figure 11D] 12 is an XRPD overlay of crystalline forms obtained by repeating the method of Example 12. [Figure 12A]1 is an X-ray powder diffraction (XRPD) pattern of crystalline form L of the present disclosure. [Figure 12B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form L of the present disclosure. [Figure 12C] 1 is a 1H NMR pattern of crystalline form L of the present disclosure. [Figure 12D] FIG. 1 is a schematic diagram of the asymmetric unit of the single crystal structure of crystalline form L of the present disclosure. [Figure 13A] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form M of the present disclosure. [Figure 13B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form M of the present disclosure. [Figure 14A] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form N of the present disclosure. [Figure 14B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form N of the present disclosure. [Figure 14C] 1 is a 1H NMR pattern of crystalline form N of the present disclosure. [Figure 14D] 1 is a variable temperature XRPD overlay of crystalline form N of the present disclosure. [Figure 15A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form O of the present disclosure. [Figure 15B] 1 is a differential scanning calorimetry (DSC) pattern and a thermogravimetric analysis (TGA) pattern of crystalline form O of the present disclosure. [Figure 15C] 1 is a H NMR pattern of crystalline form O of the present disclosure. [Figure 15D] FIG. 1 is a variable temperature XRPD overlay of crystalline form O of the present disclosure. [Figure 15E] 1 is a H NMR pattern of crystalline form O of the present disclosure after heating. [Figure 16A] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form P of the present disclosure. [Figure 16B] 1 is an XRPD overlay of crystalline form P of the present disclosure before and after drying. [Figure 17]FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form Q of the present disclosure. [Figure 18] 1 shows the DVS pattern of crystalline form A in the hygroscopicity test of Test Example 1. [Figure 19] 1 shows the DVS pattern of crystalline form B in the hygroscopicity test of Test Example 1. [Figure 20A] 1 is an XRPD overlay of the solids after suspension competition in Test Example 4. [Figure 20B] 1 is an XRPD overlay of the solids after suspension competition in Test Example 4. [Figure 21A] 1 is an X-ray powder diffraction (XRPD) pattern of amorphous substance Z of compound of formula (I) in Example 1. [Figure 21B] 1 is a differential scanning calorimetry (DSC) pattern of amorphous substance Z of compound of formula (I) in Example 1. [Figure 21C] 1 is a thermogravimetric analysis (TGA) pattern of amorphous substance Z of compound of formula (I) in Example 1. [Figure 22A] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form R of the present disclosure. [Figure 22B] 1 shows a DVS test pattern of crystalline form R in Test Example 1. [Figure 22C] 1 is an isothermal adsorption graph of crystalline form R in Test Example 1. [Figure 23] FIG. 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form S of the present disclosure. [Figure 24A] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form T of the present disclosure. [Figure 24B] 1 is a 1H NMR pattern of crystalline form T of the present disclosure. [Figure 25A] 1 is an X-ray powder diffraction (XRPD) pattern of crystalline form U of the present disclosure. [Figure 25B] 1 is a 1H NMR pattern of crystalline form U of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0294] The technical solutions of the present disclosure will be described in more detail below with reference to specific examples. The following examples are merely for illustrative purposes and are not to be construed as limiting the scope of the claims of the present disclosure. Any technology realized based on the above content of the present disclosure is included within the scope of the claims of the present disclosure.

[0295] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or may be prepared by known methods.

[0296] Unless otherwise specified, the following examples employ the following instruments and measurement methods.

[0297] I. Inspection equipment and methods X-ray powder diffraction (XRPD) XRPD results are from PANalytical Empyrean and X'Pert 3 The data were collected using an X-ray powder diffraction analyzer, and the scan parameters are shown in the table below.

[0298] [Table 22]

[0299] Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) TGA and DSC patterns were collected on a TA Discovery 5500 thermogravimetric analyzer and a TA Discovery 2500 differential scanning calorimeter, respectively, and the scan parameters are shown in the table below.

[0300] [Table 23]

[0301] Dynamic Water Sorption (DVS) Dynamic moisture sorption (DVS) curves were collected with an SMS (Surface Measurement Systems) DVS Intrinsic. Relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. DVS test parameters are shown in the table below.

[0302] [Table 24]

[0303] Proton liquid nuclear magnetic resonance ( 1 H Solution NMR Proton liquid state nuclear magnetic resonance spectra were collected on a Bruker 400M nuclear magnetic resonance instrument using DMSO-d6 as the solvent.

[0304] II. Solvent Name Correspondence Table

[0305] [Table 25]

[0306] Example 1: Preparation of amorphous compound of formula (I)

[0307] [ka]

[0308] According to the method of Example 9 of PCT patent application PCT / CN2020 / 107049, 4-(6-(6-((6-methoxypyridin-3-)methylene)3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-1H-pyrazole[3',4':3,4]pyrazole[1,5-a]pyridin-6-ol (150 mg, 0.3 mmol) in DMF (10.0 mL) was added 2-iodoethane (47 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol), heated to 60 °C, and reacted for 12 hours. Water was added, extracted with ethyl acetate, and the organic phases were combined and washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by column chromatography, and the solvent was removed by rotary evaporation to obtain amorphous Z, the compound of formula (I) described in the present disclosure. The X-ray powder diffraction (XRPD) pattern of amorphous material Z is shown in FIG. 21A, the differential scanning calorimetry (DSC) pattern is shown in FIG. 21B, and the thermogravimetric analysis (TGA) pattern is shown in FIG. 21C.

[0309] Example 2: Preparation of anhydrous crystalline form A 20 mg of amorphous substance Z of compound of formula (I) prepared in Example 1 was placed in a 20 mL vial, and a mixed solvent of ethyl acetate and dichloromethane (9:1, v:v) was added to dissolve the solid. The solution was then filtered through a membrane filter. The resulting clear filtrate was sealed with a sealing film and pierced with five pinholes. The solution was allowed to slowly evaporate at room temperature. The solid obtained after evaporation was collected to obtain crystalline form A. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 1A, the differential scanning calorimetry (DSC) pattern measured after pre-heating the sample to remove surface-adsorbed solvent is shown in Figure 1B, and the thermogravimetric analysis (TGA) pattern is shown in Figure 1C. 1 The 1 H NMR pattern is shown in Figure 1D.

[0310] A sample of Form A was purged under N2 for 20 min, heated to 150°C, and cooled to 30°C. No change in the crystal form was observed. 1 According to the H NMR results, crystalline form A was analyzed to be an anhydrous crystalline form.

[0311] Example 3: Preparation of anhydrous crystalline form B 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, 0.5 mL of the solvent acetone was added, the resulting suspension was magnetically stirred (~750 rpm) at 60°C for about 6 days, and the solid was centrifuged to obtain crystalline form B. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 2A, and the differential scanning calorimetry (DSC) pattern and thermogravimetric analysis (TGA) pattern are shown in Figure 2B. 1 The 1 H NMR pattern is shown in Figure 2C.

[0312] 1 H NMR analysis revealed that a small amount of acetone (0.2 wt%) remained in the sample. TGA showed that the weight loss before decomposition was relatively small (0.5 wt%), and DSC showed no clear endothermic peak before melting. Based on these results, crystalline form B was determined to be an anhydrous crystalline form.

[0313] Example 4: Preparation of anhydrous crystalline form C 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, 0.5 mL of solvent acetone was added, and the mixture was stirred at room temperature for 30 min, heated to 60°C and stirred for 30 min, cooled to 0-5°C and stirred for 6 h. The solid was centrifuged, and 0.5 mL of solvent water was added. The resulting suspension was magnetically stirred (~750 rpm) at room temperature for approximately 2 weeks. The solid was centrifuged to obtain crystalline form C. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 3A, and the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns, measured after pre-heating the sample to remove surface-adsorbed solvent / water, are shown in Figure 3B. 1 The 1 H NMR pattern is shown in Figure 3C.

[0314] A sample of crystalline form C was purged under N2 for 20 min, heated to 100°C, and cooled to 30°C. No change in crystalline form was observed. 1According to the H NMR results, crystalline form C was analyzed to be an anhydrous crystalline form.

[0315] In addition, when the solvent in the above method was changed to a mixed solvent of acetone and water (6:4, v:v), crystalline form C was obtained in the same manner.

[0316] Example 5: Preparation of hydrate crystalline form D 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, 0.5 mL of acetone solvent was added, and the mixture was stirred at room temperature for 30 min, heated to 60°C and stirred for 30 min, cooled to 0-5°C and stirred for 6 h. The solid was centrifuged, and 0.5 mL of a mixed solvent of acetone and water (86:14, v:v) was added. The resulting suspension was magnetically stirred (~750 rpm) at room temperature for about 9 days. The solid was centrifuged to obtain crystalline form D. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 4A, and the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns are shown in Figure 4B. 1 The 1 H NMR pattern is shown in Figure 4C. 1 H NMR results showed that the sample of crystalline form D contained very little (~0.5 wt%) acetone residue.

[0317] In addition, when the solvent in the above method was changed to a mixed solvent of acetone and water (4:1, v:v), crystalline form D was obtained in the same manner.

[0318] Variable-temperature XRPD results (FIG. 4D) showed that when a sample of crystalline form D was purged under N2 protection for 20 min, changes in the diffraction peaks were observed. When the sample was heated to 150°C and cooled to 30°C, a change in the crystalline form was observed, and the resulting new crystalline form was crystalline form Q. After the sample was heated to 150°C, cooled to room temperature, and exposed to air, changes in some of the diffraction peaks were observed, and the resulting new crystalline form was crystalline form M. In line with the change in the crystalline form observed after purging and heating the sample of crystalline form D with N2, DSC results showed one relatively broad endothermic signal (peak temperature 63.7°C) before the melting peak, and 1H NMR results showed that the sample contained very little acetone residue (much less than the mass loss in TGA), and therefore crystalline form D was analyzed to be a hydrate.

[0319] Example 6: Preparation of methanol solvate crystalline form E 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, 0.5 mL of solvent MeOH was added, the resulting suspension was magnetically stirred at room temperature overnight, and the solid was centrifuged to obtain crystalline form E. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 5A, and the differential scanning calorimetry (DSC) pattern and thermogravimetric analysis (TGA) pattern are shown in Figure 5B. 1 The 1 H NMR pattern is shown in Figure 5C. 1 The H NMR results (FIG. 5C) showed that 2.5 wt % of MeOH was detected (the molar ratio of MeOH to the compound of formula (I) was 0.4:1).

[0320] Form E was identified by heating test, and the results are shown in Figure 5D. When Form E was heated to 48°C, cooled to room temperature, and exposed to air, no change in the crystalline form was observed. When the sample was heated to 100°C, cooled to room temperature, and exposed to air, a new crystalline form was observed, which was Form N. When the sample was subsequently heated to 115°C, cooled to room temperature, and exposed to air, an amorphous substance was observed to be formed. 1 Considering the H NMR results (Figure 5E, no obvious change in solvent content compared to before heating) and the TGA / DSC results comprehensively, the crystalline form was analyzed to be a MeOH solvate.

[0321] Example 7: Preparation of ethanol solvate crystalline form F 20 mg of amorphous substance Z prepared according to the method of Example 1 was weighed into an HPLC vial, and 0.5 mL of a mixed solvent of acetone and ethanol (1:1, v:v) was added. The resulting suspension was magnetically stirred (~750 rpm) at room temperature for about 4 days, and the solid was centrifuged to obtain crystalline form F. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 6A, and the differential scanning calorimetry (DSC) pattern and thermogravimetric analysis (TGA) pattern are shown in Figure 6B. 1 The 1 H NMR pattern is shown in Figure 6C.

[0322] 1 H NMR analysis detected approximately 2.1 wt% residual ethanol (the molar ratio of ethanol to compound of formula (I) was 0.23:1) and approximately 0.2 wt% residual acetone. Crystalline form F was identified by a heating test, and the results are shown in Figure 6D. When crystal form F was heated to 100°C, cooled to room temperature, and exposed to air, no change in crystal form was observed, and when the sample was heated to 160°C, cooled to room temperature, and exposed to air, conversion to crystal form M was observed. The crystal form F of a sample after heating to 100°C was 1 Considering the TGA / DSC results together with the H NMR results (Figure 6E, no obvious change in solvent content compared to before heating), the crystalline form was analyzed to be an ethanol solvate.

[0323] Example 8: Preparation of acetonitrile solvate crystalline form G 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, 0.5 mL of solvent acetone was added, and the mixture was stirred at room temperature for 30 min, heated to 60°C and stirred for 30 min, cooled to 0-5°C and stirred for 6 h, the solid was centrifuged, and 0.5 mL of ACN was added. The resulting suspension was magnetically stirred (~750 rpm) at 50°C for about 4 days, and the solid was centrifuged to obtain crystalline form G. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 7A, and the differential scanning calorimetry (DSC) pattern and thermogravimetric analysis (TGA) pattern are shown in Figure 7B. 1 The 1 H NMR pattern is shown in Figure 7C.

[0324] Form G was identified by a heating test. When a sample of free form G was heated to 75°C, cooled to room temperature, and exposed to air, no change in the crystal form was observed. However, when the sample was subsequently heated to 150°C, cooled to room temperature, and exposed to air, conversion to form A was observed. 1 Taking into consideration the H NMR results (Figure 7D, no change in solvent content compared to before heating) and the TGA / DSC results, the crystalline form was analyzed to be an acetonitrile solvate.

[0325] Example 9: Preparation of dichloromethane solvate crystalline form H 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, 0.5 mL of acetone solvent was added, and the mixture was stirred at room temperature for 30 minutes, heated to 60°C and stirred for 30 minutes, cooled to 0-5°C and stirred for 6 hours. The centrifuged solid was subjected to gas-solid infiltration in a dichloromethane atmosphere for 12 days to obtain crystalline form H. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 8A, and the differential scanning calorimetry (DSC) pattern and thermogravimetric analysis (TGA) pattern are shown in Figure 8B. 1 The 1 H NMR pattern is shown in Figure 8C.

[0326] 1 The H NMR results showed that 6.1 wt% of dichloromethane remained (the molar ratio of dichloromethane to the compound of formula (I) was 0.38:1). The free crystalline form H was identified by a heating test, and the results are shown in Figure 8D. When the free crystalline form H was heated to 125°C, cooled to room temperature, and exposed to air, a low-crystallinity sample was observed. After subsequent heating to 140°C and 172°C, the formation of amorphous samples was observed. The TGA / DSC and 1 Taking into consideration the H NMR results, the crystalline form was determined to be a dichloromethane solvate.

[0327] Example 10: Preparation of Crystalline Form I 20 mg of amorphous substance Z prepared according to the method of Example 1 was weighed into a 3 mL vial, and the solid was dissolved using 1.0-1.5 mL of solvent NMP (N-methylpyrrolidone). The solution was then filtered through a membrane filter to obtain a clear filtrate. Approximately 4 mL of antisolvent ACN was added to another 20 mL vial, and the 3 mL vial containing the filtrate was placed open in another 20 mL vial. The 20 mL vial was then sealed and allowed to stand at room temperature. Upon precipitation, the solid was collected to obtain crystalline form I. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 9. However, crystalline form I converted to crystalline form A after drying at room temperature.

[0328] Example 11: Preparation of 1,4-dioxane solvate crystalline form J 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, 0.5 mL of solvent acetone was added, and the mixture was stirred at room temperature for 30 min, heated to 60°C and stirred for 30 min, cooled to 0-5°C and stirred for 6 h, and the solid was centrifuged. 0.5 mL of solvent 1,4-dioxane was added, and the resulting suspension was magnetically stirred (~750 rpm) at 50°C to obtain a clear solution. The suspension was then transferred to room temperature and stirred for approximately 4 days. The solid was centrifuged to obtain crystalline form J. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 10A, and the differential scanning calorimetry (DSC) pattern and thermogravimetric analysis (TGA) pattern are shown in Figure 10B. 1 The 1 H NMR pattern is shown in Figure 10C.

[0329] 1 H NMR results showed that the sample contained 3.0 wt% 1,4-dioxane (the molar ratio of 1,4-dioxane to compound of formula (I) was 0.18:1). Form J was identified by a heating test, and the results are shown in Figure 10D. When a sample of form J was heated to 100°C, cooled to room temperature, and exposed to air, no change in the crystal form was observed. After subsequent heating to 160°C, a sample with low crystallinity was observed. 1Considering the H NMR results (Figure 10E, no change in solvent content compared to before heating) and the TGA / DSC results together, the crystalline form was analyzed to be a 1,4-dioxane solvate.

[0330] Example 12: Preparation of crystalline form K 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, 0.5 mL of acetone solvent was added, and the mixture was stirred at room temperature for 30 min. The temperature was raised to 60°C and stirred for 30 min. The mixture was then cooled to 0-5°C and stirred for 6 h. The solid was centrifuged, and a mixed solvent of MeOH and HO (4:1, v:v) was added to dissolve the solid. After filtering through a membrane filter, the resulting clear filtrate was sealed with a sealing film and pierced with five pinholes. The filtrate was allowed to evaporate slowly at room temperature. The resulting solid was collected and used to obtain crystalline form K. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 11A, and the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns are shown in Figure 11B. 1 The 1 H NMR pattern is shown in Figure 11C.

[0331] 1 The H NMR results showed that the sample contained 0.9 wt% MeOH. However, repeated attempts to obtain the above-mentioned form K were not successful, and in some cases, the form O or the form L (Figure 11D) was obtained.

[0332] Example 13: Preparation of methanol-water cosolvate crystalline form L Approximately 20 mg of 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. The solution was then filtered through a membrane filter. The resulting clear filtrate was sealed with a sealing film and pierced with five pinholes. The solution was allowed to evaporate slowly at room temperature. The solid obtained after evaporation was collected to obtain crystalline form L. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 12A, and the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns are shown in Figure 12B. 1The 1 H NMR pattern is shown in Figure 12C.

[0333] 1 H NMR results showed that the sample contained 6.1 wt% residual methanol (methanol to compound of formula (I) molar ratio 1:1). The sample was used for single crystal structure analysis, and the analytical results showed that the free crystalline form L is a methanol-water cosolvate (FIG. 12D).

[0334] Example 14: Preparation of hydrate crystalline form M Approximately 20 mg of crystalline form D prepared according to the method of Example 5 was weighed and heated to 150°C, then cooled to room temperature and exposed to air to obtain crystalline form M. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 13A, and the differential scanning calorimetry (DSC) pattern and thermogravimetric analysis (TGA) pattern are shown in Figure 13B.

[0335] Example 15: Preparation of anhydrous crystalline form N Approximately 20 mg of crystalline form E, prepared according to the method of Example 6, was weighed and heated to 100°C, then cooled to room temperature and exposed to air to obtain crystalline form N. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 14A, and the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns after heating the sample at 100°C to remove surface-adsorbed water / solvent are shown in Figure 14B. 1 The 1 H NMR pattern is shown in Figure 14C.

[0336] 1 H NMR results showed that the sample of crystalline form N contained no residual methanol. As shown in the variable-temperature XRPD overlay of crystalline form E in Figure 14D, crystalline form N was obtained by heating crystalline form E under the protection of N2 to remove methanol, and therefore crystalline form N was analyzed to be an anhydrous crystalline form.

[0337] Example 16: Preparation of methanol solvate crystalline form O Approximately 20 mg of amorphous material Z prepared according to the method of Example 1 was weighed out, dissolved in MeOH / HO (4:1, v:v) and clarified, and then allowed to evaporate slowly at room temperature to obtain crystalline form O. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 15A, and the differential scanning calorimetry (DSC) pattern and thermogravimetric analysis (TGA) pattern are shown in Figure 15B. 1 The 1 H NMR pattern is shown in Figure 15C.

[0338] 1 H NMR results showed 1.8 wt% methanol. Form O was identified by a heating test, and the results are shown in Figure 15D. When a sample of form O was heated to 145°C, cooled to room temperature, and exposed to air, a shift in the diffraction peaks was observed. After subsequent heating to 175°C, conversion to free form form M was observed. 1 Considering the H NMR results (Figure 15E, no obvious change in solvent content compared to before heating) and the TGA / DSC results comprehensively, the crystalline form was analyzed to be a MeOH solvate.

[0339] Example 17: Preparation of hydrate crystalline form P 20 mg of crystalline form L prepared according to the method of Example 13 was weighed into an HPLC vial, and 0.5 mL of acetone solvent was added. The mixture was stirred at room temperature for 30 min, heated to 60°C and stirred for 30 min, cooled to 0-5°C and stirred for 6 h. The solid was centrifuged and then added to a mixed solvent of MEK, THF, and HO (1:0.1:2, v:v:v) and slurried at 5°C for 4 days to obtain crystalline form P. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 16A.

[0340] After leaving a wet sample of crystalline form P in air for about 10 min, conversion to crystalline form C was observed. After drying in air, crystalline form P converted to anhydrous crystalline form C. Therefore, crystalline form P was determined to be a hydrate.

[0341] Example 18: Preparation of anhydrous crystalline form Q Approximately 20 mg of crystalline form D prepared according to the method of Example 5 was weighed out and purged under N2 for 20 min. The sample was heated to 150°C and cooled to 30°C to obtain crystalline form Q. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 17.

[0342] As shown in Figure 4D, form Q was obtained by heating form D under N2 purging, and therefore, form Q was analyzed as an anhydrous form. At the same time, form Q was converted to hydrate form M after being left at room temperature and humidity.

[0343] Example 18: Preparation of crystalline form R 100 mg of amorphous material Z prepared according to the method of Example 1 was weighed into a vial, and 35 mL of a mixed solvent of dichloromethane and acetone (6:1, v:v) was added. The mixture was stirred to dissolve and clarify, and then concentrated under reduced pressure to dryness. 4 mL of acetone was added, and the mixture was heated at 60°C to dissolve and clarify. Approximately 3 mL of purified water was added, and the mixture was allowed to cool to room temperature. The mixture was stirred for 2 hours and filtered to obtain crystalline form R. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 22A, which is an anhydrous form.

[0344] Example 19: Preparation of crystalline form S 100 mg of amorphous material Z prepared according to the method of Example 1 was weighed into a vial, 5 mL of 1,4-dioxane was added, and the mixture was stirred at 35°C to dissolve and clarify the solid. 11 mL of water was added at room temperature to precipitate a solid. After stirring for 1 hour, the solid was filtered, washed with approximately 5 mL of water, and dried overnight at 25°C to obtain crystalline form S. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 23, which is a hydrate.

[0345] Example 20: Preparation of Maleate Crystalline Form T 1 g of amorphous material Z prepared according to the method of Example 1 was weighed into a vial, 14 mL of chloroform was added, and the mixture was stirred at 35°C to dissolve and clarify, yielding Solution 1. 102.64 mg of maleic acid was dissolved in 2 mL of ethanol and clarified to yield Solution 2. 551 μL of Solution 2 was added to 0.7 mL of Solution 1 while stirring at room temperature, and no precipitation occurred. After stirring for 5 hours, the mixture was transferred to 4-8°C and allowed to stand overnight, resulting in no precipitation. 0.8 mL of methyl tert-butyl ether was added, yielding a cloudy solution. An oil was obtained under stirring. 0.4 mL of methyl tert-butyl ether was added, followed by stirring overnight, centrifuging, and drying under vacuum at 25°C to obtain crystalline form T. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 24A. As shown in Figure 24B, the crystalline form 1 H-NMR analysis showed decomposition.

[0346] Example 21: Preparation of methanesulfonate salt crystalline form U 1 g of amorphous material Z prepared according to the method of Example 1 was weighed into a vial and 14 mL of chloroform was added to obtain Solution 1. 107.35 mg of methanesulfonic acid was dissolved in 2 mL of chloroform to obtain Solution 2. 441 μL of Solution 2 was added to 0.7 mL of Solution 1 while stirring at room temperature, resulting in the precipitation of a small amount of particles, which dissolved after 45 minutes. After stirring for 5 hours, a cloudy solution was obtained. This was further stirred for one day and dried under vacuum at 25°C to obtain crystalline form U. The X-ray powder diffraction pattern of this crystalline form is shown in Figure 25A. As shown in Figure 25B, the crystalline form 1 H-NMR analysis showed decomposition.

[0347] Test Example 1: Hygroscopicity test The hygroscopicity of crystalline forms A and B was evaluated by DVS testing at 25°C in the range of 0%RH to 95%RH, and the evaluation was performed with reference to the 2015 edition of the Chinese Pharmacopoeia.

[0348] The DVS test results for Form A and Form B are shown in Figures 18 and 19, respectively. At 25°C / 80%RH, the moisture-induced weight gain of Form A was approximately 1.1%, and that of Form B was approximately 1.0%, indicating that both Form A and Form B are slightly hygroscopic. XRPD results also showed that the crystalline forms of Form A and Form B remained unchanged after the DVS test.

[0349] The DVS pattern of crystalline form R is shown in Figure 22B, and the adsorption isotherm is shown in Figure 22C. The results show that crystalline forms R and S are easily converted to each other under the influence of environmental humidity: crystalline form R absorbs moisture obviously at 50% RH and starts to convert to hydrated crystalline form S, while crystalline form S dehydrates and starts to convert to anhydrous crystalline form R at 40% RH.

[0350] Test Example 2: Solid Stability Test Appropriate amounts of samples of crystalline form A and crystalline form B were weighed and left at 60°C in a closed state for 24 hours, and then left at 25°C / 60%RH and 40°C / 75%RH in an open state for 2, 4, or 6 weeks. The solid samples left under different conditions were analyzed for changes in crystalline form by XRPD, and their purity was measured by HPLC to evaluate their chemical stability.

[0351] The XRPD characterization results before and after the stability test are summarized in Table 2-1 and Table 2-2. The results show that there was no significant decrease in the HPLC purity of the samples of crystalline form A and crystalline form B under the test conditions, and the crystalline form remained unchanged.

[0352] [Table 26]

[0353] [Table 27]

[0354] Test Example 3: Solubility test Test I Approximately 2 mg of a sample of crystalline form A prepared according to Example 2 was weighed and placed in an HPLC vial, and the corresponding solvent was gradually added (50 / 50 / 200 / 700 μL in sequence) and shaken until the solid dissolved and became clear. If the sample did not dissolve and become clear even after adding 1 mL of solvent, no further solvent was added. Based on the mass of the solid sample, the volume of solvent added, and the observed dissolution phenomenon, the solubility range was calculated, and the results are summarized in Table 3-1.

[0355] [Table 28]

[0356] Test II (1) Chromatography conditions Column: Waters XTERRA RP18, 4.6 mm x 150 mm, 3.5 μm, or a column of equivalent potency.

[0357] Mobile phase: 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).

[0358] The detection wavelength was 250 nm, the column temperature was 40°C, the flow rate was 1.0 mL / min, and the sample injection volume was 10 μL.

[0359] Solvent: dimethyl sulfoxide-methanol = 1:9 Control concentration: 0.1 mg / mL Solubility media: water, acetate buffer salts at pH 4.5, phosphate buffer salts at pH 6.8.

[0360] See Table 3-2 for gradient elution conditions.

[0361] [Table 29]

[0362] (2) Preparation of medium: Water: Distilled water Acetic acid buffer salt of pH 4.5: 0.59806 g of sodium acetate trihydrate was taken and placed in a 200 mL measuring flask, dissolved in an appropriate amount of water, and then 1.6 mL of glacial acetic acid was added and diluted to the mark with water to obtain the solution.

[0363] Phosphate buffer salt of pH 6.8: 1.38501 g of potassium dihydrogen phosphate and 0.18086 g of sodium hydroxide were taken and placed in the same 200 mL measuring flask, dissolved in water, and diluted to the mark.

[0364] (3) Preparation of solutions: For both samples of crystalline form A and crystalline form B, supersaturated solutions were prepared by the following method.

[0365] 10.0 mL of each of the above media was precisely weighed and placed in separate 25 mL measuring flasks, and an appropriate amount of the test crystal form was added. The flasks were sealed and shaken on a plate shaker at 37°C for 24 hours to obtain supersaturated solutions.

[0366] 1) Preparation of sample solution of crystalline form B: pH 6.8 phosphate buffer sample solution: obtained by taking a supersaturated solution of pH 6.8 phosphate buffer medium and filtering it.

[0367] Water sample solution: A supersaturated solution of water medium was taken and filtered. Acetate buffer sample solution of pH 4.5: A supersaturated solution of acetate buffer medium of pH 4.5 was taken and filtered, and 1.0 mL of the filtrate was precisely measured and placed in a 10 mL measuring flask and diluted to the mark with acetate buffer medium of pH 4.5. Another 1.0 mL of this solution was precisely measured and placed in a 10 mL measuring flask and diluted to the mark with methanol to obtain the sample solution.

[0368] 2) Preparation of sample solution of crystalline form A: pH 6.8 phosphate buffer sample solution: obtained by taking a supersaturated solution of pH 6.8 phosphate buffer medium and filtering it.

[0369] Water sample solution: A supersaturated solution of water medium was taken and filtered. Acetate buffer sample solution of pH 4.5: A supersaturated solution of acetate buffer medium of pH 4.5 was taken and filtered, and 1.0 mL of the filtrate was precisely measured and placed in a 10 mL measuring flask and diluted to the mark with acetate buffer medium of pH 4.5. Another 1.0 mL of this solution was precisely measured and placed in a 25 mL measuring flask and diluted to the mark with methanol to obtain the sample solution.

[0370] (4) Sample measurement: A sample solution of each medium was taken, and 10 μL of the test solution was precisely measured and injected into the liquid chromatograph according to the above chromatography conditions, and the chromatogram was recorded. The degree of saturation of each medium was calculated according to the following formula:

[0371]

number

[0372] In the ceremony: W R = weighed amount of control solution, mg, P R = purity factor of the control product, A S = peak area of ​​the main peak in the test solution, D S = dilution factor of the test solution, A R = peak area of ​​the main peak in the control solution, D R = dilution ratio of the control solution, (5) See Table 3-3 for test data

[0373] [Table 30]

[0374] Test Example 4: Suspension competition test At room temperature, in the ethanol / water solvent system, different water activities (a w= 0, 0.2, 0.4, 0.6, 0.8, 1.0), suspension competition experiments were carried out between crystalline form B and crystalline forms D, M, N, and P. The XRPD patterns of the solids obtained in the tests are shown in Figure 20A (Tests 1-5) or Figure 20B (Test 6), and the results are shown in Table 22-1. The starting crystalline forms in Tests 1-4 and 6 were B, D, M, and N, and the starting crystalline forms in Test 5 were B, D, M, N, and P.

[0375] [Table 31]

[0376] The result is a w Under the condition of a = 0 to 0.2, anhydrous crystalline form B is obtained, and w = 0.4 to 0.8, hydrate crystal form D is obtained, and w = 1.0 (pure water), a mixture of hydrated crystalline form P and anhydrous crystalline form C was obtained, indicating that the signal of crystalline form C may have arisen from the crystal transformation of crystalline form P during the XRPD test process.

[0377] Test Example 5: Pharmacokinetics test Six SPF SD rats were prepared and weighed before administration, and the dose was calculated based on body weight. Appropriate amounts of crystalline form A and crystalline form B samples were weighed, added to 5% DMSO saline, and thoroughly mixed by vortexing or sonication to obtain a 1 mg / mL dosing solution. These were then orally administered intragastrically at 10 mg / kg. The rats were weighed before administration and the dose was calculated based on body weight. Three rats were used for each crystalline form. Oral intragastric administration was performed. After administration, samples were collected via the jugular vein or other appropriate means at 0.25, 0.5, 1, 2, 4, 8, and 24 hours. Approximately 0.20 mL of each sample was collected, and the plasma was centrifuged within 2 hours. Compound I was detected, and plasma concentration-time curves were plotted. Pharmacokinetic parameters were calculated using WinNonlin based on the blood drug concentration data at different time points. The results showed that the systemic absorption of crystalline form A was significantly superior to that of crystalline form B.

[0378] [Table 32]

[0379] In the description of this specification, the reference terms "embodiment," "example," and the like mean that the specific feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the descriptive expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific feature, structure, material, or characteristic described may be combined in any appropriate manner in any one or more embodiments or examples. Furthermore, while the embodiments of the present disclosure have been shown and described above, the above embodiments are illustrative and should not be construed as limiting the present disclosure. Those skilled in the art will understand that changes, modifications, substitutions, and variations can be made to the above embodiments within the scope of the present disclosure without departing from the principles and purpose of the present disclosure.

Claims

1. A solid form of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 wherein the solid form is selected from anhydrous, hydrated, organic solvate, or cosolvate solid forms of water and organic solvent; Solid form.

2. The solid form is one, two, three or more selected from the following crystalline forms: It is crystalline form A, of which: The X-ray powder diffraction pattern of the crystalline form A has one or two characteristic peaks located at 2θ values ​​selected from 6.91°±0.20° and 10.32°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form A has one, two or all characteristic peaks located at 2θ values ​​selected from 6.91°±0.20°, 10.32°±0.20°, and 25.72°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form A has one, two, more or all characteristic peaks located at 2θ values ​​selected from 6.91°±0.20°, 10.32°±0.20°, 13.88°±0.20°, and 25.72°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form A has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the X-ray powder diffraction pattern of crystalline form A has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the X-ray powder diffraction pattern of crystalline form A further comprises one, two, more or all characteristic peaks located at 2θ values ​​selected from 15.86°±0.20°, 17.00°±0.20°, 17.18°±0.20°, and 24.51°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form A has one, two, more or all characteristic peaks located at 2θ values ​​selected from the following: Table 1 Preferably, said crystalline form A has an X-ray powder diffraction pattern essentially as shown in FIG. 1A; Preferably, the differential scanning calorimetry (DSC) pattern of 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; Preferably, the crystalline form A has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 1B; Preferably, the crystalline form A exhibits a weight loss of about 0.45% to about 0.55% upon heating from room temperature to 190°C in thermogravimetric analysis (TGA); Preferably, the crystalline form A has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 1C; Preferably, said crystalline form A is an anhydrous crystalline form, Or, It is crystalline form B, of which: the X-ray powder diffraction pattern of crystalline form B has one, two or all characteristic peaks located at 2θ values ​​selected from 18.19°±0.20°, 25.74°±0.20°, and 26.95°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form B has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°, and 26.95°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form B has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, said crystalline form B has an X-ray powder diffraction pattern essentially as shown in Figure 2A; Preferably, the differential scanning calorimetry (DSC) pattern of crystalline form B has an endothermic peak with an onset temperature of about 186.7°C and / or a peak temperature of about 189.8°C; Preferably, the crystalline form B has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 2B; Preferably, the crystalline form B exhibits a weight loss of about 0.5% to about 0.6% (e.g., about 0.54%) upon heating from room temperature to 150°C in thermogravimetric analysis (TGA); Preferably, the crystalline form B has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 2B; Preferably, said crystalline form B is an anhydrous crystalline form.

2. The solid form of claim 1.

3. The solid form is one, two, three or more selected from the following crystalline forms: It is crystalline form C, of ​​which: the X-ray powder diffraction pattern of crystalline form C has one, two or all characteristic peaks located at 2θ values ​​selected from 7.25°±0.20°, 16.53°±0.20°, and 18.84°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form C has one, two, more or all characteristic peaks located at 2θ values ​​selected from 7.25°±0.20°, 14.48°±0.20°, 16.53°±0.20°, 18.84°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form C has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, said crystalline form C has an X-ray powder diffraction pattern essentially as shown in Figure 3A; Preferably, the differential scanning calorimetry (DSC) pattern of crystalline form C has an endothermic peak at a peak temperature of about 109.1°C and an onset temperature of about 123.4°C, and / or a peak temperature of about 132.5°C; Preferably, the crystalline form C has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 3B; Preferably, the crystalline form C exhibits a weight loss of about 0.2% to about 0.3% (e.g., about 0.27%) upon heating from room temperature to 200°C in thermogravimetric analysis (TGA); Preferably, the crystalline form C has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 3B; Preferably, said crystalline form C is an anhydrous crystalline form, Or, Crystal form D, of which: the X-ray powder diffraction pattern of crystalline form D has one, two or all characteristic peaks located at 2θ values ​​selected from 11.01°±0.20°, 25.01°±0.20°, and 26.42°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form D has one, two, more or all characteristic peaks located at 2θ values ​​selected from 4.26°±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°; Preferably, the X-ray powder diffraction pattern of crystalline form D has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the crystalline form D has an X-ray powder diffraction pattern essentially as shown in Figure 4A; Preferably, the differential scanning calorimetry (DSC) pattern of 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; Preferably, the crystalline form D has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 4B; Preferably, the crystalline form D exhibits a weight loss of about 3.3% to about 3.4% (e.g., about 3.35%) upon heating from room temperature to 200°C in thermogravimetric analysis (TGA); Preferably, the crystalline form D has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 4B; Preferably, said crystalline form D is a hydrate; Or, It is crystalline form E, of which: the X-ray powder diffraction pattern of the crystalline form E has one, two or all characteristic peaks located at 2θ values ​​selected from 5.98°±0.20°, 12.73°±0.20°, and 14.53°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form E has one, two, more or all characteristic peaks located at 2θ values ​​selected from 5.98°±0.20°, 10.66±0.20°, 11.95±0.20°, 12.73°±0.20°, 14.53°±0.20°, 17.67°±0.20°, and 22.91°±0.20°; Preferably, the crystalline form E has an X-ray powder diffraction pattern essentially as shown in Figure 5A; Preferably, the differential scanning calorimetry (DSC) pattern of crystalline form E has a peak temperature of about 114.9°C and an endothermic peak at a peak temperature of about 127.9°C; Preferably, the crystalline form E has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 5B; Preferably, the crystalline form E exhibits a weight loss of about 1.9% to about 2.0% (e.g., about 1.95%) when heated from room temperature to 50°C, and a weight loss of about 3.0% to about 3.1% (e.g., about 3.02%) when heated from 50°C to 150°C in thermogravimetric analysis (TGA); Preferably, the crystalline form E has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 5B; Preferably, said crystalline form E is a methanol solvate; Preferably, the crystalline form E has a variable temperature XRPD pattern essentially as shown in FIG. 5D.

2. The solid form of claim 1.

4. The solid form is one, two, three or more selected from the following crystalline forms: It is crystalline form F, of which: the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from 11.07°±0.20°, 24.79°±0.20°, and 26.42°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from 11.07°±0.20°, 17.83°±0.20°, 22.44°±0.20°, 24.79°±0.20°, and 26.42°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from 11.07°±0.20°, 17.83°±0.20°, 22.44°±0.20°, 24.79°±0.20° and 26.42°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form F has one, two or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the crystalline form F has an X-ray powder diffraction pattern essentially as shown in Figure 6A; Preferably, the differential scanning calorimetry (DSC) pattern of 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; Preferably, the crystalline form F has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 6B; Preferably, in thermogravimetric analysis (TGA), crystalline form F exhibits a weight loss of about 2.2% to about 2.3% (e.g., about 2.25%) when heated from room temperature to 100°C, and a weight loss of about 2.7% to about 2.8% (e.g., about 2.79%) when heated from 100°C to 200°C; Preferably, the crystalline form F has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 6B; Preferably, said crystalline form F is an ethanol solvate; Preferably, said crystalline form F has a variable-temperature XRPD pattern essentially as shown in FIG. 6D; Or, It is crystalline form G, of which: the X-ray powder diffraction pattern of the crystalline form G has one, two or all characteristic peaks located at 2θ values ​​selected from 6.97°±0.20°, 13.39°±0.20°, and 25.81°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form G has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the crystalline form G has an X-ray powder diffraction pattern essentially as shown in Figure 7A; Preferably, the differential scanning calorimetry (DSC) pattern of crystalline form G has an endothermic peak at a peak temperature of about 122.6°C and an onset temperature of about 168.5°C, and / or a peak temperature of about 173.1°C; The crystalline form G has a differential scanning calorimetry (DSC) pattern essentially as shown in FIG. 7B; Preferably, in thermogravimetric analysis (TGA), Form G exhibits a weight loss of about 1.2% to about 1.4% (e.g., about 1.3%) when heated from room temperature to 75°C, and a weight loss of about 2.6% to about 2.7% (e.g., about 2.69%) when heated from 75°C to 150°C; Preferably, the crystalline form G has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 7B; Preferably, said crystalline form G is an acetonitrile solvate; Or, It is crystalline form H, of which: The X-ray powder diffraction pattern of the crystalline form H has one, two or all characteristic peaks located at 2θ values ​​selected from 12.92°±0.20°, 15.82°±0.20°, and 17.25°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form H has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the crystalline form H has an X-ray powder diffraction pattern essentially as shown in Figure 8A; Preferably, the differential scanning calorimetry (DSC) pattern of 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; Preferably, the crystalline form H has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 8B; Preferably, the crystalline form H exhibits a weight loss of about 1.7% to about 1.8% (e.g., about 1.73%) when heated from room temperature to 70°C, and a weight loss of about 7.9% to about 8.0% (e.g., about 7.98%) when heated from 70°C to 150°C in thermogravimetric analysis (TGA). Preferably, the crystalline form H has a thermogravimetric analysis (TGA) pattern essentially as shown in FIG. 8B ; Preferably, said crystalline form H is a dichloromethane solvate; Preferably, the crystalline form H has a variable-temperature XRPD pattern essentially as shown in Figure 8D.

2. The solid form of claim 1.

5. The solid form is one, two, three or more selected from the following crystalline forms: It is crystalline form I, of which: the X-ray powder diffraction pattern of the crystalline form I has one, two, more or all characteristic peaks located at 2θ values ​​selected from 4.45°±0.20°, 13.35°±0.20°, and 17.82°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline Form I has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, said crystalline form I has an X-ray powder diffraction pattern essentially as shown in Figure 9; Or, It is crystalline form J, of which: the X-ray powder diffraction pattern of the crystalline form J has one, two or all characteristic peaks located at 2θ values ​​selected from 4.22°±0.20°, 7.15°±0.20°, and 25.24°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form J has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°, and 25.24°±0.20°; Preferably, the crystalline form J has an X-ray powder diffraction pattern essentially as shown in Figure 10A; Preferably, the differential scanning calorimetry (DSC) pattern of crystalline form J has an endothermic peak with 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; Preferably, the crystalline form J has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 10B; Preferably, in thermogravimetric analysis (TGA), Form J exhibits a weight loss of about 1.4% to about 1.5% (e.g., about 1.41%) when heated from room temperature to 100°C, and a weight loss of about 3.3% to about 3.4% (e.g., about 3.38%) when heated from 100°C to 200°C; Preferably, the crystalline form J has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 10B; Preferably, said crystalline form J is a 1,4-dioxane solvate; Preferably, the crystalline form J has a variable-temperature XRPD pattern essentially as shown in Figure 10D; Or, It is crystalline form K, of which: the X-ray powder diffraction pattern of the crystalline form K has one, two or all characteristic peaks located at 2θ values ​​selected from 4.19°±0.20°, 6.48°±0.20°, 6.95°±0.20°, and 19.54°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form K has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the crystalline form K has an X-ray powder diffraction pattern essentially as shown in Figure 11A; Preferably, the crystalline form K has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 1 IB; Preferably, the crystalline form K has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 11B.

2. The solid form of claim 1.

6. The solid form is one, two, three or more selected from the following crystalline forms: It is crystalline form L, of which: the X-ray powder diffraction pattern of crystalline form L has one, two or all characteristic peaks located at 2θ values ​​selected from 18.85°±0.20°, 22.30°±0.20°, and 29.35°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form L has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the crystalline form L has an X-ray powder diffraction pattern essentially as shown in Figure 12A; Preferably, the differential scanning calorimetry (DSC) pattern of crystalline form L has an endothermic peak with 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; Preferably, the crystalline form L has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 12B; Preferably, in thermogravimetric analysis (TGA), crystalline form L exhibits a weight loss of about 8.9% to about 9.0% (e.g., about 8.98%) when heated from room temperature to 100°C, a weight loss of about 2.5% to about 2.6% (e.g., about 2.56%) when heated from 100°C to 125°C, and a weight loss of about 1.8% to about 1.9% (e.g., about 1.81%) when heated from 125°C to 150°C; Preferably, the crystalline form L has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 12B; Preferably, said crystalline form L is a methanol-water cosolvate; Preferably, the crystalline form L is essentially as shown in Figure 12C. 1 H NMR pattern: Preferably, the single crystal of crystalline form L has the asymmetric unit schematic of the single crystal structure shown in Figure 12D, Preferably, the crystalline form L has the following structural parameters: Table 2 Or, It is crystalline form M, of which: the X-ray powder diffraction pattern of crystalline form M has one, two or all characteristic peaks located at 2θ values ​​selected from 4.22°±0.20°, 18.59°±0.20°, and 25.31°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form M has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the crystalline form M has an X-ray powder diffraction pattern essentially as shown in Figure 13A; Preferably, the differential scanning calorimetry (DSC) pattern of 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; Preferably, the crystalline form M has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 13B; Preferably, the crystalline form M exhibits a weight loss of about 2.0% to about 2.1% (e.g., about 2.05%) upon heating from room temperature to 200°C in thermogravimetric analysis (TGA); Preferably, the crystalline form M has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 13B; Preferably, said crystalline form M is a hydrate; Or, It is crystalline form N, of which: the X-ray powder diffraction pattern of the crystalline form N has one, two or all characteristic peaks located at 2θ values ​​selected from 5.82°±0.20°, 13.96°±0.20°, and 20.24°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form N has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°, and 20.24°±0.20°; Preferably, the crystalline form N has an X-ray powder diffraction pattern essentially as shown in Figure 14A; Preferably, the differential scanning calorimetry (DSC) pattern of crystalline form N has an endothermic peak with an onset temperature of about 118.0°C and / or a peak temperature of about 125.9°C; Preferably, the crystalline form N has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 14B; Preferably, the crystalline form N exhibits a weight loss of about 0.1% to about 0.2% (e.g., about 0.19%) upon heating from room temperature to 200°C in thermogravimetric analysis (TGA); Preferably, the crystalline form N has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 14B; Preferably, said crystalline form N is an anhydrous crystalline form, Preferably, the crystalline form N has a variable-temperature XRPD pattern essentially as shown in Figure 14D.

2. The solid form of claim 1.

7. The solid form is one, two, three or more selected from the following crystalline forms: It is crystalline form O, of which: the X-ray powder diffraction pattern of crystalline form O has one, two or all characteristic peaks located at 2θ values ​​selected from 11.06°±0.20°, 24.85°±0.20°, and 26.44°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form O has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, said crystalline form O has an X-ray powder diffraction pattern essentially as shown in Figure 15A; Preferably, the differential scanning calorimetry (DSC) pattern of crystalline form O has endothermic peaks at peak temperatures of about 174.7°C and about 187.1°C; Preferably, the crystalline form O has a differential scanning calorimetry (DSC) pattern essentially as shown in Figure 15B; Preferably, in thermogravimetric analysis (TGA), crystalline form O exhibits a weight loss of about 4.0% to about 4.1% (e.g., about 4.03%) when heated from room temperature to 150°C, and a weight loss of about 1.5% to about 1.7% (e.g., about 1.60%) when heated from 150°C to 200°C; Preferably, the crystalline form O has a thermogravimetric analysis (TGA) pattern essentially as shown in Figure 15B; Preferably, said crystalline form O is a methanol solvate; According to an embodiment of the present disclosure, crystalline form O has a variable-temperature XRPD pattern essentially as shown in FIG. 15D ; Or, It is crystalline form P, of which: the X-ray powder diffraction pattern of crystalline form P has one, two or all characteristic peaks located at 2θ values ​​selected from 6.36°±0.20°, 16.15°±0.20°, and 21.05°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form P has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°; Preferably, the crystalline form P has an X-ray powder diffraction pattern essentially as shown in Figure 16A; Preferably, the crystalline form P is a hydrate, Or, It is crystalline form Q, of which: the X-ray powder diffraction pattern of the crystalline form Q has one, two or all characteristic peaks located at 2θ values ​​selected from 18.41°±0.20°, 25.19°±0.20°, and 26.36°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form Q has one, two, more or all characteristic peaks located at 2θ values ​​selected from 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°, and 26.36°±0.20°; Preferably, the crystalline form Q has an X-ray powder diffraction pattern essentially as shown in Figure 17; Preferably, the crystalline form Q is an anhydrous crystalline form.

2. The solid form of claim 1.

8. The solid form is one, two, three or more selected from the following crystalline forms: It is crystalline form R, of which: the X-ray powder diffraction pattern of crystalline form R has one, two or all characteristic peaks located at 2θ values ​​selected from 7.22°±0.20°, 13.03°±0.20°, and 18.81°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form R has one, two, more or all characteristic peaks located at 2θ values ​​selected from 7.22°±0.20°, 13.03°±0.20°, 18.81°±0.20°, 19.15°±0.20°; Preferably, the crystalline form R has an X-ray powder diffraction pattern essentially as shown in Figure 22A; Preferably, said crystalline form R is an anhydrous crystalline form, Or, It is crystalline form S, of which: the X-ray powder diffraction pattern of crystalline form S has one, two or all characteristic peaks located at 2θ values ​​selected from 6.30°±0.20°, 16.11°±0.20°, and 21.01°±0.20°; Preferably, the X-ray powder diffraction pattern of crystalline form S has one, two, more or all characteristic peaks located at 2θ values ​​selected from 6.30°±0.20°, 11.06°±0.20°, 16.11°±0.20°, and 21.01°±0.20°; Preferably, the crystalline form S has an X-ray powder diffraction pattern essentially as shown in Figure 23; Preferably, the crystalline form S is a hydrate; Or, crystalline form T, wherein said crystalline form T has an X-ray powder diffraction pattern essentially as shown in Figure 24A; Or, and crystalline form U, wherein said crystalline form U has an X-ray powder diffraction pattern essentially as shown in Figure 25A.

2. The solid form of claim 1.

9. A method for producing the solid form according to any one of claims 1 to 8, wherein the method for producing comprises one selected from the following methods: The method for preparing crystalline form A includes dissolving compound of formula (I) (e.g., its amorphous form) in a mixed solvent of ethyl acetate and dichloromethane, and volatilizing the resulting solution at room temperature to obtain crystalline form A. Preferably, in the method for preparing crystalline form A, the volume ratio of ethyl acetate to dichloromethane is 1:1 to 20:1, for example, 9:1; Alternatively, the method for preparing crystalline form A includes heating crystalline form G to 150°C, cooling to room temperature, and exposing to air to obtain crystalline form A; Alternatively, the method for preparing crystalline form A includes drying crystalline form I at room temperature to obtain crystalline form A; The method for preparing crystalline form L includes mixing the compound of formula (I) (e.g., its amorphous form) with a mixed solvent of methanol and water to obtain a solution, and evaporating the resulting solution at room temperature to obtain crystalline form L. Preferably, in the method for preparing crystalline form L, the volume ratio of methanol to water may be 1:1 to 20:1, for example, 4:1; The method for preparing crystalline form B includes stirring crystalline form L in acetone to obtain crystalline form B, preferably the mass / volume ratio of crystalline form L to acetone is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL, and preferably the stirring is carried out at 50 to 70°C, for example, 60°C; The method for preparing crystalline form C includes first stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and further mixing and stirring the separated solid with water to obtain crystalline form C. Preferably, the mass / volume ratio of crystalline form L to acetone is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL, and the mass / volume ratio of crystalline form L to water is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL. Preferably, 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 to 5°C, and when the separated solid is further stirred in water, it is stirred at room temperature; Alternatively, crystalline form L is stirred in a mixed solvent of acetone and water, wherein the volume ratio of acetone to water is (1-2):1, for example, 1.5:1; Alternatively, a wet sample of crystalline form P is dried in air to obtain crystalline form C, The method for preparing crystalline form D includes first stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and stirring the separated solid in a mixed solvent of acetone and water, preferably, the mass-volume ratio of crystalline form L to acetone is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL, and the mass-volume ratio of crystalline form L to the mixed solvent of acetone and water is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL, and preferably, the volume ratio of acetone to water in the mixed solvent of acetone and water is (5-7):1, for example, 1.5:1; Preferably, 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 to 5°C. When the separated solid is further stirred in a mixed solvent of acetone and water, it is stirred at room temperature. Alternatively, crystalline form L is stirred in a mixed solvent of acetone and water, wherein the volume ratio of acetone to water is (3-6):1, for example, 4:1; The method for preparing crystalline form E includes stirring crystalline form L in methanol to obtain crystalline form E, preferably, the stirring is performed at room temperature, and preferably, the mass-volume ratio of crystalline form L to methanol is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL; Alternatively, the method for preparing crystalline form F includes stirring the compound of formula (I) (e.g., an amorphous form thereof) in a mixed solvent of acetone and ethanol to obtain crystalline form F. Preferably, in the method for preparing crystalline form L, the volume ratio of acetone to ethanol may be 1:1; The method for preparing crystalline form G includes first stirring crystalline form L in acetone, and further stirring the separated solid in acetonitrile to obtain crystalline form G. Preferably, the mass / volume ratio of crystalline form L to acetone is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL, and the mass / volume ratio of crystalline form L to acetonitrile is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL. The method for producing crystalline form H includes stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and subjecting the separated solid to gas-solid permeation in a dichloromethane atmosphere to obtain crystalline form H. Preferably, the mass-volume ratio of crystalline form L to acetone is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL; The method for preparing the crystalline form I includes dissolving the compound of formula (I) (e.g., an amorphous form thereof) in N-methylpyrrolidone, adding an antisolvent such as acetonitrile, and allowing the mixture to stand at room temperature to precipitate a solid, thereby obtaining the crystalline form I. Preferably, the mass-volume ratio of the compound of formula (I) to N-methylpyrrolidone may be 20 mg:(1.0-1.5 mL), and the mass-volume ratio of the compound of formula (I) to N-methylpyrrolidone may be 20 mg:(3-5 mL), for example, 20 mg:4 mL. The method for preparing crystalline form J includes stirring crystalline form L in acetone at room temperature, heating to 60°C and stirring, further cooling to 0-5°C and stirring, and separating the solid obtained by mixing with 1,4-dioxane, stirring at 50°C, and further stirring at room temperature to obtain crystalline form J. Preferably, the mass-volume ratio of crystalline form L to acetone is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL. The mass-volume ratio of crystalline form L to 1,4-dioxane is 20 mg:(0.1-1 mL), for example, 20 mg:0.5 mL. The method for preparing crystalline form M includes heating crystalline form D to 150°C, then cooling to room temperature and exposing to air for 10 minutes to obtain crystalline form M; Alternatively, the method for preparing crystalline form M comprises heating crystalline form F to 160°C, cooling to room temperature, and exposing to air to obtain crystalline form M; Alternatively, the method for preparing crystalline form M comprises heating a sample of crystalline form O to 175°C to obtain crystalline form M; Alternatively, the method for producing crystalline form M includes leaving crystalline form Q under room temperature and humidity conditions to obtain crystalline form M; The method for preparing crystalline form N includes heating crystalline form E to 100°C, then cooling to room temperature and exposing to air to obtain crystalline form N; The method for preparing the crystalline form O includes dissolving the compound of formula (I) (e.g., its amorphous form) in a mixed solvent of methanol and water, and volatilizing the solution at room temperature to obtain the crystalline form O. Preferably, the volume ratio of methanol to water in the mixed solvent of methanol and water is (3-5):1, for example, 4:1; The method for producing the crystalline form P is as follows: first, crystalline form L is stirred in acetone at room temperature, heated to 60°C and stirred, further cooled to 0-5°C and stirred, and the separated solid is dissolved in MEK, THF, and H 2 2. The method of claim 1, further comprising: slurrying the crystalline form P in a mixture of MEK, THF, and H O to obtain crystalline form P; 2 In a mixed solvent of MEK, THF and H 2 The volume ratio of O may be 1:0.1:2, The method for producing the crystalline form Q is to convert the crystalline form D into N 2 purging for 20 min under the protection of , heating the sample to 150 ° C and cooling to 30 ° C to obtain crystalline form Q; The method for preparing the crystalline form R includes mixing the compound of formula (I) (e.g., amorphous) with a mixed solvent of dichloromethane and acetone, dissolving and clarifying the compound, concentrating the mixture under reduced pressure until dry, adding acetone, dissolving and clarifying the compound by heating, adding water, allowing the compound to cool to room temperature, stirring, and filtering to obtain the crystalline form R. The method for preparing the crystalline form S includes mixing the compound of formula (I) (e.g., amorphous substance) with 1,4-dioxane, dissolving and clarifying the mixture, adding water to precipitate a solid, filtering, and drying the solid to obtain the crystalline form S; The method for preparing the crystalline form T includes mixing the compound of formula (I) (e.g., amorphous substance) with chloroform to obtain solution 1, mixing maleic acid with ethanol to obtain solution 2, mixing solution 2 with solution 1, adding methyl tert-butyl ether, stirring, centrifuging, and drying to obtain the crystalline form T; The method for preparing the crystalline form U includes mixing the compound of formula (I) (e.g., amorphous) with chloroform to obtain solution 1, mixing methanesulfonic acid with chloroform to obtain solution 2, mixing solution 2 with solution 1, stirring, and drying to obtain crystalline form U. Manufacturing method.

10. A mixture, wherein the mixture comprises at least one solid form of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, Preferably, the weight percentage content of crystalline form A relative to the total weight of the compound of formula (I) in the mixture is 80% or more, preferably 95% or more, more preferably 99% or more. mixture.

11. A pharmaceutical composition, wherein the pharmaceutical composition comprises at least one solid form of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, or the pharmaceutical composition comprises the mixture; Preferably, the pharmaceutical composition may further comprise a pharmaceutically acceptable adjuvant, More preferably, the pharmaceutical composition further comprises at least one additional therapeutic agent. Pharmaceutical compositions.

12. Use of a solid form of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, a mixture according to claim 10, or a pharmaceutical composition according to claim 11, wherein said use comprises: Use for inhibiting cell proliferation in vitro or in vivo; or Use for treating a RET kinase mediated disease, or Use for inhibiting RET kinase activity, or Use for treating cancer and / or inhibiting metastasis associated with certain cancers; or for treating irritable bowel syndrome (IBS) or pain associated with IBS; or for use in providing supportive care to cancer patients, said supportive care including the prevention or minimization of gastrointestinal symptoms such as diarrhea associated with treatment (including chemotherapy treatment); or for use in treating a RET-related disease or condition; or Use for reversing or preventing acquired resistance to anticancer drugs; or Use for delaying and / or preventing the development of anti-cancer drug resistance in an individual; or Use for treating an individual suffering from cancer and having an increased likelihood of developing resistance to anticancer drugs, use.

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