Crystal polymorphs of GLP-1R agonists, production methods thereof, and uses

Abstract

The present invention provides crystalline polymorphs of the GLP-1R agonist compound III, and methods for producing and using the same. Compared with the amorphous form of compound III, the crystalline polymorphs of the present invention have higher stability and better processing performance, and are also more suitable for the production of drugs for the prevention or treatment of diseases related to the GLP-1R target and its signal transduction pathway, such as type 2 diabetes, prediabetes, obesity, non-alcoholic fatty liver, non-alcoholic steatohepatitis, kidney disease, gout, hyperuricemia, and cardiovascular disease. 【Chemical 1】 JPEG2025523988000109.jpg44169

Description

Technical Field

[0001] The present invention claims the priority of a prior application filed with the China National Intellectual Property Administration on July 18, 2022, with a patent application number of 2022108454100 and a title of "Crystal Polymorphs of GLP-1R Agonist Compounds, Their Production Methods and Uses", and claims the priority of a prior application filed with the China National Intellectual Property Administration on July 18, 2022, with a patent application number of 2022108438979 and a title of "Crystal Polymorphs of GLP-1R Agonists, Their Production Methods and Uses", and the full text of the prior application is incorporated herein by reference.

[0002] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to crystal polymorphs of GLP-1R agonist compounds, their production methods and uses.

Background Art

[0003] Diabetes is a chronic disease characterized by hyperglycemia caused by insufficient insulin secretion (relative or absolute) or insulin action disorder in the human body. According to the 9th edition of the World Diabetes Atlas newly released by the International Diabetes Federation (IDF), in 2019, approximately 463 million adults (aged 20-79) worldwide suffered from diabetes, and it is expected that the number of diabetes patients will reach 578 million in 2030. If this trend continues, there will be 700 million diabetes patients worldwide in 2045. Therefore, diabetes has become one of the most serious social health problems faced worldwide in the 21st century.

[0004] Currently, there are various pharmacological methods for treating hyperglycemia and associated T2DM (Hampp et al., "Use of Antidiabetic Drugs in the U.S.", 2003 - 2012, Diabetes Care 37:1367 - 1374, 2014). These methods can be classified into six major classes, and each class acts by different major mechanisms.

[0005] Insulin secretagogues include sulfonylureas, dipeptidyl peptidase IV (PP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1R) agonists, which act on pancreatic β-cells to improve insulin secretion. Sulfonylureas have limited efficacy and tolerability, cause weight gain, and often induce hypoglycemia. DP-IV inhibitors have limited efficacy. Commercially available GLP-1R agonists are peptides administered by subcutaneous injection, and liraglutide is approved for the treatment of obesity.

[0006] Biguanides (e.g., metformin) are thought to act mainly by reducing glucose production in the liver. Biguanides often cause gastrointestinal discomfort and lactic acidosis, and their use is further restricted.

[0007] α-Glucosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption. These drugs often cause gastrointestinal discomfort.

[0008] Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on specific receptors in the liver, muscle, and adipose tissue. They regulate lipid metabolism and subsequently enhance the response of these tissues to insulin action. Frequent use of these drugs can cause weight gain and may induce edema and anemia.

[0009] Insulin, when used alone or in combination with the above drugs in more severe cases and when used frequently, can cause weight gain and may also pose a risk of hypoglycemia.

[0010] Sodium-glucose co-transporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit glucose reabsorption in the kidney and thereby reduce blood glucose content. Such a new class of drugs may be associated with ketoacidosis and urinary tract infections.

[0011] However, except for GLP-1R agonists and SGLT2 inhibitors, the efficacy of the above drugs is limited, and the most important problems of β-cell function decline and correlated obesity have not been solved. Therefore, there is a need for more effective drug intervention with relatively few side effects and convenient administration.

[0012] GLP-1 is an incretin hormone 30 amino acids in length secreted by intestinal L cells in response to food intake. GLP-1 has been shown to stimulate insulin secretion physiologically and glucose-dependently, reduce glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate β-cell proliferation. In preclinical studies, GLP-1 promotes sustained β-cell capacity by stimulating important gene transcription for glucose-dependent insulin secretion and promoting β-cell neogenesis (Meier et al., "Biodrugs." 17(2):93-102, 2013).

[0013] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion in the pancreas, thereby increasing peripheral glucose absorption. GLP-1 also inhibits glucagon secretion and reduces glucose output from the liver. In addition, GLP-1 delays gastric emptying and slows intestinal motility to delay food absorption. In people with T2DM, postprandial GLP-1 either does not rise normally or the amount of increase decreases (Vilsbol1 et al., "Diabetes," 50:609-613, 2001).

[0014] Scientific research has appropriately modified and optimized the structure of GLP-1 to increase its half-life and further extend its in vivo biological effects. However, currently clinically used long-acting GLP-1 analogs, such as liraglutide and exenatide, are all polypeptides, and due to the relatively poor patient compliance caused by frequent multiple injections, the development of small molecule GLP-1R agonists has broad clinical market prospects for the purposes of improving patient compliance, dosing convenience, and reducing drug side effects.

[0015] Hangzhou Deruizhi Pharmaceutical Technology Co., Ltd. (Mindrank AI Ltd.) has developed small molecule compounds with novel structures and strong agonist activity for GLP-1R. Among them, the compound with the chemical name (S)-2-(4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, and the compound with the chemical name (S)-2-(4-(6-(4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid have strong agonist activity and good drug development potential, and their structures are as follows.

[0016] [Chemical Structure]

[0017] The free compounds of formula (I) and formula (II) have been identified as amorphous compounds by the inventors. They are prone to moisture absorption or softening, and are likely to undergo crystalline form transformation during long-term storage, which is inconvenient for the development of clinical formulations. To meet the needs of clinical research and commercially available pharmaceutical formulations, the development of an aggregated form suitable for drug development to overcome the defects existing in the prior art is eagerly desired.

[0018] Success in the development of the solid form of a drug usually means having a solid form that can be conveniently separated and purified after synthesis, applicable to industrial production, capable of relatively long-term storage and minimal water absorption, capable of decomposition or transformation into other solid forms, and applicable to properties such as a dosage form that can be rapidly absorbed by an individual after administration (for example, soluble in water and gastric juice). To meet the needs of clinical research and commercially available pharmaceutical formulations, the development of a drug solid form that can be conveniently separated and purified, applicable to industrial production, and has stable physicochemical properties is eagerly desired.

Summary of the Invention

[0019] To solve the problems existing in the prior art, the first aspect of the present invention provides a crystalline polymorph of compound III as shown below,

[0020]

Chemical formula

[0021] Among them, X is selected from Cl or CN.

[0022] According to an embodiment of the present invention, the above crystalline polymorph may be an unsolvated crystal form, a hydrate crystal form or a solvate crystal form of compound III.

[0023] According to an embodiment of the present invention, compound III has a structure shown in compound I or compound II.

[0024]

Chem.

[0025] The solvent-free crystal form of Compound I may be the following crystal forms A, B, C, D, E, F, the hydrate crystal form of Compound I may be the following crystal form G, and the solvate crystal form of Compound I may be the following crystal forms H, I-1, I-2, J, K, L, M, N, O, P, Q, R, S, T.

[0026] The solvent-free crystal form of Compound II may be the following crystal forms 2A, 2B, 2C, 2D, 2E, the hydrate crystal form of Compound II may be the following crystal forms 2F and 2G, and the solvate crystal form of Compound II may be the following crystal forms 2H, 2I, 2J-1, 2J-2, 2K, 2L-1, 2L-2, 2M-1, 2M-2, 2N, 2O, 2P, 2Q-1, 2Q-2, 2R, 2S, 2T, 2U.

[0027] The present invention provides crystal form A of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 19.79±0.2°, 13.13±0.2°, 22.07±0.2° and 9.48±0.2°.

[0028] Preferably, it further includes peaks located at diffraction angles (2θ) of 7.80±0.2°, 13.59±0.2°, 11.43±0.2°, 18.07±0.2° and 12.45±0.2°.

[0029] More preferably, it further includes peaks located at diffraction angles (2θ) of 14.58±0.2°, 24.66±0.2°, 14.24±0.2°, 4.85±0.2°, 23.70±0.2° and 26.51±0.2°.

[0030] Preferably, the X-ray powder diffraction pattern of the above crystal form A has the diffraction angles (2θ) shown in Table 1, among which the error range of the above 2θ angle is ±0.20°.

[0031]

Table 1

[0032] Preferably, the above crystal form A has the X-ray powder diffraction intensity shown in Table 1.

[0033] Preferably, the above crystal form A basically has the X-ray powder diffraction pattern shown in FIG. 1.

[0034] Preferably, in the DSC analysis of the above crystal form A, when heated to near the peak temperature of 99.81 °C, an endothermic peak appears.

[0035] Preferably, the above crystal form A basically has the DSC pattern shown in FIG. 22.

[0036] Preferably, the above crystal form A basically has the TGA pattern shown in FIG. 43.

[0037] The present invention provides a crystal form B of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 13.79 ± 0.2°, 22.36 ± 0.2°, 17.66 ± 0.2° and 27.41 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 11.31 ± 0.2°, 23.16 ± 0.2°, 25.40 ± 0.2°, 5.59 ± 0.2° and 8.74 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 20.20 ± 0.2°, 28.85 ± 0.2°, 11.96 ± 0.2°, 24.19 ± 0.2°, 24.39 ± 0.2° and 7.28 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form B has the diffraction angles (2θ) shown in Table 2, among which the error range of the above 2θ angle is ±0.20°.

[0038]

Table 2

[0039] Preferably, the above crystal form B has the X-ray powder diffraction intensity shown in Table 2.

[0040] Preferably, the above crystal form B basically has the X-ray powder diffraction pattern shown in FIG. 2.

[0041] Preferably, in the DSC analysis of the above crystal form B, when heated to near the peak temperature of 177.71 °C, an endothermic peak appears.

[0042] Preferably, the above crystal form B basically has the DSC pattern shown in FIG. 23.

[0043] Preferably, the above crystal form B basically has the TGA pattern shown in FIG. 44.

[0044] The present invention provides a crystal form C of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 11.27 ± 0.2°, 19.30 ± 0.2°, 17.92 ± 0.2° and 20.04 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 14.70 ± 0.2°, 22.75 ± 0.2°, 21.21 ± 0.2°, 10.48 ± 0.2° and 18.83 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 4.84 ± 0.2°, 10.20 ± 0.2°, 14.16 ± 0.2°, 22.15 ± 0.2°, 20.41 ± 0.2° and 10.98 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form C has the diffraction angles (2θ) shown in Table 3, among which the error range of the above 2θ angle is ±0.20°.

[0045]

Table 3

[0046] Preferably, the above crystal form C has the X-ray powder diffraction intensity shown in Table 3.

[0047] Preferably, the above crystal form C basically has the X-ray powder diffraction pattern shown in FIG. 3.

[0048] Preferably, in the DSC analysis of the above crystal form C, an endothermic peak appears when heated to around a peak temperature of 104.51 °C.

[0049] Preferably, the above crystal form C basically has the DSC pattern shown in FIG. 24.

[0050] Preferably, the above crystal form C basically has the TGA pattern shown in FIG. 45.

[0051] The present invention provides a crystal form D of compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 14.49 ± 0.2°, 16.98 ± 0.2°, 11.51 ± 0.2° and 18.17 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 24.02 ± 0.2°, 21.87 ± 0.2°, 3.58 ± 0.2°, 14.04 ± 0.2° and 20.68 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 19.59 ± 0.2°, 25.60 ± 0.2°, 22.30 ± 0.2°, 22.61 ± 0.2°, 23.53 ± 0.2° and 9.70 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form D has the diffraction angles (2θ) shown in Table 4, among which the error range of the above 2θ angle is ±0.20°.

[0052]

Table 4

[0053] Preferably, the above crystal form D has the X-ray powder diffraction intensity shown in Table 4.

[0054] Preferably, the above crystal form D basically has the X-ray powder diffraction pattern shown in FIG. 4.

[0055] Preferably, in the DSC analysis of the above crystal form D, an endothermic peak appears when heated to around the peak temperature of 167.48 °C.

[0056] Preferably, the above crystal form D basically has the DSC pattern shown in FIG. 25.

[0057] Preferably, the above crystal form D basically has the TGA pattern shown in FIG. 46.

[0058] The present invention provides a crystal form E of compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 11.49 ± 0.2°, 12.17 ± 0.2°, 21.15 ± 0.2° and 20.16 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 14.35 ± 0.2°, 26.49 ± 0.2°, 19.40 ± 0.2°, 4.32 ± 0.2° and 17.51 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 10.87 ± 0.2°, 25.13 ± 0.2°, 24.68 ± 0.2°, 18.01 ± 0.2°, 16.83 ± 0.2° and 15.19 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form E has the diffraction angles (2θ) shown in Table 5, among which the error range of the 2θ angle is ±0.20°.

[0059]

Table 5

[0060] Preferably, the above crystal form E has the X-ray powder diffraction intensity shown in Table 5.

[0061] Preferably, the above crystal form E basically has the X-ray powder diffraction pattern shown in FIG. 5.

[0062] Preferably, in the DSC analysis of the above crystal form E, an endothermic peak appears when heated to around the peak temperature of 112.00 °C.

[0063] Preferably, the above crystal form E basically has the DSC pattern shown in FIG. 26.

[0064] Preferably, the above crystal form E basically has the TGA pattern shown in FIG. 47.

[0065] The present invention provides a crystal form F of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 18.77 ± 0.2°, 25.50 ± 0.2°, 20.98 ± 0.2° and 23.45 ± 0.2°, preferably, it further includes peaks located at diffraction angles (2θ) of 10.77 ± 0.2°, 12.70 ± 0.2°, 21.33 ± 0.2°, 24.50 ± 0.2° and 16.89 ± 0.2°, more preferably, it further includes peaks located at diffraction angles (2θ) of 14.72 ± 0.2°, 19.24 ± 0.2°, 9.68 ± 0.2°, 11.7 ± 0.2°, 20.49 ± 0.2° and 13.26 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form F has the diffraction angles (2θ) shown in Table 6, among which the error range of the 2θ angle is ±0.20°.

[0066]

Table 6

[0067] Preferably, the above crystal form F has the X-ray powder diffraction intensity shown in Table 6.

[0068] Preferably, the above crystal form F basically has the X-ray powder diffraction pattern shown in FIG. 6.

[0069] Preferably, in the DSC analysis of the above crystal form F, an endothermic peak appears when heated to near the peak temperature of 169.00 °C.

[0070] Preferably, the above crystal form F basically has the DSC pattern shown in FIG. 27.

[0071] Preferably, the above crystal form F basically has the TGA pattern shown in FIG. 48.

[0072] The present invention provides a hydrate crystal form G of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 18.66±0.2°, 18.81±0.2°, 3.62±0.2° and 22.24±0.2°, preferably, further includes peaks located at diffraction angles (2θ) of 15.33±0.2°, 17.88±0.2°, 14.76±0.2°, 20.51±0.2° and 11.08±0.2°, more preferably, further includes peaks located at diffraction angles (2θ) of 19.94±0.2°, 26.57±0.2°, 23.22±0.2°, 24.37±0.2°, 7.32±0.2° and 23.44±0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form G has the diffraction angles (2θ) shown in Table 7, among which the error range of the 2θ angle is ±0.20°.

[0073]

Table 7

[0074] Preferably, the above crystal form G has the X-ray powder diffraction intensity shown in Table 7.

[0075] Preferably, the above crystal form G basically has the X-ray powder diffraction pattern shown in FIG. 7.

[0076] Preferably, in the DSC analysis of the above crystal form G, when heated to near peak temperatures of 89.95°C and 104.07°C, endothermic peaks appear.

[0077] Preferably, the above crystal form G basically has the DSC pattern shown in FIG. 28.

[0078] Preferably, the above crystal form G basically has the TGA pattern shown in FIG. 49.

[0079] Preferably, the above crystal form G is a dihydrate of Compound I.

[0080] The present invention provides a crystal form H of a methyl isobutyl ketone solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 10.75 ± 0.2°, 8.61 ± 0.2°, 19.84 ± 0.2° and 18.48 ± 0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 16.79 ± 0.2°, 25.92 ± 0.2°, 9.11 ± 0.2°, 21.15 ± 0.2° and 15.43 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 22.55 ± 0.2°, 3.16 ± 0.2°, 18.95 ± 0.2°, 21.70 ± 0.2°, 12.54 ± 0.2° and 17.86 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the above crystal form H has diffraction angles (2θ) shown in Table 8, among which the error range of the 2θ angle is ±0.20°.

[0081]

Table 8

[0082] Preferably, the above crystal form H has the X-ray powder diffraction intensity shown in Table 8.

[0083] Preferably, the above crystal form H basically has the X-ray powder diffraction pattern shown in Figure 8.

[0084] Preferably, in the DSC analysis of the above crystal form H, an endothermic peak appears when heated to near the peak temperature of 87.76 °C.

[0085] Preferably, the above crystal form H basically has the DSC pattern shown in Figure 29.

[0086] Preferably, the above crystal form H basically has the TGA pattern shown in Figure 50.

[0087] Preferably, the above crystal form H is a 0.5 methyl isobutyl ketone solvate of Compound I.

[0088] The present invention provides a crystal form I-1 of a methyl tert-butyl ether solvate of Compound I, the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 8.53 ± 0.2°, 10.75 ± 0.2°, 4.22 ± 0.2° and 18.39 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 17.22 ± 0.2°, 21.48 ± 0.2°, 16.85 ± 0.2°, 17.53 ± 0.2° and 9.11 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 12.49 ± 0.2°, 19.61 ± 0.2°, 12.87 ± 0.2°, 15.66 ± 0.2°, 26.02 ± 0.2° and 22.40 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form I-1 has the diffraction angles (2θ) shown in Table 9, among which the error range of the 2θ angle is ±0.20°.

[0089]

Table 9

[0090] Preferably, the above crystal form I-1 has the X-ray powder diffraction intensity shown in Table 9.

[0091] Preferably, the above crystal form I-1 basically has the X-ray powder diffraction pattern shown in Figure 9.

[0092] Preferably, in the DSC analysis of the above crystal form I-1, an endothermic peak appears when heated to near the peak temperature of 103.27 °C.

[0093] Preferably, the above crystal form I-1 basically has the DSC pattern shown in Figure 30.

[0094] Preferably, the above crystal form I-1 basically has the TGA pattern shown in Figure 51.

[0095] Preferably, the above crystal form I-1 is a monomethyl tert-butyl ether solvate of Compound I.

[0096] The present invention provides a crystal form I-2 of a methyl tert-butyl ether solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 16.88±0.2°, 18.87±0.2°, 20.90±0.2° and 9.60±0.2°, preferably, it further includes peaks located at diffraction angles (2θ) of 10.98±0.2°, 8.39±0.2°, 17.68±0.2°, 20.51±0.2° and 19.97±0.2°, more preferably, it further includes peaks located at diffraction angles (2θ) of 21.25±0.2°, 17.99±0.2°, 14.10±0.2°, 16.42±0.2°, 7.40±0.2° and 21.93±0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form I-2 has the diffraction angles (2θ) shown in Table 10, among which the error range of the 2θ angle is ±0.20°.

[0097]

Table 10

[0098] Preferably, the above crystal form I-2 has the X-ray powder diffraction intensity shown in Table 10.

[0099] Preferably, the above crystal form I-2 basically has the X-ray powder diffraction pattern shown in Figure 10.

[0100] Preferably, in the DSC analysis of the above crystal form I-2, an endothermic peak appears when heated to near the peak temperature of 97.11°C.

[0101] Preferably, the above crystal form I-2 basically has the DSC pattern shown in Figure 31.

[0102] Preferably, the above crystal form I-2 basically has the TGA pattern shown in FIG. 52.

[0103] Preferably, the above crystal form I-2 is a 1.5 methyl tert-butyl ether solvate of Compound I.

[0104] The present invention relates to a crystal form J of an acetone solvate of Compound I, the X-ray powder diffraction pattern thereof including peaks located at diffraction angles (2θ) of 12.02 ± 0.2°, 18.03 ± 0.2°, 8.04 ± 0.2° and 7.67 ± 0.2°, Preferably, further including peaks located at diffraction angles (2θ) of 19.54 ± 0.2°, 23.50 ± 0.2°, 16.05 ± 0.2°, 21.21 ± 0.2° and 13.83 ± 0.2°, More preferably, further including peaks located at diffraction angles (2θ) of 11.10 ± 0.2°, 17.43 ± 0.2°, 16.54 ± 0.2°, 8.92 ± 0.2°, 22.59 ± 0.2° and 27.39 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form J has the diffraction angles (2θ) shown in Table 11, among which the error range of the 2θ angle is ±0.20°.

[0105]

Table 11

[0106] Preferably, the above crystal form J has the X-ray powder diffraction intensity shown in Table 11.

[0107] Preferably, the above crystal form J basically has the X-ray powder diffraction pattern shown in FIG. 11.

[0108] Preferably, in the DSC analysis of the above crystal form J, an endothermic peak appears when heated to near the peak temperature of 93.18 °C.

[0109] Preferably, the above crystal form J basically has the DSC pattern shown in FIG. 32.

[0110] Preferably, the above crystal form J basically has the TGA pattern shown in FIG. 53.

[0111] Preferably, the above crystal form J is a 0.5 acetone solvate of Compound I.

[0112] The present invention provides a crystal form K of an n-heptane solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 12.19 ± 0.2°, 18.02 ± 0.2°, 7.69 ± 0.2° and 19.69 ± 0.2°, preferably, it further includes peaks located at diffraction angles (2θ) of 21.36 ± 0.2°, 8.98 ± 0.2°, 23.63 ± 0.2°, 16.07 ± 0.2° and 20.72 ± 0.2°, more preferably, it further includes peaks located at diffraction angles (2θ) of 6.85 ± 0.2°, 8.12 ± 0.2°, 13.75 ± 0.2°, 6.54 ± 0.2°, 14.53 ± 0.2° and 13.26 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form K has the diffraction angles (2θ) shown in Table 12, among which the error range of the 2θ angle is ±0.20°.

[0113]

Table 12

[0114] Preferably, the above crystal form K has the X-ray powder diffraction intensity shown in Table 12.

[0115] Preferably, the above crystal form K basically has the X-ray powder diffraction pattern shown in FIG. 12.

[0116] Preferably, in the DSC analysis of the above crystal form K, when heated to near the peak temperature of 91.51 °C, an endothermic peak appears.

[0117] Preferably, the above crystal form K basically has the DSC pattern shown in FIG. 33.

[0118] Preferably, the above crystal form K basically has the TGA pattern shown in FIG. 54.

[0119] Preferably, the above crystal form K is a 0.12n-heptane solvate of Compound I.

[0120] The present invention provides a crystal form L of a methylcyclohexane solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 10.98 ± 0.2°, 15.54 ± 0.2°, 9.09 ± 0.2° and 19.01 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 20.39 ± 0.2°, 17.94 ± 0.2°, 8.74 ± 0.2°, 21.03 ± 0.2° and 13.46 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 22.86 ± 0.2°, 18.25 ± 0.2°, 25.63 ± 0.2°, 16.90 ± 0.2°, 24.74 ± 0.2° and 25.95 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form L has the diffraction angles (2θ) shown in Table 13, among which the error range of the 2θ angle is ±0.20°.

[0121]

Table 13

[0122] Preferably, the above crystal form L has the X-ray powder diffraction intensity shown in Table 13.

[0123] Preferably, the above crystal form L basically has the X-ray powder diffraction pattern shown in FIG. 13.

[0124] Preferably, in the DSC analysis of the above crystal form L, an endothermic peak appears when heated to near the peak temperature of 88.68°C.

[0125] Preferably, the above crystal form L basically has the DSC pattern shown in FIG. 34.

[0126] Preferably, the above crystal form L basically has the TGA pattern shown in FIG. 55.

[0127] Preferably, the above crystal form L is a 0.15 methylcyclohexane solvate of Compound I.

[0128] The present invention provides a crystal form M of a toluene solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 18.62 ± 0.2°, 9.60 ± 0.2°, 16.34 ± 0.2° and 21.62 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 14.84 ± 0.2°, 19.05 ± 0.2°, 19.36 ± 0.2°, 13.08 ± 0.2° and 22.11 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 26.65 ± 0.2°, 24.48 ± 0.2°, 22.36 ± 0.2°, 11.19 ± 0.2°, 20.47 ± 0.2° and 18.19 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form M has the diffraction angles (2θ) shown in Table 14, among which the error range of the 2θ angle is ±0.20°.

[0129] [Table 14]

[0130] Preferably, the above crystal form M has the X-ray powder diffraction intensity shown in Table 14.

[0131] Preferably, the above crystal form M basically has the X-ray powder diffraction pattern shown in FIG. 14.

[0132] Preferably, in the DSC analysis of the above crystal form M, when heated to near the peak temperature of 102.43 °C, an endothermic peak appears.

[0133] Preferably, the above crystal form M basically has the DSC pattern shown in FIG. 35.

[0134] Preferably, the above crystal form M basically has a TGA pattern shown in FIG. 56.

[0135] Preferably, the above crystal form M is a monotoluene solvate of Compound I.

[0136] The present invention provides a crystal form N of a dioxane solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 17.10 ± 0.2°, 20.66 ± 0.2°, 22.71 ± 0.2° and 18.21 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 21.70 ± 0.2°, 15.05 ± 0.2°, 20.27 ± 0.2°, 21.97 ± 0.2° and 8.53 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 19.59 ± 0.2°, 7.52 ± 0.2°, 11.14 ± 0.2°, 16.83 ± 0.2°, 17.47 ± 0.2° and 23.57 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form N has diffraction angles (2θ) shown in Table 15, among which the error range of the 2θ angle is ±0.20°.

[0137] [Table 15]

[0138] Preferably, the above crystal form N has the X-ray powder diffraction intensity shown in Table 15.

[0139] Preferably, the above crystal form N basically has an X-ray powder diffraction pattern shown in FIG. 15.

[0140] Preferably, in the DSC analysis of the above crystal form N, when heated to near the peak temperature of 116.48 °C, an endothermic peak appears.

[0141] Preferably, the above crystal form N basically has a DSC pattern shown in FIG. 36.

[0142] Preferably, the above crystal form N basically has the TGA pattern shown in FIG. 57.

[0143] Preferably, the above crystal form N is a 1,4-dioxane solvate of Compound I.

[0144] The present invention provides a crystal form O of a DMF solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 17.72 ± 0.2°, 13.14 ± 0.2°, 15.08 ± 0.2° and 24.77 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 8.72 ± 0.2°, 21.52 ± 0.2°, 9.70 ± 0.2°, 14.26 ± 0.2° and 25.46 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 12.19 ± 0.2°, 20.15 ± 0.2°, 25.90 ± 0.2°, 23.66 ± 0.2°, 28.75 ± 0.2° and 21.73 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form O has the diffraction angles (2θ) shown in Table 16, among which the error range of the 2θ angle is ±0.20°.

[0145] [Table 16]

[0146] Preferably, the above crystal form O has the X-ray powder diffraction intensity shown in Table 16.

[0147] Preferably, the above crystal form O basically has the X-ray powder diffraction pattern shown in FIG. 16.

[0148] Preferably, in the DSC analysis of the above crystal form O, an endothermic peak appears when heated to near the peak temperature of 123.26°C.

[0149] Preferably, the above crystal form O basically has the DSC pattern shown in FIG. 37.

[0150] Preferably, the above crystal form O basically has the TGA pattern shown in FIG. 58.

[0151] Preferably, the above crystal form O is a mono-DMF solvate of Compound I.

[0152] The present invention provides a crystal form P of an N-methylpyrrolidone solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 14.63 ± 0.2°, 13.16 ± 0.2°, 16.98 ± 0.2° and 14.36 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 21.66 ± 0.2°, 23.94 ± 0.2°, 20.22 ± 0.2°, 6.60 ± 0.2° and 8.41 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 20.02 ± 0.2°, 11.63 ± 0.2°, 25.14 ± 0.2°, 24.87 ± 0.2°, 21.15 ± 0.2° and 16.63 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form P has the diffraction angles (2θ) shown in Table 17, and among them, the error range of the 2θ angle is ±0.20°.

[0153] [Table 17]

[0154] Preferably, the above crystal form P has the X-ray powder diffraction intensity shown in Table 17.

[0155] Preferably, the above crystal form P basically has the X-ray powder diffraction pattern shown in FIG. 17.

[0156] Preferably, in the DSC analysis of the above crystal form P, when heated to near the peak temperature of 117.63 °C, an endothermic peak appears.

[0157] Preferably, the above crystal form P basically has the DSC pattern shown in FIG. 38.

[0158] Preferably, the above crystal form P basically has the TGA pattern shown in FIG. 59.

[0159] Preferably, the above crystal form P is a mono N-methylpyrrolidone solvate of Compound I.

[0160] The present invention provides a crystal form Q of an n-butanol solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 18.05 ± 0.2°, 10.71 ± 0.2°, 12.54 ± 0.2° and 18.78 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 20.68 ± 0.2°, 24.89 ± 0.2°, 26.45 ± 0.2°, 22.24 ± 0.2° and 19.81 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 15.21 ± 0.2°, 9.00 ± 0.2°, 8.70 ± 0.2°, 23.84 ± 0.2°, 16.55 ± 0.2° and 24.31 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form Q has the diffraction angles (2θ) shown in Table 18, among which the error range of the above 2θ angle is ±0.20°.

[0161]

Table 18

[0162] Preferably, the above crystal form Q has the X-ray powder diffraction intensity shown in Table 18.

[0163] Preferably, the above crystal form Q basically has the X-ray powder diffraction pattern shown in FIG. 18.

[0164] Preferably, in the DSC analysis of the above crystal form Q, an endothermic peak appears when heated to near the peak temperature of 100.61°C.

[0165] Preferably, the above crystal form Q basically has the DSC pattern shown in FIG. 39.

[0166] Preferably, the above crystal form Q basically has the TGA pattern shown in FIG. 60.

[0167] Preferably, the above crystal form Q is a 0.5n-butanol solvate of Compound I.

[0168] The present invention provides a crystal form R of an n-propanol solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 10.67 ± 0.2°, 12.52 ± 0.2°, 18.08 ± 0.2° and 8.98 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 6.54 ± 0.2°, 20.68 ± 0.2°, 18.84 ± 0.2°, 7.55 ± 0.2° and 8.67 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 19.85 ± 0.2°, 26.59 ± 0.2°, 15.19 ± 0.2°, 13.05 ± 0.2°, 14.06 ± 0.2° and 16.55 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form R has the diffraction angles (2θ) shown in Table 19, among which the error range of the 2θ angle is ±0.20°.

[0169]

Table 19

[0170] Preferably, the above crystal form R has the X-ray powder diffraction intensity shown in Table 19.

[0171] Preferably, the above crystal form R basically has the X-ray powder diffraction pattern shown in FIG. 19.

[0172] Preferably, in the DSC analysis of the above crystal form R, an endothermic peak appears when heated to near the peak temperature of 110.90 °C.

[0173] Preferably, the above crystal form R basically has the DSC pattern shown in FIG. 40.

[0174] Preferably, the above crystal form R basically has the TGA pattern shown in FIG. 61.

[0175] Preferably, the above crystal form R is a monopropanol solvate of Compound I.

[0176] The present invention provides a crystal form S of a tetrahydrofuran solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 12.17 ± 0.2°, 8.19 ± 0.2°, 7.67 ± 0.2° and 13.96 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 8.95 ± 0.2°, 18.01 ± 0.2°, 16.50 ± 0.2°, 19.71 ± 0.2° and 23.70 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 13.69 ± 0.2°, 13.22 ± 0.2°, 14.45 ± 0.2°, 20.64 ± 0.2°, 15.83 ± 0.2° and 6.48 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form S has the diffraction angles (2θ) shown in Table 20, and among them, the error range of the 2θ angle is ±0.20°.

[0177]

Table 20

[0178] Preferably, the above crystal form S has the X-ray powder diffraction intensity shown in Table 20.

[0179] Preferably, the above crystal form S basically has the X-ray powder diffraction pattern shown in FIG. 20.

[0180] Preferably, in the DSC analysis of the above crystal form S, an endothermic peak appears when heated to near the peak temperature of 96.26°C.

[0181] Preferably, the above crystal form S basically has the DSC pattern shown in FIG. 41.

[0182] Preferably, the above crystal form S basically has the TGA pattern shown in FIG. 62.

[0183] Preferably, the above crystal form S is a 0.5 tetrahydrofuran solvate of Compound I.

[0184] The present invention provides a crystal form T of a 2-methyltetrahydrofuran solvate of Compound I, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 10.79 ± 0.2°, 8.66 ± 0.2°, 9.12 ± 0.2° and 16.87 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 18.64 ± 0.2°, 15.54 ± 0.2°, 21.27 ± 0.2°, 13.57 ± 0.2° and 6.72 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 4.29 ± 0.2°, 14.41 ± 0.2°, 19.99 ± 0.2°, 7.71 ± 0.2°, 16.57 ± 0.2° and 19.42 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form T has the diffraction angles (2θ) shown in Table 21, among which the error range of the 2θ angle is ±0.20°.

[0185]

Table 21

[0186] Preferably, the above crystal form T has the X-ray powder diffraction intensity shown in Table 21.

[0187] Preferably, the above crystal form T basically has the X-ray powder diffraction pattern shown in FIG. 21.

[0188] Preferably, in the DSC analysis of the above crystal form T, an endothermic peak appears when heated to near the peak temperature of 112.95°C.

[0189] Preferably, the above crystal form T basically has the DSC pattern shown in FIG. 42.

[0190] Preferably, the above crystal form T basically has the TGA pattern shown in FIG. 63.

[0191] Preferably, the above crystal form T is a mono-2-methyltetrahydrofuran solvate of Compound I.

[0192] The solvent-free crystal form of Compound II may be the following crystal forms 2A, 2B, 2C, 2D, 2E, the hydrate crystal form of Compound II may be the following crystal forms 2F and 2G, and the solvate crystal form of Compound II may be the following crystal forms 2H, 2I, 2J-1, 2J-2, 2K, 2L-1, 2L-2, 2M-1, 2M-2, 2N, 2O, 2P, 2Q-1, 2Q-2, 2R, 2S, 2T, 2U.

[0193] The present invention provides crystal form 2A of Compound II, and the X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 13.94±0.2°, 22.07±0.2°, 17.96±0.2° and 17.57±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 13.36±0.2°, 5.92±0.2°, 12.33±0.2°, 23.04±0.2° and 11.02±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 22.41±0.2°, 7.42±0.2°, 25.07±0.2°, 27.00±0.2°, 8.71±0.2° and 16.60±0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2A has the diffraction angles (2θ) shown in Table 2-1, among which the error range of the 2θ angle is ±0.20°.

[0194]

Table 22

[0195] Preferably, the above crystal form 2A has the X-ray powder diffraction intensity shown in Table 2-1.

[0196] Preferably, the above crystal form 2A basically has the X-ray powder diffraction pattern shown in FIG. 2-1.

[0197] Preferably, in the DSC analysis of the above crystal form 2A, an endothermic peak appears when heated to around the peak temperature of 189.90 °C.

[0198] Preferably, the above crystal form 2A basically has the DSC pattern shown in FIG. 2-26.

[0199] Preferably, the above crystal form 2A basically has the TGA pattern shown in FIG. 2-51.

[0200] The present invention provides a crystal form 2B of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 13.16 ± 0.2°, 21.31 ± 0.2°, 25.46 ± 0.2° and 10.61 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 16.79 ± 0.2°, 20.99 ± 0.2°, 18.76 ± 0.2°, 19.59 ± 0.2° and 9.71 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 23.72 ± 0.2°, 11.68 ± 0.2°, 23.92 ± 0.2°, 20.57 ± 0.2°, 16.48 ± 0.2° and 20.23 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2B has the diffraction angles (2θ) shown in Table 2-2, among which the error range of the above 2θ angle is ±0.20°.

[0201] [Table 23]

[0202] Preferably, the above crystal form 2B has the X-ray powder diffraction intensity shown in Table 2-2.

[0203] Preferably, the above crystal form 2B basically has the X-ray powder diffraction pattern shown in FIG. 2-2.

[0204] Preferably, in the DSC analysis of the above crystal form 2B, an endothermic peak appears when heated to around the peak temperature of 181.06 °C.

[0205] Preferably, the above crystal form 2B basically has the DSC pattern shown in FIG. 2-27.

[0206] Preferably, the above crystal form 2B basically has the TGA pattern shown in FIG. 2-52.

[0207] The present invention provides a crystal form 2C of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 13.63 ± 0.2°, 5.62 ± 0.2°, 17.12 ± 0.2° and 17.68 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 11.94 ± 0.2°, 13.89 ± 0.2°, 22.65 ± 0.2°, 23.63 ± 0.2° and 17.97 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 7.46 ± 0.2°, 27.52 ± 0.2°, 8.80 ± 0.2°, 25.15 ± 0.2°, 19.36 ± 0.2° and 5.88 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2C has the diffraction angles (2θ) shown in Table 2-3, among which the error range of the 2θ angle is ±0.20°.

[0208]

Table 24

[0209] Preferably, the above crystal form 2C has the X-ray powder diffraction intensity shown in Table 2-3.

[0210] Preferably, the above crystal form 2C basically has the X-ray powder diffraction pattern shown in FIG. 2-3.

[0211] Preferably, in the DSC analysis of the above crystal form 2C, when heated to near the peak temperature of 171.63 °C, an endothermic peak appears.

[0212] Preferably, the above crystal form 2C basically has the DSC pattern shown in FIG. 2-28.

[0213] Preferably, the above crystal form 2C basically has the TGA pattern shown in FIG. 2-53.

[0214] The present invention provides a crystal form 2D of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 5.62 ± 0.2°, 12.01 ± 0.2°, 5.24 ± 0.2°, and 17.72 ± 0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 13.65 ± 0.2°, 17.16 ± 0.2°, 23.63 ± 0.2°, 19.30 ± 0.2°, and 16.43 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 15.85 ± 0.2°, 11.04 ± 0.2°, 7.50 ± 0.2°, 5.90 ± 0.2°, 22.18 ± 0.2°, and 22.65 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the above crystal form 2D has the diffraction angles (2θ) shown in Table 2-4, among which the error range of the above 2θ angle is ±0.20°.

[0215]

Table 25

[0216] Preferably, the above crystal form 2D has the X-ray powder diffraction intensity shown in Table 2-4.

[0217] Preferably, the above crystal form 2D basically has the X-ray powder diffraction pattern shown in FIG. 2-4.

[0218] Preferably, in the DSC analysis of the above crystalline form 2D, an endothermic peak appears when heated to around the peak temperature of 168.79 °C.

[0219] Preferably, the above crystalline form 2D basically has the DSC pattern shown in Figure 2-29.

[0220] Preferably, the above crystalline form 2D basically has the TGA pattern shown in Figure 2-54.

[0221] The present invention provides a crystalline form 2E of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 17.96 ± 0.2°, 3.34 ± 0.2°, 5.63 ± 0.2°, and 13.63 ± 0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 17.14 ± 0.2°, 11.96 ± 0.2°, 12.19 ± 0.2°, 13.98 ± 0.2°, and 7.46 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 19.53 ± 0.2°, 22.14 ± 0.2°, 8.87 ± 0.2°, 19.32 ± 0.2°, 23.90 ± 0.2°, and 19.83 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the above crystalline form 2E has the diffraction angles (2θ) shown in Table 2-5, among which the error range of the above 2θ angle is ±0.20°.

[0222]

Table 26

[0223] Preferably, the above crystalline form 2E has the X-ray powder diffraction intensity shown in Table 2-5.

[0224] Preferably, the above crystalline form 2E basically has the X-ray powder diffraction pattern shown in Figure 2-5.

[0225] Preferably, in the DSC analysis of the above crystalline form 2E, endothermic peaks appear when heated to around the peak temperatures of 110.30 °C and 169.27 °C.

[0226] Preferably, the above crystal form 2E basically has the DSC pattern shown in FIG. 2-30.

[0227] Preferably, the above crystal form 2E basically has the TGA pattern shown in FIG. 2-55.

[0228] The present invention provides a hydrate crystal form 2F of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 19.51±0.2°, 13.71±0.2°, 14.29±0.2° and 18.09±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 6.42±0.2°, 12.11±0.2°, 24.93±0.2°, 17.86±0.2° and 20.57±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 21.37±0.2°, 13.34±0.2°, 23.39±0.2°, 25.15±0.2°, 30.64±0.2° and 17.25±0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2F has the diffraction angles (2θ) shown in Table 2-6, among which the error range of the 2θ angle is ±0.20°.

[0229]

Table 27

[0230] Preferably, the above crystal form 2F has the X-ray powder diffraction intensity shown in Table 2-6.

[0231] Preferably, the above crystal form 2F basically has the X-ray powder diffraction pattern shown in FIG. 2-6.

[0232] Preferably, in the DSC analysis of the above crystal form 2F, an endothermic peak appears when heated to near the peak temperature of 114.41°C.

[0233] Preferably, the above crystal form 2F basically has the DSC pattern shown in FIG. 2-31.

[0234] Preferably, the above crystal form 2F basically has the TGA pattern shown in FIG. 2-56.

[0235] Preferably, the above crystal form 2F is the trihydrate of Compound II.

[0236] The present invention provides a hydrate crystal form 2G of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 17.45±0.2°, 13.63±0.2°, 5.61±0.2° and 5.24±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 13.89±0.2°, 10.69±0.2°, 11.78±0.2°, 23.53±0.2° and 23.86±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 20.98±0.2°, 27.54±0.2°, 15.46±0.2°, 22.52±0.2°, 6.89±0.2° and 22.08±0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2G has the diffraction angles (2θ) shown in Table 2-7, among which the error range of the above 2θ angle is ±0.20°.

[0237]

Table 28

[0238] Preferably, the above crystal form 2G has the X-ray powder diffraction intensity shown in Table 2-7.

[0239] Preferably, the above crystal form 2G basically has the X-ray powder diffraction pattern shown in FIG. 2-7.

[0240] Preferably, in the DSC analysis of the above crystal form 2G, an endothermic peak appears when heated to near the peak temperature of 169.22°C.

[0241] Preferably, the above crystal form 2G basically has the DSC pattern shown in FIG. 2-32.

[0242] Preferably, the above crystal form 2G basically has the TGA pattern shown in FIG. 2-57.

[0243] Preferably, the above crystal form 2G is a dihydrate of Compound II.

[0244] The present invention provides a crystal form 2H of a dimethyl sulfoxide solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 14.84 ± 0.2°, 13.42 ± 0.2°, 24.68 ± 0.2° and 21.70 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 8.45 ± 0.2°, 24.46 ± 0.2°, 20.22 ± 0.2°, 17.22 ± 0.2° and 3.23 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 14.61 ± 0.2°, 25.32 ± 0.2°, 15.56 ± 0.2°, 22.01 ± 0.2°, 18.52 ± 0.2° and 21.21 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2H has the diffraction angles (2θ) shown in Table 2-8, among which the error range of the 2θ angle is ±0.20°.

[0245]

Table 29

[0246] Preferably, the above crystal form 2H has the X-ray powder diffraction intensity shown in Table 2-8.

[0247] Preferably, the above crystal form 2H basically has the X-ray powder diffraction pattern shown in FIG. 2-8.

[0248] Preferably, in the DSC analysis of the above crystal form 2H, an endothermic peak appears when heated to near the peak temperature of 118.06°C.

[0249] Preferably, the above crystal form 2H basically has the DSC pattern shown in FIG. 2-33.

[0250] Preferably, the above crystal form 2H basically has the TGA pattern shown in FIG. 2-58.

[0251] Preferably, the above crystal form 2H is a monodimethylsulfoxide solvate of Compound II.

[0252] The present invention provides a crystal form 2I of a methyl tert-butyl ether solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 8.74 ± 0.2°, 10.94 ± 0.2°, 4.32 ± 0.2° and 17.66 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 13.18 ± 0.2°, 9.25 ± 0.2°, 18.79 ± 0.2°, 17.12 ± 0.2° and 12.79°, More preferably, it further includes peaks located at diffraction angles (2θ) of 22.13 ± 0.2°, 25.90 ± 0.2°, 19.38 ± 0.2°, 20.90 ± 0.2°, 15.91 ± 0.2° and 6.91 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2I has the diffraction angles (2θ) shown in Table 2-9, among which the error range of the 2θ angle is ±0.20°.

[0253] [Table 30]

[0254] Preferably, the above crystal form 2I has the X-ray powder diffraction intensity shown in Table 2-9.

[0255] Preferably, the above crystal form 2I basically has the X-ray powder diffraction pattern shown in FIG. 2-9.

[0256] Preferably, in the DSC analysis of the above crystal form 2I, an endothermic peak appears when heated to near the peak temperature of 115.84°C.

[0257] Preferably, the above crystal form 2I basically has the DSC pattern shown in FIG. 2-34.

[0258] Preferably, the above crystal form 2I basically has the TGA pattern shown in FIG. 2-59.

[0259] Preferably, the above crystal form 2I is a 0.5 methyl tert-butyl ether solvate of Compound II.

[0260] The present invention provides a crystal form 2J-1 of an n-heptane solvate of Compound II, the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 12.15 ± 0.2°, 8.91 ± 0.2°, 8.18 ± 0.2° and 7.63 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 13.93 ± 0.2°, 17.94 ± 0.2°, 19.48 ± 0.2°, 23.72 ± 0.2° and 15.81 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 14.37 ± 0.2°, 20.43 ± 0.2°, 6.75 ± 0.2°, 22.68 ± 0.2°, 13.60 ± 0.2° and 27.41 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2J-1 has the diffraction angles (2θ) shown in Table 2-10, among which the error range of the above 2θ angle is ±0.20°.

[0261]

Table 31

[0262] Preferably, the above crystal form 2J-1 has the X-ray powder diffraction intensity shown in Table 2-10.

[0263] Preferably, the above crystal form 2J-1 basically has the X-ray powder diffraction pattern shown in FIG. 2-10.

[0264] Preferably, in the DSC analysis of the above crystal form 2J-1, an endothermic peak appears when heated to around the peak temperature of 103.13 °C.

[0265] Preferably, the above crystal form 2J-1 basically has the DSC pattern shown in Fig. 2-35.

[0266] Preferably, the above crystal form 2J-1 basically has the TGA pattern shown in Fig. 2-60.

[0267] Preferably, the above crystal form 2J-1 is a 0.2n-heptane solvate of Compound II.

[0268] The present invention provides a crystal form 2J-2 of an n-heptane solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 3.52 ± 0.2°, 17.76 ± 0.2°, 14.19 ± 0.2° and 10.61 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 7.05 ± 0.2°, 21.35 ± 0.2°, 16.24 ± 0.2° and 19.49 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2J-2 has the diffraction angles (2θ) shown in Table 2-11, among which the error range of the above 2θ angle is ±0.20°.

[0269]

Table 32

[0270] Preferably, the above crystal form 2J-2 has the X-ray powder diffraction intensity shown in Table 2-11.

[0271] Preferably, the above crystal form 2J-2 basically has the X-ray powder diffraction pattern shown in Fig. 2-11.

[0272] Preferably, in the DSC analysis of the above crystal form 2J-2, an endothermic peak appears when heated to around the peak temperature of 76.82 °C.

[0273] Preferably, the above crystal form 2J-2 basically has the DSC pattern shown in FIG. 2-36.

[0274] Preferably, the above crystal form 2J-2 basically has the TGA pattern shown in FIG. 2-61.

[0275] Preferably, the above crystal form 2J-2 is a 0.5n-heptane solvate of Compound II.

[0276] The present invention provides a crystal form 2K of a toluene solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 9.52 ± 0.2°, 18.45 ± 0.2°, 19.09 ± 0.2° and 21.48 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 16.24 ± 0.2°, 14.76 ± 0.2°, 13.04 ± 0.2°, 22.11 ± 0.2° and 3.50 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 18.23 ± 0.2°, 17.96 ± 0.2°, 26.57 ± 0.2°, 20.31 ± 0.2°, 14.53 ± 0.2° and 23.76 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2K has the diffraction angles (2θ) shown in Table 2-12, among which the error range of the 2θ angle is ±0.20°.

[0277]

Table 33

[0278] Preferably, the above crystal form 2K has the X-ray powder diffraction intensity shown in Table 2-12.

[0279] Preferably, the above crystal form 2K basically has the X-ray powder diffraction pattern shown in FIG. 2-12.

[0280] Preferably, in the DSC analysis of the above crystal form 2K, endothermic peaks appear when heated to around peak temperatures of 107.92 °C, 172.19 °C, and 184.68 °C.

[0281] Preferably, the above crystal form 2K basically has the DSC pattern shown in Fig. 2-37.

[0282] Preferably, the above crystal form 2K basically has the TGA pattern shown in Fig. 2-62.

[0283] Preferably, the above crystal form 2K is a 0.75 toluene solvate of Compound II.

[0284] The present invention provides a crystal form 2L-1 of a methyl isobutyl ketone solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 8.66 ± 0.2°, 10.79 ± 0.2°, 26.00 ± 0.2°, and 19.62 ± 0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 9.13 ± 0.2°, 18.60 ± 0.2°, 16.90 ± 0.2°, 15.58 ± 0.2°, and 19.43 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 13.03 ± 0.2°, 17.43 ± 0.2°, 6.74 ± 0.2°, 26.72 ± 0.2°, 26.27 ± 0.2°, and 22.40 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the above crystal form 2L-1 has the diffraction angles (2θ) shown in Table 2-13, and among them, the error range of the 2θ angle is ±0.20°.

[0285]

Table 34

[0286] Preferably, the above crystal form 2L-1 has the X-ray powder diffraction intensity shown in Table 2-13.

[0287] Preferably, the above crystal form 2L-1 basically has the X-ray powder diffraction pattern shown in Fig. 2-13.

[0288] Preferably, in the DSC analysis of the above crystal form 2L-1, an endothermic peak appears when heated to near the peak temperature of 106.45 °C.

[0289] Preferably, the above crystal form 2L-1 basically has the DSC pattern shown in Fig. 2-38.

[0290] Preferably, the above crystal form 2L-1 basically has the TGA pattern shown in Fig. 2-63.

[0291] Preferably, the above crystal form 2L-1 is a 0.75 methyl isobutyl ketone solvate of Compound II.

[0292] The present invention provides a crystal form 2L-2 of a methyl isobutyl ketone solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 8.68 ± 0.2°, 10.83 ± 0.2°, 13.10 ± 0.2° and 11.06 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 17.49 ± 0.2°, 9.15 ± 0.2°, 16.96 ± 0.2°, 18.69 ± 0.2° and 6.74 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 12.62 ± 0.2°, 19.63 ± 0.2°, 19.37 ± 0.2°, 22.01 ± 0.2°, 15.65 ± 0.2° and 21.33 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2L-2 has the diffraction angles (2θ) shown in Table 2-14, among which the error range of the above 2θ angle is ±0.20°.

[0293]

Table 35

[0294] Preferably, the above crystal form 2L-2 has the X-ray powder diffraction intensity shown in Table 2-14.

[0295] Preferably, the above crystal form 2L-2 basically has the X-ray powder diffraction pattern shown in Figure 2-14.

[0296] Preferably, in the DSC analysis of the above crystal form 2L-2, an endothermic peak appears when heated to around the peak temperature of 102.87 °C.

[0297] Preferably, the above crystal form 2L-2 basically has the DSC pattern shown in Figure 2-39.

[0298] Preferably, the above crystal form 2L-2 basically has the TGA pattern shown in Figure 2-64.

[0299] Preferably, the above crystal form 2L-2 is a 0.3 methyl isobutyl ketone solvate of Compound II.

[0300] The present invention provides a crystal form 2M-1 of a cyclopentyl methyl ether solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 8.78 ± 0.2°, 10.98 ± 0.2°, 17.67 ± 0.2° and 17.20 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 19.32 ± 0.2°, 25.69 ± 0.2°, 13.23 ± 0.2°, 22.24 ± 0.2° and 9.29 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 18.93 ± 0.2°, 26.53 ± 0.2°, 26.04 ± 0.2°, 15.87 ± 0.2°, 21.25 ± 0.2° and 12.85 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2M-1 has the diffraction angles (2θ) shown in Table 2-15, among which the error range of the above 2θ angle is ±0.20°.

[0301]

Table 36

[0302] Preferably, the above crystal form 2M-1 has the X-ray powder diffraction intensity shown in Table 2-15.

[0303] Preferably, the above crystal form 2M-1 basically has the X-ray powder diffraction pattern shown in FIG. 2-15.

[0304] Preferably, in the DSC analysis of the above crystal form 2M-1, when heated to near the peak temperature of 113.56 °C, an endothermic peak appears.

[0305] Preferably, the above crystal form 2M-1 basically has the DSC pattern shown in FIG. 2-40.

[0306] Preferably, the above crystal form 2M-1 basically has the TGA pattern shown in FIG. 2-65.

[0307] Preferably, the above crystal form 2M-1 is a monocyclopentylmethyl ether solvate of Compound II.

[0308] The present invention provides a crystal form 2M-2 of a cyclopentylmethyl ether solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 5.16 ± 0.2°, 10.83 ± 0.2°, 15.66 ± 0.2° and 21.29 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 17.63 ± 0.2°, 17.90 ± 0.2°, 8.80 ± 0.2°, 13.03 ± 0.2° and 23.88 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 25.73 ± 0.2°, 11.99 ± 0.2°, 19.28 ± 0.2°, 20.20 ± 0.2°, 23.57 ± 0.2° and 22.20 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2M-2 has the diffraction angles (2θ) shown in Table 2-16, among which the error range of the above 2θ angle is ±0.20°.

[0309]

Table 37

[0310] Preferably, the above crystal form 2M-2 has the X-ray powder diffraction intensity shown in Table 2-16.

[0311] Preferably, the above crystal form 2M-2 basically has the X-ray powder diffraction pattern shown in FIG. 2-16.

[0312] Preferably, in the DSC analysis of the above crystal form 2M-2, an endothermic peak appears when heated to around peak temperatures of 110.50 °C and 165.01 °C.

[0313] Preferably, the above crystal form 2M-2 basically has the DSC pattern shown in FIG. 2-41.

[0314] Preferably, the above crystal form 2M-2 basically has the TGA pattern shown in FIG. 2-66.

[0315] Preferably, the above crystal form 2M-2 is a monocyclopentylmethyl ether solvate of Compound II.

[0316] The present invention provides a crystal form 2N of a methyl ethyl ketone solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 3.34 ± 0.2 °, 10.88 ± 0.2 °, 9.13 ± 0.2 °, and 6.64 ± 0.2 °, Preferably, it further includes peaks located at diffraction angles (2θ) of 7.73 ± 0.2 °, 19.87 ± 0.2 °, 8.78 ± 0.2 °, 12.78 ± 0.2 °, and 6.25 ± 0.2 °, More preferably, it further includes peaks located at diffraction angles (2θ) of 18.29 ± 0.2 °, 19.08 ± 0.2 °, 21.19 ± 0.2 °, 11.69 ± 0.2 °, 19.49 ± 0.2 °, and 17.01 ± 0.2 °, Preferably, the X-ray powder diffraction pattern of the above crystal form 2N has diffraction angles (2θ) shown in Table 2-17, among which the error range of the 2θ angle is ±0.20°.

[0317]

Table 38

[0318] Preferably, the above crystal form 2N has X-ray powder diffraction intensities shown in Table 2-17.

[0319] Preferably, the above crystal form 2N basically has an X-ray powder diffraction pattern shown in Figure 2-17.

[0320] Preferably, in the DSC analysis of the above crystal form 2N, when heated to around peak temperatures of 102.66 °C and 113.16 °C, endothermic peaks appear.

[0321] Preferably, the above crystal form 2N basically has a DSC pattern shown in Figure 2-42.

[0322] Preferably, the above crystal form 2N basically has a TGA pattern shown in Figure 2-67.

[0323] Preferably, the above crystal form 2N is a 0.3 methyl ethyl ketone solvate of Compound II.

[0324] The present invention provides a crystal form 2O of a methylcyclohexane solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 8.72 ± 0.2°, 10.92 ± 0.2°, 13.14 ± 0.2° and 9.23 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 17.10 ± 0.2°, 18.78 ± 0.2°, 17.55 ± 0.2°, 15.79 ± 0.2° and 6.89 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 22.05 ± 0.2°, 12.77 ± 0.2°, 19.30 ± 0.2°, 20.84 ± 0.2°, 23.74 ± 0.2° and 26.45 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the above crystal form 2O has diffraction angles (2θ) shown in Table 2-18, among which the error range of the above 2θ angle is ±0.20°.

[0325]

Table 39

[0326] Preferably, the above crystal form 2O has the X-ray powder diffraction intensity shown in Table 2-18.

[0327] Preferably, the above crystal form 2O basically has the X-ray powder diffraction pattern shown in Figure 2-18.

[0328] Preferably, in the DSC analysis of the above crystal form 2O, when heated to near the peak temperature of 111.80 °C, an endothermic peak appears.

[0329] Preferably, the above crystal form 2O basically has the DSC pattern shown in Figure 2-43.

[0330] Preferably, the above crystal form 2O basically has the TGA pattern shown in Figure 2-68.

[0331] Preferably, the above crystal form 2O is a monomethylcyclohexane solvate of Compound II.

[0332] The present invention provides a DMF solvate crystal form 2P of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 10.98 ± 0.2°, 9.31 ± 0.2°, 17.68 ± 0.2° and 25.67 ± 0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 19.65 ± 0.2°, 5.78 ± 0.2°, 6.24 ± 0.2°, 16.54 ± 0.2° and 21.19 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 24.09 ± 0.2°, 18.25 ± 0.2°, 25.26 ± 0.2°, 20.67 ± 0.2°, 18.84 ± 0.2° and 22.19 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the above crystal form 2P has diffraction angles (2θ) shown in Table 2-19, among which the error range of the 2θ angle is ±0.20°.

[0333]

Table 40

[0334] Preferably, the above crystal form 2P has the X-ray powder diffraction intensity shown in Table 2-19.

[0335] Preferably, the above crystal form 2P basically has the X-ray powder diffraction pattern shown in Figure 2-19.

[0336] Preferably, in the DSC analysis of the above crystal form 2P, an endothermic peak appears when heated to near the peak temperature of 105.14 °C.

[0337] Preferably, the above crystal form 2P basically has the DSC pattern shown in Figure 2-44.

[0338] Preferably, the above crystal form 2P basically has the TGA pattern shown in Figure 2-69.

[0339] Preferably, the above crystal form 2P is a mono-DMF solvate of Compound II.

[0340] The present invention provides crystal form 2Q-1 of the 2-methyltetrahydrofuran solvate of compound II, the X-ray powder diffraction pattern of which contains peaks located at diffraction angles (2θ) of 8.74±0.2°, 10.89±0.2°, 3.53±0.2° and 17.90±0.2°, preferably, further contains peaks located at diffraction angles (2θ) of 18.77±0.2°, 17.65±0.2°, 16.93±0.2°, 7.54±0.2° and 9.19±0.2°, more preferably, further contains peaks located at diffraction angles (2θ) of 13.18±0.2°, 8.45±0.2°, 9.63±0.2°, 22.07±0.2°, 6.76±0.2° and 12.81±0.2°, preferably, the X-ray powder diffraction pattern of the above crystal form 2Q-1 has the diffraction angles (2θ) shown in Table 2-20, among which the error range of the 2θ angle is ±0.20°.

[0341]

Table 41

[0342] Preferably, the above crystal form 2Q-1 has the X-ray powder diffraction intensity shown in Table 2-20.

[0343] Preferably, the above crystal form 2Q-1 basically has the X-ray powder diffraction pattern shown in Figure 2-20.

[0344] Preferably, in the DSC analysis of the above crystal form 2Q-1, an endothermic peak appears when heated to near the peak temperature of 111.13°C.

[0345] Preferably, the above crystal form 2Q-1 basically has the DSC pattern shown in Figure 2-45.

[0346] Preferably, the above crystal form 2Q-1 basically has the TGA pattern shown in Figure 2-70.

[0347] Preferably, the above crystal form 2Q-1 is a mono-2-methyltetrahydrofuran solvate of Compound II.

[0348] The present invention provides a crystal form 2Q-2 of a 2-methyltetrahydrofuran solvate of Compound II, the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 8.76 ± 0.2°, 10.89 ± 0.2°, 9.21 ± 0.2° and 17.02 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 18.80 ± 0.2°, 6.79 ± 0.2°, 19.65 ± 0.2°, 17.63 ± 0.2° and 26.08 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 13.18 ± 0.2°, 15.68 ± 0.2°, 4.34 ± 0.2°, 13.70 ± 0.2°, 12.74 ± 0.2° and 21.46 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2Q-2 has diffraction angles (2θ) shown in Table 2-21, among which the error range of the 2θ angle is ±0.20°.

[0349]

Table 42

[0350] Preferably, the above crystal form 2Q-2 has the X-ray powder diffraction intensity shown in Table 2-21.

[0351] Preferably, the above crystal form 2Q-2 basically has the X-ray powder diffraction pattern shown in Figure 2-21.

[0352] Preferably, in the DSC analysis of the above crystal form 2Q-2, an endothermic peak appears when heated to near a peak temperature of 114.18°C.

[0353] Preferably, the above crystal form 2Q-2 basically has the DSC pattern shown in Figure 2-46.

[0354] Preferably, the above crystal form 2Q-2 basically has the TGA pattern shown in Figure 2-71.

[0355] Preferably, the above crystal form 2Q-2 is a mono-2-methyltetrahydrofuran solvate of Compound II.

[0356] The present invention provides a crystal form 2R of an N-methylpyrrolidone solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 10.79±0.2°, 9.15±0.2°, 3.44±0.2°, and 17.63±0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 25.83±0.2°, 19.26±0.2°, 20.86±0.2°, 16.76±0.2°, and 25.48±0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 16.51±0.2°, 9.55±0.2°, 17.18±0.2°, 19.54±0.2°, 14.08±0.2°, and 7.34±0.2°. Preferably, the X-ray powder diffraction pattern of the above crystal form 2R has the diffraction angles (2θ) shown in Table 2-22, among which the error range of the above 2θ angle is ±0.20°.

[0357]

Table 43

[0358] Preferably, the above crystal form 2R has the X-ray powder diffraction intensity shown in Table 2-22.

[0359] Preferably, the above crystal form 2R basically has the X-ray powder diffraction pattern shown in Figure 2-22.

[0360] Preferably, in the DSC analysis of the above crystal form 2R, when heated to near the peak temperature of 128.45°C, an endothermic peak appears.

[0361] Preferably, the above crystal form 2R basically has the DSC pattern shown in Figure 2-47.

[0362] Preferably, the above crystal form 2R basically has the TGA pattern shown in FIG. 2-72.

[0363] Preferably, the above crystal form 2R is a mono N-methylpyrrolidone solvate of Compound II.

[0364] The present invention provides a crystal form 2S of a trifluoroethanol solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 17.64 ± 0.2°, 4.01 ± 0.2°, 8.72 ± 0.2° and 8.28 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 13.63 ± 0.2°, 10.89 ± 0.2°, 12.17 ± 0.2°, 19.65 ± 0.2° and 23.65 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 26.08 ± 0.2°, 15.8 ± 0.2°, 21.35 ± 0.2°, 7.61 ± 0.2°, 22.49 ± 0.2° and 5.61 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2S has the diffraction angles (2θ) shown in Table 2-23, and among them, the error range of the 2θ angle is ±0.20°.

[0365] [Table 44]

[0366] Preferably, the above crystal form 2S has the X-ray powder diffraction intensity shown in Table 2-23.

[0367] Preferably, the above crystal form 2S basically has the X-ray powder diffraction pattern shown in FIG. 2-23.

[0368] Preferably, in the DSC analysis of the above crystal form 2S, when heated to near peak temperatures of 123.79 °C and 169.39 °C, endothermic peaks appear.

[0369] Preferably, the above crystal form 2S basically has the DSC pattern shown in Figure 2-48.

[0370] Preferably, the above crystal form 2S basically has the TGA pattern shown in Figure 2-73.

[0371] Preferably, the above crystal form 2S is a monotrifluoroethanol solvate of Compound II.

[0372] The present invention provides a crystal form 2T of a tetrahydrofuran solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 12.17 ± 0.2°, 8.92 ± 0.2°, 7.63 ± 0.2° and 8.22 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 13.99 ± 0.2°, 17.96 ± 0.2°, 9.27 ± 0.2°, 19.51 ± 0.2° and 13.57 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 11.10 ± 0.2°, 15.89 ± 0.2°, 14.33 ± 0.2°, 19.77 ± 0.2°, 20.39 ± 0.2° and 16.61 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2T has the diffraction angles (2θ) shown in Table 2-24, among which the error range of the 2θ angle is ±0.20°.

[0373]

Table 45

[0374] Preferably, the above crystal form 2T has the X-ray powder diffraction intensity shown in Table 2-24.

[0375] Preferably, the above crystal form 2T basically has the X-ray powder diffraction pattern shown in Figure 2-24.

[0376] Preferably, in the DSC analysis of the above crystal form 2T, when heated to near the peak temperature of 110.50 °C, an endothermic peak appears.

[0377] Preferably, the above crystal form 2T basically has the DSC pattern shown in FIG. 2-49.

[0378] Preferably, the above crystal form 2T basically has the TGA pattern shown in FIG. 2-74.

[0379] Preferably, the above crystal form 2T is a 0.3 tetrahydrofuran solvate of Compound II.

[0380] The present invention provides a crystal form 2U of a dioxane solvate of Compound II, and its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 8.86±0.2°, 10.98±0.2°, 9.27±0.2° and 17.12±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 19.05±0.2°, 19.55±0.2°, 15.70±0.2°, 13.36±0.2° and 6.79±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 25.85±0.2°, 12.87±0.2°, 22.48±0.2°, 13.69±0.2°, 4.39±0.2° and 17.86±0.2°, Preferably, the X-ray powder diffraction pattern of the above crystal form 2U has the diffraction angles (2θ) shown in Table 2-25, among which the error range of the 2θ angle is ±0.20°.

[0381]

Table 46

[0382] Preferably, the above crystal form 2U has the X-ray powder diffraction intensity shown in Table 2-25.

[0383] Preferably, the above crystal form 2U basically has the X-ray powder diffraction pattern shown in FIG. 2-25.

[0384] Preferably, in the DSC analysis of the above crystal form 2U, when heated to around the peak temperature of 109.16 °C, an endothermic peak appears.

[0385] Preferably, the above crystal form 2U basically has the DSC pattern shown in Figure 2-50.

[0386] Preferably, the above crystal form 2U basically has the TGA pattern shown in Figure 2-75.

[0387] Preferably, the above crystal form 2U is a 0.5 dioxane solvate of Compound II.

[0388] The second aspect of the present invention provides a method for producing a crystal polymorph of the above Compound III, which is selected from the following production methods.

[0389] Method 1: Step 1, dissolve or disperse Compound III in a solvent; Step 2, crystallize by stirring at 0 to 50 °C, or add a poor solvent to a clear solution of the compound to precipitate, or gradually volatilize the clear solution of the compound. Method 2: Disperse Compound III in a solvent and in the atmosphere of these media to obtain crystals. Method 3: Combine and use Method 1 and Method 2 to produce and obtain the crystal polymorph of Compound III.

[0390] In a more preferred form, the solvent is water, an organic solvent or a mixed solvent thereof, and the organic solvent is selected from alcohol-based, chloroalkane, ketone-based, ether-based, cyclic ether-based, ester-based, alkane-based, cycloalkane-based, benzene-based, amide-based, sulfoxide-based organic solvents or mixtures thereof. Preferably, the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene or a mixture thereof.

[0391] The third aspect of the present invention provides a pharmaceutical composition comprising at least one of the crystalline polymorphs of the above compound III and a pharmaceutically acceptable carrier.

[0392] The fourth aspect of the present invention provides the application of the crystalline polymorphs of the above compound III in the manufacture of therapeutic drugs for metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0393] The fifth aspect of the present invention provides the crystalline polymorphs of the above compound III for use as therapeutic drugs for metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0394] The sixth aspect of the present invention provides a crystalline polymorph of the above compound III for use in the prevention or treatment of T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea syndrome, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular compliance disorder, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorder, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and for use as a therapeutic agent for addictions.

[0395] In a preferred form, the crystalline polymorph of the above compound III is used as a therapeutic agent for T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia.

[0396] The present invention further provides a method for treating a disease, which comprises administering to an individual in need thereof at least one of a crystalline polymorph of the above compound III or the above pharmaceutical composition in a therapeutically effective amount.

[0397] According to an embodiment of the present invention, the above disease is selected from metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0398] According to an embodiment of the present invention, the above disease is selected from T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea syndrome, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular compliance disorder, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient cerebral ischemia attack, vascular restenosis, glucose metabolism disorder, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, high apoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive dysfunction, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome.

Advantages of the Invention

[0399] The present invention provides a crystalline polymorph of Compound III and a method for producing the same. The obtained crystalline polymorph has advantages such as high stability, high fluidity, and easy pulverization compared to amorphous substances, and is further suitable for the development of clinical formulations. The present invention provides a production method with a simple process, easy implementation, mild reaction conditions, and high product yield. In addition, it is not necessary to perform purification multiple times, the operation is safe and environmentally friendly, which is advantageous for the industrial production of crystalline polymorphs, can meet the development needs of clinical pharmaceutical formulations, has very important clinical application value, and can be expected to accelerate the development of new generation GLP-1R small molecule agonists.

Brief Description of the Drawings

[0400]

Figure 1

Figure 2

Figure 3

Figure 4

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Mode for Carrying Out the Invention

[0401] Definition and Explanation of Terms Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular phrase or term should not be considered uncertain or unclear when not specifically defined, but should be understood in its ordinary meaning. When a trade name is described in this specification, it is intended to refer to the corresponding product or its active ingredient.

[0402] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this specification or their physiological / pharmaceutically acceptable salts or prodrugs with other chemical components, as well as other components such as physiological / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body, contribute to the absorption of the active ingredient, and further exert biological activity.

[0403] As used herein, "crystalline polymorph" refers to crystal forms that have the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that make up the crystal. Crystalline polymorphs have the same chemical composition, but their packing and geometric arrangements are different, and they may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and similar properties. Two crystalline polymorphs may be monotropic or enantiotropic depending on their temperature-stability relationship. In a monotropic system, the relative stability between the two solid phases does not change as the temperature changes. In contrast, in an enantiotropic system, there is a transition temperature at which the stability of the two phases switches (Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN: -8247-0237). The phenomenon in which such compounds exist in different crystal structures is called drug crystal polymorphism.

[0404] The various crystal structures of the present invention can be distinguished from each other using various analytical techniques known to those skilled in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0405] As used herein, the term "room temperature" or "RT" refers to an environmental temperature of 20-25°C (68-77°F).

[0406] The term "substantially identical" with respect to X-ray diffraction peak positions as used herein means taking into account typical peak positions and intensity variability. For example, as would be understood by one of ordinary skill in the art, the peak position (2θ) can vary in the measured values due to differences in XRPD equipment, and sometimes such variations can reach up to 0.2°. Otherwise, as would be understood by one of ordinary skill in the art, factors such as the method of manufacturing the XRPD sample, the XRPD equipment, the crystallinity of the sample, the amount of sample used, and the preferred orientation of the crystal can result in changes in the relative peak intensities in the sample XRPD diffraction pattern.

[0407] The intermediate compounds according to the present invention can be prepared by a plurality of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combinations with other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0408] The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the above solvent must be suitable for the chemical changes of the present invention and its necessary reagents and materials. In order to obtain the compounds of the present invention, those skilled in the art may need to modify or select the synthetic steps or reaction processes based on the existing embodiments.

[0409] Hereinafter, the present invention will be specifically described by way of examples, but these examples do not limit the present invention.

[0410] All solvents used in the present invention are commercially available and can be used without further purification.

[0411] Unless otherwise specified, all reactions of the present invention are carried out with continuous magnetic stirring, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C).

[0412] Methods and Materials The structure of the compound is determined by nuclear magnetic resonance (NMR). The NMR shift (δ) is expressed in parts per million (ppm). For NMR measurement, a Bruker avance-400 MHz nuclear magnetic device is used, the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4), the internal standard is tetramethylsilane (TMS), and the chemical shift is 10 -6 ppm as the unit.

[0413] For HPLC measurement, an Agilent 1260 high-performance liquid chromatograph or a high-performance liquid chromatograph with equivalent efficacy (Sunfire C18 150×4.6 m column or a column with equivalent efficacy) is used.

[0414] The crystalline polymorphs of Compound III are characterized by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the above salts are collected on a Bruker D8 Advance powder diffractometer operating in reflection mode using Cu Kα radiation. The instrument employs Cu Kα irradiation (40 kV, 40 mA) and is performed at room temperature using an SSD160-2 detector. The scanning range is 3° to 40° in the 2θ interval, and the scanning speed is 0.1 s / step. The diffraction patterns are analyzed using DIFFRAC.MEA.CENTER software.

[0415] The production of XRPD samples is carried out by placing the sample on a single-crystal silicon wafer and pressing the sample powder with a glass plate or equivalent to ensure that the surface of the sample is flat and has an appropriate height. Next, the sample holder is placed in a Bruker D8 Advance instrument, and an X-ray powder diffraction pattern is collected using the above instrument parameters. The differences in measurements correlated with such X-ray powder diffraction analysis results arise from multiple factors, including (a) errors in the sample product (e.g., the height of the sample), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors occurring when measuring peak positions), and (e) the nature of the substance (e.g., preferred orientation error). Calibration errors and sample height errors always result in a shift in the same direction for all peaks. Generally, this calibration coefficient can match the measured peak position with the predicted peak position and be within the range of the predicted 2θ value ±0.2°.

[0416] The experimental method for characterizing the crystalline form of the acidic or basic salt of Compound III using differential scanning calorimetry (DSC) is to take a small amount of the crystalline polymorph of Compound III, set it up with the instrument, place it in a capping-capable aluminum crucible, cap it with an aluminum disk after placing the sample, and then send it into the instrument for detection. The model number of all instruments used in the differential scanning calorimetry method in the present invention is METTLER TOLEDO DSC 3, and the scanning parameters are provided such that a nitrogen gas atmosphere is adopted and the heating rate is 10.0 k / min.

[0417] The experimental method for characterizing the crystalline polymorph of Compound III using thermogravimetric analysis (TGA) is to take a small amount of the powder of the crystalline polymorph of Compound III, place it in an alumina crucible set up with the instrument, and send it into the instrument for detection after placing the sample. The model number of all instruments used in the differential scanning calorimetry method in the present invention is METTLER TOLEDO TGA 2, and the scanning parameters are provided such that a nitrogen gas atmosphere is adopted and the heating rate is 10.0 k / min.

[0418] The experimental method for characterizing the acidic or basic salts of Compound III using the dynamic vapor sorption (DVS) method is to take a small amount of the powder of the crystalline polymorphs of Compound III, place it in a precision sample tray that is set up with the instrument, and after placing the sample, send it into the instrument for detection. The model number of all the instruments used in the dynamic vapor sorption method in the present invention is Intrinsic PLUS. The experimental parameters are set such that the constant temperature is 25 °C, and the criterion for determining equilibrium attainment is that the mass percentage change rate per unit time (dm / dt) = 0.02% / min, and the programmed humidity change cycle is set such that the initial relative humidity is 0% and the relative humidity at the end point is 90%.

[0419] [Embodiments for Carrying Out the Invention] Hereinafter, in accordance with specific examples, the technical solutions of the present invention will be described in more detail. It should be understood that the following examples are merely illustrative explanations and interpretations of the present invention and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0420] Unless otherwise specified, all the raw materials and reagents used in the following examples are commercially available products or may be manufactured by known methods.

[0421] Example 1 Preparation of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (the amorphous form of Compound I)

[0422] [Chemical Formula]

[0423] Step 1: Synthesis of Methyl (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (S)-Methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.5 g, 5.1 mmol), 2-(4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-yloxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) were dissolved in N,N-dimethylformamide (80 mL). The mixed solution was stirred at 60 °C for 3 hours, then quenched with water (100 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.0 g, yield 33.5%).

[0424] Step 2: Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic Acid (S)-Methyl 2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.0 g, 1.7 mmol) was dissolved in a mixed solution of tetrahydrofuran / water (20 mL / 20 mL), and lithium hydroxide (0.13 g, 5.4 mmol) was added. The mixture was stirred at room temperature for 16 h. The mixture obtained was adjusted to pH = 5 - 6 with formic acid, and the solvent was removed in vacuo. The residue was purified by reverse-phase flash column chromatography to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (0.69 g, yield 70.5%). It was characterized by XRPD, DSC and TGA. The obtained Compound I was amorphous, and its X-ray powder diffraction pattern, DSC pattern and TGA pattern are shown in Figures 64, 65 and 66, respectively. 11H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1 H), 7.80 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.44 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.28 (t, J = 8.8 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.12 - 5.06 (m, 1 H), 4.95 - 4.93 (m, 1 H), 4.81 - 4.76 (m, 1 H), 4.66 - 4.62 (m, 1 H), 4.51 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.94 (d, J = 13.6 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1 H), 2.79 - 2.67 (m, 2 H), 2.46 - 2.41 (m, 1 H), 2.32 (s, 2 H), 1.92 - 1.91 (m, 2 H), 1.63 - 1.59 (m, 2 H). Example 2 Preparation of Crystal Form A of Compound I 200 mg of Compound I was added to 7.5 mL of isopropanol, and ultrasonic waves were used to promote dissolution at 50 °C. After filtration, the filtrate was stirred at 5 °C for about 16 h, then filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form A of the compound. The product was characterized by XRPD (Figure 1), DSC (Figure 22), and TGA (Figure 43) analyses.

[0425] Example 3 Preparation of Crystal Form B of Compound I 200 mg of Compound I was added to 3 mL of ethyl acetate, and ultrasonic waves were used to promote dissolution at 50 °C. After filtration, the filtrate was stirred at 5 °C for about 16 h, then filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form B of the compound. The product was characterized by XRPD (Figure 2), DSC (Figure 23), and TGA (Figure 44) analyses.

[0426] Example 4 Preparation of Crystal Form C of Compound I 200 mg of Compound I was added to 9 mL of acetonitrile, and ultrasonic waves were used to facilitate dissolution at 50 °C. It was filtered, and the filtrate was stirred at 5 °C for about 16 h, then filtered. The filter cake was dried in an oven at 50 °C to obtain crystalline form C of the compound, and the product was characterized by XRPD (Figure 3), DSC (Figure 24), and TGA (Figure 45) analyses.

[0427] Example 5 Preparation of Crystalline Form D of Compound I 200 mg of Compound I was added to 2.5 mL of isopropyl ether / ethyl acetate (6:1 v:v), stirred at 50 °C for 2 h, then cooled to 5 °C and stirred for 2 h. It was filtered, and the filter cake was dried in an oven at 50 °C to obtain crystalline form D of the compound, and the product was characterized by XRPD (Figure 4), DSC (Figure 25), and TGA (Figure 46) analyses.

[0428] Example 6 Preparation of Crystalline Form E of Compound I 20 mg of Compound I was suspended in 0.5 mL of n-hexane / dichloromethane (3:1 v:v), stirred at 5 °C for 3 days, then filtered. The filter cake was dried in an oven at 50 °C to obtain crystalline form E of the compound, and the product was characterized by XRPD (Figure 5), DSC (Figure 26), and TGA (Figure 47) analyses.

[0429] Example 7 Preparation of Crystalline Form F of Compound I 20 mg of Compound I was suspended in 0.5 mL of water / acetone (6:1 v:v), stirred at 50 °C for 2 h, then cooled to 5 °C and stirred for 2 h. It was filtered, and the filter cake was dried in an oven at 50 °C to obtain crystalline form F of the compound, and the product was characterized by XRPD (Figure 6), DSC (Figure 27), and TGA (Figure 48) analyses.

[0430] Example 8 Preparation of Hydrate Crystalline Form G of Compound I 100 mg of Compound I was suspended in 2.5 mL of water, stirred at 5 °C for 3 days, then filtered. The filter cake was dried in an oven at 50 °C to obtain hydrate crystalline form G of the compound, and the product was characterized by XRPD (Figure 7), DSC (Figure 28), and TGA (Figure 49) analyses.

[0431] Example 9 Preparation of Crystal Form H of the Methyl Isobutyl Ketone Solvate of Compound I 20 mg of Compound I was suspended in 0.5 mL of methyl isobutyl ketone, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 40 °C to obtain Crystal Form H of the methyl isobutyl ketone solvate of the compound. The product was characterized by XRPD (Figure 8), DSC (Figure 29), and TGA (Figure 50) analyses. 1 H NMR (400 MHz, DMSO-d6): δ 12.73 (br, 1H), 8.27 (s, 1 H), 7.81 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.74 (t, J = 7.6 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.43 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.30 (t, J = 8.8 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.95 - 4.93 (m, 1 H), 4.78 - 4.76 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.51 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.95 (d, J = 13.6 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1 H), 2.73 - 2.69 (m, 3 H), 2.32 - 2.28 (m, 4 H), 2.06 - 1.91 (m, 4 H), 1.63 - 1.59 (m, 2 H), 0.86 - 0.84 (d, J = 6.8 Hz, 4H). Example 10 Preparation of Crystal Form I-1 of the Methyl tert-Butyl Ether Solvate of Compound I 20 mg of Compound I was suspended in 1.0 mL of ethyl acetate and filtered to obtain a clear solution. Next, the solution was placed in a 20 mL vial containing 3 mL of methyl tert-butyl ether. The 20 mL vial was sealed with a lid and left at room temperature for 3 days, then filtered. The filter cake was dried in an oven at 50 °C to obtain crystalline Form I-1 of the methyl tert-butyl ether solvate of the compound. The product was characterized by XRPD (Figure 9), DSC (Figure 30), and TGA (Figure 51) analysis. 1 H NMR (400 MHz, DMSO-d6): δ 12.72 (br, 1H), 8.27 (s, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.75 (t, J = 7.6 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.44 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.30 (t, J = 8.8 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.03 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.95 - 4.93 (m, 1 H), 4.78 - 4.76 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.50 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.96 (d, J = 13.6 Hz, 1 H), 3.79 (d, J = 13.6 Hz, 1 H), 3.08 (s, 3 H), 2.72 - 2.70 (m, 3 H), 2.32 - 2.28 (m, 4 H), 1.99 - 1.91 (m, 4 H), 1.63 - 1.59 (m, 2 H), 1.11 (s, 8H). Example 11 Preparation of Crystalline Form I-2 of the Methyl tert-Butyl Ether Solvate of Compound I 20 mg of Compound I was suspended in 0.5 mL of methyl-tert-butyl ether / isopropyl acetate (4:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain crystalline Form I-2 of the methyl tert-butyl ether solvate of the compound. The product was characterized by XRPD (Figure 10), DSC (Figure 31), and TGA (Figure 52) analyses. 1 H NMR (400 MHz, DMSO-d6): δ 12.72 (br, 1H), 8.27 (s, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.76 (t, J = 7.6 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.45 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.31 (t, J = 8.8 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.11 - 5.09 (m, 1 H), 4.96 - 4.94 (m, 1 H), 4.78 - 4.76 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.50 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.96 (d, J = 13.6 Hz, 1 H), 3.79 (d, J = 13.6 Hz, 1 H), 3.08 (s, 4 H), 2.73 - 2.70 (m, 3 H), 2.32 - 2.28 (m, 3 H), 1.99 - 1.91 (m, 2 H), 1.63 - 1.59 (m, 2 H), 1.11 (s, 12H). Example 12 Preparation of Crystalline Form J of the Acetone Solvate of Compound I Approximately 20 mg of Compound I was weighed, and 0.5 mL of acetone was added in three portions, with each portion being ground for 5 min. The resulting solid was dried in an oven at 50 °C to obtain crystalline Form J of the acetone solvate of the compound. The product was characterized by XRPD (Figure 11), DSC (Figure 32), and TGA (Figure 53) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.70 (br, 1H), 8.27 (s, 1 H), 7.81 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.72 (t, J=7.6 Hz, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.44 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.28 (t, J=8.8 Hz, 1 H), 7.18 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.2 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 5.18 (s, 2 H), 5.12-5.07 (m, 1 H), 4.95-4.92 (m, 1 H), 4.81-4.77 (m, 1 H), 4.66-4.63 (m, 1 H), 4.52-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.94 (d, J=13.6 Hz, 1 H), 3.78 (d, J=13.6 Hz, 1 H), 2.73-2.69 (m, 3 H), 2.46-2.32 (m, 3H), 2.09 (s, 3 H), 1.92-1.91 (m, 2 H), 1.63-1.59 (m, 2 H). Example 13 Preparation of Crystal Form K of the n-Heptane Solvate of Compound I Weighed about 20 mg of Compound I, suspended it in 0.5 mL of n-heptane / tetrahydrofuran (3:1 v:v), stirred it at 5 °C for 3 days, filtered it, and dried the filter cake in an oven at 50 °C to obtain Crystal Form K of the n-heptane solvate of the compound. The product was characterized by XRPD (Figure 12), DSC (Figure 33), and TGA (Figure 54) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.80 (br, 1H), 8.26 (s, 1 H), 7.81 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.45 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J = 8.8 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.94 - 4.92 (m, 1 H), 4.81 - 4.78 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.50 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.94 (d, J = 13.6 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1 H), 2.73 - 2.69 (m, 3 H), 2.43 - 2.32 (m, 3H), 1.92 - 1.91 (m, 2 H), 1.63 - 1.61 (m, 2 H), 1.24 (s, 1.2 H), 0.87 - 0.85 (m, 0.7 H). Example 14 Preparation of Crystal Form L of the Methylcyclohexane Solvate of Compound I Weighed about 20 mg of Compound I, suspended it in 0.5 mL of methylcyclohexane / tetrahydrofuran (6:1 v:v), stirred at 50 °C for 2 hours, then cooled to 5 °C and stirred for 2 hours, filtered, and dried the filter cake in an oven at 50 °C to obtain Crystal Form L of the methylcyclohexane solvate of the compound. The product was characterized by XRPD (Figure 13), DSC (Figure 34), and TGA (Figure 55) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.81 (br, 1H), 8.26 (s, 1 H), 7.81 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.45 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J = 8.8 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.94 - 4.92 (m, 1 H), 4.81 - 4.78 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.50 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.95 (d, J = 13.6 Hz, 1 H), 3.79 (d, J = 13.6 Hz, 1 H), 2.73 - 2.70 (m, 3 H), 2.43 - 2.32 (m, 3H), 1.92 - 1.91 (m, 2 H), 1.63 - 1.59 (m, 2 H), 1.25 - 0.83 (m, 2 H). Example 15 Preparation of Crystal Form M of the Toluene Solvate of Compound I Approximately 20 mg of Compound I was weighed, dissolved in 0.5 mL of toluene, and filtered to obtain a clear solution. Next, the solution was placed in a 20 mL vial containing 3 mL of isopropyl ether. The 20 mL vial was sealed with a cap, left at room temperature for 2 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form M of the toluene solvate of the compound, and the product was characterized by XRPD (Figure 14), DSC (Figure 35), and TGA (Figure 56) analysis. 11H NMR (400 MHz, DMSO-d6): δ 12.73 (br, 1H), 8.26 (s, 1 H), 7.81 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.45 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.30 - 7.14 (m, 8 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.94 - 4.92 (m, 1 H), 4.81 - 4.78 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.50 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.95 (d, J = 13.6 Hz, 1 H), 3.79 (d, J = 13.6 Hz, 1 H), 2.73 - 2.70 (m, 3 H), 2.43 - 2.30 (m, 7 H), 1.92 - 1.91 (m, 2 H), 1.63 - 1.59 (m, 2 H). Example 16 Preparation of Crystal Form N of the Dioxane Solvate of Compound I Weighed about 20 mg of Compound I, suspended it in 0.5 mL of n-heptane / dioxane (3:1 v:v), stirred at 5 °C for 3 days, filtered, and dried the filter cake in an oven at 50 °C to obtain Crystal Form N of the dioxane solvate of the compound. The product was characterized by XRPD (Figure 15), DSC (Figure 36), and TGA (Figure 57) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.81 (br, 1H), 8.26 (s, 1 H), 7.81 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J=7.6 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 7.45 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J=8.8 Hz, 1 H), 7.19 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.2 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.94 - 4.92 (m, 1 H), 4.81 - 4.78 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.50 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.94 (d, J=13.6 Hz, 1 H), 3.79 (d, J=13.6 Hz, 1 H), 3.57 (s, 14 H), 2.73 - 2.69 (m, 3 H), 2.51 - 2.32 (m, 3H), 1.92 - 1.91 (m, 2 H), 1.63 - 1.61 (m, 2 H). Example 17 Preparation of Crystal Form O of the DMF Solvate of Compound I Weigh about 20 mg of Compound I, dissolve it in 0.5 mL of DMF / isopropyl ether (1:4 v:v), allow the solution to stand open at room temperature for 1 day to volatilize, filter, dry the filter cake in an oven at 50 °C to obtain Crystal Form O of the DMF solvate of the compound, and characterize the product by XRPD (Figure 16), DSC (Figure 37), and TGA (Figure 58) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.81 (br, 1H), 8.26 (s, 1 H), 7.81 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.45 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J = 8.8 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.94 - 4.92 (m, 1 H), 4.78 - 4.76 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.51 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.94 (d, J = 13.6 Hz, 1 H), 3.79 (d, J = 13.6 Hz, 1 H), 2.89 (s, 3H), 2.73 - 2.70 (m, 3 H), 2.43 - 2.32 (m, 3H), 1.92 - 1.91 (m, 2 H), 1.63 - 1.59 (m, 2 H). Example 18 Preparation of Crystal Form P of the N-Methylpyrrolidone Solvate of Compound I Weighed about 20 mg of Compound I, suspended it in 0.5 mL of N-methylpyrrolidone / isopropyl ether (1:9 v:v), stirred at 5 °C for 3 days, filtered, and dried the filter cake in an oven at 50 °C to obtain Crystal Form P of the N-methylpyrrolidone solvate of the compound. The product was characterized by XRPD (Figure 17), DSC (Figure 38), and TGA (Figure 59) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.76 (br, 1H), 8.27 (s, 1 H), 7.81 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J=7.6 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 7.45 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J=8.8 Hz, 1 H), 7.19 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.2 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 5.19 (s, 2 H), 5.10 - 5.09 (m, 1 H), 4.94 - 4.92 (m, 1 H), 4.81 - 4.78 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.50 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.96 (d, J=13.5 Hz, 1 H), 3.78 (d, J=13.5 Hz, 1 H), 3.32 - 3.29 (m, 3 H), 2.73 - 2.70 (m, 6 H), 2.43 - 2.32 (m, 3H), 2.20 - 2.16 (m, 2 H), 1.94 - 1.88 (m, 4 H), 1.63 - 1.61 (m, 2 H). Example 19 Preparation of Crystal Form Q of the n-Butanol Solvate of Compound I Weighed about 20 mg of Compound I, suspended it in 0.5 mL of n-butanol, stirred at 50 °C for 3 days, filtered, and dried the filter cake in an oven at 50 °C to obtain Crystal Form Q of the n-butanol solvate of the compound. The product was characterized by XRPD (Figure 18), DSC (Figure 39), and TGA (Figure 60) analysis. 11H NMR (400 MHz, DMSO-d6): δ 12.73 (br, 1H), 8.27 (s, 1 H), 7.81 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J=7.6 Hz, 1 H), 7.73 (d, J=8.4 Hz, 1 H), 7.45 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J=8.8 Hz, 1 H), 7.20 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.2 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10-5.08 (m, 1 H), 4.94-4.92 (m, 1 H), 4.81-4.78 (m, 1 H), 4.66-4.63 (m, 1 H), 4.50-4.49 (m, 1 H), 4.39-4.31 (m, 1.8 H), 3.94 (d, J=13.6 Hz, 1 H), 3.79 (d, J=13.6 Hz, 1 H), 3.39-3.38 (m, 1.6 H), 2.70-2.69 (m, 3 H), 2.43-2.32 (m, 3H), 1.92-1.91 (m, 2 H), 1.63-1.59 (m, 2 H), 1.39-1.28 (m, 3.2 H), 0.88-0.85 (m, 2.3H). Example 20 Preparation of Crystal Form R of the n-Propanol Solvate of Compound I Weighed about 20 mg of Compound I, suspended it in 0.5 mL of methyl tert-butyl ether / n-propanol (1:1 v:v), stirred it at 50 °C for 3 days, filtered it, dried the filter cake in an oven at 50 °C to obtain Crystal Form R of the n-propanol solvate of the compound, and characterized the product by XRPD (Figure 19), DSC (Figure 40), and TGA (Figure 61) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.80 (br, 1H), 8.27 (s, 1 H), 7.81 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.45 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J = 8.8 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.94 - 4.92 (m, 1 H), 4.81 - 4.78 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.50 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1.6 H), 3.95 (d, J = 13.6 Hz, 1 H), 3.79 (d, J = 13.6 Hz, 1 H), 3.36 - 3.32 (m, 1H), 2.71 - 2.69 (m, 3 H), 2.49 - 2.32 (m, 3H), 1.92 - 1.91 (m, 2 H), 1.63 - 1.59 (m, 2 H), 1.44 - 1.39 (m, 1.6 H), 0.85 - 0.82 (m, 2.5 H). Example 21 Preparation of Crystal Form S of the Tetrahydrofuran Solvate of Compound I Approximately 20 mg of Compound I was weighed, dissolved in 0.5 mL of tetrahydrofuran, and the solution was placed in a 20 mL vial containing 3 mL of isopropyl ether. The 20 mL vial was sealed with a cap and allowed to stand at room temperature for 2 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form S of the tetrahydrofuran solvate of the compound, and the product was characterized by XRPD (Figure 20), DSC (Figure 41), and TGA (Figure 62) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.80 (br, 1H), 8.26 (s, 1 H), 7.81 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J=7.6 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 7.45 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J=8.8 Hz, 1 H), 7.19 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.2 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10-5.08 (m, 1 H), 4.94-4.92 (m, 1 H), 4.78-4.76 (m, 1 H), 4.66-4.63 (m, 1 H), 4.50-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.95 (d, J=13.6 Hz, 1 H), 3.79 (d, J=13.6 Hz, 1 H), 3.62-3.59 (m, 2.8 H), 2.73-2.69 (m, 3 H), 2.43-2.32 (m, 3H), 1.92-1.90 (m, 2 H), 1.78-1.74 (m, 2.7 H), 1.63-1.61 (m, 2 H). Example 22 Preparation of Crystal Form T of the 2-Methyltetrahydrofuran Solvate of Compound I Weighed about 20 mg of Compound I, dissolved it in 0.5 mL of 2-methyltetrahydrofuran, and placed the solution in a 20 mL vial containing 3 mL of ethyl ether. The 20 mL vial was sealed with a lid and allowed to stand at room temperature for 2 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form T of the 2-methyltetrahydrofuran solvate of the compound, and the product was characterized by XRPD (Figure 21), DSC (Figure 42), and TGA (Figure 63) analysis. 11H NMR (400 MHz, DMSO-d6): δ 12.80 (br, 1H), 8.27 (s, 1 H), 7.81 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.79 (t, J=7.6 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 7.45 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.29 (t, J=8.8 Hz, 1 H), 7.19 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.2 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 5.18 (s, 2 H), 5.10-5.08 (m, 1 H), 4.94-4.92 (m, 1 H), 4.78-4.76 (m, 1 H), 4.66-4.63 (m, 1 H), 4.50-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.95 (d, J=13.6 Hz, 1 H), 3.83-3.74 (m, 2.5 H), 3.56-3.54 (m, 1 H), 2.73-2.69 (m, 3 H), 2.43-2.32 (m, 3H), 1.94-1.89 (m, 3 H), 1.89-1.79 (m, 1.6 H), 1.63-1.61 (m, 2 H), 1.36-1.26 (m, 2H), 1.12 (d, J=6.8 Hz, 2.3H). Example 2-1 Preparation of (S)-2-((4-((6-((4-Cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0432]

Chemical Structure

[0433] Step 1: Synthesis of Methyl (S)-2-((4-((6-((4-Cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (S)-Methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.5 g, 5.1 mmol), 2-(4-Cyano-2-fluorophenoxy)methyl)-6-(piperidin-4-yloxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) were dissolved in N,N-dimethylformamide (80 mL). The resulting mixture was stirred at 60 °C for 3 h, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give methyl (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.1 g, yield 37.2%).

[0434] Step 2: Synthesis of (S)-2-((4-((6-((4-Cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic Acid (S)-Methyl 2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.1 g, 1.9 mmol) was dissolved in a mixed solution of tetrahydrofuran / water (20 mL / 20 mL), and lithium hydroxide (0.13 g, 5.4 mmol) was added. The mixture was stirred at room temperature for 16 h. The mixture obtained was adjusted to pH = 5 - 6 with formic acid, and the solvent was removed in vacuo. The residue was purified by reverse-phase flash column chromatography to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (0.70 g, yield 65.5%). Characterized by XRPD, DSC and TGA, the obtained Compound II is a low crystalline compound, and its X-ray powder diffraction pattern, DSC pattern and TGA pattern are shown in Figures 2-76, 2-77 and 2-78, respectively. 1HNMR (400 MHz, DMSO-d6): δ 8.23 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.6 Hz, 1 H), 7.80 (dd, J = 1.6, 8.8 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.67 (d, J =8.4 Hz, 1 H), 7.60 (d, J =8.8 Hz, 1 H), 7.45 (t, J = 8.4 Hz, 1 H), 7.06 (d, J =7.6 Hz, 1 H), 6.74 (d, J =8.4 Hz, 1 H), 5.31 (s, 2 H), 5.10-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.80-4.74 (m, 1 H), 4.65-4.61 (m, 1 H), 4.50-4.47 (m, 1 H), 4.40-4.35 (m, 1 H), 3.93 (d, J = 13.6 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1 H), 2.79-2.67 (m, 3 H), 2.51-2.41 (m, 1 H), 2.32-2.27 (m, 2 H), 1.92-1.89 (m, 2 H) 1.63-1.60 (m, 2 H). Example 2-2 Preparation of Crystal Form 2A of Compound II 200 mg of Compound II was added to 5.0 mL of isopropanol, stirred at room temperature for 1 day, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2A of Compound II, and the product was characterized by XRPD (Figure 2-1), DSC (Figure 2-26), and TGA (Figure 2-51) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.76 (s, 1 H), 8.27 (s, 1 H), 7.88 (dd, J = 2.0 Hz, 11.6 Hz, 1 H), 7.80 (dd, J = 1.6, 8.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.71 - 7.64 (m, 2 H), 7.44 (t, J = 8.4 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 5.31 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.92 - 4.90 (m, 1 H), 4.80 - 4.74 (m, 1 H), 4.66 - 4.61 (m, 1 H), 4.51 - 4.49 (m, 1 H), 4.40 - 4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.73 - 2.69 (m, 3 H), 2.50 - 2.30 (m, 3 H), 1.91 - 1.89 (m, 2 H) 1.63 - 1.61 (m, 2 H). Example 2-3 Preparation of Crystal Form 2B of Compound II 20 mg of Compound II was added to 0.5 mL of acetone / water (1:6 v:v), stirred at 50 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2B of Compound II, and the product was characterized by XRPD (Figure 2-2), DSC (Figure 2-27), and TGA (Figure 2-52) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.76 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J = 2.0 Hz, 11.6 Hz, 1 H), 7.80 (dd, J = 1.6, 8.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.71 - 7.65 (m, 2 H), 7.45 (t, J = 8.4 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.74 (d, J = 8.4 Hz, 1 H), 5.31 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.92 - 4.90 (m, 1 H), 4.80 - 4.74 (m, 1 H), 4.66 - 4.63 (m, 1 H), 4.51 - 4.49 (m, 1 H), 4.40 - 4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.70 - 2.69 (m, 3 H), 2.51 - 2.30 (m, 3 H), 1.91 - 1.89 (m, 2 H) 1.61 - 1.59 (m, 2 H). Example 2 - 4 Preparation of Crystal Form 2C of Compound II 20 mg of Compound II was dissolved in 0.2 mL of ethanol / toluene (2:1 v:v), left at room temperature, the solvent was gradually evaporated, and the resulting solid was dried at 50 °C to obtain Crystal Form 2C of Compound II. The product was characterized by XRPD (Figure 2 - 3), DSC (Figure 2 - 28), and TGA (Figure 2 - 53) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.76 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.6 Hz, 1 H), 7.80 (dd, J = 1.6, 8.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.71-7.65 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.05 (d, J =7.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.10-5.09 (m, 1 H), 4.92-4.91 (m, 1H), 4.80-4.75 (m, 1 H), 4.66-4.64 (m, 1 H), 4.51-4.49 (m, 1 H), 4.39-4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.70-2.69 (m, 3 H), 2.50-2.30 (m, 3 H), 1.91-1.89 (m, 2 H) 1.61-1.59 (m, 2 H). Example 2-5 Preparation of Crystal Form 2D of Compound II 20 mg of Compound II was added to 0.5 mL of isopropyl acetate / dichloromethane (6:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2D of Compound II, and the product was characterized by XRPD (Figure 2-4), DSC (Figure 2-29), and TGA (Figure 2-54) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.77 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.06 (d, J =7.5 Hz, 1 H), 6.74 (d, J =8.6 Hz, 1 H), 5.31 (s, 2 H), 5.10-5.08 (m, 1 H), 4.92-4.91 (m, 1H), 4.80-4.75 (m, 1 H), 4.66-4.64 (m, 1 H), 4.51-4.49 (m, 1 H), 4.39-4.36 (m, 1 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.76 (d, J = 13.5 Hz, 1 H), 2.76-2.71 (m, 3 H), 2.50-2.30 (m, 3 H), 1.96-1.90 (m, 2 H) 1.61-1.59 (m, 2 H). Example 2-6 Preparation of Crystal Form 2E of Compound II 20 mg of Compound II was suspended in 0.5 mL of chloroform / n-heptane (1:9 v:v), stirred at 50 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2E of Compound II, and the product was characterized by XRPD (Figure 2-5), DSC (Figure 2-30), and TGA (Figure 2-55) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.75 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.72 (t, J = 8.1 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.45 (t, J = 8.6 Hz, 1 H), 7.05 (d, J =7.5 Hz, 1 H), 6.73 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.11-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.80-4.77 (m, 1 H), 4.66-4.64 (m, 1 H), 4.50-4.48 (m, 1 H), 4.38-4.36 (m, 1 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.67-2.60 (m, 3 H), 2.50-2.30 (m, 3 H), 1.90-1.88 (m, 2 H) 1.62-1.60 (m, 2 H). Example 2-7 Preparation of Hydrate Crystal Form 2F of Compound II 20 mg of Compound II was suspended in 0.5 mL of ethanol / water (1:4 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2F of Compound II, and the product was characterized by XRPD (Figure 2-6), DSC (Figure 2-31), and TGA (Figure 2-56) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.69 (br, 1 H), 8.26 (s, 1 H), 7.87 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.44 (t, J = 8.6 Hz, 1 H), 7.06 (d, J =7.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.11-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.80-4.77 (m, 1 H), 4.66-4.64 (m, 1 H), 4.50-4.48 (m, 1 H), 4.38-4.36 (m, 1 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.67-2.60 (m, 3 H), 2.50-2.30 (m, 3 H), 1.90-1.88 (m, 2 H),1.62-1.60 (m, 2 H). Example 2-8 Preparation of Hydrate Crystal Form 2G of Compound II 20 mg of Compound II was suspended in 0.5 mL of ethyl acetate / toluene (1:3 v:v), stirred at 50 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Hydrate Crystal Form 2G of Compound II, and the product was characterized by XRPD (Figure 2-7), DSC (Figure 2-32), and TGA (Figure 2-57) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.71 (br, 1 H), 8.26 (s, 1 H), 7.87 (dd, J = 2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.71 - 7.63 (m, 2 H), 7.445 (t, J = 8.5 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 5.31 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.92 - 4.90 (m, 1 H), 4.80 - 4.78 (m, 1 H), 4.66 - 4.64 (m, 1 H), 4.50 - 4.48 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.70 - 2.69 (m, 3 H), 2.50 - 2.30 (m, 3 H), 1.90 - 1.88 (m, 2 H) 1.61 - 1.59 (m, 2 H). Example 2 - 9 Preparation of Crystal Form 2H of the Dimethyl Sulfoxide Solvate of Compound II 20 mg of Compound II was placed in a 3 mL vial, which was then placed in a 20 mL vial containing 3 mL of DMSO. The 20 mL vial was sealed with a cap and kept at room temperature for 10 days. The resulting solid was dried in an oven at 50 °C to obtain Crystal Form 2H of the hydrate of Compound II, and the product was characterized by XRPD (Figure 2 - 8), DSC (Figure 2 - 33), and TGA (Figure 2 - 58) analyses. 11H NMR (400 MHz, CD3OD): δ 8.23 (s, 1 H), 7.97 (dd, J = 8.5 Hz, 1.2 Hz, 1 H), 7.69 - 7.65 (m, 2 H), 7.56 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.50 (d, J = 11.2 Hz, 2.0 Hz, 1 H), 7.32 (t, J = 8.7 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1 H), 7.51 - 7.49 (m, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 5.25 (s, 3 H), 5.15 - 5.03 (m, 1 H), 4.74 - 4.73 (m, 2 H), 4.51 - 4.49 (m, 1 H), 4.04 (d, J = 13.5 Hz, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 2.83 - 2.79 (m, 3 H), 2.65 (s, 6 H), 2.48 - 2.46 (m, 3 H), 2.01 - 1.99 (m, 2 H), 1.30 - 1.29 (m, 2 H). Example 2 - 10 Preparation of Crystal Form 2I of the Methyl tert - Butyl Ether Solvate of Compound II 20 mg of Compound II was suspended in 0.5 mL of dioxane / methyl tert - butyl ether (1:9 v:v), stirred at 50 °C for 2 hours, then cooled to 5 °C and stirred for 2 hours, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2I of the methyl tert - butyl ether solvate of Compound II, and the product was characterized by XRPD (Figure 2 - 9), DSC (Figure 2 - 34), and TGA (Figure 2 - 59) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.76 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.75 (t, J = 8.1 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.05 (d, J =5.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.91-4.90 (m, 1H), 4.79-4.76 (m, 1 H), 4.65-4.62 (m, 1 H), 4.50-4.47 (m, 1 H), 4.38-4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 3.57 (s, 1.5 H), 2.75-2.69 (m, 3 H), 2.50-2.41 (m, 3 H), 1.91-1.89 (m, 2 H),1.63-1.58 (m, 2 H),1.11 (s, 4.5 H). Example 2-11 Preparation of Crystal Form 2J-1 of the n-Heptane Solvate of Compound II 20 mg of Compound II was suspended in 0.5 mL of acetone / n-heptane (1:4 v:v), stirred at 5 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2J-1 of the n-heptane solvate of Compound II, and the product was characterized by XRPD (Figure 2-10), DSC (Figure 2-35), and TGA (Figure 2-60) analyses. 11H NMR (400 MHz, DMSO-d6) δ 12.75 (br, 1 H), 8.26 (s, 1 H), 7.87 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.05 (d, J =5.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.91-4.90 (m, 1H), 4.79-4.76 (m, 1 H), 4.65-4.61 (m, 1 H), 4.51-4.48 (m, 1 H), 4.38-4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.70-2.69 (m, 3 H), 2.50-2.43 (m, 3 H), 1.90-1.88 (m, 2 H),1.61-1.59 (m, 2 H),1.24 (s, 2 H), 0.86 (s, 1.3 H). Example 2-12 Preparation of Crystal Form 2J-2 of the n-Heptane Solvate of Compound II 20 mg of Compound II was dissolved in 3.0 mL of chloroform / n-heptane (2:1 v:v), left at room temperature, the solvent was gradually evaporated, and the resulting solid was dried at 50 °C to obtain Crystal Form 2J-2 of the n-heptane solvate of Compound II. The product was characterized by XRPD (Figure 2-11), DSC (Figure 2-36), and TGA (Figure 2-61) analyses. 11H NMR (400 MHz, DMSO-d6) δ 12.55 (br, 1 H), 8.27 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.43 (t, J = 8.5 Hz, 1 H), 7.06 (d, J =5.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.91-4.90 (m, 1H), 4.78-4.76 (m, 1 H), 4.67-4.65 (m, 1 H), 4.51-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.80 (d, J = 13.5 Hz, 1 H), 2.70-2.69 (m, 3 H), 2.33-2.30 (m, 3 H), 1.90-1.88 (m, 2 H),1.61-1.59 (m, 2 H),1.24 (s, 4 H), 0.87-0.86 (m, 2.5 H). Example 2-13 Preparation of Crystal Form 2K of the Toluene Solvate of Compound II Weighed about 20 mg of Compound II, suspended it in 0.5 mL of toluene, stirred it at 50 °C for 2 hours, then cooled it to 5 °C and stirred for 2 hours, filtered it, and dried the filter cake in an oven at 50 °C to obtain Crystal Form 2K of the toluene solvate of Compound II. The product was characterized by XRPD (Figure 2-12), DSC (Figure 2-37), and TGA (Figure 2-62) analyses. 11H NMR (400 MHz, DMSO-d6) δ 12.73 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.27-7.13 (m, 4 H), 7.06 (d, J =5.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.81-4.79 (m, 1 H), 4.65-4.62 (m, 1 H), 4.52-4.49 (m, 1 H), 4.40-4.36 (m, 1 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.80 (d, J = 13.5 Hz, 1 H), 2.75-2.69 (m, 3 H), 2.46-2.41 (m, 3 H), 2.30 (s, 2.5 H), 1.90-1.88 (m, 2 H),1.63-1.58 (m, 2 H). Example 2-14 Preparation of Crystal Form 2L-1 of Methyl Isobutyl Ketone Solvate of Compound II Weighed about 20 mg of Compound II, suspended it in 0.5 mL of methyl isobutyl ketone, stirred it at room temperature for 3 days, filtered it, dried the filter cake in an oven at 50 °C to obtain Crystal Form 2L-1 of the methyl isobutyl ketone solvate of Compound II, and characterized the product by XRPD (Figure 2-13), DSC (Figure 2-38) and TGA (Figure 2-63) analyses. 11H NMR (400 MHz, DMSO-d6) δ 12.76 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.79 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.67-7.62 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.06 (d, J =5.5 Hz, 1 H), 6.73 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.81-4.79 (m, 1 H), 4.65-4.62 (m, 1 H), 4.52-4.49 (m, 1 H), 4.40-4.36 (m, 1 H), 3.93 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.70-2.69 (m, 3 H), 2.43-2.30 (m, 5 H), 2.06 (s, 2 H), 2.00-1.98 (m, 0.6 H), 1.90-1.88 (m, 2 H),1.61-1.59 (m, 2 H), 0.85 (d, J = 5.8 Hz, 4 H). Example 2-15 Preparation of Crystal Form 2L-2 of Methyl Isobutyl Ketone Solvate of Compound II Weighed about 20 mg of Compound II, suspended it in 0.5 mL of methyl isobutyl ketone / chloroform (9:1 v:v), stirred it at 50 °C for 2 hours, then cooled it to 5 °C and stirred for 2 hours, filtered it, and dried the filter cake in an oven at 50 °C to obtain Crystal Form 2L-2 of Methyl Isobutyl Ketone Solvate of Compound II. The product was characterized by XRPD (Figure 2-14), DSC (Figure 2-39), and TGA (Figure 2-64) analysis. 11H NMR (400 MHz, DMSO-d6) δ 12.76 (br, 1 H), 8.26 (s, 1 H), 7.89 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.79 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.06 (d, J =5.5 Hz, 1 H), 6.73 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.81-4.79 (m, 1 H), 4.65-4.62 (m, 1 H), 4.51-4.49 (m, 1 H), 4.39-4.36 (m, 1 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.70-2.69 (m, 3 H), 2.43-2.29 (m, 3.5 H), 2.06 (s, 1 H), 2.00-1.98 (m, 0.3 H), 1.91-1.89 (m, 2 H),1.61-1.59 (m, 2 H), 0.85 (d, J = 5.8 Hz, 2.2 H). Example 2-16 Preparation of Crystal Form 2M-1 of the Cyclopentylmethyl Ether Solvate of Compound II Weighed about 20 mg of Compound II, suspended it in 0.5 mL of methanol / cyclopentylmethyl ether (1:6 v:v), stirred it at room temperature for 3 days, filtered it, and dried the filter cake in an oven at 50 °C to obtain Crystal Form 2M-1 of the cyclopentylmethyl ether solvate of Compound II. The product was characterized by XRPD (Figure 2-15), DSC (Figure 2-40), and TGA (Figure 2-65) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.74 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.81 (dd, J = 1.7, 8.8 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.06 (d, J =7.5 Hz, 1 H), 6.74 (d, J =8.6 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.81-4.76 (m, 1 H), 4.66-4.62 (m, 1 H), 4.52-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.79 (d, J = 13.5 Hz, 1 H), 3.75-3.74 (m, 1H), 3.31 (s, 3 H), 2.75-2.69 (m, 3 H), 2.50-2.30 (m, 3 H), 1.91-1.89 (m, 2 H), 1.63-1.46 (m, 10 H). Example 2-17 Preparation of Crystal Form 2M-2 of the Cyclopentylmethyl Ether Solvate of Compound II Weighed about 20 mg of Compound II, dissolved it in 0.8 mL of dioxane / toluene (1:1 v:v), added the solution dropwise to 3.0 mL of cyclopentylmethyl ether, filtered it, dried the filter cake in an oven at 50 °C to obtain Crystal Form 2M-2 of the cyclopentylmethyl ether solvate of Compound II, and characterized the product by XRPD (Figure 2-16), DSC (Figure 2-41), and TGA (Figure 2-66) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.88 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.8 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.06 (d, J =7.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.77-4.76 (m, 1 H), 4.66-4.62 (m, 1 H), 4.50-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.93 (d, J = 13.5 Hz, 1 H), 3.77 (d, J = 13.5 Hz, 1 H), 3.75-3.74 (m, 0.3 H), 3.32 (s, 1.2 H), 2.75-2.69 (m, 3 H), 2.50-2.30 (m, 3 H), 1.91-1.90 (m, 2 H), 1.63-1.50 (m, 6 H). Example 2-18 Preparation of Crystal Form 2N of the Methyl Ethyl Ketone Solvate of Compound II Weighed about 20 mg of Compound II, suspended it in 0.5 mL of methyl ethyl ketone / acetonitrile (1:2 v:v), stirred it at 50 °C for 3 days, filtered it, and dried the filter cake in an oven at 50 °C to obtain Crystal Form 2N of the methyl ethyl ketone solvate of Compound II. The product was characterized by XRPD (Figure 2-17), DSC (Figure 2-42), and TGA (Figure 2-67) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.65 (br, 1 H), 8.26 (s, 1 H), 7.87 (dd, J = 2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.71 - 7.63 (m, 2 H), 7.45 (t, J = 8.6 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 6.74 (d, J = 8.5 Hz, 1 H), 5.31 (s, 2 H), 5.10 - 5.08 (m, 1 H), 4.92 - 4.90 (m, 1 H), 4.80 - 4.78 (m, 1 H), 4.66 - 4.64 (m, 1 H), 4.50 - 4.48 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.79 (d, J = 13.5 Hz, 1 H), 2.70 - 2.69 (m, 3 H), 2.46 - 2.30 (m, 4 H), 2.07 (s, 1.2 H), 1.91 - 1.89 (m, 2 H), 1.61 - 1.59 (m, 2 H), 0.93 - 0.89 (m, 1.2 H). Example 2 - 19 Preparation of Crystal Form 2O of the Methylcyclohexane Solvate of Compound II Weighed about 20 mg of Compound II, suspended it in 0.5 mL of acetone / methylcyclohexane (1:4 v:v), stirred it at room temperature for 3 days, filtered it, dried the filter cake in an oven at 50 °C to obtain Crystal Form 2O of the methylcyclohexane solvate of Compound II, and characterized the product by XRPD (Figure 2 - 18), DSC (Figure 2 - 43), and TGA (Figure 2 - 68) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.77 (br, 1 H), 8.26 (s, 1 H), 7.87 (dd, J = 2.0 Hz, 11.5 Hz, 1 H), 7.79 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.71 - 7.62 (m, 2 H), 7.45 (t, J = 8.6 Hz, 1 H), 7.05 (d, J = 7.5 Hz, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 5.31 (s, 2 H), 5.11 - 5.08 (m, 1 H), 4.92 - 4.90 (m, 1 H), 4.80 - 4.77 (m, 1 H), 4.66 - 4.64 (m, 1 H), 4.50 - 4.48 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.93 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.70 - 2.69 (m, 3 H), 2.50 - 2.32 (m, 3 H), 1.90 - 1.88 (m, 2 H), 1.62 - 1.60 (m, 7 H), 1.55 - 1.05 (m, 5 H), 0.84 (d, J = 3.9 Hz, 4 H). Example 2 - 20 Preparation of Crystal Form 2P of the DMF Solvate of Compound II Weighed approximately 20 mg of Compound II, suspended it in 0.5 mL of DMF / methyl tert-butyl ether (1:9 v:v), stirred it at 50 °C for 3 days, filtered it, dried the filter cake in an oven at 50 °C to obtain Crystal Form 2P of the DMF solvate of Compound II, and characterized the product by XRPD (Figure 2 - 19), DSC (Figure 2 - 44), and TGA (Figure 2 - 69) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.72 (br, 1 H), 8.26 (s, 1 H), 7.86 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.46 (t, J = 8.5 Hz, 1 H), 7.05 (d, J =7.5 Hz, 1 H), 6.73 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.11-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.80-4.77 (m, 1 H), 4.66-4.64 (m, 1 H), 4.50-4.48 (m, 1 H), 4.39-4.37 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.89-2.69 (m, 9 H), 2.50-2.30 (m, 3 H), 1.91-1.89 (m, 2 H) 1.61-1.59 (m, 2 H). Example 2-21 Preparation of Crystal Form 2Q-1 of the 2-Methyltetrahydrofuran Solvate of Compound II Weighed about 20 mg of Compound II, suspended it in 0.5 mL of 2-methyltetrahydrofuran, stirred it at 5 °C for 3 days, filtered it, and dried the filter cake in an oven at 50 °C to obtain Crystal Form 2Q-1 of the 2-methyltetrahydrofuran solvate of Compound II. The product was characterized by XRPD (Figure 2-20), DSC (Figure 2-45), and TGA (Figure 2-70) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.55 (br, 1 H), 8.27 (s, 1 H), 7.88 (dd, J=2.1 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.68-7.63 (m, 2 H), 7.45 (t, J = 8.6 Hz, 1 H), 7.06 (d, J =7.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.10-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.80-4.77 (m, 1 H), 4.66-4.64 (m, 1 H), 4.51-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.85-3.52 (m, 6 H), 2.70-2.69 (m, 3 H), 2.45-2.30 (m, 3 H), 1.95-1.77 (m, 7 H),1.62-1.60 (m, 2 H), 1.34-1.29 (m, 2 H), 1.24 (d, J = 6.8 Hz, 5H). Example 2-22 Preparation of Crystal Form 2Q-2 of the 2-Methyltetrahydrofuran Solvate of Compound II Weighed about 20 mg of Compound II, suspended it in 0.5 mL of 2-methyltetrahydrofuran / n-hexane (1:2 v:v), stirred it at 50 °C for 2 hours, then cooled it to 5 °C and stirred for 2 hours, filtered it, and dried the filter cake in an oven at 50 °C to obtain Crystal Form 2Q-2 of the 2-methyltetrahydrofuran solvate of Compound II. The product was characterized by XRPD (Figure 2-21), DSC (Figure 2-46), and TGA (Figure 2-71) analysis. 1HNMR (400 MHz, DMSO-d6): δ 12.75 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.1 Hz, 11.5 Hz, 1 H), 7.81 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.68-7.62 (m, 2 H), 7.45 (t, J = 8.6 Hz, 1 H), 7.06 (d, J =6.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.77-4.75 (m, 1 H), 4.66-4.64 (m, 1 H), 4.51-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.81-3.54 (m, 3 H), 2.70-2.69 (m, 3 H), 2.45-2.30 (m, 3 H), 1.92-1.79 (m, 2 H), 1.63-1.60 (m, 2 H), 1.34-1.29 (m, 2 H), 1.24 (d, J = 6.8 Hz, 2H). Example 2-23 Preparation of Crystal Form 2R of the N-Methylpyrrolidone Solvate of Compound II 20 mg of Compound II was dissolved in 0.5 mL of N-methylpyrrolidone / ethyl acetate (1:1 v:v), added dropwise to 4.0 mL of methyl tert-butyl ether, stirred at room temperature for 1 hour, filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2R of the N-methylpyrrolidone solvate of Compound II. The product was characterized by XRPD (Figure 2-22), DSC (Figure 2-47), and TGA (Figure 2-72) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.70 (br, 1 H), 8.26 (s, 1 H), 7.87 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.5 Hz, 1 H), 7.73 (t, J = 8.1 Hz, 1 H), 7.67-7.63 (m, 2 H), 7.45 (t, J = 8.6 Hz, 1 H), 7.06 (d, J =7.5 Hz, 1 H), 6.74 (d, J =8.5 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.79-4.77 (m, 1 H), 4.66-4.62 (m, 1 H), 4.52-4.47 (m, 1 H), 4.40-4.35 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 2.75-2.70 (m, 8 H), 2.50-2.30 (m, 3 H), 2.20-2.16 (m, 3 H), 1.94-1.86 (m, 5 H) 1.61-1.59 (m, 2 H). Example 2-24 Preparation of Crystal Form 2S of the Trifluoroethanol Solvate of Compound II 20 mg of Compound II was dissolved in 0.2 mL of trifluoroethanol / ethyl acetate (1:1 v:v), and the solution was placed in a 20 mL vial containing 3.0 mL of methyl tert-butyl ether. The 20 mL vial was sealed with a cap, kept at room temperature for 2 days, then filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2S of the trifluoroethanol solvate of Compound II, and the product was characterized by XRPD (Figure 2-23), DSC (Figure 2-48), and TGA (Figure 2-73) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.75 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.06 (d, J =6.5 Hz, 1 H), 6.74 (d, J =8.6 Hz, 1 H), 5.31 (s, 2 H), 5.10-5.08 (m, 1 H), 4.92-4.91 (m, 1H), 4.80-4.75 (m, 1 H), 4.66-4.64 (m, 1 H), 4.51-4.49 (m, 1 H), 4.39-4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.92-3.86 (m, 1H), 3.78 (d, J = 13.5 Hz, 1 H), 2.70-2.69 (m, 3 H), 2.50-2.30 (m, 3 H), 1.90-1.88 (m, 2 H), 1.61-1.59 (m, 2 H). Example 2-25 Preparation of Crystal Form 2T of the Tetrahydrofuran Solvate of Compound II 20 mg of Compound II was dissolved in 0.5 mL of tetrahydrofuran and gradually volatilized at room temperature for 2 days, then filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2T of the tetrahydrofuran solvate of Compound II. The product was characterized by XRPD (Figure 2-24), DSC (Figure 2-49), and TGA (Figure 2-74) analyses. 1HNMR (400 MHz, DMSO-d6): δ 12.78 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.5 Hz, 1 H), 7.80 (dd, J = 1.7, 8.8 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.06 (d, J =7.5 Hz, 1 H), 6.74 (d, J =8.6 Hz, 1 H), 5.31 (s, 2 H), 5.09-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.81-4.76 (m, 1 H), 4.66-4.62 (m, 1 H), 4.51-4.49 (m, 1 H), 4.40-4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 3.62-3.59 (m, 1.4 H), 2.75-2.69 (m, 3 H), 2.50-2.30 (m, 3 H), 1.90-1.88 (m, 2 H), 1.78-1.76 (m, 1.4 H), 1.63-1.60 (m, 2 H). Example 2-26 Preparation of Crystal Form 2U of the Dioxane Solvate of Compound II 20 mg of Compound II was dissolved in 0.3 mL of dioxane, and the solution was placed in a 20 mL vial containing 3.0 mL of n-hexane. The 20 mL vial was sealed with a lid, kept at room temperature, left standing for 11 days, then filtered, and the filter cake was dried in an oven at 50 °C to obtain Crystal Form 2U of the dioxane solvate of Compound II, and the product was characterized by XRPD (Figure 2-25), DSC (Figure 2-50), and TGA (Figure 2-75) analyses. 11H NMR (400 MHz, DMSO-d6): δ 12.78 (br, 1 H), 8.26 (s, 1 H), 7.88 (dd, J = 2.0 Hz, 11.6 Hz, 1 H), 7.79 (dd, J = 1.6, 8.8 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.68 - 7.63 (m, 2 H), 7.45 (t, J = 8.5 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 6.74 (d, J = 8.5 Hz, 1 H), 5.31 (s, 2 H), 5.10 - 5.09 (m, 1 H), 4.92 - 4.91 (m, 1 H), 4.80 - 4.75 (m, 1 H), 4.66 - 4.64 (m, 1 H), 4.51 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.94 (d, J = 13.5 Hz, 1 H), 3.78 (d, J = 13.5 Hz, 1 H), 3.57 (s, 6 H), 2.70 - 2.69 (m, 3 H), 2.50 - 2.30 (m, 3 H), 1.90 - 1.88 (m, 2 H), 1.61 - 1.59 (m, 2 H). Test Example 1: Study on the equilibrium solubility of the crystalline polymorphs of Compound I in biological media For the amorphous solid of Compound I and the crystalline form D of Compound I, the equilibrium solubilities in water (H2O), simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF) were measured. In the test, the solid was prepared as a suspension (~10 mg / mL) in the corresponding buffer solution and mixed at 37 ± 2 °C. After 24 hours, the suspension was sampled, the supernatant was filtered, the concentration was measured, and XRPD measurement of the solid was performed. The detection results are shown in the following table.

[0435]

Table 47

[0436] As can be seen from the above experimental results, the crystalline form D of Compound I is clearly superior in stability in a biological medium to the amorphous solid of Compound I. In the FaSSGF system, except that the crystalline form changed to the hydrochloride, no change in the crystalline form was observed in any of the other samples. Its solubility in the FaSSIF system was also clearly improved, and it can meet the requirements for the clinical formulation development of the drug. Therefore, the free form of Compound I can obtain remarkable improvements in terms of solubility and drug release behavior after salt formation.

[0437] Study on the Solid Stability of the Crystal Polymorphs of Compound I The amorphous solid of Compound I and the crystalline form D of Compound I were each left standing for 7 days under the conditions of long-term (25°C / 60%RH), accelerated (40°C / 75%RH), and high temperature (60°C, RH < 30%). The changes in HPLC purity and crystalline form were measured to examine the solid stability, and the results are shown in the following table.

[0438]

Table 48

[0439] As can be seen from the above experimental results, for the amorphous solid of Compound I, there was no obvious change in purity after standing for 7 days under long-term conditions, but significant decomposition occurred after 7 days under accelerated and high-temperature conditions. For the crystalline form D of Compound I, there was no obvious change in purity after standing for 7 days under long-term conditions, and there was only a slight decrease after standing for 7 days under accelerated and high-temperature conditions, and no obvious change in the crystalline form. The stability of the crystalline form D is clearly superior to that of the amorphous solid.

[0440] Measurement of the Hygroscopic Behavior of Compound I The inventors evaluated the stability risk of the sample with the change in humidity at 25°C according to the dynamic moisture adsorption method, performed DVS measurement on the typical crystalline form D of Compound I, evaluated the hygroscopicity of the crystalline form of the compound. The DVS pattern of the amorphous solid of the compound is shown in Figure 67, and the DVS pattern of the crystalline form D of the compound is shown in Figure 68. The obtained results are shown in the following table.

[0441]

Table 49

[0442] As can be seen from the above experimental results, in the adsorption curve of 0 - 90% RH, at the condition of 80% RH, both the amorphous solid of Compound I and the sample of Crystal Form D were slightly hygroscopic, with no obvious difference, and no change in the solid form was observed for either of them.

[0443] A summary of the thermal analysis of some crystal forms of the compound of the present invention is shown in the following table.

[0444]

Table 50

[0445] Test Example 2 Study on the Equilibrium Solubility of the Crystal Polymorphs of Compound II in Biological Media For Crystal Form 2A of Compound II, the equilibrium solubilities in water (H2O), simulated fasting gastric juice (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF) were measured. In the test, the solid was prepared as a suspension (~10 mg / mL) in the corresponding buffer solution and mixed at 37 ± 2°C. After 24 hours, the suspension was sampled, the supernatant was filtered, the concentration was measured, and XRPD measurement of the solid was performed. The detection results are shown in the following table.

[0446]

Table 51

[0447] As can be seen from the above experimental results, Crystal Form 2A of Compound II is significantly more stable in biological media than the amorphous solid of Compound II. Crystal Form 2A of Compound II has relatively good stability in other biological media except that the crystal form changed to hydrochloride in the FaSSGF system, and no change in the crystal form was observed, which can meet the requirements for the clinical formulation development of the drug.

[0448] Study on the Solid Stability of the Crystal Polymorphs of Compound II The crystal form 2A of Compound II was left standing for 7 days under the conditions of long-term (25°C / 60% RH), accelerated (40°C / 75% RH), and high temperature (60°C, RH < 30%) respectively, and the changes in HPLC purity and crystal form were measured to examine the solid stability. The results are shown in the following table.

[0449]

Table 52

[0450] As can be seen from the above experimental results, the crystal form 2A of Compound II showed no obvious change in purity and no change in crystal form after standing for 7 days under long-term conditions, accelerated conditions, and high temperature conditions, suggesting that the solid stability of crystal form 2A is relatively good.

[0451] Measurement of the Moisture Absorption Behavior of Compound II The inventors evaluated the stability risk of the sample with the change of humidity at 25°C according to the dynamic moisture adsorption method, performed DVS measurement on the representative crystal form 2A of Compound II, evaluated the hygroscopicity of the crystal form of the compound, and the DVS pattern of the crystal form 2A of Compound II is shown in Figure 2-79, and the obtained results are shown in the following table.

[0452]

Table 53

[0453] As can be seen from the above experimental results, in the adsorption curve of 0 - 90% RH, under the condition of 80% RH, the sample of the crystal form 2A of Compound II was slightly hygroscopic and no change in solid form was observed.

[0454] A summary of the thermal analysis of some crystal forms of Compound II of the present invention is shown in the following table.

[0455]

Table 54

[0456] The embodiments of the technical solution of the present invention have been exemplarily described above. It should be understood that the claims of the present invention are not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the scope of not departing from the gist and principles of the present invention should all be included within the scope of the claims of this application.

Claims

1. 【Fig. 1】 X is selected from Cl or CN, a crystalline polymorph of Compound III. **Claim 2** The crystalline polymorph may be a solvate-free crystal form, a hydrate crystal form or a solvate crystal form of Compound III, preferably, Compound III has a structure shown in Compound I or Compound II, The crystalline polymorph according to Claim 1. 【Chemical 2】 **Claim 3** The crystalline polymorph is a solvate-free crystal form of Compound I including the following solvent-free crystal forms A, B, C, D, E, F, among which, the crystal form A has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 19.79±0.2°, 13.13±0.2°, 22.07±0.2° and 9.48±0.2°, preferably, further includes peaks located at diffraction angles (2θ) of 7.80±0.2°, 13.59±0.2°, 11.43±0.2°, 18.07±0.2° and 12.45±0.2°, more preferably, further includes peaks located at diffraction angles (2θ) of 14.58±0.2°, 24.66±0.2°, 14.24±0.2°, 4.85±0.2°, 23.70±0.2° and 26.51±0.2°, preferably, the X-ray powder diffraction pattern of the crystal form A has diffraction angles (2θ) shown in Table 1, among which, the error range of the 2θ angle is ±0.20°, 【Table 1】 preferably, the crystal form A has X-ray powder diffraction intensities shown in Table 1, preferably, the crystal form A basically has an X-ray powder diffraction pattern shown in Figure 1, preferably, in the DSC analysis of the crystal form A, when heated to near the peak temperature of 99.81 °C, an endothermic peak appears, preferably, the crystal form A basically has a DSC pattern shown in Figure 22, preferably, the crystal form A basically has a TGA pattern shown in Figure 43, the crystal form B has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 13.79±0.2°, 22.36±0.2°, 17.66±0.2° and 27.41±0.2°, preferably, further includes peaks located at diffraction angles (2θ) of 11.31±0.2°, 23.16±0.2°, 25.40±0.2°, 5.59±0.2° and 8.74±0.2°, more preferably, further includes peaks located at diffraction angles (2θ) of 20.20±0.2°, 28.85±0.2°, 11.96±0.2°, 24.19±0.2°, 24.39±0.2° and 7.28±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form B has diffraction angles (2θ) shown in Table 2, among which the error range of the 2θ angle is ±0.20°, 【Table 2】 Preferably, the crystalline form B has X-ray powder diffraction intensities shown in Table 2, Preferably, the crystalline form B basically has the X-ray powder diffraction pattern shown in FIG. 2, Preferably, in the DSC analysis of the crystalline form B, when heated to near the peak temperature of 177.71 °C, an endothermic peak appears, Preferably, the crystalline form B basically has the DSC pattern shown in FIG. 23, Preferably, the crystalline form B basically has the TGA pattern shown in FIG. 44, The crystalline form C has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 11.27±0.2°, 19.30±0.2°, 17.92±0.2° and 20.04±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 14.70±0.2°, 22.75±0.2°, 21.21±0.2°, 10.48±0.2° and 18.83±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 4.84±0.2°, 10.20±0.2°, 14.16±0.2°, 22.15±0.2°, 20.41±0.2° and 10.98±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form C has diffraction angles (2θ) shown in Table 3, among which the error range of the 2θ angle is ±0.20°, 【Table 3】 Preferably, the crystalline form C has X-ray powder diffraction intensities shown in Table 3, Preferably, the crystalline form C basically has the X-ray powder diffraction pattern shown in FIG. 3, Preferably, in the DSC analysis of the crystalline form C, when heated to near the peak temperature of 104.51 °C, an endothermic peak appears, Preferably, the crystalline form C basically has the DSC pattern shown in FIG. 24, Preferably, the crystalline form C basically has the TGA pattern shown in FIG. 45, The crystalline form D has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 14.49±0.2°, 16.98±0.2°, 11.51±0.2° and 18.17±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 24.02±0.2°, 21.87±0.2°, 3.58±0.2°, 14.04±0.2° and 20.68±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 19.59±0.2°, 25.60±0.2°, 22.30±0.2°, 22.61±0.2°, 23.53±0.2° and 9.70±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form D has diffraction angles (2θ) shown in Table 4, among which the error range of the 2θ angle is ±0.20°, 【Table 4】 Preferably, the crystalline form D has X-ray powder diffraction intensities shown in Table 4, Preferably, the crystalline form D basically has the X-ray powder diffraction pattern shown in FIG. 4, Preferably, in the DSC analysis of the crystalline form D, when heated to near the peak temperature of 167.48 °C, an endothermic peak appears, Preferably, the crystalline form D basically has the DSC pattern shown in FIG. 25, Preferably, the crystalline form D basically has the TGA pattern shown in FIG. 46, The crystalline form E includes peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 11.49±0.2°, 12.17±0.2°, 21.15±0.2° and 20.16±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 14.35±0.2°, 26.49±0.2°, 19.40±0.2°, 4.32±0.2° and 17.51±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 10.87±0.2°, 25.13±0.2°, 24.68±0.2°, 18.01±0.2°, 16.83±0.2° and 15.19±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form E has diffraction angles (2θ) shown in Table 5, among which the error range of the 2θ angle is ±0.20°, 【Table 5】 Preferably, the crystalline form E has X-ray powder diffraction intensities shown in Table 5, Preferably, the crystalline form E basically has the X-ray powder diffraction pattern shown in FIG. 5, Preferably, in the DSC analysis of the crystalline form E, when heated to near the peak temperature of 112.00 °C, an endothermic peak appears, Preferably, the crystalline form E basically has the DSC pattern shown in FIG. 26, Preferably, the crystalline form E basically has the TGA pattern shown in FIG. 47, The crystalline form F includes peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 18.77±0.2°, 25.50±0.2°, 20.98±0.2° and 23.45±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 10.77±0.2°, 12.70±0.2°, 21.33±0.2°, 24.50±0.2° and 16.89±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 14.72±0.2°, 19.24±0.2°, 9.68±0.2°, 11.7±0.2°, 20.49±0.2° and 13.26±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form F has diffraction angles (2θ) shown in Table 6, among which the error range of the 2θ angle is ±0.20°, 【Table 6】 Preferably, the crystalline form F has X-ray powder diffraction intensities shown in Table 6, Preferably, the crystalline form F basically has an X-ray powder diffraction pattern shown in FIG. 6, Preferably, in the DSC analysis of the crystalline form F, when heated to near the peak temperature of 169.00 °C, an endothermic peak appears, Preferably, the crystalline form F basically has a DSC pattern shown in FIG. 27, Preferably, the crystalline form F basically has a TGA pattern shown in FIG. 48, Preferably, the crystalline polymorph is the hydrate crystalline form G of Compound I, The hydrate crystalline form G includes peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 18.66±0.2°, 18.81±0.2°, 3.62±0.2° and 22.24±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 15.33±0.2°, 17.88±0.2°, 14.76±0.2°, 20.51±0.2° and 11.08±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 19.94±0.2°, 26.57±0.2°, 23.22±0.2°, 24.37±0.2°, 7.32±0.2° and 23.44±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form G has diffraction angles (2θ) shown in Table 7, among which the error range of the 2θ angle is ±0.20°, 【Table 7】 Preferably, the crystalline form G has X-ray powder diffraction intensities shown in Table 7, Preferably, the crystalline form G basically has an X-ray powder diffraction pattern shown in FIG. 7, Preferably, in the DSC analysis of the crystalline form G, when heated to near the peak temperatures of 89.95 °C and 104.07 °C, endothermic peaks appear, Preferably, the crystalline form G basically has a DSC pattern shown in FIG. 28, Preferably, the crystalline form G basically has the TGA pattern shown in FIG. 49, Preferably, the crystalline form G is a dihydrate of Compound I, Preferably, the crystalline polymorphs are solvate crystalline forms of Compound I including the following solvate crystalline forms H, I-1, I-2, J, K, L, M, N, O, P, Q, R, S, T, among which, The crystalline form H of the methyl isobutyl ketone solvate has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 10.75±0.2°, 8.61±0.2°, 19.84±0.2° and 18.48±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 16.79±0.2°, 25.92±0.2°, 9.11±0.2°, 21.15±0.2° and 15.43±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 22.55±0.2°, 3.16±0.2°, 18.95±0.2°, 21.70±0.2°, 12.54±0.2° and 17.86±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form H has the diffraction angles (2θ) shown in Table 8, among which the error range of the 2θ angle is ±0.20°, 【Table 8】 Preferably, the crystalline form H has the X-ray powder diffraction intensities shown in Table 8, Preferably, the crystalline form H basically has the X-ray powder diffraction pattern shown in FIG. 8, Preferably, in the DSC analysis of the crystalline form H, when heated to near the peak temperature of 87.76 °C, an endothermic peak appears, Preferably, the crystalline form H basically has the DSC pattern shown in FIG. 29, Preferably, the crystalline form H basically has the TGA pattern shown in FIG. 50, Preferably, the crystalline form H is a 0.5 methyl isobutyl ketone solvate of Compound I, The crystalline form I-1 of the methyl tert-butyl ether solvate has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 8.53±0.2°, 10.75±0.2°, 4.22±0.2° and 18.39±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 17.22±0.2°, 21.48±0.2°, 16.85±0.2°, 17.53±0.2° and 9.11±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 12.49±0.2°, 19.61±0.2°, 12.87±0.2°, 15.66±0.2°, 26.02±0.2° and 22.40±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form I-1 has diffraction angles (2θ) shown in Table 9, among which the error range of the 2θ angle is ±0.20°. 【Table 9】 Preferably, the crystalline form I-1 has X-ray powder diffraction intensities shown in Table 9. Preferably, the crystalline form I-1 basically has the X-ray powder diffraction pattern shown in FIG.

9. Preferably, in the DSC analysis of the crystalline form I-1, when heated to near the peak temperature of 103.27 °C, an endothermic peak appears. Preferably, the crystalline form I-1 basically has the DSC pattern shown in FIG.

30. Preferably, the crystalline form I-1 basically has the TGA pattern shown in FIG.

51. Preferably, the crystalline form I-1 is a monomethyl tert-butyl ether solvate of Compound I. The crystalline form I-2 of the methyl tert-butyl ether solvate includes peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 16.88±0.2°, 18.87±0.2°, 20.90±0.2° and 9.60±0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 10.98±0.2°, 8.39±0.2°, 17.68±0.2°, 20.51±0.2° and 19.97±0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 21.25±0.2°, 17.99±0.2°, 14.10±0.2°, 16.42±0.2°, 7.40±0.2° and 21.93±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form I-2 has diffraction angles (2θ) shown in Table 10, among which the error range of the 2θ angle is ±0.20°. 【Table 10】 Preferably, the crystalline form I-2 has X-ray powder diffraction intensities shown in Table 10. Preferably, the crystalline form I-2 basically has the X-ray powder diffraction pattern shown in FIG.

10. Preferably, in the DSC analysis of the crystalline form I-2, when heated to near the peak temperature of 97.11 °C, an endothermic peak appears. Preferably, the crystalline form I-2 basically has the DSC pattern shown in FIG.

31. Preferably, the crystalline form I-2 basically has the TGA pattern shown in FIG.

52. Preferably, the crystalline form I-2 is a 1.5 methyl tert-butyl ether solvate of Compound I, The crystalline form J of the acetone solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 12.02 ± 0.2°, 18.03 ± 0.2°, 8.04 ± 0.2° and 7.67 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 19.54 ± 0.2°, 23.50 ± 0.2°, 16.05 ± 0.2°, 21.21 ± 0.2° and 13.83 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 11.10 ± 0.2°, 17.43 ± 0.2°, 16.54 ± 0.2°, 8.92 ± 0.2°, 22.59 ± 0.2° and 27.39 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form J has diffraction angles (2θ) shown in Table 11, among which the error range of the 2θ angle is ±0.20°, 【Table 11】 Preferably, the crystalline form J has the X-ray powder diffraction intensity shown in Table 11, Preferably, the crystalline form J basically has the X-ray powder diffraction pattern shown in Figure 11, Preferably, in the DSC analysis of the crystalline form J, when heated to near the peak temperature of 93.18 °C, an endothermic peak appears, Preferably, the crystalline form J basically has the DSC pattern shown in Figure 32, Preferably, the crystalline form J basically has the TGA pattern shown in Figure 53, Preferably, the crystalline form J is a 0.5 acetone solvate of Compound I, The crystalline form K of the n-heptane solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 12.19 ± 0.2°, 18.02 ± 0.2°, 7.69 ± 0.2° and 19.69 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 21.36 ± 0.2°, 8.98 ± 0.2°, 23.63 ± 0.2°, 16.07 ± 0.2° and 20.72 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 6.85 ± 0.2°, 8.12 ± 0.2°, 13.75 ± 0.2°, 6.54 ± 0.2°, 14.53 ± 0.2° and 13.26 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form K has diffraction angles (2θ) shown in Table 12, among which the error range of the 2θ angle is ±0.20°, 【Table 12】 Preferably, the crystalline form K has the X-ray powder diffraction intensity shown in Table 12, Preferably, the crystalline form K basically has the X-ray powder diffraction pattern shown in FIG. 12, Preferably, in the DSC analysis of the crystalline form K, an endothermic peak appears when heated to near the peak temperature of 91.51 °C, Preferably, the crystalline form K basically has the DSC pattern shown in FIG. 33, Preferably, the crystalline form K basically has the TGA pattern shown in FIG. 54, Preferably, the crystalline form K is a 0.12 n-heptane solvate of Compound I, The crystalline form L of the methylcyclohexane solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 10.98 ± 0.2°, 15.54 ± 0.2°, 9.09 ± 0.2° and 19.01 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 20.39 ± 0.2°, 17.94 ± 0.2°, 8.74 ± 0.2°, 21.03 ± 0.2° and 13.46 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 22.86 ± 0.2°, 18.25 ± 0.2°, 25.63 ± 0.2°, 16.90 ± 0.2°, 24.74 ± 0.2° and 25.95 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form L has the diffraction angles (2θ) shown in Table 13, among which the error range of the 2θ angle is ±0.20°, 【Table 13】 Preferably, the crystalline form L has the X-ray powder diffraction intensity shown in Table 13, Preferably, the crystalline form L basically has the X-ray powder diffraction pattern shown in FIG. 13, Preferably, in the DSC analysis of the crystalline form L, an endothermic peak appears when heated to near the peak temperature of 88.68 °C, Preferably, the crystalline form L basically has the DSC pattern shown in FIG. 34, Preferably, the crystalline form L basically has the TGA pattern shown in FIG. 55, Preferably, the crystalline form L is a 0.15 methylcyclohexane solvate of Compound I, The crystalline form M of the toluene solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 18.62 ± 0.2°, 9.60 ± 0.2°, 16.34 ± 0.2° and 21.62 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 14.84 ± 0.2°, 19.05 ± 0.2°, 19.36 ± 0.2°, 13.08 ± 0.2° and 22.11 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 26.65±0.2°, 24.48±0.2°, 22.36±0.2°, 11.19±0.2°, 20.47±0.2° and 18.19±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form M has diffraction angles (2θ) shown in Table 14, among which the error range of the 2θ angle is ±0.20°. 【Table 14】 Preferably, the crystalline form M has the X-ray powder diffraction intensity shown in Table 14. Preferably, the crystalline form M basically has the X-ray powder diffraction pattern shown in FIG.

14. Preferably, in the DSC analysis of the crystalline form M, when heated to near the peak temperature of 102.43 °C, an endothermic peak appears. Preferably, the crystalline form M basically has the DSC pattern shown in FIG.

35. Preferably, the crystalline form M basically has the TGA pattern shown in FIG.

56. Preferably, the crystalline form M is a monotoluene solvate of Compound I. The crystalline form N of the dioxane solvate includes peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 17.10±0.2°, 20.66±0.2°, 22.71±0.2° and 18.21±0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 21.70±0.2°, 15.05±0.2°, 20.27±0.2°, 21.97±0.2° and 8.53±0.2°. Even more preferably, it further includes peaks located at diffraction angles (2θ) of 19.59±0.2°, 7.52±0.2°, 11.14±0.2°, 16.83±0.2°, 17.47±0.2° and 23.57±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form N has diffraction angles (2θ) shown in Table 15, among which the error range of the 2θ angle is ±0.20°. 【Table 15】 Preferably, the crystalline form N has the X-ray powder diffraction intensity shown in Table 15. Preferably, the crystalline form N basically has the X-ray powder diffraction pattern shown in FIG.

15. Preferably, in the DSC analysis of the crystalline form N, when heated to near the peak temperature of 116.48 °C, an endothermic peak appears. Preferably, the crystalline form N basically has the DSC pattern shown in FIG.

36. Preferably, the crystalline form N basically has the TGA pattern shown in FIG.

57. Preferably, the crystalline form N is a 1.5 dioxane solvate of Compound I. The crystal form O of the DMF solvate has a peak in its X-ray powder diffraction pattern at diffraction angles (2θ) of 17.72 ± 0.2°, 13.14 ± 0.2°, 15.08 ± 0.2° and 24.77 ± 0.2°, preferably further including peaks at diffraction angles (2θ) of 8.72 ± 0.2°, 21.52 ± 0.2°, 9.70 ± 0.2°, 14.26 ± 0.2° and 25.46 ± 0.2°, more preferably further including peaks at diffraction angles (2θ) of 12.19 ± 0.2°, 20.15 ± 0.2°, 25.90 ± 0.2°, 23.66 ± 0.2°, 28.75 ± 0.2° and 21.73 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystal form O has diffraction angles (2θ) shown in Table 16, among which the error range of the 2θ angle is ±0.20°, 【Table 16】 preferably, the crystal form O has X-ray powder diffraction intensities shown in Table 16, preferably, the crystal form O basically has the X-ray powder diffraction pattern shown in Figure 16, preferably, in the DSC analysis of the crystal form O, when heated to near the peak temperature of 123.26 °C, an endothermic peak appears, preferably, the crystal form O basically has the DSC pattern shown in Figure 37, preferably, the crystal form O basically has the TGA pattern shown in Figure 58, preferably, the crystal form O is a mono-DMF solvate of Compound I, The crystal form P of the N-methylpyrrolidone solvate has a peak in its X-ray powder diffraction pattern at diffraction angles (2θ) of 14.63 ± 0.2°, 13.16 ± 0.2°, 16.98 ± 0.2° and 14.36 ± 0.2°, preferably further including peaks at diffraction angles (2θ) of 21.66 ± 0.2°, 23.94 ± 0.2°, 20.22 ± 0.2°, 6.60 ± 0.2° and 8.41 ± 0.2°, more preferably further including peaks at diffraction angles (2θ) of 20.02 ± 0.2°, 11.63 ± 0.2°, 25.14 ± 0.2°, 24.87 ± 0.2°, 21.15 ± 0.2° and 16.63 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystal form P has diffraction angles (2θ) shown in Table 17, among which the error range of the 2θ angle is ±0.20°, 【Table 17】 preferably, the crystal form P has X-ray powder diffraction intensities shown in Table 17, preferably, the crystal form P basically has the X-ray powder diffraction pattern shown in Figure 17, Preferably, in the DSC analysis of the crystalline form P, when heated up to around the peak temperature of 117.63 °C, an endothermic peak appears. Preferably, the crystalline form P basically has the DSC pattern shown in FIG.

38. Preferably, the crystalline form P basically has the TGA pattern shown in FIG.

59. Preferably, the crystalline form P is a mono-N-methylpyrrolidone solvate of Compound I. The crystalline form Q of the n-butanol solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 18.05 ± 0.2°, 10.71 ± 0.2°, 12.54 ± 0.2° and 18.78 ± 0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 20.68 ± 0.2°, 24.89 ± 0.2°, 26.45 ± 0.2°, 22.24 ± 0.2° and 19.81 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 15.21 ± 0.2°, 9.00 ± 0.2°, 8.70 ± 0.2°, 23.84 ± 0.2°, 16.55 ± 0.2° and 24.31 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form Q has the diffraction angles (2θ) shown in Table 18, among which the error range of the 2θ angle is ±0.20°. 【Table 18】 Preferably, the crystalline form Q has the X-ray powder diffraction intensity shown in Table 18. Preferably, the crystalline form Q basically has the X-ray powder diffraction pattern shown in FIG.

18. Preferably, in the DSC analysis of the crystalline form Q, when heated up to around the peak temperature of 100.61 °C, an endothermic peak appears. Preferably, the crystalline form Q basically has the DSC pattern shown in FIG.

39. Preferably, the crystalline form Q basically has the TGA pattern shown in FIG.

60. Preferably, the crystalline form Q is a 0.5 n-butanol solvate of Compound I. The crystalline form R of the n-propanol solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 10.67 ± 0.2°, 12.52 ± 0.2°, 18.08 ± 0.2° and 8.98 ± 0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 6.54 ± 0.2°, 20.68 ± 0.2°, 18.84 ± 0.2°, 7.55 ± 0.2° and 8.67 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 19.85 ± 0.2°, 26.59 ± 0.2°, 15.19 ± 0.2°, 13.05 ± 0.2°, 14.06 ± 0.2° and 16.55 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form R has diffraction angles (2θ) shown in Table 19, among which the error range of the 2θ angle is ±0.20°. 【Table 19】 Preferably, the crystalline form R has the X-ray powder diffraction intensity shown in Table 19. Preferably, the crystalline form R basically has the X-ray powder diffraction pattern shown in Figure 19. Preferably, in the DSC analysis of the crystalline form R, when heated to near the peak temperature of 110.90 °C, an endothermic peak appears. Preferably, the crystalline form R basically has the DSC pattern shown in Figure 40. Preferably, the crystalline form R basically has the TGA pattern shown in Figure 61. Preferably, the crystalline form R is the monohydrate of compound I in n-propanol. The crystalline form S of the tetrahydrofuran solvate includes peaks located at diffraction angles (2θ) of 12.17 ± 0.2°, 8.19 ± 0.2°, 7.67 ± 0.2° and 13.96 ± 0.2° in its X-ray powder diffraction pattern. Preferably, it further includes peaks located at diffraction angles (2θ) of 8.95 ± 0.2°, 18.01 ± 0.2°, 16.50 ± 0.2°, 19.71 ± 0.2° and 23.70 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 13.69 ± 0.2°, 13.22 ± 0.2°, 14.45 ± 0.2°, 20.64 ± 0.2°, 15.83 ± 0.2° and 6.48 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form S has diffraction angles (2θ) shown in Table 20, among which the error range of the 2θ angle is ±0.20°. 【Table 20】 Preferably, the crystalline form S has the X-ray powder diffraction intensity shown in Table 20. Preferably, the crystalline form S basically has the X-ray powder diffraction pattern shown in Figure 20. Preferably, in the DSC analysis of the crystalline form S, when heated to near the peak temperature of 96.26 °C, an endothermic peak appears. Preferably, the crystalline form S basically has the DSC pattern shown in Figure 41. Preferably, the crystalline form S basically has the TGA pattern shown in Figure 62. Preferably, the crystalline form S is the 0.5 tetrahydrofuran solvate of compound I. The crystalline form T of the 2-methyltetrahydrofuran solvate has an X-ray powder diffraction pattern including peaks located at diffraction angles (2θ) of 10.79 ± 0.2°, 8.66 ± 0.2°, 9.12 ± 0.2° and 16.87 ± 0.2°, preferably further including peaks located at diffraction angles (2θ) of 18.64 ± 0.2°, 15.54 ± 0.2°, 21.27 ± 0.2°, 13.57 ± 0.2° and 6.72 ± 0.2°, more preferably further including peaks located at diffraction angles (2θ) of 4.29 ± 0.2°, 14.41 ± 0.2°, 19.99 ± 0.2°, 7.71 ± 0.2°, 16.57 ± 0.2° and 19.42 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystalline form T has diffraction angles (2θ) shown in Table 21, among which the error range of the 2θ angle is ±0.20°, 【Table 21】 preferably, the crystalline form T has X-ray powder diffraction intensities shown in Table 21, preferably, the crystalline form T basically has an X-ray powder diffraction pattern shown in Figure 21, preferably, in the DSC analysis of the crystalline form T, when heated to near the peak temperature of 112.95 °C, an endothermic peak appears, preferably, the crystalline form T basically has a DSC pattern shown in Figure 42, preferably, the crystalline form T basically has a TGA pattern shown in Figure 63, preferably, the crystalline form T is a mono-2-methyltetrahydrofuran solvate of Compound I, The crystalline polymorph according to Claim 1 or 2.

4. The crystalline polymorph is a solvent-free crystalline form of Compound II including the following solvent-free crystalline forms 2A, 2B, 2C, 2D, 2E, among which, the crystalline form 2A has an X-ray powder diffraction pattern including peaks located at diffraction angles (2θ) of 13.94 ± 0.2°, 22.07 ± 0.2°, 17.96 ± 0.2° and 17.57 ± 0.2°, preferably further including peaks located at diffraction angles (2θ) of 13.36 ± 0.2°, 5.92 ± 0.2°, 12.33 ± 0.2°, 23.04 ± 0.2° and 11.02 ± 0.2°, more preferably further including peaks located at diffraction angles (2θ) of 22.41 ± 0.2°, 7.42 ± 0.2°, 25.07 ± 0.2°, 27.00 ± 0.2°, 8.71 ± 0.2° and 16.60 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2A has diffraction angles (2θ) shown in Table 2-1, among which the error range of the 2θ angle is ±0.20°, 【Table 22】 Preferably, the crystalline form 2A has X-ray powder diffraction intensities shown in Table 2-1, Preferably, the crystalline form 2A basically has an X-ray powder diffraction pattern shown in FIG. 2-1, Preferably, in the DSC analysis of the crystalline form 2A, when heated up to around the peak temperature of 189.90 °C, an endothermic peak appears, Preferably, the crystalline form 2A basically has a DSC pattern shown in FIG. 2-26, Preferably, the crystalline form 2A basically has a TGA pattern shown in FIG. 2-51, The X-ray powder diffraction pattern of the crystalline form 2B includes peaks located at diffraction angles (2θ) of 13.16 ± 0.2°, 21.31 ± 0.2°, 25.46 ± 0.2° and 10.61 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 16.79 ± 0.2°, 20.99 ± 0.2°, 18.76 ± 0.2°, 19.59 ± 0.2° and 9.71 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 23.72 ± 0.2°, 11.68 ± 0.2°, 23.92 ± 0.2°, 20.57 ± 0.2°, 16.48 ± 0.2° and 20.23 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2B has diffraction angles (2θ) shown in Table 2-2, among which the error range of the 2θ angle is ±0.20°, 【Table 23】 Preferably, the crystalline form 2B has X-ray powder diffraction intensities shown in Table 2-2, Preferably, the crystalline form 2B basically has an X-ray powder diffraction pattern shown in FIG. 2-2, Preferably, in the DSC analysis of the crystalline form 2B, when heated up to around the peak temperature of 181.06 °C, an endothermic peak appears, Preferably, the crystalline form 2B basically has a DSC pattern shown in FIG. 2-27, Preferably, the crystalline form 2B basically has a TGA pattern shown in FIG. 2-52, The X-ray powder diffraction pattern of the crystalline form 2C includes peaks located at diffraction angles (2θ) of 13.63 ± 0.2°, 5.62 ± 0.2°, 17.12 ± 0.2° and 17.68 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 11.94 ± 0.2°, 13.89 ± 0.2°, 22.65 ± 0.2°, 23.63 ± 0.2° and 17.97 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 7.46±0.2°, 27.52±0.2°, 8.80±0.2°, 25.15±0.2°, 19.36±0.2° and 5.88±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form 2C has diffraction angles (2θ) shown in Table 2-3, among which the error range of the 2θ angle is ±0.20°. 【Table 24】 Preferably, the crystalline form 2C has X-ray powder diffraction intensities shown in Table 2-3. Preferably, the crystalline form 2C basically has an X-ray powder diffraction pattern shown in Figure 2-3. Preferably, in the DSC analysis of the crystalline form 2C, when heated to near the peak temperature of 171.63 °C, an endothermic peak appears. Preferably, the crystalline form 2C basically has a DSC pattern shown in Figure 2-28. Preferably, the crystalline form 2C basically has a TGA pattern shown in Figure 2-53. The crystalline form 2D includes peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 5.62±0.2°, 12.01±0.2°, 5.24±0.2° and 17.72±0.2°. Preferably, it further includes peaks located at diffraction angles (2θ) of 13.65±0.2°, 17.16±0.2°, 23.63±0.2°, 19.30±0.2° and 16.43±0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 15.85±0.2°, 11.04±0.2°, 7.50±0.2°, 5.90±0.2°, 22.18±0.2° and 22.65±0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form 2D has diffraction angles (2θ) shown in Table 2-4, among which the error range of the 2θ angle is ±0.20°. 【Table 25】 Preferably, the crystalline form 2D has X-ray powder diffraction intensities shown in Table 2-4. Preferably, the crystalline form 2D basically has an X-ray powder diffraction pattern shown in Figure 2-4. Preferably, in the DSC analysis of the crystalline form 2D, when heated to near the peak temperature of 168.79 °C, an endothermic peak appears. Preferably, the crystalline form 2D basically has a DSC pattern shown in Figure 2-29. Preferably, the crystalline form 2D basically has a TGA pattern shown in Figure 2-54. The crystalline form 2E has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 17.96 ± 0.2°, 3.34 ± 0.2°, 5.63 ± 0.2° and 13.63 ± 0.2°, preferably further having peaks located at diffraction angles (2θ) of 17.14 ± 0.2°, 11.96 ± 0.2°, 12.19 ± 0.2°, 13.98 ± 0.2° and 7.46 ± 0.2°, more preferably further having peaks located at diffraction angles (2θ) of 19.53 ± 0.2°, 22.14 ± 0.2°, 8.87 ± 0.2°, 19.32 ± 0.2°, 23.90 ± 0.2° and 19.83 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystalline form 2E has diffraction angles (2θ) shown in Table 2-5, among which the error range of the 2θ angle is ±0.20°, 【Table 26】 preferably, the crystalline form 2E has X-ray powder diffraction intensities shown in Table 2-5, preferably, the crystalline form 2E basically has an X-ray powder diffraction pattern shown in Figure 2-5, preferably, in the DSC analysis of the crystalline form 2E, when heated to near peak temperatures of 110.30 °C and 169.27 °C, endothermic peaks appear, preferably, the crystalline form 2E basically has a DSC pattern shown in Figure 2-30, preferably, the crystalline form 2E basically has a TGA pattern shown in Figure 2-55, preferably, the crystalline polymorph is a hydrate crystalline form of Compound II including the following hydrate crystalline forms 2F and 2G, among which, the hydrate crystalline form 2F has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 19.51 ± 0.2°, 13.71 ± 0.2°, 14.29 ± 0.2° and 18.09 ± 0.2°, preferably further having peaks located at diffraction angles (2θ) of 6.42 ± 0.2°, 12.11 ± 0.2°, 24.93 ± 0.2°, 17.86 ± 0.2° and 20.57 ± 0.2°, more preferably further having peaks located at diffraction angles (2θ) of 21.37 ± 0.2°, 13.34 ± 0.2°, 23.39 ± 0.2°, 25.15 ± 0.2°, 30.64 ± 0.2° and 17.25 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystalline form 2F has diffraction angles (2θ) shown in Table 2-6, among which the error range of the 2θ angle is ±0.20°, 【Table 27】 preferably, the crystalline form 2F has X-ray powder diffraction intensities shown in Table 2-6, Preferably, the crystalline form 2F basically has the X-ray powder diffraction pattern shown in FIG. 2-6, Preferably, in the DSC analysis of the crystalline form 2F, an endothermic peak appears when heated to around the peak temperature of 114.41 °C, Preferably, the crystalline form 2F basically has the DSC pattern shown in FIG. 2-31, Preferably, the crystalline form 2F basically has the TGA pattern shown in FIG. 2-56, Preferably, the crystalline form 2F is the trihydrate of Compound II, The hydrate crystalline form 2G has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 17.45 ± 0.2°, 13.63 ± 0.2°, 5.61 ± 0.2° and 5.24 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 13.89 ± 0.2°, 10.69 ± 0.2°, 11.78 ± 0.2°, 23.53 ± 0.2° and 23.86 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 20.98 ± 0.2°, 27.54 ± 0.2°, 15.46 ± 0.2°, 22.52 ± 0.2°, 6.89 ± 0.2° and 22.08 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2G has the diffraction angles (2θ) shown in Table 2-7, among which the error range of the 2θ angle is ±0.20°, 【Table 28】 Preferably, the crystalline form 2G has the X-ray powder diffraction intensity shown in Table 2-7, Preferably, the crystalline form 2G basically has the X-ray powder diffraction pattern shown in FIG. 2-7, Preferably, in the DSC analysis of the crystalline form 2G, an endothermic peak appears when heated to around the peak temperature of 169.22 °C, Preferably, the crystalline form 2G basically has the DSC pattern shown in FIG. 2-32, Preferably, the crystalline form 2G basically has the TGA pattern shown in FIG. 2-57, Preferably, the crystalline form 2G is the dihydrate of Compound II, Preferably, the crystalline polymorphs are solvate crystalline forms of Compound II including the following solvate crystalline forms 2H, 2I, 2J-1, 2J-2, 2K, 2L-1, 2L-2, 2M-1, 2M-2, 2N, 2O, 2P, 2Q-1, 2Q-2, 2R, 2S, 2T, 2U, among which, The crystal form 2H of the dimethyl sulfoxide solvate has an X-ray powder diffraction pattern including peaks located at diffraction angles (2θ) of 14.84 ± 0.2°, 13.42 ± 0.2°, 24.68 ± 0.2°, and 21.70 ± 0.2°, preferably further including peaks located at diffraction angles (2θ) of 8.45 ± 0.2°, 24.46 ± 0.2°, 20.22 ± 0.2°, 17.22 ± 0.2°, and 3.23 ± 0.2°, more preferably further including peaks located at diffraction angles (2θ) of 14.61 ± 0.2°, 25.32 ± 0.2°, 15.56 ± 0.2°, 22.01 ± 0.2°, 18.52 ± 0.2°, and 21.21 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystal form 2H has diffraction angles (2θ) shown in Table 2-8, among which the error range of the 2θ angle is ±0.20°, 【Table 29】 preferably, the crystal form 2H has X-ray powder diffraction intensities shown in Table 2-8, preferably, the crystal form 2H basically has an X-ray powder diffraction pattern shown in Figure 2-8, preferably, in the DSC analysis of the crystal form 2H, when heated to near the peak temperature of 118.06 °C, an endothermic peak appears, preferably, the crystal form 2H basically has a DSC pattern shown in Figure 2-33, preferably, the crystal form 2H basically has a TGA pattern shown in Figure 2-58, preferably, the crystal form 2H is a monodimethyl sulfoxide solvate of Compound II, The crystal form 2I of the methyl tert-butyl ether solvate has an X-ray powder diffraction pattern including peaks located at diffraction angles (2θ) of 8.74 ± 0.2°, 10.94 ± 0.2°, 4.32 ± 0.2°, and 17.66 ± 0.2°, preferably further including peaks located at diffraction angles (2θ) of 13.18 ± 0.2°, 9.25 ± 0.2°, 18.79 ± 0.2°, 17.12 ± 0.2°, and 12.79°, more preferably further including peaks located at diffraction angles (2θ) of 22.13 ± 0.2°, 25.90 ± 0.2°, 19.38 ± 0.2°, 20.90 ± 0.2°, 15.91 ± 0.2°, and 6.91 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystal form 2I has diffraction angles (2θ) shown in Table 2-9, among which the error range of the 2θ angle is ±0.20°, 【Table 30】 preferably, the crystal form 2I has X-ray powder diffraction intensities shown in Table 2-9, Preferably, the crystalline form 2I basically has the X-ray powder diffraction pattern shown in FIG. 2-9, Preferably, in the DSC analysis of the crystalline form 2I, an endothermic peak appears when heated to around the peak temperature of 115.84 °C, Preferably, the crystalline form 2I basically has the DSC pattern shown in FIG. 2-34, Preferably, the crystalline form 2I basically has the TGA pattern shown in FIG. 2-59, Preferably, the crystalline form 2I is a 0.5 methyl tert-butyl ether solvate of Compound II, The crystalline form 2J-1 of the n-heptane solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 12.15 ± 0.2°, 8.91 ± 0.2°, 8.18 ± 0.2° and 7.63 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 13.93 ± 0.2°, 17.94 ± 0.2°, 19.48 ± 0.2°, 23.72 ± 0.2° and 15.81 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 14.37 ± 0.2°, 20.43 ± 0.2°, 6.75 ± 0.2°, 22.68 ± 0.2°, 13.60 ± 0.2° and 27.41 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2J-1 has the diffraction angles (2θ) shown in Table 2-10, wherein the error range of the 2θ angle is ±0.20°, 【Table 31】 Preferably, the crystalline form 2J-1 has the X-ray powder diffraction intensity shown in Table 2-10, Preferably, the crystalline form 2J-1 basically has the X-ray powder diffraction pattern shown in FIG. 2-10, Preferably, in the DSC analysis of the crystalline form 2J-1, an endothermic peak appears when heated to around the peak temperature of 103.13 °C, Preferably, the crystalline form 2J-1 basically has the DSC pattern shown in FIG. 2-35, Preferably, the crystalline form 2J-1 basically has the TGA pattern shown in FIG. 2-60, Preferably, the crystalline form 2J-1 is a 0.2 n-heptane solvate of Compound II, The crystalline form 2J-2 of the n-heptane solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 3.52 ± 0.2°, 17.76 ± 0.2°, 14.19 ± 0.2° and 10.61 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 7.05 ± 0.2°, 21.35 ± 0.2°, 16.24 ± 0.2° and 19.49 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2J-2 has diffraction angles (2θ) shown in Table 2-11, among which the error range of the 2θ angle is ±0.20°, 【Table 32】 Preferably, the crystalline form 2J-2 has X-ray powder diffraction intensities shown in Table 2-11, Preferably, the crystalline form 2J-2 basically has the X-ray powder diffraction pattern shown in Figure 2-11, Preferably, in the DSC analysis of the crystalline form 2J-2, when heated to near the peak temperature of 76.82 °C, an endothermic peak appears, Preferably, the crystalline form 2J-2 basically has the DSC pattern shown in Figure 2-36, Preferably, the crystalline form 2J-2 basically has the TGA pattern shown in Figure 2-61, Preferably, the crystalline form 2J-2 is a 0.5n-heptane solvate of Compound II, The crystalline form 2K of the toluene solvate includes peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 9.52 ± 0.2°, 18.45 ± 0.2°, 19.09 ± 0.2° and 21.48 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 16.24 ± 0.2°, 14.76 ± 0.2°, 13.04 ± 0.2°, 22.11 ± 0.2° and 3.50 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 18.23 ± 0.2°, 17.96 ± 0.2°, 26.57 ± 0.2°, 20.31 ± 0.2°, 14.53 ± 0.2° and 23.76 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2K has diffraction angles (2θ) shown in Table 2-12, among which the error range of the 2θ angle is ±0.20°, 【Table 33】 Preferably, the crystalline form 2K has X-ray powder diffraction intensities shown in Table 2-12, Preferably, the crystalline form 2K basically has the X-ray powder diffraction pattern shown in Figure 2-12, Preferably, in the DSC analysis of the crystalline form 2K, when heated to near the peak temperatures of 107.92 °C, 172.19 °C and 184.68 °C, endothermic peaks appear, Preferably, the crystalline form 2K basically has the DSC pattern shown in Figure 2-37, Preferably, the crystalline form 2K basically has the TGA pattern shown in Figure 2-62, Preferably, the crystalline form 2K is a 0.75 toluene solvate of Compound II, The crystalline form 2L-1 of the methyl isobutyl ketone solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 8.66 ± 0.2°, 10.79 ± 0.2°, 26.00 ± 0.2°, and 19.62 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 9.13 ± 0.2°, 18.60 ± 0.2°, 16.90 ± 0.2°, 15.58 ± 0.2°, and 19.43 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 13.03 ± 0.2°, 17.43 ± 0.2°, 6.74 ± 0.2°, 26.72 ± 0.2°, 26.27 ± 0.2°, and 22.40 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2L-1 has diffraction angles (2θ) shown in Table 2-13, among which the error range of the 2θ angle is ±0.20°, 【Table 34】 Preferably, the crystalline form 2L-1 has the X-ray powder diffraction intensity shown in Table 2-13, Preferably, the crystalline form 2L-1 basically has the X-ray powder diffraction pattern shown in Figure 2-13, Preferably, in the DSC analysis of the crystalline form 2L-1, when heated to near the peak temperature of 106.45 °C, an endothermic peak appears, Preferably, the crystalline form 2L-1 basically has the DSC pattern shown in Figure 2-38, Preferably, the crystalline form 2L-1 basically has the TGA pattern shown in Figure 2-63, Preferably, the crystalline form 2L-1 is a 0.75 methyl isobutyl ketone solvate of Compound II, The crystalline form 2L-2 of the methyl isobutyl ketone solvate has a peak in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 8.68 ± 0.2°, 10.83 ± 0.2°, 13.10 ± 0.2°, and 11.06 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 17.49 ± 0.2°, 9.15 ± 0.2°, 16.96 ± 0.2°, 18.69 ± 0.2°, and 6.74 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 12.62 ± 0.2°, 19.63 ± 0.2°, 19.37 ± 0.2°, 22.01 ± 0.2°, 15.65 ± 0.2°, and 21.33 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2L-2 has diffraction angles (2θ) shown in Table 2-14, among which the error range of the 2θ angle is ±0.20°, 【Table 35】 Preferably, the crystalline form 2L-2 has X-ray powder diffraction intensities shown in Table 2-14, Preferably, the crystalline form 2L-2 basically has the X-ray powder diffraction pattern shown in Figure 2-14, Preferably, in the DSC analysis of the crystalline form 2L-2, when heated to near the peak temperature of 102.87 °C, an endothermic peak appears, Preferably, the crystalline form 2L-2 basically has the DSC pattern shown in Figure 2-39, Preferably, the crystalline form 2L-2 basically has the TGA pattern shown in Figure 2-64, Preferably, the crystalline form 2L-2 is a 0.3 methyl isobutyl ketone solvate of Compound II, For the crystalline form 2M-1 of the cyclopentyl methyl ether solvate, its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 8.78 ± 0.2°, 10.98 ± 0.2°, 17.67 ± 0.2° and 17.20 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 19.32 ± 0.2°, 25.69 ± 0.2°, 13.23 ± 0.2°, 22.24 ± 0.2° and 9.29 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 18.93 ± 0.2°, 26.53 ± 0.2°, 26.04 ± 0.2°, 15.87 ± 0.2°, 21.25 ± 0.2° and 12.85 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2M-1 has diffraction angles (2θ) shown in Table 2-15, among which the error range of the 2θ angle is ±0.20°, 【Table 36】 Preferably, the crystalline form 2M-1 has X-ray powder diffraction intensities shown in Table 2-15, Preferably, the crystalline form 2M-1 basically has the X-ray powder diffraction pattern shown in Figure 2-15, Preferably, in the DSC analysis of the crystalline form 2M-1, when heated to near the peak temperature of 113.56 °C, an endothermic peak appears, Preferably, the crystalline form 2M-1 basically has the DSC pattern shown in Figure 2-40, Preferably, the crystalline form 2M-1 basically has the TGA pattern shown in Figure 2-65, Preferably, the crystalline form 2M-1 is a monocyclopentyl methyl ether solvate of Compound II, The crystal form 2M-2 of the cyclopentyl methyl ether solvate has an X-ray powder diffraction pattern including peaks located at diffraction angles (2θ) of 5.16 ± 0.2°, 10.83 ± 0.2°, 15.66 ± 0.2°, and 21.29 ± 0.2°, preferably further including peaks located at diffraction angles (2θ) of 17.63 ± 0.2°, 17.90 ± 0.2°, 8.80 ± 0.2°, 13.03 ± 0.2°, and 23.88 ± 0.2°, more preferably further including peaks located at diffraction angles (2θ) of 25.73 ± 0.2°, 11.99 ± 0.2°, 19.28 ± 0.2°, 20.20 ± 0.2°, 23.57 ± 0.2°, and 22.20 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystal form 2M-2 has diffraction angles (2θ) shown in Table 2-16, among which the error range of the 2θ angle is ±0.20°, 【Table 37】 preferably, the crystal form 2M-2 has X-ray powder diffraction intensities shown in Table 2-16, preferably, the crystal form 2M-2 basically has an X-ray powder diffraction pattern shown in Figure 2-16, preferably, in the DSC analysis of the crystal form 2M-2, when heated to near peak temperatures of 110.50 °C and 165.01 °C, endothermic peaks appear, preferably, the crystal form 2M-2 basically has a DSC pattern shown in Figure 2-41, preferably, the crystal form 2M-2 basically has a TGA pattern shown in Figure 2-66, preferably, the crystal form 2M-2 is a monocyclopentyl methyl ether solvate of Compound II, The crystal form 2N of the methyl ethyl ketone solvate has an X-ray powder diffraction pattern including peaks located at diffraction angles (2θ) of 3.34 ± 0.2°, 10.88 ± 0.2°, 9.13 ± 0.2°, and 6.64 ± 0.2°, preferably further including peaks located at diffraction angles (2θ) of 7.73 ± 0.2°, 19.87 ± 0.2°, 8.78 ± 0.2°, 12.78 ± 0.2°, and 6.25 ± 0.2°, more preferably further including peaks located at diffraction angles (2θ) of 18.29 ± 0.2°, 19.08 ± 0.2°, 21.19 ± 0.2°, 11.69 ± 0.2°, 19.49 ± 0.2°, and 17.01 ± 0.2°, preferably, the X-ray powder diffraction pattern of the crystal form 2N has diffraction angles (2θ) shown in Table 2-17, among which the error range of the 2θ angle is ±0.20°, 【Table 38】 Preferably, the crystalline form 2N has the X-ray powder diffraction intensity shown in Table 2-17, Preferably, the crystalline form 2N basically has the X-ray powder diffraction pattern shown in Figure 2-17, Preferably, in the DSC analysis of the crystalline form 2N, when heated to around the peak temperatures of 102.66 °C and 113.16 °C, endothermic peaks appear, Preferably, the crystalline form 2N basically has the DSC pattern shown in Figure 2-42, Preferably, the crystalline form 2N basically has the TGA pattern shown in Figure 2-67, Preferably, the crystalline form 2N is a 0.3 methyl ethyl ketone solvate of Compound II, The crystalline form 2O of the methylcyclohexane solvate has an X-ray powder diffraction pattern including peaks located at diffraction angles (2θ) of 8.72 ± 0.2°, 10.92 ± 0.2°, 13.14 ± 0.2° and 9.23 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 17.10 ± 0.2°, 18.78 ± 0.2°, 17.55 ± 0.2°, 15.79 ± 0.2° and 6.89 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 22.05 ± 0.2°, 12.77 ± 0.2°, 19.30 ± 0.2°, 20.84 ± 0.2°, 23.74 ± 0.2° and 26.45 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2O has the diffraction angles (2θ) shown in Table 2-18, among which the error range of the 2θ angle is ±0.20°, 【Table 39】 Preferably, the crystalline form 2O has the X-ray powder diffraction intensity shown in Table 2-18, Preferably, the crystalline form 2O basically has the X-ray powder diffraction pattern shown in Figure 2-18, Preferably, in the DSC analysis of the crystalline form 2O, when heated to around the peak temperature of 111.80 °C, an endothermic peak appears, Preferably, the crystalline form 2O basically has the DSC pattern shown in Figure 2-43, Preferably, the crystalline form 2O basically has the TGA pattern shown in Figure 2-68, Preferably, the crystalline form 2O is a monomethylcyclohexane solvate of Compound II, The crystalline form 2P of the DMF solvate has an X-ray powder diffraction pattern including peaks located at diffraction angles (2θ) of 10.98 ± 0.2°, 9.31 ± 0.2°, 17.68 ± 0.2° and 25.67 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 19.65 ± 0.2°, 5.78 ± 0.2°, 6.24 ± 0.2°, 16.54 ± 0.2° and 21.19 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 24.09 ± 0.2°, 18.25 ± 0.2°, 25.26 ± 0.2°, 20.67 ± 0.2°, 18.84 ± 0.2° and 22.19 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystal form 2P has diffraction angles (2θ) shown in Table 2-19, among which the error range of the 2θ angle is ±0.20°, 【Table 40】 Preferably, the crystal form 2P has X-ray powder diffraction intensities shown in Table 2-19, Preferably, the crystal form 2P basically has the X-ray powder diffraction pattern shown in Figure 2-19, Preferably, in the DSC analysis of the crystal form 2P, when heated to near the peak temperature of 105.14 °C, an endothermic peak appears, Preferably, the crystal form 2P basically has the DSC pattern shown in Figure 2-44, Preferably, the crystal form 2P basically has the TGA pattern shown in Figure 2-69, Preferably, the crystal form 2P is a mono-DMF solvate of Compound II, For the crystal form 2Q-1 of the 2-methyltetrahydrofuran solvate, its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 8.74 ± 0.2°, 10.89 ± 0.2°, 3.53 ± 0.2° and 17.90 ± 0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 18.77 ± 0.2°, 17.65 ± 0.2°, 16.93 ± 0.2°, 7.54 ± 0.2° and 9.19 ± 0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 13.18 ± 0.2°, 8.45 ± 0.2°, 9.63 ± 0.2°, 22.07 ± 0.2°, 6.76 ± 0.2° and 12.81 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystal form 2Q-1 has diffraction angles (2θ) shown in Table 2-20, among which the error range of the 2θ angle is ±0.20°, 【Table 41】 Preferably, the crystal form 2Q-1 has X-ray powder diffraction intensities shown in Table 2-20, Preferably, the crystal form 2Q-1 basically has the X-ray powder diffraction pattern shown in Figure 2-20, Preferably, in the DSC analysis of the crystal form 2Q-1, when heated to near the peak temperature of 111.13 °C, an endothermic peak appears, Preferably, the crystalline form 2Q-1 basically has the DSC pattern shown in Figure 2-45, Preferably, the crystalline form 2Q-1 basically has the TGA pattern shown in Figure 2-70, Preferably, the crystalline form 2Q-1 is a mono 2-methyltetrahydrofuran solvate of Compound II, The crystalline form 2Q-2 of the 2-methyltetrahydrofuran solvate has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 8.76±0.2°, 10.89±0.2°, 9.21±0.2° and 17.02±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 18.80±0.2°, 6.79±0.2°, 19.65±0.2°, 17.63±0.2° and 26.08±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 13.18±0.2°, 15.68±0.2°, 4.34±0.2°, 13.70±0.2°, 12.74±0.2° and 21.46±0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2Q-2 has the diffraction angles (2θ) shown in Table 2-21, wherein the error range of the 2θ angle is ±0.20°, 【Table 42】 Preferably, the crystalline form 2Q-2 has the X-ray powder diffraction intensity shown in Table 2-21, Preferably, the crystalline form 2Q-2 basically has the X-ray powder diffraction pattern shown in Figure 2-21, Preferably, in the DSC analysis of the crystalline form 2Q-2, an endothermic peak appears when heated to near the peak temperature of 114.18 °C, Preferably, the crystalline form 2Q-2 basically has the DSC pattern shown in Figure 2-46, Preferably, the crystalline form 2Q-2 basically has the TGA pattern shown in Figure 2-71, Preferably, the crystalline form 2Q-2 is a mono 2-methyltetrahydrofuran solvate of Compound II, The crystalline form 2R of the N-methylpyrrolidone solvate has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 10.79±0.2°, 9.15±0.2°, 3.44±0.2° and 17.63±0.2°, Preferably, it further includes peaks located at diffraction angles (2θ) of 25.83±0.2°, 19.26±0.2°, 20.86±0.2°, 16.76±0.2° and 25.48±0.2°, More preferably, it further includes peaks located at diffraction angles (2θ) of 16.51 ± 0.2°, 9.55 ± 0.2°, 17.18 ± 0.2°, 19.54 ± 0.2°, 14.08 ± 0.2° and 7.34 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form 2R has diffraction angles (2θ) shown in Table 2-22, among which the error range of the 2θ angle is ±0.20°. 【Table 43】 Preferably, the crystalline form 2R has X-ray powder diffraction intensities shown in Table 2-22. Preferably, the crystalline form 2R basically has an X-ray powder diffraction pattern shown in Figure 2-22. Preferably, in the DSC analysis of the crystalline form 2R, when heated to near the peak temperature of 128.45 °C, an endothermic peak appears. Preferably, the crystalline form 2R basically has a DSC pattern shown in Figure 2-47. Preferably, the crystalline form 2R basically has a TGA pattern shown in Figure 2-72. Preferably, the crystalline form 2R is a mono-N-methylpyrrolidone solvate of Compound II. For the crystalline form 2S of the trifluoroethanol solvate, its X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 17.64 ± 0.2°, 4.01 ± 0.2°, 8.72 ± 0.2° and 8.28 ± 0.2°. More preferably, it further includes peaks located at diffraction angles (2θ) of 13.63 ± 0.2°, 10.89 ± 0.2°, 12.17 ± 0.2°, 19.65 ± 0.2° and 23.65 ± 0.2°. Even more preferably, it further includes peaks located at diffraction angles (2θ) of 26.08 ± 0.2°, 15.8 ± 0.2°, 21.35 ± 0.2°, 7.61 ± 0.2°, 22.49 ± 0.2° and 5.61 ± 0.2°. Preferably, the X-ray powder diffraction pattern of the crystalline form 2S has diffraction angles (2θ) shown in Table 2-23, among which the error range of the 2θ angle is ±0.20°. 【Table 44】 Preferably, the crystalline form 2S has X-ray powder diffraction intensities shown in Table 2-23. Preferably, the crystalline form 2S basically has an X-ray powder diffraction pattern shown in Figure 2-23. Preferably, in the DSC analysis of the crystalline form 2S, when heated to near the peak temperatures of 123.79 °C and 169.39 °C, endothermic peaks appear. Preferably, the crystalline form 2S basically has a DSC pattern shown in Figure 2-48. Preferably, the crystalline form 2S basically has a TGA pattern shown in Figure 2-73. Preferably, the crystalline form 2S is a monotrifluoroethanol solvate of Compound II, The crystalline form 2T of the tetrahydrofuran solvate has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 12.17 ± 0.2°, 8.92 ± 0.2°, 7.63 ± 0.2° and 8.22 ± 0.2°, Preferably, it further has peaks located at diffraction angles (2θ) of 13.99 ± 0.2°, 17.96 ± 0.2°, 9.27 ± 0.2°, 19.51 ± 0.2° and 13.57 ± 0.2°, More preferably, it further has peaks located at diffraction angles (2θ) of 11.10 ± 0.2°, 15.89 ± 0.2°, 14.33 ± 0.2°, 19.77 ± 0.2°, 20.39 ± 0.2° and 16.61 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2T has diffraction angles (2θ) shown in Table 2-24, among which the error range of the 2θ angle is ±0.20°, 【Table 45】 Preferably, the crystalline form 2T has X-ray powder diffraction intensities shown in Table 2-24, Preferably, the crystalline form 2T basically has an X-ray powder diffraction pattern shown in Figure 2-24, Preferably, in the DSC analysis of the crystalline form 2T, when heated up to around the peak temperature of 110.50 °C, an endothermic peak appears, Preferably, the crystalline form 2T basically has a DSC pattern shown in Figure 2-49, Preferably, the crystalline form 2T basically has a TGA pattern shown in Figure 2-74, Preferably, the crystalline form 2T is a 0.3 tetrahydrofuran solvate of Compound II, The crystalline form 2U of the dioxane solvate has peaks in its X-ray powder diffraction pattern located at diffraction angles (2θ) of 8.86 ± 0.2°, 10.98 ± 0.2°, 9.27 ± 0.2° and 17.12 ± 0.2°, Preferably, it further has peaks located at diffraction angles (2θ) of 19.05 ± 0.2°, 19.55 ± 0.2°, 15.70 ± 0.2°, 13.36 ± 0.2° and 6.79 ± 0.2°, More preferably, it further has peaks located at diffraction angles (2θ) of 25.85 ± 0.2°, 12.87 ± 0.2°, 22.48 ± 0.2°, 13.69 ± 0.2°, 4.39 ± 0.2° and 17.86 ± 0.2°, Preferably, the X-ray powder diffraction pattern of the crystalline form 2U has diffraction angles (2θ) shown in Table 2-25, among which the error range of the 2θ angle is ±0.20°, 【Table 46】 Preferably, the crystalline form 2U has the X-ray powder diffraction intensity shown in Table 2-25, Preferably, the crystalline form 2U basically has the X-ray powder diffraction pattern shown in FIG. 2-25, Preferably, in the DSC analysis of the crystalline form 2U, when heated to around the peak temperature of 109.16 °C, an endothermic peak appears, Preferably, the crystalline form 2U basically has the DSC pattern shown in FIG. 2-50, Preferably, the crystalline form 2U basically has the TGA pattern shown in FIG. 2-75, Preferably, the crystalline form 2U is a 0.5 dioxane solvate of Compound II, The crystalline polymorph according to claim 1 or 2.

5. A method for producing the crystalline polymorph according to any one of claims 1 to 4, comprising the following method, namely, Method 1: Step 1, dissolve or disperse Compound III in a solvent, Step 2, stir and crystallize at 0 to 50 °C, or add a poor solvent to a clear solution of the compound to precipitate, or gradually evaporate the clear solution of the compound, Method 2: Disperse Compound III in a solvent and in the atmosphere of these media to obtain crystals, Method 3: Combine and use Method 1 and Method 2 to produce and obtain the crystalline polymorph of Compound III, Manufacturing method.

6. The solvent is water, an organic solvent, or a mixed solvent thereof. The organic solvent is selected from alcohol-based, chloroalkanes, ketone-based, ether-based, cyclic ether-based, ester-based, alkane-based, cycloalkane-based, benzene-based, amide-based, sulfoxide-based organic solvents, or a mixture thereof. Preferably, the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene, or a mixture thereof, characterized in that The production method according to claim 5.

7. Comprising at least one of the crystalline polymorphs according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier. Pharmaceutical composition.

8. Use of the crystalline polymorph according to any one of claims 1 to 4 in the manufacture of a drug for treating a metabolic disease, tumor, autoimmune disease, or metastatic disease. Application.

9. The metabolic disease, tumor, autoimmune disease or metastatic disease is characterized by being selected from T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea syndrome, obesity, eating disorder, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular compliance disorder, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorder, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcer, ulcerative colitis, high apoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome. The application according to claim 8.

10. The metabolic disease, tumor, autoimmune disease or metastatic disease is characterized by being selected from T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorder, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia. The application according to claim 8.

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