Polymorphic substance of GLP-1R agonist as well as preparation method and application of polymorphic substance

Abstract

# imgabs0 #. The invention provides a polymorphic substance of a GLP-1R agonist compound (III) as well as a preparation method and application of the polymorphic substance. Compared with the amorphous substance of the compound (III), the polymorphic substance provided by the invention has higher stability and better processability; and the compound is more suitable for preparing medicines for preventing or treating diseases related to GLP-1R targets and signal channels thereof, such as type 2 diabetes mellitus, prediabetes mellitus, obesity, non-alcoholic fatty liver diseases, non-alcoholic steatohepatitis, nephropathy, gout, hyperhematuria, cardiovascular diseases and the like.

Description

A polymorph of a GLP-1R agonist and its preparation method and use

[0001] The present invention claims:

[0002] Priority to the prior application, patent application number 2022108454100, filed with the State Intellectual Property Office of China on July 18, 2022, entitled “A polymorph of a GLP-1R agonist compound, its preparation method and use”;

[0003] Priority to the prior application, patent application number 2022108438979, filed with the State Intellectual Property Office of China on July 18, 2022, entitled “A polymorph of a GLP-1R agonist, its preparation method, and use”;

[0004] The entire content of this prior application is incorporated into this application by reference. Technical Field

[0005] The present invention belongs to the field of medicinal chemistry, and specifically relates to a polymorph of a GLP-1R agonist compound, a preparation method and uses thereof. Background Art

[0006] Diabetes is a chronic disease characterized by high blood sugar levels, caused by insufficient insulin secretion (relative or absolute) or impaired insulin action. According to the ninth edition of the World Diabetes Atlas, published by the International Diabetes Federation (IDF), approximately 463 million adults (aged 20-79) worldwide suffered from diabetes in 2019, and the number is projected to reach 578 million by 2030. If this trend continues, there will be 700 million people with diabetes worldwide by 2045. Therefore, diabetes has become one of the most serious global health issues of the 21st century.

[0007] Various pharmacological approaches are currently used to treat hyperglycemia and the accompanying T2DM (Hampp et al., Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 37:1367-1374, 2014). These approaches can be divided into six main categories, each of which works through a different primary mechanism.

[0008] Insulin secretagogues, including sulfonylureas, dipeptidyl peptidase IV (PP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1R) agonists, increase insulin secretion by acting on pancreatic beta cells. Sulfonylureas have limited efficacy and tolerability, causing weight gain and often inducing hypoglycemia. DP-IV inhibitors have limited efficacy. Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is approved for the treatment of obesity.

[0009] Biguanides (eg, metformin) are thought to act primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal discomfort and lactic acidosis, further limiting their use.

[0010] Alpha-glucosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption. These agents often cause gastrointestinal discomfort.

[0011] Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on specific receptors in the liver, muscle, and adipose tissue. They modulate lipid metabolism and subsequently enhance the responsiveness of these tissues to insulin. Frequent use of these drugs can lead to weight gain and may induce edema and anemia.

[0012] Insulin, alone or in combination with the above agents, is used in more severe cases, and regular use may also lead to weight gain and carries the risk of hypoglycemia.

[0013] Sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit glucose reabsorption in the kidneys and thereby lower blood glucose levels. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

[0014] However, with the exception of GLP-1R agonists and SGLT2 inhibitors, these drugs have limited efficacy and do not address the most important issue: β-cell dysfunction and related obesity. Therefore, more effective drug interventions with fewer side effects and convenient administration are needed.

[0015] GLP-1 is a 30-amino acid incretin hormone secreted by intestinal L cells in response to food intake. GLP-1 has been shown to stimulate insulin secretion, reduce glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate beta-cell proliferation in a physiological and glucose-dependent manner. In nonclinical trials, GLP-1 promoted sustained beta-cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis (Meier et al., Biodrugs., 17(2):93-102, 2013).

[0016] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion from the pancreas, thereby increasing peripheral glucose absorption. GLP-1 also inhibits glucagon secretion, reducing hepatic glucose excretion. Furthermore, GLP-1 delays gastric emptying and slows small intestinal motility, thereby delaying food absorption. In people with T2DM, postprandial GLP-1 levels do not rise normally or rise to a reduced level (Vilsbol et al., Diabetes, 50:609-613, 2001).

[0017] Scientific research has led to structural modifications and alterations in GLP-1 to increase its half-life and thus prolong its biological effects in vivo. However, long-acting GLP-1 analogs currently in clinical use, such as liraglutide and exenatide, are peptides, and frequent, multiple injections lead to poor patient compliance. Therefore, the development of small-molecule GLP-1R agonists, with the goal of improving patient compliance, facilitating medication administration, and reducing side effects, holds broad clinical market potential.

[0018] Hangzhou Mindrank AI Ltd. has developed a novel class of small molecule compounds with potent GLP-1R agonist activity. 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-(oxetane-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-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid have potent agonist activity and good drugability. Their structures are as follows:

[0019] The inventors have identified the free forms of the compounds of Formula (I) and Formula (II) as amorphous compounds, which are susceptible to moisture absorption and softening, and are prone to crystal transformation upon long-term storage. This makes them inconvenient for clinical formulation development. To meet the needs of clinical research and marketed pharmaceutical formulations, there is an urgent need to develop an aggregated form suitable for drug development to overcome the shortcomings of existing technologies.

[0020] The successful development of a solid form of a drug usually requires that it can be easily separated and purified after synthesis, be suitable for industrial production, be able to be stored for a long period of time with minimal absorption of water, decomposition or conversion to other solid forms, and be suitable for a dosage form that can be rapidly absorbed by the individual after administration (such as being soluble in water and gastric juice). In order to meet the needs of clinical research and marketed drug formulations, it is urgent to develop a solid form of drug that can be easily separated and purified, is suitable for industrial production, and has stable physical and chemical properties.

[0021] Summary of the Invention

[0022] In order to solve the problems existing in the prior art, the first aspect of the present invention provides a polymorph of Compound III as shown below:

[0023] wherein X is selected from Cl or CN.

[0024] According to an embodiment of the present invention, the polymorph may be a non-solvate crystalline form, a hydrate crystalline form or a solvate crystalline form of Compound III.

[0025] According to an embodiment of the present invention, compound III has the structure shown in compound I or compound II:

[0026] The unsolvated crystalline form of Compound I may be the following crystalline forms A, B, C, D, E, and F; the hydrated crystalline form of Compound I may be the following crystalline form G; the solvated crystalline form of Compound I may be the following crystalline forms H, I-1, I-2, J, K, L, M, N, O, P, Q, R, S, and T.

[0027] The unsolvated crystalline form of Compound II may be the following crystalline forms 2A, 2B, 2C, 2D, and 2E; the hydrated crystalline form of Compound II may be the following crystalline forms 2F and 2G; the solvated crystalline form of Compound II may be the following 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, and 2U.

[0028] The present invention provides Form A of Compound I, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 19.79±0.2°, 13.13±0.2°, 22.07±0.2° and 9.48±0.2°.

[0029] Preferably, peaks 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° are also included.

[0030] More preferably, peaks 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° are also included.

[0031] Preferably, the X-ray powder diffraction pattern of the crystalline form A has a diffraction angle (2θ) as shown in Table 1, wherein the error range of the 2θ angle is ±0.20°:

[0032] Table 1

[0033] Preferably, the crystalline form A has the X-ray powder diffraction intensity shown in Table 1.

[0034] Preferably, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG1 .

[0035] Preferably, the DSC analysis of the crystalline form A shows an endothermic peak when heated to a peak temperature of 99.81°C.

[0036] Preferably, the crystalline form A has a DSC spectrum substantially as shown in Figure 22.

[0037] Preferably, the crystalline form A has a TGA graph substantially as shown in Figure 43.

[0038] The present invention provides Form B of Compound I, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 13.79±0.2°, 22.36±0.2°, 17.66±0.2°, and 27.41±0.2°;

[0039] Preferably, it further includes peaks 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°;

[0040] More preferably, the peaks 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° are further included;

[0041] Preferably, the X-ray powder diffraction pattern of the crystalline form B has a diffraction angle (2θ) as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°:

[0042] Table 2

[0043] Preferably, the crystalline form B has the X-ray powder diffraction intensity shown in Table 2.

[0044] Preferably, the crystalline form B has an X-ray powder diffraction pattern substantially as shown in FIG2 .

[0045] Preferably, the DSC analysis of the crystalline form B shows an endothermic peak when heated to a peak temperature of approximately 177.71°C.

[0046] Preferably, the crystalline form B has a DSC spectrum substantially as shown in Figure 23.

[0047] Preferably, the crystalline Form B has a TGA graph substantially as shown in Figure 44.

[0048] The present invention provides Form C of Compound I, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 11.27±0.2°, 19.30±0.2°, 17.92±0.2°, and 20.04±0.2°;

[0049] Preferably, the peaks 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° are further included;

[0050] More preferably, the peaks 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° are further included;

[0051] Preferably, the X-ray powder diffraction pattern of the crystalline form C has a diffraction angle (2θ) as shown in Table 3, wherein the error range of the 2θ angle is ±0.20°:

[0052] Table 3

[0053] Preferably, the crystalline form C has the X-ray powder diffraction intensity shown in Table 3.

[0054] Preferably, the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG3 .

[0055] Preferably, the DSC analysis of the crystalline form C shows an endothermic peak when heated to a peak temperature of approximately 104.51°C.

[0056] Preferably, the crystalline form C has a DSC spectrum substantially as shown in Figure 24.

[0057] Preferably, the crystalline form C has a TGA pattern substantially as shown in Figure 45.

[0058] The present invention provides Form D of Compound I, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 14.49±0.2°, 16.98±0.2°, 11.51±0.2°, and 18.17±0.2°;

[0059] Preferably, the peaks 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° are further included;

[0060] More preferably, the peaks 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° are further included;

[0061] Preferably, the X-ray powder diffraction pattern of the crystalline form D has a diffraction angle (2θ) as shown in Table 4, wherein the error range of the 2θ angle is ±0.20°:

[0062] Table 4

[0063] Preferably, the crystalline form D has the X-ray powder diffraction intensity shown in Table 4.

[0064] Preferably, the crystalline form D has an X-ray powder diffraction pattern substantially as shown in FIG4 .

[0065] Preferably, the DSC analysis of the crystalline form D shows an endothermic peak when heated to a peak temperature of approximately 167.48°C.

[0066] Preferably, the crystalline form D has a DSC spectrum substantially as shown in Figure 25.

[0067] Preferably, the crystalline form D has a TGA pattern substantially as shown in Figure 46.

[0068] The present invention provides Form E of Compound I, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 11.49±0.2°, 12.17±0.2°, 21.15±0.2°, and 20.16±0.2°;

[0069] Preferably, the peaks 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° are further included;

[0070] More preferably, the peaks 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° are further included;

[0071] Preferably, the X-ray powder diffraction pattern of the crystalline form E has a diffraction angle (2θ) as shown in Table 5, wherein the error range of the 2θ angle is ±0.20°:

[0072] Table 5

[0073] Preferably, the crystalline form E has the X-ray powder diffraction intensity shown in Table 5.

[0074] Preferably, the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG5 .

[0075] Preferably, the DSC analysis of the crystalline form E shows an endothermic peak when heated to a peak temperature of approximately 112.00°C.

[0076] Preferably, the crystalline form E has a DSC spectrum substantially as shown in Figure 26.

[0077] Preferably, the crystalline form E has a TGA graph substantially as shown in Figure 47.

[0078] The present invention provides Form F of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 18.77±0.2°, 25.50±0.2°, 20.98±0.2°, and 23.45±0.2°;

[0079] Preferably, the peaks 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° are further included;

[0080] More preferably, the peaks 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° are further included;

[0081] Preferably, the X-ray powder diffraction pattern of the crystalline form F has a diffraction angle (2θ) as shown in Table 6, wherein the error range of the 2θ angle is ±0.20°:

[0082] Table 6

[0083] Preferably, the crystalline form F has the X-ray powder diffraction intensity shown in Table 6.

[0084] Preferably, the crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG6 .

[0085] Preferably, the DSC analysis of the crystalline form F shows an endothermic peak when heated to a peak temperature of approximately 169.00°C.

[0086] Preferably, the crystalline form F has a DSC spectrum substantially as shown in Figure 27.

[0087] Preferably, the crystalline form F has a TGA graph substantially as shown in Figure 48.

[0088] The present invention provides a hydrated form G of Compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 18.66±0.2°, 18.81±0.2°, 3.62±0.2°, and 22.24±0.2°;

[0089] Preferably, the peaks 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° are further included;

[0090] More preferably, the peaks 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° are further included;

[0091] Preferably, the X-ray powder diffraction pattern of the crystalline form G has a diffraction angle (2θ) as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°:

[0092] Table 7

[0093] Preferably, the crystalline form G has the X-ray powder diffraction intensity shown in Table 7.

[0094] Preferably, the crystalline form G has an X-ray powder diffraction pattern substantially as shown in FIG7 .

[0095] Preferably, the DSC analysis of the crystalline form G shows endothermic peaks near the peak temperatures of 89.95°C and 104.07°C.

[0096] Preferably, the crystalline form G has a DSC spectrum substantially as shown in Figure 28.

[0097] Preferably, the crystalline form G has a TGA graph substantially as shown in Figure 49.

[0098] Preferably, the crystalline form G is a dihydrate of compound I.

[0099] The present invention provides a crystalline form H of a methyl isobutyl ketone solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.75±0.2°, 8.61±0.2°, 19.84±0.2°, and 18.48±0.2°;

[0100] Preferably, the peaks 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° are further included;

[0101] More preferably, the peaks 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° are further included;

[0102] Preferably, the X-ray powder diffraction pattern of the crystalline form H has a diffraction angle (2θ) as shown in Table 8, wherein the error range of the 2θ angle is ±0.20°:

[0103] Table 8

[0104] Preferably, the crystalline form H has the X-ray powder diffraction intensity shown in Table 8.

[0105] Preferably, the crystalline form H has an X-ray powder diffraction pattern substantially as shown in FIG8 .

[0106] Preferably, the DSC analysis of the crystalline form H shows an endothermic peak when heated to a peak temperature of approximately 87.76°C.

[0107] Preferably, the crystalline form H has a DSC spectrum substantially as shown in Figure 29.

[0108] Preferably, the crystalline form H has a TGA graph substantially as shown in Figure 50.

[0109] Preferably, the crystalline form H is a 0.5 methyl isobutyl ketone solvate of compound I.

[0110] The present invention provides a crystalline form I-1 of a methyl tert-butyl ether solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.53±0.2°, 10.75±0.2°, 4.22±0.2°, and 18.39±0.2°;

[0111] Preferably, the peaks 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° are further included;

[0112] More preferably, the peaks 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° are further included;

[0113] Preferably, the X-ray powder diffraction pattern of the crystalline form I-1 has a diffraction angle (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°:

[0114] Table 9

[0115] Preferably, the crystalline form I-1 has the X-ray powder diffraction intensity shown in Table 9.

[0116] Preferably, the crystalline form I-1 has an X-ray powder diffraction pattern substantially as shown in FIG9 .

[0117] Preferably, the DSC analysis of the crystalline form I-1 shows an endothermic peak when heated to a peak temperature of approximately 103.27°C.

[0118] Preferably, the crystalline form I-1 has a DSC spectrum substantially as shown in FIG30 .

[0119] Preferably, the crystalline form I-1 has a TGA graph substantially as shown in Figure 51.

[0120] Preferably, the crystalline form I-1 is a monomethyl tert-butyl ether solvate of compound I.

[0121] The present invention provides a crystalline form I-2 of a methyl tert-butyl ether solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 16.88±0.2°, 18.87±0.2°, 20.90±0.2°, and 9.60±0.2°;

[0122] Preferably, the peaks 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° are further included;

[0123] More preferably, the peaks 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° are further included;

[0124] Preferably, the X-ray powder diffraction pattern of the crystalline form I-2 has a diffraction angle (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°:

[0125] Table 10

[0126] Preferably, the crystalline form I-2 has the X-ray powder diffraction intensity shown in Table 10.

[0127] Preferably, the crystalline form I-2 has an X-ray powder diffraction pattern substantially as shown in FIG10 .

[0128] Preferably, the DSC analysis of the crystalline form I-2 shows an endothermic peak when heated to a peak temperature of 97.11°C.

[0129] Preferably, the crystalline form I-2 has a DSC spectrum substantially as shown in Figure 31.

[0130] Preferably, the crystalline form I-2 has a TGA graph substantially as shown in Figure 52.

[0131] Preferably, the crystalline form I-2 is a 1.5-methyl tert-butyl ether solvate of compound I.

[0132] The present invention provides Form J of an acetone solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 12.02±0.2°, 18.03±0.2°, 8.04±0.2°, and 7.67±0.2°;

[0133] Preferably, the peaks 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° are further included;

[0134] More preferably, the peaks 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° are further included;

[0135] Preferably, the X-ray powder diffraction pattern of the crystalline form J has a diffraction angle (2θ) as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°:

[0136] Table 11

[0137] Preferably, the crystalline form J has the X-ray powder diffraction intensity shown in Table 11.

[0138] Preferably, the crystalline form J has an X-ray powder diffraction pattern substantially as shown in FIG11 .

[0139] Preferably, the DSC analysis of the crystal form J shows an endothermic peak when heated to a peak temperature of 93.18°C.

[0140] Preferably, the crystalline form J has a DSC spectrum substantially as shown in Figure 32.

[0141] Preferably, the crystalline Form J has a TGA pattern substantially as shown in Figure 53.

[0142] Preferably, the crystalline form J is a 0.5 acetone solvate of compound I.

[0143] The present invention provides a crystalline form K of an n-heptane solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 12.19±0.2°, 18.02±0.2°, 7.69±0.2°, and 19.69±0.2°;

[0144] Preferably, the peaks 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° are further included;

[0145] More preferably, the peaks 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° are further included;

[0146] Preferably, the X-ray powder diffraction pattern of the crystalline form K has a diffraction angle (2θ) as shown in Table 12, wherein the error range of the 2θ angle is ±0.20°:

[0147] Table 12

[0148] Preferably, the crystalline form K has the X-ray powder diffraction intensity shown in Table 12.

[0149] Preferably, the crystalline form K has an X-ray powder diffraction pattern substantially as shown in FIG12 .

[0150] Preferably, the DSC analysis of the crystal form K shows an endothermic peak when heated to a peak temperature of 91.51°C.

[0151] Preferably, the crystalline form K has a DSC spectrum substantially as shown in Figure 33.

[0152] Preferably, the crystalline form K has a TGA graph substantially as shown in Figure 54.

[0153] Preferably, the crystalline form K is a 0.12 n-heptane solvate of compound I.

[0154] The present invention provides a crystalline form L of a methylcyclohexane solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.98±0.2°, 15.54±0.2°, 9.09±0.2°, and 19.01±0.2°;

[0155] Preferably, the peaks 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° are further included;

[0156] More preferably, the peaks 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° are further included;

[0157] Preferably, the X-ray powder diffraction pattern of the crystalline form L has a diffraction angle (2θ) as shown in Table 13, wherein the error range of the 2θ angle is ±0.20°:

[0158] Table 13

[0159] Preferably, the crystalline form L has the X-ray powder diffraction intensity shown in Table 13.

[0160] Preferably, the crystalline form L has an X-ray powder diffraction pattern substantially as shown in FIG13 .

[0161] Preferably, the DSC analysis of the crystalline form L shows an endothermic peak when heated to a peak temperature of approximately 88.68°C.

[0162] Preferably, the crystalline form L has a DSC spectrum substantially as shown in Figure 34.

[0163] Preferably, the crystalline form L has a TGA graph substantially as shown in Figure 55.

[0164] Preferably, the crystalline form L is a 0.15-methylcyclohexane solvate of compound I.

[0165] The present invention provides a crystalline form M of a toluene solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 18.62±0.2°, 9.60±0.2°, 16.34±0.2°, and 21.62±0.2°;

[0166] Preferably, the peaks 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° are further included;

[0167] More preferably, the peaks 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° are further included;

[0168] Preferably, the X-ray powder diffraction pattern of the crystalline form M has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°:

[0169] Table 14

[0170] Preferably, the crystalline form M has the X-ray powder diffraction intensity shown in Table 14.

[0171] Preferably, the crystalline form M has an X-ray powder diffraction pattern substantially as shown in FIG14 .

[0172] Preferably, the DSC analysis of the crystalline form M shows an endothermic peak when heated to a peak temperature of approximately 102.43°C.

[0173] Preferably, the crystalline form M has a DSC spectrum substantially as shown in Figure 35.

[0174] Preferably, the crystalline form M has a TGA graph substantially as shown in Figure 56.

[0175] Preferably, the crystalline form M is a monotoluene solvate of compound I.

[0176] The present invention provides a crystalline form N of a dioxane solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 17.10±0.2°, 20.66±0.2°, 22.71±0.2°, and 18.21±0.2°;

[0177] Preferably, the peaks 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° are further included;

[0178] More preferably, the peaks 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° are further included;

[0179] Preferably, the X-ray powder diffraction pattern of the crystalline form N has a diffraction angle (2θ) as shown in Table 15, wherein the error range of the 2θ angle is ±0.20°:

[0180] Table 15

[0181] Preferably, the crystalline form N has the X-ray powder diffraction intensity shown in Table 15.

[0182] Preferably, the crystalline form N has an X-ray powder diffraction pattern substantially as shown in FIG15 .

[0183] Preferably, the DSC analysis of the crystalline form N shows an endothermic peak when heated to a peak temperature of approximately 116.48°C.

[0184] Preferably, the crystalline form N has a DSC spectrum substantially as shown in Figure 36.

[0185] Preferably, the crystalline form N has a TGA graph substantially as shown in Figure 57.

[0186] Preferably, the crystalline form N is a 1.5-dioxane solvate of compound I.

[0187] The present invention provides a crystalline Form O of a DMF solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 17.72±0.2°, 13.14±0.2°, 15.08±0.2°, and 24.77±0.2°;

[0188] Preferably, the 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° are further included;

[0189] More preferably, the 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° are further included;

[0190] Preferably, the X-ray powder diffraction pattern of the crystalline form O has a diffraction angle (2θ) as shown in Table 16, wherein the error range of the 2θ angle is ±0.20°:

[0191] Table 16

[0192] Preferably, the crystalline form O has the X-ray powder diffraction intensity shown in Table 16.

[0193] Preferably, the crystalline form O has an X-ray powder diffraction pattern substantially as shown in FIG16 .

[0194] Preferably, the DSC analysis of the crystalline form O shows an endothermic peak when heated to a peak temperature of approximately 123.26°C.

[0195] Preferably, the crystalline form O has a DSC spectrum substantially as shown in FIG37 .

[0196] Preferably, the crystalline Form O has a TGA graph substantially as shown in Figure 58.

[0197] Preferably, the crystalline form O is a mono-DMF solvate of compound I.

[0198] The present invention provides a crystalline form P of an N-methylpyrrolidone solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 14.63±0.2°, 13.16±0.2°, 16.98±0.2°, and 14.36±0.2°;

[0199] Preferably, the 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° are further included;

[0200] More preferably, the 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° are further included;

[0201] Preferably, the X-ray powder diffraction pattern of the crystalline form P has a diffraction angle (2θ) as shown in Table 17, wherein the error range of the 2θ angle is ±0.20°:

[0202] Table 17

[0203] Preferably, the crystalline form P has the X-ray powder diffraction intensity shown in Table 17.

[0204] Preferably, the crystalline form P has an X-ray powder diffraction pattern substantially as shown in FIG17 .

[0205] Preferably, the DSC analysis of the crystalline form P shows an endothermic peak when heated to a peak temperature of approximately 117.63°C.

[0206] Preferably, the crystalline form P has a DSC spectrum substantially as shown in Figure 38.

[0207] Preferably, the crystalline form P has a TGA graph substantially as shown in Figure 59.

[0208] Preferably, the crystalline form P is a mono-N-methylpyrrolidone solvate of compound I.

[0209] The present invention provides a crystalline form Q of an n-butanol solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 18.05±0.2°, 10.71±0.2°, 12.54±0.2°, and 18.78±0.2°;

[0210] Preferably, the peaks 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° are further included;

[0211] More preferably, the peaks 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° are further included;

[0212] Preferably, the X-ray powder diffraction pattern of the crystalline form Q has a diffraction angle (2θ) as shown in Table 18, wherein the error range of the 2θ angle is ±0.20°:

[0213] Table 18

[0214] Preferably, the crystalline form Q has the X-ray powder diffraction intensity shown in Table 18.

[0215] Preferably, the crystalline form Q has an X-ray powder diffraction pattern substantially as shown in Figure 18.

[0216] Preferably, the DSC analysis of the crystalline form Q shows an endothermic peak when heated to a peak temperature of approximately 100.61°C.

[0217] Preferably, the crystalline form Q has a DSC spectrum substantially as shown in Figure 39.

[0218] Preferably, the crystalline form Q has a TGA graph substantially as shown in Figure 60.

[0219] Preferably, the crystalline form Q is a 0.5-n-butanol solvate of compound I.

[0220] The present invention provides a crystalline form R of an n-propanol solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.67±0.2°, 12.52±0.2°, 18.08±0.2°, and 8.98±0.2°;

[0221] Preferably, the peaks 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° are further included;

[0222] More preferably, the peaks 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° are further included;

[0223] Preferably, the X-ray powder diffraction pattern of the crystalline form R has a diffraction angle (2θ) as shown in Table 19, wherein the error range of the 2θ angle is ±0.20°:

[0224] Table 19

[0225] Preferably, the crystalline form R has the X-ray powder diffraction intensity shown in Table 19.

[0226] Preferably, the crystalline form R has an X-ray powder diffraction pattern substantially as shown in Figure 19.

[0227] Preferably, the DSC analysis of the crystalline form R shows an endothermic peak when heated to a peak temperature of approximately 110.90°C.

[0228] Preferably, the crystalline form R has a DSC spectrum substantially as shown in Figure 40.

[0229] Preferably, the crystalline form R has a TGA graph substantially as shown in Figure 61.

[0230] Preferably, the crystalline form R is a mono-n-propanol solvate of compound I.

[0231] The present invention provides a crystalline Form S of a tetrahydrofuran solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 12.17±0.2°, 8.19±0.2°, 7.67±0.2°, and 13.96±0.2°;

[0232] Preferably, the peaks 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° are further included;

[0233] More preferably, the peaks 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° are further included;

[0234] Preferably, the X-ray powder diffraction pattern of the crystalline form S has a diffraction angle (2θ) as shown in Table 20, wherein the error range of the 2θ angle is ±0.20°:

[0235] Table 20

[0236] Preferably, the crystalline form S has the X-ray powder diffraction intensity shown in Table 20.

[0237] Preferably, the crystalline form S has an X-ray powder diffraction pattern substantially as shown in Figure 20.

[0238] Preferably, the DSC analysis of the crystalline form S shows an endothermic peak when heated to a peak temperature of approximately 96.26°C.

[0239] Preferably, the crystalline form S has a DSC spectrum substantially as shown in Figure 41.

[0240] Preferably, the crystalline form S has a TGA graph substantially as shown in Figure 62.

[0241] Preferably, the crystalline form S is a 0.5 tetrahydrofuran solvate of compound I.

[0242] The present invention provides a crystalline Form T of a 2-methyltetrahydrofuran solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.79±0.2°, 8.66±0.2°, 9.12±0.2°, and 16.87±0.2°;

[0243] Preferably, the peaks 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° are further included;

[0244] More preferably, the peaks 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° are further included;

[0245] Preferably, the X-ray powder diffraction pattern of the crystalline form T has a diffraction angle (2θ) as shown in Table 21, wherein the error range of the 2θ angle is ±0.20°:

[0246] Table 21

[0247] Preferably, the crystalline form T has the X-ray powder diffraction intensity shown in Table 21.

[0248] Preferably, the crystalline form T has an X-ray powder diffraction pattern substantially as shown in Figure 21.

[0249] Preferably, the DSC analysis of the crystalline form T shows an endothermic peak when heated to a peak temperature of approximately 112.95°C.

[0250] Preferably, the crystalline form T has a DSC spectrum substantially as shown in Figure 42.

[0251] Preferably, the crystalline form T has a TGA graph substantially as shown in Figure 63.

[0252] Preferably, the crystalline form T is a mono-2-methyltetrahydrofuran solvate of compound I.

[0253] The unsolvated crystalline form of Compound II may be the following crystalline forms 2A, 2B, 2C, 2D, and 2E; the hydrated crystalline form of Compound II may be the following crystalline forms 2F and 2G; the solvated crystalline form of Compound II may be the following 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, and 2U.

[0254] The present invention provides Form 2A of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 13.94±0.2°, 22.07±0.2°, 17.96±0.2°, and 17.57±0.2°;

[0255] Preferably, the peaks 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° are further included;

[0256] More preferably, the peaks 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° are further included;

[0257] Preferably, the X-ray powder diffraction pattern of the crystalline form 2A has a diffraction angle (2θ) as shown in Table 2-1, wherein the error range of the 2θ angle is ±0.20°:

[0258] Table 2-1

[0259] Preferably, the crystalline form 2A has the X-ray powder diffraction intensity shown in Table 2-1.

[0260] Preferably, the crystalline form 2A has an X-ray powder diffraction pattern substantially as shown in Figure 2-1.

[0261] Preferably, the DSC analysis of the crystalline form 2A shows an endothermic peak when heated to a peak temperature of approximately 189.90°C.

[0262] Preferably, the crystalline form 2A has a DSC spectrum substantially as shown in Figure 2-26.

[0263] Preferably, the crystalline form 2A has a TGA pattern substantially as shown in Figure 2-51.

[0264] The present invention provides Form 2B of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 13.16±0.2°, 21.31±0.2°, 25.46±0.2°, and 10.61±0.2°;

[0265] Preferably, the peaks 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° are further included;

[0266] More preferably, the peaks 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° are further included;

[0267] Preferably, the X-ray powder diffraction pattern of the crystalline form 2B has a diffraction angle (2θ) as shown in Table 2-2, wherein the error range of the 2θ angle is ±0.20°:

[0268] Table 2-2

[0269] Preferably, the crystalline form 2B has the X-ray powder diffraction intensity shown in Table 2-2.

[0270] Preferably, the crystalline form 2B has an X-ray powder diffraction pattern substantially as shown in Figure 2-2.

[0271] Preferably, the DSC analysis of the crystalline form 2B shows an endothermic peak when heated to a peak temperature of approximately 181.06°C.

[0272] Preferably, the crystalline form 2B has a DSC spectrum substantially as shown in Figure 2-27.

[0273] Preferably, the crystalline form 2B has a TGA pattern substantially as shown in Figure 2-52.

[0274] The present invention provides Form 2C of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 13.63±0.2°, 5.62±0.2°, 17.12±0.2°, and 17.68±0.2°;

[0275] Preferably, the peaks 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° are further included;

[0276] More preferably, the peaks 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° are further included;

[0277] Preferably, the X-ray powder diffraction pattern of the crystalline form 2C has a diffraction angle (2θ) as shown in Table 2-3, wherein the error range of the 2θ angle is ±0.20°:

[0278] Table 2-3

[0279] Preferably, the crystalline form 2C has the X-ray powder diffraction intensity shown in Table 2-3.

[0280] Preferably, the Form 2C has an X-ray powder diffraction pattern substantially as shown in Figures 2-3.

[0281] Preferably, the DSC analysis of the crystalline form 2C shows an endothermic peak when heated to a peak temperature of approximately 171.63°C.

[0282] Preferably, the crystalline form 2C has a DSC spectrum substantially as shown in Figure 2-28.

[0283] Preferably, the crystalline form 2C has a TGA pattern substantially as shown in Figure 2-53.

[0284] The present invention provides Form 2D of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 5.62±0.2°, 12.01±0.2°, 5.24±0.2°, and 17.72±0.2°;

[0285] Preferably, the peaks 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° are further included;

[0286] More preferably, the peaks 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° are further included;

[0287] Preferably, the X-ray powder diffraction pattern of the crystalline form 2D has a diffraction angle (2θ) as shown in Table 2-4, wherein the error range of the 2θ angle is ±0.20°:

[0288] Table 2-4

[0289] Preferably, the crystal form 2D has the X-ray powder diffraction intensity shown in Table 2-4.

[0290] Preferably, the Form 2D has an X-ray powder diffraction pattern substantially as shown in Figures 2-4.

[0291] Preferably, the DSC analysis of the crystal form 2D shows an endothermic peak when heated to a peak temperature of approximately 168.79°C.

[0292] Preferably, the crystalline form 2D has a DSC spectrum substantially as shown in Figure 2-29.

[0293] Preferably, the crystalline form 2D has a TGA pattern substantially as shown in Figure 2-54.

[0294] The present invention provides Form 2E of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 17.96±0.2°, 3.34±0.2°, 5.63±0.2°, and 13.63±0.2°;

[0295] Preferably, the peaks 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° are further included;

[0296] More preferably, the peaks 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° are further included;

[0297] Preferably, the X-ray powder diffraction pattern of the crystalline form 2E has a diffraction angle (2θ) as shown in Table 2-5, wherein the error range of the 2θ angle is ±0.20°:

[0298] Table 2-5

[0299] Preferably, the crystalline form 2E has the X-ray powder diffraction intensity shown in Table 2-5.

[0300] Preferably, the Form 2E has an X-ray powder diffraction pattern substantially as shown in Figures 2-5.

[0301] Preferably, the DSC analysis of the crystalline form 2E shows endothermic peaks near the peak temperatures of 110.30°C and 169.27°C.

[0302] Preferably, the crystalline form 2E has a DSC spectrum substantially as shown in Figure 2-30.

[0303] Preferably, the crystalline form 2E has a TGA pattern substantially as shown in Figure 2-55.

[0304] The present invention provides a hydrated form 2F of Compound II, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 19.51±0.2°, 13.71±0.2°, 14.29±0.2°, and 18.09±0.2°;

[0305] Preferably, the peaks 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° are further included;

[0306] More preferably, the peaks 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° are further included;

[0307] Preferably, the X-ray powder diffraction pattern of the crystalline form 2F has a diffraction angle (2θ) as shown in Table 2-6, wherein the error range of the 2θ angle is ±0.20°:

[0308] Table 2-6

[0309] Preferably, the crystalline form 2F has the X-ray powder diffraction intensity shown in Table 2-6.

[0310] Preferably, the Form 2F has an X-ray powder diffraction pattern substantially as shown in Figures 2-6.

[0311] Preferably, the DSC analysis of the crystalline form 2F shows an endothermic peak when heated to a peak temperature of 114.41°C.

[0312] Preferably, the crystalline form 2F has a DSC spectrum substantially as shown in Figure 2-31.

[0313] Preferably, the crystalline form 2F has a TGA pattern substantially as shown in Figure 2-56.

[0314] Preferably, the crystalline form 2F is a trihydrate of compound II.

[0315] The present invention provides a hydrated form 2G of Compound II, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 17.45±0.2°, 13.63±0.2°, 5.61±0.2°, and 5.24±0.2°;

[0316] Preferably, the peaks 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° are further included;

[0317] More preferably, the peaks 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° are further included;

[0318] Preferably, the X-ray powder diffraction pattern of the crystalline form 2G has a diffraction angle (2θ) as shown in Table 2-7, wherein the error range of the 2θ angle is ±0.20°:

[0319] Table 2-7

[0320] Preferably, the crystalline form 2G has the X-ray powder diffraction intensity shown in Table 2-7.

[0321] Preferably, the Form 2G has an X-ray powder diffraction pattern substantially as shown in Figures 2-7.

[0322] Preferably, the DSC analysis of the crystalline form 2G shows an endothermic peak when heated to a peak temperature of approximately 169.22°C.

[0323] Preferably, the crystalline form 2G has a DSC spectrum substantially as shown in Figure 2-32.

[0324] Preferably, the crystalline form 2G has a TGA pattern substantially as shown in Figure 2-57.

[0325] Preferably, the crystalline form 2G is a dihydrate of compound II.

[0326] The present invention provides a crystalline form 2H of a dimethyl sulfoxide solvate of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 14.84±0.2°, 13.42±0.2°, 24.68±0.2°, and 21.70±0.2°;

[0327] Preferably, the peaks 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° are further included;

[0328] More preferably, the peaks 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° are further included;

[0329] Preferably, the X-ray powder diffraction pattern of the crystalline form 2H has a diffraction angle (2θ) as shown in Table 2-8, wherein the error range of the 2θ angle is ±0.20°:

[0330] Table 2-8

[0331] Preferably, the crystalline form 2H has the X-ray powder diffraction intensity shown in Table 2-8.

[0332] Preferably, the Form 2H has an X-ray powder diffraction pattern substantially as shown in Figures 2-8.

[0333] Preferably, the DSC analysis of the crystalline form 2H shows an endothermic peak near the peak temperature of 118.06°C.

[0334] Preferably, the crystalline form 2H has a DSC spectrum substantially as shown in Figure 2-33.

[0335] Preferably, the Form 2H has a TGA pattern substantially as shown in Figure 2-58.

[0336] Preferably, the crystalline form 2H is a mono-dimethyl sulfoxide solvate of compound II.

[0337] The present invention provides a crystalline form 2I of a methyl tert-butyl ether solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.74±0.2°, 10.94±0.2°, 4.32±0.2°, and 17.66±0.2°;

[0338] Preferably, the peaks at diffraction angles (2θ) of 13.18±0.2°, 9.25±0.2°, 18.79±0.2°, 17.12±0.2° and 12.79° are further included;

[0339] More preferably, the peaks 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° are further included;

[0340] Preferably, the X-ray powder diffraction pattern of the crystalline form 2I has a diffraction angle (2θ) as shown in Table 2-9, wherein the error range of the 2θ angle is ±0.20°:

[0341] Table 2-9

[0342] Preferably, the crystalline form 2I has the X-ray powder diffraction intensity shown in Table 2-9.

[0343] Preferably, the Form 2I has an X-ray powder diffraction pattern substantially as shown in Figures 2-9.

[0344] Preferably, the DSC analysis of the crystalline form 2I shows an endothermic peak when heated to a peak temperature of 115.84°C.

[0345] Preferably, the crystalline form 2I has a DSC spectrum substantially as shown in Figure 2-34.

[0346] Preferably, the Form 2I has a TGA pattern substantially as shown in Figure 2-59.

[0347] Preferably, the crystalline form 2I is a 0.5 methyl tert-butyl ether solvate of compound II.

[0348] The present invention provides a crystalline form 2J-1 of an n-heptane solvate of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 12.15±0.2°, 8.91±0.2°, 8.18±0.2°, and 7.63±0.2°;

[0349] Preferably, the peaks 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° are further included;

[0350] More preferably, the peaks 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° are further included;

[0351] Preferably, the X-ray powder diffraction pattern of the crystalline form 2J-1 has a diffraction angle (2θ) as shown in Table 2-10, wherein the error range of the 2θ angle is ±0.20°:

[0352] Table 2-10

[0353] Preferably, the crystalline form 2J-1 has the X-ray powder diffraction intensity shown in Table 2-10.

[0354] Preferably, the crystalline form 2J-1 has an X-ray powder diffraction pattern substantially as shown in Figure 2-10.

[0355] Preferably, the DSC analysis of the crystalline form 2J-1 shows an endothermic peak when heated to a peak temperature of approximately 103.13°C.

[0356] Preferably, the crystalline form 2J-1 has a DSC spectrum substantially as shown in Figure 2-35.

[0357] Preferably, the crystalline form 2J-1 has a TGA pattern substantially as shown in Figure 2-60.

[0358] Preferably, the crystalline form 2J-1 is a 0.2 n-heptane solvate of compound II.

[0359] The present invention provides a crystalline form 2J-2 of an n-heptane solvate of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 3.52±0.2°, 17.76±0.2°, 14.19±0.2°, and 10.61±0.2°;

[0360] Preferably, the peaks at diffraction angles (2θ) of 7.05±0.2°, 21.35±0.2°, 16.24±0.2° and 19.49±0.2° are further included;

[0361] Preferably, the X-ray powder diffraction pattern of the crystalline form 2J-2 has a diffraction angle (2θ) as shown in Table 2-11, wherein the error range of the 2θ angle is ±0.20°:

[0362] Table 2-11

[0363] Preferably, the crystalline form 2J-2 has the X-ray powder diffraction intensity shown in Table 2-11.

[0364] Preferably, the crystalline form 2J-2 has an X-ray powder diffraction pattern substantially as shown in Figure 2-11.

[0365] Preferably, the DSC analysis of the crystalline form 2J-2 shows an endothermic peak when heated to a peak temperature of 76.82°C.

[0366] Preferably, the crystalline form 2J-2 has a DSC spectrum substantially as shown in Figure 2-36.

[0367] Preferably, the crystalline form 2J-2 has a TGA pattern substantially as shown in Figure 2-61.

[0368] Preferably, the crystalline form 2J-2 is a 0.5 n-heptane solvate of compound II.

[0369] The present invention provides a crystalline form 2K of a toluene solvate of Compound II, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.52±0.2°, 18.45±0.2°, 19.09±0.2°, and 21.48±0.2°;

[0370] Preferably, the spectral range further includes peaks 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°;

[0371] More preferably, the peaks 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° are further included;

[0372] Preferably, the X-ray powder diffraction pattern of the crystalline form 2K has a diffraction angle (2θ) as shown in Table 2-12, wherein the error range of the 2θ angle is ±0.20°:

[0373] Table 2-12

[0374] Preferably, the crystalline form 2K has the X-ray powder diffraction intensity shown in Table 2-12.

[0375] Preferably, the crystalline form 2K has an X-ray powder diffraction pattern substantially as shown in Figure 2-12.

[0376] Preferably, the DSC analysis of the crystalline form 2K shows endothermic peaks near peak temperatures of 107.92° C., 172.19° C., and 184.68° C. when heated.

[0377] Preferably, the crystalline form 2K has a DSC spectrum substantially as shown in Figure 2-37.

[0378] Preferably, the crystalline form 2K has a TGA graph substantially as shown in Figure 2-62.

[0379] Preferably, the crystalline form 2K is a 0.75 toluene solvate of compound II.

[0380] The present invention provides a crystalline form 2L-1 of a methyl isobutyl ketone solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.66±0.2°, 10.79±0.2°, 26.00±0.2°, and 19.62±0.2°;

[0381] Preferably, the peaks 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° are further included;

[0382] More preferably, the peaks 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° are further included;

[0383] Preferably, the X-ray powder diffraction pattern of the crystalline form 2L-1 has a diffraction angle (2θ) as shown in Table 2-13, wherein the error range of the 2θ angle is ±0.20°:

[0384] Table 2-13

[0385] Preferably, the crystalline form 2L-1 has the X-ray powder diffraction intensity shown in Table 2-13.

[0386] Preferably, the crystalline form 2L-1 has an X-ray powder diffraction pattern substantially as shown in Figure 2-13.

[0387] Preferably, the DSC analysis of the crystalline form 2L-1 shows an endothermic peak when heated to a peak temperature of approximately 106.45°C.

[0388] Preferably, the crystalline form 2L-1 has a DSC spectrum substantially as shown in Figure 2-38.

[0389] Preferably, the crystalline form 2L-1 has a TGA pattern substantially as shown in Figure 2-63.

[0390] Preferably, the crystalline form 2L-1 is a 0.75 methyl isobutyl ketone solvate of compound II.

[0391] The present invention provides a crystalline form 2L-2 of a methyl isobutyl ketone solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.68±0.2°, 10.83±0.2°, 13.10±0.2°, and 11.06±0.2°;

[0392] Preferably, the peaks 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° are further included;

[0393] More preferably, the peaks 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° are further included;

[0394] Preferably, the X-ray powder diffraction pattern of the crystalline form 2L-2 has a diffraction angle (2θ) as shown in Table 2-14, wherein the error range of the 2θ angle is ±0.20°:

[0395] Table 2-14

[0396] Preferably, the crystalline form 2L-2 has the X-ray powder diffraction intensity shown in Table 2-14.

[0397] Preferably, the crystalline form 2L-2 has an X-ray powder diffraction pattern substantially as shown in Figure 2-14.

[0398] Preferably, the DSC analysis of the crystalline form 2L-2 shows an endothermic peak when heated to a peak temperature of approximately 102.87°C.

[0399] Preferably, the crystalline form 2L-2 has a DSC spectrum substantially as shown in Figure 2-39.

[0400] Preferably, the crystalline form 2L-2 has a TGA pattern substantially as shown in Figure 2-64.

[0401] Preferably, the crystalline form 2L-2 is a 0.3 methyl isobutyl ketone solvate of compound II.

[0402] The present invention provides a crystalline form 2M-1 of a cyclopentyl methyl ether solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.78±0.2°, 10.98±0.2°, 17.67±0.2°, and 17.20±0.2°;

[0403] Preferably, the peaks 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° are further included;

[0404] More preferably, the peaks 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° are further included;

[0405] Preferably, the X-ray powder diffraction pattern of the crystalline form 2M-1 has a diffraction angle (2θ) as shown in Table 2-15, wherein the error range of the 2θ angle is ±0.20°:

[0406] Table 2-15

[0407] Preferably, the crystalline form 2M-1 has the X-ray powder diffraction intensity shown in Table 2-15.

[0408] Preferably, the crystalline form 2M-1 has an X-ray powder diffraction pattern substantially as shown in Figure 2-15.

[0409] Preferably, the DSC analysis of the crystalline form 2M-1 shows an endothermic peak when heated to a peak temperature of approximately 113.56°C.

[0410] Preferably, the crystalline form 2M-1 has a DSC spectrum substantially as shown in Figure 2-40.

[0411] Preferably, the crystalline form 2M-1 has a TGA graph substantially as shown in Figure 2-65.

[0412] Preferably, the crystalline form 2M-1 is a monocyclopentyl methyl ether solvate of compound II.

[0413] The present invention provides a crystalline form 2M-2 of a cyclopentyl methyl ether solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 5.16±0.2°, 10.83±0.2°, 15.66±0.2°, and 21.29±0.2°;

[0414] Preferably, the peaks 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° are further included;

[0415] More preferably, the peaks 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° are further included;

[0416] Preferably, the X-ray powder diffraction pattern of the crystalline form 2M-2 has a diffraction angle (2θ) as shown in Table 2-16, wherein the error range of the 2θ angle is ±0.20°:

[0417] Table 2-16

[0418] Preferably, the crystalline form 2M-2 has the X-ray powder diffraction intensity shown in Table 2-16.

[0419] Preferably, the crystalline form 2M-2 has an X-ray powder diffraction pattern substantially as shown in Figure 2-16.

[0420] Preferably, the DSC analysis of the crystalline form 2M-2 shows endothermic peaks near the peak temperatures of 110.50°C and 165.01°C.

[0421] Preferably, the crystalline form 2M-2 has a DSC spectrum substantially as shown in Figure 2-41.

[0422] Preferably, the crystalline form 2M-2 has a TGA pattern substantially as shown in Figure 2-66.

[0423] Preferably, the crystalline form 2M-2 is a monocyclopentyl methyl ether solvate of compound II.

[0424] The present invention provides a crystalline form 2N of a methyl ethyl ketone solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 3.34±0.2°, 10.88±0.2°, 9.13±0.2°, and 6.64±0.2°;

[0425] Preferably, the peaks 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° are further included;

[0426] More preferably, the peaks 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° are further included;

[0427] Preferably, the X-ray powder diffraction pattern of the crystalline form 2N has a diffraction angle (2θ) as shown in Table 2-17, wherein the error range of the 2θ angle is ±0.20°:

[0428] Table 2-17

[0429] Preferably, the crystalline form 2N has the X-ray powder diffraction intensity shown in Table 2-17.

[0430] Preferably, the Form 2N has an X-ray powder diffraction pattern substantially as shown in Figure 2-17.

[0431] Preferably, the DSC analysis of the crystalline form 2N shows endothermic peaks near the peak temperatures of 102.66°C and 113.16°C.

[0432] Preferably, the crystalline form 2N has a DSC spectrum substantially as shown in Figure 2-42.

[0433] Preferably, the crystalline form 2N has a TGA graph substantially as shown in Figure 2-67.

[0434] Preferably, the crystalline form 2N is a 0.3 methyl ethyl ketone solvate of compound II.

[0435] The present invention provides a methylcyclohexane solvate of Compound II in Form 2O, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.72±0.2°, 10.92±0.2°, 13.14±0.2°, and 9.23±0.2°;

[0436] Preferably, the peaks 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° are further included;

[0437] More preferably, the peaks 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° are further included;

[0438] Preferably, the X-ray powder diffraction pattern of the crystalline form 2O has a diffraction angle (2θ) as shown in Table 2-18, wherein the error range of the 2θ angle is ±0.20°:

[0439] Table 2-18

[0440] Preferably, the crystalline form 2O has the X-ray powder diffraction intensity shown in Table 2-18.

[0441] Preferably, the Form 20 has an X-ray powder diffraction pattern substantially as shown in FIG. 2-18 .

[0442] Preferably, the DSC analysis of the crystalline form 2O shows an endothermic peak when heated to a peak temperature of approximately 111.80°C.

[0443] Preferably, the crystalline form 2O has a DSC spectrum substantially as shown in Figure 2-43.

[0444] Preferably, the Form 2O has a TGA pattern substantially as shown in FIG. 2-68 .

[0445] Preferably, the crystalline form 2O is a monomethylcyclohexane solvate of compound II.

[0446] The present invention provides a crystalline form 2P of a DMF solvate of Compound II, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 10.98±0.2°, 9.31±0.2°, 17.68±0.2°, and 25.67±0.2°;

[0447] Preferably, the peaks 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° are further included;

[0448] More preferably, the peaks 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° are further included;

[0449] Preferably, the X-ray powder diffraction pattern of the crystalline form 2P has a diffraction angle (2θ) as shown in Table 2-19, wherein the error range of the 2θ angle is ±0.20°:

[0450] Table 2-19

[0451] Preferably, the crystalline form 2P has the X-ray powder diffraction intensity shown in Table 2-19.

[0452] Preferably, the Form 2P has an X-ray powder diffraction pattern substantially as shown in Figure 2-19.

[0453] Preferably, the DSC analysis of the crystalline form 2P shows an endothermic peak when heated to a peak temperature of approximately 105.14°C.

[0454] Preferably, the crystalline form 2P has a DSC spectrum substantially as shown in Figure 2-44.

[0455] Preferably, the crystalline form 2P has a TGA pattern substantially as shown in Figure 2-69.

[0456] Preferably, the crystalline form 2P is a mono-DMF solvate of compound II.

[0457] The present invention provides a crystalline form 2Q-1 of a 2-methyltetrahydrofuran solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.74±0.2°, 10.89±0.2°, 3.53±0.2°, and 17.90±0.2°;

[0458] Preferably, the peaks 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° are further included;

[0459] More preferably, the peaks 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° are further included;

[0460] Preferably, the X-ray powder diffraction pattern of the crystalline form 2Q-1 has a diffraction angle (2θ) as shown in Table 2-20, wherein the error range of the 2θ angle is ±0.20°:

[0461] Table 2-20

[0462] Preferably, the crystalline form 2Q-1 has the X-ray powder diffraction intensity shown in Table 2-20.

[0463] Preferably, the crystalline form 2Q-1 has an X-ray powder diffraction pattern substantially as shown in Figure 2-20.

[0464] Preferably, the DSC analysis of the crystalline form 2Q-1 shows an endothermic peak when heated to a peak temperature of approximately 111.13°C.

[0465] Preferably, the crystalline form 2Q-1 has a DSC spectrum substantially as shown in Figure 2-45.

[0466] Preferably, the crystalline form 2Q-1 has a TGA graph substantially as shown in Figure 2-70.

[0467] Preferably, the crystalline form 2Q-1 is a mono-2-methyltetrahydrofuran solvate of compound II.

[0468] The present invention provides a crystalline form 2Q-2 of a 2-methyltetrahydrofuran solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.76±0.2°, 10.89±0.2°, 9.21±0.2°, and 17.02±0.2°;

[0469] Preferably, the peaks 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° are further included;

[0470] More preferably, the peaks 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° are further included;

[0471] Preferably, the X-ray powder diffraction pattern of the crystalline form 2Q-2 has a diffraction angle (2θ) as shown in Table 2-21, wherein the error range of the 2θ angle is ±0.20°:

[0472] Table 2-21

[0473] Preferably, the crystal form 2Q-2 has the X-ray powder diffraction intensity shown in Table 2-21.

[0474] Preferably, the crystalline form 2Q-2 has an X-ray powder diffraction pattern substantially as shown in Figure 2-21.

[0475] Preferably, the DSC analysis of the crystalline form 2Q-2 shows an endothermic peak when heated to a peak temperature of approximately 114.18°C.

[0476] Preferably, the crystalline form 2Q-2 has a DSC spectrum substantially as shown in Figure 2-46.

[0477] Preferably, the crystalline form 2Q-2 has a TGA graph substantially as shown in Figure 2-71.

[0478] Preferably, the crystalline form 2Q-2 is a mono-2-methyltetrahydrofuran solvate of compound II.

[0479] The present invention provides Form 2R of an N-methylpyrrolidone solvate of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 10.79±0.2°, 9.15±0.2°, 3.44±0.2°, and 17.63±0.2°;

[0480] Preferably, the peaks 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° are further included;

[0481] More preferably, the peaks 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° are further included;

[0482] Preferably, the X-ray powder diffraction pattern of the crystalline form 2R has a diffraction angle (2θ) as shown in Table 2-22, wherein the error range of the 2θ angle is ±0.20°:

[0483] Table 2-22

[0484] Preferably, the crystalline form 2R has the X-ray powder diffraction intensity shown in Table 2-22.

[0485] Preferably, the Form 2R has an X-ray powder diffraction pattern substantially as shown in Figure 2-22.

[0486] Preferably, the DSC analysis of the crystalline form 2R shows an endothermic peak when heated to a peak temperature of approximately 128.45°C.

[0487] Preferably, the crystalline form 2R has a DSC spectrum substantially as shown in Figure 2-47.

[0488] Preferably, the crystalline form 2R has a TGA pattern substantially as shown in Figure 2-72.

[0489] Preferably, the crystalline form 2R is a mono-N-methylpyrrolidone solvate of compound II.

[0490] The present invention provides a crystalline form 2S of a trifluoroethanol solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 17.64±0.2°, 4.01±0.2°, 8.72±0.2°, and 8.28±0.2°;

[0491] Preferably, the peaks 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° are further included;

[0492] More preferably, the peaks 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° are further included;

[0493] Preferably, the X-ray powder diffraction pattern of the crystalline form 2S has a diffraction angle (2θ) as shown in Table 2-23, wherein the error range of the 2θ angle is ±0.20°:

[0494] Table 2-23

[0495] Preferably, the crystalline form 2S has the X-ray powder diffraction intensity shown in Table 2-23.

[0496] Preferably, the crystalline form 2S has an X-ray powder diffraction pattern substantially as shown in Figure 2-23.

[0497] Preferably, the DSC analysis of the crystalline form 2S shows endothermic peaks near the peak temperatures of 123.79°C and 169.39°C.

[0498] Preferably, the crystalline form 2S has a DSC spectrum substantially as shown in Figure 2-48.

[0499] Preferably, the crystalline form 2S has a TGA graph substantially as shown in Figure 2-73.

[0500] Preferably, the crystalline form 2S is a monotrifluoroethanol solvate of compound II.

[0501] The present invention provides a crystalline form 2T of a tetrahydrofuran solvate of Compound II, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 12.17±0.2°, 8.92±0.2°, 7.63±0.2°, and 8.22±0.2°;

[0502] Preferably, the peaks 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° are further included;

[0503] More preferably, the peaks 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° are further included;

[0504] Preferably, the X-ray powder diffraction pattern of the crystalline form 2T has a diffraction angle (2θ) as shown in Table 2-24, wherein the error range of the 2θ angle is ±0.20°:

[0505] Table 2-24

[0506] Preferably, the crystalline form 2T has the X-ray powder diffraction intensity shown in Table 2-24.

[0507] Preferably, the Form 2T has an X-ray powder diffraction pattern substantially as shown in Figure 2-24.

[0508] Preferably, the DSC analysis of the crystalline form 2T shows an endothermic peak when heated to a peak temperature of approximately 110.50°C.

[0509] Preferably, the crystalline form 2T has a DSC spectrum substantially as shown in Figure 2-49.

[0510] Preferably, the crystalline form 2T has a TGA graph substantially as shown in Figure 2-74.

[0511] Preferably, the crystalline form 2T is a 0.3% tetrahydrofuran solvate of compound II.

[0512] The present invention provides Form 2U of a dioxane solvate of Compound II, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.86±0.2°, 10.98±0.2°, 9.27±0.2°, and 17.12±0.2°;

[0513] Preferably, the peaks 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° are further included;

[0514] More preferably, the peaks 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° are further included;

[0515] Preferably, the X-ray powder diffraction pattern of the crystalline form 2U has a diffraction angle (2θ) as shown in Table 2-25, wherein the error range of the 2θ angle is ±0.20°:

[0516] Table 2-25

[0517] Preferably, the crystalline form 2U has the X-ray powder diffraction intensity shown in Table 2-25.

[0518] Preferably, the Form 2U has an X-ray powder diffraction pattern substantially as shown in Figure 2-25.

[0519] Preferably, the DSC analysis of the crystalline form 2U shows an endothermic peak when heated to a peak temperature of approximately 109.16°C.

[0520] Preferably, the crystalline form 2U has a DSC spectrum substantially as shown in Figure 2-50.

[0521] Preferably, the crystalline form 2U has a TGA graph substantially as shown in Figure 2-75.

[0522] Preferably, the crystalline form 2U is a 0.5-dioxane solvate of compound II.

[0523] The second aspect of the present invention provides a method for preparing the polymorph of the aforementioned compound III, selected from the following preparation methods:

[0524] Method 1: Step 1: dissolving or dispersing compound III in a solvent; Step 2: stirring at 0-50°C for crystallization; alternatively, adding an antisolvent to the clear solution of the compound for precipitation; alternatively, slowly evaporating the clear solution of the compound;

[0525] Method 2: Dispersing compound III in a solvent and in the atmosphere of these media to obtain crystals;

[0526] Method 3: Method 1 and method 2 are used in combination to prepare the polymorph of compound III.

[0527] As a further preferred embodiment, the solvent is water, an organic solvent or a mixed solvent thereof, and the organic solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxide organic solvents or mixtures 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, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene or mixtures thereof.

[0528] The third aspect of the present invention provides a pharmaceutical composition comprising at least one of the polymorphs of the aforementioned Compound III and a pharmaceutically acceptable carrier.

[0529] A fourth aspect of the present invention provides a use of a polymorph of the aforementioned Compound III in the preparation of a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0530] In a fifth aspect, the present invention provides a polymorph of the aforementioned Compound III, which is used as a drug for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0531] In a sixth aspect, the present invention provides a polymorph of the aforementioned compound III, which is used to treat T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other agents, excessive sugar addiction, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, Drugs for the prevention or treatment of hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidosis, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, poor glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and the treatment of addiction.

[0532] As a preferred embodiment, the polymorph of the aforementioned compound III is used as a drug for treating T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain caused by the use of other agents, excessive sugar addiction, dyslipidemia, and hyperinsulinemia.

[0533] The present invention also provides a method for treating a disease, comprising administering a therapeutically effective amount of at least one of the polymorphs of the aforementioned Compound III or the pharmaceutical composition to an individual in need thereof.

[0534] According to an embodiment of the present invention, the disease is selected from metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0535] According to an embodiment of the present invention, the disease is selected from T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other agents, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke. , hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidosis, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome. Beneficial effects

[0536] The present invention provides polymorphs of Compound III and methods for preparing the same. The resulting polymorphs, compared to amorphous forms, have advantages such as good stability, good fluidity, and ease of crushing, making them more suitable for clinical formulation development. The preparation method provided by the present invention features a simple process, ease of implementation, mild reaction conditions, and high product yield. Furthermore, it eliminates the need for multiple purifications, is safe and environmentally friendly, and facilitates the industrial production of polymorphs. This method can meet the needs of clinical pharmaceutical formulation development, possesses significant clinical application value, and is expected to accelerate the development of a new generation of GLP-1R small molecule agonists. BRIEF DESCRIPTION OF THE DRAWINGS

[0537] Figure 1 shows an X-ray powder diffraction pattern of the crystalline form A of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0538] Figure 2 shows an X-ray powder diffraction pattern of the crystalline form B of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0539] Figure 3 shows an X-ray powder diffraction pattern of Form C of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0540] Figure 4 shows an X-ray powder diffraction pattern of the crystalline form D of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0541] Figure 5 shows an X-ray powder diffraction pattern of the crystalline form E of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0542] Figure 6 shows an X-ray powder diffraction pattern of the crystalline form F of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0543] Figure 7 shows the X-ray powder diffraction pattern of the hydrated crystal form G of compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0544] Figure 8 shows an X-ray powder diffraction pattern of Form H of the methyl isobutyl ketone solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0545] Figure 9 shows an X-ray powder diffraction pattern of the crystalline form I-1 of the methyl tert-butyl ether solvate of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0546] Figure 10 shows the X-ray powder diffraction pattern of the crystalline form I-2 of the methyl tert-butyl ether solvate of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0547] Figure 11 shows an X-ray powder diffraction pattern of Form J of the acetone solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0548] Figure 12 shows an X-ray powder diffraction pattern of Form K of the n-heptane solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0549] Figure 13 shows an X-ray powder diffraction pattern of Form L of the methylcyclohexane solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0550] Figure 14 shows an X-ray powder diffraction pattern of the crystalline form M of the toluene solvate of Compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0551] Figure 15 shows an X-ray powder diffraction pattern of Form N of the dioxane solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0552] Figure 16 shows an X-ray powder diffraction pattern of the crystalline form O of the DMF solvate of compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0553] Figure 17 shows an X-ray powder diffraction pattern of the crystalline form P of the N-methylpyrrolidone solvate of compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0554] Figure 18 shows an X-ray powder diffraction pattern of Form Q of the n-butanol solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0555] Figure 19 shows an X-ray powder diffraction pattern of the crystalline form R of the n-propanol solvate of compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0556] Figure 20 shows an X-ray powder diffraction pattern of Form S of the tetrahydrofuran solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0557] Figure 21 shows an X-ray powder diffraction pattern of Form T of 2-methyltetrahydrofuran solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0558] Figure 22 shows a DSC chart of Form A of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0559] Figure 23 shows a DSC chart of Form B of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0560] Figure 24 shows a DSC chart of Form C of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0561] Figure 25 shows a DSC chart of Form D of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0562] Figure 26 shows a DSC chart of Form E of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0563] Figure 27 shows a DSC chart of Form F of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0564] Figure 28 shows a DSC chart of the hydrated crystal form G of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0565] 29 shows a DSC chart of methyl isobutyl ketone solvate H of compound I of the present invention. The abscissa represents temperature (° C.), and the ordinate represents heat flow (mW).

[0566] Figure 30 shows a DSC chart of the crystalline form I-1 of the methyl tert-butyl ether solvate of the compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0567] Figure 31 shows a DSC chart of Form I-2 of the methyl tert-butyl ether solvate of Compound I. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0568] Figure 32 shows a DSC chart of Form J of the acetone solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0569] Figure 33 shows a DSC chart of Form K of the n-heptane solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0570] Figure 34 shows a DSC chart of Form L of the methylcyclohexane solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0571] Figure 35 shows a DSC chart of Form M of the toluene solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0572] Figure 36 shows a DSC chart of Form N of the dioxane solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0573] Figure 37 shows a DSC chart of Form O of the DMF solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0574] Figure 38 shows a DSC chart of the crystalline form P of the N-methylpyrrolidone solvate of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0575] Figure 39 shows a DSC chart of Form Q of the n-butanol solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0576] Figure 40 shows a DSC chart of Form R of the n-propanol solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0577] Figure 41 shows a DSC chart of Form S of the tetrahydrofuran solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0578] Figure 42 shows a DSC chart of Form T of 2-methyltetrahydrofuran solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0579] Figure 43 shows a TGA chart of the crystalline form A of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0580] Figure 44 shows a TGA chart of Form B of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0581] Figure 45 shows a TGA chart of Form C of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0582] Figure 46 shows a TGA chart of Form D of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0583] Figure 47 shows a TGA chart of Form E of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0584] Figure 48 shows a TGA chart of Form F of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0585] Figure 49 shows a TGA chart of the hydrated crystal form G of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0586] Figure 50 shows a TGA chart of methyl isobutyl ketone solvate H of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0587] 51 shows a TGA chart of methyl tert-butyl ether solvate I-1 of the present invention's compound I. The abscissa represents temperature (° C.), and the ordinate represents weight (%).

[0588] Figure 52 shows a TGA chart of Form I-2 of the methyl tert-butyl ether solvate of Compound I. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0589] Figure 53 shows a TGA chart of Form J of the acetone solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0590] Figure 54 shows a TGA chart of Form K of the n-heptane solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0591] Figure 55 shows a TGA chart of Form L of the methylcyclohexane solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0592] Figure 56 shows a TGA chart of Form M of the toluene solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0593] Figure 57 shows a TGA chart of Form N of the dioxane solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0594] Figure 58 shows a TGA chart of Form O of the DMF solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0595] Figure 59 shows a TGA chart of the crystalline form P of the N-methylpyrrolidone solvate of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0596] Figure 60 shows a TGA chart of Form Q of the n-butanol solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0597] Figure 61 shows a TGA chart of Form R of the n-propanol solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0598] Figure 62 shows a TGA chart of Form S of the tetrahydrofuran solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0599] Figure 63 shows a TGA chart of Form T of 2-methyltetrahydrofuran solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0600] Figure 64 shows the X-ray powder diffraction pattern of the amorphous solid of the present invention's compound I. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0601] Figure 65 shows a DSC chart of the amorphous solid of the present invention's compound I. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0602] 66 shows a TGA chart of the amorphous solid of the present invention's compound I. The abscissa represents temperature (° C.), and the ordinate represents weight (%).

[0603] Figure 67 shows a DVS chart of the amorphous solid of the present invention's compound I. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0604] Figure 68 shows a DVS chart of Form D of Compound I of the present invention. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0605] Figure 2-1 shows the X-ray powder diffraction pattern of the crystalline form 2A of compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0606] Figure 2-2 shows the X-ray powder diffraction pattern of the crystalline form 2B of compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0607] Figure 2-3 shows the X-ray powder diffraction pattern of the crystalline form 2C of compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0608] Figure 2-4 shows the X-ray powder diffraction pattern of the crystalline form 2D of compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0609] Figure 2-5 shows the X-ray powder diffraction pattern of the crystalline form 2E of compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0610] Figure 2-6 shows the X-ray powder diffraction pattern of the hydrated crystal form 2F of compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0611] Figure 2-7 shows the X-ray powder diffraction pattern of the hydrated crystal form 2G of compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0612] Figure 2-8 shows the X-ray powder diffraction pattern of the crystalline form 2H of the dimethyl sulfoxide solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0613] Figure 2-9 shows the X-ray powder diffraction pattern of the methyl tert-butyl ether solvate of Compound II of the present invention in Form 2I. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0614] Figure 2-10 shows the X-ray powder diffraction pattern of the crystalline form 2J-1 of the n-heptane solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0615] Figure 2-11 shows the X-ray powder diffraction pattern of the crystalline form 2J-2 of the n-heptane solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0616] Figure 2-12 shows the X-ray powder diffraction pattern of the crystalline form 2K of the toluene solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0617] Figure 2-13 shows the X-ray powder diffraction pattern of the crystalline form 2L-1 of the methyl isobutyl ketone solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0618] Figure 2-14 shows the X-ray powder diffraction pattern of the crystalline form 2L-2 of the methyl isobutyl ketone solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0619] Figure 2-15 shows the X-ray powder diffraction pattern of the crystalline form 2M-1 of the cyclopentyl methyl ether solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0620] Figure 2-16 shows the X-ray powder diffraction pattern of the crystalline form 2M-2 of the cyclopentyl methyl ether solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0621] Figure 2-17 shows the X-ray powder diffraction pattern of the crystalline form 2N of the methyl ethyl ketone solvate of compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0622] Figure 2-18 shows the X-ray powder diffraction pattern of the methylcyclohexane solvate of Compound II of the present invention in Form 20. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0623] Figure 2-19 shows the X-ray powder diffraction pattern of the crystalline form 2P of the DMF solvate of compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0624] Figure 2-20 shows the X-ray powder diffraction pattern of the crystalline form 2Q-1 of the 2-methyltetrahydrofuran solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0625] Figure 2-21 shows the X-ray powder diffraction pattern of the crystalline form 2Q-2 of the 2-methyltetrahydrofuran solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0626] Figure 2-22 shows the X-ray powder diffraction pattern of the crystalline form 2R of the N-methylpyrrolidone solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0627] Figure 2-23 shows the X-ray powder diffraction pattern of the crystalline form 2S of the trifluoroethanol solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0628] Figure 2-24 shows the X-ray powder diffraction pattern of the crystalline form 2T of the tetrahydrofuran solvate of Compound II of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0629] Figure 2-25 shows the X-ray powder diffraction pattern of the dioxane solvate of Compound II of the present invention, crystalline form 2U. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0630] Figure 2-26 shows the DSC graph of the crystalline form 2A of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0631] Figure 2-27 shows the DSC graph of the crystalline form 2B of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0632] Figure 2-28 shows the DSC graph of the crystalline form 2C of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0633] Figure 2-29 shows the DSC graph of the crystalline form 2D of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0634] Figure 2-30 shows the DSC graph of the crystalline form 2E of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0635] Figure 2-31 shows the DSC graph of the hydrated crystal form 2F of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0636] Figure 2-32 shows the DSC graph of the hydrated crystal form 2G of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0637] Figure 2-33 shows the DSC graph of the crystalline form 2H of the dimethyl sulfoxide solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0638] Figure 2-34 shows the DSC graph of the methyl tert-butyl ether solvate of Compound II of the present invention in Form 2I. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0639] Figure 2-35 shows the DSC graph of the crystal form 2J-1 of the n-heptane solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0640] Figure 2-36 shows the DSC graph of the crystalline form 2J-2 of the n-heptane solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0641] Figure 2-37 shows the DSC graph of the crystalline form 2K of the toluene solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0642] Figure 2-38 shows the DSC graph of the crystalline form 2L-1 of the methyl isobutyl ketone solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0643] Figure 2-39 shows the DSC graph of the crystalline form 2L-2 of the methyl isobutyl ketone solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0644] Figure 2-40 shows the DSC graph of the crystalline form 2M-1 of the cyclopentyl methyl ether solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0645] Figure 2-41 shows the DSC graph of the crystalline form 2M-2 of the cyclopentyl methyl ether solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0646] Figure 2-42 shows the DSC graph of the crystalline form 2N of the methyl ethyl ketone solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0647] Figure 2-43 shows the DSC graph of the methylcyclohexane solvate of Compound II of the present invention in Form 20. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0648] Figure 2-44 shows the DSC graph of the crystalline form 2P of the DMF solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0649] Figure 2-45 shows the DSC chart of the crystalline form 2Q-1 of the 2-methyltetrahydrofuran solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0650] Figure 2-46 shows the DSC chart of the crystalline form 2Q-2 of the 2-methyltetrahydrofuran solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0651] Figure 2-47 shows the DSC graph of the crystalline form 2R of the N-methylpyrrolidone solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0652] Figure 2-48 shows the DSC graph of the crystalline form 2S of the trifluoroethanol solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0653] Figure 2-49 shows the DSC graph of the crystalline form 2T of the tetrahydrofuran solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0654] Figure 2-50 shows the DSC graph of the crystalline form 2U of the dioxane solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0655] Figure 2-51 shows the TGA chart of the crystalline form 2A of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0656] Figure 2-52 shows the TGA chart of the crystalline form 2B of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0657] Figure 2-53 shows the TGA chart of the crystalline form 2C of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0658] Figure 2-54 shows the TGA chart of the crystalline form 2D of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0659] Figure 2-55 shows the TGA chart of the crystalline form 2E of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0660] Figure 2-56 shows the TGA chart of the hydrated crystal form 2F of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0661] Figure 2-57 shows the TGA chart of the hydrated crystal form 2G of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0662] Figure 2-58 shows the TGA chart of the crystalline form 2H of the dimethyl sulfoxide solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0663] Figure 2-59 shows the TGA chart of the methyl tert-butyl ether solvate of Compound II of the present invention in Form 2I. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0664] Figure 2-60 shows the TGA chart of the crystal form 2J-1 of the n-heptane solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0665] Figure 2-61 shows the TGA chart of the crystal form 2J-2 of the n-heptane solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0666] Figure 2-62 shows the TGA chart of the crystalline form 2K of the toluene solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0667] Figure 2-63 shows the TGA chart of the crystalline form 2L-1 of the methyl isobutyl ketone solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0668] Figure 2-64 shows the TGA chart of the crystalline form 2L-2 of the methyl isobutyl ketone solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0669] Figure 2-65 shows the TGA chart of the crystalline form 2M-1 of the cyclopentyl methyl ether solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0670] Figure 2-66 shows the TGA chart of the crystalline form 2M-2 of the cyclopentyl methyl ether solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0671] Figure 2-67 shows the TGA chart of the crystalline form 2N of the methyl ethyl ketone solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0672] Figure 2-68 shows the TGA chart of the methylcyclohexane solvate of Compound II of the present invention in Form 20. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0673] Figure 2-69 shows the TGA chart of the crystalline form 2P of the DMF solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0674] Figure 2-70 shows the TGA chart of the crystalline form 2Q-1 of the 2-methyltetrahydrofuran solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0675] Figure 2-71 shows the TGA chart of the crystalline form 2Q-2 of the 2-methyltetrahydrofuran solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0676] Figure 2-72 shows the TGA chart of the crystalline form 2R of the N-methylpyrrolidone solvate of compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0677] Figure 2-73 shows the TGA chart of the crystalline form 2S of the trifluoroethanol solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0678] Figure 2-74 shows the TGA chart of the crystalline form 2T of the tetrahydrofuran solvate of Compound II of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0679] Figure 2-75 shows the TGA chart of the dioxane solvate of Compound II of the present invention, crystalline form 2U. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0680] Figure 2-76 shows the X-ray powder diffraction pattern of Compound II of the present invention, wherein the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0681] Figure 2-77 shows the DSC graph of Compound II of the present invention, wherein the abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

[0682] Figure 2-78 shows the TGA chart of Compound II of the present invention, wherein the abscissa represents temperature (°C) and the ordinate represents weight (%).

[0683] Figure 2-79 shows the DVS diagram of the crystalline form 2A of compound II of the present invention. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0684] Definitions and Explanations of Terms

[0685] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding product or its active ingredient.

[0686] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0687] As used herein, "polymorph" refers to a crystalline form having the same chemical composition but with different spatial arrangements of the molecules, atoms, and / or ions that make up the crystal. Although polymorphs have the same chemical composition, their packing and geometric arrangements differ and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and the like. Depending on their temperature-stability relationship, two polymorphs can be monotropic or tautotropic. In a monotropic system, the relative stability of the two solid phases remains unchanged when the temperature changes. In contrast, in a tautotropic 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). This phenomenon of a compound existing in different crystal structures is known as pharmaceutical polymorphism.

[0688] The various crystalline structures of the present invention can be distinguished from each other using various analytical techniques known to those of ordinary skill 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).

[0689] As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20 to 25°C (68-77°F).

[0690] As used herein, the term "substantially the same" with respect to X-ray diffraction peak positions is intended to take into account typical peak position and intensity variability. For example, one skilled in the art will appreciate that peak positions (2θ) will vary between XRPD instruments, sometimes by as much as 0.2°. Furthermore, one skilled in the art will appreciate that factors such as XRPD sample preparation, XRPD instrumentation, sample crystallinity, sample dosage, and preferred crystal orientation will result in variations in relative peak intensities in a sample's XRPD diffraction pattern.

[0691] The intermediate compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0692] The chemical reactions described in the specific embodiments of the present invention are carried out in a suitable solvent, which must be compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0693] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0694] All solvents used in the present invention were commercially available and used without further purification.

[0695] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C).

[0696] Methods and Materials

[0697] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) spectroscopy. NMR shifts (δ) are reported in parts per million (ppm). NMR measurements were performed using a Bruker avance-400 MHz NMR spectrometer in deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4), with tetramethylsilane (TMS) as the internal standard. Chemical shifts are reported in units of 10-6 ppm.

[0698] HPLC determination was performed using an Agilent 1260 high performance liquid chromatograph or a high performance liquid chromatograph of equivalent performance (Sunfire C18 150×4.6m column or a column of equivalent performance).

[0699] The polymorphs of Compound III were characterized by X-ray powder diffraction patterns. X-ray powder diffraction patterns of the salts were collected on a Bruker D8 Advance powder diffractometer operating in reflection mode using Cu Kα radiation. The instrument employed Cu Kα radiation (40 kV, 40 mA) and an SSD160-2 detector at room temperature. The scan range was from 3° to 40° in the 2θ region at a scan rate of 0.1 s / step. The diffraction patterns were analyzed using DIFFRAC.MEA.CENTER software.

[0700] The XRPD sample is prepared by placing the sample on a single crystal silicon wafer and pressing the sample powder with a glass sheet or equivalent to ensure that the surface of the sample is flat and has the appropriate height. The sample holder is then placed in a Bruker D8 Advance instrument and an X-ray powder diffraction pattern is collected using the instrument parameters described above. The measurement differences associated with the results of such X-ray powder diffraction analyses are caused by a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including those that occur when determining peak positions), and (e) the properties of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in displacements of all peaks in the same direction. Generally speaking, this calibration factor will make the measured peak positions consistent with the expected peak positions and can be within the range of ±0.2° of the expected 2θ value.

[0701] The experimental method for characterizing the crystalline form of the acid salt or basic salt of Compound III using differential scanning calorimetry (DSC) is to take a small amount of the crystalline polymorph of Compound III and place it in an aluminum crucible that is compatible with the instrument and can be pressed with a lid. After loading the sample, the crucible is pressed with an aluminum pan, and then the crucible is placed into the instrument for detection. The instrument model used for all differential scanning calorimetry in this invention is a METTLER TOLEDO DSC 3, and the scanning parameters are set to use a nitrogen atmosphere and a heating rate of 10.0 K / min.

[0702] The experimental method for characterizing the polymorphs of Compound III using thermogravimetric analysis (TGA) is to take a small amount of Compound III polymorph powder, place it in an alumina crucible equipped with the instrument, load the sample, and then insert it into the instrument for analysis. The differential scanning calorimetry used in this invention is a METTLER TOLEDO TGA 2 instrument, with scanning parameters set to a nitrogen atmosphere and a heating rate of 10.0 K / min.

[0703] The dynamic moisture sorption method (DVS) for characterizing the acid or basic salts of Compound III involves taking a small amount of Compound III polymorph powder and placing it in a precision sample tray compatible with the instrument. After loading the sample, the instrument is tested. The dynamic moisture sorption method employed in this invention utilizes an Intrinsic PLUS instrument. Experimental parameters include a constant temperature of 25°C, a mass percentage change per unit time (dm / dt) of 0.02% / min as the equilibrium criterion, and a programmed humidity cycle with an initial relative humidity of 0% and an endpoint relative humidity of 90%. DETAILED DESCRIPTION

[0704] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0705] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0706] 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 (amorphous form of Compound 1)

[0707] Step 1: Synthesis of (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

[0708] A mixed solution of (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-oxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) in N,N-dimethylformamide (80 mL) 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 give (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, yield: 33.5%).

[0709] Step 2: Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0710] To a solution of (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) in tetrahydrofuran / water (20 mL / 20 mL) was added lithium hydroxide (0.13 g, 5.4 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture 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%). The product was characterized by XRPD, DSC, and TGA. The obtained compound I was an amorphous substance. Its X-ray powder diffraction pattern, DSC pattern, and TGA pattern are shown in Figures 64, 65, and 66, respectively. 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.80(dd,J=8.4Hz,1.2Hz,1H),7.72(t,J=7.6Hz,1H),7.64(d,J=8.4Hz,1H),7.44(dd,J =11.2Hz,2.0Hz,1H),7.28(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H), 5.12-5.06(m,1H),4.95-4.93(m,1H),4.81-4.76(m,1H),4.66-4.62(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J= 13.6Hz,1H),3.78(d,J=13.6Hz,1H),2.79-2.67(m,2H),2.46-2.41(m,1H),2.32(s,2H),1.92-1.91(m,2H),1.63-1.59(m,2H).

[0711] Example 2 Preparation of Form A of Compound I

[0712] 200 mg of compound I was added to 7.5 mL of isopropanol, sonicated at 50°C, and filtered. The filtrate was stirred at 5°C for about 16 h, filtered, and the filter cake was oven-dried at 50°C to obtain Form A of the compound. The product was characterized by XRPD (Figure 1), DSC (Figure 22), and TGA (Figure 43).

[0713] Example 3 Preparation of Form B of Compound I

[0714] 200 mg of compound I was added to 3 mL of ethyl acetate, sonicated at 50°C, filtered, and the filtrate was stirred at 5°C for about 16 h. The filter cake was then dried in an oven at 50°C to obtain Form B of the compound. The product was characterized by XRPD (Figure 2), DSC (Figure 23), and TGA (Figure 44).

[0715] Example 4 Preparation of Form C of Compound I

[0716] 200 mg of compound I was added to 9 mL of acetonitrile, sonicated at 50°C, filtered, and the filtrate was stirred at 5°C for about 16 h. The filter cake was then dried in an oven at 50°C to obtain Form C of the compound. The product was characterized by XRPD (Figure 3), DSC (Figure 24), and TGA (Figure 45).

[0717] Example 5 Preparation of Form D of Compound I

[0718] 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 hours, cooled to 5°C and stirred for 2 hours, filtered, and the filter cake was oven-dried at 50°C to obtain Form D of the compound. The product was characterized by XRPD (Figure 4), DSC (Figure 25), and TGA (Figure 46).

[0719] Example 6 Preparation of Form E of Compound I

[0720] 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, filtered, and the filter cake was oven-dried at 50°C to obtain Form E of the compound. The product was characterized by XRPD (Figure 5), DSC (Figure 26), and TGA (Figure 47). Example 7 Preparation of Form F of Compound I

[0721] 20 mg of compound I was suspended in 0.5 mL of water / acetone (6:1 v:v), stirred at 50°C for 2 hours, cooled to 5°C and stirred for 2 hours, filtered, and the filter cake was oven-dried at 50°C to obtain Form F of the compound. The product was characterized by XRPD ( Figure 6 ), DSC ( Figure 27 ), and TGA ( Figure 48 ).

[0722] Example 8 Preparation of Form G of Hydrate of Compound I

[0723] 100 mg of compound I was suspended in 2.5 mL of water, stirred at 5°C for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain Form G of the compound hydrate. The product was characterized by XRPD (Figure 7), DSC (Figure 28), and TGA (Figure 49).

[0724] Example 9 Preparation of Form H of Methyl Isobutyl Ketone Solvate of Compound I

[0725] 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 oven-dried at 40°C to obtain 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 ). 1 H NMR (400MHz, DMSO-d6): δ12.73(br,1H),8.27(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.74(t,J=7.6Hz,1H),7.66(d,J=8.4Hz,1H),7. 43(dd,J=11.2Hz,2.0Hz,1H),7.30(t,J=8.8Hz,1H),7.17(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.71(d,J=8.0Hz,1H),5.18(s,2H), 5.10-5.08(m,1H),4.95-4.93(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.95(d,J=13.6Hz, 1H),3.78(d,J=13.6Hz,1H),2.73-2.69(m,3H),2.32-2.28(m,4H),2.06-1.91(m,4H),1.63-1.59(m,2H),0.86-0.84(d,J=6.8Hz,4H).

[0726] Example 10 Preparation of Crystalline Form I-1 of Methyl Tert-Butyl Ether Solvate of Compound I

[0727] 20 mg of Compound I was suspended in 1.0 mL of ethyl acetate and filtered to obtain a clear solution. This solution was then placed in a 20 mL vial containing 3 mL of methyl tert-butyl ether. The 20 mL vial was sealed with a cap and allowed to stand at room temperature for 3 days. The solution was then filtered and the filter cake was oven-dried at 50°C to obtain 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). 1H NMR (400MHz, DMSO-d6): δ12.72(br,1H),8.27(s,1H),7.81(d,J=8.4Hz,1H),7.75(t,J=7.6Hz,1H),7.67(d,J=8.4Hz,1H),7.44(dd ,J=11.2Hz,2.0Hz,1H),7.30(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.03(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.1 0-5.08(m,1H),4.95-4.93(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96(d,J=13.6Hz, 1H),3.79(d,J=13.6Hz,1H),3.08(s,3H),2.72-2.70(m,3H),2.32-2.28(m,4H),1.99-1.91(m,4H),1.63-1.59(m,2H),1.11(s,8H).

[0728] Example 11 Preparation of Crystalline Form I-2 of Methyl Tert-Butyl Ether Solvate of Compound I

[0729] 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 oven-dried at 50°C to obtain 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 ). 1H NMR (400MHz, DMSO-d6): δ12.72(br,1H),8.27(s,1H),7.81(d,J=8.4Hz,1H),7.76(t,J=7.6Hz,1H),7.67(d,J=8.4Hz,1H),7.45(dd ,J=11.2Hz,2.0Hz,1H),7.31(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.1 1-5.09(m,1H),4.96-4.94(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96(d,J=13.6Hz,1 H),3.79(d,J=13.6Hz,1H),3.08(s,4H),2.73-2.70(m,3H),2.32-2.28(m,3H),1.99-1.91(m,2H),1.63-1.59(m,2H),1.11(s,12H).

[0730] Example 12 Preparation of Form J of Acetone Solvate of Compound I

[0731] Approximately 20 mg of Compound I was weighed and added to 0.5 mL of acetone three times, grinding for 5 minutes each time. The resulting solid was oven-dried at 50°C to obtain Form J of the acetone solvate of the compound. The product was characterized by XRPD (Figure 11), DSC (Figure 32), and TGA (Figure 53). 1H NMR (400MHz, DMSO-d6): δ12.70(br,1H),8.27(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.72(t,J=7.6Hz,1H),7.64(d,J=8.4Hz,1H) ,7.44(dd,J=11.2Hz,2.0Hz,1H),7.28(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18( s,2H),5.12-5.07(m,1H),4.95-4.92(m,1H),4.81-4.77(m,1H),4.66-4.63(m,1H),4.52-4.49(m,1H),4.38-4.36(m,1H),3.94(d ,J=13.6Hz,1H),3.78(d,J=13.6Hz,1H),2.73-2.69(m,3H),2.46-2.32(m,3H),2.09(s,3H),1.92-1.91(m,2H),1.63-1.59(m,2H).

[0732] Example 13 Preparation of Form K of n-heptane Solvate of Compound I

[0733] Approximately 20 mg of Compound I was weighed and suspended in 0.5 mL of n-heptane / tetrahydrofuran (3:1 v:v). The mixture was stirred at 5°C for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain 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 ). 1H NMR (400MHz, DMSO-d6): δ12.80(br,1H),8.26(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45 (dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10 -5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J=13.6Hz,1H),3 .78(d,J=13.6Hz,1H),2.73-2.69(m,3H),2.43-2.32(m,3H),1.92-1.91(m,2H),1.63-1.61(m,2H),1.24(s,1.2H),0.87-0.85(m,0.7H).

[0734] Example 14 Preparation of Form L of Methylcyclohexane Solvate of Compound I

[0735] Approximately 20 mg of Compound I was weighed and suspended in 0.5 mL of methylcyclohexane / tetrahydrofuran (6:1 v:v). After stirring at 50°C for 2 hours, the temperature was lowered to 5°C and stirring was continued for 2 hours. The mixture was filtered and the filter cake was oven-dried at 50°C to obtain Form L of the methylcyclohexane solvate of the compound. The product was characterized by XRPD ( Figure 13 ), DSC ( Figure 34 ), and TGA ( Figure 55 ). 1H NMR (400MHz, DMSO-d6): δ12.81(br,1H),8.26(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H), 7.45(dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s, 2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.95(d,J=1 3.6Hz,1H),3.79(d,J=13.6Hz,1H),2.73-2.70(m,3H),2.43-2.32(m,3H),1.92-1.91(m,2H),1.63-1.59(m,2H),1.25-0.83(m,2H).

[0736] Example 15 Preparation of Form M of Toluene Solvate of Compound I

[0737] Approximately 20 mg of Compound I was weighed and dissolved in 0.5 mL of toluene and filtered to obtain a clear solution. This solution was then placed in a 20 mL vial containing 3 mL of isopropyl ether. The 20 mL vial was sealed with a cap and left at room temperature for 2 days. The solution was then filtered and the filter cake was oven-dried at 50°C to obtain Form M of the toluene solvate of the compound. The product was characterized by XRPD (Figure 14), DSC (Figure 35), and TGA (Figure 56). 1H NMR (400MHz, DMSO-d6): δ12.73(br,1H),8.26(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8 .4Hz,1H),7.45(dd,J=11.2Hz,2.0Hz,1H),7.30-7.14(m,8H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H) ,5.10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.9 5(d,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),2.73-2.70(m,3H),2.43-2.30(m,7H),1.92-1.91(m,2H),1.63-1.59(m,2H).

[0738] Example 16 Preparation of Form N of Dioxane Solvate of Compound I

[0739] Approximately 20 mg of Compound I was suspended in 0.5 mL of n-heptane / dioxane (3:1 v:v), stirred at 5°C for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain Form N of the dioxane solvate of the compound. The product was characterized by XRPD ( Figure 15 ), DSC ( Figure 36 ), and TGA ( Figure 57 ). 1H NMR (400MHz, DMSO-d6): δ12.81(br,1H),8.26(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H) ,7.45(dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18( s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.94(d, J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),3.57(s,14H),2.73-2.69(m,3H),2.51-2.32(m,3H),1.92-1.91(m,2H),1.63-1.61(m,2H).

[0740] Example 17 Preparation of Form O of DMF Solvate of Compound I

[0741] Approximately 20 mg of Compound I was weighed and dissolved in 0.5 mL of DMF / isopropyl ether (1:4 v:v). The solution was left open at room temperature to evaporate for 1 day, then filtered. The filter cake was oven-dried at 50°C to obtain Form O of the DMF solvate of the compound. The product was characterized by XRPD ( Figure 16 ), DSC ( Figure 37 ), and TGA ( Figure 58 ). 1H NMR (400MHz, DMSO-d6): δ12.81(br,1H),8.26(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H) ,7.45(dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.20(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18( s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.94(d ,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),2.89(s,3H),2.73-2.70(m,3H),2.43-2.32(m,3H),1.92-1.91(m,2H),1.63-1.59(m,2H).

[0742] Example 18 Preparation of Form P of N-methylpyrrolidone Solvate of Compound I

[0743] Approximately 20 mg of Compound I was suspended in 0.5 mL of N-methylpyrrolidone / isopropyl ether (1:9 v:v), stirred at 5°C for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain 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 ). 1H NMR (400MHz, DMSO-d6): δ12.76(br,1H),8.27(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45 (dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.19(s,2H),5.10 -5.09(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96(d,J=13.5Hz,1H),3. 78(d,J=13.5Hz,1H),3.32-3.29(m,3H),2.73-2.70(m,6H),2.43-2.32(m,3H),2.20-2.16(m,2H),1.94-1.88(m,4H),1.63-1.61(m,2H).

[0744] Example 19 Preparation of Form Q of n-Butanol Solvate of Compound I

[0745] Approximately 20 mg of Compound I was weighed and suspended in 0.5 mL of n-butanol. The mixture was stirred at 50°C for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain 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 ). 1H NMR (400MHz, DMSO-d6): δ12.73(br,1H),8.27(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz, 1H),7.73(d,J=8.4Hz,1H),7.45(dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.20(d,J=8.4Hz,1H),7.04(d,J=7 .2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m ,1H),4.50-4.49(m,1H),4.39-4.31(m,1.8H),3.94(d,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),3.39-3.38(m,1.6H),2 .70-2.69(m,3H),2.43-2.32(m,3H),1.92-1.91(m,2H),1.63-1.59(m,2H),1.39-1.28(m,3.2H),0.88-0.85(m,2.3H).

[0746] Example 20 Preparation of Form R of n-propanol solvate of Compound I

[0747] Approximately 20 mg of Compound I was weighed and suspended in 0.5 mL of methyl tert-butyl ether / n-propanol (1:1 v:v). The mixture was stirred at 50°C for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain Form R of the n-propanol solvate of the compound. The product was characterized by XRPD ( Figure 19 ), DSC ( Figure 40 ), and TGA ( Figure 61 ). 1H NMR (400MHz, DMSO-d6): δ12.80(br,1H),8.27(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(dd,J= 11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m,1H) ,4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50-4.49( m,1H),4.38-4.36(m,1.6H),3.95(d,J=13.6Hz,1H),3.79(d,J=13.6Hz, 1H),3.36-3.32(m,1H),2.71-2.69(m,3H),2.49-2.32(m,3H),1.92-1.9 1(m,2H),1.63-1.59(m,2H),1.44-1.39(m,1.6H),0.85-0.82(m,2.5H).

[0748] Example 21 Preparation of Form S of Tetrahydrofuran Solvate of Compound I

[0749] Approximately 20 mg of Compound I was dissolved in 0.5 mL of tetrahydrofuran. The solution was then 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. The mixture was then filtered and the filter cake was oven-dried at 50°C to obtain Form S of the tetrahydrofuran solvate of the compound. The product was characterized by XRPD (Figure 20), DSC (Figure 41), and TGA (Figure 62). 1H NMR (400MHz, DMSO-d6): δ12.80(br,1H),8.26(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45( dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5 .08(m,1H),4.94-4.92(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.95(d,J=13.6Hz,1H),3.79( d,J=13.6Hz,1H),3.62-3.59(m,2.8H),2.73-2.69(m,3H),2.43-2.32(m,3H),1.92-1.90(m,2H),1.78-1.74(m,2.7H),1.63-1.61(m,2H).

[0750] Example 22 Preparation of Form T of 2-Methyltetrahydrofuran Solvate of Compound I

[0751] Approximately 20 mg of Compound I was dissolved in 0.5 mL of 2-methyltetrahydrofuran (2-MTHF). The solution was then placed in a 20 mL vial containing 3 mL of ether. The 20 mL vial was sealed with a cap and allowed to stand at room temperature for 2 days. The mixture was then filtered and the filter cake was oven-dried at 50°C to obtain Form T of the 2-MTHF solvate of the compound. The product was characterized by XRPD (Figure 21), DSC (Figure 42), and TGA (Figure 63). 1H NMR (400MHz, DMSO-d6): δ12.80(br,1H),8.27(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(dd,J=11.2 Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7 .2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m,1H),4.94-4. 92(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38 -4.36(m,1H),3.95(d,J=13.6Hz,1H),3.83-3.74(m,2.5H),3.56-3.54(m, 1H),2.73-2.69(m,3H),2.43-2.32(m,3H),1.94-1.89(m,3H),1.89-1.79 (m,1.6H),1.63-1.61(m,2H),1.36-1.26(m,2H),1.12(d,J=6.8Hz,2.3H).

[0752] Example 2-1 Preparation of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0753] Step 1: Synthesis of (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

[0754] A mixed solution of (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-oxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) in N,N-dimethylformamide (80 mL) 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 give (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, yield: 37.2%).

[0755] Step 2: Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0756] To a solution of (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) in tetrahydrofuran / water (20 mL / 20 mL) was added lithium hydroxide (0.13 g, 5.4 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture 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-cyano-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%). XRPD, DSC, and TGA characterization revealed that the obtained compound II was a weakly crystalline compound. Its X-ray powder diffraction pattern, DSC pattern, and TGA pattern are shown in Figures 2-76, 2-77, and 2-78, respectively. 1HNMR (400MHz, DMSO-d6): δ8.23(s,1H),7.88(dd,J=2.0Hz,11.6Hz,1H),7.80(dd,J=1.6,8.8Hz,1H),7.73(t,J=8.0Hz,1H),7.6 7(d,J=8.4Hz,1H),7.60(d,J=8.8Hz,1H),7.45(t,J=8.4Hz,1H),7.06(d,J=7.6Hz,1H),6.74(d,J=8.4Hz,1H),5.31(s,2H),5.1 0-5.08(m,1H),4.92-4.90(m,1H),4.80-4.74(m,1H),4.65-4.61(m,1H),4.50-4.47(m,1H),4.40-4.35(m,1H),3.93(d,J=13.6 Hz,1H),3.78(d,J=13.6Hz,1H),2.79-2.67(m,3H),2.51-2.41(m,1H),2.32-2.27(m,2H),1.92-1.89(m,2H)1.63-1.60(m,2H).

[0757] Example 2-2 Preparation of Form 2A of Compound II

[0758] 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 Form 2A of compound II. The product was characterized by XRPD (Figure 2-1), DSC (Figure 2-26) and TGA (Figure 2-51). 1HNMR (400MHz, DMSO-d6): δ12.76(s,1H),8.27(s,1H),7.88(dd,J=2.0Hz,11.6Hz,1H),7.80(dd,J=1.6,8.8Hz,1H),7.7 2(t,J=8.0Hz,1H),7.71-7.64(m,2H),7.44(t,J=8.4Hz,1H),7.06(d,J=7.6Hz,1H),6.74(d,J=8.4Hz,1H),5.31(s,2H), 5.10-5.08(m,1H),4.92-4.90(m,1H),4.80-4.74(m,1H),4.66-4.61(m,1H),4.51-4.49(m,1H),4.40-4.36(m,1H),3.9 4(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.73-2.69(m,3H),2.50-2.30(m,3H),1.91-1.89(m,2H)1.63-1.61(m,2H).

[0759] Example 2-3 Preparation of Form 2B of Compound II

[0760] 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 oven-dried at 50°C to obtain Form 2B of compound II. The product was characterized by XRPD (Figure 2-2), DSC (Figure 2-27) and TGA (Figure 2-52). 1 HNMR (400MHz, DMSO-d6): δ12.76(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.6Hz,1H),7.80(dd,J=1.6,8.8Hz,1H),7. 72(t,J=8.0Hz,1H),7.71-7.65(m,2H),7.45(t,J=8.4Hz,1H),7.06(d,J=7.6Hz,1H),6.74(d,J=8.4Hz,1H),5.31(s,2H) ,5.10-5.08(m,1H),4.92-4.90(m,1H),4.80-4.74(m,1H),4.66-4.63(m,1H),4.51-4.49(m,1H),4.40-4.36(m,1H),3.9 4(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.70-2.69(m,3H),2.51-2.30(m,3H),1.91-1.89(m,2H)1.61-1.59(m,2H).

[0761] Example 2-4 Preparation of Form 2C of Compound II

[0762] 20 mg of compound II was dissolved in 0.2 mL of ethanol / toluene (2:1 v:v), left at room temperature, and the solvent was slowly evaporated. The resulting solid was dried at 50°C to obtain Form 2C of compound II. The product was characterized by XRPD (Figure 2-3), DSC (Figure 2-28) and TGA (Figure 2-53). 1 HNMR (400MHz, DMSO-d6): δ12.76(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.6Hz,1H),7.80(dd,J=1.6,8.8Hz,1H),7. 72(t,J=8.0Hz,1H),7.71-7.65(m,2H),7.45(t,J=8.5Hz,1H),7.05(d,J=7.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H) ,5.10-5.09(m,1H),4.92-4.91(m,1H),4.80-4.75(m,1H),4.66-4.64(m,1H),4.51-4.49(m,1H),4.39-4.36(m,1H),3.9 4(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.70-2.69(m,3H),2.50-2.30(m,3H),1.91-1.89(m,2H)1.61-1.59(m,2H).

[0763] Example 2-5 Preparation of Form 2D of Compound II

[0764] 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 oven-dried at 50°C to obtain Form 2D of compound II. The product was characterized by XRPD (Figure 2-4), DSC (Figure 2-29) and TGA (Figure 2-54). 1HNMR (400MHz, DMSO-d6): δ12.77(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.8Hz,1H),7. 72(t,J=8.0Hz,1H),7.71-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8.6Hz,1H),5.31(s,2H) ,5.10-5.08(m,1H),4.92-4.91(m,1H),4.80-4.75(m,1H),4.66-4.64(m,1H),4.51-4.49(m,1H),4.39-4.36(m,1H),3.9 2(d,J=13.5Hz,1H),3.76(d,J=13.5Hz,1H),2.76-2.71(m,3H),2.50-2.30(m,3H),1.96-1.90(m,2H)1.61-1.59(m,2H).

[0765] Example 2-6 Preparation of Form 2E of Compound II

[0766] 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 oven-dried at 50°C to obtain Form 2E of compound II. The product was characterized by XRPD (Figure 2-5), DSC (Figure 2-30) and TGA (Figure 2-55). 1 HNMR (400MHz, DMSO-d6): δ12.75(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7. 72(t,J=8.1Hz,1H),7.71-7.63(m,2H),7.45(t,J=8.6Hz,1H),7.05(d,J=7.5Hz,1H),6.73(d,J=8.5Hz,1H),5.31(s,2H) ,5.11-5.08(m,1H),4.92-4.90(m,1H),4.80-4.77(m,1H),4.66-4.64(m,1H),4.50-4.48(m,1H),4.38-4.36(m,1H),3.9 2(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.67-2.60(m,3H),2.50-2.30(m,3H),1.90-1.88(m,2H)1.62-1.60(m,2H).

[0767] Example 2-7 Preparation of Hydrate Form 2F of Compound II

[0768] 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 Form 2F of compound II. The product was characterized by XRPD (Figure 2-6), DSC (Figure 2-31) and TGA (Figure 2-56). 1 HNMR (400MHz, DMSO-d6): δ12.69(br,1H),8.26(s,1H),7.87(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.7 3(t,J=8.1Hz,1H),7.71-7.63(m,2H),7.44(t,J=8.6Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H), 5.11-5.08(m,1H),4.92-4.90(m,1H),4.80-4.77(m,1H),4.66-4.64(m,1H),4.50-4.48(m,1H),4.38-4.36(m,1H),3.92 (d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.67-2.60(m,3H),2.50-2.30(m,3H),1.90-1.88(m,2H),1.62-1.60(m,2H).

[0769] Example 2-8 Preparation of Hydrate Form 2G of Compound II

[0770] 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 oven-dried at 50°C to obtain the hydrated form 2G of compound II. The product was characterized by XRPD (Figure 2-7), DSC (Figure 2-32) and TGA (Figure 2-57). 1HNMR (400MHz, DMSO-d6): δ12.71(br,1H),8.26(s,1H),7.87(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.7 3(t,J=8.1Hz,1H),7.71-7.63(m,2H),7.445(t,J=8.5Hz,1H),7.06(d,J=7.5Hz,1H),6.73(d,J=8.5Hz,1H),5.31(s,2H) ,5.10-5.08(m,1H),4.92-4.90(m,1H),4.80-4.78(m,1H),4.66-4.64(m,1H),4.50-4.48(m,1H),4.38-4.36(m,1H),3.9 4(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.70-2.69(m,3H),2.50-2.30(m,3H),1.90-1.88(m,2H)1.61-1.59(m,2H).

[0771] Example 2-9 Preparation of Form 2H of Dimethyl Sulfoxide Solvate of Compound II

[0772] 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 lid and maintained at room temperature for 10 days. The resulting solid was oven-dried at 50°C to obtain Form 2H of Compound II hydrate. The product was characterized by XRPD (Figure 2-8), DSC (Figure 2-33), and TGA (Figure 2-58). 1H NMR (400MHz, CD3OD): δ8.23(s,1H),7.97(dd,J=8.5Hz,1.2Hz,1H),7.69-7.65(m,2H),7.56(dd,J=11.2Hz,2.0H z,1H),7.50(d,J=11.2Hz,2.0Hz,1H),7.32(t,J=8.7Hz,1H),7.05(d,J=8.5Hz,1H),7.51-7.49(m,1H),6.71(d, J=8.0Hz,1H),5.25(s,3H),5.15-5.03(m,1H),4.74-4.73(m,2H),4.51-4.49(m,1H),4.04(d,J=13.5Hz,1H),3. 94(d,J=13.5Hz,1H),2.83-2.79(m,3H),2.65(s,6H),2.48-2.46(m,3H),2.01-1.99(m,2H),1.30-1.29(m,2H).

[0773] Example 2-10 Preparation of Form 2I of Methyl Tert-Butyl Ether Solvate of Compound II

[0774] 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, cooled to 5°C and stirred for 2 hours, filtered, and the filter cake was oven-dried at 50°C to obtain Form 2I of methyl tert-butyl ether solvate of compound II. The product was characterized by XRPD (Figure 2-9), DSC (Figure 2-34) and TGA (Figure 2-59). 1HNMR (400MHz, DMSO-d6): δ12.76(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.75(t,J= 8.1Hz,1H),7.71-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.05(d,J=5.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H),5.09-5.08(m,1 H),4.91-4.90(m,1H),4.79-4.76(m,1H),4.65-4.62(m,1H),4.50-4.47(m,1H),4.38-4.36(m,1H),3.94(d,J=13.5Hz,1H),3.7 8(d,J=13.5Hz,1H),3.57(s,1.5H),2.75-2.69(m,3H),2.50-2.41(m,3H),1.91-1.89(m,2H),1.63-1.58(m,2H),1.11(s,4.5H).

[0775] Example 2-11 Preparation of Form 2J-1 of n-heptane Solvate of Compound II

[0776] 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 Form 2J-1 of the n-heptane solvate of compound II. The product was characterized by XRPD (Figure 2-10), DSC (Figure 2-35) and TGA (Figure 2-60). 1H NMR (400MHz, DMSO-d6) δ12.75(br,1H),8.26(s,1H),7.87(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.73(t,J=8 .1Hz,1H),7.67-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.05(d,J=5.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H),5.09-5.08(m,1 H),4.91-4.90(m,1H),4.79-4.76(m,1H),4.65-4.61(m,1H),4.51-4.48(m,1H),4.38-4.36(m,1H),3.94(d,J=13.5Hz,1H),3. 78(d,J=13.5Hz,1H),2.70-2.69(m,3H),2.50-2.43(m,3H),1.90-1.88(m,2H),1.61-1.59(m,2H),1.24(s,2H),0.86(s,1.3H).

[0777] Example 2-12 Preparation of Form 2J-2 of n-heptane solvate of Compound II

[0778] 20 mg of compound II was dissolved in 3.0 mL of chloroform / n-heptane (2:1 v:v), allowed to stand at room temperature, and the solvent was slowly evaporated. The resulting solid was dried at 50°C to obtain 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). 1H NMR (400MHz, DMSO-d6) δ12.55(br,1H),8.27(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.73(t,J=8. 1Hz,1H),7.67-7.63(m,2H),7.43(t,J=8.5Hz,1H),7.06(d,J=5.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H),5.09-5.08(m,1H) ,4.91-4.90(m,1H),4.78-4.76(m,1H),4.67-4.65(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.92(d,J=13.5Hz,1H),3.80(d ,J=13.5Hz,1H),2.70-2.69(m,3H),2.33-2.30(m,3H),1.90-1.88(m,2H),1.61-1.59(m,2H),1.24(s,4H),0.87-0.86(m,2.5H).

[0779] Example 2-13 Preparation of Form 2K of Toluene Solvate of Compound II

[0780] About 20 mg of compound II was weighed and suspended in 0.5 mL of toluene. After stirring at 50°C for 2 hours, the temperature was lowered to 5°C and stirring was continued for 2 hours. The mixture was filtered and the filter cake was dried in an oven at 50°C to obtain the toluene solvate of compound II, Form 2K. The product was characterized by XRPD (Figure 2-12), DSC (Figure 2-37) and TGA (Figure 2-62). 1H NMR (400MHz, DMSO-d6) δ12.73(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.73(t,J=8. 1Hz,1H),7.67-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.27-7.13(m,4H),7.06(d,J=5.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H) ,5.09-5.08(m,1H),4.92-4.90(m,1H),4.81-4.79(m,1H),4.65-4.62(m,1H),4.52-4.49(m,1H),4.40-4.36(m,1H),3.92(d,J=1 3.5Hz,1H),3.80(d,J=13.5Hz,1H),2.75-2.69(m,3H),2.46-2.41(m,3H),2.30(s,2.5H),1.90-1.88(m,2H),1.63-1.58(m,2H).

[0781] Example 2-14 Preparation of Crystalline Form 2L-1 of Methyl Isobutyl Ketone Solvate of Compound II

[0782] About 20 mg of compound II was weighed and 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 50°C to obtain methyl isobutyl ketone solvate of compound II, Form 2L-1. The product was characterized by XRPD (Figure 2-13), DSC (Figure 2-38) and TGA (Figure 2-63). 1H NMR (400MHz, DMSO-d6) δ12.76(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.79(dd,J=1.7,8.5Hz,1H),7.73(t,J=8.1Hz,1 H),7.67-7.62(m,2H),7.45(t,J=8.5Hz,1H),7.06(d,J=5.5Hz,1H),6.73(d,J=8.5Hz,1H),5.31(s,2H),5.09-5.08(m,1H),4.92-4.90 (m,1H),4.81-4.79(m,1H),4.65-4.62(m,1H),4.52-4.49(m,1H),4.40-4.36(m,1H),3.93(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H), 2.70-2.69(m,3H),2.43-2.30(m,5H),2.06(s,2H),2.00-1.98(m,0.6H),1.90-1.88(m,2H),1.61-1.59(m,2H),0.85(d,J=5.8Hz,4H).

[0783] Example 2-15 Preparation of Crystalline Form 2L-2 of Methyl Isobutyl Ketone Solvate of Compound II

[0784] About 20 mg of compound II was weighed and suspended in 0.5 mL of methyl isobutyl ketone / chloroform (9:1 v:v). After stirring at 50°C for 2 hours, the temperature was lowered to 5°C and stirring was continued for 2 hours. The mixture was filtered and the filter cake was dried in an oven at 50°C to obtain 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). 1H NMR (400MHz, DMSO-d6) δ12.76(br,1H),8.26(s,1H),7.89(dd,J=2.0Hz,11.5Hz,1H),7.79(dd,J=1.7,8.5Hz,1H),7.73(t,J=8.1Hz,1H ),7.67-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.06(d,J=5.5Hz,1H),6.73(d,J=8.5Hz,1H),5.31(s,2H),5.09-5.08(m,1H),4.92-4.90(m ,1H),4.81-4.79(m,1H),4.65-4.62(m,1H),4.51-4.49(m,1H),4.39-4.36(m,1H),3.92(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.7 0-2.69(m,3H),2.43-2.29(m,3.5H),2.06(s,1H),2.00-1.98(m,0.3H),1.91-1.89(m,2H),1.61-1.59(m,2H),0.85(d,J=5.8Hz,2.2H).

[0785] Example 2-16 Preparation of Crystalline Form 2M-1 of Cyclopentyl Methyl Ether Solvate of Compound II

[0786] About 20 mg of compound II was weighed and suspended in 0.5 mL of methanol / cyclopentyl methyl ether (1:6 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain cyclopentyl methyl ether solvate of compound II, Form 2M-1. The product was characterized by XRPD (Figure 2-15), DSC (Figure 2-40) and TGA (Figure 2-65). 1HNMR (400MHz, DMSO-d6): δ12.74(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.81(dd,J=1.7,8.8Hz,1H),7.73(t,J=8 .0Hz,1H),7.71-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8.6Hz,1H),5.31(s,2H),5.09-5.08(m,1H ),4.92-4.90(m,1H),4.81-4.76(m,1H),4.66-4.62(m,1H),4.52-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J=13.5Hz,1H),3.79( d,J=13.5Hz,1H),3.75-3.74(m,1H),3.31(s,3H),2.75-2.69(m,3H),2.50-2.30(m,3H),1.91-1.89(m,2H),1.63-1.46(m,10H).

[0787] Example 2-17 Preparation of Form 2M-2 of Cyclopentyl Methyl Ether Solvate of Compound II

[0788] About 20 mg of compound II was weighed and dissolved in 0.8 mL of dioxane / toluene (1:1 v:v). The solution was added dropwise to 3.0 mL of cyclopentyl methyl ether and filtered. The filter cake was dried in an oven at 50°C to obtain Form 2M-2 of the cyclopentyl methyl ether solvate of the compound. The product was characterized by XRPD (Figure 2-16), DSC (Figure 2-41) and TGA (Figure 2-66). 1HNMR (400MHz, DMSO-d6): δ12.88(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.8Hz,1H),7.73(t,J=8 .0Hz,1H),7.71-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H),5.09-5.08(m,1H) ,4.92-4.90(m,1H),4.77-4.76(m,1H),4.66-4.62(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.93(d,J=13.5Hz,1H),3.77(d, J=13.5Hz,1H),3.75-3.74(m,0.3H),3.32(s,1.2H),2.75-2.69(m,3H),2.50-2.30(m,3H),1.91-1.90(m,2H),1.63-1.50(m,6H).

[0789] Example 2-18 Preparation of Form 2N of Methyl Ethyl Ketone Solvate of Compound II

[0790] About 20 mg of compound II was weighed and suspended in 0.5 mL of methyl ethyl ketone / acetonitrile (1:2 v:v). The mixture was stirred at 50°C for 3 days, filtered, and the filter cake was dried in an oven at 50°C to obtain Form 2N of 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). 1HNMR (400MHz, DMSO-d6): δ12.65(br,1H),8.26(s,1H),7.87(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.73(t,J=8 .1Hz,1H),7.71-7.63(m,2H),7.45(t,J=8.6Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H),5.10-5.08(m,1H) ,4.92-4.90(m,1H),4.80-4.78(m,1H),4.66-4.64(m,1H),4.50-4.48(m,1H),4.38-4.36(m,1H),3.94(d,J=13.5Hz,1H),3.79(d ,J=13.5Hz,1H),2.70-2.69(m,3H),2.46-2.30(m,4H),2.07(s,1.2H),1.91-1.89(m,2H)1.61-1.59(m,2H),0.93-0.89(m,1.2H).

[0791] Example 2-19 Preparation of Form 2O of Methylcyclohexane Solvate of Compound II

[0792] About 20 mg of compound II was weighed and suspended in 0.5 mL of acetone / methylcyclohexane (1:4 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain Form 2O of methylcyclohexane solvate of compound II. The product was characterized by XRPD (Figure 2-18), DSC (Figure 2-43) and TGA (Figure 2-68). 1HNMR (400MHz, DMSO-d6): δ12.77(br,1H),8.26(s,1H),7.87(dd,J=2.0Hz,11.5Hz,1H),7.79(dd,J=1.7,8.5Hz,1H),7.73(t,J=8. 1Hz,1H),7.71-7.62(m,2H),7.45(t,J=8.6Hz,1H),7.05(d,J=7.5Hz,1H),6.73(d,J=8.5Hz,1H),5.31(s,2H),5.11-5.08(m,1H),4 .92-4.90(m,1H),4.80-4.77(m,1H),4.66-4.64(m,1H),4.50-4.48(m,1H),4.38-4.36(m,1H),3.93(d,J=13.5Hz,1H),3.78(d,J=1 3.5Hz,1H),2.70-2.69(m,3H),2.50-2.32(m,3H),1.90-1.88(m,2H),1.62-1.60(m,7H),1.55-1.05(m,5H),0.84(d,J=3.9Hz,4H).

[0793] Example 2-20 Preparation of Form 2P of DMF Solvate of Compound II

[0794] About 20 mg of compound II was weighed and suspended in 0.5 mL of DMF / methyl tert-butyl ether (1:9 v:v), stirred at 50°C for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain Form 2P of DMF solvate of compound II. The product was characterized by XRPD (Figure 2-19), DSC (Figure 2-44) and TGA (Figure 2-69). 1HNMR (400MHz, DMSO-d6): δ12.72(br,1H),8.26(s,1H),7.86(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7. 73(t,J=8.1Hz,1H),7.67-7.63(m,2H),7.46(t,J=8.5Hz,1H),7.05(d,J=7.5Hz,1H),6.73(d,J=8.5Hz,1H),5.31(s,2H) ,5.11-5.08(m,1H),4.92-4.90(m,1H),4.80-4.77(m,1H),4.66-4.64(m,1H),4.50-4.48(m,1H),4.39-4.37(m,1H),3.9 4(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),2.89-2.69(m,9H),2.50-2.30(m,3H),1.91-1.89(m,2H)1.61-1.59(m,2H).

[0795] Example 2-21 Preparation of Form 2Q-1 of 2-Methyltetrahydrofuran Solvate of Compound II

[0796] About 20 mg of compound II was weighed and suspended in 0.5 mL of 2-methyltetrahydrofuran, stirred at 5°C for 3 days, filtered, and the filter cake was oven-dried at 50°C to obtain crystalline form 2Q-1 of 2-methyltetrahydrofuran solvate of compound II. The product was characterized by XRPD (Figure 2-20), DSC (Figure 2-45), and TGA (Figure 2-70). 1HNMR (400MHz, DMSO-d6): δ12.55(br,1H),8.27(s,1H),7.88(dd,J=2.1Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.73(t,J=8.1Hz,1H),7.68 -7.63(m,2H),7.45(t,J=8.6Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8 .5Hz,1H),5.31(s,2H),5.10-5.08(m,1H),4.92-4.90(m,1H),4.80-4.77 (m,1H),4.66-4.64(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.92(d,J=13.5Hz,1H),3.85-3.52(m,6H),2.70 -2.69(m,3H),2.45-2.30(m,3H),1.95-1.77(m,7H),1.62-1.60(m,2H),1.34-1.29(m,2H),1.24(d,J=6.8Hz,5H).

[0797] Example 2-22 Preparation of Form 2Q-2 of 2-Methyltetrahydrofuran Solvate of Compound II

[0798] Approximately 20 mg of compound II was weighed and suspended in 0.5 mL of 2-methyltetrahydrofuran / n-hexane (1:2 v:v). After stirring at 50°C for 2 hours, the temperature was lowered to 5°C and stirring was continued for 2 hours. The mixture was filtered and the filter cake was dried in an oven at 50°C to obtain Form 2Q-2 of 2-methyltetrahydrofuran solvate of compound II. The product was characterized by XRPD (Figure 2-21), DSC (Figure 2-46) and TGA (Figure 2-71). 1HNMR (400MHz, DMSO-d6): δ12.75(br,1H),8.26(s,1H),7.88(dd,J=2.1Hz,11.5Hz,1H),7.81(dd,J=1.7,8.5Hz,1H),7.73(t,J=8 .1Hz,1H),7.68-7.62(m,2H),7.45(t,J=8.6Hz,1H),7.06(d,J=6.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H),5.09-5.08(m,1H) ,4.92-4.90(m,1H),4.77-4.75(m,1H),4.66-4.64(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.92(d,J=13.5Hz,1H),3.81-3. 54(m,3H),2.70-2.69(m,3H),2.45-2.30(m,3H),1.92-1.79(m,2H),1.63-1.60(m,2H),1.34-1.29(m,2H),1.24(d,J=6.8Hz,2H).

[0799] Example 2-23 Preparation of Form 2R of N-methylpyrrolidone Solvate of Compound II

[0800] 20 mg of compound II was dissolved in 0.5 mL of N-methylpyrrolidone / ethyl acetate (1:1 v:v), 4.0 mL of methyl tert-butyl ether was added dropwise, and the mixture was stirred at room temperature for 1 hour. The mixture was filtered and the filter cake was dried in an oven at 50°C to obtain Form 2R of N-methylpyrrolidone solvate of compound II. The product was characterized by XRPD (Figure 2-22), DSC (Figure 2-47) and TGA (Figure 2-72). 1HNMR (400MHz, DMSO-d6): δ12.70(br,1H),8.26(s,1H),7.87(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.5Hz,1H),7.73(t ,J=8.1Hz,1H),7.67-7.63(m,2H),7.45(t,J=8.6Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H),5.09-5. 08(m,1H),4.92-4.90(m,1H),4.79-4.77(m,1H),4.66-4.62(m,1H),4.52-4.47(m,1H),4.40-4.35(m,1H),3.94(d,J=13.5Hz ,1H),3.78(d,J=13.5Hz,1H),2.75-2.70(m,8H),2.50-2.30(m,3H),2.20-2.16(m,3H),1.94-1.86(m,5H)1.61-1.59(m,2H).

[0801] Example 2-24 Preparation of Form 2S of Trifluoroethanol Solvate of Compound II

[0802] 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 and kept at room temperature for 2 days. The mixture was then filtered, and the filter cake was oven-dried at 50°C to obtain Form 2S of the trifluoroethanol solvate of Compound II. The product was characterized by XRPD (Figure 2-23), DSC (Figure 2-48), and TGA (Figure 2-73). 1HNMR (400MHz, DMSO-d6): δ12.75(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.8Hz,1H),7.72(t, J=8.0Hz,1H),7.71-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.06(d,J=6.5Hz,1H),6.74(d,J=8.6Hz,1H),5.31(s,2H),5.10-5.0 8(m,1H),4.92-4.91(m,1H),4.80-4.75(m,1H),4.66-4.64(m,1H),4.51-4.49(m,1H),4.39-4.36(m,1H),3.94(d,J=13.5Hz, 1H),3.92-3.86(m,1H),3.78(d,J=13.5Hz,1H),2.70-2.69(m,3H),2.50-2.30(m,3H),1.90-1.88(m,2H),1.61-1.59(m,2H).

[0803] Example 2-25 Preparation of Form 2T of Tetrahydrofuran Solvate of Compound II

[0804] 20 mg of compound II was dissolved in 0.5 mL of tetrahydrofuran, and slowly evaporated at room temperature for 2 days. The mixture was then filtered and the filter cake was dried in an oven at 50°C to obtain 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). 1HNMR (400MHz, DMSO-d6): δ12.78(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.5Hz,1H),7.80(dd,J=1.7,8.8Hz,1H),7.72(t,J=8.0 Hz,1H),7.71-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8.6Hz,1H),5.31(s,2H),5.09-5.08(m,1H),4. 92-4.90(m,1H),4.81-4.76(m,1H),4.66-4.62(m,1H),4.51-4.49(m,1H),4.40-4.36(m,1H),3.94(d,J=13.5Hz,1H),3.78(d,J=13 .5Hz,1H),3.62-3.59(m,1.4H),2.75-2.69(m,3H),2.50-2.30(m,3H),1.90-1.88(m,2H),1.78-1.76(m,1.4H),1.63-1.60(m,2H).

[0805] Example 2-26 Preparation of Form 2U of Dioxane Solvate of Compound II

[0806] 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 cap and allowed to stand at room temperature for 11 days. The solution was then filtered, and the filter cake was oven-dried at 50°C to obtain Form 2U of the dioxane solvate of Compound II. The product was characterized by XRPD (Figure 2-25), DSC (Figure 2-50), and TGA (Figure 2-75). 1HNMR (400MHz, DMSO-d6): δ12.78(br,1H),8.26(s,1H),7.88(dd,J=2.0Hz,11.6Hz,1H),7.79(dd,J=1.6,8.8Hz,1H),7.73( t,J=8.0Hz,1H),7.68-7.63(m,2H),7.45(t,J=8.5Hz,1H),7.06(d,J=7.5Hz,1H),6.74(d,J=8.5Hz,1H),5.31(s,2H),5.10- 5.09(m,1H),4.92-4.91(m,1H),4.80-4.75(m,1H),4.66-4.64(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J=13 .5Hz,1H),3.78(d,J=13.5Hz,1H),3.57(s,6H),2.70-2.69(m,3H),2.50-2.30(m,3H),1.90-1.88(m,2H)1.61-1.59(m,2H).

[0807] Test Example 1 Study on the equilibrium solubility of polymorphs of Compound I in biological media

[0808] The equilibrium solubility of Compound I amorphous solid and Form D of Compound I was tested in water (H2O), simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated full intestinal fluid (FeSSIF). In the test, the solid was prepared into a suspension (~10 mg / mL) in the corresponding buffer and mixed at 37±2°C. After 24 hours, the suspension was sampled, the supernatant was filtered to determine the concentration, and the solid was tested by XRPD. The test results are shown in the following table:

[0809] The above experimental results demonstrate that Form D of Compound I exhibits significantly better stability in biological media than the amorphous solid form of Compound I. With the exception of Form D, which transformed to the hydrochloride salt in the FaSSGF system, no changes in form were observed in the remaining samples. Its solubility in the FaSSIF system was also significantly improved, meeting the requirements for clinical drug formulation development. Therefore, the solubility and drug release behavior of the free form of Compound I can be significantly improved after salt formation.

[0810] Solid-state stability study of polymorphs of Compound I

[0811] Compound I amorphous solid and Compound I Form D were placed under long-term (25°C / 60% RH), accelerated (40°C / 75% RH), and high-temperature (60°C, RH <30%) conditions for 7 days, respectively. HPLC purity and crystal form changes were tested to investigate solid stability. The results are shown in the following table:

[0812] From the above experimental results, it can be seen that the purity of the amorphous solid of Compound I did not change significantly after 7 days under long-term conditions, but was severely degraded after 7 days under accelerated conditions and high temperature conditions; the purity of Form D of Compound I did not change significantly after 7 days under long-term conditions, but decreased slightly after 7 days under accelerated and high temperature conditions, and there was no significant change in the crystal form. The stability of Form D is significantly better than that of the amorphous solid.

[0813] Hygroscopic behavior test of compound I

[0814] The inventors evaluated the stability risk of samples at 25°C as the humidity changes according to the dynamic moisture sorption method. DVS testing was performed on the representative crystalline form D of compound I to evaluate the hygroscopicity of the compound crystalline form. The DVS spectrum of the amorphous solid of the compound is shown in FIG67 , and the DVS spectrum of the crystalline form D of the compound is shown in FIG68 . The results are shown in the following table:

[0815] From the above experimental results, it can be seen that on the adsorption curve of 0-90% RH, under 80% RH conditions, both the amorphous solid of Compound I and the crystalline form D sample are slightly hygroscopic, with no obvious difference, and no solid morphology change is observed.

[0816] The thermal analysis of some crystalline forms of Compound I of the present invention is summarized in the following table:

[0817] Test Example 2 Study on the equilibrium solubility of polymorphs of Compound II in biological media

[0818] Form 2A of Compound II was tested for equilibrium solubility in water (H2O), simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated full intestinal fluid (FeSSIF). In this test, the solid was prepared into a suspension (~10 mg / mL) in the corresponding buffer and mixed at 37±2°C. After 24 hours, the suspension was sampled, the supernatant was filtered for concentration determination, and the solid was tested by XRPD. The test results are shown in the following table:

[0819] From the above experimental results, it can be seen that the stability of the crystalline form 2A of compound II in biological media is significantly better than that of the amorphous solid of compound II. Except for the crystal form transformation to hydrochloride in the FaSSGF system, the crystalline form 2A of compound II has good stability in other biological media, and no crystal form change is observed, which can meet the needs of drug clinical formulation development.

[0820] Solid-state stability study of polymorphs of compound II

[0821] Form 2A of Compound II was placed under long-term (25°C / 60% RH), accelerated (40°C / 75% RH), and high-temperature (60°C, RH <30%) conditions for 7 days to test HPLC purity and crystal form changes, and investigate solid stability. The results are shown in the following table:

[0822] From the above experimental results, it can be seen that the purity of Form 2A of Compound II did not change significantly after being placed under long-term, accelerated and high-temperature conditions for 7 days, and the crystal form did not change, indicating that Form 2A has good solid-state stability.

[0823] Hygroscopic behavior test of compound II

[0824] The inventors evaluated the stability risk of samples at 25°C as the humidity changes according to the dynamic moisture sorption method. DVS testing was performed on the representative crystalline form 2A of Compound II to evaluate the hygroscopicity of the compound crystal form. The DVS spectrum of the crystalline form 2A of Compound II is shown in Figure 2-79. The results are shown in the following table:

[0825] From the above experimental results, it can be seen that on the adsorption curve of 0-90% RH, under the condition of 80% RH, the compound II crystal form 2A sample is slightly hygroscopic and no solid morphology change is observed.

[0826] The thermal analysis of some crystalline forms of Compound II of the present invention is summarized in the following table:

[0827] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. Polymorphs of Compound III: in, X is selected from Cl or CN.

2. The polymorph according to claim 1, characterized in that The polymorph may be a non-solvate crystalline form, a hydrate crystalline form or a solvate crystalline form of Compound III; Preferably, compound III has the structure shown in compound I or compound II:

3. The polymorph according to claim 1 or 2, characterized in that The polymorphs are solvent-free crystalline forms of Compound 1, including the following solvent-free crystalline forms A, B, C, D, E, and F, wherein: The crystalline form A has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 19.79±0.2°, 13.13±0.2°, 22.07±0.2° and 9.48±0.2°. Preferably, peaks 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° are also included. More preferably, peaks 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° are also included. Preferably, the X-ray powder diffraction pattern of the crystalline form A has a diffraction angle (2θ) as shown in Table 1, wherein the error range of the 2θ angle is ±0.20°: Table 1 Preferably, the crystalline form A has an X-ray powder diffraction intensity as shown in Table 1; Preferably, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 1; Preferably, the DSC analysis of the crystalline form A shows an endothermic peak when heated to a peak temperature of 99.81°C; Preferably, the crystalline form A has a DSC spectrum substantially as shown in Figure 22; Preferably, the crystalline Form A has a TGA pattern substantially as shown in Figure 43; The crystalline form B has an X-ray powder diffraction pattern comprising peaks 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 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, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form B has a diffraction angle (2θ) as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°: Table 2 Preferably, the crystalline form B has the X-ray powder diffraction intensity shown in Table 2; Preferably, the crystalline Form B has an X-ray powder diffraction pattern substantially as shown in FIG2 ; Preferably, the DSC analysis of the crystalline form B shows an endothermic peak when heated to a peak temperature of 177.71°C; Preferably, the crystalline Form B has a DSC spectrum substantially as shown in Figure 23; Preferably, the crystalline Form B has a TGA pattern substantially as shown in Figure 44; The crystalline form C has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 11.27±0.2°, 19.30±0.2°, 17.92±0.2°, and 20.04±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form C has a diffraction angle (2θ) as shown in Table 3, wherein the error range of the 2θ angle is ±0.20°: Table 3 Preferably, the crystalline form C has an X-ray powder diffraction intensity as shown in Table 3; Preferably, the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG3 ; Preferably, the DSC analysis of the crystalline form C shows an endothermic peak when heated to a peak temperature of approximately 104.51°C; Preferably, the crystalline form C has a DSC spectrum substantially as shown in Figure 24; Preferably, the crystalline form C has a TGA pattern substantially as shown in Figure 45; The crystalline form D has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 14.49±0.2°, 16.98±0.2°, 11.51±0.2°, and 18.17±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form D has a diffraction angle (2θ) as shown in Table 4, wherein the error range of the 2θ angle is ±0.20°: Table 4 Preferably, the crystalline form D has the X-ray powder diffraction intensity shown in Table 4; Preferably, the crystalline form D has an X-ray powder diffraction pattern substantially as shown in FIG4 ; Preferably, the DSC analysis of the crystalline form D shows an endothermic peak when heated to a peak temperature of 167.48°C; Preferably, the crystalline form D has a DSC spectrum substantially as shown in Figure 25; Preferably, the crystalline form D has a TGA pattern substantially as shown in Figure 46; The crystalline form E has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 11.49±0.2°, 12.17±0.2°, 21.15±0.2°, and 20.16±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form E has a diffraction angle (2θ) as shown in Table 5, wherein the error range of the 2θ angle is ±0.20°: Table 5 Preferably, the crystalline form E has an X-ray powder diffraction intensity as shown in Table 5; Preferably, the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG5 ; Preferably, the DSC analysis of the crystalline form E shows an endothermic peak when heated to a peak temperature of approximately 112.00°C; Preferably, the crystalline form E has a DSC spectrum substantially as shown in Figure 26; Preferably, the crystalline Form E has a TGA pattern substantially as shown in Figure 47; The crystalline form F has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 18.77±0.2°, 25.50±0.2°, 20.98±0.2°, and 23.45±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form F has a diffraction angle (2θ) as shown in Table 6, wherein the error range of the 2θ angle is ±0.20°: Table 6 Preferably, the crystalline form F has the X-ray powder diffraction intensity shown in Table 6; Preferably, the crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG6 ; Preferably, the DSC analysis of the crystalline form F shows an endothermic peak when heated to a peak temperature of approximately 169.00°C; Preferably, the crystalline form F has a DSC spectrum substantially as shown in Figure 27; Preferably, the crystalline Form F has a TGA pattern substantially as shown in Figure 48; Preferably, the polymorph is the hydrate form G of compound I; The hydrate crystalline form G has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 18.66±0.2°, 18.81±0.2°, 3.62±0.2° and 22.24±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form G has a diffraction angle (2θ) as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°: Table 7 Preferably, the crystalline form G has the X-ray powder diffraction intensity shown in Table 7; Preferably, the crystalline form G has an X-ray powder diffraction pattern substantially as shown in FIG7 ; Preferably, the DSC analysis of the crystalline form G shows endothermic peaks near the peak temperatures of 89.95°C and 104.07°C; Preferably, the crystalline form G has a DSC spectrum substantially as shown in Figure 28; Preferably, the crystalline Form G has a TGA pattern substantially as shown in Figure 49; Preferably, the crystalline form G is a dihydrate of compound I; Preferably, the polymorph is a solvate crystalline form of Compound 1, including the following solvate crystalline forms H, I-1, I-2, J, K, L, M, N, O, P, Q, R, S, and T, wherein: The crystalline form H of the methyl isobutyl ketone solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 10.75±0.2°, 8.61±0.2°, 19.84±0.2°, and 18.48±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form H has a diffraction angle (2θ) as shown in Table 8, wherein the error range of the 2θ angle is ±0.20°: Table 8 Preferably, the crystalline form H has the X-ray powder diffraction intensity shown in Table 8; Preferably, the crystalline form H has an X-ray powder diffraction pattern substantially as shown in FIG8 ; Preferably, the DSC analysis of the crystalline form H shows an endothermic peak when heated to a peak temperature of 87.76°C; Preferably, the crystalline form H has a DSC spectrum substantially as shown in Figure 29; Preferably, the crystalline Form H has a TGA pattern substantially as shown in Figure 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.53±0.2°, 10.75±0.2°, 4.22±0.2° and 18.39±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form I-1 has a diffraction angle (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°: Table 9 Preferably, the crystalline form I-1 has the X-ray powder diffraction intensity shown in Table 9; Preferably, the crystalline form I-1 has an X-ray powder diffraction pattern substantially as shown in FIG9 ; Preferably, the DSC analysis of the crystalline form I-1 shows an endothermic peak when heated to a peak temperature of approximately 103.27°C; Preferably, the crystalline form I-1 has a DSC spectrum substantially as shown in FIG30 ; Preferably, the crystalline form I-1 has a TGA pattern substantially as shown in Figure 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 has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 16.88±0.2°, 18.87±0.2°, 20.90±0.2° and 9.60±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form I-2 has a diffraction angle (2θ) as shown in Table 10, wherein the 2θ angle is The error range is ±0.20°: Table 10 Preferably, the crystalline form I-2 has the X-ray powder diffraction intensity shown in Table 10; Preferably, the crystalline form I-2 has an X-ray powder diffraction pattern substantially as shown in Figure 10; Preferably, the DSC analysis of the crystalline form I-2 shows an endothermic peak when heated to a peak temperature of 97.11°C; Preferably, the crystalline form I-2 has a DSC spectrum substantially as shown in Figure 31; Preferably, the crystalline form I-2 has a TGA pattern substantially as shown in Figure 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 12.02±0.2°, 18.03±0.2°, 8.04±0.2° and 7.67±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form J has a diffraction angle (2θ) as shown in Table 11, wherein 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 has an X-ray powder diffraction pattern substantially as shown in Figure 11; Preferably, the DSC analysis of the crystal form J shows an endothermic peak when heated to a peak temperature of 93.18°C; Preferably, the crystalline form J has a DSC spectrum substantially as shown in Figure 32; Preferably, the crystalline Form J has a TGA pattern substantially as 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 an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 12.19±0.2°, 18.02±0.2°, 7.69±0.2°, and 19.69±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form K has a diffraction angle (2θ) as shown in Table 12, wherein 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 has an X-ray powder diffraction pattern substantially as shown in FIG12 ; Preferably, the DSC analysis of the crystal form K shows an endothermic peak near the peak temperature of 91.51°C; Preferably, the crystalline form K has a DSC spectrum substantially as shown in FIG33 ; Preferably, the crystalline form K has a TGA pattern substantially as shown in Figure 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 10.98±0.2°, 15.54±0.2°, 9.09±0.2°, and 19.01±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form L has a diffraction angle (2θ) as shown in Table 13, wherein 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 has an X-ray powder diffraction pattern substantially as shown in Figure 13; Preferably, the DSC analysis of the crystalline form L shows an endothermic peak when heated to a peak temperature of 88.68°C; Preferably, the crystalline form L has a DSC spectrum substantially as shown in Figure 34; Preferably, the crystalline form L has a TGA pattern substantially as shown in Figure 55; Preferably, the crystalline form L is a 0.15-methylcyclohexane solvate of compound I; The crystalline form M of the toluene solvate has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 18.62±0.2°, 9.60±0.2°, 16.34±0.2°, and 21.62±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form M has a diffraction angle (2θ) as shown in Table 14, wherein 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 has an X-ray powder diffraction pattern substantially as shown in Figure 14; Preferably, the DSC analysis of the crystalline form M shows an endothermic peak when heated to a peak temperature of approximately 102.43°C; Preferably, the crystalline form M has a DSC spectrum substantially as shown in Figure 35; Preferably, the crystalline Form M has a TGA pattern substantially as shown in Figure 56; Preferably, the crystalline form M is a monotoluene solvate of compound I; The crystalline form N of the dioxane solvate, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 17.10±0.2°, 20.66±0.2°, 22.71±0.2° and 18.21±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form N has a diffraction angle (2θ) as shown in Table 15, wherein 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 has an X-ray powder diffraction pattern substantially as shown in Figure 15; Preferably, the DSC analysis of the crystalline form N shows an endothermic peak when heated to a peak temperature of 116.48°C; Preferably, the crystalline form N has a DSC spectrum substantially as shown in Figure 36; Preferably, the crystalline Form N has a TGA pattern substantially as shown in Figure 57; Preferably, the crystalline form N is a 1.5-dioxane solvate of compound I; The crystalline form O of the DMF solvate has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 17.72±0.2°, 13.14±0.2°, 15.08±0.2°, and 24.77±0.2°; Preferably, the 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° are further included; More preferably, the 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form O has a diffraction angle (2θ) as shown in Table 16, wherein the error range of the 2θ angle is ±0.20°: Table 16 Preferably, the crystalline form O has an X-ray powder diffraction intensity as shown in Table 16; Preferably, the crystalline form O has an X-ray powder diffraction pattern substantially as shown in Figure 16; Preferably, the DSC analysis of the crystalline form O shows an endothermic peak when heated to a peak temperature of approximately 123.26°C; Preferably, the crystalline form O has a DSC spectrum substantially as shown in FIG37 ; Preferably, the crystalline Form O has a TGA pattern substantially as shown in Figure 58; Preferably, the crystalline form O is a mono-DMF solvate of compound I; The crystalline form P of the N-methylpyrrolidone solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 14.63±0.2°, 13.16±0.2°, 16.98±0.2°, and 14.36±0.2°; Preferably, the 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° are further included; More preferably, the 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form P has a diffraction angle (2θ) as shown in Table 17, wherein the error range of the 2θ angle is ±0.20°: Table 17 Preferably, the crystalline form P has the X-ray powder diffraction intensity shown in Table 17; Preferably, the crystalline form P has an X-ray powder diffraction pattern substantially as shown in Figure 17; Preferably, the DSC analysis of the crystalline form P shows an endothermic peak when heated to a peak temperature of 117.63°C; Preferably, the crystalline form P has a DSC spectrum substantially as shown in FIG38 ; Preferably, the crystalline form P has a TGA pattern substantially as shown in Figure 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 18.05±0.2°, 10.71±0.2°, 12.54±0.2°, and 18.78±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form Q has a diffraction angle (2θ) as shown in Table 18, wherein 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 has an X-ray powder diffraction pattern substantially as shown in Figure 18; Preferably, the DSC analysis of the crystalline form Q shows an endothermic peak when heated to a peak temperature of approximately 100.61°C; Preferably, the crystalline form Q has a DSC spectrum substantially as shown in Figure 39; Preferably, the crystalline Form Q has a TGA graph substantially as shown in Figure 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 an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.67±0.2°, 12.52±0.2°, 18.08±0.2°, and 8.98±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form R has a diffraction angle (2θ) as shown in Table 19, wherein 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 has an X-ray powder diffraction pattern substantially as shown in Figure 19; Preferably, the DSC analysis of the crystalline form R shows an endothermic peak when heated to a peak temperature of approximately 110.90°C; Preferably, the crystalline form R has a DSC spectrum substantially as shown in Figure 40; Preferably, the crystalline Form R has a TGA pattern substantially as shown in Figure 61; Preferably, the crystalline form R is a mono-n-propanol solvate of compound I; The crystalline form S of the tetrahydrofuran solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 12.17±0.2°, 8.19±0.2°, 7.67±0.2° and 13.96±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form S has a diffraction angle (2θ) as shown in Table 20, wherein 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 has an X-ray powder diffraction pattern substantially as shown in Figure 20; Preferably, the DSC analysis of the crystalline form S shows an endothermic peak when heated to a peak temperature of 96.26°C; Preferably, the crystalline form S has a DSC spectrum substantially as shown in Figure 41; Preferably, the crystalline Form S has a TGA pattern substantially as shown in Figure 62; Preferably, the crystalline form S is a 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 at diffraction angles (2θ) of 10.79±0.2°, 8.66±0.2°, 9.12±0.2°, and 16.87±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form T has a diffraction angle (2θ) as shown in Table 21, wherein the error range of the 2θ angle is ±0.20°: Table 21 Preferably, the crystalline form T has the X-ray powder diffraction intensity shown in Table 21; Preferably, the crystalline form T has an X-ray powder diffraction pattern substantially as shown in Figure 21; Preferably, the DSC analysis of the crystalline form T shows an endothermic peak when heated to a peak temperature of approximately 112.95°C; Preferably, the crystalline form T has a DSC spectrum substantially as shown in Figure 42; Preferably, the crystalline form T has a TGA graph substantially as shown in Figure 63; Preferably, the crystalline form T is a mono-2-methyltetrahydrofuran solvate of compound I.

4. The polymorph according to claim 1 or 2, characterized in that The polymorphs are solvent-free crystalline forms of Compound II, including the following solvent-free crystalline forms 2A, 2B, 2C, 2D, and 2E, wherein: The crystalline form 2A has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 13.94±0.2°, 22.07±0.2°, 17.96±0.2°, and 17.57±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2A has a diffraction angle (2θ) as shown in Table 2-1, wherein the error range of the 2θ angle is ±0.20°: Table 2-1 Preferably, the crystalline form 2A has the X-ray powder diffraction intensity shown in Table 2-1; Preferably, the crystalline form 2A has an X-ray powder diffraction pattern substantially as shown in FIG2-1; Preferably, the DSC analysis of the crystalline form 2A shows an endothermic peak when heated to a peak temperature of approximately 189.90°C; Preferably, the crystalline form 2A has a DSC spectrum substantially as shown in Figure 2-26; Preferably, the crystalline form 2A has a TGA pattern substantially as shown in Figure 2-51; The crystalline form 2B has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 13.16±0.2°, 21.31±0.2°, 25.46±0.2°, and 10.61±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2B has a diffraction angle (2θ) as shown in Table 2-2, wherein the error range of the 2θ angle is ±0.20°: Table 2-2 Preferably, the crystalline form 2B has the X-ray powder diffraction intensity shown in Table 2-2; Preferably, the crystalline form 2B has an X-ray powder diffraction pattern substantially as shown in FIG2-2; Preferably, the DSC analysis of the crystalline form 2B shows an endothermic peak when heated to a peak temperature of 181.06°C; Preferably, the crystalline form 2B has a DSC spectrum substantially as shown in Figure 2-27; Preferably, the crystalline form 2B has a TGA pattern substantially as shown in Figure 2-52; The crystalline form 2C has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 13.63±0.2°, 5.62±0.2°, 17.12±0.2°, and 17.68±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2C has a diffraction angle (2θ) as shown in Table 2-3, wherein the error range of the 2θ angle is ±0.20°: Table 2-3 Preferably, the crystalline form 2C has the X-ray powder diffraction intensity shown in Table 2-3; Preferably, the crystalline form 2C has an X-ray powder diffraction pattern substantially as shown in Figures 2-3; Preferably, the DSC analysis of the crystalline form 2C shows an endothermic peak when heated to a peak temperature of 171.63°C; Preferably, the crystalline form 2C has a DSC spectrum substantially as shown in Figure 2-28; Preferably, the crystalline form 2C has a TGA pattern substantially as shown in Figure 2-53; The crystalline form 2D has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 5.62±0.2°, 12.01±0.2°, 5.24±0.2°, and 17.72±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2D has a diffraction angle (2θ) as shown in Table 2-4, wherein the error range of the 2θ angle is ±0.20°: Table 2-4 Preferably, the crystalline form 2D has the X-ray powder diffraction intensity shown in Table 2-4; Preferably, the crystalline form 2D has an X-ray powder diffraction pattern substantially as shown in Figures 2-4; Preferably, the DSC analysis of the crystal form 2D shows an endothermic peak when heated to a peak temperature of 168.79°C; Preferably, the crystalline form 2D has a DSC spectrum substantially as shown in Figure 2-29; Preferably, the crystalline form 2D has a TGA pattern substantially as shown in Figure 2-54; The crystalline form 2E has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 17.96±0.2°, 3.34±0.2°, 5.63±0.2°, and 13.63±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2E has a diffraction angle (2θ) as shown in Table 2-5, wherein the error range of the 2θ angle is ±0.20°: Table 2-5 Preferably, the crystalline form 2E has the X-ray powder diffraction intensity shown in Table 2-5; Preferably, the crystalline form 2E has an X-ray powder diffraction pattern substantially as shown in Figures 2-5; Preferably, the DSC analysis of the crystalline form 2E shows endothermic peaks near the peak temperatures of 110.30°C and 169.27°C; Preferably, the crystalline form 2E has a DSC spectrum substantially as shown in FIG2-30; Preferably, the Form 2E has a TGA pattern substantially as shown in FIG2-55 ; Preferably, the polymorph is a hydrated form of Compound II, including the following hydrated forms 2F and 2G, wherein: The hydrate crystalline form 2F has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 19.51±0.2°, 13.71±0.2°, 14.29±0.2°, and 18.09±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2F has a diffraction angle (2θ) as shown in Table 2-6, wherein the error range of the 2θ angle is ±0.20°: Table 2-6 Preferably, the crystalline form 2F has the X-ray powder diffraction intensity shown in Table 2-6; Preferably, the crystalline form 2F has an X-ray powder diffraction pattern substantially as shown in Figures 2-6; Preferably, the DSC analysis of the crystalline form 2F shows an endothermic peak when heated to a peak temperature of 114.41°C; Preferably, the crystalline form 2F has a DSC spectrum substantially as shown in Figure 2-31; Preferably, the crystalline form 2F has a TGA pattern substantially as shown in Figure 2-56; Preferably, the crystalline form 2F is a trihydrate of compound II; The hydrate crystalline form 2G has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 17.45±0.2°, 13.63±0.2°, 5.61±0.2°, and 5.24±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2G has a diffraction angle (2θ) as shown in Table 2-7, wherein the error range of the 2θ angle is ±0.20°: Table 2-7 Preferably, the crystalline form 2G has the X-ray powder diffraction intensity shown in Table 2-7; Preferably, the crystalline form 2G has an X-ray powder diffraction pattern substantially as shown in Figures 2-7; Preferably, the DSC analysis of the crystalline form 2G shows an endothermic peak when heated to a peak temperature of 169.22°C; Preferably, the crystalline form 2G has a DSC spectrum substantially as shown in Figure 2-32; Preferably, the Form 2G has a TGA pattern substantially as shown in FIG2-57; Preferably, the crystalline form 2G is a dihydrate of compound II; Preferably, the polymorph is a solvate form of Compound II, including the following solvate 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, wherein: The crystalline form 2H of the dimethyl sulfoxide solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 14.84±0.2°, 13.42±0.2°, 24.68±0.2°, and 21.70±0.2°; Preferably, the peaks 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° are further included; More preferably, the above mentioned particles are located at 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°. The peak at the diffraction angle (2θ); Preferably, the X-ray powder diffraction pattern of the crystalline form 2H has a diffraction angle (2θ) as shown in Table 2-8, wherein the error range of the 2θ angle is ±0.20°: Table 2-8 Preferably, the crystalline form 2H has the X-ray powder diffraction intensity shown in Table 2-8; Preferably, the Form 2H has an X-ray powder diffraction pattern substantially as shown in Figures 2-8; Preferably, the DSC analysis of the crystalline form 2H shows an endothermic peak when heated to a peak temperature of 118.06°C; Preferably, the Form 2H has a DSC spectrum substantially as shown in Figure 2-33; Preferably, the Form 2H has a TGA pattern substantially as shown in Figure 2-58; Preferably, the crystalline form 2H is a mono-dimethyl sulfoxide solvate of compound II; The crystalline form 2I of the methyl tert-butyl ether solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.74±0.2°, 10.94±0.2°, 4.32±0.2°, and 17.66±0.2°; Preferably, the peaks at diffraction angles (2θ) of 13.18±0.2°, 9.25±0.2°, 18.79±0.2°, 17.12±0.2° and 12.79° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2I has a diffraction angle (2θ) as shown in Table 2-9, wherein the error range of the 2θ angle is ±0.20°: Table 2-9 Preferably, the crystalline form 2I has the X-ray powder diffraction intensity shown in Table 2-9; Preferably, the Form 2I has an X-ray powder diffraction pattern substantially as shown in Figures 2-9; Preferably, the DSC analysis of the crystalline form 2I shows an endothermic peak when heated to a peak temperature of 115.84°C; Preferably, the Form 2I has a DSC spectrum substantially as shown in Figure 2-34; Preferably, the Form 2I has a TGA pattern substantially as shown in Figure 2-59; Preferably, the crystalline form 2I is a 0.5 methyl tert-butyl ether solvate of compound II; The X-ray powder diffraction pattern of the crystalline form 2J-1 of the n-heptane solvate includes the following: and a peak at a diffraction angle (2θ) of 7.63 ± 0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2J-1 has a diffraction angle (2θ) as shown in Table 2-10, wherein the error range of the 2θ angle is ±0.20°: Table 2-10 Preferably, the crystalline form 2J-1 has the X-ray powder diffraction intensity shown in Table 2-10; Preferably, the crystalline form 2J-1 has an X-ray powder diffraction pattern substantially as shown in FIG2-10; Preferably, the DSC analysis of the crystalline form 2J-1 shows an endothermic peak when heated to a peak temperature of approximately 103.13°C; Preferably, the crystalline form 2J-1 has a DSC spectrum substantially as shown in Figure 2-35; Preferably, the crystalline form 2J-1 has a TGA pattern substantially as shown in FIG2-60; 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 3.52±0.2°, 17.76±0.2°, 14.19±0.2°, and 10.61±0.2°; Preferably, the peaks at diffraction angles (2θ) of 7.05±0.2°, 21.35±0.2°, 16.24±0.2° and 19.49±0.2° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2J-2 has a diffraction angle (2θ) as shown in Table 2-11, wherein the error range of the 2θ angle is ±0.20°: Table 2-11 Preferably, the crystalline form 2J-2 has the X-ray powder diffraction intensity shown in Table 2-11; Preferably, the crystalline form 2J-2 has an X-ray powder diffraction pattern substantially as shown in FIG2-11; Preferably, the DSC analysis of the crystalline form 2J-2 shows an endothermic peak near the peak temperature of 76.82°C; Preferably, the crystalline form 2J-2 has a DSC spectrum substantially as shown in Figure 2-36; Preferably, the crystalline form 2J-2 has a TGA pattern substantially as shown in Figure 2-61; Preferably, the crystalline form 2J-2 is a 0.5 n-heptane solvate of compound II; The crystalline form 2K of the toluene solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 9.52±0.2°, 18.45±0.2°, 19.09±0.2°, and 21.48±0.2°; Preferably, the spectral range further includes peaks 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, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2K has a diffraction angle (2θ) as shown in Table 2-12, wherein the error range of the 2θ angle is ±0.20°: Table 2-12 Preferably, the crystalline form 2K has the X-ray powder diffraction intensity shown in Table 2-12; Preferably, the crystalline form 2K has an X-ray powder diffraction pattern substantially as shown in FIG2-12 ; Preferably, the DSC analysis of the crystalline form 2K shows endothermic peaks near peak temperatures of 107.92°C, 172.19°C and 184.68°C; Preferably, the crystalline form 2K has a DSC spectrum substantially as shown in Figure 2-37; Preferably, the crystalline form 2K has a TGA pattern substantially as shown in FIG2-62; 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.66±0.2°, 10.79±0.2°, 26.00±0.2°, and 19.62±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2L-1 has a diffraction angle (2θ) as shown in Table 2-13, wherein the error range of the 2θ angle is ±0.20°: Table 2-13 Preferably, the crystalline form 2L-1 has the X-ray powder diffraction intensity shown in Table 2-13; Preferably, the crystalline form 2L-1 has an X-ray powder diffraction pattern substantially as shown in FIG2-13; Preferably, the DSC analysis of the crystalline form 2L-1 shows an endothermic peak when heated to a peak temperature of approximately 106.45°C; Preferably, the crystalline form 2L-1 has a DSC spectrum substantially as shown in Figure 2-38; Preferably, the crystalline form 2L-1 has a TGA pattern substantially as 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.68±0.2°, 10.83±0.2°, 13.10±0.2°, and 11.06±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2L-2 has a diffraction angle (2θ) as shown in Table 2-14, wherein the error range of the 2θ angle is ±0.20°: Table 2-14 Preferably, the crystalline form 2L-2 has the X-ray powder diffraction intensity shown in Table 2-14; Preferably, the crystalline form 2L-2 has an X-ray powder diffraction pattern substantially as shown in FIG2-14; Preferably, the DSC analysis of the crystalline form 2L-2 shows an endothermic peak when heated to a peak temperature of approximately 102.87°C; Preferably, the crystalline form 2L-2 has a DSC spectrum substantially as shown in Figure 2-39; Preferably, the crystalline form 2L-2 has a TGA pattern substantially as shown in Figure 2-64; Preferably, the crystalline form 2L-2 is a 0.3 methyl isobutyl ketone solvate of compound II; The crystalline form 2M-1 of the cyclopentyl methyl ether solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.78±0.2°, 10.98±0.2°, 17.67±0.2°, and 17.20±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2M-1 has a diffraction angle (2θ) as shown in Table 2-15, wherein the error range of the 2θ angle is ±0.20°: Table 2-15 Preferably, the crystalline form 2M-1 has the X-ray powder diffraction intensity shown in Table 2-15; Preferably, the crystalline form 2M-1 has an X-ray powder diffraction pattern substantially as shown in FIG2-15; Preferably, the DSC analysis of the crystalline form 2M-1 shows an endothermic peak when heated to a peak temperature of 113.56°C; Preferably, the crystalline form 2M-1 has a DSC spectrum substantially as shown in FIG2-40; Preferably, the crystalline form 2M-1 has a TGA pattern substantially as shown in FIG2-65; Preferably, the crystalline form 2M-1 is a monocyclopentyl methyl ether solvate of compound II; The crystalline form 2M-2 of the cyclopentyl methyl ether solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 5.16±0.2°, 10.83±0.2°, 15.66±0.2°, and 21.29±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2M-2 has a diffraction angle (2θ) as shown in Table 2-16, wherein the error range of the 2θ angle is ±0.20°: Table 2-16 Preferably, the crystalline form 2M-2 has the X-ray powder diffraction intensity shown in Table 2-16; Preferably, the crystalline form 2M-2 has an X-ray powder diffraction pattern substantially as shown in FIG2-16; Preferably, the DSC analysis of the crystalline form 2M-2 shows endothermic peaks near the peak temperatures of 110.50°C and 165.01°C; Preferably, the crystalline form 2M-2 has a DSC spectrum substantially as shown in Figure 2-41; Preferably, the crystalline form 2M-2 has a TGA pattern substantially as shown in Figure 2-66; Preferably, the crystalline form 2M-2 is a monocyclopentyl methyl ether solvate of compound II; The crystalline form 2N of the methyl ethyl ketone solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 3.34±0.2°, 10.88±0.2°, 9.13±0.2° and 6.64±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2N has a diffraction angle (2θ) as shown in Table 2-17, wherein the error range of the 2θ angle is ±0.20°: Table 2-17 Preferably, the crystalline form 2N has the X-ray powder diffraction intensity shown in Table 2-17; Preferably, the Form 2N has an X-ray powder diffraction pattern substantially as shown in Figure 2-17; Preferably, the DSC analysis of the crystalline form 2N shows endothermic peaks near the peak temperatures of 102.66°C and 113.16°C; Preferably, the crystalline form 2N has a DSC spectrum substantially as shown in Figure 2-42; Preferably, the Form 2N has a TGA pattern substantially as shown in Figure 2-67; Preferably, the crystalline form 2N is a 0.3 methyl ethyl ketone solvate of compound II; The crystalline form 20 of the methylcyclohexane solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.72±0.2°, 10.92±0.2°, 13.14±0.2°, and 9.23±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2O has a diffraction angle (2θ) as shown in Table 2-18, wherein the error range of the 2θ angle is ±0.20°: Table 2-18 Preferably, the crystalline form 2O has the X-ray powder diffraction intensity shown in Table 2-18; Preferably, the Form 2O has an X-ray powder diffraction pattern substantially as shown in FIG2-18; Preferably, the DSC analysis of the crystalline form 2O shows an endothermic peak when heated to a peak temperature of approximately 111.80°C; Preferably, the crystalline form 2O has a DSC spectrum substantially as shown in FIG2-43; Preferably, the Form 2O has a TGA pattern substantially as shown in FIG2-68; 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 at diffraction angles (2θ) of 10.98±0.2°, 9.31±0.2°, 17.68±0.2°, and 25.67±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2P has a diffraction angle (2θ) as shown in Table 2-19, wherein the error range of the 2θ angle is ±0.20°: Table 2-19 Preferably, the crystalline form 2P has the X-ray powder diffraction intensity shown in Table 2-19; Preferably, the crystalline Form 2P has an X-ray powder diffraction pattern substantially as shown in FIG2-19; Preferably, the DSC analysis of the crystalline form 2P shows an endothermic peak when heated to a peak temperature of approximately 105.14°C; Preferably, the crystalline form 2P has a DSC spectrum substantially as shown in Figure 2-44; Preferably, the crystalline form 2P has a TGA pattern substantially as shown in Figure 2-69; Preferably, the crystalline form 2P is a mono-DMF solvate of compound II; The crystalline form 2Q-1 of the 2-methyltetrahydrofuran solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.74±0.2°, 10.89±0.2°, 3.53±0.2°, and 17.90±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2Q-1 has a diffraction angle (2θ) as shown in Table 2-20, wherein the error range of the 2θ angle is ±0.20°: Table 2-20 Preferably, the crystalline form 2Q-1 has the X-ray powder diffraction intensity shown in Table 2-20; Preferably, the crystalline form 2Q-1 has an X-ray powder diffraction pattern substantially as shown in FIG2-20; Preferably, the DSC analysis of the crystalline form 2Q-1 shows an endothermic peak when heated to a peak temperature of 111.13°C; Preferably, the crystalline form 2Q-1 has a DSC spectrum substantially as shown in Figure 2-45; Preferably, the crystalline form 2Q-1 has a TGA pattern substantially as shown in FIG2-70; 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.76±0.2°, 10.89±0.2°, 9.21±0.2°, and 17.02±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2Q-2 has a diffraction angle (2θ) as shown in Table 2-21, wherein the error range of the 2θ angle is ±0.20°: Table 2-21 Preferably, the crystalline form 2Q-2 has the X-ray powder diffraction intensity shown in Table 2-21; Preferably, the crystalline form 2Q-2 has an X-ray powder diffraction pattern substantially as shown in FIG2-21; Preferably, the DSC analysis of the crystalline form 2Q-2 shows an endothermic peak when heated to a peak temperature of 114.18°C; Preferably, the crystalline form 2Q-2 has a DSC spectrum substantially as shown in Figure 2-46; Preferably, the crystalline form 2Q-2 has a TGA pattern substantially as shown in FIG2-71; 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 10.79±0.2°, 9.15±0.2°, 3.44±0.2°, and 17.63±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2R has a diffraction angle (2θ) as shown in Table 2-22, wherein the error range of the 2θ angle is ±0.20°: Table 2-22 Preferably, the crystalline form 2R has the X-ray powder diffraction intensity shown in Table 2-22; Preferably, the crystalline form 2R has an X-ray powder diffraction pattern substantially as shown in Figure 2-22; Preferably, the DSC analysis of the crystalline form 2R shows an endothermic peak when heated to a peak temperature of 128.45°C; Preferably, the crystalline form 2R has a DSC spectrum substantially as shown in Figure 2-47; Preferably, the Form 2R has a TGA pattern substantially as shown in Figure 2-72; Preferably, the crystalline form 2R is a mono-N-methylpyrrolidone solvate of compound II; The crystalline form 2S of the trifluoroethanol solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 17.64±0.2°, 4.01±0.2°, 8.72±0.2°, and 8.28±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2S has a diffraction angle (2θ) as shown in Table 2-23, wherein the error range of the 2θ angle is ±0.20°: Table 2-23 Preferably, the crystalline form 2S has the X-ray powder diffraction intensity shown in Table 2-23; Preferably, the crystalline form 2S has an X-ray powder diffraction pattern substantially as shown in FIG2-23; Preferably, the DSC analysis of the crystalline form 2S shows endothermic peaks near the peak temperatures of 123.79° C. and 169.39° C.; Preferably, the crystalline form 2S has a DSC spectrum substantially as shown in Figure 2-48; Preferably, the crystalline form 2S has a TGA pattern substantially as 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 12.17±0.2°, 8.92±0.2°, 7.63±0.2°, and 8.22±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2T has a diffraction angle (2θ) as shown in Table 2-24, wherein the error range of the 2θ angle is ±0.20°: Table 2-24 Preferably, the crystalline form 2T has the X-ray powder diffraction intensity shown in Table 2-24; Preferably, the Form 2T has an X-ray powder diffraction pattern substantially as shown in Figure 2-24; Preferably, the DSC analysis of the crystalline form 2T shows an endothermic peak when heated to a peak temperature of approximately 110.50°C; Preferably, the crystalline form 2T has a DSC spectrum substantially as shown in Figure 2-49; Preferably, the Form 2T has a TGA pattern substantially as 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 an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 8.86±0.2°, 10.98±0.2°, 9.27±0.2°, and 17.12±0.2°; Preferably, the peaks 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° are further included; More preferably, the peaks 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° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form 2U has a diffraction angle (2θ) as shown in Table 2-25, wherein the error range of the 2θ angle is ±0.20°: Table 2-25 Preferably, the crystalline form 2U has the X-ray powder diffraction intensity shown in Table 2-25; Preferably, the Form 2U has an X-ray powder diffraction pattern substantially as shown in Figure 2-25; Preferably, the DSC analysis of the crystalline form 2U shows an endothermic peak when heated to a peak temperature of approximately 109.16°C; Preferably, the crystalline form 2U has a DSC spectrum substantially as shown in Figure 2-50; Preferably, the Form 2U has a TGA pattern substantially as shown in Figure 2-75; Preferably, the crystalline form 2U is a 0.5-dioxane solvate of compound II.

5. The method for preparing the polymorph according to any one of claims 1 to 4, characterized in that: Includes the following methods: Method 1: Step 1: dissolving or dispersing compound III in a solvent; Step 2: stirring at 0-50°C for crystallization; alternatively, adding an antisolvent to the clear solution of the compound for precipitation; alternatively, slowly evaporating the clear solution of the compound; Method 2: Dispersing compound III in a solvent and in the atmosphere of these media to obtain crystals; Method 3: Method 1 and method 2 are used in combination to prepare the polymorph of compound III.

6. The preparation method according to claim 5, characterized in that The solvent is water, an organic solvent or a mixed solvent thereof, and the organic solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxide organic solvents or mixtures 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 mixtures thereof.

7. A pharmaceutical composition comprising at least one of the polymorphs according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

8. Use of the polymorph according to any one of claims 1 to 4 in the preparation of a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

9. The use according to claim 8, characterized in that The metabolic disease, tumor, autoimmune disease or metastatic disease is selected from T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by other medications, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial ischemia, 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, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, 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.

10. The use according to claim 8, characterized in that The metabolic disease, tumor, autoimmune disease or metastatic disease is selected from T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain caused by the use of other agents, excessive sugar cravings, dyslipidemia, and hyperinsulinemia.

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