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

Abstract

The # imgabs0 # provides a polymorphic substance of a GLP-1R agonist compound I as well as a preparation method and application of the polymorphic substance. Compared with the free state of the compound I, the polymorphic substance 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 compound and its preparation method and use

[0001] This application claims priority to a prior application, patent application number 2022110964440, entitled “A Polymorph of a GLP-1R Agonist Compound, Preparation Method, and Use Thereof,” filed with the State Intellectual Property Office of China on September 6, 2022. The entire text of that prior application is incorporated herein by reference. Technical Field

[0002] 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

[0003] 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.

[0004] 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.

[0005] 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.

[0006] 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.

[0007] Alpha-glucosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption. These agents often cause gastrointestinal discomfort.

[0008] 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.

[0009] 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.

[0010] 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.

[0011] 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.

[0012] 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).

[0013] 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 output. 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).

[0014] 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.

[0015] 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 tromethamine salt (1:1) of formula (I) has potent GLP1R receptor agonist activity and good drugability. Its structure is as follows:

[0016] 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 drug crystal form that can be easily separated and purified, is suitable for industrial production, and has stable physical and chemical properties.

[0017] Summary of the Invention

[0018] In order to solve the problems existing in the prior art, the first aspect of the present invention provides a polymorph of Compound I as shown below:

[0019] According to an embodiment of the present invention, the polymorph is a non-solvate crystalline form, a hydrate crystalline form, a solvate crystalline form or a metastable crystalline form of Compound 1.

[0020] According to an embodiment of the present invention, the solvent-free crystal form may be the following crystal forms A, B, and C; the hydrate crystal form may be the following crystal form D; the solvate crystal form may be the following crystal forms E, F, G, H, and I; and the metastable crystal form may be the following crystal forms J, K, L, M, and N.

[0021] The present invention provides Form A of Compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 7.42±0.2°, 3.68±0.2°, 21.85±0.2° and 18.75±0.2°.

[0022] According to the present invention, the crystalline form A preferably further includes peaks at diffraction angles (2θ) of 9.29±0.2°, 16.71±0.2°, 11.18±0.2°, 15.32±0.2° and 14.94±0.2°.

[0023] According to the present invention, the crystalline form A more preferably further includes peaks at diffraction angles (2θ) of 27.81±0.2°, 17.00±0.2°, 19.81±0.2°, 11.80±0.2°, 25.69±0.2° and 17.43±0.2°.

[0024] 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°:

[0025] Table 1

[0026] Preferably, the crystalline form A has the X-ray powder diffraction intensity shown in Table 1.

[0027] Preferably, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG1 .

[0028] Preferably, the DSC analysis of the crystalline form A shows an endothermic peak when heated to a peak temperature of 174.82°C.

[0029] Preferably, the crystalline form A has a DSC spectrum substantially as shown in FIG2 .

[0030] Preferably, the crystalline form A has a TGA graph substantially as shown in FIG3 .

[0031] The present invention provides Form B of Compound I, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 7.07±0.2°, 19.25±0.2°, 14.45±0.2°, and 15.26±0.2°;

[0032] According to the present invention, the crystalline form B preferably further includes peaks at diffraction angles (2θ) of 11.20±0.2°, 18.17±0.2°, 13.26±0.2°, 23.28±0.2° and 21.35±0.2°;

[0033] According to the present invention, the crystalline form B more preferably further includes peaks at diffraction angles (2θ) of 15.72±0.2°, 26.17±0.2°, 16.54±0.2°, 24.23±0.2°, 14.76±0.2° and 22.65±0.2°;

[0034] According to the present invention, 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°:

[0035] Table 2

[0036] Preferably, the crystalline form B has the X-ray powder diffraction intensity shown in Table 2.

[0037] Preferably, the crystalline form B has an X-ray powder diffraction pattern substantially as shown in FIG4 .

[0038] Preferably, the DSC analysis of the crystalline form B shows an endothermic peak when heated to a peak temperature of approximately 160.15°C.

[0039] Preferably, the crystalline form B has a DSC spectrum substantially as shown in FIG5 .

[0040] Preferably, the crystalline form B has a TGA graph substantially as shown in FIG6 .

[0041] The present invention provides Form C of Compound I, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 10.90±0.2°, 5.80±0.2°, 19.28±0.2°, and 14.49±0.2°;

[0042] According to the present invention, the crystalline form C preferably further includes peaks at diffraction angles (2θ) of 15.37±0.2°, 12.95±0.2°, 19.77±0.2°, 3.11±0.2° and 24.46±0.2°;

[0043] According to the present invention, the crystalline form C more preferably further includes peaks at diffraction angles (2θ) of 16.38±0.2°, 25.22±0.2°, 19.03±0.2°, 20.82±0.2°, 18.00±0.2° and 18.15±0.2°;

[0044] According to the present invention, 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°:

[0045] Table 3

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

[0047] Preferably, the crystalline form C has an X-ray powder diffraction pattern substantially as shown in FIG7 .

[0048] Preferably, the DSC analysis of the crystalline form C shows endothermic peaks near the peak temperatures of 160.99°C and 170.25°C.

[0049] Preferably, the crystalline form C has a DSC spectrum substantially as shown in FIG8 .

[0050] Preferably, the crystalline form C has a TGA graph substantially as shown in FIG9 .

[0051] The present invention provides a hydrated crystalline form D of Compound I, which has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 7.71±0.2°, 10.96±0.2°, 12.34±0.2°, and 19.38±0.2°;

[0052] According to the present invention, the crystalline form D preferably further includes peaks at diffraction angles (2θ) of 23.30±0.2°, 16.42±0.2°, 11.60±0.2°, 14.30±0.2° and 3.81±0.2°;

[0053] According to the present invention, the crystalline form D more preferably further includes peaks at diffraction angles (2θ) of 21.54±0.2°, 22.55±0.2°, 25.40±0.2°, 26.96±0.2°, 15.78±0.2° and 21.29±0.2°;

[0054] According to the present invention, 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°:

[0055] Table 4

[0056] Preferably, the crystalline form D has the X-ray powder diffraction intensity shown in Table 4.

[0057] Preferably, the crystalline form D has an X-ray powder diffraction pattern substantially as shown in FIG10 .

[0058] Preferably, the DSC analysis of the crystalline form D shows endothermic peaks near the peak temperatures of 62.09°C, 79.77°C and 173.12°C.

[0059] Preferably, the crystalline form D has a DSC spectrum substantially as shown in FIG11 .

[0060] Preferably, the crystalline form D has a TGA pattern substantially as shown in FIG12 .

[0061] The present invention provides a chloroform solvate crystalline form E of Compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 18.84±0.2°, 7.26±0.2°, 22.92±0.2°, and 9.35±0.2°;

[0062] According to the present invention, the crystalline form E preferably further includes peaks at diffraction angles (2θ) of 22.05±0.2°, 18.36±0.2°, 6.21±0.2°, 3.60±0.2° and 16.98±0.2°;

[0063] According to the present invention, the crystalline form E more preferably further includes peaks at diffraction angles (2θ) of 12.50±0.2°, 34.99±0.2°, 16.11±0.2°, 20.51±0.2°, 19.57±0.2° and 17.57±0.2°;

[0064] According to the present invention, 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°:

[0065] Table 5

[0066] Preferably, the crystalline form E has the X-ray powder diffraction intensity shown in Table 5.

[0067] Preferably, the crystalline form E has an X-ray powder diffraction pattern substantially as shown in FIG13 .

[0068] Preferably, the DSC analysis of the crystalline form E shows endothermic peaks near peak temperatures of 137.77°C, 159.79°C and 175.44°C.

[0069] Preferably, the crystalline form E has a DSC spectrum substantially as shown in FIG14 .

[0070] Preferably, the crystalline form E has a TGA pattern substantially as shown in FIG15 .

[0071] The present invention provides a crystalline form F of an N-methylpyrrolidone solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.60±0.2°, 19.57±0.2°, 5.89±0.2°, and 14.96±0.2°;

[0072] According to the present invention, the crystalline form F preferably further includes peaks at diffraction angles (2θ) of 25.69±0.2°, 3.27±0.2°, 17.49±0.2°, 19.32±0.2° and 16.89±0.2°;

[0073] According to the present invention, the crystalline form F more preferably further includes peaks at diffraction angles (2θ) of 16.01±0.2°, 18.07±0.2°, 21.13±0.2°, 22.46±0.2°, 15.48±0.2° and 27.29±0.2°;

[0074] According to the present invention, 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°:

[0075] Table 6

[0076] Preferably, the crystalline form F has the X-ray powder diffraction intensity shown in Table 6.

[0077] Preferably, the crystalline form F has an X-ray powder diffraction pattern substantially as shown in FIG16 .

[0078] Preferably, the DSC analysis of the crystalline form F shows endothermic peaks near the peak temperatures of 72.65°C, 95.65°C, 127.81°C and 159.14°C.

[0079] Preferably, the crystalline form F has a DSC spectrum substantially as shown in FIG17 .

[0080] Preferably, the crystalline form F has a TGA graph substantially as shown in FIG18 .

[0081] The present invention provides a crystalline form G of an N-methylpyrrolidone solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2°, and 22.19±0.2°;

[0082] According to the present invention, the crystalline form G preferably further includes peaks at diffraction angles (2θ) of 31.61±0.2°, 18.11±0.2°, 20.55±0.2°, 18.97±0.2° and 15.76±0.2°;

[0083] According to the present invention, the crystalline form G more preferably further includes peaks at diffraction angles (2θ) of 28.52±0.2°, 35.16±0.2°, 20.86±0.2°, 16.36±0.2°, 26.02±0.2° and 17.18±0.2°;

[0084] According to the present invention, 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°:

[0085] Table 7

[0086] Preferably, the crystalline form G has the X-ray powder diffraction intensity shown in Table 7.

[0087] Preferably, the crystalline form G has an X-ray powder diffraction pattern substantially as shown in Figure 19.

[0088] Preferably, the DSC analysis of the crystalline form G shows endothermic peaks near the peak temperatures of 109.95°C and 166.02°C.

[0089] Preferably, the crystalline form G has a DSC graph substantially as shown in FIG20 .

[0090] Preferably, the crystalline form G has a TGA graph substantially as shown in Figure 21.

[0091] The present invention provides a tetrahydrofuran solvate of Compound I, Form H, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 3.29±0.2°, 3.71±0.2°, 19.71±0.2°, and 19.24±0.2°;

[0092] According to the present invention, the crystalline form H preferably further includes peaks at diffraction angles (2θ) of 7.46±0.2°, 13.12±0.2°, 23.08±0.2°, 22.73±0.2° and 6.60±0.2°;

[0093] According to the present invention, the crystalline form H more preferably further includes peaks at diffraction angles (2θ) of 10.73±0.2°, 11.43±0.2°, 22.05±0.2°, 9.82±0.2°, 25.34±0.2° and 16.83±0.2°;

[0094] According to the present invention, 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°:

[0095] Table 8

[0096] Preferably, the crystalline form H has the X-ray powder diffraction intensity shown in Table 8.

[0097] Preferably, the crystalline form H has an X-ray powder diffraction pattern substantially as shown in Figure 22.

[0098] Preferably, the DSC analysis of the crystalline form H shows endothermic peaks near the peak temperatures of 82.80°C and 174.84°C.

[0099] Preferably, the crystalline form H has a DSC spectrum substantially as shown in FIG23 .

[0100] Preferably, the crystalline form H has a TGA graph substantially as shown in FIG. 24 .

[0101] The present invention provides a crystalline form I of an ethanol solvate of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 18.97±0.2°, 10.71±0.2°, 16.19±0.2°, and 22.67±0.2°;

[0102] According to the present invention, the crystalline form I preferably further includes peaks at diffraction angles (2θ) of 12.79±0.2°, 15.13±0.2°, 17.99±0.2°, 22.52±0.2° and 23.94±0.2°;

[0103] According to the present invention, the crystalline form I more preferably further includes peaks at diffraction angles (2θ) of 16.53±0.2°, 24.99±0.2°, 21.85±0.2°, 19.28±0.2°, 26.69±0.2° and 24.38±0.2°;

[0104] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form I has a diffraction angle (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°:

[0105] Table 9

[0106] Preferably, the crystalline form I has the X-ray powder diffraction intensity shown in Table 9.

[0107] Preferably, the crystalline Form I has an X-ray powder diffraction pattern substantially as shown in Figure 25.

[0108] Preferably, the DSC analysis of the crystalline form I shows endothermic peaks near the peak temperatures of 136.10°C and 160.74°C.

[0109] Preferably, the crystalline form I has a DSC spectrum substantially as shown in Figure 26.

[0110] Preferably, the crystalline Form I has a TGA graph substantially as shown in Figure 27.

[0111] The present invention provides a metastable crystalline form J of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 7.22±0.2°, 3.54±0.2°, 15.99±0.2°, and 19.34±0.2°;

[0112] According to the present invention, the crystalline form J preferably further includes peaks at diffraction angles (2θ) of 22.77±0.2°, 18.33±0.2°, 17.80±0.2°, 10.93±0.2° and 22.07±0.2°;

[0113] According to the present invention, the crystalline form J more preferably further includes peaks at diffraction angles (2θ) of 33.38±0.2°, 27.77±0.2°, 29.53±0.2°, 9.95±0.2°, 20.16±0.2° and 25.56±0.2°;

[0114] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form J has a diffraction angle (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°:

[0115] Table 10

[0116] Preferably, the crystalline form J has the X-ray powder diffraction intensity shown in Table 10.

[0117] Preferably, the crystalline Form J has an X-ray powder diffraction pattern substantially as shown in Figure 28.

[0118] The present invention provides a metastable crystalline form K of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 6.13±0.2°, 7.19±0.2°, 3.56±0.2° and 22.63±0.2°;

[0119] According to the present invention, the crystalline form K preferably further includes peaks at diffraction angles (2θ) of 18.56±0.2°, 12.34±0.2°, 16.83±0.2°, 9.31±0.2° and 26.20±0.2°;

[0120] According to the present invention, the crystalline form K more preferably further includes peaks at diffraction angles (2θ) of 19.63±0.2°, 20.26±0.2°, 23.72±0.2°, 17.40±0.2°, 34.48±0.2° and 24.21±0.2°;

[0121] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form K has a diffraction angle (2θ) as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°:

[0122] Table 11

[0123] Preferably, the crystalline form K has the X-ray powder diffraction intensity shown in Table 11.

[0124] Preferably, the crystalline form K has an X-ray powder diffraction pattern substantially as shown in Figure 29.

[0125] The present invention provides a metastable crystalline form L of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 8.04±0.2°, 14.49±0.2°, 19.75±0.2° and 15.95±0.2°;

[0126] According to the present invention, the crystalline form L preferably further includes peaks at diffraction angles (2θ) of 18.70±0.2°, 20.85±0.2°, 4.00±0.2°, 23.27±0.2° and 12.40±0.2°;

[0127] According to the present invention, the crystalline form L more preferably further includes peaks at diffraction angles (2θ) of 16.22±0.2°, 15.58±0.2°, 14.27±0.2°, 12.13±0.2°, 15.43±0.2° and 17.69±0.2°;

[0128] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form L has a diffraction angle (2θ) as shown in Table 12, wherein the error range of the 2θ angle is ±0.20°:

[0129] Table 12

[0130] Preferably, the crystalline form L has the X-ray powder diffraction intensity shown in Table 12.

[0131] Preferably, the crystalline form L has an X-ray powder diffraction pattern substantially as shown in Figure 30.

[0132] The present invention provides a metastable crystalline form M of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 19.96±0.2°, 12.72±0.2°, 7.92±0.2° and 11.12±0.2°;

[0133] According to the present invention, the crystalline form M preferably further includes peaks at diffraction angles (2θ) of 16.54±0.2°, 3.95±0.2°, 21.66±0.2°, 24.01±0.2° and 22.69±0.2°;

[0134] According to the present invention, the crystalline form M more preferably further includes peaks at diffraction angles (2θ) of 14.45±0.2°, 11.92±0.2°, 15.93±0.2°, 20.98±0.2°, 23.59±0.2° and 6.61±0.2°;

[0135] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form M has a diffraction angle (2θ) as shown in Table 13, wherein the error range of the 2θ angle is ±0.20°:

[0136] Table 13

[0137] Preferably, the crystalline form M has the X-ray powder diffraction intensity shown in Table 13.

[0138] Preferably, the crystalline form M has an X-ray powder diffraction pattern substantially as shown in Figure 31.

[0139] The present invention provides a metastable crystalline form N of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 10.92±0.2°, 15.37±0.2°, 19.34±0.2° and 20.46±0.2°;

[0140] According to the present invention, the crystalline form N preferably further includes peaks at diffraction angles (2θ) of 12.95±0.2°, 6.93±0.2°, 18.04±0.2°, 16.43±0.2° and 25.26±0.2°;

[0141] According to the present invention, the crystalline form N more preferably further includes peaks at diffraction angles (2θ) of 5.43±0.2°, 10.75±0.2°, 14.20±0.2°, 23.12±0.2°, 17.87±0.2° and 14.94±0.2°;

[0142] According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form N has a diffraction angle (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°:

[0143] Table 14

[0144] Preferably, the crystalline form N has the X-ray powder diffraction intensity shown in Table 14.

[0145] Preferably, the crystalline form N has an X-ray powder diffraction pattern substantially as shown in Figure 32.

[0146] A second aspect of the present invention provides a method for preparing the polymorph of the aforementioned Compound I, selected from the following preparation methods:

[0147] Step 1: dissolving or dispersing compound I in a solvent;

[0148] Step 2: stirring and crystallizing at 0-50°C; or, adding an antisolvent to the clear solution of the compound to precipitate; or, slowly volatilizing the clear solution of the compound;

[0149] As a further preferred embodiment, the solvent is water, an organic solvent or a mixed solvent thereof, wherein 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, methyl ether, cyclopentyl methyl ether, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene or a mixture thereof.

[0150] The third aspect of the present invention provides a pharmaceutical composition comprising at least one of the aforementioned polymorphs of Compound I and a pharmaceutically acceptable carrier.

[0151] A fourth aspect of the present invention provides a use of a polymorph of the aforementioned Compound I in the preparation of a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0152] In a fifth aspect, the present invention provides a polymorph of the aforementioned Compound I, which is used as a drug for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0153] In a sixth aspect, the present invention provides a polymorph of the aforementioned compound I for use in 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, 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, and 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.

[0154] As a preferred embodiment, the polymorph of the aforementioned compound I 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.

[0155] The present invention also provides a method for treating a disease, comprising administering a therapeutically effective amount of at least one of the aforementioned polymorphs of Compound I or the pharmaceutical composition to an individual in need thereof.

[0156] According to an embodiment of the present invention, the disease is selected from metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0157] 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 other medications, excessive sugar addiction, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral blood 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, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome. Beneficial effects

[0158] The present invention provides polymorphs of Compound 1 and methods for preparing the same, which 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

[0159] 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.

[0160] Figure 2 shows a DSC chart of the crystalline form A of the compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0161] Figure 3 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 (%).

[0162] Figure 4 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.

[0163] Figure 5 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).

[0164] Figure 6 shows a TGA chart of the crystalline form B of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0165] Figure 7 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.

[0166] Figure 8 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).

[0167] Figure 9 shows a TGA chart of the crystalline form C of compound I- of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0168] Figure 10 shows the X-ray powder diffraction pattern of the hydrated crystal form D of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0169] Figure 11 shows a DSC chart of the hydrated crystal form D of the compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0170] Figure 12 shows a TGA chart of the hydrated crystal form D of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0171] Figure 13 shows an X-ray powder diffraction pattern of Form E of the chloroform solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0172] Figure 14 shows a DSC chart of Form E of the chloroform solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0173] Figure 15 shows a TGA chart of the crystalline form E of the chloroform solvate of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0174] Figure 16 shows an X-ray powder diffraction pattern of Form F of the N-methylpyrrolidone formulation of Compound I of the present invention. The abscissa represents 2θ values ​​(degrees), and the ordinate represents peak intensity.

[0175] Figure 17 shows a DSC chart of Form F of the N-methylpyrrolidone solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0176] Figure 18 shows a TGA chart of Form F of N-methylpyrrolidone solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0177] Figure 19 shows an X-ray powder diffraction pattern of Form G of the N-methylpyrrolidone formulation of Compound I of the present invention. The abscissa represents 2θ values ​​(degrees), and the ordinate represents peak intensity.

[0178] Figure 20 shows a DSC chart of Form G of the N-methylpyrrolidone solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0179] Figure 21 shows a TGA chart of Form G of N-methylpyrrolidone solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0180] Figure 22 shows an X-ray powder diffraction pattern of Form H of the tetrahydrofuran solvate of Compound I of the present invention. The abscissa represents 2θ value (degrees), and the ordinate represents peak intensity.

[0181] Figure 23 shows a DSC chart of Form H of the tetrahydrofuran solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0182] Figure 24 shows a TGA chart of Form H of the tetrahydrofuran solvate of Compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0183] Figure 25 shows an X-ray powder diffraction pattern of the crystalline form I of the ethanol solvate of compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0184] Figure 26 shows a DSC chart of the crystalline form I of the ethanol solvate of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0185] Figure 27 shows a TGA chart of the crystalline form I of the ethanol solvate of compound I of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0186] Figure 28 shows the X-ray powder diffraction pattern of the metastable crystal form J of compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0187] Figure 29 shows the X-ray powder diffraction pattern of the metastable crystalline form K of compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0188] Figure 30 shows an X-ray powder diffraction pattern of the metastable crystalline form L of compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0189] Figure 31 shows the X-ray powder diffraction pattern of the metastable crystalline form M of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0190] Figure 32 shows the X-ray powder diffraction pattern of the metastable crystalline form N of the compound I of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0191] Figure 33 shows a DVS diagram of Form A of Compound I of the present invention. The abscissa represents relative humidity (%), and the ordinate represents weight change (%).

[0192] Definitions and Explanations of Terms

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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).

[0197] As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20 to 25°C (68-77°F).

[0198] 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.

[0199] 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.

[0200] 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.

[0201] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0202] All solvents used in the present invention were commercially available and used without further purification.

[0203] 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).

[0204] Methods and Materials

[0205] 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.

[0206] 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).

[0207] The polymorphs of Compound I 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. Diffraction patterns were analyzed using DIFFRAC.MEA.CENTER software.

[0208] 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.

[0209] The experimental method for characterizing the crystalline form of the acid or basic salt of Compound I using differential scanning calorimetry (DSC) is to take a small amount of the crystalline polymorph of Compound I and place it in an aluminum crucible that is compatible with the instrument and can be pressed into a lid. After loading the sample, the crucible is pressed into 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 patent 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.

[0210] The experimental method for characterizing the polymorphs of Compound I using thermogravimetric analysis (TGA) involves taking a small amount of powdered Compound I polymorphs, placing it in an alumina crucible compatible with the instrument, loading the sample, and then testing it. The differential scanning calorimetry used in this patent is a METTLER TOLEDO TGA 2 instrument, with scanning parameters set to a nitrogen atmosphere and a heating rate of 10.0 K / min.

[0211] The dynamic moisture sorption method (DVS) for characterizing the acid or basic salts of Compound I involves taking a small amount of Compound I polymorph powder and placing it in a precision sample tray supplied with the instrument. After loading, the sample is then fed into the instrument for testing. The dynamic moisture sorption method used in this patent utilizes an Intrinsic PLUS instrument. Experimental parameters include a constant temperature of 25°C, a mass percentage change rate 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

[0212] 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.

[0213] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0214] Example 1 Preparation 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 (free form of compound I)

[0215] 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

[0216] 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%).

[0217] 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

[0218] To a mixed 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%). 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).

[0219] Example 2 Preparation of Form A of Compound I

[0220] 200 mg of the free form of Compound I and 41.88 mg of tromethamine were added to 10 mL of isopropanol, stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 40°C to obtain Form A of the compound. The product was characterized by XRPD (Figure 1), DSC (Figure 2), and TGA (Figure 3). 1H NMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.67-7.57 (m, 2H), 7.20-7.03(m,4H),6.66(d,J=8.0Hz,1H),5.28-5.26(m,1H),5.13(s,2H),5.05-5.03( m,1H),4.90-4.86(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.02-3.89(m,2H),3. 64(s,6H),2.81-2.77(m,3H),2.52-2.42(m,3H),2.01-1.99(m,2H),1.78-1.76(m,2H).

[0221] Example 3 Preparation of Form B of Compound I

[0222] 200 mg of Form A of Compound I was suspended in 11 mL of methanol / methyl tert-butyl ether (7:4 v:v), stirred at 5°C for 16 h, filtered, and the filter cake was oven-dried at 50°C to obtain Form B of the compound. The product was characterized by XRPD ( Figure 4 ), DSC ( Figure 5 ), and TGA ( Figure 6 ). 1 H NMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.67-7.57 (m, 2H), 7.21-7.03(m,4H),6.67(d,J=8.0Hz,1H),5.28-5.27(m,1H),5.13(s,2H),5.05-5.03( m,1H),4.90-4.88(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.02-3.89(m,2H),3. 64(s,6H),2.83-2.77(m,3H),2.51-2.39(m,3H),2.01-1.99(m,2H),1.77-1.76(m,2H).

[0223] Example 4 Preparation of Form C of Compound I

[0224] 20 mg of Form A of Compound I was dissolved in 1 mL of methanol and filtered. 2 mg of copolyvidone was added to the filtrate and slowly evaporated at room temperature. The resulting solid was dried at 50°C to obtain Form C of the compound. The product was characterized by XRPD (Figure 7), DSC (Figure 8), and TGA (Figure 9).

[0225] Example 5 Preparation of Hydrate Form D of Compound I

[0226] 200 mg of Form A of Compound I was added to 9 mL of acetonitrile / water (6:1 v:v), stirred at 5°C for 24 h, 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 10 ), DSC ( Figure 11 ), and TGA ( Figure 12 ). 1 H NMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 8.5Hz, 1.2Hz, 1H), 7.66-7.57 (m, 2H), 7.20-7.03(m,4H),6.66(d,J=8.1Hz,1H),5.27-5.26(m,1H),5.13(s,2H),5.05-5.03( m,1H),4.90-4.85(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.02-3.89(m,2H),3. 64(s,6H),2.81-2.77(m,3H),2.52-2.39(m,3H),2.00-1.98(m,2H),1.78-1.76(m,2H).

[0227] Example 6 Preparation of Form E of the Chloroform Solvate of Compound I

[0228] 20 mg of Form A of Compound I was suspended in 1.4 mL of chloroform / trifluoroethanol (6:1 v:v), stirred at 5°C for 16 h, 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 13 ), DSC ( Figure 14 ), and TGA ( Figure 15 ). 1 H NMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.90 (s, 0.8H), 7.67-7 .57(m,2H),7.21-7.03(m,4H),6.66(d,J=8.0Hz,1H),5.28-5.26(m,1H),5.13(s,2H),5.05 -5.03(m,1H),4.90-4.86(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.02-3.89(m,2H) ,3.64(s,6H),2.81-2.77(m,3H),2.54-2.42(m,3H),2.00-1.98(m,2H),1.78-1.76(m,2H).

[0229] Example 7 Preparation of Form F of N-methylpyrrolidone Solvate of Compound I

[0230] 20 mg of Form A of Compound I was suspended in 0.5 mL of N-methylpyrrolidone / cyclopentyl methyl ether (1:5 v:v), stirred at 5°C for 3 days, 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 16 ), DSC ( Figure 17 ), and TGA ( Figure 18 ). 1 H NMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.67-7.57 (m, 2H), 7.21- 7.03(m,4H),6.67(d,J=8.0Hz,1H),5.28-5.25(1H),5.13(s,2H),5.05-5.03(m,1H),4.90-4 .88(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.02-3.89(m,2H),3.64(s,6H),3.46-3.4 2(m,3.7H),2.82-2.80(m,8.5H),2.51-2.33(m,7H),2.07-1.99(m,5.7H),1.78-1.76(m,2H).

[0231] Example 8 Preparation of N-methylpyrrolidone Solvate Form G of Compound I

[0232] 200 mg of Form A of Compound I was dissolved in 2.0 mL of N-methylpyrrolidone, and the solution was added dropwise to 15 mL of toluene. The mixture was stirred at room temperature for 16 hours, filtered, and the filter cake was oven-dried at 50°C to obtain Form G of the compound. The product was characterized by XRPD (Figure 19), DSC (Figure 20), and TGA (Figure 21). 1 H NMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.66-7.57(m,2H),7.21-7.03(m,4H),6.66(d,J=8.0Hz,1H),5.28-5.25 (1H),5.12(s,2H),5.05-5.03(m,1H),4.73-4.62(m,2H),4.47-4.45(m, 1H),4.02-3.88(m,2H),3.65(s,6H),3.44(d,J=7.2Hz,3.5H),2.82-2.7 7(m,8H),2.51-2.33(m,6.5H),2.07-1.99(m,5.5H),1.77-1.76(m,2H).

[0233] Example 9 Preparation of Tetrahydrofuran Solvate Form H of Compound I

[0234] 20 mg of Form A of Compound I was suspended in 0.5 mL of tetrahydrofuran / water (9:1 v:v), stirred at 50°C for 2 h, then cooled to 5°C and stirred for 2 h. The mixture was filtered and the filter cake was oven-dried at 50°C to obtain Form H of the compound. The product was characterized by XRPD ( Figure 22 ), DSC ( Figure 23 ), and TGA ( Figure 24 ). 1 H NMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.67-7.57 (m, 2H), 7.21 -7.03(m,4H),6.67(d,J=8.0Hz,1H),5.28-5.25(1H),5.13(s,2H),5.05-5.03(m,1H),4.73- 4.62(m,2H),4.46-4.44(m,1H),4.02-3.89(m,2H),3.74-3.71(m,1.5H),3.64(s,6H),2.81- 2.77(m,3H),2.53-2.42(m,3H),2.07-1.99(m,2H),1.88-1.85(m,1.5H),1.77-1.75(m,2H).

[0235] Example 10 Preparation of Ethanol Solvate Form I of Compound I

[0236] 100 mg of Form A of Compound I was suspended in 5 mL of ethanol / water (98:2 v:v), stirred at 5°C for 16 h, filtered, and the filter cake was oven-dried at 50°C to obtain Form I of the compound. The product was characterized by XRPD ( Figure 25 ), DSC ( Figure 26 ), and TGA ( Figure 27 ). 1 H NMR (400MHz, CD3OD): δ8.20(s,1H),7.94(dd,J=8.4Hz,1.2Hz,1H),7.67-7.57(m,2H),7.21-7.03( m,4H),6.66(d,J=8.0Hz,1H),5.27-5.25(m,1H),5.13(s,2H),5.05-5.03(m,1H),4.90-4.88(m,1H) ,4.73-4.62(m,2H),4.47-4.45(m,1H),4.02-3.89(m,2H),3.63(s,6H),3.60(q,J=8.0Hz,1.8H),2. 81-2.77(m,3H),2.52-2.42(m,3H),2.01-1.99(m,2H),1.78-1.76(m,2H),1.17(t,J=8.0Hz,2.6H).

[0237] Example 11 Preparation of Metastable Form J of Compound I

[0238] 200 mg of free form Compound I and 42 mg of tromethamine were added to 10 mL of IPA to form a suspension. After stirring at room temperature for approximately 3 days, the suspension was filtered. The resulting filter cake was metastable Form J of Compound I. The product was characterized by XRPD analysis (Figure 28). After drying at 40°C for 16 hours, Form J transformed into Form A.

[0239] Example 12 Preparation of Metastable Form K of Compound I

[0240] 100 mg of Compound I Form A was dissolved in 1.0 mL of DMF, and the solution was added dropwise to 15 mL of acetone. The mixture was stirred at room temperature for 16 hours and filtered. The resulting filter cake was metastable Form K of Compound I, which was characterized by XRPD analysis (Figure 29). After drying at 50°C for 24 hours, Form K transformed into Form A.

[0241] Example 13 Preparation of Metastable Form L of Compound I

[0242] 100 mg of Compound I Form A was suspended in 2.5 mL of H2O / EtOH (1:9 v:v) and stirred at room temperature for approximately 3 days. The suspension was then filtered and the filter cake dried at 50°C for 16 hours to obtain metastable Form L of Compound I. The product was characterized by XRPD analysis (Figure 30). After being left unopened at room temperature for approximately 16 hours, Form L transformed into Form D.

[0243] Example 14 Preparation of Metastable Form M of Compound I

[0244] 200 mg of Compound I Form A was suspended in 9 mL of ACN / H₂O (6:1 v:v), stirred at 5°C for approximately 1 day, and filtered. The resulting filter cake was metastable Form M of Compound I, which was characterized by XRPD analysis (Figure 31). Form L was then dried under vacuum at room temperature for approximately 16 hours, transforming to Form D.

[0245] Example 15 Preparation of Metastable Form N of Compound I

[0246] Form C of Compound I was heated to 80°C at 10°C / min to obtain metastable Form N of Compound I, which was characterized by XRPD analysis ( FIG32 ). After drying at 50°C for 16 h, Form N transformed into Form B.

[0247] Test Example 1 Study on the equilibrium solubility of polymorphs of Compound I in biological media

[0248] The equilibrium solubility of the free form of Compound I and Form A 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 and the supernatant was filtered to determine the concentration. The test results are shown in the following table:

[0249] The above experimental results demonstrate that Form A of Compound I exhibits significantly better solubility in several solvents than the free form of Compound I, meeting the requirements for clinical drug formulation development. Therefore, salt formation of the free form of Compound I can significantly improve its solubility and drug release behavior.

[0250] Test Example 2: Solid-state stability study of polymorphs of Compound I

[0251] The free form of Compound I and Form A of Compound I 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, and the HPLC purity and crystal form changes were tested to investigate the solid stability. The results are shown in the following table:

[0252] The purity results from the above experiments show that the purity of the free form of Compound I remained unchanged for 7 days under long-term conditions, but showed significant degradation after 7 days under accelerated and high-temperature conditions. The purity of Forms A, B, and I of Compound I remained unchanged for 7 days under long-term, accelerated, and high-temperature conditions, demonstrating significantly better stability than the free form. The crystal form results show that Form A remained unchanged for 7 days under long-term and high-temperature conditions, but partially transformed into Form D after 7 days under accelerated conditions. Form B remained unchanged for 7 days under long-term, accelerated, and high-temperature conditions. Form I changed its form after 7 days under long-term, accelerated, and high-temperature conditions, with some transforming into Form B.

[0253] Test Example 3 Competition Experimental Study of Polymorphs of Compound I

[0254] Suspension competition tests were conducted on Form A and Form B of Compound I in acetonitrile (room temperature and 50°C) and ethyl acetate (room temperature and 50°C), respectively, to test the changes in crystal form. The results are shown in the following table:

[0255] From the above experimental results, it can be seen that Form B of Compound I is converted into Form A in both acetonitrile (room temperature and 50°C) and ethyl acetate (50°C) systems. After stirring in the ethyl acetate system at room temperature for 7 days, it is still a mixed crystal of Form A and Form B, but it can be observed that Form B has a trend of transforming into Form A, indicating that in the range of room temperature to 50°C, Form A has higher thermodynamic stability than Form B.

[0256] Test Example 4 Hygroscopic behavior test of Compound I

[0257] The inventors of this patent evaluated the stability risk of samples at 25°C as humidity changes according to the dynamic moisture sorption method. They performed a DVS test on Form A, representing Compound I, to evaluate the hygroscopicity of the compound's crystal form. The DVS spectrum of Form A of the compound is shown in FIG33 . The results are shown in the following table:

[0258] From the above experimental results, it can be seen that on the adsorption curve of 0-90% RH, at 80% RH, Form A of Compound I is slightly hygroscopic, and no change in the solid morphology is observed.

[0259] Test Example 5: Drug Absorption Experiment in SD Rats

[0260] Intravenous administration in rats: Healthy SD rats were administered the free form or Form A of Compound I at a dose of D mg / kg via the tail vein. Blood samples were collected before and at different time points after administration, and plasma was separated and prepared. The drug concentration in plasma was determined by liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated according to the non-compartmental model.

[0261] Its main pharmacokinetic parameters are shown in the following table:

[0262] Oral administration in rats: Healthy SD rats were orally administered with the free form or Form A of Compound I. Blood samples were collected at different time points after administration, and plasma was separated and prepared. The drug concentration in plasma was determined by liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated according to the non-compartmental model.

[0263] Its main pharmacokinetic parameters are shown in the following table:

[0264] After dose correction, AUC 0-t Calculations show that the absolute bioavailability of the free form of Compound I after oral administration is 21.8%. The absolute bioavailability of Form A after oral administration is 43.7%, which is significantly better than that of the free form and has pharmacokinetic advantages.

[0265] The thermal analysis of some crystalline forms of Compound I of the present invention is summarized in the following table:

[0266] The above is an exemplary description of the implementation 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-mentioned implementation. 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 I:

2. The polymorph according to claim 1, characterized in that The polymorphs are solvent-free crystalline forms of the compound of formula (I), including the following solvent-free crystalline forms A, B, and C, wherein: The crystalline form A has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 7.42±0.2°, 3.68±0.2°, 21.85±0.2° and 18.75±0.2°. Preferably, peaks at diffraction angles (2θ) of 9.29±0.2°, 16.71±0.2°, 11.18±0.2°, 15.32±0.2°, and 14.94±0.2° are also included. More preferably, peaks at diffraction angles (2θ) of 27.81±0.2°, 17.00±0.2°, 19.81±0.2°, 11.80±0.2°, 25.69±0.2°, and 17.43±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 174.82°C; Preferably, the crystalline form A has a DSC spectrum substantially as shown in FIG2 ; Preferably, the crystalline form A has a TGA pattern substantially as shown in FIG3 ; The crystalline form B has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.07±0.2°, 19.25±0.2°, 14.45±0.2°, and 15.26±0.2°; Preferably, the peaks at diffraction angles (2θ) of 11.20±0.2°, 18.17±0.2°, 13.26±0.2°, 23.28±0.2° and 21.35±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 15.72±0.2°, 26.17±0.2°, 16.54±0.2°, 24.23±0.2°, 14.76±0.2° and 22.65±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 FIG4 ; Preferably, the DSC analysis of the crystalline form B shows an endothermic peak when heated to a peak temperature of approximately 160.15°C; Preferably, the crystalline form B has a DSC spectrum substantially as shown in FIG5 ; Preferably, the crystalline Form B has a TGA graph substantially as shown in FIG6 ; The crystalline form C has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.90±0.2°, 5.80±0.2°, 19.28±0.2°, and 14.49±0.2°; Preferably, the peaks at diffraction angles (2θ) of 15.37±0.2°, 12.95±0.2°, 19.77±0.2°, 3.11±0.2° and 24.46±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 16.38±0.2°, 25.22±0.2°, 19.03±0.2°, 20.82±0.2°, 18.00±0.2° and 18.15±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 FIG7 ; Preferably, the DSC analysis of the crystalline form C shows endothermic peaks when heated to peak temperatures near 160.99°C and 170.25°C; Preferably, the crystalline form C has a DSC spectrum substantially as shown in FIG8 ; Preferably, the crystalline form C has a TGA graph substantially as shown in FIG9 .

3. The polymorph according to claim 1, wherein The polymorph is the hydrate crystal form D of the compound of formula (I); The hydrate crystalline form D has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 7.71±0.2°, 10.96±0.2°, 12.34±0.2° and 19.38±0.2°; Preferably, the peaks at diffraction angles (2θ) of 23.30±0.2°, 16.42±0.2°, 11.60±0.2°, 14.30±0.2° and 3.81±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 21.54±0.2°, 22.55±0.2°, 25.40±0.2°, 26.96±0.2°, 15.78±0.2° and 21.29±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 Figure 10; Preferably, the DSC analysis of the crystalline form D shows endothermic peaks near the peak temperatures of 62.09° C., 79.77° C. and 173.12° C.; Preferably, the crystalline form D has a DSC spectrum substantially as shown in FIG11 ; Preferably, the crystalline form D has a TGA pattern substantially as shown in FIG12 .

4. The polymorph according to claim 1, characterized in that The polymorphs are solvate crystal forms of the compound of formula (I), including the following solvate crystal forms E, F, G, H, and I, wherein: The crystalline form E of the chloroform solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 18.84±0.2°, 7.26±0.2°, 22.92±0.2° and 9.35±0.2°; Preferably, the peaks at diffraction angles (2θ) of 22.05±0.2°, 18.36±0.2°, 6.21±0.2°, 3.60±0.2° and 16.98±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 12.50±0.2°, 34.99±0.2°, 16.11±0.2°, 20.51±0.2°, 19.57±0.2°, and 17.57±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 Figure 13; Preferably, the DSC analysis of the crystalline form E shows endothermic peaks near the peak temperatures of 137.77°C, 159.79°C and 175.44°C; Preferably, the crystalline form E has a DSC spectrum substantially as shown in FIG14 ; Preferably, the crystalline form E has a TGA pattern substantially as shown in Figure 15; The crystalline form F of the N-methylpyrrolidone solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 6.60±0.2°, 19.57±0.2°, 5.89±0.2°, and 14.96±0.2°; Preferably, the diffraction angles (2θ) further include those at 25.69±0.2°, 3.27±0.2°, 17.49±0.2°, 19.32±0.2° and 16.89±0.2°. The peak at More preferably, the peaks at diffraction angles (2θ) of 16.01±0.2°, 18.07±0.2°, 21.13±0.2°, 22.46±0.2°, 15.48±0.2° and 27.29±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 Figure 16; Preferably, the DSC analysis of the crystalline form F shows endothermic peaks near peak temperatures of 72.65°C, 95.65°C, 127.81°C and 159.14°C; Preferably, the crystalline form F has a DSC spectrum substantially as shown in FIG17 ; Preferably, the crystalline form F has a TGA pattern substantially as shown in Figure 18; The crystalline form G of the N-methylpyrrolidone solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2° and 22.19±0.2°; Preferably, the peaks at diffraction angles (2θ) of 31.61±0.2°, 18.11±0.2°, 20.55±0.2°, 18.97±0.2° and 15.76±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 28.52±0.2°, 35.16±0.2°, 20.86±0.2°, 16.36±0.2°, 26.02±0.2° and 17.18±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 Figure 19; Preferably, the DSC analysis of the crystalline form G shows endothermic peaks near the peak temperatures of 109.95°C and 166.02°C; Preferably, the crystalline form G has a DSC graph substantially as shown in Figure 20; Preferably, the crystalline form G has a TGA pattern substantially as shown in Figure 21; The crystalline form H of the tetrahydrofuran solvate has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 3.29±0.2°, 3.71±0.2°, 19.71±0.2°, and 19.24±0.2°; Preferably, the peaks at diffraction angles (2θ) of 7.46±0.2°, 13.12±0.2°, 23.08±0.2°, 22.73±0.2° and 6.60±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 10.73±0.2°, 11.43±0.2°, 22.05±0.2°, 9.82±0.2°, 25.34±0.2° and 16.83±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 Figure 22; Preferably, the DSC analysis of the crystalline form H shows endothermic peaks near the peak temperatures of 82.80°C and 174.84°C; Preferably, the crystalline form H has a DSC spectrum substantially as shown in FIG23 ; Preferably, the crystalline form H has a TGA pattern substantially as shown in FIG24 ; The crystalline form I of the ethanol solvate has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 18.97±0.2°, 10.71±0.2°, 16.19±0.2°, and 22.67±0.2°; Preferably, the peaks at diffraction angles (2θ) of 12.79±0.2°, 15.13±0.2°, 17.99±0.2°, 22.52±0.2° and 23.94±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 16.53±0.2°, 24.99±0.2°, 21.85±0.2°, 19.28±0.2°, 26.69±0.2° and 24.38±0.2° are further included; Preferably, the X-ray powder diffraction pattern of the crystalline form I 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 has the X-ray powder diffraction intensity shown in Table 9; Preferably, the Form I has an X-ray powder diffraction pattern substantially as shown in Figure 25; Preferably, the DSC analysis of the crystalline form I shows endothermic peaks near the peak temperatures of 136.10°C and 160.74°C; Preferably, the crystalline Form I has a DSC spectrum substantially as shown in Figure 26; Preferably, the crystalline Form I has a TGA graph substantially as shown in Figure 27.

5. The polymorph according to claim 1, characterized in that The polymorphs are metastable crystalline forms of the compound of formula (I), including the following crystalline forms J, K, L, M, and N, wherein: The metastable form J has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.22±0.2°, 3.54±0.2°, 15.99±0.2°, and 19.34±0.2°; Preferably, the peaks at diffraction angles (2θ) of 22.77±0.2°, 18.33±0.2°, 17.80±0.2°, 10.93±0.2° and 22.07±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 33.38±0.2°, 27.77±0.2°, 29.53±0.2°, 9.95±0.2°, 20.16±0.2° and 25.56±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 10, wherein the error range of the 2θ angle is ±0.20°: Table 10 Preferably, the crystalline form J has the X-ray powder diffraction intensity shown in Table 10; Preferably, the crystalline Form J has an X-ray powder diffraction pattern substantially as shown in Figure 28; The metastable form K has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.13±0.2°, 7.19±0.2°, 3.56±0.2°, and 22.63±0.2°; Preferably, the peaks at diffraction angles (2θ) of 18.56±0.2°, 12.34±0.2°, 16.83±0.2°, 9.31±0.2° and 26.20±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 19.63±0.2°, 20.26±0.2°, 23.72±0.2°, 17.40±0.2°, 34.48±0.2° and 24.21±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 11, wherein the error range of the 2θ angle is ±0.20°: Table 11 Preferably, the crystalline form K has the X-ray powder diffraction intensity shown in Table 11. Preferably, the crystalline form K has an X-ray powder diffraction pattern substantially as shown in Figure 29. The metastable form L has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.04±0.2°, 14.49±0.2°, 19.75±0.2°, and 15.95±0.2°; Preferably, the peaks at diffraction angles (2θ) of 18.70±0.2°, 20.85±0.2°, 4.00±0.2°, 23.27±0.2° and 12.40±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 16.22±0.2°, 15.58±0.2°, 14.27±0.2°, 12.13±0.2°, 15.43±0.2° and 17.69±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 12, wherein the error range of the 2θ angle is ±0.20°: Table 12 Preferably, the crystalline form L has the X-ray powder diffraction intensity shown in Table 12. Preferably, the crystalline form L has an X-ray powder diffraction pattern substantially as shown in Figure 30. The metastable crystalline form M has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 19.96±0.2°, 12.72±0.2°, 7.92±0.2°, and 11.12±0.2°; Preferably, the peaks at diffraction angles (2θ) of 16.54±0.2°, 3.95±0.2°, 21.66±0.2°, 24.01±0.2° and 22.69±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 14.45±0.2°, 11.92±0.2°, 15.93±0.2°, 20.98±0.2°, 23.59±0.2° and 6.61±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 13, wherein the error range of the 2θ angle is ±0.20°: Table 13 Preferably, the crystalline form M has the X-ray powder diffraction intensity shown in Table 13. Preferably, the crystalline form M has an X-ray powder diffraction pattern substantially as shown in Figure 31. The metastable form N has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.92±0.2°, 15.37±0.2°, 19.34±0.2°, and 20.46±0.2°; Preferably, the peaks at diffraction angles (2θ) of 12.95±0.2°, 6.93±0.2°, 18.04±0.2°, 16.43±0.2° and 25.26±0.2° are further included; More preferably, the peaks at diffraction angles (2θ) of 5.43±0.2°, 10.75±0.2°, 14.20±0.2°, 23.12±0.2°, 17.87±0.2° and 14.94±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 14, wherein the error range of the 2θ angle is ±0.20°: Table 14 Preferably, the crystalline form N has the X-ray powder diffraction intensity shown in Table 14. Preferably, the crystalline form N has an X-ray powder diffraction pattern substantially as shown in Figure 32.

6. The method for preparing the polymorph according to any one of claims 1 to 5, characterized in that: This includes the following methods: Step 1: dissolving or dispersing compound I in a solvent; Step 2: stirring and crystallizing at 0-50°C; or, adding an antisolvent to the clear solution of the compound to precipitate; or, slowly volatilizing the clear solution of the compound; 7. The preparation method according to claim 6, 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, chloroform, 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.

8. A pharmaceutical composition comprising at least one of the polymorphs according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

9. Use of the polymorph according to any one of claims 1 to 5 in the preparation of a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

10. The use according to claim 9, 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.

11. The use according to claim 9, 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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