Crystalline polymorphs of GLP-1R agonist compounds and their preparation and use

Abstract

The present invention provides a crystalline polymorph of GLP-1R agonist Compound I, and a method for preparing and using the same. Compared with the free form of Compound I, the crystalline polymorph of the present invention has higher stability and better processability, and is more suitable for producing medicaments for preventing or treating diseases related to GLP-1R targets and their signaling pathways, such as type 2 diabetes, prediabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, kidney disease, gout, hyperhematuria, and cardiovascular disease. [Formula 1] JPEG2025530809000041.jpg46169

Description

Detailed Description of the Invention

[0001] This application claims priority from a prior patent application bearing patent application number 2022110964440 and entitled "Crystalline polymorphs of GLP-1R agonist compounds and their preparation and use," filed with the State Intellectual Property Administration of China on September 6, 2022, the entire text of which is incorporated herein by reference.

[0002] [Technical Field] The present invention relates to the field of medicinal chemistry, and particularly to crystalline polymorphs of GLP-1R agonist compounds and their preparation and use.

[0003] [Background technology] Diabetes mellitus (Diabetes mellitus) is a chronic disease characterized by hyperglycemia due to a relative or absolute deficiency of insulin secretion or impaired insulin action in the human body. According to the 9th edition of the Global Diabetes Atlas, newly published by the International Diabetes Federation (IDF), approximately 463 million adults (aged 20-79) worldwide suffered from diabetes in 2019, and the number of diabetic patients is expected to reach 578 million by 2030. If this trend continues, the number of diabetic patients worldwide is expected to reach 700 million by 2045. Therefore, diabetes has become one of the most serious social health problems facing the world in the 21st century.

[0004] Currently, a variety of pharmacological approaches exist for treating hyperglycemia and associated T2DM (Hampp et al., Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 37:1367-1374, 2014). These approaches can be categorized into six main types, each of which acts by a different primary mechanism.

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

[0006] Biguanides (e.g., metformin) are thought to act primarily by reducing hepatic glucose production, and biguanides often cause gastrointestinal discomfort and lactic acid poisoning, further limiting their use.

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

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

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

[0010] Sodium-glucose cotransporter type 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit glucose reabsorption in the kidney and thereby reduce the glucose content in the blood; this new drug class may be associated with ketoacidosis and urinary tract infections.

[0011] However, with the exception of GLP-1R agonists and SGLT2 inhibitors, the efficacy of these drugs is limited, and the most important problem of beta cell dysfunction and associated obesity remains unresolved. Therefore, there is a need for more effective drug interventions with fewer side effects and easier administration.

[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, decrease glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate β-cell proliferation in a physiologically and glucose-dependent manner. In nonclinical studies, GLP-1 promotes sustained β-cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting β-cell neogenesis (Meier et al., Biodrugs. 17(2):93-102, 2013).

[0013] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose content by increasing peripheral glucose absorption through stimulating glucose-dependent insulin secretion in the pancreas. GLP-1 also inhibits glucagon secretion and reduces hepatic glucose output. GLP-1 also slows food absorption by slowing gastric emptying and small intestinal motility. In individuals with T2DM, postprandial GLP-1 does not rise normally or rises at a reduced level (Vilsboll et al., Diabetes. 50:609-613, 2001).

[0014] Scientific research has already made corresponding modifications and alterations to the structure of GLP-1, thereby increasing its half-life and further prolonging its in vivo biological effect. However, the long-acting GLP-1 analogs currently used clinically, such as liraglutide and exenatide, are all polypeptides, and are administered by frequent multiple injections, which leads to relatively poor patient compliance. Therefore, the development of small molecule GLP-1R agonists has broad clinical market prospects for improving patient compliance, improving dosing convenience, and reducing drug side effects.

[0015] Hangzhou Deruizhi Pharmaceutical Technology Co., Ltd. (Mindrank AI Ltd.) has developed small molecule compounds with novel structures and potent agonist activity for GLP-1R, among which the compound of formula (I), with chemical name (S)-2-(4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid tromethamine salt (1:1), has potent GLP1R receptor agonist activity and good drug discovery potential, and its structure is as follows: [ka]

[0016] To successfully develop a solid form of a drug, it is generally necessary to have a solid form that can be easily separated and purified after synthesis, be amenable to industrial production, be capable of long-term storage with minimal water absorption, decomposition, or transformation into other solid forms, and be a dosage form that can be rapidly absorbed by an individual after administration (e.g., soluble in water and gastric juice).To meet the needs of clinical research and commercial pharmaceutical formulations, there is a strong demand for the development of drug crystalline forms that are easy to separate and purify, suitable for industrial production, and have stable physicochemical properties.

[0017] Summary of the Invention To solve the problems existing in the prior art, a first aspect of the present invention provides a crystalline polymorph of Compound I shown below: [ka] According to an embodiment of the present invention, the crystalline polymorph is an ansolvate, a hydrate, a solvate or a metastable crystalline form of Compound I.

[0018] According to an embodiment of the present invention, the unsolvated crystalline form may be the following crystalline form A, B, or C; the hydrate crystalline form may be the following crystalline form D; the solvated crystalline form may be the following crystalline form E, F, G, H, or I; and the metastable crystalline form may be the following crystalline form J, K, L, M, or N.

[0019] The present invention provides crystalline Form A of Compound I, whose X-ray powder diffraction pattern contains peaks located at diffraction angles (2θ) of 7.42±0.2°, 3.68±0.2°, 21.85±0.2°, and 18.75±0.2°.

[0020] According to the present invention, the crystalline form A preferably further comprises peaks located 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°.

[0021] According to the present invention, the crystalline form A more preferably further comprises peaks located 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°.

[0022] Preferably, the X-ray powder diffraction pattern of the crystalline form A has diffraction angles (2θ) shown in Table 1, wherein the error range of the 2θ angles is ±0.20°; [Table 1] Preferably, the crystalline form A has the X-ray powder diffraction intensities shown in Table 1.

[0023] Preferably, said crystalline form A has an X-ray powder diffraction pattern essentially as shown in FIG.

[0024] Preferably, the DSC analysis of the crystalline form A shows an endothermic peak when heated to a peak temperature of around 174.82°C.

[0025] Preferably, the crystalline form A has a DSC pattern essentially as shown in FIG.

[0026] Preferably, the crystalline form A has a TGA pattern essentially as shown in FIG.

[0027] The present invention provides crystalline form B of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 7.07±0.2°, 19.25±0.2°, 14.45±0.2° and 15.26±0.2°; According to the present invention, the crystalline form B preferably further comprises peaks located 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°; According to the present invention, the crystalline form B more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form B has diffraction angles (2θ) shown in Table 2, wherein the error range of the 2θ angles is ±0.20°; [Table 2] Preferably, the crystalline form B has the X-ray powder diffraction intensities shown in Table 2.

[0028] Preferably, said crystalline form B has an X-ray powder diffraction pattern essentially as shown in FIG.

[0029] Preferably, the DSC analysis of the crystalline form B shows an endothermic peak when heated to a peak temperature of around 160.15°C.

[0030] Preferably, the crystalline form B has a DSC pattern essentially as shown in FIG.

[0031] Preferably, the crystalline form B has a TGA pattern essentially as shown in FIG.

[0032] The present invention provides crystalline form C of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 10.90±0.2°, 5.80±0.2°, 19.28±0.2°, and 14.49±0.2°; According to the present invention, the crystalline form C preferably further comprises peaks located 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°; According to the present invention, the crystalline form C more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form C has diffraction angles (2θ) shown in Table 3, wherein the error range of the 2θ angles is ±0.20°; [Table 3] Preferably, the crystalline form C has the X-ray powder diffraction intensities shown in Table 3.

[0033] Preferably, said crystalline form C has an X-ray powder diffraction pattern essentially as shown in FIG.

[0034] Preferably, the DSC analysis of the crystalline form C shows endothermic peaks when heated to peak temperatures around 160.99°C and 170.25°C.

[0035] Preferably, the crystalline form C has a DSC pattern essentially as shown in FIG.

[0036] Preferably, the crystalline form C has a TGA pattern essentially as shown in FIG.

[0037] The present invention provides a hydrate crystalline form D of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 7.71±0.2°, 10.96±0.2°, 12.34±0.2°, and 19.38±0.2°; According to the present invention, the crystalline form D preferably further comprises peaks located 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°; According to the present invention, the crystalline form D more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form D has diffraction angles (2θ) shown in Table 4, wherein the error range of the 2θ angles is ±0.20°; [Table 4] Preferably, the crystalline form D has the X-ray powder diffraction intensities shown in Table 4.

[0038] Preferably, said crystalline form D has an X-ray powder diffraction pattern essentially as shown in FIG.

[0039] Preferably, the DSC analysis of the crystalline form D shows endothermic peaks when heated to peak temperatures around 62.09°C, 79.77°C, and 173.12°C.

[0040] Preferably, the crystalline form D has a DSC pattern essentially as shown in FIG.

[0041] Preferably, the crystalline form D has a TGA pattern essentially as shown in FIG.

[0042] The present invention provides a trichloroethane solvate crystalline form E of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 18.84±0.2°, 7.26±0.2°, 22.92±0.2°, and 9.35±0.2°; According to the present invention, the crystalline form E preferably further comprises peaks located 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°; According to the present invention, the crystalline form E more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form E has diffraction angles (2θ) shown in Table 5, wherein the error range of the 2θ angles is ±0.20°; [Table 5] Preferably, the crystalline form E has the X-ray powder diffraction intensities shown in Table 5.

[0043] Preferably, the crystalline form E has an X-ray powder diffraction pattern essentially as shown in FIG.

[0044] Preferably, the DSC analysis of the crystalline form E shows endothermic peaks when heated to peak temperatures around 137.77°C, 159.79°C, and 175.44°C.

[0045] Preferably, the crystalline form E has a DSC pattern essentially as shown in FIG.

[0046] Preferably, the crystalline form E has a TGA pattern essentially as shown in FIG.

[0047] The present invention provides an N-methylpyrrolidone solvate crystalline form F of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 6.60±0.2°, 19.57±0.2°, 5.89±0.2°, and 14.96±0.2°; According to the present invention, the crystalline form F preferably further comprises peaks located 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°; According to the present invention, the crystalline form F more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form F has diffraction angles (2θ) shown in Table 6, wherein the error range of the 2θ angles is ±0.20°; [Table 6] Preferably, the crystalline form F has the X-ray powder diffraction intensities shown in Table 6.

[0048] Preferably, the crystalline form F has an X-ray powder diffraction pattern essentially as shown in FIG.

[0049] Preferably, the DSC analysis of crystalline form F shows endothermic peaks when heated to peak temperatures around 72.65°C, 95.65°C, 127.81°C, and 159.14°C.

[0050] Preferably, the crystalline form F has a DSC pattern essentially as shown in FIG.

[0051] Preferably, the crystalline form F has a TGA pattern essentially as shown in FIG.

[0052] The present invention provides an N-methylpyrrolidone solvate crystalline form G of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2°, and 22.19±0.2°; According to the present invention, the crystalline form G preferably further comprises peaks located 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°, According to the present invention, the crystalline form G more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form G has diffraction angles (2θ) shown in Table 7, wherein the error range of the 2θ angles is ±0.20°;

[0053] [Table 7] Preferably, the crystalline form G has the X-ray powder diffraction intensities shown in Table 7.

[0054] Preferably, the crystalline form G has an X-ray powder diffraction pattern essentially as shown in FIG.

[0055] Preferably, the DSC analysis of the crystalline form G shows endothermic peaks when heated to peak temperatures of around 109.95°C and 166.02°C.

[0056] Preferably, the crystalline form G has a DSC pattern essentially as shown in FIG.

[0057] Preferably, the crystalline form G has a TGA pattern essentially as shown in FIG.

[0058] The present invention provides a tetrahydrofuran solvate crystalline form H of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 3.29±0.2°, 3.71±0.2°, 19.71±0.2°, and 19.24±0.2°; According to the present invention, the crystalline form H preferably further comprises peaks located 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°; According to the present invention, the crystalline form H more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form H has diffraction angles (2θ) shown in Table 8, wherein the error range of the 2θ angles is ±0.20°; [Table 8] Preferably, the crystalline form H has the X-ray powder diffraction intensities shown in Table 8.

[0059] Preferably, the crystalline form H has an X-ray powder diffraction pattern essentially as shown in FIG.

[0060] Preferably, the DSC analysis of the crystalline form H shows endothermic peaks when heated to peak temperatures of around 82.80°C and 174.84°C.

[0061] Preferably, the crystalline form H has a DSC pattern essentially as shown in FIG.

[0062] Preferably, the crystalline form H has a TGA pattern essentially as shown in FIG.

[0063] The present invention provides an ethanol solvate crystalline form I of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 18.97±0.2°, 10.71±0.2°, 16.19±0.2°, and 22.67±0.2°; According to the present invention, the crystalline form I preferably further comprises peaks located 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°; According to the present invention, the crystalline form I preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form I has diffraction angles (2θ) shown in Table 9, wherein the error range of the 2θ angles is ±0.20°; [Table 9] Preferably, the crystalline form I has the X-ray powder diffraction intensities shown in Table 9.

[0064] Preferably, said crystalline form I has an X-ray powder diffraction pattern essentially as shown in FIG.

[0065] Preferably, the DSC analysis of the crystalline form I shows endothermic peaks when heated to peak temperatures of around 136.10°C and 160.74°C.

[0066] Preferably, the crystalline form I has a DSC pattern essentially as shown in FIG.

[0067] Preferably, the crystalline form I has a TGA pattern essentially as shown in FIG.

[0068] The present invention provides a metastable crystalline form J of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 7.22±0.2°, 3.54±0.2°, 15.99±0.2°, and 19.34±0.2°; According to the present invention, the crystalline form J preferably further comprises peaks located 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°; According to the present invention, the crystalline form J more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form J has diffraction angles (2θ) shown in Table 10, wherein the error range of the 2θ angles is ±0.20°; [Table 10] Preferably, the crystalline form J has the X-ray powder diffraction intensities shown in Table 10.

[0069] Preferably, the crystalline form J has an X-ray powder diffraction pattern essentially as shown in FIG.

[0070] The present invention provides a metastable crystalline form K of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 6.13±0.2°, 7.19±0.2°, 3.56±0.2° and 22.63±0.2°; According to the present invention, the crystalline form K preferably further comprises peaks located 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°; According to the present invention, the crystalline form K more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form K has diffraction angles (2θ) shown in Table 11, wherein the error range of the 2θ angles is ±0.20°; [Table 11] Preferably, the crystalline form K has the X-ray powder diffraction intensities shown in Table 11.

[0071] Preferably, the crystalline form K has an X-ray powder diffraction pattern essentially as shown in FIG.

[0072] The present invention provides a metastable crystalline form L of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 8.04±0.2°, 14.49±0.2°, 19.75±0.2° and 15.95±0.2°; According to the present invention, the crystalline form L preferably further comprises peaks located 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°, According to the present invention, the crystalline form L more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form L has diffraction angles (2θ) shown in Table 12, wherein the error range of the 2θ angles is ±0.20°; [Table 12] Preferably, the crystalline form L has the X-ray powder diffraction intensities shown in Table 12.

[0073] Preferably, the crystalline form L has an X-ray powder diffraction pattern essentially as shown in FIG.

[0074] The present invention provides a metastable crystalline form M of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 19.96±0.2°, 12.72±0.2°, 7.92±0.2° and 11.12±0.2°; According to the present invention, the crystalline form M preferably further comprises peaks located 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°, According to the present invention, the crystalline form M more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form M has diffraction angles (2θ) shown in Table 13, wherein the error range of the 2θ angles is ±0.20°; [Table 13] Preferably, the crystalline form M has the X-ray powder diffraction intensities shown in Table 13.

[0075] Preferably, the crystalline form M has an X-ray powder diffraction pattern essentially as shown in FIG.

[0076] The present invention provides a metastable crystalline form N of Compound I, whose X-ray powder diffraction pattern comprises peaks located at diffraction angles (2θ) of 10.92±0.2°, 15.37±0.2°, 19.34±0.2°, and 20.46±0.2°; According to the present invention, the crystalline form N preferably further comprises peaks located 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°; According to the present invention, the crystalline form N more preferably further comprises peaks located 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°; According to the present invention, preferably, the X-ray powder diffraction pattern of the crystalline form N has diffraction angles (2θ) shown in Table 14, wherein the error range of the 2θ angles is ±0.20°; [Table 14] Preferably, the crystalline form N has the X-ray powder diffraction intensities shown in Table 14.

[0077] Preferably, the crystalline form N has an X-ray powder diffraction pattern essentially as shown in FIG.

[0078] A second aspect of the present invention provides a method for preparing a crystalline polymorph of Compound I, comprising: Step 1: dissolving or dispersing Compound I in a solvent; a step 2 of stirring at 0 to 50°C to cause crystallization, or adding a poor solvent to a clear solution of the compound to cause precipitation, or slowly volatilizing a clear solution of the compound; In a more preferred embodiment, the solvent is water, an organic solvent, or a mixture thereof, and the organic solvent is selected from alcohol-based, chloroalkane-based, ketone-based, ether-based, cyclic ether-based, ester-based, alkane-based, cycloalkane-based, benzene-based, amide-based, and sulfoxide-based organic solvents, or a mixture thereof. Preferably, the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, 2-methylpropanol, methylisobutyl ketone ... The solvent is selected from the group consisting of methyl tetrahydrofuran, 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, and mixtures thereof.

[0079] A third aspect of the present invention provides a pharmaceutical composition comprising at least one of the crystalline polymorphs of Compound I described above and a pharmaceutically acceptable carrier.

[0080] A fourth aspect of the present invention provides the use of the crystalline polymorph of Compound I in the manufacture of a medicament for treating a metabolic disease, a tumor, an autoimmune disease or a metastatic disease.

[0081] A fifth aspect of the present invention provides a crystalline polymorph of Compound I, which is used as a drug for treating metabolic disorders, tumors, autoimmune diseases or metastatic diseases.

[0082] A sixth aspect of the present invention provides a crystalline polymorph of Compound I as described above, which is useful for treating T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy lesions, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea syndrome, obesity, eating disorders, weight gain due to the use of other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, 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. It is used as a drug for the prevention or treatment of chronic kidney disease, traumatic brain injury, pulmonary hypertension, post-angioplasty restenosis, intermittent claudication, postprandial lipemia, 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, glucose metabolism disorders, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive dysfunction, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and for the treatment of addiction.

[0083] In a preferred form, the crystalline polymorph of Compound I is used as a drug to treat T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain due to the use of other medications, excessive sugar cravings, dyslipidemia, and hyperinsulinemia.

[0084] The present invention further provides a method for treating a disease, comprising administering to an individual in need thereof a therapeutically effective amount of at least one of the crystalline polymorphs of Compound I or the pharmaceutical compositions described above.

[0085] According to an embodiment of the present invention, the disease is selected from a metabolic disease, a tumor, an autoimmune disease or a metastatic disease.

[0086] According to an embodiment of the present invention, the diseases include T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy lesions, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea syndrome, obesity, eating disorders, weight gain due to use of other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, 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, post-angioplasty restenosis, intermittent claudication, postprandial lipemia, 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, glucose metabolism disorders, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcer, 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.

[0087] [Beneficial Effects] The present invention provides a crystalline polymorph of Compound I and a method for preparing the same, which has the advantages of high stability, good flowability, and easy pulverization, and is suitable for the development of clinical formulations. The preparation method provided by the present invention is simple, easy to implement, requires mild reaction conditions, and produces a high product yield. In addition, it does not require multiple purification steps, and the operation is safe and environmentally friendly, which is advantageous for the industrial production of crystalline polymorphs. It can meet the needs of clinical pharmaceutical formulation development, has great clinical application value, and is expected to accelerate the development of a new generation of GLP-1R small molecule agonists.

[0088] BRIEF DESCRIPTION OF THE DRAWINGS 1 shows the X-ray powder diffraction pattern of crystalline form A of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities.

[0089] 2 shows the DSC pattern of crystalline form A of compound I of the present invention, where the abscissa represents the temperature (° C.) and the ordinate represents the heat flow (mW).

[0090] 3 shows the TGA pattern of crystalline form A of compound I- of the present invention, where the abscissa indicates temperature (° C.) and the ordinate indicates weight (%).

[0091] 4 shows the X-ray powder diffraction pattern of crystalline form B of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities.

[0092] 5 shows the DSC pattern of crystalline form B of compound I of the present invention, where the abscissa represents the temperature (° C.) and the ordinate represents the heat flow (mW).

[0093] 6 shows the TGA pattern of crystalline form B of compound I- of the present invention, where the abscissa represents the temperature (° C.) and the ordinate represents the weight (%).

[0094] 7 shows the X-ray powder diffraction pattern of crystalline form C of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities.

[0095] 8 shows the DSC pattern of crystalline form C of compound I of the present invention, where the abscissa represents the temperature (° C.) and the ordinate represents the heat flow (mW).

[0096] 9 shows the TGA pattern of crystalline form C of compound I- of the present invention, where the abscissa represents the temperature (° C.) and the ordinate represents the weight (%).

[0097] 10 shows the X-ray powder diffraction pattern of hydrate crystalline form D of compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities.

[0098] 11 shows the DSC pattern of hydrate crystalline form D of Compound I of the present invention, where the abscissa represents the temperature (° C.) and the ordinate represents the heat flow (mW).

[0099] 12 shows the TGA pattern of hydrate crystalline form D of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%).

[0100] 13 shows the X-ray powder diffraction pattern of crystalline form E of the trichloroethane solvate of Compound I of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0101] 14 shows the DSC pattern of crystalline form E of the trichloroethane solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW).

[0102] 15 shows the TGA pattern of crystalline form E of the trichloroethane solvate of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%).

[0103] 16 shows the X-ray powder diffraction pattern of crystalline form F of the N-methylpyrrolidone solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities.

[0104] 17 shows the DSC pattern of crystalline form F of the N-methylpyrrolidone solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW).

[0105] 18 shows the TGA pattern of crystalline form F of the N-methylpyrrolidone solvate of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%).

[0106] 19 shows the X-ray powder diffraction pattern of crystalline form G of the N-methylpyrrolidone solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities.

[0107] 20 shows the DSC pattern of crystalline form G of the N-methylpyrrolidone solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW).

[0108] 21 shows the TGA pattern of crystalline form G of the N-methylpyrrolidone solvate of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%).

[0109] 22 shows the X-ray powder diffraction pattern of crystalline form H of the tetrahydrofuran solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities.

[0110] 23 shows the DSC pattern of crystalline form H of the tetrahydrofuran solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW).

[0111] 24 shows the TGA pattern of crystalline form H of the tetrahydrofuran solvate of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%).

[0112] 25 shows the X-ray powder diffraction pattern of crystalline Form I of the ethanol solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities.

[0113] 26 shows the DSC pattern of crystalline Form I of the ethanol solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW).

[0114] 27 shows the TGA pattern of crystalline form I of the ethanol solvate of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%).

[0115] 28 shows the X-ray powder diffraction pattern of metastable crystalline form J of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities.

[0116] 29 shows the X-ray powder diffraction pattern of the metastable crystalline form K of compound I of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity.

[0117] 30 shows the X-ray powder diffraction pattern of metastable crystalline form L of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities.

[0118] 31 shows the X-ray powder diffraction pattern of the metastable crystalline form M of compound I of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity.

[0119] 32 shows the X-ray powder diffraction pattern of the metastable crystalline form N of compound I of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity.

[0120] 33 shows the DVS pattern of crystalline form A of compound I of the present invention, where the abscissa represents relative humidity (%) and the ordinate represents weight change (%).

[0121] Definitions and Explanations of Terms Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. Certain phrases or terms, unless specifically defined, should not be considered indefinite or unclear but should be understood in their ordinary sense. When trade names are mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0122] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / medicinally acceptable salts or prodrugs thereof with other chemical components, as well as other components such as physiologically / medicinally acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert their biological activity.

[0123] As used herein, "crystalline polymorph" refers to a crystalline form that has the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions that make up the crystal. Although crystalline polymorphs have the same chemical composition, they differ in their stacking and geometric arrangement, and can exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and similar properties. Depending on their temperature-stability relationship, two crystalline polymorphs may be monotropic or enantiotropic. In a monotropic system, the relative stability between the two solid phases does not change with temperature. In contrast, in an enantiotropic system, there is a transition temperature at which the stability of the two phases switches ((Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN:)-8247-0237). The phenomenon in which such compounds exist in different crystalline structures is called drug polymorphism.

[0124] The various crystalline structures of the present invention can be distinguished from one another using various analytical techniques known to those skilled in the art, including, but not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0125] As used herein, the term "room temperature" or "RT" refers to an ambient temperature of 20-25°C (68-77°F).

[0126] As used herein, the term "essentially the same" with respect to X-ray diffraction peak positions is meant 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 in measurement due to differences in XRPD instruments, and in some cases, such variations can amount to as much as 0.2°. Additionally, one skilled in the art will appreciate that factors such as the method of preparation of the XRPD sample, the XRPD instrument, the crystallinity of the sample, the amount of sample used, and the preferred orientation of the crystals will result in variations in the relative peak intensities in a sample XRPD diffraction pattern.

[0127] The intermediate compounds according to the present invention can be prepared by a variety of 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 alternative methods well known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0128] The chemical reactions of specific embodiments of the present invention are completed in a suitable solvent, which must be suitable for the chemical transformations of the present invention and the necessary reagents and materials. To obtain the compounds of the present invention, those skilled in the art may need to modify or select synthetic steps or reaction processes based on existing embodiments.

[0129] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0130] All solvents used in this invention are commercially available and can be used without further purification.

[0131] Unless otherwise specified, all reactions of the present invention are carried out with continuous magnetic stirring, solvents are dry solvents, and temperatures are in degrees Celsius (°C).

[0132] Methods and Materials The structure of the compounds was confirmed by nuclear magnetic resonance (NMR). NMR shifts (δ) are reported in parts per million (ppm). NMR measurements were performed using a Bruker Avance-400 MHz nuclear magnetic spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4) as the solvent, and tetramethylsilane (TMS) as the internal standard. Chemical shifts are reported in 10-6 ppm.

[0133] For HPLC measurements, an Agilent 1260 high performance liquid chromatograph or a high performance liquid chromatograph of equivalent efficiency (Sunfire C18 150 x 4.6 m column or a column of equivalent efficiency) is used.

[0134] The crystalline polymorphs of Compound I are characterized by X-ray powder diffraction patterns. X-ray powder diffraction patterns of the salts are collected on a Bruker D8 Advance powder diffractometer operating in reflector mode using Cu Kα radiation. The instrument employs Cu Kα radiation (40 kV, 40 mA) at room temperature with an SSD160-2 detector. The scan range is 3° to 40° in the 2θ interval, with a scan rate of 0.1 s / step. Diffraction patterns are analyzed using DIFFRAC.MEA.CENTER software.

[0135] XRPD samples are prepared by placing the sample on a single-crystal silicon wafer and pressing the sample powder with a glass plate or equivalent to ensure the sample surface is flat and of 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 listed above. Measurement differences correlated with such X-ray powder diffraction analysis results arise from several factors, including (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors introduced when measuring peak positions), and (e) material properties (e.g., preferred orientation errors). Calibration errors and sample height errors always result in shifts of all peaks in the same direction. Typically, this calibration factor allows the measured peak positions to match the predicted peak positions and can be within ±0.2° of the predicted 2θ values.

[0136] The experimental method for characterizing the crystalline form of the acid salt or base salt of Compound I using differential scanning calorimetry (DSC) is to take a small amount of crystalline polymorph of Compound I, place it in an aluminum crucible that is equipped with an instrument and can be capped, and after placing the sample, cap it with an aluminum disk, and then transfer it to the instrument for testing. All instruments used in differential scanning calorimetry in this patent are model METTLER TOLEDO DSC 3, and the scanning parameters are set to use a nitrogen atmosphere and a heating rate of 10.0 K / min.

[0137] The experimental method for characterizing the crystalline polymorphs of Compound I using thermogravimetric analysis (TGA) is to take a small amount of powder of the crystalline polymorphs of Compound I and place it in an alumina crucible set up with the instrument, and then load the sample into the instrument for measurement. All instruments used in the differential scanning calorimetry in this patent are model METTLER TOLEDO TGA 2, and the scanning parameters are set to use a nitrogen gas atmosphere and a heating rate of 10.0 K / min.

[0138] The experimental method for characterizing the acid salt or base salt of Compound I using dynamic moisture sorption spectroscopy (DVS) involves taking a small amount of powder of the crystalline polymorph of Compound I and placing it in a precision sample tray installed in the instrument, then loading the sample and feeding it into the instrument for testing. All instruments used in the dynamic moisture sorption spectroscopy in this patent are Intrinsic PLUS models, and the experimental parameters are a constant temperature of 25°C, a mass percentage change rate per unit time (dm / dt) of 0.02% / min as the equilibrium determination criterion, and a programmed humidity change cycle with an initial relative humidity of 0% and an end-point relative humidity of 90%.

[0139] [Mode for Carrying Out the Invention] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0140] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or may be prepared by known methods.

[0141] 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-formic acid (free form of Compound I) [ka] Step 1 Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate A solution of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methylformate (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 h, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was 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)-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-formate methyl ester (1.0 g, yield: 33.5%).

[0142] Step 2: Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid To a solution 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-methyl formate (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-formic acid (0.69 g, yield: 70.5%). 1 H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1 H), 7.80 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.72 (t, J=7.6 Hz, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.44 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.28 (t, J=8.8 Hz, 1 H), 7.18 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.2 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 5.18 (s, 2 H), 5.12-5.06 (m, 1H), 4.95-4.93 (m, 1 H), 4.81-4.76 (m, 1 H), 4.66-4.62 (m, 1 H), 4.51-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.94 (d, J=13.6 Hz, 1 H), 3.78 (d, J=13.6 Hz, 1 H), 2.79-2.67 (m, 2 H), 2.46-2.41 (m, 1 H), 2.32 (s, 2 H), 1.92-1.91 (m, 2 H), 1.63-1.59 (m, 2 H).

[0143] Example 2 Preparation of Crystalline Form A of Compound I 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 dried in an oven at 40°C to obtain crystalline Form A of the compound, which was characterized by XRPD (Figure 1), DSC (Figure 2), and TGA (Figure 3) analyses. 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.67-7.57 (m, 2 H), 7.20-7.03 (m, 4 H), 6.66 (d, J=8.0 Hz, 1 H), 5.28-5.26 (m, 1H), 5.13 (s, 2 H), 5.05-5.03 (m, 1 H), 4.90-4.86 (m, 1 H), 4.73-4.62 (m, 2 H), 4.47-4.45 (m, 1 H), 4.02-3.89 (m, 2 H), 3.64 (s, 6 H), 2.81-2.77 (m, 3 H), 2.52-2.42 (m, 3 H), 2.01-1.99 (m, 2 H), 1.78-1.76 (m, 2 H).

[0144] Example 3 Preparation of Crystalline Form B of Compound I 200 mg of crystalline 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 dried in an oven at 50°C to obtain crystalline form B of the compound, which was characterized by XRPD (Figure 4), DSC (Figure 5), and TGA (Figure 6) analyses. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.67-7.57 (m, 2 H), 7.21-7.03 (m, 4 H), 6.67 (d, J=8.0 Hz, 1 H), 5.28-5.27 (m, 1H), 5.13 (s, 2 H), 5.05-5.03 (m, 1 H), 4.90-4.88 (m, 1 H), 4.73-4.62 (m, 2 H), 4.47-4.45 (m, 1 H), 4.02-3.89 (m, 2 H), 3.64 (s, 6 H), 2.83-2.77 (m, 3 H), 2.51-2.39 (m, 3 H), 2.01-1.99 (m, 2 H), 1.77-1.76 (m, 2 H).

[0145] Example 4 Preparation of Crystalline Form C of Compound I 20 mg of crystalline form A of compound I was dissolved in 1 mL of methanol and filtered. 2 mg of copovidone was added to the filtrate and allowed to slowly evaporate at room temperature. The resulting solid was dried at 50°C to obtain crystalline form C of the compound, which was characterized by XRPD (Figure 7), DSC (Figure 8) and TGA (Figure 9) analyses.

[0146] Example 5 Preparation of Hydrate Crystalline Form D of Compound I 200 mg of crystalline 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 dried in an oven at 50° C. to obtain crystalline form D of the compound, which was characterized by XRPD ( FIG. 10 ), DSC ( FIG. 11 ), and TGA ( FIG. 12 ) analyses. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J=8.5 Hz, 1.2 Hz, 1 H), 7.66-7.57 (m, 2 H), 7.20-7.03 (m, 4 H), 6.66 (d, J=8.1 Hz, 1 H), 5.27-5.26 (m, 1H), 5.13 (s, 2 H), 5.05-5.03 (m, 1 H), 4.90-4.85 (m, 1 H), 4.73-4.62 (m, 2 H), 4.47-4.45 (m, 1 H), 4.02-3.89 (m, 2 H), 3.64 (s, 6 H), 2.81-2.77 (m, 3 H), 2.52-2.39 (m, 3 H), 2.00-1.98 (m, 2 H), 1.78-1.76 (m, 2 H).

[0147] Example 6 Preparation of Trichloromethane Solvate Crystalline Form E of Compound I 20 mg of crystalline form A of compound I was suspended in 1.4 mL of trichloromethane / trifluoroethanol (6:1 v:v), stirred at 5° C. for 16 h, filtered, and the filter cake was dried in an oven at 50° C. to obtain crystalline form E of the compound, which was characterized by XRPD ( FIG. 13 ), DSC ( FIG. 14 ), and TGA ( FIG. 15 ) analyses. 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.90 (s, 0.8 H), 7.67-7.57 (m, 2 H), 7.21-7.03 (m, 4 H), 6.66 (d, J=8.0 Hz, 1 H), 5.28-5.26 (m, 1H), 5.13 (s, 2 H), 5.05-5.03 (m, 1 H), 4.90-4.86 (m, 1 H), 4.73-4.62 (m, 2 H), 4.47-4.45 (m, 1 H), 4.02-3.89 (m, 2H), 3.64 (s, 6 H), 2.81-2.77 (m, 3 H), 2.54-2.42 (m, 3 H), 2.00-1.98 (m, 2 H), 1.78-1.76 (m, 2 H).

[0148] Example 7 Preparation of Crystalline Form F of N-Methylpyrrolidone Solvate of Compound I 20 mg of crystalline 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 dried in an oven at 50° C. to obtain crystalline form F of the compound, which was characterized by XRPD ( FIG. 16 ), DSC ( FIG. 17 ), and TGA ( FIG. 18 ) analyses. 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.67-7.57 (m, 2 H), 7.21-7.03 (m, 4 H), 6.67 (d, J=8.0 Hz, 1 H), 5.28-5.25 (1H), 5.13 (s, 2 H), 5.05-5.03 (m, 1 H), 4.90-4.88 (m, 1H), 4.73-4.62 (m, 2 H), 4.47-4.45 (m, 1 H), 4.02-3.89 (m, 2 H), 3.64 (s, 6 H), 3.46-3.42 (m, 3.7 H), 2.82-2.80 (m, 8.5 H), 2.51-2.33 (m, 7 H), 2.07-1.99 (m, 5.7 H), 1.78-1.76 (m, 2 H).

[0149] Example 8 Preparation of Crystalline Form G of N-Methylpyrrolidone Solvate of Compound I 200 mg of crystalline form A of compound I was dissolved in 2.0 mL of N-methylpyrrolidone, the solution was added dropwise to 15 mL of toluene, stirred at room temperature for 16 hours, filtered, and the filter cake was dried in an oven at 50°C to obtain crystalline form G of the compound, which was characterized by XRPD (Figure 19), DSC (Figure 20), and TGA (Figure 21) analyses. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.66-7.57 (m, 2 H), 7.21-7.03 (m, 4 H), 6.66 (d, J=8.0 Hz, 1 H), 5.28-5.25 (1H), 5.12 (s, 2 H), 5.05-5.03 (m, 1 H), 4.73-4.62 (m, 2 H), 4.47-4.45 (m, 1 H), 4.02-3.88 (m, 2 H), 3.65 (s, 6 H), 3.44 (d, J=7.2 Hz, 3.5 H), 2.82-2.77 (m, 8 H), 2.51-2.33 (m, 6.5 H), 2.07-1.99 (m, 5.5 H), 1.77-1.76 (m, 2 H).

[0150] Example 9 Preparation of Crystalline Form H of Tetrahydrofuran Solvate of Compound I 20 mg of crystalline form A of compound I was suspended in 0.5 mL of tetrahydrofuran / water (9:1 v:v) and stirred at 50° C. for 2 h, then cooled to 5° C. and stirred for 2 h, filtered, and the filter cake was dried in an oven at 50° C. to obtain crystalline form H of compound. The product was characterized by XRPD (FIG. 22), DSC (FIG. 23), and TGA (FIG. 24) analyses. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.67-7.57 (m, 2 H), 7.21-7.03 (m, 4 H), 6.67 (d, J=8.0 Hz, 1 H), 5.28-5.25 (1H), 5.13 (s, 2 H), 5.05-5.03 (m, 1 H), 4.73-4.62 (m, 2 H), 4.46-4.44 (m, 1 H), 4.02-3.89 (m, 2 H), 3.74-3.71 (m, 1.5 H), 3.64 (s, 6 H), 2.81-2.77 (m, 3 H), 2.53-2.42 (m, 3 H), 2.07-1.99 (m, 2 H), 1.88-1.85 (m, 1.5 H), 1.77-1.75 (m, 2 H).

[0151] Example 10 Preparation of ethanol solvate crystalline form I of compound I 100 mg of crystalline 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 dried in an oven at 50° C. to obtain crystalline form I of compound I, which was characterized by XRPD (FIG. 25), DSC (FIG. 26), and TGA (FIG. 27) analyses. 1H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.67-7.57 (m, 2 H), 7.21-7.03 (m, 4 H), 6.66 (d, J=8.0 Hz, 1 H), 5.27-5.25 (m, 1H), 5.13 (s, 2 H), 5.05-5.03 (m, 1 H), 4.90-4.88 (m, 1 H), 4.73-4.62 (m, 2 H), 4.47-4.45 (m, 1 H), 4.02-3.89 (m, 2 H), 3.63 (s, 6 H), 3.60 (q, J=8.0 Hz, 1.8 H), 2.81-2.77 (m, 3 H), 2.52-2.42 (m, 3 H), 2.01-1.99 (m, 2 H), 1.78-1.76 (m, 2 H), 1.17 (t, J=8.0 Hz, 2.6 H).

[0152] Example 11 Preparation of Metastable Crystalline Form J of Compound I 200 mg of the free form of Compound I and 42 mg of tromethamine were added to 10 mL of IPA to form a suspension, which was stirred at room temperature for about 3 days and then suction filtered. The resulting filter cake was metastable crystalline form J of Compound I, which was characterized by XRPD analysis (Figure 28). After drying at 40°C for 16 h, crystalline form J was transformed into crystalline form A.

[0153] Example 12 Preparation of Metastable Crystalline Form K of Compound I 100 mg of crystalline form A of compound I was dissolved in 1.0 mL of DMF, and the solution was added dropwise to 15 mL of acetone, stirred at room temperature for 16 h, and filtered. The resulting filter cake was the metastable crystalline form K of compound I, which was characterized by XRPD analysis (FIG. 29). After drying at 50° C. for 24 h, crystalline form K was transformed into crystalline form A.

[0154] Example 13 Preparation of Metastable Crystalline Form L of Compound I 100 mg of crystalline form A of compound I was suspended in 2.5 mL of HO / EtOH (1:9 v:v) and stirred at room temperature for about 3 days, followed by filtration. The filter cake was dried at 50°C for 16 h to obtain metastable crystalline form L of compound I. The product was characterized by XRPD analysis (Figure 30). After standing open at room temperature for about 16 h, crystalline form L transformed into crystalline form D.

[0155] Example 14 Preparation of Metastable Crystalline Form M of Compound I 200 mg of crystalline form A of compound I was suspended in 9 mL of ACN / HO (6:1 v:v), stirred at 5°C for about 1 day, and filtered. The resulting filter cake was metastable crystalline form M of compound I, which was characterized by XRPD analysis (Figure 31). After vacuum drying at room temperature for about 16 h, crystalline form L was transformed into crystalline form D.

[0156] Example 15 Preparation of Metastable Crystal Form N of Compound I Form C of compound I was heated to 80°C at 10°C / min to give metastable form N of compound I, which was characterized by XRPD (Figure 32) analysis. After drying at 50°C for 16 h, form N was transformed to form B.

[0157] Measurement Example 1: Study of the equilibrium solubility of crystalline polymorphs of Compound I in biological media The equilibrium solubilities of Compound I in the free form and Compound I crystalline Form A in water (HO), simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF) were measured. In the test, the solid was suspended in the corresponding buffer (~10 mg / mL) and mixed at 37±2°C. After 24 hours, the suspension was sampled, and the supernatant was filtered to measure the concentration. The test results are shown in the table below. [Table 15]

[0158] As can be seen from the above experimental results, the solubility of crystalline Form A of Compound I in some solvents is significantly better than that of the free form of Compound I, which can meet the needs of the development of pharmaceutical clinical formulations. Therefore, the free form of Compound I has significant improvements in solubility and drug release behavior after salt formation.

[0159] Measurement Example 2: Study of the solid-state stability of crystalline polymorphs of Compound I The free form of Compound I and crystalline form A of Compound I were respectively stored 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 changes in HPLC purity and crystalline form were measured to investigate the solid-state stability. The results are shown in the table below. [Table 16]

[0160] As can be seen from the purity results of the above experiment, when compound I was left in the free form under long-term conditions for 7 days, there was no significant change in purity, but when it was left under accelerated conditions and high-temperature conditions for 7 days, there was significant decomposition; when compound I crystalline form A, crystalline form B, and crystalline form I were left under long-term, accelerated, and high-temperature conditions for 7 days, there was no significant change in purity, and their stability was significantly superior to that of the free form. As can be seen from the results of the crystal form, when compound I was left under long-term and high-temperature conditions for 7 days, there was no change in crystal form; when it was left under accelerated conditions for 7 days, there was a partial transformation into crystal form D; when compound I was left under long-term, accelerated, and high-temperature conditions for 7 days, there was no change in crystal form, and when compound I was left under long-term, accelerated, and high-temperature conditions for 7 days, there was a partial transformation into crystal form B.

[0161] Measurement Example 3: Competition Experiment Study of Crystal Polymorphism of Compound I The crystalline form A and crystalline form B of Compound I were subjected to a suspension competition test in acetonitrile (room temperature and 50°C) and ethyl acetate (room temperature and 50°C), respectively, to determine the change in crystalline form. The results are shown in the table below. [Table 17]

[0162] As can be seen from the above experimental results, crystalline form B of compound I was transformed into crystalline form A in both acetonitrile (room temperature and 50°C) and ethyl acetate (50°C) systems. After stirring at room temperature for 7 days in the ethyl acetate system, it remained a mixed crystal of crystalline forms A and B, but crystalline form B tended to transform into crystalline form A. This indicates that crystalline form A has higher thermodynamic stability than crystalline form B in the range from room temperature to 50°C.

[0163] Measurement Example 4: Measurement of moisture absorption behavior of Compound I The inventors of this patent used dynamic moisture sorption method to evaluate the stability risk of samples with changes in humidity at 25°C, and performed DVS measurement on a representative crystalline form A of compound I to evaluate the hygroscopicity of the crystalline form of the compound. The DVS pattern of crystalline form A of compound I is shown in Figure 33, and the obtained results are shown in the table below. [Table 18] As can be seen from the above experimental results, in the adsorption curves from 0 to 90% RH, crystalline form A of Compound I was slightly hygroscopic under 80% RH conditions, and no solid form change was observed.

[0164] Measurement example 5: Drug absorption experiment in SD rats Intravenous administration in rats: Compound I in free form or crystalline form A was administered to healthy SD rats via tail vein injection at a dose of D mg / kg. Blood samples were collected before and at different time points after administration, and plasma was separated. The drug concentration in plasma was measured by liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated using a non-compartmental model.

[0165] Its main pharmacokinetic parameters are shown in the table below. [Table 19]

[0166] Intragastric administration in rats. Compound I in its free form or crystalline form A was intragastricly administered to healthy SD rats. Blood samples were collected at different time points after administration, and plasma was separated. The drug concentration in the plasma was measured by liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated using a non-compartmental model.

[0167] Its main pharmacokinetic parameters are shown in the table below. [Table 20]

[0168] After dose correction, AUC 0-t The absolute bioavailability of the free form of Compound I after intragastric administration is 21.8%. The absolute bioavailability of crystalline Form A after intragastric administration is 43.7%, which is significantly superior to the free form and has pharmacokinetic advantages.

[0169] The thermal analyses of some crystalline forms of Compound I of the present invention are summarized in the table below. [Table 21]

[0170] The above is an illustrative description of the embodiments of the technical solution of the present invention. It should be understood that the scope of the claims of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present invention should be included in the scope of the claims of the present application. [Brief explanation of the drawings]

[0171] [Figure 1] 1 shows the X-ray powder diffraction pattern of crystalline form A of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities. [Figure 2] 1 shows the DSC pattern of crystalline form A of compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 3] 1 shows the TGA pattern of crystalline form A of compound I- of the present invention, where the abscissa indicates temperature (° C.) and the ordinate indicates weight (%). [Figure 4] 1 shows the X-ray powder diffraction pattern of crystalline form B of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities. [Figure 5] 1 shows the DSC pattern of crystalline form B of compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 6] 1 shows the TGA pattern of crystalline form B of compound I- of the present invention, where the abscissa indicates temperature (° C.) and the ordinate indicates weight (%). [Figure 7] 1 shows the X-ray powder diffraction pattern of crystalline form C of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities. [Figure 8] 1 shows the DSC pattern of crystalline form C of compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 9] 1 shows the TGA pattern of crystalline form C of compound I- of the present invention, where the abscissa indicates temperature (° C.) and the ordinate indicates weight (%). [Figure 10] 1 shows the X-ray powder diffraction pattern of hydrate crystalline form D of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities. [Figure 11] 1 shows the DSC pattern of hydrate crystalline form D of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 12] 1 shows the TGA pattern of hydrate crystalline form D of compound I- of the present invention, where the abscissa indicates temperature (° C.) and the ordinate indicates weight (%). [Figure 13] 1 shows the X-ray powder diffraction pattern of crystalline form E of the trichloroethane solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities. [Figure 14] 1 shows the DSC pattern of crystalline form E of the trichloroethane solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 15]1 shows the TGA pattern of crystalline form E of the trichloroethane solvate of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 16] 1 shows the X-ray powder diffraction pattern of crystalline form F of the N-methylpyrrolidone solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities. [Figure 17] 1 shows the DSC pattern of crystalline form F of the N-methylpyrrolidone solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 18] 1 shows the TGA pattern of crystalline form F of the N-methylpyrrolidone solvate of compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 19] 1 shows the X-ray powder diffraction pattern of crystalline form G of the N-methylpyrrolidone solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities. [Figure 20] 1 shows the DSC pattern of crystalline form G of the N-methylpyrrolidone solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 21] 1 shows the TGA pattern of crystalline form G of the N-methylpyrrolidone solvate of compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 22] 1 shows the X-ray powder diffraction pattern of crystalline form H of the tetrahydrofuran solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities. [Figure 23] 1 shows the DSC pattern of crystalline form H of the tetrahydrofuran solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 24] 1 shows the TGA pattern of crystalline form H of the tetrahydrofuran solvate of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 25] 1 shows the X-ray powder diffraction pattern of crystalline Form I of the ethanol solvate of Compound I of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensities. [Figure 26] 1 shows the DSC pattern of crystalline Form I of the ethanol solvate of Compound I of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 27] 1 shows the TGA pattern of crystalline form I of the ethanol solvate of compound I- of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 28] 1 shows the X-ray powder diffraction pattern of metastable crystalline form J of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities. [Figure 29] 1 shows the X-ray powder diffraction pattern of the metastable crystalline form K of Compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities. [Figure 30] 1 shows the X-ray powder diffraction pattern of metastable crystalline form L of compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities. [Figure 31] 1 shows the X-ray powder diffraction pattern of the metastable crystalline form M of Compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities. [Figure 32] 1 shows the X-ray powder diffraction pattern of the metastable crystalline form N of Compound I of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensities. [Figure 33] 1 shows the DVS pattern of crystalline form A of compound I of the present invention, where the abscissa represents relative humidity (%) and the ordinate represents weight change (%).

Claims

【Request 1】 【Chemical 1】 That is, Crystalline polymorphs of Compound I.

2. The crystalline polymorphs are solvent-free crystalline forms of the compound of formula (I), including the following solvent-free crystalline forms A, B, and C, among which: The crystalline form A has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.42±0.2°, 3.68±0.2°, 21.85±0.2°, and 18.75±0.2°; Preferably, the compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form A has diffraction angles (2θ) shown in Table 1, wherein the error range of the 2θ angles is ±0.20°; 【Table 1】 Preferably, the crystalline form A has the X-ray powder diffraction intensities shown in Table 1, Preferably, said crystalline form A has an X-ray powder diffraction pattern essentially 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 around 174.82°C; Preferably, the crystalline form A has a DSC pattern essentially as shown in Figure 2; Preferably, said crystalline form A has a TGA pattern essentially as shown in Figure 3; 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 compound further comprises peaks located 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°, More preferably, the optically active material further comprises 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form B has diffraction angles (2θ) as shown in Table 2, wherein the error range of the 2θ angles is ±0.20°; 【Table 2】 Preferably, said crystalline form B has the X-ray powder diffraction intensities shown in Table 2, Preferably, said crystalline form B has an X-ray powder diffraction pattern essentially as shown in Figure 4; Preferably, the DSC analysis of the crystalline form B shows an endothermic peak when heated to a peak temperature of around 160.15°C; Preferably, the crystalline form B has a DSC pattern essentially as shown in Figure 5; Preferably, said crystalline form B has a TGA pattern essentially as shown in Figure 6; The crystalline form C has an X-ray powder diffraction pattern comprising peaks located at diffraction angles (2θ) of 10.90±0.2°, 5.80±0.2°, 19.28±0.2°, and 14.49±0.2°; Preferably, the compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of crystalline form C has diffraction angles (2θ) shown in Table 3, wherein the error range of the 2θ angles is ±0.20°; 【Table 3】 Preferably, the crystalline form C has the X-ray powder diffraction intensities shown in Table 3, Preferably, said crystalline form C has an X-ray powder diffraction pattern essentially as shown in Figure 7; Preferably, the DSC analysis of the crystalline form C shows endothermic peaks when heated to peak temperatures of around 160.99°C and 170.25°C; Preferably, the crystalline form C has a DSC pattern essentially as shown in Figure 8; Preferably, the crystalline form C is characterized by having a TGA pattern essentially as shown in Figure 9. The crystalline polymorph of claim 1.

3. said crystalline polymorph being hydrate crystalline form D of the compound of formula (I); The hydrate crystalline form D has an X-ray powder diffraction pattern comprising peaks located at diffraction angles (2θ) of 7.71±0.2°, 10.96±0.2°, 12.34±0.2°, and 19.38±0.2°; Preferably, the compound further comprises peaks located 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°; More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form D has diffraction angles (2θ) as shown in Table 4, wherein the error range of the 2θ angles is ±0.20°; 【Table 4】 Preferably, the crystalline form D has the X-ray powder diffraction intensities shown in Table 4, Preferably, said crystalline form D has an X-ray powder diffraction pattern essentially as shown in Figure 10; Preferably, the DSC analysis of the crystalline form D shows endothermic peaks when heated to peak temperatures of 62.09°C, 79.77°C, and 173.12°C; Preferably, the crystalline form D has a DSC pattern essentially as shown in Figure 11; Preferably, the crystalline form D is characterized by having a TGA pattern essentially as shown in Figure 12. The crystalline polymorph of claim 1.

4. The crystalline polymorphs are solvate crystalline forms of the compound of formula (I), including the following solvate crystalline forms E, F, G, H, and I, among which: Form E of the trichloromethane solvate has an X-ray powder diffraction pattern comprising 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 compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form E has diffraction angles (2θ) shown in Table 5, wherein the error range of the 2θ angles is ±0.20°; 【Table 5】 Preferably, the crystalline form E has the X-ray powder diffraction intensities shown in Table 5, Preferably, said crystalline form E has an X-ray powder diffraction pattern essentially as shown in Figure 13; Preferably, the DSC analysis of the crystalline form E shows endothermic peaks when heated to peak temperatures of 137.77°C, 159.79°C, and 175.44°C; Preferably, the crystalline form E has a DSC pattern essentially as shown in Figure 14; Preferably, the crystalline form E has a TGA pattern essentially as shown in Figure 15; The crystalline form F of the N-methylpyrrolidone solvate has 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°; Preferably, the compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of crystalline form F has diffraction angles (2θ) shown in Table 6, wherein the error range of the 2θ angles is ±0.20°; 【Table 6】 Preferably, the crystalline form F has the X-ray powder diffraction intensities shown in Table 6: Preferably, the crystalline form F has an X-ray powder diffraction pattern essentially as shown in Figure 16; Preferably, the DSC analysis of the crystalline form F shows endothermic peaks when heated to peak temperatures of around 72.65°C, 95.65°C, 127.81°C, and 159.14°C; Preferably, the crystalline form F has a DSC pattern essentially as shown in Figure 17; Preferably, the crystalline form F has a TGA pattern essentially as shown in Figure 18; The crystalline form G of the N-methylpyrrolidone solvate has 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°; Preferably, the compound further comprises peaks located 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°, More preferably, the optically active material further comprises 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form G has diffraction angles (2θ) as shown in Table 7, wherein the error range of the 2θ angles is ±0.20°; 【Table 7】 Preferably, the crystalline form G has the X-ray powder diffraction intensities shown in Table 7, Preferably, the crystalline form G has an X-ray powder diffraction pattern essentially as shown in Figure 19; Preferably, the DSC analysis of the crystalline form G shows endothermic peaks when heated to peak temperatures of 109.95°C and 166.02°C. Preferably, the crystalline form G has a DSC pattern essentially as shown in Figure 20; Preferably, the crystalline form G has a TGA pattern essentially as shown in Figure 21; The tetrahydrofuran solvate of crystalline form H 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 compound further comprises peaks located 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°; More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of crystalline form H has diffraction angles (2θ) as shown in Table 8, wherein the error range of the 2θ angles is ±0.20°; 【Table 8】 Preferably, the crystalline form H has the X-ray powder diffraction intensities shown in Table 8: Preferably, the crystalline form H has an X-ray powder diffraction pattern essentially as shown in Figure 22; Preferably, the DSC analysis of the crystalline form H shows endothermic peaks when heated to peak temperatures of 82.80°C and 174.84°C. Preferably, the crystalline form H has a DSC pattern essentially as shown in Figure 23; Preferably, the crystalline form H has a TGA pattern essentially as shown in Figure 24; Crystalline Form I of the ethanol solvate has 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°; Preferably, the compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form I has diffraction angles (2θ) as shown in Table 9, wherein the error range of the 2θ angles is ±0.20°; 【Table 9】 Preferably, said crystalline form I has the X-ray powder diffraction intensities shown in Table 9, Preferably, said crystalline form I has an X-ray powder diffraction pattern essentially as shown in Figure 25; Preferably, the DSC analysis of the crystalline form I shows endothermic peaks when heated to peak temperatures of around 136.10°C and 160.74°C; Preferably, said crystalline form I has a DSC pattern essentially as shown in Figure 26; Preferably, the crystalline form I is characterized by having a TGA pattern essentially as shown in Figure 27. The crystalline polymorph of claim 1.

5. The crystalline polymorphs are metastable crystalline forms of the compound of formula (I), including the following crystalline forms J, K, L, M, and N, among which: The metastable crystalline 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 compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form J has diffraction angles (2θ) shown in Table 10, wherein the error range of the 2θ angles is ±0.20°; 【Table 10】 Preferably, the crystalline form J has the X-ray powder diffraction intensities shown in Table 10: Preferably, the crystalline form J has an X-ray powder diffraction pattern essentially as shown in Figure 28; The metastable crystalline 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 compound further comprises peaks located 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°; More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form K has diffraction angles (2θ) shown in Table 11, wherein the error range of the 2θ angles is ±0.20°; 【Table 11】 Preferably, the crystalline form K has the X-ray powder diffraction intensities shown in Table 11: Preferably, the crystalline form K has an X-ray powder diffraction pattern essentially as shown in Figure 29; The metastable crystalline 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 compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form L has diffraction angles (2θ) as shown in Table 12, wherein the error range of the 2θ angles is ±0.20°; 【Table 12】 Preferably, the crystalline form L has the X-ray powder diffraction intensities shown in Table 12, Preferably, the crystalline form L has an X-ray powder diffraction pattern essentially 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 compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form M has diffraction angles (2θ) as shown in Table 13, wherein the error range of the 2θ angles is ±0.20°; 【Table 13】 Preferably, the crystalline form M has the X-ray powder diffraction intensities shown in Table 13, Preferably, the crystalline form M has an X-ray powder diffraction pattern essentially as shown in Figure 31; The metastable crystalline 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 compound further comprises peaks located 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°, More preferably, the optically active material further comprises peaks located 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°; Preferably, the X-ray powder diffraction pattern of the crystalline form N has diffraction angles (2θ) shown in Table 14, wherein the error range of the 2θ angles is ±0.20°; 【Table 14】 Preferably, the crystalline form N has the X-ray powder diffraction intensities shown in Table 14, Preferably, the crystalline form N is characterized by having an X-ray powder diffraction pattern essentially as shown in Figure 32. The crystalline polymorph of claim 1.

6. A method for producing the crystalline polymorph according to any one of claims 1 to 5, Step 1: dissolving or dispersing Compound I in a solvent; and step 2 of stirring at 0 to 50°C to cause crystallization, or adding a poor solvent to a clear solution of the compound to cause precipitation, or slowly evaporating a clear solution of the compound. Manufacturing method.

7. The solvent is water, an organic solvent, or a mixture thereof. The organic solvent is selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides, or mixtures thereof. Preferably, the organic solvent is methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, or 2-methyltetrahydrofuran. , N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene, or a mixture thereof, The method of claim 6.

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

9. The use of the crystalline polymorph of any one of claims 1 to 5 in the manufacture of a drug for treating a metabolic disease, a tumor, an autoimmune disease or a metastatic disease.

10. The metabolic disease, tumor, autoimmune disease or metastatic disease may be T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy lesions, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea syndrome, obesity, eating disorders, weight gain due to the use of other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, 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, post-angioplasty restenosis, intermittent claudication, postprandial lipemia, 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, glucose metabolism disorders, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcer, 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 application according to claim 9.

11. 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, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain due to the use of other medications, excessive sugar craving, dyslipidemia and hyperinsulinemia; 10. The application according to claim 9.

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