A polymorph of a glp-1r agonist compound and methods of making and using the same

Abstract

The present application provides a polymorph of GLP-1R agonist compound I and a preparation method and use thereof. Compared with the amorphous substance of compound I, the polymorph of the present application has higher stability and better processability, and is more suitable for preparing a drug for preventing or treating diseases related to GLP-1R target and its signal pathway, such as type 2 diabetes, prediabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, kidney disease, gout, hyperuricemia and cardiovascular disease.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to a polymorph of a GLP-1R agonist compound, its preparation method, and its uses. Background Technology

[0002] Diabetes mellitus is a chronic disease characterized by hyperglycemia, caused by insufficient (relative or absolute) insulin secretion or impaired insulin action. According to the latest ninth edition of the World Diabetes Atlas published by the International Diabetes Federation (IDF), diabetes has become one of the most serious social health problems facing the world in the 21st century.

[0003] Currently, various pharmacological approaches are used to treat hyperglycemia and its associated type 2 diabetes mellitus (Hampp et al., Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 37:1367-1374, 2014). These approaches can be divided into six main categories, each acting through a different primary mechanism.

[0004] Insulin secretagogues, including sulfonylureas, dipeptidyl peptidase IV (PP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1R) agonists, increase insulin secretion by acting on pancreatic β-cells. Sulfonylureas have limited efficacy and tolerability, causing weight gain and often inducing hypoglycemia. PP-IV inhibitors have limited efficacy. Commercially available GLP-1R agonists are subcutaneously administered peptides; liraglutide is approved for the treatment of obesity.

[0005] Biguanides (such as metformin) are thought to work primarily by reducing hepatic glucose production. However, biguanides often cause gastrointestinal discomfort and lactic acidosis, which further limits their use.

[0006] Alpha-glucosidase inhibitors (such as acarbose) reduce intestinal glucose absorption. These medications often cause gastrointestinal discomfort.

[0007] Thiazolidinediones (such as pioglitazone and rosiglitazone) act on specific receptors in the liver, muscle, and adipose tissue. They regulate lipid metabolism and subsequently enhance the response of these tissues to insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia.

[0008] Insulin, alone or in combination with the above-mentioned drugs, is used for more severe cases, and frequent use may also lead to weight gain and carry the risk of hypoglycemia.

[0009] Inhibitors of the sodium-glucose-linking transporter cotransporter 2 (SGLT2) (such as dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin) inhibit the reabsorption of glucose in the kidneys and thus lower blood glucose levels. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

[0010] However, apart from GLP-1R agonists and SGLT2 inhibitors, these drugs have limited efficacy and do not address the most important issues: β-cell dysfunction and associated obesity. Therefore, there is a need for more effective drug interventions with fewer side effects and easier administration.

[0011] GLP-1 is a 30-amino acid-long incretin hormone secreted by L cells in response to food intake. GLP-1 has been shown to stimulate insulin secretion, reduce glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate β-cell proliferation in a physiological and glucose-dependent manner. In non-clinical studies, GLP-1 has been shown to promote sustained β-cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and by promoting β-cell regeneration (Meier et al., Biodrugs. 17(2):93-102, 2013).

[0012] In healthy individuals, GLP-1 plays a crucial role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion from the pancreas, thereby increasing peripheral glucose uptake. GLP-1 also inhibits glucagon secretion, reducing hepatic glucose excretion. Additionally, GLP-1 delays gastric emptying and slows small intestinal motility, thus delaying food absorption. In individuals with type 2 diabetes mellitus (T2DM), postprandial GLP-1 levels do not rise normally or rise less significantly (Vilsbol1 et al., Diabetes 50609-613, 2001).

[0013] Scientific research has led to the modification and alteration of the structure of GLP-1 to increase its half-life and thus prolong its biological effects in vivo. However, currently available long-acting GLP-1 analogs such as liraglutide and exenatide are all peptides, and frequent, repeated injections result in poor patient compliance. Therefore, the development of small-molecule GLP-1R agonists, aiming to improve patient compliance, ease of administration, and reduce drug side effects, has broad clinical market prospects.

[0014] Mindrank AI Ltd. has developed a class of novel small molecule compounds with potent GLP-1R agonist activity. Among them, the compound of formula (I) with the chemical name (S)-2-(4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid exhibits potent agonist activity and good drug-forming properties. Its structure is as follows:

[0015]

[0016] The free-state compound (I) has been identified by the inventors as an amorphous compound, which is hygroscopic or softening and prone to crystal transformation during long-term storage, thus making it unsuitable for clinical formulation development. To meet the needs of clinical research and marketed drug formulations, there is an urgent need to develop an aggregation form suitable for drug development to overcome the shortcomings of existing technologies.

[0017] The successful development of solid forms of drugs typically requires properties such as easy separation and purification after synthesis, suitability for industrial production, long shelf life with minimal absorption of moisture, decomposition or conversion into other solid forms, and rapid absorption by the individual after administration (e.g., solubility in water and gastric juice). To meet the needs of clinical research and marketed drug formulations, there is an urgent need to develop a drug solid form that is easy to separate and purify, suitable for industrial production, and has stable physicochemical properties. Summary of the Invention

[0018] To address the problems existing in the prior art, a first aspect of the present invention provides a polymorph of compound I as shown below;

[0019]

[0020] According to an embodiment of the present invention, the polymorph may be a solvent-free crystalline form, a hydrated crystalline form, or a solvate crystalline form of compound I.

[0021] The solvate crystal form can be the following crystal forms A, B, C, D, E, F; the hydrate crystal form can be the following crystal form G; the solvate crystal form can be the following crystal forms H, I-1, I-2, J, K, L, M, N, O, P, Q, R, S, T.

[0022] The present invention provides a crystal form A of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 19.79±0.2°, 13.13±0.2°, 22.07±0.2° and 9.48±0.2°.

[0023] Preferably, peaks are also located at diffraction angles (2θ) of 7.80±0.2°, 13.59±0.2°, 11.43±0.2°, 18.07±0.2° and 12.45±0.2°.

[0024] More preferably, it also includes peaks located at diffraction angles (2θ) of 14.58±0.2°, 24.66±0.2°, 14.24±0.2°, 4.85±0.2°, 23.70±0.2° and 26.51±0.2°.

[0025] Preferably, the X-ray powder diffraction pattern of crystal form A has diffraction angles (2θ) as shown in Table 1, wherein the error range of the 2θ angle is ±0.20°.

[0026] Table 1

[0027]

[0028]

[0029] Preferably, the crystal form A has the X-ray powder diffraction intensity shown in Table 1.

[0030] Preferably, the crystal form A has essentially the following characteristics: Figure 1 The X-ray powder diffraction pattern shown.

[0031] Preferably, the DSC analysis of crystal form A shows an endothermic peak when heated to a peak temperature of 99.81°C.

[0032] Preferably, the crystal form A has essentially the following characteristics: Figure 22 The DSC spectrum shown.

[0033] Preferably, the crystal form A has essentially the following characteristics: Figure 43 The TGA diagram shown.

[0034] The present invention provides crystal form B of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 13.79±0.2°, 22.36±0.2°, 17.66±0.2° and 27.41±0.2°;

[0035] Preferably, it further includes peaks located at diffraction angles (2θ) of 11.31±0.2°, 23.16±0.2°, 25.40±0.2°, 5.59±0.2° and 8.74±0.2°;

[0036] More preferably, it further includes peaks located at diffraction angles (2θ) of 20.20±0.2°, 28.85±0.2°, 11.96±0.2°, 24.19±0.2°, 24.39±0.2° and 7.28±0.2°;

[0037] Preferably, the X-ray powder diffraction pattern of crystal form B has a diffraction angle (2θ) as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°.

[0038] Table 2

[0039] 2θ(°) strength% 2θ(°) strength% 5.59 11.3 23.16 17.0 7.28 2.9 24.19 3.3 8.74 8.8 24.39 3.0 11.31 17.0 25.40 14.7 11.96 3.7 27.41 19.7 13.79 100.0 28.85 5.3 16.98 17.4 29.42 2.2 17.66 70.5 30.66 2.7 20.20 6.7 31.42 2.0 22.36 71.9 32.93 2.9

[0040] Preferably, the crystal form B has the X-ray powder diffraction intensity shown in Table 2.

[0041] Preferably, the crystal form B has essentially the following characteristics: Figure 2 The X-ray powder diffraction pattern shown.

[0042] Preferably, the DSC analysis of crystal form B shows an endothermic peak when heated to a peak temperature of 177.71°C.

[0043] Preferably, the crystal form B has essentially the following characteristics: Figure 23 The DSC spectrum shown.

[0044] Preferably, the crystal form B has essentially the following characteristics: Figure 44 The TGA diagram shown.

[0045] The present invention provides crystal form C of compound I, whose X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 11.27±0.2°, 19.30±0.2°, 17.92±0.2° and 20.04±0.2°;

[0046] Preferably, it further includes peaks located at diffraction angles (2θ) of 14.70±0.2°, 22.75±0.2°, 21.21±0.2°, 10.48±0.2° and 18.83±0.2°;

[0047] More preferably, it further includes peaks located at diffraction angles (2θ) of 4.84±0.2°, 10.20±0.2°, 14.16±0.2°, 22.15±0.2°, 20.41±0.2° and 10.98±0.2°;

[0048] Preferably, the X-ray powder diffraction pattern of crystal form C has diffraction angles (2θ) as shown in Table 3, wherein the error range of the 2θ angle is ±0.20°.

[0049] Table 3

[0050] 2θ(°) strength% 2θ(°) strength% 4.84 36.3 20.41 18.0 9.74 5.0 20.65 15.0 10.20 27.6 21.21 46.9 10.48 46.1 22.15 23.2 10.98 16.3 22.75 48.7 11.27 100.0 24.41 12.2 12.03 6.7 25.33 8.5 12.54 7.8 26.26 8.9 14.16 23.4 26.88 14.3 14.70 53.2 28.22 12.5 16.45 12.6 29.01 8.5 17.27 6.1 30.74 6.5 17.92 63.1 31.40 7.6 18.83 42.1 34.65 4.0 19.30 74.2 36.35 4.8 20.04 56.3

[0051] Preferably, the crystal form C has the X-ray powder diffraction intensity shown in Table 3.

[0052] Preferably, the crystal form C has essentially the following characteristics: Figure 3 The X-ray powder diffraction pattern shown.

[0053] Preferably, the DSC analysis of the crystal form C shows an endothermic peak when heated to a peak temperature of around 104.51°C.

[0054] Preferably, the crystal form C has essentially the following characteristics: Figure 24 The DSC spectrum shown.

[0055] Preferably, the crystal form C has essentially the following characteristics: Figure 45 The TGA spectrum shown.

[0056] The present invention provides crystal form D of compound I, whose X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 14.49±0.2°, 16.98±0.2°, 11.51±0.2° and 18.17±0.2°;

[0057] Preferably, it further includes peaks located at diffraction angles (2θ) of 24.02±0.2°, 21.87±0.2°, 3.58±0.2°, 14.04±0.2° and 20.68±0.2°;

[0058] More preferably, it further includes peaks located at diffraction angles (2θ) of 19.59±0.2°, 25.60±0.2°, 22.30±0.2°, 22.61±0.2°, 23.53±0.2° and 9.70±0.2°;

[0059] Preferably, the X-ray powder diffraction pattern of crystal form D has diffraction angles (2θ) as shown in Table 4, wherein the error range of the 2θ angle is ±0.20°.

[0060] Table 4

[0061] 2θ(°) strength% 2θ(°) strength% 3.58 33.8 22.30 20.8 6.69 2.5 22.61 20.5 7.24 4.3 23.16 8.2 9.70 17.4 23.53 20.4 11.51 86.8 24.02 34.8 14.04 32.8 25.11 10.2 14.49 100.0 25.60 27.5 15.00 10.5 26.00 8.2 15.91 12.1 26.92 6.4 16.98 61.5 28.17 3.1 17.47 8.3 28.47 7.5 18.17 41.4 29.12 7.2 18.62 15.6 30.15 6.4 19.01 13.0 30.50 4.6 19.59 27.7 31.36 3.4 20.45 16.0 33.81 2.4 20.68 29.9 34.69 3.5 21.87 34.4

[0062] Preferably, the crystal form D has the X-ray powder diffraction intensity shown in Table 4.

[0063] Preferably, the crystal form D has essentially the following characteristics: Figure 4 The X-ray powder diffraction pattern shown.

[0064] Preferably, the DSC analysis of the crystal form D shows an endothermic peak when heated to a peak temperature of 167.48°C.

[0065] Preferably, the crystal form D has essentially the following characteristics: Figure 25 The DSC spectrum shown.

[0066] Preferably, the crystal form D has essentially the following characteristics: Figure 46 The TGA spectrum shown.

[0067] The present invention provides crystal form E of compound I, whose X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 11.49±0.2°, 12.17±0.2°, 21.15±0.2° and 20.16±0.2°;

[0068] Preferably, it further includes peaks located at diffraction angles (2θ) of 14.35±0.2°, 26.49±0.2°, 19.40±0.2°, 4.32±0.2° and 17.51±0.2°;

[0069] More preferably, it further includes peaks located at diffraction angles (2θ) of 10.87±0.2°, 25.13±0.2°, 24.68±0.2°, 18.01±0.2°, 16.83±0.2° and 15.19±0.2°;

[0070] Preferably, the X-ray powder diffraction pattern of crystal form E has diffraction angles (2θ) as shown in Table 5, wherein the error range of the 2θ angle is ±0.20°.

[0071] Table 5

[0072] 2θ(°) strength% 2θ(°) strength% 4.32 32.3 21.87 7.1 10.87 26.9 22.95 4.7 11.49 100.0 23.28 7.9 12.17 92.0 23.92 7.6 13.14 15.6 24.24 5.8 13.61 6.2 24.68 20.8 14.35 46.1 25.13 25.5 15.19 16.2 26.08 11.3 15.48 6.2 26.49 44.1 16.83 17.2 28.30 3.1 17.51 30.3 28.79 4.8 18.01 18.4 29.96 3.6 18.85 10.4 30.21 6.1 19.40 43.1 31.69 4.5 20.16 66.7 34.99 3.0 21.15 98.3 36.05 2.8

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

[0074] Preferably, the crystal form E has essentially the following characteristics: Figure 5 The X-ray powder diffraction pattern shown.

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

[0076] Preferably, the crystal form E has essentially the following characteristics: Figure 26 The DSC spectrum shown.

[0077] Preferably, the crystal form E has essentially the following characteristics: Figure 47 The TGA diagram shown.

[0078] The present invention provides crystal form F of compound I, whose X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 18.77±0.2°, 25.50±0.2°, 20.98±0.2° and 23.45±0.2°;

[0079] Preferably, it further includes peaks located at diffraction angles (2θ) of 10.77±0.2°, 12.70±0.2°, 21.33±0.2°, 24.50±0.2° and 16.89±0.2°;

[0080] More preferably, it further includes peaks located at diffraction angles (2θ) of 14.72±0.2°, 19.24±0.2°, 9.68±0.2°, 11.7±0.2°, 20.49±0.2° and 13.26±0.2°;

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

[0082] Table 6

[0083]

[0084]

[0085] Preferably, the crystal form F has the X-ray powder diffraction intensity shown in Table 6.

[0086] Preferably, the crystal form F has essentially the following characteristics: Figure 6 The X-ray powder diffraction pattern shown.

[0087] Preferably, the DSC analysis of the crystal form F shows an endothermic peak when heated to a peak temperature of around 169.00°C.

[0088] Preferably, the crystal form F has essentially the following characteristics: Figure 27 The DSC spectrum shown.

[0089] Preferably, the crystal form F has essentially the following characteristics: Figure 48 The TGA diagram shown.

[0090] The present invention provides a hydrate crystal form G of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 18.66±0.2°, 18.81±0.2°, 3.62±0.2° and 22.24±0.2°;

[0091] Preferably, it further includes peaks located at diffraction angles (2θ) of 15.33±0.2°, 17.88±0.2°, 14.76±0.2°, 20.51±0.2° and 11.08±0.2°;

[0092] More preferably, it further includes peaks located at diffraction angles (2θ) of 19.94±0.2°, 26.57±0.2°, 23.22±0.2°, 24.37±0.2°, 7.32±0.2° and 23.44±0.2°;

[0093] Preferably, the X-ray powder diffraction pattern of the crystal form G has diffraction angles (2θ) as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°.

[0094] Table 7

[0095]

[0096]

[0097] Preferably, the crystal form G has the X-ray powder diffraction intensity shown in Table 7.

[0098] Preferably, the crystal form G has essentially the following characteristics: Figure 7 The X-ray powder diffraction pattern shown.

[0099] Preferably, the DSC analysis of the crystal form G shows endothermic peaks near the peak temperatures of 89.95°C and 104.07°C when heated.

[0100] Preferably, the crystal form G has essentially the following characteristics: Figure 28 The DSC spectrum shown.

[0101] Preferably, the crystal form G has essentially the following characteristics: Figure 49 The TGA diagram shown.

[0102] Preferably, the crystal form G is a dihydrate of compound I.

[0103] The present invention provides a crystal form H of the methyl isobutyl ketone solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 10.75±0.2°, 8.61±0.2°, 19.84±0.2° and 18.48±0.2°;

[0104] Preferably, it further includes peaks located at diffraction angles (2θ) of 16.79±0.2°, 25.92±0.2°, 9.11±0.2°, 21.15±0.2° and 15.43±0.2°;

[0105] More preferably, it further includes peaks located at diffraction angles (2θ) of 22.55±0.2°, 3.16±0.2°, 18.95±0.2°, 21.70±0.2°, 12.54±0.2° and 17.86±0.2°;

[0106] Preferably, the X-ray powder diffraction pattern of crystal form H has diffraction angles (2θ) as shown in Table 8, wherein the error range of the 2θ angle is ±0.20°.

[0107] Table 8

[0108]

[0109]

[0110] Preferably, the crystal form H has the X-ray powder diffraction intensity shown in Table 8.

[0111] Preferably, the crystal form H has essentially the following properties: Figure 8 The X-ray powder diffraction pattern shown.

[0112] Preferably, the DSC analysis of the crystal form H shows an endothermic peak when heated to a peak temperature of 87.76°C.

[0113] Preferably, the crystal form H has essentially the following properties: Figure 29 The DSC spectrum shown.

[0114] Preferably, the crystal form H has essentially the following properties: Figure 50 The TGA diagram shown.

[0115] Preferably, the crystal form H is a 0.5-methyl isobutyl ketone solvate of compound I.

[0116] The present invention provides a crystal form I-1 of the methyl tert-butyl ether solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 8.53±0.2°, 10.75±0.2°, 4.22±0.2° and 18.39±0.2°;

[0117] Preferably, it further includes peaks located at diffraction angles (2θ) of 17.22±0.2°, 21.48±0.2°, 16.85±0.2°, 17.53±0.2° and 9.11±0.2°;

[0118] More preferably, it further includes peaks located at diffraction angles (2θ) of 12.49±0.2°, 19.61±0.2°, 12.87±0.2°, 15.66±0.2°, 26.02±0.2° and 22.40±0.2°;

[0119] Preferably, the X-ray powder diffraction pattern of crystal form I-1 has a diffraction angle (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°.

[0120] Table 9

[0121]

[0122]

[0123] Preferably, the crystal form I-1 has the X-ray powder diffraction intensity shown in Table 9.

[0124] Preferably, the crystal form I-1 has essentially the following characteristics: Figure 9 The X-ray powder diffraction pattern shown.

[0125] Preferably, the DSC analysis of the crystal form I-1 shows an endothermic peak when heated to a peak temperature of around 103.27°C.

[0126] Preferably, the crystal form I-1 has essentially the following characteristics: Figure 30 The DSC spectrum shown.

[0127] Preferably, the crystal form I-1 has essentially the following characteristics: Figure 51 The TGA diagram shown.

[0128] Preferably, the crystal form I-1 is a monomethyl tert-butyl ether solvate of compound I.

[0129] The present invention provides a crystal form I-2 of the methyl tert-butyl ether solvate of compound I, the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 16.88±0.2°, 18.87±0.2°, 20.90±0.2° and 9.60±0.2°;

[0130] Preferably, it further includes peaks located at diffraction angles (2θ) of 10.98±0.2°, 8.39±0.2°, 17.68±0.2°, 20.51±0.2° and 19.97±0.2°;

[0131] More preferably, it further includes peaks located at diffraction angles (2θ) of 21.25±0.2°, 17.99±0.2°, 14.10±0.2°, 16.42±0.2°, 7.40±0.2° and 21.93±0.2°;

[0132] Preferably, the X-ray powder diffraction pattern of crystal form I-2 has diffraction angles (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°.

[0133] Table 10

[0134]

[0135]

[0136] Preferably, the crystal form I-2 has the X-ray powder diffraction intensity shown in Table 10.

[0137] Preferably, the crystal form I-2 has essentially the following characteristics: Figure 10 The X-ray powder diffraction pattern shown.

[0138] Preferably, the DSC analysis of the crystal form I-2 shows an endothermic peak when heated to a peak temperature of 97.11°C.

[0139] Preferably, the crystal form I-2 has essentially the following characteristics: Figure 31 The DSC spectrum shown.

[0140] Preferably, the crystal form I-2 has essentially the following characteristics: Figure 52 The TGA diagram shown.

[0141] Preferably, the crystal form I-2 is a 1,5-methyl tert-butyl ether solvate of compound I.

[0142] The present invention provides crystal form J of the acetone solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 12.02±0.2°, 18.03±0.2°, 8.04±0.2° and 7.67±0.2°;

[0143] Preferably, it further includes peaks located at diffraction angles (2θ) of 19.54±0.2°, 23.50±0.2°, 16.05±0.2°, 21.21±0.2° and 13.83±0.2°;

[0144] More preferably, it further includes peaks located at diffraction angles (2θ) of 11.10±0.2°, 17.43±0.2°, 16.54±0.2°, 8.92±0.2°, 22.59±0.2° and 27.39±0.2°;

[0145] Preferably, the X-ray powder diffraction pattern of crystal form J has diffraction angles (2θ) as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°.

[0146] Table 11

[0147] 2θ(°) strength% 2θ(°) strength% 6.83 20.4 16.54 28.5 7.67 44.9 17.43 29.8 8.04 56.1 18.03 61.4 8.54 21.1 19.54 43.6 8.92 26.1 21.21 38.6 10.69 7.6 22.59 24.3 11.10 31.9 23.50 41.8 12.02 100.0 25.83 18.5 13.83 34.5 27.39 21.4 14.48 16.4 29.32 9.9 16.05 39.4 30.93 17.0

[0148] Preferably, the crystal form J has the X-ray powder diffraction intensity shown in Table 11.

[0149] Preferably, the crystal form J has essentially the following characteristics: Figure 11 The X-ray powder diffraction pattern shown.

[0150] Preferably, the DSC analysis of crystal form J shows an endothermic peak when heated to a peak temperature of 93.18°C.

[0151] Preferably, the crystal form J has essentially the following characteristics: Figure 32 The DSC spectrum shown.

[0152] Preferably, the crystal form J has essentially the following characteristics: Figure 53 The TGA diagram shown.

[0153] Preferably, the crystal form J is a 0.5 acetone solvate of compound I.

[0154] The present invention provides a crystal form K of the n-heptane solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 12.19±0.2°, 18.02±0.2°, 7.69±0.2° and 19.69±0.2°;

[0155] Preferably, it further includes peaks located at diffraction angles (2θ) of 21.36±0.2°, 8.98±0.2°, 23.63±0.2°, 16.07±0.2° and 20.72±0.2°;

[0156] More preferably, it further includes peaks located at diffraction angles (2θ) of 6.85±0.2°, 8.12±0.2°, 13.75±0.2°, 6.54±0.2°, 14.53±0.2° and 13.26±0.2°;

[0157] Preferably, the X-ray powder diffraction pattern of the crystal form K has diffraction angles (2θ) as shown in Table 12, wherein the error range of the 2θ angle is ±0.20°.

[0158] Table 12

[0159] 2θ(°) strength% 2θ(°) strength% 6.54 28.2 19.69 66.0 6.85 33.2 20.18 14.7 7.69 74.5 20.72 38.2 8.12 32.8 21.36 61.4 8.98 53.3 23.63 47.7 10.55 10.0 24.37 17.6 12.19 100.0 25.37 11.2 13.26 21.2 26.04 20.7 13.75 35.9 26.52 12.4 14.53 24.7 27.44 10.6 15.66 21.2 27.73 14.1 16.07 39.2 29.13 12.0 18.02 82.0 31.20 5.4

[0160] Preferably, the crystal form K has the X-ray powder diffraction intensity shown in Table 12.

[0161] Preferably, the crystal form K has essentially the following characteristics: Figure 12 The X-ray powder diffraction pattern shown.

[0162] Preferably, the DSC analysis of the crystal form K shows an endothermic peak when heated to a peak temperature of 91.51°C.

[0163] Preferably, the crystal form K has essentially the following characteristics: Figure 33 The DSC spectrum shown.

[0164] Preferably, the crystal form K has essentially the following characteristics: Figure 54 The TGA diagram shown.

[0165] Preferably, the crystal form K is a 0.12 n-heptane solvate of compound I.

[0166] The present invention provides a crystal form L of the methylcyclohexane solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 10.98±0.2°, 15.54±0.2°, 9.09±0.2° and 19.01±0.2°;

[0167] Preferably, it further includes peaks located at diffraction angles (2θ) of 20.39±0.2°, 17.94±0.2°, 8.74±0.2°, 21.03±0.2° and 13.46±0.2°;

[0168] More preferably, it further includes peaks located at diffraction angles (2θ) of 22.86±0.2°, 18.25±0.2°, 25.63±0.2°, 16.90±0.2°, 24.74±0.2° and 25.95±0.2°;

[0169] Preferably, the X-ray powder diffraction pattern of the crystal form L has diffraction angles (2θ) as shown in Table 13, wherein the error range of the 2θ angle is ±0.20°.

[0170] Table 13

[0171] 2θ(°) strength% 2θ(°) strength% 5.35 23.5 16.90 35.5 6.25 18.5 17.94 71.0 6.73 17.5 18.25 44.0 7.83 24.5 19.01 78.0 8.74 59.5 20.39 72.5 9.09 84.0 21.03 57.0 10.98 100.0 22.86 48.5 13.46 55.0 24.74 35.0 15.54 100.0 25.63 41.5 16.58 26.5 25.95 33.5

[0172] Preferably, the crystal form L has the X-ray powder diffraction intensity shown in Table 13.

[0173] Preferably, the crystal form L has essentially the following characteristics: Figure 13 The X-ray powder diffraction pattern shown.

[0174] Preferably, the DSC analysis of the crystal form L shows an endothermic peak when heated to a peak temperature of 88.68°C.

[0175] Preferably, the crystal form L has essentially the following characteristics: Figure 34 The DSC spectrum shown.

[0176] Preferably, the crystal form L has essentially the following characteristics: Figure 55 The TGA diagram shown.

[0177] Preferably, the crystal form L is a 0.15 methylcyclohexane solvate of compound I.

[0178] The present invention provides a crystal form M of a toluene solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 18.62±0.2°, 9.60±0.2°, 16.34±0.2° and 21.62±0.2°;

[0179] Preferably, it further includes peaks located at diffraction angles (2θ) of 14.84±0.2°, 19.05±0.2°, 19.36±0.2°, 13.08±0.2° and 22.11±0.2°;

[0180] More preferably, it further includes peaks located at diffraction angles (2θ) of 26.65±0.2°, 24.48±0.2°, 22.36±0.2°, 11.19±0.2°, 20.47±0.2° and 18.19±0.2°;

[0181] Preferably, the X-ray powder diffraction pattern of the crystal form M has diffraction angles (2θ) as shown in Table 14, wherein the error range of the 2θ angle is ±0.20°.

[0182] Table 14

[0183]

[0184]

[0185] Preferably, the crystal form M has the X-ray powder diffraction intensity shown in Table 14.

[0186] Preferably, the crystal form M has essentially the following characteristics: Figure 14 The X-ray powder diffraction pattern shown.

[0187] Preferably, the DSC analysis of the crystal form M shows an endothermic peak when heated to a peak temperature of around 102.43°C.

[0188] Preferably, the crystal form M has essentially the following characteristics: Figure 35 The DSC spectrum shown.

[0189] Preferably, the crystal form M has essentially the following characteristics: Figure 56 The TGA diagram shown.

[0190] Preferably, the crystal form M is a monotoluene solvate of compound I.

[0191] The present invention provides crystal form N of the dioxane solvate of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 17.10±0.2°, 20.66±0.2°, 22.71±0.2° and 18.21±0.2°;

[0192] Preferably, it further includes peaks located at diffraction angles (2θ) of 21.70±0.2°, 15.05±0.2°, 20.27±0.2°, 21.97±0.2° and 8.53±0.2°;

[0193] More preferably, it further includes peaks located at diffraction angles (2θ) of 19.59±0.2°, 7.52±0.2°, 11.14±0.2°, 16.83±0.2°, 17.47±0.2° and 23.57±0.2°;

[0194] Preferably, the X-ray powder diffraction pattern of the N crystal form has diffraction angles (2θ) as shown in Table 15, wherein the error range of the 2θ angle is ±0.20°.

[0195] Table 15

[0196] 2θ(°) strength% 2θ(°) strength% 6.85 7.6 21.70 40.1 7.17 5.1 21.97 35.1 7.52 28.2 22.71 48.0 8.53 36.8 23.57 26.5 8.87 2.2 23.84 14.5 9.77 25.7 24.44 16.9 10.75 19.5 25.12 8.2 11.14 29.4 26.08 13.7 12.63 4.2 26.98 8.4 13.38 7.1 27.27 14.0 13.71 11.6 27.58 13.2 14.34 25.9 27.94 5.5 15.05 38.1 28.50 4.9 15.34 6.7 28.81 6.3 16.12 9.4 29.16 6.3 16.83 28.4 29.57 4.7 17.10 100.0 30.37 3.7 17.47 28.2 30.86 4.5 17.67 15.4 31.61 3.2 18.21 44.1 32.43 4.6 18.46 8.5 32.78 2.4 18.91 6.8 34.46 3.0 19.17 15.7 35.99 3.7 19.59 30.8 36.62 3.9 20.27 35.3 36.99 4.3 20.66 49.5 38.20 3.0 21.19 24.9 38.95 1.1

[0197] Preferably, the crystal form N has the X-ray powder diffraction intensity shown in Table 15.

[0198] Preferably, the crystal form N has essentially the following properties: Figure 15 The X-ray powder diffraction pattern shown.

[0199] Preferably, the DSC analysis of the N crystal form shows an endothermic peak when heated to a peak temperature of around 116.48°C.

[0200] Preferably, the crystal form N has essentially the following properties: Figure 36 The DSC spectrum shown.

[0201] Preferably, the crystal form N has essentially the following properties: Figure 57 The TGA diagram shown.

[0202] Preferably, the crystal form N is a 1,5-dioxane solvate of compound I.

[0203] The present invention provides crystal form O of the DMF solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 17.72±0.2°, 13.14±0.2°, 15.08±0.2° and 24.77±0.2°;

[0204] Preferably, it further includes peaks located at diffraction angles (2θ) of 8.72±0.2°, 21.52±0.2°, 9.70±0.2°, 14.26±0.2° and 25.46±0.2°;

[0205] More preferably, it further includes peaks located at diffraction angles (2θ) of 12.19±0.2°, 20.15±0.2°, 25.90±0.2°, 23.66±0.2°, 28.75±0.2° and 21.73±0.2°;

[0206] Preferably, the X-ray powder diffraction pattern of crystal form O has diffraction angles (2θ) as shown in Table 16, wherein the error range of the 2θ angle is ±0.20°.

[0207] Table 16

[0208] 2θ(°) strength% 2θ(°) strength% 6.66 3.7 22.09 5.4 7.08 3.7 22.48 4.0 7.52 2.3 23.06 5.4 8.72 32.4 23.66 15.5 9.70 23.4 23.93 2.0 11.01 2.2 24.77 94.4 12.195 16.8 25.46 21.0 13.14 87.4 25.90 14.4 14.26 21.4 26.53 7.5 15.08 92.5 27.35 1.9 16.13 2.8 28.46 6.2 16.59 2.8 28.75 11.3 16.79 3.0 29.70 5.7 17.72 100.0 30.15 1.5 18.51 3.1 30.81 2.7 18.86 1.0 31.03 3.8 19.26 4.0 32.46 1.7 19.56 6.5 34.16 1.2 20.15 14.4 34.67 1.1 20.96 1.1 35.95 1.9 21.52 30.2 36.35 1.8 21.73 9.1 37.92 1.2

[0209] Preferably, the crystal form O has the X-ray powder diffraction intensity shown in Table 16.

[0210] Preferably, the crystal form O has a substantially as follows: Figure 16 The X-ray powder diffraction pattern shown.

[0211] Preferably, the DSC analysis of the crystalline O shows an endothermic peak when heated to a peak temperature of around 123.26°C.

[0212] Preferably, the crystal form O has a substantially as follows: Figure 37 The DSC spectrum shown.

[0213] Preferably, the crystal form O has a substantially as follows: Figure 58 The TGA diagram shown.

[0214] Preferably, the crystal form O is a mono-DMF solvate of compound I.

[0215] The present invention provides crystal form P of the N-methylpyrrolidone solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 14.63±0.2°, 13.16±0.2°, 16.98±0.2° and 14.36±0.2°;

[0216] Preferably, it further includes peaks located at diffraction angles (2θ) of 21.66±0.2°, 23.94±0.2°, 20.22±0.2°, 6.60±0.2° and 8.41±0.2°;

[0217] More preferably, it further includes peaks located at diffraction angles (2θ) of 20.02±0.2°, 11.63±0.2°, 25.14±0.2°, 24.87±0.2°, 21.15±0.2° and 16.63±0.2°;

[0218] Preferably, the X-ray powder diffraction pattern of the crystal form P has diffraction angles (2θ) as shown in Table 17, wherein the error range of the 2θ angle is ±0.20°.

[0219] Table 17

[0220] 2θ(°) strength% 2θ(°) strength% 6.60 18.6 25.14 11.6 8.41 14.9 25.69 9.7 9.70 3.6 26.20 3.8 11.63 13.6 26.53 10.0 13.16 80.7 27.27 3.8 14.36 26.8 27.48 5.1 14.63 100.0 28.76 3.8 15.15 2.1 29.29 5.9 16.63 11.0 29.51 4.2 16.98 47.9 29.86 2.2 17.90 10.1 30.33 3.3 19.54 5.1 31.16 2.3 20.02 14.6 31.77 3.1 20.22 25.9 33.08 2.9 20.86 16.6 33.66 1.3 21.15 11.3 34.22 1.0 21.66 24.6 34.73 2.9 22.32 6.9 36.49 1.4 22.77 2.7 38.25 0.8 23.36 5.6 38.64 1.1 23.94 22.3 39.17 2.1 24.87 11.4

[0221] Preferably, the crystal form P has the X-ray powder diffraction intensity shown in Table 17.

[0222] Preferably, the crystal form P has essentially the following characteristics: Figure 17 The X-ray powder diffraction pattern shown.

[0223] Preferably, the DSC analysis of the crystal form P shows an endothermic peak when heated to a peak temperature of around 117.63°C.

[0224] Preferably, the crystal form P has essentially the following characteristics: Figure 38 The DSC spectrum shown.

[0225] Preferably, the crystal form P has essentially the following characteristics: Figure 59 The TGA diagram shown.

[0226] Preferably, the crystal form P is a mono-N-methylpyrrolidone solvate of compound I.

[0227] The present invention provides crystal form Q of the n-butanol solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 18.05±0.2°, 10.71±0.2°, 12.54±0.2° and 18.78±0.2°;

[0228] Preferably, it further includes peaks located at diffraction angles (2θ) of 20.68±0.2°, 24.89±0.2°, 26.45±0.2°, 22.24±0.2° and 19.81±0.2°;

[0229] More preferably, it further includes peaks located at diffraction angles (2θ) of 15.21±0.2°, 9.00±0.2°, 8.70±0.2°, 23.84±0.2°, 16.55±0.2° and 24.31±0.2°;

[0230] Preferably, the X-ray powder diffraction pattern of the crystal form Q has diffraction angles (2θ) as shown in Table 18, wherein the error range of the 2θ angle is ±0.20°.

[0231] Table 18

[0232]

[0233]

[0234] Preferably, the crystal form Q has the X-ray powder diffraction intensity shown in Table 18.

[0235] Preferably, the crystal form Q has essentially the following characteristics: Figure 18 The X-ray powder diffraction pattern shown.

[0236] Preferably, the DSC analysis of the crystal form Q shows an endothermic peak when heated to a peak temperature of around 100.61°C.

[0237] Preferably, the crystal form Q has essentially the following characteristics: Figure 39 The DSC spectrum shown.

[0238] Preferably, the crystal form Q has essentially the following characteristics: Figure 60 The TGA diagram shown.

[0239] Preferably, the crystal form Q is a 0.5 n-butanol solvate of compound I.

[0240] The present invention provides a crystal form R of a n-propanol solvate of compound I, the X-ray powder diffraction pattern of which includes peaks located at diffraction angles (2θ) of 10.67±0.2°, 12.52±0.2°, 18.08±0.2° and 8.98±0.2°;

[0241] Preferably, it further includes peaks located at diffraction angles (2θ) of 6.54±0.2°, 20.68±0.2°, 18.84±0.2°, 7.55±0.2° and 8.67±0.2°;

[0242] More preferably, it further includes peaks located at diffraction angles (2θ) of 19.85±0.2°, 26.59±0.2°, 15.19±0.2°, 13.05±0.2°, 14.06±0.2° and 16.55±0.2°;

[0243] Preferably, the X-ray powder diffraction pattern of the crystal form R has diffraction angles (2θ) as shown in Table 19, wherein the error range of the 2θ angle is ±0.20°.

[0244] Table 19

[0245]

[0246]

[0247] Preferably, the crystal form R has the X-ray powder diffraction intensity shown in Table 19.

[0248] Preferably, the crystal form R has essentially the following characteristics: Figure 19The X-ray powder diffraction pattern shown.

[0249] Preferably, the DSC analysis of the crystal form R shows an endothermic peak when heated to a peak temperature of around 110.90°C.

[0250] Preferably, the crystal form R has essentially the following characteristics: Figure 40 The DSC spectrum shown.

[0251] Preferably, the crystal form R has essentially the following characteristics: Figure 61 The TGA diagram shown.

[0252] Preferably, the crystal form R is a mono-n-propanol solvate of compound I.

[0253] The present invention provides a crystalline form S of a tetrahydrofuran solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 12.17±0.2°, 8.19±0.2°, 7.67±0.2° and 13.96±0.2°;

[0254] Preferably, it further includes peaks located at diffraction angles (2θ) of 8.95±0.2°, 18.01±0.2°, 16.50±0.2°, 19.71±0.2° and 23.70±0.2°;

[0255] More preferably, it further includes peaks located at diffraction angles (2θ) of 13.69±0.2°, 13.22±0.2°, 14.45±0.2°, 20.64±0.2°, 15.83±0.2° and 6.48±0.2°;

[0256] Preferably, the X-ray powder diffraction pattern of the crystal form S has diffraction angles (2θ) as shown in Table 20, wherein the error range of the 2θ angle is ±0.20°.

[0257] Table 20

[0258] 2θ(°) strength% 2θ(°) strength% 4.07 8.4 20.12 4.4 6.48 10.0 20.64 12.7 6.81 9.6 21.11 7.1 7.67 42.3 21.35 6.9 8.19 69.0 21.74 1.4 8.95 33.3 22.26 3.1 10.46 6.0 22.79 5.6 12.17 100.0 23.00 2.2 13.22 13.4 23.70 18.4 13.69 15.3 24.37 5.3 13.96 38.4 25.27 1.1 14.45 14.2 25.82 6.2 15.43 3.3 26.37 4.4 15.83 14.5 27.70 4.6 16.50 22.3 29.10 3.1 17.76 7.6 30.81 1.1 18.01 37.6 31.30 1.9 19.71 21.4 31.94 0.8

[0259] Preferably, the crystal form S has the X-ray powder diffraction intensity shown in Table 20.

[0260] Preferably, the crystal form S has a substantially as follows: Figure 20 The X-ray powder diffraction pattern shown.

[0261] Preferably, the DSC analysis of the crystal form S shows an endothermic peak when heated to a peak temperature of 96.26°C.

[0262] Preferably, the crystal form S has a substantially as follows: Figure 41 The DSC spectrum shown.

[0263] Preferably, the crystal form S has a substantially as follows: Figure 62 The TGA diagram shown.

[0264] Preferably, the crystal form S is a 0.5-tetrahydrofuran solvate of compound I.

[0265] The present invention provides crystal form T of the 2-methyltetrahydrofuran solvate of compound I, the X-ray powder diffraction pattern of which includes peaks at diffraction angles (2θ) of 10.79±0.2°, 8.66±0.2°, 9.12±0.2° and 16.87±0.2°;

[0266] Preferably, it further includes peaks located at diffraction angles (2θ) of 18.64±0.2°, 15.54±0.2°, 21.27±0.2°, 13.57±0.2° and 6.72±0.2°;

[0267] More preferably, it further includes peaks located at diffraction angles (2θ) of 4.29±0.2°, 14.41±0.2°, 19.99±0.2°, 7.71±0.2°, 16.57±0.2° and 19.42±0.2°;

[0268] Preferably, the X-ray powder diffraction pattern of the crystal form T has diffraction angles (2θ) as shown in Table 21, wherein the error range of the 2θ angle is ±0.20°.

[0269] Table 21

[0270] 2θ(°) strength% 2θ(°) strength% 4.29 15.2 19.42 10.6 6.72 16.5 19.99 14.9 7.32 1.7 20.47 8.1 7.71 12.7 20.71 5.8 8.66 71.9 21.27 18.7 9.12 52.0 21.87 7.7 9.62 1.9 22.30 5.0 10.79 100.0 22.85 3.5 12.62 16.1 23.62 3.4 13.05 9.5 24.14 1.4 13.57 19.5 25.03 2.4 14.41 15.3 25.95 8.9 15.54 24.9 26.22 5.7 16.57 10.8 26.70 2.8 16.87 48.4 27.44 9.1 17.45 8.1 28.17 1.9 17.82 4.1 29.37 1.8 18.64 26.4 31.50 2.9

[0271] Preferably, the crystal form T has the X-ray powder diffraction intensity shown in Table 21.

[0272] Preferably, the crystal form T has essentially the following characteristics: Figure 21 The X-ray powder diffraction pattern shown.

[0273] Preferably, the DSC analysis of the crystal form T shows an endothermic peak when heated to a peak temperature of around 112.95°C.

[0274] Preferably, the crystal form T has essentially the following characteristics: Figure 42 The DSC spectrum shown.

[0275] Preferably, the crystal form T has essentially the following characteristics: Figure 63 The TGA diagram shown.

[0276] Preferably, the crystal form T is a mono-2-methyltetrahydrofuran solvate of compound I.

[0277] A second aspect of the present invention provides a method for preparing a polymorph of the aforementioned compound I, selected from the following preparation methods:

[0278] Method 1: Step 1: Dissolve or disperse compound I in a solvent; Step 2: Stir at 0-50°C to crystallize; or, add an antisolvent to the clear solution of the compound to precipitate; or, slowly evaporate the clear solution of the compound.

[0279] Method 2: Disperse compound I in a solvent and in the atmosphere of these media to obtain crystals;

[0280] Method 3: Using a combination of methods 1 and 2, the polymorph of compound I was prepared.

[0281] As a further preferred embodiment, 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 selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, 2-methoxyethyl ether, isopropyl ether, diethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene, or mixtures thereof.

[0282] A third aspect of the present invention provides a pharmaceutical composition comprising at least one of the polymorphs of the aforementioned compound I and a pharmaceutically acceptable carrier.

[0283] The fourth aspect of the present invention provides the use of the polymorph of the aforementioned compound I in the preparation of a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0284] The fifth aspect of the present invention provides a polymorph of the aforementioned compound I, which is used as a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0285] The sixth aspect of this invention provides a polymorph of the aforementioned compound I, which is used to treat T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar consumption, 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, and other conditions. Medications for the prevention or treatment of hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome, as well as for the treatment of addiction.

[0286] As a preferred embodiment, the polymorph of the aforementioned compound I is used as a drug for treating T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar consumption, dyslipidemia, and hyperinsulinemia.

[0287] The present invention also provides a method for treating a disease, comprising administering to an individual in need a therapeutically effective amount of a polymorph of the aforementioned compound I or at least one of the pharmaceutical compositions.

[0288] According to an embodiment of the present invention, the disease is selected from metabolic diseases, tumors, autoimmune diseases, or metastatic diseases.

[0289] According to embodiments of the present invention, the diseases are selected from T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar consumption, 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, and stroke. Hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome.

[0290] Beneficial effects

[0291] This invention provides a polymorph of compound I and its preparation method. Compared with the amorphous form, the polymorph exhibits advantages such as good stability, good flowability, and ease of pulverization, making it more suitable for clinical formulation development. The preparation method provided by this invention is simple, easy to implement, and uses mild reaction conditions, resulting in high product yield. Furthermore, it eliminates the need for multiple purification processes, is safe and environmentally friendly, and facilitates the industrial production of the polymorph, meeting the needs of clinical drug formulation development. It has significant clinical application value and is expected to accelerate the development into a new generation of GLP-1R small molecule agonists. Attached Figure Description

[0292] Figure 1 The X-ray powder diffraction pattern of crystal form A of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0293] Figure 2 The X-ray powder diffraction pattern of crystal form B of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0294] Figure 3 The X-ray powder diffraction pattern of crystal form C of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0295] Figure 4 The X-ray powder diffraction pattern of crystal form D of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0296] Figure 5 The X-ray powder diffraction pattern of crystal form E of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0297] Figure 6 The X-ray powder diffraction pattern of crystal form F of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0298] Figure 7 The X-ray powder diffraction pattern of the hydrate crystal form G of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0299] Figure 8 The X-ray powder diffraction pattern of crystal form H of the methyl isobutyl ketone solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0300] Figure 9 The X-ray powder diffraction pattern of crystal form I-1 of the methyl tert-butyl ether solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0301] Figure 10 The X-ray powder diffraction pattern of crystal form I-2 of the methyl tert-butyl ether solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0302] Figure 11 The X-ray powder diffraction pattern of crystal form J of the acetone solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0303] Figure 12 The X-ray powder diffraction pattern of crystal form K of the n-heptane solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0304] Figure 13 The X-ray powder diffraction pattern of crystal form L of the methylcyclohexane solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0305] Figure 14 The X-ray powder diffraction pattern of crystal form M of the toluene solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0306] Figure 15 The X-ray powder diffraction pattern of crystal form N of the dioxane solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0307] Figure 16 The X-ray powder diffraction pattern of crystal form O of the DMF solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0308] Figure 17 The X-ray powder diffraction pattern of crystal form P of the N-methylpyrrolidone solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0309] Figure 18 The X-ray powder diffraction pattern of crystal form Q of the n-butanol solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0310] Figure 19 The X-ray powder diffraction pattern of the crystal form R of the n-propanol solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0311] Figure 20 The X-ray powder diffraction pattern of the tetrahydrofuran solvate of compound I of the present invention, crystal form S, is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0312] Figure 21 The X-ray powder diffraction pattern of crystal form T of the 2-methyltetrahydrofuran solvate of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0313] Figure 22 The DSC plot of crystal form A of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0314] Figure 23 The DSC plot of crystal form B of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0315] Figure 24The DSC plot of crystal form C of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0316] Figure 25 The DSC plot of crystal form D of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0317] Figure 26 The DSC plot of crystal form E of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0318] Figure 27 The DSC plot of crystal form F of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0319] Figure 28 The DSC plot of the hydrate crystal form G of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0320] Figure 29 The DSC plot of the methyl isobutyl ketone solvate H of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0321] Figure 30 The DSC plot of crystal form I-1 of the methyl tert-butyl ether solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0322] Figure 31 The DSC plot of crystal form I-2 of the methyl tert-butyl ether solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0323] Figure 32 The DSC plot of crystal form J of the acetone solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0324] Figure 33 The DSC plot of the crystal form K of the n-heptane solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0325] Figure 34 The DSC plot of crystal form L of the methylcyclohexane solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0326] Figure 35The DSC plot of the crystal form M of the toluene solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0327] Figure 36 The DSC plot of crystal form N of the dioxane solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0328] Figure 37 The DSC plot of crystal form O of the DMF solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0329] Figure 38 The DSC plot of crystal form P of the N-methylpyrrolidone solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0330] Figure 39 The DSC plot of the crystal form Q of the n-butanol solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0331] Figure 40 The DSC plot of the crystal form R of the n-propanol solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0332] Figure 41 The DSC plot of the tetrahydrofuran solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0333] Figure 42 The DSC plot of crystal form T of the 2-methyltetrahydrofuran solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0334] Figure 43 The TGA plot of crystal form A of compound I- of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0335] Figure 44 The TGA plot of crystal form B of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0336] Figure 45 The TGA plot of crystal form C of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0337] Figure 46The TGA plot of crystal form D of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0338] Figure 47 The TGA plot of crystal form E of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0339] Figure 48 The TGA plot of crystal form F of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0340] Figure 49 The TGA plot of the hydrate crystal form G of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0341] Figure 50 The TGA plot of the methyl isobutyl ketone solvate H of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0342] Figure 51 The TGA plot of methyl tert-butyl ether solvate I-1 of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0343] Figure 52 The TGA plot of crystal form I-2 of the methyl tert-butyl ether solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0344] Figure 53 The TGA plot of crystal form J of the acetone solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0345] Figure 54 The TGA plot of the crystal form K of the n-heptane solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0346] Figure 55 The TGA plot of crystal form L of the methylcyclohexane solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0347] Figure 56 The TGA plot of crystal form M of the toluene solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0348] Figure 57The TGA plot of crystal form N of the dioxane solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0349] Figure 58 The TGA plot of crystal form O of the DMF solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0350] Figure 59 The TGA plot of crystal form P of the N-methylpyrrolidone solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0351] Figure 60 The TGA plot of crystal form Q of the n-butanol solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0352] Figure 61 The TGA plot of the crystal form R of the n-propanol solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0353] Figure 62 The TGA plot of the tetrahydrofuran solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0354] Figure 63 The TGA plot of crystal form T of the 2-methyltetrahydrofuran solvate of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0355] Figure 64 The X-ray powder diffraction pattern of the amorphous solid of compound I of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0356] Figure 65 The DSC plot of the amorphous solid of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0357] Figure 66 The TGA graph of the amorphous solid of compound I of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0358] Figure 67 The diagram shows the DVS of the amorphous solid of compound I of the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0359] Figure 68The diagram shows the DVS plot of crystal form D of compound I of the present invention. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0360] Terminology Definitions and Explanations

[0361] Unless otherwise stated, the terms used in the specification and claims shall have the following meanings. A particular phrase or term should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0362] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0363] The term "polymorph" as used in this article refers to a crystal form with the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions constituting the crystal. Although polymorphs have the same chemical composition, their packing and geometric arrangements differ, and they may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and similar properties. Based on their temperature-stability relationship, two polymorphs can be either monomorphic or tautomorphic. For monomorphic systems, the relative stability between the two solid phases remains constant with temperature changes. Conversely, in tautomorphic systems, there is a transition temperature at which the stability of the two phases changes (Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN: 8247-0237). This phenomenon of compounds existing in different crystal structures is called pharmaceutical polymorphism.

[0364] The various crystalline structures of this invention can be distinguished from each other using a variety of analytical techniques known to those skilled in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0365] As used in this article, the term "room temperature" or "RT" refers to an ambient temperature of 20 to 25°C (68-77°F).

[0366] The term "substantially identical" used herein to refer to X-ray diffraction peak positions means taking into account typical peak position and intensity variability. For example, those skilled in the art will understand that peak positions (2θ) will vary due to different XRPD instruments, sometimes by as much as 0.2°. Furthermore, those skilled in the art will understand that factors such as XRPD sample preparation methods, XRPD instruments, sample crystallinity, sample amount, and preferred crystal orientation will cause changes in the relative peak intensities in the sample's XRPD diffraction pattern.

[0367] The intermediate compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0368] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on existing embodiments.

[0369] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0370] All solvents used in this invention are commercially available and can be used without further purification.

[0371] Unless otherwise specified, all reactions in this invention are performed under continuous magnetic stirring, using a dry solvent, and the temperature is measured in degrees Celsius (°C).

[0372] Methods and Materials

[0373] The structure of the compound was determined by nuclear magnetic resonance (NMR). NMR shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker Avance-400MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4) as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are expressed in 10⁻⁶ ppm.

[0374] HPLC determinations were performed using an Agilent 1260 high-performance liquid chromatograph or an equivalent high-performance liquid chromatograph (Sunfire C18 150×4.6m column or equivalent column).

[0375] The polymorphs of Compound I are characterized by X-ray powder diffraction patterns. The X-ray powder diffraction pattern of the salt is collected on a Bruker D8 Advance powder diffractometer operating in reflection mode using Cu Kα radiation. The instrument uses Cu Kα irradiation (40 kV, 40 mA) and is carried out at room temperature using an SSD160-2 detector. The scanning range is in the 2θ interval from 3° to 40°, and the scanning speed is 0.1 s / step. The diffraction pattern is analyzed using DIFFRAC.MEA.CENTER software.

[0376] For the preparation of XRPD samples, the sample is placed on a single-crystalline silicon wafer, and the sample powder is pressed with a glass slide or equivalent to ensure that the surface of the sample is flat and has an appropriate height. Then the sample holder is placed in the Bruker D8 Advance instrument, and the X-ray powder diffraction pattern is collected using the instrument parameters described above. Measurement differences related to the results of such X-ray powder diffraction analysis are caused by various factors including: (a) errors in sample preparation (such as sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including those occurring in determining peak positions), and (e) the nature of the substance (such as preferred orientation errors). Calibration errors and sample height errors often result in the displacement of all peaks in the same direction. Generally, this calibration factor will make the measured peak positions consistent with the expected peak positions and can be within the range of the expected 2θ value ±0.2°.

[0377] The experimental method for characterizing the crystal form of the acid salt or base salt of Compound I by differential scanning calorimetry (DSC) is as follows: Take a small amount of the polymorph of crystalline Compound I and place it in an aluminum crucible that is compatible with the instrument and can be capped. After loading the sample, it is capped with an aluminum disc, and then sent into the instrument for detection. The instrument model used for all differential scanning calorimetry in this patent is METTLER TOLEDO DSC 3, and the scanning parameters are set to use a nitrogen atmosphere with a heating rate of 10.0 k / min.

[0378] The experimental method for characterizing the polymorphs of Compound I by thermogravimetric analysis (TGA) is as follows: Take a small amount of the powder of the polymorph of Compound I and place it in an alumina crucible that is compatible with the instrument. After loading the sample, it is sent into the instrument for detection. The instrument model used for all thermogravimetric analysis in this patent is METTLER TOLEDO TGA 2, and the scanning parameters are set to use a nitrogen atmosphere with a heating rate of 10.0 k / min.

[0379] The experimental method for characterizing the acid salt or basic salt of Compound I by dynamic vapor sorption (DVS) is as follows: Take a small amount of the polymorphic powder of Compound I and place it in a precision sample pan compatible with the instrument. After loading the sample, send it into the instrument for detection. In this patent, the instrument model used for all dynamic vapor sorption methods is Intrinsic PLUS. The experimental parameters are set as follows: The constant temperature is set at 25 °C, and the mass percentage change rate per unit time (dm / dt) = 0.02% / min is used as the criterion for reaching equilibrium. The program humidity change cycle is set such that the initial relative humidity is 0% and the relative humidity at the end point is 90%. Detailed implementation manners

[0380] The technical solution of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only for illustrative explanation of the present invention and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0381] Unless otherwise specified, the raw materials and reagents used in the following embodiments are commercially available products or can be prepared by known methods.

[0382] Preparation of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (amorphous form of Compound I)

[0383]

[0384] Step 1: Synthesis of methyl (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0385] A mixture of N,N-dimethylformamide (80 mL) containing methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (1.5 g, 5.1 mmol), 2-(4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-oxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) was stirred at 60 °C for 3 hours, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give (S)-2-((4-((6-(((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (1.0 g, yield: 33.5%).

[0386] Step 2: Synthesis of (S)-2-((4-((6-(((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid

[0387] Lithium hydroxide (0.13 g, 5.4 mmol) was added to a mixture of tetrahydrofuran / water (20 mL / 20 mL) containing methyl (S)-2-((4-((6-(((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (1.0 g, 1.7 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 under vacuum. The residue was purified by reversed-phase rapid column chromatography to give (S)-2-((4-((6-(((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (0.69 g, yield: 70.5%). It was characterized by XRPD, DSC, and TGA. Compound I was an amorphous substance, and its X-ray powder diffraction pattern, DSC pattern, and TGA pattern are shown below. Figure 64 , Figure 65 and Figure 66 . 1H NMR (400MHz, DMSO- d6): δ8.27(s,1H),7.80(dd,J=8.4Hz,1.2Hz,1H),7.72(t,J=7.6Hz,1H),7.64(d,J=8.4Hz,1H), 7.44(dd,J=11.2Hz,2.0Hz,1H),7.28(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2Hz ,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.12-5.06(m,1H),4.95-4.93(m,1H),4.81-4.76(m,1 H),4.66-4.62(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J=13.6Hz,1H),3.78(d,J =13.6Hz,1H),2.79-2.67(m,2H),2.46-2.41(m,1H),2.32(s,2H),1.92-1.91(m,2H),1.63-1.59 (m,2H).

[0388] Example 2 Preparation of crystal form A of compound I

[0389] 200 mg of compound I was added to 7.5 mL of isopropanol, sonicated at 50 °C to promote dissolution, filtered, and the filtrate was stirred at 5 °C for about 16 h. The filtrate was then filtered again, and the filter cake was dried in an oven at 50 °C to obtain crystal form A of the compound. The product was subjected to XRPD (…). Figure 1 ), DSC Figure 22 ) and TGA ( Figure 43 )Analysis and characterization.

[0390] Example 3 Preparation of crystal form B of compound I

[0391] 200 mg of compound I was added to 3 mL of ethyl acetate, sonicated at 50 °C to promote dissolution, filtered, and the filtrate was stirred at 5 °C for about 16 h. The filtrate was then filtered again, and the filter cake was dried in an oven at 50 °C to obtain crystal form B of the compound. The product was subjected to XRPD (…). Figure 2 ), DSC (Figure 23) and TGA ( Figure 44 )Analysis and characterization.

[0392] Example 4: Preparation of crystal form C of compound I

[0393] 200 mg of compound I was added to 9 mL of acetonitrile, sonicated at 50 °C to promote dissolution, filtered, and the filtrate was stirred at 5 °C for about 16 h. The filtrate was then filtered again, and the filter cake was dried in an oven at 50 °C to obtain crystal form C of the compound. The product was subjected to XRPD (…). Figure 3 ), DSC (Figure 24) and TGA ( Figure 45 )Analysis and characterization.

[0394] Example 5: Preparation of crystal form D of compound I

[0395] 200 mg of compound I was added to 2.5 mL of isopropyl ether / ethyl acetate (6:1 v:v), stirred at 50 °C for 2 hours, then cooled to 5 °C and stirred for another 2 hours. The mixture was filtered, and the filter cake was dried in a 50 °C oven to obtain crystal form D of the compound. The product was subjected to XRPD (Figure 4) and DSC (…). Figure 25 ) and TGA ( Figure 46 )Analysis and characterization.

[0396] Example 6 Preparation of crystal form E of compound I

[0397] 20 mg of compound I was suspended in 0.5 mL of n-hexane / dichloromethane (3:1 v:v), stirred at 5 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the crystal form E of the compound. The product was subjected to XRPD (…). Figure 5 ), DSC Figure 26 Characterization was performed using TGA (Figure 47).

[0398] Example 7 Preparation of crystal form F of compound I

[0399] 20 mg of compound I was suspended in 0.5 mL of water / acetone (6:1 v:v), stirred at 50 °C for 2 hours, then cooled to 5 °C and stirred for another 2 hours. The mixture was filtered, and the filter cake was dried in a 50 °C oven to obtain crystal form F of the compound. The product was subjected to XRPD (…). Figure 6 ), DSC Figure 27 ) and TGA ( Figure 48 )Analysis and characterization.

[0400] Example 8: Preparation of crystal form G of the hydrate of compound I

[0401] 100 mg of compound I was suspended in 2.5 mL of water and stirred at 5 °C for 3 days. The mixture was then filtered, and the filter cake was dried in an oven at 50 °C to obtain the hydrate crystal form G of the compound. The product was subjected to XRPD (…). Figure 7 ), DSC Figure 28 ) and TGA ( Figure 49 )Analysis and characterization.

[0402] Example 9: Preparation of crystal form H of the methyl isobutyl ketone solvate of compound I

[0403] 20 mg of compound I was suspended in 0.5 mL of methyl isobutyl ketone and stirred at room temperature for 3 days. The mixture was then filtered, and the filter cake was dried in a 40°C oven to obtain the crystalline form H of the methyl isobutyl ketone solvate of the compound. The product was subjected to XRPD (…). Figure 8 ), DSC Figure 29 ) and TGA ( Figure 50 )Analysis and characterization. 1 H NMR (400MHz, DMSO-d6): δ12.73(br,1H),8.27(s,1H),7.81(dd, J=8.4Hz,1.2Hz,1H),7.74(t,J=7.6Hz,1H),7.66(d,J=8.4Hz,1H),7.43(dd,J=11.2Hz,2.0Hz ,1H),7.30(t,J=8.8Hz,1H),7.17(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.71(d,J=8.0Hz,1 H),5.18(s,2H),5.10-5.08(m,1H),4.95-4.93(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.5 1-4.49(m,1H),4.38-4.36(m,1H),3.95(d,J=13.6Hz,1H),3.78(d,J=13.6Hz,1H),2.73-2.69(m, 3H),2.32-2.28(m,4H),2.06-1.91(m,4H),1.63-1.59(m,2H),0.86-0.84(d,J=6.8Hz,4H).

[0404] Example 10 Preparation of crystal form I-1 of the methyl tert-butyl ether solvate of compound I

[0405] 20 mg of compound I was suspended in 1.0 mL of ethyl acetate and filtered to obtain a clear solution. This solution was then transferred to a 20 mL vial containing 3 mL of methyl tert-butyl ether, sealed with the cap, and left at room temperature for 3 days. The solution was then filtered, and the filter cake was dried in a 50°C oven to obtain crystal form I-1 of the methyl tert-butyl ether solvate of the compound. The product was subjected to XRPD (…). Figure 9 ), DSC Figure 30 ) and TGA ( Figure 51 )Analysis and characterization. 1H NMR (400MHz, DMSO-d6): δ12.72 (br,1H),8.27(s,1H),7.81(d,J=8.4Hz,1H),7.75(t,J=7.6Hz,1H),7.67(d,J=8.4Hz,1H),7.4 4(dd,J=11.2Hz,2.0Hz,1H),7.30(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.03(d,J=7.2Hz,1H) ,6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m,1H),4.95-4.93(m,1H),4.78-4.76(m,1H),4 .66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96(d,J=13.6Hz,1H),3.79(d,J=13.6 Hz,1H),3.08(s,3H),2.72-2.70(m,3H),2.32-2.28(m,4H),1.99-1.91(m,4H),1.63-1.59(m,2H),1.11(s,8H).

[0406] Example 11 Preparation of crystal form I-2 of the methyl tert-butyl ether solvate of compound I

[0407] 20 mg of compound I was suspended in 0.5 mL of methyl tert-butyl ether / isopropyl acetate (4:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the crystal form I-2 of the methyl tert-butyl ether solvate of the compound. The product was subjected to XRPD (…). Figure 10 ), DSC Figure 31 ) and TGA ( Figure 52 )Analysis and characterization. 1H NMR(400MHz,DMSO-d6): δ12.72(br,1H),8.27(s,1H),7.81(d,J=8.4Hz,1H),7.76(t,J=7.6Hz,1H),7.67(d,J=8.4Hz,1 H),7.45(dd,J=11.2Hz,2.0Hz,1H),7.31(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2 Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.11-5.09(m,1H),4.96-4.94(m,1H),4.78-4.76(m ,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96(d,J=13.6Hz,1H),3.79(d, J=13.6Hz,1H),3.08(s,4H),2.73-2.70(m,3H),2.32-2.28(m,3H),1.99-1.91(m,2H),1.63-1.59(m,2H),1.11(s,12H).

[0408] Example 12 Preparation of crystal form J of acetone solvate of compound I

[0409] Approximately 20 mg of compound I was weighed and added to 0.5 mL of acetone in three portions, grinding for 5 min each time. The resulting solid was dried in an oven at 50 °C to obtain the crystal form J of the acetone solvate of the compound. The product was subjected to XRPD (…). Figure 11 ), DSC Figure 32 ) and TGA ( Figure 53 )Analysis and characterization. 1H NMR (400MHz, DMSO-d6): δ12.70(br,1H),8.27(s,1H),7.81(dd, J=8.4Hz,1.2Hz,1H),7.72(t,J=7.6Hz,1H),7.64(d,J=8.4Hz,1H),7.44(dd,J=11.2Hz,2.0Hz ,1H),7.28(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1 H),5.18(s,2H),5.12-5.07(m,1H),4.95-4.92(m,1H),4.81-4.77(m,1H),4.66-4.63(m,1H),4.5 2-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J=13.6Hz,1H),3.78(d,J=13.6Hz,1H),2.73-2.69(m, 3H),2.46-2.32(m,3H),2.09(s,3H),1.92-1.91(m,2H),1.63-1.59(m,2H).

[0410] Example 13 Preparation of crystal form K of the n-heptane solvate of compound I

[0411] Approximately 20 mg of compound I was weighed and suspended in 0.5 mL of n-heptane / tetrahydrofuran (3:1 v:v), stirred at 5 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the crystal form K of the n-heptane solvate of the compound. The product was subjected to XRPD (…). Figure 12 ), DSC Figure 33 ) and TGA ( Figure 54 )Analysis and characterization. 1H NMR(400MHz,DMSO-d6): δ12.80(br,1H),8.26(s,1 H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(dd,J=11 .2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d, J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.6 3(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J=13.6Hz,1H),3.78(d,J=13.6Hz,1H), 2.73-2.69(m,3H),2.43-2.32(m,3H),1.92-1.91(m,2H),1.63-1.61(m,2H),1.24(s,1.2H),0.87-0.85(m,0.7H).

[0412] Example 14 Preparation of crystal form L of the methylcyclohexane solvate of compound I

[0413] Approximately 20 mg of compound I was weighed and suspended in 0.5 mL of methylcyclohexane / tetrahydrofuran (6:1 v:v). The mixture was stirred at 50 °C for 2 hours, then cooled to 5 °C and stirred for another 2 hours. The mixture was filtered, and the filter cake was dried in an oven at 50 °C to obtain the crystal form L of the methylcyclohexane solvate of the compound. The product was subjected to XRPD (…). Figure 13 ), DSC Figure 34 ) and TGA ( Figure 55 )Analysis and characterization. 1H NMR (400MHz, DMSO-d6): δ12.81(br,1H),8.26(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t, J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7 .19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m, 1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m, 1H),3.95(d,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),2.73-2.70(m,3H),2.43-2.32(m,3H),1.92- 1.91(m,2H),1.63-1.59(m,2H),1.25-0.83(m,2H).

[0414] Example 15 Preparation of crystal form M of the toluene solvate of compound I

[0415] Approximately 20 mg of compound I was weighed and dissolved in 0.5 mL of toluene, and the solution was filtered to obtain a clear solution. This solution was then transferred to a 20 mL vial containing 3 mL of isopropyl ether. The vial was sealed with the cap and left at room temperature for 2 days. The solution was then filtered, and the filter cake was dried in a 50°C oven to obtain the crystal form M of the toluene solvate of the compound. The product was subjected to XRPD (…). Figure 14 ), DSC Figure 35 ) and TGA ( Figure 56 )Analysis and characterization. 1H NMR (400MHz, DMSO-d6): δ12.73(br,1H),8.26(s,1 H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(dd,J=11. 2Hz,2.0Hz,1H),7.30-7.14(m,8H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5 .10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4 .38-4.36(m,1H),3.95(d,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),2.73-2.70(m,3H),2.43-2.30 (m,7H),1.92-1.91(m,2H),1.63-1.59(m,2H).

[0416] Example 16 Preparation of crystal form N of the dioxane solvate of compound I

[0417] Approximately 20 mg of compound I was weighed and suspended in 0.5 mL of n-heptane / dioxane (3:1 v:v), stirred at 5 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the crystal form N of the dioxane solvate of the compound. The product was subjected to XRPD (Figure 15) and DSC (…). Figure 36 ) and TGA ( Figure 57 )Analysis and characterization. 1H NMR(400MHz,DMSO-d6): δ12.81(br,1H),8.26 (s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(d d,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H), 6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4 .66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J=13.6Hz,1H),3.79(d,J=13.6 Hz,1H),3.57(s,14H),2.73-2.69(m,3H),2.51-2.32(m,3H),1.92-1.91(m,2H),1.63-1.61(m,2H).

[0418] Example 17 Preparation of crystal form O of the DMF solvate of compound I

[0419] Approximately 20 mg of compound I was weighed and dissolved in 0.5 mL of DMF / isopropyl ether (1:4 v:v). The solution was left to stand open at room temperature for 1 day to evaporate. After filtration, the filter cake was dried in an oven at 50°C to obtain the crystal form O of the DMF solvate of the compound. The product was subjected to XRPD (…). Figure 16 ), DSC Figure 37 ) and TGA ( Figure 58 )Analysis and characterization. 1H NMR(400MHz,DMSO-d6):δ 12.81(br,1H),8.26(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8. 4Hz,1H),7.45(dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.20(d,J=8.4Hz,1H),7.04(d, J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.78- 4.76(m,1H),4.66-4.63(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J=13.6Hz,1H), 3.79(d,J=13.6Hz,1H),2.89(s,3H),2.73-2.70(m,3H),2.43-2.32(m,3H),1.92-1.91(m,2H), 1.63-1.59(m,2H).

[0420] Example 18 Preparation of crystal form P of N-methylpyrrolidone solvate of compound I

[0421] Approximately 20 mg of compound I was weighed and suspended in 0.5 mL of N-methylpyrrolidone / isopropyl ether (1:9 v:v), stirred at 5 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the crystal form P of the N-methylpyrrolidone solvate of the compound. The product was subjected to XRPD (…). Figure 17 ), DSC Figure 38 ) and TGA ( Figure 59 )Analysis and characterization. 1H NMR(400MHz,DMSO-d6):δ 12.76(br,1H),8.27(s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8. 4Hz,1H),7.45(dd,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d, J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.19(s,2H),5.10-5.09(m,1H),4.94-4.92(m,1H),4.81- 4.78(m,1H),4.66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1H),3.96(d,J=13.5Hz,1H), 3.78(d,J=13.5Hz,1H),3.32-3.29(m,3H),2.73-2.70(m,6H),2.43-2.32(m,3H),2.20-2.16(m,2H),1.94-1.88(m,4H),1.63-1.61(m,2H).

[0422] Example 19 Preparation of crystal form Q of the n-butanol solvate of compound I

[0423] Approximately 20 mg of compound I was weighed and suspended in 0.5 mL of n-butanol. The mixture was stirred at 50 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the crystal form Q of the n-butanol solvate of the compound. The product was subjected to XRPD (…). Figure 18 ), DSC Figure 39 ) and TGA ( Figure 60 )Analysis and characterization. 1H NMR (400MHz, DMSO-d6): δ12.73(br,1H),8.27(s,1H),7.81(dd, J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.73(d,J=8.4Hz,1H),7.45(dd,J=11.2Hz,2.0Hz ,1H),7.29(t,J=8.8Hz,1H),7.20(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1 H),5.18(s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4.66-4.63(m,1H),4.50 -4.49(m,1H),4.39-4.31(m,1.8H),3.94(d,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),3.39-3.38(m, 1.6H),2.70-2.69(m,3H),2.43-2.32(m,3H),1.92-1.91(m,2H),1.63-1.59(m,2H),1.39-1.28(m,3.2H),0.88-0.85(m,2.3H).

[0424] Example 20: Preparation of crystal form R of the n-propanol solvate of compound I

[0425] Approximately 20 mg of compound I was weighed and suspended in 0.5 mL of methyl tert-butyl ether / n-propanol (1:1 v:v), stirred at 50 °C for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the crystal form R of the n-propanol solvate of the compound. The product was subjected to XRPD (…). Figure 19 ), DSC Figure 40 ) and TGA ( Figure 61 )Analysis and characterization. 1H NMR(400MHz,DMSO-d6): δ12.80(br,1H),8.27 (s,1H),7.81(dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(d d,J=11.2Hz,2.0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H), 6.72(d,J=8.0Hz,1H),5.18(s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.81-4.78(m,1H),4. 66-4.63(m,1H),4.50-4.49(m,1H),4.38-4.36(m,1.6H),3.95(d,J=13.6Hz,1H),3.79(d,J=13.6 Hz,1H),3.36-3.32(m,1H),2.71-2.69(m,3H),2.49-2.32(m,3H),1.92-1 .91(m,2H),1.63-1.59(m,2H),1.44-1.39(m,1.6H),0.85-0.82(m,2.5H).

[0426] Example 21 Preparation of crystal form S of tetrahydrofuran solvate of compound I

[0427] Approximately 20 mg of compound I was weighed and dissolved in 0.5 mL of tetrahydrofuran. This solution was then transferred to a 20 mL vial containing 3 mL of isopropyl ether. The vial was sealed and allowed to stand at room temperature for 2 days. The solution was filtered, and the filter cake was dried in a 50°C oven to obtain the crystal form S of the tetrahydrofuran solvate of the compound. The product was subjected to XRPD (…). Figure 20 ), DSC Figure 41 ) and TGA ( Figure 62 )Analysis and characterization. 1H NMR (400MHz, DMSO-d6): δ12.80(br,1H),8.26(s,1H),7.81(dd, J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(dd,J=11.2Hz,2.0Hz, 1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H), 5.18(s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4.50- 4.49(m,1H),4.38-4.36(m,1H),3.95(d,J=13.6Hz,1H),3.79(d,J=13.6Hz,1H),3.62-3.59(m,2. 8H),2.73-2.69(m,3H),2.43-2.32(m,3H),1.92-1.90(m,2H),1.78-1.74(m,2.7H),1.63-1.61(m, 2H).

[0428] Example 22 Preparation of crystal form T of the 2-methyltetrahydrofuran solvate of compound I

[0429] Approximately 20 mg of compound I was weighed and dissolved in 0.5 mL of 2-methyltetrahydrofuran. This solution was then transferred to a 20 mL vial containing 3 mL of diethyl ether. The vial was sealed and allowed to stand at room temperature for 2 days. The solution was filtered, and the filter cake was dried in a 50°C oven to obtain crystal form T of the 2-methyltetrahydrofuran solvate of the compound. The product was subjected to XRPD (extra-X-ray distillation). Figure 21 ), DSC (Figure 42) and TGA ( Figure 63 )Analysis and characterization. 1H NMR (400MHz, DMSO-d6): δ12.80(br,1H),8.27(s,1H),7.81 (dd,J=8.4Hz,1.2Hz,1H),7.79(t,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7.45(dd,J=11.2Hz,2. 0Hz,1H),7.29(t,J=8.8Hz,1H),7.19(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz, 1H),5.18(s,2H),5.10-5.08(m,1H),4.94-4.92(m,1H),4.78-4.76(m,1H),4.66-4.63(m,1H),4 .50-4.49(m,1H),4.38-4.36(m,1H),3.95(d,J=13.6Hz,1H),3.83-3.74(m,2.5H),3.56-3.54(m, 1H),2.73-2.69(m,3H),2.43-2.32(m,3H),1.94-1.89(m,3H),1.89-1.79 (m,1.6H),1.63-1.61(m,2H),1.36-1.26(m,2H),1.12(d,J=6.8Hz,2.3H).

[0430] Study on the equilibrium solubility of polymorphs of compound I in biological media

[0431] The equilibrium solubility of compound I in water (H2O), simulated fasting gastric juice (FaSSGF), simulated fasting intestinal juice (FaSSIF), and simulated saturated intestinal juice (FeSSIF) was tested for both the amorphous solid and crystalline form D of compound I. In the experiment, the solid was prepared into suspensions (~10 mg / mL) in the corresponding buffer solutions and mixed at 37±2℃. After 24 hours, samples of the suspensions were taken, the supernatant was filtered to determine the concentration, and the solid was tested for XRPD. The results are shown in the table below:

[0432]

[0433] The experimental results above show that the stability of crystal form D of compound I in biological media is significantly better than that of the amorphous solid form of compound I. Except for the crystal form transformation to hydrochloride in the FaSSGF system, no crystal form change was observed in other samples of compound I in crystal form D. Its solubility in the FaSSIF system was also significantly improved, meeting the needs of clinical drug formulation development. Therefore, the formation of salts from the free state of compound I can significantly improve its solubility and drug release behavior.

[0434] Solid-state stability study of polymorphs of compound I

[0435] Compound I amorphous solid and its crystal form D were placed under long-term (25℃ / 60%RH), accelerated (40℃ / 75%RH), and high-temperature (60℃, RH<30%) conditions for 7 days, respectively. HPLC purity and crystal form changes were tested, and solid stability was investigated. The results are shown in the table below:

[0436]

[0437] The experimental results above show that the purity of the amorphous solid of compound I did not change significantly after 7 days of long-term storage, but it degraded significantly under accelerated and high-temperature conditions after 7 days. The purity of crystal form D of compound I did not change significantly after 7 days of long-term storage, but it decreased slightly under accelerated and high-temperature conditions after 7 days. The crystal form did not change significantly, and the stability of crystal form D was significantly better than that of the amorphous solid.

[0438] Hygroscopic behavior test of compound I

[0439] The inventors of this patent assessed the stability risk of a sample at 25°C with changes in humidity using a dynamic moisture adsorption method. A damping-viscosity (DVS) test was performed on crystal form D, representing compound I, to evaluate the hygroscopicity of the crystal form. The DVS spectrum of the amorphous solid of the compound is shown below. Figure 67 As shown, the DVS spectrum of crystal form D of the compound is as follows: Figure 68 As shown in the table below:

[0440]

[0441] The above experimental results show that, on the adsorption curves of 0-90%RH, under 80%RH conditions, both the amorphous solid of compound I and the crystalline sample D are slightly hygroscopic with no significant difference, and no change in solid morphology was observed.

[0442] The thermal analysis of some crystal forms of compound I of the present invention is summarized in the table below:

[0443]

[0444]

[0445] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the protection scope of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the protection scope of the claims of this application.

Claims

1. Crystal form D of compound I: ； in: The crystal form D has an X-ray powder diffraction pattern that includes peaks at diffraction angles (2θ) of 14.49±0.2°, 16.98±0.2°, 11.51±0.2° and 18.17±0.2°. The X-ray powder diffraction pattern of the crystal form D also includes peaks at diffraction angles (2θ) of 24.02±0.2°, 21.87±0.2°, 3.58±0.2°, 14.04±0.2° and 20.68±0.2°.

2. The crystal form D according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form D also includes peaks at diffraction angles (2θ) of 19.59±0.2°, 25.60±0.2°, 22.30±0.2°, 22.61±0.2°, 23.53±0.2° and 9.70±0.2°.

3. The crystal form D according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form D is shown in Table 4, where the error range of the 2θ angle is ±0.20°. Table 4 。 4. The crystal form D according to claim 1, characterized in that, The crystal form D has an X-ray powder diffraction pattern as shown in Figure 4.

5. The crystal form D according to claim 1, characterized in that, DSC analysis of the crystal form D showed an endothermic peak near the peak temperature of 167.48 °C when heated.

6. The crystal form D according to claim 1, characterized in that, The crystal form D has a DSC pattern as shown in Figure 25.

7. The crystal form D according to claim 1, characterized in that, The crystal form D has a TGA pattern as shown in Figure 46.

8. The method for preparing crystal form D according to any one of claims 1-7, characterized in that, Includes the following steps: Step 1: Dissolve or disperse compound I in a solvent; Step 2: Stir at 0~50℃ to crystallize; The solvent is isopropyl ether, ethyl acetate, or a mixture thereof.

9. A pharmaceutical composition comprising at least one of the crystal forms D according to any one of claims 1-7 and a pharmaceutically acceptable carrier.

10. The use of crystal form D according to any one of claims 1-7 in the preparation of a medicament for treating metabolic diseases.

11. The application according to claim 10, characterized in that, The diseases mentioned are selected from type 1 diabetes, type 2 diabetes, and obesity.

12. The application according to claim 10, characterized in that, The diseases mentioned are selected from idiopathic type 1 diabetes, adult occult autoimmune diabetes, early-onset diabetes, adolescent-onset atypical diabetes, adolescent-onset adult-onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, adipocyte dysfunction, diabetic nephropathy, diabetic retinopathy, dyslipidemia, non-alcoholic fatty liver disease, metabolic acidosis, and glucose dysmegma.

13. The application according to claim 10, characterized in that, The metabolic diseases mentioned are selected from glucose intolerance, postprandial lipemia, hepatic insulin resistance, visceral fat cell accumulation, diabetic neuropathy, and hyperinsulinemia.

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