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

Abstract

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

Description

[0001] This application claims priority to the prior application filed with the China National Intellectual Property Office on September 6, 2022, with the patent application number 2022110964440, and the name of “Polymorph of GLP-1R Agonist Compound and Preparation Method and Use Thereof”. The prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmaceutical chemistry, and specifically relates to a polymorph of a GLP-1R agonist compound and a preparation method and use thereof. BACKGROUND

[0003] Diabetes is a chronic disease characterized by high blood sugar due to insufficient insulin secretion (relative or absolute) or insulin resistance in the body. According to the ninth edition of the World Diabetes Atlas issued by the International Diabetes Federation (IDF), there were about 463 million adults (20-79 years old) with diabetes worldwide in 2019, and the number of people with diabetes is expected to reach 578 million by 2030. If this trend continues, there will be 700 million people with diabetes worldwide by 2045. Therefore, diabetes has become one of the most serious social health problems in the world in the 21st century.

[0004] There are various pharmacological methods currently used to treat hyperglycemia and accompanying T2DM (Hampp et al., Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 37:1367-1374, 2014). These methods can be divided into six main categories, each acting through a different main mechanism.

[0005] Insulin secretagogues, including sulfonylureas, dipeptidyl peptidase IV (DP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1R) agonists, increase insulin secretion by acting on pancreatic beta cells. Sulfonylureas have limited efficacy and tolerance, cause weight gain, and often induce hypoglycemia. DP-IV inhibitors have limited efficacy. The GLP-1R agonist marketed is a peptide administered by subcutaneous injection, liraglutide, which is approved for the treatment of obesity.

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

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

[0008] Thiazolidinediones (e.g. pioglitazone, rosiglitazone) act on specific receptors in the liver, muscle and fat tissue. They modulate lipid metabolism and subsequently enhance the response of these tissues to the action of insulin. Regular use of these drugs can lead to weight gain and can induce oedema and anaemia.

[0009] Insulin, alone or in combination with the above agents, is used in more severe cases, and regular use can also lead to weight gain and carries the risk of hypoglycaemia.

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

[0011] However, in addition to GLP-1 R agonists and SGLT2 inhibitors, the efficacy of the drugs is limited and the most important problems: beta cell deterioration and associated obesity are not addressed. There is therefore a need for more effective pharmacological interventions with fewer side effects and convenient administration.

[0012] GLP-1 is a 30-amino acid length incretin hormone secreted by intestinal L cells in response to food ingestion. GLP-1 has been shown to stimulate insulin secretion, decrease glucagon secretion, suppress gastric emptying, decrease appetite and stimulate beta cell hyperplasia in a physiological and glucose-dependent manner. In non-clinical trials, GLP-1 promotes sustained beta cell competence by stimulating gene transcription important for glucose-dependent insulin secretion and by promoting beta cell neogenesis (Meier et al., Biodrugs. 17(2):93-102, 2013)

[0013] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion from the pancreas, resulting in increased peripheral glucose uptake. GLP-1 also inhibits glucagon secretion, resulting in decreased hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small intestinal motility, delaying food absorption. In people with T2DM, postprandial GLP-1 does not rise normally or rises less than normal (Vilsboll T et al., Diabetes 50:609-613, 2001).

[0014] Scientific research has made corresponding modifications to the structure of GLP-1 to increase its half-life and thus prolong its biological effects in vivo. However, the long-acting GLP-1 analogs currently used in clinical practice, such as liraglutide and exenatide, are all polypeptides, and frequent multiple injections result in poor patient compliance. Therefore, the development of small molecule GLP-1R agonists will improve patient compliance, drug convenience, and reduce drug side effects, and has a broad clinical market prospect.

[0015] Mindrank AI Ltd. has developed a class of novel small molecule compounds with strong GLP-1R agonist activity, among which the compound with the structure of formula (I) (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 aminotrizol salt (1:1) has strong GLP1R receptor agonist activity and good drugability, and its structure is as follows:

[0016]

[0017] Successful development of the solid form of a drug usually has a solid form that can be easily separated and purified after synthesis, which can be suitable for industrial production, can be stored for a long period of time and minimally absorbs water, decomposes or converts into other solid forms, and is suitable for a dosage form that can be rapidly absorbed by individuals after administration (such as being soluble in water and gastric juice). In order to meet the needs of clinical research and marketed drug formulations, it is urgent to develop a pharmaceutical crystal form that can be easily separated and purified, suitable for industrial production, has stable physicochemical properties. SUMMARY

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

[0019]

[0020] According to an embodiment of the present application, the polymorph is a solvate-free crystalline form, a hydrate crystalline form, a solvate crystalline form or a metastable crystalline form of Compound I.

[0021] According to an embodiment of the present application, the solvate-free crystalline form can be Form A, B, C; the hydrate crystalline form can be Form D; the solvate crystalline form can be Form E, F, G, H, I; and the metastable crystalline form can be Form J, K, L, M, N.

[0022] The present application provides Form A of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 7.42±0.2°, 3.68±0.2°, 21.85±0.2° and 18.75±0.2°.

[0023] According to the present application, the Form A preferably further comprises peaks at diffraction angles (2Θ) of 9.29±0.2°, 16.71±0.2°, 11.18±0.2°, 15.32±0.2° and 14.94±0.2°.

[0024] According to the present application, the Form A more preferably further comprises peaks at diffraction angles (2Θ) of 27.81±0.2°, 17.00±0.2°, 19.81±0.2°, 11.80±0.2°, 25.69±0.2° and 17.43±0.2°.

[0025] Preferably, the X-ray powder diffraction pattern of the Form A has diffraction angles (2Θ) as shown in Table 1, wherein the error range of the 2Θ angles is ±0.20°:

[0026] Table 1

[0027]

[0028]

[0029] Preferably, the Form A has X-ray powder diffraction intensities as shown in Table 1.

[0030] Preferably, the Form A has an X-ray powder diffraction pattern substantially as shown in Figure 1 Preferably, the Form A has an X-ray powder diffraction pattern substantially as shown in

[0031] Preferably, the Form A has a DSC profile substantially as shown in

[0032] Preferably, the Form A has a DSC profile substantially as shown in Figure 2 Preferably, the Form A has a DSC profile substantially as shown in

[0033] Preferably, the Form A has a DSC profile substantially as shown in Figure 3the TGA pattern shown.

[0034] The present application provides a crystalline form B of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 7.07±0.2°, 19.25±0.2°, 14.45±0.2° and 15.26±0.2°;

[0035] According to the present application, the crystalline form B preferably further comprises peaks at diffraction angles (2Θ) of 11.20±0.2°, 18.17±0.2°, 13.26±0.2°, 23.28±0.2° and 21.35±0.2°;

[0036] According to the present application, the crystalline form B more preferably further comprises peaks at diffraction angles (2Θ) of 15.72±0.2°, 26.17±0.2°, 16.54±0.2°, 24.23±0.2°, 14.76±0.2° and 22.65±0.2°;

[0037] According to the present application, preferably, the X-ray powder diffraction pattern of the crystalline form B has diffraction angles (2Θ) as shown in Table 2, wherein the error range of the 2Θ angles is ±0.20°:

[0038] Table 2

[0039]

[0040] Preferably, the crystalline form B has X-ray powder diffraction intensities as shown in Table 2.

[0041] Preferably, the crystalline form B has an X-ray powder diffraction pattern substantially as shown in Figure 4 Preferably, the crystalline form B has an X-ray powder diffraction pattern substantially as shown in

[0042] Preferably, the crystalline form B has a DSC analysis showing an endothermic peak near the peak temperature of 160.15°C.

[0043] Preferably, the crystalline form B has a DSC pattern substantially as shown in Figure 5 Preferably, the crystalline form B has a DSC pattern substantially as shown in

[0044] Preferably, the crystalline form B has a TGA pattern substantially as shown in Figure 6 Preferably, the crystalline form B has a TGA pattern substantially as shown in

[0045] The present application provides a crystalline form C of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2Θ) of 10.90±0.2°, 5.80±0.2°, 19.28±0.2° and 14.49±0.2°;

[0046] According to the present application, the crystalline form C further preferably comprises peaks at diffraction angles (2θ) of 16.38±0.2°, 25.22±0.2°, 19.03±0.2°, 20.82±0.2°, 18.00±0.2° and 18.15±0.2°;

[0047] According to the present application, the crystalline form C further preferably comprises peaks at diffraction angles (2θ) of 16.38±0.2°, 25.22±0.2°, 19.03±0.2°, 20.82±0.2°, 18.00±0.2° and 18.15±0.2°;

[0048] According to the present application, preferably, the X-ray powder diffraction pattern of the crystalline form C has diffraction angles (2θ) as shown in Table 3, wherein the error range of the 2θ angles is ±0.20°:

[0049] Table 3

[0050]

[0051] Preferably, the crystalline form C has X-ray powder diffraction intensities as shown in Table 3.

[0052] Preferably, the crystalline form C has an X-ray powder diffraction pattern substantially as Figure 7 shown.

[0053] Preferably, the DSC analysis of the crystalline form C shows endothermic peaks near the peak temperatures 160.99°C and 170.25°C.

[0054] Preferably, the crystalline form C has a DSC pattern substantially as Figure 8 shown.

[0055] Preferably, the crystalline form C has a TGA pattern substantially as Figure 9 shown.

[0056] The present application provides a hydrate crystalline form D of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 7.71±0.2°, 10.96±0.2°, 12.34±0.2° and 19.38±0.2°;

[0057] According to the present application, the crystalline form D further preferably comprises peaks at diffraction angles (2θ) of 23.30±0.2°, 16.42±0.2°, 11.60±0.2°, 14.30±0.2° and 3.81±0.2°;

[0058] According to the present application, the crystalline Form D more preferably further comprises peaks at diffraction angles (2θ) of 21.54±0.2°, 22.55±0.2°, 25.40±0.2°, 26.96±0.2°, 15.78±0.2° and 21.29±0.2°;

[0059] According to the present application, preferably, the X-ray powder diffraction pattern of the crystalline Form D has diffraction angles (2θ) as shown in Table 4, wherein the error range of the 2θ angles is ±0.20°:

[0060] Table 4

[0061]

[0062] Preferably, the crystalline Form D has X-ray powder diffraction intensities as shown in Table 4.

[0063] Preferably, the crystalline Form D has an X-ray powder diffraction pattern substantially as shown in Figure 4. Figure 10

[0064] Preferably, the DSC analysis of the crystalline Form D shows endothermic peaks near the peak temperatures of 62.09°C, 79.77°C and 173.12°C.

[0065] Preferably, the crystalline Form D has a DSC pattern substantially as shown in Figure 5. Figure 11

[0066] Preferably, the crystalline Form D has a TGA pattern substantially as shown in Figure 6. Figure 12

[0067] The present application provides a trichloromethane solvate crystalline Form E of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 18.84±0.2°, 7.26±0.2°, 22.92±0.2° and 9.35±0.2°;

[0068] According to the present application, the crystalline Form E more preferably further comprises peaks at diffraction angles (2θ) of 22.05±0.2°, 18.36±0.2°, 6.21±0.2°, 3.60±0.2° and 16.98±0.2°;

[0069] According to the present application, the crystalline Form E more preferably further comprises peaks at diffraction angles (2θ) of 12.50±0.2°, 34.99±0.2°, 16.11±0.2°, 20.51±0.2°, 19.57±0.2° and 17.57±0.2°;

[0070] ​​​According to the present application, preferably, the X-ray powder diffraction pattern of said crystalline Form E has peaks at diffraction angles (2 theta) as shown in Table 5, wherein the error range for said 2 theta angles is + / - 0.20°:

[0071] Table 5

[0072]

[0073]

[0074] Preferably, said crystalline Form E has X-ray powder diffraction intensities as shown in Table 5.

[0075] Preferably, said crystalline Form E has an X-ray powder diffraction pattern substantially as Figure 13 shown in Figure 1.

[0076] Preferably, said crystalline Form E has a DSC profile substantially as

[0077] Preferably, said crystalline Form E has a DSC profile substantially as Figure 14

[0078] Preferably, said crystalline Form E has a TGA profile substantially as Figure 15

[0079] The present application provides a N-methylpyrrolidone solvate crystalline Form F of Compound I having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2 theta) of 6.60+0.2°, 19.57+0.2°, 5.89+0.2° and 14.96+0.2°;

[0080] According to the present application, said crystalline Form F preferably further comprises peaks at diffraction angles (2 theta) of 25.69+0.2°, 3.27+0.2°, 17.49+0.2°, 19.32+0.2° and 16.89+0.2°;

[0081] According to the present application, said crystalline Form F more preferably further comprises peaks at diffraction angles (2 theta) of 16.01+0.2°, 18.07+0.2°, 21.13+0.2°, 22.46+0.2°, 15.48+0.2° and 27.29+0.2°;

[0082] According to the present application, preferably, the X-ray powder diffraction pattern of said crystalline Form F has peaks at diffraction angles (2 theta) as shown in Table 6, wherein the error range for said 2 theta angles is + / - 0.20°:

[0083] Table 6

[0084] ​​

[0085] Preferably, the Form F has an X-ray powder diffraction intensity as shown in Table 6.

[0086] Preferably, the Form F has an X-ray powder diffraction pattern substantially as shown in Table 6. Figure 16

[0087] Preferably, the Form F has a DSC profile substantially as shown in Table 5.

[0088] Preferably, the Form F has a DSC profile substantially as shown in Table 5. Figure 17

[0089] Preferably, the Form F has a TGA profile substantially as shown in Table 5. Figure 18

[0090] The present application provides a N-methylpyrrolidone solvate Form G of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2° and 22.19±0.2°;

[0091] According to the present application, the Form G preferably further comprises peaks at diffraction angles (2θ) of 31.61±0.2°, 18.11±0.2°, 20.55±0.2°, 18.97±0.2° and 15.76±0.2°;

[0092] According to the present application, the Form G more preferably further comprises peaks at diffraction angles (2θ) of 28.52±0.2°, 35.16±0.2°, 20.86±0.2°, 16.36±0.2°, 26.02±0.2° and 17.18±0.2°;

[0093] According to the present application, preferably, the X-ray powder diffraction pattern of the Form G has diffraction angles (2θ) as shown in Table 7, wherein the error range of the 2θ angles is ±0.20°:

[0094] Table 7

[0095]

[0096] Preferably, the Form G has an X-ray powder diffraction intensity as shown in Table 7.

[0097] Preferably, the Form G has an X-ray powder diffraction pattern substantially as shown in Table 7. Figure 19

[0098] ​​​​Preferably, the DSC analysis of said crystalline Form G exhibits endothermic peaks around the peak temperatures of 109.95 °C and 166.02 °C.

[0099] Preferably, said crystalline Form G has a TGA pattern substantially as Figure 20 shown.

[0100] Preferably, said crystalline Form G has a TGA pattern substantially as Figure 21 shown.

[0101] The present application provides a tetrahydrofuran solvate crystalline Form H of Compound I, having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 3.29 ± 0.2°, 3.71 ± 0.2°, 19.71 ± 0.2° and 19.24 ± 0.2°;

[0102] According to the present application, said crystalline Form H further preferably comprises peaks at diffraction angles (2θ) of 7.46 ± 0.2°, 13.12 ± 0.2°, 23.08 ± 0.2°, 22.73 ± 0.2° and 6.60 ± 0.2°;

[0103] According to the present application, said crystalline Form H more preferably further comprises peaks at diffraction angles (2θ) of 10.73 ± 0.2°, 11.43 ± 0.2°, 22.05 ± 0.2°, 9.82 ± 0.2°, 25.34 ± 0.2° and 16.83 ± 0.2°;

[0104] According to the present application, preferably, the X-ray powder diffraction pattern of said crystalline Form H has diffraction angles (2θ) as shown in Table 8, wherein the error range for said 2θ angles is ± 0.20°:

[0105] Table 8

[0106]

[0107]

[0108] Preferably, said crystalline Form H has X-ray powder diffraction intensities as shown in Table 8.

[0109] Preferably, said crystalline Form H has an X-ray powder diffraction pattern substantially as Figure 22 shown.

[0110] Preferably, the DSC analysis of said crystalline Form H exhibits endothermic peaks around the peak temperatures of 82.80 °C and 174.84 °C.

[0111] Preferably, said crystalline Form H has a DSC pattern substantially as Figure 23 shown.

[0112] Preferably, the crystal form H has essentially the following properties: Figure 24 The TGA diagram shown.

[0113] The present invention provides an ethanol solvate crystal form I of compound I, whose X-ray powder diffraction pattern includes peaks located at diffraction angles (2θ) of 18.97±0.2°, 10.71±0.2°, 16.19±0.2° and 22.67±0.2°;

[0114] According to the present invention, the crystal form I preferably further includes peaks located at diffraction angles (2θ) of 12.79±0.2°, 15.13±0.2°, 17.99±0.2°, 22.52±0.2° and 23.94±0.2°;

[0115] According to the present invention, the crystal form I more preferably further includes peaks located at diffraction angles (2θ) of 16.53±0.2°, 24.99±0.2°, 21.85±0.2°, 19.28±0.2°, 26.69±0.2° and 24.38±0.2°;

[0116] According to the present invention, preferably, the X-ray powder diffraction pattern of crystal form I has a diffraction angle (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°:

[0117] Table 9

[0118]

[0119] Preferably, the crystal form I has the X-ray powder diffraction intensity shown in Table 9.

[0120] Preferably, the crystal form I has essentially the following characteristics: Figure 25 The X-ray powder diffraction pattern shown.

[0121] Preferably, the DSC analysis of crystal form I shows endothermic peaks near the peak temperatures of 136.10°C and 160.74°C when heated.

[0122] Preferably, the crystal form I has essentially the following characteristics: Figure 26 The DSC spectrum shown.

[0123] Preferably, the crystal form I has essentially the following characteristics: Figure 27 The TGA diagram shown.

[0124] The present invention provides a metastable crystal form J of compound I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 7.22±0.2°, 3.54±0.2°, 15.99±0.2° and 19.34±0.2°;

[0125] According to the present application, the crystalline Form J further preferably comprises peaks at diffraction angles (2θ) of 33.38±0.2°, 27.77±0.2°, 29.53±0.2°, 9.95±0.2°, 20.16±0.2° and 25.56±0.2°;

[0126] According to the present application, the crystalline Form J further preferably comprises peaks at diffraction angles (2θ) of 33.38±0.2°, 27.77±0.2°, 29.53±0.2°, 9.95±0.2°, 20.16±0.2° and 25.56±0.2°;

[0127] According to the present application, preferably, the X-ray powder diffraction pattern of the crystalline Form J has diffraction angles (2θ) as shown in Table 10, wherein the error range of the 2θ angles is ±0.20°:

[0128] Table 10

[0129]

[0130] Preferably, the crystalline Form J has X-ray powder diffraction intensities as shown in Table 10.

[0131] Preferably, the crystalline Form J has an X-ray powder diffraction pattern substantially as shown in Figure 28 .

[0132] The present application provides a metastable crystalline Form K of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 6.13±0.2°, 7.19±0.2°, 3.56±0.2° and 22.63±0.2°;

[0133] According to the present application, the crystalline Form K further preferably comprises peaks at diffraction angles (2θ) of 18.56±0.2°, 12.34±0.2°, 16.83±0.2°, 9.31±0.2° and 26.20±0.2°;

[0134] According to the present application, the crystalline Form K further preferably comprises peaks at diffraction angles (2θ) of 19.63±0.2°, 20.26±0.2°, 23.72±0.2°, 17.40±0.2°, 34.48±0.2° and 24.21±0.2°;

[0135] According to the present application, preferably, the X-ray powder diffraction pattern of the crystalline Form K has diffraction angles (2θ) as shown in Table 11, wherein the error range of the 2θ angles is ±0.20°:

[0136] Table 11

[0137]

[0138]

[0139] Preferably, the Form K has an X-ray powder diffraction pattern with peaks at diffraction angles (2θ) essentially as shown in Table 11.

[0140] Preferably, the Form K has an X-ray powder diffraction pattern with peaks at diffraction angles (2θ) essentially as shown in Table 11. Figure 29

[0141] The present application provides a metastable Form L of Compound I having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) at 8.04±0.2°, 14.49±0.2°, 19.75±0.2° and 15.95±0.2°;

[0142] According to the present application, the Form L preferably further comprises peaks at diffraction angles (2θ) at 18.70±0.2°, 20.85±0.2°, 4.00±0.2°, 23.27±0.2° and 12.40±0.2°;

[0143] According to the present application, the Form L more preferably further comprises peaks at diffraction angles (2θ) at 16.22±0.2°, 15.58±0.2°, 14.27±0.2°, 12.13±0.2°, 15.43±0.2° and 17.69±0.2°;

[0144] According to the present application, preferably, the Form L has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 12, wherein the error range for the 2θ angles is ±0.20°:

[0145] Table 12

[0146]

[0147] Preferably, the Form L has an X-ray powder diffraction pattern with peaks at diffraction angles (2θ) essentially as shown in Table 12.

[0148] Preferably, the Form L has an X-ray powder diffraction pattern with peaks at diffraction angles (2θ) essentially as shown in Table 12. Figure 30

[0149] The present application provides a metastable Form M of Compound I having an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) at 19.96±0.2°, 12.72±0.2°, 7.92±0.2° and 11.12±0.2°;

[0150] According to the present application, the Form M preferably further comprises peaks at diffraction angles (2θ) at 16.54±0.2°, 3.95±0.2°, 21.66±0.2°, 24.01±0.2° and 22.69±0.2°.​​

[0151] According to the present application, the crystalline Form M more preferably further comprises peaks at diffraction angles (2θ) of 14.45±0.2°, 11.92±0.2°, 15.93±0.2°, 20.98±0.2°, 23.59±0.2° and 6.61±0.2°;

[0152] According to the present application, preferably, the X-ray powder diffraction pattern of the crystalline Form M has diffraction angles (2θ) as shown in Table 13, wherein the error range of the 2θ angles is ±0.20°:

[0153] Table 13

[0154]

[0155]

[0156] Preferably, the crystalline Form M has X-ray powder diffraction intensities as shown in Table 13.

[0157] Preferably, the crystalline Form M has an X-ray powder diffraction pattern substantially as shown in Figure 31 .

[0158] The present application provides a metastable crystalline Form N of Compound I, which has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 10.92±0.2°, 15.37±0.2°, 19.34±0.2° and 20.46±0.2°;

[0159] According to the present application, the crystalline Form N preferably further comprises peaks at diffraction angles (2θ) of 12.95±0.2°, 6.93±0.2°, 18.04±0.2°, 16.43±0.2° and 25.26±0.2°;

[0160] According to the present application, the crystalline Form N more preferably further comprises peaks at diffraction angles (2θ) of 5.43±0.2°, 10.75±0.2°, 14.20±0.2°, 23.12±0.2°, 17.87±0.2° and 14.94±0.2°;

[0161] According to the present application, preferably, the X-ray powder diffraction pattern of the crystalline Form N has diffraction angles (2θ) as shown in Table 14, wherein the error range of the 2θ angles is ±0.20°:

[0162] Table 14

[0163]

[0164]

[0165] Preferably, the crystalline Form N has an X-ray powder diffraction intensity as shown in Table 14.

[0166] Preferably, the crystalline Form N has an X-ray powder diffraction pattern as substantially shown in Figure 32

[0167] The second aspect of the present application provides a preparation method of the polymorph of the aforementioned Compound I, selected from the following preparation methods:

[0168] Step 1: dissolving or dispersing Compound I in a solvent;

[0169] Step 2: stirring at 0-50℃ to crystallize; or, adding an anti-solvent to the clear solution of the compound to precipitate; or, slowly evaporating the clear solution of the compound;

[0170] As a further preferred solution, the solvent is water, an organic solvent selected from alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cyclic alkanes, benzene, amides, sulfoxide organic solvents or mixtures thereof, or a mixture solvent thereof; preferably, the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, trifluoroethanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloromethane, trichloroethane, carbon tetrachloride, methyl tert-butyl ether, cyclopentyl methyl ether, 2-methoxyethyl ether, isopropyl ether, ethyl ether, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, methylcyclohexane, benzene, toluene, xylene or a mixture thereof.

[0171] The third aspect of the present application provides a pharmaceutical composition comprising at least one of the polymorphs of the aforementioned Compound I and a pharmaceutically acceptable carrier.

[0172] The fourth aspect of the present application provides use of the polymorphs of the aforementioned Compound I in the preparation of a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0173] The fifth aspect of the present application provides the polymorphs of the aforementioned Compound I for use as a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0174] ​The sixth aspect of the present application provides a polymorph of the aforementioned Compound I for use as a medicament for the prevention or treatment of T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcer, ulcerative colitis, high apoB lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and treatment of addiction.

[0175] As a preferred aspect, the polymorph of the aforementioned Compound I for use as a medicament for the prevention or treatment of T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain caused by use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia.

[0176] The present application also provides a method of treating a disease, comprising administering to an individual in need thereof a therapeutically effective amount of at least one of the aforementioned polymorph of Compound I or the pharmaceutical composition.

[0177] According to an embodiment of the present application, the disease is selected from a metabolic disease, a tumor, an autoimmune disease or a metastatic disease.

[0178] According to an embodiment of the application, the disease is selected from the group consisting of 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 use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, angioplasty restenosis, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcer, ulcerative colitis, high apoB lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome.

[0179] Advantages

[0180] The present application provides a polymorph of Compound I and a preparation method thereof, which has good stability, good fluidity, easy to crush and other advantages, and is more suitable for clinical preparation development. The preparation method provided by the present application has the advantages of simple process, easy implementation, mild reaction condition, high product yield, no need for multiple purifications, safe and environmentally friendly operation, which is conducive to the industrialized production of polymorphs, can meet the needs of clinical drug preparation development, has very important clinical application value, and is expected to accelerate the development of a new generation of GLP-1R small molecule agonists. BRIEF DESCRIPTION OF DRAWINGS

[0181] Figure 1 The X-ray powder diffraction pattern of the crystal form A of Compound I of the present application is shown. The abscissa represents the 2θ value (degree), and the ordinate represents the peak intensity.

[0182] Figure 2 The DSC graph of the crystal form A of Compound I of the present application is shown. The abscissa represents the temperature (℃), and the ordinate represents the heat flow (mW).

[0183] Figure 3 A TGA pattern of crystalline Form A of compound I of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents weight (%).

[0184] Figure 4 An X-ray powder diffraction pattern of crystalline Form B of compound I of the present application is shown. The abscissa represents 2 theta values (degrees) and the ordinate represents peak intensity.

[0185] Figure 5 A DSC pattern of crystalline Form B of compound I of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

[0186] Figure 6 A TGA pattern of crystalline Form B of compound I- of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents weight (%).

[0187] Figure 7 An X-ray powder diffraction pattern of crystalline Form C of compound I of the present application is shown. The abscissa represents 2 theta values (degrees) and the ordinate represents peak intensity.

[0188] Figure 8 A DSC pattern of crystalline Form C of compound I of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

[0189] Figure 9 A TGA pattern of crystalline Form C of compound I- of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents weight (%).

[0190] Figure 10 An X-ray powder diffraction pattern of hydrate Form D of compound I of the present application is shown. The abscissa represents 2 theta values (degrees) and the ordinate represents peak intensity.

[0191] Figure 11 A DSC pattern of hydrate Form D of compound I of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

[0192] Figure 12 A TGA pattern of hydrate Form D of compound I- of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents weight (%).

[0193] Figure 13 An X-ray powder diffraction pattern of crystalline Form E of chloroform solvate of compound I of the present application is shown. The abscissa represents 2 theta values (degrees) and the ordinate represents peak intensity.

[0194] Figure 14A DSC pattern of crystalline Form E of the trichloromethane solvate of Compound I of the present application is shown. The abscissa indicates temperature (°C) and the ordinate indicates heat flow (mW).

[0195] Figure 15 A TGA pattern of crystalline Form E of the trichloromethane solvate of Compound I- of the present application is shown. The abscissa indicates temperature (°C) and the ordinate indicates weight (%).

[0196] Figure 16 An X-ray powder diffraction pattern of crystalline Form F of the N-methylpyrrolidone solvate of Compound I of the present application is shown. The abscissa indicates 2 theta values (degrees) and the ordinate indicates peak intensity.

[0197] Figure 17 A DSC pattern of crystalline Form F of the N-methylpyrrolidone solvate of Compound I of the present application is shown. The abscissa indicates temperature (°C) and the ordinate indicates heat flow (mW).

[0198] Figure 18 A TGA pattern of crystalline Form F of the N-methylpyrrolidone solvate of Compound I- of the present application is shown. The abscissa indicates temperature (°C) and the ordinate indicates weight (%).

[0199] Figure 19 An X-ray powder diffraction pattern of crystalline Form G of the N-methylpyrrolidone solvate of Compound I of the present application is shown. The abscissa indicates 2 theta values (degrees) and the ordinate indicates peak intensity.

[0200] Figure 20 A DSC pattern of crystalline Form G of the N-methylpyrrolidone solvate of Compound I of the present application is shown. The abscissa indicates temperature (°C) and the ordinate indicates heat flow (mW).

[0201] Figure 21 A TGA pattern of crystalline Form G of the N-methylpyrrolidone solvate of Compound I- of the present application is shown. The abscissa indicates temperature (°C) and the ordinate indicates weight (%).

[0202] Figure 22 An X-ray powder diffraction pattern of crystalline Form H of the tetrahydrofuran solvate of Compound I of the present application is shown. The abscissa indicates 2 theta values (degrees) and the ordinate indicates peak intensity.

[0203] Figure 23 A DSC pattern of crystalline Form H of the tetrahydrofuran solvate of Compound I of the present application is shown. The abscissa indicates temperature (°C) and the ordinate indicates heat flow (mW).

[0204] Figure 24A TGA plot of crystalline Form H of tetrahydrofuran solvate of compound I- of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents weight (%).

[0205] Figure 25 An X-ray powder diffraction pattern of crystalline Form I of ethanol solvate of compound I of the present application is shown. The abscissa represents 2 theta value (degrees) and the ordinate represents peak intensity.

[0206] Figure 26 A DSC plot of crystalline Form I of ethanol solvate of compound I of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

[0207] Figure 27 A TGA plot of crystalline Form I of ethanol solvate of compound I- of the present application is shown. The abscissa represents temperature (°C) and the ordinate represents weight (%).

[0208] Figure 28 An X-ray powder diffraction pattern of metastable crystalline Form J of compound I of the present application is shown. The abscissa represents 2 theta value (degrees) and the ordinate represents peak intensity.

[0209] Figure 29 An X-ray powder diffraction pattern of metastable crystalline Form K of compound I of the present application is shown. The abscissa represents 2 theta value (degrees) and the ordinate represents peak intensity.

[0210] Figure 30 An X-ray powder diffraction pattern of metastable crystalline Form L of compound I of the present application is shown. The abscissa represents 2 theta value (degrees) and the ordinate represents peak intensity.

[0211] Figure 31 An X-ray powder diffraction pattern of metastable crystalline Form M of compound I of the present application is shown. The abscissa represents 2 theta value (degrees) and the ordinate represents peak intensity.

[0212] Figure 32 An X-ray powder diffraction pattern of metastable crystalline Form N of compound I of the present application is shown. The abscissa represents 2 theta value (degrees) and the ordinate represents peak intensity.

[0213] Figure 33 A DVS plot of crystalline Form A of compound I of the present application is shown. The abscissa represents relative humidity (%) and the ordinate represents weight change (%).

[0214] Definitions and explanations of terms

[0215] Unless otherwise indicated, the following terms have the following meanings in the specification and claims. A particular phrase or term should not be construed to be indefinite or unclear unless specifically defined, but should be interpreted according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0216] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, to facilitate absorption of the active ingredient, and to facilitate the biological activity of the active ingredient.

[0217] As used herein, "polymorph" refers to crystalline forms having the same chemical composition but different spatial arrangements of the molecules, atoms, and / or ions making up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement and can exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and the like. Two polymorphs can be enantiotropic or monotropic according to their temperature-stability relationships. For monotropic systems, the relative stabilities of the two solid phases remain unchanged upon a change in temperature. In contrast, in enantiotropic systems, there is a transition temperature at which the stabilities of the two phases switch (Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids" (1999) ISBN: 0-8247-0237). The phenomenon of a compound existing in different crystal structures is known as polymorphism in pharmaceuticals.

[0218] The various crystalline structures of the present application can be distinguished from one another using various analytical techniques known to those of ordinary skill in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA).

[0219] As used herein, the term "room temperature" or "RT" means ambient temperature of 20 to 25 °C (68-77 °F).

[0220] 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.

[0221] 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.

[0222] 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.

[0223] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0224] All solvents used in this invention are commercially available and can be used without further purification.

[0225] 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).

[0226] Methods and Materials

[0227] 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.

[0228] 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).

[0229] The polymorphs of Compound I are characterized by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the salts are collected on a Bruker D8 Advance powder diffractometer operated in reflection mode using Cu Ka radiation. The instrument is operated using a SSD 160-2 detector at room temperature with Cu K alpha irradiation (40 kV, 40 mA). The scan range is from 3° to 40° in 2 theta with a scan speed of 0.1 s / step. The diffractograms are analyzed using DIFFRAC.MEA.CENTER software.

[0230] XRPD samples are prepared by placing the sample onto a single crystal silicon wafer, and using a glass slide or equivalent to press the sample powder to ensure the surface of the sample is flat and of an appropriate height. The sample holder is then placed into the Bruker D8 Advance instrument and an X-ray powder diffraction pattern is collected using the instrument parameters described above. Measurement discrepancies associated with such X-ray powder diffraction analysis results arise from a variety of factors including: (a) errors in sample preparation (e.g. sample height), (b) instrument errors, (c) calibration discrepancies, (d) operator errors (including those that arise when determining peak positions), and (e) properties of the material (e.g. preferred orientation errors). Calibration errors and sample height errors often result in shifts of all peaks in the same direction. In general, this calibration factor will bring the measured peak positions into agreement with the expected peak positions and can be in the range of ± 0.2° of the expected 2 theta value.

[0231] The experimental method for characterizing the crystalline forms of the acid or base salts of Compound I using differential scanning calorimetry (DSC) is to take a small amount of the polymorph of Compound I, place it in an aluminum crucible that is compatible with the instrument and can be crimped, and after loading the sample, crimp the aluminum pan. After crimping, the sample is placed in the instrument for testing. The instrument used in this patent for all differential scanning calorimetry is a METTLER TOLEDO DSC 3, and the scan parameters are set to use a nitrogen atmosphere with a heating rate of 10.0 k / min.

[0232] The experimental method for characterizing the polymorphs of Compound I using thermogravimetric analysis (TGA) is to take a small amount of the polymorph of Compound I, place it in an aluminum crucible that is compatible with the instrument, and after loading the sample, place it in the instrument for testing. The instrument used in this patent for all differential scanning calorimetry is a METTLER TOLEDO TGA 2, and the scan parameters are set to use a nitrogen atmosphere with a heating rate of 10.0 k / min.

[0233] The experimental method for characterizing the acid or base salt of compound I by dynamic vapor sorption (DVS) is as follows: a small amount of compound I polymorph powder is placed in a precision sample pan matched with the instrument, and after the sample is loaded, it is sent into the instrument for detection. In this patent, the instrument used for dynamic vapor sorption is Intrinsic PLUS, and the experimental parameters are set as follows: the constant temperature is set to 25°C, the mass percentage change rate (dm / dt) per unit time is 0.02% / min as the judgment standard for reaching equilibrium, and the program humidity change cycle is set as follows: the initial relative humidity is 0%, and the relative humidity at the end point is 90%. DETAILED DESCRIPTION

[0234] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope intended to be protected by the present application.

[0235] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0236] 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 (free state of compound I)

[0237]

[0238] Step one: 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

[0239] A mixture solution of (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid methyl ester (1.5 g, 5.1 mmol), 2-(4-chloro-2- fluorophenoxy)methyl)-6-(piperidin-4-yloxy)pyridine (1.8 g, 5.5 mmol) and potassium carbonate (1.8 g, 13.0 mmol) in N,N-dimethylformamide (80 mL) was stirred at 60 °C for 3 hours, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 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-l- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid methyl ester (1.0 g, yield: 33.5%).

[0240] Step two: Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2- yl)oxy)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid

[0241] To a mixture solution of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2- yl)oxy)piperidin-l-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid methyl ester (1.0 g, 1.7 mmol) in tetrahydrofuran / water (20 mL / 20 mL) was added lithium hydroxide (0.13 g, 5.4 mmol) and the mixture was stirred at room temperature for 16 hours. The resulting mixture was adjusted to pH = 5-6 with formic acid and the solvent was removed in vacuo. The residue was purified by reverse phase flash column chromatography to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-l- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid (0.69 g, yield: 70.5%). 1H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.80 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 11.2 Hz, 2.0 Hz, 1H), 7.28 (t, J = 8.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.18 (s, 2H), 5.12-5.06 (m, 1H), 4.95-4.93 (m, 1H), 4.81-4.76 (m, 1H), 4.66-4.62 (m, 1H), 4.51-4.49 (m, 1H), 4.38-4.36 (m, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 13.6 Hz, 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).

[0242] Preparation of crystalline Form A of compound I of Example 2

[0243] Free form of 200 mg of compound I and 41.88 mg of tromethamine were added into 10 mL of isopropanol, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 40 °C to obtain crystalline Form A of the compound, which was characterized by XRPD Figure 1 ), DSC Figure 2 ) and TGA Figure 3 ) analysis. 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.67-7.57 (m, 2H), 7.20-7.03 (m, 4H), 6.66 (d, J = 8.0 Hz, 1H), 5.28-5.26 (m, 1H), 5.13 (s, 2H), 5.05-5.03 (m, 1H), 4.90-4.86 (m, 1H), 4.73-4.62 (m, 2H), 4.47-4.45 (m, 1H), 4.02-3.89 (m, 2H), 3.64 (s, 6H), 2.81-2.77 (m, 3H), 2.52-2.42 (m, 3H), 2.01-1.99 (m, 2H), 1.78-1.76 (m, 2H).

[0244] Preparation of crystalline Form B of compound I of Example 3

[0245] Example 1 Preparation of crystalline Form A of Compound I Figure 4 Figure 5 Figure 6 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.67-7.57 (m, 2H), 7.21-7.03 (m, 4H), 6.67 (d, J = 8.0 Hz, 1H), 5.28-5.27 (m, 1H), 5.13 (s, 2H), 5.05-5.03 (m, 1H), 4.90-4.88 (m, 1H), 4.73-4.62 (m, 2H), 4.47-4.45 (m, 1H), 4.02-3.89 (m, 2H), 3.64 (s, 6H), 2.83-2.77 (m, 3H), 2.51-2.39 (m, 3H), 2.01-1.99 (m, 2H), 1.77-1.76 (m, 2H).

[0246] Example 4 Preparation of crystalline Form C of Compound I

[0247] Example 2 Preparation of crystalline Form B of Compound I Figure 7 Figure 8 Figure 9

[0248] Example 5 Preparation of hydrate Form D of Compound I

[0249] Example 3 Preparation of crystalline Form C of Compound I Figure 10 Figure 11 Figure 12 1 ​​​​​​​​​H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.94 (dd, J = 8.5 Hz, 1.2 Hz, 1H), 7.66-7.57 (m, 2H), 7.20-7.03 (m, 4H), 6.66 (d, J = 8.1 Hz, 1H), 5.27-5.26 (m, 1H), 5.13 (s, 2H), 5.05-5.03 (m, 1H), 4.90-4.85 (m, 1H), 4.73-4.62 (m, 2H), 4.47-4.45 (m, 1H), 4.02-3.89 (m, 2H), 3.64 (s, 6H), 2.81-2.77 (m, 3H), 2.52-2.39 (m, 3H), 2.00-1.98 (m, 2H), 1.78-1.76 (m, 2H).

[0250] Preparation of crystalline form E of Compound I trichloromethane solvate

[0251] Form A of Compound I was suspended in 1.4 mL of trichloromethane / trifluoroethanol (6:1 v:v) and stirred at 5 °C for 16 h. The suspension was filtered and the filter cake was oven dried at 50 °C to obtain Form E of Compound I. The product was characterized by XRPD ( Figure 13 ), DSC ( Figure 14 ) and TGA ( Figure 15 ). 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.90 (s, 0.8H), 7.67-7.57 (m, 2H), 7.21-7.03 (m, 4H), 6.66 (d, J = 8.0 Hz, 1H), 5.28-5.26 (m, 1H), 5.13 (s, 2H), 5.05-5.03 (m, 1H), 4.90-4.86 (m, 1H), 4.73-4.62 (m, 2H), 4.47-4.45 (m, 1H), 4.02-3.89 (m, 2H), 3.64 (s, 6H), 2.81-2.77 (m, 3H), 2.54-2.42 (m, 3H), 2.00-1.98 (m, 2H), 1.78-1.76 (m, 2H).

[0252] Preparation of crystalline form F of Compound I N-methylpyrrolidone solvate

[0253] Form A of Compound I was suspended in 0.5 mL of N-methylpyrrolidone / cyclopentyl methyl ether (1:5 v:v) and stirred at 5 °C for 3 days. The suspension was filtered and the filter cake was oven dried at 50 °C to obtain Form F of Compound I. The product was characterized by XRPD ( Figure 16), DSC ( Figure 17 ), and TGA ( Figure 18 ) analyses. 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.67-7.57 (m, 2H), 7.21-7.03 (m, 4H), 6.67 (d, J = 8.0 Hz, 1H), 5.28-5.25 (1H), 5.13 (s, 2H), 5.05-5.03 (m, 1H), 4.73-4.62 (m, 2H), 4.47-4.45 (m, 1H), 4.02-3.89 (m, 2H), 3.64 (s, 6H), 3.46-3.42 (m, 3.7H), 2.82-2.80 (m, 8.5H), 2.51-2.33 (m, 7H), 2.07-1.99 (m, 5.7H), 1.78-1.76 (m, 2H).

[0254] Preparation of N-methylpyrrolidone solvate Form G of the compound I of Example 8

[0255] Dissolve 200 mg of the compound I of the crystalline form A in 2.0 mL of N-methylpyrrolidone, drop the solution into 15 mL of toluene, stir at room temperature for 16 hours, filter, dry the filter cake in an oven at 50 °C, obtain the crystalline form G of the compound, and characterize the product by XRPD ( Figure 19 ), DSC ( Figure 20 ), and TGA ( Figure 21 ) analyses. 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.67-7.57 (m, 2H), 7.21-7.03 (m, 4H), 6.67 (d, J = 8.0 Hz, 1H), 5.28-5.25 (1H), 5.12 (s, 2H), 5.05-5.03 (m, 1H), 4.73-4.62 (m, 2H), 4.47-4.45 (m, 1H), 4.02-3.88 (m, 2H), 3.65 (s, 6H), 3.44 (d, J = 7.2 Hz, 3.5H), 2.82-2.77 (m, 8H), 2.51-2.33 (m, 6.5H), 2.07-1.99 (m, 5.5H), 1.77-1.76 (m, 2H).

[0256] Preparation of tetrahydrofuran solvate Form H of the compound I of Example 9

[0257] Example 9 Preparation of ethanol solvate Form I of Compound I Figure 22 Figure 23 Figure 24 1 H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.67-7.57 (m, 2H), 7.21-7.03 (m, 4H), 6.67 (d, J = 8.0 Hz, 1H), 5.28-5.25 (1H), 5.13 (s, 2H), 5.05-5.03 (m, 1H), 4.73-4.62 (m, 2H), 4.46-4.44 (m, 1H), 4.02-3.89 (m, 2H), 3.74-3.71 (m, 1.5H), 3.64 (s, 6H), 2.81-2.77 (m, 3H), 2.53-2.42 (m, 3H), 2.07-1.99 (m, 2H), 1.88-1.85 (m, 1.5H), 1.77-1.75 (m, 2H).

[0258] Example 10 Preparation of ethanol solvate Form I of Compound I

[0259] Example 10 Preparation of ethanol solvate Form I of Compound I Figure 25 Figure 26 Figure 27 1 ​​​​​​H NMR (400 MHz, CD3OD): δ 8.20 (s, 1H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.67-7.57 (m, 2H), 7.21-7.03 (m, 4H), 6.66 (d, J = 8.0 Hz, 1H), 5.27-5.25 (m, 1H), 5.13 (s, 2H), 5.05-5.03 (m, 1H), 4.90-4.88 (m, 1H), 4.73-4.62 (m, 2H), 4.47-4.45 (m, 1H), 4.02-3.89 (m, 2H), 3.63 (s, 6H), 3.60 (q, J = 8.0 Hz, 1.8H), 2.81-2.77 (m, 3H), 2.52-2.42 (m, 3H), 2.01-1.99 (m, 2H), 1.78-1.76 (m, 2H), 1.17 (t, J = 8.0 Hz, 2.6H).

[0260] Preparation of Metastable Form J of Compound I

[0261] A mixture of 200 mg of Compound I in free form and 42 mg tromethamine in 10 mL IPA was stirred at room temperature for about 3 days. The resulting filter cake was metastable Form J of Compound I, which was characterized by XRPD analysis. Metastable Form J of Compound I was dried at 40 °C for 16 h, and then converted to Form A. Figure 28

[0262] Preparation of Metastable Form K of Compound I

[0263] A solution of 100 mg of Compound I in Form A in 1.0 mL DMF was added dropwise to 15 mL acetone, and stirred at room temperature for 16 h. The resulting filter cake was metastable Form K of Compound I, which was characterized by XRPD analysis. Metastable Form K of Compound I was dried at 50 °C for 24 h, and then converted to Form A. Figure 29

[0264] Preparation of Metastable Form L of Compound I

[0265] A suspension of 100 mg of Compound I in Form A in 2.5 mL H2O / EtOH (1:9 v:v) was stirred at room temperature for about 3 days. The resulting filter cake was metastable Form L of Compound I, which was characterized by XRPD analysis. Metastable Form L of Compound I was dried at 50 °C for 16 h, and then converted to Form D. Figure 30

[0266] Preparation of Metastable Form M of Compound I

[0267] ​​​about 1 day at 5°C, filtered, and the resulting filter cake was metastable crystalline Form M of Compound I, which was characterized by XRPD analysis. The metastable crystalline Form M of Compound I was dried at room temperature under vacuum for about 16 h, and the Form L converted to Form D. Figure 31

[0268] Example 15 Preparation of metastable crystalline Form N of Compound I

[0269] Crystalline Form C of Compound I was heated to 80°C at 10°C / min to obtain metastable crystalline Form N of Compound I, which was characterized by XRPD analysis. After drying at 50°C for 16 h, the Form N converted to Form B. Figure 32

[0270] Test Example 1 Equilibrium solubility study of polymorphs of Compound I in biological media

[0271] The equilibrium solubility of free Compound I and crystalline Form A of Compound I was tested in water (H2O), simulated fasted state simulated gastric fluid (FaSSGF), simulated fasted state simulated intestinal fluid (FaSSIF), and simulated fed state simulated intestinal fluid (FeSSIF). In the test, the solid was prepared into a suspension (-10 mg / mL) in the corresponding buffer and mixed at 37 ± 2°C. The suspension was sampled after 24 h, and the supernatant was filtered to determine the concentration. The test results are shown in the following table:

[0272]

[0273] From the above experimental results, it can be seen that the solubility of crystalline Form A of Compound I is significantly better than that of free Compound I in several solvents, which can meet the needs of the development of clinical preparations of drugs. Therefore, the solubility and drug release behavior of Compound I can be significantly improved after salification of the free form.

[0274] Test Example 2 Solid state stability study of polymorphs of Compound I

[0275] Free Compound I and crystalline Form A of Compound I were respectively placed under long-term (25°C / 60% RH), accelerated (40°C / 75% RH), and high-temperature (60°C, RH < 30%) conditions for 7 days, and the HPLC purity and crystalline form change were tested to investigate the solid stability. The results are shown in the following table:

[0276]

[0277] ​​From the purity results of the above experiments, it can be seen that the free state of compound I has no obvious change in purity under long-term conditions for 7 days, but obvious degradation occurs under accelerated conditions and high-temperature conditions for 7 days; the crystal forms A, B and I of compound I have no obvious change in purity under long-term conditions, accelerated and high-temperature conditions for 7 days, and the stability is obviously better than that of the free state. From the crystal form results, it can be seen that crystal form A has no change in crystal form under long-term and high-temperature conditions for 7 days, and has partial conversion into crystal form D under accelerated conditions for 7 days; crystal form B has no change in crystal form under long-term, accelerated and high-temperature conditions for 7 days; crystal form I has change in crystal form under long-term, accelerated and high-temperature conditions for 7 days, and has partial conversion into crystal form B.

[0278] Test Example 3: Competitive experiment study of polymorphs of compound I

[0279] Suspension competitive experiments were carried out on crystal form A and crystal form B of compound I in acetonitrile (room temperature and 50°C) and ethyl acetate (room temperature and 50°C) respectively, and crystal form changes were tested, and the results are shown in the following table:

[0280]

[0281] From the above experimental results, it can be seen that crystal form B of compound I is converted into crystal form A in acetonitrile (room temperature and 50°C) and ethyl acetate (50°C) system, and is still a mixed crystal of crystal form A and crystal form B in ethyl acetate system stirred at room temperature for 7 days, but it can be observed that crystal form B has a trend of conversion into crystal form A, indicating that crystal form A has higher thermodynamic stability than crystal form B in the range from room temperature to 50°C.

[0282] Test Example 4: Hygroscopic behavior test of compound I

[0283] The inventors of the present patent evaluated the stability risk of the sample under humidity change at 25°C according to the dynamic water adsorption method, carried out DVS test on representative crystal form A of compound I, evaluated the hygroscopicity of the crystal form of the compound, and the DVS spectrum of crystal form A of the compound is shown in Figure 33 The obtained results are shown in the following table:

[0284]

[0285] From the above experimental results, it can be seen that on the adsorption curve of 0-90% RH, under the condition of 80% RH, crystal form A of compound I has slight hygroscopicity, and no change in solid form is observed.

[0286] Test Example 5: Drug absorption experiment of SD rats

[0287] Rat intravenous administration: healthy SD rats were administered with free form or crystal form A of compound I through rat tail vein injection at a dose of D mg / kg, blood samples were collected at different time points before and after administration, plasma was prepared by separation, liquid chromatography-tandem mass spectrometry was used to determine the concentration of drug in plasma, and pharmacokinetic parameters were calculated according to a non-compartment model.

[0288] The main pharmacokinetic parameters are shown in the following table:

[0289]

[0290] Rat intravenous administration: healthy SD rats were administered with free form or crystal form A of compound I through rat tail vein injection at a dose of D mg / kg, blood samples were collected at different time points before and after administration, plasma was prepared by separation, liquid chromatography-tandem mass spectrometry was used to determine the concentration of drug in plasma, and pharmacokinetic parameters were calculated according to a non-compartment model.

[0291] The main pharmacokinetic parameters are shown in the following table:

[0292]

[0293] After dose correction, according to AUC 0-t The absolute bioavailability of free form of compound I administered by gavage was 21.8%. The absolute bioavailability of crystal form A administered by gavage was 43.7%, which was significantly better than that of free form, and had pharmacokinetic advantage.

[0294] The thermal analysis of some crystal forms of compound I of the present application is summarized in the following table:

[0295]

[0296] The above has exemplarily described the embodiments of the technical solutions of the present application. It should be understood that the protection scope of the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

1. A polymorph of Compound I: said polymorph is Form A having an X-ray powder diffraction pattern comprising peaks at diffraction angles 7.42±0.2°, 3.68±0.2°, 21.85±0.2°, 18.75±0.2°, 9.29±0.2°, 16.71±0.2°, 11.18±0.2°, 15.32±0.2° and 14.94±0.2°.

2. The polymorph of claim 1, characterized by, said X-ray powder diffraction pattern further comprising peaks at diffraction angles 27.81±0.2°, 17.00±0.2°, 19.81±0.2°, 11.80±0.2°, 25.69±0.2° and 17.43±0.2°.

3. The polymorph of claim 1, characterized by, said X-ray powder diffraction pattern of Form A has diffraction angles and intensities as shown in Table 1, wherein the error range of the diffraction angles is ±0.20°: Table 1 。 4. The polymorph of claim 1, characterized by, said Form A has an X-ray powder diffraction pattern substantially as shown in Figure 1.

5. The polymorph of claim 1, characterized by, said Form A has a DSC profile substantially as shown in Figure 2.

6. The polymorph of claim 1, characterized by, said Form A has a TGA profile substantially as shown in Figure 3.

7. The polymorph of claim 1, characterized by, comprising the following steps:

8. Process for the preparation of polymorphs of compound I according to any one of claims 1 to 7, characterized in that, Step 1: dissolving or dispersing Compound I in isopropyl alcohol; Step 2: stirring at room temperature to crystallize; or, adding anti-solvent to the clear solution of the compound to precipitate; or, slowly evaporating the clear solution of the compound.

9. A pharmaceutical composition comprising the polymorph of Compound I according to any one of claims 1-7 and a pharmaceutically acceptable carrier.

10. Use of the polymorph of Compound I according to any one of claims 1-7 in the manufacture of a medicament for treating a metabolic disease, an autoimmune disease or a metastatic disease. said metabolic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, obesity.

11. Use according to claim 10, characterized in that, said metabolic disease is selected from the group consisting of idiopathic type 1 diabetes, pre-diabetes, latent autoimmune diabetes in adults, early-onset diabetes, juvenile-onset atypical diabetes, juvenile-onset adult-onset diabetes, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, adipocyte dysfunction, visceral adipocyte accumulation, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hyperinsulinemia, alcoholic fatty liver, metabolic acidosis, impaired glucose metabolism.

12. The use according to claim 10, characterized in that, said metabolic disease is selected from the group consisting of impaired glucose tolerance, postprandial lipemia.

13. The use according to claim 10, characterized in that, said autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, autoimmune thyroiditis, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, autoimmune thrombocytopenia, autoimmune uveitis, autoimmune hepatitis, autoimmune pancreatitis, autoimmune vasculitis, autoimmune cardiomyopathy, autoimmune myositis, autoimmune neuropathy, autoimmune nephritis, autoimmune dermatitis, autoimmune encephalitis, autoimmune colitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune orchitis, autoimmune

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