Salt and polymorph of GLP-1 receptor agonist compound, preparation method therefor, pharmaceutical composition thereof, and use thereof

Abstract

The present invention relates to a salt of a GLP-1 receptor agonist compound, a polymorph of the salt form, and a preparation method therefor, a pharmaceutical composition thereof, and the use thereof. Specifically, the GLP-1 receptor agonist is (S)-2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetanyl-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

Description

Salt, crystal form, preparation method of GLP-1 receptor agonist compound, and pharmaceutical composition and use thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and specifically relates to a salt of a GLP-1 receptor agonist, a crystal form of the salt, a preparation method of the salt, and a pharmaceutical composition and use thereof. BACKGROUND

[0002] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by intestinal epithelial L cells, which is widely distributed in the pancreas, stomach and small intestinal mucosa, and heart, lung, central nervous system. After specific binding of GLP-1 and GLP-1 receptor (GLP-1R) in vivo, the cyclic adenosine monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) pathways in the cell membrane are activated, and then various effects are exerted, such as promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting apoptosis of islet beta cells, delaying gastric emptying, and inhibiting food intake, etc. GLP-1 receptor agonists (GLP-1RAs) have been developed to treat type II diabetes. More and more clinical experiments have also confirmed that GLP-1RAs can play different roles in obesity and non-alcoholic steatohepatitis (NASH), cardiovascular disease and nervous system disease in addition to playing an advantageous role in the treatment of diabetes, in addition to which GLP-1 can also bind to related receptors in the kidney, skin, etc. to affect tissue metabolism (Sichuan Medicine, 2020, 41(10): 1089-1093.).

[0003] Currently marketed GLP-1 receptor agonists are polypeptide drugs, such as semaglutide, liraglutide, exenatide, dulaglutide, etc. However, because the oral bioavailability of peptide GLP-1 is poor, it is inconvenient to take, so there is a high expectation for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0004] International application WO2023222084A1 discloses a benzimidazole compound (S)-2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and a preparation method thereof, which has excellent GLP-1 receptor agonist activity. However, the prior art does not disclose research on salts and crystal forms thereof.

[0005] Although it is known in the art that developing an appropriate form of salt can improve the solubility of a compound, it is not simple and easy to select an appropriate salt for a specific compound because there are great differences in the physicochemical properties between different salts. Therefore, it is necessary to study the salt of the compound to find a salt with high solubility, good stability and strong drugability, so as to maximize the effectiveness of the drug, which is of great significance to drug development.

[0006] Polymorphism of drugs is a common phenomenon in drug development and is an important factor affecting drug quality. Different crystal forms often have different solubility, stability, hygroscopicity and bioavailability, thus directly affecting the quality of the pharmaceutical preparation of the drug, the absorption behavior in the human body, and ultimately affecting the therapeutic effect and the benefit ratio of side effects of the preparation in the human body. Therefore, it is necessary to study the crystal form of the compound to find a crystal form with high purity, good solubility, good stability and high bioavailability, so as to maximize the effectiveness of the drug, which is of great significance to drug development. SUMMARY

[0007] One of the purposes of the present application is to provide a pharmaceutically acceptable salt of a compound represented by formula (I) (S)-2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and various crystal forms thereof, which greatly improves the drugability of the drug, such as stability, solubility, pharmacokinetic properties, etc.

[0008] To achieve the above purpose, the present application provides the following content:

[0009] In one aspect, the present application provides a pharmaceutically acceptable salt of a compound represented by formula (I).

[0010] In one or more embodiments, the present application provides a tromethamine salt of a compound represented by formula (I).

[0011] In another aspect, the present application provides various crystal forms of a tromethamine salt of a compound represented by formula (I), which are selected from Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R and Form S crystal forms of the tromethamine salt.

[0012] In one or more embodiments, the present application provides a tromethamine salt Form A crystalline form of a compound of Formula (I), which has an X-ray powder diffraction pattern with peaks at 12.14°±0.2°, 17.03°±0.2°, 19.52°±0.2° and 22.01°±0.2°, using Cu-Ka radiation and expressed in terms of 2 theta angles.

[0013] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form A crystalline form has peaks at 4.85°±0.2°, 10.04°±0.2°, 12.14°±0.2°, 17.03°±0.2°, 17.77°±0.2°, 19.52°±0.2°, 21.57°±0.2°, 22.01°±0.2°, 23.52°±0.2°, 25.89°±0.2° and 27.77°±0.2°, using Cu-Ka radiation and expressed in terms of 2 theta angles.

[0014] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form A crystalline form is as shown in Figure 1.

[0015] In one or more embodiments, the tromethamine salt Form A crystalline form is a solvate, for example an acetonitrile solvate.

[0016] In one or more embodiments, the present application provides a tromethamine salt Form B crystalline form of a compound of Formula (I), which has an X-ray powder diffraction pattern with peaks at 5.90°±0.2°, 14.04°±0.2°, 17.75°±0.2°, 18.58°±0.2°, 21.16°±0.2°, 22.71°±0.2° and 28.50°±0.2°, using Cu-Ka radiation and expressed in terms of 2 theta angles.

[0017] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form B crystalline form has peaks at 5.90°±0.2°, 6.67°±0.2°, 10.51°±0.2°, 12.92°±0.2°, 14.04°±0.2°, 16.89°±0.2°, 17.75°±0.2°, 18.58°±0.2°, 21.16°±0.2°, 22.71°±0.2°, 23.80°±0.2°, 24.69°±0.2°, 25.49°±0.2°, 28.11°±0.2° and 28.50°±0.2°, using Cu-Ka radiation and expressed in terms of 2 theta angles.

[0018] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form B crystalline form of the compound represented by Formula (I) has the following characteristic peaks, using Cu-Ka radiation and expressed in terms of 2 theta (°) : 5.90 ± 0.2, 6.67 ± 0.2, 10.51 ± 0.2, 11.83 ± 0.2, 12.92 ± 0.2, 14.04 ± 0.2, 14.58 ± 0.2, 16.89 ± 0.2, 17.32 ± 0.2, 17.75 ± 0.2, 18.06 ± 0.2, 18.58 ± 0.2, 20.03 ± 0.2, 20.41 ± 0.2, 20.73 ± 0.2, 21.16 ± 0.2, 22.71 ± 0.2, 23.80 ± 0.2, 24.69 ± 0.2, 25.49 ± 0.2, 26.12 ± 0.2, 28.11 ± 0.2, and 28.50 ± 0.2.

[0019] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form B crystalline form of the compound represented by Formula (I) is as shown in FIG. 2, using Cu-Ka radiation and expressed in terms of 2 theta (°).

[0020] In one or more embodiments, the present application provides a tromethamine salt Form C crystalline form of the compound represented by Formula (I), which has the following characteristic peaks, using Cu-Ka radiation and expressed in terms of 2 theta (°) : 6.25 ± 0.2, 9.02 ± 0.2, 12.57 ± 0.2, 17.26 ± 0.2, 17.76 ± 0.2, 18.19 ± 0.2, and 24.28 ± 0.2.

[0021] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form C crystalline form of the compound represented by Formula (I) has the following characteristic peaks, using Cu-Ka radiation and expressed in terms of 2 theta (°) : 6.25 ± 0.2, 9.02 ± 0.2, 10.91 ± 0.2, 11.77 ± 0.2, 12.57 ± 0.2, 13.82 ± 0.2, 15.04 ± 0.2, 17.26 ± 0.2, 17.76 ± 0.2, 18.19 ± 0.2, 20.13 ± 0.2, 21.10 ± 0.2, 24.28 ± 0.2, and 26.37 ± 0.2.

[0022] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form C crystalline form of the compound represented by Formula (I) is as shown in FIG. 3, using Cu-Ka radiation and expressed in terms of 2 theta (°). In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form C crystalline form of the compound represented by Formula (I) is as shown in FIG. 3, using Cu-Ka radiation and expressed in terms of 2 theta (°).

[0023] In one or more embodiments, the present application provides a tromethamine salt Form D crystalline form of a compound represented by Formula (I), which has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation, at 9.53°±0.2°, 18.01°±0.2°, 18.69°±0.2°, 18.90°±0.2°, 19.25°±0.2°, 19.58°±0.2°, 20.06°±0.2°, and 21.29°±0.2°.

[0024] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form D crystalline form has characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation, at 9.53°±0.2°, 12.15°±0.2°, 12.60°±0.2°, 13.68°±0.2°, 18.01°±0.2°, 18.69°±0.2°, 18.90°±0.2°, 19.25°±0.2°, 19.58°±0.2°, 20.06°±0.2°, 21.05°±0.2°, 21.29°±0.2°, 21.93°±0.2°, 23.79°±0.2°, 24.14°±0.2°, 24.85°±0.2°, 26.10°±0.2°, 26.75°±0.2°, 28.04°±0.2°, and 29.94°±0.2°.

[0025] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form D crystalline form is as shown in FIG. 4.

[0026] In one or more embodiments, the present application provides a tromethamine salt Form E crystalline form of a compound represented by Formula (I), which has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation, at 17.41°±0.2°, 20.12°±0.2°, and 23.57°±0.2°.

[0027] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form E crystalline form has characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation, at 6.15°±0.2°, 9.10°±0.2°, 11.49°±0.2°, 12.37°±0.2°, 14.16°±0.2°, 15.21°±0.2°, 17.41°±0.2°, 20.12°±0.2°, 22.84°±0.2°, and 23.57°±0.2°.

[0028] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form E crystalline form of the compound according to Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 19.71°±0.2°, 21.27°±0.2° and 22.78°±0.2°.

[0029] In one or more embodiments, the present application provides a tromethamine salt Form F crystalline form of the compound according to Formula (I), the X-ray powder diffraction pattern of which has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 19.71°±0.2°, 21.27°±0.2° and 22.78°±0.2°.

[0030] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form F crystalline form of the compound according to Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 13.01°±0.2°, 14.01°±0.2°, 16.31°±0.2°, 16.81°±0.2°, 18.35°±0.2°, 19.71°±0.2°, 21.27°±0.2°, 22.33°±0.2°, 22.78°±0.2°, 24.79°±0.2°, 25.74°±0.2° and 29.01°±0.2°.

[0031] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form F crystalline form of the compound according to Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 13.01°±0.2°, 14.01°±0.2°, 16.31°±0.2°, 16.81°±0.2°, 18.35°±0.2°, 19.71°±0.2°, 21.27°±0.2°, 22.33°±0.2°, 22.78°±0.2°, 24.79°±0.2°, 25.74°±0.2° and 29.01°±0.2°.

[0032] In one or more embodiments, the present application provides a tromethamine salt Form G crystalline form of the compound according to Formula (I), the X-ray powder diffraction pattern of which has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 15.78°±0.2°, 20.16°±0.2°, 24.56°±0.2° and 25.06°±0.2°.

[0033] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form G crystalline form of the compound according to Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 15.78°±0.2°, 15.99°±0.2°, 16.98°±0.2°, 17.75°±0.2°, 19.01°±0.2°, 19.24°±0.2°, 19.75°±0.2°, 20.16°±0.2°, 21.17°±0.2°, 21.80°±0.2°, 23.47°±0.2°, 23.73°±0.2°, 24.56°±0.2°, 25.06°±0.2°, 26.49°±0.2° and 27.37°±0.2°.

[0034] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form G crystalline form of the compound represented by Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation: 9.76°±0.2°, 11.58°±0.2°, 13.12°±0.2°, 17.75°±0.2° and 23.00°±0.2°.

[0035] In one or more embodiments, the present application provides a tromethamine salt Form H crystalline form of the compound represented by Formula (I), the X-ray powder diffraction pattern of which has the following characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation: 4.82°±0.2°, 8.68°±0.2°, 9.68°±0.2°, 12.14°±0.2°, 14.76°±0.2°, 16.84°±0.2°, 21.27°±0.2° and 21.98°±0.2°.

[0036] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form H crystalline form of the compound represented by Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation: 4.82°±0.2°, 8.68°±0.2°, 9.68°±0.2°, 12.14°±0.2°, 14.76°±0.2°, 16.84°±0.2°, 21.27°±0.2° and 21.98°±0.2°.

[0037] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form H crystalline form of the compound represented by Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation: 4.82°±0.2°, 8.68°±0.2°, 9.68°±0.2°, 12.14°±0.2°, 14.76°±0.2°, 16.84°±0.2°, 21.27°±0.2° and 21.98°±0.2°.

[0038] In one or more embodiments, the present application provides a tromethamine salt Form I crystalline form of the compound represented by Formula (I), the X-ray powder diffraction pattern of which has the following characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation: 9.76°±0.2°, 11.58°±0.2°, 13.12°±0.2°, 17.75°±0.2° and 23.00°±0.2°.

[0039] In one or more embodiments, the present application provides a tromethamine salt Form J crystalline form of the compound represented by Formula (I), the X-ray powder diffraction pattern of which has the following characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation: 13.20°±0.2°, 14.31°±0.2°, 18.08°±0.2°, 19.93°±0.2°, 22.96°±0.2°, 26.09°±0.2° and 26.61°±0.2°.

[0040] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form J crystalline form of the compound of Formula (I) has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 9.14°±0.2°, 13.20°±0.2°, 14.31°±0.2°, 14.90°±0.2°, 15.28°±0.2°, 16.53°±0.2°, 18.08°±0.2°, 18.71°±0.2°, 18.92°±0.2°, 19.73°±0.2°, 19.93°±0.2°, 20.30°±0.2°, 22.96°±0.2°, 23.44°±0.2°, 23.98°±0.2°, 24.47°±0.2°, 26.09°±0.2°, 26.61°±0.2°, and 28.86°±0.2°.

[0041] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form J crystalline form of the compound of Formula (I) is as shown in FIG. 9, expressed in angles 2Q, using Cu-Ka radiation.

[0042] In one or more embodiments, the present application provides a tromethamine salt Form K crystalline form of the compound of Formula (I), which has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 6.89°±0.2° and 20.11°±0.2°.

[0043] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form K crystalline form of the compound of Formula (I) has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 6.89°±0.2°, 10.38°±0.2°, 13.62°±0.2°, 18.16°±0.2°, 19.66°±0.2°, 20.11°±0.2°, 20.80°±0.2°, 27.92°±0.2°, and 31.57°±0.2°.

[0044] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form K crystalline form of the compound of Formula (I) is as shown in FIG. 10, expressed in angles 2Q, using Cu-Ka radiation.

[0045] In one or more embodiments, the present application provides a tromethamine salt Form L crystalline form of the compound of Formula (I), which has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 10.01°±0.2°, 12.13°±0.2°, and 17.91°±0.2°.

[0046] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form L crystalline form of the compound of Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 10.01°±0.2°, 12.13°±0.2°, 14.44°±0.2°, 16.39°±0.2°, 17.91°±0.2° and 22.00°±0.2°.

[0047] In one or more embodiments, the present application provides a tromethamine salt Form M crystalline form of the compound of Formula (I), the X-ray powder diffraction pattern of which has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 9.72°±0.2°, 11.63°±0.2°, 13.33°±0.2°, 14.43°±0.2°, 17.41°±0.2°, 17.79°±0.2°, 18.42°±0.2° and 19.26°±0.2°.

[0048] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form M crystalline form of the compound of Formula (I) has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 9.72°±0.2°, 11.63°±0.2°, 13.33°±0.2°, 14.43°±0.2°, 15.40°±0.2°, 17.41°±0.2°, 17.79°±0.2°, 18.42°±0.2°, 19.26°±0.2°, 19.66°±0.2°, 21.05°±0.2°, 21.94°±0.2°, 23.79°±0.2°, 24.93°±0.2° and 25.88°±0.2°.

[0049] In one or more embodiments, the present application provides a tromethamine salt Form N crystalline form of the compound of Formula (I), the X-ray powder diffraction pattern of which has the following characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation: 6.74°±0.2°, 12.69°±0.2°, 15.98°±0.2°, 16.98°±0.2°, 17.75°±0.2°, 19.82°±0.2° and 20.15°±0.2°.

[0050] In one or more embodiments, the X-ray powder diffraction pattern of the Trospium salt Form N crystalline form of the compound represented by Formula (I) has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 6.30° ± 0.2°, 6.74° ± 0.2°, 9.52° ± 0.2°, 11.12° ± 0.2°, 12.69° ± 0.2°, 14.96° ± 0.2°, 15.59° ± 0.2°, 15.98° ± 0.2°, 16.98° ± 0.2°, 17.75° ± 0.2°, 19.16° ± 0.2°, 19.82° ± 0.2°, 20.15° ± 0.2°, 20.85° ± 0.2°, 21.80° ± 0.2°, 22.32° ± 0.2°, 23.39° ± 0.2°, 23.76° ± 0.2°, 24.18° ± 0.2°, 24.54° ± 0.2°, 25.45° ± 0.2°, and 26.15° ± 0.2°.

[0051] In one or more embodiments, the X-ray powder diffraction pattern of the Trospium salt Form N crystalline form of the compound represented by Formula (I) is as shown in FIG. 11, expressed in angles 2Q, using Cu-Ka radiation.

[0052] In one or more embodiments, the present application provides a Trospium salt Form O crystalline form of the compound represented by Formula (I), the X-ray powder diffraction pattern of which has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 7.80° ± 0.2°, 15.84° ± 0.2°, 16.32° ± 0.2°, 17.10° ± 0.2°, and 32.22° ± 0.2°.

[0053] In one or more embodiments, the X-ray powder diffraction pattern of the Trospium salt Form O crystalline form of the compound represented by Formula (I) has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 7.80° ± 0.2°, 15.84° ± 0.2°, 16.32° ± 0.2°, 16.80° ± 0.2°, 17.10° ± 0.2°, 22.27° ± 0.2°, 23.96° ± 0.2°, and 32.22° ± 0.2°.

[0054] In one or more embodiments, the X-ray powder diffraction pattern of the Trospium salt Form O crystalline form of the compound represented by Formula (I) is as shown in FIG. 12, expressed in angles 2Q, using Cu-Ka radiation.

[0055] In one or more embodiments, the present application provides a tromethamine salt Form P crystalline form of a compound represented by Formula (I), which has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation, at 6.75°±0.2°, 16.13°±0.2°, 16.38°±0.2°, 17.98°±0.2°, 19.65°±0.2°, 20.30°±0.2°, 22.15°±0.2° and 25.09°±0.2°.

[0056] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form P crystalline form has characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation, at 6.75°±0.2°, 7.39°±0.2°, 9.01°±0.2°, 15.91°±0.2°, 16.13°±0.2°, 16.38°±0.2°, 17.98°±0.2°, 19.34°±0.2°, 19.65°±0.2°, 20.30°±0.2°, 21.59°±0.2°, 22.15°±0.2°, 22.41°±0.2°, 23.68°±0.2°, 24.14°±0.2° and 25.09°±0.2°.

[0057] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form P crystalline form is as shown in Figure 13.

[0058] In one or more embodiments, the present application provides a tromethamine salt Form Q crystalline form of a compound represented by Formula (I), which has an X-ray powder diffraction pattern with characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation, at 14.37°±0.2°, 19.96°±0.2° and 23.02°±0.2°.

[0059] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form Q crystalline form has characteristic peaks, expressed in angles 2θ, using Cu-Ka radiation, at 14.37°±0.2°, 14.91°±0.2°, 18.74°±0.2°, 19.96°±0.2°, 23.02°±0.2 and 24.02°±0.2°.

[0060] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form Q crystalline form, using Cu-Ka radiation and expressed in terms of 2 theta angles, has the following characteristic peaks: 13.24° ± 0.2°, 14.37° ± 0.2°, 14.91° ± 0.2°, 18.10° ± 0.2°, 18.74° ± 0.2°, 19.96° ± 0.2°, 23.02° ± 0.2°, 23.48° ± 0.2°, and 24.02° ± 0.2°.

[0061] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form Q crystalline form, using Cu-Ka radiation and expressed in terms of 2 theta angles, has the following characteristic peaks: 13.24° ± 0.2°, 14.37° ± 0.2°, 14.91° ± 0.2°, 15.28° ± 0.2°, 18.10° ± 0.2°, 18.74° ± 0.2°, 19.76° ± 0.2°, 19.96° ± 0.2°, 20.34° ± 0.2°, 23.02° ± 0.2°, 23.48° ± 0.2°, 24.02° ± 0.2°, 24.51° ± 0.2°, 26.69° ± 0.2°, and 27.84° ± 0.2°.

[0062] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form Q crystalline form, using Cu-Ka radiation and expressed in terms of 2 theta angles, has the following characteristic peaks: 3.38° ± 0.2°, 9.20° ± 0.2°, 10.15° ± 0.2°, 13.24° ± 0.2°, 14.37° ± 0.2°, 14.91° ± 0.2°, 15.28° ± 0.2°, 16.52° ± 0.2°, 17.20° ± 0.2°, 18.10° ± 0.2°, 18.74° ± 0.2°, 18.94° ± 0.2°, 19.54° ± 0.2°, 19.76° ± 0.2°, 19.96° ± 0.2°, 20.34° ± 0.2°, 21.38° ± 0.2°, 21.64° ± 0.2°, 23.02° ± 0.2°, 23.48° ± 0.2°, 24.02° ± 0.2°, 24.51° ± 0.2°, 25.56° ± 0.2°, 26.13° ± 0.2°, 26.44° ± 0.2°, 26.69° ± 0.2°, 27.84° ± 0.2°, 28.88° ± 0.2°, 32.30° ± 0.2°, and 33.50° ± 0.2°.

[0063] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form Q crystalline form is substantially in accordance with that shown in FIG. 14, using Cu-Ka radiation and expressed in terms of 2 theta angles.

[0064] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form Q crystalline form is substantially in accordance with that shown in FIG. 14, using Cu-Ka radiation and expressed in terms of 2 theta angles.

[0065] In one or more embodiments, the tromethamine salt Form Q crystalline form is not a hydrate or solvate. In one or more embodiments, the present application provides a tromethamine salt Form R crystalline form of the compound represented by Formula (I), having an X-ray powder diffraction pattern substantially in accordance with that shown in FIG. 15, using Cu-Ka radiation and expressed in terms of 2 theta angles.

[0066] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form R crystalline form of the compound represented by Formula (I) has the following characteristic peaks, expressed in degrees 2-theta, using Cu-Kalpharadiation: 8.82°±0.2°, 9.77°±0.2°, 13.10°±0.2°, 13.93°±0.2°, 14.41°±0.2°, 15.82°±0.2°, 16.43°±0.2°, 17.77°±0.2°, 18.00°±0.2°, 18.30°±0.2°, 18.83°±0.2°, 19.51°±0.2°, 21.44°±0.2°, 22.37°±0.2°, 22.53°±0.2°, 23.69°±0.2°, 23.86°±0.2°, and 26.10°±0.2°.

[0067] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form R crystalline form of the compound represented by Formula (I) is as shown in FIG. 15, expressed in degrees 2-theta, using Cu-Kalpharadiation.

[0068] In one or more embodiments, the present application provides a tromethamine salt Form S crystalline form of the compound represented by Formula (I), which has the following characteristic peaks, expressed in degrees 2-theta, using Cu-Kalpharadiation: 11.16°±0.2°, 11.75°±0.2°, 13.87°±0.2°, 16.53°±0.2°, 16.82°±0.2°, 18.12°±0.2°, 18.38°±0.2°, 18.86°±0.2°, 19.45°±0.2°, 20.93°±0.2°, 22.19°±0.2°, 23.72°±0.2°, and 24.07°±0.2°.

[0069] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form S crystalline form of the compound of formula (I) has the following characteristic peaks, expressed in angles 2 theta, using Cu-Ka radiation: 9.67°±0.2°, 11.16°±0.2°, 11.75°±0.2°, 13.19°±0.2°, 13.87°±0.2°, 15.28°±0.2°, 16.53°±0.2°, 16.82°±0.2°, 18.12°±0.2°, 18.38°±0.2°, 18.86°±0.2°, 19.10°±0.2°, 19.45°±0.2°, 20.93°±0.2°, 22.19°±0.2°, 22.41°±0.2°, 22.67°±0.2°, 23.29°±0.2°, 23.72°±0.2°, 24.07°±0.2°, 24.59°±0.2°, 25.57°±0.2°, and 25.94°±0.2°.

[0070] In one or more embodiments, the X-ray powder diffraction pattern of the tromethamine salt Form S crystalline form of the compound of formula (I) is as shown in Figure 16.

[0071] In one or more embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula (I) (especially a tromethamine salt of the compound of formula (I)) or a crystalline form of a tromethamine salt of the compound of formula (I) as described herein, and a pharmaceutically acceptable excipient.

[0072] In one or more embodiments, there is provided the use of a pharmaceutically acceptable salt of the compound of formula (I) or a crystalline form of a tromethamine salt of the compound of formula (I) or a pharmaceutical composition as described herein as a medicament (i.e. for therapy).

[0073] In one or more embodiments, there is provided the use of a pharmaceutically acceptable salt of the compound of formula (I) or a crystalline form of a tromethamine salt of the compound of formula (I) or a pharmaceutical composition as described herein in the manufacture of a medicament for a GLP-1 receptor agonist.

[0074] In one or more embodiments, the medicament for a GLP-1 receptor agonist is a medicament for the treatment and / or prevention of diabetes mellitus type I, diabetes mellitus type II, malnutrition-related diabetes, hyperglycemia, diabetic complications, obesity, non-alcoholic steatohepatitis (NASH), insulin resistance, impaired glucose tolerance, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic syndrome, Parkinson's disease, and / or dementia.

[0075] In one or more embodiments, there is provided use of a pharmaceutically acceptable salt of a compound of Formula (I) as described herein, or a crystalline form of a tromethamine salt of a compound of Formula (I) as described herein, or a pharmaceutical composition as described herein in the manufacture of a medicament for the treatment and / or prevention of Type I diabetes, Type II diabetes, malnutrition-associated diabetes, hyperglycemia, diabetic complications, obesity, non-alcoholic steatohepatitis (NASH), insulin resistance, glucose intolerance, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic syndrome, Parkinson's disease, and / or dementia.

[0076] In one or more embodiments, there is provided a method for the treatment and / or prevention of Type I diabetes, Type II diabetes, malnutrition-associated diabetes, hyperglycemia, diabetic complications, obesity, non-alcoholic steatohepatitis (NASH), insulin resistance, glucose intolerance, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic syndrome, Parkinson's disease, and / or dementia, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula (I) as described herein, or a crystalline form of a tromethamine salt of a compound of Formula (I) as described herein, or a pharmaceutical composition as described herein.

[0077] In one or more embodiments, there is provided a method for preparing a Form A crystalline form of a tromethamine salt of a compound of Formula (I), comprising dispersing a compound of Formula (I) (S)-2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and tromethamine in a solvent to form a suspension, stirring, filtering, washing, and then drying the filter cake to obtain a crystalline material.

[0078] In one or more embodiments, the chemical ratio (molar ratio) of the compound of Formula (I) to tromethamine is 1:0.5-1:3, preferably 1:0.8-1:1.5; and the solvent is one or more of acetonitrile, dimethyl sulfoxide, tetrahydrofuran, water, preferably one or more of acetonitrile, dimethyl sulfoxide / acetonitrile, tetrahydrofuran / water, tetrahydrofuran / water / acetonitrile.

[0079] In one or more embodiments, there is provided a method for preparing a Form B crystalline form, a Form D crystalline form, a Form G crystalline form, a Form H crystalline form, a Form J crystalline form, a Form Q crystalline form of a tromethamine salt of a compound of Formula (I), comprising converting a Form A crystalline form of a tromethamine salt in a solvent to obtain.

[0080] In one or more embodiments, the solvent used for the crystallization is selected from at least one of cyclohexane, methylcyclohexane, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, acetone, butanone, methyl isobutyl ketone, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, dichloromethane, dichloroethane, acetic acid, and water.

[0081] Preferably, the solvent used for the crystallization is selected from at least one of isopropyl acetate, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, butanone, methyl isobutyl ketone, N-methylpyrrolidone, dichloromethane, methyl tert-butyl ether, methylcyclohexane.

[0082] Compared with the prior art, the present application has the following beneficial effects:

[0083] 1. The solubility of the tromethamine salt of the compound of formula (I) is significantly improved compared with the sodium salt of the compound of formula (I) and the arginine salt of the compound of formula (I). For example, in one embodiment of the present application, the solubility of the tromethamine salt of the compound of formula (I) (represented by the Form E crystal form of the tromethamine salt, which is the crystal form with the poorest solubility among the crystal forms of the tromethamine salt) under the "FaSSIF" and "FeSSIF" conditions is more than 15 times and 16 times, respectively, the solubility of the sodium salt of the compound of formula (I), and is at least 36 times and 16 times the solubility of the arginine salt of the compound of formula (I). The solubility of the tromethamine salt of the compound of formula (I) has achieved an unexpected effect compared with the sodium salt of the compound of formula (I) and the arginine salt of the compound of formula (I).

[0084] 2. The thermodynamic comparison experiments of the crystal forms of the tromethamine salt of the compound of formula (I) show that the Form B, Form G, and Form Q crystal forms of the tromethamine salt of the compound of formula (I) have high crystallinity and good thermodynamic properties, and in particular, the Form Q crystal form of the tromethamine salt has a high melting point (170.08°C) and good thermal stability, and is an advantageous crystal form.

[0085] 3、The solubility of the tromethamine salt of the compound of formula (I) is improved compared to the free form. In particular, the solubility of the tromethamine salt Form B and Form Q of the compound of formula (I) is significantly improved compared to the free form of the compound of formula (I). For example, in one embodiment of the present application, the solubility of the tromethamine salt Form B in water is 18 times that of the free form; the solubility in FeSSIF (pH = 5.0) is 63 times that of the free form; the solubility in FaSSIF (pH = 6.5) is 15.83 μg / mL, while the free form is not detected (calculated according to the detection limit of 0.05 μg / mL), which is at least 316 times that of the free form; the solubility of the tromethamine salt Form B of the compound of formula (I) is unexpectedly improved compared to the free form. The solubility of the tromethamine salt Form Q in water is 4300 times that of the free form; the solubility of Form Q in FeSSIF (pH = 5.0) is 140 times that of the free form; the solubility of Form Q in a phosphate buffer at pH 6.8 is 78 times that of the free form; the solubility of Form Q in FaSSIF (pH = 6.5) is 60 μg / mL, while the free form is not detected (calculated according to the detection limit of 0.05 μg / mL), which is at least 1200 times that of the free form; the solubility of the tromethamine salt Form Q of the compound of formula (I) is unexpectedly improved compared to the free form. Among the tromethamine salt crystal forms, the solubility of Form Q is the best.

[0086] 4、The stability of the tromethamine salt Form B and Form Q is higher than that of the free form of the compound of formula (I). For example, in one embodiment of the present application, the crystal form, purity and properties of the tromethamine salt Form B and Form Q do not change under the conditions of high temperature, high humidity and strong light. However, the purity of the free form of the compound of formula (I) changes from 99.17% to 98.87% under the condition of high temperature for 15 days, which decreases by 0.30%; the purity changes from 99.17% to 98.97% under the condition of high humidity for 15 days, which decreases by 0.20%; and the properties change from white to yellowish under the condition of light.

[0087] At the same time, according to the results of the accelerated stability and long-term stability tests, the tromethamine salt Form B and Form Q have good stability, which meets the requirements of drug stability. In particular, the stability of the tromethamine salt Form Q is better than that of other crystal forms.

[0088] 5、The Form B and Form Q of Titrated Aminitriol have excellent pharmacokinetic properties, and achieve unexpected results. For example, in the pharmacokinetic comparative study in rats, under the condition of the same dosage of 10mpk, the Cmax and exposure of Form B of Titrated Aminitriol and Form Q of Titrated Aminitriol are significantly higher than those of the compound of formula (I) (free state), for example, the Cmax and exposure of Form B of Titrated Aminitriol are about 7 times and 4 times of those of the compound of formula (I) (free state) respectively, and the Cmax and exposure of Form Q of Titrated Aminitriol are about 10 times and 9 times of those of the compound of formula (I) (free state) respectively. The exposure of Form Q of Titrated Aminitriol is about 2.3 times of that of Form B of Titrated Aminitriol. For example, in the pharmacokinetic comparative study in beagles, under the condition of the same dosage of 3mpk, the Cmax and exposure of Form Q of Titrated Aminitriol are significantly higher than those of the compound of formula (I) (free state), for example, the Cmax and exposure of Form Q of Titrated Aminitriol are about 3 times and 4.5 times of those of the compound of formula (I) (free state) respectively, and achieve unexpected results.

[0089] 6、The Form Q of Titrated Aminitriol has excellent pharmacodynamic properties, and significantly improves the activity of the compound of formula (I). BRIEF DESCRIPTION OF DRAWINGS

[0090] Figure 1 is the XRPD spectrum of Form A of Titrated Aminitriol.

[0091] Figure 2 is the XRPD spectrum of Form B of Titrated Aminitriol.

[0092] Figure 3 is the XRPD spectrum of Form C of Titrated Aminitriol.

[0093] Figure 4 is the XRPD spectrum of Form D of Titrated Aminitriol.

[0094] Figure 5 is the XRPD spectrum of Form E of Titrated Aminitriol.

[0095] Figure 6 is the XRPD spectrum of Form F of Titrated Aminitriol.

[0096] Figure 7 is the XRPD spectrum of Form G of Titrated Aminitriol.

[0097] Figure 8 is the XRPD spectrum of Form H of Titrated Aminitriol.

[0098] Figure 9 is the XRPD spectrum of Form J of Titrated Aminitriol.

[0099] Figure 10 is the XRPD spectrum of Form K of Titrated Aminitriol.

[0100] Figure 11 is an XRPD pattern of the Trostamide salt Form N crystalline form.

[0101] Figure 12 is an XRPD pattern of the Trostamide salt Form O crystalline form.

[0102] Figure 13 is an XRPD pattern of the Trostamide salt Form P crystalline form.

[0103] Figure 14 is an XRPD pattern of the Trostamide salt Form Q crystalline form.

[0104] Figure 15 is an XRPD pattern of the Trostamide salt Form R crystalline form.

[0105] Figure 16 is an XRPD pattern of the Trostamide salt Form S crystalline form.

[0106] Figure 17 is a HNMR pattern of the compound of Formula (I) in free form. 1

[0107] Figure 18 is a TGA & DSC pattern of the Trostamide salt Form A crystalline form.

[0108] Figure 19 is a HNMR pattern of the Trostamide salt Form A crystalline form. 1

[0109] Figure 20 is a TGA & DSC pattern of the Trostamide salt Form B crystalline form.

[0110] Figure 21 is a TGA & DSC pattern of the Trostamide salt Form C crystalline form.

[0111] Figure 22 is a TGA & DSC pattern of the Trostamide salt Form D crystalline form.

[0112] Figure 23 is a TGA & DSC pattern of the Trostamide salt Form E crystalline form.

[0113] Figure 24 is a TGA & DSC pattern of the Trostamide salt Form F crystalline form.

[0114] Figure 25 is a TGA & DSC pattern of the Trostamide salt Form G crystalline form.

[0115] Figure 26 is a TGA & DSC pattern of the Trostamide salt Form H crystalline form.

[0116] Figure 27 is a TGA & DSC pattern of the Trostamide salt Form I crystalline form.

[0117] Figure 28 is a TGA & DSC pattern of the Trostamide salt Form J crystalline form.

[0118] ​​Figure 29 is a TGA & DSC pattern of the Trostamide salt Form K crystalline form.

[0119] Figure 30 is a TGA & DSC pattern of the Trostamide salt Form L crystalline form.

[0120] Figure 31 is a TGA & DSC pattern of the Trostamide salt Form M crystalline form.

[0121] Figure 32 is a TGA & DSC pattern of the Trostamide salt Form N crystalline form.

[0122] Figure 33 is a DSC pattern of the Trostamide salt Form O crystalline form.

[0123] Figure 34 is a TGA & DSC pattern of the Trostamide salt Form P crystalline form.

[0124] Figure 35 is a TGA & DSC pattern of the Trostamide salt Form Q crystalline form.

[0125] Figure 36 is an XRPD pattern of the Trostamide salt Form Q crystalline form. 1 HNMR pattern.

[0126] Figure 37 is an HPLC pattern of the Trostamide salt Form Q crystalline form.

[0127] Figure 38 is a TGA & DSC pattern of the Trostamide salt Form R crystalline form.

[0128] Figure 39 is a TGA & DSC pattern of the Trostamide salt Form S crystalline form.

[0129] Figure 40 is an XRPD pattern of the L-arginine salt.

[0130] Figure 41 is an HNMR pattern of the L-arginine salt. 1 HNMR pattern.

[0131] Figure 42 is an XRPD overlay of the Trostamide salt Form Q crystalline form for accelerated stability testing.

[0132] Figure 43 is an XRPD overlay of the Trostamide salt Form Q crystalline form for long term stability testing. DETAILED DESCRIPTION

[0133] The disclosure will be explained in more detail with reference to the examples or experimental examples below, which are only used to illustrate the technical solutions in the disclosure and do not limit the essence and scope of the disclosure.

[0134] The test conditions of the instruments used in the disclosure are as follows:

[0135] The English abbreviations of solvents used in the present disclosure are as follows:

[0136] Example 1: Preparation of the compound (S)-2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid of formula (I)

[0137] First step: Preparation of intermediate 1c

[0138] In a 2L reaction flask, compound 1a (50 g, 0.251 mol), 1b (68.37 g, 0.264 mol), DMF (250 mL) and THF (250 mL) were added, and after stirring and dissolving, triethylamine (TEA, 101.63 g) was added, and the temperature was raised to 45°C, then the reaction was incubated for 8 h. TLC was used to monitor the reaction, and the heating was stopped, and the reaction solution was concentrated to remove obvious fractions, 750 mL of water was added, and a large amount of solid was precipitated, and after the drop was completed, the stirring was continued for 0.5 h, and then the filter cake was washed with water twice; then the filter cake was dried under reduced pressure at 55°C for 15 h to obtain orange-yellow solid intermediate 1c, 60.8 g, yield 90.95%. MS m / z (ESI): 289.0792 (M+Na) + ; 1 H NMR (400 MHz, DMSO) δ = 8.33 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.15 (dd, J = 8.8, 1.6 Hz, 1H), 5.03-4.97 (m, 1H), 4.58-4.53 (m, 1H), 4.46-4.41 (m, 1H), 3.88 (s, 3H), 3.71-3.60 (m, 2H), 2.72-2.64 (m, 1H), 2.57-2.53 (m, 1H).

[0139] Second step: Preparation of intermediate 1d

[0140] A 2 L reaction flask was charged with intermediate 1c (55 g, 0.206 mol) and methanol (825 mL), stirred and dispersed, then Pd / C (5.5 g) was added, and the reaction was carried out under a hydrogen atmosphere at room temperature for 20 h. TLC was used to monitor the reaction, and the reaction was stopped, the reaction liquid was filtered through diatomite, the filter cake was washed twice with methanol, then the filtrate was concentrated to obtain a brown-black oily crude product, then 25 mL of ethyl acetate was added to the crude product, the solution was stirred to clear at 50 °C, then it was slowly reduced to 10-15 °C, 200 mL of petroleum ether was added dropwise, after the dropwise addition was completed, stirring was continued for 0.5 h. Filtration, the filter cake was washed twice with petroleum ether, and the filter cake was dried under reduced pressure at 50 °C for 6 h to obtain off-white solid intermediate 1d, 46 g in total, with a yield of 94.25%. MS m / z (ESI): 237.1226 (M+H) + ; 1 H NMR (400 MHz, DMSO) δ = 7.19 (dd, J = 8.0, 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.48 (s, 2H), 4.96-4.90 (m, 1H), 4.70 (t, J = 5.6 Hz, 1H), 4.58-4.46 (m, 2H), 3.74 (s, 3H), 3.39-3.26 (m, 2H), 2.71-2.63 (m, 1H), 2.49-2.42 (m, 1H).

[0141] Third step: preparation of intermediate 1e

[0142] A 2 L reaction flask was charged with intermediate 1d (41.27 g, 174.66 mmol), 1e-1 (37 g, 158.78 mmol), THF (666 mL), DIPEA (61.56 g) was added in portions, the internal temperature of the reaction liquid was controlled at 10-30 °C, then the internal temperature was reduced to 0-10 °C, HATU (66.41 g) was added in portions, and the reaction liquid was continuously stirred at 0-10 °C for 30 min. Then the internal temperature of the reaction liquid was adjusted to 20-25 °C, and the reaction was continuously carried out at this temperature for 2 h. TLC was used to monitor the reaction, the reaction was stopped, 1332 mL of water was added, and stirring was continued for 2 h. Filtration, the filter cake was washed twice with water, then the filter cake was dried under reduced pressure at 55 °C for 20 h to obtain off-white solid intermediate 1e, 70.6 g in total, with a yield of 98.53%. MS m / z (ESI): 451.0663 (M+H) + ; 1H NMR (400 MHz, DMSO) δ = 9.68 (s, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.45-7.38 (m, 4H), 7.29-7.24 (m, 2H), 5.37 (t, J = 5.6 Hz, 1H), 4.97-4.91 (m, 1H), 4.56-4.51 (m, 1H), 4.45-4.40 (m, 1H), 3.82 (s, 3H), 3.42-3.35 (m, 3H), 2.69-2.61 (m, 1H), 2.48-2.44 (m, 1H).

[0143] Fourth step: preparation of intermediate 1f

[0144] A 1 L reaction flask was charged with intermediate 1e (65 g, 144.03 mmol), then AcOH (520 mL), and the temperature was raised to 90 °C for 2 h. TLC was used to monitor the reaction, then the reaction solution was cooled to room temperature, and the reaction solution was concentrated to one third of the volume. Then 130 mL of acetonitrile and 200 mL of water were added to the residue, and the mixture was stirred until the pH of the system was adjusted to 7-8 with 5% NaHCO3 aqueous solution. A large amount of light brown solid was precipitated, which was filtered and washed twice with water. The filter cake was dispersed in 780 mL (12V) of ACN:H2O = 2:3 mixed solvent, and the slurry was stirred at 25-30 °C for 2 h. The filter cake was filtered and washed twice with ACN:H2O = 2:3. The filter cake was dried at 55 °C under reduced pressure for 16 h to obtain 51.2 g of light gray solid intermediate 1f, with a yield of 82.05%. MS m / z (ESI): 433.0562 (M+H) + ; 1 H NMR (400 MHz, DMSO) δ = 8.27 (d, J = 1.6 Hz, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.62-7.55 (m, 2H), 7.41 (dd, J = 8.0, 2.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 5.07-5.01 (m, 1H), 4.72 (dd, J = 15.6, 7.2 Hz, 1H), 4.59 (dd, J = 15.6, 2.8 Hz, 1H), 4.51-4.44 (m, 2H), 4.39-4.30 (m, 2H), 3.87 (s, 3H), 2.74-2.66 (m, 1H), 2.40-2.32 (m, 1H).

[0145] Fifth step: preparation of intermediate 1g

[0146] Into a 500 mL reaction flask, was placed compound 1f (10 g, 23.08 mmol), bis(pinacolato)diboron (7.033 g, 27.7 mmol), Pd(dppf)Cl2(0.8 g, 1.154 mmol), potassium acetate (5.67 g, 57.7 mmol), and 1,4-dioxane (200 mL), and heated to 100 °C under nitrogen atmosphere, then the reaction was kept for 6 h. TLC was used to monitor the reaction, the heating was stopped, and the reaction was cooled to room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give yellow oil of intermediate 1g (8.27 g, 74.6% yield). MS m / z (ESI): 481.2322 (M+H) + ; 1 H NMR (400 MHz, DMSO-d6) δ = 8.27 (d, J = 8 Hz, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 7.2, 1.2 Hz, 1H), 7.39 - 7.33 (m, 2H), 5.06 - 5.00 (m, 1H), 4.70 (dd, J = 15.6, 6.8 Hz, 1H), 4.57 (dd, J = 15.6, 2.8 Hz, 1H), 4.43 - 4.30 (m, 2H), 3.94 (s, 2H), 3.87 (s, 3H), 2.73 - 2.64 (m, 1H), 2.40 - 2.31 (m, 1H), 1.30 (s, 12H).

[0147] Sixth step: preparation of intermediate 1h

[0148] Into a 250 mL reaction flask, was placed compound 1g (10.24 g, 21.32 mmol), compound 1h-1 (3.73 g, 17.77 mmol), Pd(dppf)Cl2(0.65 g, 0.89 mmol), cesium carbonate (14.48 g, 44.42 mmol), 1,4-dioxane (101 mL), and water (17 mL), and heated to 80 °C under nitrogen atmosphere, then the reaction was kept for 2 h. TLC was used to monitor the reaction, the heating was stopped, and the reaction was cooled to room temperature. The reaction mixture was filtered through celite, and the filtrate was extracted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate for three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to give white solid of intermediate 1h (7.284 g, 84.7% yield). MS m / z (ESI): 484.1246 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ = 8.28 (d, J = 1.6 Hz, 1H), 8.15 (dd, J = 8.4, 3.3 Hz, 1H), 8.07 (t, J = 8.4 Hz, 1H), 7.89-7.85 (m, 2H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.48 (t, J = 8.4 Hz, 1H), 5.05 (qd, J = 6.8, 2.8 Hz, 1H), 4.74 (dd, J = 15.6, 7.2 Hz, 1H), 4.62 (dd, J = 15.6, 2.8 Hz, 1H), 4.56-4.43 (m, 3H), 4.37-4.32 (m, 1H), 3.87 (s, 3H), 2.75-2.66 (m, 1H), 2.42-2.33 (m, 1H).

[0149] Step 7: Preparation of intermediate 1i

[0150] Into a 100 mL reaction bottle, was added compound 1h (3.2 g, 6.613 mmol), compound 1i-1 (1.81 g, 9.919 mmol), Pd2(dba)3 (0.606 g, 0.661 mmol), 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl (0.617 g, 1.323 mmol), cesium carbonate (4.31 g, 44.42 mmol), toluene (48 mL), and the mixture was heated to 110 °C under nitrogen atmosphere, then the reaction was kept for 6 h. TLC was used to monitor the reaction. After the reaction was completed, the mixture was cooled to room temperature, and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give intermediate 1i (1.154 g, 27.7%) as a white solid. MS m / z (ESI): 630.1603 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ = 8.28 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.85 - 7.77 (m, 4H), 7.66 (dd, J = 8.4, 2.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 5.85 (s, 2H), 5.08 - 5.02 (m, 1H), 4.74 (dd, J = 15.5, 6.8 Hz, 1H), 4.61 (dd, J = 15.6, 2.4 Hz, 1H), 4.54 - 4.41 (m, 3H), 4.38 - 4.32 (m, 1H), 3.87 (s, 3H), 2.77 - 2.66 (m, 1H), 2.42 - 2.33 (m, 1H).

[0151] Eighth step: preparation of the compound of formula (I)

[0152] Into a 100 mL reaction flask, compound 1i (2.458 g, 4.06 mmol), tetrahydrofuran (30 mL), methanol (7.5 mL) and water (5 mL) were added, then lithium hydroxide monohydrate (0.51 g, 12.18 mmol) was added, the system was heated to 50 °C, and then the reaction was carried out for 2 h. TLC was used to monitor the reaction. After the reaction was completed, the system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. Then 25 mL of water, 5 mL of methanol and 7.5 mL of acetone were added to the residue, and the system was stirred uniformly. Then the pH of the system was adjusted to 5-6 with saturated aqueous citric acid solution, and a solid was precipitated. The solid was filtered, and the filter cake was washed with water. Then the filter cake was dispersed in a mixed solvent of 100 mL of acetone, 5 mL of tetrahydrofuran and 5 mL of methanol, and the system was heated to 60 °C and stirred for 2 h. Then the system was slowly cooled to room temperature, and the filter cake was filtered and washed twice with a mixed solvent of acetone, methanol and tetrahydrofuran. Then the filter cake was dried under reduced pressure at 55 °C for 20 h to obtain a white solid, compound of formula (I), 1.979 g, in a yield of 79.1%. 1 HNMR spectrum is shown in Figure 17, and MS m / z (ESI): 616.1453 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ = 8.25 (d, J = 1.6 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 7.85 - 7.77 (m, 4H), 7.66 (dd, J = 8.4, 2.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.06 (d, J = 2.4 Hz, 1H), 5.85 (s, 2H), 5.05 (qd, J = 6.8, 2.8 Hz, 1H), 4.72 (dd, J = 15.6, 7.2 Hz, 1H), 4.59 (dd, J = 15.6, 2.8 Hz, 1H), 4.53 - 4.33 (m, 4H), 2.74 - 2.65 (m, 1H), 2.42 - 2.34 (m, 1H).

[0153] Example 2: Preparation of the crystalline form of the compound of formula (I) tromethamine salt Form A

[0154] Method 1:

[0155] Into a jacketed reactor, 5 g of the compound of formula (I) (S)-2-(4-(6-((4- chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid and 235 mL (47 v) of acetonitrile were added and stirred at 50 °C for 10 min to obtain a suspension. Then 1.1 eq of tromethamine was added to the suspension and the reactor wall was rinsed with 5 mL (1 v) of acetonitrile. The reaction was continued to stir at 50 °C for 30 h. Then the suspension was filtered, the filter cake was rinsed with 5 mL (1 v) of acetonitrile and the filter cake was dried in a vacuum oven at room temperature (20-25 °C) for 3 h to obtain 5.8 g of crystalline material with a yield of 97%. The dry product was subjected to XRPD, TGA, DSC, 1 HNMR test, XRPD pattern is shown in Figure 1, TGA & DSC pattern is shown in Figure 18, 1 HNMR pattern is shown in Figure 19. 1 HNMR data: 1H NMR (400 MHz, MeOH-d4) δ = 8.16 (d, J = 1.6 Hz, 1H), 7.96 (dd, J = 8.4, 1.6 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.79-7.71 (m, 2H), 7.60-7.53 (m, 2H), 7.50-7.44 (m, 2H), 7.30-7.26 (m, 2H), 6.95 (d, J = 2.0 Hz, 1H), 5.87 (s, 2H), 5.18 (qd, J = 6.8, 2.8 Hz, 1H), 4.67-4.42 (m, 6H), 3.66 (s, 6H), 2.8-2.72 (m, 1H), 2.52-2.44 (m, 1H). TGA & DSC detection chart 1 The HNMR chart has a single peak at 2.05 ppm (acetonitrile solvent peak), which indicates that the dry product is an acetonitrile solvate of the tromethamine salt (salt ratio 1:1) of the compound of formula (I), named as Form A crystal form of the tromethamine salt of the compound of formula (I).

[0156] Method 2:

[0157] Into a jacketed reactor, 4 g of the compound of formula (I) (S)-2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid, 4 mL (1 v) of dimethyl sulfoxide and 12 mL (3 v) of acetonitrile were added to form a suspension, which was stirred at 50°C. Then 1.3 eq of tromethamine was dissolved in 8 mL (2 v) of dimethyl sulfoxide and slowly added dropwise into the suspension, and the suspension became clear. The reaction solution was continuously stirred at 50°C for 2 h. Then 110 mL (27.5 v) of acetonitrile was slowly added dropwise, and the temperature was lowered to 20°C and stirred for 10 h. The suspension was filtered, and the filter cake was dried in a vacuum oven at 60°C for 17 h to obtain 4.5 g of crystalline material, with a yield of 95%.

[0158] Method 3:

[0159] Into a jacketed reactor, 5 g of (S)-2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)-5- fluoropyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylic acid, 47.5 mL (9.5 v) of tetrahydrofuran were charged and stirred at 50 °C to obtain a suspension. Then 1.1 eq of tromethamine was dissolved in 2.5 mL (0.5 v) of water and slowly added into the suspension, and the reaction was continued to stir at 70 °C for 10 h. Then 100 mL (20 v) of acetonitrile was slowly added, and the mixture was stirred at 20 °C for 10 h. The suspension was filtered, and the filter cake was dried in a vacuum oven at 50 °C for 23 h to obtain 4.8 g of crystalline material with a yield of 81%.

[0160] Example 3: Preparation of Form B of the tromethamine salt of the compound of formula (I)

[0161] Method 1: Solid-liquid suspension equilibrium experiment at 20 °C for 3 days

[0162] About 30 mg of Form A of the tromethamine salt of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass bottle, and an appropriate amount of solvent was added to form a suspension, which was stirred magnetically at 20 °C for 3 days. Then the suspension was centrifuged at room temperature (20-25 °C), and the obtained solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid.

[0163] The solid sample was tested.

[0164] Method 2: Solid-liquid suspension equilibrium experiment at 50 °C for 3 days

[0165] About 30 mg of Form A of the tromethamine salt of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass bottle, and an appropriate amount of solvent was added to form a suspension, which was stirred magnetically at 50 °C for 3 days. Then the suspension was centrifuged at room temperature (20-25 °C), and the obtained solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid.

[0166] The solid sample was tested.

[0167] Method 3: Anti-solvent crystallization experiment

[0168] About 30 mg of Form A of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass vial, and an appropriate amount of a good solvent was added to form a clear solution. Then, an inappropriate solvent was slowly added to the clear solution until a certain amount of solid was precipitated. The mixture was stirred for 24-25 h, and the separated solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid. The solid sample was tested.

[0169] The XRPD pattern of Form B of the compound of formula (I) is shown in Figure 2, and the TGA & DSC pattern is shown in Figure 20.

[0170] Example 4: Preparation of Form C of the compound of formula (I) tromethamine salt

[0171] Method 1: Solid-liquid suspension equilibrium experiment at 20 °C for 14 days

[0172] About 30 mg of Form A of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass vial, and an appropriate amount of a good solvent was added to form a clear solution. Then, an inappropriate solvent was slowly added to the clear solution until a certain amount of solid was precipitated. The mixture was stirred for 24-25 h, and the separated solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid. The solid sample was tested.

[0173] The XRPD pattern of Form C of the compound of formula (I) is shown in Figure 3, and the TGA & DSC pattern is shown in Figure 21.

[0174] Example 5: Preparation of Form D of the compound of formula (I) tromethamine salt

[0175] Method 1: Solid-liquid suspension equilibrium experiment at 20 °C for 14 days

[0176] About 30 mg of Form A of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass vial, and an appropriate amount of a good solvent was added to form a clear solution. Then, an inappropriate solvent was slowly added to the clear solution until a certain amount of solid was precipitated. The mixture was stirred for 24-25 h, and the separated solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid. The solid sample was tested.

[0177] The solid sample was tested.

[0178] Method 2: Solid-liquid suspension equilibrium experiment at 50 °C for 3 days

[0179] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, an appropriate amount of solvent was added to form a suspension, and the suspension was stirred magnetically at 50 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the resulting solid was dried under a stream of nitrogen or in a vacuum to remove residual solvent from the surface of the solid.

[0180] The solid sample was tested.

[0181] Method 3: Hot saturated solution cooling crystallization experiment:

[0182] About 50 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a glass vial, and solvent was added to form a clear or a suspension saturated solution at 50 °C ± 0.1 °C. After stirring for 1 h, the solution was filtered, and the resulting filtrate was cooled to 5 °C at a rate of 5 °C / h and stirred at 5 °C overnight. The solid product was isolated, and the resulting solid was dried under a stream of nitrogen or in a vacuum to remove residual solvent from the surface of the solid. The solid sample was tested.

[0183] The XRPD pattern of Form D of the compound of formula (I) tromethamine salt is shown in Figure 4, and the TGA & DSC pattern is shown in Figure 22.

[0184] Example 6: Preparation of Form E of the compound of formula (I) tromethamine salt

[0185] Method 1 : 20 °C solid-liquid suspension equilibration for 3 days experiment:

[0186] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, an appropriate amount of solvent was added to form a suspension, and the suspension was stirred magnetically at 20 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the resulting solid was dried under a stream of nitrogen or in a vacuum to remove residual solvent from the surface of the solid.

[0187] The solid sample was tested.

[0188] Method 2: 50 °C solid-liquid suspension equilibration for 3 days experiment:

[0189] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, an appropriate amount of solvent was added to form a suspension, and the suspension was stirred magnetically at 50 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the resulting solid was dried under a stream of nitrogen or in a vacuum to remove residual solvent from the surface of the solid.

[0190] Solid samples were tested.

[0191] The XRPD pattern of Form E of the compound of formula (I) tromethamine salt is shown in Figure 5, and the TGA & DSC pattern is shown in Figure 23.

[0192] Example 7: Preparation of Form F of the compound of formula (I) tromethamine salt

[0193] Method 1: Solid-liquid suspension equilibrium experiment at 20°C for 3 days

[0194] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained in Example 2 was weighed into a 2 mL glass bottle, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 20°C for 3 days. Subsequently, the suspension was centrifuged at room temperature (20-25°C), and the obtained solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid.

[0195] Solid samples were tested.

[0196] Method 2: Solid-liquid suspension equilibrium experiment at 50°C for 3 days

[0197] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained in Example 2 was weighed into a 2 mL glass bottle, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 50°C for 3 days. Subsequently, the suspension was centrifuged at room temperature (20-25°C), and the obtained solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid.

[0198] Solid samples were tested.

[0199] The XRPD pattern of Form F of the compound of formula (I) tromethamine salt is shown in Figure 6, and the TGA & DSC pattern is shown in Figure 24.

[0200] Example 8: Preparation of Form G of the compound of formula (I) tromethamine salt

[0201] Method: Solid-liquid suspension equilibrium experiment at 20°C for 3 days

[0202] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained in Example 2 was weighed into a 2 mL glass bottle, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 20°C for 3 days. Subsequently, the suspension was centrifuged at room temperature (20-25°C), and the obtained solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid.

[0203] Solid samples were tested.

[0204] The XRPD pattern of Form G of the compound of formula (I) tromethamine salt is shown in Figure 7 and the TGA & DSC pattern is shown in Figure 25.

[0205] Example 9: Preparation of Form H of the compound of formula (I) tromethamine salt

[0206] Method: 20°C solid-liquid suspension equilibrium for 3 days experiment:

[0207] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained in Example 2 was weighed into a 2 mL glass bottle, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 20°C for 3 days. Subsequently, the suspension was centrifuged at room temperature (20-25°C), and the obtained solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid.

[0208] Solid samples were tested.

[0209] The XRPD pattern of Form H of the compound of formula (I) tromethamine salt is shown in Figure 8 and the TGA & DSC pattern is shown in Figure 26.

[0210] Example 10: Preparation of Form I of the compound of formula (I) tromethamine salt

[0211] Method: 20°C solid-liquid suspension equilibrium for 3 days experiment:

[0212] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained in Example 2 was weighed into a 2 mL glass bottle, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 20°C for 3 days. Subsequently, the suspension was centrifuged at room temperature (20-25°C), and the obtained solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid.

[0213] Solid samples were tested.

[0214] The TGA & DSC pattern of Form I of the compound of formula (I) tromethamine salt is shown in Figure 27.

[0215] Example 11: Preparation of Form J of the compound of formula (I) tromethamine salt

[0216] Method: 50°C solid-liquid suspension equilibrium for 3 days experiment:

[0217] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, and an appropriate amount of solvent was added to form a suspension. The suspension was stirred magnetically at 50 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the solid was dried under nitrogen or vacuum to remove residual solvent on the surface of the solid.

[0218] The XRPD pattern of Form J of the compound of formula (I) tromethamine salt is shown in Figure 9, and the TGA & DSC pattern is shown in Figure 28.

[0219] Example 12: Preparation of Form K of the compound of formula (I) tromethamine salt

[0220] Method: 3-day suspension at 50 °C:

[0221] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, and an appropriate amount of solvent was added to form a suspension. The suspension was stirred magnetically at 50 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the solid was dried under nitrogen or vacuum to remove residual solvent on the surface of the solid.

[0222] The solid sample was tested.

[0223] The TGA & DSC pattern of Form K of the compound of formula (I) tromethamine salt is shown in Figure 29.

[0224] Example 13: Preparation of Form L of the compound of formula (I) tromethamine salt

[0225] Method: 3-day suspension at 50 °C:

[0226] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, and an appropriate amount of solvent was added to form a suspension. The suspension was stirred magnetically at 50 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the solid was dried under nitrogen or vacuum to remove residual solvent on the surface of the solid.

[0227] The solid sample was tested.

[0228] The TGA & DSC pattern of Form L of the compound of formula (I) tromethamine salt is shown in Figure 30.

[0229] Example 14: Preparation of Form M of the tromethamine salt of the compound of formula (I)

[0230] Method: Solid-liquid suspension equilibrium experiment at 50 °C for 3 days

[0231] About 30 mg of Form A of the tromethamine salt of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass bottle, and an appropriate amount of solvent was added to form a suspension. The suspension was stirred magnetically at 50 °C for 3 days. Subsequently, the suspension was centrifuged at room temperature (20-25 °C) to obtain a solid, which was dried by purging with nitrogen or vacuum drying to remove the residual solvent on the surface of the solid.

[0232] The solid sample was tested.

[0233] The TGA & DSC spectrum of Form M of the tromethamine salt of the compound of formula (I) is shown in Figure 31.

[0234] Example 15: Preparation of Form N of the tromethamine salt of the compound of formula (I)

[0235] Method: Anti-solvent crystallization experiment

[0236] About 30 mg of Form A of the tromethamine salt of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass bottle, and an appropriate amount of a good solvent was added to form a clear solution. Subsequently, a poor solvent was slowly added to the clear solution until a certain amount of solid was precipitated. The stirring was continued for 24-25 h, and the separated solid was dried by purging with nitrogen or vacuum drying to remove the residual solvent on the surface of the solid. The solid sample was tested.

[0237] The XRPD spectrum of Form N of the tromethamine salt of the compound of formula (I) is shown in Figure 11, and the TGA & DSC spectrum is shown in Figure 32.

[0238] Example 16: Preparation of Form O of the tromethamine salt of the compound of formula (I)

[0239] Method 1: Hot saturated solution cooling crystallization experiment

[0240] About 50 mg of Form A of the tromethamine salt of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass bottle, and a solvent was added to prepare a clear or suspended saturated solution at 50 °C ± 0.1 °C. After stirring for 1 h, the liquid was filtered, and the obtained filtrate was cooled to 5 °C at a rate of 5 °C / h and stirred at 5 °C overnight. The solid product was separated, and the obtained solid was dried by purging with nitrogen or vacuum drying to remove the residual solvent on the surface of the solid. The solid sample was tested.

[0241] Method 2: Slow evaporation experiment at room temperature

[0242] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 20 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the obtained solid was dried by purging with nitrogen or vacuum drying to remove the residual solvent on the surface of the solid.

[0243] The XRPD pattern of Form O of the compound of formula (I) tromethamine salt is shown in Figure 12, and the DSC pattern is shown in Figure 33.

[0244] Example 17: Preparation of Form P of the compound of formula (I) tromethamine salt

[0245] Method: Solid-liquid suspension equilibrium experiment at 50 °C for 3 days

[0246] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 50 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the obtained solid was dried by purging with nitrogen or vacuum drying to remove the residual solvent on the surface of the solid.

[0247] The solid sample was tested.

[0248] The XRPD pattern of Form P of the compound of formula (I) tromethamine salt is shown in Figure 13, and the TGA & DSC patterns are shown in Figure 34.

[0249] Example 18: Preparation of Form Q of the compound of formula (I) tromethamine salt

[0250] Method: Solid-liquid suspension equilibrium experiment at 50 °C for 3 days

[0251] About 30 mg of Form A of the compound of formula (I) tromethamine salt obtained from Example 2 was weighed into a 2 mL glass vial, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 50 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C), and the obtained solid was dried by purging with nitrogen or vacuum drying to remove the residual solvent on the surface of the solid.

[0252] The solid sample was tested.

[0253] The XRPD pattern of Form Q crystal of the compound of formula (I) tromethamine salt is shown in Figure 14, and the TGA & DSC pattern is shown in Figure 35. 1 The HNMR data is shown in Figure 36, the HPLC pattern is shown in Figure 37, and the purity is 98.8%. 1 HNMR data: 1 HNMR (400 MHz, DMSO-d6) δ = 8.17-8.17 (m, 1H), 7.96 (dd, J = 8.5, 1.5 Hz, 1H), 7.92 (d, J = 2.2 Hz, 1H), 7.80-7.72 (m, 2H), 7.60-7.44 (m, 4H), 7.30-7.26 (m, 2H), 6.96 (d, J = 2.2 Hz, 1H), 5.88 (s, 2H), 5.20-5.15 (m, 1H), 4.67-4.42 (m, 6H), 3.65 (s, 6H), 2.81-2.72 (m, 1H), 2.53-2.44 (m, 1H). 1 The HNMR data (Figure 36) shows that the molar ratio of acid to base is 1:1, and there is no obvious solvent residue. In combination with the TGA & DSC pattern and 1 The HNMR data shows that Form Q crystal is a non-hydrate and non-solvate.

[0254] Example 19: Preparation of Form R crystal of the compound of formula (I) tromethamine salt

[0255] Method: 50°C solid-liquid suspension equilibrium experiment for 3 days:

[0256] About 30 mg of Form A crystal of the compound of formula (I) tromethamine salt obtained in Example 2 was weighed into a 2 mL glass bottle, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 50°C for 3 days. Subsequently, the suspension was centrifuged at room temperature (20-25°C), and the obtained solid was dried by nitrogen blowing or vacuum drying to remove the residual solvent on the surface of the solid.

[0257] The solid sample was tested.

[0258] The XRPD pattern of Form R crystal of the compound of formula (I) tromethamine salt is shown in Figure 15, and the TGA & DSC pattern is shown in Figure 38.

[0259] Example 20: Preparation of Form S crystal of the compound of formula (I) tromethamine salt

[0260] Method: 50°C solid-liquid suspension equilibrium experiment for 3 days:

[0261] About 30 mg of the Form A crystalline salt of the compound of formula (I) obtained in Example 2 was weighed into a 2 mL glass vial, an appropriate amount of solvent was added to form a suspension, and the mixture was stirred magnetically at 50 °C for 3 days. The suspension was then centrifuged at room temperature (20-25 °C) to obtain a solid, which was dried by purging with nitrogen or vacuum drying to remove the residual solvent on the surface of the solid.

[0262] The solid sample was tested.

[0263] The XRPD pattern of the Form S crystalline salt of the compound of formula (I) is shown in Figure 16, and the TGA & DSC pattern is shown in Figure 39.

[0264] Example 21: Screening of salt forms of the compound of formula (I)

[0265] Based on the structure of the compound of formula (I), a screening of salt forms was carried out using 11 ligands (triaminol, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, L-arginine, L-proline, L-histidine, L-lysine, sulfuric acid, malic acid) in 7 solvent systems (EtOH, EA, Acetone, THF, ACN, EtOH / H2O = 95 / 5 (v / v), EtOH / H2O = 90 / 10 (v / v)).

[0266] Test procedure: 30 mg of the compound of formula (I) was added to a 2 mL screw cap vial, 0.5 mL or 1 mL of solvent was added, and a magnetic stirrer was added to form a suspension solution at room temperature. 1.1 eq of the ligand compound was added to a 2 mL screw cap vial, 0.5 mL of solvent was added, and a magnetic stirrer was added to form a suspension or clear solution at room temperature. The magnetic stirrer was turned on and heated at 50 °C, and the ligand solution was added dropwise to the compound of formula (I) solution, the experimental phenomena were recorded, and heating and stirring were maintained at 50 °C for 2 hours. The heating was turned off and the temperature was reduced to 25 °C, and stirring was continued at 25 °C overnight. The above solution was centrifuged and dried if it was a suspension; if it was a gel or oil, the state was recorded; if it was a clear solution, the solid was obtained by slow evaporation at 25 °C, and the solid was dried, and the compound was tested by nuclear magnetic resonance, infrared spectroscopy, XRPD, TGA & DSC analysis to confirm whether it was a salt. The results of the screening of salt forms of the compound of formula (I) are as follows:

[0267] The results show that in the 7 solvent systems (EtOH, EA, Acetone, THF, ACN, EtOH / H2O = 95 / 5 (v / v), EtOH / H2O = 90 / 10 (v / v)), the compound of formula (I) only formed a salt with triaminol, sodium hydroxide, potassium hydroxide, calcium hydroxide, and L-arginine, and no salt was formed with the other ligands. Among them, the triaminol salt of the compound of formula (I) was the most stable salt form.1 HNMR spectrum is shown in Figure 19, and the XRPD spectrum of the L-arginine salt is shown in Figure 40. 1 The HNMR spectrum is shown in Figure 41. In comparison, the tromethamine salt of the compound of formula (I) is easier to prepare and the post-treatment (e.g. isolation) is more convenient.

[0268] Example 22: Comparative study of solubility

[0269] The compound of formula (I) (free form), the compound of formula (I) tromethamine salt Form A, the compound of formula (I) tromethamine salt Form E, the compound of formula (I) tromethamine salt Form Q, the compound of formula (I) sodium salt and the compound of formula (I) arginine salt were each suspended in 15 mL of different pH solutions and placed in a constant temperature shaker with a rotation speed of 200 r / min and a temperature of 37°C for 24 h. Subsequently, the solubility was determined by HPLC, and the comparative data of solubility are as follows:

[0270] Note: "N.D." means not detected (detection limit: 0.05 μg / mL); "-" means not detected; "FaSSIF" means simulated fasted state simulated intestinal fluid; "FeSSIF" means simulated fed state simulated intestinal fluid.

[0271] The results show that:

[0272] (1): The solubility of the compound of formula (I) sodium salt and the compound of formula (I) arginine salt under the conditions of "FaSSIF" and "FeSSIF" is very low, and is not significantly improved compared with the compound of formula (I) (free form). In contrast, the solubility of the different crystal forms of the compound of formula (I) tromethamine salt (e.g. Form A, Form B, Form E, Form Q) under the conditions of "FaSSIF" and "FeSSIF" is significantly improved compared with the compound of formula (I) (free form) and the compound of formula (I) sodium salt and arginine salt. For example, the solubility of the compound of formula (I) tromethamine salt Form E, which has the worst solubility, under the conditions of "FaSSIF" and "FeSSIF" is at least 15 times and 16 times higher than that of the compound of formula (I) sodium salt, and is at least 36 times and 16 times higher than that of the compound of formula (I) arginine salt (the solubility of the compound of formula (I) arginine salt under the conditions of "FaSSIF" and "FeSSIF" is not detected, and is calculated according to the detection limit of 0.05 μg / mL).

[0273] Therefore, the solubility of the compound of formula (I) tromethamine salt has achieved an unexpected effect compared with the compound of formula (I) sodium salt and the compound of formula (I) arginine salt.

[0274] (2): The solubility of the compound of formula (I) tromethamine salt Form B in water is 18 times that of the free state; the solubility in FeSSIF (pH = 5.0) is 63 times that of the free state; the solubility in FaSSIF (pH = 6.5) is 15.83 μg / mL, while the free state is not detected (calculated according to the detection limit of 0.05 μg / mL), at least 316 times that of the free state; the solubility of the compound of formula (I) tromethamine salt Form B has achieved an unexpected effect compared with the free state.

[0275] (3): The solubility of the compound of formula (I) tromethamine salt Form Q in water is 4300 times that of the free state; the solubility in FeSSIF (pH = 5.0) is 140 times that of the free state; the solubility in pH 6.8 phosphate buffer is 78 times that of the free state; the solubility in FaSSIF (pH = 6.5) is 60 μg / mL, while the free state is not detected (calculated according to the detection limit of 0.05 μg / mL), at least 1200 times that of the free state; the solubility of the compound of formula (I) tromethamine salt Form Q has achieved an unexpected effect compared with the free state.

[0276] (4) The solubility of the compound of formula (I) tromethamine salt Form B in FaSSIF (pH = 6.5) is 3.6 times that of Form A and 8.8 times that of Form E; the solubility of the tromethamine salt Form B in FeSSIF (pH = 5.0) is 19.7 times that of Form A and 39.4 times that of Form E; the solubility of the compound of formula (I) tromethamine salt Form B has achieved an unexpected effect compared with Form A and Form E.

[0277] (5): The solubility of the compound of formula (I) tromethamine salt Form Q in water is 231 times that of Form B; the solubility in FaSSIF (pH = 6.5) is 14 times that of Form A, 3.8 times that of Form B, and 33 times that of Form E; the solubility of the tromethamine salt Form Q in FeSSIF (pH = 5.0) is 44 times that of Form A, 2.2 times that of Form B, and 88 times that of Form E; the solubility of the compound of formula (I) tromethamine salt Form Q has achieved an unexpected effect compared with Form A, Form B and Form E.

[0278] (6): "FaSSIF" simulates the fasting state of human intestinal fluid; "FeSSIF" simulates the fed state of human intestinal fluid; these two media and water and pH 6.8 phosphate buffer are very important for evaluating the properties and absorption of drugs. The solubility of the aminotrizol Form Q crystal form of the compound of formula (I) in the four media is significantly better than that of the free state and the sodium salt of the compound of formula (I) and the arginine salt of the compound of formula (I), and has very good physicochemical properties and drugability.

[0279] Example 23: Stability comparison study

[0280] (1) Comparison experiment of thermodynamic properties of the salt and aminotrizol crystal form of the compound of formula (I), and the results are shown in Table 1.

[0281] Table 1: Thermodynamic comparison experiment of the salt and aminotrizol crystal form of the compound of formula (I)

[0282] From the data in the table, the aminotrizol Form B, Form G, Form Q crystal form of the compound of formula (I) has high crystallinity and good thermodynamics, among which the aminotrizol Form Q crystal form has high crystallinity, high melting point (170.08°C) and good thermodynamics, and belongs to the dominant crystal form.

[0283] (2) Influence factor experiment:

[0284] The aminotrizol Form B, Form Q crystal form or the compound of formula (I) (free state) material was placed in a glass dish, and was placed in high temperature 60°C (closed), high humidity 92.5%±5% (open) and light (4500±500Lux, with ultraviolet) conditions, respectively, and the samples were taken at the corresponding time points in the table below for XRPD and HPLC, and the appearance color of the samples was recorded. The results are shown in Table 2.

[0285] Table 2: Influence factor experiment of aminotrizol Form B, Form Q crystal form and the compound of formula (I) (free state)

[0286] From the results in the table, the aminotrizol Form Q crystal form did not change in crystal form, purity and properties under high temperature, high humidity and strong light conditions for 5 days, 10 days, 15 days, 20 days and 30 days, and had good stability. The aminotrizol Form B crystal form also did not change in purity and properties under high temperature, high humidity and strong light conditions for 5 days and 10 days, and had good stability.

[0287] The purity of the compound of formula (I) (free form) changed from 99.17% to 98.87% under high temperature condition for 15 days, decreased by 0.30%; the purity changed from 99.17% to 98.97% under high humidity condition for 15 days, decreased by 0.20%; the purity almost did not change under light condition for 15 days, but the property changed from white to light yellow.

[0288] In comparison, the crystal form, purity and property of the aminotrizole salt Form B and Form Q crystal forms did not change under high temperature, high humidity and strong light conditions. Therefore, the stability of the aminotrizole salt Form B and Form Q crystal forms is better than that of the compound of formula (I) (free form).

[0289] (3) Accelerated stability experiment:

[0290] The aminotrizole salt Form B crystal form was placed under accelerated conditions (40°C, 75% RH), and samples were taken on the 15th day and the 30th day for HPLC testing, and samples were taken on the 30th day for HPLC and XRPD testing; the aminotrizole salt Form Q crystal form was placed under accelerated conditions (40°C, 75% RH), and samples were taken on the 6th day, 11th day, 16th day, 20th day and 30th day for XRPD and HPLC testing, the results are shown in Table 3, and the XRPD spectrum overlay of the accelerated stability experiment of the aminotrizole salt Form Q crystal form is shown in Figure 42.

[0291] Table 3: Accelerated stability experiment of aminotrizole salt Form B, Form Q crystal forms

[0292] Note: "-" means not detected.

[0293] As can be seen from the results in the table, the aminotrizole salt Form B, Form Q crystal forms did not change in crystal form, purity and property under accelerated conditions (40°C, 75% RH) for 30 days, and had good stability.

[0294] (4) Long-term stability experiment:

[0295] The aminotrizole salt Form Q crystal form was placed under long-term experiment (25°C, 60% RH), and samples were taken on the 1st week, 2nd week, 1st month, 2nd month and 3rd month for XRPD and HPLC testing, the results are shown in Table 4, and the XRPD spectrum overlay of the long-term stability experiment is shown in Figure 43.

[0296] Table 4: Results of long-term stability experiment of aminotrizole salt Form Q crystal form

[0297] From the results in the table, the TBA salt Form Q crystal form was placed for 3 months under long-term experiment (25°C, 60% RH), and the crystal form, purity and properties did not change, and the stability was good.

[0298] Example 24: Simulated granulation experiment of TBA salt Form Q crystal form

[0299] Granulation solvent was added dropwise to 30 mg of TBA salt Form Q crystal form solid until the solid was fully wetted. After grinding for 5 min (or dry grinding for 5 min without solvent), the crystal form change of TBA salt Form Q crystal form was evaluated by XRPD. The results are shown in Table 5.

[0300] Table 5: Simulated granulation experiment of TBA salt Form Q crystal form

[0301] From the results in the table, the TBA salt Form Q crystal form was placed for 3 months under long-term experiment (25°C, 60% RH), and the crystal form, purity and properties did not change, and the stability was good.

[0302] Example 25: High pressure experiment of TBA salt Form Q crystal form

[0303] After 50 mg of TBA salt Form Q crystal form material was tableted under a pressure of 10 tons and a platen time of 5 minutes, it was found by XRPD testing that the crystal form did not change, and it was still Form Q crystal form. Under the extremely high pressure of 10 tons at present, the crystal form still maintained good stability.

[0304] Experimental Example 1: In vitro activity experiment

[0305] Experimental method:

[0306] The logarithmic growth phase GLP1R / CRE-LUC HEK293 cells (purchased from Nanjing Kebai) were trypsinized, and the digested cells were resuspended in DMEM + 10% FBS culture medium, and the cell density was adjusted to 3.5*10 5 / mL. 100 μL / well was inoculated in a 96-well cell culture plate, and the culture plate was incubated in an incubator overnight (37°C, 5% CO2).

[0307] The test compound was dissolved using DMSO and prepared into a 10 mM stock solution, then serially diluted 5 times using DMSO, 10 concentration points (10000, 2000, 400, 80, 16, 3.2, 0.64, 0.12, 0.026, 0.005 μM), the 11th concentration point only added DMSO as a control. Then 1 μL of each sample diluted with DMSO was added to 99 μL of cell culture medium (DMEM), mixed and then 11 μL was transferred to a 96-well cell culture plate, the cell culture plate was incubated in an incubator for 5 hours (37°C, 5% CO2). The 96-well cell culture plate was removed, 100 μL Luciferase reagent (purchased from VKEY-BIO, A2000802N), gently mixed and placed at room temperature for 10 minutes, then the chemiluminescence signal value was measured using an enzyme marker. Microsoft Excel and GraphPad Prism6 were used to process and analyze the data to obtain the EC 50 value of the compound. The results are shown in Table 6.

[0308] Experimental results:

[0309] Table 6. Determination of the agonistic activity of the compound on GLP1R / CRE-Luc / HEK293 cells

[0310] Conclusion:

[0311] Trometamol salt Form Q has excellent biological activity and good agonistic effect on GLP-1 receptor.

[0312] Experimental Example 2: Pharmacokinetic comparative study

[0313] Experimental method: 6 healthy male SD rats (provided by Beijing Huafukang Biotechnology Co., Ltd., body weight 220-260 g) were selected (2 rats per administration group), after overnight fasting, 10 mg / kg (calculated as free state) of compound (I) (free state) or trometamol salt Form B or trometamol salt Form Q suspension (solvent: 0.5% CMC) was administered by gavage, the administration volume was 10 mL / kg. Before administration and at 0.5, 1, 2, 4, 8, 24 h after administration, about 200 μL of whole blood was collected from the rat orbital venous plexus into a centrifuge tube containing EDTA-K2 anticoagulant, then centrifuged at 3000 rpm for 10 min, the upper plasma was transferred to another clean centrifuge tube, the plasma concentration in the plasma sample was detected using the LC-MS / MS method, and the pharmacokinetic parameters were calculated using a non-compartment model. The results are shown in Table 7.

[0314] Table 7. Pharmacokinetic parameters of rats administered by gavage

[0315] Conclusion: (1): Under the condition of the same dose of 10mpk, the Cmax and exposure of TTH salt Form B and TTH salt Form Q are significantly higher than that of the compound of formula (I) (free state), for example, the Cmax and exposure of TTH salt Form B are about 7 times and 4 times of that of the compound of formula (I) (free state) respectively, and the Cmax and exposure of TTH salt Form Q are about 10 times and 9 times of that of the compound of formula (I) (free state) respectively, which achieves an unexpected effect.

[0316] (2): Under the condition of the same dose of 10mpk, the exposure of TTH salt Form Q is about 2.3 times of that of TTH salt Form B.

[0317] Experimental Example 3: Pharmacokinetic comparison study in beagle dogs

[0318] Experimental method: 4 healthy beagle dogs (2 in each administration group, provided by Sichuan Musk Raising Institute, body weight 8-10 kg) were selected, half male and half female, and after overnight fasting, 3mg / kg (calculated as free state) of the compound of formula (I) (free state) or TTH salt Form Q suspension (solvent: 0.5% CMC) was orally administered by gavage, the administration volume was 5mL / kg, and 1mL of blood was collected from the forelimb vein at 0.5, 1, 2, 4, 8, 12, 24, 48 hours after administration, and placed in a centrifuge tube containing EDTA-K2 anticoagulant, then centrifuged at 3000rpm for 10min, and the upper plasma was transferred to another clean centrifuge tube, the blood drug concentration in the plasma sample was detected by LC-MS / MS method, and the pharmacokinetic parameters were calculated by non-compartment model. The results are shown in Table 8.

[0319] Table 8. Pharmacokinetic parameters of beagle dogs after oral administration

[0320] Conclusion: In the pharmacokinetic comparison study in beagle dogs, under the condition of the same dose of 3mpk, the Cmax and exposure of TTH salt Form Q are significantly higher than that of the compound of formula (I) (free state), for example, the Cmax and exposure of TTH salt Form Q are about 3 times and 4.5 times of that of the compound of formula (I) (free state) respectively, which achieves an unexpected effect.

Claims

1. A pharmaceutically acceptable salt of the compound represented by formula (I), wherein the compound represented by formula (I) is as follows:

2. A pharmaceutically acceptable salt of the compound of formula (I) according to claim 1, wherein the salt is tromethamine salt of the compound of formula (I).

3. A crystalline form of a salt of a compound of formula (I) wherein the compound of formula (I) is: ###0001### trimethoprim salt. ​ 4. The crystalline form of tromethamine salt of the compound of formula (I) according to claim 3, wherein the crystalline form is tromethamine salt Form A, and the X-ray powder diffraction pattern of the tromethamine salt Form A has characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation, at 12.14°±0.2°, 17.03°±0.2°, 19.52°±0.2° and 22.01°±0.2°; preferably, the X-ray powder diffraction pattern of the tromethamine salt Form A has characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation, at 4.85°±0.2°, 10.04°±0.2°, 12.14°±0.2°, 17.03°±0.2°, 17.77°±0.2°, 19.52°±0.2°, 21.57°±0.2°, 22.01°±0.2°, 23.52°±0.2°, 25.89°±0.2° and 27.77°±0.2°; more preferably, the X-ray powder diffraction pattern of the tromethamine salt Form A is as shown in Figure 1.

5. The crystalline form of tromethamine salt of the compound of formula (I) according to claim 3, wherein the crystalline form is tromethamine salt Form B, and the X-ray powder diffraction pattern of the tromethamine salt Form B has characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation, at 5.90°±0.2°, 14.04°±0.2°, 17.75°±0.2°, 18.58°±0.2°, 21.16°±0.2°, 22.71°±0.2° and 28.50°±0.2°; preferably, the X-ray powder diffraction pattern of the tromethamine salt Form B has characteristic peaks, expressed in angles 2θ, using Cu-Kα radiation, at 5.90°±0.2°, 6.67°±0.2°, 10.51°±0.2°, 12.92°±0.2°, 14.04°±0.2°, 16.89°±0.2°, 17.75°±0.2°, 18.58°±0.2°, 21.16°±0.2°, 22.71°±0.2°, 23.80°±0.2°, 24.69°±0.2°, 25.49°±0.2°, 28.11°±0.2° and 28.50°±0.2°; Preferably, the X-ray powder diffraction pattern of the tromethamine salt Form B crystalline form has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 5.90°±0.2°, 6.67°±0.2°, 10.51°±0.2°, 11.83°±0.2°, 12.92°±0.2°, 14.04°±0.2°, 14.58°±0.2°, 16.89°±0.2°, 17.32°±0.2°, 17.75°±0.2°, 18.06°±0.2°, 18.58°±0.2°, 20.03°±0.2°, 20.41°±0.2°, 20.73°±0.2°, 21.16°±0.2°, 22.71°±0.2°, 23.80°±0.2°, 24.69°±0.2°, 25.49°±0.2°, 26.12°±0.2°, 28.11°±0.2° and 28.50°±0.2°; More preferably, the X-ray powder diffraction pattern of the tromethamine salt Form B crystalline form is shown in Figure 2, expressed in angles 2Q, using Cu-Ka radiation.

6. The crystalline form of the tromethamine salt of formula (I) according to claim 3, wherein said crystalline form is the tromethamine salt Form D crystalline form, having the X-ray powder diffraction pattern with the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 9.53°±0.2°, 18.01°±0.2°, 18.69°±0.2°, 18.90°±0.2°, 19.25°±0.2°, 19.58°±0.2°, 20.06°±0.2° and 21.29°±0.2°; Preferably, the X-ray powder diffraction pattern of the tromethamine salt Form D crystalline form has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 9.53°±0.2°, 12.15°±0.2°, 12.60°±0.2°, 13.68°±0.2°, 18.01°±0.2°, 18.69°±0.2°, 18.90°±0.2°, 19.25°±0.2°, 19.58°±0.2°, 20.06°±0.2°, 21.05°±0.2°, 21.29°±0.2°, 21.93°±0.2°, 23.79°±0.2°, 24.14°±0.2°, 24.85°±0.2°, 26.10°±0.2°, 26.75°±0.2°, 28.04°±0.2° and 29.94°±0.2°; More preferably, the X-ray powder diffraction pattern of the tromethamine salt Form D crystalline form is shown in Figure 4, expressed in angles 2Q, using Cu-Ka radiation.

7. The crystalline form of the compound of Formula (I) as claimed in claim 3, wherein the crystalline form is the Tro-methamine salt Form G, the X-ray powder diffraction pattern of the Tro-methamine salt Form G has characteristic peaks, using Cu-Ka radiation and expressed in terms of the 2 theta angle, at 15.78°±0.2°, 20.16°±0.2°, 24.56°±0.2° and 25.06°±0.2°; Preferably, the X-ray powder diffraction pattern of the Tro-methamine salt Form G has characteristic peaks, using Cu-Ka radiation and expressed in terms of the 2 theta angle, at 15.78°±0.2°, 15.99°±0.2°, 16.98°±0.2°, 17.75°±0.2°, 19.01°±0.2°, 19.24°±0.2°, 19.75°±0.2°, 20.16°±0.2°, 21.17°±0.2°, 21.80°±0.2°, 23.47°±0.2°, 23.73°±0.2°, 24.56°±0.2°, 25.06°±0.2°, 26.49°±0.2° and 27.37°±0.2°; More preferably, the X-ray powder diffraction pattern of the Tro-methamine salt Form G is as shown in Figure 7.

8. The crystalline form of the compound of Formula (I) as claimed in claim 3, wherein the crystalline form is the Tro-methamine salt Form H, the X-ray powder diffraction pattern of the Tro-methamine salt Form H has characteristic peaks, using Cu-Ka radiation and expressed in terms of the 2 theta angle, at 14.76°±0.2°, 16.84°±0.2° and 21.98°±0.2°; Preferably, the X-ray powder diffraction pattern of the Tro-methamine salt Form H has characteristic peaks, using Cu-Ka radiation and expressed in terms of the 2 theta angle, at 4.82°±0.2°, 8.68°±0.2°, 9.68°±0.2°, 12.14°±0.2°, 14.76°±0.2°, 16.84°±0.2°, 21.27°±0.2° and 21.98°±0.2°; More preferably, the X-ray powder diffraction pattern of the Tro-methamine salt Form H is as shown in Figure 8.

9. The crystalline form of the compound of Formula (I) as claimed in claim 3, wherein the crystalline form is the Tro-methamine salt Form J, the X-ray powder diffraction pattern of the Tro-methamine salt Form J has characteristic peaks, using Cu-Ka radiation and expressed in terms of the 2 theta angle, at 13.20°±0.2°, 14.31°±0.2°, 18.08°±0.2°, 19.93°±0.2°, 22.96°±0.2°, 26.09°±0.2° and 26.61°±0.2°; Preferably, the X-ray powder diffraction pattern of the Trospium salt Form J crystalline form has the following characteristic peaks, expressed in angles of 2Q, using Cu-Ka radiation: 9.14°±0.2°, 13.20°±0.2°, 14.31°±0.2°, 14.90°±0.2°, 15.28°±0.2°, 16.53°±0.2°, 18.08°±0.2°, 18.71°±0.2°, 18.92°±0.2°, 19.73°±0.2°, 19.93°±0.2°, 20.30°±0.2°, 22.96°±0.2°, 23.44°±0.2°, 23.98°±0.2°, 24.47°±0.2°, 26.09°±0.2°, 26.61°±0.2° and 28.86°±0.2°; More preferably, the X-ray powder diffraction pattern of the Trospium salt Form J crystalline form is as shown in Figure 9, expressed in angles of 2Q, using Cu-Ka radiation.

10. The crystalline form of the Trospium salt of formula (I) according to claim 3, wherein said crystalline form is Trospium salt Form Q, having the following characteristic peaks, expressed in angles of 2Q, using Cu-Ka radiation: 14.37°±0.2°, 19.96°±0.2° and 23.02°±0.2°; Preferably, the X-ray powder diffraction pattern of the Trospium salt Form Q crystalline form has the following characteristic peaks, expressed in angles of 2Q, using Cu-Ka radiation: 14.37°±0.2°, 14.91°±0.2°, 18.74°±0.2°, 19.96°±0.2°, 23.02°±0.2 and 24.02°±0.2°; Preferably, the X-ray powder diffraction pattern of the Trospium salt Form Q crystalline form has the following characteristic peaks, expressed in angles of 2Q, using Cu-Ka radiation: 13.24°±0.2°, 14.37°±0.2°, 14.91°±0.2°, 18.10°±0.2°, 18.74°±0.2°, 19.96°±0.2°, 23.02°±0.2°, 23.48°±0.2° and 24.02°±0.2°; Preferably, the X-ray powder diffraction pattern of the Trospium salt Form Q crystalline form has the following characteristic peaks, expressed in angles of 2 theta, using Cu-Kalpharadiation: 13.24°±0.2°, 14.37°±0.2°, 14.91°±0.2°, 15.28°±0.2°, 18.10°±0.2°, 18.74°±0.2°, 19.76°±0.2°, 19.96°±0.2°, 20.34°±0.2°, 23.02°±0.2°, 23.48°±0.2°, 24.02°±0.2°, 24.51°±0.2°, 26.69°±0.2° and 27.84°±0.2°; Preferably, the X-ray powder diffraction pattern of the Trospium salt Form Q crystalline form has the following characteristic peaks, expressed in angles of 2 theta, using Cu-Kalpharadiation: 3.38°±0.2°, 9.20°±0.2°, 10.15°±0.2°, 13.24°±0.2°, 14.37°±0.2°, 14.91°±0.2°, 15.28°±0.2°, 16.52°±0.2°, 17.20°±0.2°, 18.10°±0.2°, 18.74°±0.2°, 18.94°±0.2°, 19.54°±0.2°, 19.76°±0.2°, 19.96°±0.2°, 20.34°±0.2°, 21.38°±0.2°, 21.64°±0.2°, 23.02°±0.2°, 23.48°±0.2°, 24.02°±0.2°, 24.51°±0.2°, 25.56°±0.2°, 26.13°±0.2°, 26.44°±0.2°, 26.69°±0.2°, 27.84°±0.2°, 28.88°±0.2°, 32.30°±0.2° and 33.50°±0.2°; Preferably, the X-ray powder diffraction pattern of the Trospium salt Form Q crystalline form has the following characteristic peaks, expressed in angles 2Q, using Cu-Ka radiation: 3.38°±0.2°, 6.64°±0.2°, 9.20°±0.2°, 10.15°±0.2°, 13.24°±0.2°, 14.37°±0.2°, 14.91°±0.2°, 15.28°±0.2°, 16.52°±0.2°, 16.82°±0.2°, 17.20°±0.2°, 18.10°±0.2°, 18.74°±0.2°, 18.94°±0.2°, 19.54°±0.2°, 19.76°±0.2°, 19.96°±0.2°, 20.34°±0.2°, 21.38°±0.2°, 21.64°±0.2°, 23.02°±0.2°, 23.48°±0.2°, 24.02°±0.2°, 24.51°±0.2°, 25.33°±0.2°, 25.56°±0.2°, 26.13°±0.2°, 26.44°±0.2°, 26.69°±0.2°, 26.95°±0.2°, 27.84°±0.2°, 28.88°±0.2°, 31.01°±0.2°, 31.45°±0.2°, 32.30°±0.2° and 33.50°±0.2°; More preferably, the X-ray powder diffraction pattern of the Trospium salt Form Q crystalline form is as shown in Figure 14, using Cu-Ka radiation.

11. A pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula (I) according to claim 1 or 2, or a crystalline form of the Trospium salt of the compound of formula (I) according to claims 3 to 10, and a pharmaceutically acceptable adjuvant.

12. Use of a pharmaceutically acceptable salt of the compound of formula (I) according to claim 1 or 2, or a crystalline form of the Trospium salt of the compound of formula (I) according to claims 3 to 10, or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for GLP-1 receptor agonists.

13. Use of a pharmaceutically acceptable salt of the compound of formula (I) according to claim 1 or 2, or a crystalline form of the Trospium salt of the compound of formula (I) according to claims 3 to 10, or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment and / or prevention of diabetes mellitus type I, diabetes mellitus type II, malnutrition-related diabetes mellitus, hyperglycemia, diabetic complications, obesity, non-alcoholic steatohepatitis (NASH), insulin resistance, impaired glucose tolerance, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic syndrome, Parkinson's disease and / or dementia.

14. A method for preparing the trimethadione salt Form A crystal form of claim 4, which comprises dispersing the compound of formula (I) with trimethadione in a solvent to form a suspension, stirring, filtering, washing, and then drying the filter cake to obtain crystalline material. Preferably, the chemical ratio of the compound of formula (I) to trimethadione is 1:0.5-1:3, preferably 1:0.8-1:1.5; and the solvent is one or more of acetonitrile, dimethyl sulfoxide, tetrahydrofuran, water, preferably one or more of acetonitrile, dimethyl sulfoxide / acetonitrile, tetrahydrofuran / water, tetrahydrofuran / water / acetonitrile.

15. A method for preparing the trimethadione salt Form B crystal form, the trimethadione salt Form D crystal form, the trimethadione salt Form G crystal form, the trimethadione salt Form H crystal form, the trimethadione salt Form J crystal form, the trimethadione salt Form Q crystal form of claims 5-10, which comprises converting the trimethadione salt Form A crystal form in a solvent to obtain.

16. The method of claim 15, wherein the solvent used for the conversion is selected from at least one of cyclohexane, methylcyclohexane, methanol, ethanol, isopropanol, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide, propanone, butanone, methyl isobutyl ketone, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, dichloromethane, dichloroethane, acetic acid, and water. Preferably, the solvent used for the conversion is selected from at least one of isopropyl acetate, ethyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, propanone, butanone, methyl isobutyl ketone, N-methylpyrrolidone, dichloromethane, methyl tert-butyl ether, methylcyclohexane.

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