Pharmaceutically acceptable salts and crystalline forms of GLP-1 receptor agonists and methods for preparing same

Abstract

The present invention provides a pharma- ceutically acceptable salt of a GLP-1 receptor agonist, a crystalline form thereof, and a method for preparing the same. Specifically, the present invention provides a pharma- ceutically acceptable salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid and a crystalline form thereof.

Description

[Technical field]

[0001] This application claims priority to Chinese patent application No. 2021115845744, filed on December 23, 2021. This application cites the above Chinese patent application in full.

[0002] (Technical field) The present disclosure is in the medical field and relates to pharma- ceutically acceptable salts, crystalline forms of GLP-1 receptor agonists and methods for their preparation. [Background technology]

[0003] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L cells in the lower gastrointestinal tract. GLP-1 plays a corresponding role by binding to its ubiquitous specific receptor, and currently, the organs in which GLP-1 receptors are obviously present include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus and cardiovascular system, and GLP-1 receptors may also be present in the liver, adipose tissue and skeletal muscle. GLP-1 not only acts on β cells to promote insulin secretion, but also on α cells to inhibit glucagon secretion. In general, there is no significant difference in serum GLP-1 levels in patients with normal glucose tolerance, impaired glucose tolerance and type II diabetes. However, there is a defect in the response of β cells to GLP-1 after a meal, and under certain conditions, this response reaction is significantly enhanced after continuous infusion of GLP-1. Because the duration of action of the human body's own GLP-1 is very short (t1 / 2 of intravenous injection < 1.5 minutes), the human body's own GLP-1 is not suitable for clinical treatment of diabetes.

[0004] Peptide-type GLP-1 receptor agonists (liraglutide, exenatide, etc.) have the effect of lowering fasting and postprandial glucose levels and improving blood glucose in type II diabetes patients. However, because peptide-type GLP-1 has poor oral bioavailability and is inconvenient to take, there is a strong demand for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0005] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is a novel compound with GLP-1 receptor agonist activity (structural formula is as follows, PCT / CN2021 / 115915). [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] PCT / CN2021 / 115915 Summary of the Invention [Problem to be solved by the invention]

[0007] Half of the new molecular entities approved by the US Food and Drug Administration (FDA) are pharmaceutical salts. Salt drugs have been on a continuous growth trajectory since the first salt form was approved in 1939. At the same time, salt formation may improve some undesirable physicochemical or biological properties of drugs. It is very important to develop salts of 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid that have better properties in terms of physicochemical or pharmaceutical properties.

[0008] At the same time, in view of the importance of crystals and their stability of solid pharmaceuticals in clinical treatment, it is very important to in-depth study the crystal polymorphism of the pharma-ceutically acceptable salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid for the development of pharmaceuticals suitable for industrial production and with good biological activity. [Means for solving the problem]

[0009] (Summary of the invention) The present disclosure provides pharma- ceutically acceptable salts of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0010] In some embodiments, the pharma- ceutically acceptable salt is selected from tromethamine, ammonium, potassium, arginine, sodium, meglumine, ethanolamine, p-toluenesulfonate, tartrate, sulfate, malate, and hydrochloride salts.

[0011] In some other embodiments, the chemical ratio of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid to the alkali molecule (cation) is 1:0.5 to 1:3, including 1:0.5, 1:1, 1:2 or 1:3.

[0012] In some embodiments, the chemical ratio of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid to the alkali molecule is 1:1 or 1:2.

[0013] In some other embodiments, the chemical ratio of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid to the acid molecule (acid radical) is 1:0.5 to 1:3, including 1:0.5, 1:1, 1:2 or 1:3.

[0014] In some embodiments, the chemical ratio of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid to the acid molecule is 1:1 or 1:2.

[0015] Another aspect of the disclosure further provides a method of preparing the above pharma- ceutically acceptable salts comprising forming a salt with the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid and an acid, or forming a salt with the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid and a base.

[0016] In some embodiments, the solvent used in the salt formation reaction is selected from at least one of methanol, 2-butanone, ethyl acetate, 1,4-dioxane, methyl isobutyl ketone, methyl tert-butyl ether, dichloromethane, ethanol, isopropanol, tetrahydrofuran, dimethylsulfoxide, acetone, acetonitrile, toluene, isopropyl acetate, and water.

[0017] In some other embodiments, the volume (μl) of the solvent used in the salt formation reaction may be 1 to 200 times the mass (mg) of the compound, and in non-limiting embodiments, may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the preparation method described in the present disclosure further comprises a centrifugation, washing or drying step.

[0018] One embodiment of the present disclosure provides an amorphous form of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, having a powder X-ray diffraction pattern expressed by the diffraction angle 2θ having no significant characteristic peaks.

[0019] In some embodiments, the powder X-ray diffraction pattern, expressed as the diffraction angles 2θ of the amorphous of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, is as shown in FIG. 1 .

[0020] Another embodiment of the present disclosure further provides Form A crystals of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0021] In some embodiments, the tromethamine salt Form A crystal has characteristic peaks at 6.850, 13.789, 16.148, and 22.138 in a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ.

[0022] In some embodiments, the Form A crystal of the tromethamine salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, that has characteristic peaks at 6.850, 9.982, 13.789, 16.148, and 22.138.

[0023] In some embodiments, the Form A crystal of the tromethamine salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, having characteristic peaks at 6.850, 9.982, 12.697, 13.789, 15.763, 16.148, 18.016, 19.016, and 22.138.

[0024] In some embodiments, the Form A crystal of the tromethamine salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, having characteristic peaks at 6.850, 8.051, 9.982, 12.697, 13.789, 14.704, 14.990, 15.763, 16.148, 18.016, 19.016, 20.109, 22.138, 25.712, and 27.909.

[0025] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the crystalline form A of the tromethamine salt is as shown in FIG.

[0026] Another embodiment of the present disclosure further provides Form B crystals of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0027] In some embodiments, the B-type crystals of the tromethamine salt have characteristic peaks at 8.144, 10.511, 12.290, 20.632, and 21.699 in a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ.

[0028] In some embodiments, the tromethamine salt type B crystal has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, that has characteristic peaks at 8.144, 10.511, 12.290, 13.996, 14.665, 20.632, 21.699, and 24.74.

[0029] In some embodiments, the tromethamine salt type B crystal has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, having characteristic peaks at 8.144, 10.511, 12.290, 13.996, 14.665, 15.607, 16.520, 18.883, 20.632, 21.699, 23.741, 24.743, 26.055, and 27.035.

[0030] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the B-type crystals of the tromethamine salt is as shown in FIG.

[0031] Another embodiment of the present disclosure further provides Form C crystals of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0032] In some embodiments, the C-type crystals of the tromethamine salt have characteristic peaks at 6.551, 9.269, 13.175, and 16.906 in a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ.

[0033] In some embodiments, the C-type crystals of the tromethamine salt have a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, that has characteristic peaks at 6.551, 9.269, 13.175, 14.802, 15.864, 16.906, 18.776, 20.430, and 25.496.

[0034] In some embodiments, the tromethamine salt C-type crystal has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, having characteristic peaks at 6.551, 8.392, 9.269, 13.175, 14.802, 15.864, 16.906, 18.776, 20.430, 22.211, 22.922, 23.574, 25.496, and 26.290.

[0035] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the C-type crystals of the tromethamine salt is as shown in FIG.

[0036] Another embodiment of the present disclosure further provides crystalline Form D of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0037] In some embodiments, the D-type crystal of the tromethamine salt has characteristic peaks at 5.281, 10.292, 13.322, and 21.390 in a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ.

[0038] In some embodiments, the tromethamine salt type D crystal has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, that has characteristic peaks at 5.281, 9.912, 10.292, 10.961, 13.322, 21.390, 22.215, 23.979, 25.029, and 25.846.

[0039] In some embodiments, the Form D crystal of the tromethamine salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, having characteristic peaks at 5.281, 9.912, 10.292, 10.961, 11.613, 13.322, 15.351, 18.283, 19.214, 21.390, 22.215, 23.471, 23.979, 25.029, 25.846, 27.918, and 30.121.

[0040] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the D-form crystal of the tromethamine salt is as shown in FIG.

[0041] Another embodiment of the present disclosure further provides Form E crystals of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0042] In some embodiments, the E-form crystals of the tromethamine salt have characteristic peaks at 6.821, 10.035, 12.653, 13.727, and 14.787 in a powder X-ray diffraction pattern expressed in terms of diffraction angle 2θ.

[0043] In some embodiments, the Form E crystal of the tromethamine salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, having characteristic peaks at 6.821, 10.035, 12.653, 13.727, 14.787, 16.081, 16.648, 18.571, 20.151, and 22.204.

[0044] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the E-form crystals of the tromethamine salt is as shown in FIG.

[0045] Another aspect of the present disclosure further provides a method for preparing the above Form A, B, C, D or E crystals, comprising: (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, tromethamine and a solvent, stirring or heating to dissolve, and (b) crystallizing.

[0046] In some embodiments, the method for preparing the Form A crystals includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, tromethamine, and a solvent (1), stirring or heating to dissolve, and (b) crystallizing, wherein the solvent (1) is selected from one or more of ethanol, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, isopropanol, methanol, and water.

[0047] In some embodiments, the method for preparing the above-mentioned Type B crystals comprises: (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, tromethamine, and a 10% water / acetone solvent, stirring or heating to dissolve, and (b) crystallizing.

[0048] In some embodiments, the method for preparing the above Form C crystals comprises (a) mixing Form A crystals of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with one or more solvents selected from ethanol, acetone, isopropyl acetate, dioxane, and toluene, and (b) crystallizing the resulting crystals.

[0049] In some embodiments, the method for preparing the above-mentioned Form D crystals comprises: (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, tromethamine with one or more solvents selected from methanol, isopropanol, stirring or heating to dissolve, and (b) crystallizing.

[0050] In some embodiments, the method for preparing the above-mentioned Form E crystals includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, tromethamine, and acetonitrile solvent, stirring or heating to dissolve, and (b) crystallizing.

[0051] Another embodiment of the present disclosure further provides Form F crystals of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0052] In some embodiments, the F-type crystals of the tromethamine salt have characteristic peaks at 7.674, 10.614, 16.400, and 18.645 in a powder X-ray diffraction pattern expressed as a diffraction angle 2θ.

[0053] In some embodiments, the F-type crystals of the tromethamine salt have characteristic peaks at 6.777, 7.674, 10.614, 11.594, 14.408, 14.882, 16.400, and 18.645 in a powder X-ray diffraction pattern expressed as diffraction angles 2θ.

[0054] In some embodiments, the Form F crystal of the tromethamine salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, having characteristic peaks at 6.777, 7.674, 10.614, 11.594, 13.671, 14.408, 14.882, 16.400, 18.645, 20.849, 21.384, 21.731, 22.108, 24.721, 26.169, and 29.192.

[0055] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the F-type crystals of the tromethamine salt is as shown in FIG.

[0056] Another aspect of the present disclosure further provides a method for preparing Form F crystals of a tromethamine salt. In some embodiments, the method for preparing Form F crystals of a tromethamine salt comprises: (a) placing Form A crystals of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid at 80° C. / 0% RH for 96 hours or drying at 167° C.

[0057] Another aspect of the present disclosure further provides a crystalline form α of the potassium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0058] In some embodiments, the α-form crystals of the potassium salt have characteristic peaks at 9.564, 11.515, 14.683, 19.607, and 20.391 in a powder X-ray diffraction pattern represented by diffraction angles 2θ.

[0059] In some embodiments, the α-form crystals of the potassium salt have a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 9.564, 11.515, 14.683, 16.058, 18.859, 19.607, 20.391, 22.592, 23.320, and 25.176.

[0060] In some embodiments, the α-form crystals of the potassium salt have a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 9.564, 11.515, 14.683, 16.058, 17.033, 18.859, 19.607, 20.391, 21.064, 22.592, 23.320, 24.449, 25.176, 25.933, 27.080, and 27.708.

[0061] In some embodiments, the powder X-ray diffraction pattern, represented by the diffraction angle 2θ, of the α-form crystal of the potassium salt is as shown in FIG.

[0062] The present disclosure further provides a method for preparing α-form crystals of a potassium salt. In some embodiments, the method includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (2), adding potassium hydroxide solution, and (b) slurrying, wherein the solvent (2) is selected from one or more of ethyl acetate or methyl tert-butyl ether.

[0063] Another aspect of the present disclosure further provides Form I crystals of the sodium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0064] In some embodiments, the Form I crystal of the sodium salt has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 5.257, 5.806, 6.795, 10.106, 12.203, and 20.693.

[0065] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the Form I crystal of the sodium salt is as shown in FIG.

[0066] The present disclosure further provides a method for preparing crystals of the sodium salt Form I. In some embodiments, the method includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (3), adding sodium hydroxide solution, and (b) slurrying, wherein the solvent (3) is selected from one or more of methanol or ethyl acetate.

[0067] Another aspect of the present disclosure further provides crystalline Form II of the sodium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0068] In some embodiments, the sodium salt Form II crystal has a powder X-ray diffraction pattern represented by a diffraction angle 2θ having characteristic peaks at 9.754, 11.731, and 19.730.

[0069] In some embodiments, the Form II crystal of the sodium salt has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 5.574, 9.754, 11.731, 14.856, 16.091, 19.730, and 22.670.

[0070] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the Form II crystal of the sodium salt is as shown in FIG.

[0071] The present disclosure further provides a method for preparing the Form II crystals of the sodium salt. In some embodiments, the method includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (4), adding sodium hydroxide solution, and (b) crystallizing, wherein the solvent (4) is selected from one or more of acetone or acetonitrile.

[0072] Another aspect of the present disclosure further provides crystalline Form I of the meglumine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0073] In some embodiments, the Form I crystal of the meglumine salt has characteristic peaks at 5.498, 11.013, 14.626, and 17.942 in a powder X-ray diffraction pattern expressed as a diffraction angle 2θ.

[0074] In some embodiments, the Form I crystal of the meglumine salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, that has characteristic peaks at 5.498, 8.901, 11.013, 14.626, 17.942, 19.454, 22.668, and 25.696.

[0075] In some embodiments, the Form I crystal of the meglumine salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, having characteristic peaks at 5.498, 8.314, 8.901, 11.013, 11.891, 12.810, 14.626, 15.683, 15.931, 17.942, 18.748, 19.454, 20.393, 21.419, 22.234, 22.668, 23.391, 24.739, and 25.696.

[0076] In some embodiments, the powder X-ray diffraction pattern, expressed as a diffraction angle 2θ, of the Form I crystal of the meglumine salt is as shown in FIG.

[0077] The present disclosure further provides a method for preparing crystalline Form I of a meglumine salt. In some embodiments, the method includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with acetonitrile, adding meglumine, and (b) crystallizing.

[0078] Another aspect of the present disclosure further provides Form I crystals of the p-toluenesulfonate salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0079] In some embodiments, the Form I crystal of the p-toluenesulfonate salt has characteristic peaks at 5.453, 5.884, 8.063, 12.925, 16.071, and 19.778 in a powder X-ray diffraction pattern represented by diffraction angles 2θ.

[0080] In some embodiments, the Form I crystal of the p-toluenesulfonate salt has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 5.453, 5.884, 8.063, 12.925, 13.825, 15.399, 16.071, 18.231, 19.778, and 21.917.

[0081] In some embodiments, the Form I crystal of the p-toluenesulfonate salt has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 5.453, 5.884, 8.063, 12.925, 13.825, 15.399, 16.071, 16.560, 17.066, 18.231, 19.778, 20.861, 21.917, 23.898, and 26.744.

[0082] In some embodiments, the powder X-ray diffraction pattern, represented by the diffraction angle 2θ, of the Form I crystal of the p-toluenesulfonate salt is as shown in FIG.

[0083] The present disclosure further provides a method for preparing a crystal of p-toluenesulfonic acid salt Form I. In some embodiments, the method includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with acetonitrile, adding p-toluenesulfonic acid, and (b) crystallizing.

[0084] One embodiment of the present disclosure provides an amorphous form of the tartrate salt of compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, having a powder X-ray diffraction pattern expressed as a diffraction angle 2θ having no significant characteristic peaks.

[0085] Another aspect of the present disclosure further provides a crystalline Form I of the tartrate salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0086] In some embodiments, the Form I crystal of the tartrate salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angle 2θ, that has characteristic peaks at 12.810, 18.824, 21.890, and 24.472.

[0087] In some embodiments, the Form I crystal of the tartrate salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, having characteristic peaks at 12.810, 14.448, 15.604, 18.824, 20.410, 21.890, and 24.472.

[0088] In some embodiments, the Form I crystal of the tartrate salt has a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, having characteristic peaks at 9.342, 10.132, 10.858, 11.272, 12.810, 14.448, 15.604, 18.824, 20.410, 21.890, 24.472, and 27.880.

[0089] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the Form I crystal of the Tartrate Salt is as shown in FIG.

[0090] The present disclosure further provides a method for preparing crystalline Form I of the tartrate salt, in some embodiments, the method includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (5), adding L-tartaric acid, and (b) crystallizing, wherein the solvent (5) is selected from one or more of ethanol, ethyl acetate, and methyl tert-butyl ether.

[0091] One embodiment of the present disclosure provides an amorphous form of a malate salt of compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, the powder X-ray diffraction pattern of which expressed at the diffraction angle 2θ has no significant characteristic peaks.

[0092] Another aspect of the present disclosure further provides an α-form crystal of the malate salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0093] In some embodiments, the α-form crystals of the malate have a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 10.050, 14.508, 15.693, 18.924, and 20.240.

[0094] In some embodiments, the α-form crystals of the malate salt have a powder X-ray diffraction pattern, expressed as diffraction angles 2θ, that has characteristic peaks at 10.050, 10.818, 11.213, 12.871, 14.508, 15.693, 18.924, 20.240, 21.829, and 24.396.

[0095] In some embodiments, the α-form crystals of the malate salt have a powder X-ray diffraction pattern, expressed in terms of diffraction angles 2θ, that has characteristic peaks at 9.364, 10.050, 10.818, 11.213, 12.871, 13.774, 14.508, 15.693, 17.760, 18.924, 20.240, 21.829, 24.396, 26.200, 27.936, and 28.188.

[0096] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the α-form crystals of the Malate Salt is as shown in FIG.

[0097] The present disclosure further provides a method for preparing α-form crystals of a malate salt, in some embodiments, the method includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with a solvent (6), adding malic acid, and (b) crystallizing, wherein the solvent (6) is selected from one or more of ethyl acetate or methyl tert-butyl ether.

[0098] An embodiment of the present disclosure further provides an amorphous form of the hydrochloride salt of compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, the powder X-ray diffraction pattern of which expressed at the diffraction angle 2θ has no significant characteristic peaks.

[0099] Another aspect of the present disclosure further provides crystalline Form I of the hydrochloride salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0100] In some embodiments, the Form I crystal of the hydrochloride salt has characteristic peaks at 9.939, 14.333, 14.933, 17.523, 18.480, and 20.134 in a powder X-ray diffraction pattern expressed as a diffraction angle 2θ.

[0101] In some embodiments, the Form I crystal of the hydrochloride salt has a powder X-ray diffraction pattern represented by diffraction angles 2θ, which has characteristic peaks at 9.939, 13.123, 13.649, 14.333, 14.933, 16.616, 17.523, 18.480, 19.378, 20.134, 20.988, 26.399, and 26.970.

[0102] In some embodiments, the Form I crystal of the hydrochloride salt has a powder X-ray diffraction pattern expressed in terms of diffraction angles 2θ, which has characteristic peaks at 9.939, 12.267, 13.123, 13.649, 14.333, 14.933, 16.616, 17.523, 18.480, 19.378, 20.134, 20.988, 22.377, 23.002, 24.477, 25.322, 26.399, 26.970, 27.609, 30.822, and 33.760.

[0103] In some embodiments, the powder X-ray diffraction pattern, expressed as diffraction angles 2θ, of the Form I crystal of the hydrochloride salt is as shown in FIG.

[0104] The present disclosure further provides a method for preparing crystalline Form I of the hydrochloride salt. In some embodiments, the method includes (a) mixing the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid with water, adding hydrochloric acid, and (b) crystallizing.

[0105] The volume (μl) of the solvents (1), (2), (3), (4), (5), and (6) used in the present disclosure may be 1 to 200 times the mass (mg) of the above compound, and in non-limiting embodiments, is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, or a value between any two of the above values.

[0106] In addition, the method for preparing the above crystals of the present disclosure further comprises one or more steps of filtering, washing or drying.

[0107] The present disclosure further provides a pharmaceutical composition comprising the above-mentioned pharma- ceutically acceptable salt or a crystal thereof, and a pharmaceutical auxiliary optionally selected from pharma- ceutically acceptable excipients.

[0108] The present disclosure further provides a method for preparing a pharmaceutical composition, comprising mixing the above-mentioned pharma- ceutically acceptable salt or a crystal thereof, and a pharma- ceutically acceptable excipient.

[0109] The present disclosure further provides use of the above-mentioned pharma- ceutically acceptable salt or a crystal thereof, or the above-mentioned composition, in the preparation of a medicament for treating or preventing a disease associated with the GLP-1 receptor.

[0110] The present disclosure further provides use of the above-mentioned pharma- ceutically acceptable salt or a crystal thereof, or the above-mentioned composition, in the preparation of a medicament for treating or preventing diabetes.

[0111] "2θ or 2θ angle" as used in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and is expressed in ° or degrees, and the error range for each characteristic peak 2θ is ±0.2 (including numbers beyond one decimal place after rounding), and includes the following: -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0. 0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0112] According to the description of hygroscopic properties and the definition of hygroscopic weight increase in the 2015 edition of the Chinese Pharmacopoeia, Part 4, "9103 Guidelines on Hygroscopicity of Pharmaceuticals," Deliquescence: Absorption of enough water to form a liquid Extremely hygroscopic: Hygroscopic weight increase is 15% or more; Hygroscopic: Hygroscopic weight increase is less than 15% and is 2% or more; Slightly hygroscopic: Hygroscopic weight increase is less than 2% and more than 0.2%; No or little hygroscopicity: Hygroscopic weight increase is less than 0.2%.

[0113] "Differential scanning calorimetry or DSC" as used herein refers to the measurement of temperature and heat flow differences between a sample and a reference material during the heating or isothermal process of the sample in order to characterize all physical and chemical changes associated with thermal effects and obtain phase change information of the sample.

[0114] The drying temperature described in the present disclosure is generally 25° C. to 100° C., preferably 40° C. to 70° C., and may be dried at normal pressure or reduced pressure, with the pressure being <−0.08 MPa.

[0115] An "excipient" as referred to in this disclosure includes, but is not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, or emulsifying agent approved by the U.S. Food and Drug Administration as acceptable for human or veterinary use.

[0116] The term "slurrying" in this disclosure refers to a purification method that utilizes the poor solubility of a substance in a solvent and the good solubility of impurities in a solvent, and slurry purification can remove color, change crystals, and remove small amounts of impurities.

[0117] The starting materials used in the method for preparing crystals of the present disclosure may be compounds in any form, and specific forms include, but are not limited to, amorphous, any crystal, hydrate, solvate, etc.

[0118] The numerical values ​​such as the content of the substance in this disclosure are measured and calculated data, and some error is unavoidable. Generally, ±10% is within a reasonable error range. There will be some error variation depending on the context of use, and this error variation will not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, and is preferably ±5%.

[0119] The compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (hereinafter referred to as compound A) in the present disclosure is prepared by referring to the method in PCT / CN2021 / 115915, the relevant contents of which are hereby incorporated by reference. [Brief description of the drawings]

[0120] [Figure 1]1 is an amorphous XRPD pattern of the tromethamine salt. [Diagram 2] 1 is an XRPD pattern of crystal form A of the tromethamine salt. [Diagram 3] 1 is an XRPD pattern of crystalline form B of the tromethamine salt. [Figure 4] 1 is an XRPD pattern of crystalline form C of the tromethamine salt. [Diagram 5] 1 is an XRPD pattern of crystalline form D of the tromethamine salt. [Figure 6] 1 is an XRPD pattern of crystal form E of the tromethamine salt. [Figure 7] 1 is an XRPD pattern of crystalline form F of the tromethamine salt. [Figure 8] 1 is an XRPD pattern of α-form crystals of the potassium salt. [Figure 9] 1 is an XRPD pattern of type I crystals of the sodium salt. [Figure 10] 1 is an XRPD pattern of crystalline form II of the sodium salt. [Figure 11] 1 is an XRPD pattern of crystalline form I of the meglumine salt. [Figure 12] This is an XRPD pattern of type I crystals of p-toluenesulfonate. [Figure 13] 1 is an XRPD pattern of crystalline Form I of the tartrate salt. [Figure 14] 1 is an XRPD pattern of α-form crystals of the malate salt. [Figure 15] This is the XRPD pattern of the hydrochloride salt type I crystals. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0121] Hereinafter, the present disclosure will be described in more detail through examples or experimental examples, but the examples or experimental examples of the present disclosure are only used to explain the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.

[0122] The reagents used in this disclosure are commercially available.

[0123] Test conditions for the equipment used in the experiments of this disclosure:

[0124] 1. Differential Scanning Calorimeter (DSC) Equipment Model: Mettler Toledo DSC 3+STARe System Purge gas: Nitrogen gas, Nitrogen gas purge rate: 50mL / min Heating rate: 10.0℃ / min Temperature range: 25~350℃ or 25~300℃

[0125] 2. X-ray Powder Diffraction (XRPD) Instrument model: BRUKER D8 Discover powder X-ray diffractometer Radiation: Monochromatic Cu-Kα radiation (λ=1.5406) Scan mode: θ / 2θ, Scan range (2θ range): 3~50° Voltage: 40kV, Current: 40mA

[0126] 3. Thermogravimetric Analysis (TGA) Equipment Model: Mettler Toledo TGA2 Purge gas: Nitrogen gas, Nitrogen gas purge rate: 50mL / min Heating rate: 10.0℃ / min Temperature range: 30~350℃

[0127] 4. DVS: Dynamic Vapor Sorption Detection was performed using Surface Measurement Systems advantage 2 at 25°C, with humidity of 50%-95%-0%-95%-50% RH, with a step size of 10%, and the criteria was that the mass change dM / dT for each gradient was less than 0.002%, with a TMAX of 360 min for two cycles.

[0128] 5. The reaction process monitoring in the examples is carried out by thin layer chromatography (TLC), and the developer used in the reaction, the column chromatography eluent system used for the purification of the compound and the thin layer chromatography developer system include A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm, and the specification used in thin layer chromatography separation and purification of the product is 0.4mm-0.5mm. Silica gel column chromatography generally uses Yantai Yellow Sea silica gel 200-300 mesh silica gel as the carrier.

[0129] 6. The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is 10 -6 It is expressed in units of (ppm).

[0130] NMR measurements were performed using a Bruker AVANCE NEO 500M, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) and the internal standard is tetramethylsilane (TMS).

[0131] The MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector). THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

[0132] 7. Known starting materials in the present disclosure can be synthesized by methods known in the art or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Darui Fine Chemicals Co., Ltd.

[0133] 8. HPLC measurements were performed using an Agilent 1260DAD high-performance liquid chromatograph (ACE Excel C18 150 x 4.6 mm column) and a Thermo Dionex Ultimate 3000 high-pressure liquid chromatograph (Waters Xbridge C18 150 x 4.6 mm column). EXAMPLES

[0134] Example 1: Preparation and activity testing of compound A [ka]

[0135] Step 1 2-(4-Chloro-2-fluorophenyl)oxirane 2b Potassium tert-butoxide (1.70g, 15.14mmol, Accela Chembio Co., Ltd.) was added to tetrahydrofuran (30mL), trimethylsulfonium iodide (3.09g, 15.14mmol, Adamas Reagent Co., Ltd.) was added under ice bath and stirred for 5 minutes. 4-Chloro-2-fluorobenzaldehyde 2a (2.0g, 12.61mmol, Accela Chembio Co., Ltd.) was added, filtered, diluted with ethyl acetate (80mL), washed with saturated ammonium chloride aqueous solution (30mL x 2), washed with saturated saline (30mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2b (650mg, yield: 29.9%).

[0136] 1 H NMR (500 MHz, CDCl 3 ) δ 7.05-7.13 (m, 3H), 4.01-4.15 (m, 1H), 3.17(dd, 1H), 3.75(dd, 1H).

[0137] Step 2 2-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2d 1-(4-chloro-2-fluorophenyl)-2-(2,6-dibromophenoxy)ethanol 2e Compound 2b (520 mg, 3.01 mmol) and 2,6-dibromophenol 2c (759 mg, 3.01 mmol, TCI (SHANGHAI) Development Co., Ltd.) were mixed, and sodium methoxide (16 mg, 0.30 mmol, Adamas Reagent Co., Ltd.) was added and stirred at 130° C. for 2 hours. After cooling, the resulting residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2d (210 mg, yield: 16.4%) and compound 2e (140 mg, yield: 10.9%).

[0138] 2d MS m / z (ESI):422.9 [M-1]. 2d 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.69 (t, 1H), 7.63(d, 2H), 7.40 (dd, 1H), 7.35 (dd, 1H), 7.00 (t, 1H), 5.59 (t, 1H), 5.02 (t, 1H), 3.98-4.03 (m, 1H), 3.81-3.90 (m, 1H).

[0139] 2e 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.64(d, 2H), 7.62 (t, 1H), 7.39 (dd, 1H), 7.32 (dd, 1H), 7.02 (t, 1H), 5.82-6.01 (m, 1H), 5.28 (t, 1H), 4.07-4.12 (m, 1H), 3.95-4.00 (m, 1H).

[0140] Step 3 8-Bromo-2-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane 2f Compound 2d (595 mg, 1.40 mmol) was dissolved in anhydrous toluene (8 mL), and S-1,1'-bi-2-naphthol (159 mg, 0.55 mmol, Accela Chembio Co., Ltd.), cuprous iodide (52 mg, 0.27 mmol, Sinopharm Chemical Reagent Co., Ltd.), and cesium carbonate (912 mg, 2.80 mmol, Accela Chembio Co., Ltd.) were added in sequence, heated to reflux, and stirred for 18 hours. The mixture was cooled and concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography using elution system B to give the title compound 2f (380 mg, yield: 78.9%).

[0141] MS m / z (ESI): 343.1 [M-1]. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.57 (dd, 1H), 7.54(t, 1H), 7.43 (dd, 1H), 7.19 (dd, 1H), 6.98 (dd, 1H), 6.85 (t, 1H), 5.58 (dd, 1H), 4.51 (dd, 1H), 4.20 (dd, 1H).

[0142] Step 4 tert-Butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate 2g Compound 2f (354 mg, 1.03 mmol) and compound 1d (350 mg, 1.13 mmol, Accela Chembio Co., Ltd.) were dissolved in a mixed solution of 24 mL of 1,4-dioxane and water (V / V=5:1), sodium carbonate (218 mg, 2.06 mmol), and tetrakis(triphenylphosphine)palladium(0) (119 mg, 1.03 mmol) were added, and the mixture was stirred at 90° C. for 4 hours under nitrogen gas protection. The mixture was cooled to room temperature, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2g (410 mg, yield: 89.2%).

[0143] MS m / z (ESI): 390.1 [M-55]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.39 (t, 1H), 7.19-7.23 (m, 1H), 7.15 (dd, 1H), 6.83-6.89 (m, 2H), 6.77-6.81 (m, 1H), 5.76-5.91 (m, 1H), 5.32-5.46 (m, 1H), 5.41 (dd, 1H), 3.99-4.08 (m, 2H),3.97 (dd, 1H),3.43-3.69 (m, 2H),2.40-2.63 (m, 2H), 1.47 (s, 9H).

[0144] Step 5 tert-Butyl 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine-1-carboxylate 2h Compound 2g (220 mg, 0.49 mmol) was dissolved in ethyl acetate (10 mL) and 1,2-dichlorobenzene (0.5 mL, TCI (SHANGHAI) Development Co., Ltd.), 10% palladium carbon (50 mg, 0.47 mmol) was added, and the mixture was hydrogenated at room temperature under 1 atm of hydrogen gas for 1 hour, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2h (178 mg, yield: 80.5%).

[0145] MS m / z (ESI): 392.1 [M-55]. 1 H NMR (500 MHz, CDCl 3 ) δ 7.40 (t, 1H), 7.21-7.24 (m, 1H), 7.16 (dd, 1H), 6.82-6.88(m, 1H), 6.76-6.81(m, 2H), 5.35-5.45(m, 1H), 4.40(dd, 1H), 4.09-4.33 (m, 2H), 3.96 (dd, 1H), 2.99-3.11 (m, 1H),2.67-2.90 (m, 2H), 1.72-1.91 (m, 2H), 1.58-1.69 (m, 2H), 1.46 (s, 9H).

[0146] Step 6 4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidine p-toluenesulfonate 2i Compound 2h (178 mg, 0.40 mmol) was dissolved in ethyl acetate (5 mL), p-toluenesulfonic acid monohydrate (189 mg, 0.99 mmol) was added, and the mixture was stirred at 60° C. for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give the crude title product 2i (206 mg), which was used directly in the next step reaction without purification.

[0147] MS m / z (ESI): 348.1 [M+1].

[0148] Step 7 Methyl 2-((4-(3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate 2j Compound 1g (175 mg, 0.59 mmol) and 2i (206 mg, 0.59 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (410 mg, 2.97 mmol) was added, and the mixture was stirred at 60° C. for 3 hours. The mixture was filtered and concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography using elution system B to obtain the title compound 2j (207 mg, yield: 57.7%).

[0149] MS m / z (ESI): 606.2 [M+1].

[0150] Step 8 Methyl 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate Ia Methyl 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate Ib Compound 2j (830 mg, 1.37 mmol) was subjected to chiral preparation (separation conditions: CHIRALPAK IG 250 × 20 mm, 5 μm (with guard column); mobile phase: hexane / EtOH (0.1% DEA) = 70 / 30 (V / V), flow rate: 20 mL / min), and the corresponding components were collected and concentrated under reduced pressure to give the title product (415 mg, 340 mg).

[0151] Single configuration compound (shorter retention time Ia): MS m / z (ESI): 606.0 [M+1]; Chiral HPLC analysis: retention time 13.653 min. Single configuration compound (longer retention time Ib): MS m / z (ESI): 606.0 [M+1] ;Chiral HPLC analysis: retention time 16.422 min.

[0152] Step 9 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid I Ia (415 mg, 0.68 mmol) was dissolved in 36 mL of a mixed solvent of acetonitrile and water (V:V=6:1), lithium hydroxide monohydrate (145 mg, 3.46 mmol) was added, and the mixture was stirred at 40 ° C for 18 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 5-6 with aqueous citric acid (1 M), extracted with ethyl acetate (30 mL x 3), and the organic phase was concentrated under reduced pressure, and then purified by high performance liquid chromatography (Gilson 281, chromatography column: Boston Phlex C18 150 x 30 mm, 5 μm; mobile phase 1: water (containing 10 mmol / L ammonium bicarbonate); mobile phase 2: acetonitrile; 15 min gradient: 30% to 50%, flow rate: 30 mL / min) to obtain the title product A (310 mg, yield: 76.46%).

[0153] MS m / z (ESI): 592.2 [M+1]. 1H NMR (500 MHz, DMSO-d 6 ) δ 12.42-12.97 (brs, 1H), 8.20-8.28(m, 1H), 7.74-7.83 (m, 1H), 7.61 (d, 1H), 7.55-7.58 (m, 1H), 7.48-7.54 (m, 1H), 7.38-7.44 (m, 1H), 6.70-6.90 (m, 3H), 5.40-7.49 (m, 1H), 5.01-5.13 (m, 1H), 4.72-4.84 (m, 1H), 4.59-4.67 (m, 1H), 4.39-4.51 (m, 2H), 4.31-4.38 (m, 1H), 4.04-4.13 (m, 1H), 3.86-3.95 (m, 1H), 3.71-3.79 (m, 1H), 2.91-3.01 (m, 1H), 2.77-2.88 (m, 2H), 2.61-2.72 (m, 1H), 2.33-2.44 (m, 1H), 2.07-2.25 (m, 2H), 1.73-1.81 (m, 1H), 1.63-1.73 (m, 2H), 1.54-1.63 (m, 1H).

[0154] Test Example 1: Evaluation of GLP-1 receptor agonist activity

[0155] 1. Purpose of the test The purpose of this study is to test the agonistic activity of compound molecules on the GLP-1 receptor and to evaluate the EC 50 The aim of this study is to evaluate the in vitro activity of molecules based on their size. TM Luciferase Assay System (ONE-Glo TM Using the ONE-Glo Luciferase Assay System (Promega, E6110), the compound molecules activated the GLP-1R downstream signaling pathway, causing an increase in cAMP levels. The binding of cAMP to CRE initiated transcriptional expression of the luciferase gene downstream of CRE. Luciferase emitted fluorescence when it reacted with its substrate, and the results were analyzed using the ONE-Glo Luciferase Assay System (Promega, E6110). TMThe fluorescent signal can be measured via the reagent to reflect the agonistic activity of the compound on the GLP-1 receptor.

[0156] II. Experimental Method Construct a CHO-K1 / CRE-luc / GLP-1 receptor stably transfected cell line (GLP-1 receptor plasmid self-construct, CRE-luc plasmid Promega E8471). Digest, centrifuge and resuspend CHO-K1 / CRE-luc / GLP-1 receptor cells, mix homogenously to a single cell suspension, and culture in cell culture medium (DME / F-12 + 10% FBS) to a density of 2.5 × 10 live cells. 5 Adjust the volume of cells / ml and add 90 μl / well to a 96-well cell culture plate (Corning, #3903). Place the culture plate in an incubator (37° C., 5% CO) for 16 hours. 2 )Culture.

[0157] Dissolve the compounds in DMSO to prepare a stock solution with an initial concentration of 20 mM. The starting concentration of the small molecule compounds is 0.2 mM, then dilute 3 times, dilute 10 points, the 11th point is DMSO. Take another 96-well plate, add 95 μl of cell culture medium (DME / F-12+10% FBS) to each well, then add 5 μl of different concentrations of test samples to each well, mix evenly, then add 10 μl / well of different concentrations of test samples to the cell culture plate, set up two duplicate wells for each sample. Keep the culture plate in the incubator (37°C, 5% CO) for 6 hours. 2 ) Incubate the cells in a 96-well cell culture plate. Add 100 μl of ONE-Glo to each well. TM Add reagent and incubate for 10 minutes at room temperature. Measure chemiluminescence using a microplate reader (EnVision 2105, PE).

[0158] Data analysis Data were processed and analyzed using Microsoft Excel and Graphpad Prism 5. EC 50 The values ​​were obtained and the results are shown in Table 1.

[0159] [Table 1]

[0160] Example 2: Amorphous Form of Tromethamine Salt of Compound A Weigh out 15 mg of compound A, add 0.3 mL of water and stir, add 3.38 mg of tromethamine, perform 3 cycles of heating and cooling at 50°C to 5°C at 0.8 K / min, centrifuge, and slowly evaporate the supernatant to obtain a solid. Powder X-ray diffraction detection showed that the product was amorphous tromethamine salt, and the XRPD pattern is shown in Figure 1.

[0161] Example 3: Preparation of Form A crystals of the tromethamine salt of Compound A Weigh out 10 mg of compound A, add 200 μl of ethanol, stir, add 2.23 mg of tromethamine solid, stir, centrifuge, and dry to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 2, and its characteristic peak positions are shown in Table 2, which was defined as A-type crystal of tromethamine salt. The DSC pattern showed endothermic peaks at 163.02 °C and 174.83 °C. The TGA pattern showed that the weight loss was 2.38% from 30 to 190 °C.

[0162] [Table 2]

[0163] Example 4: Preparation of crystal form A of the tromethamine salt of compound A 10 mg of compound A was weighed, 200 μl of ethyl acetate was added, the mixture was stirred, 2.23 mg of tromethamine solid was added, the mixture was stirred, centrifuged, and dried to obtain a solid. Powder X-ray diffraction detection revealed that the product was a type A crystal of tromethamine salt.

[0164] Example 5: Preparation of crystal form A of the tromethamine salt of compound A 10 mg of compound A was weighed, 200 μl of methyl tert-butyl ether (MTBE) was added, the mixture was stirred, 2.23 mg of tromethamine solid was added, the mixture was stirred, centrifuged, and dried to obtain a solid. As a result of powder X-ray diffraction detection, the product was a type A crystal of tromethamine salt.

[0165] Example 6: Preparation of Form A crystals of the tromethamine salt of Compound A 10 mg of compound A was weighed out, 200 μl of a mixed solution of tetrahydrofuran / methyl tert-butyl ether (THF:MTBE=1:2) was added, the mixture was stirred, 2.23 mg of tromethamine solid was added, the mixture was stirred, centrifuged, and dried to obtain a solid. Powder X-ray diffraction detection revealed that the product was A-type crystal of tromethamine salt.

[0166] Example 7: Preparation of Form A crystals of the tromethamine salt of Compound A Weigh out 150mg of compound A, add 3mL of absolute ethanol, heat to 75℃, add tromethamine (33.7mg, dissolved in 5mL of absolute ethanol) cloudy solution dropwise, dissolve until transparent, add a small amount of A-type crystal seed crystal (prepared with reference to the method of Example 3), stir to crystallize, cool to room temperature, stir, filter and dry. X-ray powder diffraction detection revealed that the product was A-type crystal of tromethamine salt.

[0167] Example 8: Preparation of B-type crystals of the tromethamine salt of Compound A Weigh out 15 mg of compound A, add 0.4 mL of 10% water-acetone, stir, add 3.38 mg of tromethamine, dissolve until transparent, place at 4 ° C, stir to precipitate, centrifuge, and dry to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 3, and its characteristic peak positions are shown in Table 3, which was defined as B-type crystal of tromethamine salt. The DSC pattern showed endothermic peaks at 128.76 ° C and 160.93 ° C. The TGA pattern showed that the weight loss was 3.39% from 30 to 140 ° C.

[0168] [Table 3]

[0169] Example 9: Preparation of C-type crystals of the tromethamine salt of Compound A A 50 mg sample of the A-type crystals of the tromethamine salt of the compound was weighed into 1 mL of methyl tert-butyl ether, the suspension was stirred at room temperature for 72 h, filtered, the cake was collected and dried under vacuum to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 4, and its characteristic peak positions are shown in Table 4, which was defined as the C-type crystals of the tromethamine salt. The DSC pattern showed an endothermic peak at 158.9 °C. The TGA pattern showed a weight loss of 5.50% from 30 to 150 °C.

[0170] [Table 4]

[0171] Example 10: Preparation of C-type crystals of the tromethamine salt of Compound A 50 mg of the A-type crystals of the tromethamine salt of compound A were weighed, 1 ml of toluene was added, the suspension was stirred at room temperature for 72 hours, filtered, the cake was collected, and dried in vacuum to obtain a solid. Powder X-ray diffraction detection revealed that the product was the C-type crystals of the tromethamine salt.

[0172] Example 11: Preparation of D-type crystals of the tromethamine salt of Compound A 15 mg of compound A was weighed out, 0.3 mL of methanol was added and stirred, 3.38 mg of tromethamine was added, and the mixture was heated and cooled at 0.8 K / min from 50°C to 5°C for three cycles, centrifuged, and dried to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 5, and its characteristic peak positions are shown in Table 5. This was defined as D-type crystal of tromethamine salt.

[0173] [Table 5]

[0174] Example 12: Preparation of D-type crystals of the tromethamine salt of Compound A 1.5g of compound A was weighed into 18mL of isopropanol, heated to 75℃, tromethamine aqueous solution (308mg, dissolved in 0.77mL of water) was added dropwise, 6mL of isopropanol and 12mL of methanol were added, stirred at 75℃ for 30 minutes, solid was precipitated, cooled slowly, stirred at room temperature for 16 hours, stirred in ice bath for 30 minutes, filtered, cake core was collected, and dried to obtain solid. Powder X-ray diffraction detection revealed that the product was tromethamine salt D-type crystal.

[0175] Example 13: Preparation of E-type crystals of the tromethamine salt of Compound A Weigh out 60 mg of compound A, add 1 ml of acetonitrile, add 15.7 mg of tromethamine solid, stir to crystallize, centrifuge, and dry to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 6, and its characteristic peak positions are shown in Table 6, which was defined as E-type crystal of tromethamine salt. The DSC pattern showed endothermic peaks at 127.83 °C and 160.76 °C. The TGA pattern showed that the weight loss was 2.13% from 30 to 190 °C.

[0176] [Table 6]

[0177] Example 14: Preparation of F-type crystals of the tromethamine salt of Compound A A sample of the A-type crystals of the tromethamine salt of Compound A was placed at 80°C / 0% RH for 96 hours or dried at 167°C. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 7, and its characteristic peak positions are shown in Table 7, which was defined as the F-type crystals of the tromethamine salt. The DSC pattern showed endothermic peaks at 159.88°C and 175.93°C. The TGA pattern showed a weight loss of 2.91% from 30 to 180°C.

[0178] [Table 7]

[0179] Example 15: Amorphous preparation of the amine salt of Compound A 15 mg of compound A was weighed, 0.3 mL of acetone was added and stirred, 28 μL of 2 M aqueous ammonia was added, and three cycles of heating and cooling were performed at 50 ° C to 5 ° C at 0.8 K / min, centrifuged, and the supernatant was slowly evaporated to obtain a solid. As a result of powder X-ray diffraction detection, there was no significant characteristic peak in the powder X-ray diffraction pattern, and the product was an amorphous amine salt.

[0180] Example 16: Preparation of amorphous potassium salt of Compound A 10 mg of compound A was weighed, 200 μL of a mixed solution of tetrahydrofuran / tert-butyl dimethyl ether (THF:MTBE=1:2) was added, and 9.3 μL of a 2M aqueous potassium hydroxide solution was added, and the mixture was slurried at room temperature, centrifuged, and dried to obtain a solid. As a result of powder X-ray diffraction detection, there was no significant characteristic peak in the powder X-ray diffraction pattern, and the product was an amorphous potassium salt.

[0181] Example 17: Preparation of α-type crystals of potassium salt of Compound A 10 mg of compound A was weighed, 200 μL of ethyl acetate was added, and 9.3 μL of 2M potassium hydroxide aqueous solution was added, followed by slurrying at room temperature, centrifuging, and drying to obtain a solid. Powder X-ray diffraction detection showed that the product was an α-type crystal of potassium salt, and the XRPD pattern was shown in FIG. 8, and its characteristic peak positions were shown in Table 8. The DSC pattern showed endothermic peaks at 87.46 ° C, 159.28 ° C, and 230.06 ° C. The TGA pattern showed that the weight loss was 5.17% from 30 to 150 ° C.

[0182] [Table 8]

[0183] Example 18: Preparation of α-type crystals of potassium salt of Compound A 10 mg of compound A was weighed, 200 μL of methyl tert-butyl ether was added, and 9.3 μL of 2M potassium hydroxide aqueous solution was added, and the mixture was slurried at room temperature, centrifuged, and dried to obtain a solid. As a result of powder X-ray diffraction detection, the product was an α-type crystal of the potassium salt.

[0184] Example 19: Preparation of amorphous arginine salt of Compound A 15 mg of compound A was weighed, 0.3 mL of methanol was added and stirred, 9.72 mg of arginine was added, and three cycles of heating and cooling were performed at 50°C to 5°C at 0.8 K / min, centrifuged, and the supernatant was slowly evaporated to obtain a solid. As a result of powder X-ray diffraction detection, there was no significant characteristic peak in the powder X-ray diffraction pattern, and the product was an amorphous arginine salt.

[0185] Example 20: Preparation of amorphous sodium salt of Compound A 10 mg of compound A was weighed, 200 μL of methyl tert-butyl ether was added, and 9.3 μL of 2M aqueous sodium hydroxide solution was added, and the mixture was slurried at room temperature, centrifuged, and dried to obtain a solid. As a result of powder X-ray diffraction detection, there was no significant characteristic peak in the powder X-ray diffraction pattern, and the product was an amorphous sodium salt.

[0186] Example 21: Preparation of Form I crystals of the sodium salt of Compound A Weigh out 15 mg of compound A, add 0.3 ml of methanol, add 28 μL of 2 M aqueous sodium hydroxide solution, stir to dissolve, and perform three cycles of heating and cooling at 0.8 K / min from 50 ° C to 5 ° C, and dry to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 9, and its characteristic peak positions are shown in Table 9, which was defined as type I crystal of sodium salt. The DSC pattern showed endothermic peaks at 77.63 ° C, 157.96 ° C, 181.45 ° C, and 232.77 ° C. The TGA pattern showed that the weight loss was 3.05% from 30 to 150 ° C.

[0187] [Table 9]

[0188] Example 22: Preparation of Form I crystals of the sodium salt of Compound A Weigh out 10 mg of compound A, add 200 μL of ethyl acetate, and then add 9.3 μL of 2M aqueous sodium hydroxide solution. If the solution is not dissolved until it becomes transparent, stir overnight at room temperature, centrifuge, and dry to obtain a solid. Powder X-ray diffraction detection revealed that the product was sodium salt type I crystal.

[0189] Example 23: Preparation of Form II Crystals of Sodium Salt of Compound A Weigh out 15 mg of compound A, add 0.3 ml of acetone, add 28 μL of 2 M aqueous sodium hydroxide solution, stir to dissolve, and perform three cycles of heating and cooling at 0.8 K / min from 50 ° C to 5 ° C, centrifuge, and dry to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 10, and its characteristic peak positions are shown in Table 10, which was defined as type II crystal of sodium salt. The DSC pattern showed endothermic peaks at 118.67 ° C and 235.34 ° C. The TGA pattern showed that the weight loss was 2.85% from 30 to 150 ° C.

[0190] [Table 10]

[0191] Example 24: Preparation of Form II Crystals of Sodium Salt of Compound A 15 mg of compound A was weighed out, 0.3 ml of acetonitrile was added, and if the compound did not dissolve even after stirring, 14 μL of 2 M aqueous sodium hydroxide solution was added to dissolve the compound, and the compound was heated and cooled at 0.8 K / min from 50° C. to 5° C. for three cycles, centrifuged, and dried to obtain a solid. Powder X-ray diffraction detection revealed that the product was sodium salt type II crystal.

[0192] Example 25: Preparation of amorphous meglumine salt of Compound A 15 mg of compound A was weighed out, 0.3 mL of methanol was added and stirred, 11.0 mg of meglumine was added, and the mixture was heated and cooled at 50°C to 5°C at 0.8 K / min for three cycles, centrifuged, and the supernatant was slowly evaporated to obtain a solid. Powder X-ray diffraction detection showed that there were no significant characteristic peaks in the powder X-ray diffraction pattern, and the product was an amorphous meglumine salt.

[0193] Example 26: Preparation of Form I crystals of meglumine salt of Compound A Weigh out 15 mg of compound A, add 0.3 mL of acetonitrile, stir, add 5.5 mg of meglumine, perform three cycles of heating and cooling at 0.8 K / min from 50 ° C to 5 ° C, centrifuge, and slowly evaporate the supernatant to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 11, and its characteristic peak positions are shown in Table 11, which was defined as type I crystal of meglumine salt. The DSC pattern showed endothermic peaks at 60.00 ° C and 104.48 ° C. The TGA pattern showed that the weight loss was 0.18% from 30 to 110 ° C.

[0194] [Table 11]

[0195] Example 27: Amorphous preparation of the ethanolamine salt of Compound A 15 mg of compound A was weighed, 0.3 mL of methanol was added and stirred, 28 μL of 2 M ethanolamine aqueous solution was added, and three cycles of heating and cooling were performed at 50 ° C to 5 ° C at 0.8 K / min, centrifuged, and the supernatant was slowly evaporated to obtain a solid. As a result of powder X-ray diffraction detection, there was no significant characteristic peak in the powder X-ray diffraction pattern, and the product was an amorphous ethanolamine salt.

[0196] Example 28: Preparation of Form I crystals of p-toluenesulfonate of Compound A Weigh out 15 mg of compound A, add 0.3 ml of acetonitrile, and if it does not dissolve even after stirring, add 9.61 mg of p-toluenesulfonic acid to dissolve it, and perform three cycles of heating and cooling at 0.8 K / min from 50 ° C to 5 ° C, centrifuge, and dry to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in Figure 12, and its characteristic peak positions are shown in Table 12, which was defined as type I crystal of p-toluenesulfonate. The DSC pattern showed an endothermic peak at 191.14 ° C. The TGA pattern showed a weight loss of 0.93% from 30 to 150 ° C.

[0197] [Table 12]

[0198] Example 29: Preparation of Form I Crystals of Tartrate of Compound A Weigh out 10 mg of compound A, add 200 μL of ethanol, and if not dissolved until transparent, add 9.3 μL of 2M L-tartaric acid aqueous solution, stir, centrifuge, and dry to obtain a solid. Powder X-ray diffraction detection results show that the XRPD pattern is shown in FIG. 13, and its characteristic peak positions are shown in Table 13, which was defined as type I crystal of tartrate salt. DSC pattern showed endothermic peaks at 115.94 ° C and 138.28 ° C. TGA pattern showed that the weight loss was 2.60% from 30 to 110 ° C.

[0199] [Table 13]

[0200] Example 30: Preparation of Form I Crystals of Tartrate of Compound A 10 mg of compound A was weighed, 200 μL of ethyl acetate was added, and 9.3 μL of 2 M L-tartaric acid solution was added, followed by stirring, centrifuging, and drying to obtain a solid. Powder X-ray diffraction detection revealed that the product was a type I crystal of the tartrate salt.

[0201] Example 31: Preparation of Form I Crystals of Tartrate of Compound A 10 mg of compound A was weighed, 200 μL of methyl tert-butyl ether was added, and 9.3 μL of 2 M L-tartaric acid solution was added, followed by stirring, centrifuging, and drying to obtain a solid. Powder X-ray diffraction detection revealed that the product was a type I crystal of the tartrate salt.

[0202] Example 32: Amorphous Preparation of the Sulfate Salt of Compound A 15 mg of compound A was weighed, 0.3 mL of acetonitrile was added and stirred, 28 μL of 2 M sulfuric acid was added, and three cycles of heating and cooling were performed at 50 ° C to 5 ° C at 0.8 K / min, centrifuged, and the supernatant was slowly evaporated to obtain a solid. As a result of powder X-ray diffraction detection, there was no significant characteristic peak in the powder X-ray diffraction pattern, and the product was an amorphous sulfate salt.

[0203] Example 33: Preparation of α-type crystals of Compound A malate Weigh out 10 mg of compound A, add 200 μL of ethyl acetate, and if not dissolved until transparent, add 9.3 μL of 2M L-malic acid aqueous solution, stir, centrifuge, and dry to obtain a solid. Powder X-ray diffraction detection results show that the XRPD pattern is shown in FIG. 14, and its characteristic peak positions are shown in Table 15, which was defined as α-form crystals of malate. The DSC pattern showed that the endothermic peaks were 56.15 ° C, 98.97 ° C, and 126.79 ° C. The TGA pattern showed that the weight loss was 1.75% at 30 to 130 ° C.

[0204] [Table 14]

[0205] Example 34: Preparation of α-type crystals of Compound A malate 10 mg of compound A was weighed, 200 μL of MTBE was added, and 9.3 μL of 2 M L-malic acid solution was further added, followed by stirring, centrifuging, and drying to obtain a solid. Powder X-ray diffraction detection revealed that the product was an α-form crystal of malate.

[0206] Example 35: Preparation of Form I Crystals of the Hydrochloride of Compound A 100 mg of compound A was weighed, 1545 μl of 0.12 M aqueous hydrochloric acid was added, and the suspension was stirred overnight at room temperature, centrifuged, and dried to obtain a solid. The XRPD pattern by powder X-ray diffraction detection is shown in FIG. 15, and its characteristic peak positions are shown in Table 15, which was defined as type I crystal of the hydrochloride salt. The DSC pattern showed an endothermic peak at 163.16 °C. The TGA pattern showed a weight loss of 2.50% from 30 to 170 °C.

[0207] [Table 15]

[0208] Test Example 2: Hygroscopicity study of crystals of salt of compound A The Surface Measurement Systems intrinsic DVS was used, and the temperature was 25°C. The humidity range was 0% to 95%, the step size was 10%, and the criterion was that the mass change dM / dT for each gradient was less than 0.002%, with two cycles performed at TMAX 360 min.

[0209] [Table 16]

[0210] Test Example 3: Stability study of crystals of salt of compound A The salt-type sample of compound A was placed open and the stability of the sample was examined under the conditions of light (4500 Lux), high temperature (40°C, 60°C), and high humidity (RH75%, RH92.5%). The sampling period was 30 days.

[0211] [Table 17]

[0212] [Table 18]

[0213] [Table 19]

[0214] [Table 20]

[0215] [Table 21]

[0216] [Table 22]

[0217] Conclusion: Type D crystals of tromethamine salt, type I crystals of hydrochloride salt, type α crystals of malate salt and type I crystals of tartrate salt had good physical and chemical stability when stored under the conditions of influencing factors for 30 days; the physical properties of type A crystals of tromethamine salt were stable; type E crystals of tromethamine salt had slightly poor physical stability under high temperature and high humidity conditions; and types A and E crystals of tromethamine salt had slightly poor chemical stability under high temperature conditions, but all of them could meet the basic stability requirements for late-stage drug discovery.

[0218] Test Example 4: Long-term / accelerated stability of crystals of salt of Compound A The salt-form samples were sealed in aluminum foil bags and placed under conditions of 25°C / 60% RH and 40°C / 75% RH, respectively, to examine their stability.

[0219] [Table 23]

[0220] Conclusion: The long-term / accelerated stability experiments showed that the A-type and D-type crystals of tromethamine salt and the I-type crystal of hydrochloride salt had good physical and chemical stability under long-term accelerated conditions, and the E-type crystals of tromethamine salt and the I-type crystal of tartrate salt had good physical and chemical stability under long-term accelerated conditions.

Claims

1. A pharmaceutically acceptable salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the pharmaceutically acceptable salt is selected from the group consisting of tromethamine, ammonium, potassium, arginine, sodium, meglumine, ethanolamine, p-toluenesulfonate, tartrate, sulfate, malate, and hydrochloride salts.

2. 2. The pharmaceutically acceptable salt according to claim 1, wherein the chemical ratio of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid to an alkali molecule or an acid molecule is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1 or 1:

2.

3. A crystalline form of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 6.850, 9.982, 13.789, 16.148, and 22.138, preferably at 6.850, 9.982, 12.697, 13.789, 15.763, 16.148, 18.016, 19.016, and 22.138, and more preferably at 6.850, 8.051, 9.982, 12.697, 13.789, 14.704, 14.990, 15.763, 16.148, 18.016, 19.016, 20.109, 22.138, 25.712, and 27.909; Most preferably, the crystal is a type A crystal, The error range of the 2θ value is ±0.

2. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

4. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 8.144, 10.511, 12.290, 20.632, and 21.699, preferably at 8.144, 10.511, 12.290, 13.996, 14.665, 20.632, 21.699, and 24.743, and more preferably at 8.144, 10.511, 12.290, 13.996, 14.665, 15.607, 16.520, 18.883, 20.632, 21.699, 23.741, 24.743, 26.055, and 27.035; Most preferably, the crystal is a B-type crystal, The error range of the 2θ value is ±0.

2. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

5. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 6.551, 9.269, 13.175, and 16.906, preferably at 6.551, 9.269, 13.175, 14.802, 15.864, 16.906, 18.776, 20.430, and 25.496, and more preferably at 6.551, 8.392, 9.269, 13.175, 14.802, 15.864, 16.906, 18.776, 20.430, 22.211, 22.922, 23.574, 25.496, and 26.290; Most preferably, the crystal is a C-type crystal, The error range of the 2θ value is ±0.

2. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

6. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 5.281, 10.292, 13.322, and 21.390, preferably at 5.281, 9.912, 10.292, 10.961, 13.322, 21.390, 22.215, 23.979, 25.029, and 25.846, and more preferably at 5.281, 9.912, 10.292, 10.961, 11.613, 13.322, 15.351, 18.283, 19.214, 21.390, 22.215, 23.471, 23.979, 25.029, 25.846, 27.918, and 30.121; Most preferably, the crystal is a D-type crystal, The error range of the 2θ value is ±0.

2. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

7. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 6.821, 10.035, 12.653, 13.727, and 14.787, preferably 6.821, 10.035, 12.653, 13.727, 14.787, 16.081, 16.648, 18.571, 20.151, and 22.204; Most preferably, the crystal is an E-type crystal, The error range of the 2θ value is ±0.

2. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

8. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, expressed in terms of diffraction angle 2θ, has characteristic peaks at 7.674, 10.614, 16.400, and 18.645, preferably at 6.777, 7.674, 10.614, 11.594, 14.408, 14.882, 16.400, and 18.645, and more preferably at 6.777, 7.674, 10.614, 11.594, 13.671, 14.408, 14.882, 16.400, 18.645, 20.849, 21.384, 21.731, 22.108, 24.721, 26.169, and 29.192; Most preferably, the crystal is an F-type crystal, The error range of the 2θ value is ±0.

2. A crystal of the tromethamine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

9. A crystal of the potassium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 9.564, 11.515, 14.683, 19.607, and 20.391, preferably at 9.564, 11.515, 14.683, 16.058, 18.859, 19.607, 20.391, 22.592, 23.320, and 25.176, and more preferably at 9.564, 11.515, 14.683, 16.058, 17.033, 18.859, 19.607, 20.391, 21.064, 22.592, 23.320, 24.449, 25.176, 25.933, 27.080, and 27.708; Most preferably, the crystal is an α-type crystal, The error range of the 2θ value is ±0.

2. Crystals of the potassium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

10. A crystal of the sodium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 5.257, 5.806, 6.795, 10.106, 12.203, and 20.693, Most preferably, the crystal is a type I crystal, The error range of the 2θ value is ±0.

2. Crystals of the sodium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

11. A crystal of the sodium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 9.754, 11.731, and 19.730, more preferably 5.574, 9.754, 11.731, 14.856, 16.091, 19.730, and 22.670; Most preferably, the crystal is a type II crystal, The error range of the 2θ value is ±0.

2. Crystals of the sodium salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

12. A crystalline form of meglumine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, expressed by the diffraction angle 2θ, has characteristic peaks at 5.498, 11.013, 14.626, and 17.942, preferably at 5.498, 8.901, 11.013, 14.626, 17.942, 19.454, 22.668, and 25.696, and more preferably at 5.498, 8.314, 8.901, 11.013, 11.891, 12.810, 14.626, 15.683, 15.931, 17.942, 18.748, 19.454, 20.393, 21.419, 22.234, 22.668, 23.391, 24.739, and 25.696; Most preferably, the crystal is a type I crystal, The error range of the 2θ value is ±0.

2. A crystal of meglumine salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

13. A crystalline form of p-toluenesulfonate of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 5.453, 5.884, 8.063, 12.925, 16.071, and 19.778, preferably at 5.453, 5.884, 8.063, 12.925, 13.825, 15.399, 16.071, 18.231, 19.778, and 21.917, and more preferably at 5.453, 5.884, 8.063, 12.925, 13.825, 15.399, 16.071, 16.560, 17.066, 18.231, 19.778, 20.861, 21.917, 23.898, and 26.744; Most preferably, the crystal is a type I crystal, The error range of the 2θ value is ±0.

2. A crystal of p-toluenesulfonate of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

14. A crystalline form of the tartrate salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the powder X-ray diffraction pattern of the crystals, represented by the diffraction angle 2θ, has characteristic peaks at 12.810, 18.824, 21.890, and 24.472, preferably at 12.810, 14.448, 15.604, 18.824, 20.410, 21.890, and 24.472, and more preferably at 9.342, 10.132, 10.858, 11.272, 12.810, 14.448, 15.604, 18.824, 20.410, 21.890, 24.472, and 27.880; Most preferably, the crystal is a type I crystal, The error range of the 2θ value is ±0.

2. A crystal of the tartrate salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

15. A crystal of malate of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, Here, the powder X-ray diffraction pattern of the crystals, expressed as a diffraction angle 2θ, has characteristic peaks at 10.050, 14.508, 15.693, 18.924, and 20.240, and preferably at 10.050, 10.818, 11.213, 12.871, 14.508, 15.693, 18.924, 20.240, 21.829, and 24. and more preferably, having characteristic peaks at 9.364, 10.050, 10.818, 11.213, 12.871, 13.774, 14.508, 15.693, 17.760, 18.924, 20.240, 21.829, 24.396, 26.200, 27.936, and 28.188; Most preferably, the crystal is an α-type crystal, The error range of the 2θ value is ±0.

2. Crystals of the malate salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

16. A crystalline form of the hydrochloride salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, Here, the powder X-ray diffraction pattern of the crystals, expressed by the diffraction angle 2θ, has characteristic peaks at 9.939, 14.333, 14.933, 17.523, 18.480, and 20.134, and preferably at 9.939, 13.123, 13.649, 14.333, 14.933, 16.616, 17.523, 18.480, 19.378, 20.134, 20.988, 26.399, and 26.

970. and more preferably, has characteristic peaks at 9.939, 12.267, 13.123, 13.649, 14.333, 14.933, 16.616, 17.523, 18.480, 19.378, 20.134, 20.988, 22.377, 23.002, 24.477, 25.322, 26.399, 26.970, 27.609, 30.822, and 33.

760. Most preferably, the crystal is a type I crystal, The error range of the 2θ value is ±0.

2. A crystal of the hydrochloride salt of the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

17. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 1 or 2, or the crystal of any one of claims 3 to 16, and optionally a pharmaceutically acceptable excipient.

18. A pharmaceutical composition comprising the crystal according to any one of claims 3 to 16 and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition according to claim 18, for treating or preventing a disease associated with the GLP-1 receptor.

20. 19. The pharmaceutical composition according to claim 18 for treating or preventing diabetes.

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