Salts of GLP-1R agonists, their production methods and applications

Abstract

The present invention relates to a salt form of the GLP-1R agonist compound I, a method for producing the same, and an application thereof. The salt of the present invention has excellent GLP-1R agonist activity, good bioavailability in vivo, and is suitable for the production of preparations for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases. 【Chemical 1】 JPEG2025522923000035.jpg43169

Description

Detailed Description of the Invention

[0001] This invention claims the priority of a prior application filed with the China National Intellectual Property Administration on July 7, 2022, with a patent application number of 202210804212X and a title of "Salt of GLP-1R Agonist, Its Manufacturing Method and Application", and the above prior application is incorporated herein by reference in its entirety.

[0002] 〔Technical Field〕 This invention belongs to the field of drug development, and specifically relates to salts of GLP-1R agonists, their manufacturing methods and applications.

[0003] 〔Background Art〕 Diabetes is a chronic disease characterized by hyperglycemia caused by insufficient insulin secretion (relative or absolute) or insulin action disorder in the human body. According to the 9th edition of the newly issued World Diabetes Atlas by the International Diabetes Federation (IDF), it is shown that approximately 463 million adults (aged 20 - 79) worldwide had diabetes in 2019, and it is predicted that the number of diabetes patients will reach 578 million in 2030. If this trend continues, there will be 700 million diabetes patients worldwide in 2045. Therefore, diabetes has become one of the most serious social health problems faced worldwide in the 21st century.

[0004] Currently, there are various pharmacological methods for treating hyperglycemia and associated T2DM (Hampp et al., "Use of Antidiabetic Drugs in the U.S.", 2003 - 2012, Diabetes Care 37:1367 - 1374, 2014). These methods can be classified into six major classes, and each class acts through different major mechanisms.

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

[0006] Biguanides (e.g., metformin) are thought to act mainly by reducing glucose production in the liver, and biguanides often cause gastrointestinal discomfort and lactic acidosis, and their use is further restricted.

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

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

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

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

[0011] However, except for GLP-1R agonists and SGLT2 inhibitors, the effectiveness of the above drugs is limited, and the most important problems of β-cell function decline and associated obesity have not been solved. Therefore, there is a need for more effective drug interventions with relatively few side effects and convenient administration.

[0012] GLP-1 is an incretin hormone 30 amino acids in length secreted by intestinal L cells in response to food intake. GLP-1 has been shown to stimulate insulin secretion physiologically and glucose-dependently, reduce glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate β-cell proliferation. In preclinical studies, GLP-1 promotes sustained β-cell function by stimulating gene transcription important for glucose-dependent insulin secretion and promoting β-cell neogenesis (Meier et al., Biodrugs 17(2):93-102, 2013).

[0013] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose content by increasing peripheral glucose absorption by stimulating glucose-dependent insulin secretion in the pancreas. GLP-1 also inhibits glucagon secretion and reduces glucose output from the liver. In addition, GLP-1 delays gastric emptying and slows small intestine motility to delay food absorption. In people with T2DM, postprandial GLP-1 does not rise normally or the amount of increase decreases (Vilsbol1 et al., diabetes 50609-613, 2001).

[0014] Scientific research modifies and decorates the structure of GLP-1 appropriately to increase its half-life and further extend its in vivo biological effects. However, currently clinically used long-acting GLP-1 analogs, such as liraglutide, exenatide, etc., are all polypeptides. By frequently administering multiple injections, the compliance of patients is relatively poor. Therefore, the development of small molecule GLP-1R agonists has a promising clinical market perspective for the purposes of improving patient compliance, dosing convenience, and reducing drug side effects.

[0015] Hangzhou Mindrank AI Ltd. has developed structurally novel small molecule compounds with GLP-1R inhibitory effects. The structures of its representative compounds I-1 and I-2 are as follows.

[0016]

Chemical Structure

[0017] This type of compound can significantly improve the agonistic effect of the GLP-1R target, improve the therapeutic window, reduce clinical toxic side effects, and meet the current domestic and international needs for diabetes treatment.

[0018] The chemical name of Compound I-1 is (S)-2-(4-(6-(4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0019] The chemical name of Compound I-2 is (S)-2-(4-(6-(4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0020] The successful development of a pharmaceutical solid form of Compound I-1 or Compound I-2 usually has a solid form that can be easily separated and purified after synthesis, can be applied to large-scale production, can be stored for a relatively long period of time while absorbing a minimal amount of moisture, can be decomposed or converted into other solid forms, and has properties such as a dosage form that can be rapidly absorbed by an individual after administration (for example, can be dissolved in water and gastric juice).

[0021] To meet the needs of clinical research and commercially available pharmaceutical preparations, the development of drug solid forms that can be easily separated and purified, are suitable for industrial production, and have stable physicochemical properties has become an urgent task.

[0022] 〔Summary of the Invention〕 To solve the problems existing in the prior art, a first aspect of the present invention provides a pharmaceutically acceptable salt of a compound represented by formula (I),

[0023]

Chemical formula

[0024] Among them, R is selected from halogen or CN.

[0025] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the following Compound I-1 or Compound I-2,

[0026]

Chemical formula

[0027] According to an embodiment of the present invention, the above pharmaceutically acceptable salt refers to a pharmaceutically non-toxic acid addition salt or base addition salt. According to the embodiments of the present invention, the above acid addition salts are salts formed by a compound represented by formula (I) and an inorganic acid or an organic acid, including hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, phosphate, borate, acetate, oxalate, valerate, benzoate, lactate, toluylate, citrate, malate, maleate, fumarate, succinate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate; more preferred acid addition salts are hydrochloride, acetate, citrate, malate, succinate, tartrate, fumarate, maleate, methanesulfonate; particularly citrate and maleate, According to the embodiments of the present invention, the above base addition salts are salts formed by a compound represented by formula (I) and an inorganic base or an organic base, including salts formed with an alkali metal such as sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, and amine salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines such as tetramethylamine salt, tetraethylamine salt, methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt, meglumine salt, choline salt, tromethamine salt; more preferred base addition salts are sodium salt, potassium salt, calcium salt, magnesium salt, meglumine salt, choline salt, tromethamine salt; particularly sodium salt, potassium salt, magnesium salt, meglumine salt and tromethamine salt.

[0028] According to the embodiments of the present invention, the acid addition salts of the above compound I-1 are hydrochloride, tartrate, maleate, methanesulfonate, or citrate; the acid addition salts of the above compound I-2 are citrate, tartrate, malate (e.g., L-malate), fumarate, methanesulfonate or maleate. According to the embodiments of the present invention, the base addition salts of the above compound I-1 are sodium salt, potassium salt, meglumine salt or tromethamine salt; the base addition salts of the above compound I-2 are sodium salt, potassium salt, calcium salt, magnesium salt, meglumine salt or tromethamine salt.

[0029] According to a preferred technical solution of the present invention, the present invention provides crystalline form A of the citrate of compound I-1, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 19.77±0.2°, 16.59±0.2°, 22.47±0.2° and 20.20±0.2°.

[0030] According to a preferred technical solution of the present invention, the X-ray powder diffraction pattern (XRPD) of the crystalline form A of the citrate of compound I-1 described above contains peaks located at diffraction angles (2θ) of 16.59±0.2°, 19.77±0.2°, 22.47±0.2°, 20.20±0.2°, 24.84±0.2° and 17.51±0.2°.

[0031] Preferably, the crystalline form A of the citrate described above has an X-ray powder diffraction pattern having the diffraction angles (2θ) shown in Table 1, wherein the error range of the 2θ angle is ±0.20°,

[0032] [Table 1]

[0033] Preferably, the crystalline form A of the citrate described above has the X-ray powder diffraction intensity shown in Table 1.

[0034] Preferably, the crystalline form A of the citrate described above basically has the X-ray powder diffraction pattern shown in Figure 3.

[0035] Preferably, the crystalline form A of the citrate described above has a DSC thermogram with endothermic peaks at temperatures of about 107.80°C and 130.63°C.

[0036] Preferably, the crystalline form A of the citrate described above basically has the DSC pattern shown in Figure 4.

[0037] Preferably, the crystalline form A of the citrate described above basically has the TGA pattern shown in Figure 5.

[0038] In a more preferred embodiment, the present invention provides crystalline form A of the sodium salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 19.24 ± 0.2°, 20.68 ± 0.2°, 6.81 ± 0.2°, and 14.43 ± 0.2°.

[0039] In a more preferred embodiment, the present invention provides crystalline form A of the sodium salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 19.24 ± 0.2°, 20.68 ± 0.2°, 6.81 ± 0.2°, 14.43 ± 0.2°, 14.98 ± 0.2°, and 6.40 ± 0.2°.

[0040] Preferably, crystalline form A of the above sodium salt has an X-ray powder diffraction pattern having diffraction angles (2θ) shown in Table 2, wherein the error range of the 2θ angle is ±0.20°.

[0041] [Table 2]

[0042] Preferably, crystalline form A of the above sodium salt has the X-ray powder diffraction intensity shown in Table 2.

[0043] Preferably, crystalline form A of the above sodium salt has an X-ray powder diffraction pattern substantially as shown in Figure 8.

[0044] Preferably, crystalline form A of the above sodium salt has a DSC thermogram with endothermic peaks at temperatures of about 149.11°C and 174.11°C.

[0045] Preferably, crystalline form A of the above sodium salt has a DSC pattern substantially as shown in Figure 9.

[0046] Preferably, crystalline form A of the above sodium salt has a TGA pattern substantially as shown in Figure 10.

[0047] In a more preferred form, the present invention provides crystalline form A of the potassium salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 13.90 ± 0.2°, 14.43 ± 0.2°, 16.20 ± 0.2°, and 11.67 ± 0.2°.

[0048] In a more preferred form, the present invention provides crystalline form A of the potassium salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 13.90 ± 0.2°, 14.43 ± 0.2°, 16.20 ± 0.2°, 11.67 ± 0.2°, 20.99 ± 0.2° and 16.79 ± 0.2°.

[0049] Preferably, the crystalline form A of the potassium salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 3, with an error range of ±0.20° for the 2θ angle.

[0050]

Table 3

[0051] Preferably, the crystalline form A of the potassium salt has the X-ray powder diffraction intensity shown in Table 3.

[0052] Preferably, the crystalline form A of the potassium salt basically has the X-ray powder diffraction pattern shown in Figure 11.

[0053] In a more preferred form, the present invention provides crystalline form B of the potassium salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 5.92 ± 0.2°, 14.10 ± 0.2°, 17.62 ± 0.2°, and 17.94 ± 0.2°.

[0054] In a more preferred form, the present invention provides crystalline form B of the potassium salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which comprises peaks located at diffraction angles (2θ) of 5.92 ± 0.2°, 14.10 ± 0.2°, 17.62 ± 0.2°, 17.94 ± 0.2°, 11.92 ± 0.2° and 7.01 ± 0.2°.

[0055] Preferably, crystalline form B of the above potassium salt has an X-ray powder diffraction pattern having diffraction angles (2θ) shown in Table 4, wherein the error range of the 2θ angle is ±0.20°,

[0056] [Table 4]

[0057] Preferably, crystalline form B of the above potassium salt has the X-ray powder diffraction intensity shown in Table 4.

[0058] Preferably, crystalline form B of the above potassium salt basically has the X-ray powder diffraction pattern shown in Figure 12.

[0059] In a more preferred form, the present invention provides crystalline form A of the meglumine salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which comprises peaks located at diffraction angles (2θ) of 18.15 ± 0.2°, 12.87 ± 0.2°, 22.87 ± 0.2° and 24.66 ± 0.2°.

[0060] In a more preferred form, the present invention provides crystalline form A of the meglumine salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which comprises peaks located at diffraction angles (2θ) of 18.15 ± 0.2°, 12.87 ± 0.2°, 22.87 ± 0.2°, 24.66 ± 0.2°, 23.21 ± 0.2° and 19.57 ± 0.2°.

[0061] Preferably, crystalline form A of the above meglumine salt has an X-ray powder diffraction pattern having diffraction angles (2θ) shown in Table 5, wherein the error range of the 2θ angle is ±0.20°,

[0062]

Table 5

[0063] Preferably, the crystalline form A of the meglumine salt has the X-ray powder diffraction intensity shown in Table 5.

[0064] Preferably, the crystalline form A of the meglumine salt basically has the X-ray powder diffraction pattern shown in FIG. 13.

[0065] Preferably, the crystalline form A of the meglumine salt has a DSC thermogram with an endothermic peak at a temperature of about 120.06 °C.

[0066] Preferably, the crystalline form A of the meglumine salt basically has the DSC pattern shown in FIG. 14.

[0067] Preferably, the crystalline form A of the meglumine salt basically has the TGA pattern shown in FIG. 15.

[0068] In a more preferred form, the present invention provides a crystalline form A of the tromethamine salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which comprises peaks located at diffraction angles (2θ) of 3.50 ± 0.2°, 6.97 ± 0.2°, 13.91 ± 0.2° and 22.19 ± 0.2°.

[0069] In a more preferred form, the present invention provides a crystalline form A of the tromethamine salt of compound I-1, the X-ray powder diffraction pattern (XRPD) of which comprises peaks located at diffraction angles (2θ) of 3.50 ± 0.2°, 6.97 ± 0.2°, 13.91 ± 0.2°, 22.19 ± 0.2°, 31.61 ± 0.2°, 18.11 ± 0.2° and 20.55 ± 0.2°.

[0070] In a most preferred form, the crystalline form A of the above tromethamine salt has its X-ray powder diffraction data shown in Table 6 below.

[0071]

Table 6

[0072] Preferably, the crystalline form A of the tromethamine salt has the X-ray powder diffraction intensity shown in Table 6. Preferably, the crystalline form A of the tromethamine salt basically has the X-ray powder diffraction pattern shown in FIG. 16.

[0073] Preferably, the crystalline form A of the tromethamine salt has a DSC thermogram with endothermic peaks at temperatures of about 109.95 °C and 166.02 °C.

[0074] Preferably, the crystalline form A of the tromethamine salt basically has the DSC pattern shown in FIG. 17.

[0075] Preferably, the crystalline form A of the tromethamine salt basically has the TGA pattern shown in FIG. 18.

[0076] Preferably, the crystalline form A of the tromethamine salt is in the form of an N-methylpyrrolidone solvate.

[0077] In a more preferred form, the present invention provides a crystalline form A of the maleate salt of Compound I-2, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 5.43 ± 0.2°, 9.89 ± 0.2°, 12.76 ± 0.2° and 8.30 ± 0.2°.

[0078] In a more preferred form, the present invention provides a crystalline form A of the maleate salt of Compound I-2, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 5.43 ± 0.2°, 9.89 ± 0.2°, 12.76 ± 0.2°, 8.30 ± 0.2°, 21.31 ± 0.2° and 14.24 ± 0.2°.

[0079] Preferably, the crystalline form A of the maleate salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°,

[0080]

Table 7

[0081] Preferably, the crystalline form A of the above maleate has the X-ray powder diffraction intensity shown in Table 7.

[0082] Preferably, the crystalline form A of the above maleate basically has the X-ray powder diffraction pattern shown in FIG. 24.

[0083] Preferably, the crystalline form A of the above maleate has a DSC thermogram with an endothermic peak at a temperature of about 119.30 °C for the crystalline form.

[0084] Preferably, the crystalline form A of the above maleate basically has the DSC pattern shown in FIG. 25.

[0085] Preferably, the crystalline form A of the above maleate basically has the TGA pattern shown in FIG. 26.

[0086] In a more preferred form, the present invention provides a crystalline form A of the potassium salt of compound I-2, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 11.51 ± 0.2°, 15.42 ± 0.2°, 20.20 ± 0.2°, and 9.52 ± 0.2°.

[0087] In a more preferred form, the present invention provides a crystalline form A of the potassium salt of compound I-2, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 11.51 ± 0.2°, 15.42 ± 0.2°, 20.20 ± 0.2°, 9.52 ± 0.2°, 5.06 ± 0.2°, and 25.38 ± 0.2°.

[0088] Preferably, the crystalline form A of the above potassium salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 8, and the error range of the above 2θ angle is ±0.20°,

[0089]

Table 8

[0090] Preferably, the crystal form A of the above maleate has the X-ray powder diffraction intensity shown in Table 8.

[0091] Preferably, the crystal form A of the above potassium salt basically has the X-ray powder diffraction pattern shown in FIG. 28.

[0092] Preferably, the crystal form A of the above potassium salt has a DSC thermogram with an endothermic peak at a temperature of about 118.44 °C.

[0093] Preferably, the crystal form A of the above potassium salt basically has the DSC pattern shown in FIG. 29.

[0094] Preferably, the crystal form A of the above potassium salt basically has the TGA pattern shown in FIG. 30.

[0095] In a more preferred form, the present invention provides a crystal form A of a magnesium salt of Compound I-2, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 13.92 ± 0.2°, 13.46 ± 0.2°, 14.74 ± 0.2° and 20.43 ± 0.2°.

[0096] In a more preferred form, the present invention provides a crystal form A of a magnesium salt of Compound I-2, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 13.92 ± 0.2°, 13.46 ± 0.2°, 14.74 ± 0.2°, 20.43 ± 0.2°, 20.16 ± 0.2° and 17.21 ± 0.2°.

[0097] Preferably, the crystal form A of the above magnesium salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 9, wherein the error range of the above 2θ angle is ±0.20°,

[0098]

Table 9

[0099] Preferably, the crystalline form A of the magnesium salt has the X-ray powder diffraction intensity shown in Table 9.

[0100] Preferably, the crystalline form A of the magnesium salt basically has the X-ray powder diffraction pattern shown in FIG. 32.

[0101] In a more preferred form, the present invention provides a crystalline form A of the meglumine salt of Compound I-2, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 3.05 ± 0.2°, 9.38 ± 0.2°, 17.62 ± 0.2° and 12.01 ± 0.2°.

[0102] In a more preferred form, the present invention provides a crystalline form A of the meglumine salt of Compound I-2, the X-ray powder diffraction pattern (XRPD) of which contains peaks located at diffraction angles (2θ) of 3.05 ± 0.2°, 9.38 ± 0.2°, 17.62 ± 0.2°, 12.01 ± 0.2°, 20.39 and 14.88 ± 0.2°.

[0103] Preferably, the crystalline form A of the meglumine salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°,

[0104]

Table 10

[0105] Preferably, the crystalline form A of the meglumine salt has the X-ray powder diffraction intensity shown in Table 10.

[0106] Preferably, the crystalline form A of the meglumine salt basically has the X-ray powder diffraction pattern shown in FIG. 33.

[0107] Preferably, the crystalline form A of the meglumine salt has a DSC thermogram with an endothermic peak at a temperature of about 123.07 °C.

[0108] Preferably, the crystalline form A of the meglumine salt basically has the DSC pattern shown in FIG. 34.

[0109] Preferably, the crystalline form A of the meglumine salt basically has the TGA pattern shown in FIG. 35.

[0110] In a more preferred form, the present invention provides a crystalline form A of the tromethamine salt of Compound I-2, the X-ray powder diffraction pattern (XRPD) of which comprises peaks located at diffraction angles (2θ) of 3.68 ± 0.2°, 7.48 ± 0.2°, 17.21 ± 0.2° and 19.15 ± 0.2°.

[0111] In a more preferred form, the present invention provides a crystalline form A of the tromethamine salt of Compound I-2, the X-ray powder diffraction pattern (XRPD) of which comprises peaks located at diffraction angles (2θ) of 3.68 ± 0.2°, 7.48 ± 0.2°, 17.21 ± 0.2°, 19.15 ± 0.2°, 16.73 ± 0.2° and 15.74 ± 0.2°.

[0112] Preferably, the crystalline form A of the tromethamine salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°,

[0113]

Table 11

[0114] Preferably, the crystalline form A of the tromethamine salt has the X-ray powder diffraction intensity shown in Table 11.

[0115] Preferably, the crystalline form A of the tromethamine salt basically has the X-ray powder diffraction pattern shown in FIG. 36.

[0116] Preferably, the crystalline form A of the tromethamine salt has a DSC thermogram with an endothermic peak at a temperature of about 167.96 °C.

[0117] Preferably, the crystalline form A of the tromethamine salt basically has the DSC pattern shown in Figure 37.

[0118] Preferably, the crystalline form A of the tromethamine salt basically has the TGA pattern shown in Figure 38.

[0119] A second aspect of the present invention is a method for producing a pharmaceutically acceptable salt of Compound I-1 or Compound I-2, which includes reacting Compound I-1 or Compound I-2 with an acid or a base in a solvent to obtain a pharmaceutically acceptable salt of Compound I-1 or Compound I-2.

[0120] According to an embodiment of the present invention, the acid is selected from inorganic acids or organic acids. The inorganic acid may be selected from hydrobromic acid, hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, and boric acid. The organic acid may be selected from acetic acid, oxalic acid, valeric acid, benzoic acid, lactic acid, toluic acid, citric acid, malic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. According to an embodiment of the present invention, the base is selected from inorganic bases or organic bases. The inorganic base may be selected from hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide. The organic base may be selected from ammonia (NH3), primary amines, secondary amines, or tertiary amines such as tetramethylamine salts, tetraethylamine salts, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, meglumine, choline, and tromethamine. According to an embodiment of the present invention, in the above manufacturing method, after the reaction is completed, the method further includes a step of generating supersaturation to precipitate a product, and the method of generating the above supersaturation includes one or more of the methods of adding a seed crystal, volatilizing a solvent, adding a poor solvent, or lowering the temperature to obtain an acidic salt or a basic salt of Compound I.

[0121] According to an embodiment of the present invention, the above solvent may be selected from alcohol-based, chloroalkane, ketone-based, ether-based, cyclic ether-based, ester-based, alkane-based, cycloalkane-based, benzene-based, amide-based, sulfoxide-based, nitrile-based organic solvents, a combination of two or more of the above solvents, or a mixture of each of the above solvents or combinations with water.

[0122] According to an embodiment of the present invention, the above ketone-based may be selected from ketones having 3 to 10 carbon atoms such as acetone, butanone, pentanone, methyl ethyl ketone, methyl isobutyl ketone, 4-methyl-2-pentanone, or a combination thereof, the above nitrile-based may be selected from acetonitrile, the above alcohol-based may be selected from alcohols or halogenated alcohols having 1 to 8 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, trifluoroethanol, or a combination thereof, the above ester-based may be selected from organic formic acid esters such as methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or a combination thereof, the above ether-based may be a linear or branched alkyl ether or a cyclic ether-based compound such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a combination thereof, and the above chlorine-based may be selected from dichloromethane, chloroform, 1,2-dichloroethane.

[0123] According to an embodiment of the present invention, the solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, methyl isobutyl ketone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-methoxyethyl ether, acetonitrile, water, or a mixture thereof.

[0124] According to an embodiment of the present invention, the molar ratio of the above compound I-1 or I-2 to the above acid or base may be 1:0.8 to 1:2, preferably 1:0.9 to 1:1.8, more preferably 1:1.0 to 1:1.5.

[0125] According to an embodiment of the present invention, in the above production method, the reaction temperature can be selected from a relatively wide range. For example, it is 20°C to 80°C, preferably 25°C to 60°C.

[0126] According to an embodiment of the present invention, the above production method further includes performing filtration and / or drying steps after the reaction to obtain a pharmaceutically acceptable salt of compound I-1 or compound I-2.

[0127] According to an embodiment of the present invention, in the above production method, the drying temperature can be selected from a relatively wide range. For example, it may be 20°C to 80°C, preferably 30°C to 60°C.

[0128] The present invention further provides a method for producing a pharmaceutically acceptable salt of compound I-1.

[0129] Method 1a includes dissolving compound I-1 in acetonitrile, adding concentrated hydrochloric acid, L-tartaric acid, maleic acid, or methanesulfonic acid, stirring at room temperature, filtering, and drying to obtain the hydrochloride salt of compound I-1, the tartrate salt of compound I-1, the maleate salt of compound I-1, or the methanesulfonate salt of compound I-1. Method 1b includes dissolving compound I-1 and citric acid in acetone, stirring at room temperature, filtering, and drying to obtain the citrate salt of compound I-1. Method 1c involves dissolving Compound I-1 and sodium hydroxide or potassium hydroxide in acetonitrile or methyl isobutyl ketone, stirring at room temperature, filtering, and drying to obtain the sodium salt of Compound I-1 or the potassium salt of Compound I-1. Method 1d involves dissolving Compound I-1 and meglumine in acetonitrile, stirring at room temperature, filtering, and drying to obtain the meglumine salt of Compound I-1. Method 1e involves dissolving Compound I-1 and tromethamine in N-methylpyrrolidone, adding toluene, stirring at room temperature, filtering, and drying to obtain the tromethamine salt of Compound I-1. Preferably, the volume ratio of N-methylpyrrolidone / toluene is 2:15.

[0130] The present invention further provides a method for producing a pharmaceutically acceptable salt of Compound I-2.

[0131] Method 2a involves dissolving Compound I-2 and citric acid or L-tartaric acid in acetone, stirring at room temperature, filtering, and drying to obtain the citrate salt of Compound I-2 or the tartrate salt of Compound I-2. Method 2b involves dissolving Compound I-2 and L-malic acid or fumaric acid in acetonitrile / water, stirring at room temperature, filtering, and drying to obtain the malate salt of Compound I-2 or the fumarate salt of Compound I-2. Preferably, the volume ratio of acetonitrile / water is 1:1. Method 2c involves dissolving Compound I-2 and methanesulfonic acid or maleic acid in ethyl acetate, stirring at room temperature, filtering, and drying to obtain the methanesulfonate salt of Compound I-2 or the maleate salt of Compound I-2. Method 2d involves dissolving Compound I-2 and sodium hydroxide, potassium hydroxide, calcium hydroxide, or magnesium hydroxide in a mixed solvent of acetonitrile / water or ethyl acetate, stirring at room temperature, filtering, and drying to obtain the sodium salt of Compound I-2, the potassium salt of Compound I-2, the calcium salt of Compound I-2, or the magnesium salt of Compound I-2. Preferably, the volume ratio of acetonitrile / water is 1:1. Method 2e involves dissolving Compound I-2 and meglumine in acetone, stirring at room temperature, filtering, and drying to obtain the meglumine salt of Compound I-2. Method 2f involves dissolving Compound I-2 and tromethamine in isopropanol, stirring at room temperature, filtering, and drying to obtain the tromethamine salt of Compound I-2.

[0132] The third aspect of the present invention provides a pharmaceutical composition comprising at least one of the pharmaceutically acceptable salts of the compound represented by the above formula (I) and a pharmaceutically acceptable carrier.

[0133] The fourth aspect of the present invention provides the application of at least one of the pharmaceutically acceptable salts of the compound represented by the above formula (I) in the manufacture of a drug for treating a metabolic disease, a tumor, an autoimmune disease or a metastatic disease.

[0134] The fifth aspect of the present invention provides a pharmaceutically acceptable salt of the compound represented by the above formula (I) for use as a drug for treating a metabolic disease, a tumor, an autoimmune disease or a metastatic disease.

[0135] The sixth aspect of the present invention provides a pharmaceutically acceptable salt of the compound represented by the above formula (I) for use as a drug for the prevention or treatment of T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular compliance disorder, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorder, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive dysfunction, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and the treatment of addictions.

[0136] In a preferred form, the pharmaceutically acceptable salt of the compound represented by the above formula (I) is used as a drug for the treatment of T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia.

[0137] The present invention further provides a method for treating a disease, which comprises administering to an individual in need thereof at least one pharmaceutically acceptable salt of the compound represented by the above formula (I) or the above pharmaceutical composition in a therapeutically effective amount.

[0138] According to an embodiment of the present invention, the above disease is selected from metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0139] According to an embodiment of the present invention, the above diseases are T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular compliance disorder, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorder, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome.

[0140] (Beneficial effects) The inventors of the present invention have studied multiple acidic or basic salts of Compound I, and these salt forms significantly improve the physicochemical properties of Compound I, such as solubility, hygroscopicity, and chemical stability. The raw materials of the above salt-type compounds meet the requirements of industrial production and can meet the needs of clinical pharmaceutical formulation development, having very important clinical application value and are expected to promote the development of new-generation GLP-1R small molecule agonists.

[0141] (Brief Description of the Drawings) [Figure 1] shows the X-ray powder diffraction pattern of the hydrochloride salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (degree), and the ordinate indicates the peak intensity.

[0142] [Figure 2] shows the X-ray powder diffraction pattern of the tartrate salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (degree), and the ordinate indicates the peak intensity.

[0143] [Figure 3] shows the X-ray powder diffraction pattern of the citrate salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (degree), and the ordinate indicates the peak intensity.

[0144] [Figure 4] shows the DSC pattern of the citrate salt of Compound I-1 of the present invention. The abscissa indicates the temperature (°C), and the ordinate indicates the heat flow (mW).

[0145] [Figure 5] shows the TGA pattern of the citrate salt of Compound I-1 of the present invention. The abscissa indicates the temperature (°C), and the ordinate indicates the weight (%).

[0146] [Figure 6] shows the X-ray powder diffraction pattern of the maleate salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (degree), and the ordinate indicates the peak intensity.

[0147] [Figure 7] shows the X-ray powder diffraction pattern of the methanesulfonate salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (degree), and the ordinate indicates the peak intensity.

[0148] [Figure 8] shows the X-ray powder diffraction pattern of the sodium salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (degree), and the ordinate indicates the peak intensity.

[0149] Figure 9 shows the DSC pattern of the sodium salt of Compound I-1 of the present invention. The abscissa indicates the temperature (°C), and the ordinate indicates the heat flow (mW).

[0150] Figure 10 shows the TGA pattern of the sodium of Compound I-1 of the present invention. The abscissa indicates the temperature (°C), and the ordinate indicates the weight (%).

[0151] Figure 11 shows the X-ray powder diffraction pattern of Crystal Form A of the potassium salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (°), and the ordinate indicates the peak intensity.

[0152] Figure 12 shows the X-ray powder diffraction pattern of Crystal Form B of the potassium salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (°), and the ordinate indicates the peak intensity.

[0153] Figure 13 shows the X-ray powder diffraction pattern of the meglumine salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (°), and the ordinate indicates the peak intensity.

[0154] Figure 14 shows the DSC pattern of the meglumine salt of Compound I-1 of the present invention. The abscissa indicates the temperature (°C), and the ordinate indicates the heat flow (mW).

[0155] Figure 15 shows the TGA pattern of the meglumine salt of Compound I-1 of the present invention. The abscissa indicates the temperature (°C), and the ordinate indicates the weight (%).

[0156] Figure 16 shows the X-ray powder diffraction pattern of the tromethamine salt of Compound I-1 of the present invention. The abscissa indicates the 2θ value (°), and the ordinate indicates the peak intensity.

[0157] Figure 17 shows the DSC pattern of the tromethamine salt of Compound I-1 of the present invention. The abscissa indicates the temperature (°C), and the ordinate indicates the heat flow (mW).

[0158] [Figure 18] The TGA pattern of the tromethamine salt of Compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0159] [Figure 19] The X-ray powder diffraction pattern of the citrate salt of Compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0160] [Figure 20] The X-ray powder diffraction pattern of the malate salt of Compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0161] [Figure 21] The X-ray powder diffraction pattern of the tartrate salt of Compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0162] [Figure 22] The X-ray powder diffraction pattern of the fumarate salt of Compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0163] [Figure 23] The X-ray powder diffraction pattern of the methanesulfonate salt of Compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0164] [Figure 24] The X-ray powder diffraction pattern of the maleate salt of Compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0165] [Figure 25] The DSC pattern of the maleate salt of Compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flow (mW).

[0166] [Figure 26] The TGA pattern of the maleate salt of Compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0167] [Figure 27] The X-ray powder diffraction pattern of the sodium salt of Compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0168] [Figure 28] The X-ray powder diffraction pattern of the potassium salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the 2θ value (degrees), and the vertical axis indicates the peak intensity.

[0169] [Figure 29] The DSC pattern of the potassium salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the temperature (°C), and the vertical axis indicates the heat flow (mW).

[0170] [Figure 30] The TGA pattern of the potassium salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the temperature (°C), and the vertical axis indicates the weight (%).

[0171] [Figure 31] The X-ray powder diffraction pattern of the calcium salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the 2θ value (degrees), and the vertical axis indicates the peak intensity.

[0172] [Figure 32] The X-ray powder diffraction pattern of the magnesium salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the 2θ value (degrees), and the vertical axis indicates the peak intensity.

[0173] [Figure 33] The X-ray powder diffraction pattern of the meglumine salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the 2θ value (degrees), and the vertical axis indicates the peak intensity.

[0174] [Figure 34] The DSC pattern of the meglumine salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the temperature (°C), and the vertical axis indicates the heat flow (mW).

[0175] [Figure 35] The TGA pattern of the meglumine salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the temperature (°C), and the vertical axis indicates the weight (%).

[0176] [Figure 36] The X-ray powder diffraction pattern of the tromethamine salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the 2θ value (degrees), and the vertical axis indicates the peak intensity.

[0177] [Figure 37] The DSC pattern of the tromethamine salt of Compound I-2 of the present invention is shown. The horizontal axis indicates the temperature (°C), and the vertical axis indicates the heat flow (mW).

[0178] [Figure 38] shows the TGA pattern of the tromethamine salt of Compound I-2 of the present invention. The abscissa indicates temperature (°C), and the ordinate indicates weight (%).

[0179] [Figure 39] shows the DVS pattern of Compound I-1 of the present invention. The abscissa indicates relative humidity (%), and the ordinate indicates weight change (%).

[0180] [Figure 40] shows the DVS pattern of Compound I-2 of the present invention. The abscissa indicates relative humidity (%), and the ordinate indicates weight change (%).

[0181] [Figure 41] shows the DVS pattern of the tromethamine salt of Compound I-1 of the present invention. The abscissa indicates relative humidity (%), and the ordinate indicates weight change (%).

[0182] [Figure 42] shows the DVS pattern of the tromethamine salt of Compound I-2 of the present invention. The abscissa indicates relative humidity (%), and the ordinate indicates weight change (%).

[0183] (Definitions and Explanations of Terms) Unless otherwise stated, the following terms used in the specification and claims have the following meanings. Specific phrases or terms should not be considered uncertain or unclear when not specifically defined, but should be understood in their ordinary meanings. When a trade name is described in this specification, it is intended to refer to the corresponding product or its active ingredient.

[0184] "Pharmaceutical composition" means a mixture of one or more compounds described in this specification or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body, contribute to the absorption of the active ingredient, and further exert biological activity.

[0185] As used herein, "salt" refers to a compound produced by the reaction of an organic acid or a basic drug with a pharmaceutically acceptable inorganic or organic acid or base.

[0186] The intermediate compounds according to the present invention can be produced by a plurality of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of these and other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0187] The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the above solvent must be suitable for the chemical changes of the present invention and its necessary reagents and materials. In order to obtain the compounds of the present invention, those skilled in the art may need to modify or select the synthetic steps or reaction processes based on the existing embodiments.

[0188] Hereinafter, the present invention will be specifically described by way of examples, but these examples do not limit the present invention.

[0189] All solvents used in the present invention are commercially available and can be used without further purification.

[0190] Unless otherwise specified, all reactions of the present invention are carried out with continuous magnetic stirring, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C).

[0191] (Methods and Materials) The structure of the compound is determined by nuclear magnetic resonance (NMR). The NMR shift (δ) is shown in parts per million (ppm). For the measurement of NMR, a Bruker avance-400MHz nuclear magnetic device is used. The measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4), the internal standard is tetramethylsilane (TMS), and the chemical shift is 10 -6 ppm).

[0192] For HPLC measurement, an Agilent 1260 high performance liquid chromatograph or a high performance liquid chromatograph of equivalent efficacy (Sunfire C18 150×4.6 m column or a column of equivalent efficacy) is used.

[0193] The crystalline forms of the acidic or basic salts of Compound I are characterized by X-ray powder diffraction patterns. The X-ray powder diffraction patterns of the above salts are collected on a Bruker D8 Advance powder diffractometer operating in reflection mode using Cu Kα radiation. The instrument employs Cu Kα irradiation (40 kV, 40 mA) and is performed at room temperature using an SSD160-2 detector. The scanning range is 3° to 40° in the 2θ interval and the scanning speed is 0.1 s / step. The diffraction patterns are analyzed using DIFFRAC.MEA.CENTER software.

[0194] The production of XRPD samples is carried out by placing the sample on a single crystal silicon wafer and pressing the sample powder with a glass plate or equivalent to ensure that the surface of the sample is flat and has an appropriate height. Next, the sample holder is placed in the Bruker D8 Advance instrument and the X-ray powder diffraction pattern is collected using the above instrument parameters. The differences in measurements correlated with such X-ray powder diffraction analysis results arise from multiple factors including (a) errors in the sample fabrication (e.g., the height of the sample), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors occurring when measuring peak positions), and (e) properties of the substance (e.g., preferred orientation errors). Calibration errors and sample height errors always result in a shift in the same direction for all peaks. Generally, this calibration factor can match the measured peak positions with the predicted peak positions and be within the range of the predicted 2θ values ±0.2°.

[0195] The experimental method for characterizing the crystalline form of the acidic or basic salt of Compound I using differential scanning calorimetry (DSC) is to take a small amount of the powder of the acidic or basic salt of Compound I in crystalline form, set it up with the instrument, place it in an aluminum crucible that can be capped, cap it with an aluminum disk after placing the sample, and then send it into the instrument for detection after capping. The model number of all the instruments used in the differential scanning calorimetry in this patent is METTLER TOLEDO DSC 3, and the scanning parameters are set to adopt a nitrogen atmosphere and a heating rate of 10.0 k / min.

[0196] The experimental method for characterizing the crystalline form of the acidic or basic salt of Compound I using thermogravimetric analysis (TGA) is to take a small amount of the powder of the acidic or basic salt of Compound I in crystalline form, place it in an alumina crucible set up with the instrument, and send it into the instrument for detection after placing the sample. The model number of all the instruments used in the differential scanning calorimetry in this invention is METTLER TOLEDO TGA 2, and the scanning parameters are set to adopt a nitrogen atmosphere and a heating rate of 10.0 k / min.

[0197] The experimental method for characterizing the acidic or basic salt of Compound I using dynamic vapor sorption (DVS) is to take a small amount of the powder of the acidic or basic salt of Compound I, place it in a precision sample pan set up with the instrument, and send it into the instrument for detection after placing the sample. The model number of all the instruments used in the dynamic vapor sorption in this invention is Intrinsic PLUS, and the experimental parameters are set such that the constant temperature is set at 25°C, the criterion for judging equilibrium attainment is a mass percentage change rate per unit time (dm / dt) = 0.02% / min, and the programmed humidity change cycle is set such that the initial relative humidity is 0% and the final relative humidity at the end point is 90%.

[0198] (Mode for Carrying Out the Invention) Hereinafter, in accordance with specific examples, the technical solution of the present invention will be described in more detail. It should be understood that the following examples are merely illustrative explanations and interpretations of the present invention, and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

[0199] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available products or may be prepared by known methods.

[0200] Example 1 Preparation of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-1)

[0201]

Chemical formula

[0202] Step 1: Synthesis of methyl (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (S)-Methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.5 g, 5.1 mmol), 2-((4-chloro-2-fluorophenoxy)methyl)-6-(piperidin-4-yloxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) were dissolved in N,N-dimethylformamide (80 mL). The resulting mixture was stirred at 60 °C for 3 h, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give (S)-methyl 2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.0 g, 33.5% yield).

[0203] Step 2: Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (S)-Methyl 2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.0 g, 1.7 mmol) was dissolved in a mixed solution of tetrahydrofuran / water (20 mL / 20 mL), and lithium hydroxide (0.13 g, 5.4 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture obtained was adjusted to pH = 5 - 6 with formic acid, and the solvent was removed in vacuo. The residue was purified by reverse-phase flash column chromatography to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (0.69 g, yield 70.5%). 1 1H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1 H), 7.80 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.72 (t, J = 7.6 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.44 (dd, J = 11.2 Hz, 2.0 Hz, 1 H), 7.28 (t, J = 8.8 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 5.18 (s, 2 H), 5.12 - 5.06 (m, 1 H), 4.95 - 4.93 (m, 1 H), 4.81 - 4.76 (m, 1 H), 4.66 - 4.62 (m, 1 H), 4.51 - 4.49 (m, 1 H), 4.38 - 4.36 (m, 1 H), 3.94 (d, J = 13.6 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1 H), 2.79 - 2.67 (m, 2 H), 2.46 - 2.41 (m, 1 H), 2.32 (s, 2 H), 1.92 - 1.91 (m, 2 H), 1.63 - 1.59 (m, 2 H).

[0204] Example 2 Preparation of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-2)

[0205] [Chemical formula]

[0206] Step 1: Synthesis of methyl (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate A mixed solution of N,N-dimethylformamide (80 mL) in which (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.5 g, 5.1 mmol), 2-(4-cyano-2-fluorophenoxy)methyl)-6-(piperidin-4-yloxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) were dissolved was stirred at 60 °C for 3 hours, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain methyl (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (1.1 g, yield 37.2%).

[0207] Step 2: Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (S)-2-((4-((6-((4-Cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (1.1 g, 1.9 mmol) was dissolved in a mixed solution of tetrahydrofuran / water (20 mL / 20 mL), and lithium hydroxide (0.13 g, 5.4 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture obtained with formic acid was adjusted to pH = 5 - 6, and the solvent was removed under vacuum. The residue was purified by reverse-phase flash column chromatography to obtain (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (0.70 g, yield 65.5%). 1HNMR (400 MHz, DMSO-d6): δ 8.23 (s, 1 H), 7.88 (dd, J=2.0 Hz, 11.6 Hz, 1 H), 7.80 (dd, J = 1.6, 8.8 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.67 (d, J =8.4 Hz, 1 H), 7.60 (d, J =8.8 Hz, 1 H), 7.45 (t, J = 8.4 Hz, 1 H), 7.06 (d, J =7.6 Hz, 1 H), 6.74 (d, J =8.4 Hz, 1 H), 5.31 (s, 2 H), 5.10-5.08 (m, 1 H), 4.92-4.90 (m, 1H), 4.80-4.74 (m, 1 H), 4.65-4.61 (m, 1 H), 4.50-4.47 (m, 1 H), 4.40-4.35 (m, 1 H), 3.93 (d, J = 13.6 Hz, 1 H), 3.78 (d, J = 13.6 Hz, 1 H), 2.79-2.67 (m, 3 H), 2.51-2.41 (m, 1 H), 2.32-2.27 (m, 2 H), 1.92-1.89 (m, 2 H) 1.63-1.60 (m, 2 H).

[0208] Example 3 Preparation of the hydrochloride salt of Compound I-1 20 mg of Compound I-1 was added to 1 mL of acetonitrile, 10 mg of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 1 day, filtered, and the filter cake was dried in an oven at 50 °C to obtain the hydrochloride salt of Compound I-1, and the product was characterized by XRPD (Figure 1) analysis.

[0209] Example 4 Preparation of the tartrate salt of Compound I-1 20 mg of Compound I-1 was added to 1 mL of acetonitrile, 7.7 mg of L-tartaric acid was added, and the mixture was stirred at room temperature for 1 day, filtered, and the filter cake was dried in an oven at 50 °C to obtain the tartrate salt of Compound I-1, and the product was characterized by XRPD (Figure 2) analysis.

[0210] Example 5 Preparation of the citrate salt of Compound I-1 199.8 mg of Compound I-1 and 66.8 mg of citric acid were added to 5 mL of acetone, stirred at room temperature for 1 day, filtered, and the filter cake was dried in an oven at 50 °C to obtain the citrate salt of Compound I-1. Analytical data including characterization of the product by XRPD (Figure 3), DSC (Figure 4), and TGA (Figure 5) were collected. The citrate salt was shown to have a DSC thermogram with endothermic peaks at temperatures of approximately 107.80 °C and 130.63 °C. 1 H NMR (400 MHz, CD3OD): δ 8.33 (s, 1 H), 7.98 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.71-7.65 (m, 2 H), 7.21-7.05 (m, 4 H), 6.69 (d, J=8.0 Hz, 1 H), 5.25-5.23 (1H), 5.13 (s, 3 H), 4.72-4.62 (m, 3 H), 4.48-4.43 (m, 1 H), 4.26-4.13 (m, 2 H), 3.06-3.01 (m, 2 H), 2.89-2.75 (m, 7 H), 2.56-2.49 (m, 1 H), 2.08-2.06 (m, 2 H), 1.89-1.87 (m, 2 H).

[0211] Example 6 Preparation of the maleate salt of Compound I-1 20 mg of Compound I-1 was added to 1 mL of acetonitrile, 5 mg of maleic acid was added, stirred at room temperature for 1 day, filtered, and the filter cake was dried in an oven at 50 °C to obtain the maleate salt of Compound I-1, and the product was characterized by XRPD (Figure 6) analysis.

[0212] Example 7 Preparation of the methanesulfonate salt of Compound I-1 20 mg of Compound I-1 was added to 1 mL of acetonitrile, 5.0 mg of methanesulfonic acid was added, stirred at room temperature for 1 day, filtered, and the filter cake was dried in an oven at 50 °C to obtain the methanesulfonate salt of Compound I-1, and the product was characterized by XRPD (Figure 7) analysis.

[0213] Example 8 Preparation of the sodium salt of Compound I-1 199.8 mg of Compound I-1 and 16.5 mg of sodium hydroxide were added to 10 mL of acetonitrile, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the sodium salt of Compound I-1. Analytical data including characterization by XRPD (Figure 8), DSC (Figure 9), and TGA (Figure 10) were collected for the product. The sodium salt was shown to have a DSC thermogram with endothermic peaks at temperatures of approximately 149.11 °C and 174.11 °C.

[0214] Example 9 Preparation of the Potassium Salt of Compound I-1 20 mg of Compound I-1 was added to 0.4 mL of methyl isobutyl ketone, 2.3 mg of potassium hydroxide was added, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 40 °C to obtain the potassium salt of Compound I-1. Analytical data were collected for the product, and the product was characterized by XRPD (Figure 11) analysis.

[0215] Example 10 Preparation of the Potassium Salt of Compound I-1 20 mg of Compound I-1 was added to 0.4 mL of acetonitrile, 2.3 mg of potassium hydroxide was added, stirred at room temperature for 16 hours, filtered, and the filter cake was dried in an oven at 40 °C to obtain the potassium salt of Compound I-1. Analytical data were collected for the product, and the product was characterized by XRPD (Figure 12) analysis.

[0216] Example 11 Preparation of the Meglumine Salt of Compound I-1 199.9 mg of Compound I-1 and 67.5 mg of meglumine were added to 10 mL of acetonitrile, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 40 °C to obtain the meglumine salt of Compound I-1. Analytical data including characterization by XRPD (Figure 13), DSC (Figure 14), and TGA (Figure 15) were collected for the product. The meglumine salt was shown to have a DSC thermogram with an endothermic peak at a temperature of approximately 120.06 °C. 11H NMR (400 MHz, CD3OD): δ 8.19 (s, 1 H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.67 - 7.57 (m, 2 H), 7.20 - 7.03 (m, 4 H), 6.66 (d, J = 8.0 Hz, 1 H), 5.28 - 5.26 (1H), 5.13 (s, 2 H), 5.05 - 5.04 (m, 1 H), 4.90 - 4.86 (m, 2 H), 4.73 - 4.62 (m, 2 H), 4.47 - 4.45 (m, 1 H), 4.04 - 3.64 (m, 9 H), 3.14 - 3.12 (m, 2 H), 2.81 - 2.77 (m, 3 H), 2.68 (s, 3 H), 2.52 - 41 (m, 3 H), 2.00 - 1.98 (m, 2 H), 1.78 - 1.76 (m, 2 H).

[0217] Example 12 Preparation of the Tromethamine Salt of Compound I-1 200 mg of Compound I-1 and 42 mg of tromethamine were added to 2.0 mL of N-methylpyrrolidone, and the solution was added dropwise to 15 mL of toluene. The mixture was stirred at room temperature for 16 hours, filtered, and the filter cake was dried in an oven at 50 °C to obtain the tromethamine salt of Compound I-1. Analytical data including characterization of the product by XRPD (Figure 16), DSC (Figure 17), and TGA (Figure 18) were collected. The tromethamine salt showed a DSC thermogram with endothermic peaks at temperatures of approximately 109.95 °C and 166.02 °C. 11H NMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J = 8.4 Hz, 1.2 Hz, 1 H), 7.66 - 7.57 (m, 2 H), 7.21 - 7.03 (m, 4 H), 6.66 (d, J = 8.0 Hz, 1 H), 5.28 - 5.25 (1H), 5.12 (s, 2 H), 5.05 - 5.03 (m, 1 H), 4.73 - 4.62 (m, 2 H), 4.47 - 4.45 (m, 1 H), 4.02 - 3.88 (m, 2 H), 3.65 (s, 6 H), 3.44 (d, J = 7.2 Hz, 3.5 H), 2.82 - 2.77 (m, 8 H), 2.51 - 2.33 (m, 6.5 H), 2.07 - 1.99 (m, 5.5 H), 1.77 - 1.76 (m, 2 H).

[0218] Example 13 Preparation of the citrate salt of Compound I-2 20 mg of Compound I-2 and 6.7 mg of citric acid were added to 0.4 mL of acetone, stirred at room temperature for 1 day, filtered, and the filter cake was dried in an oven at 50 °C to obtain the citrate salt of Compound I-2, and the product was characterized by XRPD (Figure 19) analysis.

[0219] Example 14 Preparation of the malate salt of Compound I-2 20 mg of Compound I-2 and 5.6 mg of L-malic acid were added to 0.4 mL of acetonitrile / water (1:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the malate salt of Compound I-2, and the product was characterized by XRPD (Figure 20) analysis.

[0220] Example 15 Preparation of the tartrate salt of Compound I-2 20 mg of Compound I-2 and 6.3 mg of L-tartaric acid were added to 0.4 mL of acetone, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the tartrate salt of Compound I-2, and the product was characterized by XRPD (Figure 21) analysis.

[0221] Example 16 Preparation of fumarate of Compound I-2 20 mg of Compound I-2 and 4.9 mg of fumaric acid were added to 0.4 mL of acetonitrile / water (1:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the fumarate of Compound I-2. The product was characterized by XRPD (Figure 22) analysis.

[0222] Example 17 Preparation of methanesulfonate of Compound I-2 20 mg of Compound I-2 and 4.0 mg of methanesulfonic acid were added to 0.4 mL of ethyl acetate, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the methanesulfonate of Compound I-2. The product was characterized by XRPD (Figure 23) analysis.

[0223] Example 18 Preparation of maleate of Compound I-2 200.1 mg of Compound I-2 and 48.6 mg of maleic acid were added to 5 mL of ethyl acetate, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the maleate of Compound I-2. Analytical data including characterization by XRPD (Figure 24), DSC (Figure 25), and TGA (Figure 26) were collected for the product. The maleate showed a DSC thermogram with an endothermic peak at a temperature of approximately 119.30 °C. 1 HNMR (400 MHz, CD3OD): δ 8.34 (s, 1 H), 8.02 (d, J = 2.2, 8.6 Hz, 1 H), 7.79 - 7.71 (m, 2 H), 7.58 - 7.50 (m, 2 H), 7.33 - 7.31 (m, 1 H), 7.12 (d, J =7.6 Hz, 1 H), 6.78 (d, J =8.5 Hz, 1 H), 6.26 (s, 2H), 5.28 - 5.24 (m, 4 H), 4.86 - 4.67 (m, 5 H), 4.45 - 4.42 (m, 1 H), 3.52 - 3.45 (m, 4H), 2.90 - 2.88 (m, 1 H), 2.51 - 2.49 (m, 1 H), 2.25 - 2.05 (m, 4 H).

[0224] Example 19 Preparation of the Sodium Salt of Compound I-2 20 mg of Compound I-2 and 2.8 mg of sodium hydroxide were added to 0.4 mL of acetonitrile / water (1:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the sodium salt of Compound I-2, and the product was characterized by XRPD (Figure 27) analysis.

[0225] Example 20 Preparation of the Potassium Salt of Compound I-2 199.8 mg of Compound I-2 and 23.6 mg of potassium hydroxide were added to 5 mL of ethyl acetate, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the potassium salt of Compound I-2. Analytical data including characterization by XRPD (Figure 28), DSC (Figure 29), and TGA (Figure 30) were collected for the product. The potassium salt showed a DSC thermogram with an endothermic peak at a temperature of about 118.44 °C. 1 HNMR (400 MHz, CD3OD): δ 8.21 (s, 1 H), 7.94 (d, J = 8.6 Hz, 1 H), 7.65 (dd, J = 1.6, 8.5 Hz, 1 H), 7.64 - 7.55 (m, 2 H), 7.51 - 7.49 (m, 1 H), 7.34 - 7.30 (m, 1 H), 7.04 (d, J =7.6 Hz, 1 H), 6.68 (d, J =8.5 Hz, 1 H), 5.26 - 5.24 (m, 3 H), 5.10 - 5.08 (m, 1 H), 4.90 - 4.88 (m, 1 H), 4.73 - 4.62 (m, 2 H), 4.46 - 4.44 (m, 1 H), 4.02 - 3.92 (m, 2 H), 2.81 - 2.77 (m, 3 H), 2.50 - 2.40 (m, 3 H), 1.92 - 1.89 (m, 2 H), 1.78 - 1.75 (m, 2 H).

[0226] Example 21 Preparation of the Calcium Salt of Compound I-2 20 mg of Compound I-2 and 5.2 mg of calcium hydroxide were added to 0.4 mL of acetonitrile / water (1:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the calcium salt of Compound I-2, and the product was characterized by XRPD (Figure 31) analysis.

[0227] Example 22 Preparation of the Magnesium Salt of Compound I-2 199.8 mg of Compound I-2 and 22.4 mg of magnesium hydroxide were added to 5 mL of acetonitrile / water (1:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the magnesium salt of Compound I-2, and the product was characterized by XRPD (Figure 32) analysis.

[0228] Example 23 Preparation of the Meglumine Salt of Compound I-2 200.0 mg of Compound I-2 and 82.0 mg of meglumine were added to 5 mL of acetone, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the meglumine salt of Compound I-2. Analytical data including characterization by XRPD (Figure 33), DSC (Figure 34), and TGA (Figure 35) were collected for the product. The meglumine salt was shown to have a DSC thermogram with an endothermic peak at a temperature of about 123.07 °C. 11H NMR (400 MHz, CD3OD): δ 8.19 (s, 1 H), 7.94 (dd, J = 2.0 Hz, 8.6 Hz, 1 H), 7.66 (dd, J = 1.6, 8.5 Hz, 1 H), 7.64-7.55 (m, 2 H), 7.51-7.49 (m, 1 H), 7.32 (t, J = 8.5 Hz, 1 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.68 (d, J = 8.5 Hz, 1 H), 5.27-5.24 (m, 3 H), 5.10-5.08 (m, 1 H), 4.90-4.85 (m, 1 H), 4.72-4.62 (m, 2 H), 4.47-4.45 (m, 1 H), 4.03-4.01 (m, 2 H), 3.98-3.92 (m, 1 H), 3.89-3.81 (m, 2 H), 3.79-3.62 (m, 3 H), 3.13-3.11 (m, 2 H), 2.80-2.77 (m, 3 H), 2.68 (s, 3H), 2.51-2.40 (m, 3 H), 2.00-1.98 (m, 2 H), 1.78-1.76 (m, 2 H).

[0229] Example 24 Preparation of the tromethamine salt of compound I-2 20 mg of compound I-2 and 4.2 mg of tromethamine were added to 0.5 mL of isopropanol, stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the tromethamine salt of compound I-2. Analytical data including characterization of the product by XRPD (Figure 36), DSC (Figure 37), and TGA (Figure 38) were collected. The tromethamine salt was shown to have a DSC thermogram with an endothermic peak at a temperature of approximately 167.96 °C. 1HNMR (400 MHz, CD3OD): δ 8.20 (s, 1 H), 7.94 (dd, J = 2.0 Hz, 8.6 Hz, 1 H), 7.66 (dd, J = 1.6, 8.5 Hz, 1 H), 7.64 - 7.54 (m, 2 H), 7.51 - 7.50 (m, 1 H), 7.32 (t, J = 8.5 Hz, 1 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.68 (d, J = 8.5 Hz, 1 H), 5.27 - 5.24 (m, 3 H), 5.10 - 5.08 (m, 1 H), 4.90 - 4.88 (m, 1 H), 4.73 - 4.62 (m, 2 H), 4.47 - 4.45 (m, 1 H), 4.00 (d, J = 13.5 Hz, 1 H), 3.90 (d, J = 13.5 Hz, 1 H), 3.65 (s, 6 H), 2.81 - 2.77 (m, 3 H), 2.51 - 2.41 (m, 3 H), 1.91 - 1.89 (m, 2 H), 1.79 - 1.76 (m, 2 H).

[0230] Example 25 Study on the solubility of compound salt forms in water The equilibrium solubilities of free compounds I-1 and I-2 and their corresponding representative tromethamine salts in water (H2O) were measured. In the test, the solid was prepared as a suspension (~10 mg / mL) in the corresponding buffer solution and stirred at 37 ± 2 °C. After 24 hours, the suspension was sampled, the supernatant was filtered, the concentration was measured, and the test results are shown in the following table.

[0231] [Table 12]

[0232] As can be seen from the above experimental results, compared with the free form, most representative salt forms of compound I-1 of the present invention, such as tromethamine salt, sodium salt, potassium salt and meglumine salt, have significantly improved solubility in water (H2O), with an improvement of several to dozens of times.

[0233] Example 26 Study on the Solubility of Tromethamine Salt of Compounds in Other Media For the free compounds I-1 and I-2 and their corresponding representative tromethamine salts, their equilibrium solubilities in simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF) were measured. In the test, the solid was prepared as a suspension (~10 mg / mL) in the corresponding buffer solution and stirred at 37 ± 2 °C. After 24 hours, the suspension was sampled, the supernatant was filtered, the concentration was measured, and the test results are shown in the following table.

[0234] [Table 13]

[0235] As can be seen from the above experimental results, compared with the free state, the representative tromethamine salts of compounds I-1 and I-2 have significantly better solubility in simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), or simulated fed intestinal fluid (FeSSIF) than the free compounds.

[0236] Example 27 Measurement of Hygroscopic Behavior The hygroscopic behavior of compounds affects the manufacture, storage, stability, and quality of drugs. The inventors evaluated the stability risk of samples with changes in humidity at 25 °C according to the dynamic moisture adsorption method, performed DVS measurements on the tromethamine salts, which are representative salt forms of compounds I-1 and I-2, to evaluate the hygroscopicity of the compound salt forms. The DVS pattern of free compound I-1 is shown in Figure 39, the DVS pattern of free compound I-2 is shown in Figure 40, the DVS pattern of the tromethamine salt of compound I-1 is shown in Figure 41, and the DVS pattern of the tromethamine salt of compound I-2 is shown in Figure 42. The obtained results are shown in the following table.

[0237] [Table 14]

[0238] From the above experimental results, unexpectedly, it was found that compared with the base, the solubility after salt formation increased significantly, but the hygroscopicity did not change significantly. In the adsorption curve of 0 - 90% RH, at the condition of 80% RH, both the free compounds I-1 and I-2 and the tromethamine salts of compounds I-1 and I-2 were slightly hygroscopic, with no obvious difference, and no change in the solid form was observed for any of them.

[0239] A summary of the thermal analysis of some salt forms of the compounds of the present invention is shown in the following table.

[0240]

Table 15

[0241] As described above, the embodiments of the technical solution of the present invention have been exemplarily described. It should be understood that the claims of the present invention are not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the scope of not departing from the gist and principles of the present invention should all be included within the scope of the claims of this application.

Brief Description of the Drawings

[0242]

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Figure 13

Figure 14

Figure 15

Figure 16

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Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

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Figure 25

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Figure 28

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Figure 31

Figure 32

Figure 33

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Figure 42

Claims

1. A pharmaceutically acceptable salt of the compound represented by formula (I), wherein 【Chemical 1】 R is selected from halogen or CN, the pharmaceutically acceptable salt refers to a pharmaceutically non-toxic acid addition salt or base addition salt, preferably, the acid addition salt is a salt formed by the compound represented by formula (I) and an inorganic acid or organic acid, including hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, phosphate, borate, acetate, oxalate, valerate, benzoate, lactate, toluylate, citrate, malate, maleate, fumarate, succinate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate; more preferably, the acid addition salts are hydrochloride, acetate, citrate, malate, succinate, tartrate, fumarate, maleate, methanesulfonate; particularly citrate and maleate, Preferably, the base addition salt is a salt formed with an alkali metal such as a sodium salt, a lithium salt, a potassium salt, a calcium salt, a magnesium salt, etc., and ammonia (NH 3 ), a primary amine, a secondary amine or a tertiary amine, and an amine salt formed with an inorganic base or an organic base of the compound represented by the formula (I). More preferred base addition salts are sodium salt, potassium salt, calcium salt, magnesium salt, meglumine salt, choline salt, tromethamine salt, and particularly sodium salt, potassium salt, magnesium salt, meglumine salt and tromethamine salt. preferably, the compound represented by formula (I) is selected from the following compound I-1 or compound I-2, 【Chemical 2】 preferably, the acid addition salts of the compound I-1 are hydrochloride, tartrate, maleate, methanesulfonate, or citrate; the acid addition salts of the compound I-2 are citrate, tartrate, malate (e.g., L-malate), fumarate, methanesulfonate or maleate, preferably, the base addition salts of the compound I-1 are sodium salt, potassium salt, meglumine salt or tromethamine salt; the base addition salts of the compound I-2 are sodium salt, potassium salt, calcium salt, magnesium salt, meglumine salt or tromethamine salt, A pharmaceutically acceptable salt of the compound represented by formula (I).

2. The crystalline form A of the citrate of compound I-1 according to claim 1, the X-ray powder diffraction pattern (XRPD) of which includes peaks located at diffraction angles (2θ) of 19.77±0.2°, 16.59±0.2°, 22.47±0.2° and 20.20±0.2°, preferably, the X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 16.59±0.2°, 19.77±0.2°, 22.47±0.2°, 20.20±0.2°, 24.84±0.2° and 17.51±0.2°, preferably, the crystalline form A of the citrate has an X-ray powder diffraction pattern having the diffraction angles (2θ) shown in Table 1, wherein the error range of the 2θ angle is ±0.20°, 【Table 1】 Preferably, the crystalline form A of the citrate has the X-ray powder diffraction intensity shown in Table 1, Preferably, the crystalline form A of the citrate basically has the X-ray powder diffraction pattern shown in FIG. 3, Preferably, the crystalline form A of the citrate has a DSC thermogram with endothermic peaks at temperatures of about 107.80 °C and 130.63 °C, Preferably, the crystalline form A of the citrate basically has the DSC pattern shown in FIG. 4, Preferably, the crystalline form A of the citrate basically has the TGA pattern shown in FIG. 5, Crystalline form A of the citrate of Compound I-1.

3. Crystalline form A of the sodium salt of Compound I-1 according to claim 1, wherein its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 19.24 ± 0.2°, 20.68 ± 0.2°, 6.81 ± 0.2° and 14.43 ± 0.2°, Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 19.24 ± 0.2°, 20.68 ± 0.2°, 6.81 ± 0.2°, 14.43 ± 0.2°, 14.98 ± 0.2° and 6.40 ± 0.2°, Preferably, the crystalline form A of the sodium salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°, 【Table 2】 Preferably, the crystalline form A of the sodium salt has the X-ray powder diffraction intensity shown in Table 2, Preferably, the crystalline form A of the sodium salt basically has the X-ray powder diffraction pattern shown in FIG. 8, Preferably, the crystalline form A of the sodium salt has a DSC thermogram with endothermic peaks at temperatures of about 149.11 °C and 174.11 °C, Preferably, the crystalline form A of the sodium salt basically has the DSC pattern shown in FIG. 9, Preferably, the crystalline form A of the sodium salt basically has the TGA pattern shown in FIG. 10, Crystalline form A of the sodium salt of Compound I-1.

4. Crystalline form A of the potassium salt of Compound I-1 according to claim 1, wherein its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 13.90 ± 0.2°, 14.43 ± 0.2°, 16.20 ± 0.2°, and 11.67 ± 0.2°, Preferably, the X-ray powder diffraction pattern (XRPD) thereof includes peaks located at diffraction angles (2θ) of 13.90 ± 0.2°, 14.43 ± 0.2°, 16.20 ± 0.2°, 11.67 ± 0.2°, 20.99 ± 0.2° and 16.79 ± 0.2°. Preferably, the crystalline form A of the potassium salt has an X-ray powder diffraction pattern having diffraction angles (2θ) shown in Table 3, wherein the error range of the 2θ angle is ±0.20°. 【Table 3】 Preferably, the crystalline form A of the potassium salt has an X-ray powder diffraction intensity shown in Table 3. Preferably, the crystalline form A of the potassium salt basically has an X-ray powder diffraction pattern shown in FIG.

11. Crystalline form A of the potassium salt of Compound I-1.

5. Crystalline form B of the potassium salt of Compound I-1 according to claim 1, wherein the X-ray powder diffraction pattern (XRPD) thereof includes peaks located at diffraction angles (2θ) of 5.92 ± 0.2°, 14.10 ± 0.2°, 17.62 ± 0.2°, and 17.94 ± 0.2°. Preferably, the X-ray powder diffraction pattern (XRPD) thereof includes peaks located at diffraction angles (2θ) of 5.92 ± 0.2°, 14.10 ± 0.2°, 17.62 ± 0.2°, 17.94 ± 0.2°, 11.92 ± 0.2° and 7.01 ± 0.2°. Preferably, the crystalline form B of the potassium salt has an X-ray powder diffraction pattern having diffraction angles (2θ) shown in Table 4, wherein the error range of the 2θ angle is ±0.20°. 【Table 4】 Preferably, the crystalline form B of the potassium salt has an X-ray powder diffraction intensity shown in Table 4. Preferably, the crystalline form B of the potassium salt basically has an X-ray powder diffraction pattern shown in FIG.

12. Crystalline form B of the potassium salt of Compound I-1.

6. Crystalline form A of the meglumine salt of Compound I-1 according to claim 1, wherein the X-ray powder diffraction pattern (XRPD) thereof includes peaks located at diffraction angles (2θ) of 18.15 ± 0.2°, 12.87 ± 0.2°, 22.87 ± 0.2° and 24.66 ± 0.2°. Preferably, the X-ray powder diffraction pattern (XRPD) thereof includes peaks located at diffraction angles (2θ) of 18.15 ± 0.2°, 12.87 ± 0.2°, 22.87 ± 0.2°, 24.66 ± 0.2°, 23.21 ± 0.2° and 19.57 ± 0.2°. Preferably, the meglumine salt of crystalline form A has an X-ray powder diffraction pattern having diffraction angles (2θ) shown in Table 5, wherein the error range of the 2θ angle is ±0.20°, 【Table 5】 Preferably, the meglumine salt of crystalline form A has the X-ray powder diffraction intensity shown in Table 5, Preferably, the meglumine salt of crystalline form A basically has the X-ray powder diffraction pattern shown in FIG. 13, Preferably, the meglumine salt of crystalline form A has a DSC thermogram with an endothermic peak at a temperature of about 120.06 °C, Preferably, the meglumine salt of crystalline form A basically has the DSC pattern shown in FIG. 14, Preferably, the meglumine salt of crystalline form A basically has the TGA pattern shown in FIG. 15, Crystalline form A of the meglumine salt of Compound I-1.

7. Crystalline form A of the tromethamine salt of Compound I-1 according to Claim 1, wherein its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 3.50 ± 0.2°, 6.97 ± 0.2°, 13.91 ± 0.2° and 22.19 ± 0.2°, Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 3.50 ± 0.2°, 6.97 ± 0.2°, 13.91 ± 0.2°, 22.19 ± 0.2°, 31.61 ± 0.2°, 18.11 ± 0.2° and 20.55 ± 0.2°, Preferably, the crystalline form A of the tromethamine salt has its X-ray powder diffraction data shown in Table 6 below, 【Table 6】 Preferably, the crystalline form A of the tromethamine salt has the X-ray powder diffraction intensity shown in Table 6, Preferably, the crystalline form A of the tromethamine salt basically has the X-ray powder diffraction pattern shown in FIG. 16, Preferably, the crystalline form A of the tromethamine salt has a DSC thermogram with endothermic peaks at temperatures of about 109.95 °C and 166.02 °C, Preferably, the crystalline form A of the tromethamine salt basically has the DSC pattern shown in FIG. 17, Preferably, the crystalline form A of the tromethamine salt basically has the TGA pattern shown in FIG. 18, Preferably, the crystalline form A of the tromethamine salt is an N-methylpyrrolidone solvate, Crystalline form A of the tromethamine salt of Compound I-1.

8. Crystal form A of the maleate salt of compound I-2 according to claim 1, wherein its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 5.43 ± 0.2°, 9.89 ± 0.2°, 12.76 ± 0.2°, and 8.30 ± 0.2°, Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 5.43 ± 0.2°, 9.89 ± 0.2°, 12.76 ± 0.2°, 8.30 ± 0.2°, 21.31 ± 0.2°, and 14.24 ± 0.2°, Preferably, the crystal form A of the maleate salt has an X-ray powder diffraction pattern having diffraction angles (2θ) shown in Table 7, wherein the error range of the 2θ angle is ±0.20°, 【Table 7】 Preferably, the crystal form A of the maleate salt has an X-ray powder diffraction intensity shown in Table 7, Preferably, the crystal form A of the maleate salt has an X-ray powder diffraction pattern substantially shown in Figure 24, Preferably, the crystal form A of the maleate salt has a DSC thermogram with an endothermic peak at a temperature of about 119.30 °C, Preferably, the crystal form A of the maleate salt has a DSC pattern substantially shown in Figure 25, Preferably, the crystal form A of the maleate salt has a TGA pattern substantially shown in Figure 26, Crystal form A of the maleate salt of compound I-2.

9. Crystal form A of the potassium salt of compound I-2 according to claim 1, wherein its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 11.51 ± 0.2°, 15.42 ± 0.2°, 20.20 ± 0.2°, and 9.52 ± 0.2°, Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 11.51 ± 0.2°, 15.42 ± 0.2°, 20.20 ± 0.2°, 9.52 ± 0.2°, 5.06 ± 0.2°, and 25.38 ± 0.2°, Preferably, the crystal form A of the potassium salt has an X-ray powder diffraction pattern having diffraction angles (2θ) shown in Table 8, wherein the error range of the 2θ angle is ±0.20°, 【Table 8】 Preferably, the crystal form A of the maleate salt has an X-ray powder diffraction intensity shown in Table 8, Preferably, the crystal form A of the potassium salt has an X-ray powder diffraction pattern substantially shown in Figure 28, Preferably, the crystal form A of the potassium salt has a DSC thermogram with an endothermic peak at a temperature of about 118.44 °C, Preferably, the crystalline form A of the potassium salt basically has the DSC pattern shown in FIG. 29, Preferably, the crystalline form A of the potassium salt basically has the TGA pattern shown in FIG.

30. Crystalline form A of the potassium salt of Compound I-2.

10. Crystalline form A of the magnesium salt of Compound I-2 according to claim 1, wherein its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 13.92 ± 0.2°, 13.46 ± 0.2°, 14.74 ± 0.2° and 20.43 ± 0.2°, Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 13.92 ± 0.2°, 13.46 ± 0.2°, 14.74 ± 0.2°, 20.43 ± 0.2°, 20.16 ± 0.2° and 17.21 ± 0.2°, Preferably, the crystalline form A of the magnesium salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°, 【Table 9】 Preferably, the crystalline form A of the magnesium salt has the X-ray powder diffraction intensity shown in Table 9, Preferably, the crystalline form A of the magnesium salt basically has the X-ray powder diffraction pattern shown in FIG. 32, Crystalline form A of the magnesium salt of Compound I-2.

11. Crystalline form A of the meglumine salt of Compound I-2 according to claim 1, wherein its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 3.05 ± 0.2°, 9.38 ± 0.2°, 17.62 ± 0.2° and 12.01 ± 0.2°, Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 3.05 ± 0.2°, 9.38 ± 0.2°, 17.62 ± 0.2°, 12.01 ± 0.2°, 20.39 and 14.88 ± 0.2°, Preferably, the crystalline form A of the meglumine salt has a diffraction angle (2θ) in its X-ray powder diffraction pattern as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°, 【Table 10】 Preferably, the crystalline form A of the meglumine salt has the X-ray powder diffraction intensity shown in Table 10, Preferably, the crystalline form A of the meglumine salt basically has the X-ray powder diffraction pattern shown in FIG. 33, Preferably, the crystalline form A of the meglumine salt has a DSC thermogram with an endothermic peak at a temperature of about 123.07 °C, Preferably, the meglumine salt of crystalline form A basically has the DSC pattern shown in FIG. 34, Preferably, the meglumine salt of crystalline form A basically has the TGA pattern shown in FIG. 35, Crystalline form A of the meglumine salt of Compound I-2.

12. Crystalline form A of the tromethamine salt of Compound I-2 according to claim 1, wherein its X-ray powder diffraction pattern (XRPD) includes four or more peaks located at diffraction angles (2θ) of 3.68±0.2°, 7.48±0.2°, 17.21±0.2° and 19.15±0.2°, Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks located at diffraction angles (2θ) of 3.68±0.2°, 7.48±0.2°, 17.21±0.2°, 19.15±0.2°, 16.73±0.2° and 15.74±0.2°, Preferably, the crystalline form A of the tromethamine salt has a diffraction angle (2θ) of its X-ray powder diffraction pattern shown in Table 11, and the error range of the 2θ angle is ±0.20°, 【Table 11】 Preferably, the crystalline form A of the tromethamine salt has the X-ray powder diffraction intensity shown in Table 11, Preferably, the crystalline form A of the tromethamine salt basically has the X-ray powder diffraction pattern shown in FIG. 36, Preferably, the crystalline form A of the tromethamine salt has a DSC thermogram with an endothermic peak at a temperature of about 167.96°C, Preferably, the crystalline form A of the tromethamine salt basically has the DSC pattern shown in FIG. 37, Preferably, the crystalline form A of the tromethamine salt basically has the TGA pattern shown in FIG. 38, Crystalline form A of the tromethamine salt of Compound I-2.

13. A method for producing a pharmaceutically acceptable salt, crystalline form A of Compound I-1 or Compound I-2 according to any one of claims 1 to 12, which comprises reacting Compound I-1 or Compound I-2 with an acid or a base in a solvent to obtain a pharmaceutically acceptable salt of Compound I-1 or Compound I-2, Preferably, the acid is selected from inorganic acids or organic acids, the inorganic acid may be selected from hydrobromic acid, hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, boric acid, and the organic acid may be selected from acetic acid, oxalic acid, valeric acid, benzoic acid, lactic acid, toluic acid, citric acid, malic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Preferably, the base is selected from inorganic bases or organic bases. The inorganic base may be selected from hydroxides of alkali metals such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or hydroxides of alkaline earth metals. The organic base may be selected from ammonia, primary amines, secondary amines, or tertiary amines such as tetramethylamine salts, tetraethylamine salts, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, meglumine, choline, tromethamine, etc. Preferably, the molar ratio of the compound I-1 or I-2 to the acid or base may be 1:0.8 to 1:2, preferably 1:0.9 to 1:1.

8. Production method.

14. The method for producing a pharmaceutically acceptable salt of compound I-1 includes the following methods 1a to 1e: Method 1a: Dissolve compound I-1 in acetonitrile, add concentrated hydrochloric acid, L-tartaric acid, maleic acid, or methanesulfonic acid, stir at room temperature, then filter and dry to obtain the hydrochloride salt of compound I-1, the tartrate salt of compound I-1, the maleate salt of compound I-1, or the methanesulfonate salt of compound I-1. Method 1b: Dissolve compound I-1 and citric acid in acetone, stir at room temperature, then filter and dry to obtain the citrate salt of compound I-1. Method 1c: Dissolve compound I-1 and sodium hydroxide or potassium hydroxide in acetonitrile or methyl isobutyl ketone, stir at room temperature, then filter and dry to obtain the sodium salt of compound I-1 or the potassium salt of compound I-1. Method 1d: Dissolve compound I-1 and meglumine in acetonitrile, stir at room temperature, then filter and dry to obtain the meglumine salt of compound I-1. Method 1e: Dissolve compound I-1 and tromethamine in N-methylpyrrolidone, then add toluene, stir at room temperature, then filter and dry to obtain the tromethamine salt of compound I-1, preferably with a volume ratio of N-methylpyrrolidone / toluene of 2:

15. The method for producing a pharmaceutically acceptable salt of compound I-2 includes the following methods 2a to 2f: Method 2a: Dissolve compound I-2 and citric acid or L-tartaric acid in acetone, stir at room temperature, then filter and dry to obtain the citrate salt of compound I-2 or the tartrate salt of compound I-2. Method 2b, which comprises dissolving Compound I-2 and L-malic acid or fumaric acid in acetonitrile / water, stirring at room temperature, filtering, and drying to obtain the malate salt of Compound I-2 or the fumarate salt of Compound I-2. Preferably, the volume ratio of acetonitrile / water is 1:

1. Method 2c, which comprises dissolving Compound I-2 and methanesulfonic acid or maleic acid in ethyl acetate, stirring at room temperature, filtering, and drying to obtain the methanesulfonate salt of Compound I-2 or the maleate salt of Compound I-2. Method 2d, which comprises dissolving Compound I-2 and sodium hydroxide, potassium hydroxide, calcium hydroxide, or magnesium hydroxide in a mixed solvent of acetonitrile / water or ethyl acetate, stirring at room temperature, filtering, and drying to obtain the sodium salt of Compound I-2, the potassium salt of Compound I-2, the calcium salt of Compound I-2, or the magnesium salt of Compound I-2. Preferably, the volume ratio of acetonitrile / water is 1:

1. Method 2e, which comprises dissolving Compound I-2 and meglumine in acetone, stirring at room temperature, filtering, and drying to obtain the meglumine salt of Compound I-2. Method 2f, which comprises dissolving Compound I-2 and tromethamine in isopropanol, stirring at room temperature, filtering, and drying to obtain the tromethamine salt of Compound I-2. The production method according to claim 13.

15. A pharmaceutical composition comprising at least one of the pharmaceutically acceptable salts of the compound represented by formula (I) according to any one of claims 1 to 12, crystalline form A, and a pharmaceutically acceptable carrier.

16. The application of at least one of the pharmaceutically acceptable salts of the compound represented by formula (I) according to any one of claims 1 to 12, crystalline form A, in the manufacture of a drug for treating metabolic diseases, tumors, autoimmune diseases, or metastatic diseases. Preferably, the disease is selected from T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorder, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, vascular compliance disorder, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorder, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcer, ulcerative colitis, high apoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and addiction. Application.

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