Salt of GLP-1r agonist, preparation method therefor and use thereof

Abstract

The present invention relates to a salt form of compound I, which is a GLP-1R agonist, a preparation method therefor, and use thereof. The salt of the present invention has excellent GLP-1R agonistic activity and has good bioavailability in animals, thus being suitable for preparing a preparation for treating metabolic diseases, tumors, autoimmune diseases, or metastatic diseases.

Description

Salt of GLP-1R agonist and its preparation method and application Technical Field

[0001] The present invention belongs to the field of drug development, and particularly relates to a salt of a GLP-1R agonist, a preparation method thereof, and an application thereof. Background Art

[0002] Diabetes is a chronic disease characterized by high blood sugar levels, caused by insufficient insulin secretion (relative or absolute) or impaired insulin action. According to the ninth edition of the World Diabetes Atlas, published by the International Diabetes Federation (IDF), approximately 463 million adults (aged 20-79) worldwide suffered from diabetes in 2019, and the number is projected to reach 578 million by 2030. If this trend continues, there will be 700 million people with diabetes worldwide by 2045. Therefore, diabetes has become one of the most serious global health issues of the 21st century.

[0003] Various pharmacological approaches are currently used to treat hyperglycemia and the accompanying T2DM (Hampp et al., Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 37:1367-1374, 2014). These approaches can be divided into six main categories, each of which works through a different primary mechanism.

[0004] Insulin secretagogues, including sulfonylureas, dipeptidyl peptidase IV (PP-IV) inhibitors, and glucagon-like peptide-1 receptor (GLP-1R) agonists, increase insulin secretion by acting on pancreatic beta cells. Sulfonylureas have limited efficacy and tolerability, cause weight gain, and often induce hypoglycemia. DP-IV inhibitors have limited efficacy. Marketed GLP-1R agonists are peptides administered by subcutaneous injection. Liraglutide is also approved for the treatment of obesity.

[0005] Biguanides (eg, metformin) are thought to act primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal upset and lactic acidosis, further limiting their use.

[0006] Alpha-glucosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption. These agents often cause gastrointestinal discomfort.

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

[0008] Insulin, alone or in combination with the above agents, is used in more severe cases, and regular use may also lead to weight gain and carries the risk of hypoglycemia.

[0009] Sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit glucose reabsorption in the kidneys and thereby lower blood glucose levels. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

[0010] However, with the exception of GLP-1R agonists and SGLT2 inhibitors, these drugs have limited efficacy and do not address the most important issue: β-cell dysfunction and related obesity. Therefore, more effective drug interventions with fewer side effects and convenient administration are needed.

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

[0012] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion from the pancreas, thereby increasing peripheral glucose absorption. GLP-1 also inhibits glucagon secretion, reducing hepatic glucose excretion. Furthermore, GLP-1 delays gastric emptying and slows small intestinal motility, thereby delaying food absorption. In people with T2DM, postprandial GLP-1 levels do not rise normally or rise to a reduced level (Vilsbol et al., Diabetes, 50:609-613, 2001).

[0013] Scientific research has led to structural modifications and alterations in GLP-1 to increase its half-life and thus prolong its biological effects in vivo. However, long-acting GLP-1 analogs currently in clinical use, such as liraglutide and exenatide, are peptides, and frequent, multiple injections lead to poor patient compliance. Therefore, the development of small-molecule GLP-1R agonists, with the goal of improving patient compliance, facilitating medication administration, and reducing side effects, holds broad clinical market potential.

[0014] Hangzhou Mindrank AI Ltd. has developed a novel small molecule compound with GLP-1R inhibitory effects. The structures of its representative compounds I-1 and I-2 are as follows:

[0015] This type of compound can significantly enhance the agonistic effect of the GLP-1R target, increase the therapeutic window, reduce clinical toxic and side effects, and meet the current demand for diabetes treatment at home and abroad.

[0016] 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.

[0017] 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.

[0018] The successful development of a pharmaceutical solid form of Compound I-1 or Compound I-2 generally requires properties such as a solid form that can be easily isolated and purified after synthesis, is suitable for large-scale manufacturing, can be stored for a long period of time with minimal absorption of water, decomposition, or conversion to other solid forms, and is suitable for a dosage form that can be rapidly absorbed by an individual after administration (e.g., soluble in water and gastric fluid).

[0019] In order to meet the needs of clinical research and marketed drug preparations, there is an urgent need to develop a solid form of drug that can be easily separated and purified, is suitable for industrial production, and has stable physical and chemical properties.

[0020] Summary of the Invention

[0021] In order to solve the problems existing in the prior art, the first aspect of the present invention provides a pharmaceutically acceptable salt of a compound represented by formula (I);

[0022] wherein R is selected from halogen or CN.

[0023] 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;

[0024] According to an embodiment of the present invention, the pharmaceutically acceptable salt refers to a pharmaceutically non-toxic acid addition salt or base addition salt;

[0025] According to an embodiment of the present invention, the acid addition salt is a salt formed by the 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, toluene, 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; in particular, citrate and maleate;

[0026] According to an embodiment of the present invention, the base addition salt is a salt formed by the compound represented by formula (I) with an inorganic base or an organic base, including, for example, salts formed with alkali metals, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc.; amine salts, including salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines, such as: tetramethylamine salts, tetraethylamine salts, methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, meglumine salts, choline salts, tromethamine salts; more preferred base addition salts are sodium salts, potassium salts, calcium salts, magnesium salts, meglumine salts, choline salts, tromethamine salts; in particular, sodium salts, potassium salts, magnesium salts, meglumine salts and tromethamine salts.

[0027] According to an embodiment of the present invention, the acid addition salt of the compound I-1 is hydrochloride, tartrate, maleate, methanesulfonate, or citrate; the acid addition salt of the compound I-2 is citrate, tartrate, malate (such as L-malate), fumarate, methanesulfonate or maleate;

[0028] According to an embodiment of the present invention, the base addition salt of the compound I-1 is a sodium salt, potassium salt, meglumine salt or tromethamine salt; the base addition salt of the compound I-2 is a 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 a citrate salt form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes peaks 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 citrate salt form A of the compound I-1 includes peaks 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 citrate salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 1, wherein the error range of the 2θ angle is ±0.20°:

[0032] Table 1

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

[0034] Preferably, the citrate salt form A has an X-ray powder diffraction pattern substantially as shown in FIG3 .

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

[0036] Preferably, the citrate salt form A has a DSC graph substantially as shown in FIG4 .

[0037] Preferably, the citrate salt form A has a TGA graph substantially as shown in FIG5 .

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

[0039] As a further preferred embodiment, the present invention provides a sodium salt form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes peaks 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, the sodium salt form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°:

[0041] Table 2

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

[0043] Preferably, the sodium salt form A has an X-ray powder diffraction pattern substantially as shown in FIG8 .

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

[0045] Preferably, the sodium salt form A has a DSC graph substantially as shown in FIG9 .

[0046] Preferably, the sodium salt form A has a TGA graph substantially as shown in FIG10 .

[0047] As a further preferred embodiment, the present invention provides a potassium salt form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 13.90±0.2°, 14.43±0.2°, 16.20±0.2°, and 11.67±0.2°.

[0048] As a further preferred embodiment, the present invention provides a potassium salt form A of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes peaks 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 potassium salt crystal form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 3, wherein the error range of the 2θ angle is ±0.20°:

[0050] Table 3

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

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

[0053] As a further preferred embodiment, the present invention provides a potassium salt form B of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 5.92±0.2°, 14.10±0.2°, 17.62±0.2°, and 17.94±0.2°.

[0054] As a further preferred embodiment, the present invention provides a potassium salt form B of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes peaks 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, the potassium salt crystal form B has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 4, wherein the error range of the 2θ angle is ±0.20°:

[0056] Table 4

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

[0058] Preferably, the potassium salt form B has an X-ray powder diffraction pattern substantially as shown in FIG12 .

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

[0060] As a further preferred embodiment, the present invention provides a crystalline form A of the meglumine salt of compound I-1, whose X-ray powder diffraction pattern (XRPD) includes peaks 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, the meglumine salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 5, wherein the error range of the 2θ angle is ±0.20°:

[0062] Table 5

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

[0064] Preferably, the meglumine salt Form A has an X-ray powder diffraction pattern substantially as shown in FIG13 .

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

[0066] Preferably, the meglumine salt crystalline form A has a DSC graph substantially as shown in FIG14 .

[0067] Preferably, the meglumine salt crystalline form A has a TGA pattern substantially as shown in FIG15 .

[0068] As a further preferred embodiment, the present invention provides a tromethamine salt of compound I-1, Form A, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2° and 22.19±0.2°.

[0069] As a further preferred embodiment, the present invention provides a tromethamine salt of compound I-1, Form A, whose X-ray powder diffraction pattern (XRPD) includes peaks 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] As the most preferred embodiment, the X-ray powder diffraction data of the tromethamine salt crystal form A are shown in Table 6 below:

[0071] Table 6

[0072] Preferably, the tromethamine salt Form A has an X-ray powder diffraction intensity as shown in Table 6. Preferably, the tromethamine salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 16.

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

[0074] Preferably, the tromethamine salt Form A has a DSC graph substantially as shown in FIG17 .

[0075] Preferably, the tromethamine salt Form A has a TGA pattern substantially as shown in FIG18 .

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

[0077] As a further preferred embodiment, the present invention provides a maleate salt form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 5.43±0.2°, 9.89±0.2°, 12.76±0.2° and 8.30±0.2°.

[0078] As a further preferred embodiment, the present invention provides a maleate salt form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes peaks 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 maleate salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°:

[0080] Table 7

[0081] Preferably, the maleate salt form A has an X-ray powder diffraction intensity as shown in Table 7.

[0082] Preferably, the maleate salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 24.

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

[0084] Preferably, the maleate salt form A has a DSC graph substantially as shown in FIG25 .

[0085] Preferably, the maleate salt Form A has a TGA pattern substantially as shown in FIG26 .

[0086] As a further preferred embodiment, the present invention provides a potassium salt form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 11.51±0.2°, 15.42±0.2°, 20.20±0.2°, and 9.52±0.2°.

[0087] As a further preferred embodiment, the present invention provides a potassium salt form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes peaks 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 potassium salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 8, wherein the error range of the 2θ angle is ±0.20°:

[0089] Table 8

[0090] Preferably, the maleate salt form A has an X-ray powder diffraction intensity as shown in Table 8.

[0091] Preferably, the potassium salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 28.

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

[0093] Preferably, the potassium salt crystalline form A has a DSC graph substantially as shown in Figure 29.

[0094] Preferably, the potassium salt crystalline form A has a TGA graph substantially as shown in Figure 30.

[0095] As a further preferred embodiment, the present invention provides a magnesium salt form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 13.92±0.2°, 13.46±0.2°, 14.74±0.2° and 20.43±0.2°.

[0096] As a further preferred embodiment, the present invention provides a magnesium salt form A of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes peaks 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 magnesium salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°:

[0098] Table 9

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

[0100] Preferably, the magnesium salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 32.

[0101] As a further preferred embodiment, the present invention provides a crystalline form A of the meglumine salt of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 3.05±0.2°, 9.38±0.2°, 17.62±0.2° and 12.01±0.2°.

[0102] As a further preferred embodiment, the present invention provides a crystalline form A of the meglumine salt of compound I-2, whose X-ray powder diffraction pattern (XRPD) includes peaks 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 meglumine salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°:

[0104] Table 10

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

[0106] Preferably, the meglumine salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 33.

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

[0108] Preferably, the meglumine salt crystalline form A has a DSC graph substantially as shown in FIG34 .

[0109] Preferably, the meglumine salt crystalline form A has a TGA pattern substantially as shown in FIG35 .

[0110] As a further preferred embodiment, the present invention provides a tromethamine salt of compound I-2, Form A, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 3.68±0.2°, 7.48±0.2°, 17.21±0.2° and 19.15±0.2°.

[0111] As a further preferred embodiment, the present invention provides a tromethamine salt of compound I-2, Form A, whose X-ray powder diffraction pattern (XRPD) includes peaks 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 tromethamine salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°:

[0113] Table 11

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

[0115] Preferably, the tromethamine salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 36.

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

[0117] Preferably, the tromethamine salt Form A has a DSC pattern substantially as shown in FIG. 37 .

[0118] Preferably, the tromethamine salt Form A has a TGA pattern substantially as shown in FIG38 .

[0119] The second aspect of the present invention provides a method for preparing a pharmaceutically acceptable salt of Compound I-1 or Compound I-2, which comprises reacting Compound I-1 or Compound I-2 with an acid or a base in a solvent to prepare 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 an inorganic acid or an organic acid. The inorganic acid can be selected from hydrobromic acid, hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, and boric acid; the organic acid can 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.

[0121] According to an embodiment of the present invention, the base is selected from an inorganic base or an organic base. The inorganic base can be selected from an alkali metal hydroxide or an alkaline earth metal hydroxide, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide; the organic base can be selected from ammonia (NH3), a primary amine, a secondary amine or a tertiary amine, such as tetramethylamine salt, tetraethylamine salt, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, meglumine, choline, tromethamine;

[0122] According to an embodiment of the present invention, the preparation method further includes a step of creating supersaturation to precipitate the product after the reaction is completed, and the method of creating supersaturation includes one or more of the following: adding seed crystals, volatilizing solvents, adding anti-solvents, or obtaining an acid salt or basic salt of Compound I by cooling.

[0123] According to an embodiment of the present invention, the solvent can be selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides, nitriles, combinations of two or more of the solvents, or mixtures of the above solvents or combinations with water.

[0124] According to an embodiment of the present invention, the ketones 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 nitriles may be selected from acetonitrile; the alcohols 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 esters may be selected from organic formates, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate or a combination thereof; the ethers may be linear or branched alkyl ethers or cyclic ether compounds, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran or a combination thereof; the chlorines may be selected from dichloromethane, chloroform, 1,2-dichloroethane.

[0125] 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.

[0126] According to an embodiment of the present invention, 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, and more preferably 1:1.0 to 1:1.5.

[0127] According to an embodiment of the present invention, in the preparation method, the reaction temperature can be selected within a wide range, for example, 20°C to 80°C, preferably 25°C to 60°C.

[0128] According to an embodiment of the present invention, the preparation method further comprises the steps of filtering and / or drying after the reaction is completed to prepare a pharmaceutically acceptable salt of Compound I-1 or Compound I-2.

[0129] According to an embodiment of the present invention, in the preparation method, the drying temperature can be selected within a wide range, for example, it can be 20°C to 80°C, preferably 30°C to 60°C.

[0130] The present invention also provides a method for preparing a pharmaceutically acceptable salt of compound I-1:

[0131] Method 1a, comprising: 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 a hydrochloride salt of compound I-1, a tartrate salt of compound I-1, a maleate salt of compound I-1, or a methanesulfonate salt of compound I-1;

[0132] Method 1b, comprising: dissolving compound I-1 and citric acid in acetone, stirring at room temperature, filtering, and drying to obtain a citrate salt of compound I-1;

[0133] Method 1c, comprising: 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 a sodium salt of compound I-1 or a potassium salt of compound I-1;

[0134] Method 1d, comprising: dissolving compound I-1 and meglumine in acetonitrile, stirring at room temperature, filtering, and drying to obtain the meglumine salt of compound I-1;

[0135] Method 1e, comprising: dissolving compound I-1 and tromethamine in N-methylpyrrolidone, adding the mixture to toluene, stirring at room temperature, filtering, and drying to obtain a tromethamine salt of compound I-1; preferably, the volume ratio of N-methylpyrrolidone / toluene is 2:15.

[0136] The present invention also provides a method for preparing a pharmaceutically acceptable salt of compound I-2:

[0137] Method 2a, comprising: dissolving compound I-2 and citric acid or L-tartaric acid in acetone, stirring at room temperature, filtering, and drying to obtain a citrate salt of compound I-2 or a tartrate salt of compound I-2;

[0138] Method 2b, comprising: dissolving compound 1-2 and L-malic acid or fumaric acid in acetonitrile / water, stirring at room temperature, filtering, and drying to obtain a malate salt of compound 1-2 or a fumarate salt of compound 1-2; preferably, the volume ratio of acetonitrile / water is 1:1;

[0139] Method 2c, comprising: dissolving compound I-2 and methanesulfonic acid or maleic acid in ethyl acetate, stirring at room temperature, filtering, and drying to obtain a methanesulfonic acid salt of compound I-2 or a maleic acid salt of compound I-2;

[0140] Method 2d, comprising: dissolving compound 1-2 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 a sodium salt of compound 1-2, a potassium salt of compound 1-2, a calcium salt of compound 1-2, and a magnesium salt of compound 1-2; preferably, the volume ratio of acetonitrile / water is 1:1;

[0141] Method 2e, comprising: dissolving compound I-2 and meglumine in acetone, stirring at room temperature, filtering, and drying to obtain a meglumine salt of compound I-2;

[0142] Method 2f comprises: dissolving compound I-2 and tromethamine in isopropanol, stirring at room temperature, filtering, and drying to obtain a tromethamine salt of compound I-2.

[0143] The third aspect of the present invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable salt of the compound represented by formula (I) and a pharmaceutically acceptable carrier.

[0144] A fourth aspect of the present invention provides a use of at least one pharmaceutically acceptable salt of the compound represented by formula (I) in the preparation of a drug for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0145] In a fifth aspect, the present invention provides a pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I), which is used as a drug for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0146] In a sixth aspect, the present invention provides a pharmaceutically acceptable salt of a compound represented by the aforementioned formula (I), which is used to treat T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other agents, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, and myocardial infarction. , stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidosis, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, poor glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome and the treatment of addiction.

[0147] As a preferred embodiment, a pharmaceutically acceptable salt of the compound represented by the aforementioned formula (I) is used as a drug for treating T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain caused by the use of other drugs, excessive sugar addiction, dyslipidemia, and hyperinsulinemia.

[0148] The present invention also provides a method for treating a disease, comprising administering to an individual in need thereof a therapeutically effective amount of at least one of the pharmaceutically acceptable salts of the compound represented by formula (I) or the pharmaceutical composition.

[0149] According to an embodiment of the present invention, the disease is selected from metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0150] According to an embodiment of the present invention, 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, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other medications, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke. , hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidosis, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, impaired fasting glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome. Beneficial effects

[0151] The inventors of the present invention have studied various acidic or basic salts of Compound I. This salt form greatly improves the physicochemical properties of Compound I, such as solubility, hygroscopicity and chemical stability. The raw materials of the salt compound meet the requirements of industrial production and can meet the needs of clinical drug preparation development. It has very important clinical application value and is expected to accelerate the development into a new generation of GLP-1R small molecule agonists. BRIEF DESCRIPTION OF THE DRAWINGS

[0152] Figure 1 shows the X-ray powder diffraction pattern of the hydrochloride salt of compound I-1 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0153] Figure 2 shows the X-ray powder diffraction pattern of the tartrate salt of compound I-1 of the present invention, wherein the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0154] Figure 3 shows the X-ray powder diffraction pattern of the citrate salt of compound I-1 of the present invention, wherein the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0155] Figure 4 shows a DSC graph of the citrate salt of compound I-1 of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0156] Figure 5 shows a TGA chart of the citrate salt of compound I-1 of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0157] Figure 6 shows the X-ray powder diffraction pattern of the maleate salt of compound I-1 of the present invention, wherein the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0158] Figure 7 shows the X-ray powder diffraction pattern of the methanesulfonate of compound I-1 of the present invention, wherein the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0159] Figure 8 shows the X-ray powder diffraction pattern of the sodium salt of compound I-1 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0160] Figure 9 shows a DSC chart of the sodium salt of compound I-1 of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0161] Figure 10 shows a TGA chart of sodium of compound I-1 of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0162] Figure 11 shows the X-ray powder diffraction pattern of the potassium salt of compound I-1 of the present invention, Form A. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0163] Figure 12 shows the X-ray powder diffraction pattern of the potassium salt of compound I-1 of the present invention, Form B. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0164] Figure 13 shows the X-ray powder diffraction pattern of the meglumine salt of compound I-1 of the present invention, wherein the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0165] Figure 14 shows a DSC graph of the meglumine salt of compound I-1 of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0166] Figure 15 shows the TGA chart of the meglumine salt of compound I-1 of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0167] Figure 16 shows the X-ray powder diffraction pattern of the tromethamine salt of compound I-1 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0168] Figure 17 shows a DSC chart of the tromethamine salt of compound I-1 of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0169] Figure 18 shows a TGA chart of the tromethamine salt of compound I-1 of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0170] Figure 19 shows the X-ray powder diffraction pattern of the citrate salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0171] Figure 20 shows the X-ray powder diffraction pattern of the malate salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0172] Figure 21 shows the X-ray powder diffraction pattern of the tartrate salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0173] Figure 22 shows the X-ray powder diffraction pattern of the fumarate of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0174] Figure 23 shows the X-ray powder diffraction pattern of the methanesulfonate of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0175] Figure 24 shows the X-ray powder diffraction pattern of the maleate salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0176] Figure 25 shows a DSC chart of the maleate salt of compound I-2 of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0177] Figure 26 shows the TGA chart of the maleate salt of compound I-2 of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0178] Figure 27 shows the X-ray powder diffraction pattern of the sodium salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0179] Figure 28 shows the X-ray powder diffraction pattern of the potassium salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0180] Figure 29 shows a DSC chart of the potassium salt of compound I-2 of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0181] Figure 30 shows the TGA chart of the potassium salt of compound I-2 of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0182] Figure 31 shows the X-ray powder diffraction pattern of the calcium salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0183] Figure 32 shows the X-ray powder diffraction pattern of the magnesium salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0184] Figure 33 shows the X-ray powder diffraction pattern of the meglumine salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0185] Figure 34 shows a DSC chart of the meglumine salt of compound I-2 of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0186] Figure 35 shows the TGA chart of the meglumine salt of compound I-2 of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0187] Figure 36 shows the X-ray powder diffraction pattern of the tromethamine salt of compound I-2 of the present invention. The abscissa represents the 2θ value (degrees), and the ordinate represents the peak intensity.

[0188] Figure 37 shows a DSC chart of the tromethamine salt of compound I-2 of the present invention. The abscissa represents temperature (°C), and the ordinate represents heat flow (mW).

[0189] Figure 38 shows a TGA chart of the tromethamine salt of compound I-2 of the present invention. The abscissa represents temperature (°C), and the ordinate represents weight (%).

[0190] Figure 39 shows a DVS graph of compound I-1 of the present invention, wherein the abscissa represents relative humidity (%) and the ordinate represents weight change (%).

[0191] Figure 40 shows a DVS graph of compound I-2 of the present invention, wherein the abscissa represents relative humidity (%) and the ordinate represents weight change (%).

[0192] Figure 41 shows a DVS graph of the tromethamine salt of compound I-1 of the present invention, wherein the abscissa represents relative humidity (%) and the ordinate represents weight change (%).

[0193] Figure 42 shows a DVS graph of the tromethamine salt of compound I-2 of the present invention, wherein the abscissa represents relative humidity (%) and the ordinate represents weight change (%).

[0194] Definitions and Explanations of Terms

[0195] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding product or its active ingredient.

[0196] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0197] As used herein, "salt" refers to a compound prepared by reacting an organic acid or base drug with a pharmaceutically acceptable inorganic or organic acid or base.

[0198] The intermediate compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0199] The chemical reactions described in the specific embodiments of the present invention are carried out in a suitable solvent, which must be compatible with the chemical transformations described herein and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0200] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0201] All solvents used in the present invention were commercially available and used without further purification.

[0202] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring, the solvent is a dry solvent, and the temperature unit is degrees Celsius (°C).

[0203] Methods and Materials

[0204] The structures of the compounds were determined by nuclear magnetic resonance (NMR). NMR shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker avance-400 MHz NMR spectrometer in deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4), with tetramethylsilane (TMS) as the internal standard. Chemical shifts were expressed in 10 -6 ppm) as the unit.

[0205] HPLC determination was performed using an Agilent 1260 high performance liquid chromatograph or a high performance liquid chromatograph of equivalent performance (Sunfire C18 150×4.6m column or a column of equivalent performance).

[0206] The crystalline forms of the acid or basic salts of Compound I were characterized by X-ray powder diffraction patterns. X-ray powder diffraction patterns of the salts were collected on a Bruker D8 Advance powder diffractometer operating in reflection mode using Cu Kα radiation. The instrument employed Cu Kα radiation (40 kV, 40 mA) and an SSD160-2 detector at room temperature. The scan range was from 3° to 40° in the 2θ interval at a scan rate of 0.1 s / step. The diffraction patterns were analyzed using DIFFRAC.MEA.CENTER software.

[0207] The XRPD sample is prepared by placing the sample on a single crystal silicon wafer and pressing the sample powder with a glass sheet or equivalent to ensure that the surface of the sample is flat and has the appropriate height. The sample holder is then placed in a Bruker D8 Advance instrument and an X-ray powder diffraction pattern is collected using the instrument parameters described above. The measurement differences associated with the results of such X-ray powder diffraction analyses are caused by a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including those that occur when determining peak positions), and (e) the properties of the material (e.g., preferred orientation errors). Calibration errors and sample height errors often result in displacements of all peaks in the same direction. Generally speaking, this calibration factor will make the measured peak positions consistent with the expected peak positions and can be within the range of ±0.2° of the expected 2θ value.

[0208] The experimental method for characterizing the crystalline form of the acid or basic salt of Compound I using differential scanning calorimetry (DSC) is to take a small amount of powder of the crystalline acid or basic salt of Compound I and place it in an aluminum crucible that is compatible with the instrument and has a press-fit lid. After loading the sample, the crucible is press-fitted with an aluminum pan, which is then inserted into the instrument for testing. The differential scanning calorimetry used in this patent is a METTLER TOLEDO DSC 3 instrument, with scanning parameters set to a nitrogen atmosphere and a heating rate of 10.0 K / min.

[0209] The experimental method for characterizing the crystalline form of the acid or basic salt of Compound I using thermogravimetric analysis (TGA) is to take a small amount of powder of the crystalline acid or basic salt of Compound I and place it in an alumina crucible equipped with the instrument. After loading the sample, the crucible is tested. The differential scanning calorimetry instrument used in this invention is a METTLER TOLEDO TGA 2, with scanning parameters set to a nitrogen atmosphere and a heating rate of 10.0 k / min.

[0210] The dynamic moisture sorption method (DVS) for characterizing the acid or basic salt of Compound I involves taking a small amount of powdered acid or basic salt of Compound I and placing it in a precision sample tray supplied with the instrument. After loading, the sample is placed into the instrument for testing. The dynamic moisture sorption method used in this invention utilizes an Intrinsic PLUS instrument. Experimental parameters include a constant temperature of 25°C, a mass percentage change per unit time (dm / dt) of 0.02% / min as the equilibrium criterion, and a programmed humidity cycle with an initial relative humidity of 0% and an endpoint relative humidity of 90%. DETAILED DESCRIPTION

[0211] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0212] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0213] Example 1 Preparation of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-1)

[0214] Step 1: Synthesis of (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

[0215] A mixed solution of (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-oxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) in N,N-dimethylformamide (80 mL) was stirred at 60°C for 3 hours, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 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, yield: 33.5%).

[0216] Step 2: Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0217] To a solution of (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) in tetrahydrofuran / water (20 mL / 20 mL) was added lithium hydroxide (0.13 g, 5.4 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was adjusted to pH 5-6 with formic acid, and the solvent was removed in vacuo. The residue was purified by reverse phase flash column chromatography to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (0.69 g, yield: 70.5%). 1 H NMR (400MHz, DMSO-d6): δ8.27(s,1H),7.80(dd,J=8.4Hz,1.2Hz,1H),7.72(t,J=7.6Hz,1H),7.64(d,J=8.4Hz,1H),7.44(dd,J =11.2Hz,2.0Hz,1H),7.28(t,J=8.8Hz,1H),7.18(d,J=8.4Hz,1H),7.04(d,J=7.2Hz,1H),6.72(d,J=8.0Hz,1H),5.18(s,2H), 5.12-5.06(m,1H),4.95-4.93(m,1H),4.81-4.76(m,1H),4.66-4.62(m,1H),4.51-4.49(m,1H),4.38-4.36(m,1H),3.94(d,J= 13.6Hz,1H),3.78(d,J=13.6Hz,1H),2.79-2.67(m,2H),2.46-2.41(m,1H),2.32(s,2H),1.92-1.91(m,2H),1.63-1.59(m,2H).

[0218] Example 2 Preparation of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-2)

[0219] Step 1: Synthesis of (S)-methyl 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

[0220] A mixed solution of (S)-methyl 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-oxy)pyridine (1.8 g, 5.5 mmol), and potassium carbonate (1.8 g, 13.0 mmol) in N,N-dimethylformamide (80 mL) was stirred at 60°C for 3 hours, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 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-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%).

[0221] Step 2: Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0222] To a solution of (S)-methyl 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, 1.9 mmol) in tetrahydrofuran / water (20 mL / 20 mL) was added lithium hydroxide (0.13 g, 5.4 mmol), and the mixture was stirred at room temperature for 16 hours. The resulting mixture was adjusted to pH 5-6 with formic acid, and the solvent was removed in vacuo. The residue was purified by reverse phase flash column chromatography to give (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (0.70 g, yield: 65.5%). 1HNMR (400MHz, DMSO-d6): δ8.23(s,1H),7.88(dd,J=2.0Hz,11.6Hz,1H),7.80(dd,J=1.6,8.8Hz,1H),7.73(t,J=8.0Hz,1H),7.6 7(d,J=8.4Hz,1H),7.60(d,J=8.8Hz,1H),7.45(t,J=8.4Hz,1H),7.06(d,J=7.6Hz,1H),6.74(d,J=8.4Hz,1H),5.31(s,2H),5.1 0-5.08(m,1H),4.92-4.90(m,1H),4.80-4.74(m,1H),4.65-4.61(m,1H),4.50-4.47(m,1H),4.40-4.35(m,1H),3.93(d,J=13.6 Hz,1H),3.78(d,J=13.6Hz,1H),2.79-2.67(m,3H),2.51-2.41(m,1H),2.32-2.27(m,2H),1.92-1.89(m,2H)1.63-1.60(m,2H).

[0223] Example 3 Preparation of the hydrochloride salt of compound I-1

[0224] 20 mg of compound I-1 was added to 1 mL of acetonitrile, and 10 mg of concentrated hydrochloric acid was added. 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 of compound I-1. The product was characterized by XRPD analysis (Figure 1).

[0225] Example 4 Preparation of tartrate salt of compound I-1

[0226] 20 mg of compound I-1 was added to 1 mL of acetonitrile, and 7.7 mg of L-tartaric acid was added. 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. The product was characterized by XRPD analysis (Figure 2).

[0227] Example 5 Preparation of Citrate Salt of Compound I-1

[0228] 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 oven-dried at 50°C to obtain the citrate salt of Compound I-1. Analytical data were collected for the product, including characterization by XRPD (Figure 3), DSC (Figure 4), and TGA (Figure 5). The citrate salt exhibited a DSC thermogram with endothermic peaks at approximately 107.80°C and 130.63°C. 1H NMR (400MHz, CD3OD): δ8.33 (s, 1H), 7.98 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.71-7.65 (m,2H),7.21-7.05(m,4H),6.69(d,J=8.0Hz,1H),5.25-5.23(1H),5.13(s,3H ),4.72-4.62(m,3H),4.48-4.43(m,1H),4.26-4.13(m,2H),3.06-3.01(m,2H) ,2.89-2.75(m,7H),2.56-2.49(m,1H),2.08-2.06(m,2H),1.89-1.87(m,2H).

[0229] Example 6 Preparation of the maleate salt of compound I-1

[0230] 20 mg of compound I-1 was added to 1 mL of acetonitrile, and 5 mg of maleic acid was added. 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 maleate salt of compound I-1. The product was characterized by XRPD analysis ( FIG. 6 ).

[0231] Example 7 Preparation of the Methanesulfonate of Compound I-1

[0232] 20 mg of compound I-1 was added to 1 mL of acetonitrile, and 5.0 mg of methanesulfonic acid was added. 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 methanesulfonate salt of compound I-1. The product was characterized by XRPD analysis ( FIG. 7 ).

[0233] Example 8 Preparation of the sodium salt of compound I-1

[0234] 199.8 mg of compound I-1 and 16.5 mg of sodium hydroxide were added to 10 mL of acetonitrile and stirred at room temperature for 3 days. The mixture was filtered and the filter cake was oven-dried at 50°C to obtain the sodium salt of compound I-1. Analytical data were collected for the product, including characterization by XRPD (Figure 8), DSC (Figure 9), and TGA (Figure 10). The sodium salt exhibited a DSC thermogram with endothermic peaks at approximately 149.11°C and 174.11°C.

[0235] Example 9 Preparation of Potassium Salt of Compound I-1

[0236] 20 mg of compound I-1 was added to 0.4 mL of methyl isobutyl ketone, followed by 2.3 mg of potassium hydroxide. The mixture was stirred at room temperature for 3 days, filtered, and the filter cake was oven-dried at 40°C to obtain the potassium salt of compound I-1. Analytical data was collected for the product, and the product was characterized by XRPD analysis (Figure 11).

[0237] Example 10 Preparation of Potassium Salt of Compound I-1

[0238] 20 mg of compound I-1 was added to 0.4 mL of acetonitrile, and 2.3 mg of potassium hydroxide was added. The mixture was stirred at room temperature for 16 hours, filtered, and the filter cake was oven-dried at 40° C. to obtain the potassium salt of compound I-1. Analytical data was collected for the product, and the product was characterized by XRPD analysis ( FIG12 ).

[0239] Example 11 Preparation of the meglumine salt of compound I-1

[0240] 199.9 mg of Compound I-1 and 67.5 mg of meglumine were added to 10 mL of acetonitrile and stirred at room temperature for 3 days. The mixture was filtered and the filter cake was oven-dried at 40°C to obtain the meglumine salt of Compound I-1. Analytical data were collected for the product, including characterization by XRPD (Figure 13), DSC (Figure 14), and TGA (Figure 15). The meglumine salt exhibited a DSC thermogram with an endothermic peak at approximately 120.06°C. 1 H NMR (400MHz, CD3OD): δ8.19 (s, 1H), 7.94 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.67-7.57 (m, 2H), 7.2 0-7.03(m,4H),6.66(d,J=8.0Hz,1H),5.28-5.26(1H),5.13(s,2H),5.05-5.04(m,1H),4. 90-4.86(m,2H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.04-3.64(m,9H),3.14-3.12(m,2 H),2.81-2.77(m,3H),2.68(s,3H),2.52-41(m,3H),2.00-1.98(m,2H),1.78-1.76(m,2H).

[0241] Example 12 Preparation of the Tromethamine Salt of Compound I-1

[0242] 200 mg of compound I-1 and 42 mg of tromethamine were added to 2.0 mL of N-methylpyrrolidone. The solution was added dropwise to 15 mL of toluene and stirred at room temperature for 16 hours. The mixture was filtered and the filter cake was oven-dried at 50°C to obtain the tromethamine salt of compound I-1. Analytical data were collected for the product, including characterization by XRPD ( Figure 16 ), DSC ( Figure 17 ), and TGA ( Figure 18 ). The tromethamine salt exhibited a DSC thermogram with endothermic peaks at approximately 109.95°C and 166.02°C. 1H NMR (400MHz, CD3OD): δ8.20 (s, 1H), 7.94 (dd, J = 8.4Hz, 1.2Hz, 1H), 7.66-7.57 (m, 2H), 7. 21-7.03(m,4H),6.66(d,J=8.0Hz,1H),5.28-5.25(1H),5.12(s,2H),5.05-5.03(m,1H), 4.73-4.62(m,2H),4.47-4.45(m,1H),4.02-3.88(m,2H),3.65(s,6H),3.44(d,J=7.2Hz, 3.5H),2.82-2.77(m,8H),2.51-2.33(m,6.5H),2.07-1.99(m,5.5H),1.77-1.76(m,2H).

[0243] Example 13 Preparation of Citrate Salt of Compound I-2

[0244] 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. The product was characterized by XRPD analysis ( FIG. 19 ).

[0245] Example 14 Preparation of the malate salt of compound I-2

[0246] 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 oven-dried at 50°C to obtain the malate salt of compound I-2. The product was characterized by XRPD analysis (Figure 20).

[0247] Example 15 Preparation of tartrate salt of compound I-2

[0248] 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. The product was characterized by XRPD analysis ( FIG. 21 ).

[0249] Example 16 Preparation of Fumarate Salt of Compound I-2

[0250] 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 salt of compound I-2. The product was characterized by XRPD analysis (Figure 22).

[0251] Example 17 Preparation of the Methanesulfonate of Compound I-2

[0252] 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 analysis ( FIG. 23 ).

[0253] Example 18 Preparation of maleate salt of compound I-2

[0254] 200.1 mg of compound I-2 and 48.6 mg of maleic acid were added to 5 mL of ethyl acetate and stirred at room temperature for 3 days. The mixture was filtered and the filter cake was oven-dried at 50°C to obtain the maleate salt of compound I-2. Analytical data were collected for the product, including characterization by XRPD (Figure 24), DSC (Figure 25), and TGA (Figure 26). The maleate salt exhibited a DSC thermogram with an endothermic peak at approximately 119.30°C. 1 HNMR (400MHz, CD3OD): δ8.34 (s, 1H), 8.02 (d, J = 2.2, 8.6Hz, 1H), 7.79-7.71 (m ,2H),7.58-7.50(m,2H),7.33-7.31(m,1H),7.12(d,J=7.6Hz,1H),6.78(d,J=8 .5Hz,1H),6.26(s,2H),5.28-5.24(m,4H),4.86-4.67(m,5H),4.45-4.42(m,1H ),3.52-3.45(m,4H),2.90-2.88(m,1H),2.51-2.49(m,1H),2.25-2.05(m,4H).

[0255] Example 19 Preparation of the sodium salt of compound I-2

[0256] 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. The product was characterized by XRPD analysis (Figure 27).

[0257] Example 20 Preparation of Potassium Salt of Compound I-2

[0258] 199.8 mg of compound I-2 and 23.6 mg of potassium hydroxide were added to 5 mL of ethyl acetate and stirred at room temperature for 3 days. The mixture was filtered and the filter cake was oven-dried at 50°C to obtain the potassium salt of compound I-2. Analytical data were collected for the product, including characterization by XRPD (Figure 28), DSC (Figure 29), and TGA (Figure 30). The potassium salt exhibited a DSC thermogram with an endothermic peak at approximately 118.44°C. 1HNMR (400MHz, CD3OD): δ8.21(s,1H),7.94(d,J=8.6Hz,1H),7.65(dd,J=1.6,8.5Hz,1H),7.64-7 .55(m,2H),7.51-7.49(m,1H),7.34-7.30(m,1H),7.04(d,J=7.6Hz,1H),6.68(d,J=8.5Hz,1H), 5.26-5.24(m,3H),5.10-5.08(m,1H),4.90-4.88(m,1H),4.73-4.62(m,2H),4.46-4.44(m,1H), 4.02-3.92(m,2H),2.81-2.77(m,3H),2.50-2.40(m,3H),1.92-1.89(m,2H),1.78-1.75(m,2H).

[0259] Example 21 Preparation of the calcium salt of compound I-2

[0260] 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 oven-dried at 50°C to obtain the calcium salt of compound I-2. The product was characterized by XRPD analysis (Figure 31).

[0261] Example 22 Preparation of the magnesium salt of compound I-2

[0262] 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 oven-dried at 50°C to obtain the magnesium salt of compound I-2. The product was characterized by XRPD analysis (Figure 32).

[0263] Example 23 Preparation of the meglumine salt of compound I-2

[0264] 200.0 mg of compound I-2 and 82.0 mg of meglumine were added to 5 mL of acetone and stirred at room temperature for 3 days. The mixture was filtered and the filter cake was oven-dried at 50°C to obtain the meglumine salt of compound I-2. Analytical data were collected for the product, including characterization by XRPD ( Figure 33 ), DSC ( Figure 34 ), and TGA ( Figure 35 ). The meglumine salt exhibited a DSC thermogram with an endothermic peak at approximately 123.07°C. 1HNMR (400MHz, CD3OD): δ8.19(s,1H),7.94(dd,J=2.0Hz,8.6Hz,1H),7.66(dd,J=1.6,8.5Hz,1H),7.64-7.55(m,2H),7.51 -7.49(m,1H),7.32(t,J=8.5Hz,1H),7.04(d,J=7.6Hz,1H),6.68(d,J=8.5Hz,1H),5.27-5.24(m,3H),5.10-5.08(m,1H), 4.90-4.85(m,1H),4.72-4.62(m,2H),4.47-4.45(m,1H),4.03-4.01(m,2H),3.98-3.92(m,1H),3.89-3.81(m,2H),3.79- 3.62(m,3H),3.13-3.11(m,2H),2.80-2.77(m,3H),2.68(s,3H),2.51-2.40(m,3H),2.00-1.98(m,2H),1.78-1.76(m,2H).

[0265] Example 24 Preparation of the Tromethamine Salt of Compound I-2

[0266] 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 oven-dried at 50°C to obtain the tromethamine salt of compound I-2. Analytical data were collected for the product, including characterization by XRPD ( Figure 36 ), DSC ( Figure 37 ), and TGA ( Figure 38 ). The tromethamine salt exhibited a DSC thermogram with an endothermic peak at approximately 167.96°C. 1HNMR (400MHz, CD3OD): δ8.20(s,1H),7.94(dd,J=2.0Hz,8.6Hz,1H),7.66(dd,J=1.6,8.5Hz,1H),7.64-7.54( m,2H),7.51-7.50(m,1H),7.32(t,J=8.5Hz,1H),7.04(d,J=7.6Hz,1H),6.68(d,J=8.5Hz,1H),5.27-5.24(m, 3H),5.10-5.08(m,1H),4.90-4.88(m,1H),4.73-4.62(m,2H),4.47-4.45(m,1H),4.00(d,J=13.5Hz,1H),3.9 0(d,J=13.5Hz,1H),3.65(s,6H),2.81-2.77(m,3H),2.51-2.41(m,3H),1.91-1.89(m,2H),1.79-1.76(m,2H).

[0267] Example 25 Study on the solubility of the salt form of the compound in water

[0268] The equilibrium solubility of free compounds I-1 and I-2, as well as their representative tromethamine salts, in water (H2O) was tested. The solids were prepared into suspensions (~10 mg / mL) in the corresponding buffer and stirred at 37±2°C. After 24 hours, the suspensions were sampled, and the supernatant was filtered and the concentration determined. The results are shown in the following table:

[0269] From the above experimental results, it can be seen that compared with the free form, the solubility of most representative salt forms of compound I-1 of the present invention, such as tromethamine salt, sodium salt, potassium salt and meglumine salt, in water (H2O) is significantly improved, with the increase ranging from several to several dozen times.

[0270] Example 26 Solubility Study of Tromethamine Salt in Other Media

[0271] The equilibrium solubility of free compounds I-1 and I-2, as well as their representative tromethamine salts, was tested in simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated full intestinal fluid (FeSSIF). In the test, the solids were prepared into a suspension (~10 mg / mL) in the corresponding buffer and stirred at 37±2°C. After 24 hours, the suspension was sampled and the supernatant was filtered to determine the concentration. The test results are shown in the following table:

[0272] From the above experimental results, it can be seen that compared with the free state, the solubility of representative tromethamine salts of compound I-1 and compound I-2 in simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF) or simulated full intestinal fluid (FeSSIF) is significantly better than that of the free compound.

[0273] Example 27 Hygroscopic behavior test

[0274] The hygroscopic behavior of compounds affects the production, storage, stability, and quality of drugs. The inventors used the dynamic moisture sorption method to assess the stability risk of samples at 25°C as a function of humidity. DVS testing was performed on representative salt forms of compounds I-1 and I-2, tromethamine salts, to evaluate the hygroscopicity of the compound salt forms. The DVS spectrum of the free form of compound I-1 is shown in Figure 39 , the DVS spectrum of the free form of compound I-2 is shown in Figure 40 , the DVS spectrum of the tromethamine salt of compound I-1 is shown in Figure 41 , and the DVS spectrum of the tromethamine salt of compound I-2 is shown in Figure 42 . The results are shown in the following table:

[0275] The above experimental results unexpectedly revealed that, despite a significant increase in solubility after salt formation compared to the base, hygroscopicity did not change significantly. On the adsorption curves from 0-90% RH, at 80% RH, the free forms of Compounds I-1 and I-2 and their tromethamine salts exhibited only slight hygroscopicity, with no significant differences. No changes in solid form were observed.

[0276] The thermal analysis of some salt forms of the compounds of the present invention are summarized in the following table:

[0277] The above is an exemplary description of the implementation methods of the technical solution of the present invention. It should be understood that the scope of protection of the present invention is not limited to the above implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the scope of protection of the claims of this application.

Claims

1. A pharmaceutically acceptable salt of a compound represented by formula (I); in, 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 an organic acid, including hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, phosphate, borate, acetate, oxalate, valerate, benzoate, lactate, toluate, 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; in particular, citrate and maleate; Preferably, the base addition salt is a salt of the compound represented by formula (I) and an inorganic base or an organic base, including, for example, salts formed with alkali metals, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc.; amine salts include salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines, such as tetramethylamine salts, tetraethylamine salts, methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, meglumine salts, choline salts, tromethamine salts; more preferred base addition salts are sodium salts, potassium salts, calcium salts, magnesium salts, meglumine salts, choline salts, tromethamine salts; in particular, sodium salts, potassium salts, magnesium salts, meglumine salts and tromethamine salts; Preferably, the compound represented by formula (I) is selected from the following compound I-1 or compound I-2: Preferably, the acid addition salt of the compound I-1 is hydrochloride, tartrate, maleate, methanesulfonate, or citrate; the acid addition salt of the compound I-2 is citrate, tartrate, malate (such as L-malate), fumarate, methanesulfonate, or maleate; Preferably, the base addition salt of the compound I-1 is a sodium salt, potassium salt, meglumine salt or tromethamine salt; the base addition salt of the compound I-2 is a sodium salt, potassium salt, calcium salt, magnesium salt, meglumine salt or tromethamine salt.

2. The citrate salt form A of compound I-1 according to claim 1, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 19.77±0.2°, 16.59±0.2°, 22.47±0.2°, and 20.20±0.2°; Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks 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 citrate salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 1, wherein the error range of the 2θ angle is ±0.20°: Table 1 Preferably, the citrate salt crystalline form A has an X-ray powder diffraction intensity as shown in Table 1; Preferably, the citrate salt form A has an X-ray powder diffraction pattern substantially as shown in FIG3 ; Preferably, the citrate salt crystalline form A has a DSC thermogram with endothermic peaks at temperatures of about 107.80° C. and 130.63° C.; Preferably, the citrate salt form A has a DSC pattern substantially as shown in FIG4 ; Preferably, the citrate salt form A has a TGA graph substantially as shown in FIG5 .

3. The sodium salt form A of compound I-1 according to claim 1, whose X-ray powder diffraction pattern (XRPD) includes peaks 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) comprises peaks 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 sodium salt form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°: Table 2 Preferably, the sodium salt crystal form A has an X-ray powder diffraction intensity as shown in Table 2; Preferably, the sodium salt form A has an X-ray powder diffraction pattern substantially as shown in FIG8 ; Preferably, the sodium salt crystalline form A has a DSC thermogram with endothermic peaks at temperatures of about 149.11° C. and 174.11° C.; Preferably, the sodium salt form A has a DSC graph substantially as shown in FIG9 ; Preferably, the sodium salt form A has a TGA graph substantially as shown in FIG10 .

4. The potassium salt form A of compound I-1 according to claim 1, whose X-ray powder diffraction pattern (XRPD) includes peaks at diffraction angles (2θ) of 13.90±0.2°, 14.43±0.2°, 16.20±0.2°, and 11.67±0.2°; Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks 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 potassium salt crystal form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 3, wherein the error range of the 2θ angle is ±0.20°: Table 3 Preferably, the potassium salt crystal form A has an X-ray powder diffraction intensity as shown in Table 3; Preferably, the potassium salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 11.

5. The potassium salt Form B of Compound I-1 according to claim 1, having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 5.92±0.2°, 14.10±0.2°, 17.62±0.2°, and 17.94±0.2°; Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks 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 potassium salt crystal form B has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 4, wherein the error range of the 2θ angle is ±0.20°: Table 4 Preferably, the potassium salt crystal form B has an X-ray powder diffraction intensity as shown in Table 4; Preferably, the potassium salt form B has an X-ray powder diffraction pattern substantially as shown in FIG12 .

6. The meglumine salt Form A of Compound I-1 according to claim 1, having an X-ray powder diffraction pattern (XRPD) comprising peaks at diffraction angles (2θ) of 18.15±0.2°, 12.87±0.2°, 22.87±0.2°, and 24.66±0.2°; Preferably, its X-ray powder diffraction pattern (XRPD) includes peaks 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 crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 5, wherein the error range of the 2θ angle is ±0.20°: Table 5 Preferably, the meglumine salt crystal form A has the X-ray powder diffraction intensity shown in Table 5; Preferably, the meglumine salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 13; Preferably, the meglumine salt crystalline form A has a DSC thermogram with an endothermic peak at a temperature of about 120.06° C.; Preferably, the meglumine salt crystalline form A has a DSC pattern substantially as shown in FIG14 ; Preferably, the meglumine salt crystalline form A has a TGA pattern substantially as shown in FIG15 .

7. The tromethamine salt Form A of Compound I-1 according to claim 1, having an X-ray powder diffraction pattern (XRPD) comprising peaks 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 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 X-ray powder diffraction data of the tromethamine salt crystal form A are shown in Table 6 below: Table 6 Preferably, the tromethamine salt crystal form A has the X-ray powder diffraction intensity shown in Table 6; Preferably, the tromethamine salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 16; Preferably, the tromethamine salt crystalline form A has a DSC thermogram with endothermic peaks at temperatures of about 109.95° C. and 166.02° C.; Preferably, the tromethamine salt Form A has a DSC pattern substantially as shown in Figure 17; Preferably, the tromethamine salt Form A has a TGA pattern substantially as shown in Figure 18; Preferably, the tromethamine salt crystal form A is an N-methylpyrrolidone solvate.

8. The maleate salt form A of compound I-2 according to claim 1, having an X-ray powder diffraction pattern (XRPD) comprising peaks 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 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 maleate salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°: Table 7 Preferably, the maleate salt form A has an X-ray powder diffraction intensity as shown in Table 7; Preferably, the maleate salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 24; Preferably, the maleate salt crystalline form A has a DSC thermogram with an endothermic peak at a temperature of about 119.30° C.; Preferably, the maleate salt Form A has a DSC pattern substantially as shown in Figure 25; Preferably, the maleate salt Form A has a TGA pattern substantially as shown in FIG26 .

9. The potassium salt Form A of Compound I-2 according to claim 1, having an X-ray powder diffraction pattern (XRPD) comprising peaks 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) comprises peaks 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 potassium salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 8, wherein the error range of the 2θ angle is ±0.20°: Table 8 Preferably, the maleate salt form A has an X-ray powder diffraction intensity as shown in Table 8; Preferably, the potassium salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 28; Preferably, the potassium salt crystalline form A has a DSC thermogram with an endothermic peak at a temperature of about 118.44° C.; Preferably, the potassium salt crystalline form A has a DSC pattern substantially as shown in Figure 29; Preferably, the potassium salt crystalline form A has a TGA graph substantially as shown in Figure 30.

10. The magnesium salt form A of compound I-2 according to claim 1, wherein the X-ray powder diffraction pattern (XRPD) includes positions at 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 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 magnesium salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°: Table 9 Preferably, the magnesium salt crystalline form A has an X-ray powder diffraction intensity as shown in Table 9; Preferably, the magnesium salt crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 32.

11. The meglumine salt Form A of Compound I-2 according to claim 1, having an X-ray powder diffraction pattern (XRPD) comprising peaks 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) comprises peaks 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 meglumine salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°: Table 10 Preferably, the meglumine salt crystal form A has the X-ray powder diffraction intensity shown in Table 10; Preferably, the meglumine salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 33; Preferably, the meglumine salt crystalline form A has a DSC thermogram with an endothermic peak at a temperature of about 123.07° C.; Preferably, the meglumine salt crystalline form A has a DSC pattern substantially as shown in FIG34 ; Preferably, the meglumine salt crystalline form A has a TGA pattern substantially as shown in FIG35 .

12. The tromethamine salt Form A of Compound I-2 according to claim 1, having an X-ray powder diffraction pattern (XRPD) comprising four or more peaks 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 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 tromethamine salt crystalline form A has an X-ray powder diffraction pattern having a diffraction angle (2θ) as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°: Table 11 Preferably, the tromethamine salt crystal form A has the X-ray powder diffraction intensity shown in Table 11; Preferably, the tromethamine salt Form A has an X-ray powder diffraction pattern substantially as shown in Figure 36; Preferably, the tromethamine salt crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 167.96° C.; Preferably, the tromethamine salt Form A has a DSC pattern substantially as shown in Figure 37; Preferably, the tromethamine salt Form A has a TGA pattern substantially as shown in Figure 38.

13. A method for preparing a pharmaceutically acceptable salt or crystalline form A of Compound I-1 or Compound I-2 according to any one of claims 1 to 12, comprising reacting Compound I-1 or Compound I-2 with an acid or a base in a solvent to prepare a pharmaceutically acceptable salt of Compound I-1 or Compound I-2; Preferably, the acid is selected from an inorganic acid or an organic acid. 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. Preferably, the base is selected from an inorganic base or an organic base. The inorganic base can be selected from an alkali metal hydroxide or an alkaline earth metal hydroxide, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide; the organic base can be selected from ammonia, a primary amine, a secondary amine or a tertiary amine, such as tetramethylamine salt, tetraethylamine salt, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, meglumine, choline, tromethamine; 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.

14. The preparation method according to claim 13, characterized in that The preparation methods of pharmaceutically acceptable salts of compound I-1 include the following methods 1a-1e: Method 1a, comprising: 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 a hydrochloride salt of compound I-1, a tartrate salt of compound I-1, a maleate salt of compound I-1, or a methanesulfonate salt of compound I-1; Method 1b, comprising: dissolving compound I-1 and citric acid in acetone, stirring at room temperature, filtering, and drying to obtain a citrate salt of compound I-1; Method 1c, comprising: 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 a sodium salt of compound I-1 or a potassium salt of compound I-1; Method 1d, comprising: 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, comprising: dissolving compound I-1 and tromethamine in N-methylpyrrolidone, adding the mixture to toluene, stirring at room temperature, filtering, and drying to obtain a tromethamine salt of compound I-1; preferably, the volume ratio of N-methylpyrrolidone to toluene is 2:15; The preparation methods of pharmaceutically acceptable salts of compound I-2 include the following methods 2a-2f: Method 2a, comprising: dissolving compound I-2 and citric acid or L-tartaric acid in acetone, stirring at room temperature, filtering, and drying to obtain a citrate salt of compound I-2 or a tartrate salt of compound I-2; Method 2b, comprising: dissolving compound 1-2 and L-malic acid or fumaric acid in acetonitrile / water, stirring at room temperature, filtering, and drying to obtain a malate salt of compound 1-2 or a fumarate salt of compound 1-2; preferably, the volume ratio of acetonitrile / water is 1:1; Method 2c, comprising: dissolving compound I-2 and methanesulfonic acid or maleic acid in ethyl acetate, stirring at room temperature, filtering, and drying to obtain a methanesulfonic acid salt of compound I-2 or a maleic acid salt of compound I-2; Method 2d, comprising: dissolving compound 1-2 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 a sodium salt of compound 1-2, a potassium salt of compound 1-2, a calcium salt of compound 1-2, and a magnesium salt of compound 1-2; preferably, the volume ratio of acetonitrile / water is 1:1; Method 2e, comprising: dissolving compound I-2 and meglumine in acetone, stirring at room temperature, filtering, and drying to obtain a meglumine salt of compound I-2; Method 2f comprises: dissolving compound I-2 and tromethamine in isopropanol, stirring at room temperature, filtering, and drying to obtain a tromethamine salt of compound I-2.

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

16. Use of at least one of the pharmaceutically acceptable salts and crystalline form A of the compound of formula (I) according to any one of claims 1 to 12 in the preparation of a medicament 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, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain caused by the use of other medications, excessive sugar cravings, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, Drugs for the prevention or treatment of stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidosis, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, poor glucose metabolism, impaired fasting blood glucose conditions, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, impaired cognitive function, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and the treatment of addiction.

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