Salts of GLP-1R agonists, and methods for producing and using the same

Abstract

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

Description

Detailed Description of the Invention

[0001] The present invention claims priority from a prior application filed with the State Intellectual Property Office of China on July 7, 2022, bearing patent application number 202210804212X and entitled "GLP-1R agonist salts and their preparation methods and applications," which is incorporated herein by reference in its entirety.

[0002] [Technical Field] The present invention relates to the field of drug development, and specifically to salts of GLP-1R agonists and their preparation methods and applications.

[0003] [Background technology] Diabetes mellitus (Diabetes mellitus) is a chronic disease characterized by hyperglycemia due to a relative or absolute deficiency of insulin secretion or impaired insulin action in the human body. According to the 9th edition of the Global Diabetes Atlas, newly published by the International Diabetes Federation (IDF), approximately 463 million adults (aged 20-79) worldwide suffered from diabetes in 2019, and the number of diabetic patients is expected to reach 578 million by 2030. If this trend continues, there will be 700 million diabetic patients worldwide by 2045. Therefore, diabetes has become one of the most serious social and health problems facing the world in the 21st century.

[0004] Currently, various pharmacological approaches exist for treating hyperglycemia and associated 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 major classes, each of which acts by a different primary mechanism.

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

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

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

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

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

[0010] Sodium-glucose cotransporter type 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit glucose reabsorption in the kidney and thereby reduce blood glucose levels, and this new drug class may be associated with ketoacidosis and urinary tract infections.

[0011] However, with the exception of GLP-1R agonists and SGLT2 inhibitors, the effectiveness of these drugs is limited, and the most important problem of beta cell dysfunction and associated obesity remains unresolved. Therefore, there is a need for more effective drug interventions with fewer side effects and easier administration.

[0012] 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 physiologically and glucose-dependent manner. In non-clinical studies, GLP-1 promotes sustained β-cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting β-cell neogenesis (Meier et al., Biodrugs. 17(2):93-102, 2013).

[0013] In healthy individuals, GLP-1 plays an important role in regulating postprandial blood glucose content by increasing peripheral glucose absorption through stimulating glucose-dependent insulin secretion in the pancreas. GLP-1 also inhibits glucagon secretion and reduces hepatic glucose output. GLP-1 also delays gastric emptying and slows small intestinal motility, slowing food absorption. In individuals with T2DM, postprandial GLP-1 does not rise normally or rises at a reduced level (Vilsbol et al., Diabetes. 50609-613, 2001).

[0014] Scientific research has correspondingly altered and modified the structure of GLP-1 to increase its half-life and further prolong its in vivo biological effect.However, the long-acting GLP-1 analogs currently used clinically, such as liraglutide and exenatide, are all polypeptides, and are administered by frequent multiple injections, which leads to relatively poor patient compliance.Therefore, the development of small molecule GLP-1R agonists has broad clinical market prospects for the purposes of improving patient compliance, convenience of administration, and reducing drug side effects.

[0015] Hangzhou Deruizhi Pharmaceutical Technology Co., Ltd. (Mindrank AI Ltd.) has developed structurally novel small molecule compounds with GLP-1R inhibitory effects, the structures of which are representative compounds I-1 and I-2 as follows:

[0016] [ka]

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

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

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

[0020] Successful development of a pharmaceutical solid form of Compound I-1 or Compound I-2 typically requires properties such as a solid form that can be easily separated and purified after synthesis, is amenable to large-scale manufacturing, can be stored for relatively long periods of time while absorbing minimal moisture, decomposing, or being converted to another solid form, and is a dosage form that can be rapidly absorbed by an individual after administration (e.g., is soluble in water and gastric juices).

[0021] To meet the needs of clinical research and commercial pharmaceutical formulations, there is an urgent need to develop solid drug forms that can be easily separated and purified, are suitable for industrial production, and have stable physicochemical properties.

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

[0023] [ka]

[0024] wherein R is selected from halogen or CN.

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

[0026] [ka]

[0027] 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, According to an embodiment of the present invention, the acid addition salt is a salt formed between the compound of formula (I) and an inorganic or organic acid, including hydrobromide, hydrochloride, sulfate, hydrogensulfate, sulfite, phosphate, borate, acetate, oxalate, valerate, benzoate, lactate, toluate, citrate, malate, maleate, fumarate, succinate, tartrate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate, and more preferred acid addition salts are hydrochloride, acetate, citrate, malate, succinate, tartrate, fumarate, maleate, and methanesulfonate, and particularly preferred are citrate and maleate. According to an embodiment of the present invention, the base addition salt is a salt formed between the compound of formula (I) and an inorganic or organic base, including salts formed with, for example, alkali metals such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and amine salts including salts formed with ammonia (NH), 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, and tromethamine salts. More preferred base addition salts are sodium salts, potassium salts, calcium salts, magnesium salts, meglumine salts, choline salts, and tromethamine salts, and particularly sodium salts, potassium salts, magnesium salts, meglumine salts, and tromethamine salts.

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

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

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

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

[0032] [Table 1]

[0033] Preferably, crystalline Form A of the Citrate Salt has the X-ray powder diffraction intensities shown in Table 1.

[0034] Preferably, crystalline Form A of the Citrate Salt has an X-ray powder diffraction pattern essentially as shown in FIG.

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

[0036] Preferably, crystalline Form A of the Citrate Salt has a DSC pattern essentially as shown in FIG.

[0037] Preferably, crystalline Form A of the Citrate Salt has a TGA pattern essentially as shown in FIG.

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

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

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

[0041] [Table 2]

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

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

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

[0045] Preferably, the crystalline form A of the sodium salt has a DSC pattern essentially as shown in FIG.

[0046] Preferably, the crystalline form A of the sodium salt has a TGA pattern essentially as shown in FIG.

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

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

[0049] Preferably, the crystalline form A of the potassium salt has an X-ray powder diffraction pattern with diffraction angles (2θ) shown in Table 3, wherein the error range of the 2θ angles is ±0.20°;

[0050] [Table 3]

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

[0052] Preferably, crystalline form A of the potassium salt has an X-ray powder diffraction pattern essentially as shown in FIG.

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

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

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

[0056] [Table 4]

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

[0058] Preferably, crystalline form B of the potassium salt has an X-ray powder diffraction pattern essentially as shown in FIG.

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

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

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

[0062] [Table 5]

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

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

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

[0066] Preferably, the crystalline form A of the meglumine salt has a DSC pattern essentially as shown in FIG.

[0067] Preferably, the crystalline form A of the meglumine salt has a TGA pattern essentially as shown in FIG.

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

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

[0070] The most preferred form is crystalline form A of the tromethamine salt, the X-ray powder diffraction data of which is shown in Table 6 below.

[0071] [Table 6]

[0072] Preferably, the crystalline form A of the tromethamine salt has X-ray powder diffraction intensities as shown in Table 6. Preferably, the crystalline form A of the tromethamine salt has an X-ray powder diffraction pattern essentially as shown in Figure 16.

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

[0074] Preferably, the crystalline form A of the tromethamine salt has a DSC pattern essentially as shown in FIG.

[0075] Preferably, the crystalline form A of the tromethamine salt has a TGA pattern essentially as shown in FIG.

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

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

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

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

[0080] [Table 7]

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

[0082] Preferably, crystalline Form A of the maleate salt has an X-ray powder diffraction pattern essentially as shown in FIG.

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

[0084] Preferably, crystalline Form A of the maleate salt has a DSC pattern essentially as shown in FIG.

[0085] Preferably, the crystalline form A of the maleate salt has a TGA pattern essentially as shown in FIG.

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

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

[0088] Preferably, the crystalline form A of the potassium salt has an X-ray powder diffraction pattern with diffraction angles (2θ) shown in Table 8, wherein the error range of the 2θ angles is ±0.20°;

[0089] [Table 8]

[0090] Preferably, the crystalline form A of the maleate salt has the X-ray powder diffraction intensities shown in Table 8.

[0091] Preferably, crystalline form A of the potassium salt has an X-ray powder diffraction pattern essentially as shown in FIG.

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

[0093] Preferably, crystalline form A of the potassium salt has a DSC pattern essentially as shown in FIG.

[0094] Preferably, the crystalline form A of the potassium salt has a TGA pattern essentially as shown in FIG.

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

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

[0097] Preferably, the crystalline form A of the magnesium salt has an X-ray powder diffraction pattern with diffraction angles (2θ) shown in Table 9, wherein the error range of the 2θ angles is ±0.20°;

[0098] [Table 9]

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

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

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

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

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

[0104] [Table 10]

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

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

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

[0108] Preferably, the crystalline form A of the meglumine salt has a DSC pattern essentially as shown in FIG.

[0109] Preferably, the crystalline form A of the meglumine salt has a TGA pattern essentially as shown in FIG.

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

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

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

[0113] [Table 11]

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

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

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

[0117] Preferably, the crystalline form A of the tromethamine salt has a DSC pattern essentially as shown in FIG.

[0118] Preferably, the crystalline form A of the tromethamine salt has a TGA pattern essentially as shown in FIG.

[0119] A second aspect of the present invention provides a method for producing a pharmaceutically acceptable salt of compound I-1 or compound I-2, the method comprising reacting compound I-1 or compound I-2 with an acid or a base in a solvent to produce and obtain a pharmaceutically acceptable salt of compound I-1 or compound I-2.

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

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

[0122] According to an embodiment of the present invention, the ketone 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 nitrile may be selected from acetonitrile; the alcohol 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 ester may be selected from organic formates, such as methyl formate, ethyl acetate, isobutyl formate, isopropyl acetate, or a combination thereof; the ether may be a linear or branched alkyl ether or a cyclic ether compound, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or a combination thereof; and the chlorine may be selected from dichloromethane, chloroform, and 1,2-dichloroethane.

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

[0124] According to an embodiment of the present invention, the molar ratio of the 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, more preferably 1:1.0 to 1:1.5.

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

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

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

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

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

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

[0131] Method 2a includes 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 includes dissolving compound I-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 I-2 or a fumarate salt of compound I-2, preferably in an acetonitrile / water volume ratio of 1:1; Method 2c includes dissolving compound I-2 and methanesulfonic acid or maleic acid in ethyl acetate, stirring at room temperature, filtering, and drying to obtain the methanesulfonic acid salt of compound I-2 or the maleic acid salt of compound I-2; Method 2d includes dissolving compound I-2 and sodium hydroxide, potassium hydroxide, calcium hydroxide, or magnesium hydroxide in a mixed solvent of acetonitrile / water or ethyl acetate, stirring at room temperature, filtering, and drying to obtain the sodium salt of compound I-2, the potassium salt of compound I-2, the calcium salt of compound I-2, or the magnesium salt of compound I-2, preferably in an acetonitrile / water volume ratio of 1:1; Method 2e involves dissolving compound I-2 and meglumine in acetone, stirring at room temperature, and then filtering and drying to obtain the meglumine salt of compound I-2; Method 2f involves dissolving compound I-2 and tromethamine in isopropanol and stirring at room temperature, followed by filtering and drying to obtain the tromethamine salt of compound I-2.

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

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

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

[0135] A sixth aspect of the present invention relates to a method for treating T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to the use of other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, 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 Provided is a pharmaceutically acceptable salt of the compound represented by formula (I) for use as a drug for the prevention or treatment of claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorder, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorder, psoriasis, foot ulcer, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive dysfunction, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome, and for the treatment of addiction.

[0136] In a preferred embodiment, the pharmaceutically acceptable salt of the compound represented by the above 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, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, obesity, eating disorders, weight gain due to the use of other drugs, excessive sugar craving, dyslipidemia, and hyperinsulinemia.

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

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

[0139] According to an embodiment of the present invention, the diseases include T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to use of other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, 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, ischemia. The disease is selected from the group consisting of acute stroke, traumatic brain injury, pulmonary hypertension, post-angioplasty restenosis, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorders, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcer, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome.

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

[0141] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] The X-ray powder diffraction pattern of the hydrochloride salt of compound I-1 of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity.

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

[0143] Figure 3 shows the X-ray powder diffraction pattern of the citrate salt of compound I-1 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

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

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

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

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

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

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

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

[0151] Figure 11 shows the X-ray powder diffraction pattern of the crystalline form A of the potassium salt of compound I-1 of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity.

[0152] Figure 12 shows the X-ray powder diffraction pattern of the crystalline form B of the potassium salt of compound I-1 of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity.

[0153] Figure 13 shows the X-ray powder diffraction pattern of the meglumine salt of compound I-1 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

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

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

[0156] Figure 16 shows the X-ray powder diffraction pattern of the tromethamine salt of compound I-1 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

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

[0158] Figure 18 shows the TGA pattern of the tromethamine salt of compound I-1 of the present invention, where the abscissa represents temperature (°C) and the ordinate represents weight (%).

[0159] Figure 19 shows the X-ray powder diffraction pattern of the citrate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

[0160] Figure 20 shows the X-ray powder diffraction pattern of the malate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

[0161] Figure 21 shows the X-ray powder diffraction pattern of the tartrate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

[0162] Figure 22 shows the X-ray powder diffraction pattern of the fumarate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

[0163] Figure 23 shows the X-ray powder diffraction pattern of the methanesulfonate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

[0164] Figure 24 shows the X-ray powder diffraction pattern of the maleate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

[0165] Figure 25 shows the DSC pattern of the maleate salt of compound I-2 of the present invention, where the abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

[0166] Figure 26 shows the TGA pattern of the maleate salt of compound I-2 of the present invention, where the abscissa represents temperature (°C) and the ordinate represents weight (%).

[0167] Figure 27 shows the X-ray powder diffraction pattern of the sodium salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

[0168] Figure 28 shows the X-ray powder diffraction pattern of the potassium salt of compound I-2 of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0169] Figure 29 shows the DSC pattern of the potassium salt of compound I-2 of the present invention, where the abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

[0170] Figure 30 shows the TGA pattern of the potassium salt of compound I-2 of the present invention, where the abscissa represents temperature (°C) and the ordinate represents weight (%).

[0171] Figure 31 shows the X-ray powder diffraction pattern of the calcium salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity.

[0172] Figure 32 shows the X-ray powder diffraction pattern of the magnesium salt of compound I-2 of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensity.

[0173] Figure 33 shows the X-ray powder diffraction pattern of the meglumine salt of compound I-2 of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity.

[0174] Figure 34 shows the DSC pattern of the meglumine salt of compound I-2 of the present invention, where the abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

[0175] Figure 35 shows the TGA pattern of the meglumine salt of compound I-2 of the present invention, where the abscissa represents temperature (°C) and the ordinate represents weight (%).

[0176] Figure 36 shows the X-ray powder diffraction pattern of the tromethamine salt of compound I-2 of the present invention, where the abscissa represents 2θ values ​​(degrees) and the ordinate represents peak intensity.

[0177] Figure 37 shows the DSC pattern of the tromethamine salt of compound I-2 of the present invention, where the abscissa represents temperature (°C) and the ordinate represents heat flow (mW).

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

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

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

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

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

[0183] (Definition and explanation of terms) Unless otherwise specified, the following terms used in the specification and claims have the following meanings: Certain phrases or terms, unless specifically defined, should not be considered indefinite or unclear but should be understood in their ordinary sense. When trade names are mentioned herein, it is intended to refer to the corresponding product or its active ingredient.

[0184] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein or physiologically / pharmaceutically acceptable salts or prodrugs thereof with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredients to further exert biological activity.

[0185] As used herein, "salt" refers to a compound prepared by reaction of an organic acid or base drug with a medicamentous inorganic or organic acid or base.

[0186] The intermediate compounds according to the present invention can be prepared by a variety of 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 alternative methods well known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

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

[0188] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

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

[0190] Unless otherwise specified, all reactions of this invention are carried out with continuous magnetic stirring, solvents are dry solvents, and temperatures are in degrees Celsius (°C).

[0191] Methods and Materials The structure of the compound is confirmed by nuclear magnetic resonance (NMR). The NMR shifts (δ) are given in parts per million (ppm). A Bruker Avance-400 MHz nuclear magnetic spectrometer was used for NMR measurements. The solvent used was deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4), the internal standard was tetramethylsilane (TMS), and the chemical shifts were 10 -6 The unit is ppm.

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

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

[0194] XRPD samples are prepared by placing the sample on a single-crystal silicon wafer and pressing the sample powder with a glass plate or equivalent to ensure the sample surface is flat and of 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 listed above. Measurement differences correlated with such X-ray powder diffraction analysis results arise from multiple factors, including (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors encountered when measuring peak positions), and (e) material properties (e.g., preferred orientation errors). Calibration errors and sample height errors always result in shifts of all peaks in the same direction. Typically, this calibration factor will match the measured peak positions with the predicted peak positions and can be within ±0.2° of the predicted 2θ values.

[0195] The experimental method for characterizing the crystalline form of the acid salt or base salt of Compound I using differential scanning calorimetry (DSC) is to take a small amount of powder of the crystalline form of the acid salt or base salt of Compound I, place it in an aluminum crucible that is equipped with an instrument and can be capped, place the sample in it, cap it with an aluminum disk, and then insert it into the instrument for measurement. All instruments used in the differential scanning calorimetry in this patent are model METTLER TOLEDO DSC 3, and the scanning parameters are set to use a nitrogen atmosphere and a heating rate of 10.0 K / min.

[0196] The experimental method for characterizing the crystalline form of the acid salt or base salt of Compound I using thermogravimetric analysis (TGA) is to take a small amount of powder of the crystalline form of the acid salt or base salt of Compound I and place it in an alumina crucible set up with the instrument, and then load the sample into the instrument for measurement. All instruments used in the differential scanning calorimetry of the present invention are model METTLER TOLEDO TGA 2, and the scanning parameters are set to adopt a nitrogen atmosphere and a heating rate of 10.0 K / min.

[0197] The experimental method for characterizing the acid salt or base salt of Compound I using dynamic moisture sorption spectroscopy (DVS) involves taking a small amount of powder of the acid salt or base salt of Compound I and placing it on a precision sample tray attached to an instrument, then loading the sample and feeding it into the instrument for measurement. All instruments used in the dynamic moisture sorption spectroscopy in this invention are Intrinsic PLUS models, and the experimental parameters are a constant temperature of 25°C, a mass percentage change rate per unit time (dm / dt) of 0.02% / min as the equilibrium determination criterion, and a programmed humidity change cycle with an initial relative humidity of 0% and an end-point relative humidity of 90%.

[0198] (Mode for Carrying Out the Invention) The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely intended to illustrate and explain the present invention and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included within the scope of the claims of the present invention.

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

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

[0201] [ka]

[0202] Step 1: Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl A solution of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methylformate (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 h, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was 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)-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-formate methyl ester (1.0 g, yield 33.5%).

[0203] Step 2: Synthesis of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid To a solution of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate (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-formic acid (0.69 g, 70.5% yield). 1 H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1 H), 7.80 (dd, J=8.4 Hz, 1.2 Hz, 1 H), 7.72 (t, J=7.6 Hz, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.44 (dd, J=11.2 Hz, 2.0 Hz, 1 H), 7.28 (t, J=8.8 Hz, 1 H), 7.18 (d, J=8.4 Hz, 1 H), 7.04 (d, J=7.2 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 5.18 (s, 2 H), 5.12-5.06 (m, 1H), 4.95-4.93 (m, 1 H), 4.81-4.76 (m, 1 H), 4.66-4.62 (m, 1 H), 4.51-4.49 (m, 1 H), 4.38-4.36 (m, 1 H), 3.94 (d, J=13.6 Hz, 1 H), 3.78 (d, J=13.6 Hz, 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).

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

[0205] [ka]

[0206] Step 1: Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formate methyl A solution of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methylformate (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 h, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was 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)-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-formate methyl ester (1.1 g, yield 37.2%).

[0207] Step 2: Synthesis of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-formic acid To a solution of (S)-2-((4-((6-((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-methyl formate (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-formic acid (0.70 g, 65.5% yield). 1HNMR (400 MHz, DMSO-d6): δ 8.23 ​​(s, 1 H), 7.88 (dd, J=2.0 Hz, 11.6 Hz, 1 H), 7.80 (dd, J = 1.6, 8.8 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.67 (d, J =8.4 Hz,1 H), 7.60 (d, J =8.8 Hz, 1 H), 7.45 (t, J = 8.4 Hz, 1 H), 7.06 (d, J =7.6 Hz, 1 H), 6.74 (d, J =8.4 Hz, 1 H), 5.31 (s, 2 H), 5.10-5.08 (m, 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 = 1.63-1.60 (m, 2 H).

[0208] Example 3 Preparation of the hydrochloride salt of compound I-1 20 mg of compound I-1 was added to 1 mL of acetonitrile, 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 salt of compound I-1. The product was characterized by XRPD (Figure 1).

[0209] Example 4 Preparation of the tartrate salt of compound I-1 20 mg of compound I-1 was added to 1 mL of acetonitrile, 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 (Figure 2).

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

[0211] Example 6 Preparation of the maleate salt of compound I-1 20 mg of compound I-1 was added to 1 mL of acetonitrile, 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 (Figure 6).

[0212] Example 7 Preparation of methanesulfonic acid salt of compound I-1 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 methanesulfonic acid salt of compound I-1. The product was characterized by XRPD (Figure 7).

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

[0214] Example 9 Preparation of potassium salt of compound I-1 20 mg of compound I-1 was added to 0.4 mL of methyl isobutyl ketone, 2.3 mg of potassium hydroxide was added, and the mixture was stirred at room temperature for 3 days. The mixture was filtered, and the filter cake was dried in an oven 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 (FIG. 11).

[0215] Example 10 Preparation of potassium salt of compound I-1 20 mg of compound I-1 was added to 0.4 mL of acetonitrile, 2.3 mg of potassium hydroxide was added, and the mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filter cake was dried in an oven 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 (FIG. 12).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0231] [Table 12]

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

[0233] Example 26: Solubility studies of compound tromethamine salts in other media The equilibrium solubilities of free compounds I-1 and I-2 and their representative tromethamine salts in simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated fed intestinal fluid (FeSSIF) were measured. In the test, the solids were suspended in the corresponding buffer solution (~10 mg / mL) and stirred at 37±2°C. After 24 hours, the suspensions were sampled, the supernatants filtered, and the concentrations were measured. The test results are shown in the table below.

[0234] [Table 13]

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

[0236] Example 27 Moisture absorption behavior measurement The hygroscopic behavior of a compound affects the manufacturing, storage, stability, and quality of a drug. The inventors used the dynamic moisture sorption method to evaluate the stability risk of a sample due to changes in humidity at 25°C. DVS measurements were performed on tromethamine salts, which are representative salt forms of compounds I-1 and I-2, to evaluate the hygroscopicity of the compound salt forms. The DVS patterns of free compound I-1 are shown in Figure 39, free compound I-2 are shown in Figure 40, tromethamine salt of compound I-1 is shown in Figure 41, and tromethamine salt of compound I-2 is shown in Figure 42. The results are shown in the following table.

[0237] [Table 14]

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

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

[0240] [Table 15]

[0241] The above is an illustrative description of the embodiments of the technical solution of the present invention. It should be understood that the scope of the claims of the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the scope of the spirit and principle of the present invention should be included within the scope of the claims of the present application. [Brief explanation of the drawings]

[0242] [Figure 1] 1 shows the X-ray powder diffraction pattern of the hydrochloride salt of compound I-1 of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity. [Figure 2] 1 shows the X-ray powder diffraction pattern of the tartrate salt of compound I-1 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 3] 1 shows the X-ray powder diffraction pattern of the citrate salt of compound I-1 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 4] 1 shows the DSC pattern of the citrate salt of compound I-1 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 5] 1 shows the TGA pattern of the citrate salt of compound I-1 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 6] 1 shows the X-ray powder diffraction pattern of the maleate salt of compound I-1 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 7] 1 shows the X-ray powder diffraction pattern of the methanesulfonate salt of compound I-1 of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity. [Figure 8] 1 shows the X-ray powder diffraction pattern of the sodium salt of compound I-1 of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity. [Figure 9] 1 shows the DSC pattern of the sodium salt of compound I-1 of the present invention, where the abscissa represents the temperature (° C.) and the ordinate represents the heat flow (mW). [Figure 10] 1 shows the TGA pattern of sodium of compound I-1 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 11] 1 shows the X-ray powder diffraction pattern of the crystalline form A of the potassium salt of compound I-1 of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity. [Figure 12] 1 shows the X-ray powder diffraction pattern of the crystalline form B of the potassium salt of compound I-1 of the present invention, where the abscissa indicates the 2θ value (degrees) and the ordinate indicates the peak intensity. [Figure 13] 1 shows the X-ray powder diffraction pattern of the meglumine salt of compound I-1 of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 14] 1 shows the DSC pattern of the meglumine salt of compound I-1 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 15] 1 shows the TGA pattern of the meglumine salt of compound I-1 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 16] 1 shows the X-ray powder diffraction pattern of the tromethamine salt of compound I-1 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 17] 1 shows the DSC pattern of the tromethamine salt of compound I-1 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 18] 1 shows the TGA pattern of the tromethamine salt of compound I-1 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 19] 1 shows the X-ray powder diffraction pattern of the citrate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 20] 1 shows the X-ray powder diffraction pattern of the malate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 21] 1 shows the X-ray powder diffraction pattern of the tartrate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 22] 1 shows the X-ray powder diffraction pattern of the fumarate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 23] 1 shows the X-ray powder diffraction pattern of the methanesulfonate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 24] 1 shows the X-ray powder diffraction pattern of the maleate salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 25] 1 shows the DSC pattern of the maleate salt of compound I-2 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 26] 1 shows the TGA pattern of the maleate salt of compound I-2 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 27] 1 shows the X-ray powder diffraction pattern of the sodium salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 28] 1 shows the X-ray powder diffraction pattern of the potassium salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 29] 1 shows the DSC pattern of the potassium salt of compound I-2 of the present invention, where the abscissa represents the temperature (° C.) and the ordinate represents the heat flow (mW). [Figure 30] 1 shows the TGA pattern of the potassium salt of compound I-2 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 31] 1 shows the X-ray powder diffraction pattern of the calcium salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 32] 1 shows the X-ray powder diffraction pattern of the magnesium salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 33] 1 shows the X-ray powder diffraction pattern of the meglumine salt of compound I-2 of the present invention, where the abscissa represents the 2θ value (degrees) and the ordinate represents the peak intensity. [Figure 34] 1 shows the DSC pattern of the meglumine salt of compound I-2 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 35] 1 shows the TGA pattern of the meglumine salt of compound I-2 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 36] 1 shows the X-ray powder diffraction pattern of the tromethamine salt of compound I-2 of the present invention, where the abscissa indicates 2θ values ​​(degrees) and the ordinate indicates peak intensity. [Figure 37] 1 shows the DSC pattern of the tromethamine salt of compound I-2 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents heat flow (mW). [Figure 38] 1 shows the TGA pattern of the tromethamine salt of compound I-2 of the present invention, where the abscissa represents temperature (° C.) and the ordinate represents weight (%). [Figure 39] 1 shows the DVS pattern of compound I-1 of the present invention, where the abscissa represents relative humidity (%) and the ordinate represents weight change (%). [Figure 40] 1 shows the DVS pattern of compound I-2 of the present invention, where the abscissa represents relative humidity (%) and the ordinate represents weight change (%). [Figure 41] 1 shows the DVS pattern of the tromethamine salt of compound I-1 of the present invention, where the abscissa represents relative humidity (%) and the ordinate represents weight change (%). [Figure 42] 1 shows the DVS pattern of the tromethamine salt of compound I-2 of the present invention, where the abscissa represents relative humidity (%) and the ordinate represents weight change (%).

Claims

1. The tromethamine salt of compound I-1 or the tromethamine salt of compound I-2. 【Chemistry 1】

2. The crystalline form A of the tromethamine salt of compound I-1 according to claim 1, wherein its X-ray powder diffraction pattern (XRPD) comprises peaks located at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2° and 22.19±0.2°. Crystalline form A of the tromethamine salt of compound I-1.

3. Its X-ray powder diffraction pattern (XRPD) contains peaks located at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2°, 22.19±0.2°, 31.61±0.2°, 18.11±0.2° and 20.55±0.2°. Crystalline form A of the tromethamine salt of compound I-1 according to claim 2.

4. The X-ray powder diffraction pattern has the diffraction angles (2θ) shown in Table 6, wherein the error range of the 2θ angles is ±0.20°. Table 1 Crystalline form A of the tromethamine salt of compound I-1 according to claim 2.

5. The crystalline form A of the tromethamine salt has X-ray powder diffraction intensities as shown in Table 6. Crystalline form A of the tromethamine salt of compound I-1 according to claim 4.

6. The crystalline form A of the tromethamine salt has a DSC thermogram with endothermic peaks at temperatures of 109.95°C and 166.02°C. Crystalline form A of the tromethamine salt of compound I-1 according to claim 2.

7. The crystalline form A of the tromethamine salt is an N-methylpyrrolidone solvate. Crystalline form A of the tromethamine salt of compound I-1 according to claim 2.

8. The crystalline form A of the tromethamine salt of compound I-2 according to claim 1, wherein the X-ray powder diffraction pattern (XRPD) contains peaks at diffraction angles (2θ) of 3.68±0.2°, 7.48±0.2°, 17.21±0.2° and 19.15±0.2°. Crystalline Form A of the tromethamine salt of compound I-2.

9. Its X-ray powder diffraction pattern (XRPD) contains peaks located at diffraction angles (2θ) of 3.68±0.2°, 7.48±0.2°, 17.21±0.2°, 19.15±0.2°, 16.73±0.2° and 15.74±0.2°. Crystalline form A of the tromethamine salt of compound I-2 according to claim 8.

10. The X-ray powder diffraction pattern has the diffraction angles (2θ) shown in Table 11, wherein the error range of the 2θ angles is ±0.20°. Table 2 Crystalline form A of the tromethamine salt of compound I-2 according to claim 8.

11. The crystalline form A of the tromethamine salt has X-ray powder diffraction intensities as shown in Table 11. Crystalline form A of the tromethamine salt of compound I-2 according to claim 10.

12. The crystalline form A of the tromethamine salt has a DSC thermogram with an endothermic peak at a temperature of 167.96°C. Crystalline form A of the tromethamine salt of compound I-2 according to claim 8.

13. A method for producing the tromethamine salt of compound I-1 or the tromethamine salt of compound I-2, crystalline form A, according to any one of claims 1 to 12, comprising the steps of: The method for preparing the tromethamine salt of compound I-1 is as follows: Compound I-1 and tromethamine are dissolved in N-methylpyrrolidone, and then the solution is added to toluene, stirred at room temperature, filtered, and dried to obtain the tromethamine salt of compound I-1, wherein the volume ratio of N-methylpyrrolidone to toluene is 2:15; The method for preparing the tromethamine salt of compound I-2 is as follows: dissolving compound I-2 and tromethamine in isopropanol, stirring at room temperature, and then filtering and drying to obtain the tromethamine salt of compound I-2; the molar ratio of compound I-1 or I-2 to tromethamine is 1:0.8 to 1:2, or 1:0.9 to 1:1.8; Manufacturing method.

14. A pharmaceutical composition comprising at least one of the tromethamine salt of compound I-1 or the tromethamine salt of compound I-2, crystalline form A, according to any one of claims 1 to 12, and a pharmaceutically acceptable carrier.

15. Use of at least one of the tromethamine salt of compound I-1 or the tromethamine salt of compound I-2, crystalline form A, according to any one of claims 1 to 12, in the manufacture of a medicament for treating a metabolic disease, a tumor, an autoimmune disease or a metastatic disease.

16. The disease is T1D, T2DM, prediabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to use of other medications, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NAS, fibrosis, sclerosis, 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, extravascular selected from traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, vascular restenosis, glucose metabolism disorders, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcer, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome; 16. The use according to claim 15.

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