Salts of glp-1r agonists and methods of making and using the same

Abstract

This invention relates to the salt form of GLP-1R agonist compound I, its preparation method, and its applications. The salt of this invention exhibits excellent GLP-1R agonist activity and good bioavailability in animals, making it suitable for preparing formulations for treating metabolic diseases, tumors, autoimmune diseases, or metastatic diseases.

Description

Technical Field

[0001] This invention belongs to the field of drug development, specifically relating to a salt of a GLP-1R agonist, its preparation method, and its application. Background Technology

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

[0003] Currently, various pharmacological approaches are used to treat hyperglycemia and its associated type 2 diabetes mellitus (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 acting 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 β-cells. Sulfonylureas have limited efficacy and tolerability, causing weight gain and often inducing hypoglycemia. PP-IV inhibitors have limited efficacy. Commercially available GLP-1R agonists are subcutaneously administered peptides. Liraglutide is also approved for the treatment of obesity.

[0005] Biguanides (such as metformin) are thought to work primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal discomfort and lactic acidosis, which further limits their use.

[0006] Alpha-glucosidase inhibitors (such as acarbose) reduce intestinal glucose absorption. These medications often cause gastrointestinal discomfort.

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

[0008] Insulin, alone or in combination with the above-mentioned drugs, is used for more severe cases, and frequent use may also lead to weight gain and carry the risk of hypoglycemia.

[0009] Inhibitors of the sodium-glucose-linking transporter cotransporter 2 (SGLT2) (such as dapagliflozin, empagliflozin, canagliflozin, and ertugliflozin) inhibit the reabsorption of glucose in the kidneys and thus lower blood glucose levels. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

[0010] However, apart from GLP-1R agonists and SGLT2 inhibitors, these drugs have limited efficacy and do not address the most important issues: β-cell dysfunction and associated obesity. Therefore, there is a need for more effective drug interventions with fewer side effects and easier administration.

[0011] GLP-1 is a 30-amino acid-long incretin hormone secreted by L cells in the gut 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 non-clinical studies, GLP-1 has been shown to promote sustained β-cell capacity by stimulating the transcription of genes important for glucose-dependent insulin secretion and by promoting β-cell regeneration (Meier et al., Biodrugs. 17(2):93-102, 2013).

[0012] In healthy individuals, GLP-1 plays a crucial role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion from the pancreas, thereby increasing peripheral glucose uptake. GLP-1 also inhibits glucagon secretion, reducing hepatic glucose excretion. Additionally, GLP-1 delays gastric emptying and slows small intestinal motility, thus delaying food absorption. In individuals with type 2 diabetes mellitus (T2DM), postprandial GLP-1 levels do not rise normally or rise less significantly (Vilsbol1 et al., Diabetes 50609-613, 2001).

[0013] Scientific research has led to the modification and alteration of the structure of GLP-1 to increase its half-life and thus prolong its biological effects in vivo. However, currently available long-acting GLP-1 analogs such as liraglutide and exenatide are all peptides, and frequent, repeated injections result in poor patient compliance. Therefore, the development of small-molecule GLP-1R agonists, aiming to improve patient compliance, ease of administration, and reduce drug side effects, has broad clinical market prospects.

[0014] 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]

[0016] These compounds can significantly enhance the agonistic effect of the GLP-1R target, increase the therapeutic window, reduce clinical toxicity and side effects, and meet the current domestic and international needs for diabetes treatment.

[0017] 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-(oxacyclobutane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid.

[0018] 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-(oxacyclobutane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid.

[0019] The successful development of pharmaceutical solid forms of compound I-1 or compound I-2 typically requires properties such as being a solid form that can be easily separated and purified after synthesis, being suitable for large-scale manufacturing, being able to be stored for a long period of time and having minimal absorption of water, decomposition or conversion into other solid forms, and being suitable for dosage forms that can be rapidly absorbed by the individual after administration (such as being soluble in water and gastric juice).

[0020] To meet the needs of clinical research and marketed drug formulations, there is an urgent need to develop a drug solid form that can be easily separated and purified, is suitable for industrial production, and has stable physicochemical properties. Summary of the Invention

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

[0022]

[0023] R is selected from halogen or CN.

[0024] According to an embodiment of the present invention, the compound represented by formula (I) is selected from the following compounds I-1 or I-2;

[0025]

[0026] According to an embodiment of the present invention, the pharmaceutically acceptable salt refers to an acid addition salt or a base addition salt that is pharmaceutically non-toxic;

[0027] According to embodiments of the present invention, the acid addition salt is a salt formed by the compound of formula (I) and an inorganic or organic acid, including hydrobromide, hydrochloride, sulfate, hydrogen sulfate, sulfite, phosphate, borate, acetate, oxalate, valerate, benzoate, lactate, toluene, citrate, malate, maleate, fumarate, succinate, tartrate, methanesulfonate, benzenesulfonate, and p-toluenesulfonate; more preferably, the acid addition salt is hydrochloride, acetate, citrate, malate, succinate, tartrate, fumarate, maleate, and methanesulfonate; particularly citrate and maleate;

[0028] According to embodiments of the present invention, the base addition salt is a salt formed by the compound of formula (I) with an inorganic or 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 preferably, the base addition salts are sodium salts, potassium salts, calcium salts, magnesium salts, meglumine salts, choline salts, tromethamine salts; particularly sodium salts, potassium salts, magnesium salts, meglumine salts and tromethamine salts.

[0029] According to an embodiment of the present invention, the acid addition salt of compound I-1 is hydrochloride, tartrate, maleate, methanesulfonate, or citrate; the acid addition salt of compound I-2 is citrate, tartrate, malate (such as L-malate), fumarate, methanesulfonate, or maleate.

[0030] According to an embodiment of the present invention, the base addition salt of compound I-1 is a sodium salt, potassium salt, meglumine salt, or tromethamine salt; the base addition salt of compound I-2 is a sodium salt, potassium salt, calcium salt, magnesium salt, meglumine salt, or tromethamine salt.

[0031] According to a preferred embodiment of the present invention, the present invention provides a citrate crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 19.77±0.2°, 16.59±0.2°, 22.47±0.2° and 20.20±0.2°.

[0032] According to a preferred embodiment of the present invention, the X-ray powder diffraction (XRPD) pattern of citrate crystal form A of compound I-1 includes peaks located at diffraction angles (2θ) of 16.59±0.2°, 19.77±0.2°, 22.47±0.2°, 20.20±0.2°, 24.84±0.2° and 17.51±0.2°.

[0033] Preferably, the citrate crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 1, wherein the error range of the 2θ angle is ±0.20°.

[0034] Table 1

[0035]

[0036]

[0037] Preferably, the citrate crystal form A has the X-ray powder diffraction intensity shown in Table 1.

[0038] Preferably, the citrate crystal form A has essentially the following properties: Figure 3 The X-ray powder diffraction pattern shown.

[0039] Preferably, the citrate crystal form A has a DSC thermogram with endothermic peaks at temperatures of approximately 107.80°C and 130.63°C.

[0040] Preferably, the citrate crystal form A has essentially the following properties: Figure 4 The DSC diagram shown.

[0041] Preferably, the citrate crystal form A has essentially the following properties: Figure 5 The TGA diagram shown.

[0042] As a further preferred embodiment, the present invention provides sodium salt crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of 19.24±0.2°, 20.68±0.2°, 6.81±0.2°, and 14.43±0.2°.

[0043] As a further preferred embodiment, the present invention provides a sodium salt crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 19.24±0.2°, 20.68±0.2°, 6.81±0.2°, 14.43±0.2°, 14.98±0.2° and 6.40±0.2°.

[0044] Preferably, the sodium salt crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 2, wherein the error range of the 2θ angle is ±0.20°.

[0045] Table 2

[0046] 2θ(°) strength% 2θ(°) strength% 4.07 36.4 18.02 40.9 6.40 47.5 19.24 100.0 6.81 55.0 20.68 90.1 14.43 53.3 24.27 34.3 14.98 52.1 24.84 29.8 17.69 37.6 26.44 26.4

[0047] Preferably, the sodium salt crystal form A has the X-ray powder diffraction intensity shown in Table 2.

[0048] Preferably, the sodium salt crystal form A has essentially the following properties: Figure 8 The X-ray powder diffraction pattern shown.

[0049] Preferably, the sodium salt crystal form A has a DSC thermogram with endothermic peaks at temperatures of approximately 149.11°C and 174.11°C.

[0050] Preferably, the sodium salt crystal form A has essentially the following properties: Figure 9 The DSC diagram shown.

[0051] Preferably, the sodium salt crystal form A has essentially the following properties: Figure 10 The TGA diagram shown.

[0052] As a further preferred embodiment, the present invention provides a potassium salt crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of 13.90±0.2°, 14.43±0.2°, 16.20±0.2°, and 11.67±0.2°.

[0053] As a further preferred embodiment, the present invention provides a potassium salt crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern 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°.

[0054] Preferably, the potassium salt crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 3, wherein the error range of the 2θ angle is ±0.20°.

[0055] Table 3

[0056] 2θ(°) strength% 2θ(°) strength% 5.80 23.5 18.95 31.1 6.60 36.0 20.39 33.9 8.76 4.8 20.99 47.4 9.99 32.7 21.95 39.3 11.67 49.1 23.06 29.2 12.11 21.0 23.62 39.0 13.42 37.7 24.91 32.8 13.90 100.0 25.45 15.2 14.43 96.1 26.39 21.0 16.20 70.6 27.80 8.3 16.79 45.8 32.76 7.2 17.25 13.5

[0057] Preferably, the potassium salt crystal form A has the X-ray powder diffraction intensity shown in Table 3.

[0058] Preferably, the potassium salt crystal form A has essentially the following properties: Figure 11 The X-ray powder diffraction pattern shown.

[0059] As a further preferred embodiment, the present invention provides a potassium salt crystal form B of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of 5.92±0.2°, 14.10±0.2°, 17.62±0.2°, and 17.94±0.2°.

[0060] As a further preferred embodiment, the present invention provides a potassium salt crystal form B of compound I-1, whose X-ray powder diffraction (XRPD) pattern 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°.

[0061] Preferably, the potassium salt crystal form B has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 4, wherein the error range of the 2θ angle is ±0.20°.

[0062] Table 4

[0063] 2θ(°) strength% 2θ(°) strength% 5.92 100.0 20.12 11.0 7.01 40.3 20.69 17.8 8.74 22.1 20.90 20.8 9.56 11.0 21.84 39.4 10.92 19.2 22.24 31.4 11.92 70.3 23.33 18.4 12.27 17.2 24.01 23.3 14.10 95.8 25.17 13.2 15.19 28.1 25.69 17.4 15.64 19.5 26.68 15.6 16.94 19.8 27.09 10.0 17.62 89.6 28.38 6.7 17.94 80.4 29.37 8.5 18.74 20.7 32.02 8.9

[0064] Preferably, the potassium salt crystal form B has the X-ray powder diffraction intensity shown in Table 4.

[0065] Preferably, the potassium salt crystal form B has essentially the following properties: Figure 12 The X-ray powder diffraction pattern shown.

[0066] As a further preferred embodiment, the present invention provides a meglumine salt crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of 18.15±0.2°, 12.87±0.2°, 22.87±0.2° and 24.66±0.2°.

[0067] As a further preferred embodiment, the present invention provides a meglumine salt crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 18.15±0.2°, 12.87±0.2°, 22.87±0.2°, 24.66±0.2°, 23.21±0.2° and 19.57±0.2°.

[0068] Preferably, the meglumine salt crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 5, wherein the error range of the 2θ angle is ±0.20°.

[0069] Table 5

[0070] 2θ(°) strength% 2θ(°) strength% 5.221 28.9 17.26 15.5 7.57 9.0 18.15 100.0 9.42 16.1 19.57 43.7 10.23 10.0 21.39 21.9 10.71 20.6 22.87 55.0 11.84 21.6 23.21 44.4 12.87 68.1 24.66 49.5 15.48 16.0 25.77 13.4

[0071] Preferably, the meglumine salt crystal form A has the X-ray powder diffraction intensity shown in Table 5.

[0072] Preferably, the meglumine salt crystal form A has essentially the following properties: Figure 13 The X-ray powder diffraction pattern shown.

[0073] Preferably, meglumine salt crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 120.06°C.

[0074] Preferably, the meglumine salt crystal form A has essentially the following properties: Figure 14 The DSC diagram shown.

[0075] Preferably, the meglumine salt crystal form A has essentially the following properties: Figure 15 The TGA diagram shown.

[0076] As a further preferred embodiment, the present invention provides an aminobutadiene triol salt crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2° and 22.19±0.2°.

[0077] As a further preferred embodiment, the present invention provides anabrominated triol salt crystal form A of compound I-1, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2°, 22.19±0.2°, 31.61±0.2°, 18.11±0.2°, and 20.55±0.2°.

[0078] As the most preferred embodiment, the X-ray powder diffraction data of the tromethamine salt crystal form A are shown in Table 6 below:

[0079] Table 6

[0080]

[0081]

[0082] Preferably, the tromethamine crystal form A has the X-ray powder diffraction intensity shown in Table 6. Preferably, the tromethamine crystal form A has essentially the following... Figure 16 The X-ray powder diffraction pattern shown.

[0083] Preferably, the tromethamine crystal form A has a DSC thermogram with endothermic peaks at temperatures of approximately 109.95°C and 166.02°C.

[0084] Preferably, the tromethamine salt crystal form A has essentially the following properties: Figure 17 The DSC diagram shown.

[0085] Preferably, the tromethamine salt crystal form A has essentially the following properties: Figure 18 The TGA diagram shown.

[0086] Preferably, the tromethamine salt crystal form A is in the form of an N-methylpyrrolidone solvate.

[0087] As a further preferred embodiment, the present invention provides maleate crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 5.43±0.2°, 9.89±0.2°, 12.76±0.2° and 8.30±0.2°.

[0088] As a further preferred embodiment, the present invention provides maleate crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 5.43±0.2°, 9.89±0.2°, 12.76±0.2°, 8.30±0.2°, 21.31±0.2° and 14.24±0.2°.

[0089] Preferably, the maleate crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 7, wherein the error range of the 2θ angle is ±0.20°.

[0090] Table 7

[0091]

[0092]

[0093] Preferably, the maleate crystal form A has the X-ray powder diffraction intensity shown in Table 7.

[0094] Preferably, the maleate crystal form A has essentially the following properties: Figure 24 The X-ray powder diffraction pattern shown.

[0095] Preferably, the maleate crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 119.30°C.

[0096] Preferably, the maleate crystal form A has essentially the following properties: Figure 25 The DSC diagram shown.

[0097] Preferably, the maleate crystal form A has essentially the following properties: Figure 26 The TGA diagram shown.

[0098] As a further preferred embodiment, the present invention provides a potassium salt crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 11.51±0.2°, 15.42±0.2°, 20.20±0.2°, and 9.52±0.2°.

[0099] As a further preferred embodiment, the present invention provides a potassium salt crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern 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°.

[0100] Preferably, the potassium salt crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 8, wherein the error range of the 2θ angle is ±0.20°.

[0101] Table 8

[0102] 2θ(°) strength% 2θ(°) strength% 5.06 14.2 17.41 6.1 7.67 11.2 19.14 3.1 9.52 15.5 20.20 25.1 11.51 100.0 21.45 4.8 13.86 4.0 25.38 12.0 15.42 59.8

[0103] Preferably, the maleate crystal form A has the X-ray powder diffraction intensity shown in Table 8.

[0104] Preferably, the potassium salt crystal form A has essentially the following properties: Figure 28 The X-ray powder diffraction pattern shown.

[0105] Preferably, the potassium salt crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 118.44°C.

[0106] Preferably, the potassium salt crystal form A has essentially the following properties: Figure 29 The DSC diagram shown.

[0107] Preferably, the potassium salt crystal form A has essentially the following properties: Figure 30The TGA diagram shown.

[0108] As a further preferred embodiment, the present invention provides a magnesium salt crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 13.92±0.2°, 13.46±0.2°, 14.74±0.2°, and 20.43±0.2°.

[0109] As a further preferred embodiment, the present invention provides a magnesium salt crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern 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°.

[0110] Preferably, the magnesium salt crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 9, wherein the error range of the 2θ angle is ±0.20°.

[0111] Table 9

[0112] 2θ(°) strength% 2θ(°) strength% 4.55 9.6 15.84 17.8 6.65 4.5 16.10 10.5 7.14 4.7 17.21 23.0 7.87 4.2 18.76 8.7 9.83 5.5 20.16 23.7 11.04 5.7 20.43 26.3 11.63 6.0 20.92 11.3 12.97 7.6 22.29 6.3 13.46 54.8 22.63 5.9 13.92 100.0 24.21 4.5 14.74 28.7 25.26 11.1 15.37 5.9 25.89 6.6

[0113] Preferably, the magnesium salt crystal form A has the X-ray powder diffraction intensity shown in Table 9.

[0114] Preferably, the magnesium salt crystal form A has essentially the following properties: Figure 32 The X-ray powder diffraction pattern shown.

[0115] As a further preferred embodiment, the present invention provides a meglumine salt crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of 3.05±0.2°, 9.38±0.2°, 17.62±0.2° and 12.01±0.2°.

[0116] As a further preferred embodiment, the present invention provides a meglumine salt crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 3.05±0.2°, 9.38±0.2°, 17.62±0.2°, 12.01±0.2°, 20.39° and 14.88±0.2°.

[0117] Preferably, the meglumine salt crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 10, wherein the error range of the 2θ angle is ±0.20°.

[0118] Table 10

[0119]

[0120]

[0121] Preferably, the meglumine salt crystal form A has the X-ray powder diffraction intensity shown in Table 10.

[0122] Preferably, the meglumine salt crystal form A has essentially the following properties: Figure 33 The X-ray powder diffraction pattern shown.

[0123] Preferably, the meglumine salt crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 123.07°C.

[0124] Preferably, the meglumine salt crystal form A has essentially the following properties: Figure 34 The DSC diagram shown.

[0125] Preferably, the meglumine salt crystal form A has essentially the following properties: Figure 35 The TGA diagram shown.

[0126] As a further preferred embodiment, the present invention provides an aminobutadiene trioxide crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 3.68±0.2°, 7.48±0.2°, 17.21±0.2° and 19.15±0.2°.

[0127] As a further preferred embodiment, the present invention provides anabrominated triol salt crystal form A of compound I-2, whose X-ray powder diffraction (XRPD) pattern includes peaks located at diffraction angles (2θ) of 3.68±0.2°, 7.48±0.2°, 17.21±0.2°, 19.15±0.2°, 16.73±0.2° and 15.74±0.2°.

[0128] Preferably, the tromethamine crystal form A has an X-ray powder diffraction pattern with diffraction angles (2θ) as shown in Table 11, wherein the error range of the 2θ angle is ±0.20°.

[0129] Table 11

[0130] 2θ(°) strength% 2θ(°) strength% 3.68 100.0 19.15 9.6 7.48 51.3 20.18 3.3 14.82 7.2 21.95 3.9 15.74 9.0 22.67 4.9 16.73 9.2 24.66 4.0 17.21 12.7 27.68 4.3

[0131] Preferably, the aminobutadiene trioxide crystal form A has the X-ray powder diffraction intensity shown in Table 11.

[0132] Preferably, the tromethamine salt crystal form A has essentially the following properties: Figure 36 The X-ray powder diffraction pattern shown.

[0133] Preferably, the tromethamine crystal form A has a DSC thermogram with an endothermic peak at a temperature of about 167.96°C.

[0134] Preferably, the tromethamine salt crystal form A has essentially the following properties: Figure 37 The DSC diagram shown.

[0135] Preferably, the tromethamine salt crystal form A has essentially the following properties: Figure 38 The TGA diagram shown.

[0136] A second aspect of the present invention provides a method for preparing 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 base in a solvent to prepare a pharmaceutically acceptable salt of compound I-1 or compound I-2.

[0137] According to an embodiment of the present invention, the acid is selected from inorganic acids or organic acids. The inorganic acid may be selected from hydrobromic acid, hydrochloric acid, sulfuric acid, sulfurous acid, phosphoric acid, and boric acid; the organic acid may be selected from acetic acid, oxalic acid, valeric acid, benzoic acid, lactic acid, tolueneic acid, citric acid, malic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0138] According to an embodiment of the present invention, the base is selected from inorganic bases or organic bases. The inorganic base may be selected from alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide. The organic base may be selected from ammonia (NH3), primary amines, secondary amines, or tertiary amines, such as tetramethylamine salt, tetraethylamine salt, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, meglumine, choline, and tromethamine.

[0139] 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. The method of creating supersaturation includes one or more of the following: adding seed crystals, evaporating solvent, adding antisolvent, or obtaining an acidic or basic salt of compound I by cooling.

[0140] According to an embodiment of the present invention, the solvent may be selected from alcohols, chloroalkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sulfoxides, nitriles, organic solvents, combinations of two or more of the solvents, or mixtures of the above solvents or combinations with water.

[0141] According to embodiments of the present invention, the ketones may be selected from ketones having 3-10 carbon atoms, such as acetone, butanone, pentanone, methyl ethyl ketone, methyl isobutyl ketone, 4-methyl-2-pentanone, or combinations thereof; the nitrile may be selected from acetonitrile; the alcohol may be selected from alcohols or haloalcohols having 1-8 carbon atoms, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentanol, trifluoroethanol, or combinations thereof; the ester may be selected from organic formate esters, such as methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, or combinations thereof; the ether may be a straight-chain or branched alkyl ether or a cyclic ether compound, such as methyl tert-butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, or combinations thereof; and the chlorine may be selected from dichloromethane, chloroform, and 1,2-dichloroethane.

[0142] 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 mixtures thereof.

[0143] According to an embodiment of the present invention, the molar ratio of compound I-1 or I-2 to the acid or base can 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.

[0144] 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℃ to 80℃, preferably 25℃ to 60℃.

[0145] According to an embodiment of the present invention, the preparation method further includes a step of filtration and / or drying after the reaction is completed, to prepare a pharmaceutically acceptable salt of compound I-1 or compound I-2.

[0146] According to an embodiment of the present invention, in the preparation method, the drying temperature can be selected within a wide range, for example, 20℃ to 80℃, preferably 30℃ to 60℃.

[0147] This invention also provides a method for preparing a pharmaceutically acceptable salt of compound I-1:

[0148] 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 hydrochloride, tartrate, maleate or methanesulfonate of compound I-1.

[0149] Method 1b includes: dissolving compound I-1 and citric acid in acetone, stirring at room temperature, filtering, and drying to obtain citrate of compound I-1;

[0150] 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 or potassium salt of compound I-1;

[0151] Method 1d includes: dissolving compound I-1 and meglumine in acetonitrile, stirring at room temperature, filtering, and drying to obtain the meglumine salt of compound I-1;

[0152] Method 1e includes: 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, the volume ratio of N-methylpyrrolidone to toluene is 2:15.

[0153] This invention also provides a method for preparing a pharmaceutically acceptable salt of compound I-2:

[0154] 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 citrate or tartrate of compound I-2;

[0155] 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 malate or fumarate of compound I-2; preferably, the volume ratio of acetonitrile / water is 1:1.

[0156] 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 methanesulfonate or maleate of compound I-2;

[0157] 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 sodium salt, potassium salt, calcium salt and magnesium salt of compound I-2; preferably, the volume ratio of acetonitrile / water is 1:1.

[0158] Method 2e includes: dissolving compound I-2 and meglumine in acetone, stirring at room temperature, filtering, and drying to obtain the meglumine salt of compound I-2;

[0159] Method 2f includes: dissolving compound I-2 and tromethamine in isopropanol, stirring at room temperature, filtering, and drying to obtain the tromethamine salt of compound I-2.

[0160] 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) and a pharmaceutically acceptable carrier.

[0161] The fourth aspect of the present invention provides the use of at least one of the pharmaceutically acceptable salts of the compounds shown in formula (I) in the preparation of medicaments for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0162] The fifth aspect of the present invention provides a pharmaceutically acceptable salt of the compound shown in formula (I) above, which is used as a medicament for treating metabolic diseases, tumors, autoimmune diseases or metastatic diseases.

[0163] The sixth aspect of the present invention provides a pharmaceutically acceptable salt of the compound shown in formula (I) above, 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, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipocyte accumulation, sleep apnea, obesity, eating disorders, weight gain due to the use of other agents, excessive sugar consumption, 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, and myocardial infarction. This medication is indicated for the prevention or treatment of stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, and polycystic ovary syndrome, as well as for the treatment of addiction.

[0164] As a preferred option, a pharmaceutically acceptable salt of the compound shown in 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 due to the use of other drugs, excessive sugar cravings, dyslipidemia, and hyperinsulinemia.

[0165] The present invention also provides a method for treating a disease, comprising administering to an individual in need a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) as described above or at least one of the pharmaceutical compositions.

[0166] According to an embodiment of the present invention, the disease is selected from metabolic diseases, tumors, autoimmune diseases, or metastatic diseases.

[0167] According to embodiments of the present invention, the diseases are 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 due to the use of other drugs, excessive sugar consumption, 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, and stroke. Hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome XI, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, impaired fasting glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue abnormalities, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome.

[0168] Beneficial effects

[0169] The inventors of this invention studied various acidic or basic salts of compound I. This salt-forming form greatly improves the physicochemical properties of compound I, such as solubility, hygroscopicity, and chemical stability. The raw materials of the salt-type compounds meet the requirements of industrial production and can meet the needs of clinical drug formulation development. They have very important clinical application value and are expected to accelerate the development into a new generation of GLP-1R small molecule agonists. Attached Figure Description

[0170] Figure 1 The X-ray powder diffraction pattern of the hydrochloride salt of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0171] Figure 2 The X-ray powder diffraction pattern of the tartrate salt of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0172] Figure 3 The X-ray powder diffraction pattern of the citrate salt of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0173] Figure 4 The DSC plot of the citrate of compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0174] Figure 5 The TGA graph of the citrate of compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0175] Figure 6 The X-ray powder diffraction pattern of the maleate salt of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0176] Figure 7 The X-ray powder diffraction pattern of the methanesulfonate of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0177] Figure 8 The X-ray powder diffraction pattern of the sodium salt of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0178] Figure 9 The DSC plot of the sodium salt of compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0179] Figure 10The TGA graph of sodium in compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0180] Figure 11 The X-ray powder diffraction pattern of potassium salt crystal form A of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0181] Figure 12 The X-ray powder diffraction pattern of potassium salt form B of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0182] Figure 13 The X-ray powder diffraction pattern of the meglumine salt of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0183] Figure 14 The DSC plot of the meglumine salt of compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0184] Figure 15 The TGA chromatogram of the meglumine salt of compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0185] Figure 16 The X-ray powder diffraction pattern of the aminobutadiene trioxide salt of compound I-1 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0186] Figure 17 The DSC plot of the aminobutadiene trioxide salt of compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0187] Figure 18 The TGA graph of the tromethamine salt of compound I-1 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0188] Figure 19 The X-ray powder diffraction pattern of the citrate salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0189] Figure 20 The X-ray powder diffraction pattern of the malate of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0190] Figure 21The X-ray powder diffraction pattern of the tartrate salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0191] Figure 22 The X-ray powder diffraction pattern of the fumarate of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0192] Figure 23 The X-ray powder diffraction pattern of the methanesulfonate of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0193] Figure 24 The X-ray powder diffraction pattern of the maleate salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0194] Figure 25 The DSC plot of the maleate salt of compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0195] Figure 26 The TGA graph of the maleate of compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0196] Figure 27 The X-ray powder diffraction pattern of the sodium salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0197] Figure 28 The X-ray powder diffraction pattern of the potassium salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0198] Figure 29 The DSC plot of the potassium salt of compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0199] Figure 30 The TGA graph of the potassium salt of compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0200] Figure 31 The X-ray powder diffraction pattern of the calcium salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0201] Figure 32The X-ray powder diffraction pattern of the magnesium salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0202] Figure 33 The X-ray powder diffraction pattern of the meglumine salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0203] Figure 34 The DSC plot of the meglumine salt of compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0204] Figure 35 The TGA chromatogram of the meglumine salt of compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0205] Figure 36 The X-ray powder diffraction pattern of the aminobutadiene trioxide salt of compound I-2 of the present invention is shown. The horizontal axis represents the 2θ value (degrees), and the vertical axis represents the peak intensity.

[0206] Figure 37 The DSC plot of the aminobutadiene trioxide salt of compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents heat flux (mW).

[0207] Figure 38 The TGA graph of the tromethamine salt of compound I-2 of the present invention is shown. The horizontal axis represents temperature (°C), and the vertical axis represents weight (%).

[0208] Figure 39 The DVS graph of compound I-1 of the present invention is shown. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0209] Figure 40 The DVS graph of compound I-2 of the present invention is shown. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0210] Figure 41 The DVS plot of the tromethamine salt of compound I-1 of the present invention is shown. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0211] Figure 42 The DVS plot of the tromethamine salt of compound I-2 of the present invention is shown. The horizontal axis represents relative humidity (%), and the vertical axis represents weight change (%).

[0212] Terminology Definitions and Explanations

[0213] Unless otherwise stated, the terms used in the specification and claims shall have the following meanings. A particular phrase or term should not be considered ambiguous or unclear unless specifically defined, but should be understood in its ordinary sense. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0214] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0215] The term "salt" as used in this article refers to compounds prepared by reacting organic acid or base drugs with pharmaceutically acceptable inorganic or organic acids or bases.

[0216] The intermediate compounds of the present invention can be prepared by various synthetic methods 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 known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0217] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on existing embodiments.

[0218] The present invention will be described in detail below through embodiments, which are not intended to limit the present invention in any way.

[0219] All solvents used in this invention are commercially available and can be used without further purification.

[0220] Unless otherwise specified, all reactions in this invention are performed under continuous magnetic stirring, using a dry solvent, and the temperature is measured in degrees Celsius (°C).

[0221] Methods and Materials

[0222] The structure of the compound was 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, with deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (MeOD-d4) as the solvent, tetramethylsilane (TMS) as the internal standard, and chemical shifts expressed in 10⁻¹⁰ ppm. -6 ppm is used as the unit.

[0223] HPLC determinations were performed using an Agilent 1260 high-performance liquid chromatograph or an equivalent high-performance liquid chromatograph (Sunfire C18 150×4.6m column or equivalent column).

[0224] The crystal forms of the acidic or basic salts of compound I were characterized by X-ray powder diffraction patterns. X-ray powder diffraction patterns of the salts were acquired on a Bruker D8 Advance powder diffractometer operating in reflective mode using Cu Kα radiation. The instrument was irradiated with Cu Kα (40 kV, 40 mA) at room temperature using an SSD160-2 detector. The scan range was from 3° to 40° in the 2θ region, with a scan rate of 0.1 s / step. The diffraction patterns were analyzed using DIFFRAC.MEA.CENTER software.

[0225] XRPD sample preparation involves placing the sample on a single-crystal silicon wafer and pressing the sample powder with a glass slide or equivalent to ensure a flat surface and appropriate height. The sample holder is then placed in a Bruker D8 Advance instrument, and X-ray powder diffraction patterns are acquired using the instrument parameters described above. Measurement variations associated with these X-ray powder diffraction analysis results are caused by several factors, including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration variations, (d) operator errors (including those occurring 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 shifts in all peaks in the same direction. Generally, this calibration factor will ensure that the measured peak positions are consistent with the expected peak positions and can be within the expected 2θ value ± 0.2°.

[0226] The experimental method for characterizing the crystal form of the acidic or basic salt of compound I using differential scanning calorimetry (DSC) is as follows: a small amount of powder of the acidic or basic salt of crystalline compound I is placed in an aluminum crucible that is compatible with the instrument and can be capped. After loading the sample, the crucible is capped with an aluminum plate and then sent to the instrument for detection. In this patent, the instrument used for differential scanning calorimetry is a METTLER TOLEDO DSC 3, and the scanning parameters are set to a nitrogen atmosphere and a heating rate of 10.0 K / min.

[0227] The experimental method for characterizing the crystal form of the acid salt or basic salt of Compound I by thermogravimetric analysis (TGA) is as follows: Take a small amount of the powder of the acid salt or basic salt of crystalline Compound I and place it in an alumina crucible compatible with the instrument. After loading the sample, send it into the instrument for detection. In this invention, the instrument model used for all differential scanning calorimetry is METTLER TOLEDO TGA 2, and the scanning parameters are set as follows: use a nitrogen atmosphere, and the heating rate is 10.0 k / min.

[0228] The experimental method for characterizing the acid salt or basic salt of Compound I by dynamic vapor sorption (DVS) is as follows: Take a small amount of the powder of the acid salt or basic salt of Compound I and place it in a precision sample pan compatible with the instrument. After loading the sample, send it into the instrument for detection. In this invention, the instrument model used for all dynamic vapor sorption is Intrinsic PLUS, and the experimental parameters are set as follows: set a constant temperature of 25 °C, and the mass percentage change rate per unit time (dm / dt) = 0.02% / min is used as the criterion for reaching equilibrium. The program humidity change cycle is set as follows: the initial relative humidity is 0%, and the relative humidity at the end point is 90%. Detailed implementation manners

[0229] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only for illustrative and explanatory purposes of the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0230] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0231] Preparation of (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin- -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound I-1)

[0232]

[0233] Step 1: Synthesis of methyl (S)-2-((4-((6-((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0234] A mixture of N,N-dimethylformamide (80 mL) containing (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-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) 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)-2-((4-((6-(((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (1.0 g, yield: 33.5%).

[0235] 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]imidazolium-6-carboxylic acid

[0236] Lithium hydroxide (0.13 g, 5.4 mmol) was added to a mixture of tetrahydrofuran / water (20 mL / 20 mL) containing methyl (S)-2-((4-((6-(((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (1.0 g, 1.7 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 under vacuum. The residue was purified by reversed-phase rapid column chromatography to give (S)-2-((4-((6-(((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid (0.69 g, yield: 70.5%). 1H 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).

[0237] 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]imidazolium-6-carboxylic acid (compound I-2)

[0238]

[0239] Step 1: Synthesis of methyl (S)-2-((4-((6-(((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate

[0240] A mixture of N,N-dimethylformamide (80 mL) containing methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-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) 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)-2-((4-((6-(((4-cyano-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxecyclobutane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylate (1.1 g, yield: 37.2%).

[0241] 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]imidazolium-6-carboxylic acid

[0242] Lithium hydroxide (0.13 g, 5.4 mmol) was added to a mixture of tetrahydrofuran / water (20 mL / 20 mL) containing methyl (1.1 g, 1.9 mmol) 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]imidazolium-6-carboxylate (2.1 g, 1.9 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 under vacuum. The residue was purified by reversed-phase rapid column chromatography to give (S)-2-((4-((6-(((4-chloro-2-fluorophenoxy)methyl)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-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).

[0243] Example 3 Preparation of the hydrochloride salt of compound I-1

[0244] 20 mg of compound I-1 was added to 1 mL of acetonitrile, followed by 10 mg of concentrated hydrochloric acid. The mixture was stirred at room temperature for one day, filtered, and the filter cake was dried in a 50°C oven to obtain the hydrochloride salt of compound I-1. The product was then subjected to XRPD (extracorporeal membrane oxygenation). Figure 1 )Analysis and characterization.

[0245] Example 4: Preparation of tartrate of compound I-1

[0246] 20 mg of compound I-1 was added to 1 mL of acetonitrile, followed by 7.7 mg of L-tartaric acid. The mixture was stirred at room temperature for one 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 subjected to XRPD (…). Figure 2 )Analysis and characterization.

[0247] Example 5: Preparation of citrate of compound I-1

[0248] 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 of compound I-1. Data were collected and analyzed from the product, including XRPD (…). Figure 3 ), DSC Figure 4 ) and TGA ( Figure 5Characterization was performed. Citrate was shown in DSC thermograms with endothermic peaks at approximately 107.80 °C and 130.63 °C. 1 H 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).

[0249] Example 6 Preparation of maleate of compound I-1

[0250] 20 mg of compound I-1 was added to 1 mL of acetonitrile, followed by 5 mg of maleic acid. The mixture was stirred at room temperature for 1 day, filtered, and the filter cake was dried in a 50°C oven to obtain the maleate salt of compound I-1. The product was subjected to XRPD (extra-X-Particle Dysfunction). Figure 6 )Analysis and characterization.

[0251] Example 7 Preparation of the methanesulfonate of compound I-1

[0252] 20 mg of compound I-1 was added to 1 mL of acetonitrile, followed by 5.0 mg of methanesulfonic acid. The mixture was stirred at room temperature for 1 day, filtered, and the filter cake was dried in a 50°C oven to obtain the methanesulfonate of compound I-1. The product was subjected to XRPD (extra-X-Particle Dysfunction). Figure 7 )Analysis and characterization.

[0253] Example 8: Preparation of the sodium salt of compound I-1

[0254] 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. Data were collected and analyzed from the product, including XRPD (…). Figure 8 ), DSC Figure 9 ) and TGA ( Figure 10 Characterization was performed. The sodium salt was shown in DSC thermograms with endothermic peaks at temperatures of approximately 149.11 °C and 174.11 °C.

[0255] Example 9 Preparation of the potassium salt of compound I-1

[0256] 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 dried in an oven at 40 °C to obtain the potassium salt of compound I-1. Data were collected and analyzed from the product, and XRPD was performed on the product. Figure 11 )Analysis and characterization.

[0257] Example 10 Preparation of the potassium salt of compound I-1

[0258] 20 mg of compound I-1 was added to 0.4 mL of acetonitrile, followed by 2.3 mg of potassium hydroxide. The mixture was stirred at room temperature for 16 hours, filtered, and the filter cake was dried in an oven at 40 °C to obtain the potassium salt of compound I-1. Data were collected and analyzed from the product, and XRPD was performed on the product. Figure 12 )Analysis and characterization.

[0259] Example 11 Preparation of meglumine salt of compound I-1

[0260] 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. Data were collected and analyzed from the product, including XRPD (…). Figure 13 ), DSC Figure 14 ) and TGA ( Figure 15 Characterization was performed. The meglumine salt was shown in 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).

[0261] Example 12 Preparation of the aminobutanetriol salt of compound I-1

[0262] 200 mg of compound I-1 and 42 mg of tromethamine were added to 2.0 mL of N-methylpyrrolidone. This solution was then added dropwise to 15 mL of toluene. The mixture was stirred at room temperature for 16 hours, filtered, and the filter cake was dried in a 50°C oven to obtain the tromethamine salt of compound I-1. Data were collected and analyzed from the product, including XRPD (…). Figure 16 ), DSC Figure 17 ) and TGA ( Figure 18 Characterization was performed. The tromethamine salt was shown in DSC thermograms with endothermic peaks at approximately 109.95 °C and 166.02 °C. 1 H 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).

[0263] Example 13 Preparation of citrate of compound I-2

[0264] 20 mg of compound I-1 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 of compound I-2. The product was subjected to XRPD. Figure 19 )Analysis and characterization.

[0265] Example 14 Preparation of malate of compound I-2

[0266] 20 mg of compound I-1 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 of compound I-2. The product was subjected to XRPD. Figure 20 )Analysis and characterization.

[0267] Example 15 Preparation of tartrate of compound I-2

[0268] 20 mg of compound I-1 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 subjected to XRPD. Figure 21 )Analysis and characterization.

[0269] Example 16 Preparation of fumarate of compound I-2

[0270] 20 mg of compound I-1 and 4.9 mg of fumaric acid were added to 0.4 mL of acetonitrile / water (1:1 v:v), stirred at room temperature for 3 days, filtered, and the filter cake was dried in an oven at 50 °C to obtain the fumarate of compound I-2. The product was subjected to XRPD (…). Figure 22 )Analysis and characterization.

[0271] Example 17 Preparation of the methanesulfonate of compound I-2

[0272] 20 mg of compound I-1 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 subjected to XRPD (extra-X-Particle Dysfunction). Figure 23 )Analysis and characterization.

[0273] Example 18 Preparation of maleate of compound I-2

[0274] 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. Data were collected and analyzed from the product, including XRPD (…). Figure 24 ), DSC Figure 25 ) and TGA ( Figure 26 Characterization was performed. Maleate was shown in a DSC thermogram with an endothermic peak at a temperature of 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).

[0275] Example 19 Preparation of the sodium salt of compound I-2

[0276] 20 mg of compound I-1 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 subjected to XRPD (…). Figure 27 )Analysis and characterization.

[0277] Example 20 Preparation of the potassium salt of compound I-2

[0278] 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. Data were collected and analyzed from the product, including XRPD (…). Figure 28 ), DSC Figure 29 ) and TGA ( Figure 30 Characterization was performed. The potassium salt was shown in a DSC thermogram with an endothermic peak at approximately 118.44 °C. 1 HNMR (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).

[0279] Example 21 Preparation of calcium salt of compound I-2

[0280] 20 mg of compound I-1 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. The product was subjected to XRPD. Figure 31 )Analysis and characterization.

[0281] Example 22 Preparation of magnesium salt of compound I-2

[0282] 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. The product was subjected to XRPD (…). Figure 32 )Analysis and characterization.

[0283] Example 23 Preparation of meglumine salt of compound I-2

[0284] 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 then filtered, and the filter cake was dried in a 50°C oven to obtain the meglumine salt of compound I-2. Data were collected and analyzed from the product, including XRPD (…). Figure 33 ), DSC Figure 34 ) and TGA ( Figure 35 Characterization was performed. The meglumine salt was shown in a DSC thermogram with an endothermic peak at approximately 123.07 °C. 1 HNMR (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).

[0285] Example 24 Preparation of the aminobutanetriol salt of compound I-2

[0286] 20 mg of compound I-1 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. Data were collected and analyzed from the product, including XRPD (…). Figure 36 ), DSC Figure 37 ) and TGA ( Figure 38Characterization was performed. The tromethamine salt was shown in a DSC thermogram with an endothermic peak at approximately 167.96 °C. 1 HNMR (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).

[0287] Example 25: Study on the solubility of the compound salt form in water

[0288] The equilibrium solubility of free compounds I-1 and I-2, as well as their corresponding representative tromethamine salts, in water (H₂O) was tested. In the experiment, the solids were prepared into suspensions (~10 mg / mL) in the corresponding buffer solutions and stirred at 37±2 °C. After 24 hours, samples of the suspensions were taken, and the supernatant was filtered to determine the concentration. The results are shown in the table below:

[0289] solid form Preparation method solution equilibrium solubility Free state compound I-1 Example 1 <![CDATA[H2O]]> 0.19 mg / mL The aminobutane triol salt of compound I-1 Example 12 <![CDATA[H2O]]> 0.44 mg / mL Sodium salt of compound I-1 Example 8 <![CDATA[H2O]]> 5.00 mg / mL Potassium salt of compound I-1 Example 10 <![CDATA[H2O]]> 3.33 mg / mL meglumine salt of compound I-1 Example 11 <![CDATA[H2O]]> 4.00 mg / mL Free state compound I-2 Example 2 <![CDATA[H2O]]> 0.09 mg / mL The aminobutadiene triol salt of compound I-2 Example 24 <![CDATA[H2O]]> 0.33 mg / mL maleate of compound I-2 Example 18 <![CDATA[H2O]]> 0.11 mg / mL Potassium salt of compound I-2 Example 20 <![CDATA[H2O]]> 0.11 mg / mL Magnesium salt of compound I-2 Example 22 <![CDATA[H2O]]> 0.13 mg / mL

[0290] The experimental results above show that, compared with the free state, the solubility of most of the representative salt forms of the compound I-1 of this invention, such as tromethamine salt, sodium salt, potassium salt and meglumine salt, in water (H2O) is significantly increased, with the increase ranging from several times to tens of times.

[0291] Example 26: Solubility study of compound aminobutadiene triol salt in other media

[0292] The equilibrium solubility of free compounds I-1 and I-2, as well as their corresponding representative tromethamine salts, in simulated fasting gastric fluid (FaSSGF), simulated fasting intestinal fluid (FaSSIF), and simulated satiated intestinal fluid (FeSSIF) was tested. In the experiment, the solids were prepared into suspensions (~10 mg / mL) in the corresponding buffer solutions and stirred at 37±2℃. After 24 hours, samples of the suspensions were taken, and the supernatant was filtered to determine the concentration. The results are shown in the table below:

[0293]

[0294] The experimental results above show that, compared with the free state, the representative tromethamine salts of compounds I-1 and I-2 have significantly better solubility in simulated fasting intestinal fluid (FaSSIF) and simulated satiated intestinal fluid (FeSSIF) than the free state compounds.

[0295] Example 27 Moisture Absorption Behavior Test

[0296] The hygroscopic behavior of compounds affects the production, storage, stability, and quality of drugs. The inventors assessed the stability risk of samples at 25°C with changes in humidity using a dynamic moisture adsorption method. DVS tests were performed on representative salt forms of compounds I-1 and I-2 (aminobutyric acid glycerol salts) to evaluate the hygroscopicity of the salt forms. The DVS spectrum of the free compound I-1 is shown below. Figure 39 As shown, the DVS spectrum of the free compound I-2 is as follows: Figure 40 As shown, the DVS spectrum of the aminobutadiene trioxide of compound I-1 is as follows: Figure 41 As shown, the DVS spectrum of the aminobutadiene trioxide of compound I-2 is as follows. Figure 42 As shown in the table below:

[0297]

[0298] The experimental results unexpectedly revealed that, compared to the base, although the solubility increased significantly after salt formation, the hygroscopicity did not change significantly. On the adsorption curves at 0-90% RH, under 80% RH conditions, the free compounds I-1 and I-2, as well as the tromethamine salts of compounds I-1 and I-2, showed only slight hygroscopicity with no significant differences, and no changes in solid form were observed.

[0299] The thermal analysis of some salt forms of the compounds of this invention is summarized in the table below:

[0300]

[0301] The embodiments of the technical solution of the present invention have been described above by way of example. It should be understood that the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made by those skilled in the art within the spirit and principles of the present invention should be included within the scope of protection of the claims of this application.

Claims

1. The tromethamine salt of compound I-1 or the tromethamine salt of compound I-2: 。 2. The crystal form A of the aminobutadiene triol salt of compound I-1 according to claim 1, wherein the X-ray powder diffraction (XRPD) pattern includes peaks at diffraction angles (2θ) of 3.50±0.2°, 6.97±0.2°, 13.91±0.2° and 22.19±0.2°.

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

4. The chromotriol salt of compound I-1 according to claim 2, wherein the X-ray powder diffraction pattern of chromotriol salt A has a diffraction angle (2θ) as shown in Table 6 below, wherein the error range of the 2θ angle is ±0.20°: Table 6 。 5. Crystal form A of the tromethamine salt of compound I-1 according to claim 4, wherein crystal form A of the tromethamine salt has the X-ray powder diffraction intensity shown in Table 6.

6. Crystal form A of the tromethamine salt of compound I-1 according to claim 2, wherein crystal form A of the tromethamine salt has an X-ray powder diffraction pattern substantially as shown in FIG16.

7. Crystal form A of the tromethamine salt of compound I-1 according to claim 2, wherein crystal form A of the tromethamine salt has a DSC thermogram with endothermic peaks at temperatures of 109.95°C and 166.02°C.

8. Crystal form A of the tromethamine salt of compound I-1 according to claim 2, wherein crystal form A of the tromethamine salt is an N-methylpyrrolidone solvate.

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

10. The crystal form A of the tromethamine salt of compound I-2 of claim 9, wherein the X-ray powder diffraction (XRPD) pattern 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°.

11. The chromotriol salt of compound I-2 according to claim 9, wherein the chromotriol salt of chromotriol salt 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 。 12. Crystal form A of the tromethamine salt of compound I-2 according to claim 11, wherein crystal form A of the tromethamine salt has X-ray powder diffraction intensity as shown in Table 11.

13. Crystal form A of the tromethamine salt of compound I-2 of claim 9, wherein crystal form A of the tromethamine salt has an X-ray powder diffraction pattern substantially as shown in FIG36.

14. Crystal form A of the tromethamine salt of compound I-2 according to claim 9, wherein crystal form A of the tromethamine salt has a DSC thermogram with an endothermic peak at a temperature of 167.96°C.

15. A method for preparing the tromethamine salt of compound I-1, the tromethamine salt of compound I-2, crystal form A of the tromethamine salt of compound I-1, or crystal form A of the tromethamine salt of compound I-2, according to any one of claims 1-14. The preparation methods of the aminobutadiene triol salt of compound I-1 include: Compound I-1 and tromethamine were dissolved in N-methylpyrrolidone, then 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 / toluene was 2:

15. The preparation methods of the aminobutadiene triol salt of compound I-2 include: Compound I-2 and tromethamine were dissolved in isopropanol, stirred at room temperature, filtered, and dried 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.

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

17. Use of at least one of the tromethamine salt of compound I-1, the tromethamine salt of compound I-2, crystal form A of the tromethamine salt of compound I-1, or crystal form A of the tromethamine salt of compound I-2 in the preparation of a medicament for treating metabolic diseases, autoimmune diseases, or metastatic diseases associated with GLP-1R small molecule agonists.

18. The application according to claim 17, characterized in that, The diseases mentioned are selected from T1D, T2DM, and obesity.

19. The application according to claim 17, characterized in that, The diseases mentioned are selected from idiopathic type 1 diabetes, prediabetes, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, adipocyte dysfunction, visceral adipocyte accumulation, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, dyslipidemia, hyperinsulinemia, NAFLD, metabolic acidosis, and glucose dysmegma.

20. The application according to claim 17, characterized in that, The metabolic diseases mentioned are selected from glucose intolerance and postprandial lipemia.

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