Salts and crystalline forms of cycloolefin compounds, and methods for producing and using the same

Abstract

This invention relates to salts and crystalline forms of cycloolefin compounds, and their preparation methods and applications. Specifically, it relates to salts and crystalline forms of the compound represented by general formula (I), preparation methods, pharmaceutical compositions containing therapeutically effective amounts of said salt forms, and their application as regulators in the manufacture of medicines for treating metabolic and related diseases.

Description

[Technical Field]

[0001] The present invention relates to the field of biopharmaceuticals, specifically to salts and crystalline forms of cycloolefin compounds, as well as their preparation methods and applications. [Background technology]

[0002] Diabetes mellitus (Diabetes mellitus) is a common endocrine and metabolic disease that causes multiple system and organ damage due to metabolic disorders caused by various causes. It has a high prevalence, with approximately 425 million people worldwide suffering from diabetes, of which the prevalence in China is approximately 10%, of which type 2 diabetes accounts for 90%. The incidence rate is still increasing, and the age at onset is becoming younger.

[0003] Currently, many drugs are available on the market for the treatment of type II diabetes, including insulin, biguanides, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase IV (DPP-IV) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and α-glycosidase inhibitors, among which GLP-1 receptor agonists have attracted the most attention.

[0004] GLP-1 is a peptide hormone secreted by human intestinal L cells, and its receptors are distributed in pancreatic islet cells, various types of gastrointestinal cells, and neurons in the central and peripheral nervous systems. Activation of GLP-1 receptors promotes insulin secretion, inhibits glucagon secretion, suppresses appetite, and delays gastric emptying, among other physiological effects. Clinical evidence has shown that, compared with other hypoglycemic drugs, GLP-1 receptor agonists have better hypoglycemic effects and are less likely to cause side effects such as hypoglycemia. Furthermore, they have additional cardiovascular benefits, can reduce food intake, and delay gastric emptying, which are beneficial for weight control.

[0005] Currently, all commercially available GLP-1 receptor agonists are polypeptide-based drugs, which often require subcutaneous administration, resulting in poor patient compliance and very low oral polypeptide bioavailability. Therefore, there is a significant clinical need for the development of oral small molecule GLP-1 receptor agonists.

[0006] Currently, no small molecule GLP-1 receptor agonists have been approved, and three small molecule GLP-1 receptor agonists have entered clinical research, including PF-06882961 and PF-07081532 developed by Pifzer, and TTP273 developed by vTv, all of which are currently in Phase I / II research. PF-06882961 demonstrated significant blood glucose lowering and weight loss effects in early clinical trials, with a safety profile similar to that of polypeptide GLP-1 receptor agonists, and is expected to provide more treatment options for patients with diabetes, obesity, and NASH in the future.

[0007] There is a huge clinical need for GLP-1 receptor agonists. Oral small molecule GLP-1 receptor agonists with lower cost and better compliance have the potential to treat various metabolic diseases and have broad market potential.

[0008] Patent Document 1 (PCT / CN2022 / 110017) discloses the structures of a series of polycyclic compounds of cycloolefin derivatives. In subsequent research and development, the present invention has conducted comprehensive research on the salt forms of the above compounds in order to facilitate the processing, filtration and drying of the products, facilitate storage, and ensure the products are stable for a long period of time and have suitable crystals. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2023 / 011539 (PCT / CN2022 / 110017) Summary of the Invention

[0010] The entire contents of Patent Document 1 are incorporated herein by reference.

[0011] An object of the present invention is to provide a compound represented by general formula (I) or a basic salt of a stereoisomer thereof, the structure of which is as represented by formula (I): [ka] where: R 1 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 haloalkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine, methoxy or -OCD3; R 2 are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, or C 1-3 Alkyl group, C 1-3 Deuterated alkyl groups, C 1-3 Haloalkyl group, C 1-3 Alkoxy group, C 1-3 Deuterated alkoxy group or C 1-3 haloalkoxy groups, preferably hydrogen, deuterium, fluorine, chlorine or methyl groups; R 3 are each independently selected from hydrogen, deuterium, or fluorine, preferably hydrogen; M1 is N or CH, preferably CH; W2 is N or CH, preferably CH; x, y, and z are each independently 0, 1, or 2; Here, the base is an organic base or an inorganic base, and the organic base is selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, meglumine, N-hydroxyethylmorpholine, piperazine, N-hydroxyethylpyrrolidine, N,N-dibenzylethylenediamine, 2-diethylaminoethanol, ethanolamine, betaine, L-arginine, lysine, phenethylbenzylamine, benzathine penicillin, dimethylaminoethanol, imidazole, or a mixture thereof, and the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water, or a mixture thereof.

[0012] In some further preferred embodiments of the present invention, the compound further comprises the following general formulae (I-1) to (I-4): [ka] As shown in the figure.

[0013] In some embodiments of the present invention, the general formula (I) is a compound as follows: [ka] [ka] [ka] is selected from.

[0014] wherein the base is an organic base or an inorganic base, wherein the organic base is selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine or a mixture thereof, and the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or a mixture thereof.

[0015] In a preferred embodiment of the present invention, there is provided a compound of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a stereoisomer or a base salt thereof, wherein the compound or a stereoisomer or a base salt thereof is a tromethamine salt.

[0016] In a further preferred embodiment of the present invention, the number of bases is 0.5 to 3, preferably 0.5, 1, 1.5, 2, 2.5 or 3, further preferably 0.5, 1, 2 or 3, and more preferably 1.

[0017] In some embodiments of the present invention, the crystalline form is a salt crystalline form of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the crystalline form is an anhydrous crystalline form.

[0018] In some embodiments of the present invention, the crystalline form is a salt crystalline form of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the crystalline form is a hydrate and contains 0.2 to 3 waters, preferably 0.5 waters, 1 water, 2 waters, or 3 waters.

[0019] In some embodiments of the present invention, the water molecules of the hydrate are tap water or water of crystallization.

[0020] In a preferred embodiment of the present invention, there is provided a compound of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid or a stereoisomer or base salt thereof, the structure of which is [ka] is.

[0021] In some embodiments of the invention, the crystalline form is tromethamine salt A of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein: The powder X-ray diffraction spectrum of tromethamine salt crystalline form A has a characteristic peak at 7.7±0.2 degrees 2θ, or has a characteristic peak at 9.8±0.2 degrees 2θ, or has a characteristic peak at 10.8±0.2 degrees 2θ, or has a characteristic peak at 11.6±0.2 degrees 2θ, or has a characteristic peak at 14.0±0.2 degrees 2θ, or has a characteristic peak at 14.5±0.2 degrees 2θ, or has a characteristic peak at 14.8±0.2 degrees 2θ, or has a characteristic peak at 15.1±0.2 degrees 2θ, or has a characteristic peak at 15.9±0.2 degrees 2θ, or has a characteristic peak at 18.0±0.2 degrees 2θ. or having a characteristic peak at 18.7±0.2 degrees 2θ, or having a characteristic peak at 19.3±0.2 degrees 2θ, or having a characteristic peak at 20.0±0.2 degrees 2θ, or having a characteristic peak at 20.5±0.2 degrees 2θ, or having a characteristic peak at 21.1±0.2 degrees 2θ, or having a characteristic peak at 22.6±0.2 degrees 2θ, or having a characteristic peak at 23.7±0.2 degrees 2θ, or having a characteristic peak at 25.1±0.2 degrees 2θ, preferably at any 2, 4, 6, 8, 10 or 12 thereof.

[0022] In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline Form A has characteristic peaks at one or more of 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, or 15.1±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4, and optionally further including characteristic peaks at one or more of 14.5±0.2°, 18.7±0.2°, 19.3±0.2°, 20.0±0.2°, 20.5±0.2°, or 21.1±0.2° 2θ, preferably including 2, 3, 4, or 6 of these, for example: 7.7±0.2°, 9.8±0.2°, and 14.0±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, and 15.1±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, and 14.5±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, and 18.7±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, and 19.3±0.2°. 7.7±0.2°, 9.8±0.2°, 14.5±0.2°, and 18.7±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, and 20.5±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, and 20.0±0.2°. 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, and 18.7±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, and 15.1±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, and 18.7±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 18.7±0.2°, and 20.0±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 19.3±0.2°, and 20.5±0.2°. 7.7±0.2°, 9.8±0.2°, 14.5±0.2°, 18.7±0.2°, and 20.5±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 19.3±0.2°, and 20.5±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 20.0±0.2°, and 21.1±0.2°. 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, 18.7±0.2°, and 21.1±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, 15.1±0.2°, and 18.7±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, 18.7±0.2°, and 19.3±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 18.7±0.2°, 19.3±0.2°, and 20.0±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 19.3±0.2°, 20.5±0.2°, and 21.1±0.2°. 7.7±0.2°, 9.8±0.2°, 14.5±0.2°, 18.7±0.2°, 20.5±0.2°, and 21.1±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 19.3±0.2°, 20.5±0.2°, and 21.1±0.2°. 7.7±0.2°, 14.0±0.2°, 14.5±0.2°, 19.3±0.2°, 20.0±0.2°, and 21.1±0.2°. 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, 18.7±0.2°, 19.3±0.2°, and 21.1±0.2°. More preferably, the powder X-ray diffraction spectrum optionally further comprises diffraction peaks located at one or more of 2θ of 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 18.0±0.2°, 20.5±0.2° or 22.6±0.2°, preferably at least any 2 to 4 or 5 to 6 of these, more preferably any 4 or 6 of these, for example 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, and 18.0±0.2°. 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, and 20.5±0.2°. 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, and 22.6±0.2°. 10.8±0.2°, 11.6±0.2°, 18.0±0.2°, and 20.5±0.2°. 11.6±0.2°, 14.5±0.2°, 18.0±0.2°, and 20.5±0.2°. 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 18.0±0.2°, and 20.5±0.2°. 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 20.5±0.2°, and 22.6±0.2°. 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 18.0±0.2°, 20.5±0.2°, and 22.6±0.2°. In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline Form A has characteristic peaks at 9.8±0.2° and 14.0±0.2° 2θ, preferably further having characteristic peaks at 7.7±0.2° and 15.1±0.2° 2θ, more preferably further having characteristic peaks at 18.7±0.2°, 19.3±0.2°, 20.0±0.2° and 21.1±0.2° 2θ, even more preferably further having characteristic peaks at 14.5±0.2° and 20.5±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 10.8±0.2°, 11.6±0.2°, 18.0±0.2° and 22.6±0.2°.

[0023] In some embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed as 2θ angles and d-spacing values ​​are as shown in Table 1.

[0024] [Table 1]

[0025] The tromethamine salt crystalline form A of the compound according to the present invention has an X-ray powder diffraction pattern essentially as shown in FIG. 1, a DSC pattern essentially as shown in FIG. 2, and a TGA pattern essentially as shown in FIG. 3.

[0026] In some embodiments of the present invention, the crystalline form is 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tromethamine salt crystalline Form B, and the powder X-ray diffraction spectrum of tromethamine salt crystalline Form B has a characteristic peak at 8.2±0.2 degrees 2θ, or has a characteristic peak at 10.1±0.2 degrees 2θ, or has a characteristic peak at 12.3±0.2 degrees 2θ, or has a characteristic peak at 14.4±0.2 degrees 2θ, or has a characteristic peak at 14.8±0.2 degrees 2θ, or has a characteristic peak at 16.0±0.2 degrees 2θ, or has a characteristic peak at 16.2±0.2 degrees 2θ. or having a characteristic peak at 17.5±0.2 degrees 2θ, or having a characteristic peak at 17.7±0.2 degrees 2θ, or having a characteristic peak at 18.3±0.2 degrees 2θ, or having a characteristic peak at 18.7±0.2 degrees 2θ, or having a characteristic peak at 19.7±0.2 degrees 2θ, or having a characteristic peak at 20.5±0.2 degrees 2θ, or having a characteristic peak at 20.9±0.2 degrees 2θ, or having a characteristic peak at 21.9±0.2 degrees 2θ, or having a characteristic peak at 22.1±0.2 degrees 2θ, or having a characteristic peak at 22.4±0.2 degrees 2θ, or having a characteristic peak at 24.7±0.2 degrees 2θ, preferably at any 2, 4, 6, 8, 10 or 12 positions therein.

[0027] In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline form B has characteristic peaks at one or more of 10.1±0.2°, 14.4±0.2°, 18.7±0.2°, or 21.9±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4 of these, and optionally further including characteristic peaks at one or more of 8.2±0.2°, 12.3±0.2°, 14.8±0.2°, 19.7±0.2°, 20.5±0.2°, or 22.1±0.2° 2θ, preferably including 2, 3, 4, or 6 of these, for example: 10.1±0.2°, 14.4±0.2°, and 18.7±0.2°. 10.1±0.2°, 14.4±0.2°, 18.7±0.2°, and 21.9±0.2°. 8.2±0.2°, 14.4±0.2°, 18.7±0.2°, and 21.9±0.2°. 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, and 18.7±0.2°. 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, and 18.7±0.2°. 10.1±0.2°, 14.4±0.2°, 18.7±0.2°, and 19.7±0.2°. 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, and 21.9±0.2°. 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, and 18.7±0.2°. 8.2±0.2°, 12.3±0.2°, 14.4±0.2°, and 18.7±0.2°. 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 18.7±0.2°, and 21.9±0.2°. 8.2±0.2°, 12.3±0.2°, 14.4±0.2°, 18.7±0.2°, and 21.9±0.2°. 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 14.8±0.2°, and 18.7±0.2°. 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, and 21.9±0.2°. 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, and 19.7±0.2°. 8.2±0.2°, 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, and 21.9±0.2°. 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, and 21.9±0.2°. 8.2±0.2°, 12.3±0.2°, 14.4±0.2°, 14.8±0.2°, and 18.7±0.2°. 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, and 21.9±0.2°. 8.2±0.2°, 12.3±0.2°, 14.4±0.2°, 18.7±0.2°, 21.9±0.2°, and 22.1±0.2°. 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, and 19.7±0.2°. 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, 21.9±0.2°, and 22.1±0.2°. 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, 19.7±0.2°, and 22.1±0.2°. 8.2±0.2°, 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 14.8±0.2°, and 21.9±0.2°. 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, 21.9±0.2°, and 22.1±0.2°. 8.2±0.2°, 12.3±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, and 22.1±0.2°. More preferably, the powder X-ray diffraction spectrum optionally further comprises diffraction peaks located at one or more of 2θ of 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, 19.7±0.2°, or 20.9±0.2°, preferably at least any 2 to 4 or 5 to 6 of these, more preferably any 4 or 6 of these, for example 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, and 18.3±0.2°. 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, and 19.7±0.2°. 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, and 20.9±0.2°. 12.3±0.2°, 16.2±0.2°, 18.3±0.2°, and 19.7±0.2°. 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, and 19.7±0.2°. 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, and 20.9±0.2°. 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, 19.7±0.2°, and 20.9±0.2°. 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, 19.7±0.2°, and 20.9±0.2°. In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline Form B has characteristic peaks at 10.1±0.2° and 14.4±0.2° 2θ, preferably further having characteristic peaks at 18.7±0.2° and 21.9±0.2° 2θ, more preferably further having characteristic peaks at 8.2±0.2°, 14.8±0.2°, 20.5±0.2° and 22.1±0.2° 2θ, even more preferably further having characteristic peaks at 12.3±0.2° and 19.7±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 16.0±0.2°, 16.2±0.2°, 18.3±0.2° and 20.9±0.2° 2θ.

[0028] In some embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed as 2θ angles and d-spacing values ​​are as shown in Table 2.

[0029] [Table 2]

[0030] The tromethamine salt crystalline form B of the compound according to the present invention has an X-ray powder diffraction pattern essentially as shown in FIG. 4 and a DSC pattern essentially as shown in FIG.

[0031] In some embodiments of the present invention, the crystalline form is 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tromethamine salt crystalline Form C, and the powder X-ray diffraction spectrum of the tromethamine salt crystalline Form C has a characteristic peak at 3.6±0.2 degrees 2θ, or has a characteristic peak at 7.1±0.2 degrees 2θ, or has a characteristic peak at 9.7±0.2 degrees 2θ, or has a characteristic peak at 10.6±0.2 degrees 2θ, or has a characteristic peak at 13.5±0.2 degrees 2θ, or has a characteristic peak at 14.1±0.2 degrees 2θ, or has a characteristic peak at 15.0±0.2 degrees 2θ, or has a characteristic peak at 16.0±0.2 degrees 2θ. or having a characteristic peak at 16.5±0.2° 2θ, or having a characteristic peak at 17.1±0.2° 2θ, or having a characteristic peak at 17.6±0.2° 2θ, or having a characteristic peak at 19.0±0.2° 2θ, or having a characteristic peak at 19.7±0.2° 2θ, or having a characteristic peak at 20.8±0.2° 2θ, or having a characteristic peak at 21.8±0.2° 2θ, or having a characteristic peak at 22.3±0.2° 2θ, or having a characteristic peak at 23.1±0.2° 2θ, or having a characteristic peak at 26.4±0.2° 2θ, or having a characteristic peak at 28.3±0.2° 2θ, preferably at any 2, 4, 6, 8, 10 or 12 thereof.

[0032] The powder X-ray diffraction spectrum of tromethamine salt crystalline form C has characteristic peaks at one or more of 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, or 16.0±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4, and optionally further including characteristic peaks at one or more of 15.0±0.2°, 16.5±0.2°, 17.1±0.2°, 17.6±0.2°, 19.7±0.2°, or 20.8±0.2° 2θ, preferably including 2, 3, 4, or 6 of these. 3.6±0.2°, 7.1±0.2°, and 9.7±0.2°, respectively. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, and 14.1±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, and 14.1±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, and 15.0±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, and 16.5±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, and 17.1±0.2°. 3.6±0.2°, 7.1±0.2°, 14.1±0.2°, and 17.6±0.2°. 3.6±0.2°, 7.1±0.2°, 17.6±0.2°, and 19.7±0.2°. 9.7±0.2°, 14.1±0.2°, 16.0±0.2°, and 17.1±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, and 16.0±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, and 15.0±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, and 16.5±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, and 17.1±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, and 17.6±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 17.6±0.2°, and 19.7±0.2°. 3.6±0.2°, 7.1±0.2°, 14.1±0.2°, 17.1±0.2°, and 17.6±0.2°. 3.6±0.2°, 9.7±0.2°, 14.1±0.2°, 17.1±0.2°, and 17.6±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 16.0±0.2°, and 17.1±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 15.0±0.2°, and 17.1±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 16.5±0.2°, and 17.6±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 17.6±0.2°, and 19.7±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 15.0±0.2°, 17.6±0.2°, and 19.7±0.2°. 3.6±0.2°, 9.7±0.2°, 14.1±0.2°, 15.0±0.2°, 16.0±0.2°, and 17.1±0.2°. 3.6±0.2°, 7.1±0.2°, 14.1±0.2°, 15.0±0.2°, 17.1±0.2°, and 17.6±0.2°. 9.7±0.2°, 14.1±0.2°, 15.0±0.2°, 16.0±0.2°, 17.1±0.2°, and 20.8±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 16.0±0.2°, 17.1±0.2°, and 20.8±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 15.0±0.2°, 17.1±0.2°, and 19.7±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 16.5±0.2°, 17.6±0.2°, and 19.7±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 17.1±0.2°, 17.6±0.2°, and 19.7±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 17.6±0.2°, 19.7±0.2°, and 20.8±0.2°. 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 15.0±0.2°, 17.6±0.2°, 19.7±0.2°, and 20.8±0.2°. 3.6±0.2°, 7.1±0.2°, 14.1±0.2°, 15.0±0.2°, 17.1±0.2°, 17.6±0.2°, and 20.8±0.2°. More preferably, the powder X-ray diffraction spectrum optionally further comprises diffraction peaks located at one or more of 2θ of 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 19.7±0.2°, 21.8±0.2°, or 26.4±0.2°, preferably at least any 2 to 4 or 5 to 6 of these, more preferably any 4 or 6 of these, for example 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, and 19.7±0.2°. 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, and 21.8±0.2°. 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, and 26.4±0.2°. 17.1±0.2°, 19.0±0.2°, 21.8±0.2°, and 26.4±0.2°. 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 21.8±0.2°, and 26.4±0.2°. 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 19.7±0.2°, and 21.8±0.2°. 17.1±0.2°, 19.0±0.2°, 19.7±0.2°, 21.8±0.2°, and 26.4±0.2°. 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 19.7±0.2°, 21.8±0.2°, and 26.4±0.2°. In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline Form C has characteristic peaks at 3.6±0.2° and 7.1±0.2° 2θ, preferably further having characteristic peaks at 9.7±0.2° and 14.1±0.2° 2θ, more preferably further having characteristic peaks at 15.0±0.2°, 16.0±0.2°, 16.5±0.2°, 17.6±0.2° and 20.8±0.2° 2θ, even more preferably further having characteristic peaks at 17.1±0.2° and 19.7±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 13.5±0.2°, 19.0±0.2°, 21.8±0.2° and 26.4±0.2°; In some embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed as 2θ angles and d-spacing values ​​are as shown in Table 3.

[0033] [Table 3]

[0034] The tromethamine salt crystalline form C of the compound according to the present invention has an X-ray powder diffraction pattern essentially as shown in FIG. 6, a DSC pattern essentially as shown in FIG. 7, and a TGA pattern essentially as shown in FIG. 8.

[0035] In some embodiments of the present invention, the tromethamine salt crystalline form C is an anhydrate crystalline form.

[0036] In some embodiments of the present invention, the crystalline form is 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tromethamine salt crystalline Form D, and the powder X-ray diffraction spectrum of tromethamine salt crystalline Form D has a characteristic peak at 7.4±0.2 degrees 2θ, or has a characteristic peak at 7.7±0.2 degrees 2θ, or has a characteristic peak at 9.8±0.2 degrees 2θ, or has a characteristic peak at 10.8±0.2 degrees 2θ, or has a characteristic peak at 11.6±0.2 degrees 2θ, or has a characteristic peak at 13.1±0.2 degrees 2θ, or has a characteristic peak at 14.0±0.2 degrees 2θ, or has a characteristic peak at 14.5±0.2 degrees 2θ. 0.2° 2θ, or having a characteristic peak at 15.1±0.2° 2θ, or having a characteristic peak at 15.4±0.2° 2θ, or having a characteristic peak at 15.8±0.2° 2θ, or having a characteristic peak at 17.9±0.2° 2θ, or having a characteristic peak at 18.8±0.2° 2θ, or having a characteristic peak at 19.3±0.2° 2θ, or having a characteristic peak at 20.0±0.2° 2θ, or having a characteristic peak at 20.5±0.2° 2θ, or having a characteristic peak at 21.2±0.2° 2θ, or having a characteristic peak at 21.8±0.2° 2θ, or having a characteristic peak at 23.3±0.2° 2θ, preferably at any 2, 4, 6, 8, 10 or 12 thereof.

[0037] In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline Form D has characteristic peaks at one or more of 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, or 14.0±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4 of these, and optionally further including characteristic peaks at one or more of 7.7±0.2°, 15.1±0.2°, 17.9±0.2°, 18.8±0.2°, 19.3±0.2°, or 20.0±0.2° 2θ, preferably including 2, 3, 4, or 6 of these, for example: 7.4±0.2°, 9.8±0.2°, and 13.1±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, and 14.0±0.2°. 7.4±0.2°, 7.7±0.2°, 9.8±0.2°, and 13.1±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, and 14.0±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, and 14.0±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, and 14.0±0.2°. 7.4±0.2°, 13.1±0.2°, 14.0±0.2°, and 17.9±0.2°. 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, and 15.1±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, and 15.1±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, and 19.3±0.2°. 7.4±0.2°, 7.7±0.2°, 9.8±0.2°, 13.1±0.2°, and 14.0±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, and 15.1±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, and 17.9±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, and 18.8±0.2°. 7.4±0.2°, 13.1±0.2°, 14.0±0.2°, 17.9±0.2°, and 18.8±0.2°. 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°, and 17.9±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 15.1±0.2°, and 17.9±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 19.3±0.2°, and 20.0±0.2°. 7.4±0.2°, 7.7±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, and 15.1±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°, and 18.8±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 17.9±0.2°, and 18.8±0.2°. 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 18.8±0.2°, and 20.0±0.2°. 7.4±0.2°, 13.1±0.2°, 14.0±0.2°, 17.9±0.2°, 18.8±0.2°, and 20.0±0.2°. 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°, 17.9±0.2°, and 18.8±0.2°. 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 15.1±0.2°, 17.9±0.2°, and 20.0±0.2°. More preferably, the powder X-ray diffraction spectrum optionally further comprises diffraction peaks located at one or more of 2θ of 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 17.9±0.2°, 19.3±0.2°, or 21.2±0.2°, preferably at least any 2 to 4 or 5 to 6 of these, more preferably any 4 or 6 of these, for example 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, and 17.9±0.2°. 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, and 19.3±0.2°. 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, and 21.2±0.2°. 14.5±0.2°, 15.8±0.2°, 17.9±0.2°, and 21.2±0.2°. 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 17.9±0.2°, and 19.3±0.2°. 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 19.3±0.2°, and 21.2±0.2°. 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 17.9±0.2°, and 21.2±0.2°. 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 17.9±0.2°, 19.3±0.2°, and 21.2±0.2°. In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline Form D has characteristic peaks at 9.8±0.2° and 14.0±0.2° 2θ, preferably further having characteristic peaks at 7.4±0.2° and 13.1±0.2° 2θ, more preferably further having characteristic peaks at 7.7±0.2°, 15.1±0.2°, 18.8±0.2°, and 20.0±0.2° 2θ, even more preferably further having characteristic peaks at 17.9±0.2° and 19.3±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, and 21.2±0.2° 2θ.

[0038] In some embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed as 2θ angles and d-spacing values ​​are as shown in Table 4.

[0039] [Table 4]

[0040] The tromethamine salt crystalline form D of the compound according to the present invention has an X-ray powder diffraction pattern essentially as shown in FIG. 9 and a DSC pattern essentially as shown in FIG.

[0041] In some embodiments of the present invention, the crystalline form is tromethamine salt Form E of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, and the powder X-ray diffraction spectrum of tromethamine salt Form E has a characteristic peak at 4.3±0.2 degrees 2θ, or has a characteristic peak at 6.3±0.2 degrees 2θ, or has a characteristic peak at 8.6±0.2 degrees 2θ, or has a characteristic peak at 9.3±0.2 degrees 2θ, or has a characteristic peak at 13.6±0.2 degrees 2θ, or has a characteristic peak at 14.1±0.2 degrees 2θ, or has a characteristic peak at 17.7±0.2 degrees 2θ. or having a characteristic peak at 2 degrees 2θ, or having a characteristic peak at 18.5±0.2 degrees 2θ, or having a characteristic peak at 18.9±0.2 degrees 2θ, or having a characteristic peak at 20.2±0.2 degrees 2θ, or having a characteristic peak at 20.5±0.2 degrees 2θ, or having a characteristic peak at 21.4±0.2 degrees 2θ, or having a characteristic peak at 21.9±0.2 degrees 2θ, or having a characteristic peak at 22.4±0.2 degrees 2θ, or having a characteristic peak at 23.4±0.2 degrees 2θ, or having a characteristic peak at 23.9±0.2 degrees 2θ, or having a characteristic peak at 25.2±0.2 degrees 2θ, preferably at any 2, 4, 6, 8, 10 or 12 thereof.

[0042] In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline Form E has characteristic peaks at one or more of 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, or 18.9±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4 of these, and optionally further including characteristic peaks at one or more of 8.6±0.2°, 14.1±0.2°, 17.7±0.2°, 20.2±0.2°, 20.5±0.2°, or 22.4±0.2° 2θ, preferably including 2, 3, 4, or 6 of these, for example: 4.3±0.2°, 6.3±0.2°, and 13.6±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, and 18.9±0.2°. 4.3±0.2°, 6.3±0.2°, 8.6±0.2°, and 13.6±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, and 14.1±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, and 17.7±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, and 18.9±0.2°. 4.3±0.2°, 8.6±0.2°, 13.6±0.2°, and 14.1±0.2°. 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, and 14.1±0.2°. 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, and 17.7±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°, and 20.2±0.2°. 4.3±0.2°, 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, and 18.9±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, and 18.9±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 17.7±0.2°, and 18.9±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°, and 20.2±0.2°. 4.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°, and 18.9±0.2°. 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°, and 20.2±0.2°. 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, 17.7±0.2°, 18.9±0.2°, and 20.2±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°, 20.2±0.2°, and 20.5±0.2°. 4.3±0.2°, 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, 18.9±0.2°, and 20.5±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°, and 20.5±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 17.7±0.2°, 18.9±0.2°, and 20.2±0.2°. 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°, 20.2±0.2°, and 20.5±0.2°. 4.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°, and 20.2±0.2°. 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°, and 22.4±0.2°. 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, 17.7±0.2°, 18.9±0.2°, and 22.4±0.2°. More preferably, the powder X-ray diffraction spectrum optionally further comprises diffraction peaks located at one or more of 2θ of 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 20.5±0.2°, 21.4±0.2°, or 21.9±0.2°, preferably at least any 2 to 4 or 5 to 6 of these, more preferably any 4 or 6 of these, for example 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, and 20.5±0.2°. 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, and 21.4±0.2°. 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, and 21.9±0.2°. 9.3±0.2°, 18.5±0.2°, 20.5±0.2°, and 21.4±0.2°. 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 20.5±0.2°, and 21.4±0.2°. 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 21.4±0.2°, and 21.9±0.2°. 14.1±0.2°, 18.5±0.2°, 20.5±0.2°, 21.4±0.2°, and 21.9±0.2°. 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 20.5±0.2°, 21.4±0.2°, and 21.9±0.2°. In some embodiments of the present invention, the powder X-ray diffraction spectrum of tromethamine salt crystalline Form E has characteristic peaks at 6.3±0.2° and 13.6±0.2° 2θ, preferably further having characteristic peaks at 4.3±0.2° and 18.9±0.2° 2θ, more preferably further having characteristic peaks at 8.6±0.2°, 17.7±0.2°, 20.2±0.2° and 22.4±0.2° 2θ, even more preferably further having characteristic peaks at 14.1±0.2° and 20.5±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 9.3±0.2°, 18.5±0.2°, 21.4±0.2° and 21.9±0.2° 2θ.

[0043] In some embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed as 2θ angles and d-spacing values ​​are as shown in Table 5.

[0044] [Table 5]

[0045] The tromethamine salt crystalline form E of the compound according to the present invention has an X-ray powder diffraction pattern essentially as shown in FIG. 11 and a DSC pattern essentially as shown in FIG.

[0046] In a further preferred embodiment of the present invention, the crystalline form is a crystalline form containing a solvent, wherein the solvent is selected from water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, tert-butanol, 2-butanone, 3-pentanone, n-heptane, ethyl formate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, and isopropyl ether.

[0047] In a further preferred embodiment of the present invention, the number of solvents is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, and more preferably 0.5, 1, 2 or 3.

[0048] The present invention further provides a method for producing a compound represented by general formula (I) or a stereoisomer and a basic salt thereof, specifically, the method comprising the steps of: 1) Weighing an appropriate amount of free acid and dissolving it in a good solvent; 2) weighing an appropriate amount of counter ion base and dissolving it in an organic solvent, the amount of the counter ion base being preferably 1.0 to 1.5 equivalents; 3) combining the two solutions and stirring to cause precipitation, or adding a poor solvent dropwise and then stirring to cause precipitation; 4) Rapid centrifugation or static evaporation to dryness to obtain the desired product; where: The good solvent is selected from acetone, tetrahydrofuran, ethyl formate, ethyl acetate, 2-methyl-tetrahydrofuran, 2-butanone, n-butanol, 1,4-dioxane, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, and tert-butanol, and is preferably 2-methyl-tetrahydrofuran, ethyl acetate, 2-butanone, acetone, or ethyl formate; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, and N,N-dimethylformamide, and is preferably methanol, ethanol, or acetonitrile. The good solvent and the organic solution must be compatible with each other when used. the anti-solvent is selected from heptane, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether, and ethyl acetate, and is preferably methyl tert-butyl ether or isopropyl ether; The counterion base is an organic base or an inorganic base. The organic base is selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, meglumine, N-hydroxyethylmorpholine, piperazine, N-hydroxyethylpyrrolidine, N,N-dibenzylethylenediamine, 2-diethylaminoethanol, ethanolamine, betaine, L-arginine, lysine, phenethylbenzylamine, benzathine penicillin, dimethylaminoethanol, imidazole, or a mixture thereof, and is preferably diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, or a mixture thereof, and more preferably tromethamine. The inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aqueous ammonia, or a mixture thereof, and is preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or a mixture thereof.

[0049] The present invention further provides a method for producing a compound represented by general formula (I) or a stereoisomer and a basic salt thereof, specifically, the method comprising: 1) weighing an appropriate amount of free acid and suspending it in a poor solvent; 2) weighing an appropriate amount of counter ion base and dissolving it in an organic solvent, the amount of the counter ion base being preferably 1.0 to 1.5 equivalents; 3) combining the two solutions, stirring and dissolving, and continuing to stir; 4) Rapid centrifugation or static evaporation to dryness to obtain the desired product; where: the anti-solvent is selected from ethanol, ethyl acetate, ethyl formate, isopropanol, isopropyl acetate, methyl tert-butyl ether, dichloromethane, methanol, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol, and 3-pentanone, and is preferably ethanol, ethyl acetate, isopropanol, or isopropyl acetate; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, and N,N-dimethylformamide, and is preferably methanol, ethanol, or acetonitrile. The good solvent and the organic solution must be compatible with each other when used. The counterion base is an organic base or an inorganic base. The organic base is selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, meglumine, N-hydroxyethylmorpholine, piperazine, N-hydroxyethylpyrrolidine, N,N-dibenzylethylenediamine, 2-diethylaminoethanol, ethanolamine, betaine, L-arginine, lysine, phenethylbenzylamine, benzathine penicillin, dimethylaminoethanol, imidazole, or a mixture thereof, and is preferably diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, or a mixture thereof, and more preferably tromethamine. The inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aqueous ammonia, or a mixture thereof, and is preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or a mixture thereof.

[0050] The present invention further provides a method for producing a compound represented by general formula (I) or a stereoisomer and a basic salt thereof, specifically, the method comprising: 1) weighing an appropriate amount of a basic salt of a compound and suspending it in a poor solvent, the suspension density being preferably 50 to 200 mg / mL; 2) shaking the obtained suspension at a certain temperature for a certain period of time, the temperature being preferably 25 to 50°C, and the period of time being preferably 1 to 15 days; 3) rapidly centrifuging the suspension, removing the supernatant, and drying the remaining solid in a vacuum drying box to a constant weight to obtain the target product; where: The anti-solvent is selected from dichloromethane, 1,4-dioxane, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tert-butyl ether, n-heptane, tert-butanol or 2-butanone.

[0051] Another object of the present invention is to provide pharmaceutical compositions containing a therapeutically effective amount of said compounds or stereoisomers and salts thereof, as defined above, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0052] Embodiments provided herein include a therapeutically effective amount of a basic salt or crystalline form thereof, wherein the therapeutically effective amount is selected from 0.0001-99%, 0.0001-95%, 0.0001-90%, 0.0001-85%, 0.0001-80%, 0.0001-75%, 0.0001-70%, 0.001-60%, 0.001-55%, 0.01-50%, 0.01-40%, 0.01-30%, 0.01-20%, 0.01-10%, or 0.01-5%.

[0053] The present invention further relates to the application of any of the compounds of the general formula shown, their stereoisomers or pharmaceutically acceptable salts thereof, or said pharmaceutical compositions in the manufacture of GLP-1 receptor agonist pharmaceuticals.

[0054] The present invention further relates to the application of the compound represented by the general formula, its stereoisomer or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof in the manufacture of a medicament for treating a metabolic-related disease, wherein the metabolic-related disease is selected from diabetes, obesity or non-alcoholic steatohepatitis-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic steatohepatitis.

[0055] The present invention further relates to a method for producing a medicament for treating metabolic and related disorders using a compound of the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0056] The present invention further relates to a method for preventing and / or treating a metabolic-related disease, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0057] The present invention further provides methods of treating disease conditions using the compounds or pharmaceutical compositions of the present invention, including, but not limited to, conditions associated with GLP-1 receptor modulators.

[0058] The present invention further relates to a method for treating a disease associated with a metabolic disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. [Brief explanation of the drawings]

[0059] [Figure 1] 1 is an XRPD representation of tromethamine salt crystalline form A. [Figure 2] 1 is a DSC diagram of tromethamine salt crystalline form A. [Figure 3] 1 is a TGA representation of tromethamine salt crystalline form A. [Figure 4] 1 is an XRPD representation of tromethamine salt crystalline form B. [Figure 5] 1 is a DSC diagram of tromethamine salt crystalline form B. [Figure 6] 1 is an XRPD representation of tromethamine salt crystalline form C. [Figure 7] 1 is a DSC diagram of tromethamine salt crystalline form C. [Figure 8] 1 is a TGA representation of tromethamine salt crystalline form C. [Figure 9] 1 is a graphical XRPD diagram of tromethamine salt crystalline form D. [Figure 10] 1 is a DSC plot of tromethamine salt crystalline form D. [Figure 11] 1 is an XRPD representation of tromethamine salt crystalline form E. [Figure 12] 1 is a DSC diagram of tromethamine salt crystalline form E. DETAILED DESCRIPTION OF THE INVENTION

[0060] Unless stated to the contrary, terms used in the specification and claims have the following meanings.

[0061] In the present invention, an alkyl group refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, and 5-methylhexyl groups. , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof.

[0062] The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available bonding site. The substituent is preferably one or more groups independently selected from alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxylate groups. In the present invention, the substituent is preferably a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a haloalkyl group, a deuterated alkyl group, an alkyl group substituted with an alkoxy group, or an alkyl group substituted with a hydroxy group. The alkyl group substituted with a hydroxy group may be a 2-hydroxyisopropyl group or a 1-hydroxyethyl group.

[0063] In the present invention, the term "alkoxy group" refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where the definition of "alkyl group" is as defined above, and is preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, and carboxylate groups. Further non-limiting examples of alkoxy groups include propane-2-oxy groups and the like.

[0064] In the present invention, a haloalkyl group refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples of haloalkyl groups include a trifluoromethyl group, a trifluoroethyl group, Non-limiting examples of haloalkyl groups further include difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, and the like.

[0065] In the present invention, a haloalkoxy group refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above; The haloalkoxy group may be perhalogenated or partially halogenated, and the number of halogen atoms may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., and the halogen atom is preferably F, Cl, Br, or I, such as a trifluoromethoxy group, a difluoromethoxy group, a 1,1,2,2-tetrafluoroethoxy group, or a perfluoroethoxy group.

[0066] In the present invention, a hydroxyalkyl group refers to an alkyl group substituted with a hydroxy group, wherein the alkyl group is as defined above.

[0067] In the present invention, a haloalkyl group refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0068] In the present invention, a haloalkoxy group refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0069] "Hydroxy" refers to an -OH group.

[0070] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0071] An "amino group" refers to -NH2.

[0072] A "cyano group" refers to -CN.

[0073] A "nitro group" refers to -NO2.

[0074] "THF" refers to tetrahydrofuran.

[0075] "EtOAc" refers to ethyl acetate.

[0076] "DMSO" refers to dimethyl sulfoxide.

[0077] "LDA" refers to lithium diisopropylamide.

[0078] "DMAP" refers to 4-dimethylaminopyridine.

[0079] "EtMgBr" refers to ethylmagnesium bromide.

[0080] "HOSu" refers to N-hydroxysuccinimide.

[0081] "EDCl" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0082] "IPA" refers to isopropanol.

[0083] "MeOH" refers to methanol.

[0084] "EtOH" refers to ethanol.

[0085] "Acetone" refers to acetone.

[0086] "MEK" refers to butanone.

[0087] "2-Me-THF" refers to 2-methyltetrahydrofuran.

[0088] "BuOH" refers to butanol.

[0089] "Dioxane" refers to dioxane.

[0090] "DMF" refers to N,N-dimethylformamide.

[0091] "DIPEA" refers to N,N-diisopropylethylamine.

[0092] "HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

[0093] "Tris" refers to tromethamine.

[0094] Various terms such as "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," and "X is A, B, and C" all mean the same thing, i.e., X can be one or more of A, B, and C.

[0095] "Optional" or "optionally" means that the subsequently described event or circumstance may occur, but need not occur, and the description includes cases where the event or circumstance has or has not occurred.

[0096] "Substituted" refers to the fact that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced with the corresponding number of substituents. Needless to say, substituents are present only at their possible chemical positions, and a person skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino group or a hydroxy group having free hydrogen may be unstable if it is bound to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0097] "Stereoisomerism" includes three types: geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0098] As used herein, the names of compounds are intended to encompass all possible isomeric forms, including stereoisomers of the compounds (e.g., enantiomers, diastereomers, racemates or racemic mixtures, and any mixtures thereof).

[0099] Any hydrogen atom described in the present invention may be substituted with its isotope, deuterium, and any hydrogen atom in the compounds of the examples of the present invention may also be substituted with a deuterium atom.

[0100] A "pharmaceutical composition" is meant to contain 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 purpose of a pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredients, thereby exerting their biological activity.

[0101] X-ray powder diffraction pattern (XRPD) refers to an experimentally observed diffraction pattern or parameters derived therefrom, characterized by peak positions (abscissa) and peak intensities (ordinate). As those skilled in the art will appreciate, experimental error therein is dependent on instrument conditions, sample preparation, and sample purity. In particular, as those skilled in the art will appreciate, X-ray diffraction patterns typically vary depending on instrument conditions. As those skilled in the art will appreciate, suitable error limits for XRPD may be 2θ±0.5°, 2θ±0.4°, 2θ±0.3°, or 2θ±0.2°. It should be noted that the relative intensities of an X-ray diffraction pattern may also vary depending on experimental conditions, and therefore the order of peak intensities is not the only or decisive factor. Furthermore, experimental factors such as sample height may affect the overall peak angle, and a certain deviation is usually acceptable. Therefore, as those skilled in the art will appreciate, any crystalline form having characteristic peaks that are the same as or similar to those of the patterns of the present invention is within the scope of the present invention.

[0102] "TGA" refers to thermogravimetric analysis (TGA) experiments.

[0103] "DSC" refers to differential scanning calorimetry (DSC) experiments.

[0104] "HPLC" refers to high performance liquid chromatography (HPLC) experiments.

[0105] "PK" refers to pharmacokinetic (PK) studies.

[0106] "KF" refers to Karl Fischer moisture determination (KF) experiment.

[0107] The present invention will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0108] Example The following examples are provided to illustrate the present invention, but should not be construed as limiting the scope of the present invention. Unless specific conditions for experimental procedures are specifically described in the examples of the present invention, the usual conditions or recommended conditions of the raw materials and product manufacturers are generally followed. Reagents for which no specific source is specified are commonly available commercially.

[0109] Intermediate Im-1 Synthesis of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester [ka]

[0110] Step 1 (S)-4-Nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester In a 50 mL reaction flask, 3-fluoro-4-(1-((6-(piperidin-4-yl)pyridin-2-yl)oxo)cyclopropyl)benzonitrile (2 g, 10.04 mmol), K2CO3 (2.78 g, 20.08 mmol) were dissolved in tetrahydrofuran (30 mL), and (S)-oxetan-2-ylmethylamine (874 mg, 10.04 mmol) was added and the reaction was stirred at room temperature for 12 hours. The reaction was stopped, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL × 2), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2.0 g, yellow solid), yield: 74.8%. MS m / z(ESI):267.0[M+1].

[0111] Step 2 (S)-4-Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (3 g, 11.27 mmol) was dissolved in methanol (30 mL), and 10% Pd / C (300 mg) was added. The mixture was purged with hydrogen gas three times and reacted for 3 hours with stirring. The reaction mixture was filtered, and the organic phase was dried and then spin-dried to give the title product (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2.6 g, yellow solid) in 97.7% yield. MS m / z(ESI):237.1[M+1].

[0112] Step 3 (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester In a 50 mL reaction flask, (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2 g, 8.46 mmol) and p-toluenesulfonic acid (86 mg, 499.41 μmol) were dissolved in tetrahydrofuran (100 mL). 2-Chloro-1,1,1-trimethoxyethane (1.3 g, 8.41 mmol) was added, and the reaction mixture was stirred at 60 °C for 1 hour. The reaction mixture was quenched, cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Im-1) (1.3 g, yellow solid), yield: 52.0%. MS m / z(ESI):295.0[M+1].

[0113] Intermediate Im-2 Synthesis of ((S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester [ka]

[0114] Step 1 (S)-5-Nitro-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester Starting from 6-chloro-5-nitro-2-pyridinecarboxylic acid methyl ester, the title product (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester was obtained by referring to Step 1 of Intermediate Im-1. MS m / z(ESI):268.1[M+1].

[0115] Step 2 (S)-5-Amino-6-((oxetan-2-ylmethyl)amino)2-pyridinecarboxylic acid methyl ester. Starting from (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester, the title product (S)-5-amino-6-((oxetan-2-ylmethyl)amino)-2-pyridinecarboxylic acid methyl ester was obtained by referring to Step 2 of Intermediate Im-1. MS m / z(ESI):238.1[M+1].

[0116] Step 3 ((S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester At room temperature, (S)-5-amino-6-((oxetan-2-ylmethyl)amino)-2-picolinate (340 mg, 1.43 mmol) was dissolved in tetrahydrofuran (5 mL), and a solution of chloroacetic anhydride (257.27 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise, stirred at room temperature for 30 minutes, heated to 60°C, reacted for 2 hours, cooled to room temperature, and completion of the reaction was indicated by LCMS. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated sodium bicarbonate solution (15 mL × 3) and saturated sodium chloride solution (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and spun to give the title product ((S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester (Im-2)) (yellow oil, 0.4 g), yield: 94.4%. The crude product was used directly in the next step. MS m / z(ESI):296.1[M+1].

[0117] Intermediate Im-3 Synthesis of 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester [ka]

[0118] Step 1 1-(Fluoromethyl)cyclopropane-1-carboxylic acid ethyl ester 1-(Hydroxymethyl)cyclopropylcarboxylic acid ethyl ester (7 g, 48.55 mmol) was dissolved in DCM (100 mL) and DAST (8.61 g, 53.41 mmol) was added thereto at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After the reaction was completed, 50 mL of water was added thereto, and the mixture was extracted with dichloromethane (50 mL × 2), washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give the title product, 1-(fluoromethyl)cyclopropane-1-carboxylic acid ethyl ester (6.5 g, yellow oil), in a yield of 91.6%. 1 H NMR (400MHz, CDCl3): δ 4.52(dd,1.5Hz,2H),4.17(q,2H),1.41-1.33(m,2H),1.26(t,3H),1.05-0.95(m,2H).

[0119] Step 2 1-(Fluoromethyl)cyclopropylmethanol 1-(Fluoromethyl)cyclopropane-1-carboxylic acid ethyl ester (6.5 g, 44.47 mmol) was dissolved in THF (60 mL), and LiAlH (2.53 g, 66.71 mmol) was added thereto in an ice-water bath. The reaction system was allowed to warm to room temperature and stirred for 16 hours. After the reaction was completed, 15 g of sodium sulfate decahydrate was added thereto to quench the reaction, followed by filtration and concentration to obtain the title product, 1-(fluoromethyl)cyclopropylmethanol (3.5 g, yellow oil), in a yield of 75.6%. 1 H NMR (400MHz, CDCl3): δ 4.36(d,2H),3.58(s,2H),0.60(m,4H).

[0120] Step 3 (1-(fluoromethyl)cyclopropyl)methyl methanesulfonate 1-(Fluoromethyl)cyclopropylmethanol (1.3 g, 12.49 mmol) was dissolved in DCM (30 mL), and methylsulfonyl chloride (1.86 g, 16.23 mmol, 1.26 mL) and triethylamine (2.53 g, 24.97 mmol, 3.48 mL) were added dropwise to the solution in an ice-water bath. The reaction mixture was stirred at 20 °C. After completion of the reaction, saturated NaHCO (10 mL) was added dropwise to quench the reaction, and the mixture was extracted with dichloromethane (20 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to give crude (1-(fluoromethyl)cyclopropyl)methyl methanesulfonate (2.0 g, pale yellow oil) in a yield of 87.0%. 1 H NMR (400MHz, CDCl3): δ 4.32(d,2H),4.19(s,2H),3.05(s,3H),0.81-0.72(m,4H).

[0121] Step 4 (1-(Fluoromethyl)cyclopropyl)methylamine (1-(Fluoromethyl)cyclopropyl)methyl methanesulfonate (1.0 g, 5.49 mmol) was dissolved in NH3 / i-PrOH (10 mL) and the reaction was heated in a microwave at 60 °C for 6 h. After the reaction was complete, it was concentrated to give the title product (1-(fluoromethyl)cyclopropyl)methylamine (600 mg, yellow oil). The crude material was used directly in the next step reaction.

[0122] Step 5 Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate Ethyl 3-fluoro-4-nitrobenzoate (1.24 g, 5.82 mmol) was dissolved in DMF (30 mL), and (1-(fluoromethyl)cyclopropyl)methylamine (600 mg, 5.82 mmol) and K2CO3 (1.61 g, 11.64 mmol) were added thereto. The reaction mixture was stirred at 20 °C for 4 hours. After the reaction was completed, the mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 2), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.2 g, pale yellow solid), in a yield of 69.6%. MS m / z(ESI):297.1[M+1]. 1 H NMR (400MHz, CDCl3): δ 8.22(d,1H),7.56(s,1H),7.25(d,1H),4.41(q,2H),4.30(d,2H),3.42(d,2H),1.41(t,3H),0.76(m,4H).

[0123] Step 6 Ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.2 g, 4.05 mmol) was dissolved in MeOH (30 mL), and Pd / C (200 mg, 10% purity) was added thereto. Hydrogen gas was purged from the reaction system three times, and then the mixture was stirred at 20°C for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain the title product, ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, yellow solid), in a yield of 92.7%. MS m / z(ESI):267.1[M+1].

[0124] Step 7 2-(Chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester Ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, 3.76 mmol) was dissolved in MeCN (30 mL), and p-toluenesulfonic acid (193.99 mg, 1.13 mmol) and 2-chloro-1,1,1-trimethoxyethane (1.16 g, 7.51 mmol) were added thereto. The reaction mixture was stirred in an oil bath at 60° C. for 4 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (700 mg, yellow solid), yield: 57.4%.

[0125] MS m / z(ESI):325.1[M+1]. 1 H NMR(400MHz,CDCl3):δ 8.21(s,1H),8.04(d,1H),7.81(d,1H),4.97(s,2H),4.47(s,2H),4.44(q,2H),4.03(d,2H),1.43(t,3H),0.92-0.82(m,4H).

[0126] Intermediate Im-4 tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate [ka]

[0127] Step 1 tert-Butyl 4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate 1-(3-Bromo-2-hydroxyphenyl)ethan-1-one Im-4a (20 g, 0.09 mol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (32 g, 0.10 mol), Pd(dppf)Cl CHCl (7.6 g, 9.40 mmol), and anhydrous potassium carbonate (39 g, 0.28 mol) were dissolved in 250 mL of a 4:1 mixture of dioxane and water. The reaction was heated to 100 °C and stirred for 8 h. The reaction was stopped, the reaction mixture was cooled to ambient temperature, filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product tert-butyl-4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate Im-4b (26 g, colorless oil), yield: 88.1%. MS m / z(ESI):318.1[M+1].

[0128] Step 2 tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate Im-4b (26 g, 0.08 mol) and Pd / C (2.6 g, 10% wt.) were dispersed in methanol (300 mL), and hydrogen gas was injected three times and the air was evacuated. The reaction mixture was stirred for 12 hours. The reaction was stopped, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-4 (25 g, white solid) in a 95.6% yield. MS m / z(ESI):320.1[M+1].

[0129] Example 1 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0130] Step 1 (E)-1-(3-Bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one To a solution of 1-(3-bromo-2-hydroxy-phenyl)ethanone (13 g, 60.45 mmol), 4-chloro-2-fluoro-benzaldehyde (10.06 g, 63.48 mmol) in ethanol (125 mL) and water (200 mL) was added sodium tetraborate decahydrate (45.97 g, 66.50 mmol), and the resulting mixture was stirred for 90 minutes. o C for 12 hours, cooled, filtered, the filter cake was washed with water, and the filter cake was dried to obtain the title product (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one (20 g, yellow solid), yield: 93.0%. MS m / z(ESI): 354.9[M+1]

[0131] Step 2 8-Bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one A solution of (E)-1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one (2 g, 5.62 mmol), concentrated hydrochloric acid (4 mL) in ethanol (10 mL) was stirred at 110° C. for 20 hours under microwave conditions, cooled, spun dry, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one (1.8 g, yellow solid), yield: 90.0%. MS m / z(ESI):355.0[M+1]

[0132] Step 3 8-Bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman To a solution of 8-bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one (1.8 g, 5.06 mmol) in tetrahydrofuran (10 mL) was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-sulfanyl)ethylamine (10 mL) dropwise, and the resulting mixture was stirred for 70 minutes. o C for 12 hours, cooled, added water to quench the reaction, extracted with dichloromethane (50 mL × 3), the organic phase was washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, spin-dried, and the obtained residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 8-bromo-2-(4-chloro-2-fluorophenyl)-4,4-difluoro-chroman (400 mg, yellow solid), yield: 20.9%. MS m / z(ESI):377.0[M+1]

[0133] Step 4 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-formic acid tert-butyl ester A mixture of 8-bromo-2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman (400 mg, 1.06 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (360.32 mg, 1.17 mmol), sodium carbonate (280.71 mg, 2.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (77.44 mg, 105.94 μmol), 1,4-dioxane (10 mL), and water (2 mL) was heated under nitrogen gas protection for 100 minutes. o C for 2 hours, cooled, added water, extracted with dichloromethane (10 mL × 2), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, spin-dried, and purified the resulting residue using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-formic acid tert-butyl ester (450 mg, yellow oil), yield: 88.5%. MS m / z(ESI):480.1[M+1]

[0134] Step 5 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-formic acid tert-butyl ester A mixture of 4-[2-(4-chloro-2-fluorophenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-formic acid tert-butyl ester (450 mg, 937.66 μmol), palladium carbon (80 mg, 10%), and ethyl acetate (30 mL) was purged with hydrogen gas three times and reacted for 5 hours with stirring. After filtration and spin-drying, the title product 4-[2-(4-chloro-2-fluorophenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-formic acid tert-butyl ester (380 mg, pale yellow oil) was obtained in 84.1% yield. MS m / z(ESI):482.2[M+1]

[0135] Step 6 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine A mixture of 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-formic acid tert-butyl ester (340 mg, 705.49 μmol) and hexafluoroisopropanol (10 mL) was heated under microwave conditions for 80 o C for 4 hours, allowed to cool, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine (40 mg, colorless oil), yield: 15.7%. MS m / z(ESI):362.1[M+1]

[0136] Step 7 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylic acid methyl ester A mixture of 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine (40 mg, 110.55 μmol), Im-1 (46.68 mg, 143.72 μmol), potassium carbonate (61.03 mg, 442.22 μmol), and acetonitrile (5 mL) was added to 50 mL of acetonitrile. o C for 3 hours, cooled, added 5 mL of water, extracted with dichloromethane (20 mL × 3), washed the organic phase with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure, and purified the resulting residue using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-formate ethyl ester (30 mg, colorless oil), yield: 43.7%. MS m / z(ESI):620.2[M+1]

[0137] Step 8 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid A mixture of 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylic acid methyl ester (30 mg, 48.38 μmol), lithium hydroxide monohydrate (20 mg, 476.62 μmol), methanol (2 mL), water (2 mL), and tetrahydrofuran (3 mL) was stirred at room temperature for 12 hours, and formic acid was added. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg, white solid), yield: 68.2%. MS m / z(ESI):606.2[M+1].

[0138] Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave the following: [ka]

[0139] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (1-A) MS m / z(ESI):606.2[M+1].

[0140] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (1-B) MS m / z(ESI):606.2[M+1].

[0141] Example 2 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0142] By replacing Im-1 with Im-2 and referring to Example 1, 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained. MS m / z(ESI):607.2[M+1].

[0143] Chiral resolution of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave the following: [ka]

[0144] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 2-A) MS m / z(ESI):607.2[M+1].

[0145] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 2-B) MS m / z(ESI):607.2[M+1].

[0146] Example 3 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0147] By replacing Im-1 with Im-3 and referring to Example 1, 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained. MS m / z(ESI):622.2[M+1].

[0148] Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave the following: [ka]

[0149] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 3-A) MS m / z(ESI):622.2[M+1].

[0150] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 3-B) MS m / z(ESI):622.2[M+1].

[0151] Example 4 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0152] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-2 as raw materials, 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI):623.2[M+1].

[0153] Chiral separation of 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave the following: [ka]

[0154] 2-((4-((R)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 4-A) MS m / z(ESI):623.2[M+1].

[0155] 2-((4-((S)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 4-B) MS m / z (ESI): 623.2 [M+1].

[0156] Example 5 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-1 as raw materials, 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI):622.2[M+1].

[0157] Chiral separation of 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave the following: [ka]

[0158] 2-((4-((R)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 5-A) MS m / z(ESI):622.2[M+1].

[0159] 2-((4-((S)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 5-B) MS m / z(ESI):622.2[M+1].

[0160] Example 6 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0161] Step 1 tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate Starting from 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one, the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate was obtained by following Steps 4 and 5 of Example 1. MS m / z(ESI):460.1[M+1].

[0162] Step 2 tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxo)-2H-chromen-8-yl)piperidine-1-carboxylate tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate (1 g, 2.17 mmol) was dissolved in 20 mL of THF, and lithium bistrimethylsilylamide (2.4 mL, 2.40 mmol) was added at −78° C. for 1 hour. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (0.94 g, 2.4 mmol) in THF (20 mL) was added at −78° C., and the mixture was slowly warmed to room temperature and stirred for 5 hours. Sodium bicarbonate (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxo)-2H-chromen-8-yl)piperidine-1-carboxylate (456 mg, yield: 35.5%). MS m / z(ESI):592.1[M+1].

[0163] Step 3 tert-Butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxo)-2H-chromen-8-yl)piperidine-1-carboxylate (0.5 g, 0.84 mmol) was dissolved in 10 mL of DMA / THF (v:v = 1:3). Nickel acetate tetrahydrate (24.8 mg, 0.1 mmol), Zn powder (10 mg, 0.16 mmol), 1,5-cyclooctadiene (11 mg, 0.1 mmol), and lithium chloride (53 mg, 1.3 mmol) were added and reacted at room temperature for 16 hours under nitrogen gas protection. Water (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate (241 mg, yield: 60.0%). MS m / z(ESI):478.1[M+1].

[0164] Step 4 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate and Im-1 as raw materials, the product 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by following steps 6 to 8 of Example 1. MS m / z(ESI):622.1[M+1].

[0165] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was resolved to give the following products: [ka]

[0166] 2-((4-((R)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 6-A) MS m / z(ESI):622.1[M+1].

[0167] 2-((4-((S)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 6-B). MS m / z(ESI):622.1[M+1].

[0168] Example 7 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate and Im-2 as raw materials, the product 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by following steps 6 to 8 of Example 1. MS m / z(ESI):623.1[M+1].

[0169] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was resolved to give the following products: [ka]

[0170] 2-((4-((R)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 7-A) MS m / z(ESI):623.1[M+1].

[0171] 2-((4-((S)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 7-B). MS m / z(ESI):623.1[M+1].

[0172] Example 8 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0173] Step 1 (E)-2-Bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (E)-1-(3-Bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one (1 g, 2.81 mmol) was dissolved in 30 mL of THF and methylmagnesium bromide (7 mL, 7 mmol) was added at 0 °C. The mixture was slowly warmed to room temperature and stirred for 3 hours. The reaction was quenched by the addition of ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain (E)-2-bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (831 mg, yield: 79.6%). MS m / z(ESI):370.9[M+1].

[0174] Step 2 8-Bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene (E)-2-Bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (0.5 g, 1.34 mmol) was dissolved in 15 mL of nitromethane, and (2,3,4,5-tetrafluorophenyl)boronic acid (52 mg, 0.26 mmol) was added. The mixture was stirred at 60 °C for 16 hours. Water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The mixture was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain 8-bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene (326 mg, yield: 68.0%). MS m / z(ESI):356.9[M+1].

[0175] Step 3 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid Using 8-bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene as a raw material, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Steps 4, 5, 7, and 8 of Example 1. MS m / z(ESI):602.2[M+1].

[0176] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was resolved to give the following products: [ka]

[0177] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 8-A) MS m / z(ESI):602.2[M+1].

[0178] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 8-B). MS m / z(ESI):602.2[M+1].

[0179] Example 9 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-chloro-2-(methoxy-d3)benzaldehyde as a raw material, the product 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to Example 2. MS m / z(ESI):622.2[M+1].

[0180] Chiral separation of 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid gave the following: [ka]

[0181] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 9-A) MS m / z(ESI):622.2[M+1].

[0182] 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 9-B) MS m / z(ESI):622.2[M+1].

[0183] Example 10 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0184] Using 4-chloro-2-(methoxy-d3)benzaldehyde as a raw material, the product 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 1. MS m / z(ESI):621.2[M+1].

[0185] Chiral separation of 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid gave the following: [ka]

[0186] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 10-A) MS m / z(ESI):621.2[M+1]. 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 10-B) MS m / z(ESI):621.2[M+1].

[0187] Example 11 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0188] Step 1 (E)-2-Bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (E)-1-(3-Bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one (500 mg, 1.41 mmol) was dissolved in methanol (15 mL), sodium borohydride (64 mg, 1.69 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water, extracted with dichloromethane (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography with an eluent of petroleum ether and ethyl acetate to give (E)-2-bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (454 mg, yield: 90.0%). MS m / z(ESI):356.9[M+1].

[0189] Step 2 8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (E)-2-Bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (300 mg, 0.84 mmol) was dissolved in dichloromethane (10 mL), p-toluenesulfonic acid (29 mg, 0.17 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography using petroleum ether and ethyl acetate as eluent to give (8-bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (200 mg, yield: 70.1%). MS m / z(ESI):338.9[M+1].

[0190] Step 3 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol 8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (200 mg, 0.59 mmol) was dissolved in THF (10 mL), and a THF solution of borane (0.71 mL, 0.71 mmol) was added. o C for 1 hour, 2 mL of water was added, followed by NaOH (71 mg, 1.77 mmol) and 0.1 mL of hydrogen peroxide solution. o The mixture was stirred at C for 2 h. The reaction was quenched by adding 10 mL of water, extracted with dichloromethane (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a petroleum ether and ethyl acetate system as an eluent to give 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol (63 mg, yield: 29.8%). MS m / z(ESI):356.9[M+1].

[0191] Step 4 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol (500 mg, 1.40 mmol) was dissolved in DCM (20 mL), and Dess-Martin oxidant (0.71 mL, 1.67 mmol) was added. o The mixture was stirred at C for 1 hour. The reaction was quenched by adding 10 mL of water, extracted with dichloromethane (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a petroleum ether and ethyl acetate system as an eluent to give 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one (448 mg, yield: 89.9%). MS m / z(ESI):354.9[M+1].

[0192] Step 5 tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate Using 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one as the raw material, the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate was obtained by following steps 3 to 5 of Example 1. MS m / z(ESI):482.2[M+1].

[0193] Step 6 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine Starting from tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate, the product 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine was obtained by following Step 6 of Example 1. MS m / z(ESI):362.1[M+1].

[0194] Step 7 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine as the raw material, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by referring to Steps 7 and 8 of Example 1. MS m / z(ESI):607.1[M+1].

[0195] 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was subjected to chiral resolution. [ka]

[0196] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 11-A) MS m / z(ESI):607.1[M+1].

[0197] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 11-B) MS m / z(ESI):607.1[M+1].

[0198] Example 12 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0199] Step 1 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 1-(4-Chloro-2-hydroxyphenyl)ethan-1-one 12a (15 g, 87.93 mmol), deuterated iodomethane (16.57 g, 114.31 mmol), and anhydrous potassium carbonate (36.46 g, 0.26 mol) were dispersed in DMF (150 mL). The reaction mixture was heated to 50 °C and reacted for 12 hours with vigorous stirring. The reaction mixture was then terminated, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product, 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 12b (15 g), in a 90.9% yield. MS m / z(ESI):188.1[M+1].

[0200] Step 2 tert-Butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-4 (25 g, 79.94 mmol) was dissolved in tetrahydrofuran (300 mL). The solution was cooled in a dry ice / ethanol bath, and LiHMDS (18.4 mL, 0.184 mol, 1 M THF solution) was slowly added thereto. After completion, the reaction was allowed to proceed with stirring for 30 minutes. 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 12b (15 g, 79.94 mmol) was dissolved in THF (30 mL), and this solution was slowly added dropwise to the reaction solution. The reaction was allowed to proceed with stirring for 40 minutes while maintaining the temperature of the dry ice / ethanol bath. The reaction was stopped, the dry ice / ethanol bath was removed, and saturated ammonium chloride solution was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (300 mL × 2). The organic phases were combined, washed with saturated sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product tert-butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 12c (31 g), yield: 76.5%. MS m / z(ESI):507.2[M+1].

[0201] Step 3 tert-Butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate tert-Butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 12c (2.00 g, 4.07 mmol) and BAST (10 mL) were dissolved in DMF (10 mL), and then ethanol (20 μL) was added to the reaction solution, and the mixture was stirred for 4 hours to react. The reaction was stopped, and the reaction solution was slowly added to ice water to quench it, and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with water (100 mL), washed with saturated sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product tert-butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate 12d (750 mg), yield: 38.7%. MS m / z(ESI):491.2[M+1].

[0202] Step 4 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine tert-Butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate 12d (750 mg, 1.53 mmol), boron trifluoride etherate (543 mg, 3.83 mmol), and powdered 4 Å molecular sieves (750 mg) were dispersed in dichloromethane (10 mL) and stirred for 3 hours at 0° C. The reaction was stopped and quenched by adding saturated sodium bicarbonate solution to the reaction mixture. The mixture was filtered through diatomaceous earth, the filtrate was settled, the organic layer was separated, the aqueous layer was extracted with dichloromethane (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography with dichloromethane and methanol as eluents to give the title product 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine 12e (490 mg), yield: 82.1%. MS m / z(ESI):391.2[M+1].

[0203] Step 5 Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine 12e (490 mg, 1.25 mmol), methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im-2 (371 mg, 1.25 mmol), and anhydrous potassium carbonate (518 mg, 3.75 mmol) were dispersed in acetonitrile (8 mL). The reaction mixture was heated to 50 °C and reacted for 3 hours with vigorous stirring. The reaction was stopped, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate as an eluent. The purified sample was separated by chiral HPLC to obtain the title product methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 12f (210 mg), yield: 26.5%. MS m / z(ESI):632.2[M+1].

[0204] Step 6 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 12f (210 mg, 332.19 μmol) and lithium hydroxide (133 mg, 3.32 mmol) were dissolved in 9 mL of a mixed solvent of THF, water, and methanol (4:4:1), and the mixture was stirred for 3 hours to react. The reaction was stopped, and formic acid was added to adjust the pH to 6. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 12 (170 mg), yield: 82.8%.

[0205] MS m / z(ESI):618.2[M+1]. 1 H NMR(400MHz,MeOD):δ 8.16-7.97(m,2H),7.29(d,J=8.2Hz,1H),7.08-6.98(m,2H),6.94-6.85(m,2H),6.81(t,J=7.5Hz,1H),6.57(d,J=9.8Hz,1H), 5.78(d,J=9.8Hz,1H),5.25(dd,J=7.5,3.0Hz,1H),4.96(dd,J=14.9,6.7Hz,1H),4.83(dd,J=14.9,3.1Hz,1H),4.66-4.53(m,1 H),4.48-4.35(m,1H),4.25(d,J=14.2Hz,1H),4.16(d,J=14.2Hz,1H),3.25(d,J=11.5Hz,1H),3.12(d,J=11.5Hz,1H),2.91(s ,1H),2.83-2.70(m,1H),2.61-2.41(m,3H),1.85(q,J=3.9Hz,2H),1.78(s,3H),1.68(d,J=3.7Hz,1H),1.59(d,J=14.9Hz,1H).

[0206] Example 13 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0207] Using 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Im-4 and 1-(4-chloro-2-fluorophenyl)ethan-1-one as starting materials, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 13 was obtained by following steps 2 to 6 of Example 12. MS m / z(ESI):621.2[M+1].

[0208] Example 14 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0209] Step 1 tert-Butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate Referring to the synthesis method of Example 13, 1-(4-chloro-2-fluorophenyl)ethan-1-one 14a (5 g, 28.97 mmol), Im-4 (9.25 g, 28.97 mmol), LiHMDS (66.6 mL, 66.63 mmol), and THF (100 mL) were added to obtain the title product tert-butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 17b (7.60 g), yield: 53.3%. MS m / z(ESI):492.2[M+1].

[0210] Step 2 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one tert-Butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 14b (5 g, 10.16 mmol) and p-toluenesulfonic acid (5.25 g, 30.48 mmol) were dissolved in toluene (50 mL). The reaction mixture was heated to 100° C. and reacted for 5 hours with stirring. The reaction was stopped, the reaction solution was cooled to room temperature, and 2M sodium hydroxide solution was added thereto to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography with dichloromethane and methanol as eluents to obtain the title product 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one 14c (2.36 g), yield: 62.1%. MS m / z(ESI):374.1[M+1].

[0211] Step 3 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-ol 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one 14c (2 g, 5.35 mmol) was dissolved in methanol (30 mL). Sodium borohydride (396 mg, 10.70 mmol) was slowly added to the solution in an ice bath in small portions. After completion, the ice bath was removed and the reaction solution was allowed to warm to ambient temperature and react for 2 hours. The reaction was stopped, saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the pH was adjusted to 10 with 1M sodium hydroxide solution. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-ol 14d (1.88 g), yield: 93.5%, and the compound was used directly in the next step reaction without purification. MS m / z(ESI):376.1[M+1].

[0212] Step 4 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-ol 14d (1.50 g, 3.99 mmol) and p-toluenesulfonic acid (2.06 g, 11.97 mmol) were dissolved in toluene (20 mL). The reaction mixture was heated to 100 ° C. and stirred for 30 minutes. The reaction mixture was stopped, cooled to room temperature, and 2 M sodium hydroxide solution was added thereto to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 14e (1.02 g), yield: 71.4%, and the compound was used directly in the next step without purification. MS m / z(ESI):358.1[M+1].

[0213] Step 5 Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Referring to the synthesis method of Step 5 of Example 13, 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 14e (500 mg, 1.40 mmol), methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im-2 (413 mg, 1.40 mmol), anhydrous potassium carbonate (5 80 mg, 4.20 mmol), acetonitrile (10 mL) were added to give the title product methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 17f (263 mg), yield: 30.5%. MS m / z(ESI):617.2[M+1].

[0214] Step 6 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Referring to the synthesis method of Step 6 of Example 13, methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 14f (100 mg, 162 μmol) and lithium hydroxide (39 mg, 1.62 mmol) were added to obtain the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 14 (76 mg), yield: 77.8%. MS m / z(ESI):603.2[M+1].

[0215] Example 15 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0216] Referring to the synthesis method of Example 12, Im-1 was used as the starting material to obtain the title product, 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid. MS m / z(ESI):617.3[M+1].

[0217] Example 16 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0218] Step 1 4-chloro-2-fluoro<α-2H>benzaldehyde 4-Chloro-2-fluoro-1-iodo-benzene (5 g, 19.50 mmol) and toluene (50 mL) were added to a 100 mL flask, and isopropanol-sodium chloride (12.9 mL, 3 M, 38.99 mmol) was added at -30 °C, and the reaction mixture was reacted at -20 °C for 2 h. N,N-dimethylformamide-D7 (3.12 g, 38.99 mmol) was then added to the reaction mixture, and the reaction mixture was continued at 0 °C for 1 h. The reaction was stopped, and the reaction mixture was quenched with saturated aqueous ammonium chloride solution, water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product 4-chloro-2-fluoro<α-2H>benzaldehyde 16b (2.7 g), yield: 86.79%. MS m / z(ESI):160.0[M+1].

[0219] Step 2 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-Chloro-2-fluoro<α-2H>benzaldehyde 16b (1.5 g, 9.40 mmol), 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Im-4 (3.00 g, 9.40 mmol), and tetrahydrofuran (40 mL) were added to a 100 mL flask, and sodium hydride (1.13 g, 28.20 mmol, 60% purity) was added at 0 °C. The reaction mixture was then reacted at 25 °C for 3 h. The reaction was stopped, and the reaction mixture was quenched with saturated aqueous ammonium chloride solution, water (20 mL) was added, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 16c (3 g), yield: 69.23%. MS m / z(ESI):461.1[M+1].

[0220] Step 3 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 16c as a starting material, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 16 was obtained by following the synthesis method of steps 3 to 6 of Example 36.

[0221] MS m / z(ESI):608.1[M+1]. 1 H NMR(400MHz,DMSO-d6):δ 8.10(d,1H),7.97(d,1H),7.54(dd,1H),7.41(t,1H),7.29(dd,1H),7.24-7.15(m,2H),6.96(t,1 H),5.67(d,1H),5.20-5.11(m,1H),4.88-4.79(m,1H),4.74-4.65(m,1H),4.53-4.43(m,1H),4.4 1-4.31(m,1H),3.97(d,1H),3.88(d,1H),2.98-2.91(m,1H),2.87-2.79(m,1H),2.75-2.62(m,2H) ),2.49-2.41(m,1H),2.25-2.07(m,2H),1.73-1.59(m,2H),1.54-1.41(m,1H),1.37-1.29(m,1H).

[0222] Example 17 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0223] Step 1 1-Bromo-4-chloro-2-(methoxy-d3)benzene Starting from 2-bromo-5-chlorophenol 17a, 1-bromo-4-chloro-2-(methoxy-d3)benzene 17b was obtained by following the synthesis method in Step 1 of Example 36. MS m / z(ESI):223.9[M+1].

[0224] Step 2 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde Using 1-bromo-4-chloro-2-(methoxy-d3)benzene 17b as a starting material, 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 17c was obtained by referring to the synthesis method in Step 1 of Example 16. MS m / z(ESI):175.0[M+1].

[0225] Step 3 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Using 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 17c as the starting material, 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 17d was obtained by following the synthesis method in Step 2 of Example 16. MS m / z(ESI):476.2[M+1].

[0226] Step 4 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 17d as a starting material, 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 17 was obtained by following the synthesis method of steps 3 to 6 of Example 12.

[0227] MS m / z(ESI):623.2[M+1]. 1 H NMR(400MHz,Methanol-d4):δ 8.14-8.04(m,2H),7.31(d,1H),7.20-7.13(m,2H),7.05(d,1H),6.96-6.87(m,2H),5.36(d, 1H),5.29-5.24(m,1H),5.03-4.93(m,1H),4.82-4.75(m,1H),4.65-4.55(m,1H),4.45-4.36( m,1H),4.20(d,1H),4.10(d,1H),3.23-3.15(m,1H),3.09-3.02(m,1H),2.91-2.86(m,1H),2. 81-2.72(m,1H),2.57-2.37(m,3H),1.88-1.78(m,2H),1.71-1.63(m,1H),1.59-1.52(m,1H).

[0228] Example 18 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0229] Step 1 4-chloro-2-fluoro<α-2H>benzaldehyde 4-Chloro-2-fluoro-1-iodo-benzene 18a (5 g, 19.50 mmol) and toluene (50 mL) were added to a 100 mL flask, and isopropanol magnesium chloride (12.9 mL, 3 M, 38.99 mmol) was added at −30° C. The reaction mixture was then reacted at −20° C. for 2 h. N,N-dimethylformamide-D7 (3.12 g, 38.99 mmol) was then added to the reaction mixture, and the reaction mixture was continued at 0° C. for 1 h. The reaction was stopped, and the reaction mixture was quenched with saturated aqueous ammonium chloride solution, water (50 mL) was added, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product 4-chloro-2-fluoro<α-2H>benzaldehyde 18b (2.7 g), yield: 86.79%. MS m / z(ESI):160.0[M+1].

[0230] Step 2 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-Chloro-2-fluoro<α-2H>benzaldehyde 18b (1.5 g, 9.40 mmol), 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Im-4 (3.00 g, 9.40 mmol), and tetrahydrofuran (40 mL) were added to a 100 mL flask, and sodium hydride (1.13 g, 28.20 mmol, 60% purity) was added at 0 °C. The reaction mixture was then reacted at 25 °C for 3 h. The reaction was stopped, and the reaction mixture was quenched with saturated aqueous ammonium chloride solution, water (20 mL) was added, and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spun dry. The resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 18c (3 g), yield: 69.23%. MS m / z(ESI):461.1[M+1].

[0231] Step 3 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 18c (3 g, 6.51 mmol) and isopropanol (50 mL) were added to a 250 mL flask, and sodium borohydride (369.33 mg, 9.76 mmol) was added at 0° C. The reaction mixture was then reacted at 20° C. for 3 hours. The reaction was stopped, and the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20 mL × 3), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spun dry to give the title product 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 18d (3 g), yield: 99.56%. MS m / z(ESI):463.1[M+1].

[0232] Step 4 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 18d (3 g, 6.48 mmol) and N,N-dimethylformamide (30 mL) were added to a 100 mL flask, and p-toluenesulfonic acid (1.67 g, 9.72 mmol) was added at 25 °C. The reaction mixture was then reacted at 50 °C for 4 hours. The reaction was stopped, and the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylic acid tert-butyl ester 18e (1.7 g), yield: 58.96%. MS m / z(ESI):445.1[M+1].

[0233] Step 5 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 4-(2-(4-Chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylic acid tert-butyl ester 18e (1.7 g, 3.82 mmol) and dichloromethane (25 mL) were added to a 100 mL flask, and 4A molecular sieves (1.7 g) and boron trifluoride etherate (1.36 g, 9.55 mmol) were added at 0 °C. The reaction mixture was then allowed to react at 0 °C for 2 h. The reaction was stopped and quenched with saturated aqueous sodium bicarbonate solution (10 mL), water was added (10 mL), extracted with dichloromethane (20 mL × 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered and spin-dried to give the title product 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 18f (1.3 g), yield: 98.67%. MS m / z(ESI): 345.1 [M+1]

[0234] Step 6 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 18f (1.3 g, 3.77 mmol) and acetonitrile (15 mL) were added to a 100 mL flask, and potassium carbonate (1.04 g, 7.54 mmol) and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Im2 (1.11 g, 3.77 mmol) were added at 25 °C. The reaction mixture was then reacted at 25 °C for 10 h. The reaction was stopped, the reaction mixture was quenched with an aqueous solution (10 mL), extracted with dichloromethane (10 mL × 3), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 18g (1.7 g), yield: 74.65%. MS m / z(ESI):604.2[M+1]

[0235] Step 7 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 18g was separated chirally to obtain 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 18h. Division conditions:DH 4.6*250 Hexane:EtOH:MeOH:DEA=70:15:15:0.1% F = 1 mL T = 35°C

[0236] Step 8 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 18h (100 mg, 165.54 μmol) and methanol (2 mL) were added to a 25 mL flask, and lithium hydroxide (39.64 mg, 1.66 mmol) was dissolved in water (1 mL) and added dropwise to the reaction mixture at 25° C. The reaction mixture was then allowed to react at 25° C. for 1 hour. The reaction was stopped, and the reaction solution was quenched with formic acid (0.1 mL), water was added (2 mL), and extracted with dichloromethane (2 mL × 3). The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 18 (70 mg), yield: 71.66%.

[0237] MS m / z(ESI):590.2[M+1] 1 H NMR(400MHz,DMSO):δ 8.08(d,1H),7.96(d,1H),7.52(dd,1H),7.34(t,1H),7.27(dd,1H),7.05(dd,1H),6.98(dd,1H),6.85( t,1H),6.75(d,1H),5.91(d,1H),5.18-5.11(m,1H),4.87-4.80(m,1H),4.72-4.65(m,1H),4.53-4.43( m,1H),4.39-4.31(m,1H),3.96(d,1H),3.87(d,1H),3.01-2.90(m,1H),2.89-2.79(m,1H),2.77-2.61( m,2H),2.48-2.45(m,1H),2.27-2.08(m,2H),1.73-1.61(m,2H),1.54-1.42(m,1H),1.42-1.34(m,1H).

[0238] Example 19 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0239] Step 1 1-Bromo-4-chloro-2-(methoxy-d3)benzene 2-Bromo-5-chlorophenol 19a (10 g, 48.20 mmol), deuterated iodomethane (10.48 g, 72.30 mmol), and anhydrous potassium carbonate (13.33 g, 96.41 mol) were dispersed in DMF (100 mL). The reaction mixture was heated to 50 °C and stirred vigorously for 12 hours. The reaction mixture was then terminated, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product, 1-bromo-4-chloro-2-(methoxy-d3)benzene 19b (10 g), in 92.5% yield. MS m / z(ESI):223.9[M+1].

[0240] Step 2 4-chloro-2-(methoxy-d3)benzaldehyde-d 1-Bromo-4-chloro-2-(methoxy-d3)benzene 19b (1.6 g, 7.13 mmol) was dissolved in tetrahydrofuran (30 mL). After purging with nitrogen, n-BuLi (2.5 M, 3.42 mL) was slowly added dropwise to the solution at −78°C. After the addition was complete, the mixture was stirred at −78°C for 1 hour, and then N,N-dimethylformamide-D7 (856.71 mg, 10.69 mmol) was added. The reaction mixture was stirred for 3 hours and allowed to warm to room temperature. Saturated ammonium chloride solution (20 mL) was slowly added dropwise thereto to quench the reaction, followed by extraction with ethyl acetate (30 mL × 3), washing with saturated brine (30 mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration to obtain a white solid, 4-chloro-2-(methoxy-d3)-benzaldehyde-d 19c (1.2 g, 6.87 mmol), with a yield of 96.42%. MS m / z(ESI):175.0[M+1].

[0241] Step 3 tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 4-Chloro-2-(methoxy-d3)-benzaldehyde-d 19c (700 mg, 4.01 mmol) and tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-4 (1.28 g, 4.01 mmol) were dissolved in tetrahydrofuran (40 mL), and sodium hydride (481.05 mg, 12.03 mmol, 60% purity) was added thereto in portions in an ice-water bath. The reaction mixture was stirred in an ice-water bath for 0.5 hours, and then 20 oThe mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, water (20 mL) was added dropwise to quench the reaction, extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product tert-butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 19d (1.5 g). The yield was 78.6%. MS m / z(ESI):476.2[M+1].

[0242] Step 4 tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 19d (1.4 g, 2.94 mmol) was dissolved in tetrahydrofuran (30 mL) and sodium borohydride (333.82 mg, 8.82 mmol) was added portionwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added dropwise to quench the reaction, extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title product tert-butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 19e (1.4 g). MS m / z(ESI):478.2[M+1].

[0243] Step 5 tert-Butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 19e (1.40 g, 2.93 mmol) was dissolved in dichloromethane (20 mL) and p-toluenesulfonic acid (151.62 mg, 880.49 μmol) was added thereto. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product tert-butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 19f (600 mg, 1.30 mmol), 44.4% yield. MS m / z(ESI):460.2[M+1].

[0244] Step 6 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine tert-Butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 19f (260 mg, 565.22 μmol) was dissolved in dichloromethane (10 mL), and 4A was added thereto in an ice-water bath. o Molecular sieves (260 mg) and boron trifluoride etherate (240.66 mg, 1.70 mmol) were added. The reaction was stirred in an ice-water bath for 1 hour. After completion of the reaction, saturated sodium bicarbonate solution (10 mL) was added dropwise to quench the reaction, which was then extracted with dichloromethane (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine 19g (200 mg). MS m / z(ESI):360.2[M+1].

[0245] Step 7 Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine 19g (200 mg, 555.74 μmol, crude), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Im-2 (180.17 mg, 611.31 μmol), and potassium carbonate (230.42 mg, 1.67 mmol) were dissolved in acetonitrile (10 mL). The reaction system was placed in an oil bath for 60 min. o The mixture was stirred at RT for 4 hours. After completion of the reaction, water (10 mL) was added to dilute the reaction mixture, extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents. The purified sample was then separated by chiral HPLC to obtain the title product, methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 19h (100 mg, 161.5 μmol), in a 29.1% yield. MS m / z(ESI):619.2[M+1].

[0246] Step 8 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 19h (100 mg, 161.5 μmol) and lithium hydroxide (38.8 mg, 1.62 mmol) were dissolved in 9 mL of a mixed solvent of THF, water, and methanol (4:4:1), and the mixture was stirred for 3 hours. The reaction was quenched, and formic acid was added to adjust the pH to 6. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 19 (60 mg), yield: 61.5%.

[0247] MS m / z(ESI):605.2[M+1]. 1 H NMR(400MHz,DMSO):δ 8.08(d,1H),7.96(d,1H),7.22(d,1H),7.14(d,1H),7.02(d,1H),6.99-6.91(m,2H),6.82(t, 1H),6.66(d,1H),5.86(d,1H),5.17-5.11(m,1H),4.86-4.77(m,1H),4.73-4.65(m,1H),4.51 -4.45(m,1H),4.38-4.30(m,1H),3.97-3.84(m,2H),2.98-2.91(m,1H),2.87-2.81(m,1H),2. 76-2.64(m,2H),2.47-2.45(m,1H),2.24-2.09(m,2H),1.70-1.64(m,2H),1.50-1.38(m,2H).

[0248] Example 20 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0249] Step 1 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d Starting from 4-chloro-2-fluoro<α-2H>benzaldehyde 20a and 1-(3-bromo-2-hydroxyphenyl)ethan-1-one, 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d 20b was obtained by following the synthesis method in Step 1 of Example 1. MS m / z(ESI):355.9[M+1].

[0250] Step 2 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d 20b as a starting material, 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 20 was obtained by following the synthesis method of Example 11. MS m / z(ESI):608.1[M+1].

[0251] Example 21 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid [ka]

[0252] Step 1 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d Using 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 21a and 1-(3-bromo-2-hydroxyphenyl)ethan-1-one as starting materials, 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d 21b was obtained by following the synthesis method in Step 1 of Example 1. MS m / z(ESI):371.0[M+1].

[0253] Step 2 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid Using 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d 21b as a starting material, 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 21 was obtained by referring to the synthesis method of Example 11. MS m / z(ESI):623.2[M+1].

[0254] Example 22 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0255] Using intermediate Im1 as a starting material, product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 16. MS m / z(ESI):607.2[M+1].

[0256] Example 23 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0257] Using intermediate Im1 as a starting material, product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 18. MS m / z(ESI):589.2[M+1].

[0258] Example 24 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0259] Method 1 The product, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid, was obtained by referring to Example 18.

[0260] Method 2 [ka]

[0261] Step 1 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-Acetyl-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester Im4 (20.3 g, 63.56 mmol) and tetrahydrofuran (300 mL) were added to a 1000 mL flask and cooled to 0 °C for 10 min. Sodium hydride (7.63 g, 190.67 mmol, 60% purity) was then added. 4-Chloro-2-fluorobenzaldehyde 24a (10.08 g, 63.56 mmol) was dissolved in THF (100 mL) and slowly added dropwise to the reaction mixture via a constant pressure addition funnel over 20 min. After completion, the mixture was warmed to 25 °C and reacted for 2 h. The reaction was stopped, and the reaction mixture was quenched with saturated aqueous ammonium chloride solution (200 mL), water was added (50 mL), and extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, ethyl acetate (60 mL) was added, slurried (stirred for 15 minutes), filtered, the filter cake was washed with petroleum ether (30 mL), and dried to give the title product 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 24b (15.2 g), yield: 52.00%. MS m / z(ESI):460.1[M+1].

[0262] Step 2 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 24b (25 g, 54.36 mmol) and isopropanol (500 mL) were added to a 1000 mL flask, and sodium borohydride (3.08 g, 81.53 mmol) was added at 0 °C. The reaction mixture was then reacted at 20 °C for 3 h. The reaction mixture was then quenched with water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to give the title product 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 24c (25 g), yield: 99.56%. MS m / z(ESI):462.1[M+1].

[0263] Step 3 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester 24c (25 g, 54.12 mmol) and N,N-dimethylformamide (300 mL) were added to a 500 mL flask, and p-toluenesulfonic acid (13.98 g, 81.18 mmol) was added at 25° C. The reaction mixture was then reacted at 50° C. for 4 hours. The reaction was stopped, and the reaction solution was quenched with water (200 mL), extracted with ethyl acetate (200 mL × 3), the organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 24d (13 g), yield: 54.11%. MS m / z(ESI):444.1[M+1].

[0264] Step 4 (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester Chiral separation of 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 24d gave (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 24e.

[0265] Split condition OD-H 4.6*150 Hexane:IPA:DEA=90:10:0.1% F = 1 mL T = 35°C MS m / z(ESI):444.1[M+1].

[0266] Step 5 (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester 24e (2.55 g, 5.74 mmol) and dichloromethane (50 mL) were added to a 100 mL flask, and 4A molecular sieves (2.55 g) and boron trifluoride etherate (2.04 g, 14.36 mmol) were added at 0° C. The reaction mixture was then reacted at 0° C. for 2 hours. The reaction was stopped, and the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL), water was added (10 mL), and extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried to give the title product (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine 24f (1.97 g), yield: 100%. MS m / z(ESI): 344.1[M+1]

[0267] Step 6 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine 24f (1.97 g, 5.73 mmol) and acetonitrile (50 mL) were added to a 100 mL flask, and potassium carbonate (1.58 g, 11.46 mmol) and (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Im2 (1.69 g, 5.73 mmol) were added at 25 °C. The reaction mixture was then reacted at 25 °C for 10 hours. The reaction was stopped, the reaction mixture was quenched with an aqueous solution (20 mL), extracted with dichloromethane (20 mL × 3), the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and the resulting residue was purified using silica gel column chromatography with petroleum ether and ethyl acetate as eluents to obtain the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 24g (3.1 g), yield: 89.71%. MS m / z(ESI):603.2[M+1]

[0268] Step 7 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 24 g (3.1 g, 5.14 mmol) of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester and 25 mL of methanol were added to a 100 mL flask, and lithium hydroxide (1.23 g, 51.40 mmol) was dissolved in water (10 mL) and added dropwise to the reaction solution at 25° C. The reaction solution was then reacted at 25° C. for 1 hour. The reaction was stopped, the reaction solution was quenched with formic acid (1 mL), water (20 mL) was added, and extracted with dichloromethane (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting residue was separated and purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 24 (2.1 g), yield: 69.35%.

[0269] MS m / z(ESI):589.1[M+1] 1 H NMR(400MHz,MeOD):δ 8.14-8.03(m,2H),7.40(t,1H),7.25(dd,1H),7.15(dd,1H),7.05(dd,1H),6.92(dd,1H),6.8 4(t,1H),6.68(dd,1H),6.21(dd,1H),5.82(dd,1H),5.30-5.24(m,1H),5.03-4.93(m,1H),4. 85-4.81(m,1H),4.64-4.54(m,1H),4.45-4.35(m,1H),4.23(d,1H),4.13(d,1H),3.25-3.18( m,1H),3.12-3.05(m,1H),2.95-2.85(m,1H),2.83-2.70(m,1H),2.57-2.38(m,3H),1.88-1.78 m,2H),1.78 -1.63(m,1H),1.59-1.51(m,1H).

[0270] Example 25 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0271] The product, 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, was obtained by referring to Example 17. MS m / z(ESI):622.2[M+1].

[0272] Example 26 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0273] The product, 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, was obtained by referring to Example 19. MS m / z(ESI):604.2[M+1].

[0274] Example 27 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0275] Using 4-cyano-2-fluorobenzaldehyde and intermediate Im-1 as raw materials, the product 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 18.

[0276] MS m / z(ESI):579.2[M+1]. 1 H NMR(400MHz,DMSO):δ 8.25(d,1H),7.95(dd,1H),7.79(dd,1H),7.70(dd,1H),7.62(d,1H),7.52(t,1H),7.07(dd,1H),6.9 9(dd,1H),6.87(t,1H),6.75(dd,1H),6.33(dd,1H),5.93(dd,1H),5.11-5.00(m,1H),4.85-4.71(m,1 H),4.67-4.58(m,1H),4.52-4.44(m,1H),4.42-4.31(m,1H),3.92(d,1H),3.75(d,1H),3.04-2.92(m ,1H),2.83-2.62(m,3H),2.46-2.38(m,1H),2.23-2.02(m,2H),1.73-1.56(m,2H),1.48-1.34(m,2H).

[0277] Example 28 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid [ka]

[0278] Using Im-1 as a raw material, the product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 24.

[0279] MS m / z(ESI):588.2[M+1]. 1 H NMR(400MHz,MeOD):δ 8.30(s,1H),7.96(dd,1H),7.66(d,1H),7.40(t,1H),7.25(s,1H),7.16(d,1H),7.04(dd,1H),6. 92(dd,1H),6.83(d,1H),6.68(dd,1H),6.23-6.19(m,1H),5.83(dd,1H),5.27-5.20(m,1H),4.85 -4.80(m,1H),4.74-4.62(m,2H),4.48-4.41(m,1H),4.05(d,1H),3.95(d,1H),3.12-3.05(m,1H) ,2.94-2.77(m,3H),2.55-2.46(m,1H),2.39-2.25(m,2H),1.82-1.73(m,2H),1.66-1.50(m,2H).

[0280] Biological Test Evaluation The present invention will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0281] 1. Measurement of the ability of the compounds of the present invention to stimulate cAMP production by a human GLP1 receptor-stabilized transgenic cell line 1. Experimental Objective: The purpose of this example is to test the ability of compounds to activate human GLP-1 receptors on the cell surface. EC2 stimulates AMP production after agonism. 50characterizes the activation ability of compounds on the human GLP-1 receptor.

[0282] 2. Experimental Reagents and Equipment: 2.1 Experimental equipment: Microplate reader (BioTek Synergy H1) Pipettes (Eppendorf & Rainin)

[0283] 2.2 Experimental reagents: DMEM / F12 medium, purchased from Gibco, catalog number 11330032; Casein, purchased from Sigma, catalog number C3400; 384-well plates purchased from Sigma, catalog number CLS4514; IBMX, purchased from Sigma and with catalog number I7018; Cisbio cAMP-Gs Dynamic kit, purchased from Cisbio, catalog number 62AM4PEC.

[0284] 3. Experimental Method: Cryopreserved human GLP1 receptor-stabilized transgenic cell line CHO-K1 / GLP-1R / CRE-luc was removed from the liquid nitrogen tank and rapidly thawed in a 37°C water bath. The cells were resuspended in DMEM / F12 medium, centrifuged, washed once, and resuspended in experimental buffer (i.e., DMEM / F12 medium containing 0.1% casein). The cell density was adjusted with experimental buffer and seeded into a 384-well plate at a density of 2500 cells / 5μL / well. 2.5μL of IBMX working solution (prepared with buffer to a final IBMX concentration of 0.5mM) and 2.5μL of gradient diluted compound samples (starting from 1000nM and diluted 3-fold for 11 concentrations) were added to each well. The cells were centrifuged at 1000 rpm for 1 minute, shaken for 30 seconds to mix uniformly, and then incubated at room temperature for 30 minutes. Detected using Cisbio cAMP-Gs Dynamic kit, and cAMP-d2 and Anti-cAMP-Eu 3+Each of the cAMP-Cryptates was diluted 20-fold with cAMP Lysis & Detection Buffer and mixed evenly. 5 μL of the diluted cAMP-d2 solution was added to each well, followed by the diluted Anti-cAMP-Eu3 + 5 μL of -Cryptate solution was added, and the mixture was mixed uniformly by shaking for 30 seconds, and then incubated at room temperature in the dark for 1 hour. HTRF signal readings were performed using a Biotek Synergy H1 microplate reader with an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm.

[0285] 4. Experimental data processing method: The signal ratio (665 nm / 620 nm * 10,000) was calculated, and a nonlinear fitting was performed in GraphPad Prism 6 using a four-parameter equation to the signal ratio and sample concentration to obtain the EC 50 got the value.

[0286] 5. Experimental results: [Table 6]

[0287] 6. Experimental Conclusion From the above scheme, it has become clear that the compounds of the examples of the present invention exhibit good biological activity in an experiment of stimulating cAMP production by a human GLP1 receptor-stabilized transgenic cell line.

[0288] 2. The effect of a single administration of the compound of the present invention on intraperitoneal glucose tolerance in GLP-1R humanized mice 1. Purpose of the test: The effect of a single dose of a compound of the present invention on blood glucose changes in an intraperitoneal glucose tolerance (ipGTT) experiment in GLP-1R humanized C57BL / 6 mice is evaluated.

[0289] 2. Experimental materials: C57BL / 6_hGLP-1R, male, 5-8 weeks old, clean bench, electronic balance, active blood glucose meter, glucose.

[0290] 3. Experimental procedures and data processing: 3.1 On the day before the experiment, the animals were randomly divided into groups of five animals according to their weight. All animals were fasted overnight after food was removed, and they were fasted for at least 16 hours before administration. 3.2 Prepare a 0.2 g / mL glucose solution in pure water, filter it through a 0.22 μm filter membrane, and then wait. 3.3 On the day of the test, measure the blood glucose level of each animal by tail snip method before administration and record it as the baseline value. Blood glucose test method: Place the mouse in a restrainer, disinfect the tip of the tail with an alcohol cotton ball, and then cut off a small portion of the tip of the tail with scissors. Discard the first drop of blood, then drop the second drop of blood onto a blood glucose test strip to measure the blood glucose level. 3.4 The animals were dosed according to their body weight, and the administration time for each animal was recorded. One hour after administration, the blood glucose level of each animal was measured sequentially and recorded as the 0-minute blood glucose level. 3.5 Then, pure water or glucose solution was immediately injected intraperitoneally according to the body weight of that day, the volume was 10 mL / kg, and the glucose dose was 2 g / kg; 3.6 Measure the blood glucose level of each mouse at 15, 30, 60, 90 and 120 minutes after injection of pure or glucose solution, and record the time and data. 3.7 After the study was completed, all animals were re-fed.

[0291] 3.8 Data Processing: A blood glucose (BG)-time curve is created and the area under the blood glucose-time curve is calculated using the following formula: AUC(mmol / L.hr)=(BG0+BG15)×0.25 / 2+(BG15+BG30)×0.25 / 2+(BG30+BG60)×0.5 / 2+(BG60+BG90)×0.5 / 2+(BG90+BG120)×0.5 / 2.

[0292] NOTE: BG0, BG15, BG30, BG60, BG90, and BG120 represent blood glucose levels before glucose loading (0 min), 15, 30, 60, 90, and 120 min after glucose loading, respectively.

[0293] Based on the mean blood glucose level and blood glucose AUC at each time point, the blood glucose reduction rate for each time point and AUC was calculated using the following formula: blood glucose reduction rate = (blood glucose of treatment group / AUC - blood glucose of model control group / AUC) / blood glucose of model control group / AUC × 100%.

[0294] 4. Experimental results: [Table 7]

[0295] 5. Experimental Conclusion The above experimental results demonstrate that the compounds of the examples of the present invention can effectively lower blood glucose in mice.

[0296] 3. Effects of long-term administration of the compound of the present invention on body weight and food intake in GLP-1R-humanized mice fed a high-fat diet Objective of the experiment: 1. The purpose of the study is to evaluate the effect of chronic administration of the compound on body weight and food intake in GLP-1R humanized C57BL / 6 mice fed a high fat diet.

[0297] 2. Experimental Reagents and Equipment C57BL / 6_hGLP-1R, male, 5-8 weeks old, 60% high-fat diet (HFD), clean bench, electronic balance.

[0298] 3. Experimental Method 3.1 On the day that the high-fat diet was started, C57BL / 6 mice were randomly divided into two groups according to their body weight. The first group was the blank group, with 7 mice fed with normal control diet. The remaining animals were the model group, and were fed with the high-fat diet until the end of the experiment.

[0299] 3.2 After 8 weeks of HFD feeding, the animals in the modeling group were randomly divided into groups of 7 animals each according to body weight. The first group was the vehicle group (Vehicle: 0.5% CMC-Na + 1% Tween 80) and was given the solvent. The remaining groups were treatment groups. The administration scheme was: the corresponding compound was orally administered once daily for 14 days at a dose of 10 mg / kg in a volume of 10 mL / kg. The blank group continued to receive normal chow without any administration manipulation.

[0300] 3.3 The day of administration was defined as Day 0.

[0301] 3.4 At each administration, the animals were weighed and the data were recorded, and the animals were orally administered according to their body weight, with the administration volume being 10 mL / kg.

[0302] 3.5 From day 0 of the experiment, the food intake of the mice in each group was measured every three days. Specifically, the mice were weighed and the feed was replaced every time they were administered, and the added and surplus amounts were recorded.

[0303] 3.6 On the final day of Day 14, all mice were euthanized according to the grouping order, dissected, and their livers were removed and weighed.

[0304] 4. Experimental Data Processing and Statistical Analysis The body weight and weight change rate of the mice after administration were collected and analyzed. The weight change rate was calculated as follows: (BWt-BW0) / BW0 x 100%. BWt represents the body weight of the mice on day t of the experiment, and BW0 represents the body weight of the mice on day 0 of the experiment.

[0305] Food intake calculation is (addition (g) - surplus (g)) / number of animals per cage, and cumulative food intake is the sum of each animal's daily food intake during the treatment period.

[0306] The experimental data were analyzed using GraphPad Prism software. Comparisons between two groups were tested using the t-test method. Comparisons between three or more groups were tested using one-way ANOVA.

[0307] 5. Experimental Results [Table 8]

[0308] [Table 9]

[0309] 6. Experimental Conclusion The above experimental results demonstrate that long-term administration of the compounds of the examples of the present invention has a favorable weight-reducing effect on GLP-1R-humanized C57BL / 6 mice fed a high-fat diet.

[0310] 4. Pharmacokinetics in SD rats 1. Research purpose: SD rats were used as test animals, and the pharmacokinetic behavior of the following compound examples in rat plasma was investigated when orally administered at a dose of 50 mg / kg.

[0311] 2. Test Scheme 2.1 Test Drugs: Solvent formulation: 0.5% CMC-Na (1% Tween 80), Example of the present invention, homemade.

[0312] 2.2 Test animals: SD rats, 3 per group, male.

[0313] 2.3 Administration: Three male SD rats per group were each administered PO after overnight fasting, with a dose of 50 mg / kg and an administration volume of 10 mL / kg.

[0314] 2.4 Sampling: 0.2 mL of blood was collected from the jugular vein of each rat before administration and at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 test tube and centrifuged at 6000 rpm at 4°C for 6 minutes to separate the plasma. The plasma was then stored at -80°C and fed to the rats 4 hours after administration.

[0315] 2.5 Sample Processing: 1) 40 μL of plasma sample was added to 160 μL of acetonitrile to precipitate, and after mixing, the mixture was centrifuged at 3500 × g for 5 to 20 minutes.

[0316] 2) 100 μL of the treated supernatant solution was taken and analyzed for the concentration of the test compound by LC / MS / MS.

[0317] 2.6 Liquid phase analysis Liquid phase conditions: Shimadzu LC-20AD pump ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer Chromatography column: phenomenex Gemiu 5um C18 50 x 4.6mm Mobile phase: Solution A is a 0.1% formic acid solution, and solution B is methanol. ●Flow rate: 1.0mL / min The elution time is 0 to 4.0 minutes, and the eluent is as follows:

[0318] [Table 10]

[0319] 3. Test results and analysis The main pharmacokinetic parameters were calculated using WinNonlin 8.2. 4. Test Results

[0320] [Table 11]

[0321] 5. Experimental conclusion: From the results of the pharmacokinetic experiments in rats in the table, the compounds of the examples of the present invention showed good metabolic properties at a dose of 50 mg / kg, and the exposure amount AUC and maximum blood concentration C max Both were shown to be good.

[0322] Salt and Crystal Form Studies 1.1 Experimental Instruments 1.1.1 Some parameters of physicochemical detection instruments [Table 12]

[0323] 1.2 Instrumentation and liquid phase analysis conditions 1.2.1 Instruments and Equipment [Table 13]

[0324] 1.2.2 Chromatographic conditions [Table 14]

[0325] Preparation of compound salt forms 2. Screening of compound salt crystal forms 2.1 Compound salt form screening 2.1.1 Experimental Objective: Different counterion bases are selected and appropriate crystallization methods are used to determine which counterion bases can form compound salts.

[0326] 2.1.2 Experimental steps: 1) Instruments and Equipment [Table 15]

[0327] 2) Operation procedure 3. Screening of salt forms of free acids 3.1 ACN-based solvent salt type screening A total of 181.82 mg of compound 28 was weighed, 2.4 ml of ACN was added, and the mixture was rolled into a ball. The solid was allowed to adhere to the wall. The solubility was measured using ultrasonic waves and heating. 400 μL of water was added, and the mixture was sonicated to gradually dissolve the solid adhering to the wall. A stock solution was prepared, slightly turbid and containing a small amount of mechanical impurities. Each solution was 245 μL (equivalent to 15.91 mg of compound), and 1.1 equivalents of alkaline solution (29.8 μL) were added. The specific amounts are shown in the table below. After overnight at room temperature, a solid precipitated. XRD analysis of the solid was obtained.

[0328] The resulting 2-3 had good crystallinity. DSC indicated that 2-3 may be a solvate or hydrate. TGA further demonstrated that 2-3 dehydrates or desolvates at low temperatures.

[0329] [Table 16]

[0330] The experimental results showed that the tromethamine salt crystalline form A was obtained as a result of the ACN-based salt form screening.

[0331] H-NMR analysis of 2-3 samples was performed to determine whether or not salts (Tris) had formed. The results showed that the chemical shift of the methylene group of Tris may overlap with the chemical shift of water, and the H of the hydroxyl group does not show a peak in H-NMR, so it is not possible to determine whether or not Tris salts had formed by H-NMR.

[0332] The free content was measured by HPLC-DAD to confirm whether or not salts were formed. As shown in the table below, the average free content of the two Tris salt samples was 80.58%, which is closest to the theoretical free content of one Tris molecule and one water molecule. Therefore, it was initially determined that the Tris salt was a hydrate with one water molecule.

[0333] [Table 17] remarks: Sample 1: ACN-H2O-Tris (crystal form A) Sample 2: MeOH-Tris-Evap-EA Slurry (Crystal Form A)

[0334] The free content was then measured by HPLC-ELSD to determine the salt formation rate. The method is shown in the table below. The results show that the average Tris content of the two Tris salt samples was 16.13%, which is closest to the theoretical Tris content of one molecule of Tris and one molecule of water.

[0335] [Table 18]

[0336] [Table 19] remarks: Sample 1: ACN-H2O-Tris (crystal form A) Sample 2: MeOH-Tris-Evap-EA Slurry (crystal form A)

[0337] Combining the DSC spectrum and TGA spectrum, the weight loss (ACN-TRIS) up to 80°C was approximately 2%, which corresponds to the theoretical water content in a Tris salt that combines one Tris molecule with one water molecule. Furthermore, it was determined that Tris salt crystalline form A is a monohydrate.

[0338] 3.2 DCM-based salt type screening A total of 147.31 mg of compound 28 was weighed out, and 2.2 ml of DCM was added to prepare a stock solution. The solution was completely dissolved, and each solution was made into 200 μl (equivalent to 13.39 mg of compound). The solution was evaporated to dryness at 40°C, and the following solvents (200 μl each) were added to dissolve the solution. Further, 1.1 equivalents of 1 mol / L tromethamine aqueous solution (25.1 μL) were added to each solution, and the solution was evaporated through a hole. The results are shown in the table below.

[0339] [Table 20]

[0340] The experimental results showed that the DCM-based salt form screening resulted in the tromethamine salt crystal forms C and E.

[0341] 3.3 Salt type screening using ACN-H2O solvent 27.69 mg of compound 28 was weighed and added with 400 μL of ACN:HO (6:1 v / v). The oil formed adhered to the wall and gradually dissolved at 40°C. 51.8 μL of 1.1 eq of 1 mol / L tromethamine aqueous solution was added and the mixture was allowed to dissolve. The mixture was then heated at 40°C for 3 hours. No solid precipitated. Stirring at room temperature did not produce any solids. After 1-2 minutes of ultrasonic treatment, a vigorous precipitation and solidification occurred. 200 μL of ACN:HO (6:1 v / v) was added and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, vacuum dried at 40°C overnight, and then characterized accordingly. The XRD pattern of the sample indicated that tromethamine salt form D was obtained. DSC spectrum indicated that the tromethamine salt form A was similar to that of the Tris salt, being a monohydrate.

[0342] 4. Methods for producing different salt forms (1) Preparation of Tromethamine Crystal Form A 15.91 mg of the free acid was weighed, and 245 μL of acetonitrile:water=6:1 (v / v) was added. Slight turbidity was observed upon ultrasonication, and slight mechanical impurities were present. 1.1 equivalents of 1 mol / L aqueous solution of tromethamine (29.8 μL) was added, and after overnight at room temperature, a solid precipitated. The mixture was quickly centrifuged, the supernatant was removed, and the solid was vacuum dried at 40°C to a constant weight to obtain tromethamine salt crystalline form A, which, upon detection analysis, has the XRPD pattern shown in FIG. 1, the DSC pattern shown in FIG. 2, and the TGA pattern shown in FIG. 3.

[0343] (2) Preparation of Tromethamine Crystalline Form B An appropriate amount of tromethamine salt crystalline form A was taken, and the sample was heated to 88°C in a TGA, held for 2 minutes, and cooled to room temperature to obtain tromethamine salt crystalline form B, which, through detection analysis, had the XRPD diagram shown in Figure 4 and the DSC diagram shown in Figure 5.

[0344] (3) Preparation of Tromethamine Crystal Form C 229.54 mg of the free salt was weighed, added with 0.4 ml of acetone, and dissolved by ultrasonication. 1.6 ml of methanol was added and dissolved at room temperature. 0.527 ml (1.1 eq) of a 0.815 mol / L Tris ethanol-water (18.44% mass fraction water) solution was added at 40°C and dissolved. 5 ml of isopropyl ether was added, resulting in a slight turbidity. After maintaining at 40°C for 30 minutes, a large amount of precipitated material was obtained. 3 ml of isopropyl ether was added, and the mixture was maintained at 40°C overnight to obtain a solid with good properties. After cooling to room temperature, the mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40°C to a constant weight to obtain tromethamine salt crystalline form C, which by detection analysis has the XRPD pattern shown in Figure 6, the DSC pattern shown in Figure 7, and the TGA pattern shown in Figure 8.

[0345] (4) Preparation of Tromethamine Salt Crystalline Form D 27.69 mg of the free salt was weighed, and 400 μL of ACN:H2O=6:1 (v / v) was added. The oil adhered to the wall and gradually dissolved at 40°C. 51.8 μL of 1.1 eq of 1 mol / L tromethamine aqueous solution was added, and the mixture was kept at 40°C for 3 hours. No solid precipitated. No solid precipitated even when stirred at room temperature. After 1-2 minutes of ultrasonic treatment, vigorously precipitated and solidified. 200 μL of ACN:H2O=6:1 (v / v) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was quickly centrifuged, the supernatant was removed, and the solid was dried under vacuum at 40°C to a constant weight to obtain tromethamine salt crystalline form D. Analysis revealed that the XRPD pattern was shown in Figure 9 and the DSC pattern in Figure 10.

[0346] (5) Preparation of Tromethamine Crystal Form E 13.39 mg of the free salt was weighed out, dissolved in 200 μL of dioxane, and 1.1 equivalents of a 1 mol / L aqueous solution of tromethamine (25.1 μL) was added. The mixture became cloudy and oily, and a hole was opened to evaporate the solution to form an oil. 200 μL of ethyl acetate was added, and the mixture was slurried at 40°C for 2 days to form a solid. After cooling to room temperature, the mixture was quickly centrifuged, the supernatant was removed, and the solid was vacuum dried at 40°C to a constant weight to obtain tromethamine salt crystalline form E. Analysis revealed that the following XRPD pattern and DSC pattern were shown in Figure 11 and Figure 12, respectively.

[0347] 5. Crystalline Thermodynamic Stability Experiments 5.1 Experimental Objective: Polycrystalline screening tests identify relatively thermodynamically stable salt crystal forms.

[0348] 5.2 Experimental plan: 5.2.1 Starting from Tromethamine Crystalline Form C 10 mg of tromethamine salt form C was taken, and 200 μL of solvent was added to each, followed by slurrying at 40°C for 2 days and centrifuging. The solid was dried under vacuum at 40°C overnight, and then subjected to relevant characterization such as XRD. The results are shown in the table below. The XRD patterns of the obtained solids were all form C, indicating that the tromethamine salt form C is very stable.

[0349] [Table 21]

[0350] 6. Solubility measurement of tromethamine salt crystalline form C 1-2 mg of compound 28 was weighed into a 1.5 mL liquid vial and 1 mL each of pH buffer, simulated gastric fluid (FaSSGF), fasting simulated intestinal fluid (FaSSIF), non-fasting simulated intestinal fluid (FeSSIF), and pure water was added. The vial was then placed in a thermostatic shaker overnight at 37°C. After 24 hours, the sample solution was filtered through a 0.45 μm mixed water fiber filter membrane. The filtrate was then tested for its content by HPLC. (See Section 1.2 for the solution stability analysis method.) The solubility of the compound in the buffer solution medium is shown in the table below.

[0351] [Table 22]

Claims

1. A basic salt of a compound represented by general formula (I) or a stereoisomer thereof, wherein the structure of the compound is as follows: 【Chemistry 1】 where: R １ are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group or C １－３ haloalkoxy groups; R ２ are each independently hydrogen, deuterium, fluorine, chlorine, a cyano group, C １－３ Alkyl group, C １－３ Deuterated alkyl groups, C １－３ Haloalkyl group, C １－３ Alkoxy group, C １－３ Deuterated alkoxy group or C １－３ haloalkoxy groups; R ３ are each independently selected from hydrogen, deuterium, or halogen; M １ is N or CH, W ２ is N or CH, x, y, and z are each independently 0, 1, or 2; wherein the base is an organic base or an inorganic base, the organic base is selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, meglumine, N-hydroxyethylmorpholine, piperazine, N-hydroxyethylpyrrolidine, N,N-dibenzylethylenediamine, 2-diethylaminoethanol, ethanolamine, betaine, L-arginine, lysine, phenethylbenzylamine, benzathine penicillin, dimethylaminoethanol, imidazole, or a mixture thereof, and the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aqueous ammonia, or a mixture thereof, a basic salt of the compound or a stereoisomer thereof.

2. R １ are each independently hydrogen, deuterium, fluorine, chlorine, a methoxy group, or -OCD ３ is selected from R ２ are each independently selected from hydrogen, deuterium, fluorine, chlorine, or a methyl group; R ３ are each independently selected from hydrogen; M １ is CH, W ２ is CH, 2. The basic salt of the compound or its stereoisomer according to claim 1, wherein x, y, and z are each independently 0, 1, or 2.

3. The compound may further be represented by the following general formulas (I-1) to (I-4): 【Chemistry 2】 2. A basic salt of the compound or its stereoisomer according to claim 1, wherein:

4. The general formula is the following compound: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 is selected from 4. The basic salt of the compound or its stereoisomer according to claim 1, wherein the base is an organic base or an inorganic base, wherein the organic base is selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine or a mixture thereof, and the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or a mixture thereof.

5. 5. The basic salt of the compound of claim 4, wherein the compound is 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid, wherein the organic base is selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, or a mixture thereof, and the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or a mixture thereof.

6. The basic salt of the compound according to any one of claims 1 to 5, wherein the number of bases is 0.5 to 3, preferably 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and even more preferably 1.

7. The basic salt is a hydrate or an anhydrous salt, preferably an anhydrous salt; The basic salt of the compound according to any one of claims 1 to 5, wherein when the basic salt is a hydrate, the number of water atoms is 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, and more preferably 0.5, 1, 2 or 3.

8. The basic salt of the compound according to claim 4, wherein the basic salt of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is in a crystalline form.

9. The basic salt crystalline form of 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is selected from tromethamine salt crystalline forms A to E, wherein: The powder X-ray diffraction spectrum of tromethamine salt crystalline form A has a characteristic peak at 7.7±0.2 degrees 2θ, or has a characteristic peak at 9.8±0.2 degrees 2θ, or has a characteristic peak at 10.8±0.2 degrees 2θ, or has a characteristic peak at 11.6±0.2 degrees 2θ, or has a characteristic peak at 14.0±0.2 degrees 2θ, or has a characteristic peak at 14.5±0.2 degrees 2θ, or has a characteristic peak at 14.8±0.2 degrees 2θ, or has a characteristic peak at 15.1±0.2 degrees 2θ, or has a characteristic peak at 15.9±0.2 degrees 2θ, or has a characteristic peak at 18.0±0.2 degrees 2θ. or having a characteristic peak at 18.7±0.2 degrees 2θ, or having a characteristic peak at 19.3±0.2 degrees 2θ, or having a characteristic peak at 20.0±0.2 degrees 2θ, or having a characteristic peak at 20.5±0.2 degrees 2θ, or having a characteristic peak at 21.1±0.2 degrees 2θ, or having a characteristic peak at 22.6±0.2 degrees 2θ, or having a characteristic peak at 23.7±0.2 degrees 2θ, or having a characteristic peak at 25.1±0.2 degrees 2θ, preferably at any 2, 4, 6, 8, 10 or 12 thereof; The powder X-ray diffraction spectrum of tromethamine salt crystalline form B has a characteristic peak at 8.2±0.2 degrees 2θ, or has a characteristic peak at 10.1±0.2 degrees 2θ, or has a characteristic peak at 12.3±0.2 degrees 2θ, or has a characteristic peak at 14.4±0.2 degrees 2θ, or has a characteristic peak at 14.8±0.2 degrees 2θ, or has a characteristic peak at 16.0±0.2 degrees 2θ, or has a characteristic peak at 16.2±0.2 degrees 2θ, or has a characteristic peak at 17.5±0.2 degrees 2θ, or has a characteristic peak at 17.7±0.2 degrees 2θ, or has a characteristic peak at 18.3±0.2 degrees 2θ. or having a characteristic peak at 18.7±0.2 degrees 2θ, or having a characteristic peak at 19.7±0.2 degrees 2θ, or having a characteristic peak at 20.5±0.2 degrees 2θ, or having a characteristic peak at 20.9±0.2 degrees 2θ, or having a characteristic peak at 21.9±0.2 degrees 2θ, or having a characteristic peak at 22.1±0.2 degrees 2θ, or having a characteristic peak at 22.4±0.2 degrees 2θ, or having a characteristic peak at 24.7±0.2 degrees 2θ, preferably at any 2, 4, 6, 8, 10 or 12 thereof; The powder X-ray diffraction spectrum of tromethamine salt crystalline Form C has a characteristic peak at 3.6±0.2 degrees 2θ, or has a characteristic peak at 7.1±0.2 degrees 2θ, or has a characteristic peak at 9.7±0.2 degrees 2θ, or has a characteristic peak at 10.6±0.2 degrees 2θ, or has a characteristic peak at 13.5±0.2 degrees 2θ, or has a characteristic peak at 14.1±0.2 degrees 2θ, or has a characteristic peak at 15.0±0.2 degrees 2θ, or has a characteristic peak at 16.0±0.2 degrees 2θ, or has a characteristic peak at 16.5±0.2 degrees 2θ, or has a characteristic peak at 17.1±0.2 degrees 2θ, or has a characteristic peak at 17.1±0.2 degrees 2θ. 2θ、3.6±0.2°、2θ、19.0±0.2°、2θ、19.7±0.2°、2θ、20.8±0.2°、2θ、21.8±0.2°、2θ、22.3±0.2°、2θ、23.1±0.2°、2θ、26.4±0.2°、2θ、28.3±0.2°、2θ、5.6±0.2°, 6 ... The powder X-ray diffraction spectrum of tromethamine salt crystalline form D has a characteristic peak at 7.4±0.2 degrees 2θ, or has a characteristic peak at 7.7±0.2 degrees 2θ, or has a characteristic peak at 9.8±0.2 degrees 2θ, or has a characteristic peak at 10.8±0.2 degrees 2θ, or has a characteristic peak at 11.6±0.2 degrees 2θ, or has a characteristic peak at 13.1±0.2 degrees 2θ, or has a characteristic peak at 14.0±0.2 degrees 2θ, or has a characteristic peak at 14.5±0.2 degrees 2θ, or has a characteristic peak at 15.1±0.2 degrees 2θ, or has a characteristic peak at 15.4 .... or having a characteristic peak at 17.9±0.2° 2θ, or having a characteristic peak at 18.8±0.2° 2θ, or having a characteristic peak at 19.3±0.2° 2θ, or having a characteristic peak at 20.0±0.2° 2θ, or having a characteristic peak at 20.5±0.2° 2θ, or having a characteristic peak at 21.2±0.2° 2θ, or having a characteristic peak at 21.8±0.2° 2θ, or having a characteristic peak at 23.3±0.2° 2θ, preferably having characteristic peaks at any of 2, 4, 6, 8, 10 or 12 positions therein; The powder X-ray diffraction spectrum of tromethamine salt crystalline form E has a characteristic peak at 4.3±0.2 degrees 2θ, or has a characteristic peak at 6.3±0.2 degrees 2θ, or has a characteristic peak at 8.6±0.2 degrees 2θ, or has a characteristic peak at 9.3±0.2 degrees 2θ, or has a characteristic peak at 13.6±0.2 degrees 2θ, or has a characteristic peak at 14.1±0.2 degrees 2θ, or has a characteristic peak at 17.7±0.2 degrees 2θ, or has a characteristic peak at 18.5±0.2 degrees 2θ, or has a characteristic peak at 18.9±0.2 degrees 2θ, or has a characteristic peak at 20.2±0.2 degrees 2θ.

9. The basic salt of the compound of claim 8, having a characteristic peak at 20.5±0.2 degrees 2θ, or having a characteristic peak at 21.4±0.2 degrees 2θ, or having a characteristic peak at 21.9±0.2 degrees 2θ, or having a characteristic peak at 22.4±0.2 degrees 2θ, or having a characteristic peak at 23.4±0.2 degrees 2θ, or having a characteristic peak at 23.9±0.2 degrees 2θ, or having a characteristic peak at 25.2±0.2 degrees 2θ, preferably at any 2, 4, 6, 8, 10 or 12 of these.

10. The powder X-ray diffraction spectrum of tromethamine salt crystalline form A has characteristic peaks at one or more of 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, or 15.1±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4, and optionally further including characteristic peaks at one or more of 14.5±0.2°, 18.7±0.2°, 19.3±0.2°, 20.0±0.2°, 20.5±0.2°, or 21.1±0.2° 2θ, preferably including 2, 3, 4, or 6 of these; The powder X-ray diffraction spectrum of tromethamine salt crystalline form B has characteristic peaks at one or more of 10.1±0.2°, 14.4±0.2°, 18.7±0.2°, or 21.9±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4, and optionally further including characteristic peaks at one or more of 8.2±0.2°, 12.3±0.2°, 14.8±0.2°, 19.7±0.2°, 20.5±0.2°, or 22.1±0.2° 2θ, preferably including 2, 3, 4, or 6 of these; The powder X-ray diffraction spectrum of tromethamine salt crystalline form C has characteristic peaks at one or more of 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, or 16.0±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4, and optionally further including characteristic peaks at one or more of 15.0±0.2°, 16.5±0.2°, 17.1±0.2°, 17.6±0.2°, 19.7±0.2°, or 20.8±0.2° 2θ, preferably including 2, 3, 4, or 6 of these; The powder X-ray diffraction spectrum of tromethamine salt crystalline form D has characteristic peaks at one or more of 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, or 14.0±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4, and optionally further including characteristic peaks at one or more of 7.7±0.2°, 15.1±0.2°, 17.9±0.2°, 18.8±0.2°, 19.3±0.2°, or 20.0±0.2° 2θ, preferably including 2, 3, 4, or 6 of these; 9. The tromethamine salt crystalline form of claim 8, wherein the powder X-ray diffraction spectrum of Form E has characteristic peaks at one or more of 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, or 18.9±0.2°, preferably including 2 to 4 of these, more preferably including 3 to 4, and most preferably including 4 of these, and optionally further including characteristic peaks at one or more of 8.6±0.2°, 14.1±0.2°, 17.7±0.2°, 20.2±0.2°, 20.5±0.2°, or 22.4±0.2° 2θ, preferably including 2, 3, 4, or 6 of these.

11. The powder X-ray diffraction spectrum of tromethamine salt crystalline form A has characteristic peaks at 9.8±0.2° and 14.0±0.2° 2θ, preferably further characteristic peaks at 7.7±0.2° and 15.1±0.2° 2θ, more preferably further characteristic peaks at 18.7±0.2°, 19.3±0.2°, 20.0±0.2° and 21.1±0.2° 2θ, even more preferably further characteristic peaks at 14.5±0.2° and 20.5±0.2° 2θ, and even more preferably further characteristic peaks at one or more of 10.8±0.2°, 11.6±0.2°, 18.0±0.2° and 22.6±0.2°; The powder X-ray diffraction spectrum of tromethamine salt crystalline form B has characteristic peaks at 10.1±0.2° and 14.4±0.2° 2θ, preferably further having characteristic peaks at 18.7±0.2° and 21.9±0.2° 2θ, more preferably further having characteristic peaks at 8.2±0.2°, 14.8±0.2°, 20.5±0.2° and 22.1±0.2° 2θ, even more preferably further having characteristic peaks at 12.3±0.2° and 19.7±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 16.0±0.2°, 16.2±0.2°, 18.3±0.2° and 20.9±0.2°; The powder X-ray diffraction spectrum of tromethamine salt crystalline form C has characteristic peaks at 3.6±0.2° and 7.1±0.2° 2θ, preferably further having characteristic peaks at 9.7±0.2° and 14.1±0.2° 2θ, more preferably further having characteristic peaks at 15.0±0.2°, 16.0±0.2°, 16.5±0.2°, 17.6±0.2° and 20.8±0.2° 2θ, even more preferably further having characteristic peaks at 17.1±0.2° and 19.7±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 13.5±0.2°, 19.0±0.2°, 21.8±0.2° and 26.4±0.2°; The powder X-ray diffraction spectrum of tromethamine salt crystalline form D has characteristic peaks at 9.8±0.2° and 14.0±0.2° 2θ, preferably further having characteristic peaks at 7.4±0.2° and 13.1±0.2° 2θ, more preferably further having characteristic peaks at 7.7±0.2°, 15.1±0.2°, 18.8±0.2°, and 20.0±0.2° 2θ, even more preferably further having characteristic peaks at 17.9±0.2° and 19.3±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, and 21.2±0.2°; 9. The tromethamine salt crystalline form of claim 8, wherein the powder X-ray diffraction spectrum of tromethamine salt Form E has characteristic peaks at 6.3±0.2° and 13.6±0.2° 2θ, preferably further having characteristic peaks at 4.3±0.2° and 18.9±0.2° 2θ, more preferably further having characteristic peaks at 8.6±0.2°, 17.7±0.2°, 20.2±0.2° and 22.4±0.2° 2θ, even more preferably further having characteristic peaks at 14.1±0.2° and 20.5±0.2° 2θ, and even more preferably further having characteristic peaks at one or more of 9.3±0.2°, 18.5±0.2°, 21.4±0.2° and 21.9±0.2° 2θ.

12. The X-ray powder diffraction pattern of crystalline form A is as shown in FIG. 1, and preferably, crystalline form A has a DSC pattern as shown in FIG. 2 or a TGA pattern as shown in FIG. 3; The powder X-ray diffraction spectrum of crystalline form B is as shown in FIG. 4 in 2θ. Preferably, crystalline form B has a DSC pattern as shown in FIG. The powder X-ray diffraction spectrum of crystalline form C is shown in FIG. 6 at 2θ. Preferably, crystalline form C has a DSC pattern shown in FIG. 7 or a TGA pattern shown in FIG. 8; The powder X-ray diffraction spectrum of crystalline form D is shown in FIG. 9 in 2θ. Preferably, crystalline form D has a DSC pattern as shown in FIG.

9. The tromethamine salt crystalline form of claim 8, wherein the powder X-ray diffraction spectrum of crystalline form E is as shown in Figure 11 in 2θ coordinates, and preferably, form E has a DSC pattern as shown in Figure 12.

13. 9. The tromethamine salt crystalline form according to claim 8, wherein the 2θ error between the positions of the top 10 diffraction peaks in terms of relative peak intensity in the X-ray powder diffraction patterns of crystalline forms A, B, C, D, and E and the diffraction peaks at the corresponding positions in Figures 1, 4, 6, 9, and 11 is ±0.2° to ±0.5°, preferably ±0.2° to ±0.3°, and more preferably ±0.2°.

14. A method for preparing a basic salt of a compound according to any one of claims 1 to 13, specifically comprising: 1) Weighing an appropriate amount of free acid and dissolving it in a good solvent; 2) Weighing an appropriate amount of counterion base and dissolving it in an organic solvent, the amount of the counterion base is preferably 1.0 to 1.5 equivalents; 3) combining the two solutions and stirring to cause precipitation, or adding a poor solvent dropwise and then stirring to cause precipitation; 4) rapid centrifugation or static evaporation to dryness to obtain the desired product; where: The good solvent is selected from acetone, tetrahydrofuran, ethyl formate, ethyl acetate, 2-methyl-tetrahydrofuran, 2-butanone, n-butanol, 1,4-dioxane, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, and tert-butanol, and is preferably 2-methyl-tetrahydrofuran, ethyl acetate, 2-butanone, acetone, or ethyl formate; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, and N,N-dimethylformamide, and is preferably methanol, ethanol, or acetonitrile. The good solvent and the organic solution must be compatible with each other when used. the anti-solvent is selected from heptane, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether, and ethyl acetate, and is preferably methyl tert-butyl ether or isopropyl ether; the counterion base is an organic base or an inorganic base, the organic base being selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, meglumine, N-hydroxyethylmorpholine, piperazine, N-hydroxyethylpyrrolidine, N,N-dibenzylethylenediamine, 2-diethylaminoethanol, ethanolamine, betaine, L-arginine, lysine, phenethylbenzylamine, benzathine penicillin, dimethylaminoethanol, imidazole, or a mixture thereof, preferably diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, or a mixture thereof, more preferably tromethamine; the inorganic base being selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aqueous ammonia, or a mixture thereof, preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or a mixture thereof; Or, 1) weighing an appropriate amount of free acid and suspending it in an anti-solvent; 2) Weighing an appropriate amount of counterion base and dissolving it in an organic solvent, the amount of the counterion base is preferably 1.0 to 1.5 equivalents; 3) combining the two solutions, stirring to dissolve, and continuing to stir; 4) Rapid centrifugation or static evaporation to dryness to obtain the desired product; where: the anti-solvent is selected from ethanol, ethyl acetate, ethyl formate, isopropanol, isopropyl acetate, methyl tert-butyl ether, dichloromethane, methanol, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol, and 3-pentanone, and is preferably ethanol, ethyl acetate, isopropanol, or isopropyl acetate; The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, and N,N-dimethylformamide, and is preferably methanol, ethanol, or acetonitrile. The good solvent and the organic solution must be compatible with each other when used. the counterion base is an organic base or an inorganic base, the organic base being selected from diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, meglumine, N-hydroxyethylmorpholine, piperazine, N-hydroxyethylpyrrolidine, N,N-dibenzylethylenediamine, 2-diethylaminoethanol, ethanolamine, betaine, L-arginine, lysine, phenethylbenzylamine, benzathine penicillin, dimethylaminoethanol, imidazole, or a mixture thereof, preferably diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine, or a mixture thereof, more preferably tromethamine; the inorganic base being selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aqueous ammonia, or a mixture thereof, preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or a mixture thereof; Or, 1) Weighing out an appropriate amount of a basic salt of a compound and suspending it in an anti-solvent, the suspension density being preferably 50-200 mg / mL; 2) shaking the resulting suspension at a certain temperature for a certain period of time, the temperature being preferably 25 to 50°C, and the period of time being preferably 1 to 15 days; 3) rapidly centrifuging the suspension, removing the supernatant, and drying the remaining solid in a vacuum drying box to a constant weight to obtain the target product; where: The anti-solvent is selected from dichloromethane, 1,4-dioxane, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, methyl tert-butyl ether, n-heptane, tert-butanol, or 2-butanone.

15. 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14, or a basic salt of a stereoisomer thereof, or a crystalline form thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. 16. The compound or stereoisomer of claim 1, wherein the basic salt or crystalline form thereof is a crystalline form of the ... therapeutically effective amount comprises 0.0001 to 99%, 0.0001 to 95%, 0.0001 to 90%, 0.0001 to 85%, 0.0001 to 80%, 0.0001 to 75%, 0.0001 to 70%, 0.001 to 60%, 0.001 to 55%, 0.01 to 50%, 0.01 to 40%, 0.01 to 30%, 0.01 to 20%, 0.01 to 10%, or 0.01 to 5%.

17. 16. Use of the compound according to any one of claims 1 to 14 or a basic salt of its stereoisomer or a crystalline form thereof, or the pharmaceutical composition according to claim 15, in the manufacture of a GLP-1 receptor agonist drug.

18. 16. The application of the compound according to any one of claims 1 to 14 or a basic salt of its stereoisomer or a crystalline form thereof, or the pharmaceutical composition according to claim 15, in the manufacture of a medicament for treating a metabolic-related disease, preferably the metabolic-related disease is selected from diabetes, obesity or non-alcoholic steatohepatitis-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic steatohepatitis.

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