Salt and crystal form of cycloalkene compound as well as preparation method and application of salt and crystal form

Abstract

Relates to a salt, a crystal form, a preparation method and an application of a cycloalkene compound. The invention specifically relates to a salt and a crystal form of a compound represented by a general formula (I), a preparation method, a pharmaceutical composition containing a therapeutically effective amount of the salt form, and an application of the pharmaceutical composition as a regulator in preparation of drugs for treating metabolic diseases and related diseases. # imgabs0 #

Description

A salt, crystal form, preparation method and application of a cycloolefin compound Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a salt, a crystal form, a preparation method and an application of a cycloolefin compound. Background Art

[0002] Diabetes mellitus is a common endocrine and metabolic disease caused by a variety of metabolic disorders, leading to multi-system and multi-organ damage. It has a high incidence rate, with approximately 425 million people suffering from diabetes worldwide. In China, the incidence rate is approximately 10%, of which type 2 diabetes accounts for 90%. The prevalence is still increasing, and the age of onset is becoming younger.

[0003] Currently, there are many types of drugs on the market for the treatment of type 2 diabetes, including insulin, biguanides, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase (DPP-IV) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, α-glucosidase inhibitors, etc., among which GLP-1 receptor agonists are the most popular.

[0004] GLP-1 is a peptide hormone secreted by human intestinal L cells. Its receptors are distributed in pancreatic islet cells, various gastrointestinal cells, and neurons in the central and peripheral nervous systems. Activation of the GLP-1 receptor has physiological effects such as promoting insulin secretion, inhibiting glucagon secretion, suppressing appetite, and delaying gastric emptying. Clinical evidence shows that compared with other hypoglycemic drugs, GLP-1 receptor agonists have a better blood sugar-lowering effect and are less likely to cause side effects such as hypoglycemia. In addition, they have additional cardiovascular benefits, can reduce food intake and delay gastric emptying, and are beneficial for weight control.

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

[0006] While no small-molecule GLP-1 receptor agonists have been approved, three have entered clinical development, including PF-06882961 and PF-07081532 developed by Pifzer, and TTP273 developed by vTv. All are currently in Phase I / II clinical trials. PF-06882961 has demonstrated significant glucose-lowering and weight-reducing effects in early clinical trials, with a safety profile similar to that of peptide-based GLP-1 receptor agonists. It is expected to provide additional treatment options for patients with diabetes, obesity, and NASH.

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

[0008] PCT / CN2022 / 110017 discloses the structures of a series of polycyclic compounds of cycloolefin derivatives. In subsequent research and development, in order to facilitate the handling, filtration and drying of the products, and to seek suitable crystals that are easy to store and have long-term stability, the present invention has conducted a comprehensive study on the salt forms of the above-mentioned compounds.

[0009] Summary of the Invention

[0010] All contents involved in patent PCT / CN2022 / 110017 are added to the present invention by reference.

[0011] The object of the present invention is to provide a compound represented by general formula (I) or a basic salt of a stereoisomer thereof, wherein the structure of the compound is shown in formula (I):

[0012] in:

[0013] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Haloalkoxy; preferably hydrogen, deuterium, fluorine, chlorine, methoxy or -OCD3;

[0014] R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3Haloalkoxy; preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0015] R 3 are each independently selected from hydrogen, deuterium or fluorine; preferably hydrogen;

[0016] M1 is N or CH; preferably CH;

[0017] W2 is N or CH; preferably CH;

[0018] x, y and z are each independently 0, 1 or 2;

[0019] 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; the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water or a mixture thereof.

[0020] In certain further preferred embodiments of the present invention, the compound is further represented by the following general formulas (I-1) to (I-4):

[0021] In certain embodiments of the present invention, the general formula (I) is selected from the following compounds:

[0022] 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; the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or a mixture thereof.

[0023] In a preferred embodiment of the present invention, 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 and a basic salt thereof is provided, wherein the compound or its stereoisomer and basic salt is a tromethamine salt.

[0024] In a further preferred embodiment of the present invention, the number of the bases is 0.5-3, preferably 0.5, 1, 1.5, 2, 2.5 or 3, further preferably 0.5, 1, 2 or 3, and even more preferably 1.

[0025] In certain embodiments of the present invention, the crystalline form is a salt 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.

[0026] In certain embodiments of the present invention, the crystalline form is a salt 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 containing 0.2 to 3 water, preferably 0.5 water, 1 water, 2 water or 3 water.

[0027] In certain embodiments of the present invention, the water molecules of the hydrate are pipeline water or crystal water.

[0028] In a preferred embodiment of the present invention, 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 and a basic salt thereof is provided, and the structure of the compound is as follows:

[0029] In certain embodiments of the present 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:

[0030] The powder X-ray diffraction pattern of the tromethamine salt crystalline form A has a characteristic peak at 7.7±0.2°, or a characteristic peak at 9.8±0.2°, or a characteristic peak at 10.8±0.2°, or a characteristic peak at 11.6±0.2°, or a characteristic peak at 14.0±0.2°, or a characteristic peak at 14.5±0.2°, or a characteristic peak at 14.8±0.2°, or a characteristic peak at 15.1±0.2°, or a characteristic peak at 15.9±0.2°, or a characteristic peak at 18.0±0.2°. The invention relates to a novel nanostructured carbon ...

[0031] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt crystalline form A has one or more characteristic peaks at 7.7±0.2°, 9.8±0.2°, 14.0±0.2° or 15.1±0.2°; preferably, 2-4 of them are included, more preferably 3-4, and most preferably 4; optionally, further, it may also include one or more characteristic peaks at 2θ 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°, preferably 2, 3, 4 or 6 of them; for example:

[0032] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°;

[0033] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 15.1±0.2°;

[0034] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 14.5±0.2°;

[0035] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 18.7±0.2°;

[0036] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 19.3±0.2°;

[0037] 7.7±0.2°、9.8±0.2°、14.5±0.2°、18.7±0.2°；

[0038] 7.7±0.2°、9.8±0.2°、14.0±0.2°、20.5±0.2°；

[0039] 7.7±0.2°、9.8±0.2°、14.0±0.2°、20.0±0.2°；

[0040] 9.8±0.2°、14.0±0.2°、14.5±0.2°、18.7±0.2°；

[0041] 7.7±0.2°、9.8±0.2°、14.0±0.2°、14.5±0.2°、15.1±0.2°；

[0042] 7.7±0.2°、9.8±0.2°、14.0±0.2°、14.5±0.2°、18.7±0.2°；

[0043] 7.7±0.2°、9.8±0.2°、14.0±0.2°、18.7±0.2°、20.0±0.2°；

[0044] 7.7±0.2°、9.8±0.2°、14.0±0.2°、19.3±0.2°、20.5±0.2°；

[0045] 7.7±0.2°、9.8±0.2°、14.5±0.2°、18.7±0.2°、20.5±0.2°；

[0046] 7.7±0.2°、9.8±0.2°、14.0±0.2°、19.3±0.2°、20.5±0.2°；

[0047] 7.7±0.2°、9.8±0.2°、14.0±0.2°、20.0±0.2°、21.1±0.2°；

[0048] 9.8±0.2°、14.0±0.2°、14.5±0.2°、18.7±0.2°、21.1±0.2°；

[0049] 7.7±0.2°、9.8±0.2°、14.0±0.2°、14.5±0.2°、15.1±0.2°、18.7±0.2°；

[0050] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, 18.7±0.2°, 19.3±0.2°;

[0051] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 18.7±0.2°, 19.3±0.2°, 20.0±0.2°;

[0052] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 19.3±0.2°, 20.5±0.2°, 21.1±0.2°;

[0053] 7.7±0.2°, 9.8±0.2°, 14.5±0.2°, 18.7±0.2°, 20.5±0.2°, 21.1±0.2°;

[0054] 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 19.3±0.2°, 20.5±0.2°, 21.1±0.2°;

[0055] 7.7±0.2°, 14.0±0.2°, 14.5±0.2°, 19.3±0.2°, 20.0±0.2°, 21.1±0.2°;

[0056] 9.8±0.2°, 14.0±0.2°, 14.5±0.2°, 18.7±0.2°, 19.3±0.2°, 21.1±0.2°;

[0057] More preferably, the powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 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 2-4, or 5-6 of them, further preferably, any 4 or 6 of them; for example:

[0058] 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 18.0±0.2°;

[0059] 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 20.5±0.2°;

[0060] 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 22.6±0.2°;

[0061] 10.8±0.2°, 11.6±0.2°, 18.0±0.2°, 20.5±0.2°;

[0062] 11.6±0.2°, 14.5±0.2°, 18.0±0.2°, 20.5±0.2°;

[0063] 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 18.0±0.2°, 20.5±0.2°;

[0064] 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 20.5±0.2°, 22.6±0.2°;

[0065] 10.8±0.2°, 11.6±0.2°, 14.5±0.2°, 18.0±0.2°, 20.5±0.2°, 22.6±0.2°;

[0066] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt crystalline form A has characteristic peaks at 9.8±0.2° and 14.0±0.2°, 2θ; preferably, it also includes characteristic peaks at 7.7±0.2° and 15.1±0.2°, 2θ; more preferably, it also includes characteristic peaks at 18.7±0.2°, 19.3±0.2°, 20.0±0.2° and 21.1±0.2°, 2θ; further preferably, it also includes characteristic peaks at 14.5±0.2° and 20.5±0.2°, 2θ; and further preferably, it also includes characteristic peaks at one or more of 10.8±0.2°, 11.6±0.2°, 18.0±0.2° and 22.6±0.2°.

[0067] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 1.

[0068] Table 1

[0069] The X-ray powder diffraction pattern of the tromethamine salt crystal form A of the compound described in the present invention is substantially as shown in FIG1 , the DSC pattern thereof is substantially as shown in FIG2 , and the TGA pattern thereof is substantially as shown in FIG3 .

[0070] In certain 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)-oxabutane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid tromethamine salt crystalline form B, and the powder X-ray diffraction pattern of the tromethamine salt crystalline form B has a characteristic peak at 2θ of 8.2±0.2°, or a characteristic peak at 2θ of 10.1±0.2°, or a characteristic peak at 2θ of 12.3±0.2°, or a characteristic peak at 2θ of 14.4±0.2°, or a characteristic peak at 2θ of 14.8±0.2°, or a characteristic peak at 2θ of 16.0±0.2°, or a characteristic peak at 2θ of 16.2±0.2°. , or has a characteristic peak at 17.5±0.2°, 2θ, or has a characteristic peak at 17.7±0.2°, 2θ, or has a characteristic peak at 18.3±0.2°, 2θ, or has a characteristic peak at 18.7±0.2°, 2θ, or has a characteristic peak at 19.7±0.2°, 2θ, or has a characteristic peak at 20.5±0.2°, 2θ, or has a characteristic peak at 20.9±0.2°, 2θ, or has a characteristic peak at 21.9±0.2°, 2θ, or has a characteristic peak at 22.1±0.2°, 2θ, or has a characteristic peak at 22.4±0.2°, 2θ, or has a characteristic peak at 24.7±0.2°; preferably, comprising optional 2, 4, 6, 8, 10 or 12 characteristic peaks.

[0071] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt form B has one or more characteristic peaks at 10.1±0.2°, 14.4±0.2°, 18.7±0.2° or 21.9±0.2°; preferably, 2-4 of them are included, more preferably, 3-4 of them are included, and most preferably, 4 of them are included; optionally, further, it may also include one or more characteristic peaks at 2θ 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°, preferably, 2, 3, 4 or 6 of them are included; for example: 10.1±0.2°, 14.4±0.2°, 18.7±0.2°; 10.1±0.2°, 14.4±0.2°, 18.7±0.2°, 21.9±0.2°; 8.2±0.2°, 14.4±0.2°, 18.7±0.2°, 21.9±0.2°; 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 18.7±0.2°; 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°; 10.1±0.2°, 14.4±0.2°, 18.7±0.2°, 19.7±0.2°; 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 21.9±0.2°; 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°; 8.2±0.2°, 12.3±0.2°, 14.4±0.2°, 18.7±0.2°; 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 18.7±0.2°, 21.9±0.2°; 8.2±0.2°, 12.3±0.2°, 14.4±0.2°, 18.7±0.2°, 21.9±0.2°; 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°; 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, 21.9±0.2°; 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, 19.7±0.2°; 8.2±0.2°, 10.1±0.2°, 12.3±0.2°, 14.4±0.2°, 21.9±0.2°; 10.1±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°, 21.9±0.2°; 8.2±0.2°, 12.3±0.2°, 14.4±0.2°, 14.8±0.2°, 18.7±0.2°; 10.1±0.2°, 12.3±0.2°、14.4±0.2°、14.8±0.2°、18.7±0.2°、21.9±0.2°； 8.2±0.2°、12.3±0.2°、14.4±0.2°、18.7±0.2°、21.9±0.2°、22.1±0.2°； 10.1±0.2°、12.3±0.2°、14.4±0.2°、14.8±0.2°、18.7±0.2°、19.7±0.2°； 10.1±0.2°、14.4±0.2°、14.8±0.2°、18.7±0.2°、21.9±0.2°、22.1±0.2°； 10.1±0.2°、14.4±0.2°、14.8±0.2°、18.7±0.2°、19.7±0.2°、22.1±0.2°； 8.2±0.2°、10.1±0.2°、12.3±0.2°、14.4±0.2°、14.8±0.2°、21.9±0.2°； 10.1±0.2°、14.4±0.2°、14.8±0.2°、18.7±0.2°、21.9±0.2°、22.1±0.2°； 8.2±0.2°、12.3±0.2°、14.4±0.2°、14.8±0.2°、18.7±0.2°、22.1±0.2°；.

[0072] More preferably, its powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 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 comprises at least any 2-4, or 5-6 thereof, further preferably comprises any 4 or 6 thereof; for example: 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 18.3±0.2°; 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 19.7±0.2°; 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 20.9±0.2°; 12.3±0.2°, 16.2±0.2°, 18.3±0.2°, 19.7±0.2°; 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, 19.7±0.2°; 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, 20.9±0.2°; 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, 19.7±0.2°, 20.9±0.2°; 12.3±0.2°, 16.0±0.2°, 16.2±0.2°, 18.3±0.2°, 19.7±0.2°, 20.9±0.2°;

[0073] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt crystalline form B has characteristic peaks at 2θ of 10.1±0.2° and 14.4±0.2°; preferably, it also includes characteristic peaks at 2θ of 18.7±0.2° and 21.9±0.2°; more preferably, it also includes characteristic peaks at 2θ of 8.2±0.2°, 14.8±0.2°, 20.5±0.2° and 22.1±0.2°; further preferably, it also includes characteristic peaks at 2θ of 12.3±0.2° and 19.7±0.2°; further preferably, it also includes characteristic peaks at one or more of 16.0±0.2°, 16.2±0.2°, 18.3±0.2° and 20.9±0.2°.

[0074] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 2.

[0075] Table 2

[0076] The X-ray powder diffraction pattern of the tromethamine salt crystal form B of the compound of the present invention is substantially as shown in FIG4 , and the DSC pattern thereof is substantially as shown in FIG5 .

[0077] In certain 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 pattern of the tromethamine salt crystalline form C has a characteristic at 2θ of 3.6±0.2°. characteristic peak at 7.1±0.2°, or at 9.7±0.2°, or at 10.6±0.2°, or at 13.5±0.2°, or at 14.1±0.2°, or at 15.0±0.2°, or at 16.0± The characteristic peak at 2θ is 16.5±0.2°, the characteristic peak at 2θ is 17.1±0.2°, the characteristic peak at 2θ is 17.6±0.2°, the characteristic peak at 2θ is 19.0±0.2°, the characteristic peak at 2θ is 19.7±0.2°, the characteristic peak at 2θ is 20.8±0.2°, or The method comprises the following steps: having a characteristic peak at 2θ of 21.8±0.2°, having a characteristic peak at 2θ of 22.3±0.2°, having a characteristic peak at 2θ of 23.1±0.2°, having a characteristic peak at 2θ of 26.4±0.2°, or having a characteristic peak at 2θ of 28.3±0.2°; preferably, comprising characteristic peaks at any of 2, 4, 6, 8, 10 or 12 locations.

[0078] The powder X-ray diffraction pattern of the tromethamine salt form C has one or more characteristic peaks at 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2° or 16.0±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also include one or more characteristic peaks at 2θ 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°, preferably 2, 3, 4 or 6 of them; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 15.0±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 16.5±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 17.1±0.2°; 3.6±0.2°, 7.1±0.2°, 14.1±0.2°, 17.6±0.2°; 3.6±0.2°, 7.1±0.2°, 17.6±0.2°, 19.7±0.2°; 9.7±0.2°, 14.1±0.2°, 16.0±0.2°, 17.1±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 16.0±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 15.0±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 16.5±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 17.1±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2°, 17.6±0.2°; 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 17.6±0.2°, 19.7±0.2°; 3.6±0.2°, 7.1±0.2°, 14.1±0.2°, 17.1±0.2°, 17.6±0.2°; 3.6±0.2°, 9.7±0.2°, 14.1±0.2°, 17.1±0.2°, 17.6±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°; 3.6±0.2°, 7.1±0.2°、9.7±0.2°、14.1±0.2°、15.0±0.2°、17.1±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°； 3.6±0.2°、7.1±0.2°、9.7±0.2°、14.1±0.2°、17.6±0.2°、19.7±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°； 3.6±0.2°、9.7±0.2°、14.1±0.2°、15.0±0.2°、16.0±0.2°、17.1±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°； 9.7±0.2°、14.1±0.2°、15.0±0.2°、16.0±0.2°、17.1±0.2°、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°、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°、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°、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°、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°、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°、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°、20.8±0.2°；.

[0079] More preferably, its powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 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 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example: 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 19.7±0.2°; 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 21.8±0.2°; 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 26.4±0.2°; 17.1±0.2°, 19.0±0.2°, 21.8±0.2°, 26.4±0.2°; 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 21.8±0.2°, 26.4±0.2°; 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 19.7±0.2°, 21.8±0.2°; 17.1±0.2°, 19.0±0.2°, 19.7±0.2°, 21.8±0.2°, 26.4±0.2°; 13.5±0.2°, 17.1±0.2°, 19.0±0.2°, 19.7±0.2°, 21.8±0.2°, 26.4±0.2°;

[0080] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt crystalline form C has characteristic peaks at 2θ of 3.6±0.2° and 7.1±0.2°; preferably, it also includes characteristic peaks at 2θ of 9.7±0.2° and 14.1±0.2°; more preferably, it also includes characteristic peaks at 2θ of 15.0±0.2°, 16.0±0.2°, 16.5±0.2°, 17.6±0.2° and 20.8±0.2°; further preferably, it also includes characteristic peaks at 2θ of 17.1±0.2° and 19.7±0.2°; further preferably, it also includes characteristic peaks at one or more of 13.5±0.2°, 19.0±0.2°, 21.8±0.2° and 26.4±0.2°;

[0081] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 3.

[0082] Table 3

[0083] The X-ray powder diffraction pattern of the tromethamine salt crystal form C of the compound of the present invention is substantially as shown in FIG6 , the DSC pattern is substantially as shown in FIG7 , and the TGA pattern is substantially as shown in FIG8 .

[0084] In certain embodiments of the present invention, the tromethamine salt crystal form C is an anhydrate crystal form.

[0085] In certain 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 pattern of the tromethamine salt crystalline form D has a characteristic at 2θ of 7.4±0.2°. characteristic peak at 7.7±0.2°, or at 9.8±0.2°, or at 10.8±0.2°, or at 11.6±0.2°, or at 13.1±0.2°, or at 14.0±0.2°, or at 14.5± The characteristic peak is at 15.1±0.2°, or at 15.4±0.2°, or at 15.8±0.2°, or at 17.9±0.2°, or at 18.8±0.2°, or at 19.3±0.2°, or The method comprises the following steps: having a characteristic peak at 2θ of 20.0±0.2°, having a characteristic peak at 2θ of 20.5±0.2°, having a characteristic peak at 2θ of 21.2±0.2°, having a characteristic peak at 2θ of 21.8±0.2°, or having a characteristic peak at 2θ of 23.3±0.2°; preferably, comprising characteristic peaks at any of 2, 4, 6, 8, 10 or 12 locations.

[0086] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt crystalline form D has one or more characteristic peaks at 7.4±0.2°, 9.8±0.2°, 13.1±0.2° or 14.0±0.2°; preferably, 2-4 of them are included, more preferably, 3-4 of them are included, and most preferably, 4 of them are included; optionally, further, it may also include one or more characteristic peaks at 2θ 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°, preferably, 2, 3, 4 or 6 of them are included; for example: 7.4±0.2°, 9.8±0.2°, 13.1±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°; 7.4±0.2°, 7.7±0.2°, 9.8±0.2°, 13.1±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°; 7.4±0.2°, 13.1±0.2°, 14.0±0.2°, 17.9±0.2°; 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°; 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 15.1±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 19.3±0.2°; 7.4±0.2°, 7.7±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 17.9±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 18.8±0.2°; 7.4±0.2°, 13.1±0.2°, 14.0±0.2°, 17.9±0.2°, 18.8±0.2°; 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°, 17.9±0.2°; 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 15.1±0.2°, 17.9±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 19.3±0.2°, 20.0±0.2°; 7.4±0.2°, 7.7±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°, 18.8±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 17.9±0.2°, 18.8±0.2°; 7.4±0.2°, 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 18.8±0.2°, 20.0±0.2°; 7.4±0.2°, 13.1±0.2°, 14.0±0.2°, 17.9±0.2°, 18.8±0.2°, 20.0±0.2°; 9.8±0.2°, 13.1±0.2°, 14.0±0.2°, 15.1±0.2°, 17.9±0.2°, 18.8±0.2°; 7.7±0.2°, 9.8±0.2°, 14.0±0.2°, 15.1±0.2°, 17.9±0.2°, 20.0±0.2°;

[0087] More preferably, its powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 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 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example: 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 17.9±0.2°; 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 19.3±0.2°; 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 21.2±0.2°; 14.5±0.2°, 15.8±0.2°, 17.9±0.2°, 21.2±0.2°; 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 17.9±0.2°, 19.3±0.2°; 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 19.3±0.2°, 21.2±0.2°; 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 17.9±0.2°, 21.2±0.2°; 14.5±0.2°, 15.4±0.2°, 15.8±0.2°, 17.9±0.2°, 19.3±0.2°, 21.2±0.2°;

[0088] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt crystalline form D has characteristic peaks at 9.8±0.2° and 14.0±0.2°, 2θ; preferably, it further comprises characteristic peaks at 7.4±0.2° and 13.1±0.2°, 2θ; more preferably, it further comprises characteristic peaks at 7.7±0.2°, 15.1±0.2°, 18.8±0.2° and 20.0±0.2°, 2θ; further preferably, it further comprises characteristic peaks at 17.9±0.2° and 19.3±0.2°, 2θ; and further preferably, it further comprises characteristic peaks at one or more of 14.5±0.2°, 15.4±0.2°, 15.8±0.2° and 21.2±0.2°.

[0089] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 4.

[0090] Table 4

[0091] The X-ray powder diffraction pattern of the tromethamine salt crystal form D of the compound of the present invention is substantially as shown in FIG9 , and the DSC pattern thereof is substantially as shown in FIG10 .

[0092] In certain 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 E, and the powder X-ray diffraction pattern of the tromethamine salt crystalline form E has a characteristic peak at 2θ of 4.3±0.2°, or a characteristic peak at 2θ of 6.3±0.2°, or a characteristic peak at 2θ of 8.6±0.2°, or a characteristic peak at 2θ of 9.3±0.2°, or a characteristic peak at 2θ of 13.6±0.2°, or a characteristic peak at 2θ of 14.1±0.2°, or a characteristic peak at 2θ of 17.7±0. .2°, or has a characteristic peak at 2θ of 18.5±0.2°, or has a characteristic peak at 2θ of 18.9±0.2°, or has a characteristic peak at 2θ of 20.2±0.2°, or has a characteristic peak at 2θ of 20.5±0.2°, or has a characteristic peak at 2θ of 21.4±0.2°, or has a characteristic peak at 2θ of 21.9±0.2°, or has a characteristic peak at 2θ of 22.4±0.2°, or has a characteristic peak at 2θ of 23.4±0.2°, or has a characteristic peak at 2θ of 23.9±0.2°, or has a characteristic peak at 2θ of 25.2±0.2°; preferably, comprises optional 2, 4, 6, 8, 10 or 12 characteristic peaks.

[0093] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt crystalline form E has one or more characteristic peaks at 4.3±0.2°, 6.3±0.2°, 13.6±0.2° or 18.9±0.2°; preferably, 2-4 of them are included, more preferably, 3-4 of them are included, and most preferably, 4 of them are included; optionally, further, it may also include one or more characteristic peaks at 2θ 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°, preferably, 2, 3, 4 or 6 of them are included; for example: 4.3±0.2°, 6.3±0.2°, 13.6±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°; 4.3±0.2°, 6.3±0.2°, 8.6±0.2°, 13.6±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 14.1±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 17.7±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°; 4.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°; 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°; 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, 17.7±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°, 20.2±0.2°; 4.3±0.2°, 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, 18.9±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 17.7±0.2°, 18.9±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°, 20.2±0.2°; 4.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°; 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°, 20.2±0.2°; 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, 17.7±0.2°, 18.9±0.2°, 20.2±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°, 20.2±0.2°, 20.5±0.2°; 4.3±0.2°, 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, 18.9±0.2°, 20.5±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°, 20.5±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 17.7±0.2°, 18.9±0.2°, 20.2±0.2°; 4.3±0.2°, 6.3±0.2°, 13.6±0.2°, 18.9±0.2°, 20.2±0.2°, 20.5±0.2°; 4.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°, 20.2±0.2°; 6.3±0.2°, 8.6±0.2°, 13.6±0.2°, 14.1±0.2°, 18.9±0.2°, 22.4±0.2°; 6.3±0.2°, 13.6±0.2°, 14.1±0.2°, 17.7±0.2°, 18.9±0.2°, 22.4±0.2°;

[0094] More preferably, its powder X-ray diffraction pattern optionally further comprises one or more diffraction peaks located at 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 2-4, or 5-6 thereof, further preferably, any 4 or 6 thereof; for example: 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 20.5±0.2°; 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 21.4±0.2°; 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 21.9±0.2°; 9.3±0.2°, 18.5±0.2°, 20.5±0.2°, 21.4±0.2°; 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 20.5±0.2°, 21.4±0.2°; 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 21.4±0.2°, 21.9±0.2°; 14.1±0.2°, 18.5±0.2°, 20.5±0.2°, 21.4±0.2°, 21.9±0.2°; 9.3±0.2°, 14.1±0.2°, 18.5±0.2°, 20.5±0.2°, 21.4±0.2°, 21.9±0.2°;

[0095] In certain embodiments of the present invention, the powder X-ray diffraction pattern of the tromethamine salt crystalline form E has characteristic peaks at 6.3±0.2° and 13.6±0.2°, 2θ; preferably, it also includes characteristic peaks at 4.3±0.2° and 18.9±0.2°, 2θ; more preferably, it also includes characteristic peaks at 8.6±0.2°, 17.7±0.2°, 20.2±0.2° and 22.4±0.2°, 2θ; further preferably, it also includes characteristic peaks at 14.1±0.2° and 20.5±0.2°, 2θ; and further preferably, it also includes characteristic peaks at one or more of 9.3±0.2°, 18.5±0.2°, 21.4±0.2° and 21.9±0.2°.

[0096] In certain embodiments of the present invention, Cu-Kα radiation is used, and the characteristic X-ray diffraction peaks expressed in terms of 2θ angles and interplanar spacing d values ​​are shown in Table 5.

[0097] Table 5

[0098] The X-ray powder diffraction pattern of the tromethamine salt crystal form E of the compound of the present invention is substantially as shown in FIG11 , and the DSC pattern thereof is substantially as shown in FIG12 .

[0099] In a further preferred embodiment of the present invention, the above-mentioned crystal form is a solvent-containing crystal form, 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 or isopropyl ether.

[0100] In a further preferred embodiment of the present invention, the number of the solvents is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

[0101] The present invention also provides a method for preparing a compound represented by general formula (I) or its stereoisomers and basic salts, which specifically comprises the following steps:

[0102] 1) Weigh an appropriate amount of free acid and dissolve it in a benign solvent;

[0103] 2) Weigh an appropriate amount of counterion base and dissolve it in an organic solvent; the amount of counterion base is preferably 1.0 to 1.5 equivalents;

[0104] 3) Combine the above two solutions and stir to precipitate or add a poor solvent dropwise and stir to precipitate;

[0105] 4) Rapidly centrifuge or allow to evaporate to dryness to obtain the target product;

[0106] in:

[0107] The benign 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 or tert-butanol; preferably 2-methyl-tetrahydrofuran, ethyl acetate, 2-butanone, acetone or ethyl formate;

[0108] 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 or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above-mentioned benign solvent and organic solvent need to be miscible when used;

[0109] The poor solvent is selected from heptane, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether, and ethyl acetate; preferably methyl tert-butyl ether and isopropyl ether;

[0110] 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; preferably diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine or a mixture thereof; further preferably tromethamine; the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water or a mixture thereof, preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or a mixture thereof.

[0111] The present invention also provides a method for preparing a compound represented by general formula (I) or its stereoisomers and basic salts, which specifically comprises the following steps:

[0112] 1) Weigh an appropriate amount of free acid and suspend it in a poor solvent;

[0113] 2) Weigh an appropriate amount of counterion base and dissolve it in an organic solvent; the amount of counterion base is preferably 1.0 to 1.5 equivalents;

[0114] 3) Combine the above two solutions and stir to dissolve, and continue stirring;

[0115] 4) Rapidly centrifuge or allow to evaporate to dryness to obtain the target product;

[0116] in:

[0117] The poor solvent is selected from ethanol, ethyl acetate, ethyl formate, isopropyl alcohol, isopropyl acetate, methyl tert-butyl ether, dichloromethane, methanol, acetonitrile, chlorobenzene, benzene, toluene, n-butanol, isobutanol or 3-pentanone; preferably ethanol, ethyl acetate, isopropyl alcohol, isopropyl acetate.

[0118] 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 or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above-mentioned benign solvent and organic solvent need to be miscible when used;

[0119] 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; preferably diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine or a mixture thereof; further preferably tromethamine; the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water or a mixture thereof, preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or a mixture thereof.

[0120] The present invention also provides a method for preparing a compound represented by general formula (I) or its stereoisomers and basic salts, which specifically comprises the following steps:

[0121] 1) Weigh an appropriate amount of the basic salt of the compound and suspend it in a poor solvent, preferably with a suspension density of 50 to 200 mg / mL;

[0122] 2) shaking the resulting suspension at a certain temperature for a certain time, preferably 25-50° C., and preferably for 1 to 15 days;

[0123] 3) The suspension was centrifuged quickly, the supernatant was removed, and the remaining solid was placed in a vacuum drying oven and dried to a constant weight to obtain the target product;

[0124] in:

[0125] The poor 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.

[0126] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or its stereoisomers and salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0127] Embodiments provided herein comprise a therapeutically effective amount of a basic salt or a 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%.

[0128] The present invention further relates to the use of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of GLP-1 receptor agonist drugs.

[0129] The present invention further relates to the use of a compound represented by the general formula, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating metabolic-related diseases, wherein the metabolic-related diseases are selected from diabetes, obesity, or non-alcoholic steatohepatitis-related diseases or other related diseases caused by diabetes, obesity, or non-alcoholic steatohepatitis.

[0130] The present invention further relates to a method for using the compound represented by the general formula, its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in preparing drugs for treating metabolic diseases and related diseases.

[0131] The present invention also relates to a method for treating, preventing and / or treating metabolic-related diseases, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0132] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with GLP-1 receptor modulators.

[0133] The present invention also relates to a method for treating metabolic disease-related diseases in mammals, comprising administering to the 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 DESCRIPTION OF THE DRAWINGS

[0134] FIG1 is an XRPD diagram of tromethamine salt Form A.

[0135] FIG2 is a DSC diagram of tromethamine salt Form A.

[0136] FIG3 is a TGA diagram of tromethamine salt Form A.

[0137] FIG4 is an XRPD diagram of tromethamine salt Form B.

[0138] FIG5 is a DSC diagram of tromethamine salt Form B.

[0139] FIG6 is an XRPD diagram of Form C of tromethamine salt.

[0140] FIG7 is a DSC diagram of tromethamine salt Form C.

[0141] FIG8 is a TGA diagram of tromethamine salt Form C.

[0142] FIG9 is an XRPD diagram of Form D of tromethamine salt.

[0143] FIG10 is a DSC diagram of tromethamine salt Form D.

[0144] FIG11 is an XRPD diagram of Form E of tromethamine salt.

[0145] FIG12 is a DSC diagram of tromethamine salt Form E. DETAILED DESCRIPTION

[0146] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0147] In the present invention, an alkyl group refers to a saturated aliphatic hydrocarbon group, which is a straight 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, 5-methylhexyl, 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.

[0148] The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention; the hydroxy-substituted alkyl may be 2-hydroxyisopropyl or 1-hydroxyethyl.

[0149] In the present invention, alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above, 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 include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate;

[0150] Non-limiting examples of alkoxy also include propan-2-oxy and the like.

[0151] In the present invention, haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above. Non-limiting examples of haloalkyl include: trifluoromethyl, trifluoroethyl;

[0152] Non-limiting examples of haloalkyl also include difluoromethyl, 1,1,2,2-tetrafluoroethyl, perfluoroethyl, and the like.

[0153] In the present invention, haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above;

[0154] The halogenated alkoxy group may be fully halogenated or partially halogenated, and the number of halogenations may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.; the halogen is preferably F, Cl, Br, I; for example, it may be trifluoromethoxy, difluoromethoxy, 1,1,2,2-tetrafluoroethoxy, perfluoroethoxy, etc.

[0155] In the present invention, hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

[0156] In the present invention, a haloalkyl group refers to an alkyl group substituted by one or more halogens, wherein the alkyl group is as defined above.

[0157] In the present invention, a haloalkoxy group refers to an alkoxy group substituted by one or more halogen groups, wherein the alkoxy group is as defined above.

[0158] "Hydroxy" refers to an -OH group.

[0159] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0160] "Amino" refers to -NH2.

[0161] "Cyano" refers to -CN.

[0162] "Nitro" refers to -NO2.

[0163] "THF" refers to tetrahydrofuran.

[0164] "EtOAc" refers to ethyl acetate.

[0165] "DMSO" refers to dimethyl sulfoxide.

[0166] "LDA" refers to lithium diisopropylamide.

[0167] "DMAP" refers to 4-dimethylaminopyridine.

[0168] "EtMgBr" refers to ethylmagnesium bromide.

[0169] "HOSu" refers to N-hydroxysuccinimide.

[0170] "EDCl" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0171] "IPA" refers to isopropyl alcohol.

[0172] "MeOH" refers to methanol.

[0173] "EtOH" refers to ethanol.

[0174] "Acetone" refers to acetone.

[0175] "MEK" refers to methyl ethyl ketone.

[0176] "2-Me-THF" refers to 2-methyltetrahydrofuran.

[0177] "BuOH" refers to butanol.

[0178] "Dioxane" refers to dioxane.

[0179] "DMF" refers to N,N-dimethylformamide.

[0180] "DIPEA" refers to N,N-diisopropylethylamine.

[0181] "HEPES" refers to 4-hydroxyethylpiperazineethanesulfonic acid.

[0182] "Tris" refers to tromethamine.

[0183] Different expressions 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 express the same meaning, that is, X can be any one or more of A, B, and C.

[0184] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0185] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0186] "Stereoisomerism" includes three types: geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.

[0187] As used herein, the name of a compound is intended to encompass all possible isomeric forms, including stereoisomers (eg, enantiomers, diastereomers, racemates or racemic mixtures, and any mixtures thereof) of the compound.

[0188] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0189] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0190] An X-ray powder diffraction pattern (XRPD) refers to an experimentally observed diffraction pattern or parameters derived therefrom, characterized by peak position (abscissa) and peak intensity (ordinate). Those skilled in the art will appreciate that experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is well known to those skilled in the art that X-ray diffraction patterns typically vary with instrument conditions, and those skilled in the art will appreciate that suitable error tolerances for XRPD may be: 2θ±0.5°; 2θ±0.4°; 2θ±0.3°; 2θ±0.2°. It is particularly important to note that the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or determining factor. Furthermore, experimental factors such as sample height can cause an overall shift in peak angles, and a certain amount of shift is generally tolerated. Therefore, those skilled in the art will appreciate that any crystalline form having characteristic peaks identical or similar to those in the pattern of the present invention falls within the scope of the present invention.

[0191] "TGA" refers to a thermogravimetric analysis (TGA) experiment.

[0192] "DSC" refers to a differential scanning calorimetry (DSC) experiment.

[0193] "HPLC" refers to high performance liquid chromatography (HPLC) experiments.

[0194] "PK" refers to pharmacokinetic (PK) studies.

[0195] “KF” refers to the Karl Fischer water determination (KF) experiment.

[0196] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0197] Example

[0198] The following examples are intended to illustrate the present invention, but should not be construed as limiting the scope of the present invention. Unless otherwise specified in the examples, the specific conditions of the experimental methods were generally based on the conventional conditions or recommended conditions of the raw materials and product manufacturers. Reagents for which the specific sources are not indicated are commercially available conventional reagents.

[0199] Intermediate Im-1

[0200] Synthesis of ((S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester)

[0201] first step

[0202] (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0203] In a 50 mL reaction flask, 3-fluoro-4-(1-((6-(piperidin-4-yl)pyridin-2-yl)oxy)cyclopropyl)benzonitrile (2 g, 10.04 mmol) and KCO (2.78 g, 20.08 mmol) were dissolved in tetrahydrofuran (30 mL). (S)-oxetan-2-ylmethylamine (874 mg, 10.04 mmol) was then added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was stopped and quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2.0 g, yellow solid) in a yield of 74.8%.

[0204] MS m / z(ESI):267.0[M+1].

[0205] Step 2

[0206] (S)-4-Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0207] Methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (3 g, 11.27 mmol) was dissolved in methanol (30 mL), followed by the addition of 10% Pd / C (300 mg). The mixture was replaced with hydrogen three times and stirred for 3 hours. The reaction mixture was filtered, and the organic phase was dried and spin-dried to afford the title product, methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (2.6 g, yellow solid) in a 97.7% yield.

[0208] MS m / z(ESI):237.1[M+1].

[0209] Step 3

[0210] (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[0211] In a 50 mL reaction flask, (S)-methyl 4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (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 then added. The reaction mixture was stirred at 60°C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Im-1) (1.3 g, yellow solid) in a 52.0% yield.

[0212] MS m / z(ESI):295.0[M+1].

[0213] Intermediate Im-2

[0214] Synthesis of ((S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester)

[0215] first step

[0216] (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)2-picolinic acid methyl ester

[0217] Starting from methyl 6-chloro-5-nitro-2-picolinate, refer to step 1 of intermediate Im-1 to obtain the title product (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)2-picolinate.

[0218] MS m / z(ESI):268.1[M+1].

[0219] Step 2

[0220] (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)2-picolinate.

[0221] Using (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)2-picolinic acid methyl ester as the starting material, refer to step 2 of intermediate Im-1 to obtain the title product, (S)-5-amino-6-((oxetan-2-ylmethyl)amino)2-picolinic acid methyl ester.

[0222] MS m / z(ESI):238.1[M+1].

[0223] Step 3

[0224] ((S)-2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester

[0225] At room temperature, (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)-2-picolinate (340 mg, 1.43 mmol) was dissolved in tetrahydrofuran (5 mL), and then a solution of chloroacetic anhydride (257.27 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes, then heated to 60°C and reacted for 2 hours. The mixture was cooled to room temperature. LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (30 mL), then washed with saturated sodium bicarbonate solution (15 mL × 3), washed with saturated sodium chloride solution (15 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give the title product ((S)-2-(chloromethyl)-3-(oxabutan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester (Im-2) (yellow oil, 0.4 g) with a yield of 94.4%. The crude product was used directly in the next step.

[0226] MS m / z(ESI):296.1[M+1].

[0227] Intermediate Im-3

[0228] Synthesis of Ethyl 2-(Chloromethyl)-1-((1-(Fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0229] first step

[0230] Ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate

[0231] Dissolve ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (7 g, 48.55 mmol) in DCM (100 mL) and add DAST (8.61 g, 53.41 mmol) at -78°C. Allow the reaction to warm to room temperature and stir for 16 hours. After completion, add 50 mL of water and extract with dichloromethane (50 mL x 2). Wash with saturated sodium chloride solution (30 mL x 2), dry over anhydrous sodium sulfate, and concentrate to obtain the title product, ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate (6.5 g, yellow oil) in a 91.6% yield.

[0232] 1 H NMR (400MHz, CDCl3): δ4.52(dd,1.5Hz,2H),4.17(q,2H),1.41–1.33(m,2H),1.26(t,3H),1.05–0.95(m,2H).

[0233] Step 2

[0234] 1-(Fluoromethyl)cyclopropylmethanol

[0235] Dissolve ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate (6.5 g, 44.47 mmol) in THF (60 mL) and add LiAlH₄ (2.53 g, 66.71 mmol) in an ice-water bath. Allow the reaction to warm to room temperature and stir for 16 hours. After completion, quench the reaction with 15 g of sodium sulfate decahydrate. Filter and concentrate to obtain the title product, 1-(fluoromethyl)cyclopropylmethanol (3.5 g, yellow oil) in a 75.6% yield.

[0236] 1 H NMR (400MHz, CDCl3): δ4.36 (d, 2H), 3.58 (s, 2H), 0.60 (m, 4H).

[0237] Step 3

[0238] (1-(Fluoromethyl)cyclopropyl)methyl methanesulfonate

[0239] 1-(Fluoromethyl)cyclopropylmethanol (1.3 g, 12.49 mmol) was dissolved in DCM (30 mL). Methanesulfonyl chloride (1.86 g, 16.23 mmol, 1.26 mL) and triethylamine (2.53 g, 24.97 mmol, 3.48 mL) were added dropwise in an ice-water bath. The reaction system was stirred at 20°C. After completion, saturated NaHCO₃ (10 mL) was added dropwise to quench the reaction. 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 afford crude (1-(fluoromethyl)cyclopropyl)methyl methanesulfonate (2.0 g, light yellow oil) in an 87.0% yield.

[0240] 1 H NMR (400MHz, CDCl3) δ4.32(d,2H),4.19(s,2H),3.05(s,3H),0.81–0.72(m,4H).

[0241] Step 4

[0242] (1-(Fluoromethyl)cyclopropyl)methylamine

[0243] Dissolve (1-(Fluoromethyl)cyclopropyl)methyl methanesulfonate (1.0 g, 5.49 mmol) in NH3 / i-PrOH (10 mL). Heat the reaction system at 60°C in a microwave oven for 6 hours. After completion, concentrate the reaction to afford the title product, (1-(fluoromethyl)cyclopropyl)methanamine (600 mg, yellow oil). The crude product is used directly in the next reaction.

[0244] Step 5

[0245] Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate

[0246] Ethyl 3-fluoro-4-nitrobenzoate (1.24 g, 5.82 mmol) was dissolved in DMF (30 mL), and (1-(fluoromethyl)cyclopropyl)methanamine (600 mg, 5.82 mmol) and K2CO3 (1.61 g, 11.64 mmol) were added. The reaction system was stirred at 20°C for four hours. After completion, the reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The 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%.

[0247] MS m / z(ESI):297.1[M+1].

[0248] 1 H NMR (400MHz, CDCl3): δ8.22(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).

[0249] Step 6

[0250] Ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate

[0251] 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. The reaction system was purged with hydrogen three times and stirred at 20°C for 2 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to afford the title product, ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, yellow solid) in a yield of 92.7%.

[0252] MS m / z(ESI):267.1[M+1].

[0253] Step 7

[0254] Ethyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0255] 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. The reaction system was stirred in an oil bath at 60°C for 4 hours. After completion, the reaction was concentrated to obtain the crude product. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to provide ethyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (700 mg, yellow solid) in a yield of 57.4%.

[0256] MS m / z(ESI):325.1[M+1].

[0257] 1H NMR (400MHz, CDCl3): δ8.21(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).

[0258] Intermediate Im-4

[0259] tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate

[0260] first step

[0261] tert-Butyl 4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0262] Dissolve 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)Cl2·CH2Cl2 (7.6 g, 9.40 mmol), and anhydrous potassium carbonate (39 g, 0.28 mol) in 250 mL of a 4:1 mixture of dioxane and water. Heat the reaction mixture to 100°C and stir for 8 hours. The reaction was stopped and the reaction solution was cooled to ambient temperature. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by 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) in a yield of 88.1%.

[0263] MS m / z(ESI):318.1[M+1].

[0264] Step 2

[0265] tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate

[0266] 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). Hydrogen was introduced three times, and air was expelled. The reaction mixture was stirred for 12 hours. The reaction was terminated, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-4 (25 g, white solid) in a yield of 95.6%.

[0267] MS m / z(ESI):320.1[M+1].

[0268] Example 1

[0269] 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

[0270] first step

[0271] (E)-1-(3-Bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one

[0272] To a solution of 1-(3-bromo-2-hydroxy-phenyl)ethanone (13 g, 60.45 mmol) and 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), followed by stirring at 90°C for 12 hours, cooling, filtering, washing the filter cake with water, and drying the filter cake to give 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) in a yield of 93.0%.

[0273] MS m / z(ESI):354.9[M+1]

[0274] Step 2

[0275] 8-Bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one

[0276] A solution of (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one (2 g, 5.62 mmol) and concentrated hydrochloric acid (4 mL) in ethanol (10 mL) was stirred at 110°C under microwave conditions for 20 hours, cooled, and dried by spin drying. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product, 8-bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one (1.8 g, yellow solid) in a yield of 90.0%.

[0277] MS m / z(ESI):355.0[M+1]

[0278] Step 3

[0279] 8-Bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chromane

[0280] 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, followed by stirring at 70°C for 12 hours, cooling, quenching the reaction with water, and extraction 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, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product 8-bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman (400 mg, yellow solid) in a yield of 20.9%.

[0281] MS m / z(ESI):377.0[M+1]

[0282] Step 4

[0283] 4-[2-(4-Chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

[0284] 8-Bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chromane (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 A mixture of 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (450 mg, yellow oil) was obtained. The mixture was cooled, water was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product, 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (450 mg, yellow oil) in a yield of 88.5%.

[0285] MS m / z(ESI):480.1[M+1]

[0286] Step 5

[0287] 4-[2-(4-Chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-carboxylic acid tert-butyl ester

[0288] A mixture of tert-butyl 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (450 mg, 937.66 μmol), palladium on carbon (80 mg, 10%), and ethyl acetate (30 mL) was replaced with hydrogen three times and stirred for 5 hours. The mixture was filtered and dried to give the title product, tert-butyl 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-carboxylate (380 mg, light yellow oil) in a yield of 84.1%.

[0289] MS m / z(ESI):482.2[M+1]

[0290] Step 6

[0291] 4-[2-(4-Chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine

[0292] A mixture of tert-butyl 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chromen-8-yl]piperidine-1-carboxylate (340 mg, 705.49 μmol) and hexafluoroisopropanol (10 mL) was stirred at 80° C. under microwave conditions for 4 hours, cooled, and the filtrate was concentrated under reduced pressure. The residue was purified by 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) in a yield of 15.7%.

[0293] MS m / z(ESI):362.1[M+1]

[0294] Step 7

[0295] 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

[0296] 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 stirred at 50°C for 3 hours, cooled, added with 5 mL of water, extracted with dichloromethane (20 mL×3), and the organic phase was washed with saturated sodium chloride solution. The mixture was washed with 4% paraformaldehyde (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, ethyl 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylate (30 mg, colorless oil) in a yield of 43.7%.

[0297] MS m / z(ESI):620.2[M+1]

[0298] Step 8

[0299] 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

[0300] A mixture of methyl 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylate (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. The mixture was stirred for 12 hours, and formic acid was added to adjust the pH to 6. The mixture was dried by spin drying, and the residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent 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) in a yield of 68.2%.

[0301] MS m / z(ESI):606.2[M+1].

[0302] 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 was chirally separated to obtain

[0303] 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)

[0304] MS m / z(ESI):606.2[M+1].

[0305] 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)

[0306] MS m / z(ESI):606.2[M+1].

[0307] Example 2

[0308] 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

[0309] Im-1 was replaced with Im-2, and 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 by referring to Example 1.

[0310] MS m / z(ESI):607.2[M+1].

[0311] 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 chirally resolved to obtain

[0312] 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)

[0313] MS m / z(ESI):607.2[M+1].

[0314] 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)

[0315] MS m / z(ESI):607.2[M+1].

[0316] Example 3

[0317] 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

[0318] Im-1 was replaced with Im-3, and reference was made to Example 1 to obtain 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.

[0319] MS m / z(ESI):622.2[M+1].

[0320] 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 chirally separated to obtain

[0321] (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)

[0322] MS m / z(ESI):622.2[M+1].

[0323] (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)

[0324] MS m / z(ESI):622.2[M+1].

[0325] Example 4

[0326] 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

[0327] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-2 as raw materials, refer to Example 1 to obtain 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

[0328] MS m / z(ESI):623.2[M+1].

[0329] 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 chirally separated to obtain

[0330] 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)

[0331] MS m / z(ESI):623.2[M+1].

[0332] 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)

[0333] MS m / z(ESI):623.2[M+1].

[0334] Example 5

[0335] 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

[0336] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-1 as raw materials, refer to Example 1 to obtain 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0337] MS m / z(ESI):622.2[M+1].

[0338] 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 chirally separated to obtain

[0339] 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)

[0340] MS m / z(ESI):622.2[M+1].

[0341] 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)

[0342] MS m / z(ESI):622.2[M+1].

[0343] Example 6

[0344] 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

[0345] first step

[0346] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate

[0347] Using 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one as starting material, refer to the fourth and fifth steps of Example 1 to obtain the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate.

[0348] MS m / z(ESI):460.1[M+1].

[0349] Step 2

[0350] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2H-chromen-8-yl)piperidine-1-carboxylate

[0351] Dissolve tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate (1 g, 2.17 mmol) in THF (20 mL). Add lithium bis(trimethylsilylamide) (2.4 mL, 2.40 mmol) at -78°C and allow to react for 1 hour. Add a solution of 2-[N,n-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (0.94 g, 2.4 mmol) in THF (20 mL) at -78°C, slowly warm to room temperature, and stir for 5 hours. Quench the reaction by adding sodium bicarbonate (10 mL), and extract with ethyl acetate (20 mL x 3). Combine the organic phases, wash with saturated sodium chloride solution (20 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The resulting residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2H-chromen-8-yl)piperidine-1-carboxylate (456 mg, yield: 35.5%).

[0352] MS m / z(ESI):592.1[M+1].

[0353] Step 3

[0354] tert-Butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate

[0355] Dissolve tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2H-chromen-8-yl)piperidine-1-carboxylate (0.5 g, 0.84 mmol) in 10 mL of DMA / THF (v:v = 1:3). Add nickel acetate tetrahydrate (24.8 mg, 0.1 mmol), zinc powder (10 mg, 0.16 mmol), 1,5-cyclooctadiene (11 mg, 0.1 mmol), and lithium chloride (53 mg, 1.3 mmol). React at room temperature under nitrogen for 16 hours. Quench the reaction with water (10 mL) and extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The resulting residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate (241 mg, yield: 60.0%).

[0356] MS m / z(ESI):478.1[M+1].

[0357] Step 4

[0358] 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

[0359] 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 from the sixth to eighth steps of Reference Example 1.

[0360] MS m / z(ESI):622.1[M+1].

[0361] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was resolved to obtain the product

[0362] 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)

[0363] MS m / z(ESI):622.1[M+1].

[0364] 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).

[0365] MS m / z(ESI):622.1[M+1].

[0366] Example 7

[0367] 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

[0368] Using tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate and Im-2 as raw materials, refer to steps 6 to 8 of Example 1 to obtain 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.

[0369] MS m / z(ESI):623.1[M+1].

[0370] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was resolved to obtain the product

[0371] 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)

[0372] MS m / z(ESI):623.1[M+1].

[0373] 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).

[0374] MS m / z(ESI):623.1[M+1].

[0375] Example 8

[0376] 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

[0377] first step

[0378] (E)-2-Bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol

[0379] (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. Methylmagnesium bromide (7 mL, 7 mmol) was added at 0°C and the mixture was slowly warmed to room temperature with stirring for 3 hours. The reaction was quenched by the addition of ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to yield (E)-2-bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (831 mg, yield: 79.6%).

[0380] MS m / z(ESI):370.9[M+1].

[0381] Step 2

[0382] 8-Bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene

[0383] (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)boric 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 x 3). The mixture was washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford 8-bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene (326 mg, 68.0% yield).

[0384] MS m / z(ESI):356.9[M+1].

[0385] Step 3

[0386] 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

[0387] Using 8-bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene as the starting material, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by reference to the fourth, fifth, seventh and eighth steps of Example 1.

[0388] MS m / z(ESI):602.2[M+1].

[0389] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is resolved to obtain the product

[0390] 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)

[0391] MS m / z(ESI):602.2[M+1].

[0392] 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).

[0393] MS m / z(ESI):602.2[M+1].

[0394] Example 9

[0395] 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

[0396] Using 4-chloro-2-(methoxy-d3)benzaldehyde as raw material, referring to Example 2, the product 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained.

[0397] MS m / z(ESI):622.2[M+1].

[0398] 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 chirally separated to obtain

[0399] 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)

[0400] MS m / z(ESI):622.2[M+1].

[0401] 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)

[0402] MS m / z(ESI):622.2[M+1].

[0403] Example 10

[0404] 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

[0405] Using 4-chloro-2-(methoxy-d3)benzaldehyde as raw material, refer to Example 1 to obtain the product 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0406] MS m / z(ESI):621.2[M+1].

[0407] 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 chirally separated to obtain

[0408] 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)

[0409] MS m / z(ESI):621.2[M+1].

[0410] 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)

[0411] MS m / z(ESI):621.2[M+1].

[0412] Example 11

[0413] 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

[0414] first step

[0415] (E)-2-Bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol

[0416] (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), and sodium borohydride (64 mg, 1.69 mmol) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was quenched by adding water. 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 residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to obtain (E)-2-bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (454 mg, yield: 90.0%).

[0417] MS m / z(ESI):356.9[M+1].

[0418] Step 2

[0419] 8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene

[0420] (E)-2-Bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (300 mg, 0.84 mmol) was dissolved in dichloromethane (10 mL), and p-toluenesulfonic acid (29 mg, 0.17 mmol) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was quenched by adding water. 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 residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give (8-bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (200 mg, yield: 70.1%).

[0421] MS m / z(ESI):338.9[M+1].

[0422] Step 3

[0423] 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol

[0424] 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. The mixture was stirred at 0°C for 1 hour, and 2 mL of water was added, followed by the addition of NaOH (71 mg, 1.77 mmol) and 0.1 mL of hydrogen peroxide solution. The mixture was stirred at 40°C for 2 hours. 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 with a petroleum ether and ethyl acetate system as eluent to give 8-bromo-2-(4-chloro-2-fluorophenyl)chromen-3-ol (63 mg, yield: 29.8%).

[0425] MS m / z(ESI):356.9[M+1].

[0426] Step 4

[0427] 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one

[0428] 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol (500 mg, 1.40 mmol) was dissolved in DCM (20 mL), and Dess-Martin periodinane (0.71 mL, 1.67 mmol) was added. The mixture was stirred at 0°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 petroleum ether and ethyl acetate as eluent to give 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one (448 mg, yield: 89.9%).

[0429] MS m / z(ESI):354.9[M+1].

[0430] Step 5

[0431] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate

[0432] 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 reference to the third to fifth steps of Example 1.

[0433] MS m / z(ESI):482.2[M+1].

[0434] Step 6

[0435] 4-(2-(4-Chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine

[0436] Using tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochromene-8-yl)piperidine-1-carboxylate as raw material, the product 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromene-8-yl)piperidine was obtained in the sixth step of Example 1.

[0437] MS m / z(ESI):362.1[M+1].

[0438] Step 7

[0439] 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

[0440] 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)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by reference to the seventh and eighth steps of Example 1.

[0441] MS m / z(ESI):607.1[M+1].

[0442] Chiral separation of 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

[0443] 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)

[0444] MS m / z(ESI):607.1[M+1].

[0445] 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)

[0446] MS m / z(ESI):607.1[M+1].

[0447] Example 12

[0448] 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

[0449] first step

[0450] 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one

[0451] 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 solution was heated to 50°C and stirred vigorously for 12 hours. The reaction was terminated, filtered through celite, 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 obtain the title product, 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 12b (15 g), in a 90.9% yield.

[0452] MS m / z(ESI):188.1[M+1].

[0453] Step 2

[0454] tert-Butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate

[0455] Dissolve tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-4 (25 g, 79.94 mmol) in tetrahydrofuran (300 mL). Cool the solution in a dry ice / ethanol bath, then slowly add LiHMDS (18.4 mL, 0.184 mol, 1 M solution in THF). Stir the reaction for 30 minutes. Dissolve 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 12b (15 g, 79.94 mmol) in THF (30 mL) and slowly add this solution dropwise to the reaction mixture. Maintain the dry ice / ethanol bath temperature and stir for 40 minutes. The reaction was stopped and the dry ice / ethanol bath was removed. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and 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 residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, tert-butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 12c (31 g) in a yield of 76.5%.

[0456] MS m / z(ESI):507.2[M+1].

[0457] Step 3

[0458] tert-Butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate

[0459] 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). Ethanol (20 μL) was then added to the reaction solution, and the reaction was stirred for 4 hours. The reaction was stopped, and the reaction solution was slowly added to ice water to quench the reaction. The mixture was 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 residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give 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) in a yield of 38.7%.

[0460] MS m / z(ESI):491.2[M+1].

[0461] Step 4

[0462] 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine

[0463] 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), powdered Molecular sieves (750 mg) were dispersed in dichloromethane (10 mL) and stirred at 0°C for 3 hours. The reaction was stopped and quenched by adding saturated sodium bicarbonate solution. The mixture was filtered through celite, the filtrate was allowed to stand, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane and methanol as eluent to obtain the title product, 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine 12e (490 mg) in an 82.1% yield.

[0464] MS m / z(ESI):391.2[M+1].

[0465] Step 5

[0466] 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

[0467] Disperse 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) in acetonitrile (8 mL). Heat the reaction mixture to 50°C and stir vigorously for 3 hours. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with ethyl acetate as eluent. The purified sample was then subjected to chiral HPLC preparative separation to give 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) in a yield of 26.5%.

[0468] MS m / z(ESI):632.2[M+1].

[0469] Step 6

[0470] 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

[0471] 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 stirred for 3 hours. The reaction was stopped, and formic acid was added to adjust the pH to 6. The reaction solution was concentrated under reduced pressure, and the 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) in a yield of 82.8%.

[0472] MS m / z(ESI):618.2[M+1].

[0473] 1 H NMR (400MHz, MeOD) δ8.16–7.97(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,1H),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).

[0474] Example 13

[0475] 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

[0476] Using tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-4 and 1-(4-chloro-2-fluorophenyl)ethan-1-one as raw materials, refer to the second to sixth steps of Example 12 to obtain 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.

[0477] MS m / z(ESI):621.2[M+1].

[0478] Example 14

[0479] 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

[0480] first step

[0481] tert-Butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate

[0482] Referring to the synthesis method of Example 13, 1-(4-chloro-2-fluorophenyl)ethane-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) in a yield of 53.3%.

[0483] MS m / z(ESI):492.2[M+1].

[0484] Step 2

[0485] 2-(4-Chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one

[0486] 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 solution was heated to 100°C and stirred for 5 hours. The reaction was stopped and cooled to room temperature. 2M sodium hydroxide solution was added to quench the reaction. The organic layer was separated, and the aqueous layer 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. The resulting residue was purified by silica gel column chromatography using dichloromethane and methanol as eluent to obtain the title product, 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one 14c (2.36 g) in a yield of 62.1%.

[0487] MS m / z(ESI):374.1[M+1].

[0488] Step 3

[0489] 2-(4-Chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-4-ol

[0490] 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-4-one 14c (2 g, 5.35 mmol) was dissolved in methanol (30 mL). Sodium borohydride (396 mg, 10.70 mmol) was slowly added portionwise to the solution under an ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature for 2 hours. The reaction was stopped and quenched by the addition of saturated ammonium chloride solution. The pH was adjusted to 10 with 1 M sodium hydroxide solution and 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 afford the title product, 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-4-ol 14d (1.88 g) in a 93.5% yield. This compound was used directly in the next step without further purification.

[0491] MS m / z(ESI):376.1[M+1].

[0492] Step 4

[0493] 4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine

[0494] 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-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 solution was heated to 100°C and stirred for 30 minutes. The reaction was stopped and cooled to room temperature. 2M sodium hydroxide solution was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 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, 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 14e (1.02 g) in a yield of 71.4%. This compound was used directly in the next reaction without further purification.

[0495] MS m / z(ESI):358.1[M+1].

[0496] Step 5

[0497] 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

[0498] Referring to the synthesis method of the fifth step 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 carbonic acid, 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), was obtained in a yield of 30.5%.

[0499] MS m / z(ESI):617.2[M+1].

[0500] Step 6

[0501] 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

[0502] Referring to the synthesis method of the sixth step 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 give 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), in a yield of 77.8%.

[0503] MS m / z(ESI):603.2[M+1].

[0504] Example 15

[0505] 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

[0506] Referring to the synthetic 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)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0507] MS m / z(ESI):617.3[M+1].

[0508] Example 16

[0509] 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

[0510] first step

[0511] 4-Chloro-2-fluoro<α-2H>benzaldehyde

[0512] 4-Chloro-2-fluoro-1-iodobenzene (5 g, 19.50 mmol) and toluene (50 mL) were added to a 100 mL flask. Isopropyl magnesium chloride (12.9 mL, 3 M, 38.99 mmol) was added at -30°C, and the reaction mixture was allowed to react 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 was continued at 0°C for 1 h. The reaction was terminated and quenched with saturated aqueous ammonium chloride. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 4-chloro-2-fluoro<α-2H>benzaldehyde 16b (2.7 g), in an 86.79% yield.

[0513] MS m / z(ESI):160.0[M+1].

[0514] Step 2

[0515] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d-2-hydroxyphenyl)piperidine-1-carboxylate

[0516] 4-Chloro-2-fluoro<α-2H>benzaldehyde 16b (1.5 g, 9.40 mmol), tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate 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, and the reaction solution was reacted at 25°C for 3 h. The reaction was stopped, and the reaction solution 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 residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 16c (3 g) in a yield of 69.23%.

[0517] MS m / z(ESI):461.1[M+1].

[0518] Step 3

[0519] 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

[0520] Using tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d-2-hydroxyphenyl)piperidine-1-carboxylate 16c as starting material, the synthesis method of steps 3 to 6 of reference example 36 was used to obtain 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.

[0521] MS m / z(ESI):608.1[M+1].

[0522] 1 H NMR(400MHz,DMSO-d6)δ8.10(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,1H),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),4.41–4.31(m,1H),3.97(d,1H),3.88(d,1H),2.98–2.91(m,1H),2.8 7–2.79(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).

[0523] Example 17

[0524] 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

[0525] first step

[0526] 1-Bromo-4-chloro-2-(methoxy-d3)benzene

[0527] Using 2-bromo-5-chlorophenol 17a as starting material, 1-bromo-4-chloro-2-(methoxy-d3)benzene 17b was obtained by referring to the synthesis method of the first step of Example 36.

[0528] MS m / z(ESI):223.9[M+1].

[0529] Step 2

[0530] 4-Chloro-2-(methoxy-d3)<α-2H>benzaldehyde

[0531] Using 1-bromo-4-chloro-2-(methoxy-d3)benzene 17b as starting material, the synthesis method of the first step of Example 16 was referred to obtain 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 17c.

[0532] MS m / z(ESI):175.0[M+1].

[0533] Step 3

[0534] tert-Butyl 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate

[0535] Using 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 17c as starting material, the synthesis method of the second step of reference example 16 was used to obtain tert-butyl 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 17d.

[0536] MS m / z(ESI):476.2[M+1].

[0537] Step 4

[0538] 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

[0539] Using tert-butyl 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 17d as starting material, the synthesis method of steps 3 to 6 of Example 12 was used to obtain 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.

[0540] MS m / z(ESI):623.2[M+1].

[0541] 1 H NMR(400MHz,Methanol-d4)δ8.14–8.04(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).

[0542] Example 18

[0543] 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

[0544] first step

[0545] 4-Chloro-2-fluoro<α-2H>benzaldehyde

[0546] 4-Chloro-2-fluoro-1-iodo-benzene 18a (5 g, 19.50 mmol) and toluene (50 mL) were added to a 100 mL flask. Isopropyl magnesium chloride (12.9 mL, 3 M, 38.99 mmol) was added at -30°C, and the reaction mixture was allowed to react 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 was continued at 0°C for 1 h. The reaction was terminated and quenched with saturated aqueous ammonium chloride. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 4-chloro-2-fluoro<α-2H>benzaldehyde 18b (2.7 g), in an 86.79% yield.

[0547] MS m / z(ESI):160.0[M+1].

[0548] Step 2

[0549] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d-2-hydroxyphenyl)piperidine-1-carboxylate

[0550] 4-Chloro-2-fluoro<α-2H>benzaldehyde 18b (1.5 g, 9.40 mmol), tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate 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, and the reaction solution was reacted at 25°C for 3 h. The reaction was stopped, and the reaction solution 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 residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 18c (3 g) in a yield of 69.23%.

[0551] MS m / z(ESI):461.1[M+1].

[0552] Step 3

[0553] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate

[0554] Tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 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 quenched with water (10 mL). 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 dried to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 18d (3 g), in a yield of 99.56%.

[0555] MS m / z(ESI):463.1[M+1].

[0556] Step 4

[0557] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate

[0558] Tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 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), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to obtain the title product, tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 18e (1.7 g), in a yield of 58.96%.

[0559] MS m / z(ESI):445.1[M+1].

[0560] Step 5

[0561] 4-(2-(4-Chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine

[0562] Tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 18e (1.7 g, 3.82 mmol) and dichloromethane (25 mL) were added to a 100 mL flask. 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 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried to afford the title product, 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 18f (1.3 g), in a yield of 98.67%.

[0563] MS m / z(ESI):345.1[M+1]

[0564] Step 6

[0565] 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

[0566] 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, followed by potassium carbonate (1.04 g, 7.54 mmol) and (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im2 (1.11 g, 3.77 mmol) at 25°C. The reaction mixture was then stirred at 25°C for 10 hours. The reaction was stopped, and the reaction solution was quenched with aqueous solution (10 mL), extracted with dichloromethane (10 mL×3), and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester 18 g (1.7 g), yield: 74.65%.

[0567] MS m / z(ESI):604.2[M+1]

[0568] Step 7

[0569] 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

[0570] 18 g of methyl 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-carboxylate was chirally resolved to give methyl 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-carboxylate 18 h.

[0571] Split condition: DH 4.6*250

[0572] Hexane:EtOH:MeOH:DEA=70:15:15:0.1%

[0573] F=1mL T=35℃

[0574] Step 8

[0575] 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

[0576] Methyl 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-carboxylate 18h (100 mg, 165.54 μmol) and methanol (2 mL) were added to a 25 mL flask. Lithium hydroxide (39.64 mg, 1.66 mmol) was dissolved in water (1 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, and the reaction solution was quenched with formic acid (0.1 mL), added with water (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, and spin-dried. The residue was purified by 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)-oxabutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 18 (70 mg), yield: 71.66%.

[0577] MS m / z(ESI):590.2[M+1]

[0578] 1 H NMR(400MHz,DMSO)δ8.08(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).

[0579] Example 19

[0580] 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

[0581] first step

[0582] 1-Bromo-4-chloro-2-(methoxy-d3)benzene

[0583] 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 solution was heated to 50°C and stirred vigorously for 12 hours. The reaction was terminated, filtered through celite, 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 obtain the title product, 1-bromo-4-chloro-2-(methoxy-d3)benzene 19b (10 g), in a yield of 92.5%.

[0584] MS m / z(ESI):223.9[M+1].

[0585] Step 2

[0586] 4-Chloro-2-(methoxy-d3)benzaldehyde-d

[0587] 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 at -78°C. After complete addition, stirring was maintained at -78°C for 1 hour, followed by the dropwise addition of N,N-dimethylformamide-d7 (856.71 mg, 10.69 mmol). The reaction system was stirred for 3 hours and allowed to warm to room temperature. Saturated ammonium chloride solution (20 mL) was slowly added dropwise to quench the reaction. The product was then extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-chloro-2-(methoxy-d3)-benzaldehyde-d19c (1.2 g, 6.87 mmol) as a white solid in a 96.42% yield.

[0588] MS m / z(ESI):175.0[M+1].

[0589] Step 3

[0590] tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate

[0591] 4-Chloro-2-(methoxy-d3)-benzaldehyde-d19c (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). Sodium hydride (481.05 mg, 12.03 mmol, 60% purity) was added portionwise in an ice-water bath. The reaction system was stirred in an ice-water bath for 0.5 hour and then allowed to stir at room temperature (20°C) for 2.5 hours. After completion, water (20 mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a system of petroleum ether and ethyl acetate as eluents to give 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). Yield: 78.6%

[0592] MS m / z(ESI):476.2[M+1].

[0593] Step 4

[0594] tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate

[0595] 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 at room temperature. The reaction system was stirred at room temperature for 2 hours. After completion of the reaction, water (20 mL) was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 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).

[0596] MS m / z(ESI):478.2[M+1].

[0597] Step 5

[0598] tert-Butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate

[0599] 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. The reaction system was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was directly 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 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 19f (600 mg, 1.30 mmol) in a yield of 44.4%.

[0600] MS m / z(ESI):460.2[M+1].

[0601] Step 6

[0602] 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine

[0603] 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. ° Molecular sieves (260 mg) and boron trifluoride etherate (240.66 mg, 1.70 mmol). The reaction system was stirred in an ice-water bath for 1 hour. After completion, saturated sodium bicarbonate solution (10 mL) was added dropwise to quench the reaction. The mixture was extracted with dichloromethane (20 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 19 g (200 mg) of crude 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine.

[0604] MS m / z(ESI):360.2[M+1].

[0605] Step 7

[0606] 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

[0607] Dissolve 19 g (200 mg, 555.74 μmol, crude) of 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine, (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im-2 (180.17 mg, 611.31 μmol), and potassium carbonate (230.42 mg, 1.67 mmol) in acetonitrile (10 mL). Stir the reaction system in an oil bath at 60°C for 4 hours. After completion, dilute the reaction solution with water (10 mL), extract with ethyl acetate (20 mL x 3), wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents, and the purified sample was then subjected to chiral HPLC preparative separation to give 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 yield of 29.1%.

[0608] MS m / z(ESI):619.2[M+1].

[0609] Step 8

[0610] 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

[0611] 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 stirred for 3 hours. The reaction was stopped, and formic acid was added to adjust the pH to 6. The reaction solution was concentrated under reduced pressure, and the 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) in a yield of 61.5%.

[0612] MS m / z(ESI):605.2[M+1].

[0613] 1 H NMR (400MHz, DMSO) δ8.08(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,1 H),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).

[0614] Example 20

[0615] 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

[0616] first step

[0617] 1-(3-Bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d

[0618] Using 4-chloro-2-fluoro<α-2H>benzaldehyde 20a and 1-(3-bromo-2-hydroxyphenyl)ethane-1-one as raw materials, the synthesis method of the first step of Example 1 was referred to to obtain 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d 20b.

[0619] MS m / z(ESI):355.9[M+1].

[0620] Step 2

[0621] 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

[0622] Using 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d 20b as starting material, the synthesis method of Example 11 was referred to to obtain 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.

[0623] MS m / z(ESI):608.1[M+1].

[0624] Example 21

[0625] 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

[0626] first step

[0627] 1-(3-Bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d

[0628] Using 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 21a and 1-(3-bromo-2-hydroxyphenyl)ethane-1-one as raw materials, the synthesis method of the first step of Example 1 was referred to to obtain 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d 21b.

[0629] MS m / z(ESI):371.0[M+1].

[0630] Step 2

[0631] 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

[0632] Using 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d 21b as starting material, the synthesis method of Example 11 was referred to to obtain 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.

[0633] MS m / z(ESI):623.2[M+1].

[0634] Example 22

[0635] 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

[0636] Using intermediate Im1 as the starting material, refer to Example 16 to obtain the 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.

[0637] MS m / z(ESI):607.2[M+1].

[0638] Example 23

[0639] 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

[0640] Using intermediate Im1 as the starting material, refer to Example 18 to obtain the 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.

[0641] MS m / z(ESI):589.2[M+1].

[0642] Example 24

[0643] 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

[0644] Method 1

[0645] Reference Example 18 was used to obtain 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.

[0646] Method 2

[0647] first step

[0648] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylate

[0649] Tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im4 (20.3 g, 63.56 mmol) and tetrahydrofuran (300 mL) were added to a 1000 mL flask and cooled at 0°C for 10 minutes. 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 then dissolved in THF (100 mL) and slowly added dropwise to the reaction mixture over 20 minutes using a constant pressure dropping funnel. After the addition was complete, the temperature was raised to 25°C and allowed to react for 2 hours. The reaction was stopped, and the reaction solution was quenched with saturated aqueous ammonium chloride solution (200 mL), water (50 mL) was added, and the mixture was 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. Ethyl acetate (60 mL) was added, and the mixture was slurried (stirred for 15 minutes). The mixture was filtered, and the filter cake was washed with petroleum ether (30 mL) and dried to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylate 24b (15.2 g), in a yield of 52.00%.

[0650] MS m / z(ESI):460.1[M+1].

[0651] Step 2

[0652] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylate

[0653] Tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylate 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 allowed to react at 20°C for 3 hours. The reaction was stopped and quenched with water (100 mL). The mixture was 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 dried to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylate 24c (25 g), in a yield of 99.56%.

[0654] MS m / z(ESI):462.1[M+1].

[0655] Step 3

[0656] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate

[0657] Tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylate 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), and the organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to obtain the title product, tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate 24d (13 g), in a yield of 54.11%.

[0658] MS m / z(ESI):444.1[M+1].

[0659] Step 4

[0660] (R)-tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate

[0661] Chiral separation of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate 24d afforded (R)-tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate 24e.

[0662] Split Condition

[0663] OD-H 4.6*150

[0664] Hexane:IPA:DEA=90:10:0.1%

[0665] F=1mL T=35℃

[0666] MS m / z(ESI):444.1[M+1].

[0667] Step 5

[0668] (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine

[0669] Tert-butyl (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate 24e (2.55 g, 5.74 mmol) and dichloromethane (50 mL) were added to a 100 mL flask. 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 allowed to react at 0°C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried to afford the title product, (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine 24f (1.97 g, 100% yield).

[0670] MS m / z(ESI):344.1[M+1]

[0671] Step 6

[0672] 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

[0673] (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. Potassium carbonate (1.58 g, 11.46 mmol) and (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im2 (1.69 g, 5.73 mmol) were then added at 25°C. The reaction mixture was then allowed to react at 25°C for 10 hours. The reaction was stopped, and the reaction solution was quenched with aqueous solution (20 mL), extracted with dichloromethane (20 mL×3), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester, 24 g (3.1 g), yield: 89.71%.

[0674] MS m / z(ESI):603.2[M+1]

[0675] Step 7

[0676] 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

[0677] 24 g (3.1 g, 5.14 mmol) of methyl 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-carboxylate and methanol (25 mL) were added to a 100 mL flask. 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, and the reaction solution was quenched with formic acid (1 mL), added with water (20 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. The residue was 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)-oxabutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 24 (2.1 g, yield: 69.35%).

[0678] MS m / z(ESI):589.1[M+1]

[0679] 1 H NMR(400MHz,MeOD)δ8.14–8.03(m,2H),7.40(t,1H),7.25(dd,1H),7.15(dd,1H),7.05(dd,1H),6.92(dd,1H), 6.84(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,1 H),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),2.9 5-2.85(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).

[0680] Example 25

[0681] 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

[0682] Reference Example 17 gave 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.

[0683] MS m / z(ESI):622.2[M+1].

[0684] Example 26

[0685] 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

[0686] Reference Example 19 gave 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.

[0687] MS m / z(ESI):604.2[M+1].

[0688] Example 27

[0689] 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

[0690] Using 4-cyano-2-fluorobenzaldehyde and intermediate Im-1 as raw materials, refer to Example 18 to obtain 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.

[0691] MS m / z(ESI):579.2[M+1].

[0692] 1 H NMR(400MHz,DMSO)δ8.25(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),6.99(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,1H),4.67–4.58(m,1H),4.52–4.44(m,1H),4.42–4.31(m,1H),3.9 2(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).

[0693] Example 28

[0694] 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

[0695] Using Im-1 as the starting material, refer to Example 24 to obtain 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.

[0696] MS m / z(ESI):588.2[M+1].

[0697] 1H NMR(400MHz,MeOD)δ8.30(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).

[0698] Biological test evaluation

[0699] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0700] I. Determination of the ability of the compounds of the present invention to stimulate cAMP production in human GLP1 receptor stably transfected cell lines 1. Experimental purpose:

[0701] The purpose of this test is to test the ability of compounds to activate human GLP-1 receptors on cell surfaces. 50 Characterize the compounds' ability to activate the human GLP-1 receptor.

[0702] 2. Experimental reagents and instruments:

[0703] 2.1 Experimental instruments:

[0704] Microplate reader (BioTek Synergy H1);

[0705] Pipette (Eppendorf & Rainin).

[0706] 2.2 Experimental reagents:

[0707] DMEM / F12 medium was purchased from Gibco, catalog number 11330032;

[0708] Casein was purchased from Sigma, product number C3400;

[0709] 384-well plates were purchased from Sigma, catalog number CLS4514;

[0710] IBMX was purchased from Sigma, product number I7018;

[0711] Cisbio cAMP-Gs Dynamic kit was purchased from Cisbio, catalog number 62AM4PEC.

[0712] 3. Experimental methods:

[0713] The frozen human GLP1 receptor stably transfected cell line CHO-K1 / GLP-1R / CRE-luc was taken out from the liquid nitrogen tank, quickly thawed in a 37°C water bath, resuspended with DMEM / F12 medium, washed once after centrifugation, and resuspended with experimental buffer, which is DMEM / F12 medium containing 0.1% casein. The cell density was adjusted with experimental buffer and plated in a 384-well plate at a density of 2500 cells / 5μL / well. Then 2.5μL of IBMX working solution prepared in buffer was added to each well, with a final concentration of IBMX of 0.5mM, and 2.5μL of serially diluted compound samples (starting at 1000nM, 3-fold dilution, 11 concentrations). The mixture was centrifuged at 1000rpm for 1min, shaken for 30 seconds to mix, and incubated at room temperature for 30 minutes. The cAMP-d2 and Anti-cAMP-Eu were detected using the Cisbio cAMP-Gs Dynamic kit. 3+ -Cryptate were diluted 20 times with cAMP Lysis & Detection Buffer and mixed well. Add 5 μL of diluted cAMP-d2 solution to each well, and then add 5 μL of diluted Anti-cAMP-Eu3 + The α-Cryptate solution was shaken for 30 seconds to mix thoroughly and incubated at room temperature in the dark for 1 hour. HTRF signals were read using a Biotek Synergy H1 microplate reader with an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm.

[0714] 4. Experimental data processing method:

[0715] The signal ratio (665 nm / 620 nm * 10,000) was calculated and the signal ratio and sample concentration were nonlinearly fitted using a four-parameter equation in GraphPad Prism 6 to obtain the EC 50 value.

[0716] 5. Experimental results:

[0717] Table 1

[0718] 6. Experimental Conclusion

[0719] The above scheme shows that the compounds of the present invention exhibit good biological activity in the experiment of stimulating human GLP1 receptor stably transfected cell lines to produce cAMP.

[0720] 2. Effects of a single administration of the compound of the present invention on intraperitoneal glucose tolerance in GLP-1R humanized mice

[0721] 1. Purpose of the test:

[0722] The effect of a single administration of the compound of the present invention on blood glucose changes in an intraperitoneal glucose tolerance test (ipGTT) test of GLP-1R humanized C57BL / 6 mice was evaluated.

[0723] 2. Experimental Materials:

[0724] C57BL / 6_hGLP-1R, male, 5-8 weeks old; clean bench; electronic balance; active blood glucose meter; glucose.

[0725] 3 Experimental operation and data processing:

[0726] 3.1. The day before the experiment, animals were randomly divided into groups based on body weight, with 5 animals in each group. All animals were deprived of food overnight and fasted for at least 16 hours until the time of dosing.

[0727] 3.2. Prepare 0.2 g / mL glucose solution using pure water and filter through a 0.22 μm filter membrane for later use.

[0728] 3.3. On the day of testing, the blood glucose level of each animal was measured by tail snip method before administration and recorded as the baseline value;

[0729] Blood glucose test method: Place the mouse in a restrainer, disinfect the tail tip with an alcohol cotton ball, then cut off a small part of the tail tip with scissors. After discarding the first drop of blood, drop the second drop of blood onto the prepared blood glucose test strip to test the blood glucose value;

[0730] 3.4. Administer the drug according to the animal's weight and record the time of administration for each animal. 1 hour after administration, measure the blood glucose level of each animal in turn and record it as the blood glucose level at 0 min.

[0731] 3.5. Immediately administer an intraperitoneal injection of pure water or glucose solution (10 mL / kg, 2 g / kg glucose dose) based on the patient's body weight.

[0732] 3.6. Measure the blood glucose level of each mouse 15, 30, 60, 90, and 120 minutes after the injection of pure water or glucose solution, and record the time and data;

[0733] 3.7. After the test, all animals resumed eating.

[0734] 3.8 Data Processing

[0735] The blood glucose (BG)-time curve was drawn, and the area under the blood glucose-time curve was 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.

[0736] Note: BG0, BG15, BG30, BG60, BG90 and BG120 represent the blood glucose values ​​before glucose administration (0 min), 15, 30, 60, 90 and 120 min after glucose administration, respectively.

[0737] The blood glucose reduction rate at each time point and AUC was calculated based on the average blood glucose value and blood glucose AUC at each time point. The calculation formula was: blood glucose reduction rate = (blood glucose of the drug group / AUC - blood glucose of the model control group / AUC) / blood glucose of the model control group / AUC × 100%.

[0738] 4 Experimental results:

[0739] 5. Experimental Conclusion

[0740] According to the above experimental results, it can be seen that the compounds of the embodiments of the present invention can effectively lower the blood sugar of mice.

[0741] 3. Effects of long-term administration of the compounds of the present invention on body weight and food intake of GLP-1R humanized mice fed a high-fat diet

[0742] 1. Experimental purpose:

[0743] The purpose of this test is to evaluate the effects of long-term administration of compounds on body weight and food intake in GLP-1R humanized C57BL / 6 mice fed a high-fat diet.

[0744] 2. Experimental Reagents and Instruments

[0745] C57BL / 6_hGLP-1R, male, 5-8 weeks old; 60% high-fat diet (HFD); ultra-clean workbench; electronic balance.

[0746] 3. Experimental Methods

[0747] 3.1 On the day of starting high-fat diet, C57BL / 6 mice were randomly divided into two groups according to body weight. The first group consisted of 7 mice, namely Blank group, which was fed with normal control diet. The remaining animals were in the modeling group, which was fed with high-fat diet until the end of the experiment.

[0748] 3.2 At week 8 of HFD feeding, the modeling group animals were randomly divided into groups based on body weight, with 7 animals per group. The first group was the vehicle group (0.5% CMC-Na + 1% Tween 80), which received the vehicle; the remaining groups were the drug-treated groups. The drug-treated group received oral administration of the corresponding compound once daily for 14 days at a dose of 10 mg / kg in a 10 mL / kg volume. The blank group continued to receive a normal diet and did not receive any drug administration.

[0749] 3.3 The day of drug administration is defined as Day 0.

[0750] 3.4 Each time the drug is administered, the animals are weighed and the data are recorded. Oral administration is performed based on body weight, with a dosage volume of 10 mL / kg.

[0751] 3.5 Starting from day 0 of the experiment, the food intake of each group of mice was measured every three days. Specifically, the feed was replaced after each dose and the added and remaining amounts were recorded.

[0752] On Day 14, all mice were euthanized according to grouping order, and their livers were removed and weighed.

[0753] 4. Experimental Data Processing and Statistical Analysis

[0754] The body weight and body weight change rate of the mice after administration were summarized and statistically analyzed. The body weight change rate was calculated as: (BWt - BW0) / BW0 × 100%. BWt represents the body weight of the mouse on experimental day t, and BW0 represents the body weight of the mouse on experimental day 0.

[0755] The food intake was calculated as follows: (added amount (g) - remaining amount (g)) / number of animals in each cage. The cumulative food intake was the sum of the daily food intake of each animal during the administration period.

[0756] Experimental data were analyzed using GraphPad Prism software. Comparisons between two groups were performed using the t-test. Comparisons between three or more groups were performed using one-way ANOVA.

[0757] 5. Experimental Results

[0758] 6. Experimental Conclusion

[0759] According to the above experimental results, it can be seen that long-term administration of the compounds of the present invention has a good weight-reducing effect on GLP-1R humanized C57BL / 6 mice fed a high-fat diet.

[0760] IV. Pharmacokinetics in SD rats

[0761] 1. Research objectives:

[0762] SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 50 mg / kg.

[0763] 2. Experimental Plan

[0764] 2.1 Investigational Drugs:

[0765] Vehicle formulation: 0.5% CMC-Na (1% Tween 80);

[0766] The embodiment of the present invention is homemade.

[0767] 2.2 Experimental Animals

[0768] There were 3 male SD rats in each group.

[0769] 2.3 Administration:

[0770] Three male SD rats were fasted overnight and administered PO to each group at a dose of 50 mg / kg in a volume of 10 mL / kg.

[0771] 2.4 Sample collection:

[0772] Before and after administration, 0.2 mL of blood was collected from the jugular vein of rats at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, placed in an EDTA-K2 test tube, and centrifuged at 6000 rpm at 4°C for 6 minutes to separate plasma, which was then stored at -80°C and eaten 4 hours after administration.

[0773] 2.5 Sample processing:

[0774] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, mixed and centrifuged at 3500 × g for 5-20 minutes.

[0775] 2) Take 100 μL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[0776] 2.6 Liquid phase analysis

[0777] Liquid phase conditions: Shimadzu LC-20AD pump

[0778] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[0779] ●Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[0780] ●Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is methanol

[0781] Flow rate: 1.0 mL / min

[0782] Elution time: 0-4.0 minutes, eluent is as follows:

[0783] 3. Test results and analysis

[0784] The main pharmacokinetic parameters were calculated using WinNonlin 8.2.

[0785] 4. Test results

[0786] 5. Experimental conclusion:

[0787] From the results of the rat pharmacokinetic experiment in the table, it can be seen that at a dose of 50 mg / kg, the compounds of the present invention showed good metabolic properties, with exposure AUC and maximum blood concentration C max All performed well.

[0788] Salt and crystal form research

[0789] 1.1 Experimental Instruments

[0790] 1.1.1 Some parameters of physical and chemical testing instruments

[0791] 1.2 Instruments and liquid analysis conditions

[0792] 1.2.1 Instruments and Equipment

[0793] 1.2.2 Chromatographic conditions

[0794] Preparation of compound salts

[0795] 2. Screening of compound salt crystal forms

[0796] 2.1 Compound salt screening

[0797] 2.1.1 Experimental Purpose:

[0798] Select different counter ion bases and detect which counter ion bases can form compound salts through appropriate crystallization methods.

[0799] 2.1.2 Experimental steps:

[0800] 1) Instruments and equipment

[0801] 2) Operating procedures

[0802] 3. Screening of salt forms of free acids

[0803] 3.1 Screening of salt types in solvent ACN system

[0804] A total of 181.82 mg of compound 28 was weighed and added to 2.4 ml of ACN. The mixture formed a pellet, which adhered to the wall. Ultrasonication and heating did not dissolve the solid. 400 μl of water was added and ultrasonication was performed. The adhered solid gradually dissolved, resulting in a slightly turbid stock solution with a small amount of mechanical impurities. Each 245 μl portion (equivalent to 15.91 mg of compound) was then added with 1.1 equivalents of alkaline solution (29.8 μl), as shown in the table below. After overnight at room temperature, a solid precipitated. XRD analysis of the solid was obtained.

[0805] The obtained 2-3 had good crystallinity. DSC showed that 2-3 might be a solvate or hydrate. TGA further showed that 2-3 was dehydrated or desolvated at low temperature.

[0806] ACN system salt type screening results

[0807] The experimental results showed that the ACN system salt type screening results obtained tromethamine salt crystal form A.

[0808] H-NMR analysis was performed on samples 2-3 to determine whether they had formed a Tris salt. The results showed that because 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 produce a peak in the H-NMR spectrum, it was impossible to determine whether they had formed a Tris salt by H-NMR.

[0809] The free-state content was measured using HPLC-DAD to determine salt formation. As shown in the table below, the average free-state percentage for the two Tris salt samples was 80.58%, which is closest to the theoretical free-state percentage for a compound bound to one Tris molecule and one water molecule. Therefore, it is preliminarily determined that the Tris salt is a hydrate bound to one water molecule.

[0810] Quantitative results of compound 28 by Tris salt HPLC-DAD

[0811] Remark:

[0812] Sample 1: ACN-H2O-Tris (Form A)

[0813] Sample 2: MeOH-Tris-Evap-EA Slurry (Form A)

[0814] The free-state content was then measured using HPLC-ELSD to determine the salt formation ratio. The method is shown in the table below. The results show that the average Tris percentage of the two Tris salt samples was 16.13%, which is closest to the theoretical percentage of Tris bound to one molecule of Tris and one molecule of water.

[0815] HPLC-ELSD quantitative determination method conditions

[0816] Quantitative results of compound 28 using Tris salt HPLC-ELSD

[0817] Remark:

[0818] Sample 1: ACN-H2O-Tris (Form A)

[0819] Sample 2: MeOH-Tris-Evap-EA Slurry (Form A)

[0820] Combined with the DSC spectrum and TGA spectrum, the weight loss (ACN-TRIS) before 80 degrees is about 2%, which is equivalent to the theoretical percentage of water in Tris salt that combines 1 molecule of Tris and 1 molecule of water. It is further determined that Tris salt crystal form A is a monohydrate.

[0821] 3.2 Salt type screening of solvent DCM system

[0822] A total of 147.31 mg of compound 28 was weighed and added to 2.2 ml of DCM to prepare a stock solution. The solution was completely dissolved. Each 200 μl portion (equivalent to 13.39 mg of compound) was evaporated at 40°C until dry. The following solvents (200 μl each) were then added to dissolve the solution. 1.1 equivalents of a 1 mol / L aqueous tromethamine solution (25.1 μl) were then added to the solution. The solution was punctured and evaporated to dryness. The results are shown in the table below.

[0823] Results of salt type screening in DCM system

[0824] The experimental results showed that the DCM system salt type screening results obtained tromethamine salt crystal forms C and E.

[0825] 3.3 Salt type screening of solvent ACN-H2O system

[0826] Compound 28 (27.69 mg) was weighed and added to 400 μl of ACN:H₂O (6:1 v / v). The oily substance adhered to the wall and gradually dissolved at 40°C. 51.8 μl of 1.1 eq of a 1 mol / L aqueous tromethamine solution was added to the solution. The solution was then held at 40°C for 3 h. No solid precipitated, nor did it precipitate under stirring at room temperature. After sonication for 1–2 min, the solution solidified. An additional 200 μl of ACN:H₂O (6:1 v / v) was added, stirred at room temperature for 3 h, filtered, and dried under vacuum at 40°C overnight. Characterization was then performed. XRD patterns of the sample indicated Form D of the tromethamine salt, while DSC patterns indicated a monohydrate similar to Form A of the Tris salt.

[0827] 4. Preparation methods of different salt types

[0828] (1) Preparation of Tromethamine Salt Form A

[0829] 15.91 mg of the free acid was weighed, 245 uL of acetonitrile: water = 6:1 (v / v) was added, and the mixture was slightly turbid by ultrasound with a small amount of mechanical impurities. 1.1 equivalents of a 1 mol / L tromethamine aqueous solution (29.8 ul) was added. After overnight at room temperature, a solid was precipitated, and the mixture was quickly centrifuged. The supernatant was removed and the solid was vacuum dried at 40°C to constant weight to obtain tromethamine salt Form A. After detection and analysis, it had an XRPD pattern as shown in Figure 1, a DSC pattern as shown in Figure 2, and a TGA pattern as shown in Figure 3.

[0830] (2) Preparation of Tromethamine Salt Form B

[0831] An appropriate amount of tromethamine salt form A was taken, and the sample was heated to 88 degrees using TGA and maintained for 2 minutes, and then cooled to room temperature to obtain tromethamine salt form B. After detection and analysis, it had an XRPD pattern as shown in Figure 4 and a DSC pattern as shown in Figure 5.

[0832] (3) Preparation of Tromethamine Salt Form C

[0833] Weigh 229.54 mg of the free state, add 0.4 ml of acetone, ultrasonically dissolve, add 1.6 ml of methanol, dissolve at room temperature, add 0.527 ml (1.1 eq) of 0.815 mol / L Tris ethanol-water (18.44% mass fraction of water) solution at 40 degrees, dissolve, add 5 ml of isopropyl ether, slightly turbid, keep at 40 degrees for 30 minutes, precipitate a lot, add 3 ml of isopropyl ether, keep at 40 degrees overnight, and obtain a solid with good properties. After cooling to room temperature, centrifuge quickly, remove the supernatant, and dry the solid in vacuum at 40 ° C to constant weight to obtain tromethamine salt Form C, which has an XRPD pattern as shown in Figure 6, a DSC pattern as shown in Figure 7, and a TGA pattern as shown in Figure 8.

[0834] (4) Preparation of Tromethamine Salt Form D

[0835] Weigh 27.69 mg of the free state, add ACN:H2O=6:1 (v / v), 400ul, the oil is sticky and gradually dissolves at 40 degrees. Add 1.1eq of 1mol / L tromethamine aqueous solution, 51.8ul, dissolve clearly, keep at 40 degrees for 3h, no solid is precipitated, no precipitation is also produced when stirring at room temperature, after ultrasonication for 1-2min, violent precipitation, solidification, add 200ul of ACN:H2O=6:1 (v / v), stir at room temperature for 3h, quickly centrifuge, remove the supernatant, and dry the solid in vacuum at 40°C to constant weight to obtain tromethamine salt form D. After detection and analysis, it has an XRPD pattern as shown in Figure 9 and a DSC pattern as shown in Figure 10.

[0836] (5) Preparation of Tromethamine Salt Form E

[0837] 13.39 mg of the free form was weighed, 200 μL of dioxane was added, and the mixture was dissolved. 1.1 equivalents of a 1 mol / L tromethamine aqueous solution (25.1 μL) was added. The solution became turbid and oily. The mixture was punctured and evaporated to dryness. 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 rapidly centrifuged, the supernatant was removed, and the solid was dried in vacuo at 40°C to constant weight to obtain tromethamine salt Form E. After analysis, the XRPD pattern is shown in Figure 11 and the DSC pattern is shown in Figure 12.

[0838] 5. Crystal thermodynamic stability experiment

[0839] 5.1 Experimental Purpose:

[0840] Through polycrystalline screening tests, we found the salt crystal form that is relatively thermodynamically stable.

[0841] 5.2 Experimental plan:

[0842] 5.2.1 Tromethamine salt Form C as starting material

[0843] Take 10 mg of tromethamine salt Form C, add 200 μl of solvent respectively, beat at 40 degrees for 2 days, centrifuge, place the solid in a vacuum oven at 40 degrees overnight, and then perform corresponding characterization such as XRD. The results are shown in the table below. The XRD results of the obtained solids all show Form C, indicating that the crystal form of tromethamine salt Form C is very stable.

[0844] 6. Solubility determination of tromethamine salt crystal form C

[0845] Weigh 1-2 mg of compound 28 into a 1.5 mL liquid phase vial. Then, add 1 mL of pH buffer, artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF), non-fasting artificial simulated intestinal fluid (FeSSIF), and pure water. The vial was placed on a constant temperature shaker overnight at 37°C. After 24 hours, the sample solution was filtered through a 0.45 μm mixed hydrofiber membrane, and the filtrate was collected and assayed by HPLC. For HPLC analysis, refer to Section 1.2 for solution stability analysis. The solubility of the compound in the buffer solution medium is shown in the table below.

[0846] Solubility results of tromethamine salt form C in buffer solutions of different pH values

Claims

1. A compound represented by general formula (I) or a basic salt of a stereoisomer thereof, the structure of the compound is as follows: in: R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Haloalkoxy; R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Haloalkoxy; R 3 are each independently selected from hydrogen, deuterium or halogen; M1 is N or CH; W2 is N or CH; x, y and z are each independently 0, 1 or 2; 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; the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water or a mixture thereof.

2. The compound according to claim 1 or a basic salt of its stereoisomer, characterized in that: R1 is each independently selected from hydrogen, deuterium, fluorine, chlorine, methoxy or -OCD3; R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine or methyl; R 3 are each independently selected from hydrogen; M1 is CH; W2 is CH; and x, y and z are each independently 0, 1 or 2.

3. The compound according to claim 1 or a basic salt of its stereoisomer, characterized in that: The compound is further represented by the following general formulas (I-1) to (I-4):

4. The compound according to claim 1-3 or a basic salt of a stereoisomer thereof, characterized in that: The general formula is selected from the following compounds: 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; the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or a mixture thereof.

5. A basic salt of a compound according to claim 4, wherein the compound is 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromene-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-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, characterized in that The number of bases is 0.5-3, 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 of the compound according to any one of claims 1 to 5, characterized in that The basic salt is a hydrate or an anhydrate, preferably an anhydrate; When the basic salt is a hydrate, the number of water is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, 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 crystalline form.

9. The basic salt of the compound according to claim 8, 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 selected from the tromethamine salt form AE, wherein: The powder X-ray diffraction spectrum of the tromethamine salt crystalline form A has a characteristic peak at 2θ of 7.7±0.2°, or a characteristic peak at 2θ of 9.8±0.2°, or a characteristic peak at 2θ of 10.8±0.2°, or a characteristic peak at 2θ of 11.6±0.2°, or a characteristic peak at 2θ of 14.0±0.2°, or a characteristic peak at 2θ of 14.5±0.2°, or a characteristic peak at 2θ of 14.8±0.2°, or a characteristic peak at 2θ of 15.1±0.2°, or a characteristic peak at 2θ of 15.9±0.2°, or a characteristic peak at 2θ of 18.0 ±0.2°, or has a characteristic peak at 2θ of 18.7±0.2°, or has a characteristic peak at 2θ of 19.3±0.2°, or has a characteristic peak at 2θ of 20.0±0.2°, or has a characteristic peak at 2θ of 20.5±0.2°, or has a characteristic peak at 2θ of 21.1±0.2°, or has a characteristic peak at 2θ of 22.6±0.2°, or has a characteristic peak at 2θ of 23.7±0.2°, or has a characteristic peak at 2θ of 25.1±0.2°; preferably, it comprises 2, 4, 6, 8, 10 or 12 of which have characteristic peaks; The powder X-ray diffraction spectrum of the tromethamine salt crystal form B has a characteristic peak at 2θ of 8.2±0.2°, or a characteristic peak at 2θ of 10.1±0.2°, or a characteristic peak at 2θ of 12.3±0.2°, or a characteristic peak at 2θ of 14.4±0.2°, or a characteristic peak at 2θ of 14.8±0.2°, or a characteristic peak at 2θ of 16.0±0.2°, or a characteristic peak at 2θ of 16.2±0.2°, or a characteristic peak at 2θ of 17.5±0.2°, or a characteristic peak at 2θ of 18.6±0.2°. The characteristic peak is 17.7±0.2°, or 18.3±0.2°, or 18.7±0.2°, or 19.7±0.2°, or 20.5±0.2°, or 20.9±0.2°, or 21.9±0.2°, or 22.1±0.2°, or 22.4±0.2°, or 22.6±0.2°. There is a characteristic peak at 24.7±0.2°; preferably, there are characteristic peaks at any of 2, 4, 6, 8, 10 or 12 positions; The powder X-ray diffraction spectrum of tromethamine salt form C has a characteristic peak at 2θ of 3.6±0.2°, or at 2θ of 7.1±0.2°, or at 2θ of 9.7±0.2°, or at 2θ of 10.6±0.2°, or at 2θ of 13.5±0.2°, or at 2θ of 14.1±0.2°, or at 2θ of 15.0±0.2°, or at 2θ of 16.0±0.2°, or at 2θ of 16.5±0.2°, or at 2θ of 17.1±0.2°, Or having a characteristic peak at 2θ of 17.6±0.2°, or having a characteristic peak at 2θ of 19.0±0.2°, or having a characteristic peak at 2θ of 19.7±0.2°, or having a characteristic peak at 2θ of 20.8±0.2°, or having a characteristic peak at 2θ of 21.8±0.2°, or having a characteristic peak at 2θ of 22.3±0.2°, or having a characteristic peak at 2θ of 23.1±0.2°, or having a characteristic peak at 2θ of 26.4±0.2°, or having a characteristic peak at 2θ of 28.3±0.2°; preferably, comprising 2, 4, 6, 8, 10 or 12 of which there are characteristic peaks; The powder X-ray diffraction spectrum of the tromethamine salt crystal form D has a characteristic peak at 2θ of 7.4±0.2°, or a characteristic peak at 2θ of 7.7±0.2°, or a characteristic peak at 2θ of 9.8±0.2°, or a characteristic peak at 2θ of 10.8±0.2°, or a characteristic peak at 2θ of 11.6±0.2°, or a characteristic peak at 2θ of 13.1±0.2°, or a characteristic peak at 2θ of 14.0±0.2°, or a characteristic peak at 2θ of 14.5±0.2°, or a characteristic peak at 2θ of 15.1±0.2°, or a characteristic peak at 2θ of 15.4±0.2°, Or having a characteristic peak at 2θ of 15.8±0.2°, or having a characteristic peak at 2θ of 17.9±0.2°, or having a characteristic peak at 2θ of 18.8±0.2°, or having a characteristic peak at 2θ of 19.3±0.2°, or having a characteristic peak at 2θ of 20.0±0.2°, or having a characteristic peak at 2θ of 20.5±0.2°, or having a characteristic peak at 2θ of 21.2±0.2°, or having a characteristic peak at 2θ of 21.8±0.2°, or having a characteristic peak at 2θ of 23.3±0.2°; preferably, comprising 2, 4, 6, 8, 10 or 12 of which there are characteristic peaks; The powder X-ray diffraction spectrum of the tromethamine salt crystal form E has a characteristic peak at 2θ of 4.3±0.2°, or at 2θ of 6.3±0.2°, or at 2θ of 8.6±0.2°, or at 2θ of 9.3±0.2°, or at 2θ of 13.6±0.2°, or at 2θ of 14.1±0.2°, or at 2θ of 17.7±0.2°, or at 2θ of 18.5±0.2°, or at 2θ of 18.9±0.2°, Or it has a characteristic peak at 2θ of 20.2±0.2°, or has a characteristic peak at 2θ of 20.5±0.2°, or has a characteristic peak at 2θ of 21.4±0.2°, or has a characteristic peak at 2θ of 21.9±0.2°, or has a characteristic peak at 2θ of 22.4±0.2°, or has a characteristic peak at 2θ of 23.4±0.2°, or has a characteristic peak at 2θ of 23.9±0.2°, or has a characteristic peak at 2θ of 25.2±0.2°; preferably, it comprises 2, 4, 6, 8, 10 or 12 of the characteristic peaks.

10. The tromethamine salt crystal form according to claim 8, characterized in that The powder X-ray diffraction spectrum of the tromethamine salt crystalline form A has one or more characteristic peaks at 7.7±0.2°, 9.8±0.2°, 14.0±0.2° or 15.1±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also contain 2θ 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°, preferably 2, 3, 4 or 6 of them; The powder X-ray diffraction spectrum of the tromethamine salt form B has one or more characteristic peaks at 10.1±0.2°, 14.4±0.2°, 18.7±0.2° or 21.9±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also include 2θ 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°, one or more characteristic peaks, preferably 2, 3, 4 or 6 of them; The powder X-ray diffraction spectrum of the tromethamine salt form C has one or more characteristic peaks at 3.6±0.2°, 7.1±0.2°, 9.7±0.2°, 14.1±0.2° or 16.0±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also include 2θ 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°, one or more characteristic peaks, preferably 2, 3, 4 or 6 of them; The powder X-ray diffraction pattern of the tromethamine salt form D has one or more characteristic peaks at 7.4±0.2°, 9.8±0.2°, 13.1±0.2° or 14.0±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also include 2θ 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°, one or more characteristic peaks, preferably 2, 3, 4 or 6 of them; The powder X-ray diffraction pattern of the tromethamine salt form E has one or more characteristic peaks at 4.3±0.2°, 6.3±0.2°, 13.6±0.2° or 18.9±0.2°; preferably 2-4 of them, more preferably 3-4, most preferably 4; optionally, further, it may also include 2θ 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°, one or more characteristic peaks, preferably 2, 3, 4 or 6 of them.

11. The tromethamine salt crystal form according to claim 8, characterized in that The powder X-ray diffraction pattern of the tromethamine salt crystalline form A has characteristic peaks at 2θ of 9.8±0.2° and 14.0±0.2°; preferably, it also includes characteristic peaks at 2θ of 7.7±0.2° and 15.1±0.2°; more preferably, it also includes characteristic peaks at 2θ of 18.7±0.2°, 19.3±0.2°, 20.0±0.2° and 21.1±0.2°; further preferably, it also includes characteristic peaks at 2θ of 14.5±0.2° and 20.5±0.2°; further preferably, it also includes characteristic peaks at one or more of 10.8±0.2°, 11.6±0.2°, 18.0±0.2° and 22.6±0.2°. There are characteristic peaks; The powder X-ray diffraction spectrum of the tromethamine salt crystal form B has characteristic peaks at 2θ of 10.1±0.2° and 14.4±0.2°; preferably, it also includes characteristic peaks at 2θ of 18.7±0.2° and 21.9±0.2°; more preferably, it also includes characteristic peaks at 2θ of 8.2±0.2°, 14.8±0.2°, 20.5±0.2° and 22.1±0.2°; further preferably, it also includes characteristic peaks at 2θ of 12.3±0.2° and 19.7±0.2°; further preferably, it also includes 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 the tromethamine salt crystal form C has characteristic peaks at 2θ of 3.6±0.2° and 7.1±0.2°; preferably, it also includes characteristic peaks at 2θ of 9.7±0.2° and 14.1±0.2°; more preferably, it also includes characteristic peaks at 2θ of 15.0±0.2°, 16.0±0.2°, 16.5±0.2°, 17.6±0.2° and 20.8±0.2°; further preferably, it also includes characteristic peaks at 2θ of 17.1±0.2° and 19.7±0.2°; further preferably, it also includes 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 pattern of the tromethamine salt crystal form D has characteristic peaks at 2θ of 9.8±0.2° and 14.0±0.2°; preferably, it also includes characteristic peaks at 2θ of 7.4±0.2° and 13.1±0.2°; more preferably, it also includes characteristic peaks at 2θ of 7.7±0.2°, 15.1±0.2°, 18.8±0.2° and 20.0±0.2°; further preferably, it also includes characteristic peaks at 2θ of 17.9±0.2° and 19.3±0.2°; further preferably, it also includes characteristic peaks at one or more of 14.5±0.2°, 15.4±0.2°, 15.8±0.2° and 21.2±0.2°; The powder X-ray diffraction pattern of the tromethamine salt form E has characteristic peaks at 2θ of 6.3±0.2° and 13.6±0.2°; preferably, it also includes characteristic peaks at 2θ of 4.3±0.2° and 18.9±0.2°; more preferably, it also includes characteristic peaks at 2θ of 8.6±0.2°, 17.7±0.2°, 20.2±0.2° and 22.4±0.2°; further preferably, it also includes characteristic peaks at 2θ of 14.1±0.2° and 20.5±0.2°; further preferably, it also includes characteristic peaks at one or more of 9.3±0.2°, 18.5±0.2°, 21.4±0.2° and 21.9±0.2°.

12. The tromethamine salt crystal form according to claim 8, characterized in that The X-ray powder diffraction spectrum of Form A is shown in FIG1 . Preferably, Form A has a DSC spectrum as shown in FIG2 , or has a TGA spectrum as shown in FIG3 ; The powder X-ray diffraction spectrum of Form B at 2θ is shown in FIG4 . Preferably, Form B has a DSC spectrum as shown in FIG5 . The powder X-ray diffraction spectrum of Form C at 2θ is shown in FIG6 . Preferably, Form C has a DSC spectrum as shown in FIG7 , or has a TGA spectrum as shown in FIG8 . The powder X-ray diffraction pattern of Form D at 2θ is shown in FIG9 . Preferably, Form D has The DSC spectrum is shown in Figure 10; The powder X-ray diffraction spectrum of Form E at 2θ is shown in FIG11 . Preferably, Form E has a DSC spectrum as shown in FIG12 .

13. The tromethamine salt crystal form according to claim 8, characterized in that The 2θ errors of the top ten diffraction peak positions with relative peak intensities in the X-ray powder diffraction patterns of Form A, Form B, Form C, Form D and Form E and the diffraction peaks at the corresponding positions in Figures 1, 4, 6, 9 and 11 are respectively ±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 the compound according to any one of claims 1 to 13, comprising the following steps: 1) Weigh an appropriate amount of free acid and dissolve it in a benign solvent; 2) Weighing an appropriate amount of counter ion base and dissolving it in an organic solvent; the amount of the counter ion base is preferably 1.0 to 1.5 equivalents; 3) combining the above two solutions, stirring to precipitate or adding a poor solvent dropwise and stirring to precipitate; 4) Rapidly centrifuge or allow to evaporate to obtain the target product; in: The benign 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 or tert-butanol; 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 or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above benign solvent and organic solution need to be miscible when used; The poor solvent is selected from heptane, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether, and ethyl acetate; preferably methyl tert-butyl ether and isopropyl ether; The counter ion 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; preferably diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine or a mixture thereof; further preferably tromethamine; the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water or a mixture thereof, preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or a mixture thereof. or, 1) Weigh an appropriate amount of free acid and suspend it with 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 is preferably 1.0 to 1.5 equivalents; 3) Combine the above two solutions and stir to dissolve, and continue stirring; 4) Rapidly centrifuge or allow to evaporate to obtain the target product; in: The poor 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 or 3-pentanone; preferably ethanol, ethyl acetate, isopropanol, 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 or N,N-dimethylformamide; preferably methanol, ethanol or acetonitrile; the above benign solvent and organic solution need to be miscible when used; The counter ion 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; preferably diethylamine, diethanolamine, triethylamine, triethanolamine, choline hydroxide, tromethamine or a mixture thereof; further preferably tromethamine; the inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia water or a mixture thereof, preferably sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or a mixture thereof. or, 1) Weigh an appropriate amount of the basic salt of the compound and suspend it with a poor solvent, and the suspension density is preferably 50 to 200 mg / mL; 2) shaking the obtained suspension at a certain temperature for a certain time, preferably at 25 to 50° C., and preferably for 1 to 15 days; 3) The above suspension was quickly centrifuged to remove the supernatant, and the remaining solid was placed in a vacuum drying oven and dried to constant weight to obtain the target product; in: The poor 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. 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. The compound according to any one of claims 1 to 14 or a basic salt of its stereoisomer or a crystalline form thereof, and the pharmaceutical composition according to claim 15, characterized in that: The invention relates to a basic salt or a crystalline form thereof comprising a therapeutically effective dose, wherein the therapeutically effective dose comprises 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%.

17. 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 preparation of a GLP-1 receptor agonist drug.

18. 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 preparation of a medicament for treating metabolic-related diseases; preferably, the metabolic-related diseases are selected from diabetes, obesity or non-alcoholic fatty liver disease-related diseases or other related diseases caused by diabetes, obesity or non-alcoholic fatty liver disease.

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