4-Alkoxybenzimidazole-6-carboxylic acid derivatives used as GLP-1 receptor agonists

Abstract

The present invention discloses 4-alkoxybenzimidazole-6-carboxylic acid derivatives for use as GLP-1 receptor agonists, the structure of which is as shown in general formula (II), and the definitions of each substituent are as described in the specification and claims. The compounds of the present invention are used as GLP-1 receptor agonists and can be used for the prevention and / or treatment of diseases or symptoms associated with disorders of the GLP-1 receptor signaling pathway. [Formula 1] TIFF2026500865000186.tif47168

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to the field of pharmaceutical chemistry, specifically to 4-alkoxybenzimidazole-6-carboxylic acid compounds, their preparation methods, and their application in the preparation of drugs. The present invention further relates to the pharmacological effects of the compounds and pharmaceutical compositions containing the compounds as GLP-1 receptor agonists, and their use in the treatment of diseases such as diabetes, obesity, metabolic syndrome, non-alcoholic fatty liver disease (NASH), and senile dementia.

[0002] [Background technology] Diabetes mellitus (DDM) is the third most serious chronic disease threatening human health after tumors, cardiovascular disease, and cerebrovascular disease. According to the 8th edition of the World Diabetes Atlas published by the International Diabetes Federation (IDF), there are currently 460 million diabetic patients worldwide, and by 2045, it is estimated that there will be approximately 700 million diabetic patients. The situation is not optimistic. As a multifactorial metabolic disease, diabetes is characterized by chronic hyperglycemia and impaired glucose, lipid, and protein metabolism caused by defective insulin secretion or action. Currently, diabetes is broadly divided into two types: type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) and type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). Type 2 diabetes accounts for more than 90% of all diabetes cases and is characterized by impaired glucose and lipid metabolism due to impaired pancreatic beta-cell function and insulin resistance in peripheral tissues such as the liver, skeletal muscle, and adipose tissue. Other related diseases include hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and nonalcoholic fatty liver disease (NAFLD). Over the past decade, three novel hypoglycemic drugs, namely glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, have been widely used in the clinical treatment of type 2 diabetes. GLP-1 receptor agonists have the advantages of potent blood glucose lowering effects, no dependency on blood glucose levels, and no increased risk of hypoglycemia. They have now become established as the primary hypoglycemic drug and are steadily expanding their market share. Another key feature of GLP-1 receptor agonists is their "one specialty, multiple functions" approach. In addition to lowering blood glucose levels, they also have excellent weight loss effects. In a large-scale Phase III clinical trial targeting obese patients, semaglutide was able to reduce body weight by more than 15%, garnering attention in the industry as a drug that could change the pattern of obesity treatment. Furthermore, GLP-1 receptor agonists are also effective in lowering blood pressure, improving dyslipidemia, reducing fatty liver, and combating Alzheimer's disease. In particular, they protect the heart and kidneys, significantly reducing the incidence of cardiovascular events and slowing the progression of diabetic nephropathy.For patients with multiple of the above diseases, GLP-1 receptor agonists would undoubtedly offer significant long-term benefits.

[0003] The GLP-1 receptor is a member of the class B family of peptide hormone G protein-coupled receptors (GPCRs) and is distributed throughout the body, including pancreatic islet cells, lungs, kidneys, brain, hypothalamus, cardiovascular system, gastrointestinal tract, and cutaneous vagus nerves. GLP-1 receptors may also be present in the liver, adipose tissue, and skeletal muscle. Its natural agonistic ligand is GLP-1 (glucagon-like peptide-1), a peptide hormone encoded by the glucagon gene and secreted from intestinal L-cells. It belongs to the incretin family. Physiologically, after the body ingests nutrients through eating, GLP-1 is released from intestinal L-cells into the circulation at low picomolar concentrations (5–15 pmol / L). These levels of GLP GLP-1 activates the GLP-1 receptor on pancreatic β cells and stimulates insulin secretion in a glucose-dependent manner, simultaneously inhibiting glucagon secretion, thereby preventing and maintaining postprandial blood glucose levels. GLP-1 also has neuromodulatory functions, suppressing appetite, inhibiting gastric emptying, and promoting pancreatic β-cell growth. Because 50% to 70% of orally ingested glucose is metabolized via the GLP-1 / insulin pathway, GLP-1 is an important hypoglycemic polypeptide. In patients with type 2 diabetes, endogenous GLP-1 secretion levels are significantly reduced, which is a major cause of poor glycemic control in these patients. Natural GLP-1 is easily and rapidly degraded and inactivated by dipeptidyl peptidase-4 (DPP-4) in the body and has an extremely short half-life of only 1 to 2 minutes, making it unsuitable for clinical diabetes treatment. The development of metabolically stable exogenous GLP-1 analogs is an important research topic in the treatment of type 2 diabetes.

[0004] Currently, commercially available GLP-1 receptor agonists and drugs under development are primarily polypeptide analogs. Exenatide, a GLP-1 mimetic, was the first GLP-1 receptor agonist approved for the treatment of type 2 diabetes. Exenatide exhibits GLP-1 receptor activating activity equivalent to that of natural GLP-1 and exhibits effective blood glucose control at plasma concentrations in the range of 40–70 pmol / L. Other potent GLP-1 receptor agonists, including liraglutide, dulaglutide, and semaglutide, have also been approved. While these drugs offer better blood glucose control to patients, their share of overall diabetes prescriptions remains limited. One important reason for this is that they are all high-molecular-weight peptide drugs, requiring invasive administration via subcutaneous injection, resulting in poor patient compliance compared to oral administration. A breakthrough in GLP-1 therapy is the development of oral semaglutide tablets containing the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino)caprylate; however, oral bioavailability is less than 1%. Furthermore, drug absorption is significantly affected by food and gastric fluids, limiting the oral administration method of semaglutide for patients. Specifically, the tablet must be taken with a certain amount of water after an overnight fast, at least 30 minutes before breakfast or other medicinal foods. Therefore, the development of a small molecule GLP-1 receptor agonist that is easy to administer orally could provide a more standardized drug formulation and a more convenient administration method.

[0005] WO2018109607 discloses compounds as shown in the following general formula and their use as GLP-1 receptor agonists, wherein Z 1 is CH or N. Example 4A-01 is a representative compound in the present application, which is currently in Phase II clinical research, and its research and development code is PF-06882961, and is used as a reference compound hereinafter.

[0006] [ka]

[0007] WO2019239319 discloses a compound as shown in the following general formula, wherein Z 1 is CR Z or N and R Z is further H, F, Cl or -CH3. Example 10 is a representative compound in this application and is used below as a reference compound.

[0008] [ka]

[0009] WO2019239371 discloses a compound as shown in the following general formula, wherein A can be the structure shown in A1, and Z 1 is CR Z or N and R Z is further H, F, Cl or -CH3. Example 1 is a representative compound in this application and is used below as a reference compound.

[0010] [ka]

[0011] WO2022109182 discloses a compound as shown in the following general formula, wherein X1 is N, CH or CR 11 is defined as R 11 Although R has a broad definition that includes many groups, in the examples, 11 The following only shows compounds where R is a halogen, alkyl group, cycloalkyl group, heteroaromatic ring, or alkynyl group. 11 The compound with the highest activity is -F, and the other substituents have poor effects. Example 21 is one of the most active compounds and is used as a reference compound below.

[0012] [ka]

[0013] CN2022114139828 discloses compounds as shown in the following general formula, where A is a 5- to 6-membered aryl or heteroaryl group, and R 4 is H, halogen or a C1-C6 alkyl group. Compounds 2, 10 and 63 in this application are used below as reference compounds.

[0014] [ka]

[0015] [Summary of the Invention] [Problem to be solved by the invention] The object of the present invention is to provide 4-alkoxybenzimidazole-6-carboxylic acid compounds with highly potent GLP-1 receptor agonist activity, their preparation methods and medical uses.

[0016] [Means for solving the problem] In a first aspect, the present invention provides a compound represented by general formula (I), its stereoisomers, its deuterated derivatives and pharmaceutically acceptable salts thereof,

[0017] [ka]

[0018] where X is the CR X or N and R X is H or halogen, and R 0 is H or a methyl group, R 1Nrepresents a 4- to 8-membered heterocyclic group, a 4- to 8-membered heterocyclic group-substituted C1-C6 alkyl group, a 5- to 8-membered heteroaryl group-substituted C1-C6 alkyl group, or a C3-C8 cycloalkyl group-substituted C1-C6 alkyl group, wherein the C1-C6 alkyl group, 4- to 8-membered heterocyclic group, 5- to 8-membered heteroaryl group, or C3-C8 cycloalkyl group is not substituted by other groups or is optionally substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl group, halogenated C1-C6 alkyl group, cyano-substituted C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group, and cyano group; R 2 is a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a cyano-substituted C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C1-C6 alkyl group substituted with a C3-C8 cycloalkyl group, a phenyl group, a phenyl-substituted C1-C6 alkyl group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryl-substituted C1-C6 alkyl group, a 4- to 8-membered heterocyclic group, or a 4- to 8-membered heterocyclic-substituted C1-C6 alkyl group, and the cycloalkyl group, phenyl group, heteroaryl group, and heterocyclic group are unsubstituted or substituted with a halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, a optionally substituted with one or more groups selected from the group consisting of halogenated C1-C6 alkyl groups, halogenated C1-C6 alkoxy groups, and cyano groups;

[0019] [ka] is a 5- to 6-membered heterocyclic group, a phenyl group, a 5- to 6-membered heteroaryl group, or a C5-C8 cycloalkyl group, and the heterocyclic group, phenyl group, heteroaryl group, or cycloalkyl group is unsubstituted or is one of m R 3 optionally substituted by a group,

[0020] [ka] teeth,

[0021] [ka] is selected from the group consisting of

[0022] [ka] is a C6-C10 aryl group or a 5- to 12-membered heteroaryl group, and the aryl group or heteroaryl group is unsubstituted or 6 group or q R 7 optionally substituted by a group,

[0023] Each R 3 , R 4 , R 7 are each independently H, halogen, a C1-C6 alkyl group, or a halogenated C1-C6 alkyl group; R 5 is H, a C1-C6 alkyl group or a halogenated C1-C6 alkyl group, Each R 6 are each independently H, halogen, cyano group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C8 cycloalkyl group, 4- to 8-membered heterocyclic group, halogenated C1-C6 alkyl group, halogenated C1-C6 alkoxy group, C3-C8 cycloalkyl group-substituted C1-C6 alkyl group, hydroxy group-substituted C1-C6 alkyl group, C1-C6 alkoxy group-substituted C1-C6 alkyl group, amino group-substituted C1-C6 alkyl group, C1-C6 alkylamino group-substituted C1-C6 alkyl C6-C10 aryl group, 5-8 membered heteroaryl group, nitro group, cyano-substituted C1-C6 alkyl group, hydroxy group, -SR 8 , -N(R 8 )2, -C(O)OR 8 , -C(O)N(R 8 )2, -C(O)R 8 , -S(O)R 8 , -S(O)2R 8 , -S(O)2N(R 8 )2 or -N(R 8)C(O)R 8 and Each R 8 are each independently H, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a halogenated C1-C6 alkyl group, a hydroxyl-substituted C1-C6 alkyl group, a C1-C6 alkoxy-substituted C1-C6 alkyl group, an amino-substituted C1-C6 alkyl group, or a C1-C6 alkylamino-substituted C1-C6 alkyl group; m, n, p, and q each independently represent an integer of 1 to 4.

[0024] In another preferred example, m is 1, 2, 3, or 4. In another preferred example, n is 1, 2, 3, or 4. In another preferred example, p is 1, 2, 3, or 4. In another preferred example, q is 1, 2, 3, or 4.

[0025] In another preferred example, X is CH. In another preferred embodiment, R 0 is H. In another preferred embodiment, R 1N is a 4- to 5-membered heterocyclic group-substituted methyl group, a 5- to 6-membered heteroaryl group-substituted methyl group, or a C3-C4 cycloalkyl group-substituted methyl group, and the heterocyclic group, heteroaryl group, or cycloalkyl group is unsubstituted or optionally substituted with 1 to 2 C1-C3 alkyl groups.

[0026] In another preferred embodiment, R 1N teeth,

[0027] [ka] is.

[0028] In another preferred embodiment, R 2is a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a deuterated C1-C4 alkyl group, a C3-C6 cycloalkyl group or a C3-C6 cycloalkyl-substituted C1-C4 alkyl group, a phenyl group, a phenyl-substituted C1-C4 alkyl group, a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl-substituted C1-C4 alkyl group, a 4- to 6-membered heterocyclic group or a 4- to 6-membered heterocyclic-substituted C1-C4 alkyl group, wherein the cycloalkyl group is unsubstituted or optionally substituted with one or more groups selected from the group consisting of halogen and a C1-C6 alkyl group. 2 is a C1-C3 alkyl group, a halogenated C1-C3 alkyl group, a deuterated C1-C3 alkyl group, a C3-C5 cycloalkyl group, a C3-C5 cycloalkyl group-substituted C1-C3 alkyl group, a phenyl group, a phenyl group-substituted C1-C3 alkyl group, a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl group-substituted C1-C3 alkyl group, a 4- to 6-membered heterocyclic group, or a 4- to 6-membered heterocyclic group-substituted C1-C3 alkyl group.

[0029] In another preferred embodiment, R 2 is a methyl group, a difluoromethyl group, a trideuterated methyl group, an ethyl group, a trifluoroethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, a benzyl group, a furanylmethyl group, or a pyridyl group.

[0030] In another preferred embodiment,

[0031] [ka] teeth,

[0032] [ka] is selected from the group consisting of:

[0033] In another preferred embodiment,

[0034] [ka] teeth,

[0035] [ka] is.

[0036] In another preferred embodiment,

[0037] [ka] teeth,

[0038] [ka] is.

[0039] In another preferred embodiment,

[0040] [ka] teeth,

[0041] [ka] is selected from the group consisting of:

[0042] In another preferred embodiment,

[0043] [ka] teeth,

[0044] [ka] is.

[0045] In another preferred embodiment, each R 3 , R 4 , R 7 are each independently H or halogen and preferably R 3 , R 4 , R 7 are all H. In another preferred embodiment, R 5 is a C1-C3 alkyl group, and in another preferred example, R 5 is a methyl group.

[0046] In another preferred embodiment, each R 6 are each independently H, a halogen, a cyano group, a C1-C4 alkyl group, a C1-C4 alkoxy group, a halogenated C1-C4 alkyl group, or a halogenated C1-C4 alkoxy group. 6 are each independently H, halogen, cyano, C1-C3 alkoxy, or halogenated C1-C3 alkyl; In another preferred embodiment, each R 6 are each independently H, F, Cl, a cyano group, a methoxy group, or a trifluoromethyl group.

[0047] Furthermore, the present invention provides a compound represented by general formula (II), a stereoisomer thereof, a deuterated product thereof, and a pharmaceutically acceptable salt thereof,

[0048] [ka]

[0049] where X is the CR X or N and R X is H or a halogen, R 1 represents a 4- to 8-membered heterocyclic group, a 5- to 8-membered heteroaryl group, or a C3-C8 cycloalkyl group, wherein the heterocyclic group, heteroaryl group, or cycloalkyl group is unsubstituted or optionally substituted with one or more groups selected from the group consisting of a halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a cyano-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, and a cyano group; R 2 is a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a cyano-substituted C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl-substituted C1-C6 alkyl group, a phenyl group, a phenyl-substituted C1-C6 alkyl group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryl-substituted C1-C6 alkyl group, a 4- to 8-membered heterocyclic group, or a 4- to 8-membered heterocyclic-substituted C1-C6 alkyl group, wherein the cycloalkyl group, phenyl group, heteroaryl group, and heterocyclic group are unsubstituted or optionally substituted with one or more groups selected from the group consisting of halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, and a cyano group;

[0050] [ka] teeth,

[0051] [ka] wherein the N on the ring is bonded to -CH2-;

[0052] [ka] teeth,

[0053] [ka] wherein the benzene ring or pyridine ring is selected from the group consisting of:

[0054] [ka] binds to

[0055] [ka] teeth,

[0056] [ka] is selected from the group consisting of

[0057] Each R 3 , R 4 , R 7 are each independently H, halogen, or a C1-C6 alkyl group; R 5 is H, a C1-C6 alkyl group or a halogenated C1-C6 alkyl group, Each R 6 are each independently H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, or halogenated C1-C6 alkoxy; m, n, p, and q each independently represent an integer of 1 to 4.

[0058] In another preferred embodiment, m is 1, 2, 3, or 4. In another preferred embodiment, n is 1, 2, 3, or 4. In another preferred embodiment, p is 1, 2, 3, or 4.

[0059] In another preferred embodiment, q is 1, 2, 3, or 4. In another preferred example, X is CH. In another preferred embodiment, R 1 is a 4- to 6-membered heterocyclic group, preferably R 1 teeth,

[0060] [ka] is.

[0061] In another preferred embodiment, R 2is a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a deuterated C1-C4 alkyl group, a C3-C8 cycloalkyl group or a C3-C8 cycloalkyl-substituted C1-C4 alkyl group, a phenyl-substituted C1-C4 alkyl group, a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl-substituted C1-C4 alkyl group, or a 5- to 6-membered heterocyclic-substituted C1-C4 alkyl group, wherein the cycloalkyl group, heteroaryl group, and heterocyclic group are unsubstituted or optionally substituted with one or more groups selected from the group consisting of a halogen atom and a C1-C4 alkyl group. 2 is a C1-C3 alkyl group, a halogenated C1-C3 alkyl group, a deuterated C1-C3 alkyl group, a C3-C5 cycloalkyl group, a C3-C5 cycloalkyl-substituted C1-C3 alkyl group, a phenyl-substituted C1-C4 alkyl group, a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl-substituted C1-C3 alkyl group, or a 5- to 6-membered heterocyclic-substituted C1-C3 alkyl group.

[0062] In another preferred embodiment, R 2 is a methyl group, a difluoromethyl group, a trideuterated methyl group, an ethyl group, a trifluoroethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a cyclopropylmethyl group, a benzyl group, a furanylmethyl group, or a pyridyl group.

[0063] In another preferred embodiment, each R 3 , R 4 , R 7 are each independently H or halogen, preferably R 3 , R 4 , R 7 are all H. In another preferred embodiment, R 5 is a C1-C3 alkyl group, and in another preferred example, R 5 is a methyl group.

[0064] In another preferred embodiment, each R 6are each independently H, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl or halogenated C1-C4 alkoxy, and preferably each R 6 are each independently H, a halogen, a cyano group, a C1-C3 alkoxy group, or a halogenated C1-C3 alkyl group, and more preferably, each R 6 are each independently H, F, Cl, a cyano group, a methoxy group, or a trifluoromethyl group.

[0065] In another preferred example, the compound represented by general formula (II) has the following structural formulas (II-a) to (II-k):

[0066] [ka] TIFF2026500865000033.tif87167

[0067] where R 2 , R 5 , R 6 The definition of p is the same as in general formula (II). In another preferred example, the compound is selected from Compound 1 to Compound 90.

[0068] In another preferred embodiment, the pharmaceutically acceptable salt is an ammonium salt or a Tris salt of the compound. A second aspect of the present invention provides a pharmaceutical composition, which comprises a safe and effective amount of a compound represented by general formula (I) or (II), a stereoisomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable auxiliary agent.

[0069] In the present invention, the "effective amount" means that a subject treated with the dose is cured, improved, effectively prevented, or has a significantly reduced incidence of a lesion or side effect, etc., compared to a subject not treated with the dose, and further includes an amount effective to enhance normal physiological functions. "Safety" means that the amount of the active ingredient is sufficient to significantly improve symptoms without causing serious side effects.

[0070] In the pharmaceutical composition, the compound of the present invention is used as an active ingredient, and its weight accounts for 0.1 to 99.9% of the total weight of the pharmaceutical composition, with the remainder being pharmaceutically acceptable auxiliary agents. The preferred ratio of the compound of the present invention to the auxiliary agents is such that the compound of the present invention as the active ingredient accounts for 60% or more of the total weight, with the remaining portion accounting for 0 to 40% of the total weight, with the amount of the remaining portion being preferably 1 to 20%, and most preferably 1 to 10%. Typically, the pharmaceutical composition contains 1 to 2000 mg of active ingredient per agent, more preferably 10 to 200 mg of active ingredient per agent. Preferably, the "single agent" is a single tablet.

[0071] The pharmaceutical composition may further contain one or more other therapeutic agents in addition to the compound represented by formula (I) or (II) as an active ingredient. In a preferred example, the other therapeutic agents are therapeutic agents for diabetes, cardiovascular disease, or obesity.

[0072] The pharmaceutical auxiliary agents include pharmaceutically acceptable carriers, excipients, sustained-release agents, flavoring agents, fragrances, etc. A "pharmaceutically acceptable vector" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of each component in the composition to be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient. Examples of pharmaceutically acceptable carriers include, but are not limited to, cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), and the like.

[0073] The compounds or pharmaceutical compositions described in the present invention can be prepared into various dosage forms, such as tablets, capsules, powders, syrups, solutions, suspensions, sprays, creams, ointments, gels, transdermal patches, etc., according to conventional methods in the field of pharmaceutical preparations, and can be present in suitable solid or liquid carriers or diluents. The pharmaceutical compositions of the present invention can also be stored in suitable sterile instruments for injection or infusion. From the viewpoint of ease of preparation and administration, preferred pharmaceutical compositions are solid compositions, particularly tablets and solid-filled or liquid-filled capsules.

[0074] The compound or pharmaceutical composition according to the present invention can be used clinically in mammals, including humans and animals. The administration method is not particularly limited, and a typical administration method is oral administration. In another preferred embodiment, the preferred route of administration of the compound or pharmaceutical composition according to the present invention is oral administration.

[0075] Solid dosage forms for oral administration of the compounds or pharmaceutical compositions described in the present invention include capsules, tablets, pills, powders, and granules.Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose, kaolin, etc., while liquid carriers include sterilized water, polyethylene glycol, nonionic surfactants, edible oils (e.g., corn oil, peanut oil, and sesame oil), etc., as long as they are compatible with the properties of the active ingredient and the specific administration method required.Additives commonly used in the preparation of pharmaceutical compositions, such as flavors, dyes, preservatives, and antioxidants, such as vitamin E, vitamin C, BHT, and BHA, can also be advantageously added.

[0076] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active ingredient, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers (e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide), and oils (e.g., cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil), or mixtures of these substances. In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and fragrances. In addition to the active ingredient, suspensions can contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures of these substances.

[0077] Injectable preparations include, but are not limited to, sterile injectable aqueous or oily solutions, suspensions, emulsions, etc. These preparations can also be prepared using appropriate parenteral diluents, dispersants, wetting agents, suspending agents, etc. Such injectable preparations can be sterilized by filtration through a bacteria-retaining filter. These preparations can also contain a bactericidal agent, which is dissolved or dispersed in the injection medium, or administered by other methods known in the art.

[0078] When used as a pharmaceutical preparation, the compound or pharmaceutical composition of the present invention can be administered once a day or in divided doses. Regardless of the method of use, the optimal dosage for each patient should be determined based on the specific treatment. Usually, the dosage starts at a low level and is gradually increased until the optimal dosage is achieved.

[0079] A third aspect of the present invention provides use of a compound represented by general formula (I) or (II) or a stereoisomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutical composition containing the compound as an active ingredient, for use in preparing a GLP-1 receptor agonist, or for use in preparing a medicament for preventing and / or treating a disease or symptom associated with a disorder of the GLP-1 receptor signaling pathway.

[0080] In another preferred example, the disease or symptom associated with a disorder of the GLP-1 receptor signaling pathway is selected from diabetes, metabolic syndrome, diabetic complications, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, hyperglycemia, impaired glucose tolerance, arteriosclerosis, hypertension, hyperlipidemia, coronary artery disease, cerebral infarction, or stroke; In another preferred embodiment, the disease or condition associated with a disorder of the GLP-1 receptor signaling pathway is type II diabetes or obesity.

[0081] A fourth aspect of the present invention provides a method for preparing a compound represented by general formula (I) or (II), a stereoisomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof.

[0082] The compounds of the present invention can be prepared by various synthetic methods, steps, and routes, and the synthetic routes shown in the following Routes A to F are representative general schemes, which, in combination with the synthetic methods for specific compounds in the Preparation Examples, constitute methods for preparing the compounds of the present invention. Furthermore, it should be understood that the methods for preparing the compounds of the present invention are not limited to the synthetic routes shown in Routes A to F, which are for illustrative purposes only and do not limit the present invention in any way.

[0083] [ka]

[0084] Route A can be used to synthesize intermediate JHS-A1 of the compound of the present invention, in which the definitions of each substituent are as described in general formula (I) or (II), and the reaction steps include the following steps:

[0085] (1.1) Intermediate A-1 is coupled with a cyanide to produce intermediate A-2. The coupling reaction is usually carried out under the action of a palladium catalyst or a copper catalyst, a ligand, and a base. The cyanide is, but is not limited to, zinc cyanide, cuprous cyanide, or potassium ferrocyanide. The palladium catalyst or copper catalyst is, but is not limited to, palladium acetate, tris(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, or cuprous iodide. The ligand is, but is not limited to, 1,1'-bis(diphenylphosphine). The base may be, but is not limited to, cesium carbonate, potassium carbonate, sodium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, or triethylamine. The reaction is carried out in a suitable organic solvent such as N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually from room temperature to 150°C.

[0086] (1.2) Intermediate A-2 is reacted in the presence of a base and water to produce intermediate A-3, the base being, but not limited to, cesium carbonate, potassium carbonate, sodium carbonate. The reaction is carried out in an appropriate organic solvent such as N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually from room temperature to 100°C.

[0087] (1.3) Intermediate A-3 and Reagent “R 2 -leaving group" is subjected to a nucleophilic substitution reaction under the action of a base, or intermediates A-3 and R 2-OH is subjected to a Mitsunobu reaction under the action of triphenylphosphine, DIAD or DEAD to produce intermediate A-4, the "leaving group" being a leaving group such as, but not limited to, -Cl, -Br, -I, -OTs, -OMs, etc., the base being, but not limited to, cesium carbonate, potassium carbonate, N,N-diisopropylethylamine, etc., the nucleophilic substitution reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, etc., the Mitsunobu reaction is carried out in a suitable organic solvent such as tetrahydrofuran, ether, dichloromethane, toluene, etc., and the reaction temperature is usually room temperature to 100°C.

[0088] (1.4) Intermediate A-2 and R 2 The -OH undergoes aromatic nucleophilic substitution under the action of a base to produce intermediate A-4, where the base is, but is not limited to, sodium hydride, sodium t-butoxide, or potassium t-butoxide. The reaction is carried out in a suitable organic solvent such as N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 120°C.

[0089] (1.5) Intermediate A-4 and R 0 -OH under acidic conditions to produce A-5, the acid being, but not limited to, thionyl chloride, hydrochloric acid, sulfuric acid, and the reaction temperature is usually room temperature to 100°C.

[0090] (1.6) Intermediate A-5 and a primary amine are subjected to aromatic nucleophilic substitution reaction under the action of a base to produce intermediate A-6. The base can be potassium carbonate, cesium carbonate, triethylamine, or N,N-diisopropylethylamine, but is not limited to these. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually room temperature to 120°C.

[0091] (1.7) Intermediate A-6 is reduced to produce intermediate A-7. The reduction reaction is carried out under a palladium / carbon catalyst, under a hydrogen gas atmosphere or under acidic conditions, under the action of a reducing agent. The reducing agent is, but is not limited to, iron powder or zinc powder. The acidic conditions include, but are not limited to, acetic acid, hydrochloric acid, and aqueous ammonium chloride solution. The reaction temperature is usually room temperature. The reaction solvent includes protic solvents and aprotic solvents, such as, but not limited to, methanol, ethanol, ethyl acetate, and THF.

[0092] (1.8) Intermediate A-7 and 2-halogeno-1,1,1-trimethoxyethane are reacted under the catalysis of an acid reagent to produce intermediate JHS-A1. The catalytic acid reagent can be p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, acetic acid, etc., but is not limited thereto. The reaction is carried out in a suitable organic solvent such as acetonitrile or toluene, and the reaction temperature is usually room temperature to 80°C.

[0093] In the general formula (I) or (II), A is

[0094] [ka] and B is

[0095] [ka]

[0049] When the compound is represented by formula (I) or (II), it can be prepared according to Route B, in which the definitions of each substituent are as described in general formula (I) or (II), and the reaction steps include the following steps:

[0096] (2.1) Intermediate B-1 and intermediate B-2 are subjected to aromatic nucleophilic substitution reaction under the action of a base to produce intermediate B-3. The base may be, but is not limited to, potassium t-butoxide, sodium hydride, or sodium t-butoxide. The reaction is carried out in a suitable organic solvent such as t-butanol, tetrahydrofuran, 1,4-dioxane, or N,N-dimethylformamide, and the reaction temperature is usually room temperature to 80°C.

[0097] (2.2) Suzuki coupling reaction of intermediate B-3 and boron ester-based starting materials (commercially purchased or synthesized according to literature methods) to produce intermediate B-4. The Suzuki coupling reaction is typically carried out under the influence of a palladium catalyst and a base. The palladium catalyst includes, but is not limited to, bis(triphenylphosphine)palladium dichloride(II), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, and tetrakis(triphenylphosphine)palladium(0). The base includes, but is not limited to, triethylamine, N,N-diisopropylethylamine, potassium carbonate, and cesium carbonate. The reaction is carried out in a suitable organic solvent, such as N,N-dimethylformamide, toluene, and 1,4-dioxane, or a mixture of an organic solvent and water. The reaction temperature is typically between room temperature and 100°C.

[0098] [ka]

[0099] (2.3) After the intermediate B-4 is hydrogenated, the t-butyloxycarbonyl (Boc) protecting group is subsequently removed under the action of acid to produce intermediate B-5. The hydrogenation reaction is carried out in the presence of a catalyst such as palladium / carbon or nickel. The reaction temperature is usually room temperature, and the reaction solvent includes protic solvents and aprotic solvents, such as, but not limited to, methanol, ethanol, ethyl acetate, and tetrahydrofuran. The acid used in the Boc removal reaction is, but not limited to, trifluoroacetic acid and hydrochloric acid. The reaction temperature is usually room temperature, and the reaction solvent includes, but is not limited to, dichloromethane, tetrahydrofuran, and 1,4-dioxane.

[0100] (2.4) Intermediate B-5 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate B-6. The base may be, but is not limited to, potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0101] (2.5) Intermediate B-6 is hydrolyzed under basic conditions to produce compound JHS-B1, where the base is, but is not limited to, lithium hydroxide or sodium hydroxide. The reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually room temperature to 50°C.

[0102] (2.6) Intermediate B-3 and intermediate B-7 are subjected to a Buchwald-Hartwig coupling reaction to produce intermediate B-8. The Buchwald-Hartwig coupling reaction is typically carried out in the presence of a palladium catalyst, a ligand, and a base. The palladium catalyst may be, but is not limited to, palladium acetate or tris(dibenzylideneacetone)palladium. The ligand may be, but is not limited to, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl. The base may be, but is not limited to, cesium carbonate, sodium t-butoxide, or potassium phosphate. The reaction is typically carried out in a suitable organic solvent such as 1,4-dioxane, toluene, or N,N-dimethylformamide, and the reaction temperature is typically between room temperature and 140°C.

[0103] (2.7) Intermediate B-8 is deprotected with Boc under the action of an acid to produce intermediate B-9, where the acid is, but is not limited to, trifluoroacetic acid or hydrochloric acid, the reaction temperature is usually room temperature, and the reaction solvent is, but is not limited to, dichloromethane, tetrahydrofuran, or 1,4-dioxane.

[0104] (2.8) Intermediate B-9 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate B-10. The base can be potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine, but is not limited to these. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0105] (2.9) Intermediate B-10 is hydrolyzed under basic conditions to produce compound JHS-B2, where the base is, but not limited to, lithium hydroxide or sodium hydroxide. The reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually between room temperature and 50°C.

[0106] [ka]

[0107] In the general formula (I) or (II), A is

[0108] [ka] and B is

[0109] [ka]

[0049] When the compound is represented by formula (I) or (II), it can be prepared according to Route C, in which the definitions of each substituent are as described in general formula (I) or (II), and the reaction steps include the following steps:

[0110] (3.1) Intermediate C-1 and intermediate C-2 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate C-3, the base being, but not limited to, cesium carbonate, potassium hydroxide, potassium t-butoxide, and the reaction can be carried out in N,N-dimethylformamide, dimethyl sulfoxide, The reaction is carried out in a suitable organic solvent, such as, but not limited to, sulfoxide, N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0111] (3.2) Intermediate C-3 is oxidatively decomposed in the presence of sodium periodate and potassium osmate dihydrate to produce intermediate C-4. The reaction is carried out in a mixture of water and an organic solvent such as tetrahydrofuran or water, and the reaction temperature is usually room temperature.

[0112] (3.3) Intermediate C-4 and t-butyloxycarbonylhydrazine are subjected to a reductive amination reaction under the action of a reducing agent to produce intermediate C-5, which can be, but is not limited to, sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride. The reaction is carried out in an organic solvent such as 1,2-dichloroethane, tetrahydrofuran, or toluene, and the reaction temperature is usually room temperature.

[0113] (3.4) Intermediate C-5 is deprotected with Boc under the action of an acid to produce intermediate C-6, where the acid is, but is not limited to, trifluoroacetic acid or hydrochloric acid, the reaction temperature is usually room temperature, and the reaction solvent is, but is not limited to, dichloromethane, tetrahydrofuran, or 1,4-dioxane.

[0114] (3.5) Intermediate C-6 and trimethyl orthoformate are reacted to produce intermediate JHS-C1, the reaction solvent is usually acetic acid, and the reaction temperature is usually room temperature to 120°C.

[0115] (3.6) Intermediate C-7 and intermediate JHS-C1 are coupled to produce intermediate C-8. The coupling reaction is typically carried out in the presence of a palladium catalyst, a ligand, and a base. The palladium catalyst may be, but is not limited to, palladium acetate or tris(dibenzylideneacetone)palladium. The ligand may be, but is not limited to, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl. The base may be, but is not limited to, cesium carbonate, sodium t-butoxide, or potassium phosphate. The reaction is typically carried out in a suitable organic solvent such as 1,4-dioxane, toluene, or N,N-dimethylformamide, and the reaction temperature is typically between room temperature and 140°C.

[0116] (3.7) Intermediate C-8 is hydrolyzed under acidic or basic conditions to produce intermediate C-9, where the acid is, but is not limited to, hydrochloric acid, and the basic condition is, but is not limited to, sodium hydroxide or hydrazine hydrate, and the reaction temperature is usually room temperature to 50°C.

[0117] (3.8) Intermediate C-9 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate C-10. The base can be potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine, but is not limited to these. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0118] (3.9) Intermediate C-10 is hydrolyzed under basic conditions to produce compound JHS-C2. The base can be, but is not limited to, lithium hydroxide or sodium hydroxide. The reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually between room temperature and 50°C.

[0119] In the general formula (I) or (II), A is

[0120] [ka] and B is

[0121] [ka]

[0049] When the compound is represented by formula (I) or (II), it can be prepared according to Route D, in which the definitions of each substituent are as described in general formula (I) or (II), and the reaction steps include the following steps:

[0122] (4.1) Intermediate B-1 and intermediate D-1 are subjected to aromatic nucleophilic substitution reaction under the action of a base to produce intermediate D-2, the base being, but not limited to, potassium t-butoxide, sodium hydride, sodium t-butoxide, the reaction being carried out in a suitable organic solvent, but not limited to, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, the reaction temperature is usually room temperature to 80°C.

[0123] (4.2) Intermediate D-2 and a boron ester-based starting material (commercially purchased or synthesized according to literature methods) are subjected to Suzuki coupling reaction to produce intermediate D-3. The Suzuki coupling reaction is typically carried out under the influence of a palladium catalyst and a base, such as, but not limited to, bis(triphenylphosphine)palladium dichloride(II), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, or tetrakis(triphenylphosphine)palladium(0). The base is typically, but not limited to, triethylamine, N,N-diisopropylethylamine, potassium carbonate, or cesium carbonate. The reaction is typically carried out in a suitable organic solvent, such as N,N-dimethylformamide, toluene, or 1,4-dioxane, or a mixture of an organic solvent and water, at a temperature typically between room temperature and 100°C.

[0124] [ka]

[0125] (4.3) After the intermediate D-3 is hydrogenated, it is subsequently deprotected under the action of acid to produce intermediate D-4. The hydrogenation reaction is carried out in the presence of a catalyst such as palladium on carbon or nickel. The reaction temperature is usually room temperature, and the reaction solvent includes protic solvents and aprotic solvents, such as, but not limited to, methanol, ethanol, ethyl acetate, and tetrahydrofuran. The acid used in the Boc protecting group removal reaction is, but not limited to, trifluoroacetic acid and hydrochloric acid. The reaction temperature is usually room temperature, and the reaction solvent includes, but is not limited to, dichloromethane, tetrahydrofuran, and 1,4-dioxane.

[0126] (4.4) Intermediate D-4 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate D-5. The base can be potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine, but is not limited to these. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0127] (4.5) Intermediate D-5 was hydrolyzed under basic conditions to give compound JHS-D1. The base may be, but is not limited to, lithium hydroxide or sodium hydroxide, and the reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually room temperature to 50°C.

[0128] (4.6) Intermediate D-2 and intermediate B-7 are subjected to a Buchwald-Hartwig coupling reaction to produce intermediate D-6. The Buchwald-Hartwig coupling reaction is typically carried out in the presence of a palladium catalyst, a ligand, and a base. The palladium catalyst may be, but is not limited to, palladium acetate or tris(dibenzylideneacetone)palladium. The ligand may be, but is not limited to, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, or 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl. The base may be, but is not limited to, cesium carbonate, sodium t-butoxide, or potassium phosphate. The reaction is typically carried out in a suitable organic solvent such as 1,4-dioxane, toluene, or N,N-dimethylformamide, and the reaction temperature is typically between room temperature and 140°C.

[0129] (4.7) Intermediate D-6 is deprotected with Boc under the action of an acid to produce intermediate D-7, where the acid is, but is not limited to, trifluoroacetic acid or hydrochloric acid, the reaction temperature is usually room temperature, and the reaction solvent is, but is not limited to, dichloromethane, tetrahydrofuran, or 1,4-dioxane.

[0130] (4.8) Intermediate D-7 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate D-8. The base can be potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine, but is not limited to these. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0131] (4.9) Intermediate D-8 is hydrolyzed under basic conditions to produce compound JHS-D2. The base can be, but is not limited to, lithium hydroxide or sodium hydroxide. The reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually between room temperature and 50°C.

[0132] [ka]

[0133] In the general formula (I) or (II), A is

[0134] [ka] and B is

[0135] [ka]

[0049] When the compound is represented by formula (I) or (II), it can be prepared according to Route E, in which the definitions of each substituent are as described in formula (I) or (II), and the reaction steps include the following steps:

[0136] (5.1) Intermediate E-1 and catechol (purchased commercially or synthesized according to literature methods) are reacted under acid catalysis to produce intermediate E-3, where the acid catalyst is, but not limited to, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, and the reaction is carried out in a suitable organic solvent such as toluene, and the reaction temperature is usually room temperature to 160°C. In another preparation method, intermediate E-2 and catechol (purchased commercially or synthesized according to literature methods) are reacted under ruthenium catalysis to produce intermediate E-3, where the ruthenium catalyst is, but not limited to, triruthenium dodecacarbonyl, and the reaction is carried out in a suitable organic solvent such as toluene, and the reaction temperature is usually room temperature to 120°C.

[0137] (5.2) Intermediate E-3 and a boron ester-based starting material (commercially purchased or synthesized according to literature methods) are subjected to Suzuki coupling reaction to produce intermediate E-4. The Suzuki coupling reaction is typically carried out under the influence of a palladium catalyst and a base, such as, but not limited to, bis(triphenylphosphine)palladium dichloride(II), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, or tetrakis(triphenylphosphine)palladium(0). The base is typically, but not limited to, triethylamine, N,N-diisopropylethylamine, potassium carbonate, or cesium carbonate. The reaction is typically carried out in a suitable organic solvent, such as N,N-dimethylformamide, toluene, or 1,4-dioxane, or a mixture of an organic solvent and water, at a temperature typically between room temperature and 100°C.

[0138] (5.3) After intermediate E-4 is hydrogenated, it is subsequently deprotected under acid to produce intermediate E-5. The hydrogenation is carried out in the presence of a catalyst such as palladium / carbon or nickel. The reaction temperature is usually room temperature, and the reaction solvent includes protic solvents and aprotic solvents, such as, but not limited to, methanol, ethanol, ethyl acetate, and tetrahydrofuran. The deprotection acid is, but not limited to, trifluoroacetic acid and hydrochloric acid. The reaction temperature is usually room temperature, and the reaction solvent includes, but is not limited to, dichloromethane, tetrahydrofuran, and 1,4-dioxane.

[0139] (5.4) Intermediate E-5 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate E-6. The base can be, but is not limited to, potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0140] (5.5) Intermediate E-6 is hydrolyzed under basic conditions to produce compound JHS-E1, where the base is, but is not limited to, lithium hydroxide or sodium hydroxide. The reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually between room temperature and 50°C.

[0141] (5.6) Intermediate E-3 and intermediate B-7 are subjected to a Buchwald-Hartwig coupling reaction to produce intermediate E-7. The Buchwald-Hartwig coupling reaction is typically carried out under the influence of a palladium catalyst, a ligand, and a base. The palladium catalyst is, but is not limited to, palladium acetate, tris(dibenzylideneacetone)palladium, the ligand is, but is not limited to, 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 1,1′-binaphthyl-2,2′-bisdiphenylphosphine, 2-dicyclohexylphosphine-2′,6′-diisopropoxy-1,1′-biphenyl, the base is, but is not limited to, cesium carbonate, sodium t-butoxide, potassium phosphate, and the reaction can be carried out in 1,4-dioxane, toluene, N The reaction is usually carried out in a suitable organic solvent such as N-dimethylformamide, and the reaction temperature is usually from room temperature to 140°C.

[0142] (5.7) Intermediate E-7 is deprotected with Boc under the action of an acid to produce intermediate E-8, where the acid is, but is not limited to, trifluoroacetic acid or hydrochloric acid, the reaction temperature is usually room temperature, and the reaction solvent is, but is not limited to, dichloromethane, tetrahydrofuran, or 1,4-dioxane.

[0143] (5.8) Intermediate E-8 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate E-9. The base can be, but is not limited to, potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0144] (5.9) Intermediate E-9 is hydrolyzed under basic conditions to produce compound JHS-E2. The base can be, but is not limited to, lithium hydroxide or sodium hydroxide. The reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually between room temperature and 50°C.

[0145] [ka]

[0146] In the general formula (I) or (II), A is

[0147] [ka] and B is

[0148] [ka] When it is, it can be prepared according to Route F, in which the definitions of each substituent are as described in general formula (I), and the reaction steps include the following steps:

[0149] (6.1) Intermediate F-1 and a boron ester-based starting material (commercially purchased or synthesized according to literature methods) are subjected to Suzuki coupling reaction to produce intermediate F-2. The Suzuki coupling reaction is typically carried out under the influence of a palladium catalyst and a base, such as, but not limited to, bis(triphenylphosphine)palladium dichloride(II), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride, or tetrakis(triphenylphosphine)palladium(0). The base is typically, but not limited to, triethylamine, N,N-diisopropylethylamine, potassium carbonate, or cesium carbonate. The reaction is typically carried out in a suitable organic solvent, such as N,N-dimethylformamide, toluene, or 1,4-dioxane, or a mixture of an organic solvent and water, at a temperature typically between room temperature and 100°C.

[0150] (6.2) Intermediate F-2 is reduced to a double bond under the action of hydrogen gas and palladium / carbon, and the benzyl protecting group is removed to generate intermediate F-3. The reaction temperature is usually room temperature, and the reaction solvent includes protic and aprotic solvents, such as, but not limited to, methanol, ethanol, ethyl acetate, and tetrahydrofuran.

[0151] (6.3) Intermediate F-3 and intermediate F-4 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate F-5. The base may be, but is not limited to, triethylamine, N,N-diisopropylethylamine, potassium carbonate, or cesium carbonate. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, or dimethyl sulfoxide, and the reaction temperature is usually between room temperature and 100°C.

[0152] (6.4) Intermediate F-5 is deprotected under the action of an acid to produce intermediate F-6, where the acid is, but is not limited to, trifluoroacetic acid or hydrochloric acid, the reaction temperature is usually room temperature, and the reaction solvent is, but is not limited to, dichloromethane, tetrahydrofuran, or 1,4-dioxane.

[0153] (6.5) Intermediate F-6 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate F-7. The base can be potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine, but is not limited to these. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0154] (6.6) Intermediate F-7 is hydrolyzed under basic conditions to produce compound JHS-F1. The base can be, but is not limited to, lithium hydroxide or sodium hydroxide. The reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually between room temperature and 50°C.

[0155] [ka]

[0156] In the general formula (I) or (II), A is

[0157] [ka] and B is

[0158] [ka]

[0049] When the compound is represented by formula (I) or (II), it can be prepared according to Route G, in which the definitions of each substituent are as described in general formula (I) or (II), and the reaction steps include the following steps:

[0159] (7.1) Intermediate E-1 and catechol (G-1, purchased commercially or synthesized according to literature methods) are reacted under acid catalysis to produce intermediate G-2. The acid catalyst can be, but is not limited to, p-toluenesulfonic acid or p-toluenesulfonic acid pyridinium salt. The reaction is carried out in a suitable organic solvent such as toluene at a temperature typically between room temperature and 160°C. In another preparation method, intermediate E-2 and catechol (G-1, purchased commercially or synthesized according to literature methods) are reacted under ruthenium catalysis to produce intermediate G-2. The ruthenium catalyst can be, but is not limited to, triruthenium dodecacarbonyl. The reaction is carried out in a suitable organic solvent such as toluene at a temperature typically between room temperature and 120°C.

[0160] (7.2) Intermediate G-2 is oxidized with a strong oxidizing agent under a basic system to produce intermediate G-3, the basic system being, but not limited to, a pyridine system, the strong oxidizing agent being, but not limited to, potassium permanganate, and the reaction temperature is usually room temperature to 100°C.

[0161] (7.3) Intermediate G-3 and an azide reagent are reacted under the action of a base to produce intermediate G-4. The azide reagent is, but is not limited to, diphenylphosphorylamide, and the base is, but is not limited to, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction is carried out in a suitable organic solvent such as dichloromethane, and the reaction temperature is usually 0°C to room temperature.

[0162] (7.4) Intermediate G-4 is heated in a t-butanol system to undergo a rearrangement reaction and react with t-butanol to produce intermediate G-5, and the reaction temperature is usually 50°C to 120°C.

[0163] (7.5) Intermediate G-5 and intermediate C-2 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate G-6, where the base is, but is not limited to, cesium carbonate, potassium hydroxide, or potassium t-butoxide. The reaction is carried out in a suitable organic solvent, such as, but not limited to, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually room temperature to 100°C.

[0164] (7.6) Intermediate G-6 is oxidatively decomposed in the presence of sodium periodate and potassium osmate dihydrate to produce intermediate G-7. The reaction is carried out in a mixture of water and an organic solvent such as tetrahydrofuran and water, and the reaction temperature is usually room temperature.

[0165] (7.7) Intermediate G-7 and t-butyloxycarbonylhydrazine are subjected to a reductive amination reaction in the presence of a reducing agent to produce intermediate G-8. The reducing agent can be, but is not limited to, sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride. The reaction is carried out in an organic solvent such as 1,2-dichloroethane, tetrahydrofuran, or toluene, and the reaction temperature is usually room temperature.

[0166] (7.8) Intermediate G-8 is deprotected by Boc-protection under the action of an acid to produce intermediate G-9. The acid may be, but is not limited to, trifluoroacetic acid or hydrochloric acid. The reaction temperature is usually 0°C to room temperature. The reaction solvent may be, but is not limited to, dichloromethane, tetrahydrofuran, or 1,4-dioxane.

[0167] (7.9) Intermediate G-9 and trimethyl orthoformate are reacted to produce intermediate G-10. The reaction solvent is, but is not limited to, acetic acid or 1,4-dioxane, and the reaction temperature is usually room temperature to 120°C.

[0168] (7.10) Intermediate G-10 is hydrolyzed under acidic or basic conditions to produce intermediate G-11, where the acid is, but is not limited to, hydrochloric acid, and the basic condition is, but is not limited to, sodium hydroxide or hydrazine hydrate, and the reaction temperature is usually room temperature to 80°C.

[0169] (7.11) Intermediate G-11 and intermediate JHS-A1 are subjected to a nucleophilic substitution reaction under the action of a base to produce intermediate G-12. The base can be, but is not limited to, potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine. The reaction is carried out in a suitable organic solvent such as acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, and the reaction temperature is usually between room temperature and 100°C.

[0170] (7.12) Intermediate G-12 is hydrolyzed under basic conditions to produce compound JHS-G1. The base can be, but is not limited to, lithium hydroxide or sodium hydroxide. The reaction is carried out in a suitable organic solvent such as acetonitrile, tetrahydrofuran, 1,4-dioxane, or methanol, and the reaction temperature is usually between room temperature and 50°C.

[0171] In the present invention, suitable protecting groups and protection and deprotection methods using such protecting groups are well known to those skilled in the art, and examples thereof are described in literature or references, such as T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th Edition), John Wiley & Sons (2007), the entire text of which is incorporated herein by reference. Those skilled in the art can appropriately adjust the reaction conditions according to the literature or the actual situation encountered during the synthesis process.

[0172] [Effects of the invention] It should be understood that within the scope of the present invention, the above-mentioned technical features and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature providing the same, equivalent, or similar purpose. Due to space limitations, they will not be repeated here. [Brief explanation of the drawings]

[0173] [Figure 1] Concentration-activation effect curves (n=3) of compounds that recruit β-arrestin 1 are shown. [Figure 2] Concentration-activation effect curves (n=3) of compounds that recruit β-arrestin 2 are shown. [Figure 3] FIG. 1 shows blood glucose concentration-time curves of the ammonium salt of compound 20 and the positive control PF-06882961 in a mouse oral glucose tolerance test (n=5, mean±SEM, **p<0.01 vs. blank control, ***p<0.001 vs. blank control). [Figure 4] The area under the blood glucose curve (AUC(0-90)) from 0 to 90 minutes for the ammonium salt of compound 20 and the positive control PF-06882961 in a mouse oral glucose tolerance test is shown (n=5, mean±SEM, ***p<0.001 vs. blank control, #p<0.05, compound 20 vs. PF). [Figure 5] FIG. 1 shows the blood glucose concentration-time curves of the ammonium salt of compound 19 and the positive control PF-06882961 in a mouse oral glucose tolerance test (n=8, means±SEM, *p<0.05 vs. blank control, **p<0.01 vs. blank control, ***p<0.001 vs. blank control). [Figure 6]The area under the blood glucose curve (AUC(0-90)) from 0 to 90 minutes (A) and the area under the blood glucose curve (AUC(180-270) from 180 to 270 minutes (B) are shown for the ammonium salt of compound 19 and the positive control PF-06882961 in an oral glucose tolerance test in mice (n=8, mean ± SEM, **p<0.01 vs. blank control, ***p<0.001 vs. blank control, ###p<0.001, compound 19 vs. PF). [Figure 7] Changes in food intake at 2.5, 5, and 12 hours after oral administration of the ammonium salt of compound 19 and the positive control PF-06882961 to mice are shown (n=5, means±SEM, *p<0.05 vs. blank control, **p<0.01 vs. blank control, ***p<0.001 vs. blank control). [Figure 8] Changes in food intake at 2.5, 5, and 12 hours after oral administration of the ammonium salt of compound 76-1 and the positive control PF-06882961 to mice are shown (n=7, means±SD, *p<0.05 vs. blank control, **p<0.01 vs. blank control, ***p<0.001 vs. blank control). [Figure 9] The effects of the ammonium salt of compound 76-1 and the positive control PF-06882961 on the body weight of HFD-induced obese mice are shown (n=9, mean±SD, *p<0.05 vs. blank control, **p<0.01 vs. blank control, ***p<0.001 vs. blank control). [Figure 10] The effects of the ammonium salts of compound 76-1 and the positive control PF-06882961 on fat (left) and lean meat (right) contents in HFD-induced obese mice are shown (n=9, mean±SD, ***p<0.001 vs. blank control). [Figure 11] The blood glucose concentration-time curves (A) and the area under the blood glucose curve (B) of the ammonium salts of compound 76-1 and the positive control PF-06882961 in a mouse oral glucose tolerance test are shown (n=6, means±SEM, **p<0.01 vs. blank control, ***p<0.001 vs. blank control). [Figure 12]Changes in food intake at 2.5, 5, 12, and 24 hours after oral administration of the Tris salts of compounds 81-1, 82-1, and the positive control PF-06882961 to mice are shown (n=8, means ± SD, *p<0.05 vs. blank control, **p<0.01 vs. blank control, ***p<0.001 vs. blank control, #p<0.05 compound 81-1 vs. PF-06882961). DETAILED DESCRIPTION OF THE INVENTION

[0174] As a result of extensive and thorough research, the present inventors have developed 4-alkoxybenzimidazole-6-carboxylic acid compounds, and have found that -OR is attached to the 4-position of the benzimidazole. 2 The introduction of - provides unexpected effects compared to the substituents disclosed in the prior art, such as -H, halogen, alkyl, and cycloalkyl groups, which (1) enhance the GLP-1 receptor agonist activity of the compound by several to several tens of times, reaching the level of endogenous GLP-1, and (2) weaken the activation effect on the downstream β-arrestin pathway of the GLP-1 receptor, increasing signal bias. Due to these biological properties, the compounds of the present invention exhibit superior blood glucose lowering and appetite suppressing effects in animal experiments, which are therefore expected to translate into superior clinical efficacy when used in therapy, resulting in greater clinical benefit for patients.

[0175] term In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art.

[0176] In the present invention, the halogen is F, Cl, Br or I. In the present invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5 or 6 carbon atoms, the term "C3-C8" refers to having 3, 4, 5, 6, 7 or 8 carbon atoms, the term "C1-C3" refers to having 1, 2 or 3 carbon atoms, and so on. "5- to 6-membered" refers to having 5 or 6 ring atoms, and "4- to 8-membered" refers to having 4, 5, 6, 7 or 8 ring atoms, and so on. The same applies below.

[0177] In the present invention, the term "alkyl group" refers to a saturated linear or branched hydrocarbon moiety, for example, the term "C1-C6 alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, and n-hexyl groups.

[0178] In the present invention, the term "alkoxy group" refers to an "-O-alkyl" group. For example, the term "C1-C6 alkoxy group" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, etc.

[0179] In the present invention, the term "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon moiety containing at least one double bond. For example, the term "C2-C6 alkenyl group" refers to a straight-chain or branched-chain alkenyl group containing at least one double bond and having 2 to 6 carbon atoms, including, but not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0180] In the present invention, the term "alkynyl group" refers to a straight-chain or branched-chain alkynyl group containing at least one triple bond, for example, the term "C2-C6 alkynyl group" refers to a straight-chain or branched-chain alkynyl group containing at least one triple bond and having 2 to 6 carbon atoms, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl groups.

[0181] In the present invention, the term "cycloalkyl group" refers to a non-aromatic cyclic aliphatic hydrocarbon group having a specific number of ring carbon atoms. For example, the term "C3-C8 cycloalkyl group" refers to a cyclic aliphatic hydrocarbon group consisting of 3 to 8 ring carbon atoms, and the same applies hereinafter. It should be understood that the "cycloalkyl group" described in the present invention includes not only monocyclic aliphatic hydrocarbon groups, but also fused ring systems, spiro ring systems, and bridged ring systems consisting of multiple cyclic aliphatic hydrocarbons. The "cycloalkyl group" described in the present invention includes not only aliphatic hydrocarbon groups having completely saturated carbon atoms, but also aliphatic hydrocarbon groups having a portion of carbon atoms with unsaturated bonds, but does not include an aromatic ring consisting of multiple unsaturated carbon atoms. Examples of the "cycloalkyl group" described in the present invention include:

[0182] [ka] It should be understood that when a "cycloalkyl group" is used as a substituent or a linker, the connecting site with the molecular body can be located at any position on the "cycloalkyl group" as long as a chemical bond is permitted.

[0183] In the present invention, the term "aryl group" refers to a monocyclic or polycyclic ring system that is made up of a specific number of carbon atoms and conforms to the Huckel rule. It should be understood that when the "aryl group" described in the present invention is a polycyclic ring system, it includes not only cases in which all rings are aromatic rings, but also cases in which only one ring is aromatic and the other rings are non-aromatic aliphatic rings. For example, a "C6-C10 aryl group" refers to an aryl group having 6 to 10 carbon atoms and at least The term "aryl group" refers to a ring system in which one ring is an aromatic ring, and the same applies below. Examples of the "aryl group" described in the present invention include:

[0184] [ka] and the like, and it should be understood that when an "aryl group" is used as a substituent or linker, the attachment site of the molecular entity is on the aromatic ring.

[0185] In the present invention, the term "heterocyclic group" refers to a non-aromatic cyclic group having a specific number of ring atoms, containing 1 to 4 ring heteroatoms (e.g., N, O, or S), which is saturated or partially unsaturated. The "heterocyclic group" described in the present invention includes not only monocyclic heterocyclic systems but also polycyclic heterocyclic systems such as fused ring systems, spirocyclic systems, and bridged ring systems. When the "heterocyclic group" is a polycyclic system, at least one ring contains a ring heteroatom, and the other rings may be heterocyclic or aliphatic. For example, the term "4- to 8-membered heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic system containing 4 to 8 ring atoms, at least one ring atom of which is a heteroatom, and the same applies hereinafter. Examples of the "heterocyclic group" described in the present invention include:

[0186] [ka] It should be understood that when a "heterocyclic group" is used as a substituent or a linker, the attachment site of the molecular entity may be at any position on the "heterocyclic group" where chemical bonding is permitted.

[0187] In the present invention, the term "heteroaryl group" refers to a cyclic group having a specific number of ring atoms, containing 1 to 4 ring heteroatoms (e.g., N, O, or S), and having aromaticity. It should be understood that the "heteroaryl group" described in the present invention includes not only monocyclic heteroaromatic systems but also polycyclic heteroaromatic systems. When the "heteroaryl group" is a polycyclic heteroaromatic system, at least one ring is aromatic and the other rings may be aromatic or non-aromatic, and the heteroatom may be present in the aromatic ring or in the non-aromatic ring. For example, the term "5- to 12-membered heteroaryl group" refers to a monocyclic or polycyclic system having 5 to 12 ring atoms, at least one of which is a heteroatom, and at least one ring is aromatic. Examples of the "heteroaryl group" described in the present invention include:

[0188] [ka] It should be understood that when a "heteroaryl group" is used as a substituent or linker, the attachment site of the molecular entity is on the aromatic ring.

[0189] The term "independently" as used herein means that when several simultaneously defined substituents are selected from the same candidate group, they do not affect each other and may be the same or different.

[0190] The term "substituted" as used herein refers to substitution with one or more groups. When no specific atom is specified as being substituted, it means that any atom may be substituted if the number of substituents does not reach saturation.

[0191] The term "pharmaceutically acceptable salt" as used herein refers to a salt formed between a positively charged group of a compound represented by formula (I) or (II) and an anion, or a salt formed between a negatively charged group of a compound represented by formula (I) or (II) and a cation. Suitable anions include, but are not limited to, chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate, or maleate. Suitable cations include, but are not limited to, sodium, potassium, magnesium, calcium, ammonium, or the like.

[0192] In another preferred embodiment, the pharmaceutically acceptable salt according to the present invention is a salt of a compound represented by general formula (I) or (II) with hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoromethanesulfonic acid, or a salt formed by a compound represented by general formula (I) or (II) with an acid selected from the group consisting of acetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, etc.; or a sodium salt, potassium salt, calcium salt, aluminum salt, or ammonium salt formed by a compound represented by general formula (I) or (II) with an inorganic base; or a methylamine salt, ethylamine salt, or ethanolamine salt formed by a compound represented by general formula (I) or (II) with an organic base.

[0193] In another preferred example, the pharmaceutically acceptable salt is a sodium salt. In another preferred embodiment, the pharmaceutically acceptable salt is an ammonium salt.

[0194] In another preferred embodiment, the pharmaceutically acceptable salt is preferably 1,3-dihydroxy-2-(hydroxymethyl)propyl-2-amine (tris(hydroxymethyl)amine). It is a salt of methyltrimethamine (also known as tromethamine, thromycin, etc., and abbreviated as Tris).

[0195] The compound of the present invention represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof may be distilled, precipitated, crystallized, or recrystallized from water or an organic solvent, and the compound may contain molecules of the solvent used. Furthermore, different crystallization conditions may result in different crystalline forms of the compound. Therefore, all crystalline forms of the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, which have different stoichiometries of the crystallization solvent, are included within the scope of the present invention.

[0196] Some compounds represented by general formula (I) or (II) of the present invention have chiral centers, potential chiral centers, or unsaturated bonds, and can form various stereoisomers, such as racemates, enantiomers, diastereomers, E / Z isomers, cis-trans isomers, and tautomers. Unless otherwise specified, in this specification and the appended claims, a given chemical formula or name is intended to include all forms of stereoisomers, as well as mixtures of individual isomers in different proportions, and pharmaceutically acceptable salts thereof. Those skilled in the art can separate compounds having asymmetric centers in the present invention to obtain single isomers using separation methods commonly used in laboratories, but this does not detract from the novelty of the compounds of the present invention.

[0197] Replacing hydrogen atoms with deuterium atoms to alter the physicochemical properties of a compound is a structural modification method well known to those skilled in the art. Unless otherwise specified, the present invention also contemplates that deuterated forms of the compounds represented by general formula (I) or (II) are included within the scope of the present invention.

[0198] "Diabetic complications" are complications caused by diabetes or hyperglycemia, and may be acute or chronic. The term "acute complications" includes ketoacidosis and infectious diseases (e.g., skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), and "chronic complications" includes, for example, microangiopathy (e.g., nephropathy, retinopathy), neuropathy (e.g., sensory neuropathy, motor neuropathy, autonomic neuropathy), and gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.

[0199] "Coronary artery disease" includes silent myocardial ischemia (occult coronary artery disease), myocardial infarction, angina pectoris, ischemic heart failure (ischemic cardiomyopathy), and sudden death. "Dementia" includes, for example, Alzheimer's disease, early-onset dementia (EOD), vascular dementia, and diabetic dementia.

[0200] The compounds of the present invention can be administered alone or in combination with other drugs known to treat or ameliorate similar conditions. The compounds of the present invention can be used in combination with one or more other drugs for the treatment, prevention, or amelioration of diseases for which the compounds of the present invention or other drugs may be effective, and the combination of these drugs is safer or more effective than any drug used alone. The other drugs can be administered simultaneously with, before, or after the compounds of the present invention, using commonly used administration routes and dosages. When the compounds described in the present invention are used in combination with one or more other drugs, a pharmaceutical composition containing the other drugs and the compounds of the present invention in a unit dosage is preferred. However, the drug combination can also include the compounds described herein and one or more other drug therapies in different overlapping schemes. When used in combination with one or more other active ingredients, the compounds of the present invention and the other drugs can be used in lower doses than when used alone.

[0201] Drugs or active ingredients that can be used in combination with the compounds described in the present invention include glucagon-like peptide-1 (GLP-1) analogs (e.g., semaglutide), glucagon (GCG) analogs, peptide YY (PYY) analogs, oxyntomodulin (OXM) analogs, pancreatic polypeptide (PP) analogs, cholecystokinin (CCK) analogs, leptin analogs, amylin analogs, fibroblast growth factor 21 (FGF21) analogs, neuropeptide Y receptor type 2 (Y-2R) agonists, melanocortin receptor 4 (MC4R) agonists, glucose-dependent insulin polypeptide (GIP) receptor agonists, lipase inhibitors (e.g., orlistat), AMP receptor agonists, and the like. These include, but are not limited to, obesity treatment drugs such as K agonists, neuropeptide Y5 receptor antagonists, GPR40 agonists, cannabinoid type 1 receptor blockers, naltrexone / bupropion, lorcaserin, phentermine / topiramate obesity vaccines, or GLP-1 receptor-based dual or multiple receptor modulators, such as GLP-1 / GIP dual receptor agonists (e.g., tirzepatide), GLP-1 receptor agonist / GIP receptor antagonist conjugates, GLP-1 / GCG dual receptor agonists, GLP-1 / GIP / GCG triple receptor agonists, and GLP-1 / FGF21 fusion proteins.

[0202] Drugs or active ingredients that can be used in combination with the compounds described in the present invention include, but are not limited to, drugs for treating diabetes such as biguanides, thiazolidinediones, glinides, sulfonylureas, DPP4 inhibitors, SGLT1 and / or SGLT2 inhibitors, GPR40 agonists, α-glucosidase inhibitors, glucokinase agonists, insulin, insulin analogs, GLP-1 analogs, or GLP-1 receptor-based dual or multiple receptor modulators, such as GLP-1 / GIP dual receptor agonists (e.g., tirzepatide), GLP-1 receptor agonist / GIP receptor antagonist conjugates, GLP-1 / GCG dual receptor agonists, GLP-1 / GIP / GCG triple receptor agonists, and GLP-1 / FGF21 fusion proteins.

[0203] Drugs or active ingredients that can be used in combination with the compounds described in the present invention include, but are not limited to, drugs for treating NASH such as FXR receptor agonists, PPARα / δ agonists, fibroblast growth factor 19 / 21 analogs, thyroid hormone receptor β agonists, SGLT1 and / or SGLT2 inhibitors, acetyl-CoA carboxylase inhibitors, chemokine receptor-2 / 5 inhibitors, anti-apoptotic signal-regulating kinase 1 inhibitors, ATP-binding transporter 1 agonists, 5-lipoxygenase inhibitors, or vascular adhesion protein 1 inhibitors.

[0204] When a pharmaceutical composition is used, a safe and prevalent amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, and the dosage at the time of administration is the considered effective dose, and for a person weighing 60 kg, the daily dose is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0205] The present invention will be further described below with reference to examples. Note that these examples are intended to illustrate the present invention and are not intended to limit the present invention in any way. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those familiar to those skilled in the art. Furthermore, methods and materials similar or equivalent to those described herein can be applied to the present invention. The preferred implementation methods and materials described herein are for illustrative purposes only.

[0206] Preparation Examples Unless otherwise specified, the packing material used for column chromatographic separation is silica gel. In the following examples, experimental methods for which specific conditions are not specified are generally performed according to conventional conditions (e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual (Ne The reaction is carried out according to the conditions described in (New York: Cold Spring Harbor Laboratory Press, 1989) or the conditions recommended by the manufacturer. All parameters in the examples and the remaining description are by weight unless otherwise specified. Percentages and parts are by weight unless otherwise specified.

[0207] Example 1: Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 1)

[0208] [ka]

[0209] (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 1) is prepared according to the route shown in Scheme A above.

[0210] Step a: 5-Bromo-1,3-difluoro-2-nitrobenzene (5 g, 21.1 mmol), zinc cyanide (4.96 g, 42.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene (468 mg, 0.84 mmol), and tris(dibenzylideneacetone)palladium (386 mg, 0.42 mmol) were dissolved in 30 mL of N,N-dimethylformamide and reacted at 110 °C for 12 hours under nitrogen gas protection. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was separated by column chromatography to obtain 3.57 g of 3,5-difluoro-4-nitrobenzonitrile.

[0211] Step b: 3,5-Difluoro-4-nitrobenzonitrile (3.57 g, 19.4 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by the addition of potassium carbonate (5.35 g, 38.8 mmol) and water (698 mg, 38.8 mmol), and the reaction was carried out at 80°C for 4 hours. After the reaction was completed, the mixture was adjusted to pH 4-5 with 2 M hydrochloric acid solution, extracted three times with ethyl acetate, and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was separated by column chromatography to give 2.8 2 g of 3-fluoro-5-hydroxy-4-nitrobenzonitrile are obtained.

[0212] Step c: 3-Fluoro-5-hydroxy-4-nitrobenzonitrile (2.82 g, 15.5 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by the addition of potassium carbonate (4.28 g, 31.0 mmol). After stirring at room temperature for 15 minutes, iodomethane (2.87 g, 20.2 mmol) was added and the mixture was reacted at 50° C. for 3 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was separated by column chromatography to obtain 2.98 g of 3-fluoro-5-methoxy-4-nitrobenzonitrile.

[0213] Step d: 30 mL of methanol is placed in a round-bottom flask, and under nitrogen gas protection, 10 mL of thionyl chloride is added dropwise in an ice-salt bath. 3-Fluoro-5-methoxy-4-nitrobenzonitrile (2.98 g, 15.2 mmol) is added, and the reaction mixture is brought to room temperature and stirred overnight, then brought to 80 °C and reacted for 2 hours. After the reaction is completed, the mixture is concentrated under reduced pressure, and the crude product is separated by column chromatography to obtain 3.4 g of 3-fluoro-5-methoxy-4-nitrobenzoic acid methyl ester. LCMS (ESI): m / z = 229.0 (M + H). + .

[0214] Step e: 3-Fluoro-5-methoxy-4-nitrobenzoic acid methyl ester (3.4 g, 14.8 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by the addition of potassium carbonate (4.08 g, 29.6 mmol) and (S)-oxetane-2-methylamine (1.3 g, 15.5 mmol), and the mixture was allowed to react at 80 °C for 2 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was separated by column chromatography to obtain 3.9 g of (S)-3-methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester. LCMS (ESI): m / z = 296.1 (M+H). + .

[0215] Step f: (S)-3-Methoxy-4-nitro-5-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (1 g, 3.4 mmol) was dissolved in a mixed solvent of 10 mL of methanol and 10 mL of ethyl acetate, 100 mg of 10% palladium carbon (m / m, water content 55%) was added, hydrogen gas was replaced, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 860 mg of (S)-4-amino-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester. LCMS (ESI): m / z = 266.1 (M+H). + .

[0216] Step g: (S)-4-amino-3-methoxy-5-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (860 mg, 3.2 mmol) was dissolved in 15 mL of acetonitrile, and 2-chloro-1,1,1-trimethoxyethane (986 mg, 6.4 mmol) and p-toluenesulfonic acid (110 mg, 0.64 mmol) were added, and the mixture was reacted at 60 ° C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 830 mg of (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 1). LCMS (ESI): m / z = 324.1 (M + H). + .

[0217] 3-Fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 2) is prepared according to the route shown in Scheme B above.

[0218] Step h: 3-Fluoro-4-(hydroxymethyl)benzonitrile (1 g, 6.6 mm (6-bromopyridin-2-yl)oxymethyl)-3-fluorobenzonitrile. LCMS (ESI): m / z = 306.0 (M+H). + .

[0219] Step i: 4-(((6-bromopyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (1.7 g, 5.6 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.1 g, 6.7 mmol), cesium carbonate (3.7 g, 11.2 mmol), and 1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride (205 mg, 0.28 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water, and the mixture was reacted at 100° C. for 3 hours under nitrogen gas protection. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was separated by column chromatography to obtain 1.8 g of 6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester. LCMS (ESI): m / z=409.2 (M+H). + .

[0220] Step j: 6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid t-butyl ester (1.8 g, 4.4 mmol) is dissolved in 20 mL of ethyl acetate, 180 mg of 10% palladium on carbon (water content 55%) is added, hydrogen gas is purged, and the mixture is stirred at room temperature for 3 hours. After the reaction is completed, the mixture is filtered, the filtrate is concentrated under reduced pressure, the resulting oil is dissolved in 20 mL of dichloromethane, 4 mL of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 4 hours. After the reaction is completed, the mixture is concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution is added, and the mixture is extracted three times with dichloromethane. The organic phase is collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated to dryness to obtain 960 mg of 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 2). LCMS(ESI): m / z=311.1(M+H) + .

[0221] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 1) is prepared according to the route shown in Scheme B above.

[0222] Step k: (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (intermediate 1, 50 mg, 0.15 mmol), 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (intermediate 2, 56 mg, 0.18 mmol), potassium carbonate (41 mg, 0.3 mmol) and a catalytic amount of potassium iodide are dissolved in 5 mL of acetonitrile and reacted at 80° C. for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by preparative thin layer chromatography to obtain 72 mg of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester. LCMS (ESI): m / z = 599.3 (M+H). + .

[0223] Step 1: (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (72 mg, 0.12 mmol) is dissolved in 3 mL of 1,4-dioxane, 2 M NaOH (300 μL, 0.6 mmol) is added, and the reaction is carried out at 40° C. overnight. After the reaction was completed, the pH was adjusted to 5-6 with 2M hydrochloric acid, and the mixture was separated using a preparative liquid to obtain 56 mg of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 1). LCMS (ESI): m / z = 585.2 (M+H). + . 1 H NMR (500 MHz, DMSO) δ 7.92-7.86(m,2H),7.73-7.68(m,2H),7.65(t,J=7.7Hz,1H),7.26(s,1H),6.89(d,J=7.3Hz,1H),6.72(d,J= 8.1Hz,1H),5.47(s,2H),5.14-5.05(m,1H),4.80-4.72(m,1H),4.68-4.60(m,1H),4.51-4.43(m,1H),4.40-4 .32(m,1H),3.96(s,3H),3.91(d,J=13.4Hz,1H),3.76(d,J=13.5Hz,1H),2.97(d,J=11.3Hz,1H),2.83(d,J= 11.3Hz, 1H), 2.73-2.65 (m, 1H), 2.64-2.53 (m, 1H), 2.46-2.39 (m, 1H), 2.25-2.11 (m, 2H), 1.80-1.59 (m, 4H).

[0224] Example 2: Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 2)

[0225] [ka]

[0226] (S)-2-(chloromethyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 3) was prepared according to the route shown in Scheme A above, and the specific synthesis method is described in reference to Intermediate 1. LCMS (ESI): m / z = 338.1 (M+H). + .

[0227] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 2) was prepared according to the route shown in formula B above. The specific synthesis method was the same as in Example 1, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z=599.3 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.92-7.87(m,2H),7.73-7.68(m,2H),7.65(t,J=7.8Hz,1H), 7.25(d,J=1.2Hz,1H),6.89(d,J=7.3Hz,1H),6.73(d,J=8.2Hz,1H),5.47(s,2H),5.14-5.06(m,1H),4. 81-4.73(m,1H),4.68-4.61(m,1H),4.51-4.44(m,1H),4.42-4.32(m,1H),4.25(q,J=6.9Hz,2H),3.91(d ,J=13.4Hz,1H),3.77(d,J=13.4Hz,1H),2.96(d,J=11.1Hz,1H),2.83(d,J=11.3Hz,1H),2.75-2.64(m, 1H),2.63-2.53(m,1H),2.48-2.37(m,1H),2.25-2.11(m,2H),1.84-1.56(m,4H),1.43(t,J=7.0Hz,3H).

[0228] Example 3 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-4-propoxy-1H-benzo[d]imidazole-6-carboxylic acid (Compound 3)

[0229] [ka]

[0230] (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-4-propoxy-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 4) was prepared according to the route shown in Scheme A above, and the specific synthesis method is described in reference to Intermediate 1. LCMS (ESI): m / z = 352.1 (M+H). + .

[0231] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-4-propoxy-1H-benzo[d]imidazole-6-carboxylic acid (compound 3) was prepared according to the route shown in formula B above. The specific synthesis method was the same as in Example 1, except that intermediate 1 was replaced with intermediate 4. LCMS (ESI): m / z=613.3 (M+H). + . 1H NMR(500MHz,DMSO)δ 7.93-7.88(m,2H),7.77-7.60(m,3H),7.27-7.21(m,1H),6.90(d,J=7.5Hz,1H),6.74(d,J=7.9Hz,1H),5.48(s,2H), 5.10-5.07(m,1H),4.82-4.74(m,1H),4.69-4.62(m,1H),4.52-4.44(m,1H),4.38-4.34(m,1H),4.16(t,J=6.7Hz,2H) ,3.91(d,J=13.4Hz,1H),3.77(d,J=13.4Hz,1H),2.96(d,J=11.1Hz,1H),2.82(d,J=11.2Hz,1H),2.74-2.65(m,1H),2 .66-2.57(m,1H),2.47-2.36(m,1H),2.30-2.06(m,2H),1.87-1.79(m,2H),1.78-1.57(m,4H),1.04(t,J=7.4Hz,3H).

[0232] Example 4 Preparation of (S)-2-((4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 4)

[0233] [ka]

[0234] 3-Methoxy-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile (Intermediate 5) was prepared according to the route shown in formula B, and the specific synthesis method was the same as that of Intermediate 2. LCMS (ESI): m / z = 323.2 (M+H) + .

[0235] (S)-2-((4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 4) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 2 was replaced with intermediate 5. LCMS (ESI): m / z=597.3 (M+H) + . 1 H NMR(500MHz,DMSO)δ 7.91(d,J=1.3Hz,1H),7.64(dd,J=8.2,7.3Hz,1H),7.57-7.51(m,2H),7.42(dd,J=7.6,1.5Hz,1H),7.26(d,J=1.3Hz,1H),6.87( d,J=7.3Hz,1H),6.72(d,J=8.2Hz,1H),5.38(s,2H),5.13-5.04(m,1H),4.75(dd,J=15.2,7.1Hz,1H),4.63(dd,J=15.2,2.9Hz,1H ),4.50-4.42(m,1H),4.39-4.31(m,1H),3.96(s,3H),3.89(s,3H),3.91(d,J=13.1Hz,1H),3.75(d,J=13.0Hz,1H),2.97(d,J=11. 0Hz,1H),2.84(d,J=11.0Hz,1H),2.74-2.63(m,1H),2.62-2.54(m,1H),2.46-2.38(m,1H),2.28-2.08(m,2H),1.82-1.59(m,4H).

[0236] Example 5 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-(cyclopropylmethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 5)

[0237] [ka]

[0238] (S)-2-(chloromethyl)-4-(cyclopropylmethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 6) was prepared according to the route shown in Formula A, and the specific synthesis method was the same as that of Intermediate 1. LCMS (ESI): m / z = 364.1 (M+H). + .

[0239] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-(cyclopropylmethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 5) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 1 was replaced with intermediate 6. LCMS (ESI): m / z=625.3 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.89(d,J=9.8Hz,1H),7.73-7.67(m,3H),7.65(t,J=7.8Hz,1H),7.26(s,1H),6.89(d,J=7.3Hz,1H),6.72(d,J=8.1Hz,1H),5. 47(s,2H),5.13-5.06(m,1H),4.73-4.66(m,1H),4.62-4.56(m,1H),4.50-4.44(m,1H),4.39-4.32(m,1H),3.99(d,J=7.0Hz,2 H),3.88(d,J=13.3Hz,1H),3.76(d,J=13.3Hz,1H),2.96(d,J=11.1Hz,1H),2.85(d,J=11.2Hz,1H),2.72-2.63(m,1H),2.61-2 .55(m,1H),2.47-2.40(m,1H),2.23-2.11(m,2H),1.81-1.60(m,4H),0.88-0.83(m,1H),0.64-0.57(m,2H),0.40-0.35(m,2H).

[0240] Example 6 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-(furan-2-ylmethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 6)

[0241] [ka]

[0242] (S)-2-(Chloromethyl)-4-(furan-2-ylmethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 7) was prepared according to the route shown in Formula A, and the specific synthesis method was the same as that of Intermediate 1. LCMS (ESI): m / z = 390.1 (M+H). + .

[0243] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-(furan-2-ylmethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 6) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 1 was replaced with intermediate 7. LCMS (ESI): m / z=651.3 (M+H). + .

[0244] Example 7 Preparation of (S)-4-(benzyloxy)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 7)

[0245] [ka]

[0246] (S)-4-(benzyloxy)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 8) was prepared according to the route shown in Scheme A, and the specific synthesis method is referred to Intermediate 1. LCMS (ESI): m / z = 400.1 (M+H). + .

[0247] (S)-4-(benzyloxy)-2-((4-(6-((4-cyano-2-fluoro Benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 7) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 1 was replaced with intermediate 8. LCMS (ESI): m / z = 661.3 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.89(d,J=9.9Hz,1H),7.80(s,1H),7.72-7.67(m,2H),7.64(t,J=7.7Hz,1H),7.54-7.50(m,2H),7.44-7.37(m,3H),7.37-7 .32(m,1H),6.89(d,J=7.3Hz,1H),6.72(d,J=8.2Hz,1H),5.47(s,2H),5.31(s,2H),5.13-5.06(m,1H),4.76-4.68(m,1H),4 .65-4.58(m,1H),4.51-4.44(m,1H),4.40-4.33(m,1H),3.89(d,J=13.4Hz,1H),3.75(d,J=13.3Hz,1H),2.95(d,J=11.1Hz, 1H),2.84(d,J=11.2Hz,1H),2.75-2.64(m,1H),2.62-2.54(m,1H),2.47-2.38(m,1H),2.23-2.11(m,2H),1.80-1.59(m,4H).

[0248] Example 8 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 8)

[0249] [ka]

[0250] 4-(6-chloropyridin-2-yl)-5,6-dihydro-1,2,4-triazine-1(4H)-carbaldehyde (Intermediate 9) was prepared according to the route shown in Scheme C: Step a: 2-Boc-amino-6-chloropyridine (2 g, 8.7 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and cesium carbonate (5.7 g, 17.4 mmol) and 3-bromopropene (2.1 g, 17.4 mmol) were added. The mixture was reacted at 70 ° C for 4 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to obtain 2.2 g of t-butyl allyl (6-chloropyridin-2-yl) carbamate. LCMS (ESI): m / z = 268.1 (M+H). + .

[0251] Step b: t-Butyl allyl (6-chloropyridin-2-yl)carbamate (2.2 g, 8.2 mmol) was dissolved in a mixture of 20 mL of tetrahydrofuran and 20 mL of water, and potassium osmate(VI) dihydrate (26 mg, 0.08 mmol) and periodate (100 mL). Sodium thiophosphate (5.3 g, 24.6 mmol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, 100 mL of saturated aqueous sodium thiosulfate was added, and the mixture was stirred for 10 minutes. The mixture was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 1.8 g of t-butyl (6-chloropyridin-2-yl) (2-oxoethyl) carbamate. LCMS (ESI): m / z = 270.1 (M+H). + .

[0252] Step c: t-Butyl (6-chloropyridin-2-yl)(2-oxoethyl)carbamate (1.8 g, 6.7 mmol) was dissolved in 30 mL of ultra-dry 1,2-dichloroethane, t-butyl carbazate (1.3 g, 10 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After that, sodium triacetoxyborohydride (4.3 g, 20.1 mmol) and sodium cyanoborohydride (1.3 g, 20.1 mmol) were added, and the mixture was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted three times with dichloromethane, and the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to give 1.9 g of 2-(2-((t-butoxycarbonyl)(6-chloropyridin-2-yl)amino)ethyl)hydrazine-1-carboxylic acid t-butyl ester. LCMS(ESI): m / z=386.2(M+H) + .

[0253] Step d: Dissolve 2-(2-((t-butoxycarbonyl)(6-chloropyridin-2-yl)amino)ethyl)hydrazine-1-carboxylic acid t-butyl ester (1.9 g, 4.9 mmol) in 20 mL of dichloromethane, add 4 M hydrogen chloride in 1,4-dioxane (6.1 mL, 24.5 mmol) dropwise, and stir at room temperature for 4 hours. After completion of the reaction, concentrate the reaction solution under reduced pressure to give 911 mg of 6-chloro-N-(2-hydrazineethyl)pyridin-2-amine hydrochloride. LCMS (ESI): m / z = 186.1 (M+H). + .

[0254] Step e: 6-chloro-N-(2-hydrazineethyl)pyridin-2-amine hydrochloride (911 mg, 4.9 mmol) was dissolved in 15 mL of acetic acid, 3 mL of trimethyl orthoformate was added, and the mixture was reacted at 100° C. for 3 hours under nitrogen gas protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 880 mg of 4-(6-chloropyridin-2-yl)-5,6-dihydro-1,2,4-triazine-1(4H)-carbaldehyde (Intermediate 9). LCMS (ESI): m / z=224.1 (M+H). + .

[0255] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 8) was prepared according to the route shown in formula C: Step f: 4-(6-chloropyridin-2-yl)-5,6-dihydro-1,2,4-triazine-1(4H)-carbaldehyde (100 mg, 0.45 mmol), 3-fluoro-4-(hydroxymethyl)benzonitrile (88 mg, 0.58 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (47 mg, 0.1 mmol), cesium carbonate (293 mg, 0.9 mmol) and 8 mL of toluene were added to a pressure tube and reacted at 120°C for 3 hours under nitrogen gas protection. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 140 mg of 3-fluoro-4-((6-(1-formyl-5,6-dihydro-1,2,4-triazin-4(1H)-yl)pyridin-2-yl)oxy)methyl)benzonitrile. LCMS (ESI): m / z=339.1 (M+H). + .

[0256] Step g: 3-fluoro-4-((6-(1-formyl-5,6-dihydro-1,2,4-triazin-4(1H)-yl)pyridin-2-yl)oxy)methyl)benzonitrile (140 mg, 0.41 mmol) was dissolved in a mixture of 4 mL of dichloromethane and 4 mL of methanol, and 4 M hydrochloric acid (410 μL, 1.64 mmol) was added dropwise in an ice bath. The mixture was then cooled to room temperature and stirred overnight. After the reaction was completed, the pH was adjusted to neutral with 2 M NaOH, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 115 mg of 4-((6-(5,6-dihydro-1,2,4-triazin-4(1H)-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (Intermediate 10). LCMS(ESI): m / z=311.1(M+H) + .

[0257] Step h: (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 1, 50 mg, 0.15 mmol), 4-((6-(5,6-dihydro-1,2,4-triazin-4(1H)-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (Intermediate 10, 47 mg, 0.15 mmol), potassium carbonate (41 mg, 0.3 mmol) and a catalytic amount of potassium iodide are dissolved in 5 mL of acetonitrile and reacted at 80° C. for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by preparative thin layer chromatography to obtain 68 mg of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazine-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester. LCMS (ESI): m / z=599.2 (M+H) + .

[0258] Step i: (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (68 mg, 0.11 mmol) is dissolved in 3 mL of 1,4-dioxane, 2 M NaOH (300 μL, 0.6 mmol) is added, and the reaction is carried out at 40° C. overnight. After the reaction was completed, the pH was adjusted to 5-6 with 2M hydrochloric acid, and the mixture was separated using a preparative liquid to obtain 50 mg of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 8). LCMS (ESI): m / z = 585.2 (M+H). + . 1 H NMR (500 MHz, DMSO) δ 7.94-7.88(m,2H),7.74-7.62(m,4H),7.33(d,J=1.0Hz,1H),6.54(d,J=8.1Hz ,1H),6.45(d,J=8.0Hz,1H),5.46(s,2H),5.09-5.00(m,1H),4.71-4.63(m,1H ),4.60-4.53(m,1H),4.51-4.39(m,2H),4.36-4.28(m,2H),3.90(s,3H),3.73 (t,J=5.3Hz,2H),3.05(t,J=5.3Hz,2H),2.71-2.61(m,1H),2.44-2.36(m,1H).

[0259] Example 9 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 9)

[0260] [ka]

[0261] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 9) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z=599.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.89-7.84(m,2H),7.71-7.60(m,4H),7.31(s,1H),6.51(d,J=8.0Hz,1H),6.42(d,J =8.0Hz,1H),5.44(s,2H),5.06-4.98(m,1H),4.69-4.61(m,1H),4.58-4.51(m,1H), 4.48-4.37(m,2H),4.34-4.25(m,2H),4.19(q,J=7.0Hz,2H),3.71(t,J=5.2Hz,2H), 3.02(t,J=5.2Hz,2H),2.68-2.58(m,1H),2.41-2.31(m,1H),1.39(t,J=7.0Hz,3H).

[0262] Example 10 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(oxetan-2-ylmethyl)-4-propoxy-1H-benzo[d]imidazole-6-carboxylic acid (Compound 10)

[0263] [ka]

[0264] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(oxetan-2-ylmethyl)-4-propoxy-1H-benzo[d]imidazole-6-carboxylic acid (compound 10) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 4. LCMS (ESI): m / z=613.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.86(d,J=9.6Hz,2H),7.71-7.59(m,4H),7.33(d,J=1.1Hz,1H),6.51(d,J=8.0Hz,1H),6.42(d,J=8.0Hz,1H),5.43(s,2H),5.06-4.98(m,1 H),4.70-4.62(m,1H),4.59-4.51(m,1H),4.50-4.37(m,2H),4.34-4.26(m,2H),4.10(t,J=6.7Hz,2H),3.71(t,J=5.2Hz,2H),3.02(t,J=5.2 Hz,2H),2.68-2.58(m,1H),2.41-2.31(m,1H),1.84-1.72(m,2H),1.01(t,J=7.4Hz,3H).

[0265] Example 11 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(difluoromethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 11)

[0266] [ka]

[0267] (S)-2-(chloromethyl)-4-(difluoromethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 11) was prepared according to the route shown in Scheme A, and the specific synthesis method was the same as that of Intermediate 1. LCMS (ESI): m / z = 360.1 (M+H). + .

[0268] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(difluoromethoxy)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 11) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 11. LCMS (ESI): m / z=621.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.99(d,J=1.2Hz,1H),7.93-7.87(m,2H),7.74-7.66(m,3H),7.66-7.42(m,2H) ,6.55(d,J=8.0Hz,1H),6.45(d,J=8.0Hz,1H),5.46(s,2H),5.10-5.01(m,1H),4 .83-4.73(m,1H),4.69-4.61(m,1H),4.52-4.44(m,2H),4.39-4.31(m,2H),3.7 5(t,J=5.1Hz,2H),3.10(t,J=5.5Hz,2H),2.75-2.63(m,1H),2.45-2.36(m,1H).

[0269] Example 12 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 12)

[0270] [ka]

[0271] (S)-2-(chloromethyl)-4-(methoxy-d3)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 12) was prepared according to the route shown in Scheme A, and the specific synthesis method was the same as that of Intermediate 1. LCMS (ESI): m / z = 327.1 (M+H). + .

[0272] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 12) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 12. LCMS (ESI): m / z=588.2 (M+H). + . 1 H NMR (600 MHz, DMSO) δ 7.92-7.87(m,2H),7.74(s,1H),7.73-7.63(m,3H),7.32(s,1H),6.54(d,J= 8.0Hz,1H),6.45(d,J=8.0Hz,1H),5.46(s,2H),5.08-5.01(m,1H),4.74-4. 68(m,1H),4.63-4.57(m,1H),4.50-4.40(m,2H),4.39-4.25(m,2H),3.73(t ,J=5.2Hz,2H),3.06(t,J=5.2Hz,2H),2.70-2.61(m,1H),2.42-2.33(m,1H).

[0273] Example 13 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-cyclopropoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 13)

[0274] [ka]

[0275] (S)-2-(chloromethyl)-4-cyclopropoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (intermediate 13) was prepared according to the route shown in Scheme A: Step a: Cyclopropanol (377 mg, 6.5 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by the addition of potassium hydroxide (5.35 g, 38.8 mmol) and 3,5-difluoro-4-nitrobenzonitrile (1 g, 5.4 mmol), and the mixture was allowed to react overnight at 80° C. After the reaction was completed, the pH was adjusted to 7 with 2 M hydrochloric acid, extracted three times with ethyl acetate, and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 720 mg of 3-cyclopropoxy-5-fluoro-4-nitrobenzonitrile.

[0276] Subsequent reaction steps refer to the preparation of Intermediate 1 to give (S)-2-(chloromethyl)-4-cyclopropoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 13). LCMS (ESI): m / z = 350.1 (M+H). + .

[0277] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-cyclopropoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 13) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 13. LCMS (ESI): m / z=611.2 (M+H). + . 1H NMR(500MHz,DMSO)δ 7.91(d,J=9.7Hz,2H),7.74-7.64(m,4H),7.62(d,J=1.1Hz,1H),6.54(d,J=8.0Hz,1H),6. 45(d,J=8.0Hz,1H),5.46(s,2H),5.08-5.00(m,1H),4.72-4.64(m,1H),4.60-4.53(m,1H) ,4.51-4.38(m,2H),4.36-4.28(m,2H),4.02-3.95(m,1H),3.73(t,J=5.3Hz,2H),3.03(t, J=5.3Hz,2H),2.71-2.61(m,1H),2.44-2.33(m,1H),0.84-0.78(m,2H),0.75-0.70(m,2H).

[0278] Example 14 Preparation of (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(oxetan-2-ylmethyl)-4-(pyridin-3-yloxy)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 14)

[0279] [ka]

[0280] (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-4-(pyridin-3-yloxy)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 14) was prepared according to the route shown in Scheme A, and the specific synthesis method was the same as that of Intermediate 13. LCMS (ESI): m / z = 387.1 (M+H). + .

[0281] (S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(oxetan-2-ylmethyl)-4-(pyridin-3-yloxy)-1H-benzo[d]imidazole-6-carboxylic acid (compound 14) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 14. LCMS (ESI): m / z=648.2 (M+H). + . 1 H NMR(600MHz,DMSO)δ 8.40(s,1H),8.35-8.30(m,1H),8.01(s,1H),7.92-7.87(m,2H),7.73-7.63(m,3H),7.4 0-7.36(m,2H),7.34(s,1H),6.55(d,J=8.0Hz,1H),6.45(d,J=7.9Hz,1H),5.46(s,2H), 5.11-5.04(m,1H),4.83-4.76(m,1H),4.69-4.63(m,1H),4.52-4.42(m,2H),4.40-4.29 (m,2H),3.73(t,J=5.1Hz,2H),3.07-2.98(m,2H),2.75-2.65(m,1H),2.46-2.39(m,1H).

[0282] Example 15 Preparation of (S)-2-((4-(6-((4-cyano-2,3-dihydrobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 15)

[0283] [ka]

[0284] 7-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)-2,3-dihydrobenzofuran-4-carbonitrile (Intermediate 15) was prepared according to the route shown in formula B, and the specific synthesis method was the same as that of Intermediate 2. LCMS (ESI): m / z = 335.2 (M+H) + .

[0285] (S)-2-((4-(6-((4-cyano-2,3-dihydrobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 15) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 2 was replaced with intermediate 15. LCMS (ESI): m / z = 609.3 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.89(s,1H),7.62(t,J=7.8Hz,1H),7.35(d,J=7.9Hz,1H),7.27-7.23(m,2H),6.86(d,J=7.3Hz,1H),6.68(d,J=8.2Hz,1 H),5.31(s,2H),5.12-5.05(m,1H),4.76-4.72(m,1H),4.70(t,J=8.8Hz,2H),4.65-4.59(m,1H),4.50-4.43(m,1H),4.38 -4.32(m,1H),3.96(s,3H),3.91(d,J=13.5Hz,1H),3.75(d,J=13.5Hz,1H),3.38(t,J=8.8Hz,2H),2.99(d,J=11.2Hz,1H) ,2.85(d,J=11.3Hz,1H),2.75-2.65(m,1H),2.62-2.52(m,1H),2.47-2.39(m,1H),2.26-2.13(m,2H),1.80-1.62(m,4H).

[0286] Example 16: Preparation of (S)-2-((4-(6-((4-chloro-2,3-dihydrobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 16)

[0287] [ka]

[0288] 2-((4-chloro-2,3-dihydrobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine (Intermediate 16) was prepared according to the route shown in formula B, and the specific synthesis method was the same as that of Intermediate 2. LCMS (ESI): m / z = 344.1 (M+H) + .

[0289] (S)-2-((4-(6-((4-chloro-2,3-dihydrobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 16) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 2 was replaced with intermediate 16. LCMS (ESI): m / z=618.2 (M+H). + . 1H NMR(600MHz,DMSO)δ 7.95(s,1H),7.66(t,J=7.7Hz,1H),7.32(s,1H),7.29(d,J=8.2Hz,1H),6.93(d,J=8.2Hz,1H),6.91(d,J=7.3Hz,1H),6.69(d ,J=8.2Hz,1H),5.29(s,2H),5.19-5.12(m,1H),4.84-4.77(m,1H),4.72(t,J=8.7Hz,2H),4.72-4.66(m,1H),4.55-4.49(m,1 H),4.45-4.38(m,1H),4.02(s,3H),3.98(d,J=13.5Hz,1H),3.82(d,J=13.4Hz,1H),3.28(t,J=8.7Hz,2H),3.06(d,J=11.2Hz) ,1H),2.92(d,J=11.3Hz,1H),2.81-2.71(m,1H),2.70-2.62(m,1H),2.53-2.44(m,1H),2.32-2.19(m,2H),1.89-1.72(m,4H).

[0290] Example 17 Preparation of (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 17)

[0291] [ka]

[0292] 4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-1,4,5,6-tetrahydro-1,2,4-triazine (Intermediate 17) was prepared according to the route shown in formula C, and the specific synthesis method was the same as that of Intermediate 10. LCMS (ESI): m / z = 320.1 (M+H) + .

[0293] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 17) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 10 was replaced with intermediate 17. LCMS (ESI): m / z=594.2 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.93(s,1H),7.81(s,1H),7.64(t,J=8.0Hz,1H),7.53(t,J=8.1Hz,1H),7.47(dd,J=10.0,2. 1Hz,1H),7.32-7.27(m,2H),6.53(d,J=8.0Hz,1H),6.40(d,J=8.0Hz,1H),5.35(s,2H),5.08 -5.01(m,1H),4.78-4.71(m,1H),4.66-4.60(m,1H),4.50-4.43(m,2H),4.38-4.28(m,2H),3 .94(s,3H),3.76(t,J=5.2Hz,2H),3.13-3.03(m,2H),2.71-2.62(m,1H),2.42-2.33(m,1H).

[0294] Example 18 Preparation of (S)-2-((4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 18)

[0295] [ka]

[0296] 4-((6-(5,6-dihydro-1,2,4-triazin-4(1H)-yl)pyridin-2-yl)oxy)methyl)-3-methoxybenzonitrile (Intermediate 18) was prepared according to the route shown in formula C, and the specific synthesis method was the same as that of Intermediate 10. LCMS (ESI): m / z = 323.1 (M+H) + .

[0297] (S)-2-((4-(6-((4-cyano-2-methoxybenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 18) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 10 was replaced with intermediate 18. LCMS (ESI): m / z=597.2 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.85(s,1H),7.75(s,1H),7.65(t,J=8.0Hz,1H),7.51(s,1H),7.49(d,J=7.7Hz,1H),7.41(dd,J= 7.8,1.5Hz,1H),7.32(s,1H),6.50(d,J=8.0Hz,1H),6.45(d,J=8.0Hz,1H),5.35(s,2H),5.08-5. 00(m,1H),4.76-4.69(m,1H),4.63-4.57(m,1H),4.50-4.40(m,2H),4.36-4.28(m,2H),3.93(s,3 H),3.89(s,3H),3.71(t,J=5.2Hz,2H),3.10-3.00(m,2H),2.70-2.61(m,1H),2.42-2.33(m,1H).

[0298] Example 19 Preparation of (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 19)

[0299] [ka]

[0300] 2-((4-chloro-2-fluorobenzyl)oxy)-6-(piperidin-4-yl)pyridine (Intermediate 19) was prepared according to the route shown in formula B, and the specific synthesis method was the same as that of Intermediate 2. LCMS (ESI): m / z = 320.1 (M+H) + .

[0301] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 19) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 2 was replaced with intermediate 19. LCMS (ESI): m / z = 594.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.73(d,J=1.1Hz,1H),7.63(dd,J=8.2,7.3Hz,1H),7.57(t,J=8.2Hz,1H),7.47(dd,J=10.0,2.1Hz,1H),7.32(d,J=1.1Hz,1H),7 .30(dd,J=8.2,2.1Hz,1H),6.88(d,J=7.3Hz,1H),6.67(d,J=8.2Hz,1H),5.38(s,2H),5.15-5.06(m,1H),4.73-4.65(m,1H),4.65 -4.52(m,1H),4.51-4.43(m,1H),4.40-4.33(m,1H),3.91(s,3H),3.88(d,J=13.3Hz,1H),3.74(d,J=13.3Hz,1H),2.98(d,J=11. 1Hz,1H), 2.86(d,J=11.2Hz,1H),2.72-2.64(m,1H),2.64-2.56(m,1H),2.49-2.39(m,1H),2.25-2.10(m,2H),1.86-1.63(m,4H).

[0302] Example 20 Preparation of (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 20)

[0303] [ka]

[0304] 4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-1,4,5,6-tetrahydro-1,2,4-triazine (Intermediate 20) was prepared according to the route shown in formula C, and the specific synthesis method was the same as that of Intermediate 10. LCMS (ESI): m / z = 332.1 (M+H) + .

[0305] (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 20) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 10 was replaced with intermediate 20. LCMS (ESI): m / z=606.2 (M+H). + . 1H NMR(600MHz,DMSO)δ 7.91(s,1H),7.78(s,1H),7.63(t,J=8.0Hz,1H),7.34(d,J=8.1Hz,1H),7.31(s,1H),7.10(d,J=2.0 Hz,1H),6.99(dd,J=8.1,2.0Hz,1H),6.49(d,J=8.0Hz,1H),6.40(d,J=8.0Hz,1H),5.26(s,2H),5.0 8-5.01(m,1H),4.77-4.71(m,1H),4.65-4.59(m,1H),4.50-4.42(m,2H),4.37-4.28(m,2H),3.94(s ,3H),3.83(s,3H),3.74(t,J=5.2Hz,2H),3.11-3.02(m,2H),2.70-2.62(m,1H),2.42-2.33(m,1H).

[0306] Example 21 Preparation of (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 21)

[0307] [ka]

[0308] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl (4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 21) was prepared according to the route shown in formula C, and the specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 3 and intermediate 10 was replaced with intermediate 17. LCMS (ESI): m / z = 608.2 (M+H). + . 1H NMR(600MHz,DMSO)δ 7.94(s,1H),7.66-7.63(m,2H),7.53(t,J=8.2Hz,1H),7.47(dd,J=9.9,2.1Hz,1H),7.32(s,1H),7.3 0(dd,J=8.2,2.2Hz,1H),6.52(d,J=8.0Hz,1H),6.40(d,J=8.0Hz,1H),5.36(s,2H),5.08-5.01(m,1H) ,4.71-4.65(m,1H),4.60-4.54(m,1H),4.49-4.41(m,2H),4.36-4.28(m,2H),4.21(q,J=7.0Hz,2H),3 .75(t,J=5.3Hz,2H),3.08-3.02(m,2H),2.70-2.61(m,1H),2.43-2.34(m,1H),1.41(t,J=7.0Hz,3H).

[0309] Example 22 Preparation of (S)-2-((4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 22)

[0310] [ka]

[0311] 4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-1,4,5,6-tetrahydro-1,2,4-triazine (Intermediate 21) was prepared according to the route shown in formula C, and the specific synthesis method was the same as that of Intermediate 10. LCMS (ESI): m / z = 354.1 (M+H) + .

[0312] (S)-2-((4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 22) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 10 was replaced with intermediate 21. LCMS (ESI): m / z=628.2 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.92(s,1H),7.76-7.70(m,3H),7.66(t,J=8.0Hz,1H),7.61(d,J=8.0Hz,1H),7.34(s,1H),6.54(d,J=8.0Hz,1H),6.44(d,J=8.0Hz,1 H),5.47(s,2H),5.08-5.01(m,1H),4.73-4.66(m,1H),4.62-4.56(m,1H),4.49-4.41(m,2H),4.36-4.28(m,2H),3.92(s,3H),3.74(t, J=5.3Hz,2H),3.10-3.02(m,2H),2.70-2.61(m,1H),2.42-2.33(m,1H).

[0313] Example 23 Preparation of (S)-4-methoxy-2-((4-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 23)

[0314] [ka]

[0315] 4-(6-((2-Methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-1,4,5,6-tetrahydro-1,2,4-triazine (Intermediate 22) was prepared according to the route shown in formula C, and the specific synthesis method was the same as that of Intermediate 10. LCMS (ESI): m / z = 366.1 (M+H) + .

[0316] (S)-4-Methoxy-2-((4-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 23) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 10 was replaced with intermediate 22. LCMS (ESI): m / z=640.2 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.88(s,1H),7.77(s,1H),7.65(t,J=8.0Hz,1H),7.54(d,J=8.0Hz,1H),7.34-7.28(m,3 H),6.51(d,J=8.0Hz,1H),6.44(d,J=7.9Hz,1H),5.37(s,2H),5.08-5.01(m,1H),4.76-4 .70(m,1H),4.64-4.58(m,1H),4.49-4.42(m,2H),4.36-4.28(m,2H),3.93(s,3H),3.91 (s,3H),3.73(t,J=5.2Hz,2H),3.10-3.01(m,2H),2.70-2.61(m,1H),2.41-2.33(m,1H).

[0317] Example 24 Preparation of (S)-4-ethoxy-2-((4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 24)

[0318] [ka]

[0319] (S)-4-Ethoxy-2-((4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 24) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 3 and intermediate 10 was replaced with intermediate 21. LCMS (ESI): m / z=642.2 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.91(s,1H),7.88(s,1H),7.72(d,J=9.1Hz,2H),7.66(t,J=8.0Hz,1H),7.60(d,J=8.0Hz,1H),7. 25(s,1H),6.55(d,J=8.0Hz,1H),6.45(d,J=8.0Hz,1H),5.47(s,2H),5.08-5.01(m,1H),4.81-4. 74(m,1H),4.69-4.63(m,1H),4.49-4.43(m,2H),4.39-4.29(m,2H),4.27(q,J=7.0Hz,2H),3.75( t,J=5.2Hz,2H),3.13-3.03(m,2H),2.70-2.62(m,1H),2.41-2.32(m,1H),1.42(t,J=6.9Hz,3H).

[0320] Example 25 Preparation of (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-cyclopropoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 25)

[0321] [ka]

[0322] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-cyclopropoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 25) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 13 and intermediate 10 was replaced with intermediate 17. LCMS (ESI): m / z=620.2 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.93(s,1H),7.68-7.60(m,3H),7.53(t,J=8.2Hz,1H),7.47(dd,J=10.1,2.1Hz,1H),7.30(dd,J=8. 4,2.1Hz,1H),6.52(d,J=8.0Hz,1H),6.40(d,J=8.0Hz,1H),5.36(s,2H),5.07-5.00(m,1H),4.71-4. 64(m,1H),4.60-4.54(m,1H),4.50-4.39(m,2H),4.35-4.28(m,2H),4.01-3.95(m,1H),3.74(t,J=5.4H z,2H),3.06-3.01(m,2H),2.70-2.61(m,1H),2.43-2.34(m,1H),0.83-0.78(m,2H),0.74-0.68(m,2H).

[0323] Example 26 Preparation of (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 26)

[0324] [ka]

[0325] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 26) was prepared according to the route shown in formula C. The specific synthesis method was the same as in Example 8, except that intermediate 1 was replaced with intermediate 12 and intermediate 10 was replaced with intermediate 17. LCMS (ESI): m / z=597.2 (M+H). + . 1 H NMR(600MHz,DMSO)δ 7.94(s,1H),7.68-7.61(m,2H),7.53(t,J=8.2Hz,1H),7.47(dd,J=9.9,2.1Hz,1H),7.34( s,1H),7.30(dd,J=8.1,2.1Hz,1H),6.52(d,J=8.1Hz,1H),6.40(d,J=7.9Hz,1H),5.36(s, 2H),5.08-5.01(m,1H),4.72-4.65(m,1H),4.61-4.54(m,1H),4.50-4.39(m,2H),4.36-4. 28(m,2H),3.75(t,J=5.3Hz,2H),3.07-3.04(m,2H),2.70-2.62(m,1H),2.43-2.34(m,1H).

[0326] Example 27 Preparation of (S)-2-((4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 27)

[0327] [ka]

[0328] 2-((2-Fluoro-4-(trifluoromethyl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Intermediate 23) was prepared according to the route shown in formula B, and the specific synthesis method was the same as that of Intermediate 2. LCMS (ESI): m / z = 354.1 (M+H) + .

[0329] (S)-2-((4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 27) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 2 was replaced with intermediate 23. LCMS (ESI): m / z=628.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.83(d,J=1.3Hz,1H),7.72(t,J=7.6Hz,1H),7.68(dd,J=10.0,1.8Hz,1H),7.65-7.60(m,1H),7.57(dd,J=8.1,1.8Hz,1H),7. 26(d,J=1.2Hz,1H),6.86(d,J=7.3Hz,1H),6.69(d,J=8.2Hz,1H),5.46(s,2H),5.12-5.03(m,1H),4.76-4.68(m,1H),4.64-4.5 6(m,1H),4.51-4.41(m,1H),4.37-4.29(m,1H),3.92(s,3H),3.88(d,J=13.4Hz,1H),3.73(d,J=13.4Hz,1H),2.94(d,J=11.2H) z,1H),2.81(d,J=11.2Hz,1H),2.72-2.61(m,1H),2.61-2.52(m,1H),2.45-2.35(m,1H),2.22-2.09(m,2H),1.80-1.55(m,4H).

[0330] Example 28 Preparation of (S)-4-ethoxy-2-((4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 28)

[0331] [ka]

[0332] (S)-4-Ethoxy-2-((4-(6-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 28) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 1 was replaced with intermediate 3 and intermediate 2 was replaced with intermediate 23. LCMS (ESI): m / z=642.3 (M+H). + . 1H NMR(500MHz,DMSO)δ 7.85(d,J=1.3Hz,1H),7.72(t,J=7.6Hz,1H),7.68(dd,J=10.2,1.7Hz,1H),7.62(dd,J=8.2,7.4Hz,1H),7.57(dd,J=8.0,1.8Hz,1H),7.2 2(d,J=1.3Hz,1H),6.86(d,J=7.3Hz,1H),6.69(d,J=8.1Hz,1H),5.46(s,2H),5.12-5.03(m,1H),4.78-4.70(m,1H),4.65-4.58(m,1H),4 .49-4.41(m,1H),4.39-4.29(m,1H),4.23(q,J=7.0Hz,2H),3.89(d,J=13.4Hz,1H),3.74(d,J=13.3Hz,1H),2.94(d,J=11.3Hz,1H),2.80 (d,J=11.3Hz,1H),2.72-2.62(m,1H),2.62-2.52(m,1H),2.45-2.35(m,1H),2.24-2.09(m,2H),1.79-1.56(m,4H),1.40(t,J=6.9Hz,3H).

[0333] Example 29 Preparation of (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 29)

[0334] [ka]

[0335] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 29) was prepared according to the route shown in formula B. The specific synthesis method was the same as in Example 1, except that intermediate 1 was replaced with intermediate 3 and intermediate 2 was replaced with intermediate 19. LCMS (ESI): m / z=608.2 (M+H).+ . 1 H NMR(500MHz,DMSO)δ 7.86(s,1H),7.61(t,J=7.8Hz,1H),7.54(t,J=8.2Hz,1H),7.44(dd,J=9.9,2.1Hz,1H),7.27(dd,J=8.2,2.1Hz,1H),7 .22(d,J=1.2Hz,1H),6.85(d,J=7.3Hz,1H),6.65(d,J=8.2Hz,1H),5.36(s,2H),5.12-5.04(m,1H),4.78-4.70(m,1H), 4.65-4.58(m,1H),4.48-4.40(m,1H),4.38-4.30(m,1H),4.23(q,J=6.9Hz,2H),3.90(d,J=13.4Hz,1H),3.74(d,J=13. 4Hz,1H),2.96(d,J=11.2Hz,1H),2.82(d,J=11.3Hz,1H),2.73-2.63(m,1H),2.62-2.55(m,1H),2.46-2.35(m,1H),2.2 4-2.10(m,2H),1.81-1.60(m,4H),1.40(t,J=7.0Hz,3H).

[0336] Example 30 Preparation of (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 30)

[0337] [ka]

[0338] 1-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine (Intermediate 24) was prepared according to the route shown in Scheme B: Step a: (4-Chloro-2-fluorophenyl)methanol (1 g, 6.3 mmol) was dissolved in 20 mL of THF, and potassium t-butoxide (1.4 g, 12.6 mmol) was added in an ice bath. After stirring for 15 minutes, 2-bromo-6-fluoropyridine (1.7 g, 9.9 mmol) was added, and the mixture was transferred to room temperature and stirred for 3 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated aqueous ammonium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to obtain 1.7 g of 2-bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine. LCMS (ESI): m / z = 315.0 (M+H). + .

[0339] Step b: 2-Bromo-6-((4-chloro-2-fluorobenzyl)oxy)pyridine (500 mg, 1.6 mmol), 1-t-butyloxycarbonylpiperazine (446 mg, 2.4 mmol), tris(dibenzylideneacetone)palladium (73 mg, 0.08 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (100 mg, 0.16 mmol), cesium carbonate (1 g, 3.2 mmol), and 15 mL of toluene were added to a pressure tube and reacted at 120 °C for 4 hours under nitrogen gas protection. After completion of the reaction, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 593 mg of 4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylic acid t-butyl ester. LCMS(ESI): m / z=421.2(M+H) + .

[0340] Step c: 4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (593 mg, 1.4 mmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 400 mg of 1-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester. Benzyl)oxy)pyridin-2-yl)piperazine (Intermediate 24) is obtained. LCMS (ESI): m / z=321.1 (M+H) + .

[0341] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperazin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 30) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 2 was replaced with intermediate 24. LCMS (ESI): m / z = 595.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.85(s,1H),7.52(t,J=8.2Hz,1H),7.48-7.44(m,2H),7.33-7.27(m,2H),6.33(d,J=8. 2Hz,1H),6.09(d,J=7.8Hz,1H),5.30(s,2H),5.13-5.05(m,1H),4.77-4.69(m,1H),4.6 5-4.57(m,1H),4.52-4.44(m,1H),4.40-4.32(m,1H),3.94(s,3H),3.92(d,J=13.4Hz,1 H),3.78(d,J=13.4Hz,1H),3.45(t,J=5.1Hz,8H),2.74-2.63(m,1H),2.47-2.38(m,1H).

[0342] Example 31 Preparation of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 31)

[0343] [ka]

[0344] 2-((4-chloro-2-fluorobenzyl)oxy)-3-(piperidin-4-yl)pyridine (Intermediate 25) was prepared according to the route shown in Scheme D: Step a: (4-Chloro-2-fluorophenyl)methanol (1 g, 6.3 mmol) was dissolved in 20 mL of THF, and potassium t-butoxide (1.4 g, 12.6 mmol) was added in an ice bath. After stirring for 15 minutes, 2-fluoro-3-bromopyridine (1.7 g, 9.9 mmol) was added, and the mixture was transferred to room temperature and stirred for 3 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated aqueous ammonium chloride solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to obtain 1.7 g of 3-bromo-2-((4-chloro-2-fluorobenzyl)oxy)pyridine. LCMS (ESI): m / z = 315.0 (M+H). + .

[0345] Step b: 3-bromo-2-((4-chloro-2-fluorobenzyl)oxy)pyridine (1.7 g, 5.4 mmol), N-Boc-1,2,5,6-tetrahydropyridine- 4-Boronic acid pinacol ester (2.1 g, 6.7 mmol), cesium carbonate (3.7 g, 11.2 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (205 mg, 0.28 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water and reacted at 100 °C for 3 hours under nitrogen gas protection. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was separated by column chromatography to give 1.8 g of 2-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester. LCMS (ESI): m / z = 418.2 (M+H). + .

[0346] Step c: 2-((4-chloro-2-fluorobenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid t-butyl ester (1.8 g, 4.3 mmol) was dissolved in 20 mL of ethyl acetate, 180 mg of 10% palladium-carbon (water content 55%) was added, hydrogen gas was replaced, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting oil was dissolved in 20 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1 g of 2-((4-chloro-2-fluorobenzyl)oxy)-3-(piperidin-4-yl)pyridine (Intermediate 25). LCMS(ESI): m / z=320.1(M+H) + .

[0347] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 31) was prepared according to the route shown in scheme D: Step d: (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (intermediate 1, 50 mg, 0.15 mmol), 2-((4-chloro-2-fluorobenzyl)oxy)-3-(piperidin-4-yl)pyridine (intermediate 25, 58 mg, 0.18 mmol), potassium carbonate (41 mg, 0.3 mmol) and a catalytic amount of potassium iodide are dissolved in 5 mL of acetonitrile and reacted at 80° C. for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by preparative thin layer chromatography to obtain 75 mg of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester. LCMS (ESI): m / z=608.2 (M+H). + .

[0348] Step e: ((S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (75 mg, 0.12 mmol) was dissolved in 3 mL of 1,4-dioxane to give a 2M Add NaOH (300 μL, 0.6 mmol) and react overnight at 40 °C. After the reaction is complete, adjust the pH to 5-6 with 2 M hydrochloric acid and separate using a preparative liquid to obtain 60 mg of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 31). LCMS (ESI): m / z = 594.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.98(dd,J=5.0,1.8Hz,1H),7.82(d,J=1.2Hz,1H),7.57(dd,J=7.5,1.9Hz,1H),7.52(t,J=8 .2Hz,1H),7.47(dd,J=10.1,2.1Hz,1H),7.31(dd,J=8.2,2.0Hz,1H),7.26(d,J=1.2Hz,1H),6.95(dd,J=7.4,4.9 Hz,1H),5.38(s,2H),5.08-5.00(m,1H),4.74-4.65(m,1H),4.60-4.55(m,1H),4.49-4.41(m,1H),4.35-4.27(m,1 H),3.92(s,3H),3.86(d,J=13.4Hz,1H),3.74(d,J=13.4Hz,1H),2.94(d,J=11.2Hz,1H),2.84(d,J=11.2Hz,1H),2 .78-2.69(m,1H),2.69-2.57(m,1H),2.42-2.31(m,1H),2.23-2.09(m,2H),1.79-1.67(m,2H),1.67-1.51(m,2H).

[0349] Example 32 Preparation of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 32)

[0350] [ka]

[0351] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 32) was prepared according to the route shown in formula D, and the specific synthesis method was the same as in Example 31, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z = 608.2 (M+H). + . 1H NMR(500MHz,DMSO)δ 8.01(dd,J=5.0,1.8Hz,1H),7.87(s,1H),7.61(d,J=7.3Hz,1H),7.55(t,J=8.1Hz,1H),7.51(dd,J=9.9,2.1Hz,1H),7.34(dd,J=8.2,2.1H z,1H),7.24(s,1H),6.98(dd,J=7.4,4.9Hz,1H),5.41(s,2H),5.09-5.04(m,1H),4.78-4.70(m,1H),4.64-4.58(m,1H),4.51-4.43(m,1H) ,4.37-4.30(m,1H),4.24(q,J=6.9Hz,2H),3.90(d,J=13.4Hz,1H),3.77(d,J=13.4Hz,1H),2.96(d,J=11.1Hz,1H),2.84(d,J=11.0Hz,1H) ,2.80-2.72(m,1H),2.71-2.64(m,1H),2.42-2.32(m,1H),2.24-2.10(m,2H),1.80-1.70(m,2H),1.69-1.55(m,2H),1.42(t,J=6.9Hz,3H).

[0352] Example 33 Preparation of (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 33)

[0353] [ka]

[0354] (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 33) was prepared according to the route shown in formula D. The specific synthesis method was the same as in Example 31, except that intermediate 1 was replaced with intermediate 3 and intermediate 25 was replaced with intermediate 26. LCMS (ESI): m / z = 599.3 (M+H). + . 1 H NMR(500MHz,DMSO)δ 8.00(dd,J=5.0,1.8Hz,1H),7.93(dd,J=9.9,1.5Hz,1H),7.86(d,J=1.2Hz,1H),7.75(dd,J=7.8,1.6Hz,1H),7.68(t,J=7.6Hz,1H),7.63(dd,J= 7.4,1.9Hz,1H),7.25(d,J=1.3Hz,1H),7.00(dd,J=7.4,5.0Hz,1H),5.5 1(s,2H),5.12-5.03(m,1H),4.79-4.71(m,1H),4.66-4.59(m,1H),4.52- 4.44(m,1H),4.38-4.30(m,1H),4.24(q,J=6.9Hz,2H),3.91(d,J=13.3H z,1H),3.78(d,J=13.3Hz,1H),2.98(d,J=11.1Hz,1H),2.87(d,J=11.1H z,1H),2.84-2.76(m,1H),2.74-2.64(m,1H),2.44-2.34(m,1H),2.28-2 .13(m,2H),1.83-1.74(m,2H),1.70-1.56(m,2H),1.42(t,J=6.9Hz,3H).

[0355] Example 34 Preparation of (S)-2-((4-(2-((4-cyano-2-methoxybenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 34)

[0356] [ka]

[0357] (S)-2-((4-(2-((4-cyano-2-methoxybenzyl)oxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 34) was prepared according to the route shown in formula D, and the specific synthesis method was the same as in Example 31, except that intermediate 25 was replaced with intermediate 27. LCMS (ESI): m / z=59 7.3(M+H) + . 1 H NMR(600MHz,DMSO)δ 7.99(dd,J=4.9,1.8Hz,1H),7.90(d,J=1.1Hz,1H),7.61(dd,J=7.5,1.9Hz,1H),7.52(d,J=1.3Hz,1H),7.50-7.44(m,2H),7.26 (s,1H),6.98(dd,J=7.4,4.9Hz,1H),5.41(s,2H),5.11-5.04(m,1H),4.79-4.72(m,1H),4.66-4.60(m,1H),4.51-4.44(m,1H),4 .38-4.31(m,1H),3.96(s,3H),3.92(d,J=13.6Hz,1H),3.90(s,3H),3.79(d,J=13.5Hz,1H),3.00(d,J=11.1Hz,1H),2.88(d,J= 12.1Hz,1H),2.86-2.79(m,1H),2.75-2.65(m,1H),2.44-2.35(m,1H),2.29-2.15(m,2H),1.84-1.75(m,2H),1.71-1.57(m,2H).

[0358] Example 35 Preparation of (S)-2-((4-(2-((4-cyano-2,3-dihydrobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 35)

[0359] [ka]

[0360] (S)-2-((4-(2-((4-cyano-2,3-dihydrobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 35) was prepared according to the route shown in formula D, and the specific synthesis method was the same as in Example 31, except that intermediate 25 was replaced with intermediate 28. LCMS (ESI): m / z = 609.3 (M+H). + . 1 H NMR (600 MHz, DMSO) δ 7.99(dd,J=4.9,1.8Hz,1H),7.90(s,1H),7.60(dd,J=7.5,1.9Hz,1H),7.33-7.25(m,3H),6.97(dd,J=7.3,5.0Hz,1H),5.35 (s,2H),5.11-5.04(m,1H),4.79-4.72(m,1H),4.69(t,J=8.8Hz,2H),4.65-4.59(m,1H),4.51-4.44(m,1H),4.38-4.31(m,1H) ),3.96(s,3H),3.91(d,J=13.3Hz,1H),3.78(d,J=13.4Hz,1H),3.41(t,J=8.8Hz,2H),2.99(d,J=11.2Hz,1H),2.87(d,J=11. 3Hz,1H),2.84-2.76(m,1H),2.74-2.65(m,1H),2.44-2.35(m,1H),2.27-2.14(m,2H),1.82-1.74(m,2H),1.69-1.55(m,2H).

[0361] Example 36 Preparation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 36)

[0362] [ka]

[0363] 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidine (Intermediate 29) was prepared according to the route shown in Scheme E: Step a: 4'-chloro-2'-fluoroacetophenone (10 g, 58.1 mmol), 3-bromobenzene-1,2-diol (10 g, 53.3 mmol), and p-toluenesulfonic acid (1 g, 5.8 mmol) were dissolved in 100 mL of toluene and reacted under nitrogen gas protection using a water separator at 160 °C for 72 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 3.5 g of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]oxadiazole. LCMS (ESI): m / z = 342.0 (M+H). + .

[0364] Step b: 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]oxadiazole (1 g, 2.9 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (1.1 g, 3.5 mmol), cesium carbonate (1.9 g, 5.8 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (106 mg, 0.15 mmol) are dissolved in 20 mL of 1,4-dioxane and 4 mL of water, and the mixture is reacted at 100° C. for 3 hours under nitrogen gas protection. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was separated by column chromatography to obtain 1.1 g of 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. LCMS (ESI): m / z=445.2 (M+H). + .

[0365] Step c: 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxi-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.1 g, 2.5 mmol) was dissolved in 20 mL of ethyl acetate, 110 mg of 10% palladium-carbon (water content 55%) was added, hydrogen gas was replaced, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in 20 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 790 mg of 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidine (Intermediate 29). obtain. LCMS(ESI):m / z=347.1(M+H) + .

[0366] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxi-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 36) is prepared according to the route shown in Scheme E.

[0367] Step d: (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 1, 50 mg, 0.15 mmol), 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidine (Intermediate 29, 62 mg, 0.18 mmol), potassium carbonate (41 mg, 0.3 mmol) and a catalytic amount of potassium iodide are dissolved in 5 mL of acetonitrile and reacted at 80° C. for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by preparative thin layer chromatography to obtain 67 mg of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester. LCMS (ESI): m / z=635.2 (M+H) + .

[0368] Step e: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxi-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (67 mg, 0.11 mmol) is dissolved in 3 mL of 1,4-dioxane, 2 M NaOH (300 μL, 0.6 mmol) is added, and the reaction is carried out at 40° C. overnight. After the reaction was completed, the pH was adjusted to 5-6 with 2M hydrochloric acid, and the mixture was separated using a preparative liquid to obtain 50 mg of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 36). LCMS (ESI): m / z = 621.2 (M+H). + . 1H NMR(600MHz,DMSO)δ 7.76(d,J=2.3Hz,1H),7.59-7.52(m,2H),7.34(dd,J=8.5,2.0Hz,1H),7.31(s,1H),6.80-6.73(m,3H),5. 13-5.06(m,1H),4.72-4.65(m,1H),4.60-4.55(m,1H),4.50-4.42(m,1H),4.39-4.32(m,1H),3.92(s,3H) ,3.89(dd,J=13.4,3.4Hz,1H),3.74(d,J=13.3Hz,1H),2.99(d,J=10.8Hz,1H),2.87(d,J=11.2Hz,1H),2. 73-2.63(m,2H),2.48-2.40(m,1H),2.25-2.19(m,1H),2.19-2.12(m,1H),2.02(s,3H),1.83-1.64(m,4H).

[0369] Example 37 Preparation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 37)

[0370] [ka]

[0371] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 37) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 36, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z = 635.2 (M+H). + . 1H NMR(500MHz,DMSO)δ 7.85(s,1H),7.58-7.50(m,2H),7.32(dd,J=8.5,2.1Hz,1H),7.23(s,1H),6.79-6.76(m,2H),6.75-6.71(m,1 H),5.12-5.03(m,1H),4.76-4.68(m,1H),4.64-4.56(m,1H),4.49-4.39(m,1H),4.38-4.29(m,1H),4.23(q,J =7.0Hz,2H),3.90(dd,J=13.4,2.8Hz,1H),3.74(d,J=13.4Hz,1H),3.00-2.94(m,1H),2.87-2.80(m,1H),2.7 2-2.59(m,2H),2.45-2.37(m,1H),2.26-2.10(m,2H),2.00(s,3H),1.77-1.63(m,4H),1.40(t,J=7.0Hz,3H).

[0372] Example 38 Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 38)

[0373] [ka]

[0374] 5-Chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxi-2-yl)pyridine (Intermediate 30) was prepared according to the route shown in Scheme E: Step a: 5-chloro-2-alkynylpyridine (1 g, 7.3 mmol), 3-bromobenzene-1,2-diol (1.8 g, 9.5 mmol), triruthenium dodecacarbonyl (192 mg, 0.3 mmol), and 20 mL of toluene were added to a pressure-resistant tube and purged with nitrogen gas. The mixture was reacted overnight at 100°C under nitrogen protection. After the reaction was completed, the insoluble catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 900 mg of 2-(4-bromo-2-methylbenzo[d][1,3]dioxol-2-yl)-5-chloropyridine. LCMS (ESI): m / z = 325.0 (M+H). + .

[0375] The subsequent steps refer to the preparation method of Intermediate 29 to obtain 5-chloro-2-(2-methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxi-2-yl)pyridine (Intermediate 30). LCMS (ESI): m / z = 330.1 (M+H). + .

[0376] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 38) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 36, except that intermediate 29 was replaced with intermediate 30. LCMS (ESI): m / z = 604.2 (M+H). + . 1H NMR(500MHz,DMSO)δ 8.70(t,J=2.3Hz,1H),7.98(dd,J=8.5,2.5Hz,1H),7.70(s,1H),7.58(d,J=8.4Hz,1H),7.29(d,J=1.1Hz,1H) ,6.81-6.70(m,3H),5.11-5.02(m,1H),4.67-4.59(m,1H),4.56-4.49(m,1H),4.47-4.37(m,1H),4.37-4.29( m,1H),3.88(s,3H),3.85(dd,J=13.3,2.5Hz,1H),3.70(dd,J=13.3,3.4Hz,1H),2.96(d,J=11.2Hz,1H),2.84 (d,J=11.3Hz,1H),2.70-2.59(m,2H),2.47-2.36(m,1H),2.22-2.07(m,2H),1.99(s,3H),1.78-1.66(m,4H).

[0377] Example 39 Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 39)

[0378] [ka]

[0379] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 39) was prepared according to the route shown in formula E. The specific synthesis method was the same as in Example 36, except that intermediate 1 was replaced with intermediate 3 and intermediate 29 was replaced with intermediate 30. LCMS (ESI): m / z=618.2 (M+H). + . 1H NMR(500MHz,DMSO)δ 8.70(t,J=2.3Hz,1H),7.98(dd,J=8.5,2.5Hz,1H),7.64(d,J=1.0Hz,1H),7.58(d, J=8.5Hz,1H),7.28(d,J=1.1Hz,1H),6.81-6.71(m,3H),5.11-5.02(m,1H),4.66-4. 57(m,1H),4.55-4.48(m,1H),4.47-4.37(m,1H),4.37-4.28(m,1H),4.17(q,J =7.0Hz,2H),3.84(dd,J=13.4,2.0Hz,1H),3.70(dd,J=13.3,2.8Hz,1H),2.96 (d,J=11.1Hz,1H),2.84(d,J=11.3Hz,1H),2.70-2.57(m,2H),2.47-2.36(m,1 H),2.22-2.07(m,2H),1.99(s,3H),1.78-1.64(m,4H),1.38(t,J=7.0Hz,3H).

[0380] Example 40 Preparation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperazin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 40)

[0381] [ka]

[0382] 1-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxi-4-yl)piperazine (Intermediate 31) was prepared according to the route shown in Scheme E: Step a: 4'-chloro-2'-fluoroacetophenone (10 g, 58.1 mmol), 3-bromobenzene-1,2-diol (10 g, 53.3 mmol), and p-toluenesulfonic acid (1 g, 5.8 mmol) were dissolved in 100 mL of toluene and reacted under nitrogen gas protection using a water separator at 160 °C for 72 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 3.5 g of 4-bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]oxadiazole. LCMS (ESI): m / z = 342.0 (M+H). + .

[0383] Step b: 4-Bromo-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]oxadiazole (550 mg, 1.6 mmol), 1-t-butyloxycarbonylpiperazine (446 mg, 2.4 mmol), tris(dibenzylideneacetone)palladium (73 mg, 0.08 mmol), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (100 mg, 0.16 mmol), cesium carbonate (1 g, 3.2 mmol), and 15 mL of toluene were added to a pressure-resistant tube and reacted at 120° C. for 4 hours under nitrogen gas protection. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 600 mg of 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperazine-1-carboxylic acid tert-butyl ester. LCMS (ESI): m / z = 448.2 (M +H) + .

[0384] Step c: 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxi-4-yl)piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.4 mmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 400 mg of 1-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxi-4-yl)piperazine (Intermediate 31). LCMS (ESI): m / z = 348.1 (M+H). + .

[0385] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxi-4-yl)piperazin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 40) was prepared according to the route shown in scheme E, the subsequent steps being similar to compound 36, except for replacing intermediate 29 with intermediate 31. LCMS (ESI): m / z = 622.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.90(d,J=1.2Hz,1H),7.59-7.51(m,2H),7.36-7.30(m,1H),7.27(d,J=1.2Hz,1H),6.75(t,J=8.1Hz ,1H),6.56(d,J=7.8Hz,1H),6.44(d,J=8.4Hz,1H),5.12-5.03(m,1H),4.79-4.69(m,1H),4.66-4.57( m,1H),4.51-4.43(m,1H),4.40-4.30(m,1H),3.96(s,3H),3.93(d,J=13.4Hz,1H),3.80(d,J=13.4Hz, 1H),3.17(t,J=5.1Hz,4H),3.07(t,J=5.1Hz,4H),2.73-2.65(m,1H),2.46-2.36(m,1H),2.01(s,3H).

[0386] Example 41 Preparation of (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Compound 41)

[0387] [ka]

[0388] (S)-2-((4-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 41) is prepared according to the route shown in formula B and is obtained as an intermediate to compound 19. LCMS (ESI): m / z = 594.2 (M+H). + . 1 H NMR(500MHz,DMSO)δ 7.91(d,J=1.4Hz,1H),7.61(t,J=7.7Hz,1H),7.54(t,J=8.2Hz,1H),7.44(dd,J=9.9,2.1Hz,1H),7.27(dd,J=8.3,2.1Hz,1H),7.24(d ,J=1.3Hz,1H),6.85(d,J=7.3Hz,1H),6.65(d,J=8.1Hz,1H),5.36(s,2H),5.12-5.04(m,1H),4.8 0-4.72(m,1H),4.67-4.59(m,1H),4.48-4.40(m,1H),4.37-4.29(m,1H),3.95(s,3H),3.91(d,J= 13.4Hz,1H),3.85(s,3H),3.74(d,J=13.5Hz,1H),2.97(d,J=11.1Hz,1H),2.82(d,J=11.3Hz,1H) ,2.73-2.62(m,1H),2.61-2.53(m,1H),2.46-2.33(m,1H),2.25-2.10(m,2H),1.81-1.60(m,4H).

[0389] Example 42: Preparation of (S)-2-((4-(3-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 42)

[0390] [ka]

[0391] 4-(3-hydroxyphenyl)piperidine-1-carboxylic acid t-butyl ester (Intermediate 32) was prepared according to the route shown in Scheme F: Step a: 1-(benzyloxy)-3-bromobenzene (1.4 g, 5.4 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.1 g, 6.7 mmol), cesium carbonate (3.7 g, 11.2 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (205 mg, 0.28 mmol) were dissolved in 20 mL of 1,4-dioxane and 4 mL of water and reacted at 100 °C for 3 hours under nitrogen gas protection. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to obtain 1.6 g of 4-(3-(benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester. LCMS (ESI): m / z = 365.2 (M+H) + .

[0392] Step b: 4-(3-(benzyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g, 4.3 mmol) was dissolved in 20 mL of ethyl acetate, 160 mg of 10% palladium-carbon (water content 55%) was added, hydrogen gas was purged, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to give 1.1 g of 4-(3-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 32). LCMS (ESI): m / z = 277.2 (M+H). + .

[0393] (S)-2-((4-(3-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 42) was prepared according to the route shown in formula F: Step c: 4-(3-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 32, 200 mg, 0.7 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and cesium carbonate (456 mg, 1.4 mmol) and 4-(bromomethyl)-3-methoxybenzonitrile (225 mg, 1 mmol) were added. The mixture was then reacted at 70° C. for 2 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to obtain 250 mg of 4-(3-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester. LCMS (ESI): m / z=422.2 (M+H). + .

[0394] Step d: 4-(3-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidine-1-carboxylic acid t-butyl ester (250 mg, 0.6 mmol) is dissolved in 5 mL of dichloromethane, 0.5 mL of trifluoroacetic acid is added, and the mixture is stirred at room temperature for 2 hours. After the reaction is completed, the reaction mixture is concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution is added, and the mixture is extracted three times with dichloromethane. The organic phase is collected, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give 155 mg of 3-methoxy-4-((3-(piperidin-4-yl)phenoxy)methyl)benzonitrile. LCMS (ESI): m / z=322.2 (M+H). + .

[0395] Step e: (S)-2-(chloromethyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 1, 50 mg, 0.15 mmol), 3-methoxy-4-((3-(piperidin-4-yl)phenoxy)methyl)benzonitrile (Intermediate 32, 58 mg, 0.18 mmol), potassium carbonate (41 mg, 0.3 mmol) and a catalytic amount of potassium iodide are dissolved in 5 mL of acetonitrile and reacted at 80° C. for 2 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by preparative thin layer chromatography to obtain 65 mg of (S)-2-((4-(3-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester. LCMS (ESI): m / z=610.3 (M+H). + .

[0396] Step f: (S)-2-((4-(3-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (65 mg, 0.11 mmol) was dissolved in 3 mL of 1,4-dioxane, and 2 M NaOH (300 μL, 0.6 mmol) was added. The mixture was incubated at 40 °C overnight. After the reaction was completed, the pH was adjusted to 5-6 with 2 M hydrochloric acid. The mixture was separated by aliquoting to obtain 50 mg of (S)-2-((4-(3-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 42). LCMS(ESI): m / z=596.3(M+H) + . 1 H NMR(500MHz,DMSO)δ 7.91(d,J=1.3Hz,1H),7.58(d,J=7.7Hz,1H),7.54(d,J=1.5Hz,1H),7.46(dd,J=7.7,1.5Hz,1H),7.26(d,J=1.3Hz,1H),7.21 (t,J=7.9Hz,1H),6.88(t,J=2.0Hz,1H),6.85(d,J=7.6Hz,1H),6.81(dd,J=8.2,2.5Hz,1H),5.10(s,2H),5.10-5.04(m,1H), 4.81-4.73(m,1H),4.68-4.60(m,1H),4.53-4.45(m,1H),4.39-4.32(m,1H),3 .96(s,3H),3.93(d,J=13.4Hz,1H),3.90(s,3H),3.78(d,J=13.4Hz,1H),2.98( d,J=11.1Hz,1H),2.86(d,J=11.1Hz,1H),2.76-2.65(m,1H),2.55-2.46(m,1H ),2.46-2.36(m,1H),2.27-2.11(m,2H),1.79-1.70(m,2H),1.69-1.53(m,2H).

[0397] Example 43 Preparation of (S)-2-((4-(3-((4-cyano-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 43)

[0398] [ka]

[0399] (S)-2-((4-(3-((4-cyano-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 43) was prepared according to the route shown in formula F. The specific synthesis method is the same as in Example 42, where the raw material 4-(bromomethyl)-3-methoxybenzonitrile is replaced with 7-(bromomethyl)-2,3-dihydrobenzofuran-4-carbonitrile. LCMS (ESI): m / z=608.3 (M+H). + . 1H NMR(600MHz,DMSO)δ 7.96(d,J=1.3Hz,1H),7.45(d,J=7.9Hz,1H),7.34(d,J=7.9Hz,1H),7.32(d,J=1.3Hz,1H),7.26(t,J=7.9Hz,1H),6.94(t,J=2.2Hz,1H),6.90 (d,J=7.4Hz,1H),6.87(dd,J=8.2,2.5Hz,1H),5.18-5.11(m,1H),5.10(s,2H),4.85-4.80(m,1H),4.77(t,J=8.8Hz,2H),4.74-4.66(m,1H),4 .57-4.52(m,1H),4.45-4.38(m,1H),4.01(s,3H),3.97(d,J=13.4Hz,1H),3.83(d,J=13.4Hz,1H),3.47(t,J=8.8Hz,2H),3.04(d,J=11.2Hz,1 H),2.92(d,J=11.3Hz,1H),2.81-2.72(m,1H),2.59-2.53(m,1H),2.52 -2.44(m,1H),2.31-2.16(m,2H),1.84-1.76(m,2H),1.74-1.61(m,2H).

[0400] Example 44: Preparation of (S)-2-((4-(2-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 44)

[0401] [ka]

[0402] (S)-2-((4-(2-((4-cyano-2-methoxybenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 44) ​​was prepared according to the route shown in formula F, and the specific synthesis method was the same as in Example 42. LCMS (ESI): m / z = 596.3 (M+H). + . 1H NMR(600MHz,DMSO)δ 7.90(d,J=1.3Hz,1H),7.57(d,J=7.7Hz,1H),7.55(d,J=1.4Hz,1H),7.50(dd,J=7.7,1.5Hz,1H),7.26(d,J=1.3Hz,1H),7.20(dd,J=7.6,1. 7Hz,1H),7.17-7.14(m,1H),6.98(d,J=8.1Hz,1H),6.93(t,J=7.5Hz,1H),5.13(s,2H),5.12-5.05(m,1H),4.79-4.72(m,1H),4.67-4.61(m, 1H),4.51-4.45(m,1H),4.38-4.32(m,1H),3.96(s,3H),3.92(d,J=13.4Hz,1H),3.90(s,3H),3.78(d,J=13.4Hz,1H),2.99(d,J=11.1Hz,1H) ,2.96-2.91(m,1H),2.87(d,J=11.2Hz,1H),2.72-2.65(m,1H),2.45- 2.36(m,1H),2.26-2.14(m,2H),1.77-1.69(m,2H),1.68-1.53(m,2H).

[0403] Example 45 Preparation of (S)-2-((4-(2-((4-chloro-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 45)

[0404] [ka]

[0405] (S)-2-((4-(2-((4-chloro-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 45) was prepared according to the route shown in formula F, and the specific synthesis method was the same as in Example 42. LCMS (ESI): m / z = 617.2 (M+H). + .1 H NMR(600MHz,DMSO)δ 7.89(s,1H),7.27(s,1H),7.21(d ,J=8.2Hz,1H),7.17(dd,J=7.8,1.7Hz,1H),7.16-7.12(m,1H),7.02(d,J=8.2Hz,1H),6.93(d,J=8.2Hz,1H),6.90(t,J=7.4Hz, 1H),5.10-5.05(m,1H),4.99(s,2H),4.78-4.71(m,1H),4.64(t,J=8.8Hz,2H),4.63-4.59(m,1H),4.51-4.45(m,1H),4.37-4.31 (m,1H),3.95(s,3H),3.90(d,J=13.4Hz,1H),3.77(d,J=13.4Hz,1H),3.25(t,J=8.7Hz,2H),2.97(d,J=11.0Hz,1H),2.93-2.87 (m,1H),2.85(d,J=11.3Hz,1H),2.75-2.65(m,1H),2.44-2.35(m,1H),2.23-2.10(m,2H),1.73-1.65(m,2H),1.64-1.52(m,2H).

[0406] Example 46: Preparation of (S)-2-((4-(2-((4-cyano-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 46)

[0407] [ka]

[0408] (S)-2-((4-(2-((4-cyano-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 46) was prepared according to the route shown in formula F, and the specific synthesis method was the same as in Example 42. LCMS (ESI): m / z = 608.2 (M+H). +. 1 H NMR(600MHz,DMSO)δ 7.90(d,J=1.2Hz,1H),7.37(d,J=7.9Hz,1H),7.32(d,J=7.9Hz,1H),7.26(d,J=1.1Hz,1H),7.19(dd,J=7.6,1.7Hz,1H),7.17-7.13(m,1H),7 .01(d,J=8.1Hz,1H),6.92(t,J=7.4Hz,1H),5.08(s,2H),5.08-5.04(m,1H),4.79-4.73(m,1H),4.70(t,J=8.8Hz,2H),4.66-4.60(m,1H),4.5 2-4.45(m,1H),4.38-4.31(m,1H),3.96(s,3H),3.91(d,J=13.5Hz,1H),3.78(d,J=13.5Hz,1H),3.42(t,J=8.8Hz,2H),2.98(d,J=11.2Hz,1H ),2.95-2.90(m,1H),2.86(d,J=11.2Hz,1H),2.74-2.66(m,1H),2.45- 2.36(m,1H),2.25-2.12(m,2H),1.75-1.68(m,2H),1.66-1.54(m,2H).

[0409] Example 47: Preparation of (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 47)

[0410] [ka]

[0411] (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 47) was prepared according to the route shown in formula F, and the specific synthesis method was the same as in Example 42. LCMS (ESI): m / z = 584.2 (M+H). + . 1H NMR(500MHz,DMSO)δ 7.94(dd,J=9.9,1.5Hz,1H),7.90(d,J=1.3Hz,1H),7.80(dd,J=7.9,1.5Hz,1H),7.74(t,J=7.5Hz,1H),7.26(d,J=1.3Hz,1H),7.21(dd,J=7. 6,1.7Hz,1H),7.20-7.14(m,1H),7.07(dd,J=8.3,1.2Hz,1H),6.95(td,J=7.5,1.1Hz,1H),5.26(s,2H),5.12-5.03(m,1H),4.79-4.71(m,1H) ,4.66-4.59(m,1H),4.52-4.44(m,1H),4.38-4.31(m,1H),3.95(s,3H),3.91(d,J=13.5Hz,1H),3.77(d,J=13.5Hz,1H),2.98(d,J=11.0Hz,1H) ),2.95-2.88(m,1H),2.85(d,J=11.1Hz,1H),2.74-2.67(m,1H),2.45- 2.36(m,1H),2.26-2.11(m,2H),1.75-1.66(m,2H),1.65-1.51(m,2H).

[0412] Example 48 Preparation of (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 48)

[0413] [ka]

[0414] (S)-2-((4-(2-((4-chloro-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 48) was prepared according to the route shown in formula F, and the specific synthesis method was the same as in Example 42. LCMS (ESI): m / z = 593.2 (M+H). + . 1H NMR(500MHz,DMSO)δ 7.89(s,1H),7.57(t,J=8.1Hz,1H),7.52(dd, J=10.0,2.1Hz,1H),7.37(dd,J=8.3,2.1Hz,1H),7.26(s,1H),7.21-7.12(m,2H),7.08(d,J=8.0Hz,1H),6.94( t,J=7.4Hz,1H),5.14(s,2H),5.10-5.03(m,1H),4.78-4.70(m,1H),4.65-4.57(m,1H),4.52-4.44(m,1H),4.3 8-4.30(m,1H),3.95(s,3H),3.89(d,J=13.5Hz,1H),3.76(d,J=13.4Hz,1H),2.95(d,J=11.1Hz,1H),2.90-2.8 4(m,1H),2.82(d,J=11.1Hz,1H),2.74-2.59(m,1H),2.44-2.34(m,1H),2.21-2.08(m,2H),1.72-1.53(m,4H).

[0415] Example 49 Preparation of (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 49)

[0416] [ka]

[0417] 2-((4-chloro-2-methoxybenzyl)oxy)-6-(piperidin-4-yl)pyridine (Intermediate 33) was prepared according to the route shown in formula B, and the specific synthesis method was the same as that of Intermediate 2. LCMS (ESI): m / z = 332.1 (M+H) + .

[0418] (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-methoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 49) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 2 was replaced with intermediate 33. LCMS (ESI): m / z=606.2 (M+H). + .

[0419] Example 50 Preparation of (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 50)

[0420] [ka]

[0421] (S)-2-((4-(6-((4-chloro-2-methoxybenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 50) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 49, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z = 620.2 (M+H). + .

[0422] Example 51 Preparation of (S)-4-methoxy-2-((4-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 51)

[0423] [ka]

[0424] 2-((2-Methoxy-4-(trifluoromethyl)benzyl)oxy)-6-(piperidin-4-yl)pyridine (Intermediate 34) was prepared according to the route shown in formula B, and the specific synthesis method was the same as that of Intermediate 2. LCMS (ESI): m / z = 366.2 (M+H) + .

[0425] (S)-4-Methoxy-2-((4-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 51) was prepared according to the route shown in formula B, and the specific synthesis method was the same as in Example 1, except that intermediate 2 was replaced with intermediate 34. LCMS (ESI): m / z=640.3 (M+H). + .

[0426] Example 52 Preparation of (S)-4-ethoxy-2-((4-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 52)

[0427] [ka]

[0428] (S)-4-Ethoxy-2-((4-(6-((2-methoxy-4-(trifluoromethyl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 52) was prepared according to the route shown in formula B. The specific synthesis method was the same as in Example 51, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z = 654.3 (M+H). + .

[0429] Example 53 Preparation of 2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 53)

[0430] [ka]

[0431] 4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidine (Intermediate 35) was prepared according to the route shown in formula E, and the specific synthesis method was the same as that of Intermediate 29. LCMS (ESI): m / z = 381.1 (M+H). + .

[0432] 2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 53) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 36, except that intermediate 29 was replaced with intermediate 35. LCMS (ESI): m / z = 655.2 (M+H). + .

[0433] Example 54 Preparation of 4-ethoxy-2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 54)

[0434] [ka]

[0435] 4-Ethoxy-2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 54) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 53, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z = 669.3 (M+H). + .

[0436] Example 55 Preparation of 4-methoxy-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 55)

[0437] [ka]

[0438] 2-(2-Methyl-4-(piperidin-4-yl)benzo[d][1,3]dioxi-2-yl)-5-(trifluoromethyl)pyridine (Intermediate 36) was prepared according to the route shown in formula E, and the specific synthesis method was the same as that of Intermediate 30. LCMS (ESI): m / z = 364.1 (M+H). + .

[0439] 4-Methoxy-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 55) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 38, except that intermediate 30 was replaced with intermediate 36. LCMS (ESI): m / z = 638.2 (M+H). + .

[0440] Example 56 Preparation of 4-ethoxy-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 56)

[0441] [ka]

[0442] 4-Ethoxy-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 56) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 55, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z = 652.3 (M+H). + .

[0443] Example 57 Preparation of 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 57)

[0444] [ka]

[0445] 4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidine (Intermediate 37) was prepared according to the route shown in formula E, and the specific synthesis method was the same as that of Intermediate 29. LCMS (ESI): m / z = 359.1 (M+H) + .

[0446] 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 57) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 36, except that intermediate 29 was replaced with intermediate 37. LCMS (ESI): m / z = 633.2 (M+H). + .

[0447] Example 58 Preparation of 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 58)

[0448] [ka]

[0449] 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 58) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 57, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z = 647.2 (M+H). + .

[0450] Example 59 Preparation of 4-methoxy-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylic acid (Compound 59)

[0451] [ka]

[0452] 4-(2-(2-Methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidine (Intermediate 38) was prepared according to the route shown in formula E, and the specific synthesis method was the same as that of Intermediate 29. LCMS (ESI): m / z = 393.2 (M+H) + .

[0453] 4-Methoxy-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylic acid (compound 59) was prepared according to the route shown in formula E, and the specific synthesis method was the same as in Example 36, except that intermediate 29 was replaced with intermediate 38. LCMS (ESI): m / z = 667.3 (M+H). + .

[0454] Example 60 Preparation of 4-ethoxy-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylic acid (Compound 60)

[0455] [ka]

[0456] 4-Ethoxy-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxy-4-yl)piperidin-1-yl)methyl)-1-((S)-oxetan-2-yl)methyl]-1H-benzo[d]imidazole-6-carboxylic acid (compound 60) was prepared according to the route shown in formula E, and the specific synthesis method was the same as that in Example 59, except that intermediate 1 was replaced with intermediate 3. LCMS (ESI): m / z = 681.3 (M+H). + .

[0457] Example 61 Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 61)

[0458] [ka]

[0459] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 61) is prepared according to the route shown in formula E. LCMS (ESI): m / z = 607.3 (M+H). + .

[0460] Example 62 Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 62)

[0461] [ka]

[0462] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 62) is prepared according to the route shown in formula E. LCMS (ESI): m / z = 640.2 (M+H). + .

[0463] Example 63 Preparation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 63)

[0464] [ka]

[0465] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 63) is prepared according to the route shown in formula G. LCMS (ESI): m / z = 621.2 (M+H). + .

[0466] Example 64: Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(2,2,2-trifluorooxy)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 64)

[0467] [ka]

[0468] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-4-(2,2,2-trifluoro-1H-benzo[d]imidazole-6-carboxylic acid (compound 64) is prepared according to the route shown in formula E. LCMS (ESI): m / z = 672.2 (M+H). + .

[0469] Example 65 Preparation of 4-methoxy-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 65)

[0470] [ka]

[0471] 4-Methoxy-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 65) is prepared according to the route shown in formula G. LCMS (ESI): m / z = 638.2 (M+H). + .

[0472] Example 66 Preparation of 4-ethoxy-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 66)

[0473] [ka]

[0474] 4-Ethoxy-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 66) is prepared according to the route shown in formula G. LCMS (ESI): m / z=652.2 (M+H). + .

[0475] Example 67 Preparation of 4-(methoxy-d3)-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 67)

[0476] [ka]

[0477] 4-(Methoxy-d3)-2-((4-(2-methyl-2-(5-(trifluoromethyl)pyridin-2-yl)benzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 67) is prepared according to the route shown in formula E. LCMS (ESI): m / z = 641.3 (M+H). + .

[0478] Example 68 Preparation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 68)

[0479] [ka]

[0480] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 68) is prepared according to the route shown in formula G. LCMS (ESI): m / z = 635.2 (M+H). + .

[0481] Preparation of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 68-1) and 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 68-2):

[0482] [ka]

[0483] The chiral resolution and preparation methods of compounds 68-1 and 68-2 are the same as those of compounds 76-1 and 76-2 below. Example 69 Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 69)

[0484] [ka]

[0485] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 69) is prepared according to the route shown in formula G. LCMS (ESI): m / z = 618.2 (M+H). + .

[0486] Example 70 Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 70)

[0487] [ka]

[0488] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 70) is prepared according to the route shown in formula G. LCMS (ESI): m / z=607.2 (M+H). + .

[0489] Example 71 Preparation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 71)

[0490] [ka]

[0491] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 71) is prepared according to the route shown in formula G. LCMS (ESI): m / z = 624.2 (M+H). + .

[0492] Example 72 Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 72)

[0493] [ka]

[0494] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 72) is prepared according to the route shown in formula E. LCMS (ESI): m / z = 623.3 (M+H). + .

[0495] Example 73 Preparation of 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 73)

[0496] [ka]

[0497] 2-((4-(2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 73) is prepared according to the route shown in formula G. LCMS (ESI): m / z=623.3 (M+H). + .

[0498] Example 74 Preparation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 74)

[0499] [ka]

[0500] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 74) is prepared according to the route shown in formula E. LCMS (ESI): m / z = 624.3 (M+H). + .

[0501] Example 75 Preparation of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 75)

[0502] [ka]

[0503] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 75) is prepared according to the route shown in formula E. LCMS (ESI): m / z = 640.3 (M+H). + .

[0504] Example 76: 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-trimethylbenzo[d][1,3]dioxol-4-yl)- Preparation of riazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 76)

[0505] [ka]

[0506] 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 76) is prepared according to the route shown in formula G. LCMS (ESI): m / z=640.3 (M+H). + .

[0507] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 76-1) and 2 Preparation of -((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 76-2)

[0508] [ka]

[0509] Step a: 4'-chloro-2'-fluoroacetophenone (20 g, 116.2 mmol), 3-methylbenzene-1,2-diol (14.4 g, 116.2 mmol), and p-toluenesulfonic acid (2 g, 11.6 mmol) were dissolved in 500 mL of toluene and reacted under nitrogen gas protection using a water separator at 160 °C for 72 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 25 g of 2-(4-chloro-2-fluorophenyl)-2,4-dimethylbenzo[d][1,3]dioxole. LCMS (ESI): m / z = 278.1 (M+H). + .

[0510] Step b: 2-(4-chloro-2-fluorophenyl)-2,4-dimethylbenzo[d][1,3]dioxole (25 g, 89.9 mmol) was dissolved in a mixture of 250 mL of pyridine and 250 mL of water, and the mixture was heated to 80°C. Potassium permanganate (85 g, 539.4 mmol) was added in batches and stirred overnight. After the reaction was complete, the insoluble solids were filtered off. The filtrate was diluted with ethyl acetate and the pyridine was washed with 2M hydrochloric acid. The organic phase was collected and dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to give 16 g of 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole-4-carboxylic acid. LCMS (ESI): m / z = 308.0 (M+H). + .

[0511] Step c: Dissolve 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole-4-carboxylic acid (16 g, 51.9 mmol) in 250 mL of dichloromethane, add triethylamine (15.8 g, 155.7 mmol), add diphenylphosphorylamide (18.6 g, 67.5 mmol) dropwise under nitrogen gas protection, and stir at room temperature for 2 hours. After the reaction is complete, concentrate the reaction solution under reduced pressure at room temperature, and the crude product is purified by column chromatography. Chromatographic separation gives 17 g of 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole-4-carbonyl azide. LCMS (ESI): m / z=333.0 (M+H). + .

[0512] Step d: 2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole-4-carbonyl azide (17 g, 51.1 mmol) and 150 mL of ultra-dry t-butanol are added to a pressure tube and reacted overnight at 90°C under nitrogen gas protection. After completion of the reaction, the reaction solution is concentrated under reduced pressure, and the crude product is separated by column chromatography to obtain 18 g of (2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxole-4-yl)carbamic acid t-butyl ester. LCMS (ESI): m / z = 379.1 (M+H). + .

[0513] Step e: (2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)carbamic acid t-butyl ester (18 g, 47.5 mmol) was dissolved in 100 mL of N,N-dimethylformamide, and cesium carbonate (31 g, 95 mmol) and 3-bromopropene (11.5 g, 95 mmol) were added. The mixture was reacted at 70 ° C. for 4 hours. After the reaction was completed, the mixture was extracted three times with ethyl acetate and washed three times with saturated brine. The organic phase was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to obtain 18.5 g of allyl (2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)carbamic acid t-butyl ester. LCMS (ESI): m / z = 419.2 (M + H). + .

[0514] Step f: Allyl (2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)carbamic acid t-butyl ester (18.5 g, 44.1 mmol) was dissolved in 200 mL of a mixed solvent of tetrahydrofuran and 200 mL of water, and potassium osmate(VI) dihydrate (162 mg, 0.44 mmol) and sodium periodate (37.7 g, 176.4 mmol) were added and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was filtered. The filtrate was diluted with EA and washed with saturated aqueous sodium thiosulfate. The organic phase was collected and dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography to obtain 14 g of (2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)(2-oxoethyl)carbamic acid t-butyl ester. LCMS(ESI): m / z=421.1(M+H) + .

[0515] Step g: (2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)(2-oxoethyl)carbamic acid t-butyl ester (14 g, 33.2 mmol) is dissolved in 200 mL of ultra-dry 1,2-dichloroethane, t-butyl carbazate (8.8 g, 66.4 mmol) is added, and the mixture is stirred at room temperature for 1 hour. After that, sodium triacetoxyborohydride (14 g, 66.4 mmol) and sodium cyanoborohydride (6.3 g, 99.6 mmol) are added, and the mixture is reacted at room temperature for 1 hour. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 15.5 g of 2-(2-((t-butoxycarbonyl)(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)amino)ethyl)hydrazine-1-carboxylic acid t-butyl ester. LCMS (ESI): m / z = 537.2 (M+H) + .

[0516] Step h: 2-(2-((t-butoxycarbonyl)(2-(4-chloro-2-fluoro)methyl)methyl)methyl Dissolve 2-(4-chloro-2-fluorophenyl)-N-(2-hydrazineethyl)-2-methylbenzo[d][1,3]dioxol-4-yl)amino)ethyl)hydrazine-1-carboxylic acid t-butyl ester (15.5 g, 28.9 mmol) in 200 mL of dichloromethane, add 4 M hydrogen chloride in 1,4-dioxane (58 mL, 231.2 mmol) dropwise, and stir at room temperature for 4 hours. After completion of the reaction, concentrate the reaction solution under reduced pressure to obtain 2-(4-chloro-2-fluorophenyl)-N-(2-hydrazineethyl)-2-methylbenzo[d][1,3]dioxol-4-amine hydrochloride. LCMS (ESI): m / z = 337.1 (M+H). + .

[0517] Step i: 2-(4-chloro-2-fluorophenyl)-N-(2-hydrazineethyl)-2-methylbenzo[d][1,3]dioxol-4-amine hydrochloride was dissolved in 100 mL of acetic acid, 50 mL of trimethyl orthoformate was added, and the mixture was reacted at 100°C for 3 hours under nitrogen gas protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 7.6 g of 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazine-1(4H)-carbaldehyde. LCMS (ESI): m / z = 375.1 (M+H). + .

[0518] Step j: 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazine-1(4H)-carbaldehyde (7.6 g, 20.3 mmol) is dissolved in 105 mL of a hydrolysis solution of methanol:tetrahydrofuran:water=3:3:1, and sodium hydroxide (8.1 g, 203 mmol) is added. The mixture is allowed to react at room temperature for 6 hours. After the reaction was completed, 100 mL of saturated ammonium chloride solution was poured into the mixture, followed by extraction with dichloromethane three times. The organic phase was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 6.5 g of 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,4,5,6-tetrahydro-1,2,4-triazine (Intermediate 39). LCMS (ESI): m / z = 347.1 (M+H). + .

[0519] Step k: 4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,4,5,6-tetrahydro-1,2,4-triazine (Intermediate 39, 6.5 g, 18.7 mmol), (S)-2-(chloromethyl)-4-(ethoxy-d5)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Intermediate 40, 7.1 g, 20.6 mmol), potassium carbonate (5.2 g, 37.4 mmol) and a catalytic amount of potassium iodide are dissolved in 100 mL of acetonitrile and reacted at 80° C. for 2 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain 10 g of 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazine-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester. LCMS (ESI): m / z=654.3 (M+H). + .

[0520] The compound 2-((4-(2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester was separated into n-hexafluorobenzoates using a preparative liquid chromatography system (Shimadzu, model: LC-20AD) and a CHIRALPAK IA (IA00CE-VD015) chiral chromatography column (Shanghai DAICEL, column size: 0.46 cm ID × 25 cm L). The mixture was eluted with a mobile phase of ethanol (60 / 40 V / V) at a flow rate of 1.0 ml / min and a detection wavelength of 214 nm. The corresponding components were collected and the solvent was removed by rotary evaporation to give the two enantiomers, 2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d] Imidazole-6-carboxylic acid methyl ester and 2-((4-(((R)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazine-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester were obtained with retention times of 10.14 and 14.59 min, respectively, and all showed ee values ​​greater than 98% upon detection.

[0521] Step 1: 2-((4-(((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (4.5 g, 6.9 mmol) was dissolved in 100 mL of 1,4-dioxane to give a 2 M solution. Add NaOH (14 mL, 27.6 mmol) and react overnight at 40 °C. After the reaction is complete, adjust the pH to 5-6 with 2 M hydrochloric acid and separate using a preparative liquid (mobile phase: 0.1% aqueous ammonia-acetonitrile) to obtain 3.5 g of the ammonium salt of compound 76-1. LCMS (ESI): m / z = 640.3 (M+H) + .

[0522] The ammonium salt of 76-1 is dissolved in a 10:1 DCM:MeOH mixture and adjusted to pH 4-5 by adding 2M hydrochloric acid dropwise in an ice bath. The organic phase is collected, dried, and filtered, and the filtrate is concentrated under reduced pressure to obtain the prototype of 76-1.

[0523] 2-((4-(((R)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (4.6 g, 6.9 mmol) was dissolved in 100 mL of 1,4-dioxane, 2 M NaOH (14 mL, 27.6 mmol) was added, and the mixture was incubated at 40 °C overnight. After the reaction was complete, the pH was adjusted to 5-6 with 2 M hydrochloric acid. The ammonium salt of compound 76-2 (3.5 g) was obtained by separation using a preparative liquid (mobile phase: 0.1% aqueous ammonia-acetonitrile). LCMS (ESI): m / z = 640.3 (M+H). + .

[0524] Following the same method as compound 76-1, a prototype of compound 76-2 is prepared. Preparation of the tris(hydroxymethyl)aminomethane (Tris) salt of 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 76-1): The prototype 76-1 and tris(hydroxymethyl)aminomethane were dissolved in methanol in a molar ratio of 1:1, sonicated for 10 minutes, concentrated under reduced pressure at 45°C, and lyophilized to obtain the Tris salt of 76-1.

[0525] Example 77: 2-((4-(2-(4-chloro-2,3-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S Preparation of )-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 77)

[0526] [ka]

[0527] 2-((4-(2-(4-chloro-2,3-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 77) is prepared according to the route shown in formula G. LCMS (ESI): m / z=658.3 (M+H). + .

[0528] Example 78 Preparation of 2-((4-(2-(4-chloro-2,3-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 78)

[0529] [ka]

[0530] 2-((4-(2-(4-chloro-2,3-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 78) is prepared according to the route shown in formula G. LCMS (ESI): m / z=653.2 (M+H). + .

[0531] Example 79 Preparation of 2-((4-(2-(4-chloro-2,5-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 79)

[0532] [ka]

[0533] 2-((4-(2-(4-chloro-2,5-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 79) is prepared according to the route shown in formula G. LCMS (ESI): m / z=653.2 (M+H). + .

[0534] Example 80 Preparation of 2-((4-(2-(4-chloro-2,5-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 80)

[0535] [ka]

[0536] 2-((4-(2-(4-chloro-2,5-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 80) is prepared according to the route shown in formula G. LCMS (ESI): m / z=658.3 (M+H). + .

[0537] Example 81 Preparation of 4-ethoxy-2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 81)

[0538] [ka]

[0539] 4-Ethoxy-2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 81) is prepared according to the route shown in formula G. LCMS (ESI): m / z=669.3 (M+H). + .

[0540] 4-Ethoxy-2-((4-((S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 81-1) and 4 Preparation of -ethoxy-2-((4-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 81-2):

[0541] [ka]

[0542] The chiral resolution and preparation methods of compounds 81-1 and 81-2 are similar to those of compounds 76-1 and 76-2. Preparation of the Tris salt of 4-ethoxy-2-((4-((S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 81-1): The prototype 81-1 and tris(hydroxymethyl)aminomethane were dissolved in methanol in a molar ratio of 1:1, sonicated for 10 minutes, concentrated under reduced pressure at 45°C, and lyophilized to obtain the Tris salt of 81-1.

[0543] Example 82: 4-(ethoxy-d5)-2-((4-(2-(2-fluoro-4-(trimethylsilyl)methyl)-4-methyl-2-methyl ... Preparation of (trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 82)

[0544] [ka]

[0545] 4-(Ethoxy-d5)-2-((4-(2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-((((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 82) is prepared according to the route shown in formula G. LCMS (ESI): m / z = 675.3 (M+H). + .

[0546] 4-(ethoxy-d5)-2-((4-((S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 82-1) and 4 Preparation of -(ethoxy-d5)-2-((4-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 82-2)

[0547] [ka]

[0548] The chiral resolution and preparation methods of compounds 82-1 and 82-2 are similar to those of compounds 76-1 and 76-2. Preparation of the Tris salt of 4-(ethoxy-d5)-2-((4-((S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 82-1): The prototype 82-1 and tris(hydroxymethyl)aminomethane were dissolved in methanol in a molar ratio of 1:1, sonicated for 10 minutes, concentrated under reduced pressure at 45°C, and lyophilized to obtain the Tris salt of 82-1.

[0549] Example 83: 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0550] [ka]

[0551] 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-methoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 83) is prepared according to the route shown in formula G. LCMS (ESI): m / z=634.3 (M+H). + .

[0552] Example 84: 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0553] [ka]

[0554] 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(methoxy-d3)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 84) is prepared according to the route shown in formula G. LCMS (ESI): m / z = 637.3 (M+H). + .

[0555] Example 85: 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0556] [ka]

[0557] 2-((4-(2-(4-chloro-2-methoxyphenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 85) is prepared according to the route shown in formula G. LCMS (ESI): m / z=648.3 (M+H). + .

[0558] Example 86: 2-((4-(2-(2,4-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0559] [ka]

[0560] 2-((4-(2-(2,4-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-ethoxy-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 86) is prepared according to the route shown in formula G. LCMS (ESI): m / z=620.3 (M+H) + .

[0561] Example 87: 2-((4-(2-(2,4-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0562] [ka]

[0563] 2-((4-(2-(2,4-difluorophenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-4-(ethoxy-d5)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 87) is prepared according to the route shown in formula G. LCMS (ESI): m / z=625.4 (M+H). + .

[0564] Example 88: 4-Methoxy-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0565] [ka]

[0566] 4-Methoxy-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 88) is prepared according to the route shown in formula G. LCMS (ESI): m / z=668.4 (M+H) + .

[0567] Example 89: 4-(Methoxy-d3)-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0568] [ka]

[0569] 4-(Methoxy-d3)-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 89) is prepared according to the route shown in formula G. LCMS (ESI): m / z = 671.3 (M+H). + .

[0570] Example 90: 4-ethoxy-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0571] [ka]

[0572] 4-Ethoxy-2-((4-(2-(2-methoxy-4-(trifluoromethyl)phenyl)-2-methylbenzo[d][1,3]dioxol-4-yl)-5,6-dihydro-1,2,4-triazin-1(4H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 90) is prepared according to the route shown in formula G. LCMS (ESI): m / z=682.3 (M+H). + .

[0573] H NMR spectrum of the compound:

[0574] [Table 1] TIFF2026500865000152.tif234160TIFF2026500865000153.tif234160TIFF2026500865000154.tif23316 0TIFF2026500865000155.tif234160TIFF2026500865000156.tif235160TIFF2026500865000157.tif46160

[0575] Pharmacological Examples 1. Measurement of GLP-1 receptor-mediated agonist activity (1) Test Method: The agonist activity of compounds for the GLP-1 receptor was characterized by their effect on cAMP levels in the hGLP-1R / HEK293 cell line. The human GLP-1 receptor gene (hGLP-1R) was amplified from cDNA of the human colon adenocarcinoma cell line NCl-H716 (Cell Bank of the Chinese Academy of Sciences, #TCHu210) and cloned into the HA-pcDNA3.1 vector (Addgene, #128034) so ​​that the HA-tag was located at the N-terminus of hGLP-1R. The hGLP-1R / HA-pcDNA3.1 plasmid was then introduced into HEK293 cells to establish a stable hGLP-1R / HEK293 cell line. The hGLP-1R / HEK293 cells were digested, centrifuged, and resuspended in culture medium (DMEM + 0.2% BSA, m / v) to a cell density of 2 × 10 5 Adjust the cell suspension to 10 cells / mL and add 5 μL (1 x 10 cells / mL) of IBMX (3-isobutyl-1-methylxanthine, final concentration 0.5 mM). 3Compounds were dissolved in DMSO to prepare a 10 mM stock solution. Starting at 100 μM, the compounds were diluted 10-fold for seven dilution points, with the eighth point in DMSO. 2 μL of different concentrations of test compound were added to 98 μL of culture medium, vortexed, and 5 μL was added to the 384-well plate (final concentrations of test compound ranged from 0 to 100 nM, and final DMSO concentration was 1%, v / v). The mixture was incubated in a dark incubator (37°C, 5% CO2) for 30 minutes, after which 10 μL of cAMP detection reagent (LANCE Ultra cAMP Detection Kit, PerkinElmer, #TRF0264) was added, mixed thoroughly, and incubated at room temperature for 1 hour in the dark. After the reaction was completed, HTRF signals were read using an Envision 2104 multimode microplate reader. All samples were tested in triplicate wells, and the excitation signal ratio of each single-hole receptor donor was calculated using the formula: Ratio = Signal 665 nm / Signal 620 nm. The HTRF signal ratio and the corresponding compound concentration were analyzed and processed using GraphPad Prism 8 software, and an S-shaped dose-response curve was fitted to calculate the EC of the compound. 50 Get the value.

[0576] (2) Test results

[0577] [Table 2] TIFF2026500865000159.tif24160

[0578] As can be seen from Table 1, the compounds of the present invention are highly potent hGLP-1 receptor agonists. The activity of most of the test compounds is greater than that of the control compound PF-06882961.

[0579] (3) Comparative data The structural feature of the compounds of the present invention represented by the general formulas (I) and (II) is that the substituent at the 4-position of the "benzimidazole-6-carboxylic acid" skeleton is -OR. 2 In the prior art, the situation of a substituent such as -H, halogen, alkyl group, alkynyl group, heterocyclic group, etc. at the position is disclosed, but the situation where the position is -OR 2 It is not clearly stated whether the position is -OR 2 The effect of the present invention has not been clarified. 2 The introduction of -OR has had unexpected effects, especially 2 It has been found that the introduction of -OR into the 4-position of "benzimidazole-6-carboxylic acid" significantly improves the agonist activity of the compound against the hGLP-1 receptor. 2 The remarkable effect of introducing the following will be further explained.

[0580] As can be seen from Table 2, compared with various types of compounds disclosed in the prior art, when other structural features are completely consistent, simply introducing a group such as a methoxy group, an ethoxy group, or a cyclopropoxy group at the 4-position of "benzimidazole-6-carboxylic acid" or replacing other substituents with a group such as a methoxy group, an ethoxy group, or a cyclopropoxy group can improve the activity of the compound by several to several tens of times, and the activity of some compounds is comparable to or even exceeds the level of endogenous GLP-17-36.

[0581] [Table 3] TIFF2026500865000161.tif224160TIFF2026500865000162.tif237160TIFF2026500865000163.tif57160

[0582] 2. Evaluation of Compound Effects on β-arrestin Recruitment (1) Test method The Promega NanoBiT protein-protein reaction system was used to detect the recruitment of GLP-1R to β-arrestin 1 and β-arrestin 2. The NanoBit protein-protein reaction system is a two-subunit system based on NanoLuc luciferase and can be used to study intracellular protein interactions. Here, the LgBiT (17.6 kDa) and SmBiT (11 amino acids) subunits are fused to a protein of interest, respectively. When the protein of interest interacts, the two subunits come into close proximity to form a catalytically active enzyme that catalyzes the luminescence of the luciferase substrate. The human GLP-1R gene was first ligated to the N-terminus of LgBiT, and the β-arrestin 1 / 2 gene was cloned to the C-terminus of SmBiT. The fusion proteins were then introduced into the pcDNA3.0 vector to construct plasmids expressing the fusion proteins, such as hGLP-1R-LgBiT and SmBiT-β-arrestin 1 / 2, respectively. hGLP-1R-LgBit plasmid and SmBit-β-arrestin 1 (or SmBit-β-arrestin 2) plasmid were added at 1 μg of plasmid / 2 × 10 6 Immediately after transfection, the cells were co-transfected with 4 x 10 5 The cells are added to a 96-well white-bottom plate at a density of 100 cells / well, and the cells are cultured in an incubator (37°C, 5% CO2) for 20 hours.

[0583] After 20 hours, discard the liquid in the wells and add 40 μL of fresh culture medium (DMEM + 0.2% BSA, m / v) followed by 10 μL of Nano-Glo Live Cell Detection Solution (Promega, #N2011). Then, place the cells in an incubator and incubate for 10 minutes. Compounds were dissolved in DMSO to prepare 10 mM stock solutions. Starting at 100 μM, these were diluted 10-fold and stocked with 3 μL of the test compound at different concentrations. (The final GLP-1 concentrations ranged from 0 to 10 μM, while the remaining compounds ranged from 0 to 100 μM. The final DMSO concentration was 1% (v / v) for all compounds.) After incubating the cells for 10 minutes, add 25 μL of compound-containing culture medium to each well and incubate at room temperature for 5 minutes. The fluorescent signal was then detected using an Envision 2104 multimode microplate reader (PerkinElmer). All samples were tested in triplicate wells, and the fluorescence signal ratios and corresponding compound concentrations were analyzed and processed using GraphPad Prism 8 software to fit S-shaped dose-response curves and calculate the EC values ​​of the compounds. 50 Get the value.

[0584] (2) Test results In addition to G proteins, β-arrestin is another major signaling protein for the GLP-1 receptor. As can be seen in Figures 1 and 2, endogenous G The maximum agonist effect (E) of LP-1 on the recruitment of β-arrestin 1 and β-arrestin 2 was max) is 100%. PF-06882961 and ref. C2 are Example 4A-01 and Compound 2, respectively, disclosed in the aforementioned invention applications WO2018109607 and CN2022114139828. Their maximum agonistic effects on β-arrestin 1 and β-arrestin 2 are 75-80%. Compound 20, Compound 4, and Compound 3 are compounds disclosed in the present invention. Their agonistic activity on G protein cAMP signaling is increased several to several tens of times, but their maximum agonistic effects on β-arrestin 1 and β-arrestin 2 recruitment are significantly reduced to 30-50%. This suggests that introducing an alkoxy group at the 4-position of "benzimidazole-6-carboxylic acid" unexpectedly increases the signaling bias downstream of the GLP-1 receptor. Many studies have shown that β-arrestin mediates the desensitization of GLP-1 receptors and reduces the recruitment of β-arrestin, thereby enhancing blood glucose levels and weight loss effects (Br J Pharmacol. 2022, 179:492-510). The compounds of the present invention exhibit stronger agonistic effects on G protein signaling and weaker agonistic effects on β-arrestin signaling, and are therefore expected to achieve better blood glucose levels and weight loss effects.

[0585] 3. Pharmacodynamic Experiments 3.1.Animals Recombinant hGLP-1R gene knock-in mice, male, 8-10 weeks old, specific pathogen-free (SPF) grade, were purchased from BIOCYTOGEN Jiangsu Gene Biology Technology Co., Ltd. All experimental animals were housed in an SPF-grade environment in the National Chemical Library Animal Room, with a temperature of 24±2°C, a relative humidity of 40-60%, air cleanliness level 7, and a 12-hour light / dark cycle. They were continuously fed a cobalt-60 ice-line sterilized complete pelleted mouse diet (Shanghai Shilin Bioscience and Technology Co., Ltd., rat and mouse maintenance diet) ad libitum and continuously provided with tap water (used after autoclaving). The cages used were transparent polyetherimide cages (CP-8 type mouse cages, Suzhou Fengshi Group Laboratory Animal Equipment Co., Ltd.), and the bedding was corn cobs (Dezhou Gumei Agricultural Science and Technology Co., Ltd., used after autoclaving). Each cage contained 3-5 animals, and the cage card was labeled with information such as the IACUC approval number, experiment number, start time of the experiment, person in charge, experimenter, animal source, group, and animal number. Purchased mice were allowed to acclimate to the housing environment for at least 7 days before use. The animal use procedures for this experiment were approved by the Shanghai Institute of Materia Medica IACUC Committee.

[0586] 3.2. Oral glucose tolerance experiment in mice (1) Mouse model: the above-mentioned hGLP-1 receptor knock-in mice, 8 to 10 weeks old, 5 to 8 male mice per experimental group.

[0587] (2) Compound preparation: blank control group, ultrapure water containing 1% DMSO (v / v), PF-06882961 ammonium salt (1 mg / kg) dissolved in a small amount of DMSO and added to pure water, and ammonium salt of the test compound (1 mg / kg) dissolved in a small amount of DMSO and added to pure water.

[0588] (3) Experimental procedure: The mice were fasted overnight, and blood glucose levels were measured at the tail of the mice. After oral administration for 60 minutes, blood glucose levels were measured again as the zero blood glucose level. Then, 2 g / kg of glucose was orally administered. Blood glucose levels were measured using a blood glucose meter 15, 30, 60, and 90 minutes after administration. To examine the effect of long-term administration on glucose tolerance, blood glucose levels were measured again 240 minutes after administration. 2g / kg of glucose was orally administered, and changes in blood glucose levels were measured at 180 minutes, 195 minutes, 210 minutes, 240 minutes, and 270 minutes.

[0589] (4) Experimental results As shown in Figures 3 and 4, the ammonium salt of compound 20 of the present invention can significantly reduce blood glucose concentration and area under the blood glucose curve at an oral dose of 1 mg / kg, and its effect is superior to that of the positive control PF-06882961 ammonium salt at the same dose, demonstrating its superior ability to treat diabetes.

[0590] As shown in Figures 5 and 6, the ammonium salt of compound 19 of the present invention can significantly reduce blood glucose concentration and area under the blood glucose curve at an oral dose of 1 mg / kg, and its effect is superior to that of the positive control PF-06882961 ammonium salt at the same dose. In particular, the ammonium salt of compound 19 showed a more significant blood glucose lowering effect in a long-term oral glucose tolerance test, indicating that its efficacy is more sustained and it has better antidiabetic ability.

[0591] 3.3. Mouse feeding suppression experiment 3.3.1. Effect of Compound 19 (1) Mouse model: the above-mentioned hGLP-1 receptor knock-in mice, 10 weeks old, 5 males per experimental group.

[0592] (2) Compound preparation: For the blank control group, ultrapure water containing 10% DMSO (v / v) was used. PF-06882961 ammonium salt (30 mg / kg) was dissolved in a small amount of DMSO and then added to the solvent. The ammonium salt of the test compound (30 mg / kg) was dissolved in a small amount of DMSO and then added to the solvent.

[0593] (3) Experimental process: The mice were given food and water as normal. One mouse was placed in a cage and given the drug orally at the beginning of the night cycle (7:00 PM). The food in each cage was weighed at 0, 2.5, 5, 12 (7:00 AM, the beginning of the day cycle), and 24 hours after administration, and the amount of food consumed by the mouse was calculated.

[0594] (4) Experimental results As shown in Figure 7, the ammonium salt of compound 19 of the present invention significantly suppressed food intake in experimental mice within 0 to 12 hours after oral administration, an effect superior to that of the positive control PF-06882961 ammonium salt at the same dose. Peptidomimetic GLP-1 receptor agonists currently used in clinical settings are known to suppress appetite and reduce body weight. Therefore, the compounds of the present invention may also be used as raw materials for small molecule GLP-1 receptor agonists.

[0595] 3.3.2. Effect of Compound 76-1 (1) Mouse model: the above-mentioned hGLP-1 receptor knock-in mice, 10 weeks old, 7 males in each experimental group.

[0596] (2) Compound preparation: blank control group, ultrapure water containing 10% DMSO (v / v); PF-06882961 ammonium salt, 10 or 30 mg / kg, dissolved in a small amount of DMSO and then added to the solvent; and compound 76-1 ammonium salt, 10 or 30 mg / kg, dissolved in a small amount of DMSO and then added to the solvent.

[0597] (3) Experimental procedure: Each mouse was placed in a cage and fasted for 6 hours before the experiment. At the beginning of the night cycle (7:00 PM), the drug was orally administered by force. After administration, the mice were then fed 2.5, 5, and 12 mg / kg of the drug. The weight of the food in each cage is weighed at 7:00 AM (the start of the circadian cycle) and 24 hours later, and the amount of food consumed by the mice is calculated.

[0598] (4) Experimental results As shown in Figure 8, the ammonium salt of compound 76-1 of the present invention can significantly suppress the food intake of experimental mice within 0 to 12 hours after oral administration of 10 or 30 mg / kg, and the effect is superior to that of the positive control PF-06882961 ammonium salt at the same dose.

[0599] 3.4. Long-term weight loss experiment of compound 76-1 in hGLP-1R mice (1) Mouse model: the above-mentioned hGLP-1 receptor knock-in mice, male, 20 weeks old, weighing 35-40 g, 9 mice per experimental group.

[0600] (2) Compound preparation: blank control group: ultrapure water containing 5% DMSO (v / v); PF-06882961 ammonium salt (30 mg / kg) was dissolved in a small amount of DMSO and then added to the solvent; and the compound to be tested: 76-1 ammonium salt (30 mg / kg) was dissolved in a small amount of DMSO and then added to the solvent.

[0601] (3) Experimental procedure: Three mice per cage were fed a high-fat diet (Research Diets, Catalog No. D12492) and administered the test compound by oral gavage once a day for 15 consecutive days. The mice were weighed daily, and 24 hours after administration, the fat mass and muscle mass of the mice were detected using a Bruker benchtop nuclear magnetic resonance spectroscopy (Model LF90II).

[0602] (4) Experimental results As shown in Figure 9, after feeding a high-fat diet (HFD), the weight of mice in the blank control group gradually increased, but administration of the ammonium salt of PF-06882961 or the ammonium salt of compound 76-1 of the present invention effectively suppressed weight gain in the mice. Compared with the blank control group, 30 mg / kg of the ammonium salt of PF-06882961 and 30 mg / kg of the ammonium salt of compound 76-1 reduced body weight by 10.2% and 20.4%, respectively, after 15 days of administration. This indicates that the compounds of the present invention have a more effective weight-reducing effect than PF-06882961 at the same dose. After 15 days of administration, the body fat and muscle mass of the mice were detected (Figure 10). Compared with healthy mice, the fat mass of HFD mice was significantly increased and the lean meat mass was decreased. 30 mg / kg of the ammonium salt of compound 76-1 could effectively inhibit these changes, indicating its excellent potential in the treatment of obesity.

[0603] 3.5. Hypoglycemic effect of compound 76-1 (1) Experimental method Mouse model: hGLP-1R transgenic mice, 6 female mice per experimental group.

[0604] Compound preparation: blank control group, ultrapure water containing 1% DMSO; positive drug PF-06882961 ammonium salt, 0.3 mg / kg, dissolved in a small amount of DMSO and added to pure water; compound 76-1 ammonium salt, 0.1 mg / kg, 0.3 mg / kg, dissolved in a small amount of DMSO and added to pure water.

[0605] Experimental procedure: The mice were fasted overnight, and the blood glucose level at the tail of the mice was measured. 30 minutes after oral administration, the blood glucose level was measured again as the zero-point blood glucose level. Then, 2 g / kg of sugar was orally administered, and the blood glucose level was measured using a blood glucose meter 15, 30, 60, and 90 minutes after the administration of sugar.

[0606] (2) Experimental results As shown in Figure 11A and Figure 11B, compound 76-1 ammonium salt can dose-dependently reduce blood glucose levels and the area under the blood glucose curve (AUC) in mice, with an effective dose as low as 0.1 mg / kg, indicating its potential as an excellent antidiabetic agent.

[0607] 3.6. Anti-phagy effect of Tris salts of compounds 81-1 and 82-1 (1) Experimental method Mouse model: hGLP-1R KI mice, 8 female mice per experimental group.

[0608] Compound preparation: The blank control group was a 2:98 (v / v) Tween 80 / 0.5% (w / v) methylcellulose A4M (CMC-A4M) aqueous solution. The positive compounds PF-06882961 and compounds 81-1 and 82-1 were all first prepared in Tris salt and then in the above solvents, with a dose of 30 mg / kg.

[0609] Experimental process: The mice were separated and fasted 6 hours before the start of the experiment, and then orally administered with gavage at the beginning of the night cycle (7:00 PM). The food weight in each cage was weighed at 0, 2.5, 5, 12 (7:00 AM, the beginning of the night cycle), and 24 hours after administration, and the amount of food consumed by the mice was calculated.

[0610] (2) Experimental results As shown in Figure 12, the Tris salts of compounds 81-1 and 82-1 can significantly reduce food intake in mice after a single oral administration, and this effect can be maintained for 24 hours. The effect of the Tris salt of compound 81-1 is particularly significant, as its food intake suppression effect at 5, 12, and 24 hours is significantly greater than that of the Tris salt of the positive control PF-06882961 at the same dose, indicating that the compounds of the present invention have better weight loss potential.

[0611] 4. hERG channel inhibitory effect test (1)Cell preparation CHO cells expressing hERG protein were cultured at 175 cm 2 Culture in a culture flask. When the cell density reaches 60-80%, remove the culture medium, wash once with 7 mL of PBS, and then add 3 mL of Detachin for digestion. After complete digestion, neutralize the cells with 7 mL of culture medium, then centrifuge. Aspirate the supernatant and resuspend in 5 mL of culture medium to ensure a cell density of 2-5 x 106 / mL.

[0612] (2) Solution preparation

[0613] [Table 4]

[0614] (3) Electrophysiological recording process The Qpatch instrument automatically completed the single-cell high-impedance sealing and whole-cell recording process. After switching to whole-cell recording mode, the cell was clamped at -80 mV and given a 5-second +20 mV depolarizing stimulus. A 50-ms pre-voltage of -50 mV was applied, followed by a 5-second repolarization to -50 mV and a return to -80 mV. This voltage stimulus was applied every 15 seconds, and after 2 minutes of recording, extracellular solution was added for 2 minutes, and then administration began. Compound concentrations were tested, starting with the lowest test concentration. Each test concentration was administered for 2 minutes. After all concentrations had been administered, 10 μM Cisapride, a positive control compound, was administered. Each concentration was tested on at least three cells (n ≥ 3).

[0615] (4) Compound preparation The compound stock solution was diluted with extracellular solution, and 5 μL of 20 mM compound stock solution was added to 2495 μL of extracellular solution, followed by a 500-fold dilution to 40 μM. The final concentrations to be tested were then serially diluted 3-fold with extracellular solution containing 0.2% DMSO (v / v). The highest test concentration of the compound was 40 μM, followed by six successive concentrations of 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM, respectively. The highest test concentration of the positive compound, Cisapride, was 3 μM, followed by six successive concentrations of 3, 1, 0.333, 0.111, 0.037, and 0.012 μM, respectively. The DMSO content in the final test concentrations did not exceed 0.2% (v / v), as DMSO at this concentration does not affect the hERG potassium channel.

[0616] (5) Data analysis The experimental data are analyzed by XLFit software. (6) Test results As can be seen from Table 3, compared with PF-06882961, the compounds of the present invention have a lower inhibitory effect on the hERG potassium channel, and in particular, when the A ring in general formula (II) is

[0617] [ka] In the field of medicinal chemistry, hERG channel blockade is considered an indicator of low cardiotoxicity risk. The data in Table 3 show that compounds of the present invention have a lower risk of cardiotoxicity.

[0618] [Table 5]

[0619] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A compound represented by general formula (II), a stereoisomer thereof, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 where X is CR Ｘ or N, and R Ｘ is H or a halogen, R １ is a 4- to 8-membered heterocyclic group, a 5- to 8-membered heteroaryl group, or a C3-C8 cycloalkyl group, wherein the heterocyclic group, heteroaryl group, or cycloalkyl group is unsubstituted or optionally substituted with one or more groups selected from the group consisting of halogen, a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a cyano-substituted C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group, and a cyano group; R ２ is a C1-C6 alkyl group, a halogenated C1-C6 alkyl group, a deuterated C1-C6 alkyl group, a cyano-substituted C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl-substituted C1-C6 alkyl group, a phenyl group, a phenyl-substituted C1-C6 alkyl group, a 5- to 8-membered heteroaryl group, a 5- to 8-membered heteroaryl-substituted C1-C6 alkyl group, a 4- to 8-membered heterocyclic group, or a 4- to 8-membered heterocyclic-substituted C1-C6 alkyl group, wherein the cycloalkyl group, phenyl group, heteroaryl group, and heterocyclic group are unsubstituted or optionally substituted with one or more groups selected from the group consisting of halogen, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl group, a halogenated C1-C6 alkoxy group, and a cyano group; 【Chemistry 2】 teeth, 【Transformation 3】 wherein N on the ring is selected from the group consisting of -CH ２ -bonded to 【Chemistry 4】 teeth, 【Transformation 5】 wherein the benzene ring or pyridine ring is selected from the group consisting of: 【Transformation 6】 binds to 【Transformation 7】 teeth, 【Transformation 8】 is selected from the group consisting of Each R ３ , R ４ , R ７ are each independently H, halogen, or a C1-C6 alkyl group; R ５ is H, a C1-C6 alkyl group or a halogenated C1-C6 alkyl group, Each R ６ are each independently H, a halogen, a cyano group, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogenated C1-C6 alkyl group, or a halogenated C1-C6 alkoxy group, The compound as described above, wherein m, n, p, and q each independently represent an integer of 1 to 4.

2. R １ is a 4- to 6-membered heterocyclic group The compound of claim 1.

3. R ２ is a C1-C4 alkyl group, a halogenated C1-C4 alkyl group, a deuterated C1-C4 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyl-substituted C1-C4 alkyl group, a phenyl-substituted C1-C4 alkyl group, a 5- to 6-membered heteroaryl group, a 5- to 6-membered heteroaryl-substituted C1-C4 alkyl group, or a 5- to 6-membered heterocyclic-substituted C1-C4 alkyl group, wherein the cycloalkyl group, heteroaryl group, or heterocyclic group is unsubstituted or optionally substituted with one or more groups selected from the group consisting of a halogen atom and a C1-C6 alkyl group. The compound of claim 1.

4. R ５ is a C1-C3 alkyl group The compound of claim 1.

5. Each R ６ are each independently H, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, or halogenated C1-C4 alkoxy. The compound of claim 1.

6. The compound represented by general formula (II) has the following structural formulae (II-a) to (II-k): 【Chemistry 9】 【change】 Here, R ２ , R ５ , R ６ , p are defined as the same as in general formula (II). The compound of claim 1.

7. The compound is characterized in that it is selected from the group consisting of: The compound of claim 1. 【Chemistry 10】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

8. 1. A pharmaceutical composition comprising: A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, a stereoisomer thereof, a deuterated product thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary agent.

9. Use of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8, The use as described above, characterized in that it is used for the preparation of a GLP-1 receptor agonist, or for the preparation of a medicament for preventing and / or treating a disease or symptom associated with a disorder of the GLP-1 receptor signaling pathway.

10. The disease or symptom associated with a disorder of the GLP-1 receptor signaling pathway is selected from diabetes, metabolic syndrome, diabetic complications, obesity, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), Parkinson's disease, dementia, hyperglycemia, impaired glucose tolerance, arteriosclerosis, hypertension, hyperlipidemia, coronary artery disease, cerebral infarction, and cerebral apoplexy, and the disease or symptom is preferably type II diabetes or obesity.

10. The use according to claim 9.

11. An intermediate (III) for preparing a compound represented by general formula (II), 【Chemistry 11】 Here, the definition of each substituent is as described in general formula (II), intermediate (III) for preparing the compound represented by general formula (II).

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