TWI816437B - Benzimidazole or azabenzimidazole-6-carboxylic acid compounds and applications thereof - Google Patents

Abstract

The present disclose a benzimidazole or azabenzimidazole-6-carboxylic acid compounds and application thereof. The benzimidazole or azabenzimidazole-6-carboxylic acid compounds has a structure as shown in formula (I). The benzimidazole or azabenzimidazole-6-carboxylic acid compounds can effectively activate the GLP-1R downstream signal pathway and improve cAMP expression, thereby achieving the effects of promoting insulin secretion, treating diabetes and its complications, which has a great application value.

Description

Benzimidazoles or azabenzimidazole-6-carboxylic acid compounds and their applications

The invention relates to the technical field of chemical medicine, and specifically relates to a benzimidazole or azabenzimidazole-6-carboxylic acid compound and its application.

Type 2 diabetes (T2DM) and its complications have become a chronic non-communicable disease that seriously threatens human health, and the number of cases is increasing year by year. Pancreatic β-cell dysfunction and insulin resistance are important pathogenesis of T2DM (N Engl J Med, 2007. 356: 213-215). Current diabetes treatment drugs mainly include insulin and its analogs, dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), sodium-glucose synergistic Transporter-2 inhibitors (SGLT-2i), metformin, α-glucosidase inhibitors, sulfonylureas (SU), thiazolidinediones (TZDs), glinides, etc. (Biomed Pharmacother, 2020 . 131: 110708). GLP-1 RA has the advantages of strong glucose-dependent hypoglycemia, no increase in the risk of hypoglycemia, weight reduction, and mild blood pressure reduction. Most of the drugs have also been confirmed to have cardiovascular benefits, and their market share has grown significantly in recent years. (Cell Metab, 2018. 27: 740-756). More and more clinical trials have confirmed that GLP-1 RA plays a role in non-alcoholic steatohepatitis (NASH) (Adv Exp Med Biol, 2021. 1307: 417-440) and improves cardiovascular prognosis (Diabetes Metab Syndr, 2021. 15: 837 -843), Alzheimer's disease (Diabetes, 2014. 63: 2262-72), and has a significant role in protecting the kidneys and improving the outcome of diabetic nephropathy (N Engl J Med, 2021. 384: e42).

Glucagon-like peptide-1 receptor (GLP-1R) is mainly expressed in tissues such as the small intestine, pancreas, cardiovascular, brain, and salivary glands (Endocrinology, 2014. 155: 1280-1290). It belongs to the 7-transmembrane G A member of the protein-coupled receptor (GPCR) B family, which is initiated by glucagon-like peptide-1 (GLP-1) secreted by intestinal L cells and increases intracellular cyclic adenosine monophosphate (cAMP). ) level induces the opening of voltage-gated Ca ²⁺ channels, thereby promoting the proliferation and differentiation of pancreatic beta cells to regulate blood sugar (J Mol Biol, 2020. 432: 1347-1366).

Currently, there are multiple injectable peptide GLP-1 RAs approved for the treatment of T2DM, such as liraglutide, exenatide, dulaglutide, semaglutide, polydiethanol loxenatide, etc. Liraglutide is also approved for the treatment of obesity due to its role in weight reduction (Mol Metab, 2021. 46: 101102; ACS Pharmacol Transl Sci, 2019. 2: 468-484). In September 2020, the U.S. FDA officially approved the launch of the world's first oral GLP-1 antidiabetic drug, semaglutide, for use in combination with diet and exercise to improve blood sugar control in patients with type II diabetes. Since semaglutide is a polypeptide drug, an oral formula is formed by combining semaglutide with the small molecule absorption enhancer SNAC. The combination with SNAC allows semaglutide to be absorbed in the stomach, and the partial dissolution of SNAC can A relatively high pH environment is formed locally in the stomach, thereby increasing the solubility of semaglutide and reducing the degradation effect of intragastric peptidases. The main disadvantages are that its oral bioavailability is extremely low (only 0.4%-1%), the cost increases significantly, and the main adverse reactions are gastrointestinal reactions, with the incidence of nausea being about 15~20% (Ann Pharmacotherapy, 2019, 54: 478- 485). Small molecule GLP-1R agonists can overcome the oral absorption disorder of peptide drugs, and they can more easily penetrate the blood-brain barrier and act on GLP-1R in the arcuate nucleus of the hypothalamus to reduce appetite, ultimately lowering blood sugar at the same time. , may have a better weight loss effect (J Clin Invest, 2014. 124: 4223-4226).

At present, small molecule oral GLP-1R agonists mainly include OWL833 (Proc Natl Acad Sci U S A, 2020. 117: 29959-29967), PF-06882961 (Proc Natl Acad Sci U S A, 2020. 117: 29959-29967) and TTP273 ( Nature, 2020. 577: 432-436). Phase I clinical results of PF-06882961 show that it has significant effects on blood sugar lowering and weight loss in patients with type 2 diabetes. In patients with type 2 diabetes, PF-06882961 was administered twice daily in combination with metformin. After 28 days of treatment, the 120 mg dose reduced HBA1c by 1.2% and reduced weight by 7.9 kg (ClinicalTrials.gov Identifier: NCT03538743).

Based on the fact that the overall incidence of type 2 diabetes is very high and there are currently no effective oral small molecule drugs approved to treat it, the present invention provides a new class of benzimidazole or azabenzimidazole-6-carboxylic acid compounds that can effectively It activates the GLP-1R downstream signaling pathway and increases the expression of cAMP, thereby promoting insulin secretion and treating diabetes and its complications, which has great application value.

Specifically, the present invention provides benzimidazole or azabenzimidazole-6-carboxylic acid compounds represented by formula (I) or their pharmaceutically acceptable salts or their stereoisomers: (I) Among them: R ₁ and R ₂ are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R ₃ and R ₄ are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy; or R ₃ and R ₄ are connected to form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring; R ₅ is selected from: C1-C4 alkyl substituted by a 3-8 membered heterocyclic group, 5 -10-membered heteroaryl-substituted C1-C4 alkyl, C1-C6 alkoxy-substituted C1-C4 alkyl; wherein, the 3-8-membered heterocyclyl and 5-10-membered heteroaryl in R ₅ The group can be independently optionally substituted by one or more R ₁₀ ; R ₆ and R ₇ are independently selected from: H, C1-C6 alkyl; or R ₆ and R ₇ together form G, G is selected from =O; each R ₈ and R ₉ are independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen substitution C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, amine-substituted C1-C6 alkyl, C1-C6 alkylamine-substituted C1 -C6 alkyl, aryl, heteroaryl, nitro, cyano, -OR, -N(R) ₂ , -SR, -C(O)OR, -C(O)N(R) ₂ , - C(O)R, -S(O)R, -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -N(R)C(O)R; R is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl base, C1-C6 alkyl substituted by C1-C6 alkoxy, C1-C6 alkyl substituted by amine, C1-C6 alkyl substituted by C1-C6 alkylamine; n is selected from: 0, 1 or 2 ; p is selected from: 1 or 2; m is selected from: 1, 2 or 3; W is selected from: O, S, NR ₁₀ ; W ₁ is selected from: O, S; Q is selected from: C, CH, N; X Selected from: N, CR ₁₀ ; Y is selected from: N, CR ₁₁ ; R ₁₀ is selected from: H, C1-C6 alkyl, C1-C6 alkoxy; R ₁₁ is selected from: H, C1-C6 alkyl, C1-C6 alkoxy; or R ₁₁ and R ₆ are connected to form a 5-8 membered heterocyclic ring; the dotted line between Q and adjacent C indicates that the chemical bond between Q and adjacent C can be a single bond or a double bond.

In some embodiments, the benzimidazole or azabenzimidazole-6-carboxylic acid compound has the structure shown in the following formula (II) or formula (III): (II) (III).

In some embodiments, the benzimidazole or azabenzimidazole-6-carboxylic acid compound has the structure shown in the following formula (IV) or formula (V): (IV) (V).

In some embodiments, the benzimidazole or azabenzimidazole-6-carboxylic acid compound has the structure shown in the following formula (VI) or formula (VII): (VI) (VII).

In some embodiments, W is O, and R ₆ and R ₇ are each independently selected from: H, C1-C6 alkyl.

In some of these embodiments, W ₁ is 0.

In some of these embodiments, Q is selected from: C, CH.

In some of these embodiments, X is selected from: N, CH.

In some embodiments, R ₁ and R ₂ are each independently selected from: H, halogen, C1-C3 alkyl, C1-C3 alkoxy.

In some embodiments, R ₃ and R ₄ are each independently selected from: H, C1-C3 alkyl, C1-C3 alkoxy.

In some embodiments, R ₅ is selected from: C1-C4 alkyl substituted by 3-4 membered heterocyclyl, C1-C4 alkyl substituted by 5-6 membered heteroaryl, C1-C3 alkoxy substituted C1-C4 alkyl; wherein, the 3-4-membered heterocyclyl and 5-6-membered heteroaryl in R ₅ can be independently optionally substituted by one or more R ₁₀ .

In some embodiments, R ₅ is selected from: 3-4-membered heterocyclyl-substituted methyl, 3-4-membered heterocyclyl-substituted ethyl, 5-6-membered heteroaryl-substituted methyl, 5- 6-membered heteroaryl-substituted ethyl; wherein, the 3-4-membered heterocyclyl and 5-6-membered heteroaryl in R ₅ can be independently optionally substituted by one or more R ₁₀ , and R ₁₀ is selected from From: H, C1-C3 alkyl.

In some embodiments, _R5 is selected from: oxetane-substituted methyl, oxetane-substituted ethyl, ethylimidazole-substituted methyl, ethylimidazole-substituted ethyl.

In some embodiments, R ₆ and R ₇ are each independently selected from: H, C1-C3 alkyl.

In some embodiments, each R ₈ and R ₉ are independently selected from: H, halogen, cyano, C1-C3 alkyl, halogen-substituted C1-C3 alkyl.

In some embodiments, each R ₈ is independently selected from: H, halogen, C1-C3 alkyl; each R ₉ is independently selected from: H, halogen, cyano, C1-C3 alkyl, trifluoromethyl .

In some embodiments, each R ₈ is independently selected from: H, Cl, F, and methyl; each R ₉ is independently selected from: cyano, Cl, and methyl.

In some embodiments, the benzimidazole or azabenzimidazole-6-carboxylic acid compound is selected from the following compounds: Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 10 Compound 11 Compound 12 Compound 13 Compound 14 Compound 15 Compound 16 Compound 17 Compound 18 Compound 19 Compound 20 Compound 21 Compound 22 Compound 23 Compound 24 Compound 25 Compound 26 Compound 27 Compound 28 Compound 29 Compound 30 Compound 31 Compound 32 Compound 33 Compound 34 Compound 35 Compound 36 Compound 37 Compound 38 Compound 39 Compound 40 Compound 41 Compound 42 Compound 43 Compound 44 Compound 45 Compound 46 Compound 47 Compound 48 Compound 49 Compound 50 Compound 51 Compound 52 Compound 53 Compound 54 Compound 55 Compound 56 Compound 57 Compound 58 Compound 59 Compound 60 Compound 61 Compound 62 Compound 63 Compound 64 Compound 65 Compound 66.

The present invention also provides the use of the above-mentioned benzimidazole or azabenzimidazole-6-carboxylic acid compounds or their pharmaceutically acceptable salts or their stereoisomers.

The specific technical solutions are as follows:

Use of the above-mentioned benzimidazole or azabenzimidazole-6-carboxylic acid compounds or their pharmaceutically acceptable salts or their stereoisomers in the preparation of GLP-1R agonists.

The above-mentioned benzimidazole or azabenzimidazole-6-carboxylic acid compounds or their pharmaceutically acceptable salts or their stereoisomers are used for the prevention and/or treatment of diseases related to the GLP-1R downstream signaling pathway. and/or symptomatic drug use.

Among them, the diseases and/or symptoms related to the GLP-1R downstream signaling pathway are selected from but not limited to: diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, diabetic nephropathy, Hypertension, cataracts, osteoporosis, hyperuricemia and infections caused by diabetes, obesity, metabolic syndrome, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, Cirrhosis, liver cancer, metabolic acidosis, ketosis, cardiovascular complaints, epilepsy, atherosclerosis, Parkinson's disease and Alzheimer's disease, etc.

The use of the above-mentioned benzimidazole or azabenzimidazole-6-carboxylic acid compounds or their pharmaceutically acceptable salts or their stereoisomers in the preparation of drugs for promoting insulin secretion.

The use of the above-mentioned benzimidazole or azabenzimidazole-6-carboxylic acid compounds or their pharmaceutically acceptable salts or their stereoisomers in the preparation of hypoglycemic drugs.

The use of the above-mentioned benzimidazole or azabenzimidazole-6-carboxylic acid compounds or their pharmaceutically acceptable salts or their stereoisomers in the preparation of drugs for preventing and/or treating diabetes.

Wherein, the diabetes is selected from, but is not limited to: type 1 diabetes (T1DM), type 2 diabetes (T2DM), gestational diabetes and other special types of diabetes (idiopathic T1D, early-onset T2DM, adult-onset diabetes of the young, adolescent Atypical diabetes, malnutrition-related diabetes, latent autoimmune diabetes in adults, etc.

The present invention also provides a pharmaceutical composition for preventing and/or treating diabetes and its complications.

The specific technical solutions are as follows:

A pharmaceutical composition for preventing and/or treating diabetes and its complications, including active ingredients and pharmaceutically acceptable excipients and/or carriers, and the active ingredients include the above-mentioned benzimidazole or azabenzimidazole-6 -Carboxylic acid compounds or pharmaceutically acceptable salts or stereoisomers thereof.

The new imidazole or azabenzimidazole-6-carboxylic acid compounds or their pharmaceutically acceptable salts or their stereoisomers provided by the present invention can effectively activate the GLP-1R downstream signaling pathway and increase the expression of cAMP. This can promote insulin secretion and treat diabetes and its complications, and has great application value.

In the compounds described in the present invention, when any variable (such as R, etc.) appears more than once in any component, the definition of each occurrence is independent of the definition of each other occurrence. Likewise, combinations of substituents and variables are allowed as long as the combination renders the compound stable. A line drawn from a substituent into a ring system indicates that the bond indicated can be attached to any substitutable ring atom. If a ring system is polycyclic, it means that such bonds are only to any appropriate carbon atoms adjacent to the ring. It will be understood that one of ordinary skill in the art can select substituents and substitution patterns of the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by techniques in the art and the methods set forth below. If a substituent is itself substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.

The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon radicals having the specified number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

The term "alkoxy" refers to a group in which an alkyl group is directly connected to oxygen, that is, a group with an -O-alkyl structure, such as -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -O -CH ₂ CH(CH ₃ ) ₂ , -OCH ₂ CH ₂ CH ₂ CH ₃ , -O-CH(CH ₃ ) ₂ , etc.

The term "cycloalkyl" or "carbocycle" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.

The term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent in which one or more ring atoms are selected from N, O or S(O)m (where m is heteroatoms (an integer from 0 to 2), and the remaining ring atoms are carbon, for example: morpholinyl, pyridinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroisoxazolyl, dihydroisoxazolyl, dihydroiso Thiazolyl, dihydroxadiazolyl, dihydroxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydropyrrolyl Hydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc., and their N-oxides, heterocyclic substitutions The attachment of the radicals can be through carbon atoms or through heteroatoms.

The term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N or S. Heteroaryl groups within the scope of the present invention include but are not limited to: quinolyl, pyrazolyl, pyrrolyl , thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuranyl, benzothienyl, benzo oxazole, indolyl, etc.; "heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group.

The term "substituted" refers to the replacement of a hydrogen group in a particular structure with a group specifying the substituent.

As understood by those skilled in the art, "halo" or "halo" as used herein means chlorine, fluorine, bromine and iodine.

Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocycloalkyl substituents may be unsubstituted or substituted. For example, a C1-C6 alkyl group may be substituted by one, two or three substituents selected from OH, halogen, alkoxy, dialkylamino or heterocyclyl such as morpholinyl, piridinyl and the like.

The present invention includes the free form of the compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII), as well as pharmaceutically acceptable compounds thereof. Salts and stereoisomers. Pharmaceutically acceptable salts of the invention may be synthesized by conventional chemical methods from compounds of the invention containing a basic or acidic moiety. Generally, salts of basic compounds are prepared by ion-exchange chromatography or by reaction of the free salt with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with appropriate inorganic or organic salts.

Thus, pharmaceutically acceptable salts of the compounds of the present invention include conventional nontoxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc., as well as salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard acid, etc. Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, parapic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2- Salts prepared from acetyloxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

If the compound of the present invention is acidic, then appropriate "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic salts including inorganic and organic salts. Salts derived from inorganic salts include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Salts derived from pharmaceutically acceptable organic non-toxic amines, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as spermine Acid, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine , ethylenediamine, N-ethylmorpholine, N-ethylpiridine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine , piperazine, pyridine, guac, polyamine resin, procaine, purine, cocoaline, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.

Berg et al., "Pharmaceutical Salts," J. Pharm. Sci .' 1977: 66: 1-19, describe in greater detail the preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts.

Since under physiological conditions a deprotonated acidic moiety such as a carboxyl group in a compound can be anionic, this charge can then be charged by an internally cationic protonated or alkylated basic moiety such as a tetravalent The nitrogen atom balance cancels out, so it should be noted that the compounds of this invention are potential internal salts or zwitterions.

In one embodiment, the present invention provides a method using a structure represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) The compounds and their pharmaceutically acceptable salts or stereoisomers are used to treat diseases and/or symptoms related to the GLP-1R downstream signaling pathway in humans or other mammals.

Among them, the diseases and/or symptoms related to the GLP-1R downstream signaling pathway can be selected from, but are not limited to: type 1 diabetes (T1DM), type 2 diabetes (T2DM), gestational diabetes and other special types of diabetes (idiopathic diabetes mellitus). T1D, early-onset T2DM, adult-onset diabetes of the young, juvenile-onset atypical diabetes, malnutrition-related diabetes, latent autoimmune diabetes in adults, etc.), diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy , insulin resistance, hyperglycemia, diabetic nephropathy, hypertension, cataracts, osteoporosis, hyperuricemia and various infections caused by diabetes, obesity, metabolic syndrome, dyslipidemia, non-alcoholic fatty liver disease (NAFLD) , non-alcoholic steatohepatitis (NASH), fibrosis, heart disease, stroke, cirrhosis, liver cancer, metabolic acidosis, ketosis, cardiovascular complaints, epilepsy and atherosclerosis, Parkinson's disease and Alzheimer's Heimer and other diseases.

Combination medication: Compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) can be used with compounds known to treat or improve similar conditions. Use in combination with other drugs. During combined administration, the original administration method and dosage of the drug remain unchanged, and formula (I), formula (II), formula (III), formula (IV), formula (V), formula ( VI) or compounds of formula (VII). When the compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) is taken at the same time with one or several other drugs, it is preferably used at the same time Pharmaceutical compositions containing one or more known drugs and a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII). Drug combination also includes taking a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) with another or Several known drugs. When the compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) is used in combination with one or several other drugs, the formula The dosage of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) or a known drug may be lower than when used alone .

Drugs or active ingredients that can be combined with compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) include but are not limited to Limited to the following drugs for the treatment of diabetes: biguanides (such as metformin), sulfonylureas (hexylurea acetate, chlorpropamide, tolbutamide, tolazamide, sulfonamide, glibenclamide, glyburide Zide, glipizide, gliaquidone, glyburide, glipide, and glimepiride), thiazolidinediones (such as troglitazone, rosiglitazone, pioglitazone, cycloglitazone etazone), meglifloureas (such as nateglinide, repaglinide, mitiglinide), dipeptidyl peptidase 4 inhibitors (sitagliptin, vildagliptin, saxagliptin , alogliptin, linagliptin, gemagliptin and ticagliptin), sodium-glucose transporter 2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, empagliflozin net, lupagliflozin and togliflozin), sodium-glucose transporter 1/2 inhibitor, GPR40 agonist, GIPR agonist, GIP/GLP-1 dual receptor agonist, alpha-glucosidase inhibitor , insulin or insulin analogs.

Drugs or active ingredients that can be combined with compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) include but are not limited to Limited to the following drugs for the treatment of obesity: peptide YY or its analogs, neuropeptide Y receptor type 2 agonist, melanocortin receptor 4 agonist, amylin, GIPR agonist, phosphodiesterase, AMP priming Protein kinase, neuropeptide Y5 receptor antagonist, GPR40 agonist, GIP/GLP-1 dual receptor agonist, naltrexone/bupropion, lorcaserin , phentermine/topiramate, orlistat, liraglutide.

Drugs or active ingredients that can be combined with compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) include but are not limited to Limited to the following drugs for the treatment of NASH: farnesoid -1/2 inhibitor, acetyl-CoA carboxylase inhibitor, chemokine receptor-2/5 inhibitor, anti-apoptotic signal-regulated kinase 1 inhibitor, ATP-binding transporter 1 agonist, 5-lipid Oxidase inhibitor, vascular adhesion protein 1 inhibitor.

Synthetic Methods: In addition to the standard methods known in the literature or exemplified in experimental procedures, the compounds of the present invention can be prepared using the methods in the following synthetic schemes (Schemes 1-10). Combining the following synthesis schemes, the compounds and synthesis methods described in the present invention can be better understood. The synthetic schemes describe methods that can be used to prepare the compounds described in the present invention. The methods described are merely illustrative scheme descriptions for illustrative purposes and do not constitute a limitation on the scope of the present invention.

plan 1

Scenario 2

Option 3

Option 4

Option 5

Option 6

Option 7

Option 8

Option 9

Option 10

The following are specific examples.

Example 1 : 4- ( 6- Chloropyridine -2- base) guadine -1- tert-butyl carboxylate (Intermediate 0104-1 ) preparation ( Prepare according to route 1 of Scheme 1)

Step 1a: Preparation of 1-(tert-butyl) 4-methyl 4-(6-chloropyridin-2-yl)piridin-1,4-dicarboxylate (compound 0102-1): under nitrogen protection , to a solution of methyl N-tert-butoxycarbonyl-4-picolinecarboxylate (3.00 g, 12.33 mmol, 1.0 equiv) in tetrahydrofuran (40 ml) was added dropwise lithium bis(trimethylsilyl)amide in tetrahydrofuran. Solution (1.0 mol/L, 25 mL, 24.66 mmol, 2.0 equiv). The mixture was stirred at 0°C for 1.5 hours, then a solution of 2,6-dichloropyridine (2.00 g, 13.51 mmol, 1.1 equiv) in tetrahydrofuran (5 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 2.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and separated between water (70 mL) and ethyl acetate (160 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 1-(tert-butyl) 4-methyl 4-(6-chloropyridin-2-yl)piridin-1,4- Dicarboxylic acid ester (4.49 g, yield: 103%). The product was used directly in the next step without further purification.

Step 1b: Preparation of 1-(tert-butoxycarbonyl)-4-(6-chloropyridin-2-yl)piridine-4-carboxylic acid (compound 0103-1): At 43°C, the crude product 1- (tert-Butyl)4-Methyl 4-(6-chloropyridin-2-yl)piridin-1,4-dicarboxylate (0102-1) (4.49 g) was dissolved in methanol (12 ml) , add 4 mol/L sodium hydroxide aqueous solution (9 ml) dropwise within 20 minutes. The mixture was warmed to 50°C and stirred for 35 minutes. The mixture was cooled to room temperature and the pH was adjusted to ~2 with 6 mol/L aqueous hydrochloric acid (6 ml) in an ice-water bath, after which a solid precipitated. The slurry was diluted with water (10 ml) and stirred for 40 minutes, then the solid was collected by filtration, washed with water and dried under vacuum to give 1-(tert-butoxycarbonyl)-4-(6-chloropyridin-2-yl) as a white solid ) Piridine-4-carboxylic acid (3.85 g, yield: 89.0%). LCMS (ESI): m/z=341 (M+H) ⁺ .

Step 1c: Preparation of 4-(6-chloropyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (compound 0104-1): Under nitrogen protection, 1-(tert-butoxycarbonyl)-4 A solution of -(6-chloropyridin-2-yl)pipidine-4-carboxylic acid (0103-1) (3.85 g, 11.32 mmol) in 1,2-dichloroethane (30 ml) was heated to 82 °C. and stir overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The crude product was purified by column chromatography (PE/EA = 10/1) to obtain 4-(6-chloropyridin-2--2-yl)piridin-1-carboxylic acid tert-butyl ester (1.61g) as a white solid , Yield: 48.0%). LCMS (ESI): m/z=297 (M+H) ⁺ .

Example 2 : (S)-2-( Chloromethyl )-3-( Oxetane -2- Methyl )-3H- Imidazo [4,5-b] Pyridine -5- Methyl carboxylate ( Intermediates 0116-1) Preparation ( Prepare according to route 1 of Scheme 1)

Step 2a: Preparation of 6-chloro-5-nitropyridine-2-carboxylic acid (compound 0106-1): At room temperature, add 2-chloro-6-methyl-3-nitropyridine (0105-1) Chromium trioxide (8.6 g, 87.3 mmol, 3.0 equiv) was added portionwise to a solution of concentrated sulfuric acid (20 ml) (5.0 g, 29.1 mmol, 1.0 equiv). The mixture was stirred at 60°C overnight. After cooling to room temperature, the mixture was poured into ice water, and the solid was filtered and dried under vacuum to obtain 6-chloro-5-nitropyridine-2-carboxylic acid as a gray solid (4.15 g, yield: 71%). LCMS(ESI): m/z=201 (MH) ^- .

Step 2b: Preparation of 6-chloro-5-nitropyridine-2-carboxylic acid methyl ester (compound 0107-1): Nitrogen protection, 0°C, to 6-chloro-5-nitropyridine-2-carboxylic acid (0106-1) (4.0 g, 19.8 mmol, 1.0 equiv) and N,N-dimethylformamide (2 drops) in dichloromethane (60 ml) was added oxalate chloride (5.0 g, 39.6 mmol) mole, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. Methanol (4 ml) was added and the mixture was stirred at room temperature for 10 minutes. Water is added and the mixture is separated. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1 to 5/1) to obtain 6-chloro-5-nitropyridine-2-carboxylic acid as a white solid Methyl ester (4.2 g, yield: 97.7%). LCMS (ESI): m/z=217 (M+H) ⁺ .

Step 2c: Preparation of: (S)-2-((benzyloxy)methyl)oxetane (compound 0109): Under nitrogen protection, at room temperature, add potassium tert-butoxide (13.6 g, 122.0 mmol, To a mixture of tert-butanol (180 mL) and 2.0 equiv) was added trimethyltylene iodide (26.8 g, 122.0 mmol, 2.0 equiv). The mixture was stirred at 60°C for 30 minutes. (S)-2-((benzyloxy)methyl)oxirane (0108) (10.0 g, 61.0 mmol, 1.0 equivalent) was added, and the mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was washed with water and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1 to 10/1) to obtain colorless oily liquid (S)-2-((benzyloxy)methyl)oxygen Heterocyclobutane (4.1 g, yield: 38%).

Step 2d: Preparation of (S)-2-hydroxymethyloxetane (compound 0110): (S)-2-((benzyloxy)methyl)oxetane (0109) under hydrogen conditions ) (9.2 g, 51.7 mmol, 1.0 equivalent) and Pd/C (1.8 g, 10% mass ratio) in methanol (100 ml) was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain (S)-2-hydroxymethyloxetane (5.0 g, yield: 111%) as a colorless liquid.

Step 2c Preparation of (S)-oxetane-2-ylmethylmethanesulfonate (compound 0111): Under nitrogen protection, at 0°C, add (S)-2-hydroxymethyloxetane To a mixture of alkane (0110) (5.0 g, 56.8 mmol, 1.0 equiv) and triethylamine (217.2 g, 170.4 mmol, 3.0 equiv) in dichloromethane (80 ml) was added dropwise methanesulfonyl chloride (9.1 g, 79.5 mmol, 1.4 equiv). The mixture was stirred at room temperature for 3 hours. The mixture was washed with water and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain colorless oily liquid (S)-oxetane-2-ylmethylmethane. Sulfonate ester (5.8 g, yield: 61.7%).

Step 2d Preparation of (S)-oxetan-2-ylmethylamine (compound 0113): (S)-oxetan-2-ylmethylmethanesulfonate (0111) (5.8 g , 35 mmol, 1.0 equiv), sodium azide (2.7 g, 42 mmol, 1.2 equiv) and potassium iodide (1.2 g, 7.0 mmol, 0.2 equiv) in N,N-dimethylformamide (80 ml) solution was stirred at 60°C overnight. After cooling to room temperature, methyl tert-butyl ether was added, and the mixture was washed with water. The organic layer was concentrated, the residue was dissolved in tetrahydrofuran, and Pd/C (600 mg, 10% mass ratio) was added. The mixture was stirred at room temperature overnight under hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain (S)-oxetan-2-ylmethylamine as a colorless oil. This product was used directly in the next step without further purification.

Step 2e Preparation of: (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)pyridine-2-carboxylic acid methyl ester (compound 0114-1): 6- Chloro-5-nitropyridine-2-carboxylic acid methyl ester (0107-1) (1.2 g, 5.6 mmol, 1.0 equiv), N,N-diisopropylethylamine (2.2 g, 16.8 mmol, 3.0 Equivalent) and (S)-oxetan-2-ylmethanamine (0113) (1.0 g, 11.2 mmol, 2.0 Equivalent) in N,N-dimethylformamide (30 mL) in room Stir overnight at warm temperature. Ethyl acetate and water were added, the mixture was separated, and the organic layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 8/1 to 2/1) to obtain yellow solid (S)-5-nitro-6-((oxetane) -2-ylmethyl)amino)pyridine-2-carboxylic acid methyl ester (1.0 g, yield: 80.6%). LCMS (ESI): m/z=268 (M+H) ⁺ .

Step 2f Preparation of: (S)-5-amino-6-((oxetan-2-ylmethyl)amino)pyridine-2-carboxylic acid methyl ester (compound 0115-1): hydrogen conditions Bottom, (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)pyridine-2-carboxylic acid methyl ester (0114-1) (1.0 g, 3.7 mmol , 1.0 eq) and Pd/C (100 mg, 10% mass ratio) in methanol (30 ml) was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain (S)-5-amino-6-((oxetan-2-ylmethyl)amino)pyridine-2-carboxylic acid methyl ester (800 mg, Yield: 90.1%). LCMS (ESI): m/z=238 (M+H) ⁺ .

Step 2g: (S)-2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Preparation of (Compound 0116-1): (S)-5-amino-6-((oxetan-2-ylmethyl)amino)pyridine-2-carboxylic acid methyl ester under nitrogen protection conditions A mixture of (0115-1) (800 mg, 3.4 mmol, 1.0 equiv) and 2-chloroacetic anhydride (872 mg, 5.1 mmol, 1.5 equiv) in tetrahydrofuran (50 mL) was stirred at 70°C overnight. After cooling to room temperature, sodium carbonate aqueous solution and ethyl acetate were added, and the mixture was separated. The organic layer was washed with saturated brine and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 200/1 to 100/1) to obtain a yellow solid (S)-2-(chloromethyl)-3-(oxetane) Alk-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (1.0 g, yield: 100%). LCMS (ESI): m/z=296 (M+H) ⁺ .

Example 3 : (S)-2-( Chloromethyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- Methyl carboxylate ( Intermediates 0116-3) Preparation ( Prepare according to route 1 of Scheme 1)

Step 3a: Preparation of (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (compound 0114-3): under nitrogen protection conditions, 3 -Methyl fluoro-4-nitrobenzoate (0107-3) (6.23 g, 31.30 mmol, 1.0 equivalent), (S)-oxetan-2-ylmethylamine (0113) (3.00 g, A mixture of N,N-dimethylformamide (60 ml) and potassium carbonate (8.97 g, 64.87 mmol, 2.0 equiv) and potassium carbonate (8.97 g, 64.87 mmol, 2.0 equiv) was stirred at room temperature for 3 hours. The reaction was quenched with water (90 ml) and extracted with ethyl acetate (80 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 5/1) to obtain a white solid (S)-4-nitro-3-((oxetan-2-yl) Methyl)amino)benzoate (6.61 g, yield: 79.4%). LCMS (ESI): m/z=267 (M+H) ⁺ .

Step 3b Preparation of (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (compound 0115-3): Under hydrogen conditions, (S )-4-Nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (0114-3) (6.61 g, 24.84 mmol, 1.0 equiv) and palladium on carbon ( 661 mg, 10% mass ratio) in tetrahydrofuran (80 ml) and stirred at room temperature for 4 hours. The reaction solution was filtered, and the filtrate was concentrated in vacuo to obtain pale solid (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (5.88 g, yield :100.2%). LCMS(ESI): m/z=237(M+H) ⁺ .

Step 3c: (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Compound 0116- Preparation of 3): Under dry conditions, (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (0115-3) (5.88 g, 24.89 mmol, 1.0 equiv), 2-chloro-1,1,1-trimethoxyethane (4.62 g, 29.86 mmol, 1.2 equiv) and p-toluenesulfonic acid monohydrate (514 mg, 2.99 mmol , 0.12 eq) in tetrahydrofuran (60 ml) was heated to 45°C and stirred overnight. After cooling to room temperature, the reaction solution was diluted with water (40 ml) and diluted with ethyl acetate (60 ml). The crude product was purified by column chromatography (dichloromethane/methanol = 50/1) to obtain a white solid (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylic acid methyl ester (6.54 g, yield: 74.5%). LCMS (ESI): m/z=295 (M+H) ⁺ .

Example 4 : (S)-2-((4-(6-((4- Cyanobenzofuran -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-3-( Oxetane -2- Methyl )-3H- Imidazo [4,5-b] Pyridine -5- carboxylic acid ( compound 1) Preparation ( Prepare according to the second route of plan)

Step 4a: Preparation of 7-(hydroxymethyl)benzofuran-4-nitrile (compound 0201-1):

Under nitrogen protection conditions, 5-bromo-2-methylphenol (2.0 g, 10.7 mmol, 1.0 equivalent), 2-bromo-1,1-diethoxyethane (2.5 g, 12.8 mmol, 1.2 Equivalent), potassium carbonate (3.0 g, 21.4 mmol, 2.0 equivalent) and potassium iodide (0.2 g, 10% mass ratio) in N,N-dimethylformamide was stirred at 120°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 4-bromo-2-(2,2-diethoxyethoxy)-1-methylbenzene (2.88 g, yield :88.9%). The product was used directly in the next step without further purification.

Under nitrogen protection conditions, 4-bromo-2-(2,2-diethoxyethoxy)-1-methylbenzene (2.9 g, 9.55 mmol, 1.0 equivalent) and polyphosphoric acid ( 8.0 g, 23.75 mmol, 2.5 equiv) of the dichloroethane mixture was refluxed overnight. After cooling to room temperature, the reaction was quenched with water (40 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 4-bromo-7-methylbenzofuran (1.61 g, yield: 80.5%) as a yellow oil. LCMS (ESI): m/z=211 (M+H) ⁺ .

Under nitrogen protection conditions, add the above-obtained 4-bromo-7-methylbenzofuran (800 mg, 3.8 mmol, 1.0 equivalent) and cuprous cyanide (1.7 g, 19.0 mmol, 5.0 equivalent) to N, A mixture of N-dimethylformamide (15 ml) was stirred at 120°C overnight. After cooling to room temperature, the reaction was filtered through celite and washed with ethyl acetate (15 ml). The filtrate was diluted with water (30 ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 7-methylbenzofuran-4-carbonitrile (305 mg, yield: 51.3) as a white solid %). LCMS (ESI): m/z=158 (M+H) ⁺ .

Under nitrogen protection conditions, the 7-methylbenzofuran-4-carbonitrile (305 mg, 1.94 mmol, 1.0 equivalent) and N-bromosuccinimide (416 mg, 2.33 mmol, 1.2 equivalent) obtained above were mixed. ) and azobisisobutyronitrile (65 mg, 0.39 mmol, 0.2 equiv) in dichloroethane (10 mL) was stirred at 72 °C overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with water (20 ml) and extracted with petroleum ether/ethyl acetate = 2/1 (30 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain white solid 7-(bromomethyl)benzofuran-4-carbonitrile (377 mg, yield: 82.0% ). LCMS (ESI): m/z=236 (M+H) ⁺ .

The 7-(bromomethyl)benzofuran-4-carbonitrile (326 mg, 1.38 mmol, 1.0 equivalent) and potassium acetate (1.35 g, 13.76 mmol, 10.0 equivalent) obtained above were mixed with N,N-dimethyl The mixture of methamide (10 ml) was stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product (4-cyanobenzofuran-7-yl)methyl acetate (190 mg, yield: 64.2%). The product was used directly in the next step without further purification.

To the solution of (4-cyanobenzofuran-7-yl)methyl acetate (168 mg, 0.78 mmol, 1.0 equivalent) in tetrahydrofuran (5 ml) obtained above, a methanol solution of sodium methoxide (5.4 mol/ liter, 282 mg, 1.56 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. The pH of the reaction solution was adjusted to approximately 6 with 1 mol/L hydrochloric acid, and then a solid precipitate was formed. The slurry was diluted with water (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 4/1) to obtain yellow solid 7-(hydroxymethyl)benzofuran-4-carbonitrile (135 mg, yield: 100.0 %). LCMS (ESI): m/z=174 (M+H) ⁺ .

Step 4b: Preparation of tert-butyl 4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0202-1) : Under nitrogen protection conditions, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (125 mg, 0.44 mmol, 1.0 equivalent), 7-(hydroxy Methyl)benzofuran-4-nitrile (0201-1) (106 mg, 0.61 mmol, 1.4 equivalents), cesium carbonate (400 mg, 1.22 mmol, 2.0 equivalents), 2-dicyclohexylphosphonium-2' , 6'-diisopropoxy-1,1'-biphenyl (58 mg, 0.12 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (57 mg, 0.06 mmol, A mixture of (0.1 eq) in toluene (10 ml) was refluxed at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite and the solid was washed with ethyl acetate (15 ml). The filtrate was diluted with water (20 ml) and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain white solid 4-(6-((4-cyanobenzofuran-7-yl)methoxy) )pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (165 mg, yield: 86.8%). LCMS (ESI): m/z=434 (M+H) ⁺ .

Step 4c: 7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-nitrile p-toluenesulfonate (compound 0203-1) Preparation: tert-butyl 4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pipidine-1-carboxylate (0202-1) (165 mg , 0.38 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (197 mg, 1.14 mmol, 3.0 equiv) in ethyl acetate (15 ml) was stirred at 60°C overnight. After cooling to room temperature, the reaction solution was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum to obtain 7-(((6-(pyridin-4-yl)pyridyl-2-yl)oxy) as a white solid )Methyl)benzofuran-4-nitrile p-toluenesulfonate (150 mg, yield: 90.9%). LCMS (ESI): m/z=343 (M+H) ⁺ .

Step 4d: (S)-2-((4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl) Preparation of -3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (compound 0204-1): 7-(( (6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-nitrile p-toluenesulfonate (0203-1) (150 mg, 0.29 mmol, 1.2 equivalent), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester A solution of (0116-1) (72 mg, 0.24 mmol, 1.0 equiv) and potassium carbonate (115 mg, 0.83 mmol, 4.0 equiv) in acetonitrile (5 ml) was stirred at 60°C for 4 hours. After cooling to room temperature, add water and extract with methylene chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-((4-(6-((4-cyanobenzofuran-7-yl) )methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine -5-Carboxylic acid methyl ester (132 mg, yield: 75.9%). LCMS (ESI): m/z=593 (M+H) ⁺ .

Step 4e: (S)-2-((4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl) Preparation of -3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 1): (S)-2-(( 4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-3-(oxetane-2 -methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (0204-1) (132 mg, 0.22 mmol, 1.0 equiv) and lithium hydroxide monohydrate (11 mg , 0.25 mmol, 1.1 equiv) a mixture of acetonitrile/water = 5/1 (6 ml) was stirred at 40°C overnight. After the mixture was cooled to room temperature, the pH was adjusted to about 6 with 1 mol/L hydrochloric acid, and then a solid precipitate formed. The slurry was diluted with water (12 mL) and stirred for 4 hours, then the solids were collected by filtration. The solid was washed with water and dried under vacuum. The solid was dissolved in dichloromethane/methanol = 1/2 (5 ml), and then filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dried under vacuum to obtain a white solid (S)-2-((4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1- methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (97 mg, yield: 75.2%). LCMS (ESI): m/z=579 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 13.04 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.68 – 7.61 (m, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 6.87 ( d, J = 7.3 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 5.72 (s, 2H), 5.24 – 5.15 (m, 1H), 4.84 (dd, J = 14.6, 6.4 Hz, 1H ), 4.72 (dd, J = 14.6, 4.3 Hz, 1H), 4.53 – 4.46 (m, 1H), 4.37 (dt, J = 8.9, 6.0 Hz, 1H), 3.94 (dd, J = 32.0, 13.7 Hz, 2H), 2.97 – 2.87 (m, 2H), 2.73 – 2.63 (m, 1H), 2.56 (ddd, J = 16.8, 8.5, 4.7 Hz, 1H), 2.47 (d, J = 7.1 Hz, 1H), 2.22 (tt, J = 16.1, 8.1 Hz, 2H), 1.73 (d, J = 10.1 Hz, 4H).

Example 5 : (S)-2-((6-((4- Cyanobenzofuran -7- base ) Methoxy )-3' , 6'- dihydrogen -[2,4'- Bipyridine ]-1'(2'H)- base ) methyl )-3-( Oxetane -2- Methyl )-3H- Imidazo [4,5-b] Pyridine -5- carboxylic acid ( compound 2) Preparation ( Prepare according to the plan three lines)

Step 5a: Preparation of 6-chloro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (compound 0302-2): Nitrogen protection Next, 2-bromo-6-chloropyridine (0301-2) (2.00 g, 10.39 mmol, 1.0 equivalent), N-tert-butoxycarbonyl-1,2,5,6-tetrahydropyridine-4-boronic acid Pinacol ester (3.21 g, 10.39 mmol, 1.0 equiv), sodium carbonate (2.20 g, 20.78 mmol, 2.0 equiv) and [1,1'-bis(diphenylphosphine)ferrocene] dichloride A mixture of palladium(II) (761 mg, 1.04 mmol, 0.1 equiv) in dioxane/water = 10/1 (30 ml) was stirred at 90°C overnight. After cooling to room temperature, the reaction was filtered through celite and washed with ethyl acetate (30 ml). The filtrate was diluted with water (30 ml) and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain a white solid 6-chloro-3',6'-dihydro-[2,4'-bipyridine] -1'(2'H)-tert-butylcarboxylate (2.51 g, yield: 81.9%). LCMS (ESI): m/z=295 (M+H) ⁺ .

Step 5b: 6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H) - Preparation of tert-butyl carboxylate (compound 0303-2): Under nitrogen protection conditions, 6-chloro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H )-tert-butyl carboxylate (0302-2) (491 mg, 1.67 mmol, 1.2 equiv), 7-(hydroxymethyl)benzofuran-4-carbonitrile (0201-1) (241 mg, 1.39 mmol) , 1.0 equivalent), cesium carbonate (906 mg, 2.78 mmol, 2.0 equivalent), 2-dicyclohexylphosphon-2',6'-diisopropoxy-1,1'-biphenyl (130 mg, 0.28 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (127 mg, 0.14 mmol, 0.1 equiv) in toluene (10 mL) was refluxed at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite and the solid was washed with ethyl acetate (15 ml). The filtrate was diluted with water (20 ml) and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain white solid 6-((4-cyanobenzofuran-7-yl)methoxy)-3 ',6'-Dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (462 mg, yield: 76.9%). LCMS (ESI): m/z=432 (M+H) ⁺ .

Step 5c: 7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridin]]-6-yl)oxy)methyl)benzofuran-4- Preparation of nitrile hydrochloride (compound 0304-2): 6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'- Bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (0303-2) (462 mg, 1.07 mmol, 1.0 equivalent) was dissolved in dioxane hydrochloride solution (4 mol/L, 5 ml) , the reaction solution was stirred at room temperature overnight. The reaction solution was then filtered, and the filter cake was washed with ethyl acetate and dried under vacuum to obtain a white solid 7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridine] ]-6-yl)oxy)methyl)benzofuran-4-nitrile hydrochloride (400 mg, yield: 100.0%). LCMS (ESI): m/z=332 (M+H) ⁺ .

Step 5d: (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (Compound 0305-2) Preparation: 7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]]-6-yl)oxy)methyl )Benzofuran-4-nitrile hydrochloride (0304-2) (200 mg, 0.54 mmol, 1.0 equivalent), (S)-2-(chloromethyl)-3-(oxetane-2 -methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (0116-1) (160 mg, 0.54 mmol, 1.0 equiv) and potassium carbonate (298 mg, 2.16 mg mol, 4.0 eq) in acetonitrile (5 mL) was stirred at 60°C for 4 h. The reaction mixture was cooled to room temperature, water was added, and dichloromethane was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy yl)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl )-3H-Imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (212 mg, yield: 66.7%). LCMS (ESI): m/z=590 (M+H) ⁺ .

Step 5e: (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound Preparation of 2): (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'- Bipyridyl]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxy A mixture of methyl acid ester (0305-2) (70 mg, 0.12 mmol, 1.0 equiv) and lithium hydroxide monohydrate (25 mg, 0.48 mmol, 4.0 equiv) in acetonitrile/water = 5/1 (3 ml) was added. Stir overnight at 40°C. After the mixture was cooled to room temperature, the pH was adjusted to about 6 with 1 mol/L hydrochloric acid, and then a solid precipitate formed. The slurry was diluted with water (12 ml) and stirred for 4 hours. The solid was then collected by filtration, washed with water, and dried under vacuum. The solid was dissolved in dichloromethane/methanol = 1/2 (5 ml) and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After vacuum drying, a white solid (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'- Pyridine]-1'(2'H)-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (47 mg, yield: 69.1%). LCMS (ESI): m/z=576 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.32 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.20 (s, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.63 (s, 1H), 5.74 (s, 2H), 4.99 (s, 1H), 4.83 (dd, J = 14.3, 7.4 Hz, 1H), 4.65 (d, J = 14.0 Hz, 1H), 4.42 (d, J = 6.9 Hz, 1H), 4.33 (d, J = 7.2 Hz, 1H), 4.16 (d, J = 13.5 Hz, 1H), 3.91 (d, J = 13.4 Hz, 1H), 3.20 (s, 2H), 2.71 (s, 2H), 2.51 (s, 1H), 2.44 (s, 2H), 2.29 (s, 1H).

Example 6 : (S)-2-((4-(6-((4- Cyanobenzofuran -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 3) Preparation ( Prepare according to the second route of plan)

Step 6a: (S)-2-((4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl) Preparation of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-3): 7-(((6-( Piridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-nitrile p-toluenesulfonate (0203-1) (105 mg, 0.24 mmol, 1.2 equiv), ( S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (60 mg , 0.20 mmol, 1.0 equiv) and potassium carbonate (111 mg, 0.81 mmol, 4.0 equiv) in acetonitrile (5 ml) was stirred at 60°C for 4 hours. The reaction mixture was cooled to room temperature, water was added, and dichloromethane was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-((4-(6-((4-cyanobenzofuran-7-yl) )methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxy Acid methyl ester (78 mg, yield: 65.5%). LCMS (ESI): m/z=592 (M+H) ⁺ .

Step 6b: (S)-2-((4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl) Preparation of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 3): (S)-2-((4-(6 -((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl )-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-3) (78 mg, 0.13 mmol, 1.0 equiv) and lithium hydroxide monohydrate (11 mg, 0.26 mmol, 2.0 equiv) A mixture of acetonitrile/water = 5/1 (3 ml) was stirred at 40 °C overnight. After the mixture was cooled to room temperature, the pH was adjusted to about 6 with 1 mol/L hydrochloric acid, and then a solid precipitate formed. The slurry was diluted with water (12 mL) and stirred for 4 hours, then the solid was collected by filtration, washed with water, and dried under vacuum. The solid was dissolved in dichloromethane/methanol = 1/2 (5 ml) and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dried under vacuum to obtain a white solid (S)-2-((4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1- methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (54 mg, yield: 71.1%). LCMS (ESI): m/z=578 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.65 (s, 1H), 8.28 (d, J = 22.1 Hz, 2H), 7.80 (dd, J = 28.6, 7.5 Hz, 2H), 7.64 (d, J = 7.0 Hz, 2H), 7.54 (d, J = 7.4 Hz, 1H), 7.18 (s, 1H), 6.87 (d, J = 6.9 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 5.72 ( s, 2H), 5.10 (s, 1H), 4.76 (s, 1H), 4.64 (d, J = 14.4 Hz, 1H), 4.45 (d, J = 5.8 Hz, 1H), 4.36 (s, 1H), 3.95 (d, J = 12.5 Hz, 1H), 3.79 (d, J = 11.9 Hz, 1H), 2.97 (d, J = 8.7 Hz, 1H), 2.84 (s, 1H), 2.68 (s, 1H), 2.57 (s, 1H), 2.42 (s, 1H), 2.21 (d, J = 29.3 Hz, 2H), 1.72 (d, J = 12.1 Hz, 4H).

Example 7 : (S)-2-((6-((4- Cyanobenzofuran -7- base ) Methoxy )-3' , 6'- dihydrogen -[2,4'- Bipyridine ]-1'(2'H)- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 4) Preparation ( Prepare according to the plan three lines)

Step 7a: (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Compound 0305- 4) Preparation: 7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridin]]-6-yl)oxy)methyl)benzofuran -4-nitrile hydrochloride (0304-2) (100 mg, 0.27 mmol, 1.0 equiv), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl )-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (80 mg, 0.27 mmol, 1.0 equiv) and potassium carbonate (149 mg, 1.08 mmol, 3.0 equiv) in acetonitrile ( 5 ml) mixture was stirred at 60°C for 4 hours. The reaction mixture was cooled to room temperature, water was added, and dichloromethane was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy yl)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl )-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (97 mg, yield: 60.9%). LCMS (ESI): m/z=590 (M+H) ⁺ .

Step 7b: (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine] Preparation of -1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 4) : (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1 '(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0305-4) ( A mixture of 97 mg, 0.16 mmol, 1.0 equiv) and lithium hydroxide monohydrate (25 mg, 0.48 mmol, 3.0 equiv) in acetonitrile/water = 5/1 (3 ml) was stirred at 40°C overnight. After the mixture was cooled to room temperature, the pH was adjusted to about 6 with 1 mol/L hydrochloric acid, and then a solid precipitate formed. The slurry was diluted with water (12 mL) and stirred for 4 hours, then the solid was collected by filtration, washed with water, and dried under vacuum. The solid was dissolved in dichloromethane/methanol = 1/2 (5 ml), and then filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After vacuum drying, a white solid (S)-2-((6-((4-cyanobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'- Pyridine]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (68 mg, Yield: 76.6%). LCMS (ESI): m/z=576 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.79 (dd, J = 18.0, 8.0 Hz, 2H), 7.74 – 7.61 (m , 2H), 7.55 (d, J = 7.7 Hz, 1H), 7.21 (s, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.62 (s , 1H), 5.74 (s, 2H), 5.05 (d, J = 5.3 Hz, 1H), 4.79 (dd, J = 15.2, 7.3 Hz, 1H), 4.64 (d, J = 13.4 Hz, 1H), 4.46 (dd, J = 13.8, 7.3 Hz, 1H), 4.35 (dd, J = 14.6, 5.9 Hz, 1H), 4.05 (d, J = 13.5 Hz, 1H), 3.91 (d, J = 13.5 Hz, 1H) , 3.22 – 3.15 (m, 2H), 2.77 – 2.60 (m, 3H), 2.46 – 2.31 (m, 3H).

Example 8 : (S)-2-((4-(6-((4- Cyano -2- Methylbenzofuran -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 5) Preparation ( Prepare according to the second route of plan)

Step 8a: Preparation of 7-(hydroxymethyl)-2-methylbenzofuran-4-nitrile (Compound 0201-5):

Under nitrogen protection, 4-bromo-2-hydroxybenzoic acid methyl ester (1.0 g, 4.33 mmol, 1.0 equivalent), 3-bromopropyne (618 mg, 5.19 mmol, 1.2 equivalent), and potassium carbonate (896 mg , 6.49 mmol, 1.5 equiv) of N,N-dimethylformamide was stirred at 50°C for 5 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was dissolved in N,N-diethylaniline (5 ml). Cesium fluoride (855 mg, 5.63 mmol, 1.3 equiv) was added to the mixture. The mixture was stirred at 220°C for 3 hours. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain yellow solid 4-bromo-2-methylbenzofuran-7-carboxylic acid methyl ester. (563 mg, yield: 48.53%). LCMS (ESI): m/z=269 (M+H) ⁺ .

Under nitrogen protection conditions, 4-bromo-2-methylbenzofuran-7-carboxylic acid methyl ester (500 mg, 1.86 mmol, 1.0 equivalent) and tetrakis triphenylphosphine palladium (215 mg, 0.186 mmol, 0.1 equiv) and zinc cyanide (326 mg, 2.79 mmol, 1.5 equiv) in N,N-dimethylformamide (5 ml) was stirred at 90°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain yellow solid 4-cyano-2-methylbenzofuran-7-carboxylic acid. Methyl ester (290 mg, yield: 72.68%). LCMS (ESI): m/z=216 (M+H) ⁺ .

Under nitrogen protection and ice bath, add the 4-cyano-2-methylbenzofuran-7-carboxylic acid methyl obtained above to the tetrahydrofuran mixture of lithium aluminum tetrahydrogen (62 mg, 1.618 mmol, 1.2 equivalents). Ester (290 mg, 1.348 mmol, 1.0 equiv). The mixture was stirred in an ice bath for 1 hour. The reaction was quenched with water. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-2/1) to obtain a yellow solid 7-(hydroxymethyl)-2-methylbenzofuran-4- Nitrile (248 mg, yield: 98.41%). LCMS (ESI): m/z=188 (M+H) ⁺ .

Step 8b: tert-butyl 4-(6-((4-cyano-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0202 Preparation of -5): Under nitrogen protection conditions, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (220 mg, 0.74 mmol, 1.0 equivalent), 7-(hydroxymethyl)-2-methylbenzofuran-4-carbonitrile (0201-5) (166 mg, 0.88 mmol, 1.2 equiv), cesium carbonate (481 mg, 1.48 mmol, 2.0 equiv), 2-Dicyclohexylphosphon-2',6'-diisopropoxy-1,1'-biphenyl (138 mg, 0.296 mmol, 0.4 equiv) and tris(dibenzylideneacetone)dipalladium (0 ) (135 mg, 0.148 mmol, 0.2 equiv) in toluene (10 mL) was stirred at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain a yellow oily substance 4-(6-((4-cyano-2 - Methylbenzofuran-7-yl)methoxy)pyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (237 mg, yield: 71.60%). LCMS (ESI): m/z=448 (M+H) ⁺ .

Step 8c: 2-methyl-7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-carbonitrile hydrochloride (Compound 0203- Preparation of 5): tert-butyl 4-(6-((4-cyano-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate A solution of (0202-5) (248 mg, 0.55 mmol, 1.0 equiv) and hydrochloric acid in dioxane (4M, 1 mL) in dioxane (4 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain 2-methyl-7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-carbonitrile hydrochloride ( 105 mg, crude product), this product was used directly in the next step without further purification. LCMS (ESI): m/z=348 (M+H) ⁺ .

Step 8d: (S)-2-((4-(6-((4-cyano-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1- Preparation of (methyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (compound 0204-5): 2-methyl -7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-carbonitrile hydrochloride (0203-5) (98 mg, 0.255 mg mol, 1.5 equiv), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( 0116-3) (50 mg, 0.17 mmol, 1.0 equiv) and potassium carbonate (140 mg, 1.01 mmol, 4.0 equiv) in acetonitrile (5 ml) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain yellow solid (S)-2-((4-(6-((4-cyano-2-methylbenzo) Furan-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d] Imidazole-6-carboxylic acid methyl ester (70 mg, yield: 68.03%). LCMS (ESI): m/z=606 (M+H) ⁺ .

Step 8e: (S)-2-((4-(6-((4-cyano-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1- Preparation of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 5): (S)-2-(( 4-(6-((4-cyano-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxa Cyclobutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-5) (27.6 mg, 0.045 mmol, 1.0 equiv) and lithium hydroxide monohydrate (4 mg, 0.09 mmol, 2.0 equiv) a mixture of acetonitrile/water = 5/1 (6 ml) was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH value of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, and then a solid precipitated. The mixture is filtered. Wash the residue with water. The residue was purified by thick preparative thin-layer silica gel chromatography (eluent: dichloromethane/methanol=10/1) to obtain a yellow solid (S)-2-((4-(6-((4-cyano) -2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-benzo[d]imidazole-6-carboxylic acid (21.6 mg, yield: 80.12%). LCMS (ESI): m/z=592 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 8.26 (s, 1H), 7.81 (dd, J = 8.4, 1.3 Hz, 1H), 7.73 – 7.59 (m, 3H), 7.44 (d , J = 7.8 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.83 (d, J = 1.0 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 5.68 (s, 2H ), 5.10 (ddd, J = 14.5, 7.2, 2.8 Hz, 1H), 4.77 (dd, J = 15.2, 7.1 Hz, 1H), 4.64 (dd, J = 15.2, 2.6 Hz, 1H), 4.46 (dt, J = 13.8, 7.0 Hz, 1H), 4.36 (dt, J = 9.0, 5.9 Hz, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 13.5 Hz, 1H), 2.97 ( d, J = 11.1 Hz, 1H), 2.84 (d, J = 11.2 Hz, 1H), 2.74 – 2.65 (m, 1H), 2.59 – 2.54 (m, 1H), 2.48 (d, J = 0.8 Hz, 3H ), 2.43 (ddd, J = 11.1, 9.0, 5.6 Hz, 1H), 2.19 (dt, J = 32.3, 10.5 Hz, 2H), 1.80 – 1.60 (m, 4H).

Example 9 : (S)-2 ^- ((4-(6 ^- ((2- chlorine -4- Cyanobenzofuran -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 6) Preparation ( Prepare according to the second route of plan)

Step 9a: tert-butyl 4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0202- Preparation of 6): Under nitrogen protection and -70°C, add 4-(6-((4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridine-1-carboxylic acid Lithium diisopropylamide (0.42 ml, 2 mol/L tetrahydrofuran, 0.843 mmol, 2 equivalent). The mixture was stirred at -70°C for 1 hour. A solution of hexachloroethane (98.5 mg, 0.416 mmol, 1 equiv) in tetrahydrofuran (1 mL) was added to the mixture. The mixture was stirred at -70°C for 1 hour. The reaction was quenched with ammonium chloride. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified using a silica gel thin layer chromatography preparatory plate (eluent: petroleum ether/ethyl acetate = 5/1) to obtain a transparent oily substance 4-(6 ^- ((2-chloro-4-cyanobenzo Furan-7-yl)methoxy)pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (54 mg, yield: 27.74%). LCMS (ESI): m/z=468 (M+H) ⁺ .

Step 9b: 2-Chloro-7 ^- (((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-nitrile 4-methylbenzenesulfonate ( Preparation of compound 0203-6): in 4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylic acid To a solution of butyl ester (0202-6) (54 mg, 0.115 mmol, 1.0 equiv) in ethyl acetate (10 mL) was added p-toluenesulfonic acid monohydrate (59 mg, 0.346 mmol, 3.0 equiv). The mixture was stirred at 60°C overnight. The mixture was concentrated under reduced pressure to obtain the crude product 2-chloro-7 ^- (((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-nitrile 4-methylbenzene Sulfonate (93 mg, crude). The product was used directly in the next step without further purification.

Step 9c: (S)-2-((4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl )Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-6): 2-Chloro- 7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-4-nitrile 4-methylbenzenesulfonate (0203-6) (93 mg , 0.173 mmol, 1.5 equiv), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid A mixture of methyl ester (0116-3) (34 mg, 0.115 mmol, 1.0 equiv) and potassium carbonate (63.6 mg, 0.461 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain white solid (S)-2-((4-(6-((2-chloro-4-cyanobenzofuran) -7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-Carboxylic acid methyl ester (60 mg, yield: 83.34%). LCMS (ESI): m/z=626 (M+H) ⁺ .

Step 9d: (S)-2 ^- ((4-(6 ^- ((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl )Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 6) Preparation: (S)-2-(( 4-(6-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxaheterocycle Butan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-6) (60 mg, 0.096 mmol, 1.0 equiv) and lithium hydroxide monohydrate (12 mg , 0.288 mmol, 3 equivalents), a mixture of tetrahydrofuran/water = 5/1 (6 ml) was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l dilute sulfuric acid, after which a solid precipitated. The mixture is filtered. The residue was purified using a silica gel thin layer chromatography preparatory plate (eluent: dichloromethane/methanol=10/1) to obtain a white solid (S)-2 ^- ((4-(6 ^- ((2-chloro-4) -Cyanobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid (32.7 mg, yield: 55.66%). LCMS (ESI): m/z=612 (M+H) ⁺ . Melting point: 125~130℃; ¹ H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 8.27 (d, J = 0.7 Hz, 1H), 7.87 – 7.76 (m, 2H), 7.70 – 7.60 (m , 2H), 7.55 (d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 5.68 (s , 2H), 5.10 (qd, J = 7.2, 2.8 Hz, 1H), 4.78 (dd, J = 15.2, 7.2 Hz, 1H), 4.65 (dd, J = 15.2, 2.7 Hz, 1H), 4.47 (dt, J = 13.8, 7.0 Hz, 1H), 4.36 (dt, J = 9.0, 5.9 Hz, 1H), 3.93 (d, J = 13.5 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 2.96 ( d, J = 10.8 Hz, 1H), 2.84 (d, J = 11.0 Hz, 1H), 2.74 – 2.65 (m, 1H), 2.59 – 2.53 (m, 1H), 2.43 (ddd, J = 11.1, 8.9, 5.6 Hz, 1H), 2.18 (dt, J = 29.7, 11.0 Hz, 2H), 1.77 – 1.54 (m, 4H).

Example 10 : ( S )-2-((4-(6-((4- Cyanobenzo [ b ] Thiophene -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl ) -1H- Benzo [ d ] imidazole -6- carboxylic acid ( compound 8) Preparation ( Prepare according to the second route of plan)

Step 10a: Preparation of 7-(hydroxymethyl)benzo[ b ]thiophene-4-nitrile (Compound 0201-8):

2-Amino-4-bromobenzoic acid methyl ester (2.3 g, 10.0 mmol, 1.0 equiv) was added to dilute hydrochloric acid (2 ml concentrated hydrochloric acid and 8 ml water). The mixture was stirred at 80°C for 15 minutes and then cooled to 0°C. Sodium nitrite (828 mg, 12 mmol, 1.2 equivalents) was dissolved in 8 ml of water and added dropwise to the above mixture, and the mixture was stirred at 0°C for 2 hours. Potassium ethyl xanthate (2.72 g, 17 mmol, 1.7 equivalents) was added to 8 ml of water and stirred at 65°C. The diazonium salt mixture obtained above was added to the mixture over 20 minutes, and the mixture was stirred at 65°C for 2 hours. Add dichloromethane to extract, and wash with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was added to a solution of potassium hydroxide (5.6 g, 100 mmol, 10.0 equiv) in 10 ml of ethanol and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and water was added. Adjust the pH of the aqueous phase to 1 by adding concentrated hydrochloric acid. Add ethyl acetate to extract, and wash with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain N,N- The dimethylformamide mixture was stirred at 50°C for 3 hours. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain 4-bromo-2-mercaptobenzoic acid (2.19 g, crude product) as a red oil, which was used directly in the next step without further purification. MS (ES ^- ): m/z =231(MH) ^- .

Dissolve the 4-bromo-2-mercaptobenzoic acid (2.19 g, 9.48 mmol, 1.0 equivalent) obtained above in 50 ml of methanol, and add trisethylene chloride (3.38 g, 28.44 mmol, 3.0) dropwise at 0°C. equivalent). The mixture was stirred at 75°C for 3 hours. The mixture was concentrated under reduced pressure, and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain methyl 4-bromo-2-mercaptobenzoate (2.23 g, crude product) as a yellow oil, which was used directly in the next step without further purification. MS (ES ^- ): m/z =245(MH) ^- .

The 4-bromo-2-mercaptobenzoic acid methyl ester obtained above (2.23 g, 9.03 mmol, 1.0 equivalent), 2-bromo-1,1-diethoxyethane (2.13 g, 10.84 mmol, 1.2 Equivalent) and potassium carbonate (2.49 g, 18.03 mmol, 2.0 equivalent) in 35 ml of N,N-dimethylformamide at 70 Stir for 3 hours at ℃. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 30/1 to 10/1) to obtain a yellow oily substance 4-bromo-2-((2,2- Diethoxyethyl)thio)benzoic acid methyl ester (1.46 g, yield: 44.5%).

A toluene mixture of 4-bromo-2-((2,2-diethoxyethyl)thio)benzoate (1.26 g, 3.47 mmol, 1.0 equivalent) and 1.29 g of polyphosphoric acid obtained above Place at 120°C and stir overnight. After cooling to room temperature, add water, acidify with ethyl acetate and a well-known mixture by adding concentrated hydrochloric acid, and extract the mixture by adding a mixed solvent of ethyl acetate and petroleum ether. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 to 50/1) to obtain red solid 4-bromobenzo[ b ]thiophene-7-carboxylic acid. Methyl ester (849 mg, yield: 90.6%).

The 4-bromobenzo[ b ]thiophene-7-carboxylic acid methyl ester (800 mg, 2.96 mol, 1.0 equivalent) obtained above was dissolved in 25 ml of ethanol, and the mixture was stirred at 45°C. Sodium borohydride (1.14 g, 30 mmol, 10 equiv) was added and the mixture was stirred overnight. The mixture was concentrated under reduced pressure, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1 to 5/1) to obtain a yellow solid (4-bromobenzo[ b ]thiophene-7- base) methanol (470 mg, yield: 65.6%). LCMS(ESI): m /z =225(M+HH ₂ O) ⁺ .

Under nitrogen protection, the (4-bromobenzo[ b ]thiophen-7-yl)methanol (440 mg, 1.82 mmol, 1.0 equivalent) and copper cyanide (1.63 g, 18.2 mmol, 10.0 equivalent) obtained above were mixed. Equivalent) and a mixture of N-methylpyrrolidone (15 ml) was stirred at 190°C for 8 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The mixture was filtered through celite, and the filtrate was washed with saturated brine, and then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 4/1) to obtain 7-(hydroxymethyl)benzo[ b ]thiophene- 4-nitrile (125 mg, yield: 36.3%). LCMS(ESI): m /z =172(M+HH ₂ O) ⁺ .

Step 10b: tert-butyl 4-(6-((4-cyanobenzo[ b ]thiophen-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0202-8 ) Preparation: Under nitrogen protection, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (138 mg, 0.46 mmol, 1.0 equivalent), 7-( Hydroxymethyl)benzo[ b ]thiophene-4-nitrile (0201-8) (105 mg, 0.56 mmol, 1.2 equiv), cesium carbonate (378 mg, 1.16 mmol, 2.5 equiv), 2-bicyclohexyl Phosphine-2',6'-diisopropoxybiphenyl (33 mg, 0.07 mmol, 0.15 equiv) and tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.042 mmol, 0.09 equiv) ) and toluene (50 ml) were refluxed at 125 °C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 6/1) to obtain a yellow solid 4-(6-((4-cyanobenzo[ b ]thiophene- 7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylic acid tert-butyl ester (192 mg, yield: 92.3%). LCMS(ESI): m /z =450 (M+H) ⁺ .

Step 10c: 7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzo[ b ]thiophene-4-carbonitrile hydrochloride (compound 0203-8) Preparation: To 4-(6-((4-cyanobenzo[ b ]thiophen-7-yl)methoxy)pyridin-2-yl)piridine-1-carboxylic acid tert-butyl ester (0202-8 ) (192 mg, 0.43 mmol, 1.0 equiv) To 5 ml of the dioxane mixture, add 1 ml of a 4M solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under reduced pressure to obtain 7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzo[ b ]thiophene-4-carbonitrile hydrochloride as a white solid Salt (240 mg, crude). LCMS(ESI): m /z =350(M+H) ⁺ .

Step 10d: ( S )-2-((4-(6-((4-cyanobenzo[ b ]thiophen-7-yl)methoxy)pyridin-2-yl)piridin-1-yl) Preparation of methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylate (compound 0204-8): 7-(( (6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzo[ b ]thiophene-4-carbonitrile hydrochloride (0203-8) (240 mg, 0.43 mmol, 2.5 equiv) was added to 5 ml of N -methylpyrrolidone, and then N,N -diisopropylethylamine (175 mg, 1.36 mmol, 8.0 equiv) was added. The mixture was stirred at room temperature for 5 minutes. Add ( S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.17 mmol, 1.0 equiv) and the mixture was stirred at 60 °C overnight. The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: dichloromethane/methanol=20/1) to obtain a yellow solid ( S )-2-((4-(6-((4- Cyanobenzo[ b ]thiophen-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1 H -Benzo[ d ]imidazole-6-carboxylic acid methyl ester (89 mg, yield: 86.1%). m/z =608(M+H) ⁺ .

Step 10e: ( S )-2-((4-(6-((4-cyanobenzo[ b ]thiophen-7-yl)methoxy)pyridin-2-yl)piridin-1-yl) Preparation of methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid (compound 8): ( S )-2-((4 -(6-((4-cyanobenzo[ b ]thiophen-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetane -2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (0204-8) (80 mg, 0.13 mmol, 1.0 equiv) and lithium hydroxide monohydrate (44 mg, A mixture of 1.05 mmol, 8.0 equiv) in a mixed solvent of 5 ml acetonitrile and 1 ml water was stirred at 40 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. Add dilute sulfuric acid to adjust the pH value of the residue to 6, add ethyl acetate to extract, and wash with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain a yellow solid ( S )-2-((4-(6) -((4-cyanobenzo[ b ]thiophen-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetane-2- (Methyl) -1H -benzo[ d ]imidazole-6-carboxylic acid (49 mg, yield: 62.0%). LCMS(ESI): m /z =594 (M+H) ⁺ , melting point: 124~126℃. ¹ H NMR (500 MHz, DMSO) δ 12.73 (s, 1H), 8.28 (s, 1H), 8.12 (d, J = 5.5 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.81 ( dd, J = 8.4, 1.0 Hz, 1H), 7.71 – 7.55 (m, 4H), 6.88 (d, J = 7.3 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 5.71 (s, 2H ), 5.10 (qd, J = 7.2, 2.8 Hz, 1H), 4.79 (dd, J = 15.2, 7.1 Hz, 1H), 4.66 (dd, J = 15.2, 2.4 Hz, 1H), 4.46 (dd, J = 13.7, 7.6 Hz, 1H), 4.36 (dt, J = 9.0, 5.9 Hz, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.80 (s, 1H), 2.95 (d, J = 10.7 Hz, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.75 – 2.65 (m, 1H), 2.56 (t, J = 11.5 Hz, 1H), 2.47 – 2.38 (m, 1H), 2.28 – 2.10 (m , 2H), 1.75 – 1.55 (m, 4H).

Example 11 : (S)-2-((4-(6-((4- Chlorobenzofurans -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 12) Preparation ( Prepare according to the second route of plan)

Step 11a Preparation of: (4-chlorobenzofuran-7-yl)methanol (Compound 0201-12):

Under nitrogen protection, 5-chloro-2-methylphenol (2.0 g, 14.03 mmol, 1.0 equivalent), 2-bromo-1,1-diethoxyethane (3.31 g, 16.83 mmol, 1.2 equivalent) ), and a mixture of potassium carbonate (2.9 g, 21.04 mmol, 1.5 equiv) in N,N-dimethylformamide was stirred at 120°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo to give 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene (4 g, crude). The product was used directly in the next step without further purification.

Under nitrogen protection conditions, the 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene (4.18 g, 14.03 mmol, 1.0 equivalent) and polyphosphoric acid ( 7.09 g, 21.04 mmol, 1.5 equiv) of the dichloroethane mixture was refluxed overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 4-chloro-7-methylbenzofuran (1.98 g, yield: 84.98%) as a transparent oil.

Under nitrogen protection conditions, the 4-chloro-7-methylbenzofuran (1.98 g, 11.93 mmol, 1.0 equivalent) and N-bromosuccinimide (2.54 g, 14.31 mmol, 1.2 equivalent) obtained above were mixed ) and a solution of azobisisobutyronitrile (391 mg, 2.38 mmol, 0.2 equiv) in dichloroethane (10 mL) was stirred at 72°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain a yellow oily substance 7-(bromomethyl)-4-chlorobenzofuran (2.54 g, yield: 87.28%).

N,N-dimethyl of 7-(bromomethyl)-4-chlorobenzofuran (2.54 g, 10.37 mmol, 1.0 equivalent) and potassium acetate (10.16 g, 103.7 mmol, 10.0 equivalent) obtained above The formamide mixture (20 ml) was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain (4-chlorobenzofuran-7-yl)methyl acetate (2.29 g, crude product), which was used directly in the next step without further purification.

A methanol solution of sodium methoxide (5.4 mol/ liter, 3.8 ml, 20.44 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 200/1-4/1) to obtain (4-chlorobenzofuran-7-yl)methanol. (1.3 g, yield: 69.89%) was a yellow solid. LCMS (ESI): m/z=183 (M+H) ⁺ .

Step 11b: 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylic acid tert-butyl ester (compound 0202-12) Preparation: Under nitrogen protection conditions, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (160 mg, 0.548 mmol, 1 equivalent), (4- Chlorobenzofuran-7-yl)methanol (0201-12) (120 mg, 0.66 mmol, 1.2 equiv), cesium carbonate (356 mg, 1.096 mmol, 2.0 equiv), 4,5-bisdiphenylphosphine -9,9-dimethylxanthene (76 mg, 0.131 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.065 mmol, 0.1 equiv) in toluene ( 10 ml) of the mixture was stirred at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain a yellow oily substance 4-(6-((4-chlorobenzofuran) -tert-butyl 7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (235 mg, yield: 98.74%). LCMS (ESI): m/z=443 (M+H) ⁺ .

Step 11c: Preparation of 2-((4-chlorobenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine hydrochloride (Compound 0203-12): To 4-( 6-((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (0202-12) (235 mg, 0.53 mmol, 1.0 equiv ) and hydrogen chloride in dioxane (4M, 1 ml) was added dioxane (2 ml), and the mixture was stirred at room temperature overnight. The mixture is filtered. The residue is washed with dioxane. The residue was dried to obtain 2-((4-chlorobenzofuran-7-yl)methoxy)-6-(piridin-4-yl)pyridine hydrochloride (142 mg, yield: 70.64%) as a yellow solid ). LCMS(ESI): m/z=343 (M+H) ⁺ .

Step 11d: (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-12): 2-((4-chlorobenzofuran) -7-yl)methoxy)-6-(pyridin-4-yl)pyridine hydrochloride (0203-12) (142 mg, 0.374 mmol, 1.5 equiv), (S)-2-(chloromethyl (0116-3) (73 mg, 0.249 mmol, 1.0 equiv) and a solution of N,N-diisopropylethylamine (161 mg, 1.248 mmol, 4.0 equiv) in N-methylpyrrolidone (5 mL) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain yellow solid (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)) Methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Methyl ester (115 mg, yield: 77.18%). LCMS(ESI): m/z=601 (M+H) ⁺ .

Step 11e: (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 12): (S)-2-((4-(6-() (4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H -Methyl benzo[d]imidazole-6-carboxylate (0204-12) (115 mg, 0.19 mmol, 1.0 equiv) and lithium hydroxide monohydrate (16 mg, 0.38 mmol, 2.0 equiv) in acetonitrile/ The water=5/1 (6 ml) mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, and a solid precipitate formed. The mixture is filtered. Wash the residue with water. The mixture was slurried with methanol to obtain a white solid (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (88 mg, yield: 78.57%). LCMS (ESI): m/z=587 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.29 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.82 (s, 1H), 7.75 – 7.60 (m, 2H ), 7.44 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.1 Hz, 1H), 6.88 (d, J = 7.1 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 5.63 (s, 2H), 5.10 (d, J = 5.6 Hz, 1H), 4.80 (dd, J = 15.3, 7.2 Hz, 1H), 4.72 – 4.63 (m , 1H), 4.46 (dd, J = 13.7, 7.4 Hz, 1H), 4.36 (dt, J = 9.0, 5.9 Hz, 1H), 3.95 (s, 1H), 3.78 (d, J = 10.6 Hz, 1H) , 2.93 (d, J = 71.7 Hz, 2H), 2.76 – 2.56 (m, 2H), 2.42 (s, 1H), 2.34 – 2.03 (m, 2H), 1.80 (s, 4H).

Example 12 : (S)-2-((4-(6-((4- Chlorobenzofurans -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-3-( Oxetane -2- Methyl )-3H- Imidazo [4,5-b] Pyridine -5- carboxylic acid ( compound 14) Preparation ( Prepare according to the second route of plan)

Step 12a: (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (compound 0204-14): 2-((4 -Chlorobenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine hydrochloride (0203-12) (139 mg, 0.366 mmol, 1.5 equiv), (S)- 2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (0116-1) (72 mg, 0.244 mmol, 1.0 equiv) and N,N-diisopropylethylamine (126 mg, 0.976 mmol, 4.0 equiv) in N-methylpyrrolidone (5 mL) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain yellow solid (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)) Methoxy)pyridin-2-yl)piridin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine- 5-Carboxylic acid methyl ester (70 mg, yield: 47.62%). LCMS (ESI): m/z=602 (M+H) ⁺ .

Step 12b: (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 14): (S)-2-((4 -(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-3-(oxetan-2-yl Methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (0204-14) (70 mg, 0.116 mmol, 1.0 equiv) and lithium hydroxide monohydrate (10 mg, 0.232 mmol, 2.0 equiv) of acetonitrile/water = 5/1 (6 mL) mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, after which a solid precipitated. The mixture is filtered. Wash the residue with water. The residue was purified using a silica gel thin layer chromatography preparatory plate (eluent: dichloromethane/methanol=10/1) to obtain a yellow solid (S)-2-((4-(6-((4-chlorobenzo) Furan-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4, 5-b]pyridine-5-carboxylic acid (30 mg, yield: 44.12%). LCMS (ESI): m/z=588 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.99 (s, 1H), 8.39 – 7.93 (m, 3H), 7.61 (d, J = 6.7 Hz, 1H), 7.41 (s, 1H), 7.32 (d, J = 6.9 Hz, 1H), 7.01 (s, 1H), 6.87 (s, 1H), 6.67 (d, J = 7.7 Hz, 1H), 5.61 (s, 2H), 5.29 (d, J = 93.9 Hz, 1H ), 4.80 (d, J = 53.8 Hz, 2H), 4.42 (d, J = 50.8 Hz, 2H), 3.89 (d, J = 105.4 Hz, 2H), 2.97 (s, 2H), 2.75 – 2.51 (m , 3H), 2.31 (d, J = 53.9 Hz, 2H), 1.77 (d, J = 15.7 Hz, 4H).

Example 13 : (S)-2-((4-(6-((2,4- Dichlorobenzofuran -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 15) Preparation ( Prepare according to the second route of plan)

Step 13a: tert-butyl 4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0202-15) Preparation: Under nitrogen protection and -70°C, add tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-carboxylate To a solution of ester (0202-12) (200 mg, 0.452 mmol, 1 equiv) in 10 mL of tetrahydrofuran was added lithium diisopropylamide (0.45 mL, 2 mol/L tetrahydrofuran, 0.905 mmol, 2 equiv). The mixture was stirred at -70°C for 1 hour. To the mixture was added hexachloroethane (107 mg, 0.452 mmol, 1 equiv) in tetrahydrofuran (1 mL). The mixture was stirred at -70°C for 1 hour. The reaction was quenched with ammonium chloride. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain a transparent oily substance 4-(6-((2,4-dichlorobenzo Furan-7-yl)methoxy)pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (180 mg, yield: 83.72%). LCMS (ESI): m/z=477 (M+H) ⁺ .

Step 13b: 2-((2,4-Dichlorobenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (Compound 0203-15 ) Preparation: tert-butyl 4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (0202-15 ) (180 mg, 0.377 mmol, 1.0 equiv) and p-toluenesulfonic acid (195 mg, 1.132 mmol, 3.0 equiv) in ethyl acetate (15 ml) was stirred at 60°C overnight. The mixture was cooled to room temperature. The mixture is filtered. The residue was washed with ethyl acetate. The residue was dried to obtain a white solid 2-((2,4-dichlorobenzofuran-7-yl)methoxy)-6-(piridin-4-yl)pyridine 4-methylbenzenesulfonate ( 253 mg, crude). LCMS (ESI): m/z=377 (M+H) ⁺ .

Step 13c: (S)-2-((4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl Preparation of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (compound 0204-15): 2-((2,4 -Dichlorobenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (0203-15) (206 mg, 0.377 mmol, 1.2 equiv ), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (92 mg, 0.314 mmol, 1.0 equiv) and potassium carbonate (173 mg, 1.256 mmol, 4.0 equiv) in acetonitrile (5 mL) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-((4-(6-((2,4-dichlorobenzofuran- 7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole- 6-Carboxylic acid methyl ester (180 mg, yield: 90.9%). LCMS (ESI): m/z=635 (M+H) ⁺ .

Step 13d: (S)-2-((4-(6-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 15): (6-((2,4-Dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetane-2 -methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-15) (64 mg, 0.1 mmol, 1.0 equiv) and lithium hydroxide monohydrate (13 mg, 0.3 mmol , 3.0 eq) a mixture of acetonitrile/water = 5/1 (6 ml) was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l sulfuric acid, after which a solid precipitated. The mixture is filtered. Wash the residue with water. The residue was purified using silica gel thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain a white solid (S)-2-((4-(6-((2,4- Dichlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzene And [d]imidazole-6-carboxylic acid (55 mg, yield: 88.71%). LCMS (ESI): m/z=621 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 8.26 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 12.7, 8.1 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.59 (s, 2H), 5.11 (d, J = 5.0 Hz, 1H), 4.79 (dd, J = 15.2, 7.0 Hz, 1H), 4.65 (d, J = 14.0 Hz, 1H), 4.46 (dd, J = 13.5, 7.1 Hz, 1H), 4.41 – 4.31 (m, 1H), 3.94 (d, J = 13.5 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 2.99 (d , J = 10.4 Hz, 1H), 2.85 (d, J = 10.7 Hz, 1H), 2.76 – 2.66 (m, 1H), 2.58 (s, 1H), 2.45 (d, J = 8.9 Hz, 1H), 2.20 (dt, J = 21.7, 10.4 Hz, 2H), 1.83 – 1.64 (m, 4H).

Example 14 : (S)-2-((4-(6-((4- chlorine -2- Fluorobenzofurans -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 16) Preparation ( Prepare according to the second route of plan)

Step 14a: tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0202-16 ): Preparation of 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridine-1-carboxylic acid under nitrogen protection and -70°C. To a solution of butyl ester (0202-12) (500 mg, 1.13 mmol, 1 equiv) in 10 mL of tetrahydrofuran was added lithium diisopropylamide (1.13 mL, 2 mol/L tetrahydrofuran, 2.26 mmol, 2 equiv). The mixture was stirred at -70°C for 1 hour. To the mixture was added N-fluorobenzenesulfonamide (356 mg, 1.13 mmol, 1 equiv) in tetrahydrofuran (1 mL). The mixture was stirred at -70°C for 1 hour. The reaction was quenched with ammonium chloride. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain a transparent oily substance 4-(6-((4-chloro-2-fluorobenzene) Furan-7-yl)methoxy)pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (200 mg, yield: 38.38%). LCMS (ESI): m/z=461 (M+H) ⁺ .

Step 14b: 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piridin-4-yl)pyridine 4-methylbenzenesulfonate (Compound 0203- Preparation of 16): tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridine-1-carboxylate (0202 A solution of -16) (200 mg, 0.43 mmol, 1.0 equiv) and p-toluenesulfonic acid (224 mg, 1.3 mmol, 3.0 equiv) in ethyl acetate (15 mL) was stirred at 60°C overnight. The mixture was cooled to room temperature. The mixture is filtered. The residue was washed with ethyl acetate. The residue was dried to obtain 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate as a white solid (208 mg, crude). LCMS (ESI): m/z=361 (M+H) ⁺ .

Step 14c: (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl) Preparation of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (compound 0204-16): 2-((4- Chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (0203-16) (104 mg, 0.203 mmol, 1.2 equivalents), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116- 3) A solution of (50 mg, 0.169 mmol, 1.0 equiv) and potassium carbonate (93 mg, 0.676 mmol, 4.0 equiv) in acetonitrile (5 ml) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran) -7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole -6-Carboxylic acid methyl ester (76 mg, yield: 72.38%). LCMS (ESI): m/z=619 (M+H) ⁺ .

Step 14d: (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl) Preparation of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 16): (S)-2-((4- (6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-16) (76 mg, 0.123 mmol, 1.0 equiv) and lithium hydroxide monohydrate (15 mg, 0.369 mm mol, 3.0 eq) of acetonitrile/water = 5/1 (6 ml) mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l sulfuric acid, after which a solid precipitated. The mixture is filtered. Wash the residue with water. The residue was purified using a silica gel thin layer chromatography preparatory plate (eluent: dichloromethane/methanol=10/1) to obtain a yellow solid (S)-2-((4-(6-((4-chloro- 2-Fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid (54 mg, yield: 72.97%). LCMS (ESI): m/z=605 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 8.26 (d, J = 0.8 Hz, 1H), 7.80 (dd, J = 8.4, 1.5 Hz, 1H), 7.68 – 7.57 (m, 2H ), 7.42 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 6.4 Hz, 1H), 5.56 (s, 2H), 5.11 (qd, J = 7.2, 2.7 Hz, 1H), 4.79 (dd, J = 15.2, 7.2 Hz, 1H), 4.65 (dd , J = 15.2, 2.7 Hz, 1H), 4.47 (dt, J = 13.7, 7.0 Hz, 1H), 4.37 (dt, J = 9.0, 5.9 Hz, 1H), 4.00 – 3.89 (m, 1H), 3.78 ( d, J = 13.5 Hz, 1H), 2.99 (d, J = 11.2 Hz, 1H), 2.85 (d, J = 11.3 Hz, 1H), 2.74 – 2.66 (m, 1H), 2.62 – 2.54 (m, 1H ), 2.43 (ddd, J = 11.1, 8.9, 5.6 Hz, 1H), 2.28 – 2.11 (m, 2H), 1.84 – 1.60 (m, 4H).

Example 15 : (S)-2-((4-(6-((4- chlorine -2- Methylbenzofuran -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 17) Preparation ( Prepare according to the second route of plan)

Step 15a Preparation of: (4-chloro-2-methylbenzofuran-7-yl)methanol (compound 0201-17):

Under nitrogen protection, 4-chloro-2-hydroxybenzoic acid methyl ester (1.87 g, 10.0 mmol, 1.0 equivalent), 3-bromopropyne (1.42 g, 12 mmol, 1.2 equivalent), and potassium carbonate (2.1 g, 15 mmol, 1.5 equiv) of N,N-dimethylformamide mixture was stirred at 50°C for 5 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was dissolved in N,N-diethylaniline (15 ml). Cesium fluoride (2.67 g, 17.63 mmol, 1.3 equiv) was added to the mixture. The mixture was stirred at 220°C for 3 hours. After cooling to room temperature, the reaction was quenched with water, the pH of the residue was adjusted to 6 with 2 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain yellow solid 4-chloro-2-methylbenzofuran-7-carboxylic acid methyl ester (1.34 g, Yield: 59.56%). LCMS (ESI): m/z=225 (M+H) ⁺ .

Under nitrogen protection conditions, combine the above-obtained methyl 4-chloro-2-methylbenzofuran-7-carboxylate (1.34 g, 5.98 mmol, 1.0 equivalent), sodium borohydride (4.55 g, 119.64 mmol, A solution of 20 eq) in methanol (13 ml) was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain yellow solid (4-chloro-2-methylbenzofuran-7-yl)methanol (1.1 g , Yield: 93.86%). LCMS (ESI): m/z=196 (M+H) ⁺ .

Step 15b: tert-butyl 4-(6-((4-chloro-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0202- Preparation of 17): Under nitrogen protection conditions, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (137 mg, 0.46 mol, 1.0 equivalent), (4 -Chloro-2-methylbenzofuran-7-yl)methanol (0201-17) (100 mg, 0.51 mmol, 1.1 equiv), cesium carbonate (333 mg, 1.02 mmol, 2.0 equiv), 4,5 -Bisdiphenylphosphine-9,9-dimethylxanthene (59 mg, 0.05 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (47 mg, 0.148 mmol, A mixture of 0.2 eq) in toluene (10 ml) was refluxed at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain a yellow oily substance 4-(6-((4-chloro-2-methylbenzo Furan-7-yl)methoxy)pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (145 mg, yield: 69.13%). LCMS (ESI): m/z=456 (M+H) ⁺ .

Step 15c: 2-((4-chloro-2-methylbenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (Compound 0203 -17) Preparation: tert-butyl 4-(6-((4-chloro-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piridine-1-carboxylate A solution of (0202-17) (145 mg, 0.31 mmol, 1.0 equiv) and p-toluenesulfonic acid (159 mg, 0.93 mmol, 3.0 equiv) in ethyl acetate (10 mL) was stirred at 60°C overnight. The mixture was washed with water, the pH of the residue was adjusted to 8 with 2 mol/l sodium hydroxide solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-((4-chloro-2-methylbenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4 - Toluene sulfonate (92 mg, crude), which was used in the next step without further purification. LCMS (ESI): m/z=357 (M+H) ⁺ .

Step 15d: (S)-2-((4-(6-((4-chloro-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl Preparation of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-17): 2-(( 4-Chloro-2-methylbenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (0203-17) (90 mg, 0.24 mmol, 1.2 equiv), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester A solution of (0116-3) (60 mg, 0.20 mmol, 1.0 equiv) and potassium carbonate (110 mg, 0.80 mmol, 4.0 equiv) in acetonitrile (5 ml) was stirred at 60°C for 16 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel thin layer chromatography (eluent: ethyl acetate/petroleum ether = 2/1) to obtain a white solid (S)-2-((4-(6-((4-chloro- 2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H - Benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, yield: 81.30%). LCMS (ESI): m/z=615 (M+H) ⁺ .

Step 15e: (S)-2-((4-(6-((4-chloro-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl )Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 17) Preparation: (S)-2-((4 -(6-((4-chloro-2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetane Alk-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-17) (100 mg, 0.16 mmol, 1.0 equiv) and lithium hydroxide monohydrate (21 mg, 0.49 mmol, 3.0 equiv) of acetonitrile/water = 5/1 (12 ml) mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, after which a solid precipitated. The mixture was filtered and the residue was washed with water. The residue was purified by thick preparative thin-layer silica gel chromatography (eluent: dichloromethane/methanol=10/1) to obtain a yellow solid (S)-2-((4-(6-((4-chloro- 2-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H - Benzo[d]imidazole-6-carboxylic acid (56 mg, yield: 58.24%). LCMS(ESI): m/z=601 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 8.27 (s, 1H), 7.80 (s, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.33 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 7.0 Hz, 1H), 6.67 (d, J = 13.6 Hz, 2H), 5.59 (s, 2H), 5.10 ( s, 1H), 4.78 (s, 1H), 4.66 (d, J = 14.2 Hz, 1H), 4.46 (dd, J = 13.7, 7.5 Hz, 1H), 4.36 (dt, J = 8.9, 5.9 Hz, 1H ), 3.94 (s, 1H), 3.79 (s, 1H), 2.99 (s, 1H), 2.86 (s, 1H), 2.70 (dt, J = 16.1, 8.0 Hz, 1H), 2.62 (d, J = 18.8 Hz, 1H), 2.40 (d, J = 42.1 Hz, 4H), 2.21 (d, J = 33.5 Hz, 2H), 1.76 (s, 4H).

Example 16 : (S)-2-((4-(6-(4- chlorine -2- Methylbenzofuran -7- Formamide group ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid (compound 20 ) preparation ( Prepare according to the second route of plan)

Step 16a: tert-butyl 4-(6-(4-chloro-2-methylbenzofuran-7-methamide)pyridin-2-yl)pipidine-1-carboxylate (Compound 0202-20) Preparation:

To a solution of methyl 4-chloro-2-methylbenzofuran-7-carboxylate (885 mg, 3.95 mmol, 1 equiv) in 10 mL of tetrahydrofuran was added 2N sodium hydroxide solution (5 mL). The mixture was stirred at 40°C for 16 hours. The reaction was cooled to room temperature. The pH of the mixture was adjusted to 1 with 2N hydrochloric acid, after which a solid precipitated. The mixture is filtered. Wash the residue with water. The residue was dried to give 4-chloro-2-methylbenzofuran-7-carboxylic acid as a yellow solid (700 mg, yield: 84.03%). LCMS (ESI): m/z=211 (M+H) ⁺ .

Under nitrogen protection conditions, 6-bromopyridin-2-amine (519 mg, 3 mmol, 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1113 mg, 3.6 mmol, 1.2 equiv), sodium carbonate (636 mg, 6 mmol, A mixture of toluene/ethanol/water (10/5/5 ml) and bistriphenylphosphine palladium dichloride (210 mg, 0.3 mmol, 0.1 equiv) in toluene/ethanol/water (10/5/5 ml) was stirred at 110°C for 16 hours. After cooling to room temperature, the reaction solution was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-2/1) to obtain a yellow oily substance 6-amino-3',6'-dihydro-[ 2,4'-Bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (600 mg, yield: 72.46%). LCMS (ESI): m/z=276 (M+H) ⁺ .

6-Amino-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (600 mg, 2.18 mmol, 1.0 equiv) and A solution of palladium on carbon (60 mg, Wt% = 10%) in methanol (15 ml) was stirred at room temperature for 5 hours. The mixture is filtered. The residue was washed with methanol. The residue was concentrated under reduced pressure to obtain white solid tert-butyl 4-(6-aminopyridin-2-yl)pyridine-1-carboxylate (553 mg, crude product). LCMS (ESI): m/z=278 (M +H) ⁺ .

Under nitrogen protection and ice bath, add 4-chloro-2-methylbenzofuran-7-carboxylic acid (100 mg, 0.476 mmol, 1 equivalent) to dichloromethane/tetrahydrofuran/N,N-dimethyl To the solution of formamide (10/5/0.01 ml), oxalic acid chloride (181 mg, 1.428 mmol, 3 equivalents) was added dropwise. The mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in 5 ml of dichloromethane. To the solution were added tert-butyl 4-(6-aminopyridin-2-yl)pipidine-1-carboxylate (131 mg, 0.476 mmol, 1 equivalent) and triethylamine (144 mg, 1.428 mmol, 3 equivalents). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water. The mixture was extracted with dichloromethane. The organic phase was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-2/1) to obtain white solid 4-(6-(4-chloro-2-methylbenzofuran) -tert-butyl 7-methamide)pyridin-2-yl)pipidine-1-carboxylate (143 mg, yield: 64.41%). LCMS (ESI): m/z=470 (M+H) ⁺ .

Step 16b: 4-chloro-2-methyl-N-(6-(pyridin-4-yl)pyridin-2-yl)benzofuran-7-methamide 4-methylbenzenesulfonate (compound 0203-20) Preparation: tert-butyl 4-(6-(4-chloro-2-methylbenzofuran-7-methamide)pyridin-2-yl)pipidine-1-carboxylate ( A solution of compound 0202-20) (143 mg, 0.305 mmol, 1.0 equiv) and p-toluenesulfonic acid (158 mg, 0.915 mmol, 3.0 equiv) in ethyl acetate (5 mL) was stirred at 60°C overnight. The mixture was cooled to room temperature. The mixture is filtered. The residue was washed with ethyl acetate. The residue was dried to obtain 4-chloro-2-methyl-N-(6-(pyridin-4-yl)pyridin-2-yl)benzofuran-7-methamide 4-methylbenzenesulfonate as a white solid Acid salt (200 mg, crude product). LCMS (ESI): m/z=370 (M+H) ⁺ .

Step 16c: (S)-2-((4-(6-(4-chloro-2-methylbenzofuran-7-methamide)pyridin-2-yl)piridin-1-yl)methane Preparation of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (compound 0204-20): 4-chloro-2-methyl Base-N-(6-(pyridin-4-yl)pyridin-2-yl)benzofuran-7-methamide 4-methylbenzenesulfonate (0203-20) (106 mg, 0.203 mmol , 1.2 equivalents), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116- 3) A solution of (50 mg, 0.169 mmol, 1.0 equiv) and potassium carbonate (93 mg, 0.676 mmol, 4.0 equiv) in acetonitrile (5 ml) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-((4-(6-(4-chloro-2-methylbenzofuran) -7-methamide)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole- 6-Carboxylic acid methyl ester (70 mg, yield: 66.03%). LCMS(ESI): m/z=628 (M+H) ⁺ .

Step 16d: (S)-2-((4-(6-(4-chloro-2-methylbenzofuran-7-methamide)pyridin-2-yl)piridin-1-yl)methane Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 20): (6-(4-chloro-2-methylbenzofuran-7-methamide)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetane-2 -methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-20) (70 mg, 0.11 mmol, 1.0 equiv) and lithium hydroxide monohydrate (14 mg, 0.33 mmol , 3.0 eq) a mixture of acetonitrile/water = 5/1 (6 ml) was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l sulfuric acid, after which a solid precipitated. The mixture is filtered. Wash the residue with water. The residue was purified using silica gel thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain a white solid (S)-2-((4-(6-(4-chloro-2) -Methylbenzofuran-7-methamide)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzene And [d]imidazole-6-carboxylic acid (48 mg, yield: 70.03%). LCMS (ESI): m/z=614 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.57 (s, 1H), 10.33 (s, 1H), 8.26 (d, J = 0.8 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.79 ( dd, J = 8.7, 7.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.09 ( d, J = 7.5 Hz, 1H), 6.79 (d, J = 1.0 Hz, 1H), 5.09 (ddd, J = 14.4, 7.2, 2.8 Hz, 1H), 4.82 (dd, J = 15.2, 7.2 Hz, 1H ), 4.67 (dd, J = 15.2, 2.7 Hz, 1H), 4.49 (dd, J = 13.6, 7.7 Hz, 1H), 4.37 (dt, J = 9.0, 5.9 Hz, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.81 (d, J = 13.5 Hz, 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.89 (d, J = 11.2 Hz, 1H), 2.78 – 2.62 (m, 2H) , 2.55 (s, 3H), 2.42 (ddd, J = 15.9, 11.1, 7.0 Hz, 1H), 2.23 (dt, J = 29.5, 10.7 Hz, 2H), 1.86 (t, J = 13.5 Hz, 2H), 1.81 – 1.67 (m, 2H).

Example 17 : 2-((4-(6-((4- Chlorobenzofurans -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-(2- Methoxyethyl )-1H- Benzo [d] imidazole -6- carboxylic acid (compound twenty three ) preparation ( Prepare according to plan 1 and 2 lines)

Step 17a: Preparation of methyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate (compound 0118-23): To methyl 3-fluoro-4-nitrobenzoate (compound 0118-23) 0107-23) (1.0 g, 5.02 mmol, 1.0 equiv) and N,N-diisopropylethylamine (1.34 mL, 7.53 mmol, 1.5 equiv) was added to a mixture of tetrahydrofuran (15 mL) and 2-methyl Oxyethylamine (0.45 g, 6.03 mmol, 1.2 equiv). The mixture was heated to 55°C for overnight reaction. The solvent was removed under reduced pressure. The residue was diluted with water (30 ml). The aqueous layer was extracted with ethyl acetate (30 ml × 4). The combined organic layers were washed with saturated brine (30 ml × 1), dried over anhydrous sodium sulfate and concentrated to obtain methyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate as a yellow solid. Ester (1.17 g, yield: 91%). LCMS (ESI): m/z 255[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 5:1).

Step 17b: Preparation of methyl 4-amino-3-((2-methoxyethyl)amino)benzoate (compound 0119-23): To 3-((2-methoxyethyl)amine To a mixture of methyl)-4-nitrobenzoate (0118-23) (1.17 g, 4.61 mmol, 1.0 equiv) in methanol (30 ml) was added palladium on carbon (0.22 g). The mixture was stirred at room temperature under hydrogen balloon pressure for 3.5 hours. The mixture is filtered. The filtrate was concentrated under reduced pressure to obtain methyl 4-amino-3-((2-methoxyethyl)amino)benzoate (1.03 g, yield: 100%) as a white solid. LCMS (ESI): m/z 225[M+1] ⁺ ; TLC: Rf 0.3 (petroleum ether: ethyl acetate = 5:1).

Step 17c: Preparation of 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Compound 0120-23): Go to 4- Amino-3-((2-methoxyethyl)amino)benzoic acid methyl ester (0119-23) (1.03 g, 4.60 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (17.5 mg, 0.09 mmol, 0.02 equiv) To a mixture of tetrahydrofuran (20 mL) was added 2-chloro-1,1,1-trimethoxyethane (0.78 g, 5.06 mmol, 1.1 equiv). The mixture was heated to 45°C for overnight reaction. The solvent was removed under reduced pressure. The residue was subjected to column chromatography separation on silica gel (petroleum ether: ethyl acetate 5:1) to obtain a white solid 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzo[d ]imidazole-6-carboxylic acid methyl ester (1.25 g, yield: 93%). LCMS (ESI): m/z 283[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 2:1).

Step 17d: 2 ^- ((4-(6 ^- ((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(2 -Methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0205-23): To 2-((4-chlorobenzofuran-7-yl)methoxy (0203-12) (90 mg, 0.18 mmol, 1.1 equiv) and 2-(chloromethyl)-1-(2-methyl Oxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0120-23) (45 mg, 0.16 mmol, 1.0 equiv) was added to a mixture of acetonitrile (6 mL) and potassium carbonate ( 66 mg, 0.48 mmol, 3.0 equiv). The mixture was heated to 60°C for overnight reaction. The solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate 1:1) to give 2 ^- ((4-(6 ^- ((4-chlorobenzofuran-7-yl)methoxy)pyridine) as a white solid -2-yl)pyridin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (69 mg, yield: 74%). LCMS (ESI): m/z 589[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 1:1).

Step 17e: 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(2 Preparation of -methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 23): To 2 ^- ((4-(6 ^- ((4-chlorobenzofuran-7-yl) )methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( 0205-23) (69 mg, 0.12 mmol, 1.0 equiv) To a mixture of tetrahydrofuran (6 mL) and water (3 mL) was added lithium hydroxide monohydrate (15 mg, 0.36 mmol, 3.0 equiv). The mixture was heated to 40°C for overnight reaction. The mixture was diluted with water (15 ml). 1N dilute hydrochloric acid solution was added to adjust pH = 5, and then the aqueous layer was extracted with ethyl acetate (20 ml × 3). The combined organic layers were washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridine) as a white solid -2-yl)piridin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (52 mg, yield: 78% ). LCMS (ESI): m/z 575[M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane: methanol = 10:1); melting point: 123-126°C. ¹ H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 8.24 – 8.11 (m, 2H), 7.81 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 7.8 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.67 ( d, J = 8.2 Hz, 1H), 5.61 (s, 2H), 4.60 (s, 2H), 3.84 (s, 2H), 3.75 (t, J = 5.0 Hz, 2H), 3.21 (s, 3H), 2.92 (d, J = 10.8 Hz, 2H), 2.61 (dd, J = 19.2, 7.7 Hz, 1H), 2.21 (t, J = 10.7 Hz, 2H), 1.75 (dd, J = 33.6, 10.7 Hz, 4H ).

Example 18 : (S)-2-((4-(6-((4- Chlorobenzofurans -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-(( Tetrahydrofuran -2- base ) methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound twenty four) Preparation ( Prepare according to plan 1 and 2 lines)

Step 18a Preparation of: (S)-4-nitro-3-((tetrahydrofuran-2-yl)methyl)amino)benzoic acid methyl ester (compound 0118-24): Under nitrogen protection, 3-fluoro- Methyl 4-nitrobenzoate (0107-23) (894.8 mg, 4.4937 mmol, 1.0 equiv), (S)-(tetrahydrofuran-2-yl)methanamine (500 mg, 4.9431 mmol, 1.1 equiv) and A solution of potassium carbonate (1242 mg, 8.987 mmol, 2.0 equiv) in a mixture of N,N-dimethylformamide (10 ml) was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1) to obtain (S)-4-nitro-3-(tetrahydrofuran-2- Methyl)methyl)amino)benzoate (1120 mg, yield: 88.96%) was a yellow solid. LCMS (ESI): m/z=281 (M+H) ⁺ .

Step 18b Preparation of: (S)-4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoic acid methyl ester (compound 0119-24): (S)-4 under hydrogen -Methyl nitro-3-((tetrahydrofuran-2-yl)methyl)amino)benzoate (0118-24) (1120 mg, 3.996 mmol, 1.0 equiv) and palladium on carbon (112 mg, 10% Mass ratio) of tetrahydrofuran mixture (13 ml) was stirred at room temperature overnight. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow oily substance (S)-4-amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoic acid methyl ester (1090 mg, yield 109%). The product was used directly in the next step without further purification.

Step 18c: ((S)-2-(chloromethyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Compound 0120-24 ) Preparation: (S)-4-Amino-3-(((tetrahydrofuran-2-yl)methyl)amino)benzoic acid methyl ester (0119-24) (1090 mg, 4.35 mmol) under nitrogen , 1.0 equivalent), 2-chloro-1,1,1-trimethoxyethane (807 mg, 5.55 mmol, 1.2 unit amount) and p-toluenesulfonic acid monohydrate (89.889 mg, 0.522 mmol, 0.12 unit amount) ) in tetrahydrofuran (10 ml) was heated to 45°C and stirred overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was subtracted Concentrate under pressure to obtain (S)-2-(chloromethyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (609.5 mg, collected Ratio: 45.44%) was a yellow solid. LCMS (ESI): m/z=309 (M+H) ⁺ .

Step 18d: (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0205-24): 2-((4-chlorobenzo Furan-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (compound 0203-12) (96.82 mg, 0.1948 mmol, 1.2 equiv) and potassium carbonate (89.5896 mg, 0.6492 mmol, 4.0 equiv) in acetonitrile (5 mL) was stirred at 60°C to pH 7~8, then (S)-2-(chloromethyl)-1-(tetrahydrofuran Methyl -2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (0120-24) (50 mg, 0.1623 mmol, 1.0 equiv) was added to the mixture and stirred overnight. After cooling to room temperature, the reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain yellow solid compound (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)) Methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (79.8 mg, yield 79.94). LCMS (ESI): m/z=616 (M+H) ⁺ .

Step 18e: (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 24): (S)-2-((4-(6-((4 -Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[ d] Methyl imidazole-6-carboxylate (0205-24) (79.8 mg, 0.1298 mmol, 1.0 equiv) and lithium hydroxide monohydrate (10.98 mg, 0.1298 mmol, 10 units) in acetonitrile/water = 5 /1 (6 ml) mixture was stirred at 40°C overnight. The mixture was then cooled to room temperature and the pH was adjusted to approximately 6°C by adding 1.0 M H2SO4, after which a solid precipitated. The mixture is filtered. Wash the residue with water. The mixture was slurried with methanol to obtain a yellow solid (S)-2-(4-(6-(4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl )-1-((tetrahydrofuran-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (49.8 mg, yield 63.86%). LCMS (ESI): m/z=602 ( M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 8.21 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.62 ( dd, J = 14.0, 6.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.86 ( d, J = 7.3 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.61 (s, 2H), 4.55 (d, J = 13.6 Hz, 1H), 4.44 (dd, J = 14.6, 8.1 Hz, 1H), 4.32 – 4.23 (m, 1H), 3.99 (d, J = 13.6 Hz, 1H), 3.77 (dt, J = 22.8, 10.4 Hz, 2H), 3.60 (dd, J = 14.0, 7.3 Hz , 1H), 3.01 (d, J = 11.2 Hz, 1H), 2.85 (d, J = 10.8 Hz, 1H), 2.61 (td, J = 11.2, 5.6 Hz, 1H), 2.27 (t, J = 10.7 Hz , 1H), 2.17 (t, J = 10.6 Hz, 1H), 2.11 – 2.01 (m, 1H), 1.76 (dd, J = 15.5, 8.4 Hz, 5H), 1.71 – 1.61 (m, 2H).

Example 19 : 2-((4-(6-((4- Chlorobenzofurans -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-((1- Ethyl -1H- imidazole -5- base ) methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 25) Preparation ( Prepare according to the plan 1 and 2 lines)

Step 19a: Preparation of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (Compound 0119-25):

A solution of 1-ethyl-1H-imidazole-5-carboxylic acid (500 mg, 3.6 mmol, 1.0 equiv) in tyrene chloride (5 mL) was refluxed for two hours. After cooling to room temperature, the solvent was spun off under vacuum, the residue was dissolved in tetrahydrofuran (6 ml), and an ammonia dioxane solution (1 ml) of 0.4 mol per liter was added dropwise at 0°C. After the addition was complete, the mixture was stirred for 30 minutes. Potassium carbonate (1 g) was added and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain 1-ethyl-1H-imidazole-5-carboxamide (500 mg, yield: 100%) as a white solid. LCMS(ESI): m/z=140 (MH) ⁺ .

To a solution of 1-ethyl-1H-imidazole-5-carboxamide (500 mg, 3.6 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) was added a 10 mol/L solution of borane dimethyl sulfide (0.72 mL, 7.2 mmol, 2.0 equiv). The mixture was stirred at room temperature for 3 hours. Methanol (2 ml) was added and the mixture was stirred for 30 minutes. The mixture was concentrated in vacuo, 5 moles per liter of methanol hydrochloride (5 ml) was added, and the mixture was stirred for 10 minutes. The mixture was concentrated in vacuo to obtain (1-ethyl-1H-imidazole-5-)methanamine hydrochloride (550 mg, yield: 94.8%) as a white solid. LCMS (ESI): m/z=126 (M+H) ⁺ .

Mix 3-fluoro-4-nitrobenzoic acid methyl ester (367 mg, 1.85 mmol, 1.0 equiv), potassium carbonate (511 g, 3.70 mmol, 2.0 equiv) and (1-ethyl-1H-imidazole-5 -) A mixture of methylamine hydrochloride (300 mg, 1.85 mmol, 1.0 equiv) in N-methylpyrrolidone (10 mL) was stirred at room temperature overnight. Ethyl acetate and water were added, the mixture was separated, and the organic layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 100/1 to 30/1) to obtain a yellow solid 3-(((1-ethyl-1H-imidazol-5-yl)methyl) methyl)amino)-4-nitrobenzoate (340 mg, yield: 60.5%). LCMS (ESI): m/z=305 (M+H) ⁺ .

Under hydrogen, 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate methyl ester (340 mg, 1.1 mmol, 1.0 equiv) and A mixture of Pd/C (34 mg, 10% mass ratio) and methanol (6 ml) was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (300 mg, yield: 98.0%). LCMS (ESI): m/z=275 (M+H) ⁺ .

Step 19b: 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(( Preparation of 1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0205-25):

2-((4-Chlorobenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (0203-12) (231 mg, 0.45 mg mol, 1.5 equiv), ethyl 2-bromoacetate (50 mg, 0.30 mmol, 1.0 equiv) and potassium carbonate (165 mg, 1.20 mmol, 4.0 equiv) in N,N-dimethylformamide (10 ml) solution was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1-1/1) to obtain a white solid 2-(4-(6-((4-chlorobenzofuran-7) -ethyl)methoxy)pyridin-2-yl)piridin-1-yl)acetate (120 mg, yield: 93.24%). LCMS (ESI): m/z=429 (M+H) ⁺ .

In ethyl 2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)acetate (120 mg, 0.28 mmol, To a solution of 1.0 equivalent) methanol/tetrahydrofuran = 2/1 (9 ml), add an aqueous solution of sodium hydroxide (2 mol/L, 5 ml). The mixture was stirred at room temperature for 3 hours. The pH of the mixture was adjusted to 7 with 1 mol/l dilute hydrochloric acid, after which a solid precipitated. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product 2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)acetic acid (120 mg ,Crude). The product was used directly in the next step without further purification.

In 2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)acetic acid (120 mg, 0.30 mmol, 1.0 equiv. ), 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoic acid was added to a solution of N,N-dimethylformamide (10 ml) Methyl ester (0119-25) (73 mg, 0.27 mmol, 0.9 equiv) and N,N-diisopropylethylamine (109 mg, 0.84 mmol, 2.8 equiv). 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (136.8 mg, 0.36 mmol, 1.2 equiv) was added last to the reaction. The mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (eluent: dichloromethane/methanol=15/1) to obtain yellow oil 4-(2-(4-(6-() (4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)acetamide)-3-(((1-ethyl-1H-imidazole) -Methyl 5-yl)methyl)amino)benzoate (50 mg, yield: 28.19%). LCMS (ESI): m/z=657 (M+H) ⁺ .

4-(2-(4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)acetamide)-3-( A solution of (((1-ethyl-1H-imidazole)-5-yl)methyl)amino)benzoate in acetic acid (10 ml) was stirred at 55°C for 16 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain yellow solid methyl 2-((4-(6-((4 -Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (34 mg, yield: 69.96%). LCMS (ESI): m/z=639 (M+H) ⁺ .

Step 19c: 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(( Preparation of 1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 25): Methyl 2-((4-(6-(( 4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl methyl)-1H-benzo[d]imidazole-6-carboxylate (0205-25) (34 mg, 0.053 mmol, 1.0 equiv) and lithium hydroxide monohydrate (6.7 mg, 0.16 mmol, 3 equiv. ) acetonitrile/water =5/1 (6 ml) mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l dilute sulfuric acid, after which a solid precipitated. The mixture is filtered. The residue was purified by silica gel thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain a yellow solid 2-((4-(6-((4-chlorobenzofuran-7- yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d ] Imidazole-6-carboxylic acid (18.3 mg, yield: 55.25%). LCMS (ESI): m/z=625 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 8.15 (d, J = 1.9 Hz, 1H), 8.06 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.76 – 7.55 (m, 3H), 7.42 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 6.67 (t, J = 7.1 Hz, 1H), 6.46 (s, 1H), 5.73 (s, 2H), 5.61 (s, 2H), 3.98 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 2.87 (d, J = 10.8 Hz, 2H), 2.53 (d, J = 11.4 Hz, 1H), 2.15 (t, J = 11.1 Hz, 2H), 1.72 (d, J = 11.8 Hz, 2H), 1.60 – 1.42 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H).

Example 20 : (S)-2-((4-(6-((4- Fluorobenzofurans -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 28) Preparation ( Prepare according to the second route of plan)

Step 20a Preparation of: (4-fluorobenzofuran-7-yl)methanol (compound 0201-28):

Under nitrogen protection conditions, 5-fluoro-2-methylphenol (3.0 g, 23.8 mmol, 1.0 equivalent), 2-bromo-1,1-diethoxyethane (5.63 g, 28.5 mmol, 1.2 Equivalent), potassium carbonate (4.92 g, 35.7 mmol, 1.5 equivalent) and potassium iodide (0.3 g, 10% mass ratio) in N,N-dimethylformamide mixture was stirred at 120°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 2-(2,2-diethoxyethoxy)-4-fluoro-1-methylbenzene (5.3 g, product rate: 92.0%). The product was used directly in the next step without further purification.

Under nitrogen protection conditions, 2-(2,2-diethoxyethoxy)-4-fluoro-1-methylbenzene (1.0 g, 4.13 mmol, 1.0 equivalent) obtained above was mixed with polyphosphoric acid (3.5 g, 10.3 mmol, 2.5 equiv) in 1,2-dichloroethane (20 mL) was refluxed overnight. After cooling to room temperature, the reaction was quenched with water (40 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 4-fluoro-7-methylbenzofuran (300 mg, yield: 49.0%) as a yellow oil. LCMS (ESI): m/z=151 (M+H) ⁺ .

Under nitrogen protection conditions, the 4-fluoro-7-methylbenzofuran (300 mg, 2.00 mmol, 1.0 equivalent) and N-bromosuccinimide (415 mg, 2.40 mmol, 1.2 equivalent) obtained above were mixed ) and azobisisobutyronitrile (66 mg, 0.4 mmol, 0.2 equiv) in 1,2-dichloroethane (10 mL) was stirred at 72 °C overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with water (20 ml) and extracted with petroleum ether/ethyl acetate = 2/1 (30 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain white solid 7-(bromomethyl)-4-fluorobenzofuran (400 mg, yield: 87.3 %). LCMS (ESI): m/z=229 (M+H) ⁺ .

The 7-(bromomethyl)-4-fluorobenzofuran (400 mg, 1.73 mmol, 1.0 equivalent) and potassium acetate (1.67 g, 17.3 mmol, 10.0 equivalent) obtained above were mixed with N,N-dimethyl A mixture of methamide (15 ml) was stirred at room temperature for 3 hours. The reaction was quenched with water (20 ml) and extracted with ethyl acetate (30 ml). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (4-fluorobenzofuran-7-yl)methyl acetate (500 mg of crude product). The product was used directly in the next step without further purification.

A methanol solution of sodium methoxide (5.4 mol/ liter, 0.7 ml, 3.64 mmol, 1.5 equiv). The mixture was stirred at room temperature for 1 hour. The pH of the reaction was adjusted to approximately 6 with 1 mol/L hydrochloric acid, and then a solid precipitate formed. The slurry was diluted with water (15 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 4/1) to obtain yellow solid (4-fluorobenzofuran-7-yl)methanol (195 mg, yield: 67.9%) ). LCMS (ESI): m/z=167 (M+H) ⁺ .

Step 20b: Preparation of 4-(6 ^- ((4-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylic acid tert-butyl ester (compound 0202-28): Under nitrogen protection conditions, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (195 mg, 0.66 mmol, 1.0 equivalent), (4-fluorobenzene Furan-7-yl)methanol (0201-28) (132 mg, 0.79 mmol, 1.2 equiv), cesium carbonate (430 mg, 1.32 mmol, 2.0 equiv), 2-dicyclohexylphosphonium-2',6 '-Diisopropoxy-1,1'-biphenyl (61 mg, 0.132 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (55 mg, 0.06 mmol, 0.1 equiv) ) in toluene (10 ml) was refluxed at 120°C overnight. After cooling to room temperature, the reaction solution was filtered through celite and the solid was washed with ethyl acetate (15 ml). The filtrate was diluted with water (20 ml) and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain white solid 4-(6 ^- ((4-fluorobenzofuran-7-yl)methoxy) Pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (230 mg, yield: 82.1%). LCMS (ESI): m/z=427 (M+H) ⁺ .

Step 20c: Preparation of 2-((4-fluorobenzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine hydrochloride (compound 0203-28): 4-( 6 ^- ((4-Fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0202-28) (110 mg, 0.258 mmol, 1.0 equiv ), add dioxane hydrochloride (15 ml) solution and stir at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain 2 ^- ((4-fluorobenzofuran-7-yl)methoxy)-6-(piridin-4-yl)pyridine hydrochloride (84 mg crude product) as a white solid. (ESI): m/z=327 (M+H) ⁺ .

Step 20d: (S)-2-((4-(6 ^- ((4-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-28): 2-((4-fluorobenzo Furan-7-yl)methoxy)-6-(pyridin-4-yl)pyridine hydrochloride (0203-28) (84 mg, 0.257 mmol, 1.2 equiv), (S)-2-(chloro Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Compound 0116-3) (60 mg, 0.21 mmol, 1.0 Equivalent) and N,N-diisopropylethylamine (0.5 ml) in N-methylpyrrolidone (5 ml) were stirred at 60°C for 4 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2 ^- ((4-(6 ^- ((4-fluorobenzofuran-7-yl)) Methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Methyl ester (99 mg, yield: 80.4%). LCMS (ESI): m/z=585 (M+H) ⁺ .

Step 20e: (S)-2-((4-(6-((4-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 28): (S)-2 ^- ((4-(6- ((4-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylic acid methyl ester (0204-28) (99 mg, 0.184 mmol, 1.0 equiv) and lithium hydroxide monohydrate (24 mg, 0.553 mmol, 3.0 equiv) in acetonitrile /water=5/1 (6 ml) mixture was stirred at 40°C overnight. After the mixture was cooled to room temperature, the pH was adjusted to about 6 with 1 mol/L hydrochloric acid, and then a solid precipitate formed. The slurry was diluted with water (12 mL) and stirred for 4 hours, then the solids were collected by filtration. The solid was washed with water and dried under vacuum. The solid was dissolved in dichloromethane/methanol = 1/2 (5 ml), and then filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dried under vacuum to obtain a white solid (S)-2-((4-(6-((4-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl). )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (42 mg, yield: 40.0%). LCMS(ESI): m/z=571 (M+H) ⁺ . Melting point: 131~143 ℃; ¹ H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.70 – 7.56 (m, 2H), 7.44 (dd, J = 7.8, 5.5 Hz, 1H), 7.08 (dd, J = 8.9, 5.5 Hz, 2H), 6.86 (d, J = 7.2 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.60 (s, 2H), 5.11 (d, J = 5.2 Hz, 1H), 4.79 (dd, J = 15.1, 7.1 Hz, 1H), 4.66 (d, J = 13.7 Hz, 1H), 4.46 (dd, J = 13.6, 7.2 Hz, 1H), 4.37 (dd, J = 14.3, 5.8 Hz, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 3.00 (d, J = 10.5 Hz, 1H), 2.86 (d, J = 10.7 Hz, 1H), 2.70 (dt, J = 16.0, 7.8 Hz, 1H), 2.61 (t, J = 11.5 Hz, 1H), 2.44 (t, J = 13.0 Hz, 1H), 2.22 (dt, J = 21.6, 10.6 Hz, 2H), 1.86 – 1.65 (m, 4H).

Example twenty one : ( S )-2-((4-(6-((4- Methylbenzofuran -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl ) -1H- Benzo [ d ] imidazole -6- carboxylic acid ( compound 30) Preparation ( Prepare according to the second route of plan)

Step 21a Preparation of: (4-methylbenzofuran-7-yl)methanol (Compound 0201-30):

Combine 2-hydroxy-4-methylbenzoic acid methyl ester (831 mg, 5.0 mmol, 1.0 equiv), 2-bromo-1,1-diethoxyethane (1.48 g, 7.5 mmol, 1.5 equiv) A mixture of N,N-dimethylformamide and potassium carbonate (1.73 g, 12.5 mmol, 2.5 equiv) was stirred at 120°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a yellow oily substance, 2-(2,2-diethoxyethoxy)-4-methylbenzoic acid methyl ester (4 g, crude product). This product was used directly without further purification. to the next step.

The 2-(2,2-diethoxyethoxy)-4-methylbenzoate methyl ester obtained above (1.72 g, 5.0 mmol, 1.0 equivalent) and polyphosphoric acid (300 mg, 0.88 mmol) , 0.18 eq) toluene mixture was refluxed overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 50/1) to obtain colorless oily substance 4-methylbenzofuran-7-carboxylic acid methyl ester (496 mg, yield: 52.2%).

Under nitrogen protection, the 4-methylbenzofuran-7-carboxylic acid methyl ester (430 mg, 2.26 mmol, 1.0 equivalent) obtained above was dissolved in anhydrous tetrahydrofuran. The mixture was cooled to 0°C. Lithium aluminum hydride (129 mg, 3.39 mmol, 1.5 equiv) was added and the mixture was stirred for 1.5 hours. Add 0.13 ml of water, 0.13 ml of 15% sodium hydroxide aqueous solution and 0.39 ml of water in sequence at 0°C. The mixture was stirred for 15 minutes. 1.6 g of anhydrous sodium sulfate were added and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (4-methylbenzofuran-7-yl)methanol (391 mg, crude product) as a yellow solid. LCMS(ESI): m /z =145(M+HH ₂ O) ⁺ .

Step 21b: ( S )-2-((4-(6-chloropyridin-2-yl)piridin1-yl)methyl)-1-(oxetan-2-ylmethyl)-1 Preparation of H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (compound 0204-20): 4-(6-chloropyridin-2-yl)piridin-1-carboxylic acid tert-butyl ester (0104- 1) (200 mg, 0.67 mmol, 1.0 equiv) Add 1.5 ml of 4M hydrogen chloride in dioxane to 4 ml of dioxane mixture. The mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under reduced pressure. The residue was added to 5 ml of N -methylpyrrolidone, followed by N,N -diisopropylethylamine (432 mg, 3.35 mmol, 5.0 equiv). The mixture was stirred at room temperature for 5 minutes. Add ( S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (compound 0116-3 ) (180 mg, 0.61 mmol, 0.9 equiv) and the mixture was stirred at 60 °C overnight. The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain a yellow solid ( S )-2-((4-(6- Chloropyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylic acid methyl ester ( 245 mg, yield: 80.3%). LCMS(ESI): m /z =455(M+H) ⁺ . Under nitrogen protection, the ( S )-2-((4-(6-chloropyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-yl) obtained above was Methyl) -1H -benzo[ d ]imidazole-6-carboxylate (120 mg, 0.264 mmol, 1.0 equiv), (4-methylbenzofuran-7-yl)methanol (0201-30 ) (52 mg, 0.317 mmol, 1.2 equivalents), cesium carbonate (215 mg, 0.66 mmol, 2.5 equivalents), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (12 mg , 0.026 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.013 mmol, 0.05 equiv) in toluene (20 ml) was refluxed at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=33/1) to obtain a yellow solid ( S )-2-((4-(6-((4-methylbenzofuran-7) -yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole- 6-Carboxylic acid methyl ester (68 mg, yield: 44.4%). LCMS(ESI): m /z =581 (M+H) ⁺ .

Step 21c: ( S )-2-((4-(6-((4-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl) Preparation of -1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid (compound 30): ( S )-2-((4-(6 -((4-methylbenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl )-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (0204-30) (68 mg, 0.12 mmol, 1.0 equiv) and lithium hydroxide monohydrate (10 mg, 0.23 mmol, 2.0 equiv) ) in a mixed solvent of 5 ml acetonitrile and 1 ml water and stirred overnight at 40 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with dilute sulfuric acid, after which a solid precipitated. The mixture is filtered. Wash the residue with water. The mixture was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=15/1) to obtain a yellow solid ( S )-2-((4-(6-((4-methylbenzofuran-7- yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl) -1H -benzo[ d ]imidazole-6 - Carboxylic acid (45 mg, yield: 67.1%). LCMS(ESI): m /z =567 (M+H) ⁺ , melting point: 105~107℃. ¹ H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 8.28 (s, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.73 – 7.56 (m, 2H), 7.31 (d, J = 7.4 Hz, 1H), 7.03 (t, J = 4.5 Hz, 2H), 6.86 (d, J = 7.2 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 5.59 (s, 2H), 5.11 (d, J = 5.2 Hz, 1H), 4.79 (dd, J = 15.3, 7.2 Hz, 1H), 4.66 (dd, J = 15.2, 2.6 Hz, 1H ), 4.46 (dd, J = 13.7, 7.6 Hz, 1H), 4.36 (dt, J = 9.0, 5.9 Hz, 1H), 3.96 (s, 1H), 3.79 (s, 1H), 3.03 (s, 1H) , 2.87 (s, 1H), 2.76 – 2.56 (m, 2H), 2.45 (d, J = 16.4 Hz, 4H), 2.20 (dd, J = 29.0, 21.6 Hz, 2H), 1.79 (d, J = 30.1 Hz, 4H).

Example twenty two : ( S )-2-((4-(6-((2- methyl -4-( trifluoromethyl ) benzofurans -7- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl ) -1H- Benzo [ d ] imidazole -6- carboxylic acid ( compound 31) Preparation ( Prepare according to the second route of plan)

Step 22a Preparation of: (2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methanol (Compound 0201-31):

Combine 2-bromo-5-(trifluoromethyl)phenol (964 mg, 4.0 mmol, 1.0 equiv), 3-bromopropyne (619 mg, 5.2 mmol, 1.3 equiv) and potassium carbonate (884 mg, 6.4 mmol, 1.6 equiv) of N,N-dimethylformamide mixture was stirred at 50°C for 3 hours. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain 1-bromo-2-(prop-2-yn-1-yloxy)-4-(trifluoromethyl)benzene (920 mg, yield: 82.1%). This product was not Further purification is required and used directly in the next step.

Under nitrogen protection, 1-bromo-2-(prop-2-yn-1-yloxy)-4-(trifluoromethyl)benzene (920 mg, 3.3 mmol, 1.0 equivalent) and A mixture of cesium fluoride (752 mg, 4.95 mmol, 14.5 equiv) in N,N-diethylaniline was stirred at 220°C for 5 hours. After cooling to room temperature, the mixture was acidified by adding concentrated hydrochloric acid, and a mixture of ethyl acetate and petroleum ether was added for extraction. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 7-bromo-2-methyl-4-(trifluoromethyl)benzofuran (650 mg, yield :70.6%).

The 7-bromo-2-methyl-4-(trifluoromethyl)benzofuran (580 mg, 2.08 mmol, 1.0 equivalent) and 1,3-bis(diphenylphosphine)propane (172 mg, 0.42 mmol, 0.2 equiv), palladium acetate (95 mg, 0.42 mmol, 0.2 equiv) and triethylamine (2.1 g, 20.8 mmol, 10.0 equiv) in 25 mL methanol and 5 mL N,N-di The mixture of methylformamide mixed solvent is added to the pressurized reaction kettle. The reaction kettle was filled with 0.3 MPa carbon monoxide and stirred at 80°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 50/1 to 20/1) to obtain a yellow solid 2-methyl-4-(trifluoromethyl)benzofuran-7- Methyl carboxylate (521 mg, yield: 97.1%).

Under nitrogen protection, the 2-methyl-4-(trifluoromethyl)benzofuran-7-carboxylic acid methyl ester (521 mg, 2.0 mol, 1.0 equivalent) obtained above was dissolved in anhydrous tetrahydrofuran. The mixture was cooled to 0℃. Lithium aluminum hydride (116 mg, 3.0 mmol, 1.5 equiv) was added and the mixture was stirred for 1.5 hours. Add 0.12 ml of water, 0.12 ml of 15% sodium hydroxide aqueous solution and 0.36 ml of water in sequence at 0°C. The mixture was stirred for 15 minutes. 1.5 g of anhydrous sodium sulfate were added and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain (2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methanol (507 mg, crude product) as a yellow oil. LCMS(ESI): m /z =175(M+HH ₂ O) ⁺ .

Step 22b: tert-butyl 4-(6-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate Preparation of ester (compound 0202-31): Under nitrogen protection, tert-butyl 4-(6-chloropyridin-2-yl)piridin-1-carboxylate (0104-1) (150 mg, 0.51 mmol, 1.0 equiv), (2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methanol (0201-31) (140 mg, 0.61 mmol, 1.2 equiv), cesium carbonate (416 mg, 1.28 mmol, 2.5 equiv), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (36 mg, 0.077 mmol, 0.15 equiv) and tris(dibenzylideneacetone)dipalladium A mixture of (0) (42 mg, 0.046 mmol, 0.09 equiv) in toluene (50 mL) was refluxed at 125 °C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by preparative silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1 to 6/1) to obtain a yellow solid 4-(6-((2-methyl-4-(trifluoro Methyl)benzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (220 mg, yield: 88.0%). LCMS(ESI): m /z =491 (M+H) ⁺ .

Step 22c: 2-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)-6-(pyridin-4-yl)pyridine hydrochloride (Compound 0203 Preparation of -31): To 4-(6-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1- Tert-butyl carboxylate (0202-31) (220 mg, 0.45 mmol, 1.0 equiv) was added to 5 ml of dioxane mixture and 1 ml of 4M hydrogen chloride in dioxane was added. The mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under reduced pressure to obtain 2-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)-6-(pyridin-4-yl) as a white solid Pyridine hydrochloride (250 mg, crude). LCMS(ESI): m /z =391(M+H) ⁺ .

Step 22d: ( S )-2-((4-(6-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)qua Preparation of benzo[ d ]imidazole-6-carboxylic acid methyl ester (compound 0204-31) : 2-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)-6-(piridin-4-yl)pyridine hydrochloride (0203-21 ) (250 mg, 0.45 mmol, 2.6 equivalents) was added to 10 ml of N -methylpyrrolidone, and then N,N -diisopropylethylamine (171 mg, 1.25 mmol, 7.3 equivalents) was added. The mixture was stirred at room temperature for 5 minutes. Add ( S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.17 mmol, 1.0 equiv) and the mixture was stirred at 60 °C overnight. The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: petroleum ether/ethyl acetate=2/1) to obtain a yellow solid ( S )-2-((4-(6-((2 -Methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetane- 2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (74 mg, yield: 67.2%). m/z =649(M+H) ⁺ .

Step 22e: ( S )-2-((4-(6-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)qua Preparation of (din-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid (compound 31): ( S ) -2-((4-(6-((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl) Methyl)-1-(oxetan-2-ylmethyl) -1H -benzo[ d ]imidazole-6-carboxylate (0204-31) (74 mg, 0.11 mmol, 1.0 Equivalent) and lithium hydroxide monohydrate (12 mg, 0.8 mmol, 2.5 equivalent) in a mixed solvent of 5 ml acetonitrile and 1 ml water was stirred overnight at 40 °C. The mixture was cooled to room temperature and concentrated under reduced pressure. Add dilute sulfuric acid to adjust the pH value of the residue to 6, add ethyl acetate to extract, and wash with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain a yellow solid ( S )-2-((4-(6) -((2-methyl-4-(trifluoromethyl)benzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxa Cyclobutan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid (55 mg, yield: 75.3%). LCMS(ESI): m /z =635 (M+H) ⁺ , melting point: 126~128℃. ¹ H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 8.27 (s, 1H), 7.81 (dd, J = 8.4, 1.4 Hz, 1H), 7.64 (t, J = 7.8 Hz, 2H), 7.54 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.78 – 6.67 (m, 2H), 5.68 (s, 2H ), 5.10 (qd, J = 7.2, 2.8 Hz, 1H), 4.78 (dd, J = 15.2, 7.2 Hz, 1H), 4.64 (dd, J = 15.2, 2.6 Hz, 1H), 4.45 (dt, J = 13.9, 7.0 Hz, 1H), 4.35 (dt, J = 9.0, 5.9 Hz, 1H), 3.95 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 13.6 Hz, 1H), 2.98 (d, J = 10.6 Hz, 1H), 2.85 (d, J = 10.9 Hz, 1H), 2.73 – 2.64 (m, 1H), 2.62 – 2.54 (m, 1H), 2.49 – 2.39 (m, 4H), 2.21 (dt , J = 21.7, 10.6 Hz, 2H), 1.81 – 1.62 (m, 4H).

Example twenty three : (S)-2-((4-(6-((5- Fluorobenzofurans -6- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 32) Preparation ( Prepare according to plan four lines)

Step 23a Preparation of: (5-fluorobenzofuran-6-yl)methanol (Compound 0401-32):

Under nitrogen protection, to a solution of 2-fluoro-5-hydroxybenzoic acid methyl ester (2.0 g, 11.76 mmol, 1.0 equivalent) in acetic acid (20 ml) was added N-iodosuccinimide (2.9 g, 12.94 mmol, 1.1 equiv) and the mixture was stirred at room temperature overnight. Pour the reaction solution into water and stir for 30 minutes. The mixture was filtered, and then the filter cake was washed with water and dried under reduced pressure to obtain methyl 2-fluoro-5-hydroxy-4-iodobenzoate (2.7 g, yield: 77.59%) as a white solid. LCMS (ESI): m/z=297 (M+H) ⁺ .

Under nitrogen protection, add 2-fluoro-5-hydroxy-4-iodobenzoic acid methyl ester (2.7 g, 9.12 mmol, 1.0 equivalent) and triethylamine (2.76 g, 27.36 mmol, 3.0 equivalent) obtained above, To a solution of copper iodide (26 mg, 0.137 mmol, 0.02 equiv) and bis(triphenylphosphine)palladium dichloride (192 mg, 0.274 mmol, 0.03 equiv) in tetrahydrofuran (20 ml) was added trimethyl ethynylsilane (1.79 g, 18.24 mmol, 2.0 equiv) and the mixture was stirred at 70°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure, and methanol (20 ml), diisopropylethylamine (3.5 g, 27.36 mmol, 3.0 eq) and copper iodide (1.7 g, 9.12 mmol, 1.0 eq) were added. ). The mixture was refluxed for 2 hours. After cooling to room temperature, pour the mixture into water. A solution of PE/EA = 2/1 was added for extraction, and the organic layer was concentrated under reduced pressure. Tetrahydrofuran (20 mL) and tetrabutylammonium fluoride trihydrate (1.19 g, 4.56 mmol, 0.5 equiv) were added and the mixture was refluxed for 1 hour. After cooling to room temperature, the mixture was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 to 20/1) to obtain yellow solid 5-fluorobenzofuran-6-carboxylic acid methyl ester (1 g, collected rate: 55.87%). LCMS (ESI): m/z=195 (M+H) ⁺ .

Under nitrogen protection, lithium aluminum tetrahydrogen (94.3 mg, 2.48 mmol) was added to a solution of 5-fluorobenzofuran-6-carboxylic acid methyl ester (241 mg, 1.24 mmol, 1.0 equivalent) in tetrahydrofuran (20 ml). , 2 equivalents). The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1 to 5/1) to obtain yellow solid (5-fluorobenzofuran-6-yl)methanol (200 mg, collected rate: 97.08%). LCMS (ESI): m/z=167 (M+H) ⁺ .

Step 23b: Preparation of 4-(6-((5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piridin-1-carboxylic acid tert-butyl ester (compound 0402-32): Under nitrogen protection, 4-(6-chloropyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (0104-1) (297 mg, 1.0 mmol, 1.0 equivalent), (5-fluorobenzo Furan-6-yl)methanol (0401-32 (200 mg, 1.2 mmol, 1.2 equiv), cesium carbonate (652 mg, 2.0 mmol, 2.0 equiv), 2-dicyclohexylphosphonium-2',6'- Diisopropoxy-1,1'-biphenyl (46.7 mg, 0.1 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol, 0.05 equiv) The mixture of toluene (10 ml) was refluxed at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography ( The eluent is: petroleum ether/ethyl acetate = 20/1-5/1) The crude product is purified to obtain a yellow oily substance 4-(6-((5-fluorobenzofuran-6-yl)methoxy) )pyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (250 mg, yield: 58.55%). LCMS (ESI): m/z=427 (M+H) ⁺ .

Step 23c: Preparation of 2-((5-fluorobenzofuran-6-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (Compound 0403-32) : In tert-butyl 4-(6-((5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (0402-32) (250 mg, 0.587 To a solution of p-toluenesulfonic acid monohydrate (303 mg, 1.76 mmol, 3 equiv) in ethyl acetate (10 mL) was added. The mixture was stirred at 60°C overnight. The mixture is filtered. The residue was washed with ethyl acetate. The residue was dried to obtain 2-((5-fluorobenzofuran-6-yl)methoxy)-6-(piridin-4-yl)pyridine 4-methylbenzenesulfonate (254 mg, Yield: 86.99%). LCMS (ESI): m/z=327 (M+H) ⁺ .

Step 23d: (S)-2-((4-(6-((5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0404-32): 2-((5-fluorobenzo Furan-6-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (0403-32) (203 mg, 0.407 mmol, 1.5 equiv), (S) -2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (80 mg, 0.27 mmol, 1.0 equiv) and potassium carbonate (149 mg, 1.08 mmol, 4.0 equiv) in acetonitrile (10 mL) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white oily substance (S)-2-((4-(6-((5-fluorobenzofuran-6- yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- Methyl carboxylate (100 mg, yield: 63.29%). LCMS (ESI): m/z=585 (M+H) ⁺ .

Step 23e: (S)-2-((4-(6-((5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 32): (S)-2-((4-(6-( (5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H -Methyl benzo[d]imidazole-6-carboxylate (0404-32) (100 mg, 0.17 mmol, 1.0 equiv) and lithium hydroxide monohydrate (11 mg, 0.26 mmol, 1.5 equiv) in acetonitrile/ The water=5/1 (6 ml) mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, after which a solid precipitated. The mixture is filtered. The residue was washed with water and dried under reduced pressure to obtain a white solid (S)-2-((4-(6-((5-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piridin- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (70 mg, yield: 72.16%). LCMS(ESI): m/z=571 (M+H) ⁺ . 1H NMR (500 MHz, DMSO) δ 8.25 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.4, 1.4 Hz, 1H), 7.76 (d, J = 5.7 Hz , 1H), 7.62 (dd, J = 12.2, 4.8 Hz, 2H), 7.49 (d, J = 9.9 Hz, 1H), 6.94 (dd, J = 2.1, 0.8 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 5.46 (s, 2H), 5.11 (qd, J = 7.3, 2.8 Hz, 1H), 4.80 (dd, J = 15.2, 7.2 Hz, 1H), 4.66 (dd, J = 15.2, 2.6 Hz, 1H), 4.46 (dt, J = 13.9, 7.0 Hz, 1H), 4.37 (dt, J = 9.0, 5.9 Hz, 1H), 3.95 (d, J = 13.5 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 3.00 (d, J = 11.2 Hz, 1H), 2.86 (d, J = 11.3 Hz, 1H), 2.74 – 2.66 (m, 1H ), 2.62 (tt, J = 11.4, 4.0 Hz, 1H), 2.48 – 2.40 (m, 1H), 2.29 – 2.22 (m, 1H), 2.22 – 2.14 (m, 1H), 1.85 – 1.69 (m, 4H ).

Example twenty four : (S)-2-((4-(6-((6- Fluorobenzofurans -5- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-3-( Oxetane -2- Methyl )-3H- Imidazo [4,5-b] Pyridine -5- carboxylic acid ( compound 33) Preparation ( Prepare according to plan 5 route)

Step 24a Preparation of: (6-fluorobenzofuran-5-yl)methanol (Compound 0501-33):

To a solution of 2-fluoro-4-hydroxybenzaldehyde (5.0 g, 35.7 mmol, 1.0 equiv) in concentrated sulfuric acid (30 mL) was added N-iodosuccinimide (8.84 g, 39.3 mmol, 1.1 equiv) ) and the mixture was stirred at room temperature for 3 hours. Pour the reaction solution into ice water and stir for 1 hour. The mixture was filtered, and then the filter cake was washed with water and dried under reduced pressure to obtain the crude product 2-fluoro-4-hydroxy-5-iodobenzaldehyde. (5.6 g, crude product), this product was used directly in the next step without further purification.

Under nitrogen protection, add 2-fluoro-4-hydroxy-5-iodobenzaldehyde (5.6 g, 20.8 mmol, 1.0 equivalent), triethylamine (6.3 g, 62.4 mmol, 3.0 equivalent) and iodine obtained above. To a solution of cuprous chloride (59.3 mg, 0.31 mmol, 0.02 equiv) and bis(triphenylphosphine)palladium dichloride (438 mg, 0.62 mmol, 0.03 equiv) in tetrahydrofuran (50 ml) was added trimethyl Ethynylsilane (4.08 g, 41.6 mmol, 2.0 equiv) and the mixture was stirred at 70°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure, and methanol (150 ml), diisopropylethylamine (8.06 g, 62.4 mmol, 3.0 eq) and copper iodide (4.0 g, 20.8 mmol, 1.0 eq) were added. ). The mixture was refluxed for 2 hours. After cooling to room temperature, pour the mixture into water. A solution of PE/EA = 2/1 was added for extraction, and the organic layer was concentrated under reduced pressure. Tetrahydrofuran (50 mL) and tetrabutylammonium fluoride trihydrate (2.7 g, 10.4 mmol, 0.5 equiv) were added and the mixture was refluxed for 1 hour. After cooling to room temperature, the mixture was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1 to 20/1) to obtain yellow solid 6-fluorobenzofuran-5-carbaldehyde (2.1 g, yield: 61.19 %). LCMS (ESI): m/z=165 (M+H) ⁺ .

To a solution of 6-fluorobenzofuran-5-carbaldehyde (1 g, 6.10 mmol, 1.0 equiv) in methanol (25 mL) was added sodium borohydride (277 mg, 7.32 mmol, 1.2 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain (6-fluorobenzofuran-5-yl)methanol (947 mg, yield: 93.58%) as a yellow solid. LCMS (ESI): m/z=167 (M+H) ⁺ .

Step 24b: Preparation of tert-butyl 4-(6 ^- ((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0502-33): Under nitrogen protection, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (350 mg, 1.18 mmol, 1.0 equivalent), (6-fluorobenzo Furan-5-yl)methanol (0501-33) (235 mg, 1.416 mmol, 1.2 equiv), cesium carbonate (769 mg, 2.36 mmol, 2.0 equiv), 2-dicyclohexylphosphonium-2',6'-Diisopropoxy-1,1'-biphenyl (55 mg, 0.118 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (54 mg, 0.059 mmol, 0.05 equiv) The mixture of toluene (10 ml) was refluxed at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1-5/1) to obtain a yellow oily substance 4-(6 ^- ((6-fluorobenzofuran) -tert-butyl 5-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (450 mg, yield: 89.64%). LCMS (ESI): m/z=427 (M+H) ⁺ .

Step 24c: Preparation of 2-((6-fluorobenzofuran-5-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (Compound 0503-33) : In tert-butyl 4-(6-((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)piridine-1-carboxylate (0502-33) (450 mg, 1.06 To a solution of p-toluenesulfonic acid monohydrate (546 mg, 3.17 mmol, 3 equiv) in ethyl acetate (10 mL) was added. The mixture was stirred at 60°C overnight. The mixture is filtered. The residue was washed with ethyl acetate. The residue was dried to obtain 2-((6-fluorobenzofuran-5-yl)methoxy)-6-(piridin-4-yl)pyridine 4-methylbenzenesulfonate (510 mg, Yield: 96.59%). LCMS (ESI): m/z=327 (M+H) ⁺ .

Step 24d: (S)-2-((4-(6-((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (compound 0504-33): 2-((6 -Fluorobenzofuran-5-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (0503-33) (127 mg, 0.255 mmol, 1.5 equiv) , (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (0116 -1) A solution of (50 mg, 0.17 mmol, 1.0 equiv) and potassium carbonate (94 mg, 0.68 mmol, 4.0 equiv) in acetonitrile (10 ml) was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-((4-(6-((6-fluorobenzofuran-5-yl)) Methoxy)pyridin-2-yl)piridin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine- 5-Carboxylic acid methyl ester (66 mg, yield: 66.37%). LCMS (ESI): m/z=586 (M+H) ⁺ .

Step 24e: (S)-2-((4-(6-((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 33): (S)-2-((4- (6-((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-3-(oxetan-2-ylmethyl (methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate) 0504-33) (66 mg, 0.11 mmol, 1.0 equiv) and lithium hydroxide monohydrate (5 mg, 0.12 mg mol, 1.1 eq) a mixture of acetonitrile/water = 5/1 (6 ml) was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, after which a solid precipitated. The mixture is filtered. The residue was washed with water and dried under reduced pressure to obtain a white solid (S)-2-((4-(6-((6-fluorobenzofuran-5-yl)methoxy)pyridin-2-yl)piridin- 1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (40 mg, yield: 63.49% ). LCMS (ESI): m/z=572 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.04 (d, J = 8.1 Hz, 1H), 7.97 (dd, J = 14.1, 5.2 Hz, 2H), 7.81 (d, J = 7.3 Hz, 1H), 7.66 – 7.53 (m, 2H), 6.97 – 6.91 (m, 1H), 6.86 (d, J = 7.3 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 5.44 (s, 2H), 5.03 (d , J = 4.6 Hz, 1H), 4.87 (dd, J = 14.7, 7.4 Hz, 1H), 4.69 (dd, J = 14.7, 3.0 Hz, 1H), 4.41 (dd, J = 14.0, 7.1 Hz, 1H) , 4.32 (dt, J = 12.2, 6.1 Hz, 1H), 4.05 (d, J = 13.6 Hz, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.00 (d, J = 11.2 Hz, 1H) , 2.87 (d, J = 11.2 Hz, 1H), 2.61 (td, J = 11.0, 5.5 Hz, 1H), 2.50 (s, 1H), 2.37 – 2.16 (m, 3H), 1.88 – 1.66 (m, 4H ).

Example 25 :( S ) -2- (( 4- ( 6- (( 7- Fluorobenzofurans -6- base)methoxy)pyridine -2- base) guadine -1- base) methyl) -1- (oxetane -2- methyl group) -1H- Benzo [d] imidazole -6- carboxylic acid ( compound 44) Preparation ( Prepare according to route six of plan)

Step 25a: Preparation of (7-fluorobenzofuran-6-yl)methanol (Compound 0601-44)

Under nitrogen protection, 2-fluoro-3-methylphenol (2.5 g, 19.84 mmol, 1.0 equivalent), 2-bromo-1,1-diethoxyethane (4.69 g, 23.81 mmol, 1.2 equivalent) ), a mixture of potassium carbonate (4.11 g, 21.4 mmol, 1.5 equiv) in N,N-dimethylformamide (50 ml) was stirred at 120°C overnight. After cooling to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (petroleum ether/ethyl acetate = 10/1 to 5/1) to obtain a yellow oily product 1-(2,2-diethoxyethoxy)-2-fluoro-3-methyl. Benzene (4.78 g, yield: 99.6%).

Under nitrogen protection, 1-(2,2-diethoxyethoxy)-2-fluoro-3 was added to a solution of polyphosphoric acid (15.89 g, 47.00 mmol, 2.5 equivalents) in toluene (100 ml). - Methylbenzene (4.55 g, 18.80 mmol, 1.0 equiv), the mixture was stirred at 120°C overnight. After cooling to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain a yellow oily product, 7-fluoro-6-methylbenzofuran (2.08 g, yield: 70.2%).

Under nitrogen protection conditions, 7-fluoro-6-methylbenzofuran (2.0 g, 13.33 mmol, 1.0 equivalent), N-bromosuccinimide (2.85 g, 15.99 mmol, 1.2 equivalent) and even A solution of azodiisobutyronitrile (437 mg, 2.67 mmol, 0.2 equiv) in 1,2-dichloroethane (25 mL) was stirred at 72°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (eluent: petroleum ether) to obtain a white solid product, 6-(bromomethyl)-7-fluorobenzofuran (2.13 g, yield: 69.8%).

6-(Bromomethyl)-7-fluorobenzofuran (2.03 g, 8.86 mmol, 1.0 equiv) and potassium acetate (8.7 g, 88.6 mmol, 10.0 equiv) in N,N-dimethylformamide The mixture (40 ml) was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification.

Under nitrogen protection, add a methanol solution of sodium methoxide (5.4 mol/L, 3.33 ml) to a tetrahydrofuran solution of (7-fluorobenzofuran-6-yl)methyl acetate (1.87 g, 8.99 mmol, 1.0 equivalent) , 17.98 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 1.0 h. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (petroleum ether/ethyl acetate = 15/1 to 5/1) to obtain a yellow solid product (7-fluorobenzofuran-6-yl) methanol (1.2 g, yield: 80.4%) .

Step 25b: Preparation of tert-butyl 4-(6-((7-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piridine-1-carboxylate (Compound 0602-44): Under nitrogen protection, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (178.8 mg, 0.602 mmol, 1.0 equivalent), (7-fluorobenzofuran -6-yl) methanol (0601-44) (120 mg, 0.722 mmol, 1.2 equiv), cesium carbonate (391 mg, 1.2 mmol, 2.0 equiv), 2-dicyclohexylphosphonium-2',6'- Diisopropoxy-1,1'-biphenyl (56 mg, 0.12 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (55 mg, 0.06 mmol, 0.1 equiv) The mixture of toluene (10 ml) was stirred at 120°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (petroleum ether/ethyl acetate = 20/1 to 10/1) to obtain the yellow solid product 4-(6-((7-fluorobenzofuran-6-yl)methoxy)pyridine -2-yl)pyridin-1-carboxylic acid tert-butyl ester (254 mg, yield: 98.8%). LCMS(ESI): m/z =427[M+1]+.

Step 25c: Preparation of 2-((7-fluorobenzofuran-6-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (Compound 0603-44) : In tert-butyl 4-(6-((7-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)pipidine-1-carboxylate (0602-44) (254 mg, 0.596 To a solution of p-toluenesulfonic acid monohydrate (206 mg, 1.19 mmol, 2.0 equiv) in ethyl acetate (10 mL) was added, and the mixture was stirred at 60°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was used directly in the next step without further purification. LCMS (ESI): m/z=327 (M+H) ⁺ .

Step 25d: (S)-2-((4-(6-((7-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0604-44): 2-((7-fluorobenzofuran) -6-yl)methoxy)-6-(pyridin-4-yl)pyridine 4-methylbenzenesulfonate (0603-44) (72 mg, 0.22 mmol, 1.3 equiv), (S)- 2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.169 mg mol, 1.0 eq) and potassium carbonate (93.5 mg, 0.678 mmol, 4.0 eq) in acetonitrile (10 ml) was stirred at 60°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol=16/1) to obtain the white solid product (S)-2-((4-(6-((7-fluorobenzofuran-6-yl)) Methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid Methyl ester (89 mg, yield: 90.3%). LCMS (ESI): m/z=584 (M+H) ⁺ .

Step 25e: (S)-2-((4-(6-((7-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 44): (S)-2-((4-(6-() (7-fluorobenzofuran-6-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H -Methyl benzo[d]imidazole-6-carboxylate (0704-44) (89 mg, 0.147 mmol, 1.0 equiv) and lithium hydroxide monohydrate (16.3 mg, 0.388 mmol, 2.5 equiv) in acetonitrile/ The water=5/1 (12 ml) mixture was stirred at 40°C overnight. The reaction solution was adjusted to pH 6 with 2 mol/L hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure to obtain a white solid (S)-2-((4-(6-((7-fluoro) benzofuran-6-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Imidazole-6-carboxylic acid (76 mg, yield: 87.7%). LCMS(ESI): m/z=571 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.88 (s, 1H), 8.36 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.79 ( d, J = 8.2 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.53 – 7.41 (m, 2H), 7.12 – 7.04 (m, 1H), 6.92 (d, J = 5.6 Hz, 1H ), 6.72 (d, J = 8.2 Hz, 1H), 5.54 (s, 2H), 5.05 (d, J = 5.9 Hz, 1H), 4.84 (dd, J = 15.4, 6.9 Hz, 2H), 4.70 (d , J = 14.6 Hz, 1H), 4.49 (dd, J = 13.5, 7.2 Hz, 1H), 4.35 (dd, J = 14.7, 5.9 Hz, 1H), 3.81 (s, 2H), 3.35 (s, 3H) , 2.96 (s, 1H), 2.71 (dt, J = 16.3, 8.0 Hz, 1H), 2.35 (d, J = 7.8 Hz, 1H), 2.29 – 2.01 (m, 4H).

Example 26 : (S)-2-((6-((4- Cyano -3- Methylbenzofuran -7- base ) Methoxy )-3',6'- dihydrogen -[2,4'- Bipyridine ]-1'(2'H)- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 46) Preparation ( Prepare according to plan three lines)

Step 26a: Preparation of 7-(hydroxymethyl)-3-methylbenzofuran-4-nitrile (Compound 0201-46):

Under nitrogen protection, 4-bromo-2-hydroxybenzoic acid methyl ester (1.0 g, 4.33 mmol, 1.0 equivalent), 1-bromopropan-2-one (711 mg, 5.19 mmol, 1.2 equivalent), and carbonic acid A mixture of potassium (896 mg, 6.49 mmol, 1.5 equiv) in N,N-dimethylformamide was stirred at room temperature for 1 hour. The reaction was quenched with water and a solid precipitated. The mixture is filtered. The residue was washed with water and dried to obtain crude product 4-bromo-2-(2-oxypropoxy)benzoic acid methyl ester (1 g, crude product). The product was used directly in the next step without further purification. LCMS (ESI): m/z=287 (M+H) ⁺ .

Under nitrogen protection, 4-bromo-2-(2-oxypropoxy)benzoic acid methyl ester (1 g, 3.48 mmol, 1.0 equivalent), and polyphosphoric acid (1.76 g, 5.23 mmol, 1.5 equivalent) ) dichloroethane mixture was refluxed overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain yellow solid 4-bromo-3-methylbenzofuran-7-carboxylic acid methyl ester (357 mg, yield: 38.26%). LCMS (ESI): m/z=269 (M+H) ⁺ .

Under nitrogen protection, 4-bromo-3-methylbenzofuran-7-carboxylic acid methyl ester (320 mg, 1.19 mmol, 1.0 equivalent), tetrakis triphenylphosphine palladium (137 mg, 0.12 mmol, 0.1 Equivalents) and zinc cyanide (208 mg, 1.78 mmol, 1.5 equivalents) in N,N-dimethylformamide (5 ml) was stirred at 90°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain yellow solid 4-cyano-3-methylbenzofuran-7-carboxylic acid. Methyl ester (242 mg, yield: 95.01%). LCMS (ESI): m/z=216 (M+H) ⁺ .

Under nitrogen protection and ice bath conditions, add 4-cyano-3-methylbenzofuran-7-carboxylic acid methyl ester ( 259 mg, 1.2 mmol, 1.0 equiv). The mixture was stirred in an ice bath for 1 hour. The reaction was quenched with water. The mixture was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-2/1) to obtain a yellow solid 7-(hydroxymethyl)-3-methylbenzofuran-4- Nitrile (135 mg, yield: 60%). LCMS (ESI): m/z=188 (M+H) ⁺ .

Step 26b: 6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1' Preparation of (2'H)-tert-butylcarboxylate (compound 0303-46): 6-chloro-3',6'-dihydro-[2,4'-bipyridine]-1' under nitrogen protection conditions (2'H)-tert-butylcarboxylate (0302-2) (174 mg, 0.59 mmol, 1.2 equiv), 7-(hydroxymethyl)-3-methylbenzofuran-4-carbonitrile (0201- 46) (92 mg, 0.492 mmol, 1.0 equiv), cesium carbonate (320 mg, 0.984 mmol, 2.0 equiv), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1 A mixture of '-biphenyl (92 mg, 0.197 mmol, 0.4 equiv) and tris(dibenzylideneacetone)dipalladium(0) (89 mg, 0.098 mmol, 0.2 equiv) in toluene (10 mL) at 125 Reflux overnight at °C. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain a yellow oily substance 6-((4-cyano-3-methyl) Benzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (123 mg, product rate: 56.16%). LCMS (ESI): m/z=446 (M+H) ⁺ .

Step 26c: 3-methyl-7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridin]]-6-yl)oxy)methyl)benzene Preparation of furan-4-carbonitrile hydrochloride (compound 0304-46): 6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6 '-Dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (0303-46) (123 mg, 0.276 mmol, 1.0 equiv) and dioxane hydrochloride A solution of the ring solution (4M, 1 mL) in dioxane (4 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain crude 3-methyl-7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridin]]-6-yl)oxy) Methyl)benzofuran-4-carbonitrile hydrochloride (105 mg, crude). The product was used directly in the next step without further purification. LCMS (ESI): m/z=346 (M+H) ⁺ .

Step 26d: (S)-2-((6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4 '-Bipyridyl]-1'(2' H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl Preparation of ester (compound 0305-46): 3-methyl-7-(((1',2',3',6'-tetrahydro-[2,4'-bipyridyl]]-6-yl) Oxy)methyl)benzofuran-4-carbonitrile hydrochloride (0304-46) (105 mg, 0.276 mmol, 1.5 equiv), (S)-2-(chloromethyl)-1-(oxy Hetetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (54 mg, 0.184 mmol, 1.0 equiv) and N,N-diiso A solution of propylethylamine (95 mg, 0.736 mmol, 4.0 equiv) in N-methylpyrrolidone (5 mL) was stirred at 60°C for 16 hours. After cooling to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain yellow solid (S)-2-((6-((4-cyano-3-methylbenzofuran-7) -yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2' H)-yl)methyl)-1-(oxetane- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (80 mg, yield: 72.26%). LCMS(ESI): m/z=604 (M+H) ⁺ .

Step 26e: (S)-2-((6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4 '-Bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid ( Preparation of compound 46): (S)-2-((6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro- [2,4'-bipyridyl]-1'(2' H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 - Methyl carboxylate (0305-46) (80 mg, 0.13 mmol, 1.0 equiv) and lithium hydroxide monohydrate (11 mg, 0.26 mmol, 2.0 equiv) in acetonitrile/water = 5/1 (6 ml) The mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, and a solid precipitate formed. The mixture is filtered. Wash the residue with water. The mixture was slurried with methanol to obtain a yellow solid (S)-2-((6-((4-cyano-3-methylbenzofuran-7-yl)methoxy)-3',6'-dihydro- [2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 - Carboxylic acid (66 mg, yield: 78.14%). LCMS (ESI): m/z=590 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.25 (s, 1H), 8.05 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.76 – 7.60 (m, 3H), 7.50 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 6.61 (s, 1H), 5.70 (s, 2H), 5.05 (qd, J = 7.2, 2.8 Hz, 1H), 4.78 (dd, J = 15.2, 7.2 Hz, 1H), 4.63 (d, J = 13.0 Hz, 1H), 4.46 (dd, J = 13.7, 7.5 Hz, 1H), 4.35 (dt, J = 8.9, 5.9 Hz, 1H), 4.05 (d, J = 13.6 Hz, 1H), 3.91 (d, J = 13.5 Hz, 1H), 3.19 (d, J = 12.6 Hz, 2H), 2.65 (ddd, J = 17.7, 14.8, 12.1 Hz, 3H), 2.45 – 2.31 (m, 6H).

Example 27 : (S)-2-((4-(6-((7- Cyanobenzofuran -4- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 47) Preparation ( Prepare according to route seven of the plan)

Step 27a: Preparation of 4-(hydroxymethyl)benzofuran-7-nitrile (Compound 0701-47):

Under nitrogen protection, 4-methylbenzofuran-7-nitrile (960 mg, 6.11 mmol, 1.0 equivalent), N-bromosuccinimide (1300 mg, 7.33 mmol, 1.2 equivalent) and azo A solution of diisobutyronitrile (200 mg, 1.22 mmol, 0.2 equiv) in dichloroethane (10 mL) was stirred at 72°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 200/1-10/1) to obtain 4-(bromomethyl)benzofuran-7- Nitrile (968 mg, yield: 67.22%) was a white solid. LCMS (ESI): m/z=236 (M+H) ⁺ .

4-(bromomethyl)benzofuran-7-carbonitrile (968 mg, 4.1 mmol, 1.0 equiv) and potassium acetate (4 g, 41 mmol, 10.0 equiv) in N,N-dimethylformamide The mixture (10 ml) was stirred at room temperature for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product (7-cyanobenzofuran-4-yl)methyl acetate (766 mg, crude product). The product was used directly in the next step without further purification.

A solution of sodium methoxide in methanol (5.4 mol/L, 1.32 ml, 7.12 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 200/1-2/1) to obtain 4-(hydroxymethyl)benzofuran-7- Nitrile (968 mg, yield: 66.23%) was a yellow solid. LCMS (ESI): m/z=174 (M+H) ⁺ .

Step 27b: Preparation of tert-butyl 4-(6-((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)piridine-1-carboxylate (Compound 0702-47) : Under nitrogen protection conditions, 4-(6-chloropyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (0104-1) (178 mg, 0.6 mmol, 1.2 equivalent), 4-(hydroxymethyl base) benzofuran-7-nitrile (0701-47 (87 mg, 0.5 mmol, 1.0 equivalent), cesium carbonate (325 mg, 1 mmol, 2.0 equivalent), 2-dicyclohexylphosphonium-2',6 '-Diisopropoxy-1,1'-biphenyl (93 mg, 0.2 mmol, 0.4 equiv) and tris(dibenzylideneacetone)dipalladium(0) (91 mg, 0.1 mmol, 0.2 equiv) ) and toluene (10 ml) were stirred overnight at 125°C. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was layered on a silica gel column The crude product was purified by analysis (eluent: petroleum ether/ethyl acetate = 100/1-10/1) to obtain yellow oily substance 4-(6-((7-cyanobenzofuran-4-yl) Methoxy)pyridin-2-yl)piridin-1-carboxylic acid tert-butyl ester (94 mg, yield: 43.32%). LCMS (ESI): m/z=434 (M+H) ⁺ .

Step 27c: Preparation of 4-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-7-carbonitrile hydrochloride (compound 0703-47): Tert-butyl 4-(6-((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)pyridin-1-carboxylate (0702-47) (94 mg, 0.217 mmol, 1.0 equiv) and a solution of hydrochloric acid in dioxane (4 M, 1 mL) in dioxane (4 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain crude 4-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-7-carbonitrile hydrochloride (100 mg, crude product ). The product was used directly in the next step without further purification. LCMS (ESI): m/z=334 (M+H) ⁺ .

Step 27d: (S)-2-((4-(6-((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl) Preparation of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0704-47): 4-(((6-(gua (Din-4-yl)pyridin-2-yl)oxy)methyl)benzofuran-7-carbonitrile hydrochloride (0703-47) (80 mg, 0.217 mmol, 1.3 equiv), (S)- 2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.17 mg mol, 1.0 equiv) and N,N-diisopropylethylamine (88 mg, 0.68 mmol, 4.0 equiv) in N-methylpyrrolidone (5 mL) was stirred at 60°C for 16 hours. After cooling to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain yellow solid (S)-2-((4-(6-((7-cyanobenzofuran-4-yl) )methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxy Acid methyl ester (40 mg, yield: 40%). LCMS (ESI): m/z=592 (M+H) ⁺ .

Step 27e: (S)-2-((4-(6-((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl) Preparation of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 47): (S)-2-((4-(6- ((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl) - Methyl 1H-benzo[d]imidazole-6-carboxylate (0704-47) (40 mg, 0.068 mmol, 1.0 equiv) and lithium hydroxide monohydrate (6 mg, 0.136 mmol, 2.0 equiv) A mixture of acetonitrile/water = 5/1 (6 ml) was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, and a solid precipitate formed. The mixture is filtered. Wash the residue with water. The mixture was slurried with methanol and filtered to obtain (S)-2-((4-(6-((7-cyanobenzofuran-4-yl)methoxy)pyridin-2-yl)piridin-1 as a white solid) -(yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (33 mg, yield: 84.61%). LCMS (ESI): m/z=578 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.26 (d, J = 1.0 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.84 – 7.77 (m, 2H), 7.64 (dd, J = 8.0 , 6.9 Hz, 2H), 7.47 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 5.69 (s, 2H), 5.10 (ddd, J = 14.5, 7.2, 2.8 Hz, 1H), 4.78 (dd, J = 15.2, 7.2 Hz, 1H), 4.65 (dd, J = 15.2, 2.8 Hz, 1H), 4.46 (td, J = 7.8, 5.9 Hz, 1H), 4.36 (dt, J = 9.0, 5.9 Hz, 1H), 3.93 (d, J = 13.5 Hz, 1H), 3.77 (d, J = 13.5 Hz, 1H), 2.96 (d, J = 11.4 Hz, 1H), 2.83 (d, J = 11.3 Hz, 1H), 2.73 – 2.64 (m, 1H), 2.56 (tt, J = 11.8, 3.7 Hz, 1H), 2.46 – 2.38 (m, 1H), 2.18 (ddd, J = 31.6, 11.8, 9.6 Hz, 2H), 1.74 (t, J = 13.5 Hz, 2H), 1.70 – 1.56 (m, 2H) .

Example 28 : (S)-2-((4-(6-((4- Cyanonaphthalene -1- base ) Methoxy ) Pyridine -2- base ) Guadin -1- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 49) Preparation ( Prepare according to plan eight lines)

Step 28a: Preparation of 4-(hydroxymethyl)-1-naphthalenenitrile (Compound 0801-49):

Under nitrogen protection, N,N-dimethylformamide of 1-bromo-4-methylnaphthalene (1.5 g, 6.78 mmol, 1.0 equivalent) and copper cyanide (1.2 g, 13.57 mmol, 2 equivalents) The mixed solution of amine (20 ml) was stirred at 120°C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The mixture was filtered through celite and the solid was washed with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 15/1-10/1) to obtain 4-methyl-1-naphthalenenitrile (889 mg, Yield: 78.53%) was a yellow solid. LCMS(ESI): m/z=168 (M+H)+

Under nitrogen protection, 4-methyl-1-naphthyonitrile (400 mg, 2.4 mmol, 1.0 equivalent), N-bromosuccinimide (511 mg, 2.87 mmol, 1.2 equivalent) and azobisisobutyl A solution of nitrile (78.6 mg, 0.479 mmol, 0.2 equiv) in dichloroethane (10 mL) was stirred at 72°C overnight. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product 4-(bromomethyl)-1-naphthalenenitrile (678 mg, crude product). The product was used directly in the next step without further purification.

A mixture of 4-(bromomethyl)-1-naphthalenenitrile (678 mg, 2.76 mmol, 1.0 equiv) and potassium acetate (2.7 g, 27.6 mmol, 10.0 equiv) in N,N-dimethylformamide ( 10 ml) and stir at room temperature for 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain crude product (4-cyanonaphthalene-1-yl)methyl acetate (823 mg, crude product). The product was used directly in the next step without further purification.

To a solution of (4-cyanonaphthalen-1-yl)methyl acetate (823 mg, 3.65 mmol, 1.0 equiv) in tetrahydrofuran (5 mL) was added a solution of sodium methoxide in methanol (5.4 mol/L, 1.35 mL , 7.31 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1-2/1) to obtain 4-(hydroxymethyl)-1-naphthyonitrile ( 300 mg, yield: 44.91%) as a yellow solid. LCMS (ESI): m/z=184 (M+H) ⁺ .

Step 28b: Preparation of tert-butyl 4-(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0802-49): Nitrogen Under protective conditions, 4-(6-chloropyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (0104-1) (202 mg, 0.68 mmol, 1 equivalent), 4-(hydroxymethyl) -1-Naphthonitrile (0801-49) (150 mg, 0.82 mmol, 1.2 equivalents), cesium carbonate (443.36 mg, 1.36 mmol, 2.0 equivalents), 2-dicyclohexylphosphonium-2',6'-di Isopropoxy-1,1'-biphenyl (32 mg, 0.068 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium(0) (31 mg, 0.034 mmol, 0.05 equiv) in toluene (10 ml) of the mixture was stirred at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 100/1-8/1) to obtain a yellow oily substance 4-(6-((4-cyanonaphthalene- tert-butyl 1-yl)methoxy)pyridin-2-yl)piridine-1-carboxylate (272 mg, yield: 90.37%). LCMS (ESI): m/z=444 (M+H) ⁺ .

Step 28c: Preparation of 4-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)-1-naphthocarbonitrile hydrochloride (compound 0803-49): Divide 4 -(6-((4-Cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piridin-1-carboxylic acid tert-butyl ester (0802-49) (272 mg, 0.614 mmol, 1.0 Equivalent) and a solution of hydrochloric acid in dioxane (4M, 5 mL) were stirred at room temperature overnight. The mixture is filtered. The residue is washed with dioxane. The residue was dried to obtain yellow solid 4-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl)-1-naphthocarbonitrile hydrochloride (215 mg, yield: 92.28%). LCMS(ESI): m/z=344 (M+H) ⁺ .

Step 28d: (S)-2-(((4-(6-((4-cyanonaphth-1-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0804-49): 4 ^-( ((6-(guidine) -4-yl)pyridin-2-yl)oxy)methyl)-1-naphthalenecarbonitrile hydrochloride (0803-49) (96 mg, 0.254 mmol, 1.5 equiv), (S)-2-( Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (50 mg, 0.17 mmol, 1.0 Equivalent) and potassium carbonate (93.5 mg, 0.678 mmol, 4.0 equivalent) in acetonitrile (5 ml) was stirred at 60°C for 16 hours. After the reaction mixture was cooled to room temperature, water was added and extracted with ethyl acetate. The organic phase was Dry over anhydrous sodium sulfate and concentrate under reduced pressure. The residue is purified by silica gel thin layer chromatography (eluent: ethyl acetate) to obtain a white solid (S)-2-(((4-(6-((4 -Cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo [d] Imidazole-6-carboxylic acid methyl ester (50 mg, yield: 49.02%). LCMS (ESI): m/z=602 (M+H) ⁺ .

Step 28e: (S)-2-((4-(6-((4-cyanonaphth-1-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1 Preparation of -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 49): (S)-2-(((4-(6-() (4-cyanonaphth-1-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Benzo[d]imidazole-6-carboxylic acid methyl ester (0804-49) (50 mg, 0.083 mmol, 1.0 equiv) and lithium hydroxide monohydrate (7 mg, 0.17 mmol, 2.0 equiv) in acetonitrile/water =5/1 (6 ml) mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH value of the residue was adjusted to 6 with 1 mol/L hydrochloric acid, after which a solid precipitate formed. The mixture was filtered . The residue was washed with water and dried under reduced pressure to obtain a white solid (S)-2-((4-(6-((4-cyanonaphthalen-1-yl)methoxy)pyridin-2-yl)piridin- 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (35 mg, Yield: 71.75%). LCMS ( ESI): m/z=588 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.68 (s, 1H), 8.30 (d, J = 8.3 Hz, 2H), 8.17 (t, J = 7.0 Hz, 2H), 7.81 (ddd, J = 15.3, 14.3, 7.0 Hz, 4H), 7.67 (d, J = 7.1 Hz, 2H), 6.91 (d, J = 6.7 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 5.93 (s, 2H), 5.07 (d, J = 5.1 Hz, 1H), 4.78 (dd, J = 15.1, 6.7 Hz, 1H), 4.64 (d, J = 14.8 Hz, 1H), 4.44 (d, J = 6.3 Hz, 1H), 4.33 (dt, J = 9.0, 5.9 Hz, 1H), 3.94 (s, 1H), 3.77 (s, 1H), 2.97 (s, 1H), 2.85 (s, 1H), 2.74 – 2.55 (m, 2H), 2.44 – 2.31 (m, 1H), 2.18 (s, 2H), 1.91 (d, J = 102.8 Hz, 4H).

Example 29 :( S ) -2- (( 4- ( 6- (( 4- Cyano -6- Fluorobenzofurans -7- base)methoxy)pyridine -2- base) guadine -1- base) methyl) -1- (oxetane -2- methyl group) -1H- Benzo [d] imidazole -6- carboxylic acid ( compound 53) Preparation ( Prepare according to the second route of plan)

Step 29a: Preparation of 6-fluoro-7-(hydroxymethyl)benzofuran-4-nitrile (Compound 0201-53):

Under nitrogen protection, add a methanol solution of sodium methoxide (5.4 mol/L, 5.5 ml, 29.88 mmol, 3.0 equiv) and the mixture was stirred at room temperature for 16.0 h. The reaction solution was diluted with water, adjusted to pH=5 with 2 mol/L hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (petroleum ether/ethyl acetate = 10/1 to 5/1) to obtain a colorless oily product 4-bromo-2-fluoro-6-methoxybenzoic acid methyl ester (2.5 g, collected rate: 96.2%).

Under nitrogen protection, add boron tribromide (3.4 g, 13.69 mmol, 1.5 equiv) and the mixture was stirred at 0 °C for 1.5 h. The reaction solution was quenched with methanol, diluted with water and extracted with dichloromethane. The organic phase was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (developing solvent: methylene chloride) to obtain a white solid product, 4-bromo-2-fluoro-6-hydroxybenzoic acid methyl ester (2.03 g, yield: 89.4%). LCMS (ESI): m/z =247[M+1] ^- .

Under nitrogen protection, 4-bromo-2-fluoro-6-hydroxybenzoic acid methyl ester (1.5 g, 6.02 mmol, 1.0 equivalent), 2-bromo-1,1-diethoxyethane (1.42 g, A mixture of N,N-dimethylformamide (15 mL) (7.23 mmol, 1.2 equiv) and potassium carbonate (1.25 g, 9.03 mmol, 1.5 equiv) was stirred at 120°C overnight. After cooling to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (petroleum ether/ethyl acetate = 10/1 to 8/1) to obtain the yellow oily product 4-bromo-2-(2,2-diethoxyethoxy)-6-fluoro Benzoate (2.15 g, yield: 98.2%).

Under nitrogen protection, to a solution of polyphosphoric acid (4.98 g, 14.73 mmol, 2.5 equivalents) in toluene (80 ml) was added 4-bromo-2-(2,2-diethoxyethoxy)-6- Fluorobenzoate (2.15 g, 5 mmol, 1.0 equiv) and the mixture was stirred at 120°C overnight. After cooling to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain the yellow oily product 4-bromo-6-fluorobenzofuran-7-carboxylic acid methyl ester (1.34 g, yield: 83.4%). LCMS (ESI): m/z =273[M+1] ⁺ .

Under nitrogen protection, sodium borohydride was added to a solution of 4-bromo-6-fluorobenzofuran-7-carboxylic acid methyl ester (950 mg, 3.48 mmol, 1.0 equivalent) in methanol (30 ml) at 0°C. (2.6 g, 69.60 mmol, 20.0 equiv) and the mixture was stirred at room temperature for 3.0 h. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (eluent: petroleum ether/ethyl acetate = 10/1 to 2/1) to obtain a yellow solid product (4-bromo-6-fluorobenzofuran-7-yl)methanol (850 mg, yield: 99.6%).

Under nitrogen protection, to a solution of (4-bromo-6-fluorobenzofuran-7-yl)methanol (630 mg, 2.57 mmol, 1.0 equivalent) in N-methylpyrrolidone (20 ml) was added cuprous cyanide (2.3 g, 25.71 mmol, 10.0 equiv) was stirred at 190°C for 8 hours. After cooling to room temperature, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 2/1) to obtain the white solid product 6-fluoro-7-(hydroxymethyl)benzofuran-4-carbonitrile. (92 mg, yield: 18.8%).

Step 29b: tert-butyl 4-(6-((4-cyano-6-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (Compound 0202- Preparation of 53): Under nitrogen protection, 4-(6-chloropyridin-2-yl)pyridine-1-carboxylic acid tert-butyl ester (0104-1) (143 mg, 0.482 mmol, 1.0 equivalent), 6- Fluoro-7-(hydroxymethyl)benzofuran-4-nitrile (0201-53) (92 mg, 0.482 mmol, 1.0 equivalent), cesium carbonate (314 mg, 0.964 mmol, 2.0 equivalent), 2-bis Cyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (45 mg, 0.0964 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.0482 mmol, 0.1 equiv) in toluene (10 mL) was stirred at 120°C overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified with a silica gel column (petroleum ether/ethyl acetate = 10/1 to 5/1) to obtain the yellow solid product 4-(6-((4-cyano-6-fluorobenzofuran-7-yl) Methoxy)pyridin-2-yl)pyridin-1-carboxylic acid tert-butyl ester (180 mg, yield: 82.6%). LCMS(ESI): m/z =452[M+1]+.

Step 29c: 6-fluoro-7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl]benzofuran-4-carbonitrile hydrochloride (compound 0203- Preparation of 53) : tert-butyl 4-(6-(((4-cyano-6-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-carboxylate (0202-53) (180 mg, 0.40 mmol, 1.0 equivalent) was added to a solution of dioxane (4 ml) in hydrochloric acid-dioxane solution (4 molar solution, 1 ml), and the mixture was stirred at room temperature. overnight. The reaction solution was concentrated under reduced pressure, and the residue was directly used in the next step without further purification. LCMS (ESI): m/z=352 (M+H) ⁺ .

Step 29d: (S)-2-(((4-(6-((4-cyano-6-fluorobenzofuran-7-yl))methoxy)pyridin-2-yl)pyridin-1 Preparation of -(yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 0204-53): 6-fluoro -7-(((6-(pyridin-4-yl)pyridin-2-yl)oxy)methyl]benzofuran-4-carbonitrile hydrochloride (0203-53) (77 mg, 0.220 mmol, 1.3 equiv), (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester A solution of (0116-3) (50 mg, 0.169 mmol, 1.0 equivalent) and potassium carbonate (93.5 mg, 0.678 mmol, 4.0 equivalent) in acetonitrile (10 ml) was stirred at 60°C overnight. The reaction solution was diluted with water. And extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (dichloromethane/methanol=16/1) to obtain the yellow solid product (S)-2-((4-( 6-((4-cyano-6-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxetane -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (55 mg, yield: 53.4%). LCMS (ESI): m/z=610 (M+H) ⁺ .

Step 29e: (S)-2-((4-(6-((4-cyano-6-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl )Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 53) Preparation: (S)-2-((4 -(6-((4-cyano-6-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piridin-1-yl)methyl)-1-(oxaheterocycle Butan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0204-53) (55 mg, 0.09 mmol, 1.0 equiv) and lithium hydroxide monohydrate (5.7 mg , 0.135 mmol, 1.5 equiv) a mixture of acetonitrile/water = 5/1 (6 ml) was stirred at 42°C overnight. The reaction solution was adjusted to pH 6 with 2 mol/L hydrochloric acid, and extracted with ethyl acetate. The resulting organic phase was dried and concentrated under reduced pressure to obtain a white solid (S)-2-((4-(6-((4-cyano) (6-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)pyridin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-benzo[d]imidazole-6-carboxylic acid (39 mg, yield: 72.8%). LCMS(ESI): m/z=596(M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.26 (s, 1H), 7.89 (d, J = 10.0 Hz, 1H), 7.81 ( d, J = 8.4 Hz, 1H), 7.62 (dd, J = 16.8, 8.9 Hz, 2H), 7.20 (d, J = 2.1 Hz, 1H), 6.87 (d, J = 7.3 Hz, 1H), 6.66 ( d, J = 8.2 Hz, 1H), 5.69 (s, 2H), 5.12 (dd, J = 7.1, 2.5 Hz, 1H), 4.80 (dd, J = 15.1, 7.1 Hz, 1H), 4.67 (d, J = 12.9 Hz, 1H), 4.47 (dd, J = 13.7, 7.6 Hz, 1H), 4.37 (dt, J = 9.0, 5.9 Hz, 1H), 3.95 (d, J = 13.6 Hz, 1H), 3.80 (d , J = 13.6 Hz, 1H), 2.99 (d, J = 10.9 Hz, 1H), 2.86 (d, J = 11.0 Hz, 1H), 2.76 – 2.68 (m, 1H), 2.56 (t, J = 11.5 Hz , 1H), 2.44 (dd, J = 18.8, 8.1 Hz, 1H), 2.20 (dt, J = 21.1, 10.4 Hz, 2H), 1.78 – 1.59 (m, 4H).

Example 30 : (S)-2-((4-(6-((4- Chlorobenzofurans -7- base ) Methoxy ) Pyridine -2- base ) pipe 𠯤 -1- base ) methyl )-1-( Oxetane -2- Methyl )-1 H- Benzo [d] imidazole -6- carboxylic acid ( compound 54) Preparation ( Prepare according to route nine of plan)

steps 30a :

Preparation of 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (compound 0901-54): Under nitrogen protection, proceed to (4-chlorobenzofuran-7-yl) Methanol (0201-12) (230 mg, 1.26 mmol, 1.0 eq) was added to a mixture of tetrahydrofuran and potassium hexamethyldisilamide (1 mol/L, 3.78 mmol, 3.0 eq) at 10-15°C. , the mixture was stirred at 15°C for 1 hour. Dissolve 2-bromo-6-fluoropyridine in tetrahydrofuran and add it dropwise to the reaction system. The mixture was stirred at 15°C for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to purify the crude product to obtain a yellow solid.

Preparation of 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (compound 0901-54): Under nitrogen protection, proceed to (4-chlorobenzofuran-7-yl) Methanol (0201-12) (230 mg, 1.26 mmol, 1.0 eq) was added to a mixture of tetrahydrofuran and potassium hexamethyldisilamide (1 mol/L, 3.78 mmol, 3.0 eq) at 10-15°C. , the mixture was stirred at 15°C for 1 hour. Dissolve 2-bromo-6-fluoropyridine in tetrahydrofuran and add it dropwise to the reaction system. The mixture was stirred at 15°C for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to purify the crude product to obtain a yellow solid.

2-Bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (140 mg, yield: 32.87%). LCMS (ESI): m/z=338 (M+H) ⁺ .

Step 30b: Preparation of 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (compound 0902-54): Under nitrogen protection,

2-Bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (0901-54) (150 mg, 0.44 mmol, 1.0 equiv), 1-tert-butoxycarbonylpiperdine( 92 mg, 0.49 mmol, 1.1 equivalent), cesium carbonate (290 mg, 0.89 mmol, 2.0 equivalent), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (31 mg, 0.05 mmol, A mixture of tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol, 0.05 equiv) in toluene (15 mL) was stirred at 125°C overnight. After cooling to room temperature, the reaction solution was filtered through celite, and the solid was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain a yellow oily liquid 4-(6-((4-chlorobenzofuran-7-yl) )methoxy)pyridin-2-yl)pipiperidine-1-carboxylic acid tert-butyl ester (71 mg, yield: 36.43%). LCMS (ESI): m/z=443 (M+H) ⁺ .

Step 30c: Preparation of 1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine hydrochloride (compound 0903-54): 4-(6 -((4-Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (0902-54) (71 mg, 0.16 mmol, 1.0 equiv) and a solution of hydrochloric acid in ethyl acetate (2M, 4 ml) in methanol (4 ml) was stirred at 40°C for 2 hours. The mixture was concentrated under reduced pressure to obtain crude product 1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine hydrochloride (55 mg, crude product). This product does not Further purification is required and used directly in the next step. LCMS (ESI): m/z=343 (M+H) ⁺ .

Step 30d: (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1 H-benzo[ d ]imidazole-6-carboxylic acid methyl ester (compound 0904-54): 1-(6-((4- Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine hydrochloride (0903-54) (55 mg, 0.16 mmol, 1.2 equiv), (S)-2-(chloromethyl methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0116-3) (40 mg, 0.13 mmol, 1.0 eq) A solution of N,N-diisopropylethylamine (1 ml) in N-methylpyrrolidone (10 ml) was stirred at 60°C overnight. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate: petroleum ether = 3/1) to obtain yellow oily liquid (S)-2-((4-(6-((4- Chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H-benzene And [ d ]imidazole-6-carboxylic acid methyl ester (85 mg, yield: 100%). LCMS (ESI): m/z=603 (M+H) ⁺ .

Step 30e: (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1 H-benzo[ d ]imidazole-6-carboxylic acid (compound 54): (S)-2-((4-(6- ((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylic acid methyl ester (0904-58) (85 mg, 0.14 mmol, 1.0 equiv) and lithium hydroxide monohydrate (18 mg, 0.43 mmol, 3.0 equiv) A mixture of acetonitrile/water = 5/1 (12 ml) was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was washed with water, and the pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid. The residue was extracted with ethyl acetate and concentrated under reduced pressure. The crude product was purified using silica gel thin layer chromatography (eluent: dichloromethane: methanol = 10/1) to obtain a yellow solid (S)-2-((4-(6-((4-chlorobenzene) Furan-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H-benzo[ d] Imidazole-6-carboxylic acid (71 mg, yield: 86.25%). LCMS (ESI): m/z=588 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 8.14 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.49 – 7.42 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 6.31 (d, J = 8.1 Hz, 1H), 6.09 ( d, J = 7.8 Hz, 1H), 5.55 (s, 2H), 5.15 – 5.08 (m, 1H), 4.71 (dd, J = 15.2, 7.0 Hz, 1H), 4.59 (dd, J = 15.3, 3.1 Hz , 1H), 4.49 (dd, J = 13.3, 8.0 Hz, 1H), 4.37 (dt, J = 9.0, 5.9 Hz, 1H), 3.92 (d, J = 13.5 Hz, 1H), 3.77 (d, J = 13.4 Hz, 1H), 3.43 (dd, J = 12.0, 7.3 Hz, 4H), 3.29 – 3.24 (m, 4H), 2.73 – 2.65 (m, 1H), 2.47 – 2.41 (m, 1H).

Example 31 : (S)-2-((6-(2-(4- Chlorobenzofurans -7- base ) Ethoxy )-3',6'- dihydrogen -[2,4'- Bipyridine ]-1'(2'H)- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 55) Preparation ( Prepare according to plan three lines)

Step 31a: Preparation of 2-(4-chlorobenzofuran-7-yl)ethane-1-ol (Compound 0201-55):

Under nitrogen protection, tetrahydrofuran (10 ml) was added to 7-(bromomethyl)-4-chlorobenzofuran (1 g, 4.08 mmol, 1.0 equivalent) and potassium carbonate (1.12 g, 8.16 mmol, 2 equivalents). Trimethylsilicyanide (808 mg, 8.16 mmol, 2 equiv) was added to the solution. The mixture was stirred at 90°C for 4 hours. The reaction was cooled to room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 50/1-10/1) to obtain 2-(4-chlorobenzofuran-7-yl)acetonitrile as a yellow oil. (880 mg, crude). LCMS (ESI): m/z=192 (M+H) ⁺ .

To a solution of 2-(4-chlorobenzofuran-7-yl)acetonitrile (880 mg, 6.24 mmol, 1.0 equiv) in ethanol/water (10/10 mL) was added potassium hydroxide (1.74 g, 31.2 mmol) , 5 equivalents). The mixture was stirred at 90°C for 16 hours. The reaction was cooled to room temperature. The pH of the mixture was adjusted to 1 with 2N hydrochloric acid, after which a solid precipitated. The mixture is filtered. The residue was washed with water and dried to give 2-(4-chlorobenzofuran-7-yl)acetic acid as a yellow solid (510 mg, yield: 38.75%). LCMS (ESI): m/z=211 (M+H) ⁺ .

Under nitrogen protection, add boron dropwise to a solution of 2-(4-chlorobenzofuran-7-yl)acetic acid (510 mg, 2.43 mmol, 1.0 equivalent) in tetrahydrofuran (10 ml) between 0 and 10°C. alkane (0.64 mL, 10 mol/L dimethyl sulfide, 6.375 mmol, 2.5 equiv). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with methanol and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1-5/1) to obtain a transparent oily substance 2-(4-chlorobenzofuran-7-yl). )Ethan-1-ol (397 mg, yield: 41.18%). LCMS (ESI): m/z=197 (M+H) ⁺ .

Step 31b: 6-((2-(4-chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2' Preparation of H)-tert-butylcarboxylate (compound 0303-55): Under nitrogen protection, between 0 and 10°C, in 2-(4-chlorobenzofuran-7-yl)ethane-1-ol (0201-55) (338 mg, 1.724 mmol, 1.0 equiv) in tetrahydrofuran (20 ml) was added with potassium hexamethyldisilamide (3.5 ml, 1 mol/L tetrahydrofuran, 3.448 mmol, 2 Equivalent). The mixture was stirred at 10°C for 45 minutes. 2-Bromo-6-fluoropyridine (0301-2) (303 mg, 1.724 mmol, 1 equivalent) was added portionwise to the reaction mixture at 10°C, and the mixture was Stir at room temperature for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: : Petroleum ether/ethyl acetate = 200/1-20/1) purification to obtain a yellow solid 2-bromo-6-(2-(4-chlorobenzofuran-7-yl)ethoxy)pyridine (383 mg , yield: 63.09%). LCMS (ESI): m/z=352 (M+H) ⁺ . Under nitrogen protection, the 2-bromo-6-(2-(4-chlorobenzofuran-7) obtained above -ethoxy)pyridine (272 mg, 0.77 mmol, 1.05 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) )-tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate (226 mg, 0.73 mmol, 1 equivalent), sodium carbonate (155 mg, 1.46 mmol, 2.0 equivalent), bis(triphenyl) A mixture of palladium dichloride (51 mg, 0.073 mmol, 0.1 equiv) in N,N-dimethylformamide/water = 10/1 (11 ml) was stirred at 92°C overnight. After cooling to After room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1-10/1 ) was purified to obtain a transparent oily substance 6-((2-(4-chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridyl]- 1'(2'H)-tert-butylcarboxylate (123 mg, yield: 37.05%). LCMS (ESI): m/z=455 (M+H) ⁺ .

Step 31c: 6-((2-(4-chlorobenzofuran-7-yl)ethoxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine 4- Preparation of toluene sulfonate (compound 0304-55): 6-((2-(4-chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2 To a solution of 4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (0303-55) (100 mg, 0.22 mmol, 1.0 equivalent) in ethyl acetate (5 ml) was added p-toluene Sulfonic acid monohydrate (114 mg, 0.66 mmol, 3 equiv). The mixture was stirred at 60°C overnight. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was used in the next step without purification (103 mg, crude ). LCMS(ESI): m/z=355 (M+H) ⁺ .

Step 31d: (S)-2-((6-(2-(4-chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridine ]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Compound 0305 -55) Preparation: 6-((2-(4-chlorobenzofuran-7-yl)ethoxy)-1',2',3',6'-tetrahydro-2,4'- Bipyridyl 4-methylbenzenesulfonate (0304-55) (103 mg, 0.203 mmol, 1.2 equiv), (S)-2-(chloromethyl)-1-(oxetane-2- methyl)-1H-benzo[d]imidazole-6-carboxylate (0116-3) (50 mg, 0.17 mmol, 1.0 equiv) and potassium carbonate (94 mg, 0.68 mmol, 4.0 equiv) The acetonitrile (10 ml) solution was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was filtered with silica gel Preparation plate purification by layer chromatography (eluent: ethyl acetate) yielded yellow oily substance (S)-2-((6-(2-(4-chlorobenzofuran-7-yl)ethoxy)) -3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-Benzo[d]imidazole-6-carboxylic acid methyl ester (69 mg, yield: 66.34%). LCMS (ESI): m/z=613 (M+H) ⁺ .

Step 31e: (S)-2-((6-(2-(4-chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridine ]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 55) Preparation: (S)-2-((6-(2-(4-chlorobenzofuran-7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0604-55 ) (69 mg, 0.11 mmol, 1.0 equiv) and lithium hydroxide monohydrate (14 mg, 0.33 mmol, 3 equiv) in acetonitrile/water = 5/1 (6 ml) was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The pH of the residue was adjusted to 6 with 1 mol/l hydrochloric acid, after which a solid precipitated. The mixture is filtered. Wash the residue with water. The residue was purified by silica gel thin layer chromatography (eluent: dichloromethane/methanol=10/1) to obtain yellow solid (S)-2-((6-(2-(4-chlorobenzofuran) -7-yl)ethoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetane Alk-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (27 mg, yield: 40.29%). LCMS (ESI): m/z=599 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 8.25 (s, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 8.4, 1.4 Hz, 1H), 7.70 – 7.60 (m, 2H), 7.25 (q, J = 8.0 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.70 (s, 1H ), 6.59 (d, J = 8.2 Hz, 1H), 5.06 (ddd, J = 14.4, 7.3, 2.8 Hz, 1H), 4.79 (dd, J = 15.2, 7.3 Hz, 1H), 4.70 – 4.55 (m, 3H), 4.46 (dd, J = 13.6, 7.7 Hz, 1H), 4.35 (dt, J = 9.0, 5.9 Hz, 1H), 4.07 (d, J = 13.6 Hz, 1H), 3.92 (d, J = 13.5 Hz, 1H), 3.27 – 3.21 (m, 2H), 2.80 – 2.69 (m, 2H), 2.65 (ddd, J = 16.2, 8.7, 5.4 Hz, 1H), 2.51 (s, 2H), 2.44 – 2.34 ( m, 1H).

Example 32 : 2- (( 4- ( 2- ( 4- Chlorobenzofurans -7- base) -2- methylbenzo [d][1,3] Dioxolane -4- base) guadine -1- base) methyl) -1- ((((( S ) - Oxetane -2- base) methyl) -1H- Benzo [d] imidazole -6- Formic acid ( compound 56) Preparation ( Prepare according to plan 10 lines)

Step 32a: Preparation of tert-butyl 4-(2,3-dihydroxyphenyl)pipidine-1-carboxylate (compound 1003-56):

3-Bromocatechol (1.2 g, 6.35 mmol, 1.0 equiv) and N,N-diisopropylethylamine (2.82 ml, 15.87 mmol, 2.5 equiv) were dissolved in dichloromethane (20 ml), 2-(trimethylsilyl)ethoxymethyl chloride (2.65 g, 15.87 mmol, 2.5 equiv) was added dropwise to the mixture. The mixture was warmed to room temperature and stirred for 2 hours. The solvent was removed under reduced pressure. The residue was subjected to column chromatography separation on silica gel (petroleum ether: ethyl acetate 30:1) to obtain a colorless oily substance ((((3-bromo-1,2-phenylene)bis(oxy))bis (methylene))bis(oxy))bis(ethane-2,1-diyl))bis(trimethylsilane) (2.27 g, yield: 79%). TLC: Rf 0.5 (petroleum ether:ethyl acetate = 30:1).

To ((((3-bromo-1,2-phenylene)bis(oxy))bis(methylene)bis(oxy))bis(ethane-2,1-diyl))bis (Trimethylsilane) (2.27 g, 5.04 mmol, 1.0 equiv), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (221 mg, 0.302 mmol, 0.06 equiv) ) and sodium carbonate (1.60 g, 15.12 mmol, 3.0 equiv) were added to a mixture of dioxane (30 ml) and water (7.5 ml). 4-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaboran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.87 g, 6.05 mmol, 1.2 equiv). The mixture was incubated under nitrogen atmosphere Heat to 85°C and stir for 16 hours. The solvent is removed under reduced pressure. The residue is subjected to column chromatography on silica gel (petroleum ether: ethyl acetate 30:1) to obtain a light yellow oil 4-(2,3- Bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.37 g, Yield: 85%). LCMS (ESI): m/z 552[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 10:1).

tert-butyl 4-(2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate To a mixture of the ester (1.0 g, 1.81 mmol, 1.0 equiv) in methanol (15 mL) was added palladium on carbon (0.2 g). The mixture was stirred under hydrogen balloon pressure at room temperature overnight. The mixture is filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (petroleum ether: ethyl acetate 30:1) to obtain 4-(2,3-bis((2-(trimethylsilyl)ethoxy)methoxy) as a white solid tert-butyl)phenyl)pipidine-1-carboxylate (0.48 g, yield: 48%). LCMS (ESI): m/z 554[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 10:1).

tert-butyl 4-(2,3-bis((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pipidine-1-carboxylate (1.1 g, 1.99 mmol, 1.0 equiv.) in methanolic hydrogen chloride (4 M solution, 15 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure and dried under vacuum to give 4-(2,3-dihydroxyphenyl)pipidine hydrochloride (601 mg, crude) as a white solid. LCMS (ESI): m/z 194[M+1] ⁺ ; TLC: Rf 0.3 (dichloromethane:methanol = 10:1).

To 4-(2,3-dihydroxyphenyl)pipidine hydrochloride (454 mg, 1.99 mmol, 1.0 equiv) and sodium bicarbonate (502 mg, 5.97 mmol, 3.0 equiv) in methanol (6 mL) To the mixture was added di-tert-butyl dicarbonate (456 mg, 2.09 mmol, 1.05 equiv). The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol 30:1) to obtain gray solid tert-butyl 4-(2,3-dihydroxyphenyl)piridine-1-carboxylate (583 mg, yield: 100%). LCMS (ESI): m/z 294[M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol = 10:1).

Step 32b: 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)pyridin-1- Preparation of tert-butyl carboxylate (compound 1004-56): To 4-(2,3-dihydroxyphenyl)pyridine-1-carboxylic acid tert-butyl ester (1003-56) (0.25 g, 0.85 mmol, 1.0 equiv), triruthenium dodecacarbonyl (27 mg, 0.043 mmol, 0.05 equiv) and sodium bicarbonate (72 mg, 0.85 mmol, 1.0 equiv) were added to a mixture of toluene (10 ml) with 4-chloro-7 -Ethynylbenzofuran (Compound 1101-57) (150 mg, 0.85 mmol, 1.0 equiv). The mixture was heated to 120°C under nitrogen and stirred overnight. The solvent was removed under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether: ethyl acetate 30:1) to obtain 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzene as a light yellow oil) and [d][1,3]dioxol-4-yl)pipidine-1-carboxylic acid tert-butyl ester (70 mg, yield: 18%). LCMS (ESI): m/z 470[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 10:1).

Step 32c: 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)pipidine hydrochloride (Compound 1005-56) Preparation: 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4-yl ) A mixture of tert-butyl pyridine-1-carboxylate (1004-56) (70 mg, 0.15 mmol, 1.0 equiv) in hydrogen chloride in dioxane (4M solution, 1.5 mL) was stirred at room temperature for 1 hour. . The solvent was removed under reduced pressure and dried under vacuum to obtain 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane as a white solid -4-yl)pyridine hydrochloride (61 mg, crude). LCMS (ESI): m/z 370[M+1] ⁺ ; TLC: Rf 0.3 (dichloromethane:methanol = 10:1).

Step 32d: 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)quat (((S)-Oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (Compound 1006 -56) Preparation: To 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4-yl)quat Hydrochloride (1005-56) (61 mg, 0.15 mmol, 1.0 equiv) and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H - Benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (44 mg, 0.15 mmol, 1.0 equiv). To a mixture of acetonitrile (5 ml) was added potassium carbonate (51 mg, 0.37 mmol, 2.5 equivalent). The mixture was heated at 60°C overnight. The solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel (petroleum ether: ethyl acetate 3:1) to obtain a white solid 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methyl) Benzo[d][1,3]dioxol-4-yl)piridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl methyl)-1H-benzo[d]imidazole-6-carboxylate (81 mg, yield: 87%). LCMS (ESI): m/z 628[M+1] ⁺ ; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 1:1).

Step 32e: 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)quat (((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 56) Preparation: 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4-yl)quat (((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (1006- 56) (81 mg, 0.13 mmol, 1.0 equiv) To a mixture of tetrahydrofuran (5 mL) and water (2 mL) was added lithium hydroxide monohydrate (16 mg, 0.39 mmol, 3.0 equiv). The mixture was heated at 40°C overnight. The mixture was diluted with water (15 ml). 1N dilute hydrochloric acid solution was added to adjust pH = 5 and the aqueous layer was extracted with ethyl acetate (15 ml × 3). The combined organic layers were washed with saturated brine (15 ml × 1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol=10:1) to obtain 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzene) as a white solid And[d][1,3]dioxol-4-yl)piridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl )-1H-benzo[d]imidazole-6-carboxylic acid (53 mg, yield: 66%). LCMS (ESI): m/z 614[M+1] ⁺ ; TLC: Rf 0.5 (ethyl acetate: methanol = 10:1); melting point: 165-167°C. ¹ H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 6.3 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.1, 2.9 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 6.75 ( dd, J = 16.6, 4.4 Hz, 3H), 5.17 – 5.03 (m, 1H), 4.78 (dd, J = 15.1, 7.2 Hz, 1H), 4.65 (d, J = 15.7 Hz, 1H), 4.44 (dt , J = 13.0, 7.6 Hz, 1H), 4.41 – 4.32 (m, 1H), 3.96 (dd, J = 13.5, 3.6 Hz, 1H), 3.78 (d, J = 13.5 Hz, 1H), 3.01 (s, 1H), 2.86 (d, J = 10.5 Hz, 1H), 2.67 (dd, J = 23.9, 16.3 Hz, 2H), 2.44 (s, 1H), 2.26 (s, 1H), 2.16 (s, 4H), 1.82 – 1.67 (m, 4H).

Example 33 : 2-((4-(2-(4- Chlorobenzofurans -7- base )-2- methylbenzo [d][1,3] Dioxolane -4- base )-3,6- Dihydropyridine -1(2H)- base ) methyl )-1-(((S)- Oxetane -2- base ) methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 57) Preparation ( Prepare according to plan 10 lines)

Step 33a: Preparation of 4-chloro-7-ethynylbenzofuran (Compound 1001-57):

2-Bromo-5-chlorophenol (5.0 g, 24.1 mmol, 1.0 equiv), 2-bromo-1,1-diethoxyethane (5.7 g, 28.9 mmol, 1.2 equiv) and potassium carbonate (6.7 g, 48.2 mmol, 2.0 equiv) in N,N-dimethylformamide (70 ml) and stirred at 120°C overnight. After cooling to room temperature, the mixture was poured into water, and ethyl acetate was added for extraction. The organic layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 200/1 to 100/1) to obtain a yellow oily substance 1-bromo-4-chloro-2-(2,2-di Ethoxyethoxy)benzene (8.0 g, Yield: 102%).

Under nitrogen protection, 1-bromo-4-chloro-2-(2,2-diethoxyethoxy)benzene (8.0 g, 19.8 mmol, 1.0 equivalent) and polyphosphoric acid (12.5 g, 37.1 mmol) , 1.5 eq) in dichloroethane (150 ml) was stirred at 72°C overnight. After cooling to room temperature, water was added and the mixture was stirred for 30 minutes. After liquid separation, the organic layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain colorless liquid 7-bromo-4-chlorobenzofuran (4.2 g, yield: 73.7%).

Under nitrogen protection, 7-bromo-4-chlorobenzofuran (2.0 g, 8.6 mmol, 1.0 equivalent), ditriphenylphosphine palladium dichloride (303 mg, 0.43 mmol, 0.05 equivalent), sodium iodide A mixture of copper (41 mg, 0.215 mmol, 0.025 equiv), trimethylsilylacetylene (4.2 g, 43.0 mmol, 5.0 equiv) and triethylamine (15 mL) in tetrahydrofuran (20 mL) was stirred at 90°C overnight. . After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, potassium carbonate (1.0 g) was added, and the mixture was stirred at room temperature for 2 hours. Water is added and the mixture is separated. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain 4-chloro-7-ethynylbenzofuran (1.4 g, yield: 92.1%) as a yellow solid.

Step 33b: Preparation of 4-bromo-2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane (compound 1002-57): Under nitrogen protection, 4-chloro-7-ethynylbenzofuran (1001-57) (1.3 g, 7.4 mmol, 1.0 equivalent), 3-bromo-1,2-benzenediol (1.5 g, 8.1 mmol) , 1.1 eq), a mixture of sodium bicarbonate (622 mg, 7.4 mmol, 1.0 eq) and ruthenium dodecacarbonyl (236 mg, 0.37 mmol, 0.05 eq) in toluene (50 ml) was stirred at 120°C overnight. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether) to obtain a yellow solid 4-bromo-2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d] [1 ,3]dioxolane (0.66 g, yield: 24.4%).

Step 33c: 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6- Preparation of dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (compound 1004-57): 4-bromo-2-(4-chlorobenzofuran-7-yl)-2-methyl under nitrogen protection conditions Benzo[d][1,3]dioxolane (1002-57) (660 mg, 1.8 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1, tert-butyl 3,2-dioxaboran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (612 g, 1.98 mmol, 1.1 equiv), [1,1' - Bis(diphenylphosphino)ferrocene]palladium dichloride (132 mg, 0.18 mmol, 0.1 equiv) and sodium carbonate (572 mg, 5.4 mmol, 3.0 equiv) in dioxane/water = The 10/1 (11 ml) mixture was stirred at 90°C overnight. After cooling to room temperature, water and ethyl acetate were added. The mixture was separated and the organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 200/1 to 30/1) to obtain a yellow solid 4-(2-(4-chlorobenzofuran-7-yl)- 2-Methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (680 mg, yield: 80.5%). LCMS (ESI): m/z=468 (M+H) ⁺ .

Step 33d: 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)-1,2, Preparation of 3,6-tetrahydropyridine hydrochloride (compound 1005-57): 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d] [1,3 4 moles per A solution of dioxane hydrochloride (4 ml) was stirred at room temperature overnight. The solvent was spun off under vacuum to obtain a yellow solid 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4-yl) -1,2,3,6-Tetrahydropyridine hydrochloride, this product was used directly in the next step without further purification.

Step 33e: 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)- 3,6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Preparation of 6-carboxylic acid methyl ester (compound 1006-57): 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxy Heteropentan-4-yl)-1,2,3,6-tetrahydropyridine hydrochloride (1005-57) (80 g, 0.2 mmol, 1.0 equiv), (S)-2-(chloromethyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (0116-3) (35 g, 0.12 mmol, 0.6 equiv) and A solution of potassium carbonate (138 mg, 1.0 mmol, 5.0 equiv) in acetonitrile (6 mL) was stirred at 60°C overnight. After cooling to room temperature, ethyl acetate and water were added, and the mixture was separated. The organic layer was concentrated, and the residue was purified by silica gel thin layer chromatography (eluent: ethyl acetate/methanol=30/1) to obtain a white solid 2-((4-(2-(4-chlorobenzofuran) -7-yl)-2-methylbenzo[d] [1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (55 mg, yield: 44.4%). LCMS(ESI): m/z=626 (M+H) ⁺ .

Step 33f: 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)- 3,6-Dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Preparation of 6-carboxylic acid (compound 57): 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxa Pentyl-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H -Methyl benzo[d]imidazole-6-carboxylate (1006-57) (55 mg, 0.09 mmol, 1.0 equiv) and lithium hydroxide monohydrate (19 mg, 0.45 mmol, 5.0 equiv) in acetonitrile/ The water=5/1 (6 ml) mixture was stirred at 40°C overnight. After cooling to room temperature, add water and add 1.0 mole per liter of hydrochloric acid to adjust pH=6-7. Dichloromethane was added for extraction, and the organic layer was concentrated in vacuo. The residue was purified by silica gel thin layer chromatography (eluent: dichloromethane/methanol=12/1) to obtain a white solid 2-((4-(2-(4-chlorobenzofuran-7-yl) )-2-methylbenzo[d][1,3]dioxol-4-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(( (S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (40 mg, yield: 74.1%). LCMS (ESI): m/z=612 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.53 (s, 1H), 8.25 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.65 ( d, J = 8.1 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.90 – 6.79 ( m, 3H), 6.39 (d, J = 3.5 Hz, 1H), 5.11 – 5.02 (m, 1H), 4.83 – 4.74 (m, 1H), 4.64 (d, J = 13.1 Hz, 1H), 4.49 – 4.40 (m, 1H), 4.34 (tt, J = 11.8, 5.9 Hz, 1H), 4.06 (d, J = 13.7 Hz, 1H), 3.92 (d, J = 13.6 Hz, 1H), 3.25 – 3.19 (m, 2H), 2.75 (s, 2H), 2.65 (dd, J = 17.6, 8.4 Hz, 1H), 2.54 (s, 1H), 2.47 – 2.35 (m, 2H), 2.15 (s, 3H).

Example 34 : 2- (( 4- ( 2- ( 4- Chlorobenzofurans -7- base) -2- methylbenzo [d][1,3] Dioxolane -4- base) guadine -1- base) methyl) -3- (((( S ) - Oxetane -2- base) methyl) -3H- Imidazo [4,5-b] Pyridine -5- carboxylic acid ( compound 58)( Prepare according to plan 10 lines)

Step 34a: 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)quat Methyl (((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Preparation of ester (compound 1006-58): To 4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4 -yl)pyridine hydrochloride (1005-56) (33 mg, 0.08 mmol, 1.0 equiv) and (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl) methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (0116-1) (24 mg, 0.08 mmol, 1.0 eq.) To a mixture of acetonitrile (4 ml) was added potassium carbonate ( 28 mg, 0.20 mmol, 2.5 equiv). The mixture was heated at 60°C overnight. The solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol 60:1) to give 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzene) as a pale yellow solid And[d][1,3]dioxol-4-yl)piridin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl )-3H-Imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (29 mg, yield: 57%). LCMS (ESI): m/z 629[M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane:methanol = 30:1).

Step 34b: 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)quat (ridin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid ( Preparation of compound 58): To 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4 -(yl)pyridin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5 - Methyl carboxylate (1006-58) (29 mg, 0.05 mmol, 1.0 equiv) In a mixture of tetrahydrofuran (4 ml) and water (2 ml) was added lithium hydroxide monohydrate (6 mg, 0.15 mmol) , 3.0 equivalent). The mixture was heated at 40°C overnight. The mixture was diluted with water (15 ml). 1N dilute hydrochloric acid solution was added to adjust pH = 5 and the aqueous layer was extracted with ethyl acetate (20 ml × 3). The combined organic layers were washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=6:1) to obtain 2-((4-(2-(4-chlorobenzofuran-7-yl)-2-methylbenzene) as a white solid And[d][1,3]dioxol-4-yl)piridin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl )-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (18 mg, yield: 64%). LCMS (ESI): m/z 615[M+1] ⁺ ; TLC: Rf 0.5 (dichloromethane: methanol = 6:1); melting point: 129-132°C. ¹ H NMR (500 MHz, DMSO) δ 8.22 (s, 1H), 8.08 (s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 ( d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.76 (d, J = 11.1 Hz, 3H), 5.19 (s, 1H), 4.82 (s, 1H), 4.72 (s, 1H), 4.45 (s, 1H), 4.36 (s, 1H), 3.98 (s, 1H), 3.87 (d, J = 13.9 Hz, 1H), 2.99 (s, 1H), 2.90 (s, 1H), 2.67 (s , 2H), 2.52 (s, 1H), 2.24 (dd, J = 26.5, 14.2 Hz, 2H), 2.17 (d, J = 12.3 Hz, 3H), 1.87 – 1.63 (m, 4H).

Example 35 : 2-((4-(2-(4- Cyanobenzofuran -7- base )-2- methylbenzo [d][1,3] Dioxolane -4- base ) Guadin -1- base ) methyl )-1-((( S)- Oxetane -2- base ) methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 61) Preparation ( Prepare according to plan 10 lines)

Step 35a: Preparation of 7-ethynylbenzofuran-4-nitrile (Compound 1001-61):

A mixture of 7-(hydroxymethyl)benzofuran-4-carbonitrile (441 mg, 2.55 mmol, 1.0 equiv) and manganese dioxide (3.33 g, 38.26 mmol, 15.0 equiv) in dichloromethane (10 mL) Stir at room temperature overnight. The reaction was filtered through celite and washed with dichloromethane (15 ml). The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain white solid 7-formylbenzofuran-4-carbonitrile (288 mg, yield: 65.7%) . LCMS (ESI): m/z=172 (M+H) ⁺ .

Under nitrogen protection conditions, 7-formylbenzofuran-4-carbonitrile (251 mg, 1.47 mmol, 1.0 equivalent), (1-diazo-2-side oxypropyl)phosphonic acid dimethyl ester ( A mixture of 338 mg, 1.76 mmol, 1.2 equiv) and potassium carbonate (405 mg, 2.94 mmol, 2.0 equiv) in methanol (6 mL) was stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain 7-ethynylbenzofuran-4-carbonitrile (228 mg, yield: 92.3%) as a white solid. LCMS (ESI): m/z=168 (M+H) ⁺ .

Step 35b: 4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piridin-1 - Preparation of tert-butyl carboxylate (compound 1004-61): 7-ethynylbenzofuran-4-carbonitrile (1001-61) (228 mg, 1.37 mmol, 1.0 equivalent), 4- (2,3-Dihydroxyphenyl)pipidine-1-carboxylic acid tert-butyl ester (1003-56) (442 mg, 1.51 mmol, 1.1 equiv), sodium bicarbonate (115 mg, 1.37 mmol, 1.0 equiv) ) and triruthenium dodecacarbonyl (44 mg, 0.07 mmol, 0.05 equiv) in toluene (6 mL) was refluxed at 120°C overnight. After cooling to room temperature, the reaction was filtered through celite and washed with ethyl acetate (12 ml). The filtrate was diluted with water (15 ml) and extracted with ethyl acetate (10 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain white solid 4-(2-(4-cyanobenzofuran-7-yl)-2-methyl tert-butylbenzo[d][1,3]dioxol-4-yl)pipidine-1-carboxylate (80 mg, yield: 12.7%). LCMS (ESI): m/z=461 (M+H) ⁺ .

Step 35c: 7-(2-methyl-4-(pyridin-4-yl)benzo[d][1,3]dioxol-2-yl)benzofuran-4-nitrile hydrochloride Preparation of salt (Compound 1005-61): To 4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane- To a solution of tert-butyl 4-yl)pipidine-1-carboxylate (1004-61) (80 mg, 0.17 mmol, 1.0 equiv) in dioxane (2 ml) was added hydrogen chloride in dioxane (4.0 mol/L, 4 mL) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to obtain the crude product 7-(2-methyl-4-(pyridin-4-yl)benzo[d][1,3]dioxol-2-yl)benzofuran-4 -Nitrile hydrochloride. The product was used directly in the next step without further purification. LCMS (ESI): m/z=361 (M+H) ⁺ .

Step 35d: 2-((4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl) Piridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (compound 1006-61) Preparation: 7-(2-methyl-4-(pyridin-4-yl)benzo[d][1,3]dioxol-2-yl)benzofuran- 4-nitrile hydrochloride (1005-61) (80 mg, assumed to be 0.17 mmol, 1.0 equiv), (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl (0116-3) (52 mg, 0.17 mmol, 1.0 equiv) and potassium carbonate (96 mg, 0.70 mmol, 4.0 equiv) in acetonitrile (5 ml) of the mixture was stirred at 60°C for 4 hours. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: petroleum ether/ethyl acetate = 1/10) to obtain a white solid 2-((4-(2-(4-cyanobenzofuran-7) -yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piridin-1-yl)methyl)-1-(((S)-oxetane Butan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (50 mg, yield: 46.7%). LCMS (ESI): m/z=619 (M+H) ⁺ .

Step 35e: 2-((4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolan-4-yl) Piridin-1-yl)methyl)-1-((( S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 61) Preparation: 2-((4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane-4-yl )-1-((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( 1006-61) (50 mg, 0.08 mmol, 1.0 equiv) and lithium hydroxide monohydrate (7 mg, 0.16 mmol, 2.0 equiv) in acetonitrile/water = 5/1 (3 ml) mixture was stirred at 40°C. Stay overnight. After the mixture was cooled to room temperature, the pH was adjusted to about 6 with 1 mol/L hydrochloric acid, and then a solid precipitate formed. The slurry was diluted with water (12 mL) and stirred for 4 hours, then the solids were collected by filtration. The solid was washed with water and dried under vacuum. The solid was dissolved in dichloromethane/methanol=1/2 (5 ml), and then filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dried under vacuum to obtain a white solid 2-((4-(2-(4-cyanobenzofuran-7-yl)-2-methylbenzo[d][1,3]dioxolane- 4-yl)piridin-1-yl)methyl)-1-((( S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (40 mg, yield: 81.6%). LCMS (ESI): m/z=605 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 8.38 (dd, J = 7.9, 2.2 Hz, 1H), 8.27 (d, J = 3.0 Hz, 1H), 7.82 (t, J = 7.9 Hz, 2H), 7.64 (d, J = 8.3 Hz, 1H), 7.59 (dd, J = 7.9, 2.9 Hz, 1H), 7.24 (t, J = 2.1 Hz, 1H), 6.79 (dd, J = 6.6 , 3.4 Hz, 2H), 6.77 – 6.73 (m, 1H), 5.12 (tt, J = 12.1, 3.6 Hz, 1H), 4.78 (dd, J = 14.6, 6.6 Hz, 1H), 4.65 (dd, J = 12.5, 4.7 Hz, 1H), 4.50 – 4.42 (m, 1H), 4.37 (td, J = 12.2, 6.1 Hz, 1H), 3.96 (dd, J = 13.5, 4.7 Hz, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.02 (d, J = 9.2 Hz, 1H), 2.87 (d, J = 8.9 Hz, 1H), 2.68 (dt, J = 18.9, 6.5 Hz, 2H), 2.53 (d, J = 8.0 Hz, 1H), 2.48 – 2.42 (m, 1H), 2.25 (d, J = 10.9 Hz, 1H), 1.74 (dd, J = 29.5, 15.3 Hz, 4H).

Example 36 biological activity test

The control compound used in the present invention is PF-06882961, with the following structure:

Moreover, the present invention also synthesized the following 4 control compounds:

Its synthesis method is as follows:

1. ( S )-2-((6-( Benzo [ d ][1,3] Dioxolane -5- Methoxy )-3',6'- dihydrogen -[2,4'- Bipyridine ]-1'(2' H )- base ) methyl )-1-( Oxetane -2- Methyl ) -1H- Benzo [ d ] imidazole -6- carboxylic acid ( compound 24067) Preparation

Step 1-1: Preparation of 2-(benzo[ d ][1,3]dioxolane-5-ylmethoxy)-6-bromopyridine:

Under nitrogen protection, (benzo[ d ][1,3]dioxol-5-yl)methanol (304 mg, 2.0 mmol, 1.0 equivalent) was added to anhydrous tetrahydrofuran (10 ml), and cooled to 0℃. A 1M solution of potassium hexamethyldisilamide in tetrahydrofuran (4.0 ml, 4.0 mmol, 2.0 equiv) was added dropwise to the mixture and stirred at 0°C for one hour. A solution of 2-bromo-6-fluoropyridine (388 mg, 2.2 mmol, 1.1 equiv) in tetrahydrofuran was added dropwise to the above mixture and stirred at room temperature for one hour. Add ammonium chloride aqueous solution to quench, and extract with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1) to obtain a white solid 2-(benzo[ d ][1,3]dioxolane- 5-ylmethoxy)-6-bromopyridine (600 mg, yield: 97.4%). LCMS(ESI): m/z=308(M+H) ⁺ .

Step 1-2: 6-(benzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine] Preparation of -1'( 2'H )-tert-butylcarboxylate:

Under nitrogen protection, 2-(benzo[ d ][1,3]dioxolane-5-ylmethoxy)-6-bromopyridine (600 mg, 1.95 mmol, 1.0 equivalent), 4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl The ester (723 mg, 2.34 mmol, 1.2 equiv), bis(triphenylphosphine)palladium dichloride (69 mg, 0.098 mmol, 0.05 equiv) and sodium carbonate (414 mg, 3.9 mmol, 2.0 equiv) were added. In a mixed solvent of toluene (20 ml), ethanol (10 ml) and water (10 ml), stir and react at 110°C for two hours. Extract with ethyl acetate, wash with water and saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify through silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 3/1) An anhydrous oily substance 6-(benzo[ d ][1,3]dioxol-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine] was obtained. -1'( 2'H )-tert-butylcarboxylate (815 mg, yield: 96%). LCMS(ESI): m/z=411(M+H) ⁺ .

Step 1-3: ( S )-2-((6-(benzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[ 2,4'-bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6 - Preparation of methyl carboxylate:

6-(benzo[ d ][1,3]dioxola-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridyl ]-1'( 2'H )-tert-butylcarboxylate (200 mg, 0.49 mmol, 1.8 equivalent) was dissolved in 5 ml of dioxane, 1 ml of 4M hydrogen chloride in dioxane was added, and the mixture was Stir at room temperature for 50 minutes. The mixture was concentrated to dryness under reduced pressure, and the resulting residue was added to 5 ml of N -methylpyrrolidone. Add 1 ml of diisopropylethylamine and ( S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl) -1H -benzo[ d ]imidazole-6- Methyl carboxylate (80 mg, 0.27 mmol, 1.0 equiv) and the mixture was stirred at 60 °C overnight. Add ethyl acetate, wash with water and saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify through preparative thin layer chromatography (developing agent: petroleum ether/ethyl acetate = 1/1) to obtain a yellow solid ( S ) -2-((6-(benzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (46 mg , Yield: 29.8%). LCMS(ESI): m/z=569(M+H) ⁺ .

Step 1-4: ( S )-2-((6-(benzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[ 2,4'-bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6 - Preparation of carboxylic acid (compound 24067):

( S )-2-((6-(benzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[2,4'-Bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl The ester (46 mg, 0.081 mmol, 1.0 equiv) and lithium hydroxide monohydrate (11 mg, 0.243 mmol, 3.0 equiv) were added to a mixed solvent of 5 ml acetonitrile and 1 ml water, and the mixture was stirred at 40°C overnight. . The mixture was cooled to room temperature and concentrated under reduced pressure. Add dilute sulfuric acid to adjust the pH value of the residue to 6, add ethyl acetate to extract, and wash with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=15/1) to obtain a yellow solid ( S )-2-((6-(benzene) And[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2' H )- (22 mg , yield: 48.8%). LCMS(ESI): m/z=555 (M+H) ⁺ , melting point: 144~146℃. ¹ H NMR (500 MHz, DMSO) δ 12.71 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 8.0, 5.8 Hz, 2H), 7.06 (d, J = 7.5 Hz, 1H), 7.00 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.75 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 5.99 (s, 2H), 5.26 (s, 2H), 5.06 (dt, J = 7.2, 4.8 Hz, 1H), 4.80 (dd, J = 15.2, 7.2 Hz , 1H), 4.66 (dd, J = 15.2, 2.3 Hz, 1H), 4.47 (dd, J = 13.7, 7.6 Hz, 1H), 4.36 (dt, J = 8.9, 5.9 Hz, 1H), 4.07 (d, J = 13.5 Hz, 1H), 3.93 (d, J = 13.5 Hz, 1H), 3.21 (d, J = 17.6 Hz, 2H), 2.81 – 2.71 (m, 2H), 2.66 (dt, J = 16.3, 7.7 Hz, 1H), 2.54 (s, 2H), 2.44 – 2.34 (m, 1H).

2. ( S )-2-((6-(2,2- Difluorobenzo [ d ][1,3] Dioxolane -5- Methoxy )-3',6'- dihydrogen -[2,4'- Bipyridine ]-1'(2' H )- base ) methyl )-1-( Oxetane -2- Methyl ) -1H- Benzo [ d ] imidazole -6- carboxylic acid ( compound 24068) Preparation

Step 2-1: Preparation of 2-bromo-6-(2,2-difluorobenzo[ d ][1,3]dioxol-5-ylmethoxy)pyridine:

Under nitrogen protection, 2,2-difluorobenzo[ d ][1,3]dioxol-5-ylmethanol (376 mg, 2.0 mmol, 1.0 equiv) was added to anhydrous tetrahydrofuran (10 ml ), cool to 0°C. A 1M solution of potassium hexamethyldisilamide in tetrahydrofuran (4.0 ml, 4.0 mmol, 2.0 equiv) was added dropwise to the mixture and stirred at 0°C for one hour. A solution of 2-bromo-6-fluoropyridine (388 mg, 2.2 mmol, 1.1 equiv) in tetrahydrofuran was added dropwise to the above mixture and stirred at room temperature for one hour. Add ammonium chloride aqueous solution to quench, and extract with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 20/1) to obtain colorless solid 2-bromo-6-(2,2-difluorobenzo[ d ][ 1,3]dioxol-5-ylmethoxy)pyridine (626 mg, yield: 90.9%). LCMS(ESI): m/z=344(M+H) ⁺ .

Step 2-2: 6-(2,2-difluorobenzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[2, Preparation of 4'-bipyridyl]-1'(2' H )-carboxylic acid tert-butyl ester:

Under nitrogen protection, 2-bromo-6-(2,2-difluorobenzo[ d ][1,3]dioxol-5-ylmethoxy)pyridine (626 mg, 1.82 mmol , 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H )-tert-butyl carboxylate (675 mg, 2.18 mmol, 1.2 equiv), bis(triphenylphosphine)palladium dichloride (64 mg, 0.09 mmol, 0.05 equiv) and sodium carbonate (386 mg, 3.64 mmol , 2.0 equivalents) was added to a mixed solvent of toluene (20 ml), ethanol (10 ml) and water (10 ml), and the reaction was stirred at 110°C for two hours. Extract with ethyl acetate, wash with water and saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify through silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 3/1) Obtained as a yellow solid 6-(2,2-difluorobenzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[2,4'-Bipyridyl]-1'(2' H )-carboxylic acid tert-butyl ester (800 mg, yield: 98.4%). LCMS(ESI): m/z=447(M+H) ⁺ .

Step 2-3: ( S )-2-((6-(2,2-difluorobenzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6 '-Dihydro-[2,4'-bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo Preparation of [ d ]imidazole-6-carboxylic acid methyl ester:

6-(2,2-Difluorobenzo[ d ][1,3]dioxola-5-ylmethoxy)-3',6'-dihydro-[2 ,4'-bipyridyl]-1'( 2'H )-carboxylic acid tert-butyl ester (300 mg, 0.67 mmol, 3.3 equivalents) was dissolved in 5 ml of dioxane, and 1 ml of 4M hydrogen chloride in dioxane was added. Hexacyclic solution, the mixture was stirred at room temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, and the resulting residue was added to 5 ml of N -methylpyrrolidone. Add 1 ml of diisopropylethylamine and ( S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl) -1H -benzo[ d ]imidazole-6- Methyl carboxylate (60 mg, 0.20 mmol, 1.0 equiv) and the mixture was stirred at 60 °C overnight. Add ethyl acetate, wash with water and saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify through preparative thin layer chromatography (developing solvent: ethyl acetate) to obtain yellow oil ( S )-2-((( 6-(2,2-Difluorobenzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine ]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (57 mg, yield: 46.3%). LCMS(ESI): m/z=605(M+H) ⁺ .

Step 2-4: ( S )-2-((6-(2,2-difluorobenzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6 '-Dihydro-[2,4'-bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo Preparation of [ d ]imidazole-6-carboxylic acid (compound 24068):

( S )-2-((6-(2,2-difluorobenzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro -[2,4'-bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole -Methyl 6-carboxylate (57 mg, 0.094 mmol, 1.0 equivalent) and lithium hydroxide monohydrate (12 mg, 0.284 mmol, 3.0 equivalent) were added to a mixed solvent of 5 ml acetonitrile and 1 ml water, and the mixture Stir overnight at 40°C. The mixture was cooled to room temperature and concentrated under reduced pressure. Add dilute sulfuric acid to adjust the pH value of the residue to 6, add ethyl acetate to extract, and wash with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=12/1) to obtain a yellow solid ( S )-2-((6-(2 ,2-Difluorobenzo[ d ][1,3]dioxolane-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid (36 mg, Yield: 64.8 %). LCMS(ESI): m/z=591 (M+H) ⁺ , melting point: 102~104℃. ¹ H NMR (500 MHz, DMSO) δ 12.69 (s, 1H), 8.26 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.67 (dd, J = 12.3, 7.9 Hz, 2H), 7.49 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.78 – 6.68 (m, 2H ), 5.36 (s, 2H), 5.07 (d, J = 7.1 Hz, 1H), 4.80 (dd, J = 15.1, 7.2 Hz, 1H), 4.65 (d, J = 14.8 Hz, 1H), 4.46 (dd , J = 13.9, 6.9 Hz, 1H), 4.36 (dd, J = 14.2, 6.2 Hz, 1H), 4.07 (d, J = 13.5 Hz, 1H), 3.93 (d, J = 13.5 Hz, 1H), 3.21 (d, J = 17.1 Hz, 2H), 2.75 (s, 2H), 2.66 (dd, J = 17.6, 7.9 Hz, 1H), 2.52 (s, 2H), 2.39 (dd, J = 17.6, 8.5 Hz, 1H).

3. ( S )-2-((6-((1- methyl -1H- Benzo [ d ] imidazole -6- base ) Methoxy )-3',6'- dihydrogen -[2,4'- Bipyridine ]-1'(2' H )- base ) methyl )-1-( Oxetane -2- Methyl ) -1H- Benzo [ d ] imidazole -6- carboxylic acid ( compound 24069) Preparation

Step 3-1: Preparation of (1-methyl- 1H -benzo[ d ]imidazol-6-yl)methanol:

Under nitrogen protection, 1-methyl-1H-benzo[ d ]imidazole-6-carboxylic acid (300 mg, 1.7 mmol, 1.0 equiv) was added to anhydrous tetrahydrofuran (10 ml) and cooled to 0°C. Lithium aluminum hydride (260 mg, 6.8 mmol, 4.0 equiv) was added to the mixture and stirred at room temperature for three hours. Under an ice bath, add 0.26 ml of water, 0.26 ml of 15% sodium hydroxide aqueous solution and 0.78 ml of water in sequence, raise to room temperature, add anhydrous sodium sulfate, stir, filter, and concentrate the filtrate under reduced pressure, and purify through silica gel column chromatography. (Eluant: dichloromethane/methanol = 20/1) A white solid (1-methyl-1 H -benzo[ d ]imidazol-6-yl)methanol (126 mg, yield: 45.6%) was obtained. LCMS(ESI): m/z=163(M+H) ⁺ .

Step 3-2: Preparation of 6-(((6-bromopyridin-2-yl)oxy)methyl)-1-methyl- 1H -benzo[ d ]imidazole:

Under nitrogen protection, (1-methyl- 1H -benzo[ d ]imidazol-6-yl)methanol (159 mg, 1.0 mmol, 1.0 equivalent) was added to anhydrous tetrahydrofuran (10 ml) and cooled to 0℃. A 1 M solution of potassium hexamethyldisilamide in tetrahydrofuran (2.0 ml, 2.0 mmol, 2.0 equiv) was added dropwise to the mixture and stirred at 0°C for one hour. A solution of 2-bromo-6-fluoropyridine (194 mg, 1.1 mmol, 1.1 equiv) in tetrahydrofuran was added dropwise to the above mixture and stirred at room temperature for one hour. Add ammonium chloride aqueous solution to quench, and extract with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain a white solid 6-(((6-bromopyridin-2-yl)oxy)methyl) -1-Methyl-1 H -benzo[ d ]imidazole (288 mg, yield: 91.1%). LCMS(ESI): m/z=318(M+H) ⁺ .

Step 3-3: 6-(1-methyl-1 H -benzo[ d ]imidazol-6-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridyl]- Preparation of 1'( 2'H )-tert-butylcarboxylate:

Under nitrogen protection, 6-(((6-bromopyridin-2-yl)oxy)methyl)-1-methyl- 1H -benzo[ d ]imidazole (288 mg, 0.91 mmol, 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2 H ) - tert-butyl carboxylate (337 mg, 1.09 mmol, 1.2 equiv), bis(triphenylphosphine)palladium dichloride (32 mg, 0.046 mmol, 0.05 equiv) and sodium carbonate (193 mg, 1.82 mmol, 2.0 equivalents) was added to a mixed solvent of toluene (10 ml), ethanol (5 ml) and water (5 ml), and the reaction was stirred at 110°C for two hours. Extract with ethyl acetate, wash with water and saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify through silica gel column chromatography (eluent: dichloromethane/methanol = 33/1) to obtain a yellow solid 6- (1-Methyl-1 H -benzo[ d ]imidazol-6-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2' H ) - tert-butyl carboxylate (374 mg, yield: 97.3%). LCMS(ESI): m/z=421(M+H) ⁺ .

Step 3-4: ( S )-2-((6-(1-methyl-1 H -benzo[ d ]imidazol-5-ylmethoxy)-3',6'-dihydro-[2 ,4'-bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6- Preparation of methyl carboxylate:

6-(1-Methyl-1 H -benzo[ d ]imidazol-6-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridyl] at room temperature -1'( 2'H )-tert-butylcarboxylate (187 mg, 0.45 mmol, 2.25 equivalents) was dissolved in 5 ml of dioxane, 1 ml of 4M hydrogen chloride in dioxane was added, and the mixture was placed in the chamber Stir at warm temperature for 60 minutes. The mixture was concentrated to dryness under reduced pressure, and the resulting residue was added to 5 ml of N -methylpyrrolidone. Add 1 ml of diisopropylethylamine and ( S )-2-(chloromethyl)-1-(oxetan-2-ylmethyl) -1H -benzo[ d ]imidazole-6- Methyl carboxylate (60 mg, 0.20 mmol, 1.0 equiv) and the mixture was stirred at 60 °C overnight. Add ethyl acetate, wash with water and saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and purify through preparative thin layer chromatography (developing solvent: dichloromethane/methanol = 15/1) to obtain a yellow oil ( S )-2-((6-(1-methyl-1 H -benzo[ d ]imidazol-5-ylmethoxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (67 mg , Yield: 57.8%). LCMS(ESI): m/z=579(M+H) ⁺ .

Step 3-5: ( S )-2-((6-((1-methyl-1 H -benzo[ d ]imidazol-6-yl)methoxy)-3',6'-dihydro- [2,4'-bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole- Preparation of 6-carboxylic acid (compound 24069):

( S )-2-((6-(1-methyl-1 H -benzo[ d ]imidazol-5-ylmethoxy)-3',6'-dihydro-[2,4'- Bipyridyl]-1'(2' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid methyl ester (67 mg, 0.116 mmol, 1.0 equiv) and lithium hydroxide monohydrate (19 mg, 0.46 mmol, 4.0 equiv) were added to a mixed solvent of 5 ml acetonitrile and 1 ml water, and the mixture was stirred at 40°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. Add dilute sulfuric acid to adjust the pH value of the residue to 6, add ethyl acetate to extract, and wash with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (eluent: dichloromethane/methanol=12/1) to obtain a yellow solid ( S )-2-((6-((( 1-Methyl-1 H -benzo[ d ]imidazol-6-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2' H ) -(yl)methyl)-1-(oxetan-2-ylmethyl)-1 H -benzo[ d ]imidazole-6-carboxylic acid (41 mg, yield: 62.5%). LCMS(ESI): m/z=565 (M+H) ⁺ , melting point: 135~137℃. ¹ H NMR (500 MHz, DMSO) δ 12.61 (s, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.82 (dd, J = 8.4, 1.5 Hz, 1H), 7.70 – 7.64 (m , 3H), 7.62 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 8.3, 1.3 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 6.78 (s, 1H), 6.71 (d, J = 8.2 Hz, 1H), 5.49 (s, 2H), 5.07 (ddd, J = 14.5, 7.3, 2.8 Hz, 1H), 4.80 (dd, J = 15.3, 7.3 Hz, 1H), 4.66 ( dd, J = 15.2, 2.7 Hz, 1H), 4.47 (dt, J = 14.0, 7.1 Hz, 1H), 4.36 (dt, J = 9.0, 5.9 Hz, 1H), 4.08 (d, J = 13.5 Hz, 1H ), 3.97 – 3.90 (m, 1H), 3.81 (s, 3H), 3.26 (d, J = 12.6 Hz, 2H), 2.80 – 2.74 (m, 2H), 2.70 – 2.62 (m, 1H), 2.60 – 2.53 (m, 2H), 2.45 – 2.38 (m, 1H).

4. (S)-2-((6-((2 , 3- Dihydrobenzo [b][1 , 4] dioxane -6- base ) Methoxy )-3 ', 6 '- dihydrogen -[twenty four '- Bipyridine ]-1 '(2 ' H)- base ) methyl )-1-( Oxetane -2- Methyl )-1H- Benzo [d] imidazole -6- carboxylic acid ( compound 24070) Preparation

Step 4-1: Preparation of 6-chloro-3', 6'-dihydro-[2, 4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester:

Under nitrogen protection conditions, 2-bromo-6-chloropyridine (1.0 g, 5.20 mmol, 1.0 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.6 g, 5.20 mmol, 1.0 equiv), 1,1'-bis(diphenylphosphine) Ferrocene]palladium dichloride and sodium carbonate were added to a mixed solvent (11 ml) of dioxane and water (10:1), and stirred at 90°C overnight. The reaction solution was cooled to room temperature, then quenched with water, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 10/1) to obtain yellow solid 6-chloro-3', 6'-dihydro-[2 , 4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (3.26 g, yield: 214%). LCMS (ESI): m/z=295 (M+H) ⁺ .

Step 4-2: Preparation of 6-chloro-1', 2', 3', 6'-tetrahydro-2, 4'-bipyridyl-p-toluenesulfonate:

6-Chloro-3', 6'-dihydro-[2, 4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (2.94 mg, 9.99 mmol, 1.0 equiv) and p-toluene A mixture of sulfonic acid (4.3 g, 24.97 mmol, 2.5 units) in ethyl acetate (50 ml) was stirred at 60°C for 30 min. The reaction solution was filtered, and the filter cake obtained white solid 6-chloro-1', 2', 3', 6'-tetrahydro-2, 4'-bipyridyl p-toluenesulfonate (232 mg, yield 12%) . The product was used directly in the next step without further purification.

Step 4-3: (S)-2-((6-chloro-3 ', 6 '-dihydro-[2, 4 '-bipyridyl]-1 '(2 ' H)-yl)methyl)- Preparation of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester:

6-Chloro-1', 2', 3', 6'-tetrahydro-2,4'-bipyridine-p-toluenesulfonate (232 mg, 0.634 mmol, 1.2 equiv) and potassium carbonate (291 mg, 2.11 mmol, 4.0 single amount) in acetonitrile (10 ml) was heated to 60°C until the pH reached 7~8, and then (S)-2-(chloromethyl)-1-(oxetane- Methyl 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.528 mmol, 1.0 single amount) was added to the mixture and stirred overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain (S)-2-((6-chloro-3', 6'-dihydro-[2, 4'-bipyridyl]-1'(2'H)-yl)methyl (188.5 mg, yield: 81.74%) was a yellow solid. LCMS (ESI): m/z=453.9 (M+H) ⁺ .

Step 4-4: (S)-2-((6-((2,3-dihydrobenzo[b][1,4]dioxen-6-yl)methoxy)-3 ', 6 '-dihydro-[2, 4 '-bipyridyl]-1 '(2 ' H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Preparation of benzo[d]imidazole-6-carboxylic acid methyl ester:

(S)-2-((6-chloro-3 ', 6 '-dihydro-[2, 4 '-bipyridyl]-1 '(2 ' H)-yl)methyl)-1-(oxy Hetetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (188.5 mg, 0.417 mmol, 1.0 equiv), (2,3-dihydrobenzo[b ][1,4]dioxen-6-yl)methanol (83.1 mg, 0.500 mmol, 1.2 equiv), tris(dibenzylideneacetone)dipalladium (19.23 mg, 0.021 mmol, 0.05 equiv) ), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (19.46 mg, 0.0417 mmol, 0.1 equiv) and cesium carbonate (382.86 mg, 1.175 mmol, 2.5 equiv) in toluene ( 70 ml) mixture was stirred at 120°C overnight. After cooling to room temperature, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (eluent: petroleum ether/ethyl acetate = 1/2) to obtain a yellow solid compound (S)-2-((6-((2,3-dihydrobenzene) And[b][1,4]dioxen-6-yl)methoxy)-3 ', 6 '-dihydro-[2, 4 '-bipyridyl]-1 '(2 ' H )-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (20 mg, yield 8.44%). LCMS (ESI): m/z=583.6 (M+H) ⁺ .

Step 4-5: (S)-2-((6-((2,3-dihydrobenzo[b][1,4]dioxen-6-yl)methoxy)-3 ', 6 '-dihydro-[2, 4 '-bipyridyl]-1 '(2 ' H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H- Preparation of benzo[d]imidazole-6-carboxylic acid (compound 24070):

(S)-2-((6-((2,3-dihydrobenzo[b][1,4]dioxen-6-yl)methoxy)-3 ', 6 ' -Dihydro-[2, 4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d ] Imidazole-6-carboxylic acid methyl ester (20 mg, 0.034 mmol, 1.0 equivalent) and lithium hydroxide monohydrate (2.85 mg, 0.068 mmol, 2.0 single amount) in acetonitrile/water = 5/1 (6 ml) The mixture was stirred at 40 °C overnight. The mixture was then cooled to room temperature and the pH was adjusted to approximately 6 by adding 1.0 M sulfuric acid, after which a solid precipitated. Strain the mixture. Wash the residue with water. The mixture was slurried with methanol to obtain a yellow solid (S)-2-((6-((2,3-dihydrobenzo[b][1,4]dioxen-6-yl)methoxy) -3 ', 6 '-dihydro-[2, 4 '-bipyridyl]-1 '(2 ' H)-yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-benzo[d]imidazole-6-carboxylic acid (18 mg, 92.4% yield). LCMS (ESI): m/z=569 (M+H) ⁺ . ¹ H NMR (500 MHz, DMSO) δ 12.67 (s, 1H), 8.26 (s, 1H), 7.81 (dd, J = 8.4, 1.2 Hz, 1H), 7.65 (t, J = 8.2 Hz, 2H), 7.05 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.89 (dd, J = 8.2, 1.9 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.24 (s, 2H), 5.07 (qd, J = 7.2, 2.8 Hz, 1H), 4.80 (dd, J = 15.2, 7.3 Hz , 1H), 4.65 (dd, J = 15.2, 2.6 Hz, 1H), 4.47 (dd, J = 13.6, 7.7 Hz, 1H), 4.36 (dt, J = 8.9, 5.9 Hz, 1H), 4.20 (s, 4H), 4.07 (d, J = 13.5 Hz, 1H), 3.93 (d, J = 13.5 Hz, 1H), 3.23 (s, 2H), 2.79 – 2.72 (m, 2H), 2.66 (ddd, J = 8.8 , 8.2, 5.5 Hz, 1H), 2.54 (s, 2H), 2.40 (ddd, J = 16.1, 11.2, 7.1 Hz, 1H).

1. Determination of cyclic adenosine monophosphate (cAMP) levels in hGLP-1R 293Ta cell line

1. Experimental materials Name Source Item number cAMP detection kit Cisbio 62AM6PEB (1,000 tests) IBMX Cisbio 62AMXADA FBS Biological Industries 04-001-1ACS DMEM GIBCO C11995500BT Low volume white microplate Cisbio 66PL96025 Tecan INFINITE F NANO+ microplate reader Tecan Infinite 200 PRO

2. Experimental principle

Cisbio's Cyclic Adenosine Monophosphate Assay Kit is a competitive immunoassay designed to measure intracellular accumulation of cyclic Adenosine Monophosphate. The principle is based on HTRF® technology, where natural cyclic adenosine monophosphate or unlabeled cyclic adenosine monophosphate (standard curve) produced by cells competes with d2-labeled cyclic adenosine monophosphate (red receptor) for binding to monoclonal cyclic adenosine monophosphate Europium Cryptate Labeled antibodies (Europium donor). The specific signal is inversely proportional to the concentration of cyclic adenosine monophosphate in the standard or sample.

For all other HTRF analyses, the calculation of the fluorescence ratio (665 nm/620 nm) eliminates any possible photophysical interference, meaning that the analysis is independent of experimental medium conditions (e.g. culture medium, serum, biotin, colored compounds, etc.) influence.

3. Experimental preparation

1) Construction of hGLP-1R 293Ta stably transfected cell line: a) Suzhou Jinweizhi Biotechnology Co., Ltd. was commissioned to synthesize the hGLP-1R full-length sequence and connect it to the lentiviral vector pLEX-MCS. b) Transfect 293Ta cells with the lentiviral plasmid pLEX-MCS connected to the hGLP-1R sequence to produce lentivirus; c) Infect 293Ta cells with lentivirus, and screen with puromycin to obtain a 293Ta stably transduced cell line containing the hGLP-1R sequence.

2) Reagent preparation: a) Prepare cyclic adenosine monophosphate detection reagent (the reagent needs to be placed at room temperature for 30 minutes) Anti-Cyclic Adenosine Monophosphate-Cryptate (Europium Donor, Lyophilized Powder) 1 vial Add 1.1ml distilled water to reconstitute and mix gently. Aliquot 50ul into each tube and store at -80°C. Use Lysis & Detection Buffer 1 to prepare working solution in a ratio of 1:4 Cyclic adenosine monophosphate-d2 (red acceptor, freeze-dried powder) 1 vial Add 1.1ml distilled water to reconstitute and mix gently. Aliquot 50ul into each tube and store at -80°C. Use Lysis & Detection Buffer 1 to prepare working solution in a ratio of 1:4 Cyclic adenosine monophosphate-cyclic adenosine monophosphate-Gs HiRange standard reference substance (lyophilized powder) 1 vial Add 0.4ml distilled water to reconstitute and mix gently. Pack into 50ul per tube and store at -20°C Lysis & Detection Buffer 1 1 vial (13ml) Stimulation Buffer 1 (5X) 1 vial (8ml) Dilute with distilled water in a ratio of 1:4 (400ul+1600ul) b) 3-Isobutyl-1-methylxanthine: 3-isobutyl-1-methylxanthine (500mM) is diluted to 50mM with DMSO, aliquot 20ul into each tube, and store at 4°C. Add 2ml of Stimulation Buffer 1 to 20ul and dilute to 0.5mM.

4. Cell experiments

1) Compound dilution: dilute 2mM stock solution with DMSO to 200nM (40X), then take 2ul and add 38ul of stimulation Buffer 1 (containing 0.5mM of 3-isobutyl-1-methylxanthine) to dilute to 10nM (2X), reaction system The final concentration is 5 nM. Use stimulation Buffer 1 (containing 0.5mM 3-isobutyl-1-methylxanthine) to dilute 5 times in sequence, with a total of 8 concentration points.

2) Collect hGLP-1R 293Ta cells by digestion and centrifugation, add DMEM medium (containing 10% FBS), pipette and resuspend the cells, and count them with a Scepter automatic cell counter (Millipore #PHCC00000). Adjust the number of cells to 1X10 ⁶ cells/ml, and add 5ul to each well of the 96-well microwell white plate (ie, 5000 cells per well).

3) Add 5ul of diluted 8 concentration gradient 2X compounds to 96 wells, and add 5ul of stimulation Buffer 1 (containing 3-isobutyl-1-methylxanthine 0.5mM) to another well as a control. Close the lid and incubate at 37°C for 30 minutes.

4) Take 50ul of cyclic adenosine monophosphate-d2 and 50ul of Anti-cyclic adenosine monophosphate Eu-Cryptate and add 200ul of lysis & detection Buffer 1 to prepare the working solution. Add 5ul of cyclic adenosine monophosphate-d2 working solution to each well of the 96-well plate, and then add 5ul of Anti-cyclic adenosine monophosphate Eu-Cryptate working solution. Mix well, seal the 96-well plate with sealing film, and incubate at room temperature for 2 hours.

5) Remove the sealing film and read the HTRF signal with Tecan INFINITE F NANO+ microplate reader. Use the formula Ratio=Signal 665nm/Signal 620nm*10000 to calculate the ratio of the acceptor and donor excitation signals for each single well. Based on the HTRF signal ratio and the corresponding compound concentration, the data were processed with GraphPad Prism software, and the EC50 value was calculated through S-shaped dose-response curve fitting. The test results are shown in Table 1.

Table 1. Effects of assayed compounds on cyclic adenosine monophosphate levels in hGLP-1R 293Ta cells compound Determine EC50 pM compound Determine EC50 pM 1 11.19 2 6.10 3 11.62 4 5.82 5 34.66 6 3.56 8 55.23 12 10.35 14 15.60 15 32.03 16 6.57 17 21.65 20 2681.00 twenty three 909.30 twenty four 1029.00 25 5.39 28 81.10 30 41.96 31 244.80 32 313.00 33 127.90 44 1512.00 46 11.01 47 117.80 49 944.90 53 262.00 54 32.72 55 1686.00 56 206.50 57 68.49 58 9.40 61 109.60 PF-06882961 31.44 24067 394.9 24068 669.0 24069 1100.0 24070 342.8

As can be seen from the table above, the compounds of the present invention can activate cAMP levels in hGLP-1R 293Ta cells and are more active than the control compounds PF-06882961, 24067, 24068, 24069 and 24070.

2. Pharmacokinetics (PK) experiment

1. Experimental methods

Male SD rats, weighing 180-320 grams, were fasted overnight before the test. The compound to be tested was dissolved in 30% sulfobutyl-β-cyclodextrin (SBE-β-CD) and administered by intragastric administration in a single dose of 20 mg/kg. Blood was taken from the tail end at 15 minutes, 30 minutes and 1, 2, 4, 6, 8 and 24 hours after administration. About 0.3 ml at each time point was placed in a centrifuge tube containing K2-EDTA and centrifuged (2000 g , 10 minutes, 4 °C) to collect plasma and store it in an ultra-low temperature refrigerator at −70°C to −80°C. 50 μL of plasma sample was vortex-mixed with 135 μL acetonitrile (containing internal standard 0.5 μg/mL) for protein precipitation, centrifuged, and the supernatant was taken for LC-MS/MS analysis.

2.Experimental results

Each benzimidazole or azabenzimidazole-6-carboxylic acid compound provided by the present invention is well absorbed and has a high blood exposure after oral administration to rats. The results are shown in Figures 1, 2 and Table 2. The T _max of the benzimidazole or azabenzimidazole-6-carboxylic acid compound of the present invention is 0.5-2.67 hours, the C _max is 180-2553.33 ng/ml, and the AUC _0-24h is 934.28-9583.02 ng/ml*h. . C _max refers to the maximum plasma concentration, T _1/2 is the half-life, AUC _0-24 refers to the area under the 0-24 hour time-concentration curve, and AUC _0-inf refers to the area under the 0-Inf time-concentration curve.

Table 2. Pharmacokinetic parameters of rats administered intragastrically (20 mg/kg) compound PK parameters T _1/2 (hr) T _max (hr) C _max (ng/ml) AUC _0-24 (hr*ng/mL) AUC _0-inf (hr*ng/mL) 1 4.06 0.5 180 973.96 984.46 2 6.38 0.75 665.5 2377.02 2553.77 3 4.21 0.83 261.33 954.4 962.73 4 3.48 0.5 618 1489.7 1498.13 6 3.89 0.5 384.5 934.28 939.92 12 1.2 1 1139.33 2761.02 2797.66 16 2.54 1 2553.33 9583.02 9595.58 46 3.72 0.5 1255.33 2553.19 2565.2 58 2.77 2.67 1205.33 5977.89 5985.82 PF-06882961 3.74 2.5 99.03 648.77 656.99

3. Pharmacodynamic experiments

1. Experimental methods

Genetically engineered hGLP1R mice, male, 7 weeks old, were purchased from Biocytogen Jiangsu Gene Biotechnology Co., Ltd. Experimental animals are kept in horizontal flow independent ventilation cages with a temperature of 20-26ºC, a relative humidity of 40-70% RH, an air exchange rate of 15-30 times/hour, an air cleanliness level of 7, and alternating light and dark times between day and night. 12h/12h; continuous supply of cobalt 60 radiation-sterilized rat full-price pellet feed (Guangdong Provincial Medical Experimental Animal Center, maintenance feed for rats and mice), unlimited free intake; drinking tap water (used after high-pressure steam sterilization), uninterrupted water supply , free intake. The breeding cages are transparent polyetherimide cages (Suzhou Aikelin Purification Equipment Co., Ltd., horizontal flow mouse cages), which are free of pathogenic microorganisms; the bedding materials are corn cobs (Guangdong Medical Experimental Animal Center, high-pressure steam Use after sterilization), 2-5 animals per cage. The cage card is marked with the IACUC approval number, experiment number, experiment start time, project leader, experimenter, animal source, group and animal number, etc. The animal use method in this experiment was approved by the IACUC of Guangzhou Bibet Pharmaceutical Technology Co., Ltd.

Oral glucose tolerance test in hGLP1R mice: The animals are fasted overnight and are not allowed to drink water. The vehicle or the corresponding compound is administered orally in a single dose. The blood glucose is measured before administration of the vehicle or compound (equivalent to -60 min blood glucose value). The vehicle or compound is administered orally 60 minutes later. Give glucose (2g/kg), measure blood sugar before giving glucose (equivalent to 0min blood sugar value), and measure blood sugar value 15min, 30min, 60min, 90min, and 120min after giving glucose. The solvent is 40% PEG400+60% MCT (0.5% MC/0.1% Tween80) aqueous solution, and the compound doses are 0.3 mg/kg (n=2-4) and 1 mg/kg (n=2-4) respectively.

2. Experimental results

As shown in Figure 3 and Figure 4, when Compound 12 and Compound 16 were administered with PF-06882961 at the same dose (1 mg/kg) in a single oral administration, from the perspective of blood glucose curve and blood glucose AUC (0-2h), Compound 12 and PF-06882961 were The hypoglycemic effect of PF-06882961 is equivalent; the hypoglycemic effect of compound 16 is better than that of PF-06882961.

As shown in Figure 5 and Figure 6, when Compound 6 and Compound 16 were administered with PF-06882961 at the same dose (0.3 mg/kg) in a single oral administration, judging from the blood glucose curve and blood glucose AUC (0-2h), Compound 6 The hypoglycemic effect is slightly better than that of PF-06882961; the hypoglycemic effect of compound 16 is significantly better than that of PF-06882961.

As shown in Figures 7 and 8, when Compound 3, Compound 16 and Compound 58 were administered at the same dose (0.3 mg/kg) in a single oral administration, from the perspective of blood glucose curve and blood glucose AUC (0-2h), Compound 16 had The blood sugar lowering effect is the best.

The technical features of the above-described embodiments can be combined in any way. To simplify the description, not all possible combinations of the technical features in the following embodiments are described. However, as long as there is no contradiction in the combination of these technical features, All should be considered to be within the scope of this manual.

The above-mentioned embodiments only express several implementation modes of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the patent scope of the present invention. It should be noted that, for those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the scope of protection of the patent of the present invention shall be subject to the scope of the attached patent application.

without

Figure 1 is the average drug time curve of Compounds 1, 2, 3, 4 and Compound 6 administered intragastrically (20 mg/kg) to rats. Figure 2 is a graph showing the average drug time curve of compounds PF-06882961, 12, 16, 46 and compound 58 administered intragastrically (20 mg/kg) to rats. Figure 3 is the blood glucose curve of compound 12 and compound 16 in mouse glucose tolerance test. Figure 4 shows the AUC _(0-2h) of compound 12 and compound 16 in mouse glucose tolerance test. Figure 5 is the blood glucose curve of compound 6 and compound 16 in mouse glucose tolerance test. Figure 6 AUC _(0-2h) of compound 6 and compound 16 in mouse glucose tolerance test. Figure 7. Blood glucose curves of compound 3, compound 16 and compound 58 in mouse glucose tolerance test. Figure 8 AUC _(0-2h) of compound 3, compound 16 and compound 58 in mouse glucose tolerance test.

Claims (23)

A benzimidazole or azabenzimidazole-6-carboxylic acid compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

Among them: R ₁ and R ₂ are each independently selected from: H, halogen, C1-C3 alkyl, C1-C3 alkoxy; R ₃ and R ₄ are each independently selected from: H, C1-C6 alkyl, C1-C6 Alkoxy group; or R ₃ and R ₄ are connected to form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring; R ₅ is selected from: C1-C4 alkyl substituted by a 3-4 membered heterocyclic group, 5-6 membered Heteroaryl-substituted C1-C4 alkyl; wherein, the 3-4-membered heterocyclyl and 5-6-membered heteroaryl in R ₅ can be independently optionally substituted by one or more R ₁₀ ; R ₆ and R ₇ are independently selected from: H, C1-C6 alkyl; or R ₆ and R ₇ together form G, G is selected from =O; each R ₈ is independently selected from: H, halogen, C1-C3 alkyl; Each R ₉ is independently selected from: H, halogen, cyano, C1-C3 alkyl, trifluoromethyl n is selected from: 0; p is selected from: 1 or 2; m is selected from: 1, 2 or 3; W Selected from: O, S; W ₁ is selected from: O, S; Q is selected from: C, CH, N; X is selected from: N, CR ₁₀ ; Y is selected from: N, CR ₁₁ ; R ₁₀ is selected from: H , C1-C6 alkyl; R ₁₁ is selected from: H, C1-C6 alkyl, C1-C6 alkoxy; or R ₁₁ and R ₆ are connected to form a 5-8 membered heterocyclic ring; between Q and adjacent C The dotted line indicates that the chemical bond between Q and adjacent C can be a single bond or a double bond. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 1 is characterized in that it has the following formula (II) or formula ( III) The structure shown:

The benzimidazole or azabenzimidazole-6-carboxylic acid compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 1 is characterized in that it has the following formula (IV) or formula ( V) shows the structure:

The benzimidazole or azabenzimidazole-6-carboxylic acid compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 1 is characterized in that it has the following formula (VI) or formula ( VII) The structure shown:

(VI)

The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in claim 1, characterized in that W is O, R ₆ and R ₇ Each is independently selected from: H, C1-C6 alkyl. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in any one of claims 1 to 5, characterized in that W ₁ is O. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in any one of claims 1 to 5, characterized in that Q is selected from :C,CH. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in any one of claims 1 to 5, characterized in that, X is selected from :N,CH. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in any one of claims 1-5, characterized in that R ₃ and R ₄ are independently selected from: H, C1-C3 alkyl, C1-C3 alkoxy. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in claim 1, characterized in that R ₅ is selected from: 3-4 yuan Heterocyclyl-substituted methyl, 3-4-membered heterocyclyl-substituted ethyl, 5-6-membered heteroaryl-substituted methyl, 5-6-membered heteroaryl-substituted ethyl; wherein, the R ₅ The 3-4-membered heterocyclyl and 5-6-membered heteroaryl in can be independently optionally substituted by one or more R ₁₀ , and R ₁₀ is selected from: H, C1-C3 alkyl. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in claim 10, characterized in that R ₅ is selected from: oxetane Alkane-substituted methyl, oxetane-substituted ethyl, ethylimidazole-substituted methyl, ethylimidazole-substituted ethyl. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in any one of claims 1-5, characterized in that R ₆ and R ₇ are each independently selected from: H, C1-C3 alkyl. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in claim 1, characterized in that each R ₈ is independently selected from: H , Cl, F, methyl; each R ₉ is independently selected from: cyano, Cl, methyl. The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer as described in claim 1 is characterized in that it is selected from the following compounds:

A kind of benzimidazole or azabenzimidazole-6-carboxylic acid compound as described in any one of claims 1-14 or its pharmaceutically acceptable salt or its stereoisomer in the preparation of GLP-1R agonist applications in. A benzimidazole or azabenzimidazole-6-carboxylic acid compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in any one of claims 1-14 is used in the preparation of prevention and/or Or application in drugs to treat diseases and/or symptoms related to the GLP-1R downstream signaling pathway. The application according to claim 16, characterized in that the diseases and/or symptoms related to the GLP-1R downstream signaling pathway are selected from: diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, and insulin resistance, Hyperglycemia, diabetic nephropathy, hypertension, cataracts, osteoporosis, hyperuricemia and infections caused by diabetes, obesity, metabolic syndrome, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis , heart disease, stroke, cirrhosis of the liver , liver cancer, metabolic acidosis, ketosis, epilepsy, atherosclerosis, Parkinson's disease, and Alzheimer's disease. A kind of benzimidazole or azabenzimidazole-6-carboxylic acid compound as described in any one of claims 1-14 or its pharmaceutically acceptable salt or its stereoisomer in the preparation of drugs for promoting insulin secretion applications in. A benzimidazole or azabenzimidazole-6-carboxylic acid compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in any one of claims 1-14 in the preparation of medicines for lowering blood sugar application. A benzimidazole or azabenzimidazole-6-carboxylic acid compound as described in any one of claims 1-14 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof in the preparation of prevention and/or treatment Diabetic drug applications. The application according to claim 20, wherein the diabetes is type 1 diabetes, type 2 diabetes, gestational diabetes, adult-onset diabetes of the young, adolescent-onset atypical diabetes, or malnutrition-related diabetes. The application according to claim 21, wherein the diabetes is idiopathic type 1 diabetes, early-onset type 2 diabetes, or adult latent autoimmune diabetes. A pharmaceutical composition for preventing and/or treating diabetes and its complications, characterized in that it includes active ingredients and pharmaceutically acceptable excipients and/or carriers, and the active ingredients include any one of claims 1-14 The benzimidazole or azabenzimidazole-6-carboxylic acid compound or its pharmaceutically acceptable salt or its stereoisomer.