WO2024046342A1 - Benzo bicyclic compounds, preparation method therefor, and use thereof - Google Patents

Abstract

Disclosed are benzo bicyclic compounds and the use thereof in drugs. Specifically, the present invention relates to novel benzo bicyclic compounds and pharmaceutical compositions comprising said compounds. The present invention further relates to a method for preparing the compounds, and the use of the compounds or the pharmaceutical compositions for preparing drugs for treating GLP-1 receptor agonist-mediated diseases and/or disorders, in particular the use for preparing drugs for treating diabetes, non-alcoholic fatty liver disease and obesity.

Description

Benzodicyclic compounds and their preparation methods and applications

This application claims the following priority rights:

CN202211048114.4, application date is August 30, 2022.

Technical field

The invention relates to the technical field of chemical medicine, and in particular to a benzobicyclic compound and its preparation method and application.

Background technique

Diabetes is a metabolic disease with multiple causes, characterized by chronic hyperglycemia, accompanied by disorders of sugar, lipid, and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very old disease. It is caused by the absolute or relative lack of insulin in the human body. The concentration of glucose in the blood increases, and then a large amount of sugar is excreted in the urine, and symptoms such as polydipsia, polyuria, polyphagia, and weight loss occur. .

According to the classification of diabetes pathogenesis, diabetes can usually be divided into type I diabetes and type II diabetes. Type I diabetes is caused by the autoimmune system attacking the beta cells of the pancreas, causing it to lose its ability to secrete insulin. Type II diabetes begins with abnormal insulin resistance or cells not responding to insulin. Obesity is one of the main causes of insulin resistance, so obesity can be said to be the main risk factor for type II diabetes. Type II diabetes patients account for about 90% of diabetes patients, so the disease has become a major public health problem in developed countries where obesity is a serious problem, as well as in China, where the number of obesity continues to rise.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 plays a corresponding role by binding to its widespread specific receptors. Currently, the organs in which GLP-1 receptors are clearly present include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus and cardiovascular system, liver There may be GLP-1 receptors in fat tissue and skeletal muscle. GLP-1 not only acts on β cells to promote insulin secretion, but also acts on α cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels between patients with normal glucose tolerance, impaired glucose tolerance, and type II diabetes. However, there is a defect in the response of β cells to GLP-1 after eating. Under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. Since the action duration of the body's own GLP-1 is very short (t _1/2 <1.5 minutes after intravenous injection), the body's own GLP-1 is not suitable for clinical treatment of diabetes.

Peptide GLP-1 receptor agonists (such as liraglutide, exenatide, etc.) can reduce fasting and postprandial glucose and improve blood sugar in patients with type II diabetes. However, because the peptide GLP-1 has poor oral bioavailability and is inconvenient to take, there is an urgent clinical need for small molecule GLP-1 receptor agonists with good oral bioavailability.

At present, scientific researchers have carried out some studies in order to find therapeutic agents that can effectively stimulate GLP-1 receptors. PCT applications WO2018109607, WO2019239319, WO2019239371, WO2020103815, WO2020207474, WO2020263695, WO2021154796, WO2021112538, WO2021096304, WO2021096284, WO 2021081207, WO2021018023 and WO2021254470, WO2021249492, WO2022007979, WO2022031994, WO2022040600, WO2022068772 and WO2022116693 disclose many small molecule compounds as GLP- 1 Receptor agonists are used to prevent or treat diabetes. However, there is still an urgent clinical need for more and better GLP-1 receptor agonists.

Contents of the invention

The present invention provides a compound, or a pharmaceutical composition thereof, which can serve as an agonist of GLP-1 receptor. The present invention further relates to the use of said compound or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of diseases and/or conditions by agonizing GLP-1 receptors by said compound. The present invention further describes the synthesis method of the compound. The compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.

Specifically:

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer of a compound represented by formula (I), Geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

in:

X ₁ , X ₂ and X ₃ are each independently N or CR ¹³ ;

Y ₁ is N or CR ¹⁴ ;

Y ₂ is N or CR ⁴ ;

Y ₃ is N or CR ⁵ ;

Y ₄ is N or CR ¹⁵ ;

L is O or CR ¹⁶ R ¹⁷ ;

Z is O or S;

R ¹ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl or -C _1-6 alkylene -R ¹⁸ , the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _3-6 membered heterocyclyl and -C _1-6 alkylene The group -R ¹⁸ may be independently optionally substituted by 1, 2 or 3 R ^1a ;

R ¹⁸ is C _3-6 cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl;

R ^1a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _{1 -6} alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclyl, the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclyl can be independently optionally substituted by 1, 2 or 3 R ^1b ;

R ^1b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _{1 -6} alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclyl;

Each R ¹³ is independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkoxy or -C _1-6 alkylene-C _1-6 alkoxy;

R ² , R ³ , R ⁶ , R ⁷ , R ¹⁶ and R ¹⁷ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro or C _1-6 alkane base, the C _1-6 alkyl group can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro;

Ring B is a 5-6 membered heterocyclyl, C _5-6 cycloalkyl, phenyl or 5-6 membered heteroaryl;

Each R ^b is independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkyl Amino group, the C _1-6 alkyl group, C _1-6 alkoxy group and C _1-6 alkylamino group can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitution;

R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkylamino, the C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylamino can be independently optionally 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitution;

n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

In some embodiments, a compound of the invention has a structure represented by Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII):

Wherein, the _X1 , _X2 , _X3 , Y1, _Y2 , _{Y3 , Y4} , Z, ^R1 , ^R2 , ^R3 , ^R6 , ^R7 , ^R8 , ^R9 , ^R10 , R ¹¹ , R ¹² , R ^b and n have the meanings described in the present invention.

In some embodiments, ^R1 is H, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, or -C _1-3 alkylene-R ¹⁸ , the C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and - C _1-3 alkylene-R ¹⁸ may be independently optionally substituted by 1, 2 or 3 R ^1a ;

R ¹⁸ is C _3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl;

R ^1a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _{1 -3} alkylamino, C _3-6 cycloalkyl or 5-6 membered heterocyclyl, the C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 Alkylamino, C _3-6 cycloalkyl and 5-6 membered heterocyclyl can be independently optionally substituted by 1, 2 or 3 R ^1b ;

R ^1b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _{1 -3} alkylamino, C _5-6 cycloalkyl or 5-6 membered heterocyclyl.

In some embodiments, ^R1 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl or -CH ₂ R ¹⁸ , the methyl group base, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxa Cyclobutyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl and -CH ₂ R ¹⁸ can be independently optionally substituted by 1, 2 or 3 R ^1a ;

R ¹⁸ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, morpholinyl,

R ^1a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio , N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperidyl Azinyl or morpholinyl, the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclopropyl, Butyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl can be independently optionally substituted by 1, 2 or 3 R ^1b substitutions;

R ^1b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio , N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperidyl Azinyl or morpholinyl.

In some embodiments, ^R1 is H,

In some embodiments, each R ¹³ is independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _{1- 6hydroxyalkyl} , C _1-6 aminoalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkoxy or -C _1-6 alkylene-C _1-6 alkyl Oxygen;

R ² , R ³ , R ⁶ , R ⁷ , R ¹⁶ and R ¹⁷ are each independently H, D, F, Cl, Br _, I, CN, hydroxyl, oxo, amino, nitro or C _1-3 alkane base, the C _1-3 alkyl group can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro;

Each R ^b is independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 alkyl Amino group, the C _1-3 alkyl group, C _1-3 alkoxy group and C _1-3 alkylamino group can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitution;

R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 alkylamino, the C _1-3 alkyl, C _1-3 alkoxy and C _1-3 alkylamino can be independently optionally 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitutions.

In some embodiments, each R ¹³ is independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF ₂ , -CF ₃ , -CHFCH ₂ F, -CF ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CF ₂ CHF ₂ , hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, Ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF ₂ , -OCF ₃ , -OCHFCH ₂ F, -OCF ₂ CHF ₂ , -OCH ₂ CF ₃ , - OCH ₂ CF ₂ CHF ₂ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ CH ₂ OCH ₂ CH ₃ ;

R ² , R ³ , R ⁶ , R ⁷ , R ¹⁶ and R ¹⁷ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl , n-propyl or isopropyl, the methyl, ethyl, n-propyl and isopropyl can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or Nitro substitution;

Each R ^b is independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy base, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy , Isopropoxy, N-methylamino and N-ethylamino can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro;

R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, methane base, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, the methyl, ethyl, n-propyl Propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitution.

In some embodiments, the compound of the present invention is a compound with one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide of a compound with one of the following structures , hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug:

In one aspect, the present invention relates to a pharmaceutical composition, which comprises formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula ( The compound described in VII), or its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, auxiliaries, vehicles or combinations thereof.

In one aspect, the present invention relates to the use of the aforementioned compounds or pharmaceutical compositions thereof in the preparation of medicaments for preventing, treating or alleviating GLP-1 receptor agonist-mediated diseases in patients.

In some embodiments, the disease mediated by the GLP-1 receptor agonist of the invention is diabetes, non-alcoholic fatty liver disease, or obesity.

In some embodiments, the diabetes of the present invention is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, adult-onset diabetes of the young, and adolescent-onset atypical diabetes. , malnutrition-related diabetes or latent autoimmune diabetes in adults.

In another aspect, the present invention relates to the preparation, isolation and preparation of compounds comprised by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII). Purification methods.

The foregoing description summarizes certain aspects of the invention but is not limited to these aspects. These and other aspects are described in greater detail below.

Definitions and general terms

The present invention will list the documents corresponding to the determined specific content in detail, and the examples will be accompanied by illustrations of structural formulas and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalents which may fall within the field of existing inventions as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which could be used in the practice of the present invention. This invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ from or conflict with the present application, including but in no way limited to the definition of terms, the usage of terms, the techniques described, or the scope of control like the present application.

This invention shall apply the following definitions unless otherwise indicated. For the purposes of this invention, chemical elements are defined according to the Periodic Table of the Elements, CAS Edition and Handbook of Chemical Medicines, 75, thEd, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, so all The content is integrated with references.

The term "comprises" is an open expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

Compounds such as those described herein may be optionally substituted with one or more substituents, such as compounds of the general formula of the present invention, or as specific examples, subclasses, and classes of compounds encompassed by the present invention. . It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally", whether or not preceded by the term "substituted," means that one or more hydrogen atoms in a given structure are substituted with a specified substituent. Unless otherwise indicated, an optionally substituted group may be substituted with a substituent at each substitutable position of the group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be identically or differently substituted at each position. The substituents mentioned therein can be, but are not limited to hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxyl, alkyl, hydroxyalkyl, alkylamino, aminoalkyl Base, haloalkoxy, cycloalkyl, amino, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, cycloalkyloxy, alkoxy, alkoxyalkyl, haloalkyl, -COOH , -alkylene-C(=O)O-alkyl, -alkylene-S(=O) ₂ -alkyl, -alkylene-S(=O) ₂ -amino, -S(=O ) ₂ -Alkyl, -S(=O) ₂ -Amino, -S(=O) ₂ OH, -O-alkylene-C(=O)O-alkyl, -O-alkylene-S (=O) ₂ -alkyl, -O-alkylene-S(=O) ₂ -amino, -O-alkylene-S(=O) ₂ OH, -C(=O)NH ₂ , - C(=O)NH-alkyl, -C(=O)N(alkyl)-alkyl, -C(=O)NHS(=O) ₂ -alkyl, -C(=O)NHS(= O) ₂ -amino, -C(=O)NHS(=O) ₂ OH, -N(haloalkyl)-alkyl, -N(alkyl)-S(=O) ₂ -alkyl, -NHS( =O) ₂ -alkyl, -NHS(=O) ₂ -haloalkyl, -N(alkyl)S(=O) ₂ -haloalkyl, -N(alkyl)S(=O) ₂ -alkylamino , -NHC(=O)-alkyl, -NHC(=O)-haloalkyl, -N(alkyl)C(=O)-haloalkyl, -N(alkyl)C(=O)-alkylamino , -N(alkyl)C(=O)O-alkyl, -NHC(=O)O-alkyl, -NHC(=O)O-haloalkyl, -N(alkyl)C(=O) O-haloalkyl, -N(alkyl)C(=O)O-aminoalkyl, -NHC(=O)-NH ₂ , -NHC(=O)NH-(alkyl), -NHC(=O )NH(halogenated alkyl), -NHC(=O)N(alkyl)-alkyl, -OC(=O)-alkyl, -OC(=O)-amino, -OC(=O)-alkylamino , -OC(=O)-aminoalkyl, -OC(=O)-alkoxy, -C(=O)N(alkyl)S(=O) ₂ -alkyl, -C(=O) N(alkyl)S(=O) ₂ -amino, -C(=O)NH-S(=O) ₂ OH, -C(=NH)NH ₂ , -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH ₂ , -C(=O)NH-alkylene-S(=O) ₂ OH, -C (=O)NHC(=O)OH, -C(=O)NHC(=O)O-alkyl, -C(=O)N(alkyl)C(=O)O-alkyl, -C (=O)NH-alkylene-C(=O)OH and -C(=O)NH-alkylene-C(=O)O-alkyl, and so on.

The term "alkyl" as used herein includes 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms, or A saturated straight-chain or branched-chain monovalent hydrocarbon group with 1-2 carbon atoms, in which the alkyl group can be independently optionally substituted by one or more substituents described in the present invention. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (- CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl Base-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1 -Butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )) , 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl(-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl(-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl and n-octyl, etc. The term "alkyl" and its prefix "alkyl" as used herein include both straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical obtained by eliminating two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene base, ethylene and isopropylene, etc.

The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, alkylene groups contain 1 to 12 carbon atoms. In some embodiments, the alkylene group contains 1-6 carbon atoms; in other embodiments, the alkylene group contains 1-4 carbon atoms; in still other embodiments, the alkylene group The alkylene group contains 1-3 carbon atoms; in still some embodiments, the alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), isopropylene (-CH(CH ₃ )CH ₂ -), and the like.

The term "alkenyl" means a straight or branched monovalent chain of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Hydrocarbyl, in which at least one position is unsaturated, that is, one CC is an sp ² double bond, in which the alkenyl group can be independently and optionally substituted by one or more substituents described in the present invention, including groups with The positioning of "anti", "cis" or "E", "Z", where specific examples of alkenyl include, but are not limited to, vinyl (-CH= _CH2 ), allyl ( _-CH2CH = CH ₂ ) and so on.

The term "alkynyl" means a linear or branched monovalent hydrocarbon group of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, in which at least one The position is in an unsaturated state, that is, one CC is an sp triple bond, in which the alkynyl group can be independently and optionally substituted by one or more substituents described in the present invention. Specific examples of the alkynyl group include, but Not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), etc.

The term "heteroatom" means one or more O, S, N, P, and Si, including C, N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or in heterocycles A form in which the hydrogen on the nitrogen atom is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted NR) in the pyrrolidinyl group; or -CH ₂ - in the heterocycle is oxidized to form -C(=O)-.

The term "halogen" refers to F, Cl, Br or I.

The term "deuterium" refers to heavy hydrogen, D.

The term "unsaturated" as used herein means a moiety containing one or more degrees of unsaturation.

The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through an oxygen atom. In some embodiments, the alkoxy group is a C _1-4 alkoxy group; such examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. And the alkoxy group may be independently unsubstituted or substituted by one or more substituents described herein.

The term "alkylthio" or "alkylthio" as used herein refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through a sulfur atom. In some embodiments, the alkylthio group is a C _1-4 alkylthio group; such examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like. And the alkylthio group may be independently unsubstituted or substituted by one or more substituents described herein.

The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to other parts of the compound molecule through an N atom. In some embodiments, the alkylamino group is C _1-4 alkylamino group; such examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, butylamino group, and the like. And the alkylamino groups may be independently unsubstituted or substituted by one or more substituents described in the present invention.

The term "cycloalkyl" or "cycloalkane" refers to a monovalent or multivalent monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3 to 12 carbon atoms, which is a saturated ring or contains one or more unsaturated bonds. rings, but never contain aromatic rings. In one embodiment, the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms carbon atom. Such examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and the like. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, and never include aromatic rings, where At least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3-10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3-8 ring atoms; in another In one embodiment, "heterocyclyl" or "heterocycle" contains 5-8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3-6 ring atoms; further In one embodiment, "heterocyclyl" or "heterocycle" contains 5-6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4-6 ring atoms; unless otherwise Note that the heterocyclyl group can be a carbon group or a nitrogen group, and the heteroatom has the meaning as described in the present invention. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxopentyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl , dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxeptanyl, thieptanyl, oxaza base, dinitrogen miscellaneous base, thiazepine base, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl and 1,2,3,6-tetrahydropyridyl. Examples of the -CH ₂ - group in the heterocyclyl group substituted by -C(=O)- include, but are not limited to: 2-oxopyrrolidyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto group, 3,5-dioxopiperidinyl group, pyrimidinedione group and 5,6-dihydropyridin-2(1H)-keto group. Examples of oxidized sulfur atoms in heterocyclyl groups include, but are not limited to, sulfolane groups and 1,1-dioxothiomorpholinyl groups. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, in which at least one ring is aromatic Each ring contains a ring of 3-7 atoms and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl groups may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" means monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, at least one of which is an aromatic ring, and At least one ring system contains one or more heteroatoms, each of which contains a ring of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or "heteroaromatic compound." The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group consisting of 5 to 10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, wherein the nitrogen atom can be further oxidized.

Examples of heteroaryl groups include, but are not limited to: furyl, imidazolyl (such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (such as 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl, pyrimidinyl (such as 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (such as 5-tetrazolyl), Triazolyl, thienyl (such as 2-thienyl, 3-thienyl), pyrazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5- Thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indole Base (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinoline base, 1,3-benzodioxenyl, indolinyl, isoquinolyl (such as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo[1, 2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2 ,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1, 5-a]pyridyl, etc.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted by one or more halogen atoms. Examples of this include, but are not limited to, trifluoromethyl, trifluoromethoxy wait.

The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

The term "aminoalkyl" means an alkyl group substituted with one or more amino groups, examples of which include, but are not limited to, aminomethyl, aminoethyl, and the like.

As described in this invention, a ring system formed by a substituent bonded to a ring means that the substituent may be substituted at any substitutable position on the ring. For example, formula (a) represents that the substituent R may be mono- or poly-substituted at any possible substituted position on the pyridine ring.

As described in the present invention, a linking bond is attached to a ring to form a ring system (as shown in formula b), which means that the linking bond can be attached to the rest of the molecule at any attachable position on the ring system. Formula b represents that any possible attachment position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.

In addition, it should be noted that, unless otherwise clearly stated, the description method used throughout this article is "each...and...independently", "...and...are each independently" and "...and...are independently" are interchangeable and should be understood in a broad sense. They can refer to the specific options expressed between the same symbols in different groups. Do not affect each other, it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers): for example, R, S containing an asymmetric center Configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the invention or mixtures of enantiomers, diastereomers, geometric isomers or conformational isomers thereof are within the scope of the invention.

Unless otherwise indicated, the structural formulas and compounds described in the present invention include all isomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers), nitrogen oxides, Hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformational isomers, nitrogen oxides, hydrates, solvates, metabolites, Pharmaceutically acceptable salts and prodrugs of the compounds are also within the scope of the invention. Additionally, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

"Metabolite" refers to the product obtained through metabolism in the body of the specific compound described in the present invention or its pharmaceutically acceptable salt, analog or derivative, which exhibits the same behavior as formula (I) in vivo or in vitro , similar activity to compounds of formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII). The metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assays as described herein. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, or enzymatic cleavage, etc. Accordingly, the invention includes metabolites of compounds, including metabolites produced by contacting a compound of the invention with a mammal for a period of time sufficient to do so.

The definitions and conventions of stereochemistry used in this invention are generally referred to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist as different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to name the symbol of the plane polarized light rotation of the compound. (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

The term "tautomer" or "tautomeric form" refers to isomers of structures of different energies that can be converted into each other through a low energy barrier. For example, proton tautomers (i.e., proton-shifting tautomers) include tautomers by proton migration, such as keto-enol and imine-enamine isomerizations. Valence (valency) tautomers include recombination of bonding electrons.

"Pharmaceutically acceptable salts" used in the present invention refer to organic salts and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts formed from nontoxic acids include, but are not limited to: inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates. ; Organic acid salts, such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate; or by other methods recorded in books and literature, such as ion exchange method Get these salts. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, and bisulfate. Salt, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, tranbutene Diacid salt, glucoheptonate, glycerin Phosphate, gluconate, hemisulfate, enanthate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lactouronate, lactate, laurate, lauryl sulfate , malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamate, pectate, persulfate, 3-phenylpropanate Acid, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C _1-4 alkyl) ₄ salts. The present invention also contemplates the formation of quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that counter counter ion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -8} Sulfonates and aromatic sulfonates.

"Hydrate" in the present invention refers to an association in which solvent molecules are water.

"Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to: water, isopropyl alcohol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

The "ester" of the present invention refers to a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) containing a hydroxyl group that can be hydrolyzed in vivo. of ester. Such esters are, for example, pharmaceutically acceptable esters which hydrolyze in humans or animals to yield the parent alcohol. Groups of in vivo hydrolyzable esters of compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII) containing hydroxyl groups include, but do not Limited to: phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl, etc.

The "nitrogen oxide" of the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or a peracid such as peroxycarboxylic acid to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, the N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514), for example by reacting an amine compound with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as methylene chloride. )reaction.

The term "prodrug" used in the present invention represents a compound that is converted into formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula ( Compounds shown in VII). Such conversion is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonate esters. , carbamates and amino acid esters. For example, if a compound of the present invention contains a hydroxyl group, it can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphate esters, which are obtained by phosphorylation of the hydroxyl group of the parent. For a complete discussion of prodrugs, please refer to the following literature: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the ACSSymposium Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJHecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008 ,51, 2328-2345.

As used herein, the terms "a", "an", "the" and "the" are used in the context of the present invention (especially in the context of the claims) unless otherwise indicated herein or the context clearly contradicts the meaning. Similar terms may be construed to include both the singular and the plural.

The term "GLP-1 receptor agonist" as used herein refers to a substance that agonizes GLP-1 receptor activity.

General synthesis process

To illustrate the present invention, examples are set forth below. However, it should be understood that the present invention is not limited to these embodiments, but only provides methods for practicing the present invention.

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless further stated, wherein the substituent The definition is as described in the present invention. The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare other compounds of the invention, and that other methods for preparing compounds of the invention are considered to be within the scope of the invention. . For example, the synthesis of non-exemplary compounds according to the present invention can be successfully accomplished by one skilled in the art by modification methods, such as by appropriately protecting interfering groups, by utilizing other known reagents in addition to those described herein, or by incorporating The reaction conditions were modified with some routine modifications. In addition, the reactions disclosed in the present invention or the known reaction conditions are also recognized to be suitable for the preparation of other compounds of the present invention.

The examples described below all temperatures are in degrees Celsius unless otherwise indicated. The reagents were purchased from commodity suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagents Co., Ltd., Shanghai Merrill Chemical Technology Co., Ltd., and Shanghai McLean Biochemical Technology Co., Ltd., and were used without further purification. Unless otherwise indicated, general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Damao Chemical Reagent Factory, Yantai Jiangyou Silica Gel Development Co., Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile are obtained by drying with molecular sieves. Dichloromethane, ethyl acetate, petroleum ether, 1,2-dichloroethane and methanol were of analytical grade.

The following reactions are generally carried out under positive pressure of nitrogen or argon or with a drying tube over an anhydrous solvent (unless otherwise indicated). The reaction bottles are plugged with appropriate rubber stoppers, and the substrate is injected through a syringe. Glassware is dried.

The silica gel column was purchased from Tianjin Bona Agel Technology Co., Ltd. using Flash silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Marine Chemical Factory.

1H NMR spectra were recorded using a Bruker 500MHz nuclear magnetic resonance spectrometer. 1H NMR spectrum uses CDCl ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as the solvent (in ppm), and TMS (0ppm) or chloroform (7.26ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, single peak), d (doublet, double peak), t (triplet, triplet), q (quartet, quartet), m (multiplet, Multiplets), br (broadened, broad peaks), brs (broadened singlet, broad singlet), dd (doublet of doublets, double doublets), dt (doublet of triplets, double triplet). Coupling constant J, expressed in Hertz (Hz).

The measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50mm, 2.5 micron, 6min, flow rate 1mL/min. Mobile phase: 0% - Ratio of 95% (CH ₃ CN) in (0.1% formic acid in H ₂ O:CH ₃ CN = 90:10) using electrospray ionization (ESI) at 210 nm/254 nm, detected with DAD.

Compounds were purified using Cheetah Pro medium-pressure rapid purification and preparation chromatography of Tianjin Bona Edger Technology Co., Ltd., using UV detection at 210nm/254nm.

The following abbreviations are used throughout this disclosure:
PE petroleum ether EtOAc/EA ethyl acetate
mg milligram mmol millimole
mL milliliter g grams
M mol/L rpm rpm rpm μM Micromol/L h hour
DCM dichloromethane MeOH methanol
min minutes CDCl ₃ deuterated chloroform
DMSO-d _6deuterated dimethyl sulfoxide nM nanomol/L
HEPES 4-Hydroxyethylpiperazineethanesulfonic acid BSA Bovine serum albumin
IBMX Phosphodiesterase Inhibitor HBSS Hank's Balanced Salt Solution
nL nanoliter DMSO dimethyl sulfoxide
EDTA-K2 Dipotassium ethylenediaminetetraacetate Kolliphor-EL Ethoxylated castor oil
HP-β-CD Hydroxypropyl Beta Cyclodextrin

The following reaction schemes describe the steps for preparing compounds of the invention. Ring B' is a 5-6 membered heterocyclic group containing nitrogen atoms. Unless otherwise stated, each of X ₁ , X ₂ , X ₃ , Y 1 , Y ₂ , Y ₃ , Y ₄ , R ₄ , ^{R 5 ,} R ⁸ , ^R9 , ^R10 , ^R11 , ^R12 , ^R18 , ^Rb , n have the definitions as described in the present invention. Bn is the commonly used protecting group benzyl, Tf is the commonly used protecting group trifluoromethanesulfonyl, and Boc is the commonly used protecting group tert-butoxycarbonyl.

Reaction scheme 1

The compound represented by formula ( 7 ) can be prepared by reaction scheme 1: the compound represented by formula ( 1 ) and the compound represented by formula ( 2 ) are reacted to obtain the compound represented by formula ( 3 ). The compound represented by formula ( 3 ) reacts with polyphosphoric acid to obtain the compound represented by formula ( 4 ). The compound represented by formula ( 4 ) is brominated to obtain the compound represented by formula ( 5 ). The compound represented by formula ( 5 ) and the compound represented by formula ( 6 ) react to obtain the compound represented by formula ( 7 ).

Reaction scheme 2

The compound represented by formula ( 13 ) can be prepared by reaction scheme 2: the compound represented by formula ( 8 ) and the compound represented by formula ( 9 ) are reacted to obtain the compound represented by formula ( 10 ). The compound represented by formula ( 10 ) is subjected to reduction reaction to obtain the compound represented by formula ( 11 ). The compound represented by formula ( 11 ) and the compound represented by formula ( 12 ) are reacted to obtain the compound represented by formula ( 13 ).

Reaction scheme 3

The compound represented by formula ( 21 ) can be prepared by reaction scheme 3: the compound represented by formula ( 14 ) and the compound represented by formula ( 15 ) are reacted to obtain the compound represented by formula ( 16 ). The compound represented by formula ( 16 ) is hydrogenated and reduced to obtain the compound represented by formula ( 17 ). The compound represented by formula ( 17 ) and the compound represented by formula ( 7 ) are reacted to obtain the compound represented by formula ( 18 ). The compound represented by formula ( 18 ) can be removed from the N-Boc protecting group to obtain the compound represented by formula ( 19 ). The compound represented by formula ( 19 ) and the compound represented by formula ( 13 ) are reacted to obtain the compound represented by formula ( 20 ). The compound represented by formula ( 20 ) reacts under alkaline conditions to obtain the compound represented by formula ( 21 ).

Reaction scheme 4

The compound represented by formula ( 28 ) can be prepared by reaction scheme 4: the compound represented by formula ( 22 ) and the compound represented by formula ( 7 ) are reacted to obtain the compound represented by formula ( 23 ). The compound represented by formula ( 23 ) and the compound represented by formula ( 24 ) are reacted to obtain the compound represented by formula ( 25 ). The compound represented by formula ( 25 ) is removed from the N-Boc protecting group to obtain the compound represented by formula ( 26 ). The compound represented by formula ( 26 ) and the compound represented by formula ( 13 ) are reacted to obtain the compound represented by formula ( 27 ). The compound represented by formula ( 27 ) reacts under alkaline conditions to obtain the compound represented by formula ( 28 ).

Reaction scheme 5

The compound represented by formula ( 34 ) can be prepared by reaction scheme 5: the compound represented by formula ( 23 ) and the compound represented by formula ( 29 ) are reacted to obtain the compound represented by formula ( 30 ). The compound represented by formula ( 30 ) reacts under basic conditions to obtain the compound represented by formula ( 31 ). The compound represented by formula ( 31 ) and the compound represented by formula ( 11 ) are reacted to obtain the compound represented by formula ( 32 ). The compound represented by formula ( 32 ) forms an intramolecular ring to obtain the compound represented by formula ( 33 ). The compound represented by formula ( 33 ) reacts under basic conditions to obtain the compound represented by formula ( 34 ).

Reaction scheme 6

The compound represented by formula ( 16 ) can also be prepared by reaction scheme 6: the compound represented by formula ( 35 ) and the compound represented by formula ( 36 ) are reacted to obtain the compound represented by formula ( 37 ). The compound represented by formula ( 37 ) and the compound represented by formula ( 38 ) are reacted to obtain the compound represented by formula ( 39 ). The compound represented by formula ( 39 ) is subjected to a hydrogenation reduction reaction to obtain the compound represented by formula ( 16 ).

Reaction scheme 7

The compound represented by formula ( 10 ) can also be prepared through the reaction scheme 7: the compound represented by formula ( 40 ) is oxidized to obtain the compound represented by formula ( 41 ). The compound represented by formula ( 41 ) is esterified with methanol to obtain the compound represented by formula ( 42 ). The compound represented by formula ( 42 ) and the compound represented by formula ( 9 ) are reacted to obtain the compound represented by formula ( 10 ).

Reaction scheme 8

The compound represented by formula ( 13 ) can also be prepared by reaction scheme 8: the compound represented by formula ( 11 ) and the compound represented by formula ( 43 ) are reacted to obtain the compound represented by formula ( 44 ). The compound represented by formula ( 44 ) can undergo an intramolecular cyclization reaction to obtain the compound represented by formula ( 13 ).

Reaction scheme 9

The compound represented by formula ( 29 ) can be prepared by reaction scheme 9: the compound represented by formula ( 45 ) and the compound represented by formula ( 46 ) are reacted to obtain the compound represented by formula ( 47 ). The compound represented by formula ( 47 ) is subjected to boronation reaction to obtain the compound represented by formula ( 29 ).

Reaction scheme 10

The compound represented by formula ( 54 ) can be prepared by this reaction scheme 10: the compound represented by formula ( 48 ) and the compound represented by formula ( 15 ) are reacted to obtain the compound represented by formula ( 49 ). The compound represented by formula ( 49 ) and the compound represented by formula ( 50 ) are reacted to obtain the compound represented by formula ( 51 ). The compound represented by formula ( 51 ) is de-N-Boced to obtain the compound represented by formula ( 52 ). The compound represented by formula ( 52 ) and the compound represented by formula ( 13 ) are reacted to obtain the compound represented by formula ( 53 ). The compound represented by formula ( 53 ) reacts under basic conditions to obtain the compound represented by formula ( 54 ).

Reaction Scheme 11

The compound represented by formula ( 62 ) can be prepared by the reaction scheme 11: the compound represented by formula ( 37 ) and the compound represented by formula ( 55 ) are reacted to obtain the compound represented by formula ( 56 ). The compound represented by formula ( 56 ) is reduced to obtain the compound represented by formula ( 57 ). The compound represented by formula ( 57 ) and the compound represented by formula ( 50 ) are reacted to obtain the compound represented by formula ( 58 ). The compound represented by formula ( 58 ) reacts under basic conditions to obtain the compound represented by formula ( 59 ). The compound represented by formula ( 59 ) and the compound represented by formula ( 11 ) are reacted to obtain the compound represented by formula ( 60 ). The compound represented by formula ( 60 ) forms a ring within the molecule to obtain the compound represented by formula ( 61 ). The compound represented by formula ( 61 ) reacts under alkaline conditions to obtain the compound represented by formula ( 62 ).

Reaction Scheme 12

The compound represented by formula ( 69 ) can be prepared by reaction scheme 12: the compound represented by formula ( 35 ) is reacted with bromomethyl methyl ether to obtain the compound represented by formula ( 63 ). The compound represented by formula ( 63 ) and the compound represented by formula ( 64 ) are reacted to obtain the compound represented by formula ( 65 ). The compound represented by formula ( 65 ) is reduced to obtain the compound represented by formula ( 66 ). The compound represented by formula ( 66 ) is oxidized to obtain the compound represented by formula ( 67 ). The compound represented by formula ( 60 ) and the compound represented by formula ( 11 ) are reacted to obtain the compound represented by formula ( 68 ). The compound represented by formula ( 68 ) is deprotected by MOM to obtain the compound represented by formula ( 69 ).

Reaction Scheme 13

The compound represented by formula ( 73 ) can be prepared by reaction scheme 13: the compound represented by formula ( 70 ) and the compound represented by formula ( 71 ) are reacted to obtain the compound represented by formula ( 72 ). The compound represented by formula ( 72 ) is deprotected to obtain the compound represented by formula ( 73 ).

Reaction Scheme 14

The compound represented by formula ( 77 ) can be prepared by this reaction scheme 14: the compound represented by formula ( 63 ) and the compound represented by formula ( 74 ) are reacted to obtain the compound represented by formula ( 75 ). The compound represented by formula ( 75 ) and the compound represented by formula ( 13 ) are reacted to obtain the compound represented by formula ( 76 ). The compound represented by formula ( 76 ) is deprotected to obtain the compound represented by formula ( 77 ).

Reaction Scheme 15

The compound represented by formula ( 82 ) can be prepared by reaction scheme 15: the compound represented by formula ( 5 ) and acetate are reacted to obtain the compound represented by formula ( 78 ). The compound represented by formula ( 78 ) reacts under basic conditions to obtain the compound represented by formula ( 79 ). The compound represented by formula ( 79 ) reacts with the compound represented by formula ( 80 ) to obtain the compound represented by formula ( 81 ). The compound represented by formula ( 76 ) is fluorinated to obtain the compound represented by formula ( 77 ).

Reaction Scheme 16

The compound represented by formula ( 90 ) can be prepared by reaction scheme 16: the compound represented by formula ( 83 ) is reacted with trimethoxymethane to obtain the compound represented by formula ( 84 ). The compound represented by formula ( 84 ) and the compound represented by formula ( 13 ) are reacted to obtain a compound represented by formula ( 85 ). The compound represented by formula ( 85 ) reacts under the action of trifluoroacetic acid to obtain the compound represented by formula ( 86 ). Compounds represented by formula ( 86 ) and N-phenyl The compound represented by formula ( 87 ) is obtained by the reaction of bis(trifluoromethanesulfonyl)imide. The compound represented by formula ( 87 ) and pinacol diboronate are reacted to obtain the compound represented by formula ( 88 ). The compound represented by formula ( 88 ) and the compound represented by formula ( 82 ) are reacted to obtain the compound represented by formula ( 89 ). The compound represented by formula ( 89 ) reacts under alkaline conditions to obtain the compound represented by formula ( 90 ).

Detailed ways

The present invention will be described below with reference to specific embodiments. It should be noted that these embodiments are only illustrative and do not limit the present invention in any way.

Example 1 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl) Synthesis of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 1)

Step 1: Synthesis of 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene

Compound 5-chloro-2-methylphenol (15g, 105.2mmol), 2-bromo-1,1-diethoxyethane (25g, 126.9mmol) and potassium carbonate (29.1g, 210.4mmol) were added to In N,N-dimethylformamide (50 mL), react at 120°C for 11 hours under nitrogen protection. Cool to room temperature, add water (100mL), extract with ethyl acetate (35mL×3), combine the organic phases, wash once with saturated brine (30mL), dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent EtOAc: PE (v/v) = 1%) yielded 21.1 g of light brown liquid product with a yield of 77.5%.

¹ HNMR (500MHz, CDCl ₃ ) δ7.03 (d, J = 7.9 Hz, 1H), 6.84 ( dd, J = 7.9, 2.0 Hz, 1H), 6.81 ( d, J = 2.0 Hz, 1H), 4.84 ( t,J＝5.2Hz,1H),3.98(d,J＝5.2Hz,2H),3.81–3.74(m,2H),3.68–3.62(m,2H),2.18(s,3H),1.25(t ,J＝7.0Hz,6H).

Step 2: Synthesis of 4-chloro-7-methylbenzofuran

Compound 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene (21g, 81.2mmol) and polyphosphoric acid (16.6g, 202.9mmol) were added to 1,2- In dichloroethane (50 mL), react overnight at 85°C under nitrogen protection. Cool to room temperature, remove the solvent under reduced pressure, add water (80 mL), extract with ethyl acetate (50 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (elution (PE = 100%), 9.2 g of colorless liquid product was obtained, with a yield of 68.0%.

1HNMR (500MHz, CDCl ₃ ) δ7.63(d,J＝2.3Hz,1H),7.12(d,J＝7.9Hz,1H),7.00(d,J＝7.9Hz,1H),6.84(d,J =2.3Hz,1H),2.48(s,3H).

Step 3: Synthesis of 7-(bromomethyl)-4-chlorobenzofuran

The compound 4-chloro-7-methylbenzofuran (4.1g, 24.61mmol), azobisisobutyronitrile (810mg, 4.92mmol) and N-bromosuccinimide (5.26g, 29.53mmol) Add to 1,2-dichloroethane (30 mL) and react overnight at 75°C under nitrogen protection. Cool to room temperature, add water (50mL), extract with dichloromethane (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent PE=100% ) to obtain 4.3g of colorless liquid product with a yield of 71.2%.

¹ HNMR (500MHz, CDCl ₃ ) δ7.71(s,1H),7.24–7.20(m,2H),6.89(s,1H),4.75(s,2H).

Step 4: Synthesis of 7-(bromomethyl)-4-chloro-2-fluorobenzofuran

Compound 7-(bromomethyl)-4-chlorobenzofuran (3.4g, 13.85mmol) and N-fluorobishenylsulfonamide (5.24g, 16.62mmol) were added to anhydrous tetrahydrofuran (100mL), nitrogen Cool at -50°C under protection, and add lithium diisopropylamide (2.0 mol/L tetrahydrofuran solution) (9mL, 18mmol), reacted at this temperature for 3h. Add water (300mL), extract with ethyl acetate (50mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent PE=100%) to obtain a white solid Product 523 mg, yield 14.3%.

¹ HNMR (500MHz, CDCl ₃ ) δ7.24–7.20 (m, 2H), 6.01 (d, J = 6.6Hz, 1H), 4.65 (s, 2H).

Step 5: Synthesis of (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

Add the compound 3-fluoro-4-nitrobenzoic acid methyl ester (500mg, 2.51mmol) and anhydrous potassium carbonate (521mg, 3.77mmol) to anhydrous tetrahydrofuran (6mL), and then add (S)-oxaheterocycle Butane-2-methylamine (241 mg, 2.76 mmol), react at room temperature for 15 hours. Add water (25 mL) and ethyl acetate (10 mL) and stir to separate the organic phase. Extract the aqueous phase with ethyl acetate (5 mL × 2). Combine the organic phases, dry over anhydrous sodium sulfate for 20 min, concentrate under reduced pressure, and use a silica gel column. Chromatography purification (eluent EtOAc:PE (v/v)=1:4) obtained 522 mg of reddish-brown solid, with a yield of 78.1%.

LC-MS(ESI):[M+H] ⁺ =267.1

¹ HNMR (500MHz, DMSO-d ₆ ) δ8.32(t,J＝5.8Hz,1H),8.17(d,J＝8.9Hz,1H),7.67(d,J＝1.7Hz,1H),7.16( dd,J＝8.9,1.8Hz,1H),5.03–4.96(m,1H),4.58–4.54(m,1H),4.46–4.42(m,1H),3.88(s,3H),3.71–3.61( m,2H),2.71–2.64(m,1H),2.56–2.50(m,1H).

Step 6: Synthesis of (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

Dissolve (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (3.6g, 13.52mmol) in methanol (30mL) and tetrahydrofuran (15mL) , add 10% palladium on carbon (moisture content 60%, 1.43g), replace with hydrogen three times, and react with hydrogen overnight at room temperature and pressure. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 3.18 g of light yellow liquid product with a yield of 99.5%.

LC-MS(ESI): [M+H] ⁺ =237.1;

¹ HNMR (500MHz, DMSO-d ₆ ) δ7.17 (dd, J = 8.1, 1.9 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 5.44(s,2H),4.95–4.90(m,1H),4.67(t,J＝5.7Hz,1H),4.56–4.52(m,1H),4.50–4.46(m,1H),3.73(s, 3H),3.37–3.25(m,2H),2.70–2.63(m,1H),2.48–2.43(m,1H).

Step 7: Synthesis of (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate methyl ester (1.0g, 4.23mmol), chloroethyl trimethylorthoacetate (790mg , 5.08mmol) and p-toluenesulfonic acid monohydrate (40mg, 0.21mmol) were dissolved in anhydrous tetrahydrofuran (8mL), stirred at 45°C for 5h, cooled, concentrated under reduced pressure to remove the solvent, and added dichloromethane (6mL) to dissolve , purified by silica gel column chromatography (eluent EtOAc:PE (v/v) = 1:2) to obtain 1.1g of white solid product, with a yield of 88.2%.

LC-MS(ESI): [M+H] ⁺ =295.2;

¹ HNMR(500MHz, DMSO-d ₆ )δ8.35(s,1H),7.87(dd,J＝8.5,1.6Hz,1H),7.74(d,J＝8.5Hz,1H),5.20–5.08(m ,2H),5.09–5.04(m,1H),4.78–4.74(m,1H),4.66–4.63(m,1H),4.50–4.45(m,1H),4.35–4.30(m,1H),3.89 (s,3H),2.73–2.66(m,1H),2.41–2.34(m,1H).

Step 8: Synthesis of tert-butyl 4-(2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

The compound 2-hydroxyphenylboronic acid (1.25g, 9.05mmol), 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.0g, 9.05mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (370mg, 0.45mmol) and potassium carbonate (8.85g, 27.16mmol ) was added to 1,4-dioxane (40mL), react at 90°C overnight under nitrogen protection, cool to room temperature, add water (80mL), extract with ethyl acetate (20mL×3), combine the organic phases, and use Dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc: PE (v/v) = 16%) to obtain 1.5 g of a white solid product with a yield of 60.2%.

LC-MS(ESI): [M-55] ⁺ =220.2;

¹ HNMR (500MHz, CDCl ₃ ) δ7.15 (td, J＝7.7, 1.7Hz, 1H), 7.08 (dd, J＝7.8, 1.7Hz, 1H), 6.91–6.87 (m, 2H), 5.85 (s ,1H),5.46(s,1H),4.10–4.05(m,2H),3.65(t,J＝5.7Hz,2H),2.47–2.41(m,2H),1.50(s,9H).

Step 9: Synthesis of tert-butyl 4-(2-hydroxyphenyl)piperidine-1-carboxylate

Compound 4-(2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.5g, 5.45mmol) was dissolved in methanol (30mL). Add 10% palladium on carbon (500 mg, water content 40-60%), pass in hydrogen to react overnight at room temperature and pressure, filter out the catalyst, and concentrate the filtrate under reduced pressure to obtain 1.4 g of a white solid product with a yield of 92.7%.

LC-MS(ESI): [M+H] ⁺ =222.1;

¹ HNMR (500MHz, CDCl ₃ ) δ7.13 (dd, J＝7.6, 1.7Hz, 1H), 7.07 (td, J＝7.7, 1.7Hz, 1H), 6.94–6.87 (m, 1H), 6.77–6.71 (m,1H),4.96(s,1H),4.31–4.18(m,2H),3.06–2.99(m,1H),2.87–2.78(m,2H),1.85–1.79(m,2H),1.67 –1.60(m,2H),1.49(s,9H).

Step 10: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine-1-carboxylate

Compounds 7-(bromomethyl)-4-chlorobenzofuran (290 mg, 1.10 mmol) and 4-(2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (305 mg, 1.10 mmol) were added to into tetrahydrofuran (8 mL), cool it in an ice bath, add potassium tert-butoxide (185 mg, 1.65 mmol), transfer to room temperature and react for 1.5 h. Add water (30 mL), extract with ethyl acetate (15 mL %) to obtain 368 mg of brown oily product with a yield of 72.7%.

LC-MS(ESI): [M-55] ⁺ =404.2;

¹ HNMR (500MHz, CDCl ₃ ) δ7.29–7.23(m,2H),7.21–7.15(m,2H),6.99–6.94(m,2H),6.03(d,J＝6.5Hz,1H),5.29 (s,2H),4.31–4.12(m,2H),3.18–3.10(m,1H),2.83–2.70(m,2H),1.83–1.76(m,2H),1.64–1.56(m,2H) ,1.47(s,9H).

Step 11: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester (660 mg, 1.43 mmol) was dissolved in To dichloromethane (8 mL), add trifluoroacetic acid (3.3 mL) and react at room temperature for 30 min. Remove the solvent under reduced pressure, add saturated sodium bicarbonate to adjust pH = 8, extract with ethyl acetate (15 mL × 3), and combine the organic phases. Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain 509 mg of white solid product with a yield of 98.6%.

LC-MS(ESI): [M+H] ⁺ =360.2;

¹ HNMR (500MHz, CDCl ₃ ) δ7.29–7.20(m,4H),7.04–6.96(m,2H),6.04(d,J＝6.7Hz,1H),5.29(s,2H),3.49(d ,J＝12.6Hz,2H),3.31–3.22(m,2H),3.04–2.92(m,2H),2.07–1.97(m,4H).

Step 12: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl) Synthesis of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.34 mmol ), 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine (134mg, 0.37mmol), N,N-diisopropylethylamine (219 mg, 1.69 mmol) was added to acetonitrile (6 mL), and the reaction was carried out at 60°C overnight. Cool to room temperature, remove the solvent under reduced pressure, add water (20 mL), extract with ethyl acetate (15 mL × 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent EtOAc:PE (v/v)=50%) 165 mg of white solid product was obtained, with a yield of 78.7%.

LC-MS(ESI): [M+H] ⁺ =618.5;

¹ HNMR (500MHz, CDCl ₃ ) δ8.17(d,J＝1.6Hz,1H),7.96(dd,J＝8.5,1.6Hz,1H),7.74(d,J＝8.5Hz,1H),7.28( s,2H),7.22–7.14(m,2H),6.97(t,J＝7.1Hz,2H),6.03(d,J＝6.6Hz,1H),5.28(s,2H),5.24–5.18(m ,1H),4.78–4.59(m,3H),4.43–4.37(m,1H),3.95(s,5H),3.07–2.91(m,3H),2.77–2.70(m,1H),2.51–2.41 (m,1H),2.32–2.20(m,2H),1.86–1.79(m,2H),1.76–1.65(m,2H).

Step 13: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl) Synthesis of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (165 mg, 0.27 mmol) and lithium hydroxide monohydrate (56 mg, 1.33 mmol) Add to 1,4-dioxane (4 mL) and water (2 mL), and react at 40°C for 1 hour. Cool in an ice bath, add water (15mL), adjust pH=6 with acetic acid, and Extract with ethyl acetate (15 mL 69 mg, yield 40.1%.

LC-MS(ESI): [M+H] ⁺ =604.5;

¹ HNMR (500MHz, DMSO-d ₆ ) δ12.74(br.s,1H),8.26(s,1H),7.80(d,J＝8.4Hz,1H),7.64(d,J＝8.4Hz,1H ),7.47–7.40(m,2H),7.22–7.10(m,3H),6.93(t,J＝7.4Hz,1H),6.52(d,J＝4.2Hz,1H),5.35(s,2H) ,5.12–5.05(m,1H),4.81–4.74(m,1H),4.67–4.60(m,1H),4.51–4.46(m,1H),4.39–4.33(m,1H),3.91(d, J＝13.6Hz,1H),3.76(d,J＝13.6Hz,1H),3.01–2.81(m,3H),2.74–2.65(m,1H),2.45–2.36(m,1H),2.20–2.05 (m,2H),1.70–1.54(m,4H).

Example 2 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridine-1 Synthesis of (2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 2)

Step 1: Synthesis of 7-((2-bromophenoxy)methyl)-4-chloro-2-fluorobenzofuran

Compounds 2-bromophenol (207mg, 1.20mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (300mg, 1.14mmol) were added to N,N-dimethylformamide (8mL ), then add potassium carbonate (472 mg, 3.42 mmol). React at 60°C for 1 hour. Water (50 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. Wash with saturated brine (5mL 341 mg, yield 78.0%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.57 (dd, J＝7.9, 1.7Hz, 1H), 7.43 (d, J＝8.2Hz, 1H), 7.28 (d, J＝8.5Hz, 1H), 7.25 –7.23(m,1H),7.02–6.97(m,1H),6.87(td,J＝7.7,1.4Hz,1H),6.02(d,J＝6.6Hz,1H),5.36(s,2H).

Step 2: tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate Synthesis of esters

Compound 7-((2-bromophenoxy)methyl)-4-chloro-2-fluorobenzofuran (280 mg, 0.79 mmol) and N-Boc-1,2,5,6-tetrahydropyridine- 4-Boronic acid pinacol ester (244 mg, 0.79 mmol) was added to a mixed solution of 1,4-dioxane (6 mL) and water (1.5 mL), and then [1,1'-bis(diphenyl Phosphine) ferrocene] palladium dichloride (33 mg, 0.04 mmol) and potassium carbonate (220 mg, 1.59 mmol). Heat to 90°C for 2 hours under nitrogen protection. Cool to room temperature, dilute with water (30 mL), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate, and separate and purify by silica gel column chromatography (eluent EA: PE (v/v) = 5%) to obtain 355 mg of colorless liquid with a yield of 98.5%.

LC-MS(ESI): [M-55] ⁺ =402.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.25 (s, 2H), 7.23 (s, 1H), 7.16 (dd, J = 7.4, 1.8Hz, 1H), 6.96 (t, J = 7.8Hz, 2H) ,6.02(d,J＝6.6Hz,1H),5.73(s,1H),5.27(s,2H),4.01(s,2H),3.51(d,J＝5.9Hz,2H),2.48(s, 2H),1.48(s,9H).

Step 3: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-1,2,3,6-tetrahydropyridine

The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (341 mg, 0.74 mmol) was added to dichloromethane (5 mL), followed by trifluoroacetic acid (2.55 g, 22.34 mmol) in an ice bath. Return to room temperature and react for 30 minutes. Add saturated sodium bicarbonate solution to adjust pH=8, and extract with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 302 mg of tan solid. The crude product was used directly in the next step.

LC-MS (ESI): [M+H] ⁺ =358.1.

Step 4: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridine-1 (2H)-yl)methyl)-1-(oxetane Synthesis of alk-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-1,2,3,6-tetrahydropyridine (150 mg, 0.34 mmol), (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.34 mmol), N,N-diisopropylethylamine (220 mg, 1.70 mmol) was added to acetonitrile (5 mL), and the reaction was carried out at 60°C overnight. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EA:PE (v /v)=50%), 171 mg of yellow solid product was obtained, with a yield of 81.8%.

LC-MS(ESI): [M+H] ⁺ =616.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.16 (s, 1H), 8.00–7.94 (m, 1H), 7.75 (d, J = 8.5Hz, 1H), 7.28–7.15 (m, 4H), 6.96 ( d,J＝7.9Hz,2H),6.01(d,J＝6.6Hz,1H),5.75(s,1H),5.27(s,2H),5.21–5.15(m,1H),4.74–4.53(m ,3H),4.40–4.32(m,1H),3.95(s,3H),3.19(s,2H),2.73(t,J＝5.7Hz,2H),2.70–2.62(m,1H),2.53( br.s,2H),2.43–2.37(m,1H),2.29–2.18(m,1H),2.06–1.99(m,1H).

Step 5: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridine-1 Synthesis of (2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridine-1( 2H)-(yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (170 mg, 0.28 mmol) and lithium hydroxide Monohydrate (58 mg, 1.38 mmol) was added to 1,4-dioxane (4 mL) and water (2 mL), and the reaction was carried out at 40°C for 1.5 h. Cool to room temperature, add water to dilute (15mL), adjust the system pH to 6 with acetic acid (4M), extract three times with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 2%) yielded 89 mg of light yellow solid product with a yield of 53.6%.

LC-MS(ESI): [M+H] ⁺ =602.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.78 (br.s, 1H), 8.25 (s, 1H), 7.81 (d, J = 8.5Hz, 1H), 7.65 (d, J = 8.5Hz, 1H),7.41(s,2H),7.24(t,J＝8.0Hz,1H),7.17–7.10(m,2H),6.94(t,J＝7.5Hz,1H),6.49(d,J＝6.3 Hz,1H),5.69(s,1H),5.32(s,2H),5.12–4.95(m,1H),4.79–4.69m,1H),4.66–4.55(m,1H),4.46–4.38(m ,1H),4.35–4.28(m,1H),4.00(d,J＝13.9Hz,1H),3.86(d,J＝13.6Hz,1H),3.14–3.02(m,2H),2.74–2.55( m,3H)2.44–2.37(m,2H),2.35–2.27(m,1H).

Example 3 2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-bis Benzene]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 3) Synthesis

Step 1: Synthesis of ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate

Compounds 4-oxocyclohexane ethyl acetate (3.0g, 16.28mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (6.98g, 19.54mmol) were added to anhydrous tetrahydrofuran (30mL) , cooled at -40°C under nitrogen protection, added lithium bis(trimethylsilyl)amide (1 mol/L THF solution) (21.2 mL, 21.2 mmol), and reacted at this temperature for 2 hours. Add water (50mL) to quench the reaction, extract with ethyl acetate (30mL×2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v /v)=2%) to obtain 4.1 g of colorless liquid product with a yield of 79.6%.

¹ HNMR (500MHz, CDCl ₃ ) δ5.72 (s, 1H), 4.15 (q, J = 7.1Hz, 2H), 2.49–2.39 (m, 1H), 2.38–2.31 (m, 2H), 2.30 (d ,J＝7.1Hz,2H),2.18–2.09(m,1H),1.97–1.89(m,2H),1.57–1.48(m,1H),1.26(t,J＝7.1Hz,3H).

Step 2: 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl) Synthesis of ethyl acetate

Compound 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)ethyl acetate (3.9g, 12.33mmol), pinacol diborate ( 3.29g, 12.95mmol), tetrakistriphenylphosphine palladium (710mg, 0.62mmol) and potassium acetate (2.42g, 24.66mmol) were added to 1,4-dioxane (30mL) at 90°C under nitrogen protection. React for 1 hour, cool to room temperature, add water (100 mL) to quench the reaction, extract with ethyl acetate (50 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (wash Remove the agent EtOAc: PE (v/v) = 5%) to obtain 2.0 g of colorless liquid product, with a yield of 55.1%.

¹ HNMR(500MHz, CDCl ₃ )δ6.50(s,1H),4.15–4.10(m,2H),2.30–2.19(m,4H),2.15–2.03(m,2H),1.84–1.73(m, 2H),1.40–1.28(m,1H),1.25(s,12H),1.28–1.23(m,3H).

Step 3: Synthesis of 7-((2-bromophenoxy)methyl)-4-chloro-2-fluorobenzofuran

Compound 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (320 mg, 1.20 mmol) and 2-bromophenol (208 mg, 1.20 mmol) were added to N,N-dimethylformamide (8 mL ), then add potassium carbonate (450 mg, 3.26 mmol). React at 60°C for 1 hour. Water (40 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. Wash with saturated brine (15mL 402 mg, yield 93.1%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.57 (dd, J＝7.9, 1.7Hz, 1H), 7.43 (d, J＝8.2Hz, 1H), 7.28 (d, J＝8.5Hz, 1H), 7.24 (d,J＝1.7Hz,1H),7.06–6.96(m,1H),6.87(td,J＝7.7,1.4Hz,1H),6.02(d,J＝6.6Hz,1H),5.36(s, 2H).

Step 4: 2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl Synthesis of ]-4-yl)ethyl acetate

Compound 7-((2-bromophenoxy)methyl)-4-chloro-2-fluorobenzofuran (402 mg, 1.13 mmol) and 2-(4-(4,4,5,5-tetramethyl Ethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (345 mg, 1.17 mmol) was added to 1,4-dioxane (12mL) and water (3mL), then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (47mg, 0.06mmol) and potassium carbonate (315mg, 2.28mmol) ). Heat to 90°C for 2 hours under nitrogen protection. Cool to room temperature, dilute with water (50 ml), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate, and separate and purify by silica gel column chromatography (eluent EA: PE (v/v) = 5%) to obtain 366 mg of yellow liquid with a yield of 73.1%.

LC-MS (ESI): [M-55] ⁺ =443.1.

Step 5: 2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl Synthesis of ]-4-yl)acetic acid

Compound 2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl] -4-yl)ethyl acetate (366 mg, 0.83 mmol) was dissolved in 1,4-dioxane (8 mL) and water (4 mL), and lithium hydroxide monohydrate (105 mg, 2.50 mmol) was added, 40°C React for 2 hours, cool to room temperature, dilute with water (8mL), adjust pH=5 with dilute hydrochloric acid, extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain off-white color Solid 295 mg, yield 86.1%.

LC-MS(ESI):[M+H] ⁺ =415.1;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.01 (s, 1H), 7.45–7.37 (m, 2H), 7.22 (td, J = 7.8, 1.8Hz, 1H), 7.12 (d, J = 8.2 Hz,1H),7.08(dd,J＝7.4,1.8Hz,1H),6.92(t,J＝7.4Hz,1H),6.51(d,J＝6.4Hz,1H),5.59(dd,J＝4.8 ,2.7Hz,1H),5.31(s,2H),2.31(t,J＝5.4Hz,2H),2.19(d,J＝7.2Hz,2H),1.98–1.90(m,1H),1.83–1.69 (m,2H),1.32–1.22(m,2H).

Step 6: 4-(2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methyl)-2,3,4,5-tetrahydro-[1,1'- Synthesis of biphenyl]-4-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoic acid methyl ester

Compound 2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl] -4-yl)acetic acid (145 mg, 0.35 mmol) and (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (75 mg, 0.32 mmol) were added To dichloromethane (6 mL) and N,N-dimethylformamide (3 mL), add N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1 -urea hexafluorophosphate (182 mg, 0.48 mmol) and N, N-diisopropylethylamine (103 mg, 0.80 mmol) were reacted at 45°C overnight. The solvent was removed under reduced pressure, water (60 mL) was added, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v/v) = 20%) to obtain 137 mg of orange-pink solid, with a yield of 68.1%.

LC-MS(ESI): [M+H] ⁺ =633.5;

¹ H NMR (500MHz, DMSO-d ₆ ) δ9.40 (s, 1H), 7.43 (d, J = 8.1Hz, 1H), 7.41 (s, 2H), 7.30–7.19 (m, 3H), 7.15– 7.07(m,2H),6.93(t,J＝7.4Hz,1H),6.50(d,J＝6.4Hz,1H),5.63(s,1H),5.32(s,2H),5.26(s,1H ),4.97–4.88(m,1H),4.54–4.48(m,1H),4.45–4.40(m,1H),3.82(s,3H),3.41–3.34(m,2H),2.68–2.58(m ,1H),2.48–2.44(m,1H),2.40–2.30(m,4H),2.29–2.23(m,1H),2.11–2.02(m,1H),1.93–1.74(m,2H).

Step 7: 2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-hydroxy Synthesis of benzo[d]imidazole-6-carboxylic acid methyl ester

The compound 4-(2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methyl)-2,3,4,5-tetrahydro-[1,1'- Methyl benzene]-4-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate (130 mg, 0.21 mmol) was added to glacial acetic acid ( 5mL), react at 80°C for 3 hours. Remove the solvent under reduced pressure, add water (10 mL), adjust the system pH to 8 with sodium bicarbonate solution (2M), dichloromethane (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and silica gel Purification by column chromatography (eluent EA: PE (v/v) = 30%) gave 115 mg of colorless liquid with a yield of 91.1%.

LC-MS (ESI): [M+H] ⁺ =615.4.

Step 8: 2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-hydroxy Synthesis of benzo[d]imidazole-6-carboxylic acid

Compound 2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl ]-4-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (115 mg, 0.19mmol) and lithium hydroxide monohydrate (40mg, 0.95mmol) were added to 1,4-dioxane (4mL) and water (2mL), and the reaction was carried out at 40°C for 1.5h. Cool to room temperature, add water to dilute (15 mL), adjust the system pH to 5 with acetic acid (4M), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) yielded 85 mg of white solid product with a yield of 73.9%.

LC-MS(ESI): [M+H] ⁺ =601.3;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.65 (br.s, 1H), 8.20 (s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.62 (d, J = 8.4Hz, 1H),7.41(s,2H),7.26–7.17(m,1H),7.11(dd,J＝12.4,7.7Hz,2H),6.96–6.88(m,1H),6.49(d,J＝6.3Hz ,1H),5.61(s,1H),5.32(s,2H),5.05–4.95(m,1H),4.69–4.55(m,1H),4.52–4.37(m,2H),4.33–4.24(m ,1H),3.01–2.86(m,2H),2.72–2.62(m,1H),2.40–2.22(m,5H),2.03–1.78(m,2H),1.48–1.36(m,1H).

Example 4 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 4)

Step 1: Synthesis of 2-(benzyloxy)-1-bromo-3-fluorobenzene

Compound 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (500 mg, 2.62 mmol) and benzyl bromide (450 mg, 2.62 mmol) were added to N,N-dimethylformamide (5 mL) , then add potassium carbonate (900 mg, 6.54 mmol). React at 60°C for 4 hours. Water (50 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. Wash with water (15 mL %), 730 mg of light yellow liquid product was obtained, with a yield of 99.2%.

LC-MS(ESI): [M+H] ⁺ =282.3;

¹ H NMR (500MHz, CDCl ₃ ) δ7.55–7.50(m,2H),7.41–7.29(m,4H),7.09–7.02(m,1H),6.95–6.87(m,1H),5.13(s ,2H).

Step 2: Synthesis of tert-butyl 4-(2-(benzyloxy)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Compound 2-(benzyloxy)-1-bromo-3-fluorobenzene (730mg, 2.60mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (840mg ,2.73mmol) was added to a mixed solution of 1,4-dioxane (20mL) and water (5mL), and then [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride was added (110 mg, 0.13 mmol) and potassium carbonate (720 mg, 5.19 mmol). Heat to 90°C for 2 hours under nitrogen protection. Cool to room temperature, dilute with water (20 ml), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and separation and purification by silica gel column chromatography (eluent EA: PE (v/v) = 10%) yielded 985 mg of light yellow liquid with a yield of 98.8%.

LC-MS(ESI): [M-55] ⁺ =328.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.37–7.28(m,5H),7.06–6.94(m,2H),6.92–6.87(m,1H),5.70(s,1H),4.99(s,2H ),3.98(s,2H),3.51(t,J＝5.5Hz,2H),2.43–2.39(m,2H),1.49(s,9H).

Step 3: Synthesis of tert-butyl 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate

Compound 4-(2-(benzyloxy)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (985 mg, 2.59 mmol) was dissolved in methanol (20 mL) , add palladium on carbon (10% Pd, containing 55% water) (250 mg,), replace it with hydrogen three times, and react at room temperature overnight in a hydrogen environment. Filter through diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain 717 mg of light yellow liquid with a yield of 93.6%.

LC-MS (ESI): [M-55] ⁺ =240.1.

Step 4: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

Compound 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (350 mg, 1.19 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (450 mg, 2.62 mmol) was added to N,N-dimethylformamide (8 mL), followed by potassium carbonate (400 mg, 2.89 mmol). React at 60°C for 2 hours. Water (50 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. Wash with saturated brine (5mL 527 mg, yield 96.8%.

LC-MS(ESI): [M-55] ⁺ =422.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.25 (s, 2H), 7.04–6.95 (m, 2H), 6.92–6.86 (m, 1H), 6.03 (d, J = 6.6Hz, 1H), 5.29 ( s,2H),4.23–4.08(m,2H),3.04–2.95(m,1H),2.71–2.51(m,2H),1.52–1.47(m,4H),1.46(s,9H).

Step 5: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester (528 mg, 1.10 mmol ) was added to dichloromethane (6 mL), then trifluoroacetic acid (2.77 g, 24.30 mmol) was added under ice bath. Warm up to room temperature and react for 30 minutes. Add saturated sodium bicarbonate solution to adjust pH=8, and extract with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 412 mg of brown liquid with a yield of 98.7%.

LC-MS (ESI): [M+H] ⁺ =378.2.

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (140 mg, 0.37 mmol), (S)-2- (Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.34 mmol), N,N-diiso Propylethylamine (220 mg, 1.70 mmol) was added to acetonitrile (5 mL), and the reaction was carried out at 60°C overnight. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EA:PE (v /v)=50%), 181 mg of light yellow oily product was obtained with a yield of 83.9%.

LC-MS (ESI): [M+H] ⁺ =636.3.

Step 7: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl )Methyl)-1-(oxetan-2-yl Synthesis of methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (181 mg, 0.28 mmol) and lithium hydroxide monohydrate (60 mg ,1.43mmol) was added to 1,4-dioxane (6mL) and water (3mL), and the reaction was carried out at 40°C for 1.5h. Cool to room temperature, add water to dilute (15 mL), adjust the system pH to 5 with acetic acid (4M), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) yielded 85 mg of yellow solid product with a yield of 73.9%.

LC-MS(ESI): [M+H] ⁺ =622.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.27 (s, 1H), 7.81 (s, 1H), 7.65 (s, 1H), 7.38 (d, J = 35.3Hz, 2H), 7.18–7.05 ( m,2H),7.00(s,1H),6.55(s,1H),5.27(s,2H),5.09–5.06(m,1H),4.80–4.73(m,1H),4.66–4.60(m, 1H),4.54–4.45(m,1H),4.41–4.30(m,1H),3.98–3.83(m,1H),3.80–3.69(m,1H),3.02–2.87(m,1H),2.84– 2.61(m,3H),2.47–2.31(m,1H),2.11–1.80(m,3H),1.62–1.31(m,3H).

Example 5 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 5)

Step 1: Synthesis of 6-chloro-5-nitro-2-carboxylic acid pyridine

Compound 2-chloro-6-methyl-3-nitropyridine (8.0g, 46.36mmol) was added to concentrated sulfuric acid (40mL), and potassium dichromate (20.46g, 69.54mmol) was slowly added in an ice bath at room temperature. The reaction was stirred overnight. Cool in an ice bath, slowly add ice water (500 mL), extract with ethyl acetate (150 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 8.26 g of light yellow solid, yield 88.0% .

LC-MS (ESI): [M+H] ⁺ =203.0.

Step 2: Synthesis of 6-chloro-5-nitro-2-carboxylic acid methyl pyridine

Compound 6-chloro-5-nitro-2-carboxylic acid pyridine (200 mg, 0.99 mmol) was dissolved in methanol (15 mL), concentrated sulfuric acid (0.5 mL, 0.99 mmol) was added, and the mixture was heated to 68°C to react overnight. The solvent was concentrated, diluted with water (30 mL), extracted three times with ethyl acetate (15 ml × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purified by silica gel column chromatography (eluent PE: EtOAc (v/v) = 2:1) to obtain 185 mg of white solid, with a yield of 86.5%.

LC-MS(ESI): [M+H] ⁺ =217.1;

¹ H NMR (500MHz, CDCl ₃ ) δ8.31 (dd, J＝8.3, 0.8Hz, 1H), 8.22 (dd, J＝8.2, 0.8Hz, 1H), 4.04 (d, J＝0.9Hz, 3H) .

Step 3: Synthesis of (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate methyl ester

Compounds 6-chloro-5-nitro-2-carboxylic acid methyl ester pyridine (1.3g, 6.0mmol) and (S)-oxetane-2-methylamine (0.58g, 6.6mmol) were dissolved in tetrahydrofuran ( 20 mL), then add potassium carbonate (1.24 g, 9.00 mmol), and stir at room temperature overnight. Filter through diatomaceous earth and concentrate the filtrate. Purified by silica gel column chromatography (eluent PE: EtOAc (v/v) = 2:1) to obtain 1.09 g of yellow solid, with a yield of 68.0%.

LC-MS(ESI): [M+H] ⁺ =268.2;

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.58 (dd, J＝8.4, 1.0Hz, 1H), 8.51 (t, J＝5.8Hz, 1H), 7.31 (dd, J＝8.4, 1.0Hz, 1H),5.01–4.93(m,1H),4.56–4.52(m,1H),4.48–4.45(m,1H),3.96–3.87(m,4H),3.82(dt,J＝13.8,5.2Hz, 1H),2.68–2.58(m,1H),2.53–2.49(m,1H).

Step 4 Synthesis of: (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate methyl ester

Compound (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylic acid methyl ester (1.09g, 4.08mmol) was dissolved in tetrahydrofuran (10mL) and methanol (10mL ) into the mixed solution, then add palladium on carbon (10% Pd, containing 55% water) (185 mg, 1.74 mmol), and protect with hydrogen. The reaction was stirred at room temperature for 8 hours. Filter through diatomaceous earth and concentrate the filtrate. Separation and purification by silica gel column chromatography (eluent DCM:MeOH (v/v) = 20:1) yielded 885 mg of oily yellow viscous substance with a yield of 91.5%.

LC-MS(ESI): [M+H] ⁺ =238.1;

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.23 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 5.95 (t, J = 5.6 Hz, 1H), 5.61 (s,2H),4.92–4.87(m,1H),4.54–4.50(m,1H),4.45(dt,J＝9.0,5.9Hz,1H),3.72(s,4H),3.62(dt,J ＝13.8,5.2Hz,1H),2.65–2.57(m,1H),2.44–2.39(m,1H).

Step 5: Synthesis of (S)-5-(2-chloroacetamido)-6-((oxetan-2-ylmethyl)amino)pyridinecarboxylic acid methyl ester

Compound (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate methyl ester (500 mg, 2.11 mmol) was dissolved in tetrahydrofuran (10 mL) solution. Add N,N-diisopropylethylamine (817mg, 6.32mmol), cool in an ice bath, add chloroacetyl chloride (285mg, 2.52mmol), react at room temperature for 3h, add water (50mL), and extract with ethyl acetate ( 20 ml

LC-MS(ESI): [M+H] ⁺ =314.2;

¹ H NMR (500MHz, CDCl ₃ ) δ8.30(br.s,1H),7.88(d,J＝7.9Hz,1H),7.53(d,J＝7.9Hz,1H),5.11–5.01(m, 2H),4.73–4.69(m,1H),4.0–4.53(m,1H),4.22(s,2H),3.93(s,3H),3.80–3.73(m,1H),2.72–2.64(m, 1H),2.59–2.49(m,1H).

Step 6: (S)-2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester Synthesis

Compound (S)-5-(2-chloroacetamido)-6-((oxetan-2-ylmethyl)amino)picolinate methyl ester (300 mg, 0.24 mmol) was dissolved in acetic acid (5 mL) medium, heated to 60°C, and reacted overnight. The solvent was removed under reduced pressure, saturated sodium bicarbonate was added to adjust the pH of the system to 9, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (elution (EtOAc = 100%), 101 mg of light yellow solid was obtained, with a yield of 35.7%.

LC-MS(ESI): [M+H] ⁺ =296.2;

¹ H NMR (500MHz, CDCl ₃ ) δ8.17–7.11(m,2H),5.26–5.19(m,1H),5.15–5.03(m,2H),4.85–4.71(m,2H),4.65–4.55 (m,1H),4.36–4.28(m,1H),4.01(s,3H),2.84–2.73(m,1H),2.49–2.40(m,1H).

Step 7: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (147 mg, 0.39 mmol), (S)-2- (Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (100 mg, 0.34 mmol), N, N-Diisopropylethylamine (220 mg, 1.70 mmol) was added to acetonitrile (10 mL), and the reaction was carried out at 60°C overnight. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EA:PE (v /v)=50%), 190 mg of yellow oily product was obtained with a yield of 88.2%.

LC-MS (ESI): [M+H] ⁺ =637.4.

Step 8: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl) Methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (190 mg, 0.30 mmol) and lithium hydroxide Hydrate (63 mg, 1.50 mmol) was added to 1,4-dioxane (6 mL) and water (3 mL), and the reaction was carried out at 40°C for 1.5 h. Cool to room temperature, add water to dilute (15 mL), adjust the system pH to 5 with acetic acid (4M), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) yielded 45 mg of light yellow solid product with a yield of 22.4%.

LC-MS(ESI): [M+H] ⁺ =623.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.15 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.34 (d,J＝8.1Hz,1H),7.17–7.05(m,2H),7.01(d,J＝7.8Hz,1H),6.53(d,J＝6.3Hz,1H),5.27(s,2H) ,5.18–5.23(m,1H),4.85–4.81(m,1H),4.73–4.67(m,1H),4.53–4.45(m,1H),4.40–4.32(m,1H),4.00–3.84( m,2H),2.96–2.81(m,2H),2.75–2.65(m,2H),2.50–2.43(m,1H),2.07–1.93(m,2H),1.58–1.46(m,2H), 1.37–1.29(m,2H).

Example 6 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl) Synthesis of -3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (compound 6)

Step 1: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl) Synthesis of -3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine (150 mg, 0.42mmol), (S)-2-(chloromethyl )-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (117mg, 0.40mmol), N,N-diiso Propylethylamine (256 mg, 1.98 mmol) was added to acetonitrile (10 mL), and the reaction was carried out at 60°C overnight. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EA:PE (v /v)=50%), 240 mg of yellow liquid product was obtained, with a yield of 98.0%.

LC-MS (ESI): [M+H] ⁺ =619.5.

Step 2: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl) Synthesis of -3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)- 3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester (240 mg, 0.39 mmol) and lithium hydroxide monohydrate (82 mg ,1.95mmol) was added to 1,4-dioxane (8mL) and water (4mL), and the reaction was carried out at 40°C for 1.5h. Cool to room temperature, add water to dilute (15 mL), adjust the system pH to 5 with acetic acid (4M), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) yielded 46 mg of white solid product with a yield of 16.7%.

LC-MS(ESI): [M+H] ⁺ =605.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.10(d,J＝8.2Hz,1H),7.99(d,J＝8.2Hz,1H),7.45–7.41(m,2H),7.21–7.14( m,2H),7.12(d,J＝8.2Hz,1H),6.93(t,J＝7.4Hz,1H),6.53(d,J＝6.4Hz,1H),5.35(s,2H),5.19– 5.15(m,1H),4.84–4.71(m,2H),4.52–4.45(m,1H),4.35–4.30(m,1H),3.94(d,J＝13.7Hz,1H),3.88(d, J＝13.6Hz,1H),2.98–2.87(m,3H),2.73–2.59(m,1H),2.50–2.43(m,1H),2.21–2.11(m,2H),1.72–1.55(m, 4H).

Example 7 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)methyl)-1-( Synthesis of oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 7)

Step 1: Synthesis of 1-(benzyloxy)-2-bromobenzene

Compound 2-bromophenol (3.0g, 17.34mmol) and benzyl bromide (3.0mg, 17.54mmol) were added to N,N-dimethylformamide (20mL), and then potassium carbonate (6.0g, 43.42mmol) was added ). React at 60°C for 3 hours. Water (100 mL) was added to quench the reaction, extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. Wash with water (30 mL %), 4.21g of colorless liquid product was obtained, with a yield of 92.3%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.55(d,J＝7.6Hz,1H),7.47(d,J＝7.6Hz,2H),7.38(t,J＝7.6Hz,2H),7.31(t ,J＝7.4Hz,1H),7.25–7.18(m,1H),6.93(d,J＝8.2Hz,1H),6.83(t,J＝7.6Hz,1H),5.15(s,2H).

Step 2: Synthesis of ethyl 2-(2'-(benzyloxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate

Compound 1-(benzyloxy)-2-bromobenzene (1.8g, 6.84mmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabora) Cyclopentan-2-yl)cyclohex-3-en-1-yl)ethyl acetate (2.0g, 6.80mmol) was added to the mixed solution of 1,4-dioxane (48mL) and water (12mL) , then add [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (0.3g, 0.37mmol) and potassium carbonate (1.9g, 13.75mmol). Heat to 90°C for 2 hours under nitrogen protection. Cool to room temperature, dilute with water (50 ml), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate, and separate and purify by silica gel column chromatography (eluent EA: PE (v/v) = 5%) to obtain 1.46 g of light yellow liquid with a yield of 61.1%.

LC-MS(ESI): [M+H] ⁺ =351.3;

¹ H NMR (500MHz, CDCl ₃ ) δ7.40 (d, J = 7.0Hz, 2H), 7.36 (t, J = 7.7Hz, 2H), 7.29 (t, J = 7.2Hz, 1H), 7.17 (td ,J＝7.7,1.8Hz,1H),7.14(dd,J＝7.4,1.8Hz,1H),6.94–6.88(m,2H),5.74–5.70(m,1H),5.06(s,2H), 4.15(q,J＝7.2Hz,2H),2.51–2.45(m,2H),2.36–2.30(m,3H),2.22–2.16(m,1H),1.96–1.81(m,2H),1.49– 1.40(m,1H),1.27(t,J=7.0Hz,3H).

Step 3: Synthesis of ethyl 2-(2'-hydroxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate

Compound 2-(2'-(benzyloxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate (1.45g, 4.14mmol) Dissolve in ethanol (20 mL), add palladium on carbon (10% Pd, containing 55% water) (0.4 g, 1.69 mmol), replace it with hydrogen three times, and react overnight at room temperature in a hydrogen environment. Filter through diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain 978 mg of gray-brown liquid with a yield of 90.1%.

LC-MS(ESI): [M-55] ⁺ =263.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.21–7.14(m,1H),7.08–7.02(m,1H),6.89(t,J＝7.4Hz,1H),6.74(d,J＝7.9Hz, 1H),5.09(br,1H),4.15(q,J＝7.1Hz,2H),2.91–2.78(m,1H),2.48(d,J＝7.6Hz,1H),2.24(d,J＝6.6 Hz,1H),1.93–1.85(m,2H),1.75–1.63(m,5H),1.56–1.46(m,1H),1.30–1.24(m,3H),1.23–1.14(m,1H).

Step 4: Synthesis of ethyl 2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetate

Compound 2-(2'-hydroxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate (200 mg, 0.76 mmol) and 7-(bromo Methyl)-4-chloro-2-fluorobenzofuran (200 mg, 0.76 mmol) was added to N,N-dimethylformamide (6 mL), followed by potassium carbonate (262 mg, 1.90 mmol). Reaction at 60℃ for 1.5h. Water (50 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. Wash with saturated brine (5mL Product 251 mg, yield 74.3%.

LC-MS(ESI): [M-55] ⁺ =389.3;

¹ H NMR (500MHz, CDCl ₃ ) δ7.34–7.24(m,2H),7.26–7.18(m,1H),7.20–7.12(m,1H),6.96(t,J＝7.5Hz,2H), 6.02(d,J＝6.6Hz,1H),5.28(s,2H),4.18–4.10(m,2H),3.04–2.93(m,1H),2.41(d,J＝7.7Hz,1H),2.22 (d,J＝6.6Hz,1H),1.92–1.83(m,2H),1.64–1.60(m,1H),1.54–1.43(m,1H),1.34–1.29(m,1H),1.29–1.23 (m,5H),1.20–1.09(m,1H),0.91–0.83(m,1H).

Step 5: Synthesis of 2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetic acid

Compound 2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetate (232 mg, 0.52 mmol) was added to 1, 4-Dioxane (5mL) and water (2.5mL), lithium hydroxide monohydrate (110mg, 2.62mmol), react at 40°C for 2h, cool to room temperature, add water (5mL) to dilute, adjust pH with dilute hydrochloric acid =5, extracted with ethyl acetate (15 mL×3), combined the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 215 mg of pale pink liquid with a yield of 98.9%.

Step 6: (S)-4-(2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetamido)-3 Synthesis of -((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

Compound 2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetic acid (215 mg, 0.52 mmol) and (S)-4 -Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (76 mg, 0.32 mmol) was added to dichloromethane (6 mL) and N,N-dimethylformamide ( 3mL), add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (184mg, 0.48mmol) and N,N-diiso Propylethylamine (104 mg, 0.80 mmol), react at 45°C overnight. The solvent was removed under reduced pressure, water (60 mL) was added, extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v/v) = 20%) to obtain 200 mg of tan liquid, with a yield of 98.4%.

LC-MS(ESI): [M+H] ⁺ =635.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.01 (s, 1H), 7.81–7.76 (m, 1H), 7.70 (d, J = 19.5Hz, 1H), 7.56 (d, J = 8.3Hz, 1H) ,7.52(s,1H),7.33–7.27(m,1H),7.23–7.14(m,1H),7.00–6.94(m,2H),6.04–6.00(m,1H),5.28(s,2H) ,5.08–5.00(m,1H),4.76–4.69(m,1H),4.62–4.55(m,1H),3.89(s,3H),3.44–3.37(m,1H),3.35–3.29(m, 1H),3.06–2.98(m,1H),2.77–2.66(m,1H),2.57–2.47(m,2H),2.46–2.40(m,1H),2.34–2.30(m,1H),2.08– 1.88(m,2H),1.57–1.46(m,1H),1.01–0.91(m,1H),0.91–0.82(m,4H).

Step 7: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)methyl)-1-( Synthesis of oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound (S)-4-(2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetamido)-3- ((Oxetan-2-ylmethyl)amino)benzoic acid methyl ester (230 mg, 0.36 mmol) was added to glacial acetic acid (9 mL), and the reaction was carried out at 80°C for 3 hours. Remove the solvent under reduced pressure, add water (20mL), adjust the system pH to 8 with sodium bicarbonate solution (2M), methylene chloride (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and silica gel Purification by column chromatography (eluent EA: PE (v/v) = 30%) gave 215 mg of colorless liquid with a yield of 96.2%.

LC-MS(ESI): [M+H] ⁺ =617.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.22(t,J＝2.2Hz,1H),7.82–7.78(m,1H),7.64(d,J＝8.4Hz,1H),7.43(d, J＝2.2Hz,2H),7.30(dd,J＝7.6,1.7Hz,1H),7.21–7.09(m,2H),6.99–6.90(m,1H),6.51(dd,J＝11.8,6.4Hz ,1H),5.35(d,J＝6.5Hz,2H),5.06–4.99(m,1H),4.68–4.60(m,1H),4.55–4.43(m,2H),4.32–4.26(m,1H) ),3.87(s,3H),3.07(dd,J＝9.8,7.5Hz,1H),2.97–2.82(m,1H),2.73–2.66(m,1H),2.41–2.33(m,1H), 2.03–2.00(m,1H),1.93–1.82(m,1H),1.72(d,J＝13.1Hz,4H),1.64–1.38(m,3H),1.28(d,J＝20.0Hz,1H) .

Step 8: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)methyl)-1-( Synthesis of oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)methyl)-1-(oxy Heterocyclobutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (210 mg, 0.34 mmol) and lithium hydroxide monohydrate (72 mg, 1.72 mmol) were added to 1, 4-Dioxane (4mL) and water (2mL) were reacted at 40°C for 1.5h. Cool to room temperature, dilute with water (15mL), and adjust with acetic acid (4M) The pH of the system was raised to 5, and extracted three times with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) yielded 85 mg of light yellow solid product with a yield of 40.3%.

LC-MS(ESI): [M+H] ⁺ =603.5;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.47 (br, 1H), 8.20 (s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.62 (d, J = 8.4Hz, 1H) ,7.43(s,2H),7.30(d,J＝7.6Hz,1H),7.22–7.09(m,2H),6.99–6.91(m,1H),6.54–6.48(m,1H),5.35(d ,J＝6.6Hz,2H),5.06–5.00(m,1H),4.67–4.59(m,1H),4.53–4.44(m,2H),4.34–4.28(m,1H),3.13–3.02(m ,1H),2.99–2.81(m,2H),2.75–2.66(m,1H),2.42–2.33(m,1H),2.08–1.96(m,1H),1.86(d,J＝12.8Hz,1H ),1.78–1.68(m,4H),1.66–1.39(m,3H).

Example 8 (S)-2-((4-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-( Synthesis of oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 8)

Step 1: Synthesis of tert-butyl 4-(2-((4-chlorobenzofuran-7-yl)methoxy)-phenyl)piperazine-1-carboxylate

4-(2-Hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (500mg, 1.80mmol), 7-(bromomethyl)-4-chlorobenzofuran (440mg, 1.79mmol), potassium carbonate (496 mg, 3.59 mmol) was added to N,N-dimethylformamide (10 mL) and reacted at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 789 mg of colorless oily product with a yield of 99.2%.

LC-MS(ESI): [M+H] ⁺ =443.3;

¹ H NMR (500MHz, CDCl ₃ ) δ7.67(d,J＝2.2Hz,1H),7.37(d,J＝8.0Hz,1H),7.28–7.21(m,1H),7.04–6.90(m, 5H),5.39(s,2H),3.56–3.47(m,4H),3.10–3.02(m,4H),1.48(s,9H).

Step 2: Synthesis of 1-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazine

tert-Butyl 4-(2-((4-chlorobenzofuran-7-yl)methoxy)-phenyl)piperazine-1-carboxylate (789 mg, 1.78 mmol) was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. The solvent was concentrated under reduced pressure and evaporated to dryness. Use saturated sodium bicarbonate aqueous solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown Solid product 599 mg, yield: 98.1%.

LC-MS (ESI): [M+H] ⁺ =343.2.

Step 3: (S)-2-((4-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-( Synthesis of oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

1-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazine (150 mg, 0.44mmol), (S)-2-(chloromethyl)-1-( Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (128mg, 0.43mmol), potassium carbonate (120mg, 0.87mmol), potassium iodide (36mg, 0.22mmol) ) was added to acetonitrile (10 mL), and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 55%) yielded 162 mg of colorless oily product with a yield of 61.6%.

LC-MS(ESI): [M+H] ⁺ =601.5;

¹ H NMR (500MHz, CDCl ₃ ) δ8.16 (s, 1H), 7.97 (dd, J＝8.5, 1.5Hz, 1H), 7.75 (d, J＝8.5Hz, 1H), 7.68–7.64 (m, 1H),7.37(d,J＝8.0Hz,1H),7.27–7.26(m,1H),7.06–6.84(m,5H),5.39(s,2H),5.26–5.18(m,1H),4.77 –4.57(m,3H),4.42–4.35(m,1H),4.02–3.96(m,2H),3.95(s,3H),3.23–3.02(m,4H),2.78–2.59(m,5H) ,2.49–2.40(m,1H).

Step 4: (S)-2-((4-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-( Synthesis of oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxa Cyclobutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (142 mg, 0.24 mmol), lithium hydroxide monohydrate (49 mg, 1.17 mmol) was added to water (2 mL ) and 1.4-dioxane (5 mL), react at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 20%) to obtain 70 mg of white solid product, with a yield of 49.5%.

LC-MS(ESI): [M+H] ⁺ =587.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.68 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.82 (d, J = 8.4Hz, 1H), 7.66 (d, J＝8.4Hz,1H),7.48(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.13–7.05(m,2H),6.98–6.85(m,3H), 5.37(s,2H),5.14–5.05(m,1H),4.82–4.73(m,1H),4.68–4.60(m,1H),4.52–4.45(m,1H),4.40–4.33(m,1H ),3.95(d,J＝13.5Hz,1H),3.79(d,J＝13.6Hz,1H),3.07–2.91(m,4H),2.74–2.65(m,1H),2.62–2.47(m, 4H),2.46–2.37(m,1H).

Example 9 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl Synthesis of )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 9)

Step 1: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-phenyl)piperazine-1-carboxylate

4-(2-Hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (300mg, 1.08mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (283mg, 1.07mmol) ), potassium carbonate (297 mg, 2.15 mmol) was added to 10 mL of N,N-dimethylformamide, and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 469 mg of colorless oily product with a yield of 94.4%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.34 (d, J = 8.2Hz, 1H), 7.30–7.25 (m, 1H), 7.03–6.91 (m, 4H), 6.02 (d, J = 6.6Hz, 1H),5.32(s,2H),3.58–3.47(m,4H),3.10–2.98(m,4H),1.48(s,9H).

Step 2: Synthesis of 1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazine

4-(2-((4-Chloro-2-fluorobenzofuran-7-yl)methoxy)-phenyl)piperazine-1-carboxylic acid tert-butyl ester (450 mg, 0.98 mmol) was added to Add 4 mL of trifluoroacetic acid and 6 mL of dichloromethane and stir at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. Concentrate the solvent under reduced pressure, adjust the pH of the system to about 7 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (15 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown solid product. 315 mg, yield 89.4%.

LC-MS(ESI): [M+H] ⁺ =361.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.28 (s, 2H), 7.08–6.92 (m, 4H), 6.03 (d, J = 6.5Hz, 1H), 5.29 (s, 2H), 3.32–3.21 ( m,8H).

Step 3: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl) Synthesis of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazine (150 mg, 0.42mmol), (S)-2-(chloromethyl) -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (147mg, 0.50mmol), potassium carbonate (114mg, 0.82mmol), potassium iodide ( 34 mg, 0.20 mmol) was added to 8 mL of acetonitrile solution, and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 55%) gave 249 mg of colorless oily product with a yield of 96.7%.

LC-MS(ESI): [M+H] ⁺ =619.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.16(d,J＝1.6Hz,1H),7.99(d,J＝8.5Hz,1H),7.78(d,J＝8.5Hz,1H),7.32(d ,J＝8.2Hz,1H),7.27(d,J＝5.5Hz,1H),7.02–6.91(m,4H),6.02(d,J＝6.6Hz,1H),5.31(s,2H),5.24 –5.18(m,1H),4.84–4.74(m,1H),4.68–4.59(m,2H),4.46–4.38(m,1H),4.20–4.14(m,2H),3.95(s,3H) ,3.31–3.13(m,4H),2.96–2.80(m,4H),2.79–2.64(m,1H),2.52–2.42(m,1H).

Step 4: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl) Synthesis of -1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1 -(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (115 mg, 0.19 mmol), lithium hydroxide monohydrate (101 mg, 2.41 mmol) was added into a mixed solution of 4 mL water and 8 mL 1,4-dioxane, and react at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 20%) to obtain 63 mg of white solid product, with a yield of 49.5%.

LC-MS(ESI): [M+H] ⁺ =605.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.47(s,1H),8.27(s,1H),7.81(d,J＝8.4Hz,1H),7.65(d,J＝8.5Hz,1H) ,7.49–7.43(m,2H),7.09(d,J＝7.5Hz,1H),6.98–6.92(m,3H),6.54(d,J＝6.4Hz,1H),5.33(s,2H), 5.14–5.05(m,1H),4.84–4.74(m,1H),4.70–4.59(m,1H),4.54–4.45(m,1H),4.40–4.33(m,1H),3.95(d,J ＝13.5Hz,1H),3.79(d,J＝13.6Hz,1H),3.02–2.95(m,4H),2.79–2.65(m,1H),2.61–2.52(m,4H),2.47–2.35( m,1H).

Example 10 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 10)

Step 1: Synthesis of 2-(benzyloxy)-1-bromo-3-fluorobenzene

Compounds 2-bromo-6fluorophenol (2.5g, 13.09mmol), benzyl bromide (2.24g, 13.09mmol) and potassium carbonate (3.62g, 26.18mmol) were added to 20 mL of N,N-dimethylformamide , react at 60°C for 4 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and reduce Concentrate under pressure and purify using silica gel column chromatography (eluent PE: EA (v/v) = 10%) to obtain 3.61g of colorless oily product with a yield of 98.1%.

LC-MS(ESI): [M+H] ⁺ =282.3;

¹ H NMR (500MHz, CDCl ₃ ) δ7.59–7.45(m,2H),7.43–7.28(m,4H),7.09–7.01(m,1H),6.94–6.86(m,1H),5.13(s ,2H).

Step 2: Synthesis of tert-butyl 4-(2-(benzyloxy)-3-fluorophenyl)piperazine-1-carboxylate

2-(Benzyloxy)-1-bromo-3-fluorobenzene (200mg, 0.71mmol), piperazine-1-carboxylic acid tert-butyl ester (265mg, 1.42mmol), 1,1'-binaphthyl-2 , 2'-bisdiphenylphosphine (88.6mg, 0.14mmol), tris(dibenzylideneacetone)dipalladium (66.2mg, 0.07mmol), potassium tert-butoxide (159.6mg, 1.42mmol), were added to toluene ( 5 mL), replaced with nitrogen three times, and placed at 120°C for reaction for 20 minutes. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer After analytical purification (eluent PE: EA (v/v) = 10%), 186 mg of colorless oily product was obtained, with a yield of 67.6%.

LC-MS(ESI): [M+H] ⁺ =387.3;

¹ H NMR (500MHz, CDCl ₃ ) δ7.47–7.42(m,2H),7.40–7.29(m,3H),6.98–6.92(m,1H),6.81–6.74(m,1H),6.66(d ,J＝8.4Hz,1H),5.09(s,2H),3.54–3.56(m,4H),3.07–2.98(m,4H),1.47(s,9H).

Step 3: Synthesis of tert-butyl 4-(3-fluoro-2-hydroxyphenyl)piperazine-1-carboxylate

Add 4-(2-(benzyloxy)-3-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (1.5g, 3.88mmol) and palladium on carbon (410mg) to 25mL of methanol solution. Replace with hydrogen three times and stir at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Suction filtration was carried out through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 1.1 g of a brown solid product with a yield of 95.6%.

LC-MS(ESI): [M+H] ⁺ =297.2;

¹ H NMR (500MHz, CDCl ₃ ) δ6.94–6.85(m,2H),6.82–6.76(m,1H),3.64–3.56(m,4H),2.92–2.79(m,4H),1.49(s ,9H).

Step 4: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine-1-carboxylate

4-(3-Fluoro-2-hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.69 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran ( 444 mg, 1.69 mmol), potassium carbonate (467 mg, 3.38 mmol) were added to N,N-dimethylformamide (10 mL), and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 663 mg of colorless oily product with a yield of 82%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.30 (d, J = 8.1Hz, 1H), 7.28–7.19 (m, 1H), 7.00–6.93 (m, 1H), 6.81–6.74 (m, 1H), 6.68–6.63(m,1H),6.00(d,J＝6.6Hz,1H),5.32(s,2H),3.51–3.39(m,4H),3.06–2.92(m,4H),1.47(s, 9H).

Step 5: Synthesis of 1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine

4-(2-((4-chloro-2fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine-1-carboxylic acid tert-butyl ester (593 mg, 1.24 mmol), Add 5 mL of trifluoroacetic acid and 5 mL of methylene chloride and stir at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. The solvent was concentrated under reduced pressure and evaporated to dryness. Use saturated sodium bicarbonate aqueous solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown product. Solid product 450 mg, yield: 95.9%.

LC-MS(ESI): [M+H] ⁺ =379.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.25 (s, 2H), 7.04–6.97 (m, 1H), 6.89–6.80 (m, 1H), 6.67 (d, J = 8.3Hz, 1H), 6.02 ( d,J＝6.6Hz,1H),5.28(s,2H),3.31–3.22(m,4H),3.21–3.10(m,4H).

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine (150 mg, 0.40 mmol), (S)-2-( Chloromethyl)-1-(oxyheterocycle Butan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (116mg, 0.39mmol), potassium carbonate (110mg, 0.8mmol), potassium iodide (65mg, 0.39mmol) were added to In 8 mL of acetonitrile solution, react at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 25%) yielded 177 mg of colorless oily product with a yield of 70.2%.

LC-MS (ESI): [M+H] ⁺ =637.3.

Step 7: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl)methyl (177 mg, 0.28 mmol), lithium hydroxide monohydrate (58 mg, 1.38 mmol) was added to a mixed solution of water (2 mL) and 1,4-dioxane (6 mL), and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 20%) to obtain 89 mg of white solid product, with a yield of 49.5%.

LC-MS(ESI): [M+H] ⁺ =623.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.26(d,J＝1.6Hz,1H),7.81(dd,J＝8.5,1.6Hz,1H),7.65(d,J＝8.5Hz,1H),7.40 –7.31(m,2H),7.01(td,J＝8.2,6.1Hz,1H),6.87–6.76(m,1H),6.73(d,J＝8.3Hz,1H),6.50(d,J＝6.4 Hz,1H),5.29(s,2H),5.11–5.04(m,1H),4.77(dd,J＝15.3,7.2Hz,1H),4.66–4.59(m,1H),4.52–4.44(m, 1H),4.38–4.33(m,1H),3.94(d,J＝13.5Hz,1H),3.77(d,J＝13.5Hz,1H),3.02–2.89(m,4H),2.73–2.65(m ,1H),2.57–2.44(m,4H),2.43–2.35(m,1H).

Example 11 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine-1 Synthesis of -ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 11)

Step 1: 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine-1 Synthesis of -ethyl)-1-(((S)-(oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine (122 mg, 0.40 mmol), 2-((R)- 1-Chloroethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (150 mg, 0.40 mmol) , potassium carbonate (109 mg, 0.79 mmol), and potassium iodide (65 mg, 0.39 mmol) were added to 10 mL of acetonitrile solution, and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 25%) yielded 183 mg of colorless oily product with a yield of 71%.

LC-MS(ESI): [M+H] ⁺ =651.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.13 (s, 1H), 7.98 (dd, J＝8.6, 1.6Hz, 1H), 7.81 (d, J＝8.5Hz, 1H), 7.26 (d, J＝ 10.4Hz,1H),7.19(d,J＝8.2Hz,1H),6.97–6.89(m,1H),6.80–6.67(m,1H),6.61(d,J＝8.0Hz,1H),5.99( d,J＝6.7Hz,1H),5.28(s,2H),5.27–5.23(m,1H),5.00–4.94(m,1H),4.60–4.54(m,1H),4.54–4.46(m, 1H),4.45–4.38(m,1H),4.25–4.18(m,1H),3.94(s,3H),3.08–2.97(m,4H),2.68–2.63(m,1H),2.62–2.54( m,4H),2.43–2.29(m,1H),1.59(d,J＝6.8Hz,3H).

Step 2: 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine-1 -ethyl)-1-(((S)-oxetane Synthesis of -2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl )ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (180 mg, 0.28 mmol), hydrogen Lithium oxide monohydrate (58 mg, 1.38 mmol) was added to a mixed solution of 2 mL water and 6 mL 1,4-dioxane, and reacted at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 6 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 20%) to obtain 56 mg of white solid product, with a yield of 28.1%.

LC-MS(ESI): [M+H] ⁺ =637.3;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.70 (s, 1H), 8.27 (s, 1H), 7.80 (dd, J = 8.5, 1.6Hz, 1H), 7.68 (d, J = 8.5Hz, 1H),7.32–7.26(m,2H),7.05–6.95(m,1H),6.87–6.80(m,1H),6.69(d,J＝8.4Hz,1H),6.46(d,J＝6.4Hz ,1H),5.25(s,2H),5.16–5.09(m,1H),4.79–4.72(m,1H),4.68–4.61(m,1H),4.45–4.36(m,2H),4.20–4.13 (m,1H),2.94–2.81(m,4H),2.65–2.58(m,1H),2.47–2.40(m,4H),2.34–2.23(m,1H),1.43(d,J＝6.8Hz ,3H).

Example 12 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1 Synthesis of -ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylic acid (compound 12)

Step 1: 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1 Synthesis of -ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (300 mg, 0.97mmol), 2-((R) -1-Chloroethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (300 mg, 0.79 mmol ), potassium carbonate (220 mg, 1.59 mmol) and potassium iodide (132 mg, 0.80 mmol) were added to acetonitrile (20 mL) and reacted at 60°C for 2 hours. Cool to room temperature, add water (30mL), extract with ethyl acetate (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EA:PE (v /v)=50%), 150 mg of yellow viscous liquid product was obtained with a yield of 29.1%.

LC-MS (ESI): [M+H] ⁺ =650.4.

Step 2: 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1 Synthesis of -ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylic acid

Compound 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1- ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylic acid methyl ester (150 mg, 0.23 mmol) and hydroxide Lithium monohydrate (49 mg, 1.17 mmol) was added to 1,4-dioxane (4 mL) and water (2 mL), and the reaction was carried out at 40°C for 1.5 h. Cool to room temperature, add water to dilute (15mL), adjust the system pH to 5 with acetic acid (4M), extract three times with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) yielded 56 mg of yellow solid product with a yield of 37.2%.

LC-MS(ESI): [M+H] ⁺ =636.3;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.71 (br, 1H), 8.28 (s, 1H), 7.82 (d, J = 8.4Hz, 1H), 7.69 (d, J = 8.6Hz, 1H) ,7.36(d,J＝8.2Hz,1H),7.27(d,J＝8.2Hz,1H),7.15–7.02(m,2H),6.95(d,J＝7.8Hz,1H),6.45(d, J＝6.4Hz,1H),5.24(s,2H),5.18–5.09(m,1H),4.83–4.74(m,1H),4.70–4.59(m,1H),4.50–4.37(m,2H) ,4.22–4.12(m,1H),2.94–2.84(m,1H),2.68–2.58(m,1H),2.58–2.54(m,1H),2.36–2.21(m,2H),2.01–1.86( m, 1H),1.56–1.40(m,1H),1.44(s,3H),1.36–1.11(m,4H).

Example 13 (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 13)

Step 1: Synthesis of 3-hydroxy-3',6'-dihydro-(2,4'-bipyridine)-1'(2'H)-carboxylic acid tert-butyl ester

Compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- Tert-butyl carboxylate (2.13g, 6.90mmol) and 2-bromo-3-hydroxypyridine (1.2g, 6.90mmol) were added to 1,4-dioxane (20mL) and water (5mL), stirred and dissolved, and then added Sodium carbonate (1.83g, 17.24mmol) and tetrakis(triphenylphosphine)palladium (0.33g, 0.29mmol) were heated to 120°C under nitrogen protection and reacted overnight. After cooling to room temperature, concentrate under reduced pressure, add water (10 mL), extract with ethyl acetate (10 mL × 3), dry the organic phase with anhydrous sodium sulfate, and purify with silica gel column chromatography (eluent EtOAc:PE (v/ v)=1:5) 600 mg of off-white solid product was obtained with a yield of 37.7%.

¹ HNMR (400MHz, DMSO-d ₆ ) δ10.04(s,1H),8.03–8.01(m,1H),7.22–7.20(m,1H),7.10–7.08(m,1H),6.68(s, 1H), 4.02 (s, 2H), 3.50 (t, J = 5.6Hz, 2H), 2.57 (d, J = 1.8Hz, 2H), 1.43 (s, 9H).

Step 2: Synthesis of tert-butyl 4-(3-hydroxypyridin-2-yl)piperidine-1-carboxylate

The compound 3-hydroxy-3',6'-dihydro-(2,4'-bipyridyl)-1'(2'H)-carboxylic acid tert-butyl ester (600 mg, 2.17mmol) was added to methanol (20 mL) , 10% palladium on carbon (100 mg, 0.56 mmol) was added, and the reaction solution was stirred at room temperature under a hydrogen atmosphere overnight. Filter through diatomaceous earth, wash the filtrate with methanol (50 mL), and concentrate the filtrate under reduced pressure to obtain 600 mg of light yellow oily product with a yield of 99.3%.

¹ HNMR (400MHz, DMSO-d ₆ ) δ9.82 (s, 1H), 8.01–7.88 (m, 1H), 7.14–6.97 (m, 2H), 4.05 (d, J = 11.2Hz, 2H), 3.18 (d,J＝7.2Hz,1H),2.83(s,2H),1.72–1.51(m,4H),1.42(s,9H).

Step 3: Synthesis of tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

Compound 4-(3-hydroxypyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (600 mg, 2.16 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzene Furan (568 mg, 2.16 mmol) was added to N,N-dimethylformamide (10 mL), potassium carbonate (894 mg, 6.47 mmol) was added, and the reaction solution was heated to 60°C under nitrogen protection for 3 hours. Cool the reaction solution to room temperature, add water (50 mL), extract with ethyl acetate (30 mL × 3), dry the organic phase with anhydrous sodium sulfate, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v )=1:3) to obtain 600 mg of light yellow solid product with a yield of 60.4%.

¹ HNMR (400MHz, CDCl ₃ ) δ8.12(m,1H),7.23–7.12(m,3H),7.04(m,1H),5.98(d,J＝6.4Hz,1H),5.23(s,2H ), 4.16 (s, 2H), 3.24 (d, J = 4.0Hz, 1H), 2.73 (s, 2H), 1.76 (d, J = 39.2Hz, 4H), 1.39 (s, 9H).

Step 4: Synthesis of 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2-(piperidin-4-yl)pyridine hydrochloride

Compound 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester was added to dichloromethane ( 10 mL), add dioxane hydrochloride solution (3 mL), and keep the reaction solution at room temperature for 2 hours. Concentrate under reduced pressure to obtain 450 mg of off-white solid product with a yield of 87.0%, which was directly used in the next reaction.

Step 5: (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Synthesis of Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Compound 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2-(piperidin-4-yl)pyridine hydrochloride (300 mg, 0.83 mmol) and (S) -2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (245 mg, 0.83 mmol) was added to N, N -To dimethylformamide (2mL), add potassium carbonate (575mg, 4.16mmol) and potassium iodide (5.0mg, 0.03mmol), and add the reaction liquid under nitrogen protection. Warm to 85°C and stir for 2 hours. The reaction solution was brought to room temperature, slowly dropped into water (10 mL) to quench, extracted with ethyl acetate (10 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent DCM: MeOH (v/v)=1:20), 128 mg of light yellow solid product was obtained with a yield of 24.9%.

LC-MS (ESI): [M+H] ⁺ =619.3.

Step 6: (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl (128 mg, 0.21 mmol) was added to dioxane (2 mL) and water. (0.5 mL), add lithium hydroxide (44.0 mg, 1.05 mmol), and raise the temperature to 40°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, and the pH value was adjusted to 2-3 with acetic acid. Concentrate under reduced pressure and purify using Prep-HPLC (eluent CH ₃ CN:H ₂ O (v/v) = 60%) to obtain 17.0 mg of white solid product with a yield of 13.6%.

LC-MS(ESI): [M+H] ⁺ =605.4;

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.25 (s, 1H), 8.11 (d, J = 4.4Hz, 1H), 7.81 (d, J = 8.0Hz, 1H), 7.63 (d, J = 8.4 Hz,1H),7.53(d,J＝8.4Hz,1H),7.49–7.39(m,2H),7.20(m,1H),6.54(d,J＝6.4Hz,1H),5.41(s,2H ),5.12–5.06(m,1H),4.85–4.79(m,1H),4.68–4.57(m,1H),4.52–4.46(m,1H),4.40–4.35(m,1H),3.90(d ,J＝13.6Hz,1H),3.78(d,J＝13.6Hz,1H),2.96(d,J＝10.8Hz,1H),2.97–2.82(m,1H),3.17–3.11(m,1H) ,2.78–2.68(m,1H),2.46–2.37(m,1H),2.22–2.02(m,2H),1.783–1.74(m,2H),1.68–1.58(m,2H).

Example 14 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 14)

Step 1: Synthesis of 2-(benzyloxy)-3-bromopyridine

Compound 3-bromo-2-fluoropyridine (1.00g, 5.68mmol) and benzyl alcohol (0.68g, 6.25mmol) were added to acetonitrile (5mL), followed by cesium carbonate (1.85g, 5.68mmol). The reaction was carried out at room temperature overnight. Filter through diatomaceous earth, concentrate the filtrate under reduced pressure, and separate and purify by silica gel column chromatography (eluent EA: PE (v/v) = 10%) to obtain 1.13g of colorless liquid product with a yield of 75.3%.

¹ H NMR (500MHz, CDCl ₃ ) δ8.09 (dd, J＝4.9, 1.7Hz, 1H), 7.81 (dd, J＝7.6, 1.7Hz, 1H), 7.49 (d, J＝7.5Hz, 2H) ,7.37(t,J＝7.6Hz,2H),7.30(d,J＝7.4Hz,1H),6.77(dd,J＝7.5,4.9Hz,1H),5.46(s,2H).

Step 2: Synthesis of 2-(benzyloxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester

The compound 2-(benzyloxy)-3-bromopyridine (0.50g, 1.89mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.59g, 1.90 mmol) was added to a mixed solution of 1,4-dioxane (12 mL) and water (3 mL), and then [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (78 mg ,0.10mmol) and potassium carbonate (524mg, 3.79mmol). Heat to 90°C for 2 hours under nitrogen protection. Cool to room temperature, dilute with water (20 ml), extract three times with ethyl acetate (15 mL × 3), combine the organic phases, and dry over anhydrous sodium sulfate. Filter, concentrate the filtrate, and separate and purify by silica gel column chromatography (eluent EA: PE (v/v) = 30%) to obtain 0.59 g of light yellow liquid with a yield of 85.2%.

LC-MS(ESI): [M+H] ⁺ =367.3;

¹ H NMR (500MHz, CDCl ₃ ) δ8.07 (dd, J＝5.0, 1.9Hz, 1H), 7.45 (dd, J＝7.3, 1.9Hz, 1H), 7.42 (d, J＝6.7Hz, 2H) ,7.36(t,J＝7.6Hz,2H),7.32–7.28(m,1H),6.88(dd,J＝7.3,5.0Hz,1H),5.91–5.88(m,1H),5.43(s, 2H),4.06–4.02(m,2H),3.59–3.54(m,2H),2.53–2.47(m,2H),1.48(s,9H).

Step 3: Synthesis of tert-butyl 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylate

Dissolve compound 2-(benzyloxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (0.59g, 1.61mmol) In ethanol (13 mL), add palladium on carbon (10% Pd, containing 55% water) (0.19 g, 0.80 mmol), replace it with hydrogen three times, and react at room temperature overnight in a hydrogen environment. Filter through diatomaceous earth and concentrate the filtrate under reduced pressure to obtain 0.36g of white solid with a yield of 80.8%.

LC-MS(ESI): [M-55] ⁺ =223.0;

¹ H NMR (500MHz, DMSO-d ₆ ) δ11.46 (s, 1H), 7.24–7.19 (m, 2H), 6.12 (t, J = 6.7Hz, 1H), 4.08–4.01 (m, 2H), 2.83–2.72(m,3H),1.71(d,J＝12.9Hz,2H),1.40(s,9H),1.34(dd,J＝12.5,4.0Hz,2H).

Step 4: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylate

The compound 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (360mg, 1.29mmol) and (4-chloro-2-fluorobenzofuran-7-yl)methanol (220mg , 1.10 mmol) was added to tetrahydrofuran (10 mL), followed by triphenylphosphine (400 mg, 1.53 mmol) and diisopropyl azodicarboxylate (332 mg, 1.64 mmol). React at room temperature for 3 hours. Water (30 mL) was added to quench the reaction, extracted with ethyl acetate (15 mL × 3), and the organic phases were combined. It was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent EA: PE (v/v) = 25%) to obtain 69 mg of colorless viscous liquid with a yield of 13.6%.

LC-MS(ESI): [M+H] ⁺ =461.3;

¹ H NMR (500MHz, CDCl ₃ ) δ8.03 (dd, J＝5.0, 1.8Hz, 1H), 7.42 (dd, J＝7.3, 1.9Hz, 1H), 7.29–7.22 (m, 2H), 6.89 ( dd,J＝7.4,5.0Hz,1H),6.01(d,J＝6.6Hz,1H),5.62(s,2H),4.29–4.15(m,2H),3.02–2.95(m,1H),2.82 –2.73(m,2H),1.83(d,J＝12.8Hz,2H),1.55–1.50(m,2H),1.47(s,9H).

Step 5: Synthesis of 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol) Add to dichloromethane (1.5 mL), then add trifluoroacetic acid (544 mg, 4.77 mmol) under ice bath. Return to room temperature and react for 30 minutes. Add saturated sodium bicarbonate solution to adjust pH=8, and extract with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 82 mg of a yellow viscous solid with a yield of 104.8%.

LC-MS (ESI): [M+H] ⁺ =361.2.

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl) Synthesis of Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Compound 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine (82 mg, 0.23 mmol), (S)-2- (Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (67 mg, 0.23 mmol), N,N-diiso Propylethylamine (150 mg, 1.16 mmol) was added to acetonitrile (5 mL), and the reaction was carried out at 60°C overnight. Cool to room temperature, add water (20mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EA:PE (v /v)=50%), 92 mg of yellow solid product was obtained, with a yield of 65.4%.

LC-MS (ESI): [M+H] ⁺ =619.4.

Step 7: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (92 mg, 0.15 mmol) and lithium hydroxide monohydrate (32 mg, 0.76mmol) was added to 1,4-dioxane (4mL) and water (2mL), and the reaction was carried out at 40°C for 1.5h. Cool to room temperature, add water to dilute (15mL), adjust the system pH to 5 with acetic acid (4M), extract three times with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 3%) yielded 20 mg of yellow solid product with a yield of 22.2%.

LC-MS(ESI): [M+H] ⁺ =605.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.65 (br, 1H), 8.26 (s, 1H), 8.01 (d, J = 4.9Hz, 1H), 7.80 (d, J = 8.4Hz, 1H) ,7.62(dd,J＝18.4,7.9Hz,2H),7.44–7.38(m,2H),6.98(t,J＝6.2Hz,1H),6.51(d,J＝6.3Hz,1H),5.60( s,2H),5.11–5.04(m,1H),4.77(dd,J＝15.3,7.2Hz,1H),4.63(d,J＝15.1Hz,1H),4.51–4.45(m,1H),4.38 –4.33(m,1H),3.92(d,J＝13.5Hz,1H),3.78(d,J＝13.6Hz,1H),2.98(d,J＝11.1Hz,1H),2.86(d,J＝ 11.4Hz,1H),2.83–2.75(m,1H),2.74–2.65(m,1H),2.45–2.36(m,1H),2.25–2.11(m,2H),1.75(t,J＝14.0Hz ,2H),1.69–1.56(m,2H).

Example 15 (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluoro-[1,1'-biphenyl] Synthesis of -4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 15)

Step 1: Synthesis of 1-bromo-2-(methoxymethoxy)benzene

Compound 2-bromophenol (5g, 28.9mmol) was added to N,N-dimethylformamide (50mL), NaH (1.4g, 57.8mmol) was added, and the mixture was stirred in an ice bath for 30 minutes. Add bromo(methoxy)methane (4.3g, 34.7mmol) and stir at room temperature for two hours. Add water (50 mL), extract with dichloromethane (50 mL EtOAc:PE(v/v)=1:20) to obtain 6.15g of colorless oily product with a yield of 98.0%.

Step 2: Synthesis of methyl 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetate

Compound 1-bromo-2-(methoxymethoxy)benzene (2.0g, 9.2mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)phenyl)methyl acetate (3.0g, 10.12mmol) was added to 1,4-dioxane (20mL) and water (5mL). Add potassium carbonate (3.8g, 27.6mmol), replace it with nitrogen three times, add tetrakis triphenylphosphine palladium (0.3g, 0.26mmol), replace it with nitrogen three times again, and stir at 85°C overnight. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc:PE (v/v)=1:12) to obtain 2.4g of colorless oily product with a yield of 85.7%.

¹ HNMR(400MHz, CDCl ₃ )δ7.27–7.19(m,5H),7.15(dd,J＝8.7,1.0Hz,1H),7.04–6.99(m,1H),5.07(s,2H),3.66 (d,J＝9.4Hz,5H),3.34(s,3H).

Step 3: Synthesis of 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-ol

Compound 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetic acid methyl ester (2.4g, 7.9mmol) was added to tetrahydrofuran (20mL ), stir at 0°C for five minutes. Lithium aluminum tetrahydride (0.87g, 23.0mmol) was added and stirred at 0°C for two hours. Add water (10 mL) to quench, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography ( The eluent (EtOAc:PE (v/v)=1:5) gave 1.2g of colorless oily product with a yield of 54.5%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.27–7.15 (m, 6H), 7.01 (d, J = 1.0Hz, 1H), 5.07 (s, 2H), 3.84 (t, J = 6.6Hz, 2H), 3.35(s,3H),2.89(t,J=6.6Hz,2H).

Step 4: Synthesis of 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetaldehyde

Compound 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-ol (1.2g, 4.3mmol) was added to To methyl chloride (20 mL), Dessmartin's reagent (2.8 g, 6.5 mmol) was added and stirred in an ice bath for 1 hour, and a large amount of solid precipitated. Saturated sodium bicarbonate (5 mL) was added, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v/v) = 1:8) to obtain 550 mg of colorless oily product with a yield of 46.6%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.74 (d, J = 1.2 Hz, 1H), 7.39–7.30 (m, 5H), 7.22 (d, J = 7.8 Hz, 1H), 7.12–7.07 ( m,1H),5.19(s,2H),3.89(s,2H),3.30(d,J＝5.5Hz,3H).

Step 5: (S)-2-((3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)methyl)-1-(oxygen Heterocyclobutan-2-ylmethyl)-1H-benzo[d] Synthesis of imidazole-6-carboxylic acid methyl ester

Compound 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetaldehyde (550 mg, 2.0 mmol), (S)-4 -Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (520 mg, 2.2 mmol) was added to acetic acid (20 mL), oxygen was added, and the mixture was stirred at 60°C for 5 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 20:1) to obtain 165 mg of light brown solid product with a yield of 16.8%.

LC-MS (ESI): [M+H] ⁺ =491.3.

Step 6: (S)-2-((3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetane-2- Synthesis of methyl methyl)-1H-benzo[d]imidazole-6-carboxylate

Compound (S)-2-((3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)methyl)-1-(oxa Cyclobutan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (165 mg, 0.34 mmol) was added to dichloromethane (10 mL), cooled to -20°C, and trifluorocarbon was added Acetic acid (5 mL), stirred at -20°C for 2 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 20:1) to obtain 35 mg of light brown solid product with a yield of 23.3%.

LC-MS (ESI): [M+H] ⁺ =447.4.

Step 7: (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)benzyl)-1-(oxy Synthesis of heterocyclobutan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester

Compound (S)-2-((3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-yl Methyl)-1H-benzo[d]imidazole-6-carboxylate (35mg, 0.08mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (32.0mg ,0.12mmol) was added to N,N-dimethylformamide (2mL), potassium carbonate (33.0mg, 0.24mmol) was added, and stirred at 60°C for one hour. Add water (5 mL), extract with ethyl acetate (5 mL /v)=10:1) 28 mg of white solid product was obtained, with a yield of 56.8%.

LC-MS (ESI): [M+H] ⁺ =629.2.

Step 8: (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluoro-[1,1'-biphenyl] Synthesis of -4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)benzyl)-1-(oxa Cyclbutan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (28mg, 44.6umol) was dissolved in dioxane (2mL), water (0.5mL )middle. Lithium hydroxide (6.5 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 8 hours. Adjust pH to 6-7 with acetic acid. Concentrate under reduced pressure and purify with Prep-HPLC (eluent CH ₃ CN: H ₂ O (v/v) = 50%) to obtain 6.1 mg of white solid product, with a yield of 22.3%.

LC-MS(ESI): [M+H] ⁺ =615.3;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.22(s,1H),7.78(d,J＝8.6Hz,1H),7.57(d,J＝8.4Hz,1H),7.42–7.33(m, 5H),7.33–7.24(m,3H),7.09(t,J＝7.5Hz,1H),6.50(d,J＝6.4Hz,1H),5.38(s,2H),5.00(d,J＝5.2 Hz,1H),4.68(dd,J＝15.5,7.2Hz,1H),4.55(d,J＝13.2Hz,1H),4.49–4.40(m,2H),4.39–4.27(m,2H),2.68 –2.60(m,1H),2.33(s,1H).

Example 16 (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,3'-difluoro-[1,1'- Synthesis of biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 16)

Step 1: Synthesis of 1-bromo-3-fluoro-2-(methoxymethoxy)benzene

Add compound 2-bromo-6-fluorophenol (5.0g, 26.18mmol) to N,N-dimethylformamide (50mL), add sodium hydride (1.57g, 39.27mmol), and stir in an ice bath for ten minutes. Add bromo(methoxy)methane (3.93g, 31.41mmol) and stir at room temperature for one hour. Add water (250 mL), extract with ethyl acetate (50 mL PE(v/v)=1:20), 6.0 g of colorless oily product was obtained with a yield of 97.5%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.28–7.27(m,1H),7.02–6.96(m,1H),6.88–6.84(m,1H),5.13(s,2H),3.57(s,3H) .

Step 2: Synthesis of methyl 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetate

Compound 1-bromo-3-fluoro-2-(methoxymethoxy)benzene (1.9g, 8.08mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl) -Methyl 1,3,2-dioxaborolan-2-yl)phenyl)acetate (2.85g, 9.7mmol) was added to 1,4-dioxane (30mL) and water (7.5mL )middle. Add potassium carbonate (3.35g, 24.24mmol), replace it with nitrogen three times, add tetrakis(triphenylphosphine)palladium (0.47g, 0.4mmol), replace it with nitrogen three times again, and stir at 85°C overnight. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc:PE (v/v)=1:15) to obtain 2.2g of colorless oily product with a yield of 84.5%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.23 (d, J = 6.0Hz, 3H), 7.07–7.01 (m, 3H), 4.83 (s, 2H), 3.67–3.64 (m, 5H), 3.10 (s ,3H)

Step 3: Synthesis of 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-ol

Compound 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetic acid methyl ester (2.2g, 6.83mmol) Add tetrahydrofuran (50 mL) and stir at 0°C for five minutes. Add lithium aluminum tetrahydride (0.78g, 20.5mmol) and stir at 0°C for two hours. Add water (20 mL) to quench, extract with ethyl acetate (30 mL Remove the agent EtOAc:PE (v/v)=1:5) to obtain 1.2g of colorless oily product with a yield of 59.7%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.40 (t, J = 8.0Hz, 1H), 7.33–7.26 (m, 3H), 7.25–7.20 (m, 2H), 4.86 (s, 2H), 4.74(t,J＝5.2Hz,1H),3.65–3.61(m,2H),3.09(s,3H),2.80(t,J＝7.0Hz,2H).

Step 4: Synthesis of 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetaldehyde

Compound 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-ol (1.2g, 4.08mmol ) was added to dichloromethane (20 mL), Desmartin's reagent (2.59 g, 6.12 mmol) was added and stirred in an ice bath for 1 hour, and a large amount of solid precipitated. Water (5 mL) was added, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v/v) = 1:5) to obtain 700 mg of colorless oily product with a yield of 58.7%.

¹ HNMR (400MHz, DMSO-d ₆ ) δ9.73 (d, J＝1.2Hz, 1H), 7.40–7.30 (m, 4H), 7.24 (dd, J＝6.2, 3.2Hz, 2H), 4.88 (s ,2H),3.92(s,2H),3.08(s,3H).

Step 5: (S)-2-((3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)methyl)- Synthesis of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetaldehyde (700 mg, 2.39 mmol), ( S)-4-Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (566 mg, 2.4 mmol) was added to acetic acid (10 mL), and stirred at 60°C for 2 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EA:PE (v/v)=1:1) to obtain 155 mg of light brown solid product with a yield of 12.7%.

LC-MS (ESI): [M+H] ⁺ =509.4.

Step 6: (S)-2-((3,3'-difluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetane Synthesis of alk-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound (S)-2-((3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)methyl)-1 -(Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (155 mg, 0.3 mmol) was added to dichloromethane (12 mL) and cooled to -20°C , add trifluoroacetic acid (4mL), and stir at -20°C for 2 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 20:1) to obtain 100 mg of light brown solid product with a yield of 70.6%.

LC-MS (ESI): [M+H] ⁺ =465.4.

Step 7: (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,3'-difluoro-[1,1'- Synthesis of biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound (S)-2-((3,3'-difluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetane -2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100mg, 0.22mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzo Furan (80 mg, 0.3 mmol) was added to N,N-dimethylformamide (5 mL), potassium carbonate (90 mg, 0.65 mmol) was added, and the mixture was stirred at 60°C for one hour. Add water (10 mL), extract with ethyl acetate (10 mL /v)=10:1), 100 mg of off-white solid product was obtained, with a yield of 71.8%.

LC-MS (ESI): [M+H] ⁺ =647.4.

Step 8: (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,3'-difluoro-[1,1'- Synthesis of biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,3'-difluoro-[1,1'-bis Phenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.15 mmol) was added To dioxane (4mL), water (1mL). Lithium hydroxide (22 mg, 0.92 mmol) was added and stirred at room temperature for 4 hours. Adjust the pH to 6-7 with hydrochloric acid (0.5N), extract with ethyl acetate (5mL×3), combine the organic phases, wash the organic phases once with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and purify using Prep-HPLC (eluent CH ₃ CN: H ₂ O (v/v) = 50%) to obtain 54.0 mg of white solid product with a yield of 55.2%.

LC-MS(ESI): [M+H] ⁺ =633.2;

¹ HNMR (400MHz, DMSO-d ₆ ) δ12.74(s,1H),8.25(s,1H),7.79(dd,J＝8.4,1.3Hz,1H),7.59(d,J＝8.4Hz,1H ),7.41–7.29(m,1H),7.28–7.12(m,4H),7.06(dd,J＝12.5,9.5Hz,2H),6.96(d,J＝8.2Hz,1H),6.38(d, J＝6.4Hz,1H),5.12(s,2H),5.04(d,J＝6.8Hz,1H),4.71(dd,J＝15.6,7.0Hz,1H),4.58(d,J＝13.0Hz, 1H),4.53–4.47(m,1H),4.43(s,1H),4.40–4.32(m,2H),2.74–2.64(m,1H),2.36(dd,J＝18.6,7.9Hz,1H) .

Example 17 2-((R)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1 Synthesis of -ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 17)

Step 1: 2-((R)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1 Synthesis of -ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (350 mg, 0.93 mmol), 2-((S) -1-Chloroethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (286 mg, 0.93 mmol ), potassium carbonate (256 mg, 1.85 mmol) and potassium iodide (153 mg, 0.92 mmol) were added to acetonitrile (25 mL), and the reaction was carried out at 60°C for 2 hours. Cool to room temperature, add water (30mL), extract with ethyl acetate (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EA:PE (v /v)=50%), 123 mg of yellow viscous liquid product was obtained with a yield of 20.4%.

LC-MS (ESI): [M+H] ⁺ =650.4.

Step 2: 2-((R)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1 Synthesis of -ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound 2-((R)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1- ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylic acid methyl ester (123 mg, 0.19 mmol) and hydroxide Lithium monohydrate (40mg, 0.95mmol) plus Pour into 1,4-dioxane (4mL) and water (2mL), and react at 40°C for 1.5h. Cool to room temperature, add water to dilute (15mL), adjust the system pH to 5 with acetic acid (4M), extract three times with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purification by silica gel column chromatography (eluent MeOH:DCM (v/v) = 5%) yielded 60 mg of light yellow solid product with a yield of 49.2%.

LC-MS(ESI): [M+H] ⁺ =636.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.70 (br, 1H), 8.28 (s, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.69 (d, J = 8.5Hz, 1H) ,7.36(d,J＝8.1Hz,1H),7.27(d,J＝8.2Hz,1H),7.15–7.03(m,2H),6.95(d,J＝7.8Hz,1H),6.45(d, J＝6.3Hz,1H),5.28–5.21(m,2H),5.16–5.10(m,1H),4.77(d,J＝16.6Hz,1H),4.64(dd,J＝15.6,5.4Hz,1H ),4.48–4.39(m,2H),4.20–4.14(m,1H),2.88(d,J＝10.9Hz,1H),2.63(t,J＝8.9Hz,1H),2.58–2.52(m, 1H),2.37–2.23(m,2H),1.98–1.88(m,1H),1.55–1.47(m,1H),1.43(d,J＝6.6Hz,3H),1.36–1.25(m,3H) ,1.20–1.11(m,1H).

Example 18 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine-1 Synthesis of -(yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 18)

Step 1: Synthesis of tert-butyl 4-(2-hydroxy-3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

2-Bromo-6-methoxyphenol (800mg, 3.94mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.22g, 3.94mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride Methyl chloride complex (320 mg, 0.39 mmol) and potassium carbonate (1.09 g, 7.88 mmol) were added to a mixed solution of 3 mL of water and 12 mL of 1,4-dioxane, replaced with nitrogen three times, and placed at 90 React at ℃ for 2 hours. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer Analytical purification (eluent PE: EA (v/v) = 15%) gave 707 mg of colorless oily product with a yield of 58.8%.

LC-MS(ESI): [M-55] ⁺ =250.1.

Step 2: Synthesis of tert-butyl 4-(2-hydroxy-3-methoxyphenyl)piperidine-1-carboxylate

Add 4-(2-hydroxy-3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (756 mg, 2.48 mmol) and palladium on carbon (400 mg). In 10 mL of methanol solution, hydrogen gas was substituted three times, and the mixture was stirred at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. The product was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 631 mg of brown solid product with a yield of 82.9%.

LC-MS(ESI): [M-55] ⁺ =252.1;

¹ H NMR (500MHz, CDCl ₃ ) δ6.92–6.69(m,3H),5.75(s,1H),4.33–4.14(s,2H),3.89(s,3H),3.12–3.03(m,1H ),2.91–2.74(m,2H),1.82(d,J＝12.9Hz,2H),1.66–1.59(m,1H),1.48(s,9H).

Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine-1-carboxylate

4-(2-Hydroxy-3-methoxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (320 mg, 1.04 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzo Furan (250 mg, 0.95 mmol) and potassium carbonate (131 mg, 0.95 mmol) were added to 12 mL of N,N-dimethylformamide and reacted at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Column chromatography purification (eluent PE: EA (v/v) = 5%) obtained 350 mg of colorless oily product, yield 75.3%

LC-MS(ESI): [M-55] ⁺ =434.2.

Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine

Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine-1-carboxylate (350 mg, 0.71 mmol), added to a solution of trifluoroacetic acid (4 mL) and dichloromethane (4 mL), and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. Concentrate under reduced pressure and evaporate the solvent to dryness. Use saturated aqueous sodium bicarbonate solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown oil. The product was directly used in the next reaction.

Step 5: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine-1 Synthesis of -(yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine (264 mg, 0.68 mmol), (S)-2 -(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (199 mg, 0.68 mmol), DIPEA (437 mg, 3.39 mmol) was added to 5 mL of acetonitrile solution, and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 40%) yielded 156 mg of colorless oily product with a yield of 35.5%.

LC-MS (ESI): [M+H] ⁺ =648.4.

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine-1 Synthesis of -(yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (90 mg, 0.14 mmol), lithium hydroxide monohydrate ( 28.47 mg, 0.69 mmol) was added to a mixed solution of 2 mL water and 6 mL 1,4-dioxane, and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 6 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 20%) to obtain 28 mg of white solid product, with a yield of 31.2%.

LC-MS(ESI): [M+H] ⁺ =634.3;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.70 (s, 1H), 8.25 (s, 1H), 7.80 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H) ,7.38(d,J＝7.8Hz,1H),7.29(d,J＝8.2Hz,1H),7.02(t,J＝7.9Hz,1H),6.92(d,J＝8.2Hz,1H),6.73 (d,J＝7.9Hz,1H),6.52(d,J＝6.4Hz,1H),5.19(s,2H),5.11–5.02(m,1H),4.86–4.71(m,1H),4.69– 4.56(m,1H),4.55–4.43(m,1H),4.43–4.30(m,1H),3.93–3.80(m,4H),3.71(d,J＝13.5Hz,1H),2.89(d, J＝11.2Hz,1H),2.81–2.62(m,3H),2.45–2.35(m,1H),2.04–1.83(m,2H),1.55–1.38(m,2H),1.35–1.28(m, 2H).

Example 19 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine-1- Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 19)

Step 1: Synthesis of tert-butyl 4-(2-hydroxy-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

2-Bromo-6-methylphenol (500mg, 2.67mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (909mg, 2.94mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane Complex (218 mg, 0.27 mmol) and potassium carbonate (738 mg, 5.35 mmol) were added to a mixed solution of water (3 mL) and 1,4-dioxane (12 mL), replaced with nitrogen three times, and placed at 90°C React for 2 hours. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer analytical purification (eluent PE:EA(v/v)=15%), 815 mg of colorless oily product was obtained, with a yield of 95.9%.

LC-MS(ESI): [M-55] ⁺ =234.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.03 (d, J = 7.4Hz, 1H), 6.92 (d, J = 7.8Hz, 1H), 6.80 (t, J = 7.5Hz, 1H), 5.84 (s ,1H),4.10–4.00(m,2H),3.67–3.59(m,2H),2.49–2.35(m,2H),2.26(s,3H),1.50(s,9H).

Step 2: Synthesis of tert-butyl 4-(2-hydroxy-3-methylphenyl)piperidine-1-carboxylate

Add 4-(2-hydroxy-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (0.8g, 2.67mmol) and palladium on carbon (400mg). 12 mL of methanol solution was replaced with hydrogen three times and stirred at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Suction filtration was carried out through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 0.816g of a brown solid product with a yield of 101.3%.

LC-MS (ESI): [M-55] ⁺ =236.2.

¹ H NMR (500MHz, CDCl ₃ ) δ7.06–6.95 (m, 2H), 6.83 (t, J = 7.6Hz, 1H), 4.84 (s, 1H), 4.49–4.17 (m, 2H), 3.13– 2.91(m,1H),2.94–2.67(m,2H),2.26(s,3H),1.82(d,J＝13.0Hz,2H),1.66–1.55(m,2H),1.48(s,9H) .

Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine-1-carboxylate

4-(2-Hydroxy-3-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester (232 mg, 0.8 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran ( 21 mg, 0.8 mmol) and potassium carbonate (220 mg, 1.59 mmol) were added to 12 mL of N,N-dimethylformamide, and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 144 mg of colorless oily product with a yield of 38.1%.

LC-MS(ESI): [M-55] ⁺ =418.3.

¹ H NMR (500MHz, CDCl ₃ ) δ7.28–7.33 (m, 2H), 7.10–7.06 (m, 1H), 7.05–7.02 (m, 2H), 6.05 (d, J = 6.6Hz, 1H), 5.00(s,2H),4.35–4.15(m,2H),3.16–3.07(m,1H),2.83–2.54(m,2H),2.38(s,3H),1.71–1.53(m,4H), 1.48(s,9H).

Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester (290 mg, 0.61 mmol ), added to 1.5 mL of trifluoroacetic acid and 3 mL of methylene chloride, and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. Concentrate under reduced pressure and evaporate the solvent to dryness. Use saturated aqueous sodium bicarbonate solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a brown oil. The product was directly used in the next reaction.

¹ H NMR (500MHz, CDCl ₃ ) δ7.33–7.27(m,2H),7.18–7.05(m,3H),6.07(d,J＝6.6Hz,1H),4.98(s,2H),3.56– 3.40(m,2H),3.28–3.17(m,1H),3.02–2.80(m,2H),2.39(s,3H),2.08–1.93(m,2H),1.89–1.79(m,2H).

Step 5: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine-1- Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine (150 mg, 0.4 mmol), (S)-2- (Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (118 mg, 0.4 mmol), N,N-diiso Propylethylamine (259 mg, 2.01 mmol) was added to acetonitrile (3 mL), and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 35%) yielded 158 mg of colorless oily product with a yield of 62.3%.

LC-MS (ESI): [M+H] ⁺ =632.4.

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine-1- Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl (1H-benzo[d]imidazole-6-carboxylic acid methyl ester (95 mg, 0.15 mmol), lithium hydroxide monohydrate (31.5 mg, 0.75 mmol) was added to water (2 mL) and 1,4-di In a mixed solution of oxane (6 mL), react at 40°C for 2 hours. TLC detects that the raw material has completely disappeared and stops heating. Adjust the pH of the system to about 6 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 25%) to obtain 34 mg of white solid product, with a yield of 36%.

LC-MS (ESI): [M+H] ⁺ =618.3.

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.64 (br.s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H),7.47–7.42(m,2H),7.18–6.97(m,3H),6.56(d,J＝6.4Hz,1H),5.16–5.05(m,1H),5.00(s,2H),4.85 –4.73(m,1H),4.71–4.59(m,1H),4.54–4.46(m,1H),4.41–4.33(m,1H),3.91(d,J＝13.5Hz,1H),3.75(d ,J＝13.5Hz,1H),3.01–2.66(m,4H),2.46–2.38(m,1H),2.33(s,3H),2.12–1.94(m,2H),1.64–1.39(m,4H ).

Example 20 (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 20)

Step 1: Synthesis of 4-(benzyloxy)-3-bromopyridine

Compound 3-bromo-4-hydroxypyridine (600mg, 3.45mmol), benzyl bromide (589mg, 3.45mmol) and potassium carbonate (714mg, 5.17mmol) were added to N,N-dimethylformamide (20mL), React at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (100mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) yielded 632 mg of colorless oily product with a yield of 69.4%.

LC-MS(ESI): [M+H] ⁺ =264.0;

¹ H NMR (500MHz, CDCl ₃ ) δ7.78(d,J＝1.9,1H),7.50–7.39(m,3H),7.35(dd,J＝7.5,2.4Hz,1H),7.24–7.18(m ,2H),6.49(d,J=7.5Hz,1H),4.97(s,2H).

Step 2: Synthesis of 4-(benzyloxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester

4-(Benzyloxy)-3-bromopyridine (500 mg, 1.89 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborocyclopentane-2 -tert-butyl)-3,6-dihydropyridine-1(2H)-carboxylate (644 mg, 2.08 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride Dichloromethane complex (155 mg, 0.19 mmol) and potassium carbonate (523 mg, 3.78 mmol) were added to the mixed solution of water (1 mL) and 1,4-dioxane (4 mL), replaced with nitrogen three times, and placed React at 90°C for 2 hours. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer Analytical purification (eluent PE: EA (v/v) = 15%) yielded 0.605g of brown oily product with a yield of 87.2%.

LC-MS (ESI): [M+H] ⁺ =367.3.

Step 3: Synthesis of tert-butyl 4-(4-hydroxypyridin-3-yl)piperidine-1-carboxylate

4-(Benzyloxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (707 mg, 1.93 mmol), palladium on carbon (350 mg), added to the methanol (12 mL) solution, replaced with hydrogen three times, and stirred at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Celite suction filtration, and the filtrate was concentrated under reduced pressure to obtain 0.499g of brown solid product, with a yield of 92.9%.

LC-MS (ESI): [M-55] ⁺ =223.1.

Step 4: Synthesis of tert-butyl 4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylate

4-(4-Hydroxypyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (290mg, 1.04mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (250mg ,0.95mmol), potassium carbonate (262mg, 1.9mmol) was added to 10mL of N,N-dimethylformamide, and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 260 mg of colorless oily product with a yield of 82.3%.

LC-MS (ESI): [M+H] ⁺ =461.3.

¹ H NMR (500MHz, CDCl ₃ ) δ7.38–7.33 (m, 1H), 7.32–7.28 (m, 1H), 7.23 (s, 1H), 7.00 (d, J = 8.1Hz, 1H), 6.39 ( d,J＝7.4Hz,1H),6.06(d,J＝6.6Hz,1H),5.10(s,2H),4.27–4.10(m,2H),3.15–3.00(m,1H),2.93–2.72 (m,2H),1.90–1.85(m,4H),1.46(s,9H).

Step 5: Synthesis of 4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine

4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (232 mg, 0.5 mmol), Add to trifluoroacetic acid (2 mL) and dichloromethane (4 mL), and stir at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. The solvent was concentrated under reduced pressure and evaporated to dryness. Use saturated sodium bicarbonate aqueous solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown The solid product was used directly in the next reaction.

LC-MS (ESI): [M+H] ⁺ =361.2.

Step 6: (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl) Synthesis of Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

4-((4-Chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine (150 mg, 0.42 mmol), (S)-2-( Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (122 mg, 0.42 mmol), N,N-diisopropyl Ethylamine (268 mg, 2.08 mmol) was added to acetonitrile (5 mL), and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (5mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent DCM: MeOH (v/v) = 20%) yielded 116 mg of colorless oily product, yield 45.1%

LC-MS (ESI): [M+H] ⁺ =619.4.

Step 7: (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (116 mg, 0.19 mmol), lithium hydroxide monohydrate (39.3 mg, 0.94 mmol) was added to a mixed solution of water (2 mL) and 1,4-dioxane (6 mL), and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 6 with diluted acetic acid aqueous solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 2 5%) to obtain 53 mg of white solid product, with a yield of 44.4%.

LC-MS(ESI): [M+H] ⁺ =605.3;

¹ H NMR (500MHz, CDCl ₃ ) δ12.64(s,1H),8.25(s,1H),7.80(d,J＝8.4Hz,1H),7.67(s,2H),7.63(d,J＝ 8.5Hz,1H),7.42(d,J＝8.2Hz,1H),7.19(d,J＝8.2Hz,1H),6.53(d,J＝6.4Hz,1H),6.07(d,J＝7.5Hz ,1H),5.34(s,2H),5.11–5.02(m,1H),4.78(dd,J＝15.2,7.1Hz,1H),4.64(d,J＝15.0Hz,1H),4.52–4.41( m,1H),4.40–4.33(m,1H),3.92(d,J＝13.5Hz,1H),3.77(d,J＝13.5Hz,1H),2.99–2.91(m,1H),2.85–2.78 (m,1H),2.76–2.57(m,2H),2.44–2.36(m,1H),2.21–2.07(m,2H),1.75–1.67(m,2H),1.50–1.36(m,2H) .

Example 21 (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 21)

Step 1: Synthesis of tert-butyl 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

Compound 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.54 mmol), 7-(bromomethyl)-2,4-dichlorobenzofuran ( 227 mg, 0.81 mmol) was added to N,N-dimethylformamide (5 mL). Add potassium carbonate (224 mg, 1.62 mmol) and stir at 60°C for 1 hour. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EA:PE (v/v)=1:10) to obtain 157 mg of light brown solid product with a yield of 73.7%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.21–7.15(m,2H),6.96–6.90(m,2H),6.84–6.80(m,1H),6.67(s,1H),5.25(s,2H ),4.11–4.05(m,2H),2.97–2.87(m,1H),2.61–2.51(m,2H),1.55–1.36(m,2H),1.41(s,9H),1.21–1.16(m ,2H).

Step 2: Synthesis of 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine

Compound 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester (157 mg, 0.40 mmol) Add ethyl acetate (5 mL), add 1.4-dioxane hydrochloric acid (5 mL), and stir at room temperature for 2 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 10:1) to obtain 125 mg of light brown solid product with a yield of 79.2%.

LC-MS (ESI): [M+H] ⁺ =394.3.

Step 3: (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (68 mg, 0.23 mmol ), potassium carbonate (79 mg, 0.57 mmol), and potassium iodide (2 mg, 0.02 mmol) were added to acetonitrile (2 mL). Compound 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (125 mg, 0.19 mmol) was added to acetonitrile (2 mL), and the mixture was added dropwise. Add diisopropylethylamine (0.5 mL) to the reaction system and stir at 60°C for 2 hours. Add water (5 mL), extract with ethyl acetate (10 mL /v)=3:2), 80 mg of off-white solid product was obtained, with a yield of 64.5%.

LC-MS (ESI): [M+H] ⁺ =652.5.

Step 4: (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.12 mmol) was added to dioxane (2 mL), in water (0.5 mL). Lithium hydroxide (18 mg, 0.72 mmol) was added and stirred at 40°C for 4 hours. Adjust the pH to 6-7 with hydrochloric acid (0.5N), extract with ethyl acetate (5mL×3), combine the organic phases, wash the organic phases once with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and purify using Prep-HPLC (eluent CH ₃ CN:H ₂ O (v/v) = 50%) to obtain 34.7 mg of white solid product with a yield of 45.3%.

LC-MS(ESI): [M+H] ⁺ =638.3;

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.69 (s, 1H), 8.25 (s, 1H), 7.80 (d, J = 9.8Hz, 1H), 7.63 (d, J = 8.4Hz, 1H) ,7.40(d,J＝8.0Hz,1H),7.33(d,J＝8.0Hz,1H),7.22(s,1H),7.18–7.04(m,2H),6.98(d,J＝7.6Hz, 1H),5.29(s,2H),5.06(d,J＝7.0Hz,1H),4.76(dd,J＝15.2,7.0Hz,1H),4.62(d,J＝12.8Hz,1H),4.48( dd,J＝14.0,7.4Hz,1H),4.36(dt,J＝11.8,5.8Hz,1H),3.87(d,J＝13.4Hz,1H),3.72(d,J＝13.6Hz,1H), 2.89(d,J＝11.4Hz,1H),2.78–2.59(m,3H),2.42(d,J＝8.4Hz,1H),1.99–1.82(m,2H),1.52–1.37(m,2H) ,1.26(s,2H).

Example 22 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl) Synthesis of -1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 22)

Step 1: 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl) Synthesis of -1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (96 mg, 0.25 mmol), 2-(chloromethyl )-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (96mg, 0.3mmol), potassium carbonate (105mg, 0.76mmol) ), potassium iodide (5 mg, 0.03 mmol) was added to acetonitrile (4.5 mL), and stirred at 60°C for 1 h. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 10:1) to obtain 108 mg of light yellow floc product with a yield of 62.0%.

LC-MS(ESI): [M+1] ⁺ =659.5.

Step 2: 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl) Synthesis of -1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)- 1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (80 mg, 0.12 mmol) was added to 1,4-dioxane (1.5 mL), add lithium hydroxide (16 mg, 0.67 mmol) to water (0.5 mL) to completely dissolve, then add dropwise to the reaction system, and stir at 40°C overnight. Acetic acid (0.5 mL) was added to adjust the pH to slightly acidic. Concentrate under reduced pressure and purify using Prep-HPLC (eluent acetonitrile: water (v/v) = 40%) to obtain 16.5 mg of white solid product with a yield of 21.1%.

LC-MS(ESI): [M+1] ⁺ =645.3;

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.84(s,1H),8.25(s,1H),7.83–7.80(m,1H),7.67–7.65(m,1H),7.42(d,J ＝8Hz,1H),7.34(d,J＝8Hz,1H),7.15–6.97(m,3H),6.56(d,J＝6.4Hz,1H),5.27(s,2H),4.59(s,2H ),3.80(s,2H),2.92–2.89(m,2H),2.7–2.68(m,3H),1.96–1.9(m,2H),1.51–1.48(m,2H),1.32–1.29(m ,2H),0.75–0.67(m,4H).

Example 23 2-((4-(2-(((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl Synthesis of 1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 23)

Step 1: Synthesis of methyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate

Dissolve 3-fluoro-4-nitrobenzoic acid methyl ester (1g, 5.02mmol) and 2-methoxyethyl-1-amine (0.5mL, 6.03mmol) in DMF (15mL), then add potassium carbonate (1.39 g, 10.04 mmol) and stirred at room temperature for 2.5 h, added water, extracted three times with ethyl acetate, dried, concentrated, and purified through silica gel column (PE/EA=5/1) to obtain 920 mg of yellow oil with a yield of 72.1%.

LC-MS (ESI): [M+H] ⁺ =255.2.

Step 2: Synthesis of methyl 4-amino-3-((2-methoxyethyl)amino)benzoate

Dissolve 3-((2-methoxyethyl)amino)-4-nitrobenzoic acid methyl ester (920mg, 3.62mmol) in dioxane (10mL) and water (2.00mL), then add zinc Powder (1.2g, 18.10mmol) and ammonium chloride (968mg, 18.10mmol) were reacted at room temperature for 2h. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to obtain 730 mg of crude product as purple oil, with a yield of 90.0%.

LC-MS (ESI): [M+H] ⁺ =225.2.

Step 3: Synthesis of 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

The compound 4-amino-3-((2-methoxyethyl)amino)benzoic acid methyl ester (1g, 4.46mmol) and 2-chloro-1,1,1-trimethoxyethane (1.03g, 6.69 mmol) was added to tetrahydrofuran (10 mL), p-toluenesulfonic acid monohydrate (0.08g, 0.45mmol) was added, and the temperature was raised to 50°C under nitrogen protection for 2 hours. Cool to room temperature, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent PE:EA (v/v)=20:1) to obtain 1.15g of off-white solid product with a yield of 91.2%.

¹ HNMR (400MHz, CDCl ₃ ) δ8.05(d,J＝0.8Hz,1H),7.93(dd,J＝8.4,1.5Hz,1H),7.71(d,J＝8.4Hz,1H),4.89( s,2H),4.45(t,J＝5.2Hz,2H),3.89(s,3H),3.66(t,J＝5.2Hz,2H),3.20(s,3H).

Step 4: 2-((4-(2-(((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl Synthesis of )-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine and 2-(chloromethyl)-1-(2 -Methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (72mg, 0.25mmol) was added to acetonitrile (5mL), potassium carbonate (32mg, 0.23mmol) and potassium iodide (38mg, 0.23mmol), and the temperature was raised to 60°C for 1 hour under nitrogen protection. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 20:1) to obtain 130 mg of light yellow solid product with a yield of 90.5%.

LC-MS (ESI): [M+H] ⁺ =624.5.

Step 5: 2-((4-(2-(((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl Synthesis of )-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound 2-((4-(2-(((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl) -1-(2-Methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (130 mg, 0.21 mmol) was added with 1,4-dioxane (1 mL) and water (0.5 mL). Add lithium hydroxide (44 mg, 1.05 mmol). Raise the temperature to 40°C under nitrogen protection and react for 2 hours. Add acetic acid (1 mL) to adjust the pH to weak acidity. Concentrate under reduced pressure and purify with Prep-HPLC (elution (CH ₃ CN:H ₂ O (v/v) = 60%), 100 mg of white solid product was obtained with a yield of 77.9%.

LC-MS(ESI): [M+H] ⁺ =610.3;

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.17 (s, 1H), 7.80 (d, J = 8.4Hz, 1H), 7.63 (d, J = 8.4Hz, 1H), 7.42 (d, J = 8.0 Hz,1H),7.34(d,J＝8.4Hz,1H),7.14–7.08(m,2H),6.98(d,J＝7.6Hz,1H),6.56(d,J＝6.4Hz,1H), 5.27(s,2H),4.58(t,J＝5.2Hz,2H),3.78(s,2H),3.72(t,J＝5.2Hz,2H),3.22(s,3H),2.84(d,J ＝11.2Hz,2H),2.74–2.68(m,1H),1.93(t,J＝11.2Hz,2H),1.51–1.46(m,2H),1.31(d,J＝11.6Hz,2H).

Example 24 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 24)

Step 1: Synthesis of tert-butyl 4-(3,5-difluoro-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

2-Bromo-4,6-difluorophenol (0.6g, 3.14mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -tert-butyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.07g, 3.45mmol), [1,1'-bis(diphenylphosphine)ferrocene] dichloride Palladium dichloromethane complex (0.26g, 0.31mmol) and potassium carbonate (0.87g, 6.28mmol) were added to the mixed solution of water (3mL) and 1,4-dioxane (12mL), and replaced with nitrogen. Three times, place at 90°C for 2 hours. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer Analytical purification (eluent PE: EA (v/v) = 15%) yielded 0.896g of brown oily product with a yield of 97.2%.

¹ H NMR (500MHz, CDCl ₃ ) δ6.83–6.77(m,2H),6.04–5.75(m,2H),4.09–4.02(m,2H),3.65–3.58(m,2H),2.51–2.39 (m,2H),1.50(s,9H).

Step 2: Synthesis of tert-butyl 4-(3,5-difluoro-2-hydroxyphenyl)piperidine-1-carboxylate

Add 4-(3,5-difluoro-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1g, 3.21mmol) and palladium on carbon (550mg). into ethanol (10 mL), replaced with hydrogen three times, and stirred at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Celite suction filtration, and the filtrate was concentrated under reduced pressure to obtain 966 mg of brown solid product with a yield of 96.0%.

LC-MS(ESI): [M-55] ⁺ =258.0;

¹ H NMR (500MHz, CDCl ₃ ) δ6.74–6.60(m,2H),5.61(s,1H),4.41–4.09(m,2H),3.14–3.04(m,1H),2.88-2.74(m ,2H),1.81(d,J＝12.9Hz,2H),1.60–1.52(m,2H),1.48(s,9H).

Step 3: tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine-1-carboxylate synthesis

4-(3,5-Difluoro-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (356mg, 1.14mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzene Furan (250 mg, 0.95 mmol) and potassium carbonate (262 mg, 1.9 mmol) were added to 10 mL of N,N-dimethylformamide, and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) yielded 309 mg of colorless oily product with a yield of 54.3%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.19–7.10 (m, 2H), 6.70–6.62 (m, 1H), 6.60–6.52 (m, 1H), 5.96 (d, J = 6.5Hz, 1H), 5.16(s,2H),4.18–4.05(m,2H),2.96–2.86(m,1H),2.60–2.42(m,2H),1.61–1.46(m,2H),1.43(s,9H), 1.35–1.30(m,2H).

Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine

Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine-1-carboxylate (253 mg, 0.51 mmol), added to trifluoroacetic acid (4 mL) and dichloromethane (4 mL), and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. Concentrate the solvent to dryness under reduced pressure, adjust the pH of the system to about 6 with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown The solid product was 187 mg, and the yield was 92.6%.

LC-MS(ESI): [M+H] ⁺ =396.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.27 (s, 1H), 7.20 (d, J = 7.9Hz, 1H), 6.87–6.74 (m, 1H), 6.69 (d, J = 9.2Hz, 1H) ,6.06(d,J＝6.3Hz,1H),5.25(s,2H),3.42(d,J＝12.7Hz,2H),3.14–3.02(m,1H),2.78(t,J＝11.8Hz, 2H),1.94–1.77(m,2H),1.71–1.56(m,2H).

Step 5: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine (150 mg, 0.38 mmol), (S)- 2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (112 mg, 0.38 mmol), N,N- Diisopropylethylamine (245 mg, 1.9 mmol) was added to acetonitrile (10 mL), and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 35%) yielded 153 mg of colorless oily product with a yield of 61.6%.

LC-MS(ESI): [M+H] ⁺ =654.5;

¹ H NMR (500MHz, CDCl ₃ ) δ8.15 (s, 1H), 8.12 (s, 1H), 8.00 (d, J = 8.6Hz, 1H), 7.96 (d, J = 8.5Hz, 1H), 7.79 (d,J＝8.6Hz,1H),7.75(d,J＝8.5Hz,1H),7.28–7.20(m,1H),6.03(d,J＝6.5Hz,1H),5.21(s,2H) ,4.77–4.57(m,4H),4.40–4.36(m,1H),3.95(s,2H),3.94(s,3H),2.96–2.82(m,3H),2.80–2.67(m,2H) ,2.52–2.37(m,2H),2.17–2.07(m,2H),1.57–1.52(m,2H).

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine-1- (153 mg, 0.23 mmol), lithium hydroxide monohydrate (49 mg, 1.17 mmol) was added to a mixed solution of water (1 mL) and 1,4-dioxane (4 mL), and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v)=25%) to obtain 101 mg of white solid product, with a yield of 64.1%.

LC-MS(ESI): [M+H] ⁺ =640.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.59 (s, 1H), 8.27 (s, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.65 (d, J = 8.4Hz, 1H) ,7.42(d,J＝8.0Hz,1H),7.34(d,J＝8.1Hz,1H),7.22–7.13(m,1H),6.94–6.85(m,1H),6.54(d,J＝6.3 Hz,1H),5.23(s,2H),5.11–5.02(m,1H),4.83–4.72(m,1H),4.68–4.58(m,1H),4.55–4.46(m,1H),4.39– 4.31(m,1H),3.88(d,J＝13.5Hz,1H),3.74(d,J＝13.5Hz,1H),2.91(d,J＝11.1Hz,1H),2.80(d,J＝11.3 Hz,1H),2.76–2.63(m,2H),2.46–2.34(m,1H),2.05–1.90(m,2H),1.57–1.42(m,2H),1.36–1.26(m,2H).

Example 25 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 25)

Step 1: Synthesis of tert-butyl 4-(4-fluoro-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

2-Bromo-5-fluorophenol (0.6g, 3.14mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.07g, 3.45mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride Methane complex (0.26g, 0.31mmol) and potassium carbonate (0.87g, 6.28mmol) were added to the mixed solution of water (3mL) and 1,4-dioxane (12mL), replaced with nitrogen three times, and placed React at 90°C for 2 hours. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer After analytical purification (eluent PE: EA (v/v) = 15%), 0.697g of brown oily product was obtained, with a yield of 75.6%.

LC-MS(ESI): [M-55] ⁺ =238.2.

Step 2: Synthesis of tert-butyl 4-(4-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate

4-(4-Fluoro-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (789mg, 2.69mmol) and palladium on carbon (400mg) were added to methanol ( 15 mL), replaced with hydrogen three times, and stirred at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Celite suction filtration, and the filtrate was concentrated under reduced pressure to obtain 756 mg of a light yellow solid product with a yield of 95.2%.

LC-MS(ESI): [M-55] ⁺ =240.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.05–6.99(m,1H),6.60–6.52(m,2H),6.31(s,1H),4.36–4.17(m,2H),3.02–2.92(m ,1H),2.89–2.74(m,2H),1.83–1.75(m,2H),1.62–1.54(m,2H),1.49(s,9H).

Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidine-1-carboxylate

4-(4-Fluoro-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (308 mg, 1.04 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran ( 250 mg, 0.95 mmol), potassium carbonate (262 mg, 1.9 mmol) were added to 10 mL of N,N-dimethylformamide, and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 367 mg of colorless oily product with a yield of 80.9%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.30–7.23(m,2H),7.09(t,J＝8.5Hz,1H),6.75–6.59(m,2H),6.04(d,J＝6.6Hz, 1H),5.25(s,2H),4.30–4.12(m,2H),3.09–3.01(m,1H),2.81–2.65(m,2H),1.80–1.73(m,2H),1.61–1.49( m,2H),1.47(m,9H).

Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidine

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester (267 mg, 0.56 mmol) , was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. The solvent was concentrated under reduced pressure and evaporated to dryness. Use saturated sodium bicarbonate aqueous solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown The solid product was used directly in the next reaction.

LC-MS (ESI): [M+H] ⁺ =378.3.

Step 5: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidine (128 mg, 0.34 mmol), (S)-2-( Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.34 mmol), N,N-diisopropyl Ethylamine (220 mg, 1.75 mmol) was added to acetonitrile (5 mL), and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 35%) yielded 151 mg of colorless oily product with a yield of 69.8%.

LC-MS(ESI): [M+H] ⁺ =636.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.17(s,1H),7.96(dd,J＝8.5,1.6Hz,1H),7.75(d,J＝8.5Hz,1H),7.30–7.23(m, 2H),7.15–7.08(m,1H),6.73–6.61(m,2H),6.04(d,J＝6.6Hz,1H),5.25(s,2H),5.23–5.17(m,1H),4.79 –4.58(m,3H),4.42–4.35(m,1H),3.96(s,2H),3.94(s,3H),2.80–2.62(m,3H),2.52–2.39(m,1H),2.34 –2.18(m,1H),1.86–1.75(m,2H),1.84–1.75(m,2H),1.72–1.62(m,2H)

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Methyl(S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (92 mg, 0.14 mmol), lithium hydroxide monohydrate (30.3 mg, 0.74mmol) was added to a mixed solution of 2mL water and 6mL 1,4-dioxane, and reacted at 40°C for 2 hours. TLC detects that the raw material has completely disappeared and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 25%) to obtain 48 mg of light yellow solid product, with a yield of 50.6%.

LC-MS(ESI): [M+H] ⁺ =622.3;

¹ H NMR (500MHz, CDCl ₃ ) δ8.25(s,1H),7.80(d,J＝8.5Hz,1H),7.63(d,J＝8.4Hz,1H),7.50–7.42(m,2H) ,7.19(t,J＝7.7Hz,1H),7.07(d,J＝11.3Hz,1H),6.76–6.71(m,1H),6.54(d,J＝6.4Hz,1H),5.38(s, 2H),5.10–5.03(m,1H),4.80–4.73(m,1H),4.65–4.59(m,1H),4.51–4.45(m,1H),4.38–4.32(m,1H),3.90( d,J ＝13.5Hz,1H),3.76(d,J＝13.6Hz,1H),2.99–2.91(m,1H),2.88–2.80(m,2H),2.74–2.64(m,1H),2.44–2.36( m,1H),2.19–1.96(m,3H),1.68–1.50(m,3H).

Example 26 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 26)

Step 1: Synthesis of tert-butyl 4-(5-fluoro-6-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

2-Bromo-4-fluorophenol (600 mg, 3.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.07g, 3.45mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane Complex (0.26g, 0.31mmol) and potassium carbonate (0.86g, 6.28mmol) were added to a mixed solution of water (3mL) and 1,4-dioxane (12mL), replaced with nitrogen three times, and placed React at 90°C for 2 hours. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer After analytical purification (eluent PE: EA (v/v) = 15%), 896 mg of colorless oily product was obtained, with a yield of 97.2%.

LC-MS(ESI): [M-55] ⁺ =238.1;

¹ H NMR (500MHz, CDCl ₃ ) δ6.92–6.73 (m, 3H), 6.05–5.80 (m, 2H), 4.07 (s, 2H), 3.63 (t, J = 5.7Hz, 2H), 2.46 ( s,2H),1.50(s,9H).

Step 2: Synthesis of tert-butyl 4-(5-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate

Add 4-(5-fluoro-6-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4g, 4.77mmol) and palladium on carbon (700mg) to methanol (15mL ), replace with hydrogen three times, and stir at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Suction filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 896 mg of brown solid product, with a yield of 63.6%.

LC-MS(ESI): [M-55] ⁺ =240.2;

¹ H NMR (500MHz, CDCl ₃ ) δ6.81 (dd, J＝9.8, 2.7Hz, 1H), 6.77–6.69 (m, 2H), 6.05 (s, 1H), 4.36–4.08 (m, 2H), 3.07–2.97(m,1H),2.92–2.72(m,2H),1.88–1.76(m,2H),1.59–1.51(m,2H),1.49(s,9H).

Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidine-1-carboxylate

4-(2-Fluoro-6-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (308 mg, 1.04 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran ( 250 mg, 0.95 mmol) and potassium carbonate (262 mg, 2 mmol) were added to N,N-dimethylformamide (8 mL), and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) yielded 262 mg of colorless oily product with a yield of 57.8%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.30–7.22(m,2H),6.92–6.81(m,3H),6.04(d,J=6.6Hz,1H),5.25(s,2H),4.22( s,2H),3.15–3.05(m,1H),2.75(s,2H),1.77(d,J＝12.9Hz,2H),1.58–1.49(m,2H),1.47(s,9H).

Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidine

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester (326 mg, 0.68 mmol) , was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL), and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. Concentrate the solvent to dryness under reduced pressure, adjust the pH of the system to about 7 with saturated sodium bicarbonate aqueous solution, extract with ethyl acetate (15mL×3), combine the organic phases, Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a brown oily product which is used directly in the next step.

LC-MS(ESI): [M+H] ⁺ =378.3;

¹ H NMR (500MHz, CDCl ₃ ) δ7.29–7.19(m,2H),6.97–6.87(m,3H),6.05(d,J＝6.8Hz,1H),5.25(s,2H),3.54– 3.42(m,2H),3.27–3.18(m,1H),3.01–2.91(m,2H),2.03–1.94(m,2H),1.46–1.37(m,2H).

Step 5: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidine (192 mg, 0.51 mmol), (S)-2-( Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (150 mg, 0.51 mmol), N,N-diisopropyl Ethylamine (328 mg, 2.54 mmol) was added to acetonitrile (10 mL), and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 35%) yielded 242 mg of light yellow oily product with a yield of 74.8%.

LC-MS(ESI): [M+H] ⁺ =636.5;

¹ H NMR (500MHz, CDCl ₃ ) δ8.17(s,1H),7.96(d,J＝8.6Hz,1H),7.74(d,J＝8.5Hz,1H),7.29–7.21(m,2H) ,6.93–6.81(m,3H),6.03(d,J＝6.6Hz,1H),5.23(s,2H),4.80–4.57(m,4H),4.45–4.36(m,1H),3.96–3.94 (m,2H),3.94(s,3H),3.06–2.89(m,3H),2.80–2.69(m,1H),2.50–2.38(m,1H),2.31–2.17(m,2H),1.84 –1.75(m,2H),1.69–1.59(m,2H).

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)methyl methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (242 mg, 0.38 mmol), lithium hydroxide monohydrate (79.8 mg ,1.9mmol) was added to a mixed solution of water (3mL) and 1,4-dioxane (9mL), and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 25%) to obtain 106 mg of white solid product, with a yield of 40%.

LC-MS(ESI): [M+H] ⁺ =622.3;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.71 (s, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H) ,7.47–7.38(m,2H),7.17–7.14(m,1H),7.05–6.95(m,2H),6.53(d,J＝6.4Hz,1H),5.33(s,2H),5.11–4.96 (m,1H),4.83–4.73(m,1H),4.68–4.59(m,1H),4.54–4.44(m,1H),4.39–4.31(m,1H),3.91(d,J＝13.6Hz ,1H),3.77(d,J＝13.5Hz,1H),3.00–2.79(m,3H),2.77–2.65(m,1H),2.44–2.33(m,1H),2.18–2.04(m,2H ),1.73–1.46(m,4H).

Example 27 (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 27)

Step 1: Synthesis of 4-bromo-2-(2,2-diethoxyethoxy)-1-toluene

Compound 5-bromo-2-methylphenol (25g, 134.4mmol), 2-bromo-1,1-diethoxyethane (31.8g, 162.3mmol) and potassium carbonate (37.1g, 268.8mmol) were added into N,N-dimethylformamide (250 mL), and stirred at 120°C overnight under nitrogen protection. Add water (300 mL), extracted with ethyl acetate (100mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc: PE (v/v) = 1%) to obtain 40g of light brown liquid product, yield 98.5%.

Step 2: Synthesis of 4-bromo-7-methylbenzofuran

Compound 4-bromo-2-(2,2-diethoxyethoxy)-1-toluene (40g, 132.2mmol) and polyphosphoric acid (68g, 829.4mmol) were added to 1,2-dichloroethyl alkane (400 mL) and react overnight at 85°C under nitrogen protection. The solvent was removed under reduced pressure, water (100 mL) was added, extracted with dichloromethane (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE=100 %), 17 g of colorless liquid product was obtained, with a yield of 60.8%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.68 (d, J = 4Hz, 1H), 7.30–7.26 (m, 1H), 6.97 (d, J = 8.0Hz, 1H), 6.80 (d, J = 4Hz, 1H),2.48(s,3H).

Step 3: Synthesis of 7-methylbenzofuran-4-cyano

Add compound 4-bromo-7-methylbenzofuran (16g, 75.8mmol) to N,N-dimethylformamide (160mL), add copper cyanide (33.95g, 378.5mmol), and protect with nitrogen. React overnight at 120°C. Add water (500mL), extract with ethyl acetate (150mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent: PE=100%) to obtain The colorless liquid product was 8.3g, and the yield was 69.7%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.78 (d, J = 4Hz, 1H), 7.49 (d, J = 8Hz, 1H), 7.16 (d, J = 8Hz, 1H), 6.98 (s, 1H), 2.59(s,3H).

Step 4: Synthesis of 2-chloro-7-methylbenzofuran-4-cyano

Compound 7-methylbenzofuran-4-cyano (1 g, 6.4 mmol) was added to tetrahydrofuran (15 mL). Under nitrogen protection, cool at -78°C. At this temperature, lithium diisopropylamide (2.6 mL) was added and stirred for one hour. Add hexachloroethane (1.6g, 6.8mmol), remove the cryopump, and stir overnight. Add water (45 mL) at 0°C, add ethyl acetate (50 mL /v)=5%), 800 mg of colorless liquid product was obtained, with a yield of 65.6%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.48 (d, J = 8Hz, 1H), 7.15 (d, J = 8Hz, 1H), 6.81 (s, 1H), 2.56 (s, 3H).

Step 5: Synthesis of 7-(bromomethyl)-2-chlorobenzofuran-4-nitrile

The compound 2-chloro-7-methylbenzofuran-4-cyano (800 mg, 4.2 mmol), azobisisobutyronitrile (137 mg, 0.8 mmol) and N-bromosuccinimide (1.1 g , 6.2 mmol) was added to 1,2-dichloroethane (36 mL), and the reaction was carried out at 85°C overnight under nitrogen protection. Add water (50mL), extract with dichloromethane (30mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent EtOAc:PE (v/v) =1%), 700 mg of colorless liquid product was obtained, with a yield of 61.9%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.56 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 4.71 (s, 2H).

Step 6: Synthesis of tert-butyl 4-(2-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

Compound 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.34 mmol), 7-(bromomethyl)-2-chlorobenzofuran-4-carbonitrile (138 mg, 0.51 mmol) was added to N,N-dimethylformamide (5 mL). Add potassium carbonate (141 mg, 1.02 mmol) and stir at 60°C for 1 hour. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EA:PE (v/v)=1:10) to obtain 130 mg of light brown solid product with a yield of 78.8%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.55(d,J＝7.8Hz,1H),7.45(d,J＝7.8Hz,1H),7.01–6.90(m,2H),6.87(d,J＝6.8 Hz,1H),6.81(s,1H),5.33(s,2H),4.16–4.07(m,2H),2.97–2.92(m,1H),2.64–2.57(m,2H),1.50–1.38( m,11H),1.21–1.16(m,2H).

Step 7: Synthesis of 2-chloro-7-((2-fluoro-6-(piperidin-4-yl)phenoxy)methyl)benzofuran-4-nitrile

Compound 4-(2-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.27 mmol) was added to ethyl acetate (5 mL), 1.4-dioxane hydrochloric acid (5 mL) was added, and stirred at room temperature for 2 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 10:1) to obtain 100 mg of light brown solid product with a yield of 96.5%.

LC-MS (ESI): [M+H] ⁺ =385.4.

Step 8: (S)-2-((4-(2-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1- Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (84 mg, 0.31 mmol ), potassium carbonate (108 mg, 0.78 mmol), and potassium iodide (5 mg, 0.03 mmol) were added to acetonitrile (1 mL), stirred for five minutes, and compound 2-chloro-7-((2-fluoro-6-(piperidine- 4-yl)phenoxy)methyl)benzofuran-4-nitrile (100 mg, 0.26 mmol), stirred at 60°C for 2 hours. Add water (5 mL), extract with ethyl acetate (10 mL /v)=3:2), 100 mg of off-white solid product was obtained, with a yield of 59.9%.

LC-MS(ESI): [M+H] ⁺ =643.5;

¹ H NMR (400MHz, CDCl ₃ ) δ8.08 (s, 1H), 7.91 (d, J = 8.6Hz, 1H), 7.68 (d, J = 8.5Hz, 1H), 7.55 (d, J = 7.8Hz ,1H),7.44(d,J＝7.8Hz,1H),7.01–6.87(m,3H),6.81(s,1H),5.32(s,2H),5.17–5.09(m,1H),4.74– 4.51(m,3H),4.44–4.38(m,1H),3.91–3.85(m,2H),3.88(s,3H),2.92–2.85(m,2H),2.69–2.61(m,1H), 2.42–2.38(m,1H),2.06–2.01(m,2H),1.65–1.51(m,5H).

Step 9: (S)-2-((4-(2-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1- Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.16 mmol) was added to dioxane (2 mL ) and water (0.5 mL). Lithium hydroxide (23 mg, 0.96 mmol) was added and stirred at 40°C for 4 hours. Adjust the pH to 6-7 with hydrochloric acid (0.5N), extract with ethyl acetate (5mL×3), combine the organic phases, wash the organic phase once with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and purify using Prep-HPLC (eluent CH ₃ CN: H ₂ O (v/v) = 50%) to obtain 22.4 mg of white solid product with a yield of 22.3%.

LC-MS(ESI): [M+H] ⁺ =629.3;

¹ HNMR (400MHz, DMSO-d ₆ ) δ12.72 (s, 1H), 8.26 (s, 1H), 7.87 (d, J = 7.8Hz, 1H), 7.80 (d, J = 8.5Hz, 1H), 7.64(d,J＝8.4Hz,1H),7.55(d,J＝7.8Hz,1H),7.44(s,1H),7.12(dt,J＝13.5,8.1Hz,2H),7.01(d,J ＝7.4Hz,1H),5.39(s,2H),5.18–5.01(m,1H),4.77(dd,J＝15.2,7.2Hz,1H),4.63(d,J＝13.0Hz,1H),4.55 –4.45(m,1H),4.36(dd,J＝6.0,3.0Hz,1H),3.89(d,J＝13.5Hz,1H),3.74(d,J＝13.5Hz,1H),2.92(d, J＝10.8Hz,1H),2.79(d,J＝10.8Hz,1H),2.76-2.68(m,2H),2.47–2.37(m,1H),1.99–1.91(m,2H),1.58–1.41 (m,2H),1.36–1.33(m,2H).

Example 28 (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 28)

Step 1: Synthesis of 3-(benzyloxy)-2-chloro-4-fluoropyridine

Add compound 2-chloro-4-fluoropyridin-3-ol (500mg, 3.39mmol) to acetone (10mL), add potassium carbonate (702mg, 5.08mmol) and stir for five minutes, add benzyl bromide (695mg, 4.06mmol) Place at 50°C and stir overnight. Concentrate under reduced pressure, add water (10 mL), ethyl acetate (10 mL), extract, dry and concentrate the organic layer to obtain a crude product, which is purified by column chromatography (eluent PE: EA (v/v) = 10:1). Colorless oily product 550 mg, yield 68.3%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.00 (dd, J＝7.2, 5.6Hz, 1H), 7.41 (dd, J＝7.6, 1.6Hz, 2H), 7.36–7.24 (m, 3H), 6.95 ( dd,J＝9.6,5.2Hz,1H),5.12(s,2H).

Step 2: Synthesis of 3-(benzyloxy)-4-fluoro-3',6'-dihydro-(2,4'-bipyridyl)-1'(2'H)-carboxylic acid tert-butyl ester

Compound 3-(benzyloxy)-2-chloro-4-fluoropyridine (500 mg, 2.10 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxabor Cyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (650mg, 2.10mmol), potassium carbonate (581mg, 4.20mmol) were added to 1,4-dioxy To six rings (10 mL) and water (1 mL), replace the gas with nitrogen three times, add 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (15 mg, 0.02 mmol), and replace with nitrogen again. Place at 85°C and stir overnight. Concentrate under reduced pressure, add water (10 mL), extract with ethyl acetate (10 mL), combine the organic phases, concentrate under reduced pressure, and purify by column chromatography (eluent PE:EA (v/v) = 5:1) to obtain orange color Oily product 860 mg, yield 99%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.18(dd,J＝6.8,5.6Hz,1H),7.34–7.23(m,5H),6.91(dd,J＝10.4,5.2Hz,1H),6.28– 6.20(m,1H),4.95(s,2H),3.98(s,2H),3.49(s,2H),2.46(s,2H),1.42(s,9H).

Step 3: Synthesis of tert-butyl 4-(4-fluoro-3-hydroxypyridin-2-yl)piperidine-1-carboxylate

The compound 3-(benzyloxy)-4-fluoro-3',6'-dihydro-(2,4'-bipyridyl)-1'(2'H)-carboxylic acid tert-butyl ester (840 mg, 2.18 mmol) into methanol (10 mL), add palladium on carbon (84 mg, 0.79 mmol), replace it with hydrogen three times, and stir at room temperature for 30 minutes. Filter through diatomaceous earth, add methanol (10 mL) to wash, concentrate under reduced pressure, and purify by column chromatography (eluent PE: EA (v/v) = 1:1) to obtain 640 mg of colorless oily product, yield 98.8% .

LC-MS(ESI): [M-55] ⁺ =241.3;

¹ H NMR (400MHz, CDCl ₃ ) δ8.03–7.99(m,1H),6.90–6.86(m,1H),4.21–4.16(m,2H),3.38–3.21(m,1H),2.82–2.78 (m,2H),1.82–1.71(m,4H),1.40(s,9H).

Step 4: Synthesis of tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidine-1-carboxylate

Compound 4-(4-fluoro-3-hydroxypyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.01 mmol) was added to N,N-dimethylformamide (5 mL), and Potassium carbonate (419 mg, 3.03 mmol), stir at room temperature for 5 min, add 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (293 mg, 1.11 mmol), stir at 60°C for two hours, reduce Concentrate under pressure and purify through column chromatography (eluent PE:EA (v/v) = 8:1) to obtain 390 mg of light yellow solid product with a yield of 80.4%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.22–8.18(m,1H),7.20–7.14(m,2H),6.93–6.91(m,1H),5.98(d,J＝6.4Hz,1H), 5.27(s,2H),4.21–4.05(m,2H),3.21–2.95(m,1H),2.58(s,2H),1.81–1.65(m,4H),1.38(s,9H).

Step 5: Synthesis of 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoro-2-(piperidin-4-yl)pyridine hydrochloride

The compound 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (390 mg, 0.81 mmol) was added to dioxane hydrochloride solution (5 mL), and stirred at room temperature for 1.5 hours. Concentrate under reduced pressure to obtain 300 mg of off-white solid product with a yield of 97.3%.

LC-MS (ESI): [M+H] ⁺ =379.3.

Step 6: (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoro-2-(piperidin-4-yl)pyridine hydrochloride (130 mg, 0.34 mmol) Add to N,N-dimethylformamide (3mL), add potassium carbonate (142mg, 1.03mmol) and stir at room temperature for five minutes, add (S)-2-(chloromethyl)-1-(oxetane) Alk-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (99 mg, 0.38 mmol), stirred at 60°C for 1.5 hours. Concentrate under reduced pressure and purify through column chromatography (eluent PE:EA (v/v) = 1:1) to obtain 132 mg of light yellow solid product with a yield of 60.4%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.18 (dd, J＝7.1, 5.6Hz, 1H), 8.07 (s, 1H), 7.89 (d, J＝8.3Hz, 1H), 7.67 (d, J＝ 8.5Hz,1H),7.20–7.14(m,2H),6.88(dd,J＝10.9,5.3Hz,1H),5.97(d,J＝6.6Hz,1H),5.24(s,2H),5.14– 5.08(m,1H),4.86–4.44(m,3H),4.35–4.30(m,1H),3.88(s,3H),2.99–2.96(m,1H),2.93–2.86(m,2H), 2.74–2.57(m,1H),2.41–4.36(m,1H),2.10–1.98(m,2H),1.82–1.75(m,2H),1.58–1.38(m,4H).

Step 7: (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidine-1 -(yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (110 mg, 0.17 mmol) was added to 1,4- Dioxane (1.2 mL) and water (0.2 mL) were placed at 40°C and stirred for four hours. Acetic acid (0.1 mL) was added to adjust the pH to 5-6, and purified by Prep-HPLC (eluent acetonitrile: water (v/v) = 60%) to obtain 73 mg of white solid product with a yield of 67.9%.

LC-MS(ESI): [M+H] ⁺ =623.3;

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.75 (s, 1H), 8.29–8.27 (m, 2H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.64 (d, J = 8.4 Hz,1H),7.42(d,J＝8.0Hz,1H),7.36(d,J＝8.4Hz,1H),7.27(dd,J＝11.2,5.2Hz,1H),6.57(d,J＝6.4 Hz,1H),5.34(s,2H),5.14–4.99(m,1H),4.80(dd,J＝15.2,7.2Hz,1H),4.65(dd,J＝15.2,2.4Hz,1H),4.48 (dd,J＝13.6,7.6Hz,1H),4.43–4.36(m,1H),3.89(d,J＝13.6Hz,1H),3.72(d,J＝13.6Hz,1H),2.88–2.84( m,2H),2.79–2.63(m,2H),2.46–2.39(m,1H),2.03–1.86(m,2H),1.77–1.55(m,2H),1.27–1.24(m,2H).

Example 29 (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 29)

Step 1: Synthesis of 3-(benzyloxy)-2-chloro-5-fluoropyridine

Compound 2-chloro-5-fluoropyridin-3-ol (2g, 13.56mmol), benzyl bromide (2.78g, 16.27mmol), and potassium carbonate (3.75g, 27.11mmol) were added to N,N-dimethylmethylmethane amide (20 mL), the reaction solution was stirred at room temperature overnight, the solution was filtered, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (eluent: PE/EA (v/v) = 10:1) obtained a white solid product 2.6g, yield 80.7%.

LC-MS(ESI): [M+H] ⁺ =238.2;

¹ HNMR (400MHz, CDCl ₃ ) δ7.82 (d, J = 4.0Hz, 1H), 7.39–7.26 (m, 5H), 6.96–6.92 (m, 1H), 5.09 (s, 2H).

Step 2: Synthesis of 3-(benzyloxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester

The compound was added to 3-(benzyloxy)-2-chloro-5-fluoropyridine (2g, 8.42mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Heterocyclopentan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.1g, 10.03mmol), (1,1'-bis(diphenylphosphine)bis Ferrocene) dichloropalladium (II) (0.18g, 0.25mmol) was added to 1,4-dioxane (30mL) and water (8mL). The solution was replaced with nitrogen three times, and the reaction solution was stirred at 90°C overnight. , cooled to room temperature, concentrated the reaction solution under reduced pressure, and performed silica gel column chromatography (eluent: PE/EA (v/v) = 5:1) to obtain 2.9 g of colorless oily liquid with a yield of 89.6%.

LC-MS(ESI): [M+H] ⁺ =385.5;

1H NMR (400MHz, CDCl ₃ ) δ8.00(d,J＝2.4Hz,1H),7.38–7.23(m,5H),6.94(dd,J＝10.2,2.4Hz,1H),6.36(d,J ＝29.8Hz,1H),5.03(s,2H),4.06–3.99(m,2H),3.53(t,J＝5.6Hz,2H),2.61–2.54(m,2H),1.41(s,9H) .

Step 3: Synthesis of tert-butyl 4-(5-fluoro-3-hydroxypyridin-2-yl)piperidine-1-carboxylate

The compound 3-(benzyloxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (1g, 2.60 mmol), palladium on carbon (0.2g, 1.88mmol) was added to methanol (50mL), the solution was replaced with hydrogen three times, reacted in a hydrogen atmosphere for 2 hours, and filtered through diatomaceous earth. The filtrate was concentrated to obtain 0.7g of light yellow solid product, with a yield of 90.8%.

LC-MS(ESI): [M+H-56] ⁺ =241.3;

¹ HNMR (400MHz, DMSO-d ₆ ) δ7.96 (d, J = 2.4Hz, 1H), 7.00 (dd, J = 10.4, 2.6Hz, 1H), 4.03 (d, J = 12.2Hz, 2H), 3.20–3.11(m,1H),2.92–2.72(m,2H),1.71–1.54(m,4H),1.41(s,9H).

Step 4: 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester synthesis

Compound 4-(5-fluoro-3-hydroxypyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 1.01 mmol), 7-(bromomethyl)-4-chloro-2-fluoro -1-Benzofuran (400mg, 1.52mmol) and potassium carbonate (279mg, 2.02mmol) were added to N,N-dimethylformamide (8mL). The solution was reacted at 60°C for 2 hours, cooled to room temperature, and reduced to Concentrate the reaction solution under pressure, add water (20 mL), extract with ethyl acetate (20 mL × 3), dry with anhydrous sodium sulfate, and perform silica gel column chromatography (eluent: PE/EA (v/v) = 5:1) , 330 mg of colorless oily liquid was obtained, with a yield of 68.1%.

LC-MS(ESI): [M-55] ⁺ =423.4;

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.12 (d, J = 2.4Hz, 1H), 7.66 (dd, J = 11.0Hz, 2.4Hz, 1H), 7.46 (s, 2H), 6.56 (d, J＝6.4Hz,1H),5.46(s,2H),4.10–3.94(m,2H),3.25-3.14(m,1H),2.76(s,2H),1.70–1.51(m,4H),1.39 (s,9H).

Step 5: (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (200 mg ,0.42mmol) was added to the hydrochloric acid/1,4-dioxane solution (4M, 2mL), and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and acetonitrile (6mL) was added to the solution. N,N- Diisopropylethylamine (1mL), potassium carbonate (174mg, 1.26mmol), potassium iodide (7mg, 0.04mmol), react the solution at 60°C for 2 hours, cool to room temperature, concentrate the reaction solution under reduced pressure, and purify on a silica gel column (Eluant: DCM/MeOH (v/v) = 20:1), 140 mg of light yellow solid product was obtained, with a yield of 42.1%.

LC-MS (ESI): [M+H] ⁺ =637.5.

Step 6: (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine-1 -methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (70 mg, 0.11 mmol), lithium hydroxide (46 mg ,1.10mmol) was added to 1,4-dioxane (3mL) and water (1mL). The solution was stirred at 40°C for 2 hours, cooled to room temperature, and acetic acid was slowly added dropwise until the solution became weakly acidic. Under reduced pressure The reaction solution was concentrated and purified (eluent: ACN/H ₂ O (v/v) = 1:1) to obtain 16 mg of white solid product with a yield of 23.4%.

LC-MS(ESI): [M+H] ⁺ =623.4;

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.23 (s, 1H), 8.12 (d, J = 2.4Hz, 1H), 7.80 (d, J = 8.4Hz, 1H), 7.69–7.57 (m, 2H ),7.49–7.41(m,2H),6.56(d,J＝6.4Hz,1H),5.45(s,2H),5.14–5.05(m,1H),4.84–4.73(m 1H),4.73–4.60 (m,1H),4.52–4.45(m,1H),4.41–4.33(m,1H),3.91(d,J＝13.4Hz,1H),3.75(d,J＝13.4Hz,1H),3.12– 2.88(m,2H),2.85–2.80(m,1H),2.79–2.63(m,1H),2.45–2.40(m,1H),2.21–2.03(m,2H),1.83–1.56(m,4H ).

Example 30 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 30)

Step 1: Synthesis of tert-butyl 4-(2-fluoro-6-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

2-Bromo-3-fluorophenol (600 mg, 3.14 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.08g, 3.46mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane Complex (0.25g, 0.31mmol) and potassium carbonate (0.86g, 3.28mmol) were added to a mixed solution of water (4mL) and 1,4-dioxane (12mL), replaced with nitrogen three times, and placed React at 90°C for 2 hours. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column layer Analytical purification (eluent PE: EA (v/v) = 15%) gave 591 mg of colorless oily product with a yield of 64.1%.

Step 2: Synthesis of tert-butyl 4-(2-fluoro-6-hydroxyphenyl)piperidine-1-carboxylate

4-(2-Fluoro-6-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (591 mg, 2.01 mmol) and palladium on carbon (300 mg) were added to methanol ( 15 mL), replaced with hydrogen three times, and stirred at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Celite suction filtration, and the filtrate was concentrated under reduced pressure to obtain 563 mg of brown solid product, with a yield of 94.6%.

LC-MS(ESI): [M+H-56] ⁺ =240.2;

¹ H NMR (500MHz, CDCl ₃ ) δ6.98 (td, J＝8.2, 6.3Hz, 1H), 6.64–6.50 (m, 3H), 4.30–4.09 (m, 2H), 3.23–3.15 (m, 1H ),2.85–4.70(m,2H),2.25–4.12(m,2H),1.63–1.53(m,2H),1.49(s,9H).

Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine-1-carboxylate

4-(2-Fluoro-6-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (308 mg, 1.04 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran ( 250 mg, 0.95 mmol), potassium carbonate (262 mg, 2 mmol) were added to 10 mL of N,N-dimethylformamide, and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) yielded 262 mg of colorless oily product with a yield of 57.8%.

LC-MS(ESI): [M-55] ⁺ =422.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.35–7.20 (m, 2H), 7.14–7.07 (m, 1H), 6.76 (d, J = 8.3Hz, 1H), 6.71–6.58 (m, 1H), 6.03(d,J＝6.6Hz,1H),5.28(s,2H),4.32–4.14(m,2H),3.32–3.23(m,1H),2.82–2.61(m,2H),2.17–2.06( m,2H),1.62–1.53(m,2H),1.46(s,9H).

Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester (362 mg, 0.76 mmol) , was added to hydrochloric acid/1,4-dioxane solution (4M, 4mL), and stirred at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. The solvent was concentrated under reduced pressure and evaporated to dryness. Use saturated sodium bicarbonate aqueous solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown The solid product was 256 mg, and the yield was 89.5%.

LC-MS(ESI): [M+H] ⁺ =378.3;

¹ H NMR (500MHz, CDCl ₃ ) δ7.39–7.19(m,2H),7.16–7.08(m,1H),6.74(d,J＝8.4Hz,1H),6.69(dd,J＝10.5,8.4 Hz,1H),6.03(d,J＝6.6Hz,1H),5.32(s,2H),3.49(d,J＝12.5Hz,2H),3.42–3.32(m,1H),3.00–2.89(m ,2H),2.57–2.43(m,2H),1.83(d,J＝14.0Hz,2H).

Step 5: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidin-1-yl )Methyl)-1-(oxetan-2-yl Synthesis of methyl)-1H-benzo[d]imidazole-6-carboxylate

4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine (150 mg, 0.4 mmol), (S)-2-( Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (117 mg, 0.4 mmol), N,N-diisopropyl Ethylamine (256 mg, 1.9 mmol) was added to acetonitrile (10 mL), and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 35%) yielded 124 mg of colorless oily product with a yield of 49%.

LC-MS(ESI): [M+H] ⁺ =636.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.19(s,1H),7.96(dd,J＝8.5,1.5Hz,1H),7.73(d,J＝8.5Hz,1H),7.33–7.21(m, 2H),7.14–7.05(m,1H),6.75(d,J＝8.3Hz,1H),6.71–6.58(m,1H),6.03(d,J＝6.6Hz,1H),5.27(s,2H ),5.23–5.18(m,1H),4.74–4.58(m,3H),4.42–4.36(m,1H),3.95(s,3H),3.21–3.13(m,1H),2.98–2.81(m ,2H),2.80–2.61(m,1H),2.51–2.38(m,1H),2.26–2.12(m,4H),1.74–1.60(m,4H).

Step 6: ((S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine-1- Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidin-1-yl)methyl (126 mg, 0.2 mmol), lithium hydroxide monohydrate (41.5 mg ,0.99mmol) was added to a mixed solution of water (2mL) and 1,4-dioxane (6mL), and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material disappears completely and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 25%) to obtain 89 mg of white solid product, with a yield of 64.8%.

LC-MS(ESI): [M+H] ⁺ =622.4;

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.26 (s, 1H), 7.83–7.77 (m, 1H), 7.63 (d, J = 8.4Hz, 1H), 7.45–7.40 (m, 2H), 7.22–7.17(m,1H),7.01(d,J＝8.3Hz,1H),6.80–6.72(m,1H),6.52(d,J＝6.4Hz,1H),5.38(s,2H),5.10 –5.05(m,1H),4.73–4.69(m,1H),4.59–4.56(m,1H),4.50–4.43(m,1H),4.37–4.32(m,1H),3.89(d,J＝ 13.5Hz,1H),3.73(d,J＝13.6Hz,1H),3.11–3.03(m,1H),2.97–2.90(m,1H),2.84–2.77(m,1H),2.70–2.62(m ,1H),2.42–2.33(m,1H),2.16–1.96(m,4H),1.51–1.39(m,2H).

Example 31 (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 31)

Step 1: Synthesis of 3'-hydroxy-3,6-dihydro-[4,4'-bipyridine]-1(2H)-carboxylic acid tert-butyl ester

4-Bromopyridin-3-ol (1g, 5.75mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.78g, 5.75mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane Complex (0.47g, 0.57mmol) and potassium carbonate (1.59g, 2mmol) were added to a mixed solution of water (3mL) and 1,4-dioxane (12mL), replaced with nitrogen three times, and placed at 90 React at ℃ for 2 hours. TLC detects that the reaction is complete, stop heating, cool to room temperature, add saturated brine (50 mL), and extract with ethyl acetate (15mL The rate is 62.1%.

LC-MS(ESI): [M+H] ⁺ =277.2;

¹ H NMR (500MHz, CDCl ₃ ) δ8.30 (s, 1H), 8.05 (d, J = 5.0Hz, 1H), 7.13 (d, J = 4.9Hz, 1H), 6.23 (s, 1H), 4.15 –4.01(m,2H),3.69–3.57(m,2H),2.61–2.50(m,2H),1.50(s,9H).

Step 2: Synthesis of tert-butyl 4-(3-hydroxypyridin-4-yl)piperidine-1-carboxylate

3'-Hydroxy-3,6-dihydro-[4,4'-bipyridyl]-1(2H)-carboxylic acid tert-butyl ester (927mg, 3.35mmol) and palladium on carbon (400mg) were added to methanol ( 15 mL), replaced with hydrogen three times, and stirred at room temperature overnight. TLC detects that the raw material reaction is complete and stops the reaction. Celite suction filtration, and the filtrate was concentrated under reduced pressure to obtain 901 mg of brown solid product, with a yield of 96.5%.

LC-MS(ESI): [M+H] ⁺ =279.3;

¹ H NMR (500MHz, CDCl ₃ ) δ8.41–8.17 (s, 1H), 8.04 (d, J = 5.0Hz, 1H), 7.13 (d, J = 4.8Hz, 1H), 4.35–4.15 (m, 2H),3.22–3.03(m,1H),2.95–2.67(m,2H),1.87(d,J＝12.9Hz,2H),1.65–1.54(m,2H),1.48(s,9H).

Step 3: Synthesis of tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidine-1-carboxylate

4-(3-Hydroxypyridin-4-yl)piperidine-1-carboxylic acid tert-butyl ester (147.5 mg, 0.53 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran ( 140 mg, 0.53 mmol), potassium carbonate (146.8 mg, 2 mmol) were added to N,N-dimethylformamide (10 mL), and the reaction was carried out at 60°C for 2 hours. TLC detects that the reaction raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel Purification by column chromatography (eluent PE: EA (v/v) = 5%) gave 114 mg of colorless oily product with a yield of 46.5%.

LC-MS(ESI): [M+H] ⁺ =461.3;

¹ H NMR (500MHz, CDCl ₃ ) δ8.33 (s, 1H), 8.23 (d, J = 4.9Hz, 1H), 8.01 (s, 1H), 7.30–7.24 (m, 2H), 7.10 (d, J＝4.8Hz,1H),6.04(d,J＝6.6Hz,1H),5.38(s,2H),4.22(s,2H),3.14–3.06(m,1H),2.81–2.69(m,2H ),1.78(d,J＝13.0Hz,2H),1.60–1.53(m,1H),1.47(s,9H).

Step 4: Synthesis of 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-(piperidin-4-yl)pyridine

4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.22 mmol), Add to trifluoroacetic acid (4 mL) and dichloromethane (4 mL), and stir at room temperature for 30 minutes. TLC detected that the raw materials disappeared completely and the reaction was stopped. The solvent was concentrated under reduced pressure and evaporated to dryness. Use saturated sodium bicarbonate aqueous solution to adjust the pH of the system to about 7. Extract with ethyl acetate (15mL×3). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain brown The solid product was used directly in the next reaction.

LC-MS(ESI): [M+H] ⁺ =361.1.

Step 5: (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidin-1-yl) Synthesis of Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

3-((4-Chloro-2-fluorobenzofuran-7-yl)methoxy)-4-(piperidin-4-yl)pyridine (100 mg, 0.28 mmol), (S)-2-( Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (81 mg, 0.28 mmol), N,N-diisopropyl Ethylamine (179 mg, 1.39 mmol) was added to 10 mL of acetonitrile solution, and the reaction was carried out at 60°C overnight. TLC detects that the raw materials have completely disappeared, stop heating, cool to room temperature, add saturated brine (50mL), extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column Chromatography purification (eluent PE: EA (v/v) = 35%) yielded 87 mg of colorless oily product with a yield of 50.7%.

LC-MS(ESI): [M+H] ⁺ =619.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.32 (s, 1H), 8.23 (d, J = 4.9Hz, 1H), 8.16–8.14 (m, 1H), 7.97 (d, J = 8.5Hz, 1H) ,7.75(d,J＝8.5Hz,1H),7.30–7.23(m,2H),7.12(d,J＝4.9Hz,1H),6.04(d,J＝6.7Hz,1H),5.37(s, 2H),5.24–5.17(m,1H),4.76–4.50(m,3H),4.42–4.35(m,1H),3.98–3.95(m,2H),3.95(s,3H),3.03–2.91( m,3H),2.78–2.69(m,1H),2.49–2.40(m,1H),2.32–2.16(m,2H),1.85–1.75(m,2H),1.70–1.64(m,2H).

Step 6: (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidin-1-yl) Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

(S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (80 mg, 0.13 mmol), lithium hydroxide monohydrate (27.1 mg, 0.65 mmol) was added to a mixed solution of water (2 mL) and 1,4-dioxane (6 mL), and the reaction was carried out at 40°C for 2 hours. TLC detects that the raw material has completely disappeared and stops heating. Adjust the pH of the system to about 7 with 20% acetic acid aqueous solution, extract with ethyl acetate (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent DCM :MeOH (v/v) = 25%) to obtain 41 mg of white solid product, with a yield of 51%.

LC-MS(ESI): [M+H] ⁺ =605.4;

¹ H NMR (500MHz, CDCl ₃ ) δ8.36 (s, 1H), 8.25 (d, J = 4.9Hz, 1H), 8.19 (s, 1H), 8.05 (d, J = 8.5Hz, 1H), 7.80 (d,J＝8.5Hz,1H),7.30–7.24(m,2H),7.14(d,J＝5.0Hz,1H),6.04(d,J＝6.6Hz,1H),5.38(s,2H) ,5.24–5.16(m,1H),4.81–4.51(m,3H),4.42–4.34(m,1H),4.02(s,2H),3.09–2.96(m,3H),2.77–2.67(m, 1H),2.49–2.38(m,1H),2.38–2.25(m,2H),1.87–1.77(m,2H),1.76–1.64(m,2H).

Example 32 (S)-2-((4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 32)

Step 1: Synthesis of 1-bromo-3-chloro-2-(methoxymethoxy)benzene

Add compound 2-bromo-6-chlorophenol (5.0g, 24.10mmol) to DMF (50mL), add sodium hydride (1.27g, 53.02mmol), stir in an ice bath for ten minutes, and stir at room temperature for half an hour. Add bromo(methoxy)methane (4.48g, 36.15mmol) and stir at room temperature for one hour. Add water (100 mL), extract with ethyl acetate (100 mL EtOAc:PE (v/v)=1:40) to obtain 6.0 g of colorless oily product with a yield of 99.0%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.48 (dd, J＝8.2Hz, 1.4Hz, 1H), 7.35 (dd, J＝8.2, 1.4Hz, 1H), 6.94 (t, J＝8.2Hz ,1H),5.19(s,2H),3.71(s,3H).

Step 2: Synthesis of tert-butyl 4-(3-chloro-2-(methoxymethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Compound 1-bromo-3-chloro-2-(methoxymethoxy)benzene (2.0g, 7.95mmol), 4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.95g, 9.54mmol) was added to 1,4-dioxane (20mL ) and water (5mL). Add potassium carbonate (3.29g, 23.85mmol), replace it with nitrogen three times, add tetrakis(triphenylphosphine)palladium (184mg, 0.16mmol), replace it with nitrogen three times again, and stir at 85°C overnight. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc:PE (v/v)=1:10) to obtain 2.7g of colorless oily product with a yield of 95.7%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.23 (dd, J = 7.6Hz, 2.0Hz, 1H), 6.95 (s, 2H), 5.74 (s, 1H), 4.95 (s, 2H), 3.98 (d,J＝2.8Hz,2H),3.54(s,2H),3.50(s,3H),2.41(d,J＝1.8Hz,2H),1.42(s,9H).

Step 3: Synthesis of tert-butyl 4-(3-chloro-2-(methoxymethoxy)phenyl)piperidine-1-carboxylate

Compound 4-(3-chloro-2-(methoxymethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (530 mg, 1.50 mmol) was added to methanol ( 6mL). Palladium on carbon (53 mg, 0.48 mmol) was added, replaced with hydrogen three times, and stirred at room temperature for half an hour. Filter off the palladium on carbon, add water (10 mL) to quench, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use Purification by chromatography (eluent PE:DCM (v/v)=1:5) gave 320 mg of colorless oily product with a yield of 59.9%.

LC-MS (ESI): [M+H] ⁺ =356.3.

Step 4: Synthesis of tert-butyl 4-(3-chloro-2-hydroxyphenyl)piperidine-1-carboxylate

Compound 4-(3-chloro-2-(methoxymethoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester (320 mg, 0.90 mmol) was added to acetic acid (5 mL), and stirred at 80°C overnight . Concentrate under reduced pressure and purify using silica gel column chromatography (eluent EA:PE (v/v) = 1:20) to obtain 75 mg of colorless oily product with a yield of 26.7%.

LC-MS (ESI): [M-55] ⁺ =256.3.

Step 5: Synthesis of tert-butyl 4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine-1-carboxylate

Compound 4-(3-chloro-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (75 mg, 0.24 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (108 mg, 0.41 mmol) was added to dimethylformamide (4 mL). Then add potassium carbonate (100 mg, 0.72 mmol) and stir at 60°C for 1 hour. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EA:PE (v/v) = 1:10) to obtain 70 mg of light brown solid product with a yield of 59.0%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.34 (d, J = 8.2 Hz, 1H), 7.31–7.27 (m, 2H), 7.09–7.06 (m, 2H), 6.05 (d, J = 6.6 Hz,1H),5.19(s,2H),4.18(d,J＝13.2Hz,2H),3.11–3.01(m,1H),2.63(dd,J＝18.0,7.4Hz,2H),1.48(s ,2H),1.47(s,9H),1.30–1.25(m,2H).

Step 6: Synthesis of 4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine

The compound 4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.14 mmol ) was added to ethyl acetate (3mL), then 1.4-dioxane hydrochloric acid solution (4M, 3mL) was added, and stirred at room temperature for 2 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 10:1) to obtain 60 mg of light brown solid product with a yield of 99.0%.

LC-MS (ESI): [M+H] ⁺ =394.3.

Step 7: (S)-2-((4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (53 mg, 0.18 mmol ), potassium carbonate (62 mg, 0.45 mmol), and potassium iodide (2 mg, 0.02 mmol) were added to acetonitrile (2 ml). Compound 4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine (60 mg, 0.15 mmol) was added to acetonitrile (2 ml). Then add diisopropylethylamine (0.5 ml) dropwise, add this solution dropwise to the previous solution, and stir at 60°C for 2 hours. Add water (5 mL), extract with ethyl acetate (10 mL /v)=3:2) 60 mg of off-white solid product was obtained, with a yield of 61.3%.

LC-MS (ESI): [M+H] ⁺ =652.4.

Step 8: (S)-2-((4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 0.09 mmol) was dissolved in dioxane (2 mL) , water (0.5mL). Lithium hydroxide (13 mg, 0.54 mmol) was added and stirred at 40°C for 4 hours. Adjust the pH to 6-7 with hydrochloric acid (0.5N), extract with ethyl acetate (5mL×3), combine the organic phases, wash the organic phases once with saturated brine, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure and purify with prep-HPLC (eluent CH ₃ CN: H ₂ O (v/v) = 50%) to obtain 7.8 mg of white solid product with a yield of 13.6%.

LC-MS(ESI): [M+H] ⁺ =638.2;

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.73 (s, 1H), 8.28 (s, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.65 (d, J = 8.3Hz, 1H) ,7.48–7.34(m,3H),7.25–7.12(m,2H),6.57(dd,J＝6.3Hz,3.2Hz,1H),5.19(s,2H),5.07(d,J＝6.8Hz, 1H),4.81–4.76(m,1H),4.64(d,J＝13.2Hz,1H),4.50(dd,J＝13.6Hz,7.5Hz,1H),4.36–4.34(m,1H),3.90– 3.75(m,2H),2.96–2.70(m,4H),2.43–2.39(m,1H),1.99–1.98(m,2H),1.51–1.44(m,4H).

Example 33 (S)-2-((4-(5-chloro-2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine- 1-yl)methyl)-1-(oxetane Synthesis of alk-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 33)

Step 1: Synthesis of 1-bromo-5-chloro-3-fluoro-2-(methoxymethoxy)benzene

Add compound 2-bromo-4-chloro-6-fluorophenol (3.00g, 13.31mmol) to tetrahydrofuran (75mL), cool to 0°C, add sodium hydride (0.8g, 33.27mmol), and react at 0°C for 1 hour. Add bromo(methoxy)methane (2.00g, 15.97mmol) and keep the reaction at 0°C for 1 hour. Add water (50 mL) to quench, extract with ethyl acetate (50 mL × 2), dry the organic layer with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent PE: EA (v/v) =10:1) and purified to obtain 3.31g of colorless oily product with a yield of 92.3%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.29 (t, J = 2.0 Hz, 1H), 7.03 (dd, J = 10.4, 2.4 Hz, 1H), 5.10 (s, 2H), 3.56 (s, 3H).

Step 2: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-(methoxymethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Compound 1-bromo-5-chloro-3-fluoro-2-(methoxymethoxy)benzene (1.65g, 6.12mmol) and 4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.89g, 6.12mmol) was added to 1,4-dihydropyridine-1(2H)-carboxylate. Dissolve in oxane (33 mL) and water (8.25 mL). Add potassium carbonate (1.69g, 12.25mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.22g, 0.31mmol), and raise the temperature to 85°C under nitrogen protection to react overnight. . Cool to room temperature, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent PE:EA (v/v) = 10:1) to obtain 1.71g of light yellow oily product with a yield of 75.1%.

¹ HNMR (400MHz, CDCl ₃ ) δ6.97 (dd, J＝10.4, 2.4Hz, 1H), 6.92–6.84 (m, 1H), 5.78 (s, 1H), 4.95 (s, 2H), 3.98 (d ,J＝2.8Hz,2H),3.52(t,J＝5.6Hz,2H),3.43(s,3H),2.40(d,J＝1.6Hz,2H),1.42(s,9H).

Step 3: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-(methoxymethyloxy)phenyl)piperidine-1-carboxylate

Compound 4-(5-chloro-3-fluoro-2-(methoxymethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (640 mg, 1.72 mmol ) was added to ethyl acetate (10 mL), platinum dioxide (64 mg, 0.13 mmol) was added, and after hydrogen replacement, the temperature was raised to 45°C and reacted for 30 minutes. Filter through diatomaceous earth and concentrate under reduced pressure to obtain 640 mg of colorless oily product with a yield of 99.5%.

¹ HNMR (400MHz, CDCl ₃ ) δ6.91 (dd, J＝10.4, 2.4Hz, 1H), 6.89–6.82 (m, 1H), 5.03 (s, 2H), 4.19 (d, J＝12.8Hz, 2H ),3.51(s,3H),3.11–3.06(m,1H),2.73(t,J＝12.0Hz,2H),1.76–1.69(m,2H),1.52–1.43(m,2H),1.42( s,9H).

Step 4: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate

Compound 4-(5-chloro-3-fluoro-2-(methoxymethyloxy)phenyl)piperidine-1-carboxylic acid tert-butyl ester (644 mg, 1.72 mmol) was added to acetic acid (10 mL). The temperature was raised to 85°C under nitrogen protection and the reaction was carried out overnight. Cool to room temperature, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent: PE:EA (v/v) = 5:1) to obtain 179 mg of light yellow oily product with a yield of 31.5%.

¹ HNMR (400MHz, CDCl ₃ ) δ6.91 (dd, J = 9.6, 2.4Hz, 1H), 6.85 (d, J = 11.6Hz, 1H), 5.23 (d, J = 5.2Hz, 1H), 4.17 ( d,J＝13.2Hz,2H),2.99(tt,J＝12.0,3.2Hz,1H),2.75(t,J＝12.0Hz,2H),1.74(d,J＝12.8Hz,2H),1.57– 1.50(m,2H),1.41(s,9H).

Step 5: tert-butyl 4-(5-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate Synthesis

The compound 4-(5-chloro-3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.49 mmol) and 7-(bromomethyl)-4-chloro-2- Fluoro-1-benzofuran (153 mg, 0.58 mmol) was added to N,N-dimethylformamide (5 mL), potassium carbonate (201 mg, 1.45 mmol), nitrogen The temperature was raised to 60°C under air protection and reacted for 2 hours. Cool to room temperature, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: PE:EA (v/v) = 3:1) to obtain 206 mg of light yellow oily product with a yield of 82.9%.

¹ HNMR (400MHz, CDCl ₃ ) δ7.21–7.15(m,2H),6.95(dd,J＝10.8,2.4Hz,1H),6.81(d,J＝1.6Hz,1H),5.97(d,J ＝6.4Hz,1H),5.19(s,2H),4.08(dd,J＝10.4,6.4Hz,2H),2.95–2.82(m,1H),2.52(s,2H),1.41(s,2H) ,1.39(s,9H),0.83–0.74(m,2H).

Step 6: Synthesis of 4-(5-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine

Compound 4-(5-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester ( 100 mg, 0.20 mmol) was added to ethyl acetate (6 mL), dioxane hydrochloride solution (4 M, 6 mL) was added, and the reaction was carried out at room temperature under nitrogen protection for 2 hours. Concentrate under reduced pressure to obtain 80 mg of off-white solid product with a yield of 99.4%.

LC-MS (ESI): [M+H] ⁺ =412.3.

Step 7: (S)-2-((4-(5-chloro-2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-(5-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (80 mg, 0.19 mmol) and 2- (Chloromethyl)-3-(((2S)-oxan-2-yl)methyl)benzo[d]imidazole-5-carboxylic acid methyl ester (60 mg, 0.20 mmol) was added to acetonitrile (5 mL). Add potassium carbonate (134 mg, 0.97 mmol) and potassium iodide (0.0 mL, 0.03 mmol), and raise the temperature to 60°C for 2 hours under nitrogen protection. Cool to room temperature, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent: DCM:MeOH (v/v) = 20:1) to obtain 60 mg of light yellow solid product with a yield of 46.1%.

LC-MS (ESI): [M+H] ⁺ =670.4.

Step 8: (S)-2-((4-(5-chloro-2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine- Synthesis of 1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(5-chloro-2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1 -(yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (60 mg, 0.09 mmol) was added to 1,4-di Dissolve in oxane (2 mL) and water (0.5 mL). Lithium hydroxide (4.0 mg, 0.10 mmol) was added, and the temperature was raised to 40°C for 2 hours under nitrogen protection. Cool to room temperature and adjust pH to 6-7 with acetic acid. Concentrate under reduced pressure and purify by Prep-HPLC (eluent CH ₃ CN: H ₂ O (v/v) = 50%) to obtain 20 mg of white solid product with a yield of 34.0%.

LC-MS(ESI):[M+H]+=656.2;

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.26 (s, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.38 (ddd, J = 14.4,13.4,8.0Hz,3H),7.06(s,1H),6.56(d,J＝6.4Hz,1H),5.28(s,2H),5.09–5.04(m,1H),4.78(dd,J ＝15.2,7.2Hz,1H),4.63(d,J＝13.2Hz,1H),4.49(dd,J＝13.6,7.5Hz,1H),4.36–4.33(m,1H),3.88(d,J＝ 13.6Hz,1H),3.73(d,J＝13.6Hz,1H),2.91–2.65(m,4H),2.43–2.37(m,1H),2.02–1.81(m,2H),1.59–1.38(m ,2H),1.33–1.23(m,2H).

Example 34 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl) Synthesis of -1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 34)

Step 1: Synthesis of methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate

The compound 3-fluoro-4-nitrobenzoic acid methyl ester (150mg, 0.75mmol), (3-ethylimidazol-4-yl)methanamine (94mg, 0.75mmol), potassium carbonate (312mg, 2.26mmol), N,N-diisopropylethylamine (195mg, 1.51mmol) was added to N,N-dimethylformamide (10mL) medium and stir at 50°C for 3 hours. Cool to room temperature, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent: DCM/MeOH (v/v) = 15:1) to obtain 220 mg of yellow solid product with a yield of 96.0%.

LC-MS (ESI): [M+H] ⁺ =305.1.

Step 2: Synthesis of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate

Compound 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate methyl ester (220mg, 0.72mmol), palladium on carbon (100mg, 0.94mmol) were added into methanol (20 mL), replaced with hydrogen three times, and reacted for 1 hour. Filter through diatomaceous earth and concentrate under reduced pressure to obtain 192 mg of brown solid product with a yield of 96.8%.

LC-MS (ESI): [M+H] ⁺ =275.1.

Step 3: Synthesis of methyl 2-(chloromethyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Compound 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate methyl ester (220 mg, 0.80 mmol), 2-chloro-1,1,1- Trimethoxyethane (248 mg, 1.60 mmol) and p-toluenesulfonic acid monohydrate (76 mg, 0.40 mmol) were added to acetonitrile (10 mL) and reacted at 60°C for 2 hours. Cool to room temperature, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent: DCM/MeOH (v/v) = 1:1) to obtain 200 mg of light yellow solid product with a yield of 74.9%.

LC-MS(ESI): [M+H] ⁺ =333.2;

¹ HNMR(400MHz, DMSO-d ₆ )δ7.98–7.76(m,2H),7.50–7.46(m,2H),7.13–7.08(m,1H),5.10(s,2H),4.05–3.97( m,2H),3.91–3.87(m,2H),3.86(s,3H),1.17(t,J＝8.0Hz,3H).

Step 4: 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl) Synthesis of -1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (110 mg, 0.29mmol), 2-(chloromethyl )-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (110mg, 0.29mmol), potassium iodide (5mg, 0.03 mmol), potassium carbonate (121 mg, 0.88 mmol) was added to acetonitrile (10 mL), and the reaction was carried out at 60°C for 2 hours. Cool to room temperature, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent: DCM/MeOH (v/v) = 15:1) to obtain 45 mg of light yellow solid product with a yield of 22.9%.

LC-MS (ESI): [M+H] ⁺ =674.1.

Step 5: 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl) Synthesis of -1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)- 1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (45mg, 0.07mmol), lithium hydroxide (10mg, 0.42 mmol) was added to 1,4-dioxane (2 mL) and water (0.5 mL), and stirred at 40°C for 2 hours. Cool to room temperature and slowly add acetic acid dropwise until the pH of the solution becomes slightly acidic. Concentrate under reduced pressure and purify by Prep-HPLC (eluent: ACN/H ₂ O (v/v) = 1:1) to obtain 13.7 mg of white solid product with a yield of 31.1%.

LC-MS(ESI): [M+H] ⁺ =660.2;

¹ HNMR(400MHz, DMSO-d ₆ )δ12.83(s,1H),8.11–8.08(m,1H),7.83–7.79(m,1H),7.71–7.66(m,2H),7.43–7.39( m,1H),7.34–7.30(m,1H),7.16–7.05(m,2H),6.88–6.84(m,1H),6.57(t,J＝8.0Hz,1H),6.36(s,1H) ,5.70(s,2H),5.25(s,2H),4.05–3.95(m,2H),3.75(s,2H),2.80–2.73(m,2H),2.68–2.58(m,1H),1.90 –1.80(m,2H),1.25–1.11(m,7H).

Example 35 (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl Synthesis of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 35)

Step 1: 2-((4-methoxybenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2H)-carboxylic acid tert-butyl ester synthesis

Compound 3-bromo-2-((4-methoxybenzyl)oxy)pyridine (1.0g, 3.40mmol), 4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.26g, 4.08mmol) was added to 1,4-dioxane ( 10 mL) and water (2.5 mL). Add potassium carbonate (1.41g, 10.2mmol), replace it with nitrogen three times, add 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (124mg, 0.17mmol), replace it with nitrogen three times again, and stir at 85°C overnight. . Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc:PE (v/v) = 1:10) to obtain 1.14g of colorless oily product with a yield of 84.6%.

¹ HNMR (400MHz, CDCl ₃ ) δ8.08–8.07(m,1H),7.43(s,1H),7.36(d,J=8Hz,2H),6.91–6.86(m,3H),5.87(s, 1H),5.35(s,2H),4.03(s,2H),3.82(s,3H),3.55(s,2H),2.52(s,2H),1.48(s,9H).

Step 2: Synthesis of tert-butyl 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylate

The compound 2-((4-methoxybenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester (1.1g, 2.77mmol) was added to methanol (11mL). Palladium on carbon (110 mg, 0.89 mmol) was added, replaced with hydrogen three times, and stirred at room temperature for half an hour. Filter through diatomaceous earth, add water (10 mL), and extract with ethyl acetate (20 mL × 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EtOAc = 100%) to obtain 685 mg of colorless oily product with a yield of 88.8%.

LC-MS (ESI): [M+H] ⁺ =279.3.

Step 3: Synthesis of tert-butyl 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylate

The compound 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (685mg, 2.46mmol) and 7-(bromomethyl)-2,4-dichlorobenzofuran (972mg , 3.69 mmol) was added to N,N-dimethylformamide (10 mL). Potassium carbonate (1.0g, 7.38mmol) was added and stirred at 60°C for 1 hour. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent EA:PE (v/v)=1:5) to obtain 140 mg of light brown solid product with a yield of 11.9%.

LC-MS(ESI): [M+H] ⁺ =477.3;

¹ HNMR (400MHz, CDCl ₃ ) δ7.98 (d, J = 4Hz, 1H), 7.37 (d, J = 8Hz, 1H), 7.24–7.15 (m, 2H), 6.85 (d, J = 4Hz, 1H ),6.65(s,1H),5.59(s,2H),3.32–3.29(m,1H),2.71(t,J＝12Hz,2H),1.78(d,J＝8Hz,2H),1.55–1.46 (m,2H),1.40(s,9H),1.24–1.21(m,2H).

Step 4: Synthesis of 2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine

Compound 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.29 mmol) was added To ethyl acetate (6 mL), 1.4-dioxane hydrochloride (6 mL) was added, and the mixture was stirred at room temperature for 2 hours. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent DCM: MeOH (v/v) = 10:1) to obtain 110 mg of light brown solid product, which was directly used in the next reaction.

LC-MS (ESI): [M+H] ⁺ =377.3.

Step 5: (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Compound (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (103 mg, 0.35 mmol ), potassium carbonate (121 mg, 0.87 mmol), and potassium iodide (5 mg, 0.03 mmol) were added to acetonitrile (4 mL). Compound 2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine (110 mg, 0.29mmol), diisopropylethylamine ( 0.5 mL) was added to acetonitrile (4 mL). After it was fully dissolved, it was added dropwise to the reaction system. Stir at 60°C for 2 hours. Add water (5mL) and extract with ethyl acetate (10mL×3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent EA:PE (v/v) = 3:2) to obtain 60 mg of an off-white solid product. The rate is 32.6%.

LC-MS (ESI): [M+H] ⁺ =635.5.

Step 6: (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl Synthesis of 1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl )-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (60 mg, 0.09 mmol) was added to dioxane (2 mL), water (0.5mL). Lithium hydroxide (13 mg, 0.54 mmol) was added and stirred at 40°C for 4 hours. Adjust the pH to 6-7 with hydrochloric acid (0.5N), and extract with ethyl acetate (5mL×3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and purify using Prep-HPLC (eluent CH ₃ CN: H2O (v/v) = 50%) to obtain 21.5 mg of white solid product with a yield of 38.4%.

LC-MS(ESI): [M+H] ⁺ =621.2;

¹ HNMR (400MHz, DMSO-d ₆ ) δ12.76 (s, 1H), 8.28 (d, J = 6.4Hz, 1H), 8.02–7.80 (m, 2H), 7.65–7.59 (m, 2H), 7.42 –7.17(m,3H),6.97–6.95(m,1H),5.62(s,2H),5.08–5.07(m,1H),4.79–4.33(m,4H),3.93–3.73(m,2H) ,2.99–2.68(m,4H),2.42–2.38(m,1H),2.18–2.14(m,2H),1.74–1.60(m,4H).

Example 36 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-oxopiperate Synthesis of oxetan-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 36)

Step 1: (S)-2-((4-(2-(benzyloxy)-3-fluorophenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxaheterocycle Synthesis of butan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound (S)-1-(oxetan-2-ylmethyl)-2-((2-oxopiperazin-1-yl)methyl)-1H-benzo[d]imidazole- 6-Carboxylic acid methyl ester (200mg, 0.6mmol), 2-(benzyloxy)-1-bromo-3-fluorobenzene (236mg, 0.8mmol), 1,1-binaphthyl-2,2-biphenyl Phosphine (64 mg, 0.1 mmol) and cesium carbonate (365 mg, 1.1 mmol) were added to toluene (50 mL), triplylideneacetone dipalladium (50 mg, 0.1 mmol) was added, and the reaction was carried out at 120°C overnight after nitrogen replacement. Concentrate under reduced pressure, add water (30 mL), extract with ethyl acetate (30 mL × 3), combine the organic phases, concentrate under reduced pressure, and purify by thin layer chromatography (eluent MeOH: DCM (v/v) = 5%) , 172 mg of light yellow solid product was obtained, with a yield of 55.2%.

LC-MS: [M+H] ⁺ =559.5;

¹ H NMR (400MHz, CDCl ₃ ) δ8.18(s,1H),8.02(d,J＝8.3Hz,1H),7.79(d,J＝8.3Hz,1H),7.36–6.31(m,2H) ,7.26–21(m,3H),6.95–6.89(m,1H),6.85–6.80(m,1H),6.62(d,J＝8.2Hz,1H),5.18–5.10(m,2H),5.03 (s,2H),4.90–4.83(m,2H),4.61–4.46(m,3H),3.97(s,3H),3.81(s,2H),3.61–3.55(m,2H),3.42–3.387 (m,2H),2.78–2.75(m,1H),2.49–2.42(m,1H).

Step 2: (S)-2-((4-(3-fluoro-2-hydroxyphenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetane-2 Synthesis of -methyl)-1H-benzo[d]imidazole-6-carboxylate methyl ester

Compound (S)-2-((4-(2-(benzyloxy)-3-fluorophenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetane Alk-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.2 mmol) was added to methanol (1 mL), and palladium on carbon (10 mg) was added. Replace with hydrogen 3 times and react at room temperature for 2 hours. The product was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 85 mg of white solid product with a yield of 100%.

LC-MS: [M+H] ⁺ =469.4.

Step 3: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-oxopiperate Synthesis of methyl ethyl azin-1-yl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Compound (S)-2-((4-(3-fluoro-2-hydroxyphenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetane-2- Methyl methyl)-1H-benzo[d]imidazole-6-carboxylate (85mg, 0.2mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (57mg, 0.2mmol) ) and potassium carbonate (75 mg, 0.6 mmol) were added to N,N-dimethylformamide (4.5 mL), and the reaction was carried out at 60°C under nitrogen protection. Add water (30 mL), extract with dichloromethane (30 mL 5%), 43 mg of yellow liquid product was obtained, with a yield of 36.4%.

LC-MS: [M+H] ⁺ =651.5.

Step 4: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-oxopiperate Synthesis of oxetan-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-oxopiperazine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (43 mg, 0.06 mmol), lithium hydroxide (14 mg, 0.6 mmol) was added to 1,4-dioxane (0.8 mL) and water (0.2 mL), and the reaction was carried out at 40°C for three hours. Add acetic acid (0.2 mL) to adjust the pH to 6~7. Concentrate under reduced pressure and purify using Prep-HPLC (eluent acetonitrile: water (v/v) = 70%) to obtain 10 mg of white solid product with a yield of 23.8%.

LC-MS: [M+H] ⁺ =637.2;

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.76 (s, 1H), 8.26 (d, J = 0.8Hz, 1H), 7.81 (dd, J = 8.4, 1.6Hz, 1H), 7.61 (d, J＝8.4Hz,1H),7.33(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.06(td,J＝8.4,6.4Hz,1H),6.95–6.87( m,1H),6.80(d,J＝8.0Hz,1H),6.46(d,J＝6.4Hz,1H),5.26(d,J＝12.0Hz,2H),5.09–4.97(m,2H), 4.86–4.71(m,2H),4.60(dd,J＝15.2,2.4Hz,1H),4.47(dd,J＝13.6,7.6Hz,1H),4.34(dt,J＝8.8,6.0Hz,1H) ,3.72(s,2H),3.44(t,J＝5.2Hz,2H),3.33(s,2H),2.75–2.66(m,1H),2.38–2.27(m,1H).

Example 37 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piper Synthesis of (din-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 37)

Step 1: Synthesis of 2-(benzyloxy)-1-bromo-3-(trifluoromethyl)benzene

Add compound 2-bromo-6-(trifluoromethyl)phenol (550mg, 2.28mmol) and benzyl bromide (468mg, 2.74mmol) to N,N-dimethylformamide (10mL), stir and dissolve, and then add potassium carbonate (946mg, 6.85mmol), the reaction liquid was heated to 60°C under nitrogen protection and reacted for 2 hours. Water (30mL) was added to the reaction liquid to quench the reaction, extracted with ethyl acetate (20mL×3), and the organic layer was dried and concentrated to obtain the crude product. The crude product Purification by column chromatography (eluent PE: EA (v/v) = 1:1) gave 460 mg of an off-white solid product, with a yield of 60.9%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.73 (dd, J＝8.0Hz, 1.2Hz, 1H), 7.58–7.46 (m, 3H), 7.40–7.26 (m, 3H), 7.06 (t, J＝ 8.0Hz,1H),5.03(s,2H).

Step 2: Synthesis of tert-butyl 4-(2-(benzyloxy)-3-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

Compound 2-(benzyloxy)-1-bromo-3-(trifluoromethyl)benzene (460 mg, 1.39 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (516 mg, 1.67 mmol) was added to dioxane (10 mL) and stirred to dissolve. Then, potassium carbonate (576 mg, 4.17 mmol), tetrakis triphenylphosphine palladium (80 mg, 0.07 mmol) and water (2 mL) were added, and the reaction liquid was heated to 85°C and reacted overnight under nitrogen protection. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (eluent PE:EA (v/v)=1:1) was purified to obtain 383 mg of off-white solid product, with a yield of 63.6%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.48 (dd, J＝7.6Hz, 1.3Hz, 1H), 7.39–7.23 (m, 6H), 7.13 (s, 1H), 5.87 (s, 1H), 4.79 (br.s,2H),3.98(s,2H),3.49(br.s,2H),2.44(br.s,2H),1.42(s,9H).

Step 3: Synthesis of tert-butyl 4-(2-hydroxy-3-(trifluoromethyl)phenyl)piperidine-1-carboxylate

Compound 4-(2-(benzyloxy)-3-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (383 mg, 0.88 mmol) was added Methanol (10 mL) was stirred and dissolved, then palladium on carbon (40 mg, 0.38 mmol) was added, and the reaction solution was reacted at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated to obtain 307 mg of colorless oily product, with a yield of 100%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.37–7.22(m,2H),6.92(t,J＝7.6Hz,1H),4.19(d,J＝13.2Hz,2H),3.12–2.97(m, 1H), 2.77 (td, J＝13.2Hz, 2.4Hz, 2H), 1.76 (d, J＝13.2Hz, 2H), 1.60–1.48 (m, 2H), 1.41 (s, 9H).

Step 4: tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine-1-carboxylate Synthesis

The compound 4-(2-hydroxy-3-(trifluoromethyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester (287 mg, 0.83 mmol) and 7-(bromomethyl)-4-chloro-2- Fluorine-1-benzofuran (219 mg, 0.83 mmol) was added to N,N-dimethylformamide (5 mL), stirred and dissolved, then potassium carbonate (345 mg, 2.50 mmol) was added, and the reaction liquid was heated to 60°C under nitrogen protection. Stir for 3 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent PE:EA (v/v) = 1:1) to obtain 307 mg of off-white solid product with a yield of 70.0%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.49–7.42(m,1H),7.39(d,J＝7.6Hz,1H),7.33(d,J＝8.4Hz,1H),7.26(d,J＝ 8.4Hz,1H),7.18(d,J＝9.2Hz,1H),5.99(d,J＝6.8Hz,1H),5.02(s,2H),4.18(d,J＝13.2Hz,2H),3.30 –3.16(m,1H),2.69(td,J＝13.2,2.0Hz,2H),1.70(d,J＝12.4Hz,2H),1.58–1.47(m,2H),1.42(s,9H).

Step 5: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine

The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine-1-carboxylic acid tert-butyl ester ( 220 mg, 0.42 mmol) was added to dioxane (4 mL) and stirred to dissolve, then dioxane hydrochloride solution (4 M, 4 mL) was added, and the reaction liquid was stirred at room temperature under nitrogen protection for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 150 mg of off-white solid product, yield: 84.1%, which was used directly in the next step.

LC-MS (ESI): [M+H] ⁺ =428.3.

Step 6: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piper Synthesis of methyl (din-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine (150 mg, 0.35 mmol) and 2 -(Chloromethyl)-3-(((2S)-oxetan-2-yl)methyl)benzo[d]imidazole-5-carboxylic acid methyl ester (104 mg, 0.35 mmol) was added with N, N-dimethylformamide (5 mL) was stirred and dissolved, then potassium carbonate (243 mg, 1.76 mmol) was added, and the reaction liquid was heated to 60°C under nitrogen protection and reacted for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent DCM: MeOH (v/v) = 20:1) to obtain 150 mg of off-white solid product with a yield of 62.4%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.07 (s, 1H), 7.88 (d, J = 8.0Hz, 1H), 7.66 (dd, J = 8.4, 2.8Hz, 1H), 7.42 (d, J = 7.6Hz,2H),7.31(d,J＝8.4Hz,1H),7.28–7.18(m,1H),7.15(d,J＝7.6Hz,1H),5.98(d,J＝6.4Hz,1H) ,5.15–5.05(m,1H),4.98(s,2H),4.74–4.26(m,5H),3.95–3.75(m,2H),3.86(s,3H),3.17–3.08(m,1H) ,2.94–2.88(m 1H),2.69–2.51(m,1H),2.47–2.04(m,3H),1.75–1.70(m,4H).

Step 7: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piper Synthesis of benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine -1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (150 mg, 0.22 mmol) was added to dioxane Ring (2 mL) was stirred to dissolve, and then lithium hydroxide (46 mg, 1.10 mmol) was added to water (1 mL) to dissolve and then added to the reaction solution. The reaction solution was heated to 40°C under nitrogen protection and reacted for 2 hours. Acetic acid (0.1 mL) was added to adjust the pH to 5-6, and purified by Prep-HPLC (eluent acetonitrile: water (v/v) = 60%) to obtain 97 mg of white solid product with a yield of 66.0%.

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.81 (s, 1H), 8.28 (s, 1H), 7.81 (dd, J = 8.4, 1.6Hz, 1H), 7.70 (d, J = 7.6Hz, 1H),7.64(d,J＝8.4Hz,1H),7.59(d,J＝7.2Hz,1H),7.52(d,J＝8.0Hz,1H),7.44(d,J＝8.4Hz,1H) ,7.38(t,J＝8.0Hz,1H),6.62(d,J＝6.4Hz,1H),5.13–5.11(m,1H),5.12(s,2H),4.82(dd,J＝15.2Hz, 7.2Hz,1H),4.77–4.62(m,1H),4.56–4.51(m,1H),4.41–4.27(m,1H),3.95(d,J＝13.6Hz,1H),3.79(d,J ＝13.6Hz,1H),3.15–3.00(m,2H),2.94–2.88(m,1H),2.81–2.70(m,1H),2.47–2.37(m,1H),2.25–2.06(m,2H ),1.73–1.63(m,4H).

Example 38 (S)-2-((4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 38)

Step 1: Synthesis of tert-butyl 4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

The compound 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (500mg, 1.69mmol), 7-(bromomethyl)-2-chloro-4-fluorobenzofuran ( 450 mg, 1.69 mmol) and cesium carbonate (1.10 g, 3.39 mmol) were dissolved in DMF (8 mL). React at room temperature for 2 hours, add water (30 mL) to quench the reaction, extract with ethyl acetate (15 mL (v/v)=30%), 710 mg of colorless liquid was obtained, with a yield of 81.8%.

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.40–7.37(m,1H),7.28(s,1H),7.22–7.13(m,2H),7.13–7.03(m,1H),6.98(d ,J＝7.8Hz,1H),5.29(s,2H),3.98(d,J＝12.9Hz,2H),2.88–2.82(m,1H),2.51–2.50(m,2H),1.39(s, 9H),1.38–1.30(m,4H).

Step 2: Synthesis of 4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine

Compound 4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylic acid tert-butyl ester (710 mg, 1.49mmol) , after dissolving in dichloromethane (5 mL), add trifluoroacetic acid (1 mL) and react at room temperature for 30 min. The solvent was removed under reduced pressure, saturated sodium bicarbonate was added to adjust the pH to 9, and the mixture was extracted with dichloromethane (8 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 546 mg of a white solid with a yield of 97.3%.

¹ H NMR (500MHz, DMSO-d ₆ ) δ7.40–7.37(m,1H),7.27(s,1H),7.25–7.06(m,3H),6.97(d,J＝7.6Hz,1H), 5.28(s,2H),3.05(d,J＝12.8Hz,2H),2.88–2.84(m,1H),2.51–2.45(m,2H),1.51–1.46(m,2H),1.36–1.30( m,2H).

Step 3: (S)-2-((4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (340 mg, 0.9 mmol), (S)-2- (Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (318 mg, 1.08 mmol) was dissolved in acetonitrile (5 mL) Afterwards, N,N'-diisopropylethylamine (582 mg, 4.5 mmol) was added and the reaction was carried out at 60°C overnight. The solvent was removed under reduced pressure, 10 mL of water was added, extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography (eluent EtOAc:PE (v/v) = 50%), obtained 449 mg of white solid, with a yield of 78.4%.

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.28(d,J＝1.6Hz,1H),7.81(dd,J＝8.4,1.7Hz,1H),7.67(d,J＝8.5Hz,1H) ,7.33(dd,J＝8.3,5.2Hz,1H),7.28(s,1H),7.19–7.08(m,2H),7.09–7.05(m,1H),6.97(d,J＝7.7Hz,1H ), 5.28(s,2H),5.07(dd,J＝7.2,2.7Hz,1H),4.78(dd,J＝15.3,7.2Hz,1H),4.65–4.62(m,1H),4.52–4.45(m, 1H),4.37–4.33(m,1H),3.92–3.88(m,1H),3.87(s,3H),3.73(d,J＝13.5Hz,1H),2.90(d,J＝11.0Hz,1H ),2.77(d,J＝11.2Hz,1H),2.75–2.61(m,2H),2.46–2.35(m,1H),2.04–1.86(m,2H),1.49–1.39(m,2H), 1.36–1.22(m,2H).

Step 4: (S)-2-((4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl Synthesis of )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl) Methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (0.44g, 0.69mmol) and lithium hydroxide monohydrate ( 0.09g, 2.08mmol) was added to 1,4-dioxane (10mL) and water (5mL), and the reaction was carried out at 40°C for 1h. Cool in an ice bath, adjust pH=6 with trifluoroacetic acid, extract with ethyl acetate (15mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent MeOH:DCM (v/v)=1:30) to obtain 380 mg of light yellow solid product with a yield of 83.2%.

LC-MS(ESI): [M+H] ⁺ =622.2;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.71 (s, 1H), 8.27–8.24 (m, 1H), 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 7.64 (d, J = 8.4 Hz,1H),7.33(dd,J＝8.3,5.2Hz,1H),7.28(s,1H),7.18–7.08(m,2H),7.07–7.05(m,1H),6.98(d,J＝ 7.8Hz,1H),5.28(s,2H),5.06(dd,J＝7.1,2.8Hz,1H),4.76(dd,J＝15.3,7.2Hz,1H),4.62(dd,J＝15.2,2.8 Hz,1H),4.51–4.46(m,1H),4.39–4.30(m,1H),3.88(d,J＝13.5Hz,1H),3.72(d,J＝13.6Hz,1H),2.90(d ,J＝11.1Hz,1H),2.77(d,J＝11.0Hz,1H),2.75–2.63(m,2H),2.46–2.39(m,1H),2.00–1.86(m,2H),1.56– 1.39(m,2H),1.27(t,J＝12.6Hz,2H).

Example 39 2-(((2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiper of (ridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 39) synthesis

Step 1 Synthesis of: (S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Dissolve compound (S)-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (3.00g, 13.78mmol) in anhydrous tetrahydrofuran (30mL), move to -78°C under nitrogen atmosphere and stir the reaction After 5 minutes, lithium bis(trimethylsilyl)amide (17.9 mL, 17.92 mmol) was added dropwise, and then N-phenyl bis(trifluoromethanesulfonyl)imide (5.53 g, 15.16 mmol) was slowly added dropwise. Tetrahydrofuran solution, continue the reaction for 30 minutes after the dropwise addition is completed. Add 50 mL saturated ammonium chloride water at this temperature to quench, separate the organic phase, extract the aqueous phase with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and Purification by silica gel column chromatography (EtOAc:PE(v/v)=10%) yielded 4.68g of colorless transparent liquid with a yield of 98.3%.

Step 2: (S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- Synthesis of tert-butyl dihydropyridine-1(2H)-carboxylate

(S)-2-Methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (4.68g, 13.55 mmol), pinacol diborate (3.69g, 14.23mmol), palladium tetraphenylphosphine (0.79g, 0.68mmol) and potassium acetate (2.69g, 27.10mmol) were added to 1,4-dioxane (80 mL), heated to 90°C under nitrogen atmosphere and reacted for 20 minutes. Naturally cool to room temperature, add water (250 mL), extract with ethyl acetate (15 mL The color liquid product was 4.08g, and the yield was 93.1%.

Step 3: Synthesis of (S)-4-(2-(benzyloxy)-3-fluorophenyl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Compound (S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-di Hydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.26g, 3.90mmol), 2-(benzyloxy)-1-bromo-3-fluorobenzene (1.10g, 3.90mmol), [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (0.16g, 0.19mmol) and potassium carbonate (1.08g, 7.74mmol) were added to 1,4-dioxane (40mL ) and water (8 mL), heated to 90°C for 2 h under nitrogen atmosphere. Cool to room temperature naturally, add water (100 mL) and ethyl acetate to extract (15 mL Transparent oil 1.23g, yield 79.4%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.47–7.32(m,5H),7.11–6.99(m,2H),7.00–6.90(m,1H),5.82–5.68(m,1H),5.08–4.89 (m,2H),4.73–4.43(m,1H),4.37–4.24(m,0.5H),4.19–4.02(m,0.5H),3.72–3.57(m,0.5H),2.97–2.83(m ,0.6H),2.81–2.72(m,0.4H),2.56–2.43(m,0.5H),2.31–2.13(m,1H),1.52(s,9H),1.22(d,J＝6.7Hz, 2H),1.10(d,J＝6.8Hz,1H).

Step 4 Synthesis of: (2S)-4-(3-fluoro-2-hydroxyphenyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester

Compound (S)-4-(2-(benzyloxy)-3-fluorophenyl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.23g , 3.09 mmol) and palladium on carbon (0.24 g, mmol) were added to methanol (10 mL), and the reaction was carried out overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 0.95 g of a colorless and transparent oily product with a yield of 99.0%.

LC-MS(ESI): [M-55] ⁺ =254.1;

¹ H NMR (500MHz, CDCl ₃ ) δ6.99–6.90(m,2H),6.87–6.77(m,1H),5.57–5.38(m,1H),4.05–3.90(m,1H),3.87–3.79 (m,1H),3.34–3.25(m,1H),3.19–3.08(m,1H),2.26–2.12(m,1H),1.93–1.82(m,1H),1.65–1.56(m,1H) ,1.51(s,9H),1.26(d,J=6.3Hz,3H).

Step 5: (2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine-1- Synthesis of tert-butyl carboxylate

Compound (2S)-4-(3-fluoro-2-hydroxyphenyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.97mmol), 7-(bromomethyl)-4 -Chloro-2-fluorobenzofuran (255 mg, 0.97 mmol) and cesium carbonate (638 mg, 1.94 mmol) were dissolved in DMF (5 mL). React at room temperature for 2 hours, add water (30 mL), extract with ethyl acetate (15 mL v)=30%), 420 mg of colorless liquid was obtained, with a yield of 88.0%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.28–7.25(m,2H),7.06–6.91(m,3H),6.05–6.03(m,1H),5.37–5.28(m,2H),3.75–3.562 (m,2H),3.24–3.17(m,1H),3.08–3.03(m,1H),2.06–1.92(m,1H),1.56–1.46(m,3H),1.52–1.45(m,9H) ,1.17(d,J＝6.4Hz,3H).

Step 6 Synthesis of: (2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine

Compound (2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine-1-carboxy Acid tert-butyl ester (420 mg, 0.91 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL, 13.46 mmol) was added, and the reaction was carried out at room temperature for 30 min. Remove the solvent under reduced pressure, add water (10 mL), add saturated aqueous sodium bicarbonate solution dropwise in an ice bath to adjust pH = 9, extract with dichloromethane (8 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a light yellow oil. 328 mg, yield 98.1%.

LC-MS (ESI): [M+H] ⁺ =392.1.

Step 7: 2-(((2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiper Synthesis of methyl (((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Compound (2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine (328 mg, 0.84 mmol) and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (296 mg, 1.0 mmol) After dissolving in acetonitrile (10 mL), add N,N'-diisopropylethylamine (541 mg, 4.14 mmol) with stirring at room temperature, and heat to 60°C to react overnight. Remove the solvent under reduced pressure, add water (50 mL) and ethyl acetate (15 mL 50%) to obtain 540 mg of colorless and transparent oily product, with a yield of 99.2%.

LC-MS(ESI): [M+H] ⁺ =650.2;

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.28(d,J＝1.7Hz,1H),7.82(dd,J＝8.5,1.6Hz,1H),7.68(d,J＝8.5Hz,1H) ,7.39(d,J＝8.1Hz,1H),7.30(d,J＝8.1Hz,1H),7.14–7.02(m,2H),6.97(d,J＝7.8Hz,1H),6.52(d, J＝6.4Hz,1H),5.34–5.20(m,2H),5.18–5.08(m,1H),4.85–4.64(m,2H),4.49–4.40(m,2H),4.26–4.19(m, 1H),3.88(s,3H),3.45(d,J＝13.9Hz,1H),2.76–2.60(m,3H),2.40–2.29(m,1H),2.15–2.06(m,1H),1.43 –1.12(m,5H),1.04(d,J＝6.1Hz,3H).

Step 8: 2-(((2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiper Synthesis of (((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound 2-(((2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine -1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (540 mg, 0.83 mmol) and lithium hydroxide monohydrate (174 mg, 4.11 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL), reacted at 40°C for 1.5 h, and added dropwise in an ice bath environment Adjust the pH to about 6 with dilute glacial acetic acid, extract with ethyl acetate (15mL /v) = 10%) to obtain 113 mg of white solid product, with a yield of 19.9%.

LC-MS(ESI): [M+H] ⁺ =636.2;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.71 (br.s, 1H), 8.25 (s, 1H), 7.80 (dd, J = 8.4, 1.6Hz, 1H), 7.65 (d, J = 8.4 Hz,1H),7.40(d,J＝8.1Hz,1H),7.31(d,J＝8.1Hz,1H),7.16–7.09(m,1H),7.09–7.04(m,1H),6.97(d ,J＝7.8Hz,1H),6.52(d,J＝6.5Hz,1H),5.32–5.22(m,2H),5.17–5.11(m,1H),4.82–4.75(m,1H),4.74– 4.66(m,1H),4.51–4.40(m,2H),4.26–4.20(m,1H),3.48–3.40(m,1H),2.79–2.61(m,3H),2.38–2.30(m,1H ),2.14–2.05(m,1H),2.05–1.92(m,2H),1.43–1.35(m,1H),1.22–1.18(m,1H),1.13–1.07(m,1H),1.07–1.03 (m,3H).

Example 40 2-(((2S)-4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiper of (ridin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 40) synthesis

Step 1: (2S)-4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine-1- Synthesis of tert-butyl carboxylate

Compound (2S)-4-(3-fluoro-2-hydroxyphenyl)-2-methylpiperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.97mmol), 7-(bromomethyl)-2 -Chloro-4-fluorobenzofuran (255 mg, 0.97 mmol) and cesium carbonate (638 mg, 1.94 mmol) were dissolved in DMF (5 mL). React at room temperature for 2 hours, add water (30 mL), extract with ethyl acetate (15 mL v) = 30%), 450 mg of colorless liquid was obtained, with a yield of 94.3%.

¹ H NMR (500MHz, CDCl ₃ ) δ7.35–7.29(m,1H),7.06–6.91(m,4H),6.75–6.71(m,1H),5.36–5.31(m,2H),3.75–3.57 (m,2H),3.29–3.17(m,1H),3.14–3.02(m,1H),2.01–1.90(m,1H),1.56–1.46(m,3H),1.52–1.45(m,9H) ,1.18(d,J＝6.4Hz,3H).

Step 2 Synthesis of: (2S)-4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine

Compound (2S)-4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine-1-carboxy Tert-butyl acid ester (450 mg, 0.91 mmol) was added to dichloromethane (5 mL) to dissolve, trifluoroacetic acid (1 mL, 13.46 mmol) was added, and the reaction was carried out at room temperature for 30 min. Remove the solvent under reduced pressure, add water (10 mL), add saturated aqueous sodium bicarbonate solution dropwise in an ice bath to adjust pH = 9, extract with dichloromethane (8 mL × 3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a light yellow oil. 355 mg, yield 99.0%.

LC-MS(ESI): [M+H] ⁺ =392.2;

¹ H NMR (500MHz, CDCl ₃ ) δ7.18–7.14(m,1H),7.01–6.92(m,2H),6.91–6.82(m,2H),6.66(d,J＝2.2Hz,1H), 5.24(s,2H),3.32–3.24(m,1H),3.11–3.00(m,1H),2.95–2.84(m,1H),2.78–2.68(m,1H),1.81–1.67(m,1H ),1.59–1.43(m,3H),1.20–1.15(m,3H).

Step 3: 2-(((2S)-4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiper Synthesis of methyl (((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

Compound (2S)-4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine (355 mg, 0.91 mmol) and (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (320 mg, 1.09 mmol) After dissolving in acetonitrile (10 mL), add N,N'-diisopropylethylamine (585 mg, 4.53 mmol) with stirring at room temperature, and heat to 60°C to react overnight. The solvent was removed under reduced pressure, water (50 mL) and ethyl acetate were added for extraction (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (eluent EtOAc: PE (v/v) = 50 %) to obtain 528 mg of colorless and transparent oily product, with a yield of 89.6%.

LC-MS(ESI): [M+H] ⁺ =650.3;

¹ H NMR (500MHz, DMSO-d ₆ ) δ8.28 (s, 1H), 7.82 (d, J = 8.5, 1.6 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.31 (dd, J＝8.3,5.2Hz,1H),7.25(s,1H),7.17–7.10(m,2H),7.05(d,J＝7.9,5.3Hz,1H),6.95(d,J＝7.7Hz,1H ),5.28(q,J＝11.7Hz,2H),5.19–5.10(m,1H),4.84–4.77(m,1H),4.71(dd,J＝15.4,6.1Hz,1H),4.51–4.41( m,2H),4.26–4.19(m,1H),3.88(s,3H),3.45(d,J＝13.9Hz,1H),2.76–2.60(m,3H),2.40–2.29(m,1H) ,2.15–2.06(m,1H),1.98(s,1H),1.43–1.29(m,1H),1.27–1.20(m,2H),1.16–1.10(m,1H),1.04(d,J＝ 6.1Hz,3H).

Step 4: 2-(((2S)-4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiper Synthesis of (((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound 2-(((2S)-4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine -1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (528 mg, 0.81 mmol) and lithium hydroxide monohydrate (170 mg, 4.05 mmol) were dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (1 mL), reacted at 40°C for 1.5 h, and added dropwise in an ice bath environment Adjust the pH to about 6 with dilute glacial acetic acid, extract with ethyl acetate (15mL /v) = 10%) to obtain 314 mg of white solid product, with a yield of 58.1%.

LC-MS(ESI): [M+H] ⁺ =636.2;

¹ H NMR (500MHz, DMSO-d ₆ ) δ12.71 (br.s, 1H), 8.25 (s, 1H), 7.80 (d, J = 8.6Hz, 1H), 7.40 (d, J = 8.1Hz, 1H),7.31(d,J＝8.1Hz,1H),7.19–7.02(m,2H),6.97(d,J＝7.8Hz,1H),6.57–6.47(m,1H),5.37–5.21(m ,2H),5.18–5.09(m,1H),4.83–4.74(m,1H),4.72–4.65(m,1H),4.50–4.39(m,2H),4.27–4.18(m,1H),3.49 –3.41(m,1H),2.78–2.58(m,3H),2.40–2.30(m,1H),2.12–1.93(m,3H),1.31–1.20(m,4H),1.08–1.02(m, 3H).

Example 41 (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-6-oxo- 3,6-Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 41) synthesis

Step 1: Synthesis of 4-(3-fluoro-2-(methoxymethoxy)phenyl)-5,6-dihydropyridin-2(1H)-one

Compound 1-bromo-3-fluoro-2-(methoxymethoxy)benzene (1.5g, 6.38mmol), 4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborane-2-yl)- 5,6-Dihydropyridin-2(1H)-one (1.42g, 6.38mmol), tetraphenylphosphopalladium (0.22g, 0.19mmol), sodium acetate (1.35g, 12.76mmol) were added to 1,4 - Dioxane (40 mL) and water (10 mL), stir at 80°C for 4 hours. The reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (PE:EA (v/v) = 10:1) to obtain 1.28 g of colorless oily product with a yield of 80.2%.

LC-MS(ESI): [M+H] ⁺ =252.4;

¹ HNMR (400MHz, CDCl ₃ ) δ7.50–7.37(m,1H),7.08–6.93(m,2H),6.04(s,1H),5.05(s,2H),3.48(t,J＝8.0Hz ,2H),3.44(s,3H),2.72(t,J=8.0Hz,2H).

Step 2: (S)-2-((4-(3-fluoro-2-(methoxymethoxy)phenyl)-6-oxo-3,6-dihydropyridine-1(2H)- Synthesis of methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

Compound 4-(3-fluoro-2-(methoxymethoxy)phenyl)-5,6-dihydropyridin-2(1H)-one (350 mg, 1.39 mmol) was added to tetrahydrofuran (10 mL) , cool to 0℃. Add sodium hydride (133 mg, 5.54 mmol) and stir at 0°C for half an hour. Add (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (410 mg, 1.39 mmol) , heated to room temperature and reacted for 2 hours. Water (5 mL) was added to quench the reaction, and extracted with ethyl acetate (5 mL × 2). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA (v/v) = 5:1) to obtain 190 mg of off-white solid product with a yield of 26.8%.

LC-MS (ESI): [M+H] ⁺ =510.2.

Step 3: (S)-2-((4-(3-fluoro-2-hydroxyphenyl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1 Synthesis of -(oxetan-2-ylmethyl)-1H-benzo(d)imidazole-6-carboxylic acid methyl ester

Compound (S)-2-((4-(3-fluoro-2-(methoxymethoxy)phenyl)-6-oxo-3,6-dihydropyridin-1(2H)-yl )methyl)-1-(oxetan-2-ylmethyl)-1H-benzo(d)imidazole-6-carboxylic acid methyl ester (190 mg, 0.22 mmol) was added to dichloromethane (30 mL) medium, cooled to -10°C, then trifluoroacetic acid (5 mL) was added dropwise, and the solution was stirred at -10°C overnight. Concentrate under reduced pressure and purify by silica gel column chromatography (eluent: PE:EA (v/v) = 3:1) to obtain 65 mg of light yellow solid product with a yield of 62.4%.

LC-MS(ESI): [M+H] ⁺ =466.2;

¹ HNMR(400MHz, DMSO-d ₆ )δ10.02(s,1H),8.28(s,1H),7.86–7.80(m,1H),7.74–7.70(m,1H),7.24–7.15(m, 1H),7.13–7.07(m,1H),6.89–6.80(m,1H),6.16(s,1H),5.13–5.00(m,2H),4.93–4.70(m,2H),4.68–4.58( m,1H),4.52–4.42(m,1H),4.40–4.31(m,1H),3.88(s,3H),3.66(t,J＝8.0Hz,2H),2.78(t,J＝8.0Hz ,2H),2.84–2.65(m,1H),2.42–2.29(m,1H).

Step 4: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-6-oxo- 3,6-Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Synthesis

Compound (S)-2-((4-(3-fluoro-2-hydroxyphenyl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1- (Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (65 mg, 0.14 mmol), 7-(bromomethyl)-4-chloro-2- Fluorobenzofuran (73 mg, 0.28 mmol) and potassium carbonate (58 mg, 0.42 mmol) were added to N,N-dimethylformamide (3 mL), and the temperature was raised to 60°C under nitrogen protection for two hours. Cool to room temperature, extract with ethyl acetate (10mL×2), dry the organic layer with anhydrous sodium sulfate, concentrate under reduced pressure, and use silica gel column chromatography (eluent: DCM:MeOH (v/v)=20:1 ) was purified to obtain 70 mg of light yellow solid product with a yield of 77.4%.

LC-MS (ESI): [M+H] ⁺ =648.4.

Step 5: (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-6-oxo- Synthesis of 3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-6-oxo-3 ,6-Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester ( 70 mg, 0.11 mmol) was added to 1,4-dioxane (4 mL) and water (1 mL), lithium hydroxide (23 mg, 0.55 mmol) was added, the temperature was raised to 40°C under nitrogen protection, and stirred for 2 hours. The reaction solution was cooled to room temperature, acetic acid was added dropwise until the solution pH=6, concentrated under reduced pressure, and purified by Prep-HPLC (eluent ACN: H ₂ O (v/v) = 50%) to obtain 10.3 mg of a white solid product, yielding The rate is 15.0%.

LC-MS(ESI): [M+H] ⁺ =634.2;

¹ HNMR(400MHz, DMSO-d ₆ )δ8.26(s,1H),7.86–7.80(m,1H),7.69–7.61(m,1H),7.39–7.08(m,3H),7.19–7.08( m,2H),6.35(d,J＝4.0Hz,1H),5.82(s,1H),5.27(s,2H),5.06–4.95(m,2H),4.84–4.71(m,2H),4.65 –4.56(m,1H),4.50–4.42(m,1H),4.38–4.30(m,1H),2.75–2.64(m,2H),2.60–2.53(m,2H),2.39–2.26(m, 2H).

Example 42 (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-6-oxo-3 ,6-Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (compound 42 )Synthesis

Step 1: (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-6-oxo-3 ,6-Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester synthesis

Compound (S)-2-((4-(3-fluoro-2-hydroxyphenyl)-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1- (Oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (67 mg, 0.14 mmol) was added to N,N-dimethylformamide (2 mL). Add potassium carbonate (60 mg, 0.43 mmol) and stir for 5 min. Add 7-(bromomethyl)-2,4-dichlorobenzofuran (60 mg, 0.21 mmol) and stir at 60°C for 1.5 hours. Concentrate under reduced pressure, add water (5 mL) and ethyl acetate (5 mL), and extract. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v/v) = 1:1) to obtain light yellow floccules. The product was 90 mg, yield 94.6%.

LC-MS(ESI): [M+H] ⁺ =664.4;

¹ HNMR (400MHz, CDCl ₃ ) δ8.12 (s, 1H), 7.95 (d, J = 8.4Hz, 1H), 7.71 (d, J = 8.4Hz, 1H), 7.09–7.03 (m, 3H), 6.99–6.94(m,1H),6.84(d,J＝7.6Hz,1H),6.46(s,1H),5.81(s,1H),5.23(s,2H),5.1–5.04(m,2H) ,4.85–4.74(m,2H),4.54–4.39(m,3H),3.89(s,3H),3.51–3.48(m,2H),2.72–2.59(m,1H),2.57–2.40(m, 2H),2.38–2.35(m,1H).

Step 2: (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-6-oxo-3 ,Synthesis of 6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

Compound (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-6-oxo-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (90 mg ,0.14mmol) was added to 1,4-dioxane (1.2mL) and water (0.1mL), and lithium hydroxide (16mg, 0.67mmol) was added and the mixture was stirred at 40°C overnight. Add acetic acid (0.1 mL) to adjust the pH to 6~7. Concentrate under reduced pressure and purify by Prep-HPLC (eluent acetonitrile: water (v/v) = 0-60%) to obtain 35.2 mg of white solid product with a yield of 40%.

LC-MS(ESI): [M+H] ⁺ =650.2;

¹ H NMR (400MHz, DMSO-d ₆ ) δ12.73 (s, 1H), 8.27 (s, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.66 (d, J = 8.4Hz, 1H) ,7.38–7.29(m,3H),7.17–7.0(m,3H),5.77(s,1H),5.30(s,2H),5.02–4.98(m,2H),4.82–4.76(m,2H) ,4.64–4.63(m,1H),4.47–4.45(m,1H),4.35–4.33(m,1H),3.46(t,J＝7.0Hz,2H),2.74–2.55(m,3H),2.33 –2.29(m,1H).

Example 43 2-((4-(2-(((4-chloro-2-fluoro-1-benzofuran-7-yl)methyl)oxy)pyridin-3-yl)-6-oxo -1,2,3,6-tetrahydropyridin-1-yl)methyl)-3-(((2S)-oxaheterocycl-2-yl)methyl)benzo[d]imidazole-5-carboxy Synthesis of acid (compound 43)

Step 1 Synthesis of: (4-chlorobenzofuran-7-yl)methyl acetate

Compound 7-(bromomethyl)-4-chlorobenzofuran (0.50g, 2.04mmol) and potassium acetate (2.00g, 20.37mmol) were added to N,N-dimethylformamide (5mL) at room temperature. Stir overnight. The solution was filtered, concentrated under reduced pressure, extracted with ethyl acetate (20 mL × 3), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain 600 mg of crude pale yellow solid product, which was directly used in the next reaction.

LC-MS (ESI): [M+H] ⁺ =225.1.

Step 2 Synthesis of (4-chlorobenzofuran-7-yl)methanol

Compound (4-chlorobenzofuran-7-yl)methyl acetate (600 mg, 2.67 mmol), lithium hydroxide (641 mg, 26.71 mmol) were added to 1,4-dioxane (6 mL) and water (2 mL ), react at 40°C for 2 hours, cool to room temperature, extract with ethyl acetate (20mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent: PE/EA ( v/v)=1:1), 330 mg of white solid product was obtained, with a yield of 67.7%.

LC-MS(ESI): [M+1] ⁺ =183.1;

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.15–8.10(m,1H),7.38–7.30(m,2H),7.04–6.98(m,1H),4.78(s,2H),3.38(s, 1H).

Step 3: Synthesis of 3-bromo-2-((4-chlorobenzofuran-7-yl)methoxy)pyridine

Compound (4-chlorobenzofuran-7-yl)methanol (342 mg, 1.87 mmol) was added to tetrahydrofuran (25 mL), sodium hydride (225 mg, 5.63 mmol) was added, and after stirring for 10 min, 3-bromo-2- Fluoropyridine (330 mg, 1.88 mmol), stir at room temperature for 1 hour, slowly add water (5 mL) dropwise to quench, add water (5 mL), extract with ethyl acetate (20 mL × 3), dry over anhydrous sodium sulfate, and use silica gel column layer After analytical purification (eluent: PE/EA (v/v) = 10:1), 500 mg of white solid product was obtained with a yield of 78.8%.

LC-MS(ESI): [M+H] ⁺ =338.2;

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.22–8.17(m,2H),8.10–8.06(m,1H),7.47–7.37(m,2H),7.08–7.06(m,1H),7.03– 6.99(m,1H),5.71(m,2H).

Step 4: Synthesis of 3-bromo-2-((4-chloro-2-fluoro-1-benzofuran-7-yl)methoxy)pyridine

Compound 3-bromo-2-((4-chlorobenzofuran-7-yl)methoxy)pyridine (400 mg, 1.18 mmol), N-fluorobishenylsulfonamide (447 mg, 1.42 mmol) was added to tetrahydrofuran (10 mL), add lithium diisopropylamide (253 mg, 2.36 mmol) dropwise at -50°C and stir overnight. The reaction was quenched by adding water (5 mL) dropwise at -50°C, extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE/EA ( v/v)=20:1), 100 mg of light yellow solid product was obtained, with a yield of 23.7%.

LC-MS(ESI): [M+H] ⁺ =356.1;

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.23–8.16(m,1H),8.12–8.05(m,1H),7.48–7.40(m,2H),7.04–6.98(m,1H),6.54( d,J＝4.0Hz,1H),5.65(s,2H).

Step 5: Synthesis of 4-methoxy-5,6-dihydropyridin-2(1H)-one

The compounds piperidine-2,4-dione (1g, 8.84mmol), trimethoxymethane (1.88g, 17.68mmol), and p-toluenesulfonic acid monohydrate (0.42g, 2.21mmol) were added to methanol (10mL) , stir at 70°C for 5 hours. Cool to room temperature, concentrate under reduced pressure, and purify using silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20:1) to obtain 0.6 g of a white solid product with a yield of 53.4%.

LC-MS(ESI):[M+H] ⁺ =128.2

¹ HNMR (400MHz, DMSO-d ₆ ) δ5.93 (s, 1H), 5.00 (s, 1H), 3.63 (s, 3H), 3.36 (t, J = 4.0 Hz, 2H), 2.39 (t, J =8.0Hz,2H).

Step 6: (S)-2-((4-methoxy-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetane- Synthesis of 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound 4-methoxy-5,6-dihydropyridin-2(1H)-one (86 mg, 0.68 mmol), (S)-2-(chloromethyl)-1-(oxetane- 2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (200mg, 0.68mmol) was added to tetrahydrofuran (6mL), sodium hydride (135mg, 3.38mmol) was added, and the reaction was carried out at room temperature. 2 hours. Add water (5mL), extract with ethyl acetate (20mL×3), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20:1 ), 250 mg of light yellow solid product was obtained, with a yield of 95.9%.

LC-MS(ESI): [M+H] ⁺ =386.2;

¹ HNMR(400MHz, DMSO-d ₆ )δ8.28–8.26(m,1H),7.84–7.80(m,1H),7.70–7.66(m,1H),5.08(s,1H),5.04–4.95( m,2H),4.81–4.70(m,2H),4.63–4.55(m,1H),4.50–4.42(m,1H),4.37–4.30(m,1H),3.87(s,3H),3.66( s,3H),3.55(t,J＝8.0Hz,2H),2.74–2.64(m,1H),2.53–2.43(m,2H),2.38–2.28(m,1H).

Step 7: (S)-2-((2,4-dioxopiperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[ d] Synthesis of imidazole-6-carboxylic acid methyl ester

Compound (S)-2-((4-methoxy-6-oxo-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetane-2 -methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (250 mg, 0.65 mmol), was added to tetrahydrofuran (2 mL), added trifluoroacetic acid (2 mL, 26.93 mmol), and stirred at room temperature overnight , add saturated sodium bicarbonate solution dropwise in an ice bath until the solution becomes weakly alkaline, extract with dichloromethane (20mL×3), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent: DCM/MeOH (v/v)=20:1), 100 mg of white solid product was obtained with a yield of 41.5%.

LC-MS(ESI): [M+H] ⁺ =372.4;

¹ HNMR (400MHz, DMSO-d ₆ ) δ8.30–8.26(m,1H),7.84–7.80(m,1H),7.73–7.66(m,1H),5.11–4.89(m,3H),4.81– 4.70(m,1H),4.63–4.55(m,1H),4.50–4.42(m,1H),4.37–4.30(m,1H),3.88(s,3H),3.73(t,J＝4.0Hz, 1H),3.55–3.47(m,1H),3.46–3.36(m,2H),2.76–2.64(m,1H),2.59(t,J＝4.0Hz,1H),2.45–2.27(m,2H) .

Step 8: (S)-1-(oxetan-2-ylmethyl)-2-((6-oxo-4-((trifluoromethyl)sulfonyl)oxy)-3 ,Synthesis of 6-dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

Compound (S)-2-((2,4-dioxopiperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d ] Imidazole-6-carboxylic acid methyl ester (100mg, 0.27mmol), N-phenylbis(trifluoromethanesulfonyl)imide (115mg, 0.32mmol), triethylamine (0.1mL, 0.54mmol) were added to tetrahydrofuran (3mL). React at room temperature for 5 hours, concentrate under reduced pressure, and purify with silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20:1) to obtain 100 mg of light white solid product with a yield of 73.8%.

LC-MS (ESI): [M+H] ⁺ =504.3.

Step 9: (S)-1-(oxetan-2-ylmethyl)-2-((6-oxo-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester Synthesis

Compound (S)-1-(oxetan-2-ylmethyl)-2-((6-oxo-4-(((trifluoromethyl)sulfonyl)oxy)oxy)-3, 6-Dihydropyridin-1(2H)-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (100 mg, 0.20 mmol), pinacol diborate (56 mg, 0.22 mmol) ), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (7mg, 0.01mmol), potassium acetate (39mg, 0.40mmol) were added to 1,4-dioxane ( 5 mL), replace it with nitrogen three times, react at 70°C for 1.5 hours, and then put it directly into the next step of reaction.

Step 10: (S)-2-((2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6'-oxo-3',6'-dihydro- [3,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Synthesis of methyl carboxylate

To the reaction solution in step 9, add 3-bromo-2-(((4-chloro-2-fluoro-1-benzofuran-7-yl)methyl)oxy)pyridine (71 mg, 0.20 mmol), tetrasan Phenylphosphine palladium (11 mg, 0.01 mmol), sodium carbonate (42 mg, 0.40 mmol) and water (1 mL) were replaced with nitrogen three times at 85°C. Reaction takes 3 hours. The solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM/MeOH (v/v) = 20:1) to obtain 50 mg of light yellow solid product with a yield of 39.5%.

LC-MS (ESI): [M+H] ⁺ =631.4.

Step 11: (S)-2-((2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6'-oxo-3',6'-dihydro- [3,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6 -Synthesis of carboxylic acids

Compound (S)-2-((2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6'-oxo-3',6'-dihydro-[ 3,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- Methyl carboxylate (50 mg, 0.08 mmol) and lithium hydroxide (20 mg, 0.48 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL), and the reaction was carried out at 40°C for 2 hours. Cool to room temperature, slowly add acetic acid dropwise until the solution pH=6, concentrate under reduced pressure, and purify with Prep-HPLC (eluent: ACN/H ₂ O (v/v) = 50%) to obtain 17.7 mg of white solid product. Yield 36.2%.

LC-MS(ESI): [M+H] ⁺ =617.2;

¹ HNMR (400MHz, DMSO-d ₆ ) δ12.80 (s, 1H), 8.28–8.19 (m, 2H), 7.88–7.78 (m, 2H), 7.64 (d, J = 8.0Hz, 1H), 7.45 –7.37(m,2H),7.16–7.10(m,1H),6.51(d,J＝8.0Hz,1H),6.23(s,1H),5.65(s,2H),5.04–4.96(m,2H ),4.89–4.82(m,1H),4.77–4.69(m,1H),4.61–4.54(m,1H),4.45–4.38(m,1H),4.34–4.26(m,1H),3.59(t ,J＝8.0Hz,2H),2.74(t,J＝8.0Hz,2H),2.70–2.59(m,1H),2.35–2.24(m,1H).

Experimental Example 1 In vitro cell activity test

1.Materials

(1)Cell line

The cells were constructed by Shanghai WuXi AppTec New Drug Development Co., Ltd., as shown in Table 1 below.

Table 1

(2) See Table 2 below for reagents.

Table 2

(3) Instruments are shown in Table 3 below.

table 3

(4)Compound information

Prepare compounds in DMSO to a working concentration compound solution of 100 μM or 10 μM. Make 10 points of 4-fold dilution (the highest concentration after dilution is 1000nM or 100nM), and the automatic pipetting workstation completes the dilution.

2.Method

(1) Experimental materials

The experimental buffer is shown in Table 4 below.

Table 4

The final concentration of the detection reagent preparation is shown in Table 5 below.

table 5

(2) Experimental methods

(a) Prepare compound plate:

The compound to be tested is diluted 10 times 4 times, with a starting concentration of 100 μM, and the automatic pipetting workstation completes the dilution.

(b) Transfer compound:

(i) Use a liquid handler to transfer 100 nL of 100x compound to a 384-well plate.

(ii) Centrifuge the 384-well plate at 1000 rpm for 5 seconds.

(c) Preparation of cell suspension

(i) Quickly thaw a cryovial of HEK293 cells that highly express hGLP-1R in warm water at 37°C.

(ii) Transfer the cell suspension to a 15mL centrifuge tube and rinse gently with 10mL HBSS.

(iii) Centrifuge the tube at 1000 rpm for 1 minute at room temperature.

(iv) Discard the supernatant.

(v) Wash gently with 10ml HBSS, centrifuge to sediment the cells, and finally resuspend the cells in experimental buffer.

(vi) Use a cell counter to measure cell density and activity.

(vii) Dilute the GLP-1R cell concentration to 1.0*10 ⁵ /mL with experimental buffer.

(viii) Transfer 10 μL of diluted cell suspension into a 384-well plate.

(ix) Incubate at room temperature for 30 minutes.

(d) Testing:

(i) Add 10 μL of 800 nM gradient diluted cAMP standard into the empty wells of the 384-well plate.

(ii) Add 10μL cAMP detection reagent.

(iii) After incubating at room temperature for 60 minutes, read on a microplate reader.

The results are shown in Table 1. Table 1 shows the agonistic effects (EC ₅₀ ) of the compounds provided in some examples of the present invention.

Table 1. Experimental results of agonistic effects of compounds provided in some examples of the present invention

Results and Discussion: The compounds of the present invention showed superior agonistic ability on GLP-1 receptors.

Experimental Example 2: Study on the pharmacokinetics of the compound of the present invention in mice

1. Experimental materials

C57BL/6 mice: male, 6-8 weeks old, weighing 20-30 grams, purchased from Vitong Lever (Beijing) Experimental Animal Technology Co., Ltd.

Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, the experimental water was ultrapure water, and the remaining reagents were commercially available analytical grade.

Instrument: AB LCMS-5500 tandem mass spectrometer

2. Experimental methods

Weigh the compound and dissolve it in 10% DMSO/5% Kolliphor-EL/85% HP-β-CD (20%) or other appropriate systems. The preparations are in the form of clear solutions. The mice are administered intravenously or intragastrically. Blood samples were collected 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h later. Collect 30 μL of whole blood from each PK sampling point into EDTA-K2 anticoagulant blood collection tubes and centrifuge at 4°C within 30 minutes to collect plasma. Whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or cryopreserved until analysis.

Weigh about 1 mg of the compound and dissolve it in DMSO, vortex and sonicate to obtain a 1 mg/mL standard stock solution. The standard stock solution was diluted with 50% acetonitrile aqueous solution to obtain standard working solutions with concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000 and 10000ng/mL. Use the same dilution method to prepare quality control working solutions with concentrations of 10, 20, 500 and 8000ng/mL. 3 μL of standard working solution with concentrations of (5, 10, 20, 50, 100, 500, 1000, 5000 and 10000ng/mL) was added to 30 μL of blank C57BL/6 mouse plasma to obtain a total volume of 33 μL and a concentration of 0.5-1000ng. /mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000ng/mL) standard curve samples. Quality control samples with concentrations of (1ng/ml (low-1), 2ng/ml (low-2), 50ng/ml (medium), and 800ng/ml (high)) are separately prepared.

Add 200 μL containing internal standard to 33 μL standard sample, 33 μL quality control sample or 33 μL unknown sample (30 μL plasma and 3 μL blank solution) Acetonitrile-precipitated proteins (dexamethasone). Then the sample was vortexed for 30 seconds, centrifuged at 4000g and 4°C for 15 minutes, the supernatant was diluted 3 times with water, and 10 μL of the supernatant dilution was injected into the LC-MS/MS system for quantitative analysis. The detection conditions are as follows:

Column: Raptor Biphenyl 2.7μm 2.1×50mm

Mobile phase: Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water), perform gradient elution according to the table.

3. Data processing

Using Phoenix TM Use the non-compartmental model of 8.3 software for pharmacokinetic data analysis.

The results are shown in Table 2, which shows the pharmacokinetic parameters in mice.

Table 2. Experimental results of pharmacokinetic parameters of the compounds provided in some examples of the present invention

Results and discussion: This experiment also measured the pharmacokinetic properties of compound 3 disclosed in CN114591308A. The experimental results show that the compound of the present invention is better absorbed orally in mice, has a higher exposure and is significantly higher than that disclosed in CN114591308A. of compound 3.

Experimental Example 3: Pharmacokinetic Study in Rats

3. Experimental materials

SD rats: male, 6-8 weeks old, weighing 200-300 grams, purchased from Spefford (Beijing) Experimental Animal Technology Co., Ltd.

Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, the experimental water was ultrapure water, and the remaining reagents were commercially available analytical grade.

Instrument: AB LCMS-5500 tandem mass spectrometer

2. Experimental methods

Weigh the compound and dissolve it in 10% DMSO/5% Kolliphor-EL/85% HP-β-CD (20%) or other appropriate systems. The preparations are all in the form of clear solutions. Give the rats intravenous or intragastric administration. Blood samples were collected 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, and 24h later. Collect 200 μL of whole blood from each PK sampling point into EDTA-K2 anticoagulant blood collection tubes and centrifuge at 4°C within 30 minutes to collect plasma. Whole blood samples were placed on wet ice before centrifugation. All collected plasma samples were stored on dry ice or cryopreserved until analysis.

Weigh approximately 1 mg of the compound of the present application and dissolve it in DMSO, vortex and sonicate to obtain a 1 mg/mL standard stock solution. The standard stock solution was diluted with 50% acetonitrile aqueous solution to obtain standard working solutions with concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000 and 10000ng/mL. Use the same dilution method to prepare quality control working solutions with concentrations of 10, 20, 500 and 8000ng/mL. These quality control samples were prepared in the same manner as the standard curve samples on the day of analysis. 5 μL of standard working solution with concentrations of (5, 10, 20, 50, 100, 500, 1000, 5000 and 10000ng/mL) was added to 50 μL of blank SD rat plasma to obtain a total volume of 55 μL and a concentration of 0.5-1000ng/mL. (0.5, 1, 2, 5, 10, 50, 100, 500, 1000ng/mL) standard curve samples. The concentrations are (1ng/ml (low-1) and 2ng/ml (low-2), Quality control samples of 50ng/ml (medium) and 800ng/ml (high) are separately configured.

55μL standard sample, 55μL QC sample or 55μL unknown sample (50μL plasma sample plus 5μL 50% acetonitrile aqueous solution) add 200μL acetonitrile containing internal standard (dexamethasone) to precipitate the protein. Then the sample was vortexed for 30 seconds, centrifuged at 4000g and 4°C for 15 minutes, the supernatant was diluted 3 times with water, and 5 μL of the supernatant dilution was injected into the LC-MS/MS system for quantitative analysis. The detection conditions are as follows:

Column: HALO 90A Phenly-Hexyl, 2μm 2.1×30mm

Mobile phase: Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water), perform gradient elution according to the table.

3. Data processing

Using Phoenix TM Use the non-compartmental model of 8.3 software for pharmacokinetic data analysis.

The results are shown in Table 3, which shows the pharmacokinetic parameters in rats.

Table 3. Experimental results of pharmacokinetic parameters of compounds provided in some examples of the present invention

Results and discussion: This experiment also measured the pharmacokinetic properties of compound 3 disclosed in CN114591308A. The experimental results show that the compound of the present invention is better absorbed orally in rats, has a higher exposure and is significantly higher than that disclosed in CN114591308A. of compound 3.

In the description of this specification, reference to the terms "one embodiment,""someembodiments,""anexample,""specificexamples," or "some examples" or the like means that specific features are described in connection with the embodiment or example. , structures, materials or features are included in at least one embodiment or example of the invention. In this specification, the schematic expressions of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the specific features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine different embodiments or examples and features of different embodiments or examples described in this specification unless they are inconsistent with each other.

Claims (12)

A compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvent of a compound represented by formula (I) chemical compounds, metabolites, pharmaceutically acceptable salts or prodrugs,
in: X ₁ , X ₂ and X ₃ are each independently N or CR ¹³ ; Y ₁ is N or CR ¹⁴ ; Y ₂ is N or CR ⁴ ; Y ₃ is N or CR ⁵ ; Y ₄ is N or CR ¹⁵ ; L is O or CR ¹⁶ R ¹⁷ ; Z is O or S; R ¹ is H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl or -C _1-6 alkylene -R ¹⁸ , the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and -C _1-6 alkylene The group -R ¹⁸ may be independently optionally substituted by 1, 2 or 3 R ^1a ; R ¹⁸ is C _3-6 cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl; R ^1a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _{1 -6} alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclyl, the C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 Alkylamino, C _3-6 cycloalkyl and 3-6 membered heterocyclyl can be independently optionally substituted by 1, 2 or 3 R ^1b ; R ^1b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _{1 -6} alkylamino, C _3-6 cycloalkyl or 3-6 membered heterocyclyl; Each R ¹³ is independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkoxy or -C _1-6 alkylene-C _1-6 alkoxy; R ² , R ³ , R ⁶ , R ⁷ , R ¹⁶ and R ¹⁷ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro or C _1-6 alkane base, the C _1-6 alkyl group can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro; Ring B is a 5-6 membered heterocyclyl, C _5-6 cycloalkyl, phenyl or 5-6 membered heteroaryl; Each R ^b is independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkyl Amino group, the C _1-6 alkyl group, C _1-6 alkoxy group and C _1-6 alkylamino group can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitution; R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkylamino, the C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylamino can be independently optionally 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitution; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8. The compound according to claim 1, which has a structure represented by formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII):

The compound according to claim 1 or 2, wherein R ¹ is H, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-6 cycloalkyl, 3-6 yuan Heterocyclyl or -C _1-3 alkylene -R ¹⁸ , the C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _3-6 cycloalkyl, 3-6 The one-membered heterocyclyl group and -C _1-3 alkylene group -R ¹⁸ can be independently optionally substituted by 1, 2 or 3 R ^1a ; R ¹⁸ is C _3-6 cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl; R ^1a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _{1 -3} alkylamino, C _3-6 cycloalkyl or 5-6 membered heterocyclyl, the C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _1-3 Alkylamino, C _3-6 cycloalkyl and 5-6 membered heterocyclyl can be independently optionally substituted by 1, 2 or 3 R ^1b ; R ^1b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 alkylthio, C _{1 -3} alkylamino, C _5-6 cycloalkyl or 5-6 membered heterocyclyl. The compound according to any one of claims 1-3, wherein ^R1 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1- Propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl or -CH ₂ R ¹⁸ , the methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl and -CH ₂ R ¹⁸ may independently optionally be replaced by 1 , 2 or 3 R ^1a substitutions; R ¹⁸ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, morpholinyl, R ^1a is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio , N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidyl, piperidyl Azinyl or morpholinyl, the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclopropyl, Butyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl can be independently optionally substituted by 1, 2 or 3 R ^1b substitutions; R ^1b is D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio , N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, Pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl. The compound according to any one of claims 1-4, wherein ^R1 is H, The compound according to any one of claims 1-5, wherein each R ¹³ is independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _1-6 haloalkoxy or -C _1-6 Alkylene-C _1-6 alkoxy; R ² , R ³ , R ⁶ , R ⁷ , R ¹⁶ and R ¹⁷ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro or C _1-3 alkyl base, the C _1-3 alkyl group can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro; Each R ^b is independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 alkyl Amino group, the C _1-3 alkyl group, C _1-3 alkoxy group and C _1-3 alkylamino group can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitution; R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 alkylamino, the C _1-3 alkyl, C _1-3 alkoxy and C _1-3 alkylamino can be independently optionally 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitutions. The compound according to any one of claims 1-6, wherein each R ¹³ is independently H, D, F, Cl, Br, I, CN, hydroxyl, amino, nitro, methyl, ethyl, n-propyl base, isopropyl, -CHF ₂ , -CF ₃ , -CHFCH ₂ F, -CF ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CF ₂ CHF ₂ , hydroxymethyl, hydroxyethyl, aminomethyl , aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF ₂ , -OCF ₃ , -OCHFCH ₂ F, -OCF ₂ CHF ₂ , -OCH ₂ CF ₃ , -OCH ₂ CF ₂ CHF ₂ , -CH ₂ OCH ₃ , -CH ₂ OCH ₂ CH ₃ , -CH ₂ CH ₂ OCH ₃ or -CH ₂ CH ₂ OCH ₂ CH ₃ ; R ² , R ³ , R ⁶ , R ⁷ , R ¹⁶ and R ¹⁷ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl , n-propyl or isopropyl, the methyl, ethyl, n-propyl and isopropyl can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or Nitro substitution; Each R ^b is independently H, D, F, Cl, Br, I, CN, hydroxyl, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy base, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy , Isopropoxy, N-methylamino and N-ethylamino can be independently optionally substituted by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro; R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ and R ¹⁵ are each independently H, D, F, Cl, Br, I, CN, hydroxyl, nitro, methane base, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, the methyl, ethyl, n-propyl Propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino can be independently optionally replaced by 1, 2 or 3 F, Cl, Br, I, CN, hydroxyl, amino or nitro substitution. The compound according to any one of claims 1 to 7, which is a compound with one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxidation compound of a compound with one of the following structures compound, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug:


A pharmaceutical composition comprising the compound of any one of claims 1 to 8; the pharmaceutical composition optionally further comprises pharmaceutically acceptable excipients, carriers, adjuvants or any combination thereof. The use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of medicines for preventing, treating or alleviating GLP-1 receptor agonist-mediated symptoms in patients disease. The use according to claim 10, wherein the disease mediated by the GLP-1 receptor agonist is diabetes, non-alcoholic fatty liver disease or obesity. The use according to claim 11, wherein the diabetes is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, adult-onset diabetes of the young, adolescent-onset SARS. Type 2 diabetes, malnutrition-related diabetes, or latent autoimmune diabetes in adults.