Benzo-bicyclic compound as well as preparation method and application thereof

Abstract

The invention discloses a benzo-bicyclic compound and an application of the benzo-bicyclic compound in medicines, and particularly relates to a novel benzo-bicyclic compound and a pharmaceutical composition containing the benzo-bicyclic compound. The invention also relates to a method for preparing the compound, and application of the compound or the pharmaceutical composition in preparation of medicines for treating GLP-1 receptor agonist-mediated diseases and / or symptoms, in particular to application in preparation of medicines for treating diabetes, non-alcoholic fatty liver diseases and obesity.

Description

Benzobicyclic compounds and their preparation methods and applications

[0001] This application claims priority to:

[0002] CN202211048114.4, application date August 30, 2022. Technical Field

[0003] The present invention relates to the technical field of chemical medicine, and in particular to a benzobicyclic compound and a preparation method and application thereof. Background Art

[0004] Diabetes is a multi-factorial metabolic disease characterized by chronic hyperglycemia and disturbances in sugar, lipid, and protein metabolism caused by defects in insulin secretion or action. Diabetes is a very old disease caused by an absolute or relative deficiency of insulin, leading to elevated blood glucose concentrations and subsequent excretion of sugar in the urine. Symptoms include polydipsia, polyuria, polyphagia, and weight loss.

[0005] Based on the pathogenesis of diabetes, diabetes can generally be divided into type 1 and type 2 diabetes. Type 1 diabetes is caused by the immune system attacking pancreatic beta cells, resulting in the loss of insulin secretion. Type 2 diabetes begins with abnormal insulin resistance, or the failure of cells to respond to insulin. Obesity is one of the main causes of insulin resistance and is therefore considered a major risk factor for type 2 diabetes. Type 2 diabetes accounts for approximately 90% of all diabetics, making it a major public health concern in developed countries with severe obesity problems and in China, where the number of obese people is rising.

[0006] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells in the lower gastrointestinal tract. GLP-1 exerts its corresponding effects by binding to its widely existing specific receptors. At present, the organs where GLP-1 receptors are clearly present include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus and cardiovascular system. GLP-1 receptors may be present in the liver, adipose 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 in patients with normal glucose tolerance, impaired glucose tolerance and type 2 diabetes. However, the response of β cells to GLP-1 after eating is defective. Under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. Because the duration of action of the human body's own GLP-1 is very short (intravenous injection of t 1 / 2 <1.5 minutes), so the body's own GLP-1 is not suitable for the clinical treatment of diabetes.

[0007] Peptide GLP-1 receptor agonists (such as liraglutide and exenatide) have the effect of lowering fasting and postprandial glucose and improving blood sugar levels in patients with type 2 diabetes. However, due to the poor oral bioavailability of peptide GLP-1 and the inconvenience of administration, there is an urgent clinical need for small molecule GLP-1 receptor agonists with good oral bioavailability.

[0008] Currently, researchers have conducted some research in the hope of finding therapeutic agents that can effectively stimulate GLP-1 receptors. PCT applications include WO2018109607, WO2019239319, WO2019239371, WO2020103815, WO2020207474, WO2020263695, WO2021154796, WO2021112538, WO2021096304, WO2021096284, and WO202108 1207, WO2021018023, WO2021254470, WO2021249492, WO2022007979, WO2022031994, WO2022040600, WO2022068772, and WO2022116693 disclose a number of small molecule compounds that are used as GLP-1 receptor agonists for preventing or treating diabetes. However, there is still an urgent need for more and better GLP-1 receptor agonists in clinical practice.

[0009] Summary of the Invention

[0010] The present invention provides a compound, or a pharmaceutical composition thereof, which is useful as a GLP-1 receptor agonist. The present invention further relates to the use of the compound or pharmaceutical composition thereof for preparing a medicament for treating a disease and / or condition by stimulating the GLP-1 receptor. The present invention further describes a method for synthesizing the compound. The compound of the present invention exhibits excellent biological activity and pharmacokinetic properties.

[0011] Specifically:

[0012] In one aspect, the present invention relates to a compound, which is a compound as represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I).

[0013] in:

[0014] X1, X2 and X3 are each independently N or CR 13 ;

[0015] Y1 is N or CR 14 ;

[0016] Y2 is N or CR 4 ;

[0017] Y3 is N or CR 5 ;

[0018] Y4 is N or CR 15 ;

[0019] L is O or CR 16 R 17 ;

[0020] Z is O or S;

[0021] R 1 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group 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 heterocyclic group and -C 1-6 Alkylene-R 18 Can be optionally replaced by 1, 2 or 3 R 1a replace;

[0022] R 18 C 3-6 Cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl;

[0023] R 1a D, F, Cl, Br, I, CN, hydroxy, 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 heterocyclic group, 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 heterocyclic groups may be independently optionally substituted by 1, 2 or 3 R 1b replace;

[0024] R 1b D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0025] Each R 13 are independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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;

[0026] R 2 、R 3 、R 6 、R 7 、R 16 and R 17 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted independently with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups;

[0027] Ring B is a 5-6 membered heterocyclic group, C 5-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl;

[0028] Each R b are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, 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 may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups;

[0029] R 4 、R 5 、R 8 、R 9 、R 10 、R 11 、R 12 、R 14 and R 15 Each independently represents H, D, F, Cl, Br, I, CN, hydroxyl, nitro, C 1-6 Alkyl, C1-6 Alkoxy or C 1-6 Alkylamino, the C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 Alkylamino may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups;

[0030] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0031] In some embodiments, the compounds of the present invention have a structure represented by Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or Formula (VII):

[0032] Among them, X1, X2, X3, Y1, Y2, Y3, Y4, Z, R 1 、R 2 、R 3 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R b and n have the meanings described in the present invention.

[0033] In some embodiments, R 1 H, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group 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 heterocyclic group and -C 1-3 Alkylene-R 18 Can be optionally replaced by 1, 2 or 3 R 1a replace;

[0034] R 18 C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl;

[0035] R 1a D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, C 1-3 Alkyl, C 1-3Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl or 5-6 membered heterocyclic group, 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 heterocyclic groups may be independently optionally substituted by 1, 2 or 3 R 1b replace;

[0036] R 1b D, F, Cl, Br, I, CN, hydroxy, 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 heterocyclic group.

[0037] In some embodiments, R 1 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, or -CH2R 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 -CH2R 18 Can be optionally replaced by 1, 2 or 3 R 1a replace;

[0038] R 18 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl,

[0039] R 1ais D, F, Cl, Br, I, CN, hydroxy, 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, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally replaced by 1, 2 or 3 R 1b replace;

[0040] R 1b is D, F, Cl, Br, I, CN, hydroxy, 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.

[0041] In some embodiments, R 1 For H,

[0042] In some embodiments, each R 13 are independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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;

[0043] R 2 、R 3 、R 6 、R 7 、R 16 and R 17 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1- 3 alkyl, the C 1-3 The alkyl group may be optionally substituted independently with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups;

[0044] Each R bare independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, 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 may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups;

[0045] R 4 、R 5 、R 8 、R 9 、R 10 、R 11 、R 12 、R 14 and R 15 Each independently represents 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 The alkylamino group may be optionally substituted independently with 1, 2, or 3 F, Cl, Br, I, CN, hydroxy, amino, or nitro groups.

[0046] In some embodiments, each R 13 is independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3;

[0047] R 2 、R 3 、R 6 、R 7 、R 16 and R 17Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl or isopropyl, and the methyl, ethyl, n-propyl and isopropyl may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups;

[0048] Each R b are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro;

[0049] R 4 、R 5 、R 8 、R 9 、R 10 、R 11 、R 12 、R 14 and R 15 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino may be independently and optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro.

[0050] In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

[0051] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0052] In one aspect, the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the preparation of a medicament for preventing, treating or alleviating a GLP-1 receptor agonist-mediated disease in a patient.

[0053] In some embodiments, the disease mediated by the GLP-1 receptor agonist of the present invention is diabetes, non-alcoholic fatty liver disease or obesity.

[0054] In some embodiments, the diabetes described in the present invention is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, maturity-onset diabetes of the young, atypical diabetes of the juvenile onset, malnutrition-related diabetes or latent autoimmune diabetes of adults.

[0055] On the other hand, the present invention relates to methods for preparing, isolating and purifying compounds encompassed by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII).

[0056] The foregoing description only summarizes certain aspects of the present invention, but is not intended to limit the present invention to these aspects. These and other aspects will be described in more detail and fully below.

[0057] Definitions and General Terms

[0058] The present invention will list the literature corresponding to the specific content of the invention in detail, and the examples are accompanied by diagrams of structural formulas and chemical formulas. The present invention is intended to cover all options, variations and equivalents that may be included in the existing invention field as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be applied to the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that differ or conflict with the present application, including but not limited to the definition of terms, the usage of terms, the technology described, or the scope controlled by the present application.

[0059] The following definitions apply to the present invention unless otherwise indicated. For purposes of the present invention, the chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Chemical Handbook, 75th Ed, 1994. In addition, general principles of organic chemistry are described in "Organic Chemistry," by 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, all of which are incorporated herein by reference.

[0060] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0061] Compounds as described herein may optionally be substituted with one or more substituents, as described in the general formulae of the present invention, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with the specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from the specified group, the substituents may be the same or different at each position.The substituents may be, but are not limited to, hydrogen, F, Cl, Br, I, nitro, cyano, oxo (=O), hydroxy, alkyl, hydroxyalkyl, alkylamino, aminoalkyl, 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)2OH, -C(=O)NH2, -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)2OH, -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)-NH2, -NHC(=O)NH-(alkyl), -NHC(=O)NH(haloalkyl), -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)2OH, -C(=NH)NH2, -C(=NH)NH-alkyl, -C(=NH)N(alkyl)-alkyl, -C(=N-alkyl)-NH2, -C(=O)NH-alkylene-S(=O)2OH, -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 the like.

[0062] As used herein, the term "alkyl" includes saturated linear or branched monovalent hydrocarbon groups of 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, or 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t- -Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl -1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2C H3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl and n-octyl, etc. The term "alkyl" and its prefix "alkane" as used herein include straight and branched saturated carbon chains. The term "alkylene" or "alkylene" as used herein refers to a saturated divalent hydrocarbon radical derived from a straight or branched saturated hydrocarbon by eliminating two hydrogen atoms. Examples of such radicals include, but are not limited to, methylene, ethylene, and isopropylene, etc.

[0063] The term "alkylene" refers to a saturated divalent hydrocarbon radical derived by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-3 carbon atoms; and in still other embodiments, an alkylene group contains 1-2 carbon atoms. Examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.

[0064] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one CC is sp 2 double bond, wherein the alkenyl group can be independently and optionally substituted with one or more substituents described herein, including groups with "trans", "cis" or "E", "Z" orientations, wherein specific examples of alkenyl include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and the like.

[0065] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one position is unsaturated, i.e., one C—C is an sp triple bond, wherein the alkynyl group may be independently and optionally substituted with one or more substituents described herein. Specific examples of alkynyl include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.

[0066] The term "heteroatom" means one or more of 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 the form of a nitrogen atom in a heterocyclic ring being substituted with a hydrogen, for example, N (such as N in 3,4-dihydro-2H-pyrrolyl), NH (such as NH in pyrrolidinyl) or NR (such as NR in N-substituted pyrrolidinyl); or in the form of -CH2- in a heterocyclic ring being oxidized to form -C(=O)-.

[0067] The term "halogen" refers to F, Cl, Br or I.

[0068] The term "deuterium" refers to heavy hydrogen, D.

[0069] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0070] The term "alkoxy" or "alkyloxy" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via an oxygen atom. In some embodiments, the alkoxy group is C 1-4 Alkoxy groups; examples thereof include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy, etc., and the alkoxy groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0071] The term "alkylthio" or "alkylthio" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a sulfur atom. In some embodiments, the alkylthio group is C 1-4 Alkylthio; such examples include, but are not limited to, methylthio, ethylthio, propylthio, and butylthio, etc., and the alkylthio group can be independently unsubstituted or substituted with one or more substituents described herein.

[0072] The term "alkylamino" or "alkylamino" as used herein refers to an alkyl group, as defined herein, attached to the rest of the compound molecule via a nitrogen atom. In some embodiments, the alkylamino group is C 1-4 Alkylamino groups; examples thereof include, but are not limited to, methylamino, ethylamino, propylamino, and butylamino groups. The alkylamino groups may be independently unsubstituted or substituted with one or more substituents described herein.

[0073] The term "cycloalkyl" or "cycloalkane" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic carbon ring system containing 3-12 carbon atoms, which may be saturated or contain one or more unsaturated bonds, but never aromatic. In one embodiment, the cycloalkyl group contains 3-10 carbon atoms; in another embodiment, the cycloalkyl group contains 3-8 carbon atoms; and in yet another embodiment, the cycloalkyl group contains 3-6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0074] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, never including aromatic rings, wherein at least one ring atom is a heteroatom. In one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 10 ring atoms; in one embodiment, "heterocyclyl" or "heterocycle" contains 3 to 8 ring atoms; in another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 8 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 3 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 5 to 6 ring atoms; in yet another embodiment, "heterocyclyl" or "heterocycle" contains 4 to 6 ring atoms; unless otherwise specified, a heterocyclyl group may be a carbon group or a nitrogen group, and heteroatoms have the meanings as described herein. Examples of heterocyclic 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-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine thiazolinone Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione, and 5,6-dihydropyridin-2(1H)-one. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0075] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3-7 ring atoms, and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring". Examples of aryl groups include phenyl, naphthyl, and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.

[0076] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring contains 5-7 ring atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the 5-10 heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N, wherein the nitrogen atom can be further oxidized.

[0077] Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl, oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl, thiazole 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, 1,2,3 ... oxadiazole, pyrazinyl, 1,3,5-triazinyl; also include the following bicyclic rings, but are in no way limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), 1,2,3,4-tetrahydroisoquinolyl, 1,3-benzodioxolyl, indolinyl, isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl and [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0078] The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms. Examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.

[0079] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, and the like.

[0080] The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups. Examples include, but are not limited to, aminomethyl, aminoethyl, and the like.

[0081] As described herein, a substituent group is attached to a ring by a bond to form a ring system, which indicates that the substituent group can be substituted at any substitutable position on the ring. For example, formula (a) indicates that the substituent group R can be substituted at any substitutable position on the pyridine ring.

[0082] As described herein, a ring system formed by a linker attached to a ring (e.g., Formula b) represents that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula b represents that any available position on the octahydrocyclopenta[c]pyrrole ring can be attached to the rest of the molecule.

[0083] In addition, it should be noted that, unless explicitly stated otherwise, the descriptions used throughout this document such as "each ... and ... are independently", "... and ... are each independently", and "... and ... are respectively independently" are interchangeable and should be understood in a broad sense. They may mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0084] Unless otherwise indicated, the structural formulas described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformational isomers): for example, R and S configurations containing asymmetric centers, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of such enantiomers, diastereomers, geometric isomers, or conformational isomers thereof, are within the scope of the present invention.

[0085] Unless otherwise indicated, the structural formulas and compounds described herein include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers, or conformers), N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs. Therefore, individual stereochemical isomers, enantiomers, diastereomers, geometric isomers, conformers, N-oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs of the compounds of the present invention are also within the scope of the present invention. Furthermore, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

[0086] "Metabolite" refers to a product obtained by metabolism in vivo of a specific compound described herein or a pharmaceutically acceptable salt, analog or derivative thereof, which exhibits similar activity in vivo or in vitro to the compound of Formula (I), (II), (III), (IV), (V), (VI) or (VII). The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by assays as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, or enzymatic cleavage. Accordingly, the present invention includes metabolites of the compound, including metabolites produced by contacting the compound of the present invention with a mammal for a period of time.

[0087] The definitions and conventions of stereochemistry used herein are generally those of 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, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefix D, L or R, S is used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d, l, or (+), (-) are used to designate the sign of rotation of plane-polarized light in a compound. (-) or l means the compound is levorotatory, and the prefix (+) or d means the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and a mixture of isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereospecificity during chemical reactions. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that lacks optical activity.

[0088] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of bonding electrons.

[0089] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable salts formed with non-toxic 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 acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0090] The "hydrate" of the present invention refers to an association compound formed when the solvent molecule is water.

[0091] The "solvate" of the present invention refers to an association formed between one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.

[0092] The term "ester" herein refers to an in vivo hydrolyzable ester formed by a compound of Formula (I), (II), (III), (IV), (V), (VI), or (VII) containing a hydroxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that hydrolyzes in the human or animal body to produce the parent alcohol. Examples of in vivo hydrolyzable esters of a compound of Formula (I), (II), (III), (IV), (V), (VI), or (VII) containing a hydroxyl group include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl.

[0093] The "nitrogen oxide" of the present invention refers to when a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Special 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 (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), for example, in an inert solvent (e.g., dichloromethane), by reacting the amine compound with m-chloroperoxybenzoic acid (MCPBA).

[0094] The term "prodrug" as used in the present invention refers to a compound that is converted in vivo to a compound represented by Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI) or Formula (VII). Such conversion is affected by the prodrug being hydrolyzed in the blood or converted to the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention may be an ester. In the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the present invention containing a hydroxyl group can be acylated to produce a prodrug form. Other prodrug forms include phosphates, such as these phosphate compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see 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 SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0095] Unless otherwise indicated herein or the context clearly indicates a contrary meaning, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) may be construed to include both the singular and the plural.

[0096] The term "GLP-1 receptor agonist" as used herein refers to a substance that can agonize the activity of the GLP-1 receptor.

[0097] General synthesis process

[0098] To illustrate the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

[0099] Generally, the compounds of the present invention can be prepared by the methods described herein, wherein the substituents are as defined herein unless otherwise specified. The following reaction schemes and examples are provided to further illustrate the present invention.

[0100] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0101] In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Anhui Zesheng Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Myrel Chemical Technology Co., Ltd., and Shanghai MacLean Biochemical Technology Co., Ltd. and 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.

[0102] Anhydrous tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, and acetonitrile were dried over molecular sieves. Dichloromethane, ethyl acetate, petroleum ether, 1,2-dichloroethane, and methanol were of analytical grade.

[0103] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0104] The silica gel column was purchased from Tianjin Bona Aijieer Technology Co., Ltd. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

[0105] 1H NMR spectra were recorded on a Bruker 500 MHz NMR spectrometer. 1H NMR spectra were recorded in CDCl3, DMSO-d6, CD3OD, or acetone-d6 solvents (in ppm) using TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), and dt (doublet of triplets). Coupling constants, J, are expressed in Hertz (Hz).

[0106] Low-resolution mass spectrometry (MS) data were collected using an Agilent G6125C quadrupole HPLC-MS (column model: XBridge BEH C18, 4.6 x 50 mm, 2.5 μm, 6 min, flow rate: 1 mL / min). Mobile phase: 0%-95% (CH3CN) in (H2O containing 0.1% formic acid: CH3CN = 90:10), electrospray ionization (ESI), detection at 210 nm / 254 nm, and DAD.

[0107] Compounds were purified using Cheetah Pro medium-pressure rapid purification preparative chromatography (Tianjin Bona Aijieer Technology Co., Ltd.) at 210 nm / 254 nm with UV detection.

[0108] The following abbreviations are used throughout the present invention: PE petroleum ether EtOAc / EA ethyl acetate mg milligram mmol millimole mL milliliter g gram M mole / liter rpm revolutions / minute μM micromolar / liter h hour DCM dichloromethane MeOH methanol min minute CDCl3 deuterated chloroform DMSO-d6 deuterated dimethyl sulfoxide nM nanomole / liter HEPES 4-hydroxyethylpiperazineethanesulfonic acid BSA bovine serum albumin IBMX phosphodiesterase inhibitor HBSS Hank's balanced salt solution nL nanoliter DMSO dimethyl sulfoxide EDTA-K2 ethylenediaminetetraacetic acid dipotassium Kolliphor-EL ethoxylated castor oil HP-β-CD hydroxypropyl beta-cyclodextrin

[0109] The following reaction schemes describe the steps for preparing the compounds of the present invention. Ring B' is a 5-6 membered heterocyclic group containing a nitrogen atom. Unless otherwise indicated, each of X1, X2, X3, Y1, Y2, Y3, Y4, R 4 、R 5 、R 8 、R 9 、R 10 、R 11 、R 12 、R 18 、R b and n have the same meaning as described in the present invention. Bn is a commonly used protecting group benzyl, Tf is a commonly used protecting group trifluoromethanesulfonyl, and Boc is a commonly used protecting group tert-butyloxycarbonyl.

[0110] Reaction Scheme 1

[0111] The compound represented by formula (7) can be prepared by reaction scheme 1: the compound represented by formula (1) reacts with the compound represented by formula (2) 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) reacts with the compound represented by formula (6) to obtain the compound represented by formula (7).

[0112] Reaction Scheme 2

[0113] The compound represented by formula (13) can be prepared by reaction scheme 2: the compound represented by formula (8) is reacted with the compound represented by formula (9) 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) is reacted with the compound represented by formula (12) to obtain the compound represented by formula (13).

[0114] Reaction Scheme 3

[0115] 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 subjected to hydrogenation reduction reaction to obtain the compound represented by formula (17). The compound represented by formula (17) is reacted with the compound represented by formula (7) to obtain the compound represented by formula (18). The compound represented by formula (18) is subjected to removal of the N-Boc protecting group to obtain the compound represented by formula (19). The compound represented by formula (19) is reacted with the compound represented by formula (13) to obtain the compound represented by formula (20). The compound represented by formula (20) is reacted under alkaline conditions to obtain the compound represented by formula (21).

[0116] Reaction Scheme 4

[0117] The compound represented by formula (28) can be prepared by reaction scheme 4: the compound represented by formula (22) is reacted with the compound represented by formula (7) to obtain the compound represented by formula (23). The compound represented by formula (23) is reacted with the compound represented by formula (24) to obtain the compound represented by formula (25). The N-Boc protecting group of the compound represented by formula (25) is removed to obtain the compound represented by formula (26). The compound represented by formula (26) is reacted with the compound represented by formula (13) to obtain the compound represented by formula (27). The compound represented by formula (27) is reacted under alkaline conditions to obtain the compound represented by formula (28).

[0118] Reaction Scheme 5

[0119] 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) react to obtain the compound represented by formula (30). The compound represented by formula (30) reacts under alkaline conditions to obtain the compound represented by formula (31). The compound represented by formula (31) reacts with the compound represented by formula (11) to obtain the compound represented by formula (32). The compound represented by formula (32) undergoes intramolecular cyclization to obtain the compound represented by formula (33). The compound represented by formula (33) reacts under alkaline conditions to obtain the compound represented by formula (34).

[0120] Reaction Scheme 6

[0121] The compound represented by formula (16) can also be prepared by reaction scheme 6: the compound represented by formula (35) is reacted with the compound represented by formula (36) to obtain the compound represented by formula (37). The compound represented by formula (37) is reacted with the compound represented by formula (38) to obtain the compound represented by formula (39). The compound represented by formula (39) is subjected to hydrogenation reduction to obtain the compound represented by formula (16).

[0122] Reaction Scheme 7

[0123] The compound represented by formula (10) can also be prepared by 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) is reacted with the compound represented by formula (9) to obtain the compound represented by formula (10).

[0124] Reaction Scheme 8

[0125] The compound represented by formula (13) can also be prepared by reaction scheme 8: the compound represented by formula (11) is reacted with the compound represented by formula (43) to obtain the compound represented by formula (44). The compound represented by formula (44) undergoes intramolecular cyclization to obtain the compound represented by formula (13).

[0126] Reaction Scheme 9

[0127] 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) react to obtain the compound represented by formula (47). The compound represented by formula (47) is subjected to borylation reaction to obtain the compound represented by formula (29).

[0128] Reaction Scheme 10

[0129] The compound represented by formula (54) can be prepared by reaction scheme 10: the compound represented by formula (48) is reacted with the compound represented by formula (15) to obtain the compound represented by formula (49). The compound represented by formula (49) is reacted with the compound represented by formula (50) to obtain the compound represented by formula (51). The compound represented by formula (51) is subjected to N-Boc removal to obtain the compound represented by formula (52). The compound represented by formula (52) is reacted with the compound represented by formula (13) to obtain the compound represented by formula (53). The compound represented by formula (53) is reacted under alkaline conditions to obtain the compound represented by formula (54).

[0130] Reaction Scheme 11

[0131] The compound represented by formula (62) can be prepared by reaction scheme 11: the compound represented by formula (37) is reacted with the compound represented by formula (55) 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) is reacted with the compound represented by formula (50) to obtain the compound represented by formula (58). The compound represented by formula (58) is reacted under alkaline conditions to obtain the compound represented by formula (59). The compound represented by formula (59) is reacted with the compound represented by formula (11) to obtain the compound represented by formula (60). The compound represented by formula (60) undergoes intramolecular cyclization to obtain the compound represented by formula (61). The compound represented by formula (61) is reacted under alkaline conditions to obtain the compound represented by formula (62).

[0132] Reaction Scheme 12

[0133] 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) is reacted with the compound represented by formula (64) 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) is reacted with the compound represented by formula (11) to obtain the compound represented by formula (68). The compound represented by formula (68) is deprotected from MOM to obtain the compound represented by formula (69).

[0134] Reaction Scheme 13

[0135] The compound represented by formula (73) can be prepared by reaction scheme 13: the compound represented by formula (70) is reacted with the compound represented by formula (71) to obtain the compound represented by formula (72). The compound represented by formula (72) is deprotected to obtain the compound represented by formula (73).

[0136] Reaction Scheme 14

[0137] The compound represented by formula (77) can be prepared by reaction scheme 14: the compound represented by formula (63) is reacted with the compound represented by formula (74) to obtain the compound represented by formula (75). The compound represented by formula (75) is reacted with the compound represented by formula (13) to obtain the compound represented by formula (76). The compound represented by formula (76) is deprotected to obtain the compound represented by formula (77).

[0138] Reaction Scheme 15

[0139] The compound represented by formula (82) can be prepared by reaction scheme 15: the compound represented by formula (5) is reacted with acetate to obtain the compound represented by formula (78). The compound represented by formula (78) is reacted under alkaline conditions to obtain the compound represented by formula (79). The compound represented by formula (79) is reacted 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).

[0140] Reaction Scheme 16

[0141] The compound represented by formula (90) can be prepared by reaction scheme 16: the compound represented by formula (83) reacts with trimethoxymethane to obtain the compound represented by formula (84). The compound represented by formula (84) reacts with the compound represented by formula (13) to obtain the compound represented by formula (85). The compound represented by formula (85) reacts with trifluoroacetic acid to obtain the compound represented by formula (86). The compound represented by formula (86) reacts with N-phenylbis(trifluoromethanesulfonyl)imide to obtain the compound represented by formula (87). The compound represented by formula (87) reacts with diboronic acid pinacol ester to obtain the compound represented by formula (88). The compound represented by formula (88) reacts with the compound represented by formula (82) 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 DESCRIPTION

[0142] The present invention is described below with reference to specific examples. It should be noted that these examples are merely illustrative and do not limit the present invention in any way.

[0143] Example 1 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 1)

[0144] Step 1: Synthesis of 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene

[0145] 5-Chloro-2-methylphenol (15 g, 105.2 mmol), 2-bromo-1,1-diethoxyethane (25 g, 126.9 mmol), and potassium carbonate (29.1 g, 210.4 mmol) were added to N,N-dimethylformamide (50 mL) and reacted at 120°C under nitrogen for 11 h. After cooling to room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate (35 mL x 3). The organic phases were combined and washed once with saturated brine (30 mL). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1%) to obtain 21.1 g of the product, a light brown liquid, in a yield of 77.5%.

[0146] 1 HNMR(500MHz, CDCl3) δ7.03(d,J=7.9Hz,1H),6.84(dd,J=7.9,2.0Hz,1H),6.81(d,J=2.0Hz,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).

[0147] Step 2: Synthesis of 4-chloro-7-methylbenzofuran

[0148] 4-Chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene (21 g, 81.2 mmol) and polyphosphoric acid (16.6 g, 202.9 mmol) were added to 1,2-dichloroethane (50 mL) and reacted at 85°C overnight under nitrogen. After cooling to room temperature, the solvent was removed under reduced pressure, water (80 mL) was added, and extraction was performed with ethyl acetate (50 mL x 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%) to obtain 9.2 g of the colorless liquid product in a 68.0% yield.

[0149] 1HNMR (500MHz, CDCl3) δ7.63 (d, J = 2.3 Hz, 1H), 7.12 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 2.48 (s, 3H).

[0150] Step 3: Synthesis of 7-(bromomethyl)-4-chlorobenzofuran

[0151] 4-Chloro-7-methylbenzofuran (4.1 g, 24.61 mmol), azobisisobutyronitrile (810 mg, 4.92 mmol), and N-bromosuccinimide (5.26 g, 29.53 mmol) were added to 1,2-dichloroethane (30 mL) and reacted at 75°C overnight under nitrogen. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE = 100%) to obtain 4.3 g of the product as a colorless liquid with a yield of 71.2%.

[0152] 1 HNMR(500MHz, CDCl3)δ7.71(s,1H),7.24–7.20(m,2H),6.89(s,1H),4.75(s,2H).

[0153] Step 4: Synthesis of 7-(bromomethyl)-4-chloro-2-fluorobenzofuran

[0154] Compound 7-(Bromomethyl)-4-chlorobenzofuran (3.4 g, 13.85 mmol) and N-fluorobisbenzenesulfonamide (5.24 g, 16.62 mmol) were added to anhydrous tetrahydrofuran (100 mL). The mixture was cooled to -50°C under nitrogen. Lithium diisopropylamide (2.0 mol / L tetrahydrofuran solution) (9 mL, 18 mmol) was added and the reaction was continued at this temperature for 3 h. Water (300 mL) was added and the mixture was extracted with ethyl acetate (50 mL x 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%) to obtain 523 mg of the product as a white solid in a 14.3% yield.

[0155] 1 HNMR (500MHz, CDCl3) δ7.24–7.20 (m, 2H), 6.01 (d, J = 6.6Hz, 1H), 4.65 (s, 2H).

[0156] Step 5: Synthesis of methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate

[0157] Methyl 3-fluoro-4-nitrobenzoate (500 mg, 2.51 mmol) and anhydrous potassium carbonate (521 mg, 3.77 mmol) were added to anhydrous tetrahydrofuran (6 mL), followed by (S)-oxetane-2-methylamine (241 mg, 2.76 mmol). The mixture was allowed to react at room temperature for 15 h. Water (25 mL) and ethyl acetate (10 mL) were added, stirred, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (5 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate for 20 min, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:4) to afford 522 mg of a reddish-brown solid in a yield of 78.1%.

[0158] LC-MS(ESI):[M+H] + =267.1

[0159] 1 HNMR (500MHz, DMSO-d6) 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).

[0160] Step 6: Synthesis of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate

[0161] Methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (3.6 g, 13.52 mmol) was dissolved in methanol (30 mL) and tetrahydrofuran (15 mL). 10% palladium on carbon (60% water content, 1.43 g) was added. The atmosphere was replaced with hydrogen three times, and the reaction was allowed to proceed overnight at room temperature and pressure. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 3.18 g of the product, a light yellow liquid, with a yield of 99.5%.

[0162] LC-MS(ESI):[M+H] + =237.1;

[0163] 1HNMR(500MHz,DMSO-d6)δ7.17(dd,J=8.1,1.9Hz,1H),7.04(d,J=1.9Hz,1H),6.56(d,J=8.1Hz,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).

[0164] Step 7: Synthesis of (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0165] Compound (S)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (1.0 g, 4.23 mmol), trimethyl chloroethyl orthoacetate (790 mg, 5.08 mmol) and p-toluenesulfonic acid monohydrate (40 mg, 0.21 mmol) were dissolved in anhydrous tetrahydrofuran (8 mL) and stirred at 45°C for 5 h. The mixture was cooled and concentrated under reduced pressure to remove the solvent. Dichloromethane (6 mL) was added for dissolution and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:2) to give 1.1 g of a white solid product in a yield of 88.2%.

[0166] LC-MS(ESI):[M+H] + =295.2;

[0167] 1 HNMR(500MHz,DMSO-d6)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).

[0168] Step 8: Synthesis of tert-butyl 4-(2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0169] The compound 2-hydroxyphenylboronic acid (1.25 g, 9.05 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.0 g, 9.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (370 mg, 0.45 mmol) and potassium carbonate (8.85 g, 27.16 mmol) were added to 1,4-dioxane (40 mL), and the reaction was carried out at 90°C under nitrogen protection overnight. The mixture was cooled to room temperature, and water (80 mL) was added. The mixture was 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 (eluent EtOAc:PE (v / v) = 16%) to give 1.5 g of a white solid product with a yield of 60.2%.

[0170] LC-MS(ESI):[M-55] + =220.2;

[0171] 1 HNMR(500MHz, CDCl3)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).

[0172] Step 9: Synthesis of tert-butyl 4-(2-hydroxyphenyl)piperidine-1-carboxylate

[0173] The compound tert-butyl 4-(2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 5.45 mmol) was dissolved in methanol (30 mL), and 10% palladium on carbon (500 mg, water content 40-60%) was added. Hydrogen was introduced into the reaction mixture at room temperature and pressure overnight. The catalyst was filtered out, and the filtrate was concentrated under reduced pressure to obtain 1.4 g of a white solid product with a yield of 92.7%.

[0174] LC-MS(ESI):[M+H] + =222.1;

[0175] 1HNMR(500MHz, CDCl3)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).

[0176] Step 10: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine-1-carboxylate

[0177] Compound 7-(Bromomethyl)-4-chlorobenzofuran (290 mg, 1.10 mmol) and tert-butyl 4-(2-hydroxyphenyl)piperidine-1-carboxylate (305 mg, 1.10 mmol) were added to tetrahydrofuran (8 mL), cooled in an ice bath, and potassium tert-butoxide (185 mg, 1.65 mmol) was added. The mixture was allowed to react at room temperature for 1.5 h. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to obtain 368 mg of the product as a brown oil in a 72.7% yield.

[0178] LC-MS(ESI):[M-55] + =404.2;

[0179] 1 HNMR (500MHz, CDCl3) 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,2 H),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).

[0180] Step 11: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine

[0181] The compound tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine-1-carboxylate (660 mg, 1.43 mmol) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (3.3 mL) was added and reacted at room temperature for 30 min. The solvent was removed under reduced pressure, and saturated sodium bicarbonate was added to adjust the pH to 8. The mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 509 mg of a white solid product with a yield of 98.6%.

[0182] LC-MS(ESI):[M+H] + =360.2;

[0183] 1 HNMR(500MHz, CDCl3)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).

[0184] Step 12: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0185] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.34 mmol), 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine (134 mg, 0.37 mmol), and N,N-diisopropylethylamine (219 mg, 1.69 mmol) were added to acetonitrile (6 mL) and reacted at 60°C overnight. The mixture was cooled to room temperature, the solvent was removed under reduced pressure, and water (20 mL) was added. The mixture was extracted with ethyl acetate (15 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 50%) to give 165 mg of the product as a white solid in a yield of 78.7%.

[0186] LC-MS(ESI):[M+H] + =618.5;

[0187] 1HNMR(500MHz,CDCl3)δ8.17(d,J=1.6Hz,1H),7.96(dd,J=8.5,1.6Hz,1H),7.74(d,J=8.5Hz,1 H),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).

[0188] Step 13: Synthesis of (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

[0189] Compound (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (165 mg, 0.27 mmol) and lithium hydroxide monohydrate (56 mg, 1.33 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL) and reacted at 40°C for 1 h. The mixture was cooled in an ice bath, water (15 mL) was added, and the pH was adjusted to 6 with acetic acid. The mixture was extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 10%) to give 69 mg of the product as a white solid in a yield of 40.1%.

[0190] LC-MS(ESI):[M+H] + =604.5;

[0191] 1HNMR(500MHz,DMSO-d6)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).

[0192] Example 2 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 2)

[0193] Step 1: Synthesis of 7-((2-bromophenoxy)methyl)-4-chloro-2-fluorobenzofuran

[0194] 2-Bromophenol (207 mg, 1.20 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (300 mg, 1.14 mmol) were added to N,N-dimethylformamide (8 mL), followed by potassium carbonate (472 mg, 3.42 mmol). The mixture was reacted at 60°C for 1 h. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (5 mL x 2). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 5%) to obtain 341 mg of the yellow liquid product in a yield of 78.0%.

[0195] 1H NMR (500MHz, CDCl3) δ7.57(dd,J=7.9,1.7Hz,1H),7.43(d,J=8.2Hz,1H),7.28(d,J=8.5Hz,1H),7.2 5–7.23(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).

[0196] Step 2: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0197] 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) were added to a mixture of 1,4-dioxane (6 mL) and water (1.5 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (33 mg, 0.04 mmol) and potassium carbonate (220 mg, 1.59 mmol) were then added. The mixture was heated to 90°C under nitrogen for 2 h. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 5%) to obtain 355 mg of a colorless liquid in a 98.5% yield.

[0198] LC-MS(ESI):[M-55] + =402.2;

[0199] 1 H NMR (500MHz, CDCl3) 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).

[0200] Step 3: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-1,2,3,6-tetrahydropyridine

[0201] 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 the addition of trifluoroacetic acid (2.55 g, 22.34 mmol) under ice-cooling. The mixture was allowed to return to room temperature and reacted for 30 min. Saturated sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (20 mL x 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 a tan solid. The crude product was used directly in the next step.

[0202] LC-MS(ESI):[M+H] + =358.1.

[0203] Step 4: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0204] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-1,2,3,6-tetrahydropyridine (150 mg, 0.34 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.34 mmol), and N,N-diisopropylethylamine (220 mg, 1.70 mmol) were added to acetonitrile (5 mL) and reacted at 60°C overnight. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). 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) = 50%) to give 171 mg of the product as a yellow solid in an 81.8% yield.

[0205] LC-MS(ESI):[M+H] + =616.4;

[0206] 1H NMR(500MHz, CDCl3)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,1 H),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).

[0207] Step 5: Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0208] Compound (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (170 mg, 0.28 mmol) and lithium hydroxide monohydrate (58 mg, 1.38 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 6 with acetic acid (4 M). The mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. Purification by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 2%) afforded 89 mg of the product as a pale yellow solid in a 53.6% yield.

[0209] LC-MS(ESI):[M+H] + =602.4;

[0210] 1H NMR (500MHz, DMSO-d6) 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=6.3Hz,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=1 3.9Hz,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).

[0211] Example 3 Synthesis of 2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 3)

[0212] Step 1: Synthesis of ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate

[0213] Ethyl 4-oxocyclohexaneacetate (3.0 g, 16.28 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (6.98 g, 19.54 mmol) were added to anhydrous tetrahydrofuran (30 mL). The mixture was cooled to -40°C under nitrogen. Lithium bis(trimethylsilyl)amide (1 mol / L in THF) (21.2 mL, 21.2 mmol) was added and allowed to react at this temperature for 2 h. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 2%) to obtain 4.1 g of the product as a colorless liquid in a yield of 79.6%.

[0214] 1HNMR (500MHz, CDCl3) 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).

[0215] Step 2: Synthesis of ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate

[0216] The compound ethyl 2-(4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-en-1-yl)acetate (3.9 g, 12.33 mmol), pinacol diboron (3.29 g, 12.95 mmol), tetrakistriphenylphosphine palladium (710 mg, 0.62 mmol) and potassium acetate (2.42 g, 24.66 mmol) were added to 1,4-dioxane (30 mL), and the reaction was carried out at 90 ° C for 1 h under nitrogen protection. After cooling to room temperature, water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 5%) to obtain 2.0 g of colorless liquid product with a yield of 55.1%.

[0217] 1 HNMR(500MHz, CDCl3)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).

[0218] Step 3: Synthesis of 7-((2-bromophenoxy)methyl)-4-chloro-2-fluorobenzofuran

[0219] 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), followed by potassium carbonate (450 mg, 3.26 mmol). The mixture was reacted at 60°C for 1 h. The reaction was quenched by the addition of water (40 mL), and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (15 mL x 3). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 5%) to obtain 402 mg of the product as a white solid in a 93.1% yield.

[0220] 1 H NMR (500MHz, CDCl3) 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).

[0221] Step 4: Synthesis of ethyl 2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate

[0222] The compound 7-((2-bromophenoxy)methyl)-4-chloro-2-fluorobenzofuran (402 mg, 1.13 mmol) and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (345 mg, 1.17 mmol) were added to a mixed solution of 1,4-dioxane (12 mL) and water (3 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (47 mg, 0.06 mmol) and potassium carbonate (315 mg, 2.28 mmol) were then added. The mixture was heated to 90°C under nitrogen for 2 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate three times (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The product was separated and purified by silica gel column chromatography (eluent EA:PE (v / v) = 5%) to obtain 366 mg of a yellow liquid with a yield of 73.1%.

[0223] LC-MS(ESI):[M-55] + =443.1.

[0224] Step 5: Synthesis of 2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetic acid

[0225] The compound 2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetic acid ethyl ester (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. The reaction was carried out at 40°C for 2 h, cooled to room temperature, diluted with water (8 mL), adjusted to pH = 5 with dilute hydrochloric acid, and extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 295 mg of an off-white solid with a yield of 86.1%.

[0226] LC-MS(ESI):[M+H] + =415.1;

[0227] 1 H NMR(500MHz,DMSO-d6)δ12.01(s,1H),7.45–7.37(m,2H),7.22(td,J=7.8,1.8Hz, 1H),7.12(d,J=8.2Hz,1H),7.08(dd,J=7.4,1.8Hz,1H),6.92(t,J=7.4Hz,1H),6.5 1(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).

[0228] Step 6: Synthesis of methyl 4-(2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate

[0229] 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)-methyl 4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (75 mg, 0.32 mmol) were added to dichloromethane (6 mL) and N,N-dimethylformamide (3 mL), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (182 mg, 0.48 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol) were added, and the reaction was carried out at 45 ° C overnight. The solvent was removed under reduced pressure, water (60 mL) was added, and the mixture was 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 give 137 mg of an orange-pink solid with a yield of 68.1%.

[0230] LC-MS(ESI):[M+H] + =633.5;

[0231] 1 H NMR(500MHz,DMSO-d6)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),4.9 7–4.88(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).

[0232] Step 7: Synthesis of methyl 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-carboxylate

[0233] The compound methyl 4-(2-(2'-((4-chloro-2-fluorobenzofuran-7-yl)methyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetamido)-3-((((S)-oxetan-2-yl)methyl)amino)benzoate (130 mg, 0.21 mmol) was added to glacial acetic acid (5 mL) and reacted at 80°C for 3 h. The solvent was removed under reduced pressure, and water (10 mL) was added. The pH of the system was adjusted to 8 with sodium bicarbonate solution (2 M). Dichloromethane (15 mL × 3) was added. 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) = 30%) to obtain 115 mg of a colorless liquid with a yield of 91.1%.

[0234] LC-MS(ESI):[M+H] + =615.4.

[0235] Step 8: Synthesis of 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

[0236] 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, 0.19 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH of the system was adjusted to 5 with acetic acid (4 M). The mixture was 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%) afforded 85 mg of a white solid product with a yield of 73.9%.

[0237] LC-MS(ESI):[M+H] + =601.3;

[0238] 1H NMR(500MHz,DMSO-d6)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,1 H),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).

[0239] Example 4 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 4)

[0240] Step 1: Synthesis of 2-(benzyloxy)-1-bromo-3-fluorobenzene

[0241] 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), followed by potassium carbonate (900 mg, 6.54 mmol). The mixture was reacted at 60°C for 4 h. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with water (15 mL x 2) and saturated brine (10 mL x 1). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 5%) to obtain 730 mg of the product as a pale yellow liquid in a 99.2% yield.

[0242] LC-MS(ESI):[M+H] + =282.3;

[0243] 1 H NMR (500MHz, CDCl3) 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).

[0244] Step 2: Synthesis of tert-butyl 4-(2-(benzyloxy)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0245] 2-(Benzyloxy)-1-bromo-3-fluorobenzene (730 mg, 2.60 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (840 mg, 2.73 mmol) were added to a mixture of 1,4-dioxane (20 mL) and water (5 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (110 mg, 0.13 mmol) and potassium carbonate (720 mg, 5.19 mmol) were then added. The mixture was heated to 90°C under nitrogen for 2 h. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 10%) to obtain 985 mg of a light yellow liquid in a 98.8% yield.

[0246] LC-MS(ESI):[M-55] + =328.2;

[0247] 1 H NMR (500MHz, CDCl3) 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).

[0248] Step 3: Synthesis of tert-butyl 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate

[0249] Dissolve tert-butyl 4-(2-(benzyloxy)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (985 mg, 2.59 mmol) in methanol (20 mL). Add palladium on carbon (10% Pd, containing 55% water) (250 mg). Replace the atmosphere with hydrogen three times and allow to react overnight at room temperature under a hydrogen atmosphere. Filter through celite and concentrate the filtrate under reduced pressure to yield 717 mg of a light yellow liquid (93.6% yield).

[0250] LC-MS(ESI):[M-55] + =240.1.

[0251] Step 4: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

[0252] tert-Butyl 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate (350 mg, 1.19 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (450 mg, 2.62 mmol) were added to N,N-dimethylformamide (8 mL), followed by potassium carbonate (400 mg, 2.89 mmol). The mixture was reacted at 60°C for 2 h. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (5 mL x 2). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent EA:PE (v / v) = 5%) to obtain 527 mg of the yellow liquid product in a 96.8% yield.

[0253] LC-MS(ESI):[M-55] + =422.2;

[0254] 1 H NMR(500MHz, CDCl3)δ7.25(s,2H),7.04–6.95(m,2H),6.92–6.86(m,1H),6.03(d,J=6.6Hz,1H),5.2 9(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).

[0255] Step 5: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine

[0256] The compound tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate (528 mg, 1.10 mmol) was added to dichloromethane (6 mL), followed by the addition of trifluoroacetic acid (2.77 g, 24.30 mmol) in an ice bath. The temperature was raised to room temperature and the reaction was allowed to proceed for 30 min. Saturated sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (10 mL x 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 a brown-yellow liquid with a yield of 98.7%.

[0257] LC-MS(ESI):[M+H] + =378.2.

[0258] Step 6: Synthesis of (S)-methyl 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

[0259] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (140 mg, 0.37 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.34 mmol), and N,N-diisopropylethylamine (220 mg, 1.70 mmol) were added to acetonitrile (5 mL) and reacted at 60°C overnight. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). 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) = 50%) to give 181 mg of the product as a light yellow oil in an 83.9% yield.

[0260] LC-MS(ESI):[M+H] + =636.3.

[0261] Step 7: Synthesis of (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-carboxylic acid

[0262] Compound (S)-methyl 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, 1.43 mmol) were added to 1,4-dioxane (6 mL) and water (3 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 5 with acetic acid (4 M). The mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. Purification by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 5%) afforded 85 mg of the product as a yellow solid in a yield of 73.9%.

[0263] LC-MS(ESI):[M+H] + =622.4;

[0264] 1H NMR(500MHz,DMSO-d6)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),4.6 6–4.60(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).

[0265] Example 5 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 5)

[0266] Step 1: Synthesis of 6-chloro-5-nitro-2-pyridinecarboxylate

[0267] 2-Chloro-6-methyl-3-nitropyridine (8.0 g, 46.36 mmol) was added to concentrated sulfuric acid (40 mL). Potassium dichromate (20.46 g, 69.54 mmol) was slowly added in an ice bath. The mixture was stirred and reacted at room temperature overnight. After cooling in an ice bath, ice water (500 mL) was slowly added. The mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 8.26 g of a light yellow solid with a yield of 88.0%.

[0268] LC-MS(ESI):[M+H] + =203.0.

[0269] Step 2: Synthesis of 6-chloro-5-nitro-2-methylpyridine

[0270] Dissolve 6-chloro-5-nitro-2-pyridinecarboxylate (200 mg, 0.99 mmol) in methanol (15 mL), add concentrated sulfuric acid (0.5 mL, 0.99 mmol), and heat to 68°C overnight. Concentrate the solvent, dilute with water (30 mL), and extract three times with ethyl acetate (15 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify by silica gel column chromatography (eluent: PE:EtOAc (v / v) = 2:1) to obtain 185 mg of a white solid in an 86.5% yield.

[0271] LC-MS(ESI):[M+H] + =217.1;

[0272] 1 H NMR (500MHz, CDCl3) 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).

[0273] Step 3: Synthesis of (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)picolinic acid methyl ester

[0274] Dissolve 6-chloro-5-nitro-2-methylpyridine (1.3 g, 6.0 mmol) and (S)-oxetane-2-methylamine (0.58 g, 6.6 mmol) in tetrahydrofuran (20 mL). Add potassium carbonate (1.24 g, 9.00 mmol) and stir at room temperature overnight. Filter through celite, and concentrate the filtrate. Purify by silica gel column chromatography (eluent: PE:EtOAc (v / v) = 2:1) to obtain 1.09 g of a yellow solid in a 68.0% yield.

[0275] LC-MS(ESI):[M+H] + =268.2;

[0276] 1 H NMR (500MHz, DMSO-d6) 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).

[0277] Step 4: Synthesis of (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinic acid methyl ester

[0278] Compound (S)-methyl 5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate (1.09 g, 4.08 mmol) was dissolved in a mixture of tetrahydrofuran (10 mL) and methanol (10 mL). Palladium on carbon (10% Pd, containing 55% water) (185 mg, 1.74 mmol) was then added under hydrogen protection. The reaction was stirred at room temperature for 8 hours. Filtered through celite, the filtrate was concentrated, and the product was purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to afford 885 mg of an oily yellow viscous product in a 91.5% yield.

[0279] LC-MS(ESI):[M+H] + =238.1;

[0280] 1 H NMR (500MHz, DMSO-d6) δ7.23(d,J=7.8Hz,1H),6.68(d,J=7.8Hz,1H),5.95(t,J=5.6Hz,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).

[0281] Step 5: Synthesis of (S)-methyl 5-(2-chloroacetylamino)-6-((oxetan-2-ylmethyl)amino)picolinate

[0282] Compound (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)picolinate (500 mg, 2.11 mmol) was dissolved in tetrahydrofuran (10 mL). N,N-diisopropylethylamine (817 mg, 6.32 mmol) was added, and the mixture was cooled in an ice bath. Chloroacetyl chloride (285 mg, 2.52 mmol) was added and allowed to react at room temperature for 3 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc = 100%) to obtain 569 mg of a light brown liquid (86% yield).

[0283] LC-MS(ESI):[M+H] + =314.2;

[0284] 1 H NMR (500MHz, CDCl3) 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).

[0285] Step 6: Synthesis of (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[0286] Compound (S)-methyl 5-(2-chloroacetylamino)-6-((oxetan-2-ylmethyl)amino)picolinate (300 mg, 0.24 mmol) was dissolved in acetic acid (5 mL), heated to 60°C, and allowed to react overnight. The solvent was removed under reduced pressure, and saturated sodium bicarbonate was added to adjust the pH to 9. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc = 100%) to afford 101 mg of a pale yellow solid in a 35.7% yield.

[0287] LC-MS(ESI):[M+H] + =296.2;

[0288] 1 H NMR (500MHz, CDCl3) 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).

[0289] Step 7: Synthesis of (S)-methyl 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

[0290] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (147 mg, 0.39 mmol), (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (100 mg, 0.34 mmol), and N,N-diisopropylethylamine (220 mg, 1.70 mmol) were added to acetonitrile (10 mL) and reacted at 60°C overnight. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). 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) = 50%) to obtain 190 mg of the product as a yellow oil with a yield of 88.2%.

[0291] LC-MS(ESI):[M+H] + =637.4.

[0292] Step 8: Synthesis of (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-carboxylic acid

[0293] Compound (S)-methyl 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 monohydrate (63 mg, 1.50 mmol) were added to 1,4-dioxane (6 mL) and water (3 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 5 with acetic acid (4 M). The mixture was extracted three times with ethyl acetate (15 mL x 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%) afforded 45 mg of the product as a pale yellow solid in a yield of 22.4%.

[0294] LC-MS(ESI):[M+H] + =623.4;

[0295] 1H NMR (500MHz, DMSO-d6) δ8.15(d,J=8.2Hz,1H),8.00(d,J=8.3Hz,1H),7.41(d,J=8.1Hz,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).

[0296] Example 6 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Compound 6)

[0297] Step 1: Synthesis of (S)-methyl 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-carboxylate

[0298] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine (150 mg, 0.42 mmol), (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (117 mg, 0.40 mmol), and N,N-diisopropylethylamine (256 mg, 1.98 mmol) were added to acetonitrile (10 mL) and reacted at 60°C overnight. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). 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) = 50%) to obtain 240 mg of the yellow liquid product with a yield of 98.0%.

[0299] LC-MS(ESI):[M+H] + =619.5.

[0300] Step 2: Synthesis of (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

[0301] Compound (S)-methyl 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-carboxylate (240 mg, 0.39 mmol) and lithium hydroxide monohydrate (82 mg, 1.95 mmol) were added to 1,4-dioxane (8 mL) and water (4 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 5 with acetic acid (4 M). The mixture was extracted three times with ethyl acetate (15 mL x 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%) afforded 46 mg of the product as a white solid in a 16.7% yield.

[0302] LC-MS(ESI):[M+H] + =605.4;

[0303] 1 H NMR(500MHz,DMSO-d6)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,1 H),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=13.6H z,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).

[0304] Example 7 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 7)

[0305] Step 1: Synthesis of 1-(benzyloxy)-2-bromobenzene

[0306] 2-Bromophenol (3.0 g, 17.34 mmol) and benzyl bromide (3.0 mg, 17.54 mmol) were added to N,N-dimethylformamide (20 mL), followed by potassium carbonate (6.0 g, 43.42 mmol). The reaction was incubated at 60°C for 3 h. Water (100 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed with water (30 mL x 2) and saturated brine (15 mL x 1). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 5%) to obtain 4.21 g of the product as a colorless liquid in a 92.3% yield.

[0307] 1 H NMR (500MHz, CDCl3) 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).

[0308] Step 2: Synthesis of ethyl 2-(2'-(benzyloxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate

[0309] 1-(Benzyloxy)-2-bromobenzene (1.8 g, 6.84 mmol) and ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)acetate (2.0 g, 6.80 mmol) were added to a mixture of 1,4-dioxane (48 mL) and water (12 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.3 g, 0.37 mmol) and potassium carbonate (1.9 g, 13.75 mmol) were then added. The mixture was heated to 90°C under nitrogen for 2 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate three times (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The product was separated and purified by silica gel column chromatography (eluent EA:PE (v / v) = 5%) to obtain 1.46 g of a light yellow liquid with a yield of 61.1%.

[0310] LC-MS(ESI):[M+H] + =351.3;

[0311] 1H NMR (500MHz, CDCl3) 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),5.7 4–5.70(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).

[0312] Step 3: Synthesis of ethyl 2-(2'-hydroxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate

[0313] Ethyl 2-(2'-(benzyloxy)-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate (1.45 g, 4.14 mmol) was dissolved in ethanol (20 mL). Palladium on carbon (10% Pd, containing 55% water) (0.4 g, 1.69 mmol) was added. The atmosphere was replaced with hydrogen three times and allowed to react overnight at room temperature under a hydrogen atmosphere. Filtered through celite, the filtrate was concentrated under reduced pressure to yield 978 mg of a gray-brown liquid, with a yield of 90.1%.

[0314] LC-MS(ESI):[M-55] + =263.2;

[0315] 1 H NMR (500MHz, CDCl3) δ7.21–7.14(m,1H),7.08–7.02(m,1H),6.89(t,J=7.4H z,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=6.6Hz,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).

[0316] Step 4: Synthesis of ethyl 2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetate

[0317] Ethyl 2-(2'-hydroxy-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)acetate (200 mg, 0.76 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (200 mg, 0.76 mmol) were added to N,N-dimethylformamide (6 mL), followed by potassium carbonate (262 mg, 1.90 mmol). The mixture was reacted at 60°C for 1.5 h. The reaction was quenched by the addition of water (50 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (5 mL x 2). The organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 5%) to obtain 251 mg of the colorless liquid product in a 74.3% yield.

[0318] LC-MS(ESI):[M-55] + =389.3;

[0319] 1 H NMR (500MHz, CDCl3) 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).

[0320] Step 5: Synthesis of 2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetic acid

[0321] The compound 2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetic acid ethyl ester (232 mg, 0.52 mmol) was added to 1,4-dioxane (5 mL) and water (2.5 mL), lithium hydroxide monohydrate (110 mg, 2.62 mmol), and the reaction was carried out at 40°C for 2 h. The mixture was cooled to room temperature, diluted with water (5 mL), and the pH was adjusted to 5 with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 215 mg of a light pink liquid with a yield of 98.9%.

[0322] Step 6: Synthesis of (S)-methyl 4-(2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate

[0323] 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) were added to dichloromethane (6 mL) and N,N-dimethylformamide (3 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (184 mg, 0.48 mmol) and N,N-diisopropylethylamine (104 mg, 0.80 mmol) were added, and the reaction was carried out at 45 ° C overnight. The solvent was removed under reduced pressure, water (60 mL) was added, and the mixture was 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 give 200 mg of a brown liquid with a yield of 98.4%.

[0324] LC-MS(ESI):[M+H] + =635.4;

[0325] 1 H NMR(500MHz, CDCl3)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).

[0326] Step 7: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0327] Compound (S)-methyl 4-(2-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)acetamido)-3-((oxetan-2-ylmethyl)amino)benzoate (230 mg, 0.36 mmol) was added to glacial acetic acid (9 mL) and reacted at 80°C for 3 h. The solvent was removed under reduced pressure, and water (20 mL) was added. The pH of the system was adjusted to 8 with sodium bicarbonate solution (2 M), and dichloromethane (15 mL × 3) was added. 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) = 30%) to obtain 215 mg of a colorless liquid in a yield of 96.2%.

[0328] LC-MS(ESI):[M+H] + =617.4;

[0329] 1 H NMR (500MHz, DMSO-d6) 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,1 H),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).

[0330] Step 8: Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0331] Compound (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)cyclohexyl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (210 mg, 0.34 mmol) and lithium hydroxide monohydrate (72 mg, 1.72 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 5 with acetic acid (4 M). The mixture was extracted three times with ethyl acetate (15 mL x 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%) afforded 85 mg of the product as a pale yellow solid in a 40.3% yield.

[0332] LC-MS(ESI):[M+H] + =603.5;

[0333] 1 H NMR (500MHz, DMSO-d6) 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),5.06–5.0 0(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).

[0334] Example 8 Synthesis of (S)-2-((4-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 8)

[0335] Step 1: Synthesis of tert-butyl 4-(2-((4-chlorobenzofuran-7-yl)methoxy)-phenyl)piperazine-1-carboxylate

[0336] tert-Butyl 4-(2-hydroxyphenyl)piperazine-1-carboxylate (500 mg, 1.80 mmol), 7-(bromomethyl)-4-chlorobenzofuran (440 mg, 1.79 mmol), and potassium carbonate (496 mg, 3.59 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 60°C for 2 hours. TLC indicated that the starting material had completely disappeared. Heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 789 mg of the product as a colorless oil in a yield of 99.2%.

[0337] LC-MS(ESI):[M+H] + =443.3;

[0338] 1 H NMR(500MHz, CDCl3)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).

[0339] Step 2: Synthesis of 1-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazine

[0340] 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 indicated the complete disappearance of the starting material, and the reaction was terminated. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 599 mg of a brown solid product in a 98.1% yield.

[0341] LC-MS(ESI):[M+H] + =343.2.

[0342] Step 3: Synthesis of (S)-methyl 2-((4-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0343] 1-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazine (150 mg, 0.44 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (128 mg, 0.43 mmol), potassium carbonate (120 mg, 0.87 mmol), and potassium iodide (36 mg, 0.22 mmol) were added to acetonitrile (10 mL) and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 55%) to afford 162 mg of the product as a colorless oil in a yield of 61.6%.

[0344] LC-MS(ESI):[M+H] + =601.5;

[0345] 1 H NMR (500MHz, CDCl3) 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,5 H),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).

[0346] Step 4: Synthesis of (S)-2-((4-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0347] (S)-methyl 2-((4-(2-((4-chlorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (142 mg, 0.24 mmol) and lithium hydroxide monohydrate (49 mg, 1.17 mmol) were added to a mixture of water (2 mL) and 1.4-dioxane (5 mL) and reacted at 40°C for 2 hours. TLC indicated the complete disappearance of the starting material, and heating was discontinued. The pH of the system was adjusted to approximately 7 with 20% aqueous acetic acid, and the product was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20%) to afford 70 mg of the product as a white solid in a yield of 49.5%.

[0348] LC-MS(ESI):[M+H] + =587.4;

[0349] 1 H NMR (500MHz, DMSO-d6) 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,1 H),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=13.5H z,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).

[0350] Example 9 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 9)

[0351] Step 1: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-phenyl)piperazine-1-carboxylate

[0352] tert-Butyl 4-(2-hydroxyphenyl)piperazine-1-carboxylate (300 mg, 1.08 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (283 mg, 1.07 mmol), and potassium carbonate (297 mg, 2.15 mmol) were added to 10 mL of N,N-dimethylformamide and reacted at 60°C for 2 hours. TLC indicated the complete disappearance of the starting material. Heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 469 mg of the product as a colorless oil in a 94.4% yield.

[0353] 1 H NMR (500MHz, CDCl3) 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).

[0354] Step 2: Synthesis of 1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazine

[0355] Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazine-1-carboxylate (450 mg, 0.98 mmol) was added to 4 mL of trifluoroacetic acid and 6 mL of dichloromethane and stirred at room temperature for 30 minutes. The reaction was stopped after the complete disappearance of the starting material by TLC. The solvent was concentrated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 315 mg of a brown solid product in an 89.4% yield.

[0356] LC-MS(ESI):[M+H] + =361.2;

[0357] 1 H NMR (500MHz, CDCl3) 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).

[0358] Step 3: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0359] 1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazine (150 mg, 0.42 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (147 mg, 0.50 mmol), potassium carbonate (114 mg, 0.82 mmol), and potassium iodide (34 mg, 0.20 mmol) were added to 8 mL of acetonitrile and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 55%) to afford 249 mg of the product as a colorless oil in a 96.7% yield.

[0360] LC-MS(ESI):[M+H] + =619.4;

[0361] 1 H NMR (500MHz, CDCl3) δ8.16(d,J=1.6Hz,1H),7.99(d,J=8.5Hz,1H),7.78(d,J=8.5Hz,1H),7.3 2(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).

[0362] Step 4: Synthesis of (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

[0363] (S)-Methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (115 mg, 0.19 mmol) and lithium hydroxide monohydrate (101 mg, 2.41 mmol) were added to a mixture of 4 mL of water and 8 mL of 1,4-dioxane and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the reaction mixture was adjusted to approximately 7 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20%) to afford 63 mg of the product as a white solid in a 49.5% yield.

[0364] LC-MS(ESI):[M+H] + =605.4;

[0365] 1 H NMR (500MHz, DMSO-d6) 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,1 H),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).

[0366] Example 10 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 10)

[0367] Step 1: Synthesis of 2-(benzyloxy)-1-bromo-3-fluorobenzene

[0368] 2-Bromo-6-fluorophenol (2.5 g, 13.09 mmol), benzyl bromide (2.24 g, 13.09 mmol), and potassium carbonate (3.62 g, 26.18 mmol) were added to 20 mL of N,N-dimethylformamide and reacted at 60°C for 4 hours. TLC indicated the complete disappearance of the starting material. Heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and extraction was performed with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 10%) to obtain 3.61 g of the product as a colorless oil in a 98.1% yield.

[0369] LC-MS(ESI):[M+H] + =282.3;

[0370] 1 H NMR (500MHz, CDCl3) 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).

[0371] Step 2: Synthesis of tert-butyl 4-(2-(benzyloxy)-3-fluorophenyl)piperazine-1-carboxylate

[0372] 2-(Benzyloxy)-1-bromo-3-fluorobenzene (200 mg, 0.71 mmol), tert-butyl piperazine-1-carboxylate (265 mg, 1.42 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (88.6 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (66.2 mg, 0.07 mmol), and potassium tert-butoxide (159.6 mg, 1.42 mmol) were added to toluene (5 mL). The atmosphere was purged with nitrogen three times and the mixture was allowed to react at 120°C for 20 minutes. The reaction was complete as determined by TLC. Heating was discontinued, the mixture was cooled to room temperature, saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 10%) to afford 186 mg of the product as a colorless oil in a 67.6% yield.

[0373] LC-MS(ESI):[M+H] + =387.3;

[0374] 1H NMR (500MHz, CDCl3) 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).

[0375] Step 3: Synthesis of tert-butyl 4-(3-fluoro-2-hydroxyphenyl)piperazine-1-carboxylate

[0376] tert-Butyl 4-(2-(benzyloxy)-3-fluorophenyl)piperazine-1-carboxylate (1.5 g, 3.88 mmol) and palladium on carbon (410 mg) were added to 25 mL of methanol, replaced with hydrogen three times, and stirred at room temperature overnight. TLC confirmed the reaction was complete, and the reaction was stopped. Filtered through celite, the filtrate was concentrated under reduced pressure to yield 1.1 g of a brown solid product in a 95.6% yield.

[0377] LC-MS(ESI):[M+H] + =297.2;

[0378] 1 H NMR (500MHz, CDCl3) 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).

[0379] Step 4: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine-1-carboxylate

[0380] Tert-butyl 4-(3-fluoro-2-hydroxyphenyl)piperazine-1-carboxylate (500 mg, 1.69 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (444 mg, 1.69 mmol), and potassium carbonate (467 mg, 3.38 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 60°C for 2 hours. After TLC analysis, the reaction mixture completely disappeared. Heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 663 mg of the product as a colorless oil in an 82% yield.

[0381] 1H NMR (500MHz, CDCl3) 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).

[0382] Step 5: Synthesis of 1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine

[0383] Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine-1-carboxylate (593 mg, 1.24 mmol) was added to 5 mL of trifluoroacetic acid and 5 mL of dichloromethane and stirred at room temperature for 30 minutes. The reaction was stopped after complete disappearance of the starting material by TLC. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 450 mg of a brown solid product in a yield of 95.9%.

[0384] LC-MS(ESI):[M+H] + =379.2;

[0385] 1 H NMR(500MHz, CDCl3)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).

[0386] Step 6: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0387] 1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine (150 mg, 0.40 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (116 mg, 0.39 mmol), potassium carbonate (110 mg, 0.8 mmol), and potassium iodide (65 mg, 0.39 mmol) were added to 8 mL of acetonitrile and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 25%) to afford 177 mg of the product as a colorless oil in a 70.2% yield.

[0388] LC-MS(ESI):[M+H] + =637.3.

[0389] Step 7: Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0390] (S)-Methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (177 mg, 0.28 mmol) and lithium hydroxide monohydrate (58 mg, 1.38 mmol) were added to a mixture of water (2 mL) and 1,4-dioxane (6 mL) and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the mixture was adjusted to approximately 7 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20%) to afford 89 mg of the product as a white solid in a 49.5% yield.

[0391] LC-MS(ESI):[M+H] + =623.4;

[0392] 1H NMR (500MHz, CDCl3) 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=6.4Hz,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).

[0393] Example 11 Synthesis of 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazin-1-yl)ethyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 11)

[0394] Step 1: Synthesis of methyl 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-carboxylate

[0395] 1-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperazine (122 mg, 0.40 mmol), methyl 2-((R)-1-chloroethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (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 reacted at 60°C overnight. TLC detected that the starting material had completely disappeared. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 25%) to give 183 mg of colorless oily product with a yield of 71%.

[0396] LC-MS(ESI):[M+H] + =651.4;

[0397] 1 H NMR (500MHz, CDCl3) 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),7.1 9(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).

[0398] Step 2: Synthesis of 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

[0399] Methyl 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-carboxylate (180 mg, 0.28 mmol) and lithium hydroxide monohydrate (58 mg, 1.38 mmol) were added to a mixture of 2 mL of water and 6 mL of 1,4-dioxane and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the reaction mixture was adjusted to approximately 6 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20%) to afford 56 mg of the product as a white solid in a 28.1% yield.

[0400] LC-MS(ESI):[M+H] + =637.3;

[0401] 1 H NMR(500MHz,DMSO-d6)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).

[0402] Example 12 Synthesis of 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylic acid (Compound 12)

[0403] Step 1: Synthesis of methyl 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylate

[0404] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (300 mg, 0.97 mmol), methyl 2-((R)-1-chloroethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (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 h. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was 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 (eluent EA:PE (v / v) = 50%) to give 150 mg of the product as a yellow viscous liquid in a yield of 29.1%.

[0405] LC-MS(ESI):[M+H]+ =650.4.

[0406] Step 2: Synthesis of 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylic acid

[0407] Methyl 2-((S)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylate (150 mg, 0.23 mmol) and lithium hydroxide monohydrate (49 mg, 1.17 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 5 with acetic acid (4 M). The mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. Purification by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 5%) afforded 56 mg of the product as a yellow solid in a 37.2% yield.

[0408] LC-MS(ESI):[M+H] + =636.3;

[0409] 1 H NMR (500MHz, DMSO-d6) δ12.71(br,1H),8.28(s,1H),7.82(d,J=8.4Hz,1H),7.69(d,J=8.6Hz,1H),7.3 6(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).

[0410] Example 13 Synthesis of (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 13)

[0411] Step 1: Synthesis of tert-butyl 3-hydroxy-3',6'-dihydro-(2,4'-bipyridine)-1'(2'H)-carboxylate

[0412] Compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.13 g, 6.90 mmol) and 2-bromo-3-hydroxypyridine (1.2 g, 6.90 mmol) were added to 1,4-dioxane (20 mL) and water (5 mL) and stirred to dissolve. Sodium carbonate (1.83 g, 17.24 mmol) and tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmol) were added, and the temperature was raised to 120 ° C under nitrogen protection and the reaction was carried out overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:5) to give 600 mg of an off-white solid product in a yield of 37.7%.

[0413] 1 HNMR(400MHz,DMSO-d6)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).

[0414] Step 2: Synthesis of tert-butyl 4-(3-hydroxypyridin-2-yl)piperidine-1-carboxylate

[0415] Tert-butyl 3-hydroxy-3',6'-dihydro-(2,4'-bipyridine)-1'(2'H)-carboxylate (600 mg, 2.17 mmol) was added to methanol (20 mL), followed by 10% palladium on carbon (100 mg, 0.56 mmol). The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through celite, washed with methanol (50 mL), and concentrated under reduced pressure to afford 600 mg of the product as a light yellow oil in a 99.3% yield.

[0416] 1HNMR(400MHz,DMSO-d6)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).

[0417] Step 3: Synthesis of tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0418] The compound tert-butyl 4-(3-hydroxypyridin-2-yl)piperidine-1-carboxylate (600 mg, 2.16 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (568 mg, 2.16 mmol) were added to N,N-dimethylformamide (10 mL), and potassium carbonate (894 mg, 6.47 mmol) was added. The reaction solution was heated to 60°C under nitrogen protection and reacted for 3 hours. The reaction solution was cooled to room temperature, water (50 mL) was added, and extracted with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (eluent EtOAc:PE (v / v) = 1:3) to obtain 600 mg of a light yellow solid product with a yield of 60.4%.

[0419] 1 HNMR (400MHz, CDCl3) δ8.12(m,1H),7.23–7.12(m,3H),7.04(m,1H),5.98(d,J=6.4Hz,1H),5.2 3(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).

[0420] Step 4: Synthesis of 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-2-(piperidin-4-yl)pyridine hydrochloride

[0421] Tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate was added to dichloromethane (10 mL), followed by a dioxane hydrochloride solution (3 mL). The reaction mixture was maintained at room temperature for 2 hours. The product was concentrated under reduced pressure to afford 450 mg of an off-white solid (87.0% yield), which was used directly in the next step.

[0422] Step 5: Synthesis of (S)-methyl 2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0423] 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-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (245 mg, 0.83 mmol) were added to N,N-dimethylformamide (2 mL), and potassium carbonate (575 mg, 4.16 mmol) and potassium iodide (5.0 mg, 0.03 mmol) were added. Under nitrogen protection, the reaction solution was heated to 85°C and stirred for 2 hours. The reaction solution was cooled to room temperature and quenched by slowly adding water (10 mL). The product was extracted with ethyl acetate (10 mL × 3). The organic phase was dried over anhydrous sodium sulfate and purified by silica gel column chromatography (eluent DCM:MeOH (v / v) = 1:20) to obtain 128 mg of a light yellow solid product in a yield of 24.9%.

[0424] LC-MS(ESI):[M+H] + =619.3.

[0425] Step 6: Synthesis of (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0426] Compound (S)-methyl 2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (128 mg, 0.21 mmol) was added to dioxane (2 mL) and water (0.5 mL). Lithium hydroxide (44.0 mg, 1.05 mmol) was added, and the mixture was heated to 40°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 2-3 with acetic acid. The solution was concentrated under reduced pressure and purified by Prep-HPLC (eluent: CH3CN:H2O (v / v) = 60%) to give 17.0 mg of the product as a white solid in a yield of 13.6%.

[0427] LC-MS(ESI):[M+H] + =605.4;

[0428] 1HNMR (400MHz, DMSO-d6) δ8.25(s,1H),8.11(d,J=4.4Hz,1H),7.81(d,J=8.0Hz,1H),7.63(d,J=8.4Hz,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),2.97–2.8 2(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).

[0429] Example 14 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 14)

[0430] Step 1: Synthesis of 2-(benzyloxy)-3-bromopyridine

[0431] 3-Bromo-2-fluoropyridine (1.00 g, 5.68 mmol) and benzyl alcohol (0.68 g, 6.25 mmol) were added to acetonitrile (5 mL), followed by cesium carbonate (1.85 g, 5.68 mmol). The reaction was allowed to react at room temperature overnight. The product was filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 10%) to afford 1.13 g of the product as a colorless liquid in a 75.3% yield.

[0432] 1 H NMR (500MHz, CDCl3) δ8.09 (dd, J=4.9, 1.7Hz, 1H), 7.81 (dd, J=7.6, 1.7Hz, 1H), 7.49 (d, J=7.5H z,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).

[0433] Step 2: Synthesis of tert-butyl 2-(benzyloxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0434] 2-(Benzyloxy)-3-bromopyridine (0.50 g, 1.89 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.59 g, 1.90 mmol) were added to a mixture of 1,4-dioxane (12 mL) and water (3 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (78 mg, 0.10 mmol) and potassium carbonate (524 mg, 3.79 mmol) were then added. The mixture was heated to 90°C under nitrogen for 2 h. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated, and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 30%) to obtain 0.59 g of a light yellow liquid in an 85.2% yield.

[0435] LC-MS(ESI):[M+H] + =367.3;

[0436] 1 H NMR (500MHz, CDCl3) 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).

[0437] Step 3: Synthesis of tert-butyl 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylate

[0438] Dissolve tert-butyl 2-(benzyloxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate (0.59 g, 1.61 mmol) in ethanol (13 mL). Add palladium on carbon (10% Pd, containing 55% water) (0.19 g, 0.80 mmol). Replace the atmosphere with hydrogen three times. Allow to react overnight at room temperature under a hydrogen atmosphere. Filter through celite, and concentrate the filtrate under reduced pressure to yield 0.36 g of a white solid (80.8% yield).

[0439] LC-MS(ESI):[M-55]+ =223.0;

[0440] 1 H NMR(500MHz,DMSO-d6)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).

[0441] Step 4: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylate

[0442] tert-Butyl 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylate (360 mg, 1.29 mmol) and (4-chloro-2-fluorobenzofuran-7-yl)methanol (220 mg, 1.10 mmol) were added to tetrahydrofuran (10 mL), followed by triphenylphosphine (400 mg, 1.53 mmol) and diisopropyl azodicarboxylate (332 mg, 1.64 mmol). The reaction was allowed to react at room temperature for 3 h. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). 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) = 25%) to obtain 69 mg of a colorless viscous liquid in a 13.6% yield.

[0443] LC-MS(ESI):[M+H] + =461.3;

[0444] 1 H NMR(500MHz, CDCl3)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).

[0445] Step 5: Synthesis of 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine

[0446] 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) was added to dichloromethane (1.5 mL), followed by the addition of trifluoroacetic acid (544 mg, 4.77 mmol) under ice-cooling. The mixture was allowed to return to room temperature and reacted for 30 min. Saturated sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (10 mL x 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%.

[0447] LC-MS(ESI):[M+H] + =361.2.

[0448] Step 6: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0449] The compound 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine (82 mg, 0.23 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (67 mg, 0.23 mmol), and N,N-diisopropylethylamine (150 mg, 1.16 mmol) were added to acetonitrile (5 mL) and reacted at 60°C overnight. The mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). 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) = 50%) to give 92 mg of the product as a yellow solid in a 65.4% yield.

[0450] LC-MS(ESI):[M+H] + =619.4.

[0451] Step 7: Synthesis of (S)-2-((4-(2-((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

[0452] Compound (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (92 mg, 0.15 mmol) and lithium hydroxide monohydrate (32 mg, 0.76 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 5 with acetic acid (4 M). The mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. Purification by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 3%) afforded 20 mg of the product as a yellow solid in a 22.2% yield.

[0453] LC-MS(ESI):[M+H] + =605.4;

[0454] 1 H NMR (500MHz, DMSO-d6) δ12.65(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).

[0455] Example 15 Synthesis of (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 15)

[0456] Step 1: Synthesis of 1-bromo-2-(methoxymethoxy)benzene

[0457] 2-Bromophenol (5 g, 28.9 mmol) was added to N,N-dimethylformamide (50 mL), followed by NaH (1.4 g, 57.8 mmol). The mixture was stirred in an ice bath for 30 minutes. Bromo(methoxy)methane (4.3 g, 34.7 mmol) was added, and the mixture was stirred at room temperature for two hours. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 3). 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) = 1:20) to obtain 6.15 g of the product as a colorless oil in a 98.0% yield.

[0458] Step 2: Synthesis of methyl 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetate

[0459] 1-Bromo-2-(methoxymethoxy)benzene (2.0 g, 9.2 mmol) and methyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (3.0 g, 10.12 mmol) were added to 1,4-dioxane (20 mL) and water (5 mL). Potassium carbonate (3.8 g, 27.6 mmol) was added, and the atmosphere was purged with nitrogen three times. Tetrakistriphenylphosphine palladium (0.3 g, 0.26 mmol) was added, and the atmosphere was purged with nitrogen again three times. The mixture was stirred at 85°C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:12) to give 2.4 g of the product as a colorless oil in an 85.7% yield.

[0460] 1 HNMR (400MHz, CDCl3) 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).

[0461] Step 3: Synthesis of 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-ol

[0462] Methyl 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetate (2.4 g, 7.9 mmol) was added to tetrahydrofuran (20 mL) and stirred at 0°C for five minutes. Lithium aluminum tetrahydride (0.87 g, 23.0 mmol) was added and stirred at 0°C for two hours. The mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate (30 mL x 3). 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) = 1:5) to obtain 1.2 g of the product as a colorless oil in a 54.5% yield.

[0463] 1 HNMR (400MHz, CDCl3) 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).

[0464] Step 4: Synthesis of 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetaldehyde

[0465] The compound 2-(3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-ol (1.2 g, 4.3 mmol) was added to dichloromethane (20 mL), followed by Dess-Martin reagent (2.8 g, 6.5 mmol). The mixture was stirred on ice for 1 hour, resulting in the precipitation of a large amount of solid. Saturated sodium bicarbonate (5 mL) was added, and the mixture was concentrated under reduced pressure. Purification by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:8) afforded 550 mg of the product as a colorless oil in a 46.6% yield.

[0466] 1 H NMR(400MHz, DMSO-d6)δ9.74(d,J=1.2Hz,1H),7.39–7.30(m,5H),7.22(d,J=7 .8Hz,1H),7.12–7.07(m,1H),5.19(s,2H),3.89(s,2H),3.30(d,J=5.5Hz,3H).

[0467] Step 5: Synthesis of (S)-methyl 2-((3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0468] 2-(3-Fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetaldehyde (550 mg, 2.0 mmol) and methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (520 mg, 2.2 mmol) were added to acetic acid (20 mL), and the mixture was bubbled with oxygen and stirred at 60°C for 5 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to afford 165 mg of the product as a light brown solid in a 16.8% yield.

[0469] LC-MS(ESI):[M+H] + =491.3.

[0470] Step 6: Synthesis of (S)-methyl 2-((3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0471] Compound (S)-methyl 2-((3-fluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (165 mg, 0.34 mmol) was added to dichloromethane (10 mL), cooled to -20°C, and trifluoroacetic acid (5 mL) was added. The mixture was stirred at -20°C for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 35 mg of the product as a light brown solid in a yield of 23.3%.

[0472] LC-MS(ESI):[M+H] + =447.4.

[0473] Step 7: Synthesis of (S)-methyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0474] Compound (S)-methyl 2-((3-fluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (35 mg, 0.08 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (32.0 mg, 0.12 mmol) were added to N,N-dimethylformamide (2 mL), followed by potassium carbonate (33.0 mg, 0.24 mmol), and stirred at 60°C for one hour. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to afford 28 mg of the product as a white solid in a yield of 56.8%.

[0475] LC-MS(ESI):[M+H] + =629.2.

[0476] Step 8: Synthesis of (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0477] Compound (S)-methyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (28 mg, 44.6 μmol) was dissolved in dioxane (2 mL) and water (0.5 mL). Lithium hydroxide (6.5 mg, 0.27 mmol) was added and stirred at room temperature for 8 hours. The pH was adjusted to 6-7 with acetic acid. The solution was concentrated under reduced pressure and purified by Prep-HPLC (eluent: CH3CN:H2O (v / v) = 50%) to give 6.1 mg of a white solid product in a yield of 22.3%.

[0478] LC-MS(ESI):[M+H] + =615.3;

[0479] 1H NMR (400MHz, DMSO-d6) 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,1 H),5.38(s,2H),5.00(d,J=5.2Hz,1H),4.68(dd,J=15.5,7.2Hz,1H),4.55(d,J=1 3.2Hz,1H),4.49–4.40(m,2H),4.39–4.27(m,2H),2.68–2.60(m,1H),2.33(s,1H).

[0480] Example 16 Synthesis of (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 16)

[0481] Step 1: Synthesis of 1-bromo-3-fluoro-2-(methoxymethoxy)benzene

[0482] 2-Bromo-6-fluorophenol (5.0 g, 26.18 mmol) was added to N,N-dimethylformamide (50 mL), followed by sodium hydride (1.57 g, 39.27 mmol). The mixture was stirred in an ice bath for ten minutes. Bromo(methoxy)methane (3.93 g, 31.41 mmol) was added, and the mixture was stirred at room temperature for one hour. Water (250 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were 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) = 1:20) to obtain 6.0 g of the product as a colorless oil in a 97.5% yield.

[0483] 1 HNMR (400MHz, CDCl3) 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).

[0484] Step 2: Synthesis of methyl 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetate

[0485] 1-Bromo-3-fluoro-2-(methoxymethoxy)benzene (1.9 g, 8.08 mmol) and methyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (2.85 g, 9.7 mmol) were added to 1,4-dioxane (30 mL) and water (7.5 mL). Potassium carbonate (3.35 g, 24.24 mmol) was added, and the atmosphere was purged with nitrogen three times. Tetrakis(triphenylphosphine)palladium (0.47 g, 0.4 mmol) was added, and the atmosphere was purged with nitrogen again three times. The mixture was stirred at 85°C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:15) to obtain 2.2 g of the product as a colorless oil in an 84.5% yield.

[0486] 1 HNMR(400MHz, CDCl3)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)

[0487] Step 3: Synthesis of 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-ol

[0488] Methyl 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetate (2.2 g, 6.83 mmol) was added to tetrahydrofuran (50 mL) and stirred at 0°C for five minutes. Lithium aluminum tetrahydride (0.78 g, 20.5 mmol) was added and stirred at 0°C for two hours. The mixture was quenched by the addition of water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were 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) = 1:5) to obtain 1.2 g of the product as a colorless oil in a 59.7% yield.

[0489] 1 H NMR(400MHz, DMSO-d6)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).

[0490] Step 4: Synthesis of 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetaldehyde

[0491] The compound 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)ethan-1-ol (1.2 g, 4.08 mmol) was added to dichloromethane (20 mL), followed by Dess-Martin reagent (2.59 g, 6.12 mmol). The mixture was stirred in an ice bath for 1 hour, resulting in the precipitation of a large amount of solid. Water (5 mL) was added, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:5) to obtain 700 mg of the product as a colorless oil, with a yield of 58.7%.

[0492] 1 HNMR (400MHz, DMSO-d6) 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).

[0493] Step 5: Synthesis of (S)-methyl 2-((3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0494] 2-(3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)acetaldehyde (700 mg, 2.39 mmol) and methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (566 mg, 2.4 mmol) were added to acetic acid (10 mL) and stirred at 60°C for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:1) to afford 155 mg of the product as a light brown solid in a 12.7% yield.

[0495] LC-MS(ESI):[M+H] + =509.4.

[0496] Step 6: Synthesis of (S)-methyl 2-((3,3'-difluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0497] Compound (S)-methyl 2-((3,3'-difluoro-2'-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (155 mg, 0.3 mmol) was added to dichloromethane (12 mL), cooled to -20°C, and trifluoroacetic acid (4 mL) was added. The mixture was stirred at -20°C for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 100 mg of the product as a light brown solid in a yield of 70.6%.

[0498] LC-MS(ESI):[M+H] + =465.4.

[0499] Step 7: Synthesis of (S)-methyl 2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0500] Compound (S)-methyl 2-((3,3'-difluoro-2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.22 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (80 mg, 0.3 mmol) were added to N,N-dimethylformamide (5 mL), followed by potassium carbonate (90 mg, 0.65 mmol), and stirred at 60°C for one hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to obtain 100 mg of an off-white solid product in a yield of 71.8%.

[0501] LC-MS(ESI):[M+H] + =647.4.

[0502] Step 8: Synthesis of (S)-2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0503] Compound (S)-methyl 2-((2'-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,3'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.15 mmol) was added to dioxane (4 mL) and water (1 mL). Lithium hydroxide (22 mg, 0.92 mmol) was added and stirred at room temperature for 4 hours. The pH was adjusted to 6-7 with hydrochloric acid (0.5 N) and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (eluent: CH3CN:H2O (v / v) = 50%) to give 54.0 mg of the product as a white solid in a 55.2% yield.

[0504] LC-MS(ESI):[M+H] + =633.2;

[0505] 1 HNMR (400MHz, DMSO-d6) 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).

[0506] Example 17 Synthesis of 2-((R)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 17)

[0507] Step 1: Synthesis of methyl 2-((R)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylate

[0508] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (350 mg, 0.93 mmol), methyl 2-((S)-1-chloroethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (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 reacted at 60°C for 2 h. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was 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 (eluent EA:PE (v / v) = 50%) to give 123 mg of the product as a yellow viscous liquid with a yield of 20.4%.

[0509] LC-MS(ESI):[M+H] + =650.4.

[0510] Step 2: Synthesis of 2-((R)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0511] Methyl 2-((R)-1-(4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)ethyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-carboxylate (123 mg, 0.19 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) were added to 1,4-dioxane (4 mL) and water (2 mL) and reacted at 40°C for 1.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and the pH was adjusted to 5 with acetic acid (4 M). The mixture was extracted three times with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. Purification by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 5%) afforded 60 mg of the product as a pale yellow solid in a 49.2% yield.

[0512] LC-MS(ESI):[M+H] + =636.4;

[0513] 1 H NMR (500MHz, DMSO-d6) 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).

[0514] Example 18 Synthesis of (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 (Compound 18)

[0515] Step 1: Synthesis of tert-butyl 4-(2-hydroxy-3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0516] 2-Bromo-6-methoxyphenol (800 mg, 3.94 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.22 g, 3.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane 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 reacted at 90 ° C for 2 hours. The reaction was complete as determined by TLC. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 15%) to give 707 mg of a colorless oily product in a yield of 58.8%.

[0517] LC-MS(ESI):[M-55] + =250.1.

[0518] Step 2: Synthesis of tert-butyl 4-(2-hydroxy-3-methoxyphenyl)piperidine-1-carboxylate

[0519] Tert-butyl 4-(2-hydroxy-3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (756 mg, 2.48 mmol) and palladium on carbon (400 mg) were added to a 10 mL methanol solution. The mixture was purged with hydrogen three times and stirred at room temperature overnight. TLC confirmed the complete reaction and the reaction was stopped. The filtrate was filtered through celite and concentrated under reduced pressure to yield 631 mg of a brown solid product in an 82.9% yield.

[0520] LC-MS(ESI):[M-55] + =252.1;

[0521] 1 H NMR (500MHz, CDCl3) δ6.92–6.69(m,3H),5.75(s,1H),4.33–4.14(s,2H),3.89(s,3H),3.1 2–3.03(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).

[0522] Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine-1-carboxylate

[0523] 4-(2-hydroxy-3-methoxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (320 mg, 1.04 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (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 showed that the reaction starting material had completely disappeared. Heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 350 mg of a colorless oily product with a yield of 75.3%.

[0524] LC-MS(ESI):[M-55] + =434.2.

[0525] Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine

[0526] Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine-1-carboxylate (350 mg, 0.71 mmol) was added to a solution of trifluoroacetic acid (4 mL) and dichloromethane (4 mL) and stirred at room temperature for 30 minutes. TLC indicated the complete disappearance of the starting material, and the reaction was stopped. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a brown oily product that was used directly in the next reaction.

[0527] Step 5: Synthesis of (S)-methyl 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-carboxylate

[0528] 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methoxyphenyl)piperidine (264 mg, 0.68 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (199 mg, 0.68 mmol), and DIPEA (437 mg, 3.39 mmol) were added to 5 mL of acetonitrile and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 40%) to afford 156 mg of the product as a colorless oil in a 35.5% yield.

[0529] LC-MS(ESI):[M+H] + =648.4.

[0530] Step 6: Synthesis of (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

[0531] (S)-methyl 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-carboxylate (90 mg, 0.14 mmol) and lithium hydroxide monohydrate (28.47 mg, 0.69 mmol) were added to a mixture of 2 mL of water and 6 mL of 1,4-dioxane and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the reaction mixture was adjusted to approximately 6 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20%) to afford 28 mg of the product as a white solid in a 31.2% yield.

[0532] LC-MS(ESI):[M+H] + =634.3;

[0533] 1H NMR (500MHz, DMSO-d6) 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=13.5H z,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).

[0534] Example 19 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 19)

[0535] Step 1: Synthesis of tert-butyl 4-(2-hydroxy-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0536] 2-Bromo-6-methylphenol (500 mg, 2.67 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (909 mg, 2.94 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium 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 reacted at 90 ° C for 2 hours. The reaction was complete as detected by TLC. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 15%) to give 815 mg of a colorless oily product in a yield of 95.9%.

[0537] LC-MS(ESI):[M-55] + =234.2;

[0538] 1 H NMR (500MHz, CDCl3) δ7.03(d,J=7.4Hz,1H),6.92(d,J=7.8Hz,1H),6.80(t,J=7.5Hz,1H),5.8 4(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).

[0539] Step 2: Synthesis of tert-butyl 4-(2-hydroxy-3-methylphenyl)piperidine-1-carboxylate

[0540] Tert-butyl 4-(2-hydroxy-3-methylphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.8 g, 2.67 mmol) and palladium on carbon (400 mg) were added to 12 mL of methanol, replaced with hydrogen three times, and stirred at room temperature overnight. TLC confirmed the complete reaction, and the reaction was stopped. The filtrate was filtered through celite and concentrated under reduced pressure to yield 0.816 g of a brown solid product in a 101.3% yield.

[0541] LC-MS(ESI):[M-55] + =236.2.

[0542] 1 H NMR(500MHz, CDCl3)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).

[0543] Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine-1-carboxylate

[0544] tert-Butyl 4-(2-hydroxy-3-methylphenyl)piperidine-1-carboxylate (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 reacted at 60°C for 2 hours. After TLC analysis, the reaction mixture completely disappeared. Heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 144 mg of the product as a colorless oil in a yield of 38.1%.

[0545] LC-MS(ESI):[M-55] + =418.3.

[0546] 1 H NMR (500MHz, CDCl3) 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).

[0547] Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine

[0548] Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine-1-carboxylate (290 mg, 0.61 mmol) was added to 1.5 mL of trifluoroacetic acid and 3 mL of dichloromethane and stirred at room temperature for 30 minutes. The reaction was terminated upon complete disappearance of the starting material by TLC. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a brown oily product, which was used directly in the next reaction.

[0549] 1H NMR (500MHz, CDCl3) 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).

[0550] Step 5: Synthesis of (S)-methyl 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-carboxylate

[0551] 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-methylphenyl)piperidine (150 mg, 0.4 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (118 mg, 0.4 mmol), and N,N-diisopropylethylamine (259 mg, 2.01 mmol) were added to acetonitrile (3 mL) and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 35%) to afford 158 mg of the product as a colorless oil in a 62.3% yield.

[0552] LC-MS(ESI):[M+H] + =632.4.

[0553] Step 6: Synthesis of (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

[0554] (S)-methyl 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-carboxylate (95 mg, 0.15 mmol) and lithium hydroxide monohydrate (31.5 mg, 0.75 mmol) were added to a mixture of water (2 mL) and 1,4-dioxane (6 mL) and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the mixture was adjusted to approximately 6 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 25%) to afford 34 mg of the product as a white solid in a 36% yield.

[0555] LC-MS(ESI):[M+H] + =618.3.

[0556] 1 H NMR(500MHz,DMSO-d6)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),4.85–4.7 3(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).

[0557] Example 20 Synthesis of (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 (Compound 20)

[0558] Step 1: Synthesis of 4-(benzyloxy)-3-bromopyridine

[0559] 3-Bromo-4-hydroxypyridine (600 mg, 3.45 mmol), benzyl bromide (589 mg, 3.45 mmol), and potassium carbonate (714 mg, 5.17 mmol) were added to N,N-dimethylformamide (20 mL) and reacted at 60°C for 2 hours. TLC indicated the complete disappearance of the starting material. Heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (100 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 632 mg of the product as a colorless oil in a 69.4% yield.

[0560] LC-MS(ESI):[M+H] + =264.0;

[0561] 1 H NMR (500MHz, CDCl3) 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).

[0562] Step 2: Synthesis of tert-butyl 4-(benzyloxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate

[0563] 4-(Benzyloxy)-3-bromopyridine (500 mg, 1.89 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (644 mg, 2.08 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (155 mg, 0.19 mmol), and potassium carbonate (523 mg, 3.78 mmol) were added to a mixed solution of water (1 mL) and 1,4-dioxane (4 mL), replaced with nitrogen three times, and reacted at 90 ° C for 2 hours. The reaction was complete as determined by TLC. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 15%) to give 0.605 g of a brown oily product in an 87.2% yield.

[0564] LC-MS(ESI):[M+H] + =367.3.

[0565] Step 3: Synthesis of tert-butyl 4-(4-hydroxypyridin-3-yl)piperidine-1-carboxylate

[0566] 4-(Benzyloxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (707 mg, 1.93 mmol) and palladium on carbon (350 mg) were added to a methanol (12 mL) solution, replaced with hydrogen three times, and stirred at room temperature overnight. TLC detected that the raw material reaction was complete and the reaction was stopped. The filtrate was filtered with diatomaceous earth and concentrated under reduced pressure to obtain 0.499 g of a brown solid product with a yield of 92.9%.

[0567] LC-MS(ESI):[M-55] + =223.1.

[0568] Step 4: Synthesis of tert-butyl 4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylate

[0569] tert-Butyl 4-(4-hydroxypyridin-3-yl)piperidine-1-carboxylate (290 mg, 1.04 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (250 mg, 0.95 mmol), and potassium carbonate (262 mg, 1.9 mmol) were added to 10 mL of N,N-dimethylformamide and reacted at 60°C for 2 hours. After TLC analysis, the reaction mixture completely disappeared. Heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 260 mg of the product as a colorless oil with a yield of 82.3%.

[0570] LC-MS(ESI):[M+H] + =461.3.

[0571] 1 H NMR (500MHz, CDCl3) 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),6.0 6(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).

[0572] Step 5: Synthesis of 4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine

[0573] tert-Butyl 4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylate (232 mg, 0.5 mmol) was added to trifluoroacetic acid (2 mL) and dichloromethane (4 mL) and stirred at room temperature for 30 minutes. TLC indicated the complete disappearance of the starting material, and the reaction was terminated. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a brown solid product, which was used directly in the next reaction.

[0574] LC-MS(ESI):[M+H] + =361.2.

[0575] Step 6: Synthesis of (S)-methyl 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-carboxylate

[0576] 4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine (150 mg, 0.42 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (122 mg, 0.42 mmol), and N,N-diisopropylethylamine (268 mg, 2.08 mmol) were added to acetonitrile (5 mL) and reacted at 60°C overnight. After TLC analysis, the starting material disappeared completely. Heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20%) to afford 116 mg of the product as a colorless oil in a yield of 45.1%.

[0577] LC-MS(ESI):[M+H] + =619.4.

[0578] Step 7: Synthesis of (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

[0579] (S)-methyl 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-carboxylate (116 mg, 0.19 mmol) and lithium hydroxide monohydrate (39.3 mg, 0.94 mmol) were added to a mixture of water (2 mL) and 1,4-dioxane (6 mL) and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the reaction mixture was adjusted to approximately 6 with diluted aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 2.5%) to afford 53 mg of the product as a white solid in a 44.4% yield.

[0580] LC-MS(ESI):[M+H] + =605.3;

[0581] 1 H NMR (500MHz, CDCl3) 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=15.2,7.1 Hz,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).

[0582] Example 21 Synthesis of (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 21)

[0583] Step 1: Synthesis of tert-butyl 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

[0584] tert-Butyl 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate (160 mg, 0.54 mmol) and 7-(bromomethyl)-2,4-dichlorobenzofuran (227 mg, 0.81 mmol) were added to N,N-dimethylformamide (5 mL). Potassium carbonate (224 mg, 1.62 mmol) was added, and the mixture was stirred at 60°C for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:10) to obtain 157 mg of the product as a light brown solid in a 73.7% yield.

[0585] 1 H NMR (400MHz, CDCl3) 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).

[0586] Step 2: Synthesis of 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine

[0587] Tert-butyl 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate (157 mg, 0.40 mmol) was added to ethyl acetate (5 mL), followed by 1.4-dioxane hydrochloride (5 mL), and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to afford 125 mg of a light brown solid in a 79.2% yield.

[0588] LC-MS(ESI):[M+H] + =394.3.

[0589] Step 3: Synthesis of (S)-methyl 2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0590] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (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 diisopropylethylamine (0.5 mL) was added dropwise to the reaction system and stirred at 60°C for 2 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 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 give 80 mg of an off-white solid product with a yield of 64.5%.

[0591] LC-MS(ESI):[M+H] + =652.5.

[0592] Step 4: Synthesis of (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0593] Compound (S)-methyl 2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.12 mmol) was added to dioxane (2 mL) and water (0.5 mL). Lithium hydroxide (18 mg, 0.72 mmol) was added and stirred at 40°C for 4 hours. The pH was adjusted to 6-7 with hydrochloric acid (0.5 N) and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The product was concentrated under reduced pressure and purified by Prep-HPLC (eluent: CH3CN:H2O (v / v) = 50%) to give 34.7 mg of the product as a white solid in a yield of 45.3%.

[0594] LC-MS(ESI):[M+H] + =638.3;

[0595] 1H NMR (400MHz, DMSO-d6) 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=15.2,7.0H z,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).

[0596] Example 22 Synthesis of 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 (Compound 22)

[0597] Step 1: Synthesis of methyl 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-carboxylate

[0598] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (96 mg, 0.25 mmol), methyl 2-(chloromethyl)-1-((1-(cyanomethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (96 mg, 0.3 mmol), potassium carbonate (105 mg, 0.76 mmol), and potassium iodide (5 mg, 0.03 mmol) were added to acetonitrile (4.5 mL) and stirred at 60°C for 1 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to give 108 mg of a light yellow flocculent product in a yield of 62.0%.

[0599] LC-MS(ESI):[M+1] +=659.5.

[0600] Step 2: Synthesis of 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

[0601] 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-carboxylate (80 mg, 0.12 mmol) was added to 1,4-dioxane (1.5 mL). Lithium hydroxide (16 mg, 0.67 mmol) was added to water (0.5 mL) and completely dissolved. The mixture was then added dropwise to the reaction system and stirred at 40°C overnight. Acetic acid (0.5 mL) was added to adjust the pH to slightly acidic. The solution was concentrated under reduced pressure and purified by Prep-HPLC (eluent: acetonitrile:water (v / v) = 40%) to give 16.5 mg of the product as a white solid in a yield of 21.1%.

[0602] LC-MS(ESI):[M+1] + =645.3;

[0603] 1 H NMR(400MHz,DMSO-d6)δ12.84(s,1H),8.25(s,1H),7.83–7.80(m,1H),7.67–7.6 5(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).

[0604] Example 23 Synthesis of 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 (Compound 23)

[0605] Step 1: Synthesis of methyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate

[0606] Methyl 3-fluoro-4-nitrobenzoate (1 g, 5.02 mmol) and 2-methoxyethane-1-amine (0.5 mL, 6.03 mmol) were dissolved in DMF (15 mL). Potassium carbonate (1.39 g, 10.04 mmol) was added and stirred at room temperature for 2.5 h. Water was added and the mixture was extracted three times with ethyl acetate. The mixture was dried and concentrated. The mixture was purified on a silica gel column (PE / EA = 5 / 1) to obtain 920 mg of a yellow oil with a yield of 72.1%.

[0607] LC-MS(ESI):[M+H] + =255.2.

[0608] Step 2: Synthesis of methyl 4-amino-3-((2-methoxyethyl)amino)benzoate

[0609] Methyl 3-((2-methoxyethyl)amino)-4-nitrobenzoate (920 mg, 3.62 mmol) was dissolved in dioxane (10 mL) and water (2.00 mL). Zinc powder (1.2 g, 18.10 mmol) and ammonium chloride (968 mg, 18.10 mmol) were added and allowed to react at room temperature for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated to afford 730 mg of the crude product as a purple oil, with a yield of 90.0%.

[0610] LC-MS(ESI):[M+H] + =225.2.

[0611] Step 3: Synthesis of methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate

[0612] Methyl 4-amino-3-((2-methoxyethyl)amino)benzoate (1 g, 4.46 mmol) and 2-chloro-1,1,1-trimethoxyethane (1.03 g, 6.69 mmol) were added to tetrahydrofuran (10 mL), followed by p-toluenesulfonic acid monohydrate (0.08 g, 0.45 mmol). The mixture was heated to 50°C under nitrogen for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 20:1) to obtain 1.15 g of an off-white solid product in a 91.2% yield.

[0613] 1 HNMR(400MHz, CDCl3) 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).

[0614] Step 4: Synthesis of methyl 2-((4-(2-(((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate

[0615] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine and methyl 2-(chloromethyl)-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylate (72 mg, 0.25 mmol) were added to acetonitrile (5 mL), followed by potassium carbonate (32 mg, 0.23 mmol) and potassium iodide (38 mg, 0.23 mmol). The mixture was heated to 60°C under nitrogen for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 130 mg of the product as a light yellow solid in a 90.5% yield.

[0616] LC-MS(ESI):[M+H] + =624.5.

[0617] Step 5: Synthesis of 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

[0618] 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 to 1,4-dioxane (1 mL) and water (0.5 mL). Lithium hydroxide (44 mg, 1.05 mmol) was added. Under nitrogen protection, the temperature was raised to 40°C and the reaction was carried out for 2 hours. Acetic acid (1 mL) was added to adjust the pH to weak acidity. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (eluent CH3CN:H2O (v / v) = 60%) to obtain 100 mg of a white solid product with a yield of 77.9%.

[0619] LC-MS(ESI):[M+H] + =610.3;

[0620] 1HNMR (400MHz, DMSO-d6) δ8.17(s,1H),7.80(d,J=8.4Hz,1H),7.63(d,J=8.4Hz,1H),7.42(d,J=8. 0Hz,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=1 1.2Hz,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).

[0621] Example 24 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 24)

[0622] Step 1: Synthesis of tert-butyl 4-(3,5-difluoro-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0623] 2-Bromo-4,6-difluorophenol (0.6 g, 3.14 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.07 g, 3.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.26 g, 0.31 mmol), and potassium carbonate (0.87 g, 6.28 mmol) were added to a mixed solution of water (3 mL) and 1,4-dioxane (12 mL), replaced with nitrogen three times, and reacted at 90 ° C for 2 hours. The reaction was complete as determined by TLC. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 15%) to give 0.896 g of a brown oily product in a yield of 97.2%.

[0624] 1H NMR (500MHz, CDCl3) 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).

[0625] Step 2: Synthesis of tert-butyl 4-(3,5-difluoro-2-hydroxyphenyl)piperidine-1-carboxylate

[0626] Tert-butyl 4-(3,5-difluoro-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.21 mmol) and palladium on carbon (550 mg) were added to ethanol (10 mL). The mixture was replaced with hydrogen three times and stirred at room temperature overnight. TLC confirmed the complete reaction and the reaction was stopped. The filtrate was filtered through celite and concentrated under reduced pressure to yield 966 mg of a brown solid product in a 96.0% yield.

[0627] LC-MS(ESI):[M-55] + =258.0;

[0628] 1 H NMR(500MHz, CDCl3)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).

[0629] Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine-1-carboxylate

[0630] tert-Butyl 4-(3,5-difluoro-2-hydroxyphenyl)piperidine-1-carboxylate (356 mg, 1.14 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (250 mg, 0.95 mmol), and potassium carbonate (262 mg, 1.9 mmol) were added to 10 mL of N,N-dimethylformamide and reacted at 60°C for 2 hours. TLC indicated the complete disappearance of the starting material. Heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to afford 309 mg of the product as a colorless oil in a 54.3% yield.

[0631] 1H NMR (500MHz, CDCl3) 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,2 H),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).

[0632] Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine

[0633] Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine-1-carboxylate (253 mg, 0.51 mmol) was added to trifluoroacetic acid (4 mL) and dichloromethane (4 mL) and stirred at room temperature for 30 minutes. TLC indicated the complete disappearance of the starting material, and the reaction was stopped. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 6 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 187 mg of a brown solid product with a yield of 92.6%.

[0634] LC-MS(ESI):[M+H] + =396.2;

[0635] 1 H NMR (500MHz, CDCl3) 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).

[0636] Step 5: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0637] 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidine (150 mg, 0.38 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (112 mg, 0.38 mmol), and N,N-diisopropylethylamine (245 mg, 1.9 mmol) were added to acetonitrile (10 mL) and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 35%) to afford 153 mg of the product as a colorless oil in a 61.6% yield.

[0638] LC-MS(ESI):[M+H] + =654.5;

[0639] 1 H NMR (500MHz, CDCl3) 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,1 H),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).

[0640] Step 6: Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0641] (S)-Methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3,5-difluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (153 mg, 0.23 mmol) and lithium hydroxide monohydrate (49 mg, 1.17 mmol) were added to a mixture of water (1 mL) and 1,4-dioxane (4 mL) and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the mixture was adjusted to approximately 7 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 25%) to afford 101 mg of the product as a white solid in a 64.1% yield.

[0642] LC-MS(ESI):[M+H] + =640.4;

[0643] 1 H NMR (500MHz, DMSO-d6) 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=6.3Hz,1H),5.23(s,2H),5.11–5.02(m,1H),4.83–4.72(m,1 H),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=11.1H z,1H),2.80(d,J=11.3Hz,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).

[0644] Example 25 Synthesis of (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-carboxylic acid (Compound 25)

[0645] Step 1: Synthesis of tert-butyl 4-(4-fluoro-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0646] 2-Bromo-5-fluorophenol (0.6 g, 3.14 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.07 g, 3.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.26 g, 0.31 mmol), and potassium carbonate (0.87 g, 6.28 mmol) were added to a mixed solution of water (3 mL) and 1,4-dioxane (12 mL), replaced with nitrogen three times, and reacted at 90 ° C for 2 hours. The reaction was complete as determined by TLC. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 15%) to give 0.697 g of a brown oily product in a yield of 75.6%.

[0647] LC-MS(ESI):[M-55] + =238.2.

[0648] Step 2: Synthesis of tert-butyl 4-(4-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate

[0649] Tert-butyl 4-(4-fluoro-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (789 mg, 2.69 mmol) and palladium on carbon (400 mg) were added to methanol (15 mL). The mixture was replaced with hydrogen three times and stirred at room temperature overnight. TLC confirmed the complete reaction and the reaction was stopped. The filtrate was filtered through celite and concentrated under reduced pressure to yield 756 mg of a pale yellow solid product in a 95.2% yield.

[0650] LC-MS(ESI):[M-55] + =240.2;

[0651] 1 H NMR(500MHz, CDCl3)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).

[0652] Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidine-1-carboxylate

[0653] Tert-butyl 4-(4-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate (308 mg, 1.04 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (250 mg, 0.95 mmol), and potassium carbonate (262 mg, 1.9 mmol) were added to 10 mL of N,N-dimethylformamide and reacted at 60°C for 2 hours. After TLC analysis, the reaction mixture completely disappeared. Heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 367 mg of the product as a colorless oil in an 80.9% yield.

[0654] 1 H NMR (500MHz, CDCl3) 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).

[0655] Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidine

[0656] Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidine-1-carboxylate (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 indicated the complete disappearance of the starting material, and the reaction was terminated. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a brown solid product, which was used directly in the next reaction.

[0657] LC-MS(ESI):[M+H] + =378.3.

[0658] Step 5: Synthesis of (S)-methyl 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

[0659] 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluorophenyl)piperidine (128 mg, 0.34 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.34 mmol), and N,N-diisopropylethylamine (220 mg, 1.75 mmol) were added to acetonitrile (5 mL) and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 35%) to afford 151 mg of the product as a colorless oil in a yield of 69.8%.

[0660] LC-MS(ESI):[M+H] + =636.4;

[0661] 1 H NMR (500MHz, CDCl3) 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)

[0662] Step 6: Synthesis of (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-carboxylic acid

[0663] 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) and lithium hydroxide monohydrate (30.3 mg, 0.74 mmol) were added to a mixture of 2 mL of water and 6 mL of 1,4-dioxane and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the reaction mixture was adjusted to approximately 7 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 25%) to afford 48 mg of the product as a pale yellow solid in a 50.6% yield.

[0664] LC-MS(ESI):[M+H] + =622.3;

[0665] 1 H NMR (500MHz, CDCl3) δ8.25(s,1H),7.80(d,J=8.5Hz,1H),7.63(d,J=8.4Hz,1 H),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),4.80–4.7 3(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).

[0666] Example 26 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 26)

[0667] Step 1: Synthesis of tert-butyl 4-(5-fluoro-6-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0668] 2-Bromo-4-fluorophenol (600 mg, 3.14 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.07 g, 3.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.26 g, 0.31 mmol), and potassium carbonate (0.86 g, 6.28 mmol) were added to a mixed solution of water (3 mL) and 1,4-dioxane (12 mL), replaced with nitrogen three times, and reacted at 90 ° C for 2 hours. The reaction was complete as determined by TLC. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 15%) to give 896 mg of a colorless oily product in a yield of 97.2%.

[0669] LC-MS(ESI):[M-55] + =238.1;

[0670] 1 H NMR (500MHz, CDCl3) 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).

[0671] Step 2: Synthesis of tert-butyl 4-(5-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate

[0672] 4-(5-Fluoro-6-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.4 g, 4.77 mmol) and palladium on carbon (700 mg) were added to methanol (15 mL). The mixture was replaced with hydrogen three times and stirred at room temperature overnight. TLC confirmed the complete reaction and the reaction was stopped. The filtrate was filtered through celite and concentrated under reduced pressure to afford 896 mg of a brown solid product in a 63.6% yield.

[0673] LC-MS(ESI):[M-55] + =240.2;

[0674] 1H NMR (500MHz, CDCl3) 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).

[0675] Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidine-1-carboxylate

[0676] Tert-butyl 4-(2-fluoro-6-hydroxyphenyl)piperidine-1-carboxylate (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 reacted at 60°C for 2 hours. After TLC analysis, the reaction mixture completely disappeared. Heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 262 mg of the product as a colorless oil in a yield of 57.8%.

[0677] 1 H NMR (500MHz, CDCl3) 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).

[0678] Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidine

[0679] Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidine-1-carboxylate (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 detection showed that the starting material had completely disappeared, and the reaction was stopped. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to about 7 with saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a brown oily product that was used directly in the next step.

[0680] LC-MS(ESI):[M+H] + =378.3;

[0681] 1 H NMR (500MHz, CDCl3) 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).

[0682] Step 5: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0683] 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidine (192 mg, 0.51 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.51 mmol), and N,N-diisopropylethylamine (328 mg, 2.54 mmol) were added to acetonitrile (10 mL) and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 35%) to afford 242 mg of the product as a pale yellow oil in a yield of 74.8%.

[0684] LC-MS(ESI):[M+H] + =636.5;

[0685] 1H NMR (500MHz, CDCl3) 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,4 H),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).

[0686] Step 6: Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0687] (S)-Methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (242 mg, 0.38 mmol) and lithium hydroxide monohydrate (79.8 mg, 1.9 mmol) were added to a mixture of water (3 mL) and 1,4-dioxane (9 mL) and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the mixture was adjusted to approximately 7 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 25%) to afford 106 mg of the product as a white solid in a 40% yield.

[0688] LC-MS(ESI):[M+H] + =622.3;

[0689] 1H NMR (500MHz, DMSO-d6) δ12.71(s,1H),8.27(s,1H),7.80(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),7.47–7.3 8(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=1 3.5Hz,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).

[0690] Example 27 Synthesis of (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 27)

[0691] Step 1: Synthesis of 4-bromo-2-(2,2-diethoxyethoxy)-1-toluene

[0692] 5-Bromo-2-methylphenol (25 g, 134.4 mmol), 2-bromo-1,1-diethoxyethane (31.8 g, 162.3 mmol), and potassium carbonate (37.1 g, 268.8 mmol) were added to N,N-dimethylformamide (250 mL) and stirred at 120°C overnight under nitrogen. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were 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 40 g of the product, a light brown liquid, in a 98.5% yield.

[0693] Step 2: Synthesis of 4-bromo-7-methylbenzofuran

[0694] 4-Bromo-2-(2,2-diethoxyethoxy)-1-toluene (40 g, 132.2 mmol) and polyphosphoric acid (68 g, 829.4 mmol) were added to 1,2-dichloroethane (400 mL) and reacted at 85°C overnight under nitrogen. The solvent was removed under reduced pressure, water (100 mL) was added, and the mixture was extracted with dichloromethane (100 mL x 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%) to obtain 17 g of the product as a colorless liquid with a yield of 60.8%.

[0695] 1 HNMR (400MHz, CDCl3) 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).

[0696] Step 3: Synthesis of 7-methylbenzofuran-4-cyano

[0697] 4-Bromo-7-methylbenzofuran (16 g, 75.8 mmol) was added to N,N-dimethylformamide (160 mL), followed by cuprous cyanide (33.95 g, 378.5 mmol). The mixture was reacted at 120°C under nitrogen overnight. Water (500 mL) was added, and the mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE = 100%) to obtain 8.3 g of the product as a colorless liquid with a yield of 69.7%.

[0698] 1 HNMR (400MHz, CDCl3) 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).

[0699] Step 4: Synthesis of 2-chloro-7-methylbenzofuran-4-cyano

[0700] Compound 7-methylbenzofuran-4-cyano (1 g, 6.4 mmol) was added to tetrahydrofuran (15 mL). The mixture was cooled to -78°C under nitrogen. At this temperature, lithium diisopropylamide (2.6 mL) was added and stirred for one hour. Hexachloroethane (1.6 g, 6.8 mmol) was added, the cryogenic pump was removed, and the mixture was stirred overnight. Water (45 mL) was added at 0°C, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 5%) to obtain 800 mg of the product as a colorless liquid with a yield of 65.6%.

[0701] 1 HNMR (400MHz, CDCl3) δ7.48 (d, J = 8Hz, 1H), 7.15 (d, J = 8Hz, 1H), 6.81 (s, 1H), 2.56 (s, 3H).

[0702] Step 5: Synthesis of 7-(bromomethyl)-2-chlorobenzofuran-4-carbonitrile

[0703] 2-Chloro-7-methylbenzofuran-4-cyanopropane (800 mg, 4.2 mmol), azobisisobutyronitrile (137 mg, 0.8 mmol), and N-bromosuccinimide (1.1 g, 6.2 mmol) were added to 1,2-dichloroethane (36 mL) and reacted at 85°C overnight under nitrogen. Water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1%) to obtain 700 mg of the product as a colorless liquid in a 61.9% yield.

[0704] 1 HNMR (400MHz, CDCl3) δ7.56 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 4.71 (s, 2H).

[0705] Step 6: Synthesis of tert-butyl 4-(2-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

[0706] tert-Butyl 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate (100 mg, 0.34 mmol) and 7-(bromomethyl)-2-chlorobenzofuran-4-carbonitrile (138 mg, 0.51 mmol) were added to N,N-dimethylformamide (5 mL). Potassium carbonate (141 mg, 1.02 mmol) was added, and the mixture was stirred at 60°C for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:10) to obtain 130 mg of the product as a light brown solid in a yield of 78.8%.

[0707] 1 HNMR (400MHz, CDCl3) δ7.55(d,J=7.8Hz,1H),7.45(d,J=7.8Hz,1H),7.01–6.90(m,2H),6.87(d,J=6.8Hz,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).

[0708] Step 7: Synthesis of 2-chloro-7-((2-fluoro-6-(piperidin-4-yl)phenoxy)methyl)benzofuran-4-carbonitrile

[0709] Tert-butyl 4-(2-((2-chloro-4-cyanobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate (130 mg, 0.27 mmol) was added to ethyl acetate (5 mL), followed by 1.4-dioxane hydrochloride (5 mL), and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to afford 100 mg of the product as a light brown solid in a 96.5% yield.

[0710] LC-MS(ESI):[M+H] + =385.4.

[0711] Step 8: Synthesis of (S)-methyl 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-carboxylate

[0712] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (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) and stirred for five minutes. 2-Chloro-7-((2-fluoro-6-(piperidin-4-yl)phenoxy)methyl)benzofuran-4-carbonitrile (100 mg, 0.26 mmol) was added, and the mixture was stirred at 60°C for 2 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 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 100 mg of an off-white solid product in a yield of 59.9%.

[0713] LC-MS(ESI):[M+H] + =643.5;

[0714] 1 H NMR (400MHz, CDCl3) 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).

[0715] Step 9: Synthesis of (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

[0716] Compound (S)-methyl 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-carboxylate (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. The pH was adjusted to 6-7 with hydrochloric acid (0.5 N) and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (eluent: CH3CN:H2O (v / v) = 50%) to give 22.4 mg of the product as a white solid in a yield of 22.3%.

[0717] LC-MS(ESI):[M+H] + =629.3;

[0718] 1 HNMR (400MHz, DMSO-d6) 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).

[0719] Example 28 Synthesis of (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 28)

[0720] Step 1: Synthesis of 3-(benzyloxy)-2-chloro-4-fluoropyridine

[0721] 2-Chloro-4-fluoropyridin-3-ol (500 mg, 3.39 mmol) was added to acetone (10 mL), followed by potassium carbonate (702 mg, 5.08 mmol) and stirring for five minutes. Benzyl bromide (695 mg, 4.06 mmol) was then added and stirred at 50°C overnight. The mixture was concentrated under reduced pressure, and water (10 mL) and ethyl acetate (10 mL) were added for extraction. The organic layer was dried and concentrated to yield the crude product, which was then purified by column chromatography (eluent: PE:EA (v / v) = 10:1) to afford 550 mg of the product as a colorless oil in a 68.3% yield.

[0722] 1 H NMR (400MHz, CDCl3) 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).

[0723] Step 2: Synthesis of tert-butyl 3-(benzyloxy)-4-fluoro-3',6'-dihydro-(2,4'-bipyridine)-1'(2'H)-carboxylate

[0724] Add 3-(benzyloxy)-2-chloro-4-fluoropyridine (500 mg, 2.10 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (650 mg, 2.10 mmol), and potassium carbonate (581 mg, 4.20 mmol) to 1,4-dioxane (10 mL) and water (1 mL). Replace the atmosphere with nitrogen three times, add 1,1'-bis(diphenylphosphinoferrocenepalladium dichloride) (15 mg, 0.02 mmol), and replace the atmosphere with nitrogen again. Stir at 85°C overnight. The mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The organic phases were combined and concentrated under reduced pressure. The mixture was purified by column chromatography (eluent PE:EA (v / v) = 5:1) to give 860 mg of an orange oily product in a yield of 99%.

[0725] 1H NMR(400MHz, CDCl3)δ8.18(dd,J=6.8,5.6Hz,1H),7.34–7.23(m,5H),6.91(dd,J=10.4,5.2H z,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).

[0726] Step 3: Synthesis of tert-butyl 4-(4-fluoro-3-hydroxypyridin-2-yl)piperidine-1-carboxylate

[0727] tert-Butyl 3-(benzyloxy)-4-fluoro-3',6'-dihydro-(2,4'-bipyridyl)-1'(2'H)-carboxylate (840 mg, 2.18 mmol) was added to methanol (10 mL). Palladium on carbon (84 mg, 0.79 mmol) was added, the atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature for 30 minutes. Filtered through celite, washed with methanol (10 mL), concentrated under reduced pressure, and purified by column chromatography (eluent PE:EA (v / v) = 1:1) to give 640 mg of the product as a colorless oil in a 98.8% yield.

[0728] LC-MS(ESI):[M-55] + =241.3;

[0729] 1 H NMR (400MHz, CDCl3) 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).

[0730] Step 4: Synthesis of tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidine-1-carboxylate

[0731] The compound tert-butyl 4-(4-fluoro-3-hydroxypyridin-2-yl)piperidine-1-carboxylate (300 mg, 1.01 mmol) was added to N,N-dimethylformamide (5 mL), potassium carbonate (419 mg, 3.03 mmol) was added, and the mixture was stirred at room temperature for 5 min. 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (293 mg, 1.11 mmol) was added, and the mixture was stirred at 60°C for two hours. The mixture was concentrated under reduced pressure and purified by column chromatography (eluent PE:EA (v / v) = 8:1) to give 390 mg of a light yellow solid product with a yield of 80.4%.

[0732] 1 H NMR (400MHz, CDCl3) 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).

[0733] Step 5: Synthesis of 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoro-2-(piperidin-4-yl)pyridine hydrochloride

[0734] tert-Butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidine-1-carboxylate (390 mg, 0.81 mmol) was added to a dioxane hydrochloride solution (5 mL) and stirred at room temperature for 1.5 hours. The mixture was concentrated under reduced pressure to afford 300 mg of an off-white solid product in a 97.3% yield.

[0735] LC-MS(ESI):[M+H] + =379.3.

[0736] Step 6: Synthesis of (S)-methyl 2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0737] 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoro-2-(piperidin-4-yl)pyridine hydrochloride (130 mg, 0.34 mmol) was added to N,N-dimethylformamide (3 mL), followed by potassium carbonate (142 mg, 1.03 mmol). The mixture was stirred at room temperature for five minutes. (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (99 mg, 0.38 mmol) was then added, and the mixture was stirred at 60°C for 1.5 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (eluent PE:EA (v / v) = 1:1) to give 132 mg of the product as a light yellow solid in a 60.4% yield.

[0738] 1H NMR (400MHz, CDCl3) 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).

[0739] Step 7: Synthesis of (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0740] Compound (S)-methyl 2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-fluoropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 0.17 mmol) was added to 1,4-dioxane (1.2 mL) and water (0.2 mL) and stirred at 40°C for four hours. Acetic acid (0.1 mL) was added to adjust the pH to 5-6. The mixture was purified by Prep-HPLC (eluent: acetonitrile:water (v / v) = 60%) to give 73 mg of the product as a white solid in a 67.9% yield.

[0741] LC-MS(ESI):[M+H] + =623.3;

[0742] 1H NMR (400MHz, DMSO-d6) δ12.75(s,1H),8.29–8.27(m,2H),7.80(dd,J=8.4,1.6Hz,1H),7.64(d,J=8.4Hz,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=6.4Hz,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).

[0743] Example 29 Synthesis of (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 29)

[0744] Step 1: Synthesis of 3-(benzyloxy)-2-chloro-5-fluoropyridine

[0745] 2-Chloro-5-fluoropyridin-3-ol (2 g, 13.56 mmol), benzyl bromide (2.78 g, 16.27 mmol), and potassium carbonate (3.75 g, 27.11 mmol) were added to N,N-dimethylformamide (20 mL). The reaction solution was stirred at room temperature overnight. The solution was filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (eluent: PE / EA (v / v) = 10:1) gave 2.6 g of a white solid product in an 80.7% yield.

[0746] LC-MS(ESI):[M+H] + =238.2;

[0747] 1 HNMR (400MHz, CDCl3) δ7.82 (d, J = 4.0Hz, 1H), 7.39–7.26 (m, 5H), 6.96–6.92 (m, 1H), 5.09 (s, 2H).

[0748] Step 2: Synthesis of tert-butyl 3-(benzyloxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0749] The compound was added to 3-(benzyloxy)-2-chloro-5-fluoropyridine (2 g, 8.42 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (3.1 g, 10.03 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.18 g, 0.25 mmol) in 1,4-dioxane (30 mL) and water (8 mL). The solution was purged with nitrogen three times. The reaction solution was stirred at 90°C overnight, cooled to room temperature, and concentrated under reduced pressure. The reaction solution was purified by silica gel column chromatography (eluent: PE / EA (v / v) = 5:1) to obtain 2.9 g of a colorless oily liquid with a yield of 89.6%.

[0750] LC-MS(ESI):[M+H] + =385.5;

[0751] 1H NMR(400MHz, CDCl3)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).

[0752] Step 3: Synthesis of tert-butyl 4-(5-fluoro-3-hydroxypyridin-2-yl)piperidine-1-carboxylate

[0753] Tert-butyl 3-(benzyloxy)-5-fluoro-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (1 g, 2.60 mmol) and palladium on carbon (0.2 g, 1.88 mmol) were added to methanol (50 mL). The solution was replaced with hydrogen three times and reacted under a hydrogen atmosphere for 2 hours. The mixture was filtered through celite and the filtrate was concentrated to give 0.7 g of a light yellow solid product in a yield of 90.8%.

[0754] LC-MS(ESI):[M+H-56] + =241.3;

[0755] 1HNMR(400MHz,DMSO-d6)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).

[0756] Step 4: Synthesis of tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine-1-carboxylate

[0757] The compound tert-butyl 4-(5-fluoro-3-hydroxypyridin-2-yl)piperidine-1-carboxylate (300 mg, 1.01 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (400 mg, 1.52 mmol), and potassium carbonate (279 mg, 2.02 mmol) were added to N,N-dimethylformamide (8 mL), and the solution was reacted at 60°C for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL×3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: PE / EA (v / v) = 5:1) to obtain 330 mg of a colorless oily liquid with a yield of 68.1%.

[0758] LC-MS(ESI):[M-55] + =423.4;

[0759] 1 HNMR (400MHz, DMSO-d6) 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).

[0760] Step 5: Synthesis of (S)-methyl 2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0761] The compound tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidine-1-carboxylate (200 mg, 0.42 mmol) was added to a hydrochloric acid / 1,4-dioxane solution (4 M, 2 mL) and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and acetonitrile (6 mL), N,N-diisopropylethylamine (1 mL), potassium carbonate (174 mg, 1.26 mmol), and potassium iodide (7 mg, 0.04 mmol) were added to the solution. The solution was reacted at 60°C for 2 hours, cooled to room temperature, concentrated under reduced pressure, and purified on a silica gel column (eluent: DCM / MeOH (v / v) = 20:1) to give 140 mg of a light yellow solid product with a yield of 42.1%.

[0762] LC-MS(ESI):[M+H] + =637.5.

[0763] Step 6: Synthesis of (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0764] Compound (S)-methyl 2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (70 mg, 0.11 mmol) and lithium hydroxide (46 mg, 1.10 mmol) were added to 1,4-dioxane (3 mL) and water (1 mL). 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. The reaction solution was concentrated under reduced pressure and purified (eluent: ACN / H2O (v / v) = 1:1) to give 16 mg of the product as a white solid in a yield of 23.4%.

[0765] LC-MS(ESI):[M+H] + =623.4;

[0766] 1HNMR(400MHz,DMSO-d6)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).

[0767] Example 30 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 30)

[0768] Step 1: Synthesis of tert-butyl 4-(2-fluoro-6-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0769] 2-Bromo-3-fluorophenol (600 mg, 3.14 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.08 g, 3.46 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.25 g, 0.31 mmol), and potassium carbonate (0.86 g, 3.28 mmol) were added to a mixed solution of water (4 mL) and 1,4-dioxane (12 mL), replaced with nitrogen three times, and reacted at 90 ° C for 2 hours. The reaction was complete as detected by TLC. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 15%) to give 591 mg of a colorless oily product in a yield of 64.1%.

[0770] Step 2: Synthesis of tert-butyl 4-(2-fluoro-6-hydroxyphenyl)piperidine-1-carboxylate

[0771] Tert-butyl 4-(2-fluoro-6-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (591 mg, 2.01 mmol) and palladium on carbon (300 mg) were added to methanol (15 mL). The mixture was replaced with hydrogen three times and stirred at room temperature overnight. TLC confirmed the complete reaction and the reaction was stopped. The filtrate was filtered through celite and concentrated under reduced pressure to yield 563 mg of a brown solid product in a 94.6% yield.

[0772] LC-MS(ESI):[M+H-56] + =240.2;

[0773] 1 H NMR(500MHz, CDCl3)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).

[0774] Step 3: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine-1-carboxylate

[0775] tert-Butyl 4-(2-fluoro-6-hydroxyphenyl)piperidine-1-carboxylate (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 10 mL of N,N-dimethylformamide and reacted at 60°C for 2 hours. After TLC analysis, the reaction mixture completely disappeared. Heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to obtain 262 mg of the product as a colorless oil in a yield of 57.8%.

[0776] LC-MS(ESI):[M-55] + =422.2;

[0777] 1H NMR (500MHz, CDCl3) 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).

[0778] Step 4: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine

[0779] Tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine-1-carboxylate (362 mg, 0.76 mmol) was added to a hydrochloric acid / 1,4-dioxane solution (4 M, 4 mL) and stirred at room temperature for 30 minutes. TLC indicated the complete disappearance of the starting material, and the reaction was terminated. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 256 mg of a brown solid product in an 89.5% yield.

[0780] LC-MS(ESI):[M+H] + =378.3;

[0781] 1 H NMR (500MHz, CDCl3) δ7.39–7.19(m,2H),7.16–7.08(m,1H),6.74(d,J=8.4Hz,1H),6.69(dd,J=10.5,8.4Hz,1H),6.03(d,J=6.6 Hz,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).

[0782] Step 5: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0783] 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidine (150 mg, 0.4 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (117 mg, 0.4 mmol), and N,N-diisopropylethylamine (256 mg, 1.9 mmol) were added to acetonitrile (10 mL) and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 35%) to afford 124 mg of the product as a colorless oil in a 49% yield.

[0784] LC-MS(ESI):[M+H] + =636.4;

[0785] 1 H NMR(500MHz, CDCl3)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).

[0786] Step 6: Synthesis of ((S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0787] (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (126 mg, 0.2 mmol) and lithium hydroxide monohydrate (41.5 mg, 0.99 mmol) were added to a mixture of water (2 mL) and 1,4-dioxane (6 mL) and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the mixture was adjusted to approximately 7 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 25%) to afford 89 mg of the product as a white solid in a 64.8% yield.

[0788] LC-MS(ESI):[M+H] + =622.4;

[0789] 1 H NMR(500MHz,DMSO-d6)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,1 H),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).

[0790] Example 31 Synthesis of (S)-2-((4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 31)

[0791] Step 1: Synthesis of tert-butyl 3'-hydroxy-3,6-dihydro-[4,4'-bipyridine]-1(2H)-carboxylate

[0792] 4-Bromopyridin-3-ol (1 g, 5.75 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.78 g, 5.75 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.47 g, 0.57 mmol), and potassium carbonate (1.59 g, 2 mmol) were added to a mixed solution of water (3 mL) and 1,4-dioxane (12 mL), replaced with nitrogen three times, and reacted at 90 ° C for 2 hours. The reaction was complete after TLC detection. The heating was stopped and the mixture was cooled to room temperature. Saturated brine (50 mL) was added and extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 15%) to give 579 mg of brown oily product in a yield of 62.1%.

[0793] LC-MS(ESI):[M+H] + =277.2;

[0794] 1 H NMR(500MHz, CDCl3)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).

[0795] Step 2: Synthesis of tert-butyl 4-(3-hydroxypyridin-4-yl)piperidine-1-carboxylate

[0796] Tert-butyl 3'-hydroxy-3,6-dihydro-[4,4'-bipyridine]-1(2H)-carboxylate (927 mg, 3.35 mmol) and palladium on carbon (400 mg) were added to methanol (15 mL). The mixture was replaced with hydrogen three times and stirred at room temperature overnight. TLC confirmed the complete reaction and the reaction was stopped. The filtrate was filtered through celite and concentrated under reduced pressure to yield 901 mg of a brown solid product in a 96.5% yield.

[0797] LC-MS(ESI):[M+H] + =279.3;

[0798] 1H NMR (500MHz, CDCl3) 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).

[0799] Step 3: Synthesis of tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidine-1-carboxylate

[0800] tert-Butyl 4-(3-hydroxypyridin-4-yl)piperidine-1-carboxylate (147.5 mg, 0.53 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (140 mg, 0.53 mmol), and potassium carbonate (146.8 mg, 2 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at 60°C for 2 hours. TLC indicated the complete disappearance of the starting material. Heating was discontinued, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 5%) to afford 114 mg of the product as a colorless oil in a 46.5% yield.

[0801] LC-MS(ESI):[M+H] + =461.3;

[0802] 1 H NMR (500MHz, CDCl3) 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=6.6H z,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).

[0803] Step 4: Synthesis of 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-(piperidin-4-yl)pyridine

[0804] Tert-butyl 4-(3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-4-yl)piperidine-1-carboxylate (100 mg, 0.22 mmol) was added to trifluoroacetic acid (4 mL) and dichloromethane (4 mL) and stirred at room temperature for 30 minutes. TLC indicated the complete disappearance of the starting material, and the reaction was terminated. The solvent was evaporated under reduced pressure, and the pH of the system was adjusted to approximately 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a brown solid product, which was used directly in the next reaction.

[0805] LC-MS(ESI):[M+H] + =361.1.

[0806] Step 5: Synthesis of (S)-methyl 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-carboxylate

[0807] 3-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-4-(piperidin-4-yl)pyridine (100 mg, 0.28 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (81 mg, 0.28 mmol), and N,N-diisopropylethylamine (179 mg, 1.39 mmol) were added to 10 mL of acetonitrile solution and reacted at 60°C overnight. After complete disappearance of the starting material by TLC, heating was stopped, and the mixture was cooled to room temperature. Saturated brine (50 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 35%) to afford 87 mg of the product as a colorless oil in a 50.7% yield.

[0808] LC-MS(ESI):[M+H] + =619.4;

[0809] 1H NMR(500MHz, CDCl3)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).

[0810] Step 6: Synthesis of (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

[0811] (S)-Methyl 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-carboxylate (80 mg, 0.13 mmol) and lithium hydroxide monohydrate (27.1 mg, 0.65 mmol) were added to a mixture of water (2 mL) and 1,4-dioxane (6 mL) and reacted at 40°C for 2 hours. Heating was discontinued after complete disappearance of the starting material by TLC. The pH of the mixture was adjusted to approximately 7 with 20% aqueous acetic acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 25%) to afford 41 mg of the product as a white solid in a 51% yield.

[0812] LC-MS(ESI):[M+H] + =605.4;

[0813] 1H NMR(500MHz, CDCl3)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).

[0814] Example 32 Synthesis of (S)-2-((4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 32)

[0815] Step 1: Synthesis of 1-bromo-3-chloro-2-(methoxymethoxy)benzene

[0816] 2-Bromo-6-chlorophenol (5.0 g, 24.10 mmol) was added to DMF (50 mL), followed by sodium hydride (1.27 g, 53.02 mmol). The mixture was stirred in an ice bath for ten minutes and then at room temperature for half an hour. Bromo(methoxy)methane (4.48 g, 36.15 mmol) was added and stirred at room temperature for one hour. Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). 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) = 1:40) to obtain 6.0 g of the product as a colorless oil in a 99.0% yield.

[0817] 1 H NMR (400MHz, DMSO-d6) 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).

[0818] Step 2: Synthesis of tert-butyl 4-(3-chloro-2-(methoxymethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0819] 1-Bromo-3-chloro-2-(methoxymethoxy)benzene (2.0 g, 7.95 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.95 g, 9.54 mmol) were added to 1,4-dioxane (20 mL) and water (5 mL). Potassium carbonate (3.29 g, 23.85 mmol) was added, and the atmosphere was purged with nitrogen three times. Tetrakis(triphenylphosphine)palladium (184 mg, 0.16 mmol) was added, and the atmosphere was purged with nitrogen again three times. The mixture was stirred at 85°C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:10) to give 2.7 g of the product as a colorless oil in a 95.7% yield.

[0820] 1 H NMR (400MHz, DMSO-d6) 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).

[0821] Step 3: Synthesis of tert-butyl 4-(3-chloro-2-(methoxymethoxy)phenyl)piperidine-1-carboxylate

[0822] 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 (6 mL). Palladium on carbon (53 mg, 0.48 mmol) was added, the atmosphere was replaced with hydrogen three times, and the mixture was stirred at room temperature for half an hour. The palladium on carbon was filtered off, the mixture was quenched with water (10 mL), and extracted with ethyl acetate (20 mL x 3). 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 PE:DCM (v / v) = 1:5) to obtain 320 mg of the product as a colorless oil with a yield of 59.9%.

[0823] LC-MS(ESI):[M+H] + =356.3.

[0824] Step 4: Synthesis of tert-butyl 4-(3-chloro-2-hydroxyphenyl)piperidine-1-carboxylate

[0825] Tert-butyl 4-(3-chloro-2-(methoxymethoxy)phenyl)piperidine-1-carboxylate (320 mg, 0.90 mmol) was added to acetic acid (5 mL) and stirred overnight at 80°C. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EA:PE (v / v) = 1:20) to afford 75 mg of the product as a colorless oil in a 26.7% yield.

[0826] LC-MS(ESI):[M-55] + =256.3.

[0827] Step 5: Synthesis of tert-butyl 4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine-1-carboxylate

[0828] tert-Butyl 4-(3-chloro-2-hydroxyphenyl)piperidine-1-carboxylate (75 mg, 0.24 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (108 mg, 0.41 mmol) were added to dimethylformamide (4 mL). Potassium carbonate (100 mg, 0.72 mmol) was then added and the mixture was stirred at 60°C for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:10) to afford 70 mg of the product as a light brown solid in a 59.0% yield.

[0829] 1 H NMR (400MHz, DMSO-d6) δ7.34(d,J=8.2Hz,1H),7.31–7.27(m,2H),7.09–7.06(m,2H),6.05(d,J=6.6Hz,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).

[0830] Step 6: Synthesis of 4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine

[0831] Tert-butyl 4-(3-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)phenyl)piperidine-1-carboxylate (70 mg, 0.14 mmol) was added to ethyl acetate (3 mL), followed by a 4M solution of hydrochloric acid in 1.4-dioxane (3 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to afford 60 mg of the product as a light brown solid in a 99.0% yield.

[0832] LC-MS(ESI):[M+H] + =394.3.

[0833] Step 7: Synthesis of (S)-methyl 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

[0834] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (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), and diisopropylethylamine (0.5 ml) was added dropwise. This solution was added dropwise to the previous solution, and stirred at 60°C for 2 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 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 give 60 mg of an off-white solid product with a yield of 61.3%.

[0835] LC-MS(ESI):[M+H] + =652.4.

[0836] Step 8: Synthesis of (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-carboxylic acid

[0837] Compound (S)-methyl 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) and water (0.5 mL). Lithium hydroxide (13 mg, 0.54 mmol) was added and stirred at 40°C for 4 hours. The pH was adjusted to 6-7 with hydrochloric acid (0.5 N) and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by prep-HPLC (eluent: CH3CN:H2O (v / v) = 50%) to give 7.8 mg of the product as a white solid in a yield of 13.6%.

[0838] LC-MS(ESI):[M+H] + =638.2;

[0839] 1 H NMR (400MHz, DMSO-d6) 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).

[0840] Example 33 Synthesis of (S)-2-((4-(5-chloro-2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 33)

[0841] Step 1: Synthesis of 1-bromo-5-chloro-3-fluoro-2-(methoxymethoxy)benzene

[0842] 2-Bromo-4-chloro-6-fluorophenol (3.00 g, 13.31 mmol) was added to tetrahydrofuran (75 mL), cooled to 0°C, and sodium hydride (0.8 g, 33.27 mmol) was added. The reaction was continued at 0°C for 1 hour. Bromo(methoxy)methane (2.00 g, 15.97 mmol) was added and the reaction was maintained at 0°C for 1 hour. The mixture was quenched by the addition of water (50 mL) and extracted with ethyl acetate (50 mL x 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) = 10:1) to obtain 3.31 g of the product as a colorless oil in a 92.3% yield.

[0843] 1 HNMR (400MHz, CDCl3) δ7.29 (t, J = 2.0Hz, 1H), 7.03 (dd, J = 10.4, 2.4Hz, 1H), 5.10 (s, 2H), 3.56 (s, 3H).

[0844] Step 2: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-(methoxymethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0845] The compound 1-bromo-5-chloro-3-fluoro-2-(methoxymethoxy)benzene (1.65 g, 6.12 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.89 g, 6.12 mmol) were added to 1,4-dioxane (33 mL) and water (8.25 mL). Potassium carbonate (1.69 g, 12.25 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.22 g, 0.31 mmol) were added, and the temperature was raised to 85°C under nitrogen protection and the reaction was allowed to proceed overnight. The residue was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent PE:EA (v / v) = 10:1) to obtain 1.71 g of a light yellow oily product with a yield of 75.1%.

[0846] 1 HNMR (400MHz, CDCl3) 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).

[0847] Step 3: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-(methoxymethyloxy)phenyl)piperidine-1-carboxylate

[0848] Tert-butyl 4-(5-chloro-3-fluoro-2-(methoxymethoxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (640 mg, 1.72 mmol) was added to ethyl acetate (10 mL). Platinum dioxide (64 mg, 0.13 mmol) was added, and the mixture was replaced with hydrogen. The temperature was raised to 45°C and the reaction was allowed to proceed for 30 minutes. Filtering through celite and concentration under reduced pressure afforded 640 mg of the product as a colorless oil in a 99.5% yield.

[0849] 1HNMR(400MHz, CDCl3)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).

[0850] Step 4: Synthesis of tert-butyl 4-(5-chloro-3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate

[0851] Tert-butyl 4-(5-chloro-3-fluoro-2-(methoxymethyloxy)phenyl)piperidine-1-carboxylate (644 mg, 1.72 mmol) was added to acetic acid (10 mL) and the mixture was heated to 85°C under nitrogen and allowed to react overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 5:1) to afford 179 mg of the product as a pale yellow oil in a 31.5% yield.

[0852] 1 HNMR (400MHz, CDCl3) 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).

[0853] Step 5: Synthesis of tert-butyl 4-(5-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

[0854] tert-Butyl 4-(5-chloro-3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate (160 mg, 0.49 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (153 mg, 0.58 mmol) were added to N,N-dimethylformamide (5 mL), followed by potassium carbonate (201 mg, 1.45 mmol). The mixture was heated to 60°C under nitrogen for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 3:1) to obtain 206 mg of the product as a light yellow oil in an 82.9% yield.

[0855] 1 HNMR (400MHz, CDCl3) 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).

[0856] Step 6: Synthesis of 4-(5-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine

[0857] tert-Butyl 4-(5-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate (100 mg, 0.20 mmol) was added to ethyl acetate (6 mL). A 4M solution of dioxane hydrochloride (6 mL) was added and the mixture was reacted at room temperature under nitrogen for 2 hours. The mixture was concentrated under reduced pressure to afford 80 mg of an off-white solid product in a 99.4% yield.

[0858] LC-MS(ESI):[M+H] + =412.3.

[0859] Step 7: Synthesis of (S)-methyl 2-((4-(5-chloro-2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0860] The compound 4-(5-chloro-2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (80 mg, 0.19 mmol) and methyl 2-(chloromethyl)-3-(((2S)-oxan-2-yl)methyl)benzo[d]imidazole-5-carboxylate (60 mg, 0.20 mmol) were added to acetonitrile (5 mL). Potassium carbonate (134 mg, 0.97 mmol) and potassium iodide (0.0 mL, 0.03 mmol) were added, and the temperature was raised to 60°C under nitrogen for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to give 60 mg of the product as a light yellow solid in a yield of 46.1%.

[0861] LC-MS(ESI):[M+H] + =670.4.

[0862] Step 8: Synthesis of (S)-2-((4-(5-chloro-2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0863] Compound (S)-methyl 2-((4-(5-chloro-2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (60 mg, 0.09 mmol) was added to 1,4-dioxane (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 under nitrogen for 2 hours. The temperature was cooled to room temperature, and the pH was adjusted to 6-7 with acetic acid. The product was concentrated under reduced pressure and purified by Prep-HPLC (eluent: CH3CN:H2O (v / v) = 50%) to give 20 mg of the product as a white solid in a 34.0% yield.

[0864] LC-MS (ESI): [M+H]+=656.2;

[0865] 1 H NMR (400MHz, DMSO-d6) 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).

[0866] Example 34 Synthesis of 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 (Compound 34)

[0867] Step 1: Synthesis of methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate

[0868] Methyl 3-fluoro-4-nitrobenzoate (150 mg, 0.75 mmol), (3-ethylimidazol-4-yl)methanamine (94 mg, 0.75 mmol), potassium carbonate (312 mg, 2.26 mmol), and N,N-diisopropylethylamine (195 mg, 1.51 mmol) were added to N,N-dimethylformamide (10 mL) and stirred at 50°C for 3 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15:1) to obtain 220 mg of the product as a yellow solid in a 96.0% yield.

[0869] LC-MS(ESI):[M+H] + =305.1.

[0870] Step 2: Synthesis of methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate

[0871] Methyl 3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)-4-nitrobenzoate (220 mg, 0.72 mmol) and palladium on carbon (100 mg, 0.94 mmol) were added to methanol (20 mL). The mixture was replaced with hydrogen three times and allowed to react for 1 hour. Filtered through celite and concentrated under reduced pressure to afford 192 mg of a brown solid product in a 96.8% yield.

[0872] LC-MS(ESI):[M+H] + =275.1.

[0873] Step 3: Synthesis of methyl 2-(chloromethyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0874] Methyl 4-amino-3-(((1-ethyl-1H-imidazol-5-yl)methyl)amino)benzoate (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. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 1:1) to give 200 mg of the product as a pale yellow solid in a 74.9% yield.

[0875] LC-MS(ESI):[M+H] +=333.2;

[0876] 1 HNMR(400MHz,DMSO-d6)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).

[0877] Step 4: Synthesis of methyl 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-carboxylate

[0878] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (110 mg, 0.29 mmol), methyl 2-(chloromethyl)-1-((1-ethyl-1H-imidazol-5-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (110 mg, 0.29 mmol), potassium iodide (5 mg, 0.03 mmol), and potassium carbonate (121 mg, 0.88 mmol) were added to acetonitrile (10 mL) and reacted at 60°C for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: DCM / MeOH (v / v) = 15:1) to give 45 mg of the product as a light yellow solid in a yield of 22.9%.

[0879] LC-MS(ESI):[M+H] + =674.1.

[0880] Step 5: Synthesis of 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

[0881] The 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 (45 mg, 0.07 mmol) and lithium hydroxide (10 mg, 0.42 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL) and stirred at 40°C for 2 hours. After cooling to room temperature, acetic acid was slowly added dropwise until the solution pH was slightly acidic. The solution was concentrated under reduced pressure and purified by Prep-HPLC (eluent: ACN / H2O (v / v) = 1:1) to obtain 13.7 mg of the product as a white solid in a yield of 31.1%.

[0882] LC-MS(ESI):[M+H] + =660.2;

[0883] 1 HNMR(400MHz,DMSO-d6)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),3.7 5(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).

[0884] Example 35 Synthesis of (S)-2-((4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 35)

[0885] Step 1: Synthesis of tert-butyl 2-((4-methoxybenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2H)-carboxylate

[0886] 3-Bromo-2-((4-methoxybenzyl)oxy)pyridine (1.0 g, 3.40 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.26 g, 4.08 mmol) were added to 1,4-dioxane (10 mL) and water (2.5 mL). Potassium carbonate (1.41 g, 10.2 mmol) was added, and the atmosphere was purged with nitrogen three times. 1,1'-bis(diphenylphosphinoferrocenepalladium) dichloride (124 mg, 0.17 mmol) was added, and the atmosphere was purged with nitrogen again three times. The mixture was stirred at 85°C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:10) to afford 1.14 g of the product as a colorless oil in an 84.6% yield.

[0887] 1 HNMR (400MHz, CDCl3) 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).

[0888] Step 2: Synthesis of tert-butyl 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylate

[0889] Compound 2-((4-methoxybenzyl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (1.1 g, 2.77 mmol) was added to methanol (11 mL). Palladium carbon (110 mg, 0.89 mmol) was added, the gas was replaced with hydrogen three times, and the mixture was stirred at room temperature for half an hour. Filtered with celite, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure and purified by silica gel column chromatography (eluent EtOAc = 100%) to obtain 685 mg of a colorless oily product with a yield of 88.8%.

[0890] LC-MS(ESI):[M+H] + =279.3.

[0891] Step 3: Synthesis of tert-butyl 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylate

[0892] tert-Butyl 4-(2-hydroxypyridin-3-yl)piperidine-1-carboxylate (685 mg, 2.46 mmol) and 7-(bromomethyl)-2,4-dichlorobenzofuran (972 mg, 3.69 mmol) were added to N,N-dimethylformamide (10 mL). Potassium carbonate (1.0 g, 7.38 mmol) was added, and the mixture was stirred at 60°C for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent EA:PE (v / v) = 1:5) to obtain 140 mg of the product as a light brown solid in an 11.9% yield.

[0893] LC-MS(ESI):[M+H] + =477.3;

[0894] 1 HNMR (400MHz, CDCl3) 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).

[0895] Step 4: Synthesis of 2-((2,4-dichlorobenzofuran-7-yl)methoxy)-3-(piperidin-4-yl)pyridine

[0896] Tert-butyl 4-(2-((2,4-dichlorobenzofuran-7-yl)methoxy)pyridin-3-yl)piperidine-1-carboxylate (140 mg, 0.29 mmol) was added to ethyl acetate (6 mL), followed by 1,4-dioxane hydrochloride (6 mL), and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 10:1) to afford 110 mg of a light brown solid, which was used directly in the next reaction.

[0897] LC-MS(ESI):[M+H] + =377.3.

[0898] Step 5: Synthesis of (S)-methyl 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-carboxylate

[0899] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (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, 0.29 mmol) and diisopropylethylamine (0.5 mL) were added to acetonitrile (4 mL) and dissolved thoroughly before being added dropwise to the reaction system. Stir at 60°C for 2 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 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 with a yield of 32.6%.

[0900] LC-MS(ESI):[M+H] + =635.5.

[0901] Step 6: Synthesis of (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

[0902] Compound (S)-methyl 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-carboxylate (60 mg, 0.09 mmol) was added to dioxane (2 mL) and water (0.5 mL). Lithium hydroxide (13 mg, 0.54 mmol) was added and stirred at 40°C for 4 hours. The pH was adjusted to 6-7 with hydrochloric acid (0.5 N) and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed once with saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (eluent: CH3CN:H2O (v / v) = 50%) to give 21.5 mg of the product as a white solid in a 38.4% yield.

[0903] LC-MS(ESI):[M+H] + =621.2;

[0904] 1HNMR(400MHz,DMSO-d6)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),5.6 2(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).

[0905] Example 36 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 36)

[0906] Step 1: Synthesis of (S)-methyl 2-((4-(2-(benzyloxy)-3-fluorophenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0907] Compound (S)-1-(oxetane-2-ylmethyl)-2-((2-oxopiperazin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (200 mg, 0.6 mmol), 2-(benzyloxy)-1-bromo-3-fluorobenzene (236 mg, 0.8 mmol), 1,1-binaphthyl-2,2-bisdiphenylphosphine (64 mg, 0.1 mmol), and cesium carbonate (365 mg, 1.1 mmol) were added to toluene (50 mL), and trisdibenzylideneacetone dipalladium (50 mg, 0.1 mmol) was added. After nitrogen substitution, the reaction was carried out at 120°C overnight. The mixture was concentrated under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined and concentrated under reduced pressure, and purified by thin layer chromatography (eluent MeOH:DCM (v / v) = 5%) to obtain 172 mg of a light yellow solid product with a yield of 55.2%.

[0908] LC-MS: [M+H] + =559.5;

[0909] 1H NMR (400MHz, CDCl3) 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).

[0910] Step 2: Synthesis of (S)-methyl 2-((4-(3-fluoro-2-hydroxyphenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0911] Compound (S)-methyl 2-((4-(2-(benzyloxy)-3-fluorophenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.2 mmol) was added to methanol (1 mL) and palladium on carbon (10 mg). The mixture was replaced with hydrogen three times and allowed to react at room temperature for 2 hours. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give 85 mg of the product as a white solid in a 100% yield.

[0912] LC-MS: [M+H] + =469.4.

[0913] Step 3: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0914] Compound (S)-methyl 2-((4-(3-fluoro-2-hydroxyphenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (85 mg, 0.2 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (57 mg, 0.2 mmol), and potassium carbonate (75 mg, 0.6 mmol) were added to N,N-dimethylformamide (4.5 mL) and reacted at 60°C under nitrogen. Water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by thin-layer chromatography (eluent MeOH:DCM (v / v) = 5%) to give 43 mg of the yellow liquid product in a yield of 36.4%.

[0915] LC-MS: [M+H] + =651.5.

[0916] Step 4: Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0917] Compound (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-oxopiperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (43 mg, 0.06 mmol) and lithium hydroxide (14 mg, 0.6 mmol) were added to 1,4-dioxane (0.8 mL) and water (0.2 mL) and reacted at 40°C for three hours. Acetic acid (0.2 mL) was added to adjust the pH to 6-7. The solution was concentrated under reduced pressure and purified by Prep-HPLC (eluent: acetonitrile:water (v / v) = 70%) to give 10 mg of the product as a white solid in a yield of 23.8%.

[0918] LC-MS: [M+H] + =637.2;

[0919] 1H NMR (400MHz, DMSO-d6) 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=6.4H z,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=13.6,7.6H z,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).

[0920] Example 37 Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 37)

[0921] Step 1: Synthesis of 2-(benzyloxy)-1-bromo-3-(trifluoromethyl)benzene

[0922] The compound 2-bromo-6-(trifluoromethyl)phenol (550 mg, 2.28 mmol) and benzyl bromide (468 mg, 2.74 mmol) were added to N,N-dimethylformamide (10 mL) and stirred to dissolve. Potassium carbonate (946 mg, 6.85 mmol) was then added. The reaction solution was heated to 60°C under nitrogen protection and reacted for 2 hours. Water (30 mL) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (20 mL×3). The organic layer was dried and concentrated to give a crude product. The crude product was purified by column chromatography (eluent PE:EA (v / v) = 1:1) to give 460 mg of an off-white solid product with a yield of 60.9%.

[0923] 1 H NMR (400MHz, CDCl3) 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).

[0924] Step 2: Synthesis of tert-butyl 4-(2-(benzyloxy)-3-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0925] 2-(Benzyloxy)-1-bromo-3-(trifluoromethyl)benzene (460 mg, 1.39 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (516 mg, 1.67 mmol) were added to dioxane (10 mL) and stirred to dissolve. Potassium carbonate (576 mg, 4.17 mmol), tetrakistriphenylphosphine palladium (80 mg, 0.07 mmol), and water (2 mL) were then added. The reaction mixture was heated to 85°C under nitrogen and allowed to react overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (eluent: PE:EA (v / v) = 1:1) to obtain 383 mg of an off-white solid product in a 63.6% yield.

[0926] 1 H NMR (400MHz, CDCl3) 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).

[0927] Step 3: Synthesis of tert-butyl 4-(2-hydroxy-3-(trifluoromethyl)phenyl)piperidine-1-carboxylate

[0928] Tert-butyl 4-(2-(benzyloxy)-3-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (383 mg, 0.88 mmol) was added to methanol (10 mL) and stirred to dissolve. Palladium on carbon (40 mg, 0.38 mmol) was then added and the reaction mixture was allowed to react at room temperature under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered and concentrated to afford 307 mg of the product as a colorless oil in a 100% yield.

[0929] 1 H NMR (400MHz, CDCl3) δ7.37–7.22(m,2H),6.92(t,J=7.6Hz,1H),4.19(d,J=13.2Hz,2H),3.12–2.9 7(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).

[0930] Step 4: Synthesis of tert-butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine-1-carboxylate

[0931] tert-Butyl 4-(2-hydroxy-3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (287 mg, 0.83 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (219 mg, 0.83 mmol) were added to N,N-dimethylformamide (5 mL) and stirred to dissolve. Potassium carbonate (345 mg, 2.50 mmol) was then added. The reaction mixture was heated to 60°C under nitrogen and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (eluent PE:EA (v / v) = 1:1) to obtain 307 mg of an off-white solid product in a 70.0% yield.

[0932] 1 H NMR (400MHz, CDCl3) 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).

[0933] Step 5: Synthesis of 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine

[0934] tert-Butyl 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine-1-carboxylate (220 mg, 0.42 mmol) was added to dioxane (4 mL) and stirred to dissolve. A 4M solution of hydrochloric acid in dioxane (4 mL) was then added. The reaction mixture was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated under reduced pressure to afford 150 mg of an off-white solid product (84.1% yield), which was used directly in the next step.

[0935] LC-MS(ESI):[M+H] + =428.3.

[0936] Step 6: Synthesis of (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0937] The compound 4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidine (150 mg, 0.35 mmol) and methyl 2-(chloromethyl)-3-(((2S)-oxetan-2-yl)methyl)benzo[d]imidazole-5-carboxylate (104 mg, 0.35 mmol) were added to N,N-dimethylformamide (5 mL) and stirred to dissolve. Potassium carbonate (243 mg, 1.76 mmol) was then added. The reaction mixture was heated to 60°C under nitrogen protection and reacted for 2 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (eluent DCM:MeOH (v / v) = 20:1) to give 150 mg of an off-white solid product in a 62.4% yield.

[0938] 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),7.88(d,J=8.0Hz,1H),7.66(dd,J=8.4,2.8 Hz,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).

[0939] Step 7: Synthesis of (S)-2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0940] Compound (S)-methyl 2-((4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.22 mmol) was added to dioxane (2 mL) and stirred to dissolve. Lithium hydroxide (46 mg, 1.10 mmol) was then dissolved in water (1 mL) and 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. The product was purified by Prep-HPLC (eluent: acetonitrile:water (v / v) = 60%) to obtain 97 mg of a white solid product with a yield of 66.0%.

[0941] 1 H NMR (400MHz, DMSO-d6) 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),5.1 2(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).

[0942] Example 38 Synthesis of (S)-2-((4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 38)

[0943] Step 1: Synthesis of tert-butyl 4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate

[0944] tert-Butyl 4-(3-fluoro-2-hydroxyphenyl)piperidine-1-carboxylate (500 mg, 1.69 mmol), 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). The mixture was allowed to react at room temperature for 2 h. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 30%) to obtain 710 mg of a colorless liquid with a yield of 81.8%.

[0945] 1 H NMR (500MHz, DMSO-d6) 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).

[0946] Step 2: Synthesis of 4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine

[0947] Tert-butyl 4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine-1-carboxylate (710 mg, 1.49 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added and reacted at room temperature for 30 minutes. The solvent was removed under reduced pressure, and the pH was adjusted to 9 with saturated sodium bicarbonate. The mixture was extracted with dichloromethane (8 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 546 mg of a white solid in a 97.3% yield.

[0948] 1 H NMR (500MHz, DMSO-d6) 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).

[0949] Step 3: Synthesis of (S)-methyl 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

[0950] The compound 4-(2-((2-chloro-4-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)piperidine (340 mg, 0.9 mmol) and (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (318 mg, 1.08 mmol) were dissolved in acetonitrile (5 mL). N,N'-diisopropylethylamine (582 mg, 4.5 mmol) was added and reacted at 60°C overnight. The solvent was removed under reduced pressure, and 10 mL of water was added. The mixture was extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography (eluent: EtOAc:PE (v / v) = 50%) was used to obtain 449 mg of a white solid in a 78.4% yield.

[0951] 1 H NMR (500MHz, DMSO-d6) 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),4.65–4.6 2(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).

[0952] Step 4: Synthesis of (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-carboxylic acid

[0953] Compound (S)-methyl 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 (0.44 g, 0.69 mmol) and lithium hydroxide monohydrate (0.09 g, 2.08 mmol) were added to 1,4-dioxane (10 mL) and water (5 mL) and reacted at 40°C for 1 h. The mixture was cooled in an ice bath, adjusted to pH 6 with trifluoroacetic acid, and extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 1:30) to afford 380 mg of the product as a pale yellow solid in an 83.2% yield.

[0954] LC-MS(ESI):[M+H] + =622.2;

[0955] 1 H NMR (500MHz, DMSO-d6) δ12.71(s,1H),8.27–8.24(m,1H),7.80(dd,J=8.4,1.6Hz,1H),7.64(d,J=8.4Hz,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=15.2,2.8Hz,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).

[0956] Example 39 Synthesis of 2-(((2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidin-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Compound 39)

[0957] Step 1: Synthesis of tert-butyl (S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

[0958] Compound (S)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (3.00 g, 13.78 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). The mixture was stirred at -78°C under a nitrogen atmosphere for 5 minutes. Lithium bis(trimethylsilyl)amide (17.9 mL, 17.92 mmol) was then added dropwise, followed by a solution of N-phenylbis(trifluoromethanesulfonyl)imide (5.53 g, 15.16 mmol) in tetrahydrofuran. The reaction was continued for 30 minutes. The mixture was quenched by addition of 50 mL of saturated ammonium chloride. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc:PE (v / v) = 10%) afforded 4.68 g of a colorless, transparent liquid in a 98.3% yield.

[0959] Step 2: Synthesis of (S)-tert-butyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0960] Tert-butyl (S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (4.68 g, 13.55 mmol), pinacol diboron (3.69 g, 14.23 mmol), tetrakistriphenylphosphine palladium (0.79 g, 0.68 mmol), and potassium acetate (2.69 g, 27.10 mmol) were added to 1,4-dioxane (80 mL) and heated to 90°C under a nitrogen atmosphere for 20 minutes. The mixture was cooled to room temperature, added with water (250 mL), extracted with ethyl acetate (15 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (EtOAc:PE (v / v) = 10%) to give 4.08 g of a colorless liquid with a yield of 93.1%.

[0961] Step 3: Synthesis of tert-butyl (S)-4-(2-(benzyloxy)-3-fluorophenyl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate

[0962] Compound (S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.26 g, 3.90 mmol), 2-(benzyloxy)-1-bromo-3-fluorobenzene (1.10 g, 3.90 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.16 g, 0.19 mmol) and potassium carbonate (1.08 g, 7.74 mmol) were added to a mixed solution of 1,4-dioxane (40 mL) and water (8 mL), and the mixture was heated to 90 ° C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature naturally, extracted with water (100 mL) and ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EtOAc:PE (v / v) = 10%) to obtain 1.23 g of a colorless transparent oil with a yield of 79.4%.

[0963] 1 H NMR (500MHz, CDCl3) 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).

[0964] Step 4: Synthesis of tert-butyl (2S)-4-(3-fluoro-2-hydroxyphenyl)-2-methylpiperidine-1-carboxylate

[0965] Compound (S)-tert-butyl 4-(2-(benzyloxy)-3-fluorophenyl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (1.23 g, 3.09 mmol) and palladium on carbon (0.24 g, mmol) were added to methanol (10 mL) and reacted at room temperature under a hydrogen atmosphere overnight. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 0.95 g of the product as a colorless, transparent oil with a yield of 99.0%.

[0966] LC-MS(ESI):[M-55] + =254.1;

[0967] 1H NMR (500MHz, CDCl3) 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).

[0968] Step 5: Synthesis of tert-butyl (2S)-4-(2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3-fluorophenyl)-2-methylpiperidine-1-carboxylate

[0969] Compound (2S)-tert-butyl 4-(3-fluoro-2-hydroxyphenyl)-2-methylpiperidine-1-carboxylate (300 mg, 0.97 mmol), 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). The mixture was reacted at room temperature for 2 h. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated u...

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), in: X1, X2 and X3 are each independently N or CR 13 ; Y1 is N or CR 14 ; Y2 is N or CR 4 ; Y3 is N or CR 5 ; Y4 is N or CR 15 ; L is O or CR 16 R 17 ; Z is O or S; R 1 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group 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 heterocyclic group and -C 1-6 Alkylene-R 18 Can be optionally replaced by 1, 2 or 3 R 1a replace; R 18 C 3-6 Cycloalkyl, 3-8 membered heterocyclyl and 5-10 membered heteroaryl; R 1a D, F, Cl, Br, I, CN, hydroxy, 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 heterocyclic group, 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 heterocyclic groups may be independently optionally substituted by 1, 2 or 3 R 1b replace; R 1b D, F, Cl, Br, I, CN, hydroxy, 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 heterocyclic group; Each R 13 are independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally substituted independently with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups; Ring B is a 5-6 membered heterocyclic group, C 5-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl; Each R b are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, 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 may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups; R 4 、R 5 、R 8 、R 9 、R 10 、R 11 、R 12 、R 14 and R 15 Each independently represents 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 may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups; n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

2. 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):

3. The compound according to claim 1 or 2, wherein R 1 H, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group 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 heterocyclic group and -C 1-3 Alkylene-R 18 Can be optionally replaced by 1, 2 or 3 R 1a replace; R 18 C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl; R 1a D, F, Cl, Br, I, CN, hydroxy, 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 heterocyclic group, 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 heterocyclic groups may be independently optionally substituted by 1, 2 or 3 R 1b replace; R 1b D, F, Cl, Br, I, CN, hydroxy, 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 heterocyclic group.

4. The compound according to any one of claims 1 to 3, wherein R 1 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, or -CH2R 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 -CH2R 18 Can be optionally replaced by 1, 2 or 3 R 1a replace; R 18 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, R 1a is D, F, Cl, Br, I, CN, hydroxy, 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, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, methylthio, N-methylamino, N-ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally replaced by 1, 2 or 3 R 1b replace; R 1b is D, F, Cl, Br, I, CN, hydroxy, 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.

5. The compound according to any one of claims 1 to 4, wherein R 1 For H, 6. The compound according to any one of claims 1 to 5, wherein each R 13 are independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro or C 1-3 Alkyl, the C 1-3 The alkyl group may be optionally substituted independently with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups; Each R b are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, 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 may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups; R 4 、R 5 、R 8 、R 9 、R 10 、R 11 、R 12 、R 14 and R 15 Each independently represents 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 The alkylamino group may be optionally substituted independently with 1, 2, or 3 F, Cl, Br, I, CN, hydroxy, amino, or nitro groups.

7. The compound according to any one of claims 1 to 6, wherein each R 13 is independently H, D, F, Cl, Br, I, CN, hydroxy, amino, nitro, methyl, ethyl, n-propyl, isopropyl, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CH2CF2CHF2, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino, N-ethylamino, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCH2CF2CHF2, -CH2OCH3, -CH2OCH2CH3, -CH2CH2OCH3, or -CH2CH2OCH2CH3; R 2 、R 3 、R 6 、R 7 、R 16 and R 17 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl or isopropyl, and the methyl, ethyl, n-propyl and isopropyl may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro groups; Each R b are independently H, D, F, Cl, Br, I, CN, hydroxy, oxo, amino, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro; R 4 、R 5 、R 8 、R 9 、R 10 、R 11 、R 12 、R 14 and R 15 Each is independently H, D, F, Cl, Br, I, CN, hydroxy, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino or N-ethylamino, and the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, N-methylamino and N-ethylamino may be independently and optionally substituted with 1, 2 or 3 F, Cl, Br, I, CN, hydroxy, amino or nitro.

8. The compound according to any one of claims 1 to 7, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8; the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

10. 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 a medicament for preventing, treating or alleviating a GLP-1 receptor agonist-mediated disease in a patient.

11. 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.

12. The use according to claim 11, wherein The diabetes mellitus is type I diabetes, type II diabetes, gestational diabetes, idiopathic type I diabetes, early-onset type II diabetes, maturity-onset diabetes of the young, atypical diabetes of the juvenile onset, malnutrition-related diabetes or latent autoimmune diabetes of the adult.