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 a medicine, and particularly relates to a novel benzo-bicyclic compound and a medicine composition containing the novel 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] CN202211021965.X, application date August 24, 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] X is N or CR 16 ;

[0015] Y is O or S;

[0016] R 2For hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, 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;

[0017] R 3 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 15 , 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 15 Can be optionally replaced by 1, 2 or 3 R 3a replace;

[0018] R 15 C 3-6 Cycloalkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl;

[0019] R 3a 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 3b replace;

[0020] R 3b 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, C3-6 Cycloalkyl or 3-6 membered heterocyclic group;

[0021] R 4 、R 5 、R 8 and R 9 Each is independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups;

[0022] Ring B is a 5-6 membered heterocyclyl, phenyl or a 5-6 membered heteroaryl;

[0023] Each R b are independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups;

[0024] R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 and R 16 Each is independently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro or C 1-6 Alkyl, the C 1-6 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups;

[0025] n is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0026] In some embodiments, the compound of the present invention has a structure represented by Formula (II), Formula (III), Formula (IV), or Formula (V):

[0027] Among them, X, Y, R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12、R 13 、R 14 、R b and n have the meanings described in the present invention.

[0028] In some embodiments, R 2 For hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy or -C 1-3 Alkylene-C 1-3 alkoxy;

[0029] R 4 、R 5 、R 8 and R 9 Each is independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano or C 1-3 Alkyl, the C 1-3 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups;

[0030] Each R b are independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano or C 1-3 Alkyl, the C 1-3 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups;

[0031] R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 and R 16 Each is independently H, D, F, Cl, Br, I, hydroxyl, cyano, 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, hydroxy, cyano, amino or nitro groups.

[0032] In some embodiments, R 2is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, 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;

[0033] R 4 、R 5 、R 8 and R 9 are each independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano, 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, hydroxy, cyano, amino or nitro;

[0034] Each R b is independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl groups are independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups;

[0035] R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 and R 16 Each is independently H, D, F, Cl, Br, I, hydroxy, cyano, 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, hydroxy, cyano, amino or nitro groups.

[0036] In some embodiments, R 3 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 15 , the C 1-3 Alkyl, C 2-3Alkenyl, C 2-3 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C 1-3 Alkylene-R 15 Can be optionally replaced by 1, 2 or 3 R 3a replace;

[0037] R 15 C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl;

[0038] R 3a 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 3b replace;

[0039] R 3b 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.

[0040] In some embodiments, R 3 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, or -CH2R 15 , the methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl and -CH2R 15 Can be optionally replaced by 1, 2 or 3 R 3a replace;

[0041] R 15is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl,

[0042] R 3a 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, 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, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally replaced by 1, 2 or 3 R 3b replace;

[0043] R 3b 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, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

[0044] In some embodiments, R 3 For H,

[0045] 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:

[0046] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] In another aspect, the present invention relates to methods for preparing, isolating and purifying the compounds encompassed by formula (I).

[0051] 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.

[0052] Definitions and General Terms

[0053] 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.

[0054] 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.

[0055] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0056] 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.

[0057] As used herein, the term "alkyl" includes 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, saturated linear or branched monovalent hydrocarbon groups, wherein the alkyl groups 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 (- 2), 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)CH2CH3), 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 both 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 include, but are not limited to, methylene, ethylene, and isopropylene.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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)-.

[0062] The term "halogen" refers to F, Cl, Br or I.

[0063] The term "deuterium" refers to heavy hydrogen, D.

[0064] As used herein, the term "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] The term "cycloalkyl" or "cycloalkane" refers to a monovalent or multivalent saturated 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, a cycloalkyl group contains 3-10 carbon atoms; in another embodiment, a cycloalkyl group contains 3-8 carbon atoms; and in yet another embodiment, a cycloalkyl group contains 3-6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0069] 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-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedione. 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used throughout this document, “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.

[0079] 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.

[0080] 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.

[0081] "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 as the compound of formula (I). 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 a compound, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0082] 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, (+), and (-) are used to designate the sign of rotation of plane-polarized light in a compound. (-) or l indicates that the compound is levorotatory, and the prefix (+) or d indicates that 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.

[0083] 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.

[0084] 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.

[0085] The "hydrate" of the present invention refers to an association compound formed when the solvent molecule is water.

[0086] 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.

[0087] "Esters" herein refer to esters of compounds of formula (I) containing hydroxy groups that are hydrolyzable in vivo. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol. Examples of in vivo hydrolyzable esters of compounds of formula (I) containing hydroxy groups include, but are not limited to, phosphate, acetoxymethoxy, 2,2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, phenylacetyl, alkoxycarbonyl, dialkylcarbamoyl, and N-(dialkylaminoethyl)-N-alkylcarbamoyl groups.

[0088] 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).

[0089] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, 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.

[0090] 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.

[0091] The term "GLP-1 receptor agonist" as used herein refers to a substance that can agonize the activity of the GLP-1 receptor.

[0092] General synthesis process

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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).

[0101] 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.

[0102] 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.

[0103] The following abbreviations are used throughout the present invention: PE petroleum ether EtOAc 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 nanomolar / liter HEPES 4-hydroxyethylpiperazineethanesulfonic acid BSA bovine serum albumin IBMX phosphodiesterase inhibitor HBSS Hank's balanced salt solution nL nanoliter

[0104] The following reaction schemes describe the steps for preparing the compounds of the present invention. Ring B' and Ring B" are 5-6 membered heterocyclic groups containing nitrogen atoms. Unless otherwise specified, each of Ring B, X, R 2 、R 6 、R 7 、R 10 、R 11 、R 12 、R 14 、R 15 、R b and n have the same meanings as those described in the present invention. Boc is a commonly used protecting group tert-butyloxycarbonyl.

[0105] Reaction Scheme 1

[0106] The compound represented by formula (9) 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). The compound represented by formula (7) reacts with the compound represented by formula (8) to obtain the compound represented by formula (9).

[0107] Reaction Scheme 2

[0108] The compound represented by formula (11) can be prepared by reaction scheme 2: the compound represented by formula (10) is oxidized to obtain the compound represented by formula (11).

[0109] Reaction Scheme 3

[0110] The compound represented by formula (19) can be prepared by reaction scheme 3: the compound represented by formula (12) and the compound represented by formula (13) react to obtain the compound represented by formula (14). The compound represented by formula (14) reacts under acidic conditions to obtain the compound represented by formula (15). The compound represented by formula (15) reacts with di-tert-butyl dicarbonate to obtain the compound represented by formula (16). The compound represented by formula (16) is reduced to obtain the compound represented by formula (17). The compound represented by formula (17) reacts with the compound represented by formula (11) to obtain the compound represented by formula (18). The compound represented by formula (18) reacts with 2-chloro-1,1,1-trimethoxyethane to obtain the compound represented by formula (19).

[0111] Reaction Scheme 4

[0112] The compound represented by formula (24) can be prepared by reaction scheme 4: the compound represented by formula (9) is reacted with the compound represented by formula (20) to obtain the compound represented by formula (21). The compound represented by formula (21) is subjected to N-boc removal to obtain the compound represented by formula (22). The compound represented by formula (22) is reacted with the compound represented by formula (19) to obtain the compound represented by formula (23). The compound represented by formula (23) is hydrolyzed to obtain the compound represented by formula (24).

[0113] Reaction Scheme 5

[0114] The compound represented by formula (25) can be prepared by reaction scheme 5: the compound represented by formula (5) and the compound represented by formula (8) react to obtain the compound represented by formula (25).

[0115] Reaction Scheme 6

[0116] The compound represented by formula (21) can also be prepared by reaction scheme 6: the compound represented by formula (6) is reacted with the compound represented by formula (26) to obtain the compound represented by formula (27). The compound represented by formula (27) is reacted with the compound represented by formula (25) to obtain the compound represented by formula (21).

[0117] Reaction Scheme 7

[0118] The compound represented by formula (31) can be prepared by reaction scheme 7: The compound represented by formula (27) is reacted with the compound represented by formula (5) to obtain the compound represented by formula (28). The compound represented by formula (28) is subjected to N-Boc removal to obtain the compound represented by formula (29). The compound represented by formula (29) is reacted with the compound represented by formula (19) to obtain the compound represented by formula (30). The compound represented by formula (30) is hydrolyzed to obtain the compound represented by formula (31).

[0119] Reaction Scheme 8

[0120] The compound represented by formula (40) can be prepared by reaction scheme 8: The compound represented by formula (6) is reacted with benzyl bromide to obtain the compound represented by formula (32). The compound represented by formula (32) is reacted with the compound represented by formula (33) to obtain the compound represented by formula (34). The compound represented by formula (34) is debenzylated to obtain the compound represented by formula (35). 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 de-N-Bocated to obtain the compound represented by formula (38). The compound represented by formula (38) is reacted with the compound represented by formula (19) to obtain the compound represented by formula (39). The compound represented by formula (39) is hydrolyzed to obtain the compound represented by formula (40).

[0121] Reaction Scheme 9

[0122] The compound represented by formula (42) can be prepared by reaction scheme 9: methyl 2-hydroxyacetate and tert-butyldiphenylsilyl chloride react to obtain the compound represented by formula (41). The compound represented by formula (41) reacts with ammonia to obtain the compound represented by formula (42).

[0123] Reaction Scheme 10

[0124] The compound represented by formula (19) can also be prepared by reaction scheme 10: the compound represented by formula (43) is brominated to obtain the compound represented by formula (44). The compound represented by formula (44) is reacted with the compound represented by formula (42) to obtain the compound represented by formula (45). The compound represented by formula (45) is brominated to obtain the compound represented by formula (46). The compound represented by formula (46) is reacted with Lawesson's reagent to obtain the compound represented by formula (47). The compound represented by formula (47) is reacted with the compound represented by formula (48) to obtain the compound represented by formula (49). The compound represented by formula (49) is intramolecularly cyclized to obtain the compound represented by formula (50). The compound represented by formula (50) is deprotected from TBDPS to obtain the compound represented by formula (51). The compound represented by formula (51) is chlorinated to obtain the compound represented by formula (19).

[0125] Reaction Scheme 11

[0126] The compound represented by formula (59) can also be prepared by the reaction scheme 11: the compound represented by formula (51) is reacted with the compound represented by formula (52) to obtain the compound represented by formula (53). The compound represented by formula (53) is reduced to obtain the compound represented by formula (54). The compound represented by formula (54) is oxidized to obtain the compound represented by formula (55). The compound represented by formula (55) is reacted with the compound represented by formula (56) to obtain the compound represented by formula (57). The compound represented by formula (57) is reacted with the compound represented by formula (36) to obtain the compound represented by formula (58). The compound represented by formula (58) is hydrolyzed to obtain the compound represented by formula (59). DETAILED DESCRIPTION

[0127] 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.

[0128] Example 1 Synthesis of (S)-2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-thiazolo[2,3-d]imidazole-5-carboxylic acid (Compound 1)

[0129] Step 1: Synthesis of 4-chloro-2-(2,2-diethoxyethoxy)-1-methylbenzene

[0130] 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%.

[0131] 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).

[0132] Step 2: Synthesis of 4-chloro-7-methylbenzofuran

[0133] 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.

[0134] 1 HNMR (500MHz, CDCl3) δ7.63(d,J=2.3Hz,1H),7.12(d,J=7.9Hz,1H),7.00(d,J=7.9Hz,1H),6.84(d,J=2.3Hz,1H),2.48(s,3H).

[0135] Step 3: Synthesis of 7-(bromomethyl)-4-chlorobenzofuran

[0136] 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%.

[0137] 1 HNMR(500MHz, CDCl3)δ7.71(s,1H),7.24–7.20(m,2H),6.89(s,1H),4.75(s,2H).

[0138] Step 4: Synthesis of 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine

[0139] 7-(Bromomethyl)-4-chlorobenzofuran (600 mg, 2.44 mmol), 2-bromo-6-pyridine (467 mg, 2.68 mmol), and potassium carbonate (675 mg, 4.88 mmol) were added to N,N-dimethylformamide (6 mL) and reacted at 60°C for 1.5 h. After cooling to room temperature, water (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: EtOAc:PE (v / v) = 8%) to give 756 mg of the product as a white solid in a 91.4% yield.

[0140] 1 HNMR(500MHz, CDCl3)δ7.68(s,1H),7.41(td,J=7.9,2.9Hz,1H),7.36(dd,J=8.0,2.8Hz,1H),7.27 –7.21(m,1H),7.08(dd,J=7.5,2.9Hz,1H),6.88(s,1H),6.73(dd,J=8.2,2.9Hz,1H),6.54(s,2H).

[0141] Step 5: Synthesis of 2-bromo-6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridine

[0142] The compound 2-bromo-6-((4-chlorobenzofuran-7-yl)methoxy)pyridine (600 mg, 1.77 mmol) and N-fluorobisbenzenesulfonamide (670 mg, 2.12 mmol) were added to anhydrous tetrahydrofuran (30 mL), cooled to -40°C under nitrogen, and a solution of lithium diisopropylamide in tetrahydrofuran (2.0 mol / L) (1.4 mL, 2.80 mmol) was added. The reaction was allowed to react at this temperature for 3 h. Water (50 mL) was added, and the mixture was extracted with dichloromethane (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: EtOAc:PE (v / v) = 10%) to obtain 211 mg of the product as a white solid in a yield of 33.4%.

[0143] 1 HNMR(500MHz, CDCl3)δ7.43(t,J=7.8Hz,1H),7.33(d,J=8.1Hz,1H),7.25(d,J=8.5Hz, 1H),7.09(d,J=7.5Hz,1H),6.74(d,J=8.1Hz,1H),6.01(d,J=6.7Hz,1H),5.57(s,2H).

[0144] Step 6: Synthesis of methyl 5-((2,4-dimethoxybenzyl)amino)-4-nitrothiophene-2-carboxylate

[0145] Methyl 5-bromo-4-nitrothiophene-2-carboxylate (4 g, 15.03 mmol) and potassium carbonate (8.31 g, 60.14 mmol) were added to acetonitrile (60 mL). 2,4-Dimethoxybenzylamine (3.52 g, 21.04 mmol) was added with stirring and the mixture was allowed to react at room temperature for 3 h. Water (800 mL) was added to precipitate a large amount of solid, which was filtered and the filter cake was dissolved in dichloromethane (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5.2 g of a light yellow solid product with a yield of 98.2%.

[0146] LC-MS(ESI):[M+H] + =353.2;

[0147] 1 HNMR (500MHz, CDCl3) δ8.87 (br.s, 1H), 7.98 (s, 1H), 7.19 (d, J = 8.2Hz, 1H), 6. 51–6.44(m,2H),4.44(d,J=5.7Hz,2H),3.86(s,3H),3.85(s,3H),3.81(s,3H).

[0148] Step 7: Synthesis of methyl 5-amino-4-nitrophenol-2-carboxylate

[0149] Methyl 5-((2,4-dimethoxybenzyl)amino)-4-nitrothiophene-2-carboxylate (5.2 g, 14.76 mmol) was dissolved in dichloromethane (80 mL). Trifluoroacetic acid (8 mL) was added with stirring and the mixture was allowed to react at room temperature overnight. The solvent was removed under reduced pressure, and water (50 mL) was added. The pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with tetrahydrofuran (50 mL) and ethyl acetate (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.9 g of a light yellow solid product with a yield of 97.2%.

[0150] LC-MS(ESI):[M+H] + =203.1;

[0151] 1 HNMR(500MHz,DMSO-d6)δ9.01(br.s,2H),7.75(s,1H),3.77(s,3H).

[0152] Step 8: Synthesis of methyl 5-((tert-butoxycarbonyl)amino)-4-nitrothiophene-2-carboxylate

[0153] Methyl 5-amino-4-nitrophenol-2-carboxylate (1.8 g, 8.90 mmol) was dissolved in tetrahydrofuran (10 mL), and di-tert-butyl dicarbonate (4.86 g, 22.26 mmol) and N,N-diisopropylethylamine (2.88 g, 22.26 mmol) were added. The mixture was reacted at 60°C overnight. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (25 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) = 1:8) to obtain 2.3 g of a light yellow solid product with a yield of 85.5%.

[0154] LC-MS(ESI):[M-55] + =247.1;

[0155] 1 HNMR (500MHz, CDCl3) δ10.12(s,1H),8.09(s,1H),3.89(s,3H),1.58(s,9H).

[0156] Step 9: Synthesis of methyl 4-amino-5-((tert-butoxycarbonyl)amino)thiophene-2-carboxylate

[0157] The compound 5-((tert-Butyloxycarbonyl)amino)-4-nitrothiophene-2-carboxylic acid methyl ester (3.5 g, 11.58 mmol), iron powder (3.23 g, 57.89 mmol), and ammonium chloride (1.24 g, 23.16 mmol) were added to a mixed solvent of methanol (60 mL) and water (20 mL) and reacted at 40°C overnight. The mixture was filtered through celite, and the filter cake was washed with methanol (25 mL x 2). The filtrate was concentrated under reduced pressure to remove methanol, and extracted with dichloromethane (25 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) = 45%) to obtain 3.1 g of the product as a light brown viscous solid in a yield of 98.3%.

[0158] LC-MS(ESI):[M-55] + =217.1;

[0159] 1 HNMR(500MHz,DMSO-d6)δ9.64(s,1H),7.14(s,1H),4.72(s,2H),3.72(s,3H),1.48(s,9H).

[0160] Step 10: Synthesis of (S)-methyl 5-((tert-butoxycarbonyl)amino)-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate

[0161] Compound (S)-oxetane-2-ylmethanol (1.0 g, 11.35 mmol) was added to dichloromethane (25 mL), cooled in an ice bath, and Dess-Martin reagent (7.22 g, 17.03 mmol) was added. The reaction was allowed to react at room temperature overnight. Filtered through celite, the filter cake was washed with dichloromethane (25 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a white solid. This was washed with a mixture of EtOAc:PE (v / v) = 1:1 (20 mL x 2), and the filtrate was concentrated under reduced pressure to obtain 1.06 g of (S)-oxetane-2-carbaldehyde as a white solid.

[0162] The compound 4-amino-5-((tert-butoxycarbonyl)amino)thiophene-2-carboxylic acid methyl ester (260 mg, 0.95 mmol) and (S)-oxetane-2-carbaldehyde (411 mg, 1.91 mmol) were added to dichloromethane (10 mL), and 3 drops of glacial acetic acid were added. The mixture was stirred at room temperature for 20 min, and sodium triacetoxyborohydride (443 mg, 2.10 mmol) was added and reacted at room temperature for 1 h. Water (30 mL) was added and the mixture was extracted with dichloromethane (10 mL×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) = 33%) to obtain 177 mg of light brown liquid product with a yield of 54.1%.

[0163] LC-MS(ESI):[M+H] + =343.3;

[0164] 1 HNMR(500MHz, CDCl3)δ7.39(s,1H),4.98–4.90(m,1H),4.77–4.70(m,1H),4.66–4.58(m, 1H),3.82(s,3H),3.32–3.19(m,2H),2.73–2.64(m,1H),2.62–2.42(m,1H),1.52(s,9H).

[0165] Step 11: Synthesis of (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0166] Compound (S)-methyl 5-((tert-butoxycarbonyl)amino)-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (980 mg, 2.86 mmol) was dissolved in tetrahydrofuran (15 mL), and 2-chloro-1,1,1-trimethoxyethane (885 mg, 5.72 mmol) and p-toluenesulfonic acid monohydrate (28 mg, 0.15 mmol) were added. The mixture was reacted at 75°C for 2.5 h. The solvent was removed by concentration under reduced pressure, and the product was purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:2) to give 623 mg of the product as a light brown liquid in a yield of 72.4%.

[0167] LC-MS(ESI):[M+H] + =301.1;

[0168] 1 HNMR(500MHz, CDCl3)δ7.71(s,1H),5.22–5.16(m,1H),4.93–4.87(m,2H),4.66–4.63(m,1H),4.48 –4.39(m,2H),4.36–4.31(m,1H),3.90(s,3H),2.78–2.72(m,1H),2.45–2.38(m,1H).

[0169] Step 12: Synthesis of tert-butyl 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0170] Compound N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (599 mg, 1.94 mmol), 2-bromo-6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridine (460 mg, 1.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (106 mg, 0.13 mmol) and potassium carbonate (535 mg, 3.87 mmol) was added to a mixed solvent of 1,4-dioxane (6 mL) and water (1.5 mL), reacted at 90 ° C for 2 h under nitrogen protection, cooled to room temperature, added with water (50 mL), extracted with ethyl acetate (15 mL × 3), and 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) = 15%) to obtain 436 mg of colorless oily product with a yield of 73.6%.

[0171] LC-MS(ESI):[M+H] + =459.3;

[0172] 1 HNMR (500MHz, CDCl3) δ7.55(t,J=7.8Hz,1H),7.31(d,J=8.2Hz,1H),7.25(d,J=8.2Hz,1H),6.95(d,J=7.3Hz,1H),6.69(s,1H),6 .67(d,J=8.4Hz,1H),6.01(d,J=6.6Hz,1H),5.62(s,2H),4.14–4.10(m,2H),3.67–3.60(m,2H),2.61–3.54(m,2H),1.49(s,9H).

[0173] Step 13: Synthesis of 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine

[0174] The compound 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (420 mg, 0.92 mmol) was dissolved in dichloromethane (4 mL), and a 4 mol / L hydrogen chloride solution in 1,4-dioxane (3 mL) was added. The reaction was carried out at room temperature for 30 min. The solvent was removed under reduced pressure, and a saturated sodium bicarbonate solution 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 326 mg of a light brown solid product with a yield of 99.3%.

[0175] LC-MS(ESI):[M+H] +=359.2.

[0176] Step 14: Synthesis of (S)-methyl 2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0177] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (170 mg, 0.57 mmol), 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine (320 mg, 0.89 mmol), potassium iodide (19 mg, 0.11 mmol), and potassium carbonate (235 mg, 1.70 mmol) were added to acetonitrile (4 mL) and reacted at 50°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 mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 80%) to give 81 mg of the product as a pale yellow solid in a yield of 23.0%.

[0178] LC-MS(ESI):[M+H] + =623.3.

[0179] Step 15: Synthesis of (S)-2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thiazolo[2,3-d]imidazole-5-carboxylic acid

[0180] Compound (S)-methyl 2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (80 mg, 0.13 mmol) and lithium hydroxide monohydrate (27 mg, 0.64 mmol) were added to a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL) and reacted at 40°C for 1 h. The mixture was cooled in an ice bath, adjusted to pH 6 with hydrochloric acid, and extracted with ethyl acetate (15 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a silica gel prep plate (eluent: MeOH:DCM (v / v) = 5%) to afford 7 mg of a white solid product in a 9.0% yield.

[0181] LC-MS(ESI):[M+H] + =609.3;

[0182] 1 HNMR (500MHz, CDCl3) δ7.61 (s, 1H), 7.54 (t, J = 7.6Hz, 1H), 7.30 (d, J = 8.2Hz, 1H), 7. 22(d,J=8.3Hz,1H),6.94(d,J=7.4Hz,1H),6.71–6.64(m,2H),5.99(d,J=6.6Hz,1H) ,5.60(s,2H),5.16–5.09(m,1H),4.62–4.49(m,3H),4.38–4.32(m,1H),4.10–4.02( m,2H),3.48–3.42(m,2H),3.00–2.93(m,2H),2.70–2.63(m,2H),2.42–2.18(m,2H).

[0183] Example 2 Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 2)

[0184] Step 1: Synthesis of 7-(bromomethyl)-4-chloro-2-fluorobenzofuran

[0185] 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. A solution of lithium diisopropylamide in tetrahydrofuran (9 mL, 18 mmol, 2.0 mol / L) 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 yield of 14.3%.

[0186] 1 HNMR (500MHz, CDCl3) δ7.24–7.20 (m, 2H), 6.01 (d, J = 6.6Hz, 1H), 4.65 (s, 2H).

[0187] Step 2: Synthesis of tert-butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0188] The compound N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid (4.0 g, 23.0 mmol), 2-bromo-6-hydroxypyridine (5.2 g, 23.0 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (940 mg, 1.15 mmol) and potassium carbonate (6.35 g, 45.98 mmol) were added to a mixed solvent of 1,4-dioxane (80 mL) and water (20 mL). The reaction was carried out at 90°C under nitrogen for 2 h. The mixture was cooled to room temperature, water (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 MeOH:DCM (v / v) = 5%) to give 5.87 g of a light yellow solid product with a yield of 92.4%.

[0189] LC-MS(ESI):[M+H] + =277.3;

[0190] 1 HNMR(500MHz,DMSO-d6)δ11.18(s,1H),7.42(t,J=8.0Hz,1H),6.47(s,1H), 6.27(d,J=8.4Hz,2H),3.99(s,2H),3.48(s,2H),2.38(s,2H),1.42(s,9H).

[0191] Step 3: Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate

[0192] 6-Hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester (2.0 g, 7.24 mmol) and 10% palladium on carbon (860 mg, 40%-60% water content) were added to methanol (20 mL) and allowed to react overnight at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to afford 1.76 g of a white solid product in an 87.4% yield.

[0193] LC-MS(ESI):[M+H] + =279.2;

[0194] 1HNMR(500MHz,DMSO-d6)δ11.46(s,1H),7.33(dd,J=9.1,6.9Hz,1H),6.14(d,J=9.0Hz,1H),5.99(s,1H),4. 09–4.00(m,2H),2.80–2.64(m,2H),2.60–2.53(m,1H),1.80–1.74(m,2H),1.50–1.42(m,2H),1.40(s,9H).

[0195] Step 4: Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0196] The compound 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (150 mg, 0.57 mmol), tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (175 mg, 0.63 mmol), and potassium carbonate (236 mg, 1.71 mmol) were added to N,N-dimethylformamide (4 mL) and reacted at 60°C for 1 h. After cooling to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 15%) to give 206 mg of the product as a colorless oil with a yield of 78.4%.

[0197] LC-MS(ESI):[M+H] + =461.3;

[0198] 1 HNMR(500MHz, CDCl3)δ7.53–7.47(m,1H),7.33–7.28(m,1H),7.24–7.21(m,1H),6.74–6.70(m,1H),6.64–6.60(m,1H),6.02–5.98 (m,1H),5.58(s,2H),4.29–4.15(m,2H),2.87–2.78(m,2H),2.75–2.67(m,1H),1.90–1.82(m,2H),1.74–1.64(m,2H),1.49(s,9H).

[0199] Step 5: Synthesis of 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine

[0200] The compound tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (370 mg, 0.80 mmol) was dissolved in dichloromethane (4 mL), and a 4 mol / L solution of hydrogen chloride in 1,4-dioxane (5 mL) was added. The reaction was carried out 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 277 mg of a light brown solid product with a yield of 95.6%.

[0201] LC-MS(ESI):[M+H] + =361.2.

[0202] Step 6: Synthesis of (S)-methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0203] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (65 mg, 0.22 mmol), 2-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine (78 mg, 0.22 mmol), potassium iodide (8 mg, 0.05 mmol), and potassium carbonate (122 mg, 0.88 mmol) were added to acetonitrile (2 mL) and reacted at 50°C for 2 h. The mixture was cooled to room temperature, and water (40 mL) was added. The mixture was extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 45%) to give 76 mg of the product as a light yellow solid in a yield of 56.3%.

[0204] LC-MS(ESI):[M+H] + =625.3;

[0205] Step 7: Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0206] Compound (S)-methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (72 mg, 0.12 mmol) and lithium hydroxide monohydrate (48 mg, 1.14 mmol) were added to a mixture of 1,4-dioxane (3 mL) and water (1.5 mL) and reacted at 40°C for 1.5 h. The mixture was cooled in an ice bath, adjusted to pH 6 with dilute hydrochloric 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) = 5%) to afford 26 mg of a white solid product. Purification on a silica gel prep plate afforded 5 mg of the desired product in a 7.1% yield.

[0207] LC-MS(ESI):[M+H] + =611.4;

[0208] 1HNMR(500MHz, CDCl3)δ7.49(t,J=7.8Hz,1H),7.40(s,1H),7.30(d,J=8.2Hz,1H ),7.20(d,J=8.3Hz,1H),6.74(d,J=7.3Hz,1H),6.61(d,J=8.2Hz,1H),5.97(d,J =6.6Hz,1H),5.56(s,2H),5.11–5.02(m,1H),4.66–4.46(m,3H),4.38–4.30(m,1 H),4.14–3.99(m,2H),3.53–3.39(m,2H),2.75–2.55(m,4H),2.46–2.28(m,5H).

[0209] Example 3 Synthesis of (S)-2-((6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-thiazolo[2,3-d]imidazole-5-carboxylic acid (Compound 3)

[0210] Step 1: Synthesis of tert-butyl 6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0211] The compound 7-(bromomethyl)-4-chlorobenzofuran (200 mg, 0.81 mmol), tert-butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (225 mg, 0.81 mmol), and potassium carbonate (337 mg, 2.44 mmol) were added to N,N-dimethylformamide (4 mL) and reacted at 60°C for 5 h. After cooling to room temperature, water (25 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to obtain 322 mg of the product as a colorless oil with a yield of 90.2%.

[0212] LC-MS(ESI):[M+H] + =441.3;

[0213] 1HNMR (500MHz, CDCl3) δ7.68(d,J=2.2Hz,1H),7.54(t,J=7.8Hz,1H),7.35(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),6.94(d,J=7.5Hz,1H ),6.89(d,J=2.2Hz,1H),6.70–6.65(m,2H),5.70(s,2H),4.14–4.09(m,2H),3.63(t,J=5.7Hz,2H),2.58(d,J=6.4Hz,2H),1.49(s,9H).

[0214] Step 2: Synthesis of 6-((4-chlorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine

[0215] The compound tert-butyl 6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (188 mg, 0.43 mmol) was dissolved in dichloromethane (4 mL), and 4 mol / L hydrogen chloride in 1,4-dioxane (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 132 mg of a light brown solid product with a yield of 90.8%.

[0216] LC-MS(ESI):[M+H] + =341.2.

[0217] Step 3: Synthesis of (S)-methyl 2-((6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0218] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (109 mg, 0.36 mmol), 6-((4-chlorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine (123 mg, 0.36 mmol), potassium iodide (12 mg, 0.07 mmol), and potassium carbonate (150 mg, 1.09 mmol) were added to acetonitrile (4 mL) and reacted at 50°C for 2 h. The mixture was cooled to room temperature, water (40 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 45%) to give 148 mg of the product as a light brown oil in a 67.8% yield.

[0219] LC-MS(ESI):[M+H] + =605.3;

[0220] 1 HNMR (500MHz, CDCl3) δ7.74(s,1H),7.66(d,J=2.2Hz,1H),7.53(t,J=7.8Hz,1H),7.34(d,J=8.0H z,1H),7.21(d,J=8.0Hz,1H),6.93(d,J=7.5Hz,1H),6.88(d,J=2.2Hz,1H),6.70–6.64(m,2H),5.6 9(s,2H),5.18–5.13(m,1H),4.63–4.50(m,3H),4.38–4.34(m,1H),3.96–3.90(m,2H),3.89(s,3H ),3.27–3.21(m,2H),2.80–2.75(m,2H),2.74–2.63(m,1H),2.60–2.55(m,2H),2.44–2.37(m,1H).

[0221] Step 4: Synthesis of (S)-2-((6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thiazolo[2,3-d]imidazole-5-carboxylic acid

[0222] Compound (S)-methyl 2-((6-((4-chlorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridinyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (140 mg, 0.23 mmol) and lithium hydroxide monohydrate (50 mg, 1.19 mmol) were added to a mixture of 1,4-dioxane (4 mL) and water (4 mL) and reacted at 40°C for 1 h. The mixture was cooled in an ice bath, adjusted to pH 6 with dilute hydrochloric acid, and 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) = 5%) to afford 116 mg of a white solid product in a yield of 79.6%.

[0223] LC-MS(ESI):[M+H] + =591.4;

[0224] 1 HNMR(500MHz,DMSO-d6)δ8.15(s,1H),7.83(s,1H),7.67(t,J=7.9Hz,1H),7.42(d,J=8.0H z,1H),7.34(d,J=8.0Hz,1H),7.09–7.02(m,2H),6.76–6.67(m,2H),5.65(s,2H),5.10–5.0 0(m,1H),4.71–4.61(m,1H),4.57–4.43(m,2H),4.39–4.31(m,1H),3.98–3.82(m,2H),3.24 –3.14(m,2H),2.79–2.67(m,2H),2.66–2.59(m,1H),2.50–2.44(m,2H),2.39–2.31(m,1H).

[0225] Example 4 Synthesis of (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 4)

[0226] Step 1: Synthesis of tert-butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate

[0227] 2-Bromo-6-hydroxypyridine (4.00 g, 22.99 mmol), [1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]boronic acid (5.22 g, 22.99 mmol), potassium carbonate (6.35 g, 45.98 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (0.94 g, 1.15 mmol) were added to a mixture of 1,4-dioxane (80 mL) and water (20 mL). Under nitrogen, the mixture was heated to 85°C for 3 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, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 5%) to afford 5.87 g of a light yellow solid in a 92.4% yield.

[0228] LC-MS(ESI):[M+H] + =277.3;

[0229] 1 H NMR(500MHz,DMSO-d6))δ11.18(s,1H),7.42(t,J=8.0Hz,1H),6.47(s,1H), 6.27(d,J=8.4Hz,2H),3.99(s,2H),3.48(s,2H),2.38(s,2H),1.42(s,9H).

[0230] Step 2: Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate

[0231] tert-Butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (2.0 g, 7.24 mmol) was added to methanol (20 mL), followed by palladium on carbon (10% Pd, containing 55% water) (0.86 g, 0.36 mmol). After replacing the hydrogen atmosphere three times, the mixture was allowed to react overnight at room temperature under a hydrogen atmosphere. Filtration through celite and removal of the solvent under reduced pressure afforded 1.76 g of a white solid in an 87.4% yield.

[0232] LC-MS(ESI):[M+H] + =279.2;

[0233] 1H NMR (500MHz, DMSO-d6)) δ11.46(s,1H),7.33(dd,J=9.1,6.9Hz,1H),6.14(d,J=9.1Hz,1H),5.99(s,1H),4.04(d,J =13.1Hz,2H),2.72(s,2H),2.58-2.54(m,1H),1.78(d,J=12.7Hz,2H),1.47(td,J=12.5,4.2Hz,2H),1.40(s,9H).

[0234] Step 3: Synthesis of tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0235] Dissolve tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (210.0 mg, 0.75 mmol) and 7-(bromomethyl)-4-chlorobenzofuran (203.7 mg, 0.83 mmol) in N,N-dimethylformamide (4.0 mL), and add potassium carbonate (312.8 mg, 2.26 mmol). Heat to 60°C and react for 5 h. Add 25 mL of water, extract with ethyl acetate (15 mL x 3), and combine the organic phases. Wash the organic phases with saturated brine (25 mL x 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify the mixture by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to obtain 324 mg of a colorless oily liquid in a 97.0% yield.

[0236] LC-MS(ESI):[M+H] + =443.3;

[0237] 1 H NMR (500MHz, CDCl3) δ7.69(d,J=2.2Hz,1H),7.49(t,J=7.7Hz,1H),7.35(d,J=7 .9Hz,1H),7.22(d,J=8.0Hz,1H),6.89(d,J=2.2Hz,1H),6.71(d,J=7.3Hz,1H), 6.62(d,J=8.2Hz,1H),5.66(s,2H),4.20(s,2H),2.82(t,J=12.8Hz,2H),2.73- 2.68(m,1H),1.83(d,J=13.0Hz,2H),1.69(dd,J=12.7,4.1Hz,2H),1.49(s,9H).

[0238] Step 4: Synthesis of 2-((4-chlorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine

[0239] Dissolve tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (300 mg, 0.68 mmol) in dichloromethane (5 mL). Add a solution of hydrogen chloride in 1,4-dioxane (1.7 mL, 4 mol / L) and react at room temperature for 30 min. The mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate solution (15 mL) was added. Extraction was performed with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 200 mg of a tan solid (86.1% yield).

[0240] LC-MS(ESI):[M+H] + =343.2.

[0241] Step 5: Synthesis of (S)-methyl 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0242] Compound (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (100 mg, 0.27 mmol), 2-((4-chlorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine (109 mg, 0.32 mmol), potassium iodide (9 mg, 0.05 mmol), and potassium carbonate (110 mg, 0.80 mmol) were added to acetonitrile (4 mL) and reacted at 50°C for 2 h. The mixture was cooled to room temperature, water (10 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: EtOAc:PE (v / v) = 35%) to give 83 mg of the product as a tan oil in a 51.4% yield.

[0243] LC-MS(ESI):[M+H] + =607.3;

[0244] 1HNMR (500MHz, CDCl3) δ7.75(s,1H),7.67(d,J=2.2Hz,1H),7.49(t,J=7.7Hz,1H),7.35(d,J=7.9Hz,1H),7.21(d,J=8.0Hz ,1H),6.89(d,J=2.2Hz,1H),6.72(d,J=7.3Hz,1H),6.62(d,J=8.2Hz,1H),5.66(s,2H),5.21–5.17(m,1H),4.61(td,J=8. 0,6.0Hz,1H),4.54(t,J=3.6Hz,1H),4.38(dd,J=9.2,5.9Hz,1H),3.89(s,3H),3.81(s,2H),3.49(s,1H),3.01–2.91(m,2 H),2.76–2.66(m,1H),2.66–2.57(m,1H),2.49–2.39(m,1H),2.25(q,J=12.4Hz,2H),1.88(s,2H),1.81(t,J=12.3Hz,2H).

[0245] Step 6: Synthesis of (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0246] Compound (S)-methyl 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxypyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (70 mg, 0.12 mmol) and lithium hydroxide monohydrate (25 mg, 0.60 mmol) were added to a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL) and reacted at 40°C for 1 h. The mixture was cooled in an ice bath, adjusted to pH 6 with 2 M aqueous acetic acid, and 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) = 5%) to give 41 mg of a white solid product with a yield of 60.0%.

[0247] LC-MS(ESI):[M+H] + =593.4;

[0248] 1HNMR(500MHz, CDCl3)δ7.65(s,1H),7.52–7.39(m,2H),7.33(d,J=8.1Hz,1H),7 .19(d,J=7.9Hz,1H),6.85(s,1H),6.72(d,J=7.2Hz,1H),6.61(d,J=8.3Hz,1H), 5.63(s,2H),5.06(s,1H),4.54–4.48(m,3H),4.33(s,1H),4.06–4.00(m,2H),3 .39(d,J=33.2Hz,2H),2.74–2.68(m,3H),2.40–2.30(m,2H),2.06–1.93(m,4H).

[0249] Example 5 Synthesis of (S)-2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 5)

[0250] Step 1: Synthesis of tert-butyl 4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0251] 2-Chloro-4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine (320 mg, 1.02 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (380 mg, 1.23 mmol), potassium carbonate (424 mg, 3.07 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (84 mg, 0.10 mmol) were added to a mixture of 1,4-dioxane (8 mL) and water (2 mL). Under nitrogen, the mixture was heated to 95°C for 4 h. The reaction was quenched by adding water (10 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined. The residue was dried over anhydrous sodium sulfate, filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 15%) to obtain 236 mg of a white solid with a yield of 50.2%.

[0252] LC-MS(ESI):[M+H] + =460.3;

[0253] 1H NMR (500MHz, CDCl3) δ8.28(d,J=2.5Hz,1H),7.70(d,J=2.2Hz,1H),7.36(d,J=8.0Hz,1H),7.25(d,J=7.8Hz,1H),7.04(d ,J=4.9Hz,1H),6.91(d,J=2.2Hz,1H),5.81(s,2H),4.16–4.12(m,2H),3.60(t,J=5.6Hz,2H),2.64(s,2H),1.49(s,9H).

[0254] Step 2: Synthesis of 4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine

[0255] Compound 4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (220 mg, 0.48 mmol) was added to dichloromethane (3 mL), and trifluoroacetic acid (1.53 g, 13.46 mmol) was added under ice bath. The reaction was returned to room temperature and reacted for 20 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 171 mg of a light yellow solid with a yield of 99.4%.

[0256] LC-MS(ESI):[M+H] + =360.1.

[0257] Step 3: Synthesis of (S)-2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester

[0258] Compound (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (85 mg, 0.23 mmol), 4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (80 mg, 0.22 mmol), potassium iodide (10 mg, 0.06 mmol) and potassium carbonate (120 mg, 0.87 mmol) were added to acetonitrile (10 mL) and reacted at 50 °C for 2 h. The mixture was cooled to room temperature, and water (10 mL) was added. The mixture was 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 EtOAc:PE (v / v) = 50%) to give 110 mg of a yellow oily product with a yield of 79.3%.

[0259] LC-MS(ESI):[M+H] + =624.3;

[0260] 1 HNMR(500MHz, CDCl3)δ8.27(d,J=2.6Hz,1H),7.74(s,1H),7.67(d,J=2.2Hz,1H),7.34(d, J=8.0Hz,1H),7.24(d,J=7.9Hz,1H),7.02(s,1H),6.90(d,J=2.2Hz,1H),5.79(s,2H),5.21 –5.09(m,1H),4.65–4.57(m,1H),4.56–4.47(m,2H),4.40–4.33(m,1H),3.94(d,J=9.8Hz,2 H),3.89(s,3H),3.27(s,2H),2.77(d,J=6.3Hz,2H),2.72–2.55(m,3H),2.45–2.35(m,1H).

[0261] Step 4: Synthesis of (S)-2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0262] Compound (S)-methyl 2-((4-(4-((4-chlorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (100 mg, 0.16 mmol) and lithium hydroxide monohydrate (40 mg, 0.95 mmol) were added to a mixed solvent of 1,4-dioxane (5 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 2M aqueous acetic 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) = 5%) to afford 62 mg of a pale yellow solid product in a 63.4% yield.

[0263] LC-MS(ESI):[M+H] + =610.3;

[0264] 1 HNMR(500MHz,DMSO-d6)δ8.57(s,1H),8.18(s,1H),7.70(s,1H),7.48(d,J=8.1Hz,1H),7 .39(d,J=8.1Hz,1H),7.05(d,J=15.6Hz,2H),5.82(s,2H),5.04(d,J=7.9Hz,1H),4.66–4 .58(m,1H),4.54–4.45(m,2H),4.38–4.33(m,1H),3.92(d,J=13.6Hz,1H),3.84(d,J=13. 7Hz,1H),3.48–3.39(m,2H),3.26–3.22(m,2H),2.73–2.59(m,3H),2.36(t,J=9.2Hz,1H).

[0265] Example 6 Synthesis of (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 6)

[0266] Step 1: Synthesis of methyl (4-chloro-2-fluorobenzofuran-7-yl)acetate

[0267] Compound 7-(Bromomethyl)-4-chloro-2-fluorobenzofuran (0.60 g, 2.28 mmol) was added to N,N-dimethylformamide (12 mL), followed by potassium acetate (1.10 g, 11.21 mmol). The reaction was allowed to react at 50°C for 1.5 h. The reaction was quenched by the addition of water (100 mL), and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (15 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:20) to obtain 340 mg of a light yellow liquid in a 61.5% yield.

[0268] Step 2: Synthesis of (4-chloro-2-fluorobenzofuran-7-yl)methanol

[0269] Methyl (4-chloro-2-fluorobenzofuran-7-yl)acetate (340 mg, 1.40 mmol) was added to a mixture of 1,4-dioxane (9 mL) and water (3 mL), followed by lithium hydroxide monohydrate (177 mg, 4.22 mmol). The mixture was allowed to react at room temperature for 2 h. The mixture was diluted with water (6 mL) and extracted three times with ethyl acetate (3 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: EtOAc:PE (v / v) = 20%) to obtain 222 mg of a white solid in a 79.0% yield.

[0270] 1 H NMR (500MHz, CDCl3) δ7.24 (s, 2H), 6.00 (d, J = 6.6Hz, 1H), 4.92 (d, J = 6.1Hz, 2H).

[0271] Step 3: Synthesis of 2-chloro-4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine

[0272] Dissolve (4-chloro-2-fluorobenzofuran-7-yl)methanol (222 mg, 1.11 mmol) and 2,4-dichloro-5-fluoropyrimidine (194 mg, 1.16 mmol) in acetonitrile (10 mL). Add cesium carbonate (545 mg, 1.67 mmol) under ice-cooling. Warm to room temperature and react for 14 h. Filter through celite, and concentrate the filtrate. Purify by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to obtain 318 mg of a white solid in 86.8% yield.

[0273] LC-MS(ESI):[M+H] + =331.1;

[0274] 1H NMR (500MHz, DMSO-d6) δ8.64(d,J=2.6Hz,1H),7.50(d,J=8.2Hz,1H),7.46(d,J=8.3Hz,1H),6.55(d,J=6.4Hz,1H),5.73(s,2H).

[0275] Step 4: Synthesis of tert-butyl 4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0276] 2-Chloro-4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidine (318 mg, 0.96 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (357 mg, 1.15 mmol), potassium carbonate (398 mg, 2.88 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (78 mg, 0.10 mmol) were added to a mixture of 1,4-dioxane (8 mL) and water (2 mL). Under nitrogen, the mixture was heated to 95°C for 4.5 h. The reaction was quenched by the addition of water (10 mL), and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined. The residue was dried over anhydrous sodium sulfate, filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 15%) to obtain 290 mg of a white solid with a yield of 63.2%.

[0277] LC-MS(ESI):[M+H] + =478.2;

[0278] 1 H NMR (500MHz, CDCl3) δ8.29(d,J=2.5Hz,1H),7.32(d,J=8.2Hz,1H),7.26(d,J=5.5Hz,1H),7.07(s,1H),6. 03(d,J=6.6Hz,1H),5.73(s,2H),4.15(d,J=3.6Hz,2H),3.61(t,J=5.8Hz,2H),2.65(s,2H),1.49(s,9H).

[0279] Step 5: Synthesis of 4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine

[0280] Compound 4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (250 mg, 0.52 mmol) was added to dichloromethane (4 mL), and trifluoroacetic acid (1.92 g, 16.84 mmol) was added under ice bath. The reaction was returned to room temperature and reacted for 20 minutes. Saturated sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 192 mg of a light pink solid with a yield of 97.2%.

[0281] LC-MS(ESI):[M+H] + =378.2;

[0282] 1 H NMR(500MHz, CDCl3)δ9.77(s,1H),8.30(s,1H),7.34–7.24(m,2H),7.09(s,1H) ),6.03(d,J=6.4Hz,1H),5.72(s,2H),3.94(s,2H),3.43(s,2H),2.96(s,2H).

[0283] Step 6: Synthesis of (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester

[0284] Compound (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (120 mg, 0.40 mmol), 4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (220 mg, 0.41 mmol), and N,N-diisopropylethylamine (264 mg, 2.04 mmol) were added to acetonitrile (7 mL) and reacted at 60°C for 11 h. The mixture was cooled to room temperature, and water (20 mL) was added. 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 EtOAc:PE (v / v) = 35%) to give 234 mg of a yellow solid product with a yield of 89.4%.

[0285] LC-MS(ESI):[M+H] + =642.4.

[0286] Step 7: Synthesis of (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0287] Compound (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (234 mg, 0.36 mmol) and lithium hydroxide monohydrate (77 mg, 1.84 mmol) were added to a mixed solvent of 1,4-dioxane (6 mL) and water (3 mL) and reacted at 40°C for 1.5 h. The mixture was cooled in an ice bath, adjusted to pH 6 with 2 M aqueous acetic acid solution, extracted with ethyl acetate (15 mL x 3), and 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) = 5%) to give 125 mg of a white solid product in a yield of 52.9%.

[0288] LC-MS(ESI):[M+H] + =628.3;

[0289] 1HNMR(500MHz,DMSO-d6)δ8.57(s,1H),7.80(s,1H),7.50–7.40(m,2H),7.04(s,1H) ,6.53(d,J=6.4Hz,1H),5.76(s,2H),5.04(d,J=7.6Hz,1H),4.68–4.60(m,1H),4.55– 4.45(m,2H),4.37–4.32(m,1H),3.93(d,J=13.8Hz,1H),3.85(d,J=13.7Hz,1H),3.2 5(br.s,2H),2.69(br.s,2H),2.66–2.60(m,1H),2.52(br.s,2H),2.40–2.31(m,1H).

[0290] Example 7 Synthesis of (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 7)

[0291] Step 1: Synthesis of 2-(benzyloxy)-6-bromopyridine

[0292] The compound 2-bromo-6-hydroxypyridine (1 g, 5.75 mmol), benzyl bromide (1.08 g, 6.32 mmol) and potassium carbonate (1.59 g, 11.49 mmol) were added to 10 mL of N,N-dimethylformamide and reacted at 60°C for 2 hours. TLC detection 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 1.12 g of colorless oily product with a yield of 73.8%.

[0293] LC-MS(ESI):[M+H] + =264.2;

[0294] 1 H NMR (500MHz, CDCl3) δ7.34–7.23(m,5H),7.16(dd,J=9.2,7.1Hz,1H),6.58(dd,J=9.2,1.3Hz,1H),6.48(dd,J=7.3,1.3Hz,1H),5.52(s,2H).

[0295] Step 2: Synthesis of tert-butyl 4-(6-(benzyloxy)pyridin-2-yl)piperazine-1-carboxylate

[0296] 2-(Benzyloxy)-6-bromopyridine (6 g, 22.72 mmol), tert-butyl piperazine-1-carboxylate (8.46 g, 45.44 mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (2.83 g, 4.54 mmol), tris(dibenzylideneacetone)dipalladium (2.08 g, 2.27 mmol), and potassium tert-butoxide (5.1 g, 45.44 mmol) were added to a 50 mL toluene solution. The atmosphere was replaced with nitrogen three times and the mixture was allowed to react at 100°C for 20 minutes. The reaction was complete upon TLC analysis. 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) = 10%) to afford 7.92 g of the product as a colorless oil in a 94.4% yield.

[0297] LC-MS(ESI):[M+H] + =370.3

[0298] 1H NMR(500MHz, CDCl3)δ7.46–7.38(m,3H),7.35(t,J=7.6Hz,2H),7.31–7.26(m, 1H), 6.16 (dd, J=7.9, 4.2Hz, 2H), 5.32 (s, 2H), 3.55–3.46 (m, 8H), 1.48 (s, 9H).

[0299] Step 3: Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate

[0300] tert-Butyl 4-(6-(benzyloxy)pyridin-2-yl)piperazine-1-carboxylate (700 mg, 1.89 mmol) and palladium on carbon (350 mg) were added to 10 mL of methanol, replaced with hydrogen three times, and stirred at room temperature overnight. TLC confirmed the complete reaction and stopped the reaction. Filtered through celite, the filtrate was concentrated under reduced pressure to yield 0.643 g of a brown solid product in a 72.8% yield.

[0301] LC-MS(ESI):[M+H] + =280.2.

[0302] Step 4: Synthesis of tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate

[0303] tert-Butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate (140 mg, 0.5 mmol), 7-(bromomethyl)-4-chlorobenzofuran (122 mg, 0.5 mmol), and potassium carbonate (137 mg, 0.99 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 145 mg of the product as a colorless oil in a 65.7% yield.

[0304] 1 H NMR (500MHz, CDCl3) δ7.67(d,J=2.3Hz,1H),7.41(t,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),7.21(d,J=8 .0Hz,1H),6.89(d,J=2.2Hz,1H),6.16(t,J=8.1Hz,2H),5.61(s,2H),3.51–3.38(m,8H),1.48(s,9H).

[0305] Step 5: Synthesis of 1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine

[0306] Tert-butyl 4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate (412 mg, 0.93 mmol) was added to trifluoroacetic acid (4 mL) and dichloromethane (4 mL) and stirred at room temperature for 30 minutes. The reaction was terminated by TLC analysis of the complete disappearance of the starting material. 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 286 mg of a brown solid product with a yield of 89.6%, which was used directly in the next reaction.

[0307] LC-MS(ESI):[M+H] + =344.2;

[0308] 1 H NMR (500MHz, CDCl3) δ7.66(d,J=2.3Hz,1H),7.44(t,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),7.22(d,J=8.0Hz,1H),6.8 9(d,J=2.2Hz,1H),6.22(d,J=8.0Hz,1H),6.18(d,J=7.9Hz,1H),5.60(s,2H),3.68–3.65(m,4H),3.14–3.03(m,4H).

[0309] Step 6: Synthesis of (S)-methyl 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0310] 1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine (113 mg, 0.33 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (113 mg, 0.33 mmol), and N,N-diisopropylethylamine (177 mg, 1.37 mg) were added to 10 mL of acetonitrile solution and reacted at 60°C overnight. After TLC analysis, the starting material disappeared completely. 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) = 45%) to afford 139 mg of the product as a colorless oil in an 83.5% yield.

[0311] LC-MS(ESI):[M+H] + =608.4;

[0312] 1 H NMR (500MHz, CDCl3) δ7.75 (s, 1H), 7.65 (d, J = 2.2Hz, 1H), 7.40 (t, J = 8.0Hz, 1H), 7.3 2(d,J=8.0Hz,1H),7.21(d,J=7.9Hz,1H),6.87(d,J=2.3Hz,1H),6.15(dd,J=8.0,3. 5Hz,2H),5.59(s,2H),5.22–5.16(m,1H),4.67–4.60(m,1H),4.54–4.49(m,2H),4.4 1–4.35(m,1H),3.89(s,3H),3.83(d,J=4.2Hz,2H),3.51–3.39(m,4H),2.77–2.67(m 1H),2.61–2.54(m,4H),2.48–2.39(m,1H).

[0313] Step 7: Synthesis of (S)-2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0314] (S)-methyl 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (130 mg, 0.21 mmol) and lithium hydroxide monohydrate (25.6 mg, 1.07 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 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 50 mg of the product as a white solid in a 37.5% yield.

[0315] LC-MS(ESI):[M+H] + =594.3;

[0316] 1 H NMR (500MHz, DMSO-d6) δ8.14(d,J=2.1Hz,1H),7.77(s,1H),7.45(t,J=8.0Hz,1H),7.39(d,J=8.0Hz,1 H),7.34(d,J=8.0Hz,1H),7.04(d,J=2.2Hz,1H),6.31(d,J=8.1Hz,1H),6.10(d,J=7.8Hz,1H),5.55(s, 2H),5.16–5.05(m,1H),4.68–4.60(m,1H),4.57–4.46(m,2H),4.41–4.34(m,1H),3.82(d,J=13.7Hz,1H ),3.72(d,J=13.7Hz,1H),3.43–3.41(m,4H),2.73–2.63(m,1H),2.53–2.43(m,4H),2.42–2.34(m,1H).

[0317] Example 8 Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 8)

[0318] Step 1: Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate

[0319] Tert-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate (300 mg, 1.13 mmol), 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (297 mg, 1.13 mmol), potassium carbonate (312 mg, 2.26 mmol), and potassium fluoride (328 mg, 5.65 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 395 mg of the product as a colorless oil with a yield of 75.6%.

[0320] LC-MS(ESI):[M+H] + =462.3.

[0321] Step 2: Synthesis of 1-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine

[0322] Tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate (525 mg, 1.14 mmol) was added to trifluoroacetic acid (5 mL) and dichloromethane (5 mL) and stirred at room temperature for 30 minutes. The reaction was terminated 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 afford 396 mg of a brown solid product with a yield of 96.3%, which was used directly in the next reaction.

[0323] LC-MS(ESI):[M+H] + =362.2;

[0324] 1 H NMR (500MHz, CDCl3) δ7.46(t,J=8.0Hz,1H),7.30–7.26(m,1H),7.23(d,J=8.3Hz,1H),6.25(d,J=7.8Hz ,1H),6.20(d,J=8.0Hz,1H),6.00(d,J=6.5Hz,1H),5.51(s,2H),3.79–3.70(m,4H),3.24–3.15(m,4H).

[0325] Step 3: Synthesis of (S)-methyl 2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0326] 1-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazine (100 mg, 0.33 mmol), (S)-methyl 2-(chloromethyl)-1-(oxetane)-2-ylmethyl-1H-thieno[2,3-d]imidazole-5-carboxylate (123 mg, 0.34 mmol), and N,N-diisopropylethylamine (219 mg, 1.69 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 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) = 45%) to afford 186 mg of the product as a colorless oil in an 87.4% yield.

[0327] LC-MS(ESI):[M+H] + =626.3;

[0328] 1 H NMR(500MHz, CDCl3)δ7.75(s,1H),7.41(t,J=8.0Hz,1H),7.30–7.26(m,1H),7.22(d,J= 8.2Hz,1H),6.15(dd,J=8.0,4.0Hz,2H),5.99(d,J=6.6Hz,1H),5.52(s,2H),5.22–5.16( m,1H),4.67–4.60(m,1H),4.55–4.50(m,2H),4.41–4.35(m,1H),3.89(s,3H),3.84(d,J= 3.2Hz,2H),3.51–3.35(m,4H),2.79–2.66(m,1H),2.63–2.55(m,4H),2.44–2.38(m,1H).

[0329] Step 4: Synthesis of (S)-2-((4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0330] (S)-Methyl 2-((4-(6-((4-chlorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (130 mg, 0.21 mmol) and lithium hydroxide monohydrate (25.6 mg, 1.07 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 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 50 mg of the product as a white solid in a 37.5% yield.

[0331] LC-MS(ESI):[M+H] + =612.4;

[0332] 1 H NMR (500MHz, DMSO-d6) δ12.07(br.s,1H),7.82(s,1H),7.46(t,J=7.9Hz,1H),7.39(s,2H),6. 49(d,J=6.4Hz,1H),6.32(d,J=8.2Hz,1H),6.11(d,J=7.8Hz,1H),5.50(s,2H),5.13–5.09(m, 1H),4.72–4.59(m,1H),4.60–4.46(m,2H),4.41–4.31(m,1H),3.83(d,J=13.6Hz,1H),3.74(d ,J=13.7Hz,1H),3.47–3.39(m,4H),2.74–2.63(m,1H),2.50–2.45(m,4H),2.43–2.33(m,1H).

[0333] Example 9 Synthesis of (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-fluoro-1-(oxetane-2-ylmethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid (Compound 9)

[0334] Step 1: Synthesis of methyl 2-((tert-butyldiphenylsilyl)oxy)acetate

[0335] Methyl 2-hydroxyacetate (10 g, 111.01 mmol) was added to N,N-dimethylformamide (150 mL), followed by imidazole (8.8 mL, 130.99 mmol). Tert-butyldiphenylsilyl chloride (34.5 mL, 133.21 mmol) was slowly added dropwise under an ice bath, and the mixture was stirred at 0°C for five hours. The mixture was concentrated under reduced pressure, and ethyl acetate (300 mL) was added to precipitate a large amount of white solid. This solid was filtered and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to afford 35 g of a colorless oil in a 96.0% yield.

[0336] 1 HNMR (400MHz, CDCl3) δ7.63–7.60(m,4H),7.35–7.32(m,6H),4.17(s,2H),3.61(s,3H),1.02(s,9H).

[0337] Step 2: Synthesis of 2-((tert-butyldiphenylsilyl)oxy)acetamide

[0338] Methyl 2-((tert-butyldiphenylsilyl)oxy)acetate (5 g, 15.22 mmol) was dissolved in a methanolic amine solution (30 mL) and stirred at 50°C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 33%) to afford 3 g of a colorless oil in a 62.9% yield.

[0339] 1 HNMR (400MHz, DMSO-d6) δ7.65–7.63(m,4H),7.49–7.43(m,7H),7.11(s,1H),3.95(s,2H),1.03(s,9H).

[0340] Step 3: Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate

[0341] The compound tert-butyl 6-hydroxy-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (500 mg, 1.81 mmol) was added to methanol (3 mL) and ethyl acetate (3 mL). 10% palladium on carbon (100 mg) was added and stirred at room temperature under a hydrogen atmosphere for three hours. Filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 5%) to obtain 460 mg of a white solid in a 91.3% yield.

[0342] 1HNMR(400MHz, CDCl3)δ7.45–7.42(m,1H),6.45–6.42(m,1H),6.10–6.08(m,1H),4.24(s, 2H),2.85(s,2H),2.73–2.69(m,1H),1.95–1.93(m,2H),1.63–1.59(m,2H),1.47(s,9H).

[0343] Step 4: Synthesis of tert-butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0344] Tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (400 mg, 1.44 mmol) was added to N,N-dimethylformamide (5 mL), followed by potassium carbonate (199 mg, 1.44 mmol) and 7-(bromomethyl)-4-chloro-2-fluorobenzofuran (416 mg, 1.58 mmol). The mixture was stirred at 60°C for 1.5 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: ethyl acetate:petroleum ether (v / v) = 1:6) to afford 540 mg of the product as a colorless oil in an 81.5% yield.

[0345] 1 HNMR (400MHz, CDCl3) δ7.47–7.43(m,1H),7.26–7.24(m,1H),7.19–7.15(m,1H),6.67(d,J=7.2Hz,1H),6.57(d,J=8Hz,1H ),5.94(d,J=6.8Hz,1H),5.52(s,2H),4.16(s,2H),2.76–2.68(m,3H),1.80–1.77(m,2H),1.64–1.60(m,2H),1.42(s,9H).

[0346] Step 5: Synthesis of 2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine

[0347] tert-Butyl 4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate (490 mg, 1.06 mmol) was added to dichloromethane (5 mL). Hydrochloric acid in dioxane (5 mL) was added under ice-cooling, and the mixture was stirred at 0°C for two hours. The mixture was concentrated under reduced pressure to obtain 300 mg of a white solid product, which was used directly in the next reaction.

[0348] LC-MS(ESI):[M+H] + =361.2.

[0349] Step 6: Synthesis of methyl 5-bromo-3-fluorothiophene-2-carboxylate

[0350] Methyl 3-fluorothiophene-2-carboxylate (7.5 mL, 62.45 mmol) was added to tetrahydrofuran (500 mL). Magnesium dichloride (2,2,6,6-tetramethylpiperidinium) lithium salt (1N) (120 mL, 475.25 mmol) was slowly added dropwise at -78°C and stirred for 30 minutes. Carbon tetrabromide (20.7 g, 62.45 mmol) was added to tetrahydrofuran (25 mL) and the solution was slowly added dropwise to the reaction system. Stir overnight. HCl (0.5 N) was added to adjust the pH to 6. The tetrahydrofuran was removed by concentration under reduced pressure, and the mixture was extracted with dichloromethane (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 25%) to obtain 9.0 g of the product as a yellow solid in a 60.3% yield.

[0351] 1 HNMR (400MHz, CDCl3) δ6.88 (s, 1H), 3.86 (s, 3H).

[0352] Step 7: Synthesis of methyl 5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylate

[0353] Methyl 5-bromo-3-fluorothiophene-2-carboxylate (4.1 g, 17.15 mmol) and 2-((tert-butyldiphenylsilyl)oxy)acetamide (6.2 g, 18.87 mmol) were added to toluene (50 mL). Cesium carbonate (8.44 g, 25.90 mmol) was added, and the atmosphere was purged with nitrogen three times. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.99 g, 1.72 mmol) and tris(dibenzylideneacetone)dipalladium (1.57 g, 1.72 mmol) were then added. The mixture was stirred at 60°C under nitrogen for two hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 10%) to afford 3.3 g of a yellow solid in a 40.8% yield.

[0354] 1 HNMR (400MHz, CDCl3) δ9.21(s,1H),7.56–7.54(m,4H),7.44–7.42(m,2H),7.38–7.19(m,4H),6.34(s,1H),4.23(s,2H),3.79(s,3H),1.08(s,9H).

[0355] Step 8: Synthesis of methyl 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylate

[0356] Methyl 5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylate (3.3 g, 7.0 mmol) was added to tetrahydrofuran (20 mL). N-bromosuccinimide (1.62 g, 9.1 mmol) was slowly added under ice-cooling, and the mixture was stirred at 0°C for three hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 5%) to afford 2.6 g of a pale yellow solid in a 67.5% yield.

[0357] 1 HNMR (400MHz, CDCl3) δ9.58(s,1H),7.59–7.57(m,4H),7.42–7.34(m,6H),4.23(s,2H),3.81(s,3H),1.11(s,9H).

[0358] Step 9: Synthesis of methyl 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)ethylthioamino)-3-fluorothiophene-2-carboxylate

[0359] Methyl 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)acetamide)-3-fluorothiophene-2-carboxylate (1.3 g, 2.36 mmol) was added to 1,4-dioxane (10 mL), followed by Lawesson's reagent (2.39 g, 5.9 mmol). The mixture was stirred at 110°C overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 9%) to afford 1.2 g of a yellow solid in an 89.7% yield.

[0360] 1 HNMR (400MHz, CDCl3) δ11.18(s,1H),7.60–7.57(m,4H),7.43–7.33(m,6H),4.52(s,2H),3.83(s,3H),1.12(s,9H).

[0361] Step 10: Synthesis of methyl (S,Z)-4-bromo-5-((2-((tert-butyldiphenylsilyl)oxy)-1-((oxetan-2-ylmethyl)amino)ethylidene)amino)-3-fluorothiophene-2-carboxylate

[0362] Methyl 4-bromo-5-(2-((tert-butyldiphenylsilyl)oxy)ethylthioamino)-3-fluorothiophene-2-carboxylate (1.3 g, 2.29 mmol) was added to N,N-dimethylformamide (15 mL). Silver acetate (780 mg, 4.67 mmol) was added, the atmosphere was replaced with nitrogen three times, and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and extracted with ethyl acetate (10 mL) and water (10 mL). 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) = 17%) to yield 600 mg of a yellow solid in a 42.2% yield.

[0363] 1 HNMR(400MHz,CDCl3)δ7.63(br t,J=5.65Hz,4H),7.52–7.39(m,6H),6.95(s,1H),5.17–5.05(m,1H),4.78–4.68(m,1H),4.53(dt,J=9.22,5.93Hz ,1H),4.45–4.31(m,2H),3.88–3.77(m,4H),3.66–3.56(m,1H),2.78–2.67(m,1H),2.66–2.55(m,1H),1.10(s,9H).

[0364] Step 11: Synthesis of (S)-methyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0365] Methyl (S,Z)-4-bromo-5-((2-((tert-butyldiphenylsilyl)oxy)-1-((oxetan-2-ylmethyl)amino)ethylidene)amino)-3-fluorothiophene-2-carboxylate (600 mg, 0.97 mmol) was added to acetonitrile (8 mL), followed by N,N-dimethylethylenediamine (0.2 mL, 1.37 mmol) and cuprous iodide (200 mg, 0.63 mmol). The mixture was stirred at 85°C overnight under nitrogen. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 25%) to give 250 mg of the product as a colorless oil in a 47.9% yield.

[0366] LC-MS(ESI):[M+H] + =539.3.

[0367] Step 12: Synthesis of (S)-methyl 6-fluoro-2-(hydroxymethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0368] Compound (S)-methyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (230 mg, 0.43 mmol) was added to tetrahydrofuran (5 mL), followed by tetrabutylammonium fluoride (168 mg, 0.64 mmol), and stirred at room temperature for two hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 33%) to give 100 mg of the product as a white solid in a 78% yield.

[0369] LC-MS(ESI):[M+H] + =301.3.

[0370] Step 13: Synthesis of (S)-methyl 2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0371] Compound (S)-6-fluoro-2-(hydroxymethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (30 mg, 0.1 mmol) was added to dichloromethane (2 mL). Triethylamine (20 mg, 0.2 mmol) was added and the mixture was stirred at 0°C for five minutes. Methanesulfonyl chloride (17 mg, 0.15 mmol) was added and stirred in an ice bath for 1.5 hours. Water (2 mL) and dichloromethane (2 mL) were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate to obtain 35 mg of a white solid, which was used directly in the next reaction.

[0372] Step 14: Synthesis of (S)-methyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0373] Compound (S)-methyl 2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (35 mg, 0.11 mmol) was added to acetonitrile (2 mL), followed by potassium carbonate (45 mg, 0.33 mmol) and potassium iodide (4 mg, 0.02 mmol). 2-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-6-(piperidin-4-yl)pyridine (43 mg, 0.12 mmol) was added, and the mixture was stirred at 50°C for two hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 50%) to afford 38 mg of the product as a colorless oil in a 53.8% yield.

[0374] LC-MS(ESI):[M+H] + =643.3.

[0375] Step 15: Synthesis of (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid

[0376] Compound (S)-methyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)piperidin-1-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (28 mg, 0.04 mmol) was added to 1,4-dioxane (0.2 mL) and water (0.2 mL). Lithium hydroxide (6 mg, 0.25 mmol) was added, and the mixture was stirred at 40°C for six hours. Acetic acid (0.5 mL) was added. The mixture was concentrated under reduced pressure and purified by Prep-HPLC (acetonitrile:water = 60%) to give 20.4 mg of a white solid in a 74.5% yield.

[0377] LC-MS(ESI):[M+H] + =629.3;

[0378] 1 HNMR(400MHz,DMSO-d6)δ7.65–7.61(m,1H),7.44–7.38(m,2H),6.87(d,J=7.2 Hz,1H),6.69(d,J=8Hz,1H),6.51(d,J=6.4Hz,1H),5.56(s,2H),5.08–5.06(m ,1H),4.6–4.38(m,4H),3.83–3.69(m,2H),2.97–2.86(m,2H),2.75–2.7(m,1H ),2.57–2.55(m,1H),2.45–2.42(m,1H),2.21–2.11(m,2H),1.75–1.65(m,4H).

[0379] Example 10 Synthesis of (S)-2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-6-fluoro-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 10)

[0380] Step 1: Synthesis of (S)-methyl 2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0381] Compound (S)-methyl 2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (42 mg, 0.13 mmol) was added to acetonitrile (2 mL), followed by potassium carbonate (55 mg, 0.4 mmol) and potassium iodide (4 mg, 0.02 mmol). 6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine (52 mg, 0.14 mmol) was added, and the mixture was stirred at 50°C for two hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 75%) to afford 56 mg of the product as a pale yellow solid in a 66.3% yield.

[0382] 1 HNMR(400MHz, DMSO-d6)δ7.70(t,J=7.8Hz,1H),7.44–7.39(m,2H),7.09(d,J=7.2Hz,1H),6.76(d,J=8.4Hz,1H),6.71(s,1H),6.53(d,J=6.4Hz, 1H),5.69(s,2H),5.04–5.02(m,1H),4.63–4.37(m,4H),3.98–3.85(m,2 H),3.83(s,3H),3.33–3.21(m,4H),2.72–2.69(m,3H),2.42–2.39(1H).

[0383] Step 2: Synthesis of (S)-2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0384] Compound (S)-methyl 2-((6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (46 mg, 0.07 mmol) was added to 1,4-dioxane (1.0 mL) and water (0.2 mL). Lithium hydroxide (11 mg, 0.46 mmol) was added, and the mixture was stirred at 40°C for six hours. Acetic acid (0.5 mL) was added, and the mixture was concentrated under reduced pressure and purified by Prep-HPLC (acetonitrile:water = 60%) to obtain 26.3 mg of a white solid in a 58.5% yield.

[0385] LC-MS(ESI):[M+H] + =627.3;

[0386] 1 HNMR(400MHz, DMSO-d6)δ7.69(t,J=7.8Hz,1H),7.44–7.38(m,2H),7.08(d,J=7.6Hz,1H),6.74(d,J=8Hz,1H),6.70(s,1H),6.52(d,J=6.8Hz,1H), 5.59(s,2H),5.02–5.01(m,1H),4.61–4.36(m,4H),3.96–3.83(m,2H),3. 2–3.15(m,2H),2.72–2.69(m,3H),2.52–2.49(m,2H),2.41–2.35(m,1H).

[0387] Example 11 Synthesis of (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 11)

[0388] Step 1: Synthesis of methyl 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate

[0389] 6-Bromo-2-((methoxymethyl)oxy)pyridine (419 mg, 1.92 mmol) and methyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (470 mg, 1.60 mmol) were added to 1,4-dioxane (10 mL) and water (2.5 mL). Potassium carbonate (663 mg, 4.80 mmol) and dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium (58 mg, 0.08 mmol) were also added. The mixture was heated to 85°C and stirred overnight under nitrogen. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 1:10) to obtain 320 mg of the product as a pale yellow solid in a 65.6% yield.

[0390] 1 HNMR(400MHz,DMSO-d6)δ7.92–7.79(m,3H),7.66(d,J=7.6Hz,1H),7.46(t,J=8.0H z,1H),6.87(d,J=8.0Hz,1H),5.61(s,2H),3.80(s,2H),3.65(s,3H),3.45(s,3H).

[0391] Step 2: Synthesis of 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol

[0392] Methyl 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate (320 mg, 1.05 mmol) was added to tetrahydrofuran (10 mL) and cooled to 0°C in an ice bath. Lithium aluminum tetrahydride (150 mg, 3.95 mmol) was added and the mixture was allowed to react in an ice bath for 2 hours. The reaction was quenched by adding water (2 mL), filtered through celite, and the filter cake was washed with dichloromethane (20 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluent PE:EA (v / v) = 1:10) to obtain 190 mg of the product as a light yellow oil in a 68.4% yield.

[0393] 1 HNMR (400MHz, DMSO-d6) δ7.88–7.76(m,3H),7.64(d,J=7.6Hz,1H),7.42(t,J=8.0Hz,1H),6.85(d,J=8.0Hz ,1H),5.60(s,2H),4.76(t,J=5.2Hz,1H),3.64(dd,J=12.4,6.8Hz,2H),3.45(s,3H),2.81(t,J=6.8Hz,2H).

[0394] Step 3: Synthesis of 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde

[0395] 2-(2-Fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol (190 mg, 0.69 mmol) was added to dichloromethane (10 mL) and cooled to 0°C in an ice bath. Dess-Martin periodinane (872 mg, 2.06 mmol) was added, and the mixture was reacted at 0°C under nitrogen for 2 hours. The mixture was filtered through celite, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 1:5) to obtain 40 mg of the product as a yellow oil in a 21.2% yield.

[0396] 1 HNMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 7.95–7.84 (m, 3H), 7.67 (d, J = 7.4Hz, 1H), 7. 42(t,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),5.60(s,2H),3.92(s,2H),3.44(s,3H).

[0397] Step 4: Synthesis of (S)-methyl 2-(2-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0398] 2-(2-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde (390 mg, 1.42 mmol) and (S)-methyl 5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (412 mg, 1.70 mmol) were added to acetic acid (5 mL) and the reaction mixture was heated to 60°C under nitrogen for 8 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 1:20) to give 123 mg of a brown solid product in a 17.4% yield.

[0399] LC-MS(ESI):[M+H] + =454.4.

[0400] Step 5: Synthesis of methyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0401] Compound (S)-methyl 2-(2-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (110 mg, 0.24 mmol) was added to N,N-dimethylformamide (10 mL). 7-(Bromomethyl)-4-chloro-2-fluoro-1-benzofuran (64 mg, 0.24 mmol) and potassium carbonate (101 mg, 0.73 mmol) were added. The reaction mixture was heated to 60°C under nitrogen for 2 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: MeOH:DCM (v / v) = 1:20) to obtain 51 mg of the product as a yellow solid in a 33.1% yield.

[0402] 1 HNMR(400MHz,DMSO-d6)δ7.95(s,1H),7.87–7.78(m,3H),7.63(d,J=7.4Hz,1 H),7.47(d,J=8.0Hz,1H),7.42–7.35(m,2H),6.90(d,J=8.0Hz,1H),6.53(d,J =6.4Hz,1H),5.71(s,2H),5.03–4.98(m,1H),4.66–4.58(m,1H),4.54–4.44( m,2H),4.41–4.29(m,3H),3.82(s,3H),2.71–2.65(m,1H),2.35–2.31(m,1H).

[0403] Step 6: Synthesis of (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-thiophene[2,3-d]imidazole-5-carboxylic acid

[0404] Methyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-2-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (51 mg, 0.08 mmol) was added to 1,4-dioxane (2 mL) and water (0.5 mL), followed by the addition of lithium hydroxide (17 mg, 0.41 mmol). The reaction mixture was heated to 40°C and stirred for 2 hours under nitrogen. The mixture was cooled to room temperature and 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) = 0-50%) to obtain 30 mg of the product as a white solid in a 60.1% yield.

[0405] LC-MS(ESI):[M+H] + =622.2;

[0406] 1 HNMR(400MHz,DMSO-d6)δ12.68(br.s,1H),7.83(dd,J=8.8,5.6Hz,4H),7.63(d, J=7.2Hz,1H),7.47(d,J=8.0Hz,1H),7.39(dd,J=16.4,8.1Hz,2H),6.89(d,J=8. 0Hz,1H),6.53(d,J=6.4Hz,1H),5.71(s,2H),5.04–4.98(m,1H),4.65–4.58(m,1 H),4.52–4.47(m,2H),4.41–4.28(m,3H),2.69–4.52(m,1H),2.38–2.31(m,1H).

[0407] Example 12 Synthesis of (S)-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-carboxylic acid (Compound 12)

[0408] Step 1: Synthesis of 2-bromo-6-(methoxymethoxy)pyridine

[0409] 6-Bromopyridin-2-ol (25 g, 143.7 mmol) was added to dichloromethane (250 mL), followed by triethylamine (100.0 mL, 431.0 mmol). The mixture was stirred in an ice bath for ten minutes. Bromo(methoxy)methane (36.0 g, 287.4 mmol) was then added and 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 afford 11.1 g of the product as a colorless oil in a 35.5% yield.

[0410] 1 HNMR (400MHz, DMSO-d6) δ7.72(d,J=7.8Hz,1H),7.28(d,J=7.3Hz,1H),6.93(d,J=7.9Hz,1H),5.42(s,2H),3.42(s,3H).

[0411] Step 2: Synthesis of methyl 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate

[0412] 2-Bromo-6-(methoxymethoxy)pyridine (3.0 g, 13.7 mmol) and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (4.54 g, 16.5 mmol) were added to 1,4-dioxane (32 mL) and water (8 mL). Potassium carbonate (5.67 g, 41.1 mmol) was added, and the atmosphere was flushed with nitrogen three times. 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (0.3 g, 0.41 mmol) was added, and the atmosphere was flushed with nitrogen 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 obtain 2.2 g of the product as a colorless oil in a 55.7% yield.

[0413] 1 HNMR(400MHz, CDCl3)δ7.90(d,J=8.3Hz,2H),7.60(t,J=7.8Hz,1H),7.30(dd,J=7.6,6 .7Hz,3H),6.68(d,J=8.1Hz,1H),5.58(s,2H),3.63(s,3H),3.61(s,2H),3.49(s,3H).

[0414] Step 3: Synthesis of 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol

[0415] Methyl 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate (2.2 g, 7.7 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 1.45 g of the product as a colorless oil with a yield of 72.5%.

[0416] LC-MS(ESI):[M+H] + =260.3.

[0417] Step 4: Synthesis of 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde

[0418] The compound 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol (1.45 g, 5.6 mmol) was added to dichloromethane (20 mL), followed by Dess-Martin reagent (3.7 g, 8.6 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, the mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 1:8) to afford 750 mg of the product as a colorless oil in a 52.4% yield.

[0419] LC-MS(ESI):[M+H] + =258.3.

[0420] Step 5: Synthesis of (S)-methyl 2-(4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0421] 2-(4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde (600 mg, 2.33 mmol) and (S)-methyl 5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (860 mg, 3.38 mmol) were added to acetic acid (20 mL) 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 200 mg of a light brown solid product in a 20.0% yield.

[0422] LC-MS(ESI):[M+H] + =436.4;

[0423] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),7.92(s,1H),7.73(d,J=8.1Hz,2H),7.52(dd,J=8.8,7.1Hz,1H),7.39(d,J=8.3Hz,2H),6.66(d,J=5.6Hz, 1H),6.36(d,J=8.9Hz,1H),4.96–4.86(m,1H),4.62–4.51(m,1H),4.47( s,2H),4.35(s,3H),3.82(s,3H),2.66–2.58(m,1H),2.31–2.24(m,1H).

[0424] Step 6: 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

[0425] Compound (S)-methyl 2-(4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (110 mg, 0.25 mmol) and 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (87.0 mg, 0.32 mmol) were added to N,N-dimethylformamide (5 mL), followed by potassium carbonate (135 mg, 0.75 mmol), and stirred at 60°C for one hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 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 65 mg of a white solid product in a 39.5% yield.

[0426] LC-MS(ESI):[M+H] + =618.4;

[0427] 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.3Hz,2H),7.92(s,1H),7.80(t,J=7.8Hz,1H),7.56( d,J=7.4Hz,1H),7.47(d,J=8.2Hz,1H),7.39(dd,J=10.6,8.3Hz,3H),6.84(d,J=8.1Hz,1 H),6.53(d,J=6.4Hz,1H),5.69(s,2H),4.95–4.88(m,1H),4.63–4.51(m,1H),4.50–4.41 (m,2H),4.38–4.31(m,3H),3.82(s,3H),2.61(dd,J=11.8,5.6Hz,1H),2.33–2.24(m,1H).

[0428] Step 7: Synthesis of (S)-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-carboxylic acid

[0429] 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 (65 mg, 0.1 mmol) was dissolved in dioxane (4 mL) and water (1 mL). Lithium hydroxide (12 mg, 0.50 mmol) was added and stirred at room temperature for 2 hours. The pH was adjusted to 6-7 with acetic acid, the mixture was concentrated under reduced pressure, and purified by prep-HPLC (eluent: CH3CN:H2O (v / v) = 50%) to give 33.6 mg of the product as a white solid in a 52.9% yield.

[0430] LC-MS(ESI):[M+H] + =604.2;

[0431] 1 H NMR(400MHz, DMSO-d6)δ12.90(s,1H),7.99(d,J=8.3Hz,2H),7.86–7.73(m,2H),7 .56(d,J=7.5Hz,1H),7.47(d,J=8.2Hz,1H),7.39(dd,J=11.3,8.4Hz,3H),6.84(d, J=8.2Hz,1H),6.53(d,J=6.4Hz,1H),5.69(s,2H),4.98–4.85(m,1H),4.59–4.47(m ,1H),4.49–4.39(m,2H),4.37–4.29(m,3H),2.66–2.55(m,1H),2.33–2.21(m,1H).

[0432] Example 13 Synthesis of (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-6-fluoro-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 13)

[0433] Step 1: Synthesis of (S)-methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0434] Compound (S)-methyl 2-(chloromethyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (42 mg, 0.13 mmol) was added to acetonitrile (2 mL), followed by potassium carbonate (55 mg, 0.4 mmol) and potassium iodide (4 mg, 0.02 mmol). 4-(4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoro-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (55 mg, 0.15 mmol) was added, and the mixture was stirred at 50°C for two hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: EtOAc:PE (v / v) = 75%) to give 63.4 mg of the product as a pale yellow solid in a yield of 72.9%.

[0435] LC-MS(ESI):[M+H] + =660.2;

[0436] 1 HNMR(400MHz,DMSO-d6)δ8.22(d,J=2.4Hz,1H),7.26–7.18(m 2H),6.99(s,1H),5.96(d,J=6.8Hz,1H),5.65(s,2H),5.08–5.06(m,1H),4.58–4.53(m,2H),4.35–4.32(m,1H),3. 93(s,1H),3.83(s,3H),3.23–3.22(m,1H),2.74–2.61(m,4H),2.39–2.38(m,1H),1.98(s,2H),1.21–1.19(m,2H).

[0437] Step 2: Synthesis of (S)-2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0438] Compound (S)-methyl 2-((4-(4-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)-5-fluoropyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)methyl)-6-fluoro-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (54 mg, 0.08 mmol) was added to 1,4-dioxane (1.0 mL) and water (0.2 mL). Lithium hydroxide (10 mg, 0.42 mmol) was added, and the mixture was stirred at 40°C for two hours. Acetic acid (0.2 mL) was added, and the mixture was concentrated under reduced pressure and purified by Prep-HPLC (acetonitrile:water = 50%) to give 30 mg of a white solid in a 56.8% yield.

[0439] LC-MS(ESI):[M+H] + =646.2;

[0440] 1 HNMR(400MHz, DMSO-d6)δ13.22(s,1H),8.59(d,J=2.8Hz,1H),7.50–7.43(m,2H),7.05(s,1H),6.55(d,J=6.4Hz, 1H),5.77(s,2H),5.02–4.99(m,1H),4.59–4.36(m,4H),3.96–3.83(m,2H),3.32–3.24(m,2H),2.71–2.43(m,6H).

[0441] Example 14 Synthesis of (S)-2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (Compound 14)

[0442] Step 1: Synthesis of ethyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

[0443] Ethyl 2-(4-bromo-3-fluorophenyl)acetate (3.5 g, 13.41 mmol), pinacol diboronate (3.74 g, 14.75 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (0.29 g, 0.40 mmol), and potassium acetate (3.95 g, 40.22 mmol) were added to 1,4-dioxane (100 mL). The reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a black oily liquid, which was directly used in the next reaction.

[0444] LC-MS(ESI):[M+H] + =309.2.

[0445] Step 2: Synthesis of ethyl 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate

[0446] 2-Bromo-6-(methoxymethoxy)pyridine (3 g, 13.76 mmol), ethyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (5.69 g, 9.24 mmol), 1,1'-bis(diphenylphosphinoferrocenepalladium)dichloride (0.02 g, 0.03 mmol), and potassium carbonate (0.15 g, 1.10 mmol) were added to 1,4-dioxane (100 mL) and water (25 mL). The reaction mixture was stirred at 85°C overnight. The reaction mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 5:1) to obtain 1.8 g of the product as a colorless oily liquid in a 41.0% yield.

[0447] LC-MS(ESI):[M+1] + =320.2;

[0448] 1 HNMR(400MHz,DMSO-d6)δ8.01–7.81(m,2H),7.51–7.43(m,1H),7.31–7.20(m,2H),6.95–6.84(m ,1H),5.57(s,2H),4.16–4.07(q,J=7.2Hz,2H),3.77(s,2H),3.44(s,3H),1.21(t,J=7.2Hz,3H).

[0449] Step 3: Synthesis of 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol

[0450] Ethyl 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetate (1.75 g, 5.48 mmol) was added to tetrahydrofuran (50 mL). Lithium aluminum hydride (0.62 g, 16.44 mmol) was slowly added under ice-cooling, and stirring was continued for 2 hours. Water (5 mL) was slowly added dropwise under ice-cooling to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 3:1) to obtain 910 mg of the product as a light green solid in a 59.9% yield.

[0451] LC-MS(ESI):[M+H] +=278.2;

[0452] 1 HNMR(400MHz,DMSO-d6)δ7.93–7.80(m,2H),7.47–7.41(m,1H),7.24–7.16(m,2H),6.90–6.82(m ,1H),5.56(s,2H),4.71(t,J=4.0Hz,1H),3.70–3.63(m,2H),3.44(s,3H),2.79(t,J=8.0Hz,2H).

[0453] Step 4: Synthesis of 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde

[0454] The compound 2-(3-fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)ethan-1-ol (0.80 g, 2.88 mmol) was added to dichloromethane (70 mL). Dess-Martin periodinane (2.45 g, 5.77 mmol) was slowly added under ice-cooling, and stirring was continued for 3 hours. Saturated sodium bicarbonate solution was added to the solution until the pH reached 8. The solution was extracted with dichloromethane (30 ml x 3), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 5:1) to obtain 410 mg of a light yellow oily liquid, with a yield of 51.6%.

[0455] LC-MS(ESI):[M+H] + =276.2.

[0456] Step 5: Synthesis of (S)-methyl 2-(3-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0457] 2-(3-Fluoro-4-(6-(methoxymethoxy)pyridin-2-yl)phenyl)acetaldehyde (380 mg, 1.38 mmol) and (S)-methyl 5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (401 mg, 1.66 mmol) were added to acetic acid (10 mL). The reaction mixture was stirred at 60°C for 4 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: DCM:MeOH (v / v) = 20:1) to afford 105 mg of the product as a brown solid in a 16.8% yield.

[0458] LC-MS(ESI):[M+H] + =454.2; 1HNMR(400MHz,DMSO-d6)δ11.71(s,1H),7.95(s,1H),7.64–7.45(m,2H),7.37–7.18(m,2H),6.55–6.33(m,2H) ,5.01–4.90(m,1H),4.67–4.28(m,5H),3.82(s,3H),2.72–2.57(m,1H),2.37–2.23(m,1H),1.95–1.87(m,1H).

[0459] Step 6: Synthesis of (S)-methyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0460] Compound (S)-methyl 2-(3-fluoro-4-(6-hydroxypyridin-2-yl)benzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (105 mg, 0.23 mmol), 7-(bromomethyl)-4-chloro-2-fluoro-1-benzofuran (61 mg, 0.23 mmol), and potassium carbonate (96 mg, 0.69 mmol) were added to N,N-dimethylformamide (5 mL) and stirred at 60°C for 3 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: PE:EA (v / v) = 1:1) to give 35 mg of the product as a brown solid in a yield of 23.8%.

[0461] LC-MS(ESI):[M+H] + =636.1.

[0462] Step 7: 2-((4-(6-(((4-chloro-2-fluoro-1-benzofuran-7-yl)methyl)oxy)pyridin-2-yl)-3-fluorophenyl)methyl)-1-(((2S)-oxetan-2-yl)methyl)thienyl[2,3-d]imidazole-5-carboxylic acid

[0463] Compound (S)-methyl 2-(4-(6-((4-chloro-2-fluorobenzofuran-7-yl)methoxy)pyridin-2-yl)-3-fluorobenzyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate (35 mg, 0.06 mmol) and lithium hydroxide (7 mg, 0.29 mmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL) and stirred at 40°C for 2 hours. Acetic acid was added dropwise in an ice bath until the pH reached 6, and the mixture was concentrated under reduced pressure. Purification was performed using Pre-HPLC (eluent: ACN:H2O (v / v) = 90%) to give 7.7 mg of the product as a white solid in a 22.5% yield.

[0464] LC-MS(ESI):[M+H] + =622.1;

[0465] 1 HNMR(400MHz,DMSO-d6)δ12.95(s,1H),7.93–7.78(m,3H),7.51–7.36(m,3H),7.33–7.18(m,2H),6.90(d,J=8.0Hz,1H),6.52(d,J=8.0H z,1H),5.65(s,2H),5.00–4.91(m,1H),4.62–4.53(m,1H),4.51–4.42(m,2H),4.40–4.29(m,3H),2.71–2.58(m,1H),2.36–2.23(m,1H).

[0466] Experimental Example 1 In vitro cell activity test

[0467] 1. Materials

[0468] (1) Cell lines

[0469] The cell line was constructed by Shanghai WuXi AppTec Co., Ltd., as shown in Table 1 below.

[0470] Table 1

[0471] (2) Reagents are shown in Table 2 below.

[0472] Table 2

[0473] (3) Instruments are shown in Table 3 below.

[0474] Table 3

[0475] (4) Compound information

[0476] Prepare the compound solution in DMSO at a working concentration of 100 μM or 10 μM. Perform 10 4-fold dilutions (maximum concentration after dilution is 1000 nM or 100 nM) using an automated pipetting workstation.

[0477] 2. Methods

[0478] (1) Experimental materials

[0479] The experimental buffer is shown in Table 4 below.

[0480] Table 4

[0481] The final concentrations of the detection reagents are shown in Table 5 below.

[0482] Table 5

[0483] (2) Experimental methods

[0484] (a) Preparation of compound plates:

[0485] The test compound was diluted 4-fold at 10 points with a starting concentration of 100 μM. The dilution was completed by the automatic pipetting workstation.

[0486] (b) Transfer compounds:

[0487] (i) Use a liquid handler to transfer 100 nL of 100x compound to a 384-well plate.

[0488] (ii) Centrifuge the 384-well plate at 1000 rpm for 5 seconds.

[0489] (c) Preparation of cell suspension

[0490] (i) Thaw a cryopreserved tube of HEK293 cells expressing hGLP-1R in 37°C warm water immediately.

[0491] (ii) Transfer the cell suspension to a 15 mL centrifuge tube and gently rinse with 10 mL of HBSS.

[0492] (iii) Centrifuge the tube at 1000 rpm at room temperature for 1 minute.

[0493] (iv) Discard the supernatant.

[0494] (v) Gently rinse with 10 ml of HBSS, pellet the cells by centrifugation, and resuspend the cells in assay buffer.

[0495] (vi) Measure cell density and activity using a cell counter.

[0496] (vii) Dilute the GLP-1R cell concentration to 1.0*105 / mL.

[0497] (viii) Transfer 10 μL of the diluted cell suspension into a 384-well plate.

[0498] (ix) Incubate at room temperature for 30 minutes.

[0499] (d) Detection:

[0500] (i) Add 10 μL of 800 nM serially diluted cAMP standard to empty wells of a 384-well plate.

[0501] (ii) Add 10 μL of cAMP detection reagent.

[0502] (iii) After incubation at room temperature for 60 minutes, the plate was read on a microplate reader.

[0503] The results are shown in Table 1, which shows the agonistic effects (EC 50 ).

[0504] Table 1. Experimental results of the agonistic effect of the compounds provided in some examples of the present invention

[0505] Results and Discussion: The compounds of the present invention exhibited superior agonist ability on GLP-1 receptor.

[0506] Experimental Example 2: Pharmacokinetic Study of the Compounds of the Invention in Mice

[0507] 1. Experimental Materials

[0508] C57BL / 6 mice: male, 6-8 weeks old, weighing 20-30 g, were purchased from Weitonglihua (Beijing) Laboratory Animal Technology Co., Ltd.

[0509] Reagents: Chromatographic grade acetonitrile was purchased from Thermo Fisher Scientific, chromatographic grade formic acid was purchased from Dicoma, ultrapure water was used in the experiment, and the remaining reagents were of commercial analytical grade.

[0510] Instrument: AB LCMS-5500 tandem mass spectrometer

[0511] 2. Experimental methods

[0512] Weigh the compound and dissolve it in 10% DMSO / 5% Kolliphor-EL / 85% HP-β-CD (20%) or other appropriate system. All formulations should be clear solutions. Mice should be administered intravenously or orally. Blood samples should be collected at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. For each PK sampling point, 30 μL of whole blood should be collected into an EDTA-K2 anticoagulant blood collection tube and centrifuged at 4°C within 30 minutes to obtain plasma. Whole blood samples should be placed on wet ice before centrifugation. All collected plasma samples should be stored on dry ice or frozen until analysis.

[0513] Approximately 1 mg of compound was weighed and dissolved in DMSO, vortexed, and sonicated to obtain a 1 mg / mL standard stock solution. The standard stock solution was diluted with 50% acetonitrile in water to obtain standard working solutions at concentrations of 5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL. Quality control working solutions at concentrations of 10, 20, 500, and 8,000 ng / mL were prepared using the same dilution method. Three μL of the standard working solutions at concentrations of (5, 10, 20, 50, 100, 500, 1000, 5000, and 10,000 ng / mL) were added to 30 μL of blank C57BL / 6 mouse plasma to obtain a total volume of 33 μL of standard curve samples with concentrations ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, and 1000 ng / mL). Quality control samples with concentrations of (1 ng / ml (low-1) and 2 ng / ml (low-2), 50 ng / ml (medium), 800 ng / ml (high)) were prepared separately.

[0514] Proteins were precipitated by adding 200 μL of acetonitrile containing the internal standard (dexamethasone) to 33 μL of standard sample, 33 μL of quality control sample, or 33 μL of unknown sample (30 μL of plasma and 3 μL of blank solution). The samples were then vortexed for 30 seconds and centrifuged at 4000 g at 4°C for 15 minutes. The supernatant was diluted threefold with water, and 10 μL of the supernatant was injected into the LC-MS / MS system for quantitative analysis using the following detection conditions:

[0515] Chromatographic column: Raptor Biphenyl 2.7μm 2.1×50mm

[0516] Mobile phase: Solution A: 100% water (0.1% formic acid); Solution B: 95% acetonitrile (0.1% formic acid, 5% water), gradient elution according to the table below.

[0517] 3. Data processing

[0518] Using Phoenix™ Pharmacokinetic data were analyzed using a non-compartmental model using the software.

[0519] Results and discussion: The compounds of the present invention were well absorbed orally in mice and had high exposure and bioavailability.

[0520] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

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: X is N or CR 16 ; Y is O or S; R 2 For hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, 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 3 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 15 , 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 15 Can be optionally replaced by 1, 2 or 3 R 3a replace; R 15 C 3-6 Cycloalkyl, 3-8 membered heterocyclyl or 5-10 membered heteroaryl; R 3a 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 3b replace; R 3b 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; R 4 、R 5 、R 8 and R 9 Each is independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; Ring B is a 5-6 membered heterocyclyl, phenyl or a 5-6 membered heteroaryl; Each R b are independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano or C 1-6 Alkyl, the C 1-6 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 and R 16 Each is independently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro or C 1-6 Alkyl, the C 1-6 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, 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) or formula (V):

3. The compound according to claim 1 or 2, wherein R 2 For hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Haloalkoxy or -C 1-3 Alkylene-C 1-3 alkoxy; R 4 、R 5 、R 8 and R 9 Each is independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano or C 1-3 Alkyl, the C 1-3 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; Each R b are independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano or C 1-3 Alkyl, the C 1-3 The alkyl group may be independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 and R 16 Each is independently H, D, F, Cl, Br, I, hydroxyl, cyano, 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, hydroxy, cyano, amino or nitro groups.

4. The compound according to any one of claims 1 to 3, wherein R 2 is hydrogen, deuterium, F, Cl, Br, I, hydroxy, amino, nitro, cyano, 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 4 、R 5 、R 8 and R 9 are each independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano, 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, hydroxy, cyano, amino or nitro; Each R b is independently H, D, F, Cl, Br, I, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl or isopropyl, wherein the methyl, ethyl, n-propyl and isopropyl groups are independently optionally substituted with 1, 2 or 3 F, Cl, Br, I, hydroxy, cyano, amino or nitro groups; R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 and R 16 Each is independently H, D, F, Cl, Br, I, hydroxy, cyano, 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, hydroxy, cyano, amino or nitro groups.

5. The compound according to any one of claims 1 to 4, wherein R 3 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 15 , 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 15 Can be optionally replaced by 1, 2 or 3 R 3a replace; R 15 C 3-6 Cycloalkyl, 3-6 membered heterocyclyl or 5-10 membered heteroaryl; R 3a 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 3b replace; R 3b 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.

6. The compound according to any one of claims 1 to 5, wherein R 3 is H, methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, or -CH2R 15 , the methyl, ethyl, n-propyl, isopropyl, vinyl, allyl, ethynyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl and -CH2R 15 Can be optionally replaced by 1, 2 or 3 R 3a replace; R 15 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, R 3a 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, 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, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl and morpholinyl may be independently and optionally replaced by 1, 2 or 3 R 3b replace; R 3b 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, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl or morpholinyl.

7. The compound according to any one of claims 1 to 6, wherein R 3 For H, 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.

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