TW201728581A - Fxr receptor agonist - Google Patents

Abstract

Provided in the present invention is a compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, ester thereof or stereoisomer thereof. Also provided in the present invention also are a method for preparing the compound and a use thereof in the preparation of a drug for preventing/treating non-alcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolic disorders, diabetic complications and malignancy. R1, R2, R3, R4, m, n, W, A, Z, E, F, X and Y are as defined in the description.

Description

FXR receptor agonist

The present invention relates to FXR receptor agonists, pharmaceutically acceptable salts thereof, esters thereof and stereoisomers thereof, pharmaceutical preparations containing the same, and compounds, pharmaceutically acceptable salts thereof, esters thereof and the like Stereoisomers are useful in the preparation of a medicament for the treatment and/or prevention of FXR receptor-mediated non-alcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolic disorders, diabetic complications, and malignant tumors. the use of.

The FXR receptor (farnesol X receptor) is a member of the ligand-priming transcription factor nuclear receptor family and has a typical nuclear receptor structure, ie, a highly conserved DNA binding region (DBD) at the amino terminus, and a carboxy terminal ligand binding. The region (LBD), the amino-terminal ligand-independent transcription initiation functional region (AF1), the carboxy-terminal ligand-dependent transcription initiation functional region (AF2), and the anklet region. FXR forms a heterodimer with the retinoid X receptor (RXR). When the ligand binds to the LBD region of FXR, the FXR conformation can be altered, and the binding region of the DNA binds to the FXR response element of the target gene promoter. (IR-1) above, the release of the secondary inhibition factor (such as NCOR), recruited a secondary start factor, thereby playing a transcriptional regulatory role.

FXR is expressed in many organ tissues, including adipose tissue, liver, gastrointestinal tract, kidney, etc., and the liver is most abundantly expressed. The FXR signaling pathway can directly or indirectly regulate the expression of multiple downstream genes, such as BSEP, SHP, CYP7A1, FGFR4, OSTα/β, SREBP-1C, etc., thereby regulating various metabolic pathways such as triglycerides, cholesterol, and blood glucose. And energy stability metabolism of bile acid metabolism, has the function of treating cancer, non-alcoholic fatty liver disease, metabolic disorders, inflammation and other diseases. By inhibiting the synthesis, binding and transport of cholic acid, and regulating its metabolism, it is the main regulator of bile acid balance in the body.

Some natural bile acids can agonize FXR receptors such as chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and taurine and glycine conjugates of these cholic acids. In addition to natural compounds, FXR agonists currently developed internationally can be divided into two major categories, one is steroids, represented by Intercept's obetic acid (OCA), for nonalcoholic fatty liver adaptation. Symptoms, in clinical stage III; the other is a novel molecular entity, an early developed compound such as GW4604 (WO2000/037077), although it has strong agonistic activity, it is unstable to light and has low bioavailability. In addition, Phenex The company's PX-104 (WO2011020615A1) has been transferred to Gilead and is currently in Phase II clinical phase.

However, it is still hoped that a new type of FXR receptor agonist with high efficiency, low toxicity and good stability can be developed.

An object of the present invention is to provide a compound having a novel molecular structure which is effective for agonizing FXR receptors, enhancing the expression levels of BSEP and SHP genes, and effectively inhibiting the expression of the CYP7A1 gene. In addition, in order to achieve better therapeutic effects and better meet market demand, it is also desirable to provide FXR receptor agonists with high efficiency, low toxicity and good stability.

In particular, the object of the present invention is to provide a novel structure of FXR receptor agonist which has excellent pharmacological effects and is a FXR receptor agonist for treating nonalcoholic fatty liver disease and primary biliary cirrhosis. , lipid metabolism disorders, diabetic complications and malignant tumors offer the possibility.

Another object of the present invention is to provide a method for producing the above FXR receptor agonist.

Another object of the present invention is to provide a pharmaceutical composition and preparation containing the above FXR receptor agonist.

A further object of the present invention is to provide a medicament for the preparation of a FXR receptor agonist for the prevention and/or treatment of nonalcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications and malignant tumors. Use in.

The present inventors have conducted intensive studies in order to achieve the above object, and as a result, it has been found that a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, and a stereoisomer thereof are effective for agonizing the FXR receptor, thereby completing Up this invention.

In particular, the invention relates to the following technical solutions:

A compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof:

Wherein R ¹ and R ² are each independently selected from the group consisting of a hydrogen atom, a cyano group, a halogen atom, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 group. An alkylamino group, a di C1-6 alkylamino group, a C _1-6 alkylthio group, a C _1-6 alkylcarbonyl group, a halogenated C _1-6 alkyl group, a halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylsulfonyl, C _1-6 alkylaminosulfonyl, di C _{1- 6} alkylaminosulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyloxy, C _2-8 alkenyl or C _2-8 alkynyl; R ^{3 is} selected from hydrogen An atom, a cyano group, a halogen atom, a nitro group, an amine group, a hydroxyl group, a carboxyl group, or a C _1-6 alkyl group optionally substituted by one or more substituents P, a halogenated C _1-6 alkyl group, a hydroxyl group C _{1 -6} alkyl, carboxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, carboxy C _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylaminosulfonyl, di C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkane Sulfosulfonyloxy, 3-8 membered cycloalkyl, 3-8 membered cycloalkyl C _1-6 alkyl, 3-8 membered heterocyclic group, 3-8 membered heterocyclic C _1-6 alkyl ; P is selected from the group consisting of hydroxyl, amine, carboxyl, cyano, nitro, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di C _1-6 alkane Amino group, halogenated C _1-6 alkyl group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl group, C _1-6 alkylcarbonyl group, C _1-6 alkane a carbonyloxy group, a C _1-6 alkylsulfonyl group, a C _2-8 alkenyl group or a C _2-8 alkynyl group; and R ^{4 is} selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, Carboxyl, C _1-6 alkoxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, carboxy C _1-6 alkyl, carboxyoxy C _1-6 alkane a carboxy group, a C _1-6 alkyl group, an amino C _1-6 alkyl group, an aminocarbonyl C _1-6 alkyl group, a hydroxy C _1-6 alkoxy group, a halogenated C _1-6 alkoxy group, Carboxy C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylamino, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylaminocarbonyl, C _1-6 alkylaminosulfonyl, di C _1-6 alkylamino, 5-8 hetero Or a 3-8 membered heterocyclic group; W is selected from CH ₂ , NH, O, S, SO, SO ₂ or CO; A is selected from NH, O or S; Z is selected from one or more substituents Q Or not a substituted aryl group, a 5-8 membered heteroaryl group, a 3-8 membered cycloalkyl group or a 3-8 membered heterocyclic group; Q is selected from the group consisting of a cyano group, an amine group, a hydroxyl group, a carboxyl group, a nitro group, a halogen atom, and C. _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di C _1-6 alkylamino, halo C _1-6 alkyl, halo C _1-6 alkoxy a C _1-6 alkoxy C _1-6 alkyl group, a C _2-8 alkenyl group or a C _2-8 alkynyl group; E is selected from the group consisting of CH ₂ , NH, O, S, SO, SO ₂ or CO; Selected from the absence, CH ₂ , NH, O, S, SO, SO ₂ or CO; X is selected from CH or N; Y is selected from CH ₂ , NH, O, S, SO, SO ₂ or CO; E, X The connection between Y and F is independently selected from a single bond; m is selected from an integer from 0 to 3; and n is selected from an integer from 0 to 4.

The compound of claim 1, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a halogen atom, and a nitrate Base, amine group, hydroxyl group, carboxyl group, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylamino group, di C _1-4 alkylamino group, C _1-4 alkyl sulfide , C _1-4 alkylcarbonyl, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, C _1-4 alkylcarbonyl Oxyl, C _1-4 alkylsulfonyl, C _1-4 alkylaminosulfonyl, di C _1-4 alkylaminosulfonyl, C _2-6 alkenyl or C _2-6 alkyne R ^{3 is} selected from a hydrogen atom, a cyano group, a halogen atom, a nitro group, an amine group, a hydroxyl group, a carboxyl group, or a C _1-4 alkyl group optionally substituted by one or more substituents P, halogenated C _{1- 4-} alkyl, C _1-4 alkoxy, halogenated C _1-4 alkoxy, 3-6 membered cycloalkyl, 3-6 membered cycloalkyl C _1-4 alkyl, 3-6 membered heterocyclic ring a 3-6 membered heterocyclic group C _1-4 alkyl; P is selected from the group consisting of a hydroxyl group, an amine group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, C _1-4 alkylamino group, di C _1-4 alkylamino group, halogenated C _1-4 alkyl group, halogenated C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonyloxy, C _1-4 alkylsulfonyl, C _2-6 alkenyl or C _2-6 alkynyl; R ^{4 is} selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a C _1-4 alkoxy group, a C _1-4 alkyl group , hydroxy C _1-4 alkyl, halo C _1-4 alkyl, carboxy C _1-4 alkyl, carboxyoxy C _1-4 alkyl, carboxyamino C _1-4 alkyl, amine C _{1 -4} alkyl, aminocarbonyl C _1-4 alkyl, hydroxy C _1-4 alkoxy, halo C _1-4 alkoxy, carboxy C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 alkylamino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonyl, C _1-4 alkyl a sulfonylaminocarbonyl group, a C _1-4 alkylaminosulfonyl group, a di C _1-4 alkylamino group, a 5-6 membered heteroaryl group or a 4-7 membered heterocyclic group; W is selected from the group consisting of CH ₂ , NH, O, S, SO, SO ₂ or CO; A is selected from NH, O or S; Z is selected from aryl or 5-6 membered heteroaryl substituted or unsubstituted by one or more substituents Q, 3-6 membered cycloalkyl or 4-7 membered heterocyclic group; Q is selected from cyano, amino, hydroxy, carboxy, nitro, halogen atom, C _1-4 alkyl, C _1-4 alkoxy C _1-4 alkylamino, di-C _1-4 alkylamino, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkoxy a group, C _2-6 alkenyl or C _2-6 alkynyl; E is selected from CH ₂ , NH, O, S or CO; F is selected from the group consisting of absent, CH ₂ , NH, O or S; X is selected from CH or N; Y is selected from CH ₂ , NH, O or S; the linkage between E, X, Y, F is independently selected from a single bond; m is selected from an integer from 0 to 2; n is selected from 0 to 3 Integer.

The compound of claim 2, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a halogen atom, and a nitrate Base, amine group, hydroxyl group, carboxyl group, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylamino group, di C _1-4 alkylamino group, C _1-4 alkyl sulfide a C _1-4 alkylcarbonyl group, a halogenated C _1-4 alkyl group, a halogenated C _1-4 alkoxy group or a C _1-4 alkoxy C _1-4 alkyl group; R ^{3 is} selected from the group consisting of cyano groups, a C _1-4 alkyl group optionally substituted by one or more substituents P, a halogenated C _1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered cycloalkyl C _1-4 alkyl group, 3-6 membered heterocyclic group or 3-6 membered heterocyclic group C _1-4 alkyl; P is selected from the group consisting of a hydroxyl group, an amine group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C _1-4 alkyl group, and C _{1 a 4} -alkoxy group, a C _1-4 alkylamino group, a di-C _1-4 alkylamino group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group; R ^{4 is} selected from a hydrogen atom , halogen atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C _1-4 alkoxy group, C _1-4 alkyl group, hydroxy C _1-4 alkyl group, halogenated C _1-4 alkyl group, carboxyl group C _1-4 alkyl, carboxy-C _1-4 alkyl, carboxy C _1-4 alkyl group, amine C _1-4 alkyl, aminocarbonyl C _1-4 alkyl, hydroxy C _1-4 alkoxy, halo C _1-4 alkoxy, carboxy C _1-4 alkoxy, C _2-6 alkenyl , C _2-6 alkynyl, C _1-4 alkylamino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonyl, C _1-4 Alkylsulfonylaminocarbonyl, C _1-4 alkylaminosulfonyl, di C _1-4 alkylamino, 5-6 membered heteroaryl or 5-6 membered heterocyclic; W is selected from CH ₂ , NH, O, S, SO, SO ₂ or CO; A is selected from NH, O or S; Z is selected from phenyl substituted or unsubstituted by one or more substituents Q, containing 1-2 N a 5-6 membered heteroaryl group of an O and/or S atom, a 5-6 membered cycloalkyl group, or a 5-6 membered heterocyclic group having 1-2 N, O and/or S atoms; Q is selected from Cyano group, amine group, hydroxyl group, carboxyl group, nitro group, halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylamino group, di C _1-4 alkylamino group, Halogen C _1-4 alkyl or halo C _1-4 alkoxy; E is selected from CH ₂ , NH, O or CO; F is selected from the absence, CH ₂ , NH or O; X is selected from CH or N Y is selected from CH ₂ , NH or O; the linkage between E, X, Y, F is independently selected from a single bond; m is selected from an integer from 0 to 2; and n is selected from an integer from 0 to 3.

The compound of claim 3, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ^{3 is} selected from a cyano group, optionally substituted by one or more substituents P _1-4 alkyl, halo C _1-4 alkyl or C _3-6 cycloalkyl C _1-4 alkyl; P is selected from the group consisting of hydroxyl, amine, carboxyl, cyano, nitro, halogen atom, C _{1 -4} alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino, halo C _1-4 alkyl or halo C _1-4 alkoxy W is selected from NH, O or S; A is selected from NH, O or S; Z is selected from phenyl substituted or unsubstituted by one or more substituents Q, or contains 1-2 N, O and/ Or a 5-6 membered heteroaryl group of the S atom; Q is selected from the group consisting of a cyano group, an amine group, a hydroxyl group, a carboxyl group, a nitro group, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, and a C _1-4 An alkylamino group, a di-C _1-4 alkylamino group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group; a cyclic group composed of E, X, Y and F together with benzene The rings together form the following structure: benzodihydropyrrolyl, benzodihydrofuranyl, benzohydropyranyl, benzo1,3-dioxolyl, benzo1,4-di Oxecyclohexenyl, benzo1,3-dioxy Heterocyclohexenyl, benzotetrahydropyridyl, benzodiazepine, benzotetrahydropyrazinyl, 1,2,3,4-tetrahydroquinazolinyl, 1,2,3, 4-tetrahydroporphyrinyl, indanyl, tetrahydronaphthyl, tetralone; n is selected from an integer from 0 to 3.

The compound of claim 4, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof: R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, Bromine atom, nitro group, amine group, hydroxyl group, carboxyl group, methyl group, ethyl group, propyl group, butyl group, methoxy group, methylamino group, ethyl fluorenyl group, trifluoromethyl group, trifluoroethyl group or trifluoro Methoxy; R ^{3 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, Cyano group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group; R ^{4 is} selected from a hydrogen atom, a halogen atom, a cyanogen Base, nitro, amine, hydroxy, carboxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, ethynyl , methylamino, ethylamino, ethyl hydrazino, etidinyl, methanesulfonyl, dimethylamino, methylsulfonylaminocarbonyl, ethylsulfonylaminocarbonyl, oxadiazole, thiazole, Isothiazole, thiadiazole, Azole or tetrazole; Z is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isomers substituted or unsubstituted with one or more substituents Q An azolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl group; Q is selected from the group consisting of cyano, amine, hydroxy, carboxy, nitro, halogen atom, C _1-4 alkyl, C _1-4 Alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino, halo C _1-4 alkyl or halo C _1-4 alkoxy; E, X, Y, F together The cyclic group formed together with the benzene ring forms the following structure: n is selected from an integer of 0-2.

The compound of claim 5, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof: a cyclic group composed of E, X, Y and F together with a benzene ring forms the following structure : , , , , , or ;n is selected from 1 or 2.

The compound of claim 6, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof: R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, Methyl, ethyl, propyl, butyl, methoxy, methylamino, ethyl fluorenyl, trifluoromethyl or trifluoromethoxy; R ^{3 is} selected from methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or cyclobutyl R ^{4 is} selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxy group, an ethoxy group, Trifluoromethyl, trifluoromethoxy, ethoxymethyl, acetoguanyl, methylsulfonylaminocarbonyl, ethylsulfonylaminocarbonyl, oxadiazole, thiazole, isothiazole, thiadiazole, three Azole or tetrazole; W is selected from NH, O or S; A is selected from NH, O or S; Z is selected from phenyl, pyrrolyl, pyrazole substituted or unsubstituted by one or more substituents Q. Base, imidazolyl, thiazolyl, isothiazolyl Oxazolyl, isoxazolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl; Q is selected from the group consisting of cyano, amine, hydroxy, carboxy, nitro, fluorine, chlorine, bromine , methyl, ethyl, propyl, butyl, methoxy, ethylamino, dimethylamino, trifluoromethyl or trifluoromethoxy; n is selected from 1.

The compound according to the first aspect, the pharmaceutically acceptable salt thereof, the ester thereof or the stereoisomer thereof, has the structure of the following formula (I-1):

Wherein R ¹ and R ² are each independently selected from the group consisting of a hydrogen atom, a cyano group, a halogen atom, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a C _1-4 alkyl group, a C _1-4 alkoxy group, and a C _1-4 Alkylamino group, di-C _1-4 alkylamino group, C _1-4 alkylthio group, C _1-4 alkylcarbonyl group, halogenated C _1-4 alkyl group, halogenated C _1-4 alkoxy group C _1-4 alkoxy or C _1-4 alkyl; R ³ is selected from cyano, optionally substituted with one or more substituent P C _1-4 alkyl, halo C _1-4 alkyl, 3-6 membered cycloalkyl or 3-6 membered cycloalkyl C _1-4 alkyl; P is selected from the group consisting of hydroxyl, amine, carboxyl, cyano, nitro, halogen atom, C _1-4 alkyl, C _{1 a 4} -alkoxy group, a C _1-4 alkylamino group, a di-C _1-4 alkylamino group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group; R ^{4 is} selected from a hydrogen atom , halogen atom, cyano group, nitro group, amine group, hydroxyl group, carboxyl group, C _1-4 alkoxy group, C _1-4 alkyl group, hydroxy C _1-4 alkyl group, halogenated C _1-4 alkyl group, carboxyl group C _1-4 alkyl, amino C _1-4 alkyl, aminocarbonyl C _1-4 alkyl, hydroxy C _1-4 alkoxy, halogenated C _1-4 alkoxy, carboxy C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 alkylamino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonyl amine , C _1-4 alkylsulfonyl group, C _1-4 alkylsulfonyl aminocarbonyl, C _1-4 alkyl sulfonic acyl group, di C _1-4 alkylamino or a 5-6 membered heteroaryl Aryl; W is selected from CH ₂ , NH, O, S, SO or SO ₂ ; A is selected from NH, O or S; Z is selected from phenyl or 5 substituted or unsubstituted by one or more substituents Q -6 membered heteroaryl; Q is selected from the group consisting of cyano, amine, hydroxy, carboxy, nitro, halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, Di-C _1-4 alkylamino, halo C _1-4 alkyl or halo C _1-4 alkoxy; E is selected from CH ₂ , NH, O or CO; F is selected from the absence, CH ₂ , NH or O; X is selected from CH or N; Y is selected from CH ₂ , NH or O; the linkage between E, X, Y, F is independently selected from a single bond; n is selected from an integer from 0 to 3.

The compound of claim 8, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a fluorine atom, and a chlorine atom. Atom, bromine atom, nitro, amine, hydroxy, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, methylamino, B Anthracenyl, trifluoromethyl, trifluoroethyl or trifluoromethoxy; R ^{3 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Trifluoromethyl, trifluoroethyl, trifluoropropyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, ring Butylmethyl or cyclohexylmethyl; R ^{4 is} selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a hydroxymethyl group, Hydroxyethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, ethynyl, methylamino, ethylamino, ethyl hydrazino, ethenyl, methylsulfonyl, methyl Sulfonylcarbonyl, ethylsulfonate Aminocarbonyl, dimethylamino, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, triazole or tetrazol; W is selected from CH _2, NH, O or S; A is selected from NH, O or S; Z is selected from phenyl or 5-6 membered heteroaryl substituted or unsubstituted by one or more substituents Q; Q is selected from cyano, amine, Hydroxy, carboxyl, nitro, halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino, halogen C _1-4 Alkyl or halo C _1-4 alkoxy; E is selected from CH ₂ , NH, O or CO; F is selected from the absence, CH ₂ , NH or O; X is selected from CH or N; Y is selected from CH ₂ , NH or O; the connection between E, X, Y, F is independently selected from a single bond; n is selected from 1 or 2.

The compound of claim 9, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a fluorine atom, and a chlorine atom. Atom, methyl, ethyl, propyl, butyl, methoxy, methylamino, ethyl fluorenyl, trifluoromethyl or trifluoromethoxy; R ^{3 is} selected from methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or Cyclobutylmethyl; R ^{4 is} selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxy group, and an ethoxy group. Base, trifluoromethyl, trifluoromethoxy, ethionyl, acetoguanyl, methylsulfonylaminocarbonyl, ethylsulfonylaminocarbonyl, oxadiazole, thiazole, isothiazole, thiadiazole , triazole or tetrazole; W is selected from NH, O or S; A is selected from NH, O or S; Z is selected from phenyl or pyridyl substituted or unsubstituted by one or more substituents Q, The substituent Q is selected from the group consisting of a cyano group and an amine. , A hydroxyl group, a carboxyl group, a nitro group, a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _1-4 alkylamino, halo C _{1- 4} alkyl or halo C _1-4 alkoxy; E is selected from CH ₂ , NH, O or CO; F is selected from CH ₂ , NH or O; X is selected from CH or N; Y is selected from CH ₂ , NH Or the connection between O; E, X, Y, F is independently selected from a single bond; n is selected from 1 or 2.

The compound according to claim 10, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein a cyclic group composed of E, X, Y and F together with a benzene ring forms the following Structure: benzohydropyranyl, benzo1,4-dioxanyl, benzo1,3-dioxanyl, benzotetrahydropyridyl, benzodihydro Oxazinyl, benzotetrahydropyrazinyl, 1,2,3,4-tetrahydroquinazolinyl, 1,2,3,4-tetrahydroporphyrinyl, four Hydronaphthyl, tetralone.

The compound of claim 11, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein Z is selected from phenyl substituted or unsubstituted by one or more substituents Q, The substituent Q is selected from the group consisting of a cyano group, an amine group, a hydroxyl group, a carboxyl group, a nitro group, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, a C _1-4 alkylamino group, and a C. _{a 1-4} alkylamino group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group; a cyclic group composed of E, X, Y and F together with a benzene ring forms the following structure: , , , , , or .

The compound of claim 12, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein W is selected from O; A is selected from O; and Z is selected from 1-2 substituents. a substituted or unsubstituted phenyl group, wherein the substituent Q is selected from the group consisting of a cyano group, an amine group, a hydroxyl group, a carboxyl group, a nitro group, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a methoxy group, Ethoxy, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy; a cyclic group of E, X, Y, F together with the benzene ring forms the following structure: n is selected from 1.

The compound of claim 9, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a fluorine atom, and a chlorine atom. Atom, methyl, ethyl, propyl, butyl, methoxy, methylamino, ethyl fluorenyl, trifluoromethyl or trifluoromethoxy; R ^{3 is} selected from methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or Cyclobutylmethyl; R ^{4 is} selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxy group, and an ethoxy group. Base, trifluoromethyl, trifluoromethoxy, ethionyl, acetoguanyl, methylsulfonylaminocarbonyl, ethylsulfonylaminocarbonyl, oxadiazole, thiazole, isothiazole, thiadiazole , triazole or tetrazole; W is selected from NH, O or S; A is selected from NH, O or S; Z is selected from phenyl or pyridyl substituted or unsubstituted by one or more substituents Q, The substituent Q is selected from the group consisting of a cyano group and an amine. , A hydroxyl group, a carboxyl group, a nitro group, a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _1-4 alkylamino, halo C _{1- 4} alkyl or halo C _1-4 alkoxy; E is selected from CH ₂ , NH or O; F is selected from the absence; X is selected from CH or N; Y is selected from CH ₂ or O; E, X, Y The connection between F and F is independently selected from a single bond; n is selected from 1 or 2.

The compound of claim 14, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein a cyclic group which is composed of E, X and Y together with a benzene ring forms the following structure : benzodihydropyrrolyl, benzodihydrofuranyl, benzo1,3-dioxolyl or indanyl.

The compound of claim 15, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein W is selected from O; A is selected from O; and Z is selected from one or more substituents. a substituted or unsubstituted phenyl group, the substituent Q being selected from the group consisting of a cyano group, an amine group, a hydroxyl group, a carboxyl group, a nitro group, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, C _{a 1-4} alkylamino group, a di C _1-4 alkylamino group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group; a cyclic group composed of E, X, Y and F Together with the benzene ring, the group forms the following structure:

The compound of claim 9, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein Z is selected from phenyl substituted or unsubstituted by one or more substituents Q; Q is selected from the group consisting of cyano, amine, hydroxy, carboxyl, nitro, halogen atom, methyl, ethyl, propyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, three Fluoromethyl or trifluoromethoxy; E is selected from CH ₂ , O or CO; F is selected from the absence, CH ₂ or O; X is selected from CH or N; Y is selected from CH ₂ ; E, X, Y, The manner of attachment between F is independently selected from a single bond; n is selected from 1 or 2.

The compound of claim 17, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein E is selected from O or CH ₂ ; F is selected from the absence, CH ₂ or O; It is selected from CH; Y is selected from CH ₂ ; the linkage between E, X, Y, and F is independently selected from a single bond; n is selected from 1.

The compound of claim 18, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein E is selected from O; F is selected from the absence or CH ₂ ; X is selected from CH; Y The linking means selected from CH ₂ ; E, X, Y, F are each independently selected from a single bond; n is selected from 1.

The compound of claim 19, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein a cyclic group composed of E, X, Y, and F together with a benzene ring forms the following Structure:

The compound of claim 17, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein E is selected from CH ₂ ; F is selected from the absence or CH ₂ ; X is selected from N; Y is selected from CH ₂ ; the linkage between E, X, Y, and F is independently selected from a single bond; n is selected from 1.

The compound of claim 17, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein E, X, Y, and F are each independently selected from CH ₂ ; E, X, Y The connection between F and F is independently selected from a single bond; n is selected from 1.

The groups between the above schemes may be arbitrarily combined, and the obtained technical schemes are all described herein.

Part of the compounds of the invention

Detailed description of the invention

The "halogen atom" as used in the present invention includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The "C _1-6 alkyl group" as used in the present invention means a straight or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, "C _1-4 alkyl group" or "C _1-3 alkyl group". Etc. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, 1,1-dimethylethyl , n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, or 1,2-dimethylpropyl, and the like.

The present invention is "C _1-4 alkyl" denotes a straight-chain or branched-chain alkyl group having 1-4 carbon atoms, including, for example, "C1 _-4 alkyl", "C _1-3 alkyl" and the like Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-methylpropyl, or 1,1-dimethylethyl Wait.

The "C _2-8 alkenyl group" as used in the present invention means a linear or branched alkenyl group having 2 to 8 carbon atoms containing at least one double bond, and includes, for example, "C _2-6 alkenyl group", C _2-4 alkenyl", "C _2-3 alkenyl" and the like, specific examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 2-methyl-1-butenyl, 3 -methyl-1-butenyl, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 1-methyl-2-pentenyl, 3-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2 - dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butene Alkenyl, 2,3-dimethyl-1-butenyl, 2-ethyl-1-butenyl, 2-ethyl-3-butenyl, 2-heptenyl, 3-heptenyl 4-heptenyl, 1-octenyl, 3-octenyl, 4-octenyl, 1,3-butadiene , 2,4-pentadienyl, 1,4-hexadienyl, 2,4-hexadienyl, 1,5-heptadienyl, 2,5-heptadienyl, or 2, 6-octadienyl and the like.

The "C _2-8 alkynyl group" as used in the present invention means a linear or branched alkynyl group having 2 to 8 carbon atoms and having a triple bond, and includes, for example, "C _2-6 alkynyl group", "C". _2-4 alkynyl", "C _2-3 alkynyl" and the like, specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1- Ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3- Pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, 2-heptynyl, 3-heptynyl, 4-methyl-2-hexyne , 5-methyl-2-hexynyl, 2-methyl-3-hexynyl, 5-methyl-3-hexynyl, 2-methyl-4-hexynyl, 4-methyl -5-hexynyl, 2-octynyl, 3-octynyl, 4-octynyl, 4-methyl-2-heptynyl, 5-methyl-3-heptynyl, 6-A Alkyl-3-heptynyl, 2-methyl-4-heptynyl, 2-methyl-5-heptynyl, or 3-methyl-6-heptynyl, and the like.

The "C _1-6 alkoxy group, C _1-6 alkylamino group, di C _1-6 alkylamino group, C _1-6 alkylthio group, C _1-6 alkylcarbonyl group, C _1-6 alkylcarbonyloxy, C _1-6 alkylsulfonyl, C _1-6 alkylaminosulfonyl, di C _1-6 alkylaminosulfonyl, C _1-6 alkane A sulfonylamino group, a C _1-6 alkylsulfonyloxy group, a C _1-6 alkylsulfonylaminocarbonyl group, refers to a C _1-6 alkyl-O-, C _1-6 alkyl group- NH-, (C _1-6 alkyl) ₂ -N-, C _1-6 alkyl-S-, C _1-6 alkyl-C(O)-, C _1-6 alkyl-C(O) -O-, C _1-6 alkyl-SO ₂ -, C _1-6 alkyl-NH-SO ₂ -, (C _1-6 alkyl) ₂ -N-SO ₂ -, C _1-6 alkyl a group formed by -SO ₂ -NH-, C _1-6 alkyl-SO ₂ -O-, C _1-6 alkyl-SO ₂ -NH-C(O)-, wherein "C _1-6 alkane The definition of "base" is as described above.

The "C _1-4 alkoxy group, C _1-4 alkylamino group, di C _1-4 alkylamino group, C _1-4 alkylthio group, C _1-4 alkylcarbonyl group, C _1-4 alkylcarbonyloxy, C _1-4 alkylsulfonyl, C _1-4 alkylaminosulfonyl, di C _1-4 alkylaminosulfonyl, C _1-4 alkane Sulfosamine, C _1-4 alkylsulfonyloxy, C _1-4 alkylsulfonylaminocarbonyl, means C _1-4 alkyl-O-, C _1-4 alkyl- NH-, (C _1-4 alkyl) ₂ -N-, C _1-4 alkyl-S-, C _1-4 alkyl-C(O)-, C _1-4 alkyl-C(O) -O-, C _1-4 alkyl-SO ₂ -, C _1-4 alkyl-NH-SO ₂ -, (C _1-4 alkyl) ₂ -N-SO ₂ -, C _1-4 alkyl a group formed by -SO ₂ -NH-, C _1-4 alkyl-SO ₂ -O-, C _1-4 alkyl-SO ₂ -NH-C(O)-, wherein "C _1-4 alkane The definition of "base" is as described above.

The present invention "halogenated C _1-6 alkyl, hydroxy C _1-6 alkyl, carboxy C _1-6 alkyl, amino C _1-6 alkyl, C _1-6 alkoxy C _{1- 6} alkyl, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, carboxy C _1-6 alkoxy, carboxyoxy C _1-6 alkyl, carboxyamino C _1-6 alkane And an aminocarbonyl C _1-6 alkyl group means one to more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, a hydroxyl group, an amine group, a C _1-6 alkoxy group, The carboxyl group, the carboxyoxy group, the carboxylamino group, and the aminocarbonyl group respectively form a group formed by a hydrogen atom in a C _1-6 alkyl group or a C _1-6 alkoxy group.

The present invention "halogenated C _1-4 alkyl, hydroxy C _1-4 alkyl, carboxy C _1-4 alkyl, amino C _1-4 alkyl, C _1-4 alkoxy C _{1- 4-} alkyl, halo C _1-4 alkoxy, hydroxy C _1-4 alkoxy, carboxy C _1-4 alkoxy, carboxyoxy C _1-4 alkyl, carboxyamino C _1-4 alkane And an aminocarbonyl C _1-4 alkyl group means one to more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, a hydroxyl group, an amine group, a C _1-4 alkoxy group, The carboxyl group, the carboxyoxy group, the carboxyamino group, and the aminocarbonyl group respectively substitute a group formed by a hydrogen atom in a C _1-4 alkyl group or a C _1-4 alkoxy group.

The "3-8 membered cycloalkyl C _1-6 alkyl group and the 3-8 membered heterocyclic group C _1-6 alkyl group" as used in the present invention means a 3-8 membered cycloalkyl group and a 3-8 membered heterocyclic group. The cyclic group "substitutes a group formed by a hydrogen atom in a C _1-6 alkyl group.

The "3-6 membered cycloalkyl C _1-4 alkyl group, 3-6 membered heterocyclic group C _1-4 alkyl group" as used in the present invention means 3-6 membered cycloalkyl group, 3-6 membered hetero The cyclic group "substitutes a group formed by a hydrogen atom in a C _1-4 alkyl group.

The "aryl group" as used in the present invention means an aromatic ring such as a phenyl group, a naphthyl group, an anthracenyl group or the like.

The "5-8 membered heteroaryl group" as used in the present invention means a cyclic group having 5 to 8 unsaturated ring atoms containing at least one hetero atom, and the hetero atom has nitrogen, oxygen and sulfur. , including carbon atoms, nitrogen atoms and sulfur atoms The case of oxo. Including, for example, "5-7-membered heteroaryl", "5-6-membered heteroaryl", "7-8-membered heteroaryl", specifically "5" containing 1 to 3 O, S, and/or N -8-membered heteroaryl", "5-8-membered heteroaryl containing 1 to 2 O, S, and/or N", "5-8-membered impurities containing 2 to 3 O, S, and/or N" "Aryl", "5-6 membered heteroaryl containing 1-2 N, O and/or S atoms", "6-membered heteroaryl containing 1-2 N, O and/or S atoms". Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1, 2,3-Triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5- Oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, or 1,2,4,5-tetrazinyl, and the like.

"3-8 membered cycloalkyl" means a partially saturated or saturated monocyclic cyclic alkyl group derived from a hydrogen atom of 3 to 8 carbon atoms, including, for example, a "3-6 membered cycloalkyl group". "4-7 membered cycloalkyl group", "4-6 membered cycloalkyl group", "5-6 membered cycloalkyl group" and the like. Specifically, it may be "3-8 membered saturated cycloalkyl group", "3-8 membered partially saturated cycloalkyl group", "5-6 membered saturated cycloalkyl group", or "5-6 membered partially saturated cycloalkyl group". The 3-8 membered saturated cycloalkyl group includes, but is not limited to, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, methylcyclopropane, dimethyl Base cyclopropane group, methylcyclobutane group, dimethylcyclobutane group, methylcyclopentyl group, dimethylcyclopentyl group, methylcyclohexane group, dimethylcyclohexane group, etc. A 3-8 membered partially saturated cycloalkyl group includes, but is not limited to, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadienyl or cyclooctenyl.

"3-8 membered heterocyclyl" means a saturated or partially saturated monocyclic heterocycle containing from 3 to 8 ring atoms and containing at least one hetero atom (eg 1, 2, 3, 4 or 5 heteroatoms) A group obtained by removing a hydrogen atom from a compound. Including, for example, "3-7 membered heterocyclic group", "3-6 membered heterocyclic group", "3-5 membered heterocyclic group", "4-7 membered heterocyclic group", "4-6 membered heterocyclic group" ""5-6 membered heterocyclic group", 6-7 membered heterocyclic group", "6-8 membered heterocyclic group", etc. Specifically, it may be: "containing 1-2 N, O and/or S atoms. 3-8 membered heterocyclic group", "3-8 membered saturated heterocyclic group containing 1-2 N, O and/or S atoms", "5-6 membered saturated heterocyclic group", "1-containing 2 5-6 membered heterocyclic groups of N, O and/or S atoms", "5-6 membered saturated heterocyclic group containing 1-2 N, O and/or S atoms". 3-8 member part The saturated monoheterocyclic group means a cyclic group containing a double bond or a hetero atom. The 3-8 membered saturated monoheterocyclic group means a hetero atom-containing cyclic group which is all a saturated bond. Examples include but Limited to: aziridine, 2H-azepine, diaziryl, 3H-diazapropenyl, azetidinyl, 1,4-dioxanyl , 1,3-dioxanyl, 1,3-dioxolyl, 1,4-dioxadienyl, tetrahydrofuranyl, dihydropyrrolyl, pyrrolidinyl, Imidazolidinyl, 4,5-dihydroimidazolyl Pyrazolidinyl, 4,5-dihydropyrazolyl, 2,5-dihydrothiophenyl, tetrahydrothiophenyl, 4,5-dihydrothiazolyl, acridinyl, pyridazinyl, morpholinyl, 4,5-Dihydrooxazolyl, 4,5-dihydroisoxazolyl, 2,3-dihydroisoxazolyl, 2H-1,2-oxazinyl, 6H-1,3-oxazine , 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one, 3,4-dihydro-2H-pyranyl , 2,5-dihydrothiophenyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl, 1,2,3,6-tetrahydro Pyridyl, 1,2,3,4-tetrahydropyridyl, or 2,3,4,5-tetrahydropyridyl or the like.

The "hetero atom" as used in the present invention means N, O, S, SO, and/or SO ₂ or the like, and preferably N, O, and S.

"Partially saturated" as used herein means that the ring portion includes at least one double or triple bond.

"F is selected from the absence of" as used in the present invention means that Y is directly bonded to a phenyl group.

The cyclic group formed by E, X, Y, and F together with the benzene ring may form the following structure: , , , or Among them, preferred , , , , , or , further preferred , , , , or .

Further, the present invention provides a method of producing a compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, and a stereoisomer thereof.

Specifically, the preparation method includes, but is not limited to, the following route (wherein the abbreviations represent the following definitions: DCM: dichloromethane; DMF: N, N-dimethylformamide; DMSO: two Methyl hydrazine; EA: ethyl acetate; MeOH: methanol; NBS: N-bromosuccinimide; NCS: N-chlorobutanediimide; PE: petroleum ether; THF: tetrahydrofuran; DIBAL- H: diisobutylaluminum hydride; Pd(dppf)Cl ₂ :[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride); PPTS: p-toluenesulfonic acid pyridinium; DHP: 3,4-2H-dihydropyran; TFAA: trifluoroacetic anhydride; LiHMDS: lithium bis(trimethylsulfonyl)amine; TBSCl: tert-butyldimethylchloromethane; TBAF: tetrabutyl fluoride Ammonium trihydrate; DEAD: diethyl azodicarboxylate):

R ¹ , R ² , R ³ , R ⁴ , m, n, W, A, Z, E, F, X, and Y are as described above, and A' represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The specific exemplary steps are as follows:

1. Preparation of intermediate 1

The starting material 1 is dissolved in an organic solvent (for example, a lower alcohol such as ethanol), and the starting material 2 is slowly added in portions, and after adding, an alkaline solution (for example, a NaOH solution or the like) is added, and the mixture is heated to 60° C. to 90° C. -48 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure.

2. Preparation of intermediate 2

The intermediate 1 is dissolved in an organic solvent (for example, DMF or the like), and an electrophilic substitution reagent (for example, N-chlorobutylimine or the like) is slowly added in portions, and after the addition, the mixture is stirred for 0.2 to 5 hours, and the reaction solution is stirred. Pour into the water. It is extracted with an organic solvent (e.g., ethyl acetate, etc.), and washed with organic water and saturated sodium chloride, and dried to remove the solvent.

3. Preparation of intermediate 3

The intermediate 2 is dissolved in an organic solvent (e.g., triethylamine, etc.), and the starting material 3 is added, and the reaction is carried out for 5-20 hours. After completion of the reaction, the solvent is removed under reduced pressure, and the residue is purified by column chromatography (e.g., PE: EA = 10:1).

4. Preparation of intermediate 4

The intermediate 3 is dissolved in an organic solvent (for example, tetrahydrofuran, etc.), cooled in an ice bath, and a toluene solution of diisobutylaluminum hydride (DIBAL-H) is added, and the reaction is heated to 20-30 ° C for 5-20 hours. After completion, the reaction is quenched by adding a saturated halogenating agent (for example, an ammonium chloride solution, etc.), and extracted with an organic solvent (for example, ethyl acetate or the like), and the organic phase is saturated with a halogenating agent (for example, an ammonium chloride solution and chlorination). The sodium solution or the like is washed, dried, and the solvent is removed to obtain Intermediate 4.

5. Preparation of intermediate 5

The intermediate 4 is dissolved in an organic solvent (for example, dichloromethane or the like), triethylamine is added, and then a halide (for example, phosphorus trichloride, phosphorus tribromide, etc.) is added, and the reaction is carried out at 20 to 40 ° C for 0.5 to 5 hours. After completion of the reaction, the solvent is removed, and column chromatography (for example, PE: EA = 10:1) yields Intermediate 5.

6. Preparation of intermediate 6

Prepare or purchase intermediate 6.

7. Preparation of intermediate 7

The intermediate 6 is dissolved in an organic solvent (for example, N,N-dimethylformamide, acetonitrile, toluene, etc.), and an alkaline agent (for example, potassium carbonate, cesium carbonate, sodium iodide, etc.) and an intermediate 5 are added. Mix at 0-100 ° C (0.5-24 hours). Dilute with an organic solvent (such as ethyl acetate, etc.), wash with a saturated halogenating agent (such as sodium chloride solution, etc.) or water, dry, concentrate, and chromatographic column chromatography (for example, ethyl acetate: petroleum ether = 1:1 - 10, dichloromethane: methanol = 15:1) purified intermediate 7.

8. Preparation of a compound of formula (I)

The intermediate 7 is dissolved in an organic solvent (for example, methanol/water, tetrahydrofuran, methanol, tetrahydrofuran/methanol, methanol/tetrahydrofuran/water, etc.), and a basic compound (for example, lithium hydroxide monohydrate, sodium hydroxide, etc.) is added, 15 Stir at -60 ° C for 8-72 hours. The reaction solution is diluted with water, adjusted to pH 2-7 with an acidic solution (such as citric acid, hydrochloric acid, etc.), added with an organic solvent (such as ethyl acetate, etc.), and the organic phase is saturated with a halogenating agent (such as sodium chloride). The solution, etc., is washed, dried, concentrated, and purified (preferably, by preparative high performance liquid chromatography, silica gel column chromatography, etc.) to obtain a compound of the formula (I).

The "pharmaceutically acceptable salt" of the compound of the formula (I) of the present invention means a salt formed by an acidic functional group present in the compound of the formula (I) with a suitable inorganic or organic cation (base), including an alkali metal or an alkaline earth. a salt formed of a metal, an ammonium salt, and a salt formed with a nitrogen-containing organic base; and a salt formed by a basic functional group (for example, -NH ₂ or the like) present in the compound of the formula (I) and a suitable inorganic or organic anion (acid) Including with inorganic acids and with organic carboxylic acids.

The "ester" of the compound of the formula (I) of the present invention means an ester which can be formed by ester reaction with an alcohol when a compound of the formula (I) is present, and when the compound of the formula (I) has a hydroxyl group, it can be organic An ester formed by an esterification reaction of an acid, an inorganic acid, an organic acid salt or the like. The ester can be hydrolyzed to form the corresponding acid or alcohol in the presence of an acid or a base.

The "stereoisomers" of the compounds of the invention are classified into conformational and conformational isomers, while the configurational isomerism is further divided into cis-trans isomerization and optical isomerism. "Conformational isomerization" refers to a kind of arrangement in which organic molecules of a certain configuration have different arrangement of atoms or groups of molecules in space due to the rotation or distortion of carbon and carbon single bonds. Stereoisomerism, common structures of alkanes and naphthenes, such as the chair conformation and boat conformation that appear in cyclohexane structures. "Stereoisomer" means when the compound of the invention contains one or more asymmetric centers and thus acts as a racemate and a racemic mixture, a single enantiomer, a mixture of diastereomers and a single Diastereomers. The compounds of the invention have asymmetric centers, each of which independently produces two optical isomers, and the scope of the invention includes all possible optical isomers and mixtures of diastereomers and pure or partially Pure compound. If the compound of the present invention contains an olefinic double bond, the present invention includes a cis isomer and a trans isomer unless otherwise specified. The compounds of the invention may exist in tautomeric forms which have different hydrogen attachment points by displacement of one or more double bonds.

The present invention also provides a pharmaceutical composition comprising the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, an ester thereof and a stereoisomer thereof. In particular, the present invention provides a pharmaceutical composition for treating and/or preventing FXR-mediated diseases, which comprises the compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, and their stereo Isomer.

The present invention further provides a pharmaceutical preparation comprising the compound of the above formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, and a stereoisomer thereof and one or more pharmaceutically acceptable carriers and/or diluents, which may Made into any pharmaceutically acceptable dosage form. It is administered to a patient in need of such treatment by oral, parenteral, rectal or pulmonary administration. For oral administration, it can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution, an oral suspension, a syrup or the like. When preparing an oral preparation, a suitable filler, binder, disintegrating agent, Lubricants, etc. For parenteral administration, it can be prepared as an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection. When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug. When used for rectal administration, it can be made into a suppository or the like. When used for pulmonary administration, it can be prepared as an inhalant or a spray.

The present invention also provides a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof and stereoisomers thereof, for the preparation and use thereof for the treatment and/or prevention of FXR-mediated diseases and related diseases. The application of the drug. The diseases include: (1) chronic intrahepatic or some forms of extrahepatic cholestasis, or liver fibrosis caused by chronic cholestasis or acute intrahepatic cholestasis, cirrhosis, obstructive or chronic inflammation of the liver Sexual disorders, fatty liver and its complications, alcohol-related fatty liver and its complications, acute liver failure, cholelithiasis, and / or inflammatory bowel disease, primary biliary cirrhosis; due to forced lipids, In particular, triglycerides accumulate and then promote conditions and diseases caused by chronic fatty and fibrotic degeneration caused by the initiation of liver fibrosis, such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis; lipid or lipoprotein disorders such as atherosclerosis Hardening, dyslipidemia, thrombosis. (2) Clinical complications of type I or type II diabetes, including diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and other observed results of clinically dominant long-term diabetes. (3) Non-malignant hyperproliferative diseases or hyperproliferative diseases, selected from: hepatocellular carcinoma, colon adenoma and polyposis, colon adenocarcinoma, breast cancer, pancreatic cancer, esophageal cancer, and other forms of gastrointestinal and liver Neoplastic disease. (4) Abnormal blood lipid metabolism diseases including atherosclerosis, bile acid disorder, benign intrahepatic gallbladder Juice deposition, progressive familial intrahepatic cholestasis, primary biliary cirrhosis, primary sclerosing cholangitis, cholesterol gallstones, dyslipidemia, fibrosis-related diseases, chronic hepatitis, non-viral hepatitis, inflammatory bowel Disease, intestinal flora imbalance, liver transplantation, fatty liver, cirrhosis, hepatitis, liver failure, cholestasis, cholelithiasis, nonalcoholic fatty liver disease, alcoholic fatty liver disease, diabetes, myocardial infarction, stroke, thrombosis , cancer, etc.

The present invention also provides a method of treating and/or preventing a FXR-mediated disease comprising administering a compound represented by the above formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, and a stereoisomer thereof, to the treatment required The steps of the mammal.

The compound of the present invention has the following advantages: (1) The compound of the formula (I) of the present invention, a pharmaceutically acceptable salt thereof, an ester thereof and stereoisomers thereof have excellent FXR receptor agonistic activity and can be safely used. Treating and/or preventing non-alcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications, and malignant tumors; (2) a compound of the formula (I) of the present invention, which is pharmaceutically acceptable Salts, esters thereof and stereoisomers thereof exhibit good biostability, longer lasting action and high bioavailability; (3) compounds of the formula (I), pharmaceutically acceptable salts thereof, and esters thereof And their stereoisomers show low toxicity, good drug resistance and high safety.

The beneficial effects of the compounds of the present invention are further illustrated by biological experiments below, but it should not be understood that the compounds of the present invention have only the following beneficial effects.

Experimental Example 1: In vitro biochemical analysis of the compound of the present invention

(1) Test substance: The chemical name and preparation method of the compound of the present invention can be found in the preparation examples of the respective compounds.

(2) Experimental method:

The test compound was dissolved in 100% DMSO, diluted 1000 times, 160 nL, then 3.84 μL detection buffer; Target/Antibody mixture, diluted 2 times, then 8 μL solution; 4.0 μL diluted 4 times co-start peptide Incubate for 60 minutes at room temperature; after incubation, the data is detected and analyzed on a luciferograph.

(3) Experimental results and conclusions:

It can be seen from Table 1 that the compounds of the present invention have different degrees of agonistic effects on FXR, and are important for treating non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorders, diabetic complications, and malignant tumors. The meaning is especially compound 1, compound 2, compound 4, compound 5, compound 6, compound 7, compound 9.

Experimental Example 2: Detection of in vitro cell level of the compound of the present invention

Test substance: The compound of the present invention, the chemical name thereof and the preparation method are shown in the preparation examples of the respective compounds.

(2) Experimental method:

A polystyrene-TC treated microwell reaction plate (Corning Cat. #3712) was used in this experiment.

1000× compound 40 nL was added to the experimental plate together with 4 μL of the analysis medium; 32 μL of the cells were added to the assay medium and diluted to the appropriate cell density and added to the experimental plate; 4 μL of the analysis medium was added to all wells for the final analysis volume. 40 μL; the plate was incubated for 16-24 h in a 37 ° C / 5% CO ₂ humidified incubator; then 8 μL of substrate was added to the assay plate; the plate was incubated for 2 h at room temperature, protected from light; Fluorescent microplate reader (Tecan Safire ² ) was used to analyze the data.

(3) Experimental results and conclusions:

As can be seen from Table 2, the compounds of the present invention have different degrees of agonistic effects on UAS-bla HEK 293T cells for the treatment of nonalcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorders, diabetic complications and malignant tumors. Related diseases are of great significance, especially compound 2, compound 4 and compound 9.

Experimental Example 3: Effect of the compounds of the present invention on the relative expression of BSEP, CYP7A1 and SHP mRNA in HepG2 cells and human hepatocytes

Test substance: a compound of the present invention, its chemical name and preparation method See the preparation examples of the individual compounds.

PBS stands for phosphate buffer.

Reference drug: PX-104, the specific structure see the background art; PX-102, is the racemate of PX-104.

(2) Experimental method:

1 lay cells, add compounds and collect cells

The cells were collected by trypsinization, and the cell concentration was determined. According to the counting result, the cells were resuspended to a density of 7.5 e5 cell/mL; 6-well cell culture plates were inoculated with 2 mL of cells per well; the culture plate was placed in an incubator at 37 ° C. The culture was carried out for 24 hours under 5% CO ₂ conditions.

The test compound was diluted with DMSO to 12150, 4050, 1350, 450, 150, 50, 16.67, 5.56 and 1.85 μM; 5 μL of the stock solution obtained by the previous dilution was added to 5 mL of the medium, respectively. The working fluid concentrations obtained were 12150, 4050, 1350, 450, 150, 50, 16.67, 5.56, 1.85 nM, respectively. The control medium was prepared by using an equal volume of DMSO instead of the stock solution; the cell culture plate was taken out from the incubator, the medium was removed, the working solution and the control medium were added; the plate was returned to the incubator at 37 ° C, 5% CO ₂ conditions. Cultivate for 24 hours.

After 24 hours of treatment, the cell culture plates were removed from the incubator, the medium was removed, and the cells were washed 3 times with pre-cooled (4 ° C) PBS; 200 μL of trypsin (preheated to 37 ° C) was added to each well, and gently shaken. The pancreatin is evenly covered on the bottom of the plate. The plate was returned to the incubator for incubation until the cells were detached from the bottom of the plate. Digestion was stopped by adding 1 mL of medium. After gently pipetting several times with a pipette, all the contents of the well were aspirated into a 1.5 mL Rnase-free centrifuge tube and centrifuged at 200 × g for 5 minutes. Clock; remove the supernatant and collect cell samples.

2 Extraction and purification of RNA from cell samples

Cell lysis: Prepare fresh RNA lysate (1 mL lysate plus 10 μL 2-mercaptoethanol); add 600 μL lysate to the cell sample; vortex vigorously for 1-2 minutes to completely lyse the cells; cell lysate at 12,000 × g Centrifuge for 5 minutes; transfer the supernatant to a RNase-free 1.5 mL centrifuge tube.

RNA extraction and purification: add an equal amount of 70% ethanol to the cell lysate; shake the tube vigorously, mix well, and disperse as much as possible after the ethanol is precipitated; place the adsorption column on the collection tube and transfer the mixture to the adsorption In the column. Transfer up to 700 μL at a time; centrifuge at room temperature 12,000 x g for 15 seconds. Discard the solution in the collection tube and reposition the column on the collection tube; transfer all remaining mixture to the column. Add 700 μL of eluent I to the adsorption column; centrifuge at room temperature 12,000 x g for 15 seconds. The column was placed on a new collection tube; 500 μL of Eluent II was added to the column; and centrifuged at 12,000 x g for 15 seconds at room temperature. Discard the solution in the collection tube and reposition the adsorption column on the collection tube; add 500 μL of eluent II to the adsorption column; centrifuge at 12,000 × g for 1-2 minutes at room temperature, and place the adsorption column on the RNA collection tube. Add 50 μL of RNase-free water to the center of the column, incubate for 1 minute at room temperature, and centrifuge at room temperature 14,000 × g for 2 minutes to elute the RNA into the collection tube.

The concentration and quality of the extracted RNA were measured. RNA was stored at -80 °C.

3RNA reverse transcription to cDNA

The RNA extracted in the second step was incubated at 70 ° C for 5 minutes to denature the RNA. Place the sample on ice after treatment; RNA samples were diluted to 200 ng/μL using RNAse-free water; 10 μL of reverse transcription solution was prepared according to the following table and mixed with 10 μL of denatured RNA. The total amount of RNA in the reverse transcription reaction was 2 μg. All reagents were placed on ice during the experiment.

Reverse transcription was performed on a G-Storm GS1 thermal cycler PCR thermal cycler. The reverse transcription process was set as follows: 25 ° C for 10 minutes → 37 ° C for 120 minutes → 85 ° C for 5 minutes → 4 ° C ∞. The reverse transcription product (cDNA) was stored at -20 °C.

4 sample qPCR experiment

According to the qPCR amplification efficiency, a qPCR experiment of the sample was performed by selecting an appropriate cDNA concentration. The cDNA sample obtained by reverse transcription in the third step was diluted 7 times with 10 μL of 60 μL of Rnase-free water.

80 μL of the reaction mixture was prepared according to the following table, and 20 μL of a 96-well PCR reaction plate was pipetted, and 3 replicates (7 μL of 100 ng per reaction well) of the cDNA sample were used.

qPCR was performed on an ABI7500 real-time quantitative PCR instrument. The program settings were as follows: 50 ° C for 2 minutes → 95 ° C for 10 minutes → 95 ° C for 15 seconds → 60 ° C for 60 seconds, of which 40 cycles were set between 95 ° C for 15 seconds and 60 ° C for 60 seconds. .

(3) Experimental results and conclusions:

/mRNA (PX-102 or PX-104)]

It can be seen from Table 3 that the compound 1 of the present invention has a good agonistic effect on BSEP (EC50nM) and SHP (EC50nM), and has a good inhibitory effect on CYP7A1; from Tables 4 to 9, it is known that the compound of the present invention is in HepG2 cells. BSEP mRNA has a good expression and is of great significance for the treatment of nonalcoholic fatty liver.

Experimental Example 4: Beagle dog pharmacokinetic experiment of the compound of the present invention

Test article: The compound of the present invention is self-made, and its chemical name and preparation method are shown in the preparation examples of each compound.

The compound of the embodiment of the invention is prepared for the test solution:

The compound of the present invention was administered intravenously (iv) with a formulation of 5% DMSO + 10% PEG 400 + 85% (28% HP-β-CD).

Preparation of 28% HP-β-CD: Weigh 2.8g of HP-β-CD (hydroxypropyl β-cyclodextrin), add a small amount of sterile water for injection and dissolve it by ultrasonic wave, then dilute to 10ml with sterile water for injection, vortex Mix well.

Weigh 18.10 mg of the compound of the present invention, add 1.65 ml of DMSO, vortex to dissolve, then add 3.3 ml of PEG400, vortex and mix, then add 28.05 ml of 28% HP-β-CD, vortex and mix, and incubate at 50 ° C. In minutes, the concentration of 0.5 mg / mL intravenous administration solution was obtained.

The compounds of the examples of the invention are administered orally (po) as 0.1% Tween 80 + 2% HPC.

Preparation of 0.1% Tween 80+2% HPC: Weigh 2g of HPC (hydroxypropylcellulose), add purified water to 100ml, stir to dissolve, add 0.1ml Tween 80, stir and dissolve, shake well. That is 0.1% Tween 80+2% HPC's blank solvent.

35.04 mg of the compound of the present invention was accurately weighed, 64 ml of the above solvent was added, and the tissue was ground for 5 minutes to make the dispersion uniform, and the mixture was ground into a fine and uniform suspension, that is, a suspension solution was administered by intragastric administration at a concentration of 0.5 mg/mL.

experimental method

The test solution is administered according to the following method:

Blood collection time point:

Iv: 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h, 48h.

Po: 0.167h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h, 48h, 72h.

Plasma collection: fixed animals, 400 μl of blood was collected through the forelimb vein at each time point, placed in an EDTA-K ₂ anticoagulation tube, and the blood samples were mixed and centrifuged at 8000 rpm for 6 minutes at 4 ° C to separate the plasma. Store in a freezer at -80 °C.

Plasma sample analysis:

Plasma sample analysis was performed by protein precipitation method: 20 μl of plasma was aspirated, 200 μl of internal standard containing Tolbutamide (toluene) (50 ng/ml in acetonitrile) was added, vortexed at 1000 rpm for 10 minutes, centrifuged at 4000 rpm for 20 minutes, and aspirated. 100 μl of the supernatant, add 100 μl of water, vortex and mix. LC-MS/MS analysis.

Experimental results:

The compounds of the examples of the invention have high exposure, long half-life and bioavailability of more than 50%.

The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

Preparation Example 1: Preparation of (E)-2,6-dichlorobenzaldehyde oxime

2,6-Dichlorobenzaldehyde (25 g, 0.14 mol) was dissolved in ethanol (200 mL), and hydroxylamine hydrochloride (11 g, 0.16 mol) was slowly added in portions. After the addition, NaOH solution (6.4 g, 0.16 mol, dissolved) was added. In 100 mL of water), the mixture was heated to 90 ° C for 24 hours. After completion of the reaction, the solvent was evaporated, evaporated, evaporated, evaporated

Preparation 2: Preparation of (Z)-2,6-dichloro-N-hydroxyiminobenzyl chloride

(E)-2,6-Dichlorobenzaldehyde oxime (25.9 g, 0.136 mol) was dissolved in DMF (300 mL), and N-chlorobutanediamine (18.2 g, 0.136 mol), after the addition was completed, the mixture was stirred at 25 ° C for one hour, and the reaction solution was poured into water (500 mL). The organic layer was washed with EtOAc (EtOAc) (EtOAc)

Preparation 3: Preparation of ethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate

(Z)-2,6-Dichloro-N-hydroxyiminobenzyl chloride (28 g, 0.125 mol) was dissolved in triethylamine (100 mL), and ethyl 3-cyclopropyl-3-oxopropionate was added. (19.5 g, 0.125 mol), reacted at 25 ° C for 12 hours. After completion of the reaction, the solvent was evaporated under reduced pressure.

Preparation 4: Preparation of (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol

Ethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate (20 g, 61.3 mmol) was dissolved in tetrahydrofuran (300 mL). A solution of aluminum hydride (DIBAL-H) in toluene (1.5 mol / L, 123 mL, 0.184 mol), after the addition is completed, the temperature is raised to 25 ° C for 12 hours, the reaction is completed, ice bath, quenched with saturated ammonium chloride solution (200 mL) The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. 16 g, yield 92.0%.

Preparation 5-1: Preparation of 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (5.0 g, 17.6 mmol) was added to dichloromethane (30 mL) and triethylamine was added. (1.78 g, 17.6 mmol), then phosphorus tribromide (4.77 g, 17.6 mmol) was added and reacted at 30 ° C for 2 hours. After the completion of the reaction, the solvent was evaporated, and then purified by column chromatography (PE: EA = 10:1).

Preparation 5-2: Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (5.0 g, 17.6 mmol) was added to dichloromethane (30 mL) and triethylamine was added. (1.78 g, 17.6 mmol), then phosphorus trichloride (2.42 g, 17.6 mmol) was added and reacted at 30 ° C for 2 hours. After the completion of the reaction, the solvent was evaporated, and then purified by column chromatography (PE: EA = 10:1) to give the title compound 3.60 g.

Example 1 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of Hydropyran-6-carboxylic Acid (Compound 1)

(1) Preparation of (E)-1-(5-bromo-2-hydroxyphenyl)-3-(2-chloro-4-hydroxyphenyl)propane-2-en-1-one

1-(5-Bromo-2-hydroxyphenyl)ethanone (40.7 g, 189.26 mmol) and 2-chloro-4-hydroxybenzaldehyde (30 g, 191.61 mmol) were dissolved in ethanol (1000 mL). Potassium (42.56 g, 760 mmol). The reaction mixture was stirred at room temperature for 24 hr, EtOAc (EtOAc)

(2) Preparation of 6-bromo-2-(2-chloro-4-hydroxyphenyl)chroman-4-one

(E)-1-(5-Bromo-2-hydroxyphenyl)-3-(2-chloro-4-hydroxyphenyl)propan-2-en-1-one (42 g crude) was dissolved in acetic acid (500 mL) Concentrated hydrochloric acid (100 mL) was added and heated to reflux for 4 days. After cooling to room temperature, it was diluted with ethyl acetate (2 mL).

(3) Preparation of 4-(6-bromo-chroman-2-yl)-3-chlorophenol

Mercury dichloride (39.4 g, 0.1449 mol) was dissolved in 5 mol/L hydrochloric acid (500 mL), zinc powder (92.7 g, 1.449 mol) was added in portions, the controlled temperature was less than 20 ° C, and the mixture was stirred at room temperature for 30 minutes after the addition. The liquid was poured off, and a solid was added to 5 mol/L hydrochloric acid (500 mL), and the mixture was stirred at room temperature for 5 minutes, and the liquid was poured off. In the residual solid Add 5 mol/L hydrochloric acid (1000 mL) and 6-bromo-2-(2-chloro-4-hydroxyphenyl)chroman-4-one (34 g crude) in toluene (500 mL). The mixture was heated to 80 ° C for 4 hours, cooled to room temperature, extracted with ethyl acetate (400 mL×2). 5) Purification gave the title compound 11 g, m.

(4) Preparation of 2-(2-chloro-4-hydroxyphenyl)chroman-6-carbonitrile

4-(6-Bromo-chroman-2-yl)-3-chlorophenol (11 g, 32.5 mmol) was dissolved in N-methylpyrrolidone (200 mL) and zinc cyanide (2 g, 17 mmol) was added. And tetrakis(triphenylphosphine)palladium (1.87 g, 1.62 mmol), heated to 110 ° C under nitrogen for reaction overnight. After cooling to room temperature, it was diluted with ethyl acetate (500 mL), washed with a saturated sodium chloride solution (200 mL×3), dried over anhydrous sodium sulfate and evaporated. 5) Purification gave the title compound 3.1 g (yield: 33%).

(5) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl)chroman-6-carboxylate

2-(2-Chloro-4-hydroxyphenyl)-chroman-6-carbonitrile (3.1 g, 10.85 mmol) was dissolved in methanol (100 mL), and concentrated sulfuric acid was added dropwise with stirring at room temperature ( 10 mL), after heating, was heated to reflux for 4 days. After cooling to room temperature, it was diluted with ethyl acetate (500 mL), washed with a saturated sodium chloride solution (200 mL×3), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification gave the title compound (2 g).

(6) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of methyl hydrogenpyran-6-carboxylate

Methyl 2-(2-chloro-4-hydroxyphenyl)chroman-6-carboxylate (2 g of crude) was dissolved in N,N-dimethylformamide (30 mL). Sodium (1.89 g, 12.60 mmol), potassium carbonate (2.61 g, 18.90 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole ( 2.27 g, 7.50 mmol) of N,N-dimethylformamide solution (20 mL), warmed to 60 ° C and stirred overnight. After being diluted with ethyl acetate (200 mL), EtOAc (EtOAc m. The product was obtained (1.2 g crude).

(7) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of hydropyran-6-carboxylic acid

2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzodihydropyrrol Methyl -6-carboxylate (1.2 g, 2.00 mmol) was dissolved in methanol / water (100 mL / 20 mL). The reaction solution was diluted with water (100 mL), and the pH was adjusted to 3 with citric acid aqueous solution, ethyl acetate (500 mL) was added, and the mixture was separated. The organic phase was washed with a saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate.

Molecular formula: C ₂₉ H ₂₂ Cl ₃ NO ₅ Molecular weight: 570.85 LC-MS (negative, m/z): 570 (M+H) ⁺

¹ H-NMR (300MHz, CD ₃ OD) δ: 7.82-7.77 (m, 2H), 7.54-7.38 (m, 4H), 6.90-6.79 (m, 3H), 4.94-4.85 (m, 2H), 3.09 -2.98 (m, 1H), 2.86-2.81 (m, 2H), 2.37-2.25 (m, 2H), 1.97-1.90 (m, 1H), 1.30-1.19 (m, 4H).

Example 2 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2, 3-dihydrobenzofuran-5-carboxylic acid (Compound 2)

(1) Preparation of 2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde

2-Chloro-4-hydroxybenzaldehyde (1.0 g, 6.38 mmol), 3,4-dihydropyran (1.1 g, 13.1 mmol) and p-toluenesulfonic acid pyridinium (0.8 g, 3.18 mmol) were added to Methyl chloride (100 mL) was reacted at 25 ° C for 4 hours. After the reaction was completed, the residue was evaporated. mjjjjjjj

(2) Preparation of 2-(2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2,3-dihydrobenzofuran-5-carboxylic acid methyl ester

2-Chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde (1.1 g, 4.57 mmol), methyl 3-methyl-4-nitrobenzoate (1.07 g) , 5.48 mmol), N,N-diisopropylethylamine (1.24 g, 9.6 mmol) and tetrabutylammonium fluoride (8.2 mL, 8.2 mmol, 1 M in tetrahydrofuran) were added sequentially to tetrahydrofuran (10 mL), 80 After reacting for 16 hours at ° C., the solvent was evaporated.

(3) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl)-2,3-dihydrobenzofuran-5-carboxylate

Methyl 2-(2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2,3-dihydrobenzofuran-5-carboxylate (1.1 g, 2.83 Methyl) and p-toluenesulfonic acid (0.2 g, 1.16 mmol) were added to methanol (20 mL) and reacted at 25 ° C for 2 hours. After completion of the reaction, the solvent was removed and the residue was purified by EtOAc (EtOAc) 5:1), the title compound was obtained (yield: 0.54 g).

(4) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2, Preparation of methyl 3-dihydrobenzofuran-5-carboxylate

The preparation process is as described in Example 1, reaction step (6).

(5) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2, Preparation of 3-dihydrobenzofuran-5-carboxylic acid

The preparation process is as described in Example 1, reaction step (7).

Molecular formula: C ₂₈ H ₂₀ Cl ₃ NO ₅ Molecular weight: 556.8 LC-MS (m/z): 556.2 (M+H) ⁺

¹ H-NMR (400MHz, MeOD) δ: 7.90 (d, J = 4.4 Hz, 1H), 7.86 (s, 1H), 7.42-7.51 (m, 3H), 7.27 (d, J = 8.8 Hz, 1H) , 6.89 (d, J = 4.4 Hz, 1H), 6.86 (s, 1H), 6.73 (d, J = 8.8 Hz, 1H), 6.06 (t, J = 8.8 Hz, 1H), 4.90 (s, 2H) , 3.74-3.81 (m, 1H), 3.01-3.07 (m, 1H), 2.32 (t, J = 6.0 Hz, 1H), 1.18-1.21 (m, 4H).

Example 3 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2, Preparation of 3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid (Compound 3)

(1) Preparation of 2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde

2-Chloro-4-hydroxybenzaldehyde (2 g, 12.77 mmol) and 3,4-2H-dihydropyran (1.5 g, 17.83 mmol) were added to dichloromethane (50 mL). The salt (0.3 g, 1.19 mmol) was stirred at 25 ° C for 6 hours. The reaction mixture was concentrated to give purified crystallite crystal crystal crystal crystal crystal

(2) Preparation of 2-(3-chloro-4-vinylphenoxy)tetrahydro-2H-pyran

To the tetrahydrofuran (80 mL A solution of ((tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde (2.5 g, 10.4 mmol) in tetrahydrofuran (20 mL). After adding water (100 mL) and ethyl acetate (100 mL), EtOAc (EtOAc)EtOAc. Purification (petroleum ether: ethyl acetate = 50:1) gave the title compound (2 g).

(3) Preparation of 1-(2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethane-1,2-diol

2-(3-Chloro-4-vinylphenoxy)tetrahydro-2H-pyran (1.6 g, 6.7 mmol) was dissolved in a solvent mixture of tributanol (20 mL) and water (20 mL), cold However, to 0 ° C, AD-mix-beta (2 g) was added, and the reaction was stirred at 25 ° C for 6 hours. After adding water (50 mL) and ethyl acetate (50 mL), EtOAc (EtOAc m. Purification (petroleum ether: ethyl acetate = 3:1) gave the title compound 1.2 g.

(4) 2-((Tertiary butyldimethylmethyl)oxy)-1-(2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl) Preparation of ethanol

1-(2-Chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethane-1,2-diol (1 g, 3.67 mmol) and imidazole (0.5 g) , 7.34 mmol) was dissolved in dichloromethane (20 mL), and then butyl dimethyl chloro chlorobenzene (0.7 g, 4.64 mmol) was added, and the reaction was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated to give purified crystallite crystal crystal crystal crystal crystal

(5) 4-(2-((tert-butyldimethylmethyl)oxy)-1-(2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy) Preparation of methyl phenyl)ethoxy)-3-iodobenzoate

2-((Tertiary butyldimethylmethyl)oxy)-1-(2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanol ( 1 g, 2.58 mmol), methyl 4-hydroxy-3-iodobenzoate (0.7 g, 2.52 mmol) and triphenylphosphine (0.8 g, 3.05 mmol) dissolved in tetrahydrofuran (20 mL), cooled to 0 ° C, nitrogen Under protection Diethyl azodicarboxylate (0.6 g, 3.44 mmol) was added, and the reaction was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated to give purified crystals eluted eluted elut elut elut elut elut elut elut

(6) 4-(1-(2-Chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-hydroxyethoxy)-3-iodobenzoic acid Preparation of ester

4-(2-((Tertiary butyldimethylmethyl)oxy)-1-(2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl) Ethoxy)-3-iodobenzoate (0.9 g, 1.39 mmol) was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride trihydrate (0.44 g, 1.39 mmol) was added and stirred at 25 ° C 2 hours. The reaction mixture was concentrated to give purified crystals eluted eluted elut elut elut elut elut elut

(7) 2-(2-Chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2,3-dihydrobenzo[b][1,4] Preparation of Methyl Ester-6-carboxylate

Methyl 4-(1-(2-chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-hydroxyethoxy)-3-iodobenzoate ( 0.6 g, 1.13 mmol) was dissolved in 1,4-dioxane (10 mL), sodium tributoxide (0.11 g, 1.14 mmol), 1,10-phenanthroline (25 mg, 0.13 mmol), iodine Cuprous copper (24mg, 0.13 Methyl), heated to 100 ° C under nitrogen to stir the reaction for 16 hours. The reaction mixture was concentrated.

(8) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylate

2-(2-Chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxin The -6-formate (0.25 g, 0.62 mmol) was dissolved in anhydrous ethanol (5 mL), and p-toluenesulfonic acid pyridinium salt (20 mg, 0.08 mmol) was added, and the mixture was heated to 80 ° C and stirred for 2 hours. The reaction mixture was concentrated to give purified crystals eluted eluted elut elut elut elut elut elut elut

(9) Preparation of 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

Dissolving (5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (0.5 g, 1.76 mmol) and triphenylphosphine (0.6 g, 2.29 mmol) Tetrahydrofuran (5 mL) was cooled to 0 ° C, and carbon tetrabromide (0.76 g, 2.29 mmol) was added, and the mixture was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated to give purified crystals eluted eluted eluted elut elut elut elut elut

(10) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2, Preparation of methyl 3-dihydrobenzo[b][1,4]dioxane-6-carboxylate Prepare

2-(2-Chloro-4-hydroxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid methyl ester (0.12 g, 0.37 mmol) and 4- (Bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (0.13 g, 0.37 mmol) dissolved in N,N-dimethylformamide (5 mL) Potassium carbonate (0.1 g, 0.72 mmol) was added, and the mixture was heated to 80 ° C and stirred for 16 hours. The reaction mixture was concentrated.

(11) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2, Preparation of 3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid

2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2,3- Dihydrobenzo[b][1,4]dioxin-6-carboxylic acid methyl ester (0.12 g, 0.2 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL). A solution of 0.28 mmol of water (1 mL) was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated, and the obtained crude was purified eluted eluted eluted eluted elut elut elut elut elut elut elut elut elut .

Molecular formula: C ₂₈ H ₂₀ Cl ₃ NO ₆ Molecular weight: 572.8 LC-MS (m/z): 572.1, 574.1 (M+H) ⁺

¹ H-NMR (400 MHz, MeOD) δ: 7.41 - 7.61 (m, 6H), 6.95 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H), 6.85 (dd, J1 = 8.8 Hz, J = 2.6 Hz, 1H), 5.42 (dd, J1 = 8.4 Hz, J = 2.0 Hz, 1H), 4.96 (s, 2H), 4.45 (dd, J1 = 11.6 Hz, J = 2.4 Hz, 1H), 3.90 - 3.95 (m, 1H), 2.32-2.42 (m, 1H), 1.22-1.24 (m, 4H).

Example 4 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-6-carboxylic acid (Compound 4)

(1) Preparation of 4-((4-bromo-3-chlorophenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole

4-Bromo-3-chlorophenol (11 g, 53.02 mmol) was dissolved in N,N-dimethylformamide (150 mL), sodium iodide (16 g, 106.74 mmol), potassium carbonate (44 g, 318.36 mmol) And 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (17.6 g, 58.17 mmol) in N,N-dimethylformamide solution (50 mL), warmed to 60 ° C and stirred overnight. After cooling to room temperature, it was diluted with ethyl acetate (1 L), washed with saturated sodium chloride (200 mL × 3), dried over anhydrous sodium sulfate and evaporated. :10) Purification gave the title compound (19.6 g, m.

(2) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester

Dissolving 4-((4-bromo-3-chlorophenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (2.1 g, 4.43 mmol) 1,4-Dioxane (60 mL), adding 1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid methyl ester hydrochloride (1 g, 4.39 mmol), cesium carbonate (4.3 g, 13.20 mmol) And Brettphos-Pd (100 mg, 0.11 mmol), heated to reflux for 3 days. The reaction mixture was poured with EtOAc EtOAc EtOAc. Purification of petroleum ether = 1 : 5)

(3) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-6-carboxylic acid

Referring to the preparation method of the step (7) of Example 1, 2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-yl) was added) Methyl methoxy)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (180 mg,yield)

Molecular formula: C ₂₉ H ₂₃ Cl ₃ N ₂ O ₄ Molecular weight: 569.86 LC-MS (positive, m/z): 571 (M+H) ⁺

¹ H-NMR (300MHz, CD ₃ OCD ₃ ) δ: 7.86-7.81 (m, 2H), 7.60-7.52 (m, 3H), 7.28-7.25 (m, 1H), 7.16 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 2.7 Hz, 1H), 6.82 (dd, J1 = 3 Hz, J2 = 8.7 Hz, 1H), 4.96 (s, 2H), 4.21 (s, 2H), 3.30-3.26 (m , 2H), 3.08-2.95 (m, 2H), 2.47-2.38 (m, 1H), 1.23-1.17 (m, 4H).

Example 5 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-7-carboxylic acid (Compound 5)

(1) Preparation of methyl 4-(2-aminoethyl)benzoate

Methyl 4-(cyanomethyl)benzoate (6.0 g, 34.2 mmol) was dissolved in dihydrogen chloride in saturated aqueous hydrogen chloride (10 mL), then methanol (10 mL), palladium carbon (10%) (0.6 g) After the hydrogen gas was replaced, the reaction was carried out at 25 ° C for 24 hours, filtered, and the filter cake was washed with methanol (20 mL), and the filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 10:1) , yield 24.6%).

(2) Preparation of methyl 4-(2-(2,2,2-trifluoroethylamino)ethyl)benzoate

Add methyl 4-(2-aminoethyl)benzoate (1.5 g, 8.4 mmol) to trifluoroacetic anhydride (10 mL), stir the reaction at 25 ° C for 3 hours, then The reaction mixture was poured into 20 mL of ice water, and the mixture was stirred for 30 minutes, and the precipitated solid was filtered, washed with hexane (10 mL).

(3) Preparation of methyl 2-(2,2,2-trifluoroethenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

Add methyl 4-(2-(2,2,2-trifluoroacetamido)ethyl)benzoate (1.5 g) to a mixed solution of glacial acetic acid (6 mL) and concentrated sulfuric acid (9 mL). , 5.5mmol), paraformaldehyde (250mg, 8.3mmol), stirred at 25 ° C for 16 hours, the reaction solution was poured into 150mL of ice water, ethyl acetate extraction (100mL × 3), the organic phase was combined, column chromatography (Petroleum ether: ethyl acetate = 5:1) gave the title compound (1.3 g, yield 82.3%).

(4) Preparation of 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid methyl ester

Methyl 2-(2,2,2-trifluoroethenyl)-1,2,3,4-tetrahydroisoquinolin-7-carboxylate (1.2 g, 4.2 mmol) was dissolved in methanol (10 mL) Potassium carbonate (0.9 g, 6.5 mmol) was added to a mixed solution of water (4 mL), and the reaction was stirred at 25 ° C for 3 hours, and methanol was evaporated under reduced pressure. Water (50 mL) The organic phase was combined, EtOAcjjjjjjjj

(5) Preparation of 1-bromo-2-chloro-4-methoxybenzene

4-Bromo-3-chlorophenol (0.3 g, 1.4 mol) was dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (0.3 g, 2.2 mol), m. The reaction was stirred at 25 ° C for 2 hours, ethyl acetate (50 mL) was added, washed with water (50 mL), washed with saturated sodium chloride solution (50 mL). Ether: ethyl acetate = 10:1)m.

(6) Preparation of 2-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid

1-Bromo-2-chloro-4-methoxybenzene (0.3 g, 1.4 mmol), 1 ,2,3,4-tetrahydroisoquinoline-7-carboxylic acid methyl ester (0.3 g, 1.6 mmol) Intoluene (10 mL), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (87 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (130 mg, 0.14 mmol), Sodium tert-butoxide (270 mg, 2.8 mmol), and the mixture was heated to 100 ° C for 8 hours. After the reaction was completed, the reaction mixture was concentrated. 80 mg, yield 18%).

(7) Preparation of 2-(2-chloro-4-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid

2-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydrogen under ice bath Isoquinoline-7-carboxylic acid (80 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), boron tribromide (125 mg, 0.5 mmol) was added, and the mixture was stirred at 25 ° C for 6 hours, cooled to 0 ° C, and reacted to the reaction. 2 mL of a saturated sodium hydrogencarbonate solution was added to the mixture, and the organic layer was evaporated.

(8) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate

2-(2-Chloro-4-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolin-7-carboxylic acid (75 mg, 0.24 mmol) was dissolved in methanol (5 mL) The title compound (60 mg, yield 78.6%) was obtained from the title compound (60 mg, yield: 78.6%).

(9) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-7-carboxylic acid methyl ester

4-(Bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (66 mg, 0.19 mmol), 2-(2-chloro-4-hydroxyphenyl) Methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (60 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (5 mL). Ment), warmed to 40 ° C, stirred for 3 hours, then added water (20 mL), ethyl acetate (15 mL × 3), combined The title compound (70 mg, yield: 63.1%).

(10) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-7-carboxylic acid

2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1,2, Methyl 3,4-tetrahydroisoquinoline-7-carboxylate (70 mg, 0.12 mmol), dissolved in tetrahydrofuran (5 mL), sodium hydroxide (10 mg, 0.25 mmol), and stirred at 25 ° C for 12 hours. The title compound (40 mg, yield: 58.5%) was obtained.

Molecular formula: C ₂₉ H ₂₃ Cl ₃ N ₂ O ₄ Molecular weight: 569.9 LC-MS (m/z): 571.1 (M+H) ⁺

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 7.90 (d, J = 8.8Hz, 1H), 7.85 (s, 1H), 7.42 (d, J = 7.2Hz, 1H), 7.32-7.36 (m , 1H), 7.28 (s, 1H), 7.00 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.71 (dd, J1 = 8.8 Hz, J2 = 6.0 Hz, 1H ), 4.79 (s, 2H), 4.23 (s, 2H), 3.30-3.33 (m, 2H), 3.02-3.09 (m, 2H), 2.11-2.19 (m, 1H), 1.27-1.32 (m, 2H) ), 1.14-1.16 (m, 2H).

Example 6 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-5-carboxylic acid (Compound 6)

(1) Preparation of 5-cyanoisoquinoline

Add 5-bromoisoquinoline (2.0 g, 9.6 mmol), zinc cyanide (0.68 g, 5.8 mmol) to N,N-dimethylformamide (100 mL) and add tetrakis(triphenylbenzene) under nitrogen. Palladium (0.45 g, 0.39 mmol), heated to 100 ° C for 16 hours, TLC detection reaction was complete, cooled to 25 ° C, added water (200 mL), suction filtered, filter cake washed with water (100 mL), dried in vacuo The title compound (0.9 g, yield 60.8%).

(2) Preparation of isoquinoline-5-carboxylic acid

5-Cyanoisoquinoline (0.9 g, 5.8 mmol) was added to a 50% sulfuric acid solution (30 mL), and the mixture was heated to 100 ° C for 16 hours, cooled to 25 ° C, poured into ice water (100 mL), and stirred. The title compound (0.8 g, yield 80%) was obtained.

(3) Preparation of methyl isoquinoline-5-carboxylate

Add isoquinoline-5-carboxylic acid (0.8 g, 4.62 mmol) to methanol (30 mL), add concentrated sulfuric acid (0.5 mL), and warm to 83 ° C. After the hour, the reaction was completely detected by TLC, concentrated under reduced pressure, and the crude material was used directly in the next step.

(4) Preparation of methyl 1,2,3,4-tetrahydroisoquinoline-5-carboxylate

Methyl isoquinoline-5-carboxylate (crude) was added to glacial acetic acid (30 mL), and platinum chloride (86 mg) was added with stirring, and hydrogen was replaced and reacted at 25 ° C for 4 hours. The reaction was completed by TLC, EtOAc (EtOAc)EtOAc. g, yield 98.9%).

(5) Preparation of methyl 2-(2-chloro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate

Methyl 1,2,3,4-tetrahydroisoquinoline-5-carboxylate (0.84 g, 4.4 mmol), 2-chloro-1-fluoro-4-nitrobenzene (0.85 g, 4.8 mmol) and Cesium carbonate (2.87 g, 8.8 mmol) was added to N,N-dimethylacetamide (50 mL), and the mixture was warmed to 70 ° C for 16 hours, and the reaction was completed by TLC. Water (150 mL) and ethyl acetate (150 mL) The organic layer was dried over anhydrous sodium sulfate (MgSO4).

(6) Preparation of methyl 2-(4-amino-2-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate

Add methyl 2-(2-chloro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (0.86 g, 2.5 mmol) to tetrahydrofuran (20 mL) Raney nickel (86 mg, mass ratio 10%) was added under a nitrogen atmosphere, the hydrogen was replaced, and the reaction was carried out at 25 ° C for 1.5 hours. The reaction was completed by EtOAc (EtOAc)EtOAc.

(7) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate

Add methyl 2-(4-amino-2-chlorophenyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (700 mg, 2.2 mmol) to 1 mol/L sulfuric acid (10 mL) In a mixed solvent of methanol (2 mL), the temperature was lowered to 0 ° C, sodium nitrite (167 mg, 2.42 mmol) was added, and after reacting for 1 hour, 50% sulfuric acid (10 mL) was added, and the mixture was heated to 100 ° C for 2 hours, using 1 mol / The aqueous solution of sodium hydroxide was adjusted to pH 7. The title compound (130 mg) was obtained from ethyl acetate (200 mL). The rate is 18.6%).

(8) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-5-carboxylic acid methyl ester

The preparation process is as described in Example 5, Reaction Step (9).

(9) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-1, Preparation of 2,3,4-tetrahydroisoquinoline-5-carboxylic acid

The preparation process is as described in Example 5, Reaction Step (10).

Molecular formula: C ₂₉ H ₂₃ Cl ₃ N ₂ O ₄ Molecular weight: 569.9 LC-MS (m/z): 569.1 (M+H) ⁺

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 7.99-7.96 (m, 1H), 7.43-7.41 (m, 2H), 7.36-7.29 (m, 3H), 7.00 (d, J = 8.8Hz, 1H), 6.90 (d, J = 2.8 Hz, 1H), 6.72-6.69 (m, 1H), 4.78 (s, 2H), 4.22 (s, 2H), 3.43-3.41 (m, 2H), 3.30-3.27 (m, 2H), 2.19-2.15 (m, 1H), 1.19-1.14 (m, 4H).

Example 7 6-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-5, Preparation of 6,7,8-tetrahydronaphthalene-2-carboxylic acid (Compound 7)

(1) 6-Bromo-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate

Add 6-bromo-3,4-dihydronaphthalene-2(1H)-one (10 g, 44.43 mmol) and tetrahydrofuran (250 mL) to a three-necked flask under nitrogen. At -78 ° C, lithium bis(trimethyldecyl)amide (89.2 mL, 89.2 mmol) was then added dropwise. After stirring at -78 ° C for 1 hour, a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonium)methanesulfonamide (19.1 g, 53.46 mmol) in tetrahydrofuran (50 mL) was added dropwise. ), stirring for 30 minutes, returning to room temperature and stirring for 30 minutes. The reaction was quenched with EtOAc (3 mL, EtOAc) (EtOAc) =1:100-1:50) gave 4.6 g of the title compound.

(2) Preparation of 2-(2-chloro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-bromo-2-chloro-4-methoxybenzene (10 g, 45.15 mmol), 1,4-dioxane (200 mL), boranoic acid pinacol ester (12 g, 47.24 mmol) was added to a three-neck bottle. Potassium acetate (13.4 g, 136.54 mmol), Pd(dppf)Cl ₂ dichloromethane complex (1.86 g, 2.28 mmol). The nitrogen was replaced three times and then heated to 90 ° C to react overnight. The reaction mixture was cooled, diluted with EtOAc EtOAc (EtOAc) The residue was dried (MgSO4j418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418418

(3) Synthesis of 7-bromo-3-(2-chloro-4-methoxyphenyl)-1,2-dihydronaphthalene

2-(2-Chloro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3 g, 11.17 mmol) was added to a three-necked flask. ), 1,4-dioxane (40 mL), 6-bromo-3,4-dihydronaphthalen-2-yltrifluoromethanesulfonate (4.39 g, 12.29 mmol) and sodium carbonate (2.97 g, 27.76) Aqueous (5 mL) of aqueous solution (5 mL), Pd (dppf) Cl ₂ DCM (89.9 mg), was replaced with nitrogen three times and heated to 80 ° C overnight. It was cooled and diluted with ethyl acetate (50 mL). The mixture was washed with water (3 x 20 mL). The organic phase was dried over anhydrous sodium sulfate (MgSO4).

(4) Preparation of 6-(2-chloro-4-methoxyphenyl)-7,8-dihydronaphthalene-2-carbonitrile

Add 7-bromo-3-(2-chloro-4-methoxyphenyl)-1,2-dihydronaphthalene (1.5 g, 4.29 mmol), DMF (30 mL), dicyano zinc (in a single vial) 748 mg, 6.37 mmol) and tetrakis(triphenylphosphine)palladium (497 mg, 0.43 mmol) were replaced with nitrogen three times and reacted at 125 ° C overnight. After cooling, the insoluble solid was filtered and diluted with ethyl acetate (50mL). The mixture was washed with water (3 x 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated, and then evaporated, 0.9 g of the title compound was obtained in a yield of 71%.

(5) Preparation of methyl 6-(2-chloro-4-methoxyphenyl)-7,8-dihydronaphthalene-2-carboxylate

Add 6-(2-chloro-4-methoxyphenyl)-7,8-dihydronaphthalene-2-carbonitrile (900 mg, 3.04 mmol) and methanol (15 mL) to a single-necked bottle, then add dropwise at 0 °C. H ₂ SO ₄ (5 mL), EtOAc (EtOAc) The mixture was washed with water (3 x 20 mL). The organic phase was dried over anhydrous sodium sulfate (MgSO4).

(6) Preparation of methyl 6-(2-chloro-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

Add methyl 6-(2-chloro-4-methoxyphenyl)-7,8-dihydronaphthalene-2-carboxylate (700 mg, 2.13 mmol), ethyl acetate (20 mL), Pt. ₂ (96 mg) was hydrogenated at 0 ° C for 1 hour. The insoluble solid was filtered off, and the filtrate was concentrated to give 690 g of product (yield 98%).

(7) Preparation of methyl 6-(2-chloro-4-hydroxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate

Add methyl 6-(2-chloro-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (680 mg, 2.06 mmol), dichloromethane (50 mL). 30 mL), then BF ₃ (Me ₂ S) (2.68 g) was added dropwise to 0 °C. The reaction solution was stirred at 0 ° C for 5 hours. It was then diluted with dichloromethane (50 mL) and washed with water (3×30 mL). The organic layer was separated, dried and concentrated and purified, mjjjjjjjj

(8) (2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-5,6, Preparation of methyl 7,8-tetrahydronaphthalene-2-carboxylate

(5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (524 mg, 1.84 mmol) and dichloromethane (10 mL) were added to a 50 mL single-necked bottle, then Add SOCl ₂ (871 mg, 7.32 mmol) and N,N-dimethylformamide (2 drops) dropwise at 0 ° C, stir at 0 ° C for 30 minutes, and concentrate to add 6-(2-chloro-4-hydroxyphenyl). -5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (390 mg, 1.23 mmol), N,N-dimethylformamide (10 mL), sodium iodide (55 mg, 0.369 mmol) and K ₂ CO ₃ (1.02 g, 7.33 mmol). The mixture was stirred at 60 ° C overnight. The reaction mixture was cooled, diluted with EtOAc EtOAc (EtOAc) The organic layer was dried <RTI ID=0.0>

(9) 6-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-5, Preparation of 6,7,8-tetrahydronaphthalene-2-carboxylic acid

Add 6-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) to a 50 mL single-mouth vial An aqueous solution (1 mL) of -5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (750 mg, 1.29 mmol), methanol (20 mL) and sodium hydroxide (103 mg, 2.58 mmol), heated to 60 ° C After stirring overnight, the residue was evaporated to dryness crystall

Molecular formula: C ₃₀ H ₂₄ Cl ₃ NO ₄ Molecular weight: 568.87 LC-MS (ES, m/z): 566 (M+H) ⁺

¹ H-NMR (DMSO, ppm): δ: 7.5-7.7 (m, 5H), 7.25-7.3 (m, 3H), 6.91 (s, 1H), 6.7-6.8 (m, 1H), 4.9 (s, 2H), 2.8-2.99 (m, 5H), 1.8-1.9 (m, 2H), 1.11-1.29 (m, 5H).

Example 8 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)dihydroiso Preparation of indole-5-formic acid (Compound 8)

(1) Preparation of methyl 3,4-dimethylbenzoate

3,4-Dimethylbenzoic acid (5.0 g, 33.3 mmol) was dissolved in methanol (50 mL), and then argon chloride (7.9 g, 66.4 mmol) was added dropwise in an ice water bath, and the mixture was stirred at 25 ° C, stirring was continued. After 6 hours, the solvent was removed and the residue was taken to the next step.

(2) Preparation of methyl 3,4-di(bromomethyl)benzoate

Methyl 3,4-dimethylbenzoate (5.4 g, 32.9 mmol), N-bromosuccinimide (12.8 g, 71.9 mmol) and a catalytic amount of benzamidine peroxide (100 mg, 0.4 mmol) Dissolved in carbon tetrachloride (50 mL), heated to 80 ° C, and reacted for 12 hours. The mixture was cooled to 25 ° C, filtered, EtOAcjjjjjjjjjjjj

(3) Preparation of methyl 2-(4-methoxybenzyl)isoindole-5-carboxylate

Methyl 3,4-di(bromomethyl)benzoate (10.6 g, 32.9 mmol) was dissolved in tetrahydrofuran (50 mL) and p-methoxybenzylamine (4.5 g, 32.8 mmol) and triethylamine (6.6. g, 65.3 mmol), stirred at 25 ° C for 16 hours, the solvent was removed, ethyl acetate (100 mL) and water (30 mL) were added, and the organic phase was separated and the residue was purified by column chromatography ( petroleum ether: ethyl acetate = 2:1), the title compound was obtained 4.5 g, yield 46%.

(4) Preparation of methyl dihydroisoindoline-5-carboxylate

Methyl 2-(4-methoxybenzyl)isoindole-5-carboxylate (1.7 g, 5.7 mmol) was dissolved in dichloromethane (50 mL). g, 39.9 mmol), the reaction was stirred at 25 ° C for 30 hours, then methanol (5 mL) was added and stirring was continued for 1 hour. The solvent was removed, and ethyl acetate (100 mL) and EtOAc (EtOAc (EtOAc) The yield is 70%.

(5) Preparation of 1-bromo-2-chloro-4-methoxybenzene

4-Bromo-3-chlorophenol (2.0 g, 9.6 mmol) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (2.0 g, 14.5 mol), m. 11.3 mmol), the reaction was stirred at 25 ° C for 2 hr, ethyl acetate (50 mL) and water (50 mL). The residue was subjected to EtOAc EtOAcjjjjjjjj

(6) Preparation of methyl 2-(2-chloro-4-methoxyphenyl)dihydroisoindol-5-carboxylate

1-Bromo-2-chloro-4-methoxybenzene (0.62 g, 2.8 mmol), methyl dihydroisoindole-5-carboxylate (0.5 g, 2.8 mmol) was dissolved in toluene (10 mL) 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (0.35 g, 0.56 mmol), tris(dibenzylideneacetone)dipalladium (0.26 g, 0.28 mmol), sodium butoxide (0.82) g, 8.5 mmol), the mixture was heated to 100 ° C for 8 hours, the reaction mixture was concentrated, and the residue was purified by column chromatography ( petroleum ether: ethyl acetate = 2:1) to give the product 0.15 g.

(7) Preparation of 2-(2-chloro-4-hydroxyphenyl)dihydroisoindole-5-carboxylic acid

Methyl 2-(2-chloro-4-methoxyphenyl)dihydroisoindole-5-carboxylate (0.15 g, 0.47 mmol) was dissolved in dichloromethane (5 mL) Boron (1.9 mL, 1.9 mmol), the mixture was stirred at 25 ° C for 6 hours, cooled to 0 ° C, and then a saturated sodium hydrogen carbonate solution (2 mL) was added to the mixture : methanol = 30:1), the title compound was obtained.

(8) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl)dihydroisoindole-5-carboxylate

2-(2-Chloro-4-hydroxyphenyl)dihydroisoindole-5-carboxylic acid (0.07 g, 0.24 mmol) was dissolved in methanol (5 mL), dichlorohydrazine (0.06 g, 0.50 mmol) was added dropwise, and the mixture was heated to 90 ° C for 2 hours. The reaction mixture was concentrated and the residue was purified by column chromatography = 30:1), the title compound was obtained in a yield of 68.5%.

(9) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)dihydroiso Preparation of 吲哚-5-methyl formate

Referring to the preparation method in the step (9) of Example 5, 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (0.055 g, 0.16 mmol) was added. , 2-(2-Chloro-4-hydroxyphenyl)dihydroisoindole-5-carboxylic acid methyl ester (0.05 g, 0.16 mmol) gave mp.

(10) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)dihydroiso Preparation of 吲哚-5-formic acid

2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)dihydroisoindole -5-methyl formate (0.03 g, 0.05 mmol), dissolved in MeOH (5 mL), EtOAc (EtOAc (EtOAc) The mixture was adjusted to pH 6 with EtOAc EtOAc (EtOAc)EtOAc.

Molecular formula: C ₂₈ H ₂₁ Cl ₃ N ₂ O ₄ Molecular weight: 555.8 LC-MS (m/z): 555.1 (M+H) ⁺

^{1 H-NMR (400MHz, MeOD} ) δ: 7.94 (s, 2H), 7.48-7.53 (m, 3H), 7.37 (d, J = 8.4Hz, 1H), 7.12 (d, J = 9.2Hz, 1H) , 6.81 (d, J = 2.8 Hz, 1H), 6.72 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 4.67 (s, 2H), 4.58 (s, 4H), 2.31-2.37 (m, 1H) , 0.88-0.92 (m, 4H).

Example 9 (R)-2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl Preparation of benzodihydropyran-6-carboxylic acid (Compound 9)

(1) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl) benzohydropyran-6-carboxylate

The specific preparation method is as described in the preparation of the steps (1) to (5) of Example 1.

(2) (R)-methyl 2-(2-chloro-4-hydroxyphenyl)chroman-6-carboxylate and (S)-2-(2-chloro-4-hydroxyphenyl) Resolution of methyl benzodihydropyran-6-carboxylate

The crude product (4.5 g) of methyl 2-(2-chloro-4-hydroxyphenyl)chroman-6-carboxylate was isolated by chiral preparative column (Chiral-Prep-HPLC): chiral Column, DAICEL CHIRALPAK AD-H; mobile phase, mobile phase A: n-hexane (0.1% TFA), mobile phase B: isopropanol, A: B = 80:20. Methyl (R)-2-(2-chloro-4-hydroxyphenyl)chroman-6-carboxylate (2.3 g, crude And (S)-2-(2-chloro-4-hydroxyphenyl)chroman-6-carboxylic acid methyl ester (1.2 g).

(3) (R)-2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl Preparation of methyl benzodihydropyran-6-carboxylate

Add (5-cyclopropanyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methanol (1.066 g, 3.75 mmol) in dichloromethane (10 mL) to a 50 mL circle In the bottom flask, sulfinium chloride (10 mL) was slowly added dropwise to the solution under stirring at room temperature. After the addition was completed, the mixture was stirred at room temperature for 2.5 hr. Another 100 mL three-necked flask was charged with (R) 2-(2-chloro-4-hydroxyphenyl)chroman-6-carboxylic acid methyl ester (1 g, 3.14 mmol) in DMF ( 40 mL), potassium carbonate (2.167 g), sodium iodide (1.4 g). The crude DMF solution obtained above was slowly added dropwise thereto under stirring at room temperature. After the addition was completed, the mixture was stirred at 60 ° C for 18 h. Ethyl acetate (200 mL) was added to the mixture, and the mixture was evaporated.

(4) (R)-2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl Preparation of benzodihydropyran-6-carboxylic acid

(R)-2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzene And a solution of methyl dihydropyran-6-carboxylate (1.6 g, crude) in methanol/water (20/5 mL) was added to a 50 mL round bottom flask, and at 0 ° C, KOH was added portionwise. Lithium (328.8 mg) was stirred at room temperature for 2 days after the addition was completed. The pH of the reaction mixture was adjusted to 4-5 with EtOAc. EtOAc (EtOAc) The residue was subjected to rapid separation (EtOAc, water, 1%EtOAc)

Molecular formula: C ₂₉ H ₂₂ Cl ₃ NO ₅ Molecular weight: 570.85 LC-MS: (ES, m/z): 568.1 (M-1) ^-

¹ H-NMR (300 MHz, DMSO, ppm): δ 12.5 (brs, 1H), 7.52-7.75 (m, 5H), 7.37-7.40 (d, J = 8.7 Hz, 1H), 6.97-6.97 (d, J =2.4Hz,1H),6.82-6.89(m,2H),5.32-5.36(m,1H),4.94(s,2H),2.98-3.02(m,1H), 2.79-2.84(m,1H), 2.44 (m, 1H), 2.14-2.19 (m, 1H), 1.95-2.07 (m, 1H), 1.10- 1.23 (m, 4H).

Example 10 (S)-2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl Preparation of benzodihydropyran-6-carboxylic acid (Compound 10)

(1) (S)-2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl Preparation of methyl benzodihydropyran-6-carboxylate

Preparation Method Referring to the step (3) of Example 9, the title compound was obtained.

(2) (S)-2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl Preparation of benzodihydropyran-6-carboxylic acid

The title compound (150 mg) was obtained in the title compound.

Molecular formula: C ₂₉ H ₂₂ Cl ₃ NO ₅ Molecular weight: 570.85 LC-MS: 568.1 (M-1) ^-

^{1 H NMR (300MHz, DMSO-} d6, ppm): δ 7.52-7.73 (m, 5H), 7.37-7.40 (d, J = 8.4Hz, 1H), 6.96-6.97 (d, J = 2.4Hz, 1H) , 6.82-6.87 (m, 2H), 5.31-5.35 (m, 1H), 4.94 (s, 2H), 2.97-3.01 (m, 1H), 2.73-2.83 (m, 1H), 2.43 (m, 1H) , 2.18-2.27 (m, 1H), 1.94-1.99 (m, 1H), 1.12-1.21 (m, 4H).

Example 11 (S)-2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl Preparation of-2,3-dihydrobenzofuran-5-carboxylic acid (Compound 11)

2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2,3- Dihydrobenzofuran-5-carboxylic acid (291 mg, 0.52 mmol, preparation method see Example 2, steps 1-5) was resolved. Resolution conditions: column DAICEL CHIRALPAK AD-3 (4.6 mm × 50 mm, 3.0) μ m), column temp: 25 ° C, phase A: n-Hexane (0.1% TFA), phase B: Ethanlol, total flow: 1.0 mL/min, Wavelength: from 190 nm to 500 nm, product 60 mg, yield 20.6% The ee value is 99.66%.

Molecular formula: C ₂₈ H ₂₀ Cl ₃ NO ₅ Molecular weight: 556.8 LC-MS (m/z): 554 (MH ⁺ )

^{1 H-NMR (300MHz, DMSO} ) δ: 7.80 (d, J = 5.1Hz, 2H), 7.59-7.63 (m, 2H), 7.52-7.56 (m, 1H), 7.27 (d, J = 9.0Hz, 1H), 7.01 (d, J = 2.7 Hz, 1H), 6.96 (d, J = 3.9 Hz, 1H), 6.78 (dd, J ₁ = 2.7 Hz, J ₂ = 5.7 Hz, 1H), 6.03-6.09 ( m, 1H), 4.93 (s, 2H), 3.71-3.80 (m, 1H), 3.04-3.13 (m, 1H), 2.43-2.45 (m, 1H), 1.10- 1.22 (m, 4H).

Example 12 (R)-2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl Preparation of-2,3-dihydrobenzofuran-5-carboxylic acid (Compound 12)

2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-2,3- Dihydrobenzofuran-5-carboxylic acid (291 mg, 0.52 mmol, preparation method see Example 2, Steps 1-5) was subjected to resolution, and the resolution conditions were the same as those in Example 11, to obtain a product of 90 mg. The rate is 30.9% and the ee value is 90.48%.

Molecular formula: C ₂₈ H ₂₀ Cl ₃ NO ₅ Molecular weight: 556.8 LC-MS (m/z): 556 (M+H ⁺ )

^{1 H-NMR (300MHz, DMSO} ) δ: 7.80 (d, J = 5.7Hz, 2H), 7.59-7.63 (m, 2H), 7.52-7.56 (m, 1H), 7.27 (d, J = 9.0Hz, 1H), 7.01 (d, J = 2.7 Hz, 1H), 6.96 (d, J = 3.6 Hz, 1H), 6.78 (dd, J ₁ = 2.7 Hz, J ₂ = 5.7 Hz, 1H), 6.03-6.09 ( m, 1H), 4.93 (s, 2H), 3.71-3.80 (m, 1H), 3.04-3.13 (m, 1H), 2.43-2.45 (m, 1H), 1.10- 1.22 (m, 4H).

Example 13 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of Hydropyran-5-carboxylic Acid (Compound 13)

(1) Preparation of methyl 2-mercapto-3-hydroxybenzoate

Methyl 3-hydroxybenzoate (30.00 g, 197.2 mmol), plus Into trifluoroacetic acid (500 mL), HMTA (33.20 g, 236.8 mmol) was added slowly. After the addition, the mixture was heated to 80 ° C for 6 hours. The reaction solution was poured into 1.5 L of ice water and extracted with 1 L of ethyl acetate. The organic phase was washed with water and brine (800 mL), dried over anhydrous sodium sulfate and evaporated.

(2) Preparation of 1-(2-chloro-4-methoxyphenyl)ethan-1-one

m-Chloroanisole (30.00 g, 210.4 mmol) was added dropwise to a solution of acetonitrile (19.80 g, 252.2 mmol) and anhydrous aluminum chloride (36.45 g, 273.4 mmol) in DCM (200 mL). After the completion of the dropwise addition, the reaction was continued for 2 hours. The reaction mixture was poured into ice water (500 mL), EtOAc (EtOAc) (EtOAc) 1) The title compound was obtained in an amount of 13.7 g, yield: 35.3%.

(3) Preparation of 2-bromo-1-(2-chloro-4-methoxyphenyl)ethan-1-one

1-(2-Chloro-4-methoxyphenyl)ethan-1-one (8.01 g, 43.4 mmol) was dissolved in dichloromethane (200 mL), and bromine (6.94 g, 43.4) Methyl), after completion, the reaction was continued for 2 hours. The reaction solution was directly concentrated by column chromatography (PE: EA = 8:1) to yield 8.34 g of product.

(4) Preparation of diethyl (2-(2-chloro-4-methoxyphenyl)-2-oxoethyl)phosphonate Prepare

Add 2-bromo-1-(2-chloro-4-methoxyphenyl)ethan-1-one (8.34 g, 31.7 mmol) and triethyl phosphite (7.89 g, 47.6 mmol) to toluene (100 mL) In the reaction, the temperature was raised to 110 ° C for 24 hours. The reaction solution was directly concentrated by column chromatography (PE: EA = 5:1) to yield 4.40 g of product.

(5) Preparation of methyl 2-(3-(2-chloro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-3-hydroxybenzoate

Diethyl (2-(2-chloro-4-methoxyphenyl)-2-oxoethyl)phosphonate (4.40 g, 13.7 mmol), 2-methylmercapto-3-hydroxybenzoic acid The ester (4.90 g, 27.4 mmol) and DBU (4.20 g, 27.4 mmol) were added to THF (100 mL). After adding 200 mL of water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and evaporated. EtOAcjjjjj

(6) Preparation of methyl 2-(3-(2-chloro-4-methoxyphenyl)-3-oxopropyl)-3-hydroxybenzoate

Methyl 2-(3-(2-chloro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-3-hydroxybenzoate (1.50 g, 4.3 mmol), After adding to THF (50 mL), Pt/C (150 mg) was added, and the mixture was reacted for 2 hours under a hydrogen atmosphere. After suction filtration, the filter cake was washed with THF (10 mL) and the filtrate was applied to the next step.

(7) Preparation of methyl 2-(3-(2-chloro-4-methoxyphenyl)-3-hydroxypropyl)-3-hydroxybenzoate

The filtrate (60 mL) obtained in the above step was placed in a 250 mL flask, and sodium borohydride (197 mg, 5.2 mmol) was added, and the mixture was stirred for 1 hour. After adding 100 mL of water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and evaporated.

(8) Preparation of methyl 2-(2-chloro-4-methoxyphenyl)chroman-5-carboxylate

Methyl 2-(3-(2-chloro-4-methoxyphenyl)-3-hydroxypropyl)-3-hydroxybenzoate (1.45 g, 4.1 mmol), triphenylphosphine (5.37 g, 20.5 mmol) and DEAD (3.57 g, 20.5 mmol) were added to THF (50 mL) for 2 hours. The reaction mixture was directly dried and the residue was applied tojjjjjjjjjj

(9) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl)chroman-5-carboxylate

Methyl 2-(2-chloro-4-methoxyphenyl)chroman-5-carboxylate (800 mg, 2.4 mmol) was dissolved in DCM (20 mL). A solution of boron tribromide in DCM (7.2 mL) was added and the reaction was continued for 2 hours. Quenched by adding 5 mL of water. After adding water (50 mL) and DCM (80 mL), EtOAc (EtOAc m. The yield was 11.7%.

(10) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of methyl hydropyran-5-carboxylate

Methyl 2-(2-chloro-4-hydroxyphenyl)chroman-5-carboxylate (90 mg, 0.28 mmol), 4-(bromomethyl)-5-cyclopropyl-3- (2,6-Dichlorophenyl)isoxazole (145 mg, 0.42 mmol) and potassium carbonate (77 mg, 0.56 mmol) were added to DMF (5 mL). After adding 80 mL of water and ethyl acetate, the organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate 72.7%.

(11) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of hydropyran-5-carboxylic acid

Methyl 2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoate Methyl hydropyran-5-carboxylate (120 mg, 0.2 mmol) was added to THF (2 mL), MeOH (2 mL), water (2 mL), and then 6 hours. The pH was adjusted to 2 with 1 M EtOAc. EtOAc (EtOAc) (EtOAc) MeOH = 20:1) mp.

Molecular formula: C ₂₉ H ₂₂ Cl ₃ NO ₅ Molecular weight: 570.85 LC-MS (M/e): 570.1 (M+H ⁺ )

^{1 H-NMR (400MHz, DMSO} ) δ: 7.65-7.60 (m, 2H), 7.59-7.51 (m, 1H), 7.48-7.39 (m, 2H), 7.25-7.17 (m, 1H), 7.03 (d , J=1.2 Hz, 1H), 7.01 (d, J=1.2 Hz, 1H), 6.90-6.80 (m, 1H), 5.30-5.25 (m, 1H), 4.94 (s, 2H), 3.20-3.10 ( m, 2H), 2.49-2.40 (m, 1H), 2.22-2.10 (m, 1H), 1.89-1.80 (m, 1H), 1.23-1.17 (m, 2H), 1.17-1.11 (m, 2H).

Example 14 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of Hydropyran-7-carboxylic Acid (Compound 14)

(1) Preparation of (E)-1-(4-bromo-2-hydroxyphenyl)-3-(2-chloro-4-hydroxyphenyl)prop-2-en-1-one

Prepared according to the preparation method in the step (1) of Example 1, adding 1-(4-bromo-2-hydroxyphenyl)ethan-1-one (27.4 g, 127.42 mmol), 2-chloro-4-hydroxybenzaldehyde (20 g, 127.74 mmol) gave 36 g (yield: 80%).

(2) Preparation of 7-bromo-2-(2-chloro-4-hydroxyphenyl)chroman-4-one

(E)-1-(4-bromo-2-hydroxyphenyl)-3-(2-chloro-4-hydroxyphenyl)prop-2-en-1-one (36 g) in a 3 L four-necked flask , 101.81 mmol) was dissolved in a mixed solvent of methanol (720 mL) and hydrochloric acid (12N, 720 mL), and the mixture was heated to 73 ° C for 72 hours. The reaction solution was poured into 3 L of ice water, and a large amount of precipitate was observed, and the mixture was filtered with suction, and the cake was dried to obtain 21 g (yield: 58%).

(3) Preparation of 4-(7-bromochroman-2-yl)-3-chlorophenol

Referring to the preparation method of the step (3) of Example 1, adding 7-bromine 2-(2-Chloro-4-hydroxyphenyl)chroman-4-one (21 g, 59.39 mmol) gave 13 g (yield: 64%).

(4) Preparation of 2-(2-chloro-4-hydroxyphenyl)chroman-7-carbonitrile

4-(7-bromochroman-2-yl)-3-chlorophenol (13 g, 38.28 mmol) was added to a 250 mL three-neck round bottom flask, and the product was obtained in the same manner as in the preparation of step (4) of Example 1. Rate 55%).

(5) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl)chroman-7-carboxylate

Referring to the preparation method of the first step (5) of Example 1, 2-(2-chloro-4-hydroxyphenyl)chroman-7-carbonitrile (6 g, 21.00 mmol) was added to obtain 2.5 g of a product. The rate is 37%).

(6) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of methyl hydropyran-7-carboxylate

Referring to the preparation method of the first step (6) of Example 1, methyl 2-(2-chloro-4-hydroxyphenyl)chroman-7-carboxylate (2.5 g, 7.84 mmol), 4-(chlorine) was added. Methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (2.84 g, 9.39 mmol) gave 1.2 g (yield: 26%).

(7) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of hydropyran-7-carboxylic acid

Add 2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) to a 100 mL three-necked flask A mixed solvent of methyl benzodihydropyran-7-carboxylate (1.2 g, 2.05 mmol) in methanol and water was cooled to 0 ° C, and lithium hydroxide monohydrate (260 mg, 6.19 mmol) was added portionwise. The reaction was carried out at 30 ° C for 2 days. The pH was adjusted to 4 with hydrochloric acid (1 mol/L), ethyl acetate (500 mL) and saturated brine (500 mL) were added, and the organic layer was washed with brine (2×500 mL). Column chromatography (petroleum ether: ethyl acetate = 4:1 to 1:1) afforded 0.28 g (yield: 24%).

Molecular formula: C ₂₉ H ₂₂ Cl ₃ NO ₅ Molecular weight: 570.85 LC-MS: (ES, m/z): 570 (M+1) ⁺

¹ H NMR: (300 MHz, DMSO-d ₆ , ppm): δ 12.82 (brs, 1H), 7.64 - 7.39 (m, 5H), 7.32 - 7.31 (d, J = 1.2 Hz, 1H), 7.26-7.23 ( m, 1H), 6.70-6.69 (d, J = 2.4 Hz, 1H), 6.86-6.85 (m, 1H), 5.31-5.28 (d, J = 9.0 Hz, 1H), 4.93 (s, 2H), 3.07 -2.73 (m, 2H), 2.47-2.45 (m, 1H), 2.19-2.14 (m, 1H), 1.99-1.90 (m, 1H), 1.23-1.134 (m, 4H).

Example 15 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of hydropyran-8-carboxylic acid (Compound 15)

(1) Preparation of methyl salicylate

Salicylic acid (20.0 g, 0.14 mol) was added to methanol (100 ml), and ruthenium chloride (20.7 g, 0.17 mol) was added dropwise to the system at 25 ° C, and the mixture was stirred at 50 ° C for 12 hours. The reaction mixture was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield 90.9%).

(2) Preparation of methyl 3-aldehyde-2-hydroxybenzoate

Methyl salicylate (20.0 g, 0.13 mol) was added to trifluoroacetic acid (200 mL), and urotropine (28.0 g, 0.2 mol), cuprous oxide (14.8 g, 0.13 mol) was added to the system. The reaction mixture was stirred at 60 ° C for 24 hours. The reaction solution was poured into water (1000 ml), dichloromethane (500 ml) was added, the organic phase was separated, and the solvent was removed by rotary evaporation. Purification of petroleum ether = 1 : 10) gave the title compound (m.

(3) Preparation of diethyl (2-(2-chloro-4-methoxyphenyl)-2-oxoethyl)phosphonate

m-Chloroanisole (15.0 g, 0.11 mol) was added to trifluoroacetic anhydride (115.5 g, 0.55 mol), then diethylphosphoric acid (25.5 g, 0.13 mol) was added, and phosphoric acid was added dropwise at 25 ° C ( 15.0 g), stirring at 25 ° C for 24 hours, the reaction solution was poured into ice water (500 ml), extracted with dichloromethane (500 ml), the organic phase was separated, the reaction was concentrated, and the residue was subjected to column chromatography (dichloro Purification with methane (methanol = 50:1)

(4) (E,Z)-3-(3-(2-Chloro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-2-hydroxybenzoic acid methyl ester Preparation

Diethyl(2-(2-chloro-4-methoxyphenyl)-2-oxoethyl)phosphonate (5.9 g, 18.5 mmol), methyl 3-aldehyde-2-hydroxybenzoate (3.0 g, 16.6 mmol), 1,5-diazabicyclo[5.4.0]undec-5-ene (3.4 g, 22.2 mmol) was added to tetrahydrofuran (50 ml), and the reaction was stirred at 25 ° C for 24 hours. The reaction mixture was concentrated to give crystalljjjjjjjjjjjjjjj

(5) Preparation of methyl 3-(3-(2-chloro-4-methoxyphenyl)-3-oxopropyl)-2-hydroxybenzoate

Methyl (Z)-3-(3-(2-chloro-4-methoxyphenyl)-3-oxoprop-l-en-1-yl)-2-hydroxybenzoate (1.0 g, 2.9 mmol), which was added to tetrahydrofuran (20 ml).

(6) Preparation of methyl 3-(3-(2-chloro-4-methoxyphenyl)-3-hydroxypropyl)-2-hydroxybenzoate

Add methyl 3-(3-(2-chloro-4-methoxyphenyl)-3-oxopropyl)-2-hydroxybenzoate (900 mg, 2.6 mmol) to tetrahydrofuran (20 mL). The mixture was stirred for 2 hours at 25 ° C. (900 mg, crude).

(7) Preparation of methyl 2-(2-chloro-4-methoxyphenyl) chroman-8-carboxylate

Add methyl 3-(3-(2-chloro-4-methoxyphenyl)-3-hydroxypropyl)-2-hydroxybenzoate (900 mg, 2.6 mmol) to tetrahydrofuran (20 mL). Phenylphosphine (1.3 g, 5.0 mmol), diethyl azodicarboxylate (0.89 g, 5.13 mmol), stirred at 25 ° C for 12 hours, the reaction mixture was concentrated and purified by column chromatography 1) The product was obtained (300 mg, yield 35.0%).

(8) Preparation of methyl 2-(2-chloro-4-hydroxyphenyl) benzopyran-8-carboxylate

Add methyl 2-(2-chloro-4-methoxyphenyl)chroman-8carboxylate (300.0 mg, 0.9 mmol) to dichloromethane (20 mL). Boron tribromide (1.1 g, 4.5 mmol) was added dropwise, and the reaction was carried out for 1 hour. Methanol (10 ml) was added dropwise to the reaction mixture, and the mixture was adjusted to pH 7 with aqueous sodium hydrogen carbonate. The title compound (120 mg, yield 41.8%) was obtained.

(9) 2-(2-Chloro-4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-methoxy)phenyl)chromanol Preparation of -8-methyl formate

Methyl 2-(2-chloro-4-hydroxyphenyl)chroman-8-carboxylate (120.0 mg, 0.38 mmol), 4-bromomethyl-5-cyclopropyl-3-(2 ,6-Dichlorophenyl)isoxazole (131.9 mg, 0.38 mmol), added to N,N-dimethylformamide (10 ml) and cesium carbonate (245.3 mg, 0.75 mmol), heated to 50 ° C The reaction was stirred for 1 hour, and the mixture was evaporated. EtOAcjjjjjjjjjjjjj ).

(10) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of hydropyran-8-formic acid

2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzodihydropyrrol Methyl -8-carboxylate (100 mg, 0.17 mmol), EtOAc (2 mL, EtOAc (EtOAc) The organic layer was separated, dried over anhydrous sodium sulfate

Molecular formula: C ₂₉ H ₂₂ Cl ₃ NO ₅ Molecular weight: 570.85 LC-MS (M/e): 569.8, 571.7 (M+H ⁺ )

¹ H NMR (CDCl ₃ ) δ: 8.05-8.06 (d, J = 6.4 Hz, 1H), 7.32-7.43 (m, 5H), 7.05-7.09 (m, 1H), 6.88 (s, 1H), 6.77- 6.80 (m, 1H), 5.59-5.62 (d, J = 10.4 Hz, 1H), 4.84 (s, 2H), 2.87-3.15 (m, 2H), 2.05-2.17 (m, 3H), 1.16-1.33 ( m, 5H).

Example 16 3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of Hydropyran-7-carboxylic Acid (Compound 16)

(1) Preparation of ethyl 3-hydroxy-4-methylbenzoate

3-hydroxy-4-methylbenzoic acid (5.0 g, 32.8 mmol) was weighed into 100 mL of ethanol, 0.5 mL of concentrated sulfuric acid was added dropwise, the temperature was raised to 81 ° C for 24 hours, concentrated, and 100 mL of water and ethyl acetate were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield (5.17 g, yield: 87.5%).

(2) Preparation of 1-(bromomethyl)-2-chloro-4-methoxybenzene

2-Chloro-4-methoxy-1-methylbenzene (4.46 g, 28.5 mmol) was added to 60 mL of carbon tetrachloride, and NBS (5.06 g, 28.4 mmol) and AIBN (468 mg, 2.85 mmol), heated to 80 ° C for 2.0 hours, cooled to 25 ° C, suction filtered, filtrate concentrated, the residue obtained by column chromatography (PE: EA = 10:1) (5.52 g, yield 82.3%).

(3) Preparation of 2-(2-chloro-4-methoxyphenyl)acetonitrile

1-(Bromomethyl)-2-chloro-4-methoxybenzene (5.52 g, 23.4 mmol) and potassium carbonate (6.46 g, 46.8 mmol) were added to 100 mL of acetonitrile, and TMSCN (2.78 g, 28.0 mmol). The mixture was heated to 60 ° C for 8.0 hours, and the reaction was completed by TLC. EtOAc was evaporated. EtOAc (EtOAc) The product was obtained (4.1 g, yield 96.5%).

(4) Preparation of ethyl 3-(methoxymethoxy)-4-methylbenzoate

3-Hydroxy-4-methylbenzoic acid ethyl ester (5.17 g, 28.7 mmol) was dissolved in DCM (100 mL), cooled to 0 ° C, DIPEA (8.14 g, 63.1 mmol) and chloromethyl methyl ether (4.62 g) , 57.4mmol), the temperature was raised to 25 ° C for 24 hours, TLC detection reaction was complete, concentrated, 150 mL of water and ethyl acetate were added, the ethyl acetate phase was separated, the EA phase was washed with water, washed with saturated aqueous sodium chloride, anhydrous Dry over sodium sulfate, filter, and the filtrate was evaporated.

(5) Preparation of 2-(2-chloro-4-methoxyphenyl)acetic acid

2-(2-Chloro-4-methoxyphenyl)acetonitrile (4.1 g, 22.6 mmol) was added to a mixed solvent of HAc (60 mL) and water (60 mL), and concentrated sulfuric acid (20 mL) was added dropwise with stirring. The mixture was heated to 100 ° C for 8.0 hours, and the reaction liquid was poured into ice water, and a white precipitate was obtained by stirring, suction filtration, and the filter cake was dried to give a product (3.84 g, yield 84.8%).

(6) Preparation of 2-(2-chloro-4-methoxyphenyl)acetic acid ethyl acetate

2-(2-Chloro-4-methoxyphenyl)acetic acid (3.84 g, 19.1 mmol) and ethanol (2.64 g, 57.4 mmol) were added to 60 mL dichloromethane, and triethylamine (1.93 g, 19.1). Methyl) and EDCi (3.67 g, 19.1 mmol) were added with DMAP (93 mg, 0.76 mmol), and the reaction was carried out at 25 ° C for 4.0 hours. The reaction was completed by TLC, concentrated, water and ethyl acetate (100 mL) The ethyl acetate phase was washed with 1N EtOAc (50 mL)EtOAc.

(7) Preparation of ethyl 4-(bromomethyl)-3-(methoxymethoxy)benzoate

Ethyl 3-(methoxymethoxy)-4-methylbenzoate (2.24 g, 10 mmol) was added to 40 mL of carbon tetrachloride, and NBS (1.78 g, 10 mmol) and AIBN (164 mg, 1.0 mmol) The temperature was raised to 80 ° C for 2.0 hours, the temperature was lowered to 25 ° C, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE: EA = 5:1) (2.7 g, yield: 89.1%).

(8) Ethyl 4-(2-(2-chloro-4-methylphenyl)-3-ethoxy-3-oxopropyl)-3-(methoxymethoxy)benzoate preparation

Ethyl 2-(2-chloro-4-methoxyphenyl)acetate (1.1 g, 4.81 mmol) was dissolved in EtOAc EtOAc (EtOAc) After stirring at 0 ° C for 1.0 hour, ethyl 4-(bromomethyl)-3-(methoxymethoxy)benzoate (1.46 g, 4.82 mmol) was added, and the mixture was warmed to 25 ° C for 18 hours, and water (50 mL) was added. And EA (100 mL), the EA phase was separated, concentrated, and the residue was obtained by column chromatography (PE: EA=2:1) (1.5 g, yield: 69.1%).

(9) Preparation of ethyl 4-(2-(2-chloro-4-methoxyphenyl)-3-ethoxy-3-oxopropyl)-3-hydroxybenzoate

Ethyl 4-(2-(2-chloro-4-methylphenyl)-3-ethoxy-3-oxopropyl)-3-(methoxymethoxy)benzoate (1.5 g , 3.33 mmol) was added to 10 mL of a mixed solvent of TFA and DCM (20 mL), and reacted at 25 ° C for 4.0 hours. The reaction was completed by LC-MS, concentrated, and the residue was purified by column chromatography (PE: DCM = 1:3). (620 mg, yield 45.9%).

(10) Preparation of ethyl 4-(2-(2-chloro-4-methoxyphenyl)-3-hydroxypropyl)-3-hydroxybenzoate

Add ethyl 4-(2-(2-chloro-4-methoxyphenyl)-3-ethoxy-3-oxopropyl)-3-hydroxybenzoate (620 mg, 1.52 mmol) to 20 mL In tetrahydrofuran, the temperature was lowered to 0 ° C, and lithium aluminum hydride (58 mg, 1.53 mmol) was slowly added. After reacting for 10 min at 0 ° C, the reaction was quenched with EtOAc (EtOAc).

(11) Preparation of ethyl 3-(2-chloro-4-methoxyphenyl)chroman-7-carboxylate

Ethyl 4-(2-(2-chloro-4-methoxyphenyl)-3-hydroxypropyl)-3-hydroxybenzoate (130 mg, 0.36 mmol) was added to 20 mL of tetrahydrofuran and cooled to 0 ° C Triphenylphosphine (283 mg, 1.08 mmol) and DEAD (188 mg, 1.08 mmol) were added, and the reaction was carried out at 25 ° C for 18 hours. The reaction was completed by LC-MS, concentrated, and the residue was purified by column chromatography (PE: EA=25: 1) The product was obtained (120 mg, yield: 96.0%).

Preparation of (12) 3-(2-Chloro-4-hydroxyphenyl)chroman-7-carboxylic acid ethyl ester

Ethyl 3-(2-chloro-4-methoxyphenyl)chroman-7-carboxylate (120 mg, 0.35 mmol) was added to 5 mL DCM, cooled to 0 ° C, 1M BBr ₃ The methylene chloride solution (1.4 mL, 1.4 mmol) was heated to 10 ° C for 1.5 hours. The reaction was completed by LC-MS. 1 mL of methanol was added, concentrated, and the residue was obtained by column chromatography (PE: EA=9:1) Product (100 mg, yield 85.8%).

(13) 3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of ethyl hydropyran-7-carboxylate

Ethyl 3-(2-chloro-4-hydroxyphenyl)chroman-7-carboxylate (100 mg, 0.30 mmol) and 4-(bromomethyl)-5-cyclopropyl-3- (2,6-Dichlorophenyl)isoxazole (114 mg, 0.33 mmol) was added to 10 mL of DMF, and potassium carbonate (83 mg, 0.60 mmol) was added thereto with stirring, and the mixture was heated to 50 ° C for 2.0 hours, and the product was detected by LC-MS. It was formed, cooled to 25 ° C, 30 mL of water was added, ultrasonication was precipitated, suction filtration, and the filter cake was dried to obtain a product (130 mg, yield 72.2%).

(14) 3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of hydropyran-7-carboxylic acid

3-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzodihydropyridyl Ethyl-7-carboxylate (130 mg, 0.22 mmol) was dissolved in THF (4 mL), MeOH (2 mL) and water (1 mL). The reaction was carried out for 18 hours, and the reaction was completed by LC-MS. ethyl acetate (50 mL) and water (50 mL) were evaporated, and the ethyl acetate phase was separated and concentrated, and the residue was subjected to silica gel column chromatography (DCM:MeOH = 10:1) The product was obtained (80 mg, yield 63.7%).

Molecular formula: C ₂₉ H ₂₂ Cl ₃ NO ₅ Molecular weight: 570.85 LC-MS (M/e): 570.1 (M+H ⁺ )

¹ H-NMR (400 MHz, MeOD) δ: 7.52 - 7.42 (m, 5H), 7.20 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.72 (dd, J ₁ = 2.8 Hz, J ₂ = 8.8 Hz, 1H), 4.90 (s, 2H), 4.30 (dd, J ₁ = 3.2 Hz, J ₂ = 10.4 Hz, 1H) , 4.06 (t, 1H), 3.63 - 3.61 (m, 1H), 3.05 (d, J = 7.6 Hz, 2H), 2.34 - 2.30 (m, 1H), 1.21-1.19 (m, 4H).

Example 17 2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)chromanol- Preparation of 6-formic acid (Compound 17)

(1) Preparation of methyl 4-hydroxy-3-iodobenzoate

Methyl 4-hydroxybenzoate (3.55 g, 23.3 mmol) was dissolved in acetic acid (20 mL), and a solution of iodine chloride (3.78 g, 23.3 mmol) in acetic acid (5 mL) was added dropwise, and the mixture was heated to 65 ° C and stirred for 16 hours. . The reaction mixture was filtered, and then filtered, mjjjjjjj

(2) Preparation of 1-(4-methoxyphenyl)ethane-1-one

1-(4-Hydroxyphenyl)ethane-1-one (5 g, 36.8 mmol) was dissolved in acetonitrile (50 mL), potassium carbonate (10 g, 72.3 mmol) was added, cooled to 0 ° C, g, 44.4 mmol), the mixture was heated to 25 ° C and stirred for 3 hours. The reaction mixture was filtered, and then evaporated to crystall

(3) Preparation of 1-(4-methoxyphenyl)-2-propenyl-1-one

1-(4-Methoxyphenyl)ethane-1-one (5 g, 33.3 mmol), N-methyltrifluoroacetic acid aniline (11 g, 49.7 mmol) and paraformaldehyde (10 g, 333.3 mmol) The mixture was heated to 80 ° C in tetrahydrofuran (100 mL) and stirred for 24 hours. The reaction mixture was filtered, and ethyl acetate (100 mL) and water (150 mL) was evaporated. reaction.

(4) Methyl 4-hydroxy-3-(3-(4-methoxyphenyl)-3-oxopropyl-1-ene Preparation of -1-yl)benzoate

1-(4-Methoxyphenyl)-2-propenyl-1-one (3.5 g, crude), methyl 4-hydroxy-3-iodobenzoate (6 g, 21.6 mmol), triethylamine 7 g, 69.2 mmol), triphenylphosphine (0.3 g, 1.14 mmol), palladium acetate (0.4 g, 1.78 mmol) was added to acetonitrile (100 mL), and the mixture was stirred at 90 ° C for 16 hours. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal crystal

(5) Preparation of methyl 4-hydroxy-3-(3-(4-methoxyphenyl)-3-oxopropyl)benzoate

Dissolving methyl 4-hydroxy-3-(3-(4-methoxyphenyl)-3-oxopropyl-1-en-1-yl)benzoate (0.9 g, 2.88 mmol) Palladium carbon (0.1 g) was added to methanol (10 mL), and the reaction was stirred under a hydrogen atmosphere at 25 ° C for 16 hours. The reaction mixture was filtered, and then evaporated to crystall

(6) Preparation of methyl 4-hydroxy-3-(3-hydroxy-3-(4-methoxyphenyl)propyl) benzoate

Methyl 4-hydroxy-3-(3-(4-methoxyphenyl)-3-oxopropyl)benzoate (0.85 g, 2.7 mmol) was dissolved in anhydrous ethanol (10 mL). boron Sodium hydride (0.2 g, 5.3 mmol) was stirred at 25 ° C for 16 h. The reaction was quenched with EtOAc (EtOAc (EtOAc)EtOAc. The title compound (0.5 g, yield 58.1%) was obtained eluted from ethylamine.

(7) Preparation of methyl 2-(4-methoxyphenyl) chroman-6-carboxylate

Methyl 4-hydroxy-3-(3-hydroxy-3-(4-methoxyphenyl)propyl)benzoate (0.5 g, 1.58 mmol) and triphenylphosphine (0.5 g, 1.91 mmol) Dissolved in tetrahydrofuran (10 mL), cooled to 0 ° C, and added diethyl azodicarboxylate (0.4 g, 2.3 mmol), and the mixture was stirred at 25 ° C under nitrogen for 16 hours. After adding water (20 mL) and ethyl acetate (20 mL), EtOAc (EtOAc m. The title compound (0.37 g, yield 78.7%) was obtained.

(8) Preparation of 2-(4-hydroxyphenyl)chroman-6-carboxylic acid

Methyl 2-(4-methoxyphenyl)chroman-6-carboxylate (0.37 g, 1.24 mmol) was dissolved in dichloromethane (10 mL). Boron tribromide (0.93 g, 3.71 mmol) was added, and the mixture was heated to 25 ° C and stirred for 6 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc.

(9) Preparation of methyl 2-(4-hydroxyphenyl) chroman-6-carboxylate

2-(4-Hydroxyphenyl)chroman-6-carboxylic acid (0.3 g, 1.11 mmol) was dissolved in anhydrous methanol (10 mL). The reaction was stirred for 16 hours while heating to 60 °C. The reaction mixture was concentrated, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ = 5:1) The title compound (0.2 g, yield 63.4%).

(10) Methyl 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzodihydropyrrolidine Preparation of quaternary-6-formate

Methyl 2-(4-hydroxyphenyl)chroman-6-carboxylate (0.15 g, 0.53 mmol) and 4-(bromomethyl)-5-cyclopropyl-3-(2) 6-Dichlorophenyl)isoxazole (0.2 g, 0.58 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (0.15 g, 1.1 mmol) was added, and the mixture was stirred at 80 ° C for 6 hours. Reaction solution The title compound (0.1 g, yield: 34.5%) was obtained.

(11) 2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)chromanol- Preparation of 6-formic acid

Methyl 2-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)chromanol- The 6-formate (0.1 g, 0.18 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), and a solution of lithium hydroxide (15 mg, 0.36 mmol) in water (1 mL) was added and the mixture was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal

Molecular formula: C ₂₉ H ₂₃ Cl ₂ NO ₅ Molecular weight: 536.41 LC-MS (M/e): 536.2 (M+H ⁺ )

^{1 H-NMR (400MHz, DMSO} ) δ: 7.71 (s, 1H), 7.66 (d, J = 8.4Hz, 1H), 7.61 (d, J = 8Hz, 2H), 7.53-7.58 (m, 1H), 7.27 (d, J = 8.8 Hz, 2H), 6.80-6.85 (m, 3H), 5.08 (d, J = 10 Hz, 1H), 4.86 (s, 1H), 2.91-3.00 (m, 1H), 2.73 2.80 (m, 1H), 2.42-2.50 (m, 1H), 2.08-2.15 (m, 1H), 1.95-2.02 (m, 1H), 1.10- 1.23 (m, 4H).

Example 18 2-(6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)pyridin-3-yl)benzodihydrol Preparation of pyran-6-carboxylic acid (Compound 18)

(1) Preparation of 1-(6-(benzyloxy)pyridin-3-yl)ethanone

1-(6-Hydroxypyridin-3-yl)ethanone (3.0 g, 21.9 mmol) was dissolved in toluene (30 mL), silver carbonate (9.1 g, 33.3 mmol) was added, and benzyl bromide (3.8 g, 22.2 mmol), after completion of the dropwise addition, the mixture was heated to 100 ° C, and the reaction was stirred for 12 hr.

(2) Preparation of 1-(6-(benzyloxy)pyridin-3-yl)prop-2-en-1-one

1-(6-(Benzyloxy)pyridin-3-yl)ethanone (3.8 g, 16.7 mmol), N-methyltrifluoroacetic acid aniline (5.5 g, 24.9 mmol) and paraformaldehyde (5.0 g) 166.7 mmol) was added to tetrahydrofuran (50 mL), and the mixture was heated to 80 ° C and stirred for 24 hours. The reaction mixture was filtered, and ethyl acetate (100 mL) was evaporated.

(3) Methyl (E)-3-(3-(6-(benzyloxy)pyridin-3-yl)-3-oxoprop-1-en-1-yl)-4-hydroxybenzoate Preparation

Crude 1-(6-(benzyloxy)pyridin-3-yl)prop-2-en-1-one (2.0 g), methyl 4-hydroxy-3-iodobenzoate (2.3 g, 8.4 mmol Triethylamine (2.6 g, 25.7 mmol), triphenylphosphine (100 mg, 0.38 mmol), palladium acetate (128 mg, 0.57 mmol) was added to acetonitrile (30 mL), and the mixture was warmed to 90 ° C and stirred for 12 hours. The reaction mixture was concentrated and purified mjjjjlililililililililililili

(4) Preparation of methyl 4-hydroxy-3-(3-(6-hydroxypyridin-3-yl)-3-oxopropyl)benzoate

(E)-3-(3-(6-(Benzyloxy)pyridin-3-yl)-3-oxoprop-1-en-1-yl)-4-hydroxybenzene (0.5 g, 1.3 Methyl) was dissolved in methanol (5 mL), palladium carbon 10% (50 mg) was added, and the reaction was stirred under hydrogen at 25 ° C for 12 hours. Filtration and concentration of the filtrate gave the product (0.3 g, yield 77.5%).

(5) Preparation of methyl 4-hydroxy-3-(3-hydroxy-3-(6-hydroxypyridin-3-yl)propyl)benzoate

4-hydroxy-3-(3-(6-hydroxypyridin-3-yl)-3-oxopropyl) Methyl benzoate (0.3 g, 1.0 mmol) was dissolved in anhydrous methanol (5 mL), sodium borohydride (115 mg, 3.0 mmol) was added, and the reaction was stirred at 25 ° C for 1 hour, then cooled to 0 ° C and added to dilute hydrochloric acid (1M). The mixture was extracted with ethyl acetate (20 mL × 3), EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The rate is 96.7%).

(6) Preparation of methyl 2-(6-hydroxypyridin-3-yl)chroman-6-carboxylate

Methyl 4-hydroxy-3-(3-hydroxy-3-(6-hydroxypyridin-3-yl)propyl)benzoate (290 mg, 0.96 mmol) and triphenylphosphine (0.76 g, 2.9 mmol) After cooling to 0 ° C in tetrahydrofuran (10 mL), diethyl azodicarboxylate (0.5 g, 2.9 mmol) was added, and the reaction was stirred at 25 ° C for 12 hours under nitrogen atmosphere. After adding water (10 mL) and ethyl acetate (20 mL), EtOAc (EtOAc m. The title compound (112 mg, yield 41.0%).

(7) 2-(6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)pyridin-3-yl)benzodihydrol Preparation of methyl pyran-6-carboxylate

Methyl 2-(6-hydroxypyridin-3-yl)chroman-6-carboxylate (100 mg, 0.35 mmol), 4-(bromomethyl)-5-cyclopropyl-3-(2) ,6-dichlorophenyl) Isoxazole (122mg, 0.35mmol), silver carbonate (193mg, 0.7mmol), dissolved in toluene (5mL), warmed to 100 ° C, stirred for 12 hours, the reaction was filtered, the crude product was chromatographed ( petroleum ether The title compound (127 mg, yield: 65.8%).

(8) 2-(6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)pyridin-3-yl)benzodihydrol Preparation of pyran-6-formic acid

2-(6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)pyridin-3-yl)chromanol Methyl-6-carboxylate (120 mg, 0.22 mmol) was dissolved in THF (3 mL) and methanol (3 mL). After adding dilute hydrochloric acid (1M) to adjust to pH=7, the reaction mixture was concentrated, mjjjjjjjjj

Molecular formula: C ₂₈ H ₂₂ C _l2 N ₂ O ₅ Molecular weight: 537.39 LC-MS (M/e): 537.1 (M+H ⁺ )

^{1 H-NMR (400MHz, CDCl} 3) δ: 8.08 (s, 1H), 7.89 (d, J = 7.2Hz, 2H), 7.61 (dd, J 1 = 8.8Hz, J 2 = 6.4Hz, 1H), 7.38-7.41 (m, 2H), 7.28-7.34 (m, 1H), 6.91 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 5.31 (s, 2H), 5.09 (dd, J ₁ = 10.0 Hz, J ₂ = 2.0 Hz, 1H), 3.01-3.04 (m, 1H), 2.86-2.90 (m, 1H), 2.32 - 2.36 (m, 1H), 2.20-2.25 (m) , 1H), 2.09-2.12 (m, 1H), 1.28-1.31 (m, 2H), 1.13-1.18 (m, 2H).

Example 19 (2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzo) Preparation of dihydropyran-6-yl)methanol (Compound 19)

2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzodihydropyrrol Ethyl-6-carboxylic acid (220 mg, 0.39 mmol) was placed in a 50 mL three-neck round bottom flask, dissolved in 20 mL of tetrahydrofuran under nitrogen atmosphere, cooled to 0 ° C, and borane (1 mol/L in THF) (1.94 mL) was added dropwise. After that, it was stirred at 25 ° C and stirred for 1.0 hour. The reaction solution was cooled to 0 ° C and quenched by the addition of hydrochloric acid (2N). After adding 100 mL of ethyl acetate, the mixture was diluted with EtOAc (EtOAc) (EtOAc)

Molecular formula: C ₂₉ H ₂₄ Cl ₃ NO ₄ Molecular weight: 556.86 LC-MS: (ES, m/z): 578 (M+Na)

¹ H NMR: (CD ₃ OD, ppm) δ: 7.38-7.54 (m, 4H), 7.09-7.11 (m, 2H), 6.77-6.85 (m, 3H), 5.27-5.31 (dd, J ₁ =2.1 Hz, J ₂ = 10.2 Hz, 1H), 4.93 (s, 2H), 4.51 (s, 2H), 2.76-3.00 (m, 2H), 2.21-2.37 (m, 2H), 1.86-1.89 (m, 1H) ), 1.20-1.23 (m, 4H).

Example 20 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-N- Preparation of (methylsulfonyl)chroman-6-carboxamide (Compound 20)

Add 2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) to a 100-mL three-necked vial Phenyl)-chroman-6-carboxylic acid (200 mg, 0.35 mmol), dissolved in dichloromethane (50 mL), EDCI (134 mg, 0.70 mmol), 4-dimethylaminopyridine 128 mg, 1.05 mmol), mesylate (66.5 mg, 0.70 mmol). Stir at room temperature overnight under nitrogen. The reaction mixture was added to dichloromethane (100 mL), evaporated, evaporated, evaporated.

Molecular formula: C ₃₀ H ₂₅ Cl ₃ N ₂ O ₆ S Molecular weight: 647.95 LC-MS: (ES, m/z): 647 (M+1) ⁺

¹ H NMR (DMSO, ppm): δ 11.89 (brs, 1H), 7.82 (s, 1H), 7.71-7.74 (dd, J ₁ = 2.1 Hz, J ₂ = 8.4 Hz, 1H), 7.61-7.64 (m, 2H), 7.52-7.57 (m, 1H), 7.38-7.40 (d, J = 8.7 Hz, 1H), 6.98-6.99 (d, J = 2.7 Hz, 1H), 6.85-6.92 (m, 1H), 6.82 -6.83 (m, 1H), 5.35-5.38 (m, 1H), 4.94 (s, 2H), 3.32-3.34 (d, J = 6.6 Hz, 3H), 2.71-3.06 (m, 2H), 1.93-2.49 (m, 3H), 1.13-1.21 (m, 4H).

Example 21 4-((4-(6-(2H-tetrazol-5-yl)chroman-2-yl)-3-chlorophenoxy)methyl)-5-cyclopropyl Preparation of -3-(2,6-dichlorophenyl)isoxazole (Compound 21)

(1) 2-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzoyl Preparation of hydropyran-6-carbonitrile

Referring to the preparation method of the first step (6) of Example 1, 2-(2-chloro-4-hydroxyphenyl)chroman-6-carbonitrile (3 g, 10.50 mmol), 4-(chloromethyl) was added. -5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (3.802 g, 12.57 mmol). The product was obtained in 2.8 g, and the yield was 48.4%.

(2) 4-((4-(6-(2H-tetrazol-5-yl)chroman-2-yl)-3-chlorophenoxy)methyl)-5-cyclopropyl Preparation of -3-(2,6-dichlorophenyl)isoxazole

Add 2-(2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) to a 50 mL round bottom flask Phenyl)chroman-6-carbonitrile (500 mg, 0.91 mmol), ammonium chloride (975 mg, 18.23 mmol), N,N-dimethylformamide (15 mL), NaN ₃ (900 mg , 13.84 mmol). The reaction mixture was heated to 120 deg.] C for 12 hours, the system was added NaHSO ₃ (30mL) quench the reaction. Ethyl acetate (3 x 50 mL) was added for extraction. The combined organic layers were concentrated to give the title compound 261.

Molecular formula: C ₂₉ H ₂₂ Cl ₃ N ₅ O ₃ Molecular weight: 594.88 LC-MS (ES, m/z): 594 (M+1) ⁺

¹ H NMR (DMSO-d ₆ , ppm): δ: 7.79 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.61-7.64 (m, 2H), 7.52-7.57 (m, 1H), 7.43 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.82 - 6.88 (m, 2H), 5.32 (d, J = 8.4 Hz, 1H), 4.94 (s, 2H) ), 3.03-3.10 (m, 1H), 2.80-2.88 (m, 1H), 2.45 (d, J = 3.3 Hz, 1H), 2.14-2.19 (m, 1H), 1.92-2.00 (m, 1H), 1.10-1.22 (m, 4H).

Example 22 2-(6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)pyridine Preparation of -3-yl) chroman-6-carboxylic acid (Compound 23)

(1) Preparation of ethyl 6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylate

Add 6-oxo-2-(trifluoromethyl)-1,4,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester (90 g, 379.5 mmol) in a 2000 mL three-necked flask, CCl ₄ ( 900 mL), NBS (81.88 g, 460.05 mmol). The reaction mixture was warmed to 80 ° C for 24 hours, cooled to room temperature, and the solid was filtered, and the filtrate was added to dichloromethane (1000 mL) and washed with brine (3×2000 mL). The organic layer was separated and dried over anhydrous sodium sulfate.

Preparation of (2) 6-(Benzyloxy)-2-(trifluoromethyl)nicotinic acid ethyl ester

Add 6-oxo-2-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid ethyl ester (50 g, 212.6 mmol) in a 1000 mL three-necked flask, toluene (500 mL), Ag ₂ CO ₃ (76 g, 276.7 mmol) and BnBr (43.7 g, 255.5 mmol). The reaction mixture was heated to 50 ° C for 12 hours, cooled to room temperature, diluted with ethyl acetate (1000 mL), washed with brine (3×1000 mL). Purification by column chromatography (EtOAc /EtOAcEtOAcEtOAcEtOAc

(3) Preparation of (6-(benzyloxy)-2-(trifluoromethyl)pyridin-3-yl)methanol

A solution of 6-(benzyloxy)-2-(trifluoromethyl)nicotinic acid ethyl ester (30 g, 92.23 mmol) in tetrahydrofuran (300 mL) was added to a 2000 mL three-necked flask. At 78 ° C, DIBAL-H (1 M in toluene, 277 mL) was added dropwise, and the addition was continued while stirring at -78 ° C for 3 hours. The reaction was quenched by dropwise addition of methanol (140 mL), and the mixture was warmed to room temperature for 5 minutes, and sodium potassium tartrate (280 mL aqueous solution) was added dropwise, the solid was filtered, and the filtrate was diluted with ethyl acetate (2000 mL), and saturated brine (3×2000 mL) was added. )wash Polyester. The organic layer was dried over anhydrous sodium sulfate (MgSO4).

(4) Preparation of 6-(benzyloxy)-2-(trifluoromethyl)nicaldaldehyde

A solution of (6-(benzyloxy)-2-(trifluoromethyl)pyridin-3-yl)methanol (24 g, 84.73 mmol) in dichloromethane (500 mL) was then evaporated. The temperature was lowered to 0 ° C and Dess-Martin periodinane (43.1 g, 101.6 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 18 hours. The solid was filtered off, the filtrate was diluted with dichloromethane (500 mL) and washed with saturated brine (3×1000 mL). The organic layer was dried over anhydrous sodium sulfate (MgSO4).

(5) (E)-3-(6-(Benzyloxy)-2-(trifluoromethyl)pyridin-3-yl)-1-(5-bromo-2-hydroxyphenyl)propan-2- Preparation of ene-1-one

Add 6-(benzyloxy)-2-(trifluoromethyl)nicaldaldehyde (23 g, 81.78 mmol) in ethanol (460 mL) and 1-(5-bromo-2-hydroxyl) to a 2000 mL three-necked flask Phenyl)ethan-1-one (17.5 g, 81.38 mmol). Then add KOH (32.1g, 572.2mmol) solution in batches, heat and stir at 60 °C for 48 hours. The reaction mixture was quenched by the addition of ice/water (1000 mL). The pH of the solution was adjusted to 7 with hydrochloric acid (6 mol/L). The solid was filtered and dried under reduced pressure to give 36 g of product.

(6) Preparation of 6-bromo-2-(6-hydroxy-2-(trifluoromethyl)pyridin-3-yl)chroman-4-one

(E)-3-(6-(Benzyloxy)-2-(trifluoromethyl)pyridin-3-yl)-1-(5-bromo-2-hydroxybenzene) was added to a 2000 mL three-necked flask Propyl-2-en-1-one (36 g, 75.27 mmol), acetic acid (360 mL), hydrochloric acid (12N, 360 mL), sulfuric acid (1 mL). The reaction mixture was reacted at 88 ° C for 16 hours, cooled to room temperature, poured into ice water (2000 mL) and filtered to give a solid.

(7) Preparation of 5-(6-bromochromen-2-yl)-6-(trifluoromethyl)pyridin-2-ol

HgCl ₂ (6.96 g) and hydrochloric acid (5 N) (150 mL) were added to a 250-mL three-necked flask, and then the temperature was lowered to 0 ° C, and Zn (16.4 g) was added in portions. The system was stirred at room temperature for 30 minutes, and the liquid phase was separated. Hydrochloric acid (5N, 100 mL) was added to the remaining solid, stirred at room temperature for 10 minutes, and the liquid phase was separated, and hydrochloric acid (5N, 150 mL) and 6- A solution of bromo-2-(6-hydroxy-2-(trifluoromethyl)pyridin-3-yl)chroman-4-one (6.6 g, 17.00 mmol) in toluene (100 mL). The reaction mixture was stirred at <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The organic phase was separated, dried over anhydrous sodium sulfate and evaporated, evaporated, evaporated.

(8) Preparation of 2-(6-hydroxy-2-(trifluoromethyl)pyridin-3-yl)chroman-6-carbonitrile

Add 5-(6-bromochroman-2-yl)-6-(trifluoromethyl)pyridin-2-ol (3 g, 8.02 mmol) in a 100 mL three-necked flask, NMP (30 mL) ), ZnCN ₂ (1.12 g, 9.5 mmol), Pd(PPh ₃ ) ₄ (930 mg, 0.81 mmol). The reaction was carried out at 120 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL), EtOAc (EtOAc)EtOAc. Purification by column chromatography (ethyl acetate / petroleum ether = 1 : 10 - 1 : 6) gave 1.7 g of product.

(9) Preparation of methyl 2-(6-hydroxy-2-(trifluoromethyl)pyridin-3-yl)chroman-6-carboxylate

Add 2-(6-hydroxy-2-(trifluoromethyl)pyridin-3-yl)chroman-6-carbonitrile (1.7 g, 5.31 mmol) in a 100 mL three-necked flask, methanol (30 mL), then concentrated sulfuric acid (3 mL) was added dropwise at room temperature. Reaction liquid heating and refluxing After three days, it was cooled to room temperature, poured into ice water (200 mL), and the solid was collected, washed with water (3×50 mL), and dried under reduced pressure to give the title compound 1.3 g.

(10) 2-(6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)pyridine Preparation of -3-yl) benzodihydropyran-6-carboxylic acid methyl ester

Add 2-(6-hydroxy-2-(trifluoromethyl)pyridin-3-yl)chroman-6-carboxylic acid methyl ester (1.3 g, 3.68 mmol) to a 100 mL three-necked flask. N,N-dimethylformamide (30 mL), K ₂ CO ₃ (2.55 g, 18.45 mmol), NaI (1.66 g, 11.07 mmol), 4-(chloromethyl)-5-cyclopropyl- 3-(2,6-Dichlorophenyl 1)-isoxazole (1.33 g, 4.40 mmol). The reaction mixture was reacted at 60 ° C for 16 hours, cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with brine (3×200 mL). The organic phase was separated, dried over anhydrous sodium sulfate and evaporated.

(11) 2-(6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)pyridine Preparation of -3-yl) chroman-6-carboxylic acid

Add 2-(6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-() to a 250 mL three-necked vial trifluoromethyl) pyridin-3-yl) -chroman-6-carboxylate (700mg, 1.13mmol) in methanol (100 mL) solution, water (10mL) and LiOH.H ₂ O (143mg, 3.40 mmol). The reaction solution was stirred at room temperature for 3 days. The organic layer was concentrated under reduced pressure and the residue was applied to ice water (100mL), and the pH was adjusted to 7 with hydrochloric acid (1 mol/L). The solid was filtered, washed with EtOAc EtOAcqqqqqq

Molecular _{formula: C 29 H 21 Cl 2 F} 3 N 2 O 5 molecular weight: 605.39 LC-MS: (ES , m / z): 605.1 (M + 1) +

^{1 HNMR (300MHz, DMSO-d} 6, ppm): δ 12.60 (brs, 1H), 8.08-8.05 (d, J = 9.0Hz, 1H), 7.77 (s, 1H), 7.71-7.68 (m, 1H) , 7.57-7.46 (m, 3H), 7.00-6.98 (d, J = 8.7 Hz, 1H), 6.90-6.87 (d, J = 8.7 Hz, 1H), 5.40-5.27 (m, 3H), 3.11-3.00 (m, 1H), 2.90-2.85 (m, 1H), 2.57-2.55 (m, 1H), 2.09-2.00 (m, 2H), 1.23-1.14 (m, 4H).

Example 23 2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-fluorophenyl)benzoyl Preparation of hydropyran-6-carboxylic acid (Compound 24)

(1) Preparation of 1-(2-fluoro-4-methoxyphenyl)prop-2-en-1-one

Referring to the preparation method in the step (3) of Example 17, 1-(2-fluoro-4-methoxyphenyl)ethan-1-one (1.7 g, 10.1 mmol) was added to give the product (yield).

(2) Preparation of methyl (E)-3-(3-(2-fluoro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-4-hydroxybenzoate

The product was obtained by the preparative procedure in the step (4) of Example 17 (0.9 g,yield: 27.0%).

(3) Preparation of methyl 3-(3-(2-fluoro-4-methoxyphenyl)-3-oxopropyl)-4-hydroxybenzoate

Referring to the preparation method of the step (5) of Example 17, (E)-3-(3-(2-fluoro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl) was added. Methyl 4-hydroxybenzoate (0.83 g, 2.51 mmol) gave the product 0.8 g,yield 95.8%.

(4) Preparation of methyl 3-(3-(2-fluoro-4-methoxyphenyl)-3-hydroxypropyl)-4-hydroxybenzoate

Methyl 3-(3-(2-fluoro-4-methoxyphenyl)-3-oxopropyl)-4-hydroxybenzoate (800 mg, 2.41 mmol) was dissolved in methanol (20 mL) To 0 ° C, NaBH ₄ (146 mg, 3.86 mmol) was then added and the mixture was reacted at 0 ° C for 2 hours. The reaction mixture was poured into water (50 mL).

(5) Preparation of methyl 2-(2-fluoro-4-methoxyphenyl) chroman-6-carboxylate

Add methyl 3-(3-(2-fluoro-4-methoxyphenyl)-3-hydroxypropyl)-4-hydroxybenzoate (1.1 g, crude) to phosphoric acid (10 mL) and warm. The reaction was carried out at 90 ° C for 30 minutes. Then, it was poured into water (50 mL), neutralized to neutral with sodium carbonate, and then extracted with ethyl acetate (100 mL × 3). The organic layer was combined, concentrated, and the residue was purified by gel column chromatography = 10:1) The product was obtained in a yield of 700 mg, which was obtained in a two-step yield of 91.9%.

(6) Preparation of methyl 2-(2-fluoro-4-hydroxyphenyl) benzopyran-6-carboxylate

2- (2-fluoro-4-methoxyphenyl) chroman-6-carboxylate (700mg, 2.21mmol) was dissolved in DCM (30mL), a reduced -20 ℃, N ₂ BBr ₃ (2.7 g, 10.77 mmol) was slowly added under the protection, and the reaction was carried out for 4 hours. After the completion of the reaction, water (20 mL) was added, and the mixture was evaporated, evaporated, evaporated, evaporated. The yield was 52.3%.

(7) 2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-fluorophenyl)benzoyl Preparation of methyl hydrogenpyran-6-carboxylate

2-(2-Fluoro-4-hydroxyphenyl)chroman-6-carboxylic acid Ester (0.3 g, 0.99 mmol) and 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (0.35 g, 1.0 mmol) and potassium carbonate (0.28) g, 2.02 mmol) was added to DMF (20 mL) successively, heated to 60 ° C for 4.6 hours, then poured into water (100 mL), solids were precipitated, filtered, and the filter cake was chromatographed ( petroleum ether: ethyl acetate = 10:1) The product was obtained in 0.43 g, yield 76.2%.

(8) 2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-fluorophenyl)benzoyl Preparation of hydropyran-6-carboxylic acid

2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-fluorophenyl)benzodihydropyrrol Methyl -6-carboxylate (0.3 g, 0.528 mmol) was dissolved in THF (10 mL). Water (10 mL) and lithium hydroxide monohydrate (110 mg, 2.62 mmol) was added and the mixture was stirred at 50 ° C for 24 hours. The THF was evaporated, water (10 mL) was added, and then reduced to 0° C., and the mixture was adjusted to pH 2-3 with dilute hydrochloric acid (1M) to precipitate a solid, which was filtered. The filter cake was washed with water (20 mL), acetonitrile (20 mL) and dried. (200 mg, yield 68.4%).

Molecular formula: C ₂₉ H ₂₂ Cl ₂ FNO ₅ Molecular weight: 554.40 LC-MS (M/e): 555.2 (M ⁺ )

^{1 H-NMR (400MHz, DMSO} ) δ: 12.55 (s, 1H), 7.73 (s, 1H), 7.67 (d, J = 8.4Hz, 1H), 7.61-7.64 (m, 2H), 7.52-7.55 ( m, 1H), 7.34 (t, J = 8.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 10.8 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 5.29 (d, J = 10.0 Hz, 1H), 4.86 (s, 2H), 2.96-3.05 (m, 1H), 2.78-2.82 (m, 1H), 2.33 - 2.42 (m 1H), 1.95- 2.10 (m 1H), 1.11-1.21 (m, 4H).

Example 24 2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)benzene Preparation of benzodihydropyran-6-carboxylic acid (Compound 26)

(1) Preparation of 4-methoxy-2-trifluoromethylbenzaldehyde

The compound 1-bromo-4-methoxy-2-trifluorotoluene (12.7 g, 49.8 mmol) was placed in a 250 ml three-necked flask, dissolved in 150 ml of THF, and N _{2 was} ventilated three times after sealing. The reaction flask was stirred under dry ice at -78 °C. 22 ml of n-butyllithium (2.5 M) was added to the above reaction flask, and after stirring at -78 ° C for 30 min, 4 g of DMF was slowly added thereto, the reaction was continued for about 15 minutes, and then the reaction was carried out at room temperature, and the progress of the reaction was monitored by TLC. After the reaction was completed, the solvent was concentrated, poured into 150 ml of saturated aqueous NaCI solution, and extracted with ethyl acetate three times (150 ml×3). The organic phase was dried over anhydrous sodium sulfate, and then concentrated and then purified by gel column chromatography (EA:PE=1:30) The product was obtained (4.8 g, yield 47.1%).

(2) Preparation of 1-(4-methoxy-2-(trifluoromethyl)phenyl)prop-2-en-1-ol

The compound 4-methoxy-2-trifluoromethylbenzaldehyde (4.7 g, 23.0 mmol) was placed in a 250 ml three-necked flask, dissolved in 100 ml of THF, and N _{2 was} ventilated three times after sealing. 27.6 ml of vinylmagnesium bromide (1 M) was slowly added to the above reaction flask under ice bath, and the reaction was allowed to proceed for about 15 minutes and then moved to room temperature to continue the reaction for about 2 hours. The reaction crude ₄ Cl solution was quenched with saturated NH, and extracted three times with ethyl acetate (150ml × 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was concentrated (5.75 g of), continue to be used without purification in the next reaction .

(3) Preparation of 1-(4-methoxy-2-(trifluoromethyl)phenyl)prop-2-en-1-one

The crude 1-(4-methoxy-2-(trifluoromethyl)phenyl)prop-2-en-1-ol compound obtained in the above step was dissolved in dichloromethane and then stirred at room temperature. The oxidizing agent (12.7 g, 30.0 mmol) was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was concentrated, and the residue was purified by column chromatography (yield: 2.7 g,

(4) Preparation of methyl 4-hydroxy-3-iodobenzoate

Referring to the preparation of the step (1) of Example 17, methyl 4-hydroxybenzoate (11.8 g, 77.6 mmol) was added to give the product (7.6 g, yield: 35.2%).

(5) (E)-4-Hydroxy-3-(3-(4-methoxy-2-(trifluoromethyl)phenyl)-3-oxoprop-1-en-1-yl)- Preparation of methyl benzoate

1-(4-Methoxy-2-(trifluoromethyl)phenyl)prop-2-en-1-one (2.7 g, 11.7 mmol) and methyl 4-hydroxy-3-iodobenzoate ( 3.3g, 11.7mmol) The reaction was carried out in accordance with the step (4) of Example 17 to give the product (3.8 g, yield: 85.4%).

(6) Preparation of methyl 4-hydroxy-3-(3-(4-methoxy-2-(trifluoromethyl)phenyl)-3-oxopropyl)-benzoate

The crude product was obtained by the preparation method of the step (5) of Example 17 and used directly for the next reaction.

(7) Preparation of methyl 4-hydroxy-3-(3-hydroxy-3-(4-methoxy-2-(trifluoromethyl)phenyl)-propyl)-benzoate

Referring to the preparation of the step (4) of Example 23, the product was obtained (yield: 3.50 g, yield: 91.1%).

(8) Preparation of methyl 2-(4-methoxy-2-(trifluoromethyl)phenyl)chroman-6-carboxylate

The compound 4-hydroxy-3-(3-hydroxy-3-(4-methoxy-2-(trifluoromethyl)phenyl)propyl)-benzoic acid methyl ester (1.92 g, 5 mmol), triphenyl The phosphine (1.57 g, 6 mmol), diethyl azodicarboxylate (1.04 g, 6 mmol) was dissolved in tetrahydrofuran (30 mL), and the mixture was stirred at 0 °C. After the reaction was completed, the solvent was concentrated, and 100 ml of water was added, and then extracted with ethyl acetate three times (100 mL × 3), The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated.

(9) Preparation of methyl 2-(4-hydroxy-2-(trifluoromethyl)phenyl)chroman-6-carboxylate

The compound 2-(4-methoxy-2-(trifluoromethyl)phenyl)chroman-6-carboxylic acid methyl ester (550 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL) A solution of boron tribromide in dichloromethane (1 M, 7.5 mL) was slowly added dropwise, and the reaction was continued at -78 ° C for 3 hours while the dropwise addition was completed. At the end of the reaction, the reaction solution was moved to room temperature, and the reaction solution was poured into ice water, extracted with ethyl acetate three times (50 ml×3), and the organic phase was washed with a saturated aqueous solution of sodium chloride. The product was obtained (200 mg, yield 37.9%).

(10) 2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)benzene Preparation of methyl benzodihydropyran-6-carboxylate

Methyl 2-(4-hydroxy-2-(trifluoromethyl)phenyl)chroman-6-carboxylate (100 mg, 0.28 mmol) was dissolved in DMF (5 mL). , 0.42 mmol), stirred at 25 ° C for 10 min, then added 4-(bromomethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (97 mg, 0.28 mmol), 25 The reaction was carried out at ° C for 6 hours. After completion of the reaction, the mixture was poured into ice water, and the solid was precipitated, filtered, and the filter cake was washed with water (20 mL), and the filter cake was collected and dried to give a crude product (154 mg). Used directly in the next step.

(11) 2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)benzene Preparation of benzodihydropyran-6-carboxylic acid

2-(4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-2-(trifluoromethyl)phenyl) Methyl chroman-6-carboxylate (154 mg) was dissolved in THF (2 mL), methanol (2 mL) and water (1 mL) was added, and then lithium hydroxide monohydrate (32 mg, 0.75 mmol) was added. The reaction was carried out at 30 ° C for 2 hours. After the reaction was completed, the reaction solution was poured into 50 mL of water, and extracted with ethyl acetate three times (50 ml×3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the organic phase was concentrated, (50 mg, 30% yield in two steps).

Molecular formula: C ₃₀ H ₂₂ Cl ₂ F ₃ NO ₅ Molecular weight: 604.40 LC-MS (M/e): 604.1 (M+H) ⁺

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.91 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.8, 1H), 7.41 - 7.43 (m, 2H) , 7.32-7.36 (m, 1H), 7.23 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.04 (dd, J ₁ = 2.4 Hz, J ₂ = 8.4 Hz, 1H), 5.38 ( d, J = 10.4 Hz, 1H), 4.89 (s, 2H), 2.91-3.08 (m, 1H), 2.85-2.87 (m, 1H), 2.15-2.19 (m, 1H), 1.90 - 1.99 (m, 1H), 1.16.14.24 (m, 4H).

Example 25 2-(2,6-Dichloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of benzodihydropyran-6-carboxylic acid 27)

(1) Preparation of methyl 4-hydroxy-3-iodobenzoate

Referring to the preparation method of the step (1) of Example 17, methyl 4-hydroxybenzoate (10.1 g, 66.4 mol) was added to give the product (15.0 g, yield 81.3%).

(2) Preparation of (3,5-dichlorophenoxy)triisopropyldecane

3,5-Dichlorophenol (11.5 g, 70.6 mmol), DIPEA (13.7 g, 106.2 mmol), DMAP (861 mg, 7.06 mmol) was added to DCM (200 mL). 16.33 g, 84.7 mmol), then raised to 25 ° C for a period of 8 hours. 1N HCl (126 mL) was added, and the mixture was separated, washed with NaHCO ₃ (120 mL) and NaCI (150 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to give the product (20.0 g, yield 88.8%) .

(3) Preparation of 2,6-dichloro-4-hydroxybenzaldehyde

(3,5-Dichlorophenoxy)triisopropyldecane (20.0 g, 62.7 mmol) was added to anhydrous THF (200 mL), and nBuLi (2.4) was added dropwise at -78 °C. Mol/L, 28.7 mL, 68.9 mmol), stirring was continued for 1 hour. Further, DMF (6.87 g, 94.1 mmol) was added dropwise, and the reaction was continued at -78 ° C for 1 hour. The reaction was returned to 25 ° C for 6 hours. The mixture was extracted with 1N EtOAc (EtOAc) (EtOAc) The solid was precipitated by the addition of EtOAc (EtOAc)EtOAc.

(4) Preparation of 2,6-dichloro-4-methoxybenzaldehyde

2,6-Dichloro-4-hydroxybenzaldehyde (9.5 g, 49.7 mmol) was added to DMF (200 mL), potassium carbonate (20.6 g, 149.3 mmol) was added to the system, and then iodine was added dropwise in an ice bath. Methane (14.1 g, 99.3 mmol) was returned to the reaction at 25 ° C for 12 hours. The system was poured into 400 mL of water, suction filtered under reduced pressure, and the filter cake was washed with water (10mL) and dried to give product (8.0 g, yield 78.5%).

(5) Preparation of 1-(2,6-dichloro-4-methoxyphenyl)prop-2-en-1-ol

2,6-Dichloro-4-methoxybenzaldehyde (8.0 g, 39.0 mmol) was added to 100 ml of THF, and vinylmagnesium bromide (1 M/L, 46.8 mL, 46.8 mmol) was added dropwise in an ice bath. After the dropwise addition was completed, the reaction was continued at 25 ° C for about 6 hours. Saturated NH ₄ Cl was then quenched with a solution (30 mL), extracted with ethyl acetate (200mL) and water (100 mL) and extracted liquid separation, the organic phase was dried over anhydrous sodium sulfate, and the solvent removed by rotary evaporation to give the product (7.5 g of, yield 82.5 %).

(6) Preparation of 1-(2,6-dichloro-4-methoxyphenyl)prop-2-en-1-one

1-(2,6-Dichloro-4-methoxyphenyl)prop-2-en-1-ol (7.5 g, 32.2 mmol) was dissolved in dichloromethane (200 mL). Dess Martin oxidant (16.4 g, 38.7 mmol) was added in a second time and the reaction was continued at 25 ° C for 12 hours. The system was suction filtered under reduced pressure, and the filtrate was evaporated to dryness, and the residue was purified by column chromatography (PE: EA = 10:1) to give product (3.6 g, yield 48.4%).

(7) (E)-3-(3-(2,6-Dichloro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-4-hydroxybenzoic acid Preparation of ester

1-(2,6-Dichloro-4-methoxyphenyl)prop-2-en-1-one (3.6 g, 15.6 mmol), methyl 4-hydroxy-3-iodobenzoate (4.77 g) , 17.2 mmol), triethylamine (3.15 g, 31.2 mmol), triphenylphosphine (409 mg, 1.56 mmol), palladium acetate (175 mg, 0.78 mmol) was added to acetonitrile (150 mL). The reaction was carried out at ° C for 12 hours. After completion of the reaction, the mixture was concentrated, and the residue was applied to silica gel column (PE: EA = 3:1) to afford product (3.0 g, yield 50.5%).

(8) Preparation of methyl 3-(3-(2,6-dichloro-4-methoxyphenyl)-3-oxopropyl)-4-hydroxybenzoate

Methyl (E)-3-(3-(2,6-dichloro-4-methoxyphenyl)-3-oxoprop-1-en-1-yl)-4-hydroxybenzoate ( 3.0 g, 7.9 mmol), PtO ₂ (300 mg) was added to methanol (100 mL), and reacted at 25 ° C for 4 hours under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered, and then evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

(9) Preparation of methyl 3-(3-(2,6-dichloro-4-methoxyphenyl)-3-hydroxypropyl)-4-hydroxybenzoate

Methyl 3-(3-(2,6-dichloro-4-methoxyphenyl)-3-oxopropyl)-4-hydroxybenzoate (1.0 g, 2.6 mmol) was dissolved in THF (20 mL NaBH ₄ (290 mg, 7.8 mmol) was slowly added to the ice bath and reacted at 25 ° C for about 6 hours. The system was quenched by the addition of 1 mL of water. EtOAc (EtOAc:EtOAc:

Preparation of (10) methyl 2-(2,6-dichloro-4-methoxyphenyl)chroman-6-carboxylate

Methyl 3-(3-(2,6-dichloro-4-methoxyphenyl)-3-hydroxypropyl)-4-hydroxybenzoate (850 mg, 2.2 mmol), diethyl azodicarboxylate The ester (957 mg, 5.5 mmol) was dissolved in tetrahydrofuran (40 mL). Triphenylphosphine (1.44 g, 5.5 mmol) was added to an ice bath, and the reaction was carried out at 25 ° C for 12 hours, and the solvent was removed by rotary evaporation. Column chromatography (PE: EA = 20:1) gave product (600 mg, yield 74.3%).

Preparation of (11) methyl 2-(2,6-dichloro-4-hydroxyphenyl)chroman-6-carboxylate

Methyl 2-(2,6-dichloro-4-methoxyphenyl)chroman-6-carboxylate (600 mg, 1.6 mmol) was dissolved in dichloromethane (20 mL), -78 A solution of boron tribromide in dichloromethane (1 M/L, 8.2 mL, 8.2 mmol) in DCM was slowly added dropwise at ° C, then slowly warmed to 25 ° C and allowed to react for 2 hours. The system was quenched by the addition of 1 mL of methanol, and the product was obtained by silica gel column chromatography (PE: EA = 3:1) (60 mg, yield: 10.6%).

(12) 2-(2,6-Dichloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of methyl benzopyran-6-carboxylate

Methyl 2-(2,6-dichloro-4-hydroxyphenyl)chroman-6-carboxylate (60 mg, 0.17 mmol), 4-(bromomethyl)-5-cyclopropyl 3-(2,6-Dichlorophenyl)isoxazole (59 mg, 0.17 mmol), cesium carbonate (111 mg, 0.34 mmol) was added to DMF (10 mL). The system was extracted with ethyl acetate (50 mL) and water (30 mL), and evaporated, evaporated and evaporated.

(13) 2-(2,6-Dichloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Preparation of benzodihydropyran-6-carboxylic acid

2-(2,6-Dichloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)benzo Methyl dihydropyran-6-carboxylate (70 mg, 0.11 mmol) was added to methanol (4 mL) and THF (4 mL), and then a solution of lithium hydroxide monohydrate (24 mg, 0.57 mmol) in 2 mL of water, 50 ° C After 12 hours of reaction, the system was lowered to 25 ° C and the pH was adjusted to 3-4 with 1 M HCl. The mixture was extracted with EtOAc (EtOAc) (EtOAc)

Molecular formula: C ₂₉ H ₂₁ Cl ₄ NO ₅ Molecular weight: 605.29 LC-MS (M/e): 606.1 (M+H ⁺ )

^{1 H-NMR (400MHz, CDCl3} ) δ: 7.95-7.70 (m, 2H), 7.50-7.25 (m, 3H), 6.90-6.62 (m, 3H), 5.85-5.65 (m, 1H), 4.80 (s , 2H), 3.55-3.45 (m, 1H), 3.16-2.45 (m, 3H), 2.20- 1.83 (m, 2H), 1.38-1.02 (m, 4H).

Example 26 6-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-5- Preparation of oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (Compound 28)

(1) Preparation of 2-(4-bromo-3-chlorophenoxy)tetrahydro-2H-pyran

Referring to the preparation method in the step (1) of Example 2, 4-bromo-3-chlorophenol (10.0 g, 48.2 mmol) and 3,4-dihydropyran (10.5 g, 124.8 mmol) were added to obtain 12 g of the product. The rate is 85.4%.

(2) Preparation of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate

6-Hydroxy-3,4-dihydronaphthalen-1(2H)-one (11 g, 67.8 mmol) was dissolved in dichloromethane (150 mL), reduced to -5 ° C, and triethylamine (10.3 g, 101.8 mmol), trifluoromethanesulfonic acid (23 g, 153.3 mmol) was added slowly, and the reaction was completed, and the reaction was carried out at 25 ° C for 4 hours. After completion of the reaction, the mixture was concentrated, and the residue was subjected to silica gel chromatography ( petroleum ether: ethyl acetate = 20 : 1) The product was obtained in 13 g, yield: 65.2%.

(3) Preparation of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (10 g, 34 mmol) was dissolved in DMF (70 mL) and methanol (20 mL). (7g, 69.2mmol), DPPP (450mg, 1.09mmol), palladium acetate (450mg, 2.0mmol), carbon monoxide balloon, reaction at 70 ° C for 16 hours, after the reaction is completed, the reaction solution is poured into water, filtered, filter cake by silicone Column chromatography (petroleum ether: ethyl acetate = 5:1) gave 6.2 g of product.

(4) 6-(2-Chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene- Preparation of 2-formic acid methyl ester

Methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.6 g, 2.94 mmol), 2-(4-bromo-3-chlorophenoxy)tetrahydro-2H- Pyran (1.17g, 4.0mmol), Pd ₂ (dba) ₃ (270mg, 0.29mmol), Xantphos (340mg, 0.58mmol), cesium carbonate (1.9g, 5.8mmol), added to toluene (30mL) The mixture was subjected to a nitrogen atmosphere, and the mixture was concentrated at 120 ° C for 20 hours, and concentrated. The residue was purified by silica gel column chromatography ( petroleum ether: ethyl acetate = 10:1).

(5) Preparation of methyl 6-(2-chloro-4-hydroxyphenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate

6-(2-Chloro-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2- Methyl formate (0.2 g, 0.48 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) The residue was purified by EtOAc EtOAc (EtOAc:EtOAc)

(6) 6-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-5- Preparation of oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester

Methyl 6-(2-chloro-4-hydroxyphenyl)-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.1 g, 0.3 mmol) and 4-(bromomethyl) 5-)cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (0.125 g, 0.36 mmol) and potassium carbonate (83 mg, 0.6 mmol) were added sequentially to DMF (10 mL), 60 After reacting for 4 hours at ° C, the reaction was completed, poured into water, filtered, and the filter cake was subjected to silica gel column chromatography ( petroleum ether: ethyl acetate = 5: 1-2:1) to give product 145 mg (yield: 81.0%).

(7) 6-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-5- Preparation of oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid

6-(2-Chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)-5-oxo -5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (140 mg, 0.23 mmol) was dissolved in methanol (4 mL), tetrahydrofuran (8 mL), water (8 mL), and lithium hydroxide monohydrate (50 mg) , 1.19 mmol), stirred at 25 ° C for 16 hours. After completion of the reaction, methanol and tetrahydrofuran were evaporated under reduced pressure, and water (10 mL) was added to the residue, and the mixture was adjusted to pH 2 with dilute hydrochloric acid (1M), and extracted with ethyl acetate (20 mL×3). The product was obtained by EtOAc (EtOAc:EtOAc:EtOAc:

Molecular formula: C ₃₀ H ₂₂ Cl ₃ NO ₅ Molecular weight: 582.86 LC-MS (M/e): 582.2 (M+H ⁺ )

^{1 H-NMR (400MHz, CDCl3} ) δ: 8.16 (s, 1H), 8.04 (d, J = 8.8Hz, 2H), 7.42 (d, J = 7.6Hz, 2H), 7.32-7.37 (m, 1H) , 7.03 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 2.0 Hz, J = 8.8 Hz, 1H), 4.79 (s, 2H), 4.21. (dd, J=4.0 Hz, J=12.8 Hz, 1H), 3.12-3.26 (m, 2H), 2.31-2.42 (m, 2H), 2.10-2.21 (m, 1H), 1.21-1.32 (m, 2H) ), 1.16.19.19 (m, 2H).

Claims (17)

a compound of the formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, Wherein R ¹ and R ² are each independently selected from the group consisting of a hydrogen atom, a cyano group, a halogen atom, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a C _1-6 alkyl group, a C _1-6 alkoxy group, and a C _1-6 alkane. Amino group, di C _1-6 alkylamino group, C _1-6 alkylthio group, C _1-6 alkylcarbonyl group, halogenated C _1-6 alkyl group, halogenated C _1-6 alkoxy group, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylcarbonyloxy, C _1-6 alkylsulfonyl, C _1-6 alkylaminosulfonyl, di C _{1- 6} alkylaminosulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkylsulfonyloxy, C _2-8 alkenyl or C _2-8 alkynyl; R ^{3 is} selected from hydrogen An atom, a cyano group, a halogen atom, a nitro group, an amine group, a hydroxyl group, a carboxyl group, or a C _1-6 alkyl group optionally substituted by one or more substituents P, a halogenated C _1-6 alkyl group, a hydroxyl group C _{1 -6} alkyl, carboxy C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy C _1-6 alkoxy, carboxy C _1-6 alkoxy, C _1-6 alkylsulfonyl, C _1-6 alkylaminosulfonyl, di C _1-6 alkylaminosulfonyl, C _1-6 alkylsulfonylamino, C _1-6 alkane sulfonic yl group, a 3-8 membered cycloalkyl, 3-8 membered cycloalkyl C _1-6 alkyl, 3-8 membered heterocyclyl, 3-8 membered heterocyclyl C _1-6 alkyl P is selected from hydroxy, amino, carboxy, cyano, nitro, a halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di-C _1-6 alkyl Amino, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkylcarbonyl, C _1-6 alkyl a carbonyloxy group, a C _1-6 alkylsulfonyl group, a C _2-8 alkenyl group or a C _2-8 alkynyl group; and R ^{4 is} selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group. , C _1-6 alkoxy, C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, carboxy C _1-6 alkyl, carboxyoxy C _1-6 alkyl , carboxyamino C _1-6 alkyl, amino C _1-6 alkyl, aminocarbonyl C _1-6 alkyl, hydroxy C _1-6 alkoxy, halogenated C _1-6 alkoxy, carboxy C _1-6 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, C _1-6 alkylamino, C _1-6 alkylcarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, C _1-6 alkylsulfonylaminocarbonyl, C _1-6 alkylaminosulfonyl, di C _1-6 alkylamino, 5-8 membered heteroaryl Or a 3-8 membered heterocyclic group; W is selected from CH ₂ , NH, O, S, SO, SO ₂ or CO; A is selected from NH, O or S; Z is selected from one or more substituents Q or not Substituted aryl, 5-8 membered heteroaryl, 3-8 membered cycloalkyl or 3-8 membered heterocyclic group; Q is selected from cyano, amino, hydroxy, carboxy, nitro, halogen atom, C _{1 -6} alkyl, C _1-6 alkoxy, C _1-6 alkylamino, di C _1-6 alkylamino, halo C _1-6 alkyl, halo C _1-6 alkoxy , C _1-6 alkoxy C _1-6 alkyl, C _2-8 alkenyl or C _2-8 alkynyl; E is selected from CH ₂ , NH, O, S, SO, SO ₂ or CO; Self-existing, CH ₂ , NH, O, S, SO, SO ₂ or CO; X is selected from CH or N; Y is selected from CH ₂ , NH, O, S, SO, SO ₂ or CO; E, X, The connection between Y and F is independently selected from a single bond; m is selected from an integer from 0 to 3; n is selected from an integer from 0 to 4. The compound according to claim 1, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a halogen atom, a nitro group, and an amine. Base, hydroxy, carboxy, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino, C _1-4 alkylthio, C _1-4 alkylcarbonyl, halogenated C _1-4 alkyl, halo C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, C _1-4 alkylcarbonyloxy, C _1-4 alkylsulfonyl, C _1-4 alkylaminosulfonyl, di C _1-4 alkylaminosulfonyl, C _2-6 alkenyl or C _2-6 alkynyl; R ^{3 is} selected from a hydrogen atom, a cyano group, a halogen atom, a nitro group, an amine group, a hydroxyl group, a carboxyl group, or a C _1-4 alkyl group optionally substituted by one or more substituents P, a halogenated C _1-4 alkyl group , C _1-4 alkoxy group, halogenated C _1-4 alkoxy group, 3-6 membered cycloalkyl group, 3-6 membered cycloalkyl C _1-4 alkyl group, 3-6 membered heterocyclic group, 3 -6 membered heterocyclic group C _1-4 alkyl; P is selected from the group consisting of a hydroxyl group, an amine group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group, and C _{1- 4} alkylamino, di-C _1-4 alkylamino, halo C _1-4 alkyl, halogenated C _1-4 alkoxy , C _1-4 alkoxy C _1-4 alkyl, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonyloxy, C _1-4 alkylsulfonyl group, C _2-6 alkenyl group or C _2-6 alkynyl; R ^{4 is} selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a C _1-4 alkoxy group, a C _1-4 alkyl group, a hydroxyl group C _1-4 Alkyl, halogenated C _1-4 alkyl, carboxy C _1-4 alkyl, carboxyoxy C _1-4 alkyl, carboxyamino C _1-4 alkyl, amine C _1-4 alkyl, amine Carbocarbonyl C _1-4 alkyl, hydroxy C _1-4 alkoxy, halo C _1-4 alkoxy, carboxy C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl , C _1-4 alkylamino group, C _1-4 alkylcarbonyl group, C _1-4 alkylcarbonylamino group, C _1-4 alkylsulfonyl group, C _1-4 alkylsulfonylaminocarbonyl group, a C _1-4 alkylaminosulfonyl group, a di C _1-4 alkylamino group, a 5-6 membered heteroaryl group or a 4-7 membered heterocyclic group; W is selected from the group consisting of CH ₂ , NH, O, S, SO, SO ₂ or CO; A is selected from NH, O or S; Z is selected from aryl substituted or unsubstituted by one or more substituents Q, 5-6 membered heteroaryl, 3-6 membered naphthenic group or 4-7-membered heterocyclyl group; Q is selected from cyano, amino, hydroxy, carboxy, nitro, halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl Amino, di-C _1-4 alkylamino, halo C _1-4 alkyl, halo C _1-4 alkoxy, C _1-4 alkoxy C _1-4 alkyl, C _2-6 Alkenyl or C _2-6 alkynyl; E is selected from CH ₂ , NH, O, S or CO; F is selected from the absence, CH ₂ , NH, O or S; X is selected from CH or N; Y is selected from CH ₂ , NH, O or S; the connection between E, X, Y, F is independently selected from a single bond; m is selected from an integer from 0 to 2; and n is selected from an integer from 0 to 3. The compound according to claim 2, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a halogen atom, a nitro group, and an amine. Base, hydroxy, carboxy, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino, C _1-4 alkylthio, C _{a 1-4} alkylcarbonyl group, a halogenated C _1-4 alkyl group, a halogenated C _1-4 alkoxy group or a C _1-4 alkoxy C _1-4 alkyl group; R ^{3 is} selected from a cyano group, optionally a C _1-4 alkyl group substituted with one or more substituents P, a halogenated C _1-4 alkyl group, a 3-6 membered cycloalkyl group, a 3-6 membered cycloalkyl C _1-4 alkyl group, 3-6 a heterocyclic group or a 3-6 membered heterocyclic group C _1-4 alkyl; P is selected from the group consisting of a hydroxyl group, an amine group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C _1-4 alkyl group, and a C _1-4 alkane. An oxy group, a C _1-4 alkylamino group, a di C _1-4 alkylamino group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group; and R ^{4 is} selected from a hydrogen atom and a halogen atom. , cyano, nitro, amine, hydroxy, carboxy, C _1-4 alkoxy, C _1-4 alkyl, hydroxy C _1-4 alkyl, halo C _1-4 alkyl, carboxy C _{1- 4} alkyl, carboxy-C _1-4 alkyl, carboxy C _1-4 alkyl group, a C _1-4 alkoxy group , Aminocarbonyl C _1-4 alkyl, hydroxy C _1-4 alkoxy, halo C _1-4 alkoxy, carboxy C _1-4 alkoxy, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-4 alkylamino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonyl, C _1-4 alkylsulfonylamino a carbonyl group, a C _1-4 alkylaminosulfonyl group, a di C _1-4 alkylamino group, a 5-6 membered heteroaryl group or a 5-6 membered heterocyclic group; W is selected from the group consisting of CH ₂ , NH, O, S, SO, SO ₂ or CO; A is selected from NH, O or S; Z is selected from phenyl substituted or unsubstituted by one or more substituents Q, containing 1-2 N, O and/or S a 5-6 membered heteroaryl group of a atom, a 5-6 membered cycloalkyl group, or a 5-6 membered heterocyclic group having 1-2 N, O and/or S atoms; Q is selected from the group consisting of a cyano group, an amine group, Hydroxy, carboxyl, nitro, halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino, halogen C _1-4 Alkyl or halo C _1-4 alkoxy; E is selected from CH ₂ , NH, O or CO; F is selected from the absence, CH ₂ , NH or O; X is selected from CH or N; Y is selected from CH ₂ The connection between NH, O or O; E, X, Y, F is independently selected from a single bond; m is selected from an integer from 0 to 2; and n is selected from an integer from 0 to 3. The compound according to claim 1, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, having the structure of the following formula (I-1): Wherein R ¹ and R ² are each independently selected from the group consisting of a hydrogen atom, a cyano group, a halogen atom, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a C _1-4 alkyl group, a C _1-4 alkoxy group, and a C _1-4 alkane. An amino group, a di-C _1-4 alkylamino group, a C _1-4 alkylthio group, a C _1-4 alkylcarbonyl group, a halogenated C _1-4 alkyl group, a halogenated C _1-4 alkoxy group or C _1-4 alkoxy C _1-4 alkyl; R & lt ³ selected from cyano, optionally substituted with one or more substituent P C _1-4 alkyl, halo C _1-4 alkyl, 3 6-membered cycloalkyl or 3-6 membered cycloalkyl C1 _-4 alkyl group; P is selected from hydroxy, amino, carboxy, cyano, nitro, a halogen atom, C _1-4 alkyl, C _1-4 Alkoxy, C _1-4 alkylamino, di C _1-4 alkylamino, halo C _1-4 alkyl or halo C _1-4 alkoxy; R ^{4 is} selected from a hydrogen atom, a halogen Atom, cyano, nitro, amine, hydroxy, carboxy, C _1-4 alkoxy, C _1-4 alkyl, hydroxy C _1-4 alkyl, halo C _1-4 alkyl, carboxy C _{1 -4} alkyl, amino C _1-4 alkyl, aminocarbonyl C _1-4 alkyl, hydroxy C _1-4 alkoxy, halogenated C _1-4 alkoxy, carboxy C _1-4 alkoxy group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-4 alkylamino, C _1-4 alkylcarbonyl, C _1-4 alkylcarbonyl group C _1-4 alkylsulfonyl group, C _1-4 alkylsulfonyl aminocarbonyl, C _1-4 alkyl sulfonic acyl group, di C _1-4 alkylamino or a 5-6 membered heteroaryl W is selected from CH ₂ , NH, O, S, SO or SO ₂ ; A is selected from NH, O or S; Z is selected from phenyl substituted or unsubstituted by one or more substituents Q or 5- 6-membered heteroaryl; Q is selected from the group consisting of cyano, amine, hydroxy, carboxy, nitro, halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, and C _1-4 alkylamino, halo C _1-4 alkyl or halo C _1-4 alkoxy; E is selected from CH ₂ , NH, O or CO; F is selected from the absence, CH ₂ , NH Or O; X is selected from CH or N; Y is selected from CH ₂ , NH or O; the linkage between E, X, Y, F is independently selected from a single bond; n is selected from an integer from 0 to 3. The compound according to claim 4, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, and a bromine Atom, nitro, amine, hydroxy, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methoxy, methylamino, ethyl hydrazine, Trifluoromethyl, trifluoroethyl or trifluoromethoxy; R ^{3 is} selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl , trifluoroethyl, trifluoropropyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentyl Or cyclohexylmethyl; R ^{4 is} selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a hydroxymethyl group, a hydroxyethyl group. , methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, ethynyl, methylamino, ethylamino, ethyl hydrazino, etidinyl, methanesulfonyl, methyl sulfonate Amidinocarbonyl, ethylsulfonate Ylcarbonyl, dimethylamino, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, thiadiazole, triazole or tetrazol; W is selected from CH _2, NH, O Or S; A is selected from NH, O or S; Z is selected from phenyl or 5-6 membered heteroaryl substituted or unsubstituted by one or more substituents Q; Q is selected from cyano, amine, hydroxy , carboxyl group, nitro group, halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylamino group, di C _1-4 alkylamino group, halogenated C _1-4 alkane Or a halogenated C _1-4 alkoxy group; E is selected from CH ₂ , NH, O or CO; F is selected from the absence, CH ₂ , NH or O; X is selected from CH or N; Y is selected from CH ₂ , The connection between NH or O; E, X, Y, F is independently selected from a single bond; n is selected from 1 or 2. The compound according to claim 5, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, and a Base, ethyl, propyl, butyl, methoxy, methylamino, ethyl fluorenyl, trifluoromethyl or trifluoromethoxy; R ^{3 is} selected from methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or cyclobutylmethyl ; R ^{4 is} selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxy group, an ethoxy group, and a third group. Fluoromethyl, trifluoromethoxy, ethoxymethyl, acetoguanyl, methylsulfonylaminocarbonyl, ethylsulfonylaminocarbonyl, oxadiazole, thiazole, isothiazole, thiadiazole, trinitrogen An azole or a tetrazole; W is selected from NH, O or S; A is selected from NH, O or S; and Z is selected from phenyl or pyridyl substituted or unsubstituted by one or more substituents Q, Substituent Q is selected from the group consisting of cyano, amine, and hydroxy A carboxyl group, a nitro group, a halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di-C _1-4 alkylamino, halo C _1-4 alkyl Or halogenated C _1-4 alkoxy; E is selected from CH ₂ , NH, O or CO; F is selected from CH ₂ , NH or O; X is selected from CH or N; Y is selected from CH ₂ , NH or O; The connection between E, X, Y, and F is independently selected from a single bond; n is selected from 1 or 2. The compound according to claim 6, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein the cyclic group which is composed of E, X, Y and F together with the benzene ring forms the following structure: Benzodihydropyranyl, benzo1,4-dioxanyl, benzo1,3-dioxanyl, benzotetrahydropyridyl, benzodihydrooxazinyl , benzotetrahydropyrazinyl, 1,2,3,4-tetrahydroquinazolinyl, 1,2,3,4-tetrahydroporphyrinyl, tetrahydronaphthyl, tetralone. The compound of claim 7, a pharmaceutically acceptable salt thereof, an ester thereof, or a stereoisomer thereof, wherein Z is selected from phenyl substituted or unsubstituted by one or more substituents Q, Substituent Q is selected from the group consisting of cyano, amine, hydroxy, carboxy, nitro, halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, di C _1-4 An alkylamino group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group; a cyclic group composed of E, X, Y and F together with a benzene ring forms the following structure: The compound according to claim 8, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein W is selected from O; A is selected from O; and Z is selected from 1-2 substituents Q or An unsubstituted phenyl group, the substituent Q being selected from the group consisting of a cyano group, an amine group, a hydroxyl group, a carboxyl group, a nitro group, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a methoxy group, and an ethoxy group. A methylamino group, a dimethylamino group, a trifluoromethyl group or a trifluoromethoxy group; a cyclic group composed of E, X, Y and F together with a benzene ring forms the following structure: n is selected from 1. The compound according to claim 5, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein R ¹ and R ² are each independently selected from a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, and a Base, ethyl, propyl, butyl, methoxy, methylamino, ethyl fluorenyl, trifluoromethyl or trifluoromethoxy; R ^{3 is} selected from methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, trifluoroethyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or cyclobutylmethyl ; R ^{4 is} selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, an amine group, a hydroxyl group, a carboxyl group, a methyl group, an ethyl group, a propyl group, a hydroxymethyl group, a hydroxyethyl group, a methoxy group, an ethoxy group, and a third group. Fluoromethyl, trifluoromethoxy, ethoxymethyl, acetoguanyl, methylsulfonylaminocarbonyl, ethylsulfonylaminocarbonyl, oxadiazole, thiazole, isothiazole, thiadiazole, trinitrogen An azole or a tetrazole; W is selected from NH, O or S; A is selected from NH, O or S; and Z is selected from phenyl or pyridyl substituted or unsubstituted by one or more substituents Q, Substituent Q is selected from the group consisting of cyano, amine, and hydroxy , carboxyl group, nitro group, halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylamino group, di C _1-4 alkylamino group, halogenated C _1-4 alkane Or a halogenated C _1-4 alkoxy group; E is selected from CH ₂ , NH or O; F is selected from the absence; X is selected from CH or N; Y is selected from CH ₂ or O; E, X, Y, F The manner of attachment between them is independently selected from a single bond; n is selected from 1 or 2. The compound of claim 10, a pharmaceutically acceptable salt thereof, The ester or a stereoisomer thereof, wherein the cyclic group formed by E, X, and Y together with the benzene ring forms the following structure: benzodihydropyrrolyl, benzodihydrofuranyl, benzo 1,3 - Dioxolyl or indanyl. The compound according to claim 11, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein W is selected from O; A is selected from O; and Z is selected from one or more substituents Q or Unsubstituted phenyl, said substituent Q being selected from the group consisting of cyano, amine, hydroxy, carboxy, nitro, halogen atom, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 An alkylamino group, a di-C _1-4 alkylamino group, a halogenated C _1-4 alkyl group or a halogenated C _1-4 alkoxy group; a cyclic group formed by E, X, Y together with a benzene ring Form the following structure: The compound according to claim 1, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, wherein the compound is selected from the group consisting of: A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers and/or dilutions Agent. A compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, for use in the preparation of a medicament for the treatment and/or prevention of FXR-mediated diseases and related diseases Uses, the diseases include chronic intrahepatic or some forms of extrahepatic cholestasis, or liver fibrosis caused by chronic cholestasis or acute intrahepatic cholestasis, liver cirrhosis, obstructive or chronic inflammatory disorders of the liver , fatty liver and its complications, alcohol-related fatty liver and its complications, acute liver failure, cholelithiasis, and / or inflammatory bowel disease, primary biliary cirrhosis, chronic fatty and fibrous Conditions and diseases caused by degeneration, lipid or lipoprotein disorders, clinical complications of type I or type II diabetes, non-malignant hyperproliferative diseases or hyperproliferative diseases. The use according to claim 15, wherein the condition and disease caused by chronic fatty and fibrotic degeneration are selected from non-alcoholic fatty liver disease or nonalcoholic steatohepatitis; and the lipid or lipoprotein disorder is selected from the group consisting of atherosclerosis and blood lipids. Abnormal, thrombotic, clinical complications of type I or type II diabetes are selected from diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, and other clinically significant long-term diabetes; non-malignant hyperproliferative The disease or hyperproliferative disease is selected from the group consisting of hepatocellular carcinoma, colon adenoma and polyposis, colon adenocarcinoma, breast cancer, pancreatic cancer, esophageal cancer, and other forms of gastrointestinal and liver neoplastic diseases. An intermediate in the process for preparing a compound of the formula (I) as shown in the formula (II), Wherein R ⁴ , m, n, A, Z, E, F, X, and Y are as described in claim 6.