A biaryl compound, its preparation and use

Abstract

This invention discloses a biaryl compound, its preparation method, and its applications. The biaryl compound has the structure shown in general formula (I), general formula (II), or general formula (III), or its stereoisomers, or pharmaceutically acceptable salts, and can serve as an effective TEAD inhibitor with significant antitumor activity.

Description

Technical Field

[0001] This invention belongs to the field of anticancer drug technology, and relates to a biaryl compound, its preparation method and application. Background Technology

[0002] The Hippo signaling pathway is a highly conserved, fundamental regulatory network whose core function is to negatively regulate organ size and tissue homeostasis, playing an indispensable role in maintaining the dynamic balance of cellular physiological activities. As a core downstream effector of this pathway, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) primarily rely on phosphorylation-mediated nucleocytoplasmic shuttle processes for their biological function. Recent research in the field of oncology has confirmed that aberrant activation of YAP / TAZ is widespread in various malignant tumors, including liver cancer, colorectal cancer, lung cancer, ovarian cancer, and prostate cancer, and is closely related to the occurrence and progression of tumors, representing a key molecular event driving malignant tumor evolution. Notably, YAP / TAZ itself lacks DNA binding capacity and must form a functional complex with a family of transcriptional enhanced associated domain proteins (TEADs) with proliferative functions to initiate the transcriptional program of downstream target genes. Downstream target genes regulated by the YAP / TAZ-TEAD complex can mediate key biological processes such as cell proliferation, cell survival, immune escape, and maintenance of stem cell characteristics, thereby promoting malignant tumor progression. Due to the inherent structural disorder of YAP / TAZ, direct targeting with small molecule drugs is severely limited. This technological bottleneck has prompted researchers to shift their focus to TEAD-targeted inhibition, and several potentially active TEAD inhibitors have been successfully developed. However, current TEAD inhibitors suitable for basic research and clinical translation are still in the early stages of exploration, generally facing challenges such as a scarcity of target molecules, a single scaffold structure, insufficient inhibitory activity, and potential safety risks. Therefore, developing small molecule TEAD-targeting inhibitors with high activity, high affinity, and novel scaffold structures has become a research hotspot and important direction in the field of anti-tumor drug development. Summary of the Invention

[0003] To address the problems existing in the prior art, this invention provides a biaryl compound, its preparation method, and its application, thereby solving the technical problems of the scarcity of molecular types, the single skeleton structure, the insufficient inhibitory activity, and the potential safety risks of TEAD-targeting inhibitors in the prior art.

[0004] This invention is achieved through the following technical solution: A biaryl compound having the structure shown in general formula (I), general formula (II) or general formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: , , ; in: R 1 It is selected from one of hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxyl, substituted or unsubstituted amide, and substituted or unsubstituted sulfonamide. R 2 It is selected from one of hydrogen, hydroxyl, carboxyl, acrylamide, and C1-C6 alkoxy groups; R 3 Selected from hydrogen and substituted or unsubstituted phenoxy groups; R 4 It is selected from hydrogen, halogen, and substituted or unsubstituted phenoxy groups; R 5 Selected from hydrogen or halogen; R 6 -R 8 Independently selected from hydrogen, alkoxy, and alkyl or substituted amide groups; Ring A is independently selected from one of substituted phenyl, substituted naphthyl, and substituted quinolinyl groups; Ring B is independently selected from one of substituted or unsubstituted phenyl, pyridyl, substituted pyrazolyl, furanyl, and thiophenyl groups; The molecular structure of the general formula (I), general formula (II) or general formula (III) contains a biaryl skeleton and has at least one end connected to a pharmacophore that can bind to the TEAD protein, wherein the pharmacophore is selected from a carboxyl group, a sulfonamide group or an acrylamide group.

[0005] Preferably, for R 1 The substituted alkoxy group is a C1-C6 alkyl-substituted alkoxy group; the substituted carboxyl group is a C1-C6 alkyl-substituted carboxyl group; the substituted amide group is... Ra is selected from substituted or unsubstituted C4-C8 heterocyclic groups, Rb is selected from substituted or unsubstituted aryl groups, and the substituted sulfonamide group is a C1-C6 alkyl-substituted sulfonamide group; For R2 The C1-C6 alkoxy group is preferably methoxy; For R 3 The substituted phenoxy group, wherein the substituent is preferably a C1-C6 haloalkyl group; For R 4 For substituted phenoxy groups, the substituents are preferably C1-C6 haloalkyl groups.

[0006] Preferably, for R 6 -R 8 The alkoxy group is methoxy, the alkyl group is methyl, and the substituted amide group is... Ra is selected from substituted or unsubstituted C4-C8 heterocyclic groups, and Rb is selected from substituted or unsubstituted aryl groups.

[0007] Preferably, for ring A, the substituted phenyl group is substituted by one or two substituents selected from fluorine or substituted phenoxy groups.

[0008] Preferably, for ring B, the nitrogen atom of the substituted pyrazolyl group is optionally replaced by a C1-C4 alkyl or acryloyl group.

[0009] A pharmaceutical composition comprising one of the above-mentioned biaryl compounds and one or more pharmaceutically acceptable carriers, diluents or excipients; the pharmaceutical composition, after being supplemented with excipients via the above-mentioned biaryl compound, is formulated into tablets, capsules, soft capsules or injections; the excipients include one or more of additives, stabilizers, solubilizers, lubricants and disintegrants.

[0010] The above-mentioned biaryl compound and pharmaceutical composition are used in the preparation of TEAD inhibitor drugs and / or drugs that inhibit TEAD-YAP protein-protein interactions.

[0011] The use of the above-mentioned biaryl compound and / or pharmaceutical composition in the preparation of cancer drugs.

[0012] Preferably, the cancer includes any one of breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, stomach cancer, kidney cancer, ovarian cancer, uterine cancer, prostate cancer, mesothelioma, glioma, myelodysplastic syndrome, acute myeloid leukemia, and colorectal cancer.

[0013] The above-mentioned method for preparing a biaryl compound includes the following steps: S1: A biaryl skeleton intermediate is prepared by coupling a halophenol derivative with an arylboronic acid or its ester under a metal catalysis. S2: The biaryl skeleton intermediate is functionalized by any one of hydrolysis, esterification, reduction or amination to obtain a biaryl derivative containing carboxylic acid, amino or hydroxyl groups. S3: The obtained biaryl derivative containing carboxylic acid is subjected to an amidation condensation reaction with a nitrogen-containing heterocyclic compound or an aromatic amine compound in the presence of a condensing agent to obtain a biaryl compound represented by general formula (I) or general formula (II); S4: The obtained biaryl derivative containing an amino group undergoes an amidation reaction with acryloyl chloride, or directly undergoes a Michael addition reaction with an acrylic acid derivative, to prepare a biaryl compound represented by general formula (II) or general formula (III). Compared with the prior art, the present invention has the following beneficial technical effects: This invention discloses a biaryl compound that precisely addresses four major pain points in the development of TEAD inhibitors by constructing a three-dimensional structure with a biaryl group as the core skeleton and incorporating specific functional groups. Firstly, addressing the issues of single and scarce skeletons, the general formulas (I), (II), and (III) of this invention all employ a biaryl group as the core skeleton. This rigid structure differs from the heterocyclic or fused-ring skeletons in existing technologies. Through R… 1 To R 8 The broad definition of substituents for ring A and ring B greatly enriches the variety of molecules in chemical space. Secondly, addressing the issue of insufficient inhibitory activity, this structural formula embodies a rational "four-region synergistic" design: the biaryl skeleton occupies the hydrophobic and dorsal regions of the TEAD pocket, while R... 1 The polar groups such as carboxyl or sulfonamide groups introduced at the site point to the hydrophilic region to form hydrogen bonds. This multi-site binding mode significantly enhances the specific binding force. Finally, to address safety risks, this invention structurally incorporates both reversible and irreversible inhibitors: general formulas (II) and (III) explicitly introduce acrylamide groups as electrophilic warheads, aiming to form covalent bonds with cysteine ​​at the pocket entrance to achieve irreversible inhibition and improve efficacy; while general formula (I) retains the possibility of reversible binding. This dual structural layout provides a broad structural basis for screening candidate drugs with low toxicity and high safety, thereby effectively avoiding the potential risks brought about by a single mechanism. Attached Figure Description

[0014] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0015] Figure 1 This is the mass spectrum of Example 44 after binding with TEAD; Figure 2 Example 44 and TEAD2 222-447 Mass spectrum of the protein after binding to cysteine ​​residue 380; Figure 3 The imprinted bands and fitted curves for inhibiting TEAD palmitoylation in Example 44; Figure 4 The imprinted bands and fitted curves for suppressing YAP-TEAD interaction in Example 44 are shown. Detailed Implementation

[0016] To enable those skilled in the art to understand the features and effects of the present invention, the terms and expressions used in the specification and claims are explained and defined in general below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art regarding the present invention, and in case of conflict, the definitions in this specification shall prevail.

[0017] The theories or mechanisms described and disclosed herein, whether right or wrong, should not in any way limit the scope of the invention, that is, the contents of the invention can be implemented without being limited by any particular theory or mechanism.

[0018] In this document, all features defined by numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual numerical values ​​(including integers and fractions) within those ranges.

[0019] In this article, unless otherwise specified, “contains,” “includes,” “containing,” “has,” or similar terms cover the meanings of “composed of” and “mainly composed of,” for example, “A contains a” covers the meanings of “A contains a and others” and “A contains only a.”

[0020] For the sake of brevity, not all possible combinations of the technical features in each implementation scheme or embodiment are described herein. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each implementation scheme or embodiment can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification.

[0021] This invention provides a biaryl compound having the structure shown in general formula (I), general formula (II) or general formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: , , ; Where: R 1 It is selected from one of hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxyl, substituted or unsubstituted amide, and substituted or unsubstituted sulfonamide. Preferably, the substituted alkoxy group is a C1-C6 alkyl-substituted alkoxy group, and more preferably, the substituted alkoxy group is a methoxy group; Preferably, the substituted carboxyl group is a C1-C6 alkyl-substituted carboxyl group, and more preferably, the substituted carboxyl group is a methyl-substituted carboxyl group; Preferably, the substituted amide group is Ra is selected from substituted or unsubstituted C4-C8 heterocyclic groups, more preferably piperazine group; Rb is selected from substituted or unsubstituted aryl group, more preferably phenyl group. Preferably, the substituted sulfonamide group is a C1-C6 alkyl-substituted sulfonamide group, and more preferably a methanesulfonamide group; R 2 It is selected from one of hydrogen, hydroxyl, carboxyl, acrylamide, and C1-C6 alkoxy groups; further, C1-C6 alkoxy groups are preferably methoxy groups; R 3 Selected from hydrogen or substituted or unsubstituted phenoxy groups; further, for substituted phenoxy groups, the substituents are preferably C1-C6 haloalkyl groups; even further, the substituted phenoxy group is 4-trifluoromethylphenoxy. R 4 Selected from hydrogen, halogen, substituted or unsubstituted phenoxy groups; for substituted phenoxy groups, the substituents are preferably C1-C6 haloalkyl groups; furthermore, the substituted phenoxy group is 4-trifluoromethylphenoxy. R 5 Selected from hydrogen or halogen; More specifically: when the R 2 When the group is a carboxyl group, R 3 The radical is p-trifluoromethylphenoxy, R 1 R 4 and R 5 All bases are hydrogen; When the R 2 When the group is an acrylamide group, R 1 and R 3 All radicals are hydrogen, R 4 and R 5 All radicals are fluorine; When the R 2 When the group is methoxy, R 1 The group is a carboxyl group or a methyl carboxylate group, R 3 and R 5 All radicals are hydrogen, R 4 The radical is p-trifluoromethylphenoxy; When the R 2 The group is hydroxyl and R 4 When the radical is p-trifluoromethylphenoxy, R 1 The radicals are carboxyl groups and methyl carboxylate groups. and Any one of them, R 3 and R 5 All bases are hydrogen; When the R 2 The group is hydroxyl and R 4 and R 5 When all radicals are fluorine, R 1 Base R 3 The base is hydrogen; When the R 1 The group is a carboxyl group and R 2 R 3 and R 5 When all radicals are hydrogen, R 4 The radical is p-trifluoromethylphenoxy; When the R 1 The group is a carboxyl group and R 2 R 4 and R 5 When all radicals are hydrogen, R 3 The radical is p-trifluoromethylphenoxy; When the R 1 Base And R 2 R 4 and R 5 When all radicals are hydrogen, R 3 The radical is hydrogen or p-trifluoromethylphenoxy.

[0022] R 6 -R 8 Independently selected from hydrogen, alkoxy, alkyl, or substituted amide groups; Furthermore, the alkoxy group is preferably methoxy, the alkyl group is preferably methyl, and the substituted amide group is... Ra is selected from substituted or unsubstituted C4-C8 heterocyclic groups, preferably piperazine group; Rb is selected from substituted or unsubstituted aryl groups, preferably phenyl group. More specifically, the R 6 R 7 and R 8 All are hydrogen, or R 6 It is methoxy and R 7 and R 8 All are hydrogen, or R 6 and R 7 Both are hydrogen and R 8 It is methyl, or R 6 and R 8Both are hydrogen and R 7 for ; Ring A is independently selected from any one of substituted phenyl, substituted naphthyl, and substituted quinolinyl groups; Preferably, the substituted phenyl group is substituted by one or two substituents selected from fluorine or substituted phenoxy groups; The substituted naphthyl group is a chlorinated naphthyl group; The substituted quinolino group is a chloro-substituted quinolino group; Further preferred, ring A is independently selected from , , , , and Any one of them, R 9 The radical is p-trifluoromethylphenoxy.

[0023] Ring B is independently selected from substituted or unsubstituted phenyl, pyridyl, substituted pyrazolyl, furanyl or thiophenyl groups; Among them, fluorinated phenyl groups are preferred for substituted phenyl groups; For the substituted pyrazolyl group, the nitrogen atom is preferably optionally substituted with a C1-C4 alkyl or acryloyl group, and further, the C1-C4 alkyl group is preferably methyl; Specifically, ring B is preferred. , , , , , , , and Any one of them.

[0024] The molecular structure of the general formula (I), general formula (II) or general formula (III) contains a biaryl skeleton and has at least one end connected to a pharmacophore that can bind to the TEAD protein, wherein the pharmacophore is selected from a carboxyl group, a sulfonamide group or an acrylamide group.

[0025] The structures of these compounds, as shown in general formula (I), fully consider the structural features of the palmitoylation pocket of TEAD. Utilizing a rational design approach targeting four key regions—the pocket inlet, hydrophobic region, dorsal region, and hydrophilic region—novel reversible and irreversible TEAD inhibitors with a biaryl skeleton have been developed. By strategically occupying these four key regions of the TEAD palmitoylation pocket, the specific binding of the compounds to TEAD is enhanced, providing a series of novel structural types of compounds with strong inhibitory activity against TEAD, and offering candidates for the development of small-molecule antitumor drugs targeting TEAD.

[0026] Specifically, the preferred options are: This invention discloses a biaryl compound, comprising a compound of general formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof:

[0027] in: When the R 2 When the group is a carboxyl group, R 3 The radical is p-trifluoromethylphenoxy, R 1 R 4 and R 5 All bases are hydrogen; When the R 2 When the group is an acrylamide group, R 1 and R 3 All radicals are hydrogen, R 4 and R 5 All radicals are fluorine; When the R 2 When the group is methoxy, R 1 The group is a carboxyl group or a methyl carboxylate group, R 3 and R 5 All radicals are hydrogen, R 4 The radical is p-trifluoromethylphenoxy; When the R 2 The group is hydroxyl and R 4 When the radical is p-trifluoromethylphenoxy, R 1 The group is a carboxyl group, a methyl carboxylate group. and Any one of them, R 3 and R 5 All bases are hydrogen; When the R 2 The group is hydroxyl and R 4 and R 5 When all radicals are fluorine, R 1 Base R 3 The base is hydrogen; When the R 1 The group is a carboxyl group and R 2 R 3 and R 5 When all radicals are hydrogen, R 4 The radical is p-trifluoromethylphenoxy; When the R 1 The group is a carboxyl group and R 2 R 4 and R 5 When all radicals are hydrogen, R 3 The radical is p-trifluoromethylphenoxy; When the R 1 Base And R 2 R 4 and R 5 When all radicals are hydrogen, R 3 The radical is hydrogen or p-trifluoromethylphenoxy.

[0028] It also includes compounds represented by general formula (II), their stereoisomers, or pharmaceutically acceptable salts thereof: ; Wherein, the R 6 R 7 and R 8 All radicals are hydrogen, or R 6 The group is methoxy and R 7 and R 8 All radicals are hydrogen, or R 6 and R 7 All radicals are hydrogen and R 8 The group is methyl, or R 6 and R 8 All radicals are hydrogen and R 7 Base ; The ring A is , , , , and Any one of them, R 9 The radical is p-trifluoromethylphenoxy.

[0029] It also includes compounds represented by general formula (III), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0030] Wherein, ring B is , , , , , , , and Any one of them.

[0031] The present invention also provides a pharmaceutical composition comprising a compound or salt thereof represented by general formula (I), general formula (II) or general formula (III) of the present invention, and one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the pharmaceutical composition is formulated into tablets, capsules, soft capsules or injections by adding excipients to a compound or salt thereof of general formula (I), wherein each tablet, capsule or ampoule contains 10 to 500 mg of a compound or salt thereof represented by general formula (I), general formula (II) or general formula (III) of the present invention; the added excipients include one or more of additives, stabilizers, solubilizers, lubricants and disintegrants.

[0032] The present invention also provides the use of compounds of general formula (I), general formula (II) or general formula (III) of the present invention, or salts thereof, or the above-described pharmaceutical compositions, in the preparation of TEAD inhibitor drugs and drugs that inhibit TEAD-YAP protein-protein interactions, or in the preparation of drugs for treating cancer, wherein the cancer includes any one of breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, gastric cancer, kidney cancer, ovarian cancer, uterine cancer, prostate cancer, mesothelioma, glioma, myelodysplastic syndrome, acute myeloid leukemia, and colorectal cancer.

[0033] In addition, this invention also discloses a method for preparing biaryl compounds, comprising the following steps: S1. Coupling reaction step: The halophenol derivative is coupled with arylboronic acid or its ester under metal catalysis to obtain the biaryl skeleton intermediate. S2, Functional group transformation step: The biaryl skeleton intermediate is modified with functional groups, including any one of hydrolysis reaction, esterification reaction, reduction reaction or amination reaction, to obtain a biaryl derivative containing carboxylic acid, amino group or hydroxyl group; S3. Condensation reaction step: The obtained biaryl derivative containing carboxylic acid is subjected to an amidation condensation reaction with a nitrogen-containing heterocyclic compound or an aromatic amine compound in the presence of a condensing agent to obtain a biaryl compound represented by general formula (I) or general formula (II). S4. Michael addition step: The obtained biaryl derivative containing an amino group undergoes an amidation reaction with acryloyl chloride, or directly undergoes a Michael addition reaction with an acrylic acid derivative, to obtain a biaryl compound represented by general formula (II) or general formula (III).

[0034] The present invention also discloses a method for preparing the compound or salt thereof represented by the above general formula (I) or general formula (II), comprising the following steps: S1: React 2-iodophenol, 3-iodophenol or 4-iodophenol with 4-(trifluoromethyl)phenylboronic acid to prepare 1-iodo-2-(4-(trifluoromethyl)phenoxy)benzene, 1-iodo-3-(4-(trifluoromethyl)phenoxy)benzene or 1-iodo-4-(4-(trifluoromethyl)phenoxy)benzene; S2: The product obtained in step S1, 1-bromo-2,4-difluorobenzene, 4-bromo-7-chloroquinoline, 2-bromo-6-chloronaphthalene, 3-bromo-4-hydroxybenzoic acid, or 4-bromo-3-hydroxybenzoic acid is reacted with phenylboronic acid or pinacol esters of phenylboronic acid with different substitutions via a Suzuki coupling reaction to obtain a compound of general formula (I), wherein R 1 The group is a carboxyl group or a methyl carboxylate group, R 2 The radical is hydrogen, hydroxyl, or methoxy, R 3 and R 5 All radicals are hydrogen, R 4 The base is p-trifluoromethylphenoxy, or different carboxylic acids, methyl carboxylate, nitrobenzene, and aniline intermediates can be prepared; S3: The methyl carboxylate intermediate obtained in step S2 is hydrolyzed to obtain a compound of general formula (I), wherein R 1 The group is a carboxyl group, R 2 hydroxyl or methoxy, R 3 and R 5 All radicals are hydrogen, R 4 The radical is p-trifluoromethylphenoxy; S4: Make R obtained in step S3 1 The group is a carboxyl group, R 2 A compound of general formula (I) with a hydroxyl group is reacted with methanesulfonamide to prepare a compound of general formula (I), wherein R 1 Base R 2 The radical is a hydroxyl group, R 3 and R 5 All radicals are hydrogen, R 4 The radical is p-trifluoromethylphenoxy; S5: The carboxylic acid intermediate obtained in step S2 is reacted with methanol, and the resulting methyl carboxylic acid product is reacted with p-trifluoromethylphenylboronic acid, followed by hydrolysis to obtain a compound of general formula (I), wherein R 1 The group is a carboxyl group and R 2 The radical is hydrogen, or R 1 The radical is hydrogen and R 2 The group is a carboxyl group, R 3 The radical is hydrogen, R 4 The radical is p-trifluoromethylphenoxy; S6: The carboxylic acid intermediate obtained in step S2, or R obtained in S3 and S5. 1 Compounds of general formula (I) with a carboxyl group, or different biaryl carboxylic acid compounds, withN The reaction of phenylpiperazine-1-carboxamide yields a compound of general formula (I), wherein R 1 Base ; S7: The nitrobenzene intermediate obtained in step S2 is reacted with... N The product obtained by the reaction of 1-phenylpiperazine-1-carboxamide was reduced to prepare different aniline intermediates. S8: React the different aniline intermediates obtained in steps S2 and S7 with acryloyl chloride to prepare compounds of general formula (II).

[0035] The present invention also discloses a method for preparing the compound represented by the above general formula (III) or a salt thereof, comprising the following steps: S9: React 2-bromo-1-fluoro-4-nitrobenzene with 4-(trifluoromethyl)phenol to obtain 2-bromo-4-nitro-1-(4-(trifluoromethyl)phenoxy)benzene; S10: The 2-bromo-4-nitro-1-(4-(trifluoromethyl)phenoxy)benzene obtained in step S9 is reduced to prepare 3-bromo-4-(4-(trifluoromethyl)phenoxy)aniline; S11: React the 3-bromo-4-(4-(trifluoromethyl)phenoxy)aniline obtained in step S10 with different arylboronic acid pinacol esters to prepare anilines with different aryl substitutions at the 3-position; S12: React the aniline with different aryl substitutions at the 3-position obtained in step S11 with acryloyl chloride to prepare a compound of general formula (III).

[0036] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR determinations were performed using a Bruker AVANCE-400 NMR spectrometer or an AVANCEIII-600 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6) and deuterated chloroform (Chloroform- dThe internal standard was tetramethylsilane (TMS). GC-MS analysis was performed using a Shimadzu GCMS-TQ8040 system, and LC-MS analysis was performed using a Shimadzu LCMS-8045 system. Qingdao GF254 silica gel plates were used for thin-layer chromatography (TLC), with a diameter of 0.15–0.20 mm, and a diameter of 0.4–0.5 mm was used for TLC separation and purification. Column chromatography generally used 200–300 mesh Yantai Huanghai silica gel as the support. The starting materials used in the embodiments of this invention are known and commercially available, or can be synthesized using methods known in the art. Unless otherwise specified, all reactions of this invention were carried out under continuous magnetic stirring and a dry nitrogen atmosphere, using a dry solvent, and the reaction temperature was expressed in degrees Celsius.

[0037] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0038] The following examples use instruments and equipment conventional in the art. Experimental methods in the following examples, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. All raw materials used in the following examples are conventional commercially available products with specifications conventional in the art. In this specification and the following examples, unless otherwise specified, "%" refers to weight percentage, "parts" refers to parts by weight, and "ratio" refers to weight proportion.

[0039] Table 1 shows the specific structures of the biaryl compounds prepared in Examples 1-48 of this invention and the characterization results of the products. The Chinese names of the biaryl compounds prepared in Examples 1-48 are shown in Table 2.

[0040] Table 1 Characterization test data of the products in Examples 1-48 of the present invention

[0041] The following are the preparation methods for the biaryl compounds in Table 1: Example 1

[0042] Step 1: Preparation of 1-iodo-2-(4-(trifluoromethyl)phenoxy)benzene (intermediate 1-a) Weigh 2-iodophenol (2.00 g, 9.09 mmol), 4-trifluoromethylphenylboronic acid (3.45 g, 18.2 mmol), and copper acetate (1.98 g, 10.9 mmol) into a 250 mL round-bottom flask, dissolve in 30 mL of dichloromethane, and add pyridine (3.52 mL, 45.5 mmol) to the reaction system. Stir at room temperature for 72 h. Extract with dichloromethane, combine the organic phases, back-extract with saturated brine, dry to anhydrous sodium sulfate, and filter. Separate by silica gel column chromatography to obtain a colorless liquid (1.05 g, 32%).

[0043] GC-MS(EI): [M] + 363.95. 1 H NMR (600 MHz, Chloroform- d ) δ 7.81 (dd, J =8.0, 1.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.31 – 7.24 (m, 1H), 6.95 – 6.84 (m, 4H). Step 2: Preparation of 2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-carboxylic acid (Example 1) Intermediate 1-a (100 mg, 0.275 mmol), 3-carboxyphenylboronic acid (50 mg, 0.30 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (10 mg, 0.014 mmol), and potassium carbonate (75 mg, 0.54 mmol) were weighed and added sequentially to a reaction flask. Under N2 protection, 1,4-dioxane (5 mL) and H2O (1 mL) were added, and the mixture was heated to reflux for 2 h. After cooling to room temperature, the mixture was extracted with ethyl acetate, and the organic phases were combined. The mixture was back-extracted with saturated brine, dried over anhydrous sodium sulfate, and filtered. Separation by silica gel column chromatography yielded a white solid (82 mg, 83%).

[0044] GC-MS(EI): [M] + 358.00. 1 H NMR (400 MHz, DMSO- d 6) δ 13.00 (s, 1H), 8.05 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.64 (d,J = 8.4 Hz, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.3 Hz, 2H). Example 2

[0045] The operation steps are the same as the second step in the preparation method of Example 1, and the product is a white solid (125 mg, 60%).

[0046] GC-MS(EI): [M] + 388.05. 1 H NMR (400 MHz, DMSO- d 6) δ 7.86 (d, J = 2.4 Hz, 1H), 7.65 (dd, J = 8.7, 2.3 Hz, 3H), 7.56 (dd, J = 7.6, 1.8 Hz, 1H), 7.47 (td, J =7.7, 1.8 Hz, 1H), 7.39 (td, J = 7.5, 1.3 Hz, 1H), 7.20 (dd, J = 8.0, 1.3 Hz, 1H), 6.99 (dd, J = 8.7, 2.0 Hz, 3H), 3.83 (s, 3H). Example 3

[0047] Weigh 125 mg (0.322 mmol) of Example 2 and 64 mg (1.6 mmol) of sodium hydroxide into a reaction flask, add 2 mL of tetrahydrofuran and 4 mL of H2O, and heat to 50 °C and reflux for 5 h. Cool to room temperature, extract with saturated sodium bicarbonate solution and dichloromethane, combine the organic phases, back-extract with saturated brine, dry to anhydrous sodium sulfate, and filter. Separate by silica gel column chromatography to obtain a white solid (95 mg, 79%).

[0048] LC-MS(ESI): [MH]- 373.10. 1 H NMR (400 MHz, DMSO- d 6) δ 7.90 (d, J = 2.4Hz, 1H), 7.67 – 7.59 (m, 3H), 7.55 (dd, J = 7.6, 1.8 Hz, 1H), 7.45 (td, J = 7.7, 1.8 Hz, 1H), 7.38 (td, J = 7.5, 1.3 Hz, 1H), 7.18 (dd, J = 8.0, 1.3 Hz, 1H), 6.99(d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.6 Hz, 1H). Example 4

[0049] The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (172 mg, 79%).

[0050] GC-MS(EI): [M] + 402.05. 1 H NMR (400 MHz, DMSO- d 6) δ 7.77 (d, J = 2.3 Hz,1H), 7.69 – 7.62 (m, 3H), 7.56 (dd, J = 7.6, 1.8 Hz, 1H), 7.46 (td, J = 7.6, 1.7Hz, 1H), 7.39 (td, J = 7.5, 1.3 Hz, 1H), 7.22 – 7.13 (m, 2H), 7.00 (d, J = 8.5Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H). Example 5

[0051] The preparation procedure was the same as in Example 3, and the product was a white solid (1.15 g, 85%).

[0052] GC-MS(EI): [M]+ 388.05. 1 H NMR (400 MHz, DMSO- d 6) δ 12.63 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.68 – 7.59 (m, 3H), 7.55 (dd, J = 7.6, 1.9 Hz, 1H), 7.45(td, J = 7.7, 1.8 Hz, 1H), 7.38 (td, J = 7.5, 1.3 Hz, 1H), 7.18 (dd, J = 8.0, 1.3Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H). Example 6

[0053] The product obtained in Example 3 (100 mg, 0.267 mmol), methanesulfonamide (50 mg, 0.53 mmol), 4-dimethylaminopyridine (2 mg, 0.02 mmol), and 2-chloro-1-methylpyridine iodide (82 mg, 0.32 mmol) were weighed and added to a reaction flask. Dichloromethane (5 mL) was added to dissolve the product, followed by the addition of triethylamine (60 μL, 0.81 mmol). The mixture was stirred at room temperature for 16 h. The mixture was extracted with dichloromethane, and the combined organic phases were back-extracted with saturated brine, dried over anhydrous sodium sulfate, and filtered. Separation by silica gel column chromatography yielded a white solid (66 mg, 55%).

[0054] LC-MS(ESI): [M+H] + 453.25. 1 H NMR (400 MHz, DMSO- d 6) δ 14.15 (s, 1H), 8.09 (s, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.50 (dd, J =7.4, 2.1 Hz, 1H), 7.45 – 7.31 (m, 3H), 7.15 (dd, J= 7.8, 1.5 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.5 Hz, 1H), 2.93 (s, 3H). Example 7

[0055] Step 1: Preparation of 6-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (intermediate 7-a) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (469 mg, 95%).

[0056] LC-MS(ESI): [MH] - 213.20. 1 H NMR (400 MHz, DMSO- d 6) δ 12.53 (s, 1H),10.42 (s, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.78 (dd, J = 8.4, 2.2 Hz, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.33 (td, J = 7.0, 6.3, 1.6 Hz, 1H),7.02 (d, J = 8.4 Hz, 1H). Step 2: Preparation of methyl 6-hydroxy-[1,1'-biphenyl]-3-carboxylate (intermediate 7-b) Intermediate 7-a (200 mg, 0.934 mmol) was weighed and added to a reaction flask, dissolved in methanol (5 mL), and concentrated sulfuric acid (500 μL) was slowly added dropwise. The mixture was stirred at room temperature for 16 h. The solvent was removed by vacuum distillation, and the product was extracted with ethyl acetate. The organic phases were combined, back-extracted with saturated brine, dried over anhydrous sodium sulfate, and filtered. The product was separated by silica gel column chromatography to obtain a white solid (206 mg, 97%).

[0057] GC-MS(EI): [M] + 228.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.54 (s, 1H), 7.84 (d, J= 2.2 Hz, 1H), 7.81 (dd, J = 8.4, 2.3 Hz, 1H), 7.54 (d, J = 7.5 Hz, 2H), 7.43(t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H). Step 3: Preparation of methyl 6-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-carboxylate (intermediate 7-c) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (67 mg, 37%).

[0058] GC-MS(EI): [M] + 372.15. 1 H NMR (400 MHz, DMSO- d 6) δ 8.05 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 8.5, 2.2 Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 3.88 (s, 3H). Step 4: Preparation of 6-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-carboxylic acid (Example 7) The preparation procedure was the same as in Example 3, and the product was a white solid (28 mg, 59%).

[0059] LC-MS(ESI): [MH] - 357.15. 1 H NMR (400 MHz, DMSO- d 6) δ 8.04 (d, J= 2.2Hz, 1H), 7.99 (dd, J = 8.5, 2.2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 7.5Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.1 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 2H). Example 8

[0060] Step 1: Preparation of 2-hydroxy-[1,1'-biphenyl]-4-carboxylic acid (intermediate 8-a) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (339 mg, 69%).

[0061] LC-MS(ESI): [MH] - 213.15. 1 H NMR (400 MHz, DMSO- d 6) δ 12.82 (s, 1H), 9.93 (s, 1H), 7.63 – 7.52 (m, 3H), 7.48 – 7.40 (m, 3H), 7.35 (dd, J = 15.6, 7.7Hz, 2H). Step 2: Preparation of methyl 2-hydroxy-[1,1'-biphenyl]-4-carboxylate (intermediate 8-b) The operation steps are the same as the second step in the preparation of Example 7, and the product is a white solid (206 mg, 97%).

[0062] GC-MS(EI): [M] + 228.05. 1 H NMR (400 MHz, DMSO- d 6) δ 10.02 (s, 1H), 7.59 (d, J = 7.9 Hz, 3H), 7.48 (dd, J = 7.9, 1.7 Hz, 1H), 7.42 (q, J = 7.7 Hz, 3H), 7.35(t,J = 7.3 Hz, 1H), 3.85 (s, 3H). Step 3: Preparation of methyl 2-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-4-carboxylate (intermediate 8-c) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (90 mg, 28%).

[0063] GC-MS(EI): [M] + 372.15. 1 H NMR (400 MHz, DMSO- d 6) δ 7.94 (dd, J = 8.0, 1.7Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.63 (s, 1H), 7.55(d, J = 7.8 Hz, 2H), 7.43 – 7.38 (m, 3H), 7.10 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H). Step 4: Preparation of 2-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-4-carboxylic acid (Example 8) The preparation procedure was the same as in Example 3, and the product was a white solid (40 mg, 86%).

[0064] LC-MS(ESI): [MH] - 357.15. 1 H NMR (400 MHz, DMSO- d 6) δ 7.91 (dd, J = 7.9,1.6 Hz, 1H), 7.71 – 7.65 (m, 3H), 7.59 (s, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.42(t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H). Example 9

[0065] Weigh 100 mg (0.400 mmol) of 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid into a reaction flask, dissolve in dichloromethane (2 mL), and add O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (TBTU) (321 mg, 1.00 mmol). N , N - Diisopropylethylamine (207 mg, 1.60 mmol) was stirred at room temperature for 30 min, followed by the addition of (160 mg, 0.800 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was extracted with dichloromethane, and the combined organic phases were back-extracted with saturated brine, dried over anhydrous sodium sulfate, and filtered. Separation by silica gel column chromatography yielded a white solid (49 mg, 29%).

[0066] LC-MS(ESI): [M+H] + 438.15. 1 H NMR (400 MHz, DMSO- d 6) δ 10.16 (s, 1H),8.58 (s, 1H), 7.55 (td, J = 9.0, 6.6 Hz, 1H), 7.48 – 7.41 (m, 3H), 7.36 – 7.29(m, 2H), 7.23 (dd, J = 8.6, 7.3 Hz, 2H), 7.19 – 7.13 (m, 1H), 6.99 (d, J = 8.5Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H), 3.77 – 3.36 (m, 8H). Example 10

[0067] Step 1: Preparation of 2',4'-difluoro-[1,1'-biphenyl]-3-carboxylic acid (intermediate 10-a) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (86 mg, 72%).

[0068] LC-MS(ESI): [MH] - 233.05. 1 H NMR (400 MHz, DMSO- d 6) δ 13.14 (s, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.98 (d,J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.69– 7.60 (m, 2H), 7.41 (td, J = 10.4, 9.2, 2.6 Hz, 1H), 7.23 (td, J = 8.4, 2.6 Hz, 1H). Step 2: 4-(2',4'-difluoro-[1,1'-biphenyl]-3-formyl)- N Preparation of 1-phenylpiperazine-1-carboxamide (Example 10) The preparation procedure was the same as in Example 9, and the product was a white solid (0.73 g, 77%).

[0069] LC-MS(ESI): [M+H] + 422.10. 1 H NMR (400 MHz, DMSO- d 6) δ 8.60 (s, 1H),7.72 – 7.53 (m, 4H), 7.52 – 7.36 (m, 4H), 7.27 – 7.17 (m, 3H), 6.94 (tt, J =7.4, 1.2 Hz, 1H), 3.61 (d, J = 57.6 Hz, 8H). Example 11

[0070] The preparation procedure was the same as in Example 9, and the product was a white solid (125 mg, 64%).

[0071] LC-MS(ESI): [M+H] + 386.15. 1 H NMR (400 MHz, DMSO- d 6) δ 8.60 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 7.2 Hz, 3H), 7.56 (t, J = 7.7 Hz, 1H), 7.45 (ddt, J = 22.1, 14.6, 7.3 Hz, 6H), 7.27 – 7.17 (m, 2H), 6.94 (t, J= 7.4 Hz, 1H), 3.54 (dd, J = 68.1, 37.7 Hz, 8H). Example 12

[0072] The preparation procedure was the same as in Example 9, and the product was a white solid (81 mg, 48%).

[0073] LC-MS(ESI): [M+H] + 446.15. 1 H NMR (400 MHz, DMSO- d 6) δ 8.61 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 7.3Hz, 2H), 7.37 (d, J = 7.7 Hz, 1H), 7.28 – 7.20 (m, 4H), 7.05 (d, J = 8.3 Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H), 3.86 (s, 3H), 3.80 (s, 3H), 3.75 – 3.35 (m, 8H). Example 13

[0074] The preparation procedure was the same as in Example 9, and the product was a white solid (83 mg, 55%).

[0075] LC-MS(ESI): [MH] - 560.20. 1 H NMR (400 MHz, DMSO- d 6) δ 10.31 (s, 1H), 8.56 (s, 1H), 7.66 (dd, J = 8.5, 6.1 Hz, 1H), 7.62 (dd, J = 7.3, 5.2 Hz, 1H), 7.53 (dt, J = 7.9, 2.5 Hz, 2H), 7.46 – 7.40 (m, 3H), 7.38 (dd, J= 8.4, 2.2 Hz, 1H), 7.23 (ddd, J = 9.3, 7.6, 2.0 Hz, 2H), 7.17 (dd, J = 7.9, 1.5 Hz, 1H), 7.10 –7.03 (m, 2H), 7.03 – 6.98 (m, 2H), 6.97 – 6.91 (m, 1H), 3.52 (s, 4H), 3.18(s, 4H). Example 14

[0076] The preparation procedure was the same as in Example 9, and the product was a white solid (120 mg, 79%).

[0077] LC-MS(ESI): [MH] - 544.05. 1 H NMR (400 MHz, DMSO- d 6) δ 8.61 (s, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 2.1 Hz, 1H), 7.56 – 7.49 (m, 3H), 7.48 –7.43 (m, 2H), 7.43 – 7.37 (m, 2H), 7.37 – 7.30 (m, 1H), 7.23 (ddd, J = 9.6,5.4, 2.0 Hz, 3H), 7.12 (d, J = 8.4 Hz, 2H), 6.94 (tt, J = 7.2, 1.2 Hz, 1H), 3.58(d, J = 27.8 Hz, 8H). Example 15

[0078] Step 1: Preparation of 2',4'-difluoro-[1,1'-biphenyl]-3-amine (intermediate 15-a) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (105 mg, 99%).

[0079] LC-MS(ESI): [M+H] + 206.05. 1H NMR (400 MHz, DMSO- d 6) δ 7.48 (td, J = 8.9, 6.7 Hz, 1H), 7.30 (ddd, J = 11.5, 9.4, 2.6 Hz, 1H), 7.19 – 7.12 (m, 1H), 7.10(t, J = 7.9 Hz, 1H), 6.70 (q, J = 1.8 Hz, 1H), 6.62 (dd, J = 7.4, 1.3 Hz, 1H), 6.60– 6.57 (m, 1H), 5.19 (s, 2H). Step Two: N Preparation of 2',4'-difluoro-[1,1'-biphenyl]-3-yl)acrylamide (Example 15) Intermediate 15-a (80 mg, 0.39 mmol) was weighed and added to a reaction flask, dissolved in dichloromethane (6 mL), and cooled to 0 °C in an ice bath. Triethylamine (79 mg, 0.97 mmol) and acryloyl chloride (71 mg, 0.78 mmol) were slowly added dropwise. The mixture was brought to room temperature and reacted for 1 h. The mixture was extracted with saturated sodium bicarbonate solution and dichloromethane, dried over anhydrous sodium sulfate, filtered, and separated by silica gel column chromatography to give the product as a white solid (83 mg, 82%).

[0080] LC-MS(ESI): [MH] - 258.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.26 (s, 1H), 7.88 (q, J = 1.9 Hz, 1H), 7.70 (ddd, J = 8.2, 2.2, 1.1 Hz, 1H), 7.57 (td, J = 8.8, 6.6 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.38 (ddd, J = 11.5, 9.3, 2.6 Hz, 1H),7.24 – 7.21 (m, 1H), 7.21 – 7.18 (m, 1H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H),6.27 (dd, J= 17.0, 2.0 Hz, 1H), 5.78 (dd, J = 10.1, 2.0 Hz, 1H). Example 16

[0081] Step 1: Preparation of 2',4'-difluoro-[1,1'-biphenyl]-4-amine (intermediate 16-a) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (105 mg, 98%).

[0082] GC-MS(EI): [M] + 259.05. 1 H NMR (400 MHz, DMSO- d 6) δ 10.28 (s, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.58 (td, J = 8.9, 6.6 Hz, 1H), 7.50 (dd, J = 8.7, 1.7 Hz, 2H), 7.35 (ddd, J = 11.6, 9.3, 2.6 Hz, 1H), 7.22 – 7.14 (m, 1H), 6.46 (dd, J =17.0, 10.1 Hz, 1H), 6.29 (dd, J = 17.0, 2.0 Hz, 1H), 5.78 (dd, J = 10.0, 2.1 Hz, 1H). Step Two: N Preparation of 2',4'-difluoro-[1,1'-biphenyl]-4-yl)acrylamide (Example 16) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (67 mg, 53%).

[0083] GC-MS(EI): [M] + 259.05. 1 H NMR (400 MHz, DMSO- d 6) δ 10.28 (s, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.58 (td, J = 8.9, 6.6 Hz, 1H), 7.50 (dd,J = 8.7, 1.7 Hz, 2H), 7.35 (ddd, J = 11.6, 9.3, 2.6 Hz, 1H), 7.22 – 7.14 (m, 1H), 6.46 (dd, J =17.0, 10.1 Hz, 1H), 6.29 (dd, J = 17.0, 2.0 Hz, 1H), 5.78 (dd, J = 10.0, 2.1 Hz, 1H). Example 17

[0084] Step 1: Preparation of 2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-3-amine (intermediate 17-a) The operation steps were the same as the second step in the preparation of Example 1, and the product was a white solid (177 mg, 75%).

[0085] GC-MS(EI): [M] + 235.10. 1 H NMR (400 MHz, DMSO- d 6) δ 7.45 (td, J = 8.9, 6.7Hz, 1H), 7.28 (ddd, J = 11.5, 9.2, 2.6 Hz, 1H), 7.13 (td, J = 8.4, 2.4 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.67 (dt, J = 8.2, 1.9 Hz, 1H), 4.83 (s, 2H), 3.80 (s, 3H). Step Two: N Preparation of 2',4'-difluoro-4-methoxy-[1,1'-biphenyl]-4-yl)acrylamide (Example 17) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (97 mg, 79%).

[0086] GC-MS(EI): [M] + 298.05. 1 H NMR (400 MHz, DMSO-d 6) δ 9.49 (s, 1H), 8.27 (s, 1H), 7.52 (td, J = 8.9, 6.6 Hz, 1H), 7.34 (ddd, J = 11.5, 9.3, 2.6 Hz, 1H),7.26 (dt, J = 8.5, 2.0 Hz, 1H), 7.22 – 7.13 (m, 2H), 6.73 (dd, J = 17.0, 10.2 Hz,1H), 6.24 (dd, J = 17.0, 2.1 Hz, 1H), 5.73 (dd, J = 10.1, 2.1 Hz, 1H), 3.90 (s,3H). Example 18

[0087] Step 1: Preparation of 2',4'-difluoro-6-methyl-[1,1'-biphenyl]-3-amine (intermediate 18-a) The operation steps were the same as the second step in the preparation of Example 1, and the product was a white solid (106 mg, 91%).

[0088] GC-MS(EI): [M] + 219.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.11 (q, J = 8.4Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.83 (td, J = 8.3, 2.6 Hz, 1H), 6.79 (td, J =9.3, 2.6 Hz, 1H), 6.57 (dd, J = 8.2, 2.5 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 3.49(s, 2H), 1.98 (s, 3H). Step Two: N Preparation of 2',4'-difluoro-6-methyl-[1,1'-biphenyl]-4-yl)acrylamide (Example 18) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (124 mg, 98%).

[0089] GC-MS(EI): [M] + 273.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.17 (s, 1H), 7.58 (dd, J = 7.5, 1.5 Hz, 2H), 7.36 (dtd, J = 9.1, 7.6, 6.5, 4.7 Hz, 2H), 7.27 (d, J =8.1 Hz, 1H), 7.18 (tt, J = 8.3, 1.9 Hz, 1H), 6.42 (dd, J = 17.0, 10.1 Hz, 1H),6.23 (dd, J = 17.0, 1.8 Hz, 1H), 5.74 (dd, J = 10.1, 1.8 Hz, 1H), 2.06 (s, 3H). Example 19

[0090] Step 1: Preparation of 2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 19-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (134 mg, 74%).

[0091] GC-MS(EI): [M] + 329.05. 1 H NMR (400 MHz, DMSO- d 6) δ 7.64 (d, J = 8.5 Hz, 2H), 7.47 (dd, J = 7.5, 1.9 Hz, 1H), 7.42 (td, J = 7.7, 1.9 Hz, 1H), 7.34 (td, J =7.4, 1.3 Hz, 1H), 7.14 (dd, J = 8.0, 1.3 Hz, 1H), 6.98 (d, J= 7.0 Hz, 2H), 6.95(d, J = 5.6 Hz, 1H), 6.69 (t, J = 2.0 Hz, 1H), 6.58 (dt, J = 7.5, 1.4 Hz, 1H), 6.47(ddd, J = 8.0, 2.4, 1.1 Hz, 1H), 5.07 (s, 2H). Step Two: N Preparation of 2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 19) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (115 mg, 99%).

[0092] GC-MS(EI): [M] + 383.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.17 (s, 1H), 7.89 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.60 – 7.55 (m, 1H), 7.53 (dd, J = 7.6, 1.8Hz, 1H), 7.48 (td, J = 7.7, 1.8 Hz, 1H), 7.39 (td, J = 7.5, 1.3 Hz, 1H), 7.30 (t, J = 7.9 Hz, 1H), 7.18 (ddd, J = 10.9, 7.8, 1.3 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.43 (dd, J = 16.9, 10.1 Hz, 1H), 6.25 (dd, J = 17.0, 2.1 Hz, 1H), 5.75 (dd, J =10.0, 2.1 Hz, 1H). Example 20

[0093] Step 1: Preparation of 4-methoxy-2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 20-b) The operation steps were the same as the second step in the preparation of Example 1, and the product was a white solid (131 mg, 66%).

[0094] GC-MS(EI): [M] + 359.10. 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (d, J = 8.7 Hz, 2H), 7.45 (dd, J = 7.4, 2.0 Hz, 1H), 7.38 (td, J = 7.6, 2.0 Hz, 1H), 7.33 (td, J =7.4, 1.5 Hz, 1H), 7.12 (dd, J = 7.9, 1.4 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H), 6.82(d, J = 2.2 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.64 (dd, J = 8.2, 2.2 Hz, 1H), 4.72(s, 2H), 3.73 (s, 3H). Step Two: N Preparation of 3-(4-methoxy-2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 20) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (114 mg, 99%).

[0095] GC-MS(EI): [M] + 413.10. 1 H NMR (400 MHz, DMSO- d 6) δ 9.39 (s, 1H), 8.29 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.51 (dd, J = 7.5, 1.9 Hz, 1H), 7.44 (td, J =7.7, 1.9 Hz, 1H), 7.37 (td,J = 7.4, 1.4 Hz, 1H), 7.21 (dd, J = 8.5, 2.3 Hz, 1H), 7.17 (dd, J = 7.9, 1.4 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 2H), 6.70 (dd, J = 17.0, 10.2 Hz, 1H), 6.22 (dd, J = 17.0, 2.1 Hz, 1H), 5.71 (dd, J =10.1, 2.1 Hz, 1H), 3.83 (s, 3H). Example 21

[0096] Step 1: Preparation of 6-methyl-2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 21-b) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (140 mg, 99%).

[0097] GC-MS(EI): [M] + 343.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.36 (d, J = 8.4Hz, 2H), 7.27 (td, J = 7.7, 1.8 Hz, 1H), 7.21 (dd, J = 7.6, 1.9 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 6.99 – 6.95 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 8.4Hz, 2H), 6.47 (dd, J = 8.1, 2.5 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 3.37 (s, 2H), 1.99 (s, 3H). Step Two: NPreparation of 6-methyl-2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 21) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (98 mg, 85%).

[0098] GC-MS(EI): [M] + 397.15. 1 H NMR (400 MHz, DMSO- d 6) δ 10.05 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.53 – 7.44 (m, 3H), 7.36 (dt, J = 4.5, 0.9 Hz, 2H), 7.17(dd, J = 15.1, 8.1 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 16.9, 10.1 Hz,1H), 6.21 (dd, J = 17.0, 2.1 Hz, 1H), 5.72 (dd, J = 10.0, 2.1 Hz, 1H), 2.09 (s,3H). Example 22

[0099] Step 1: Preparation of 1-iodo-4-(4-(trifluoromethyl)phenoxy)benzene (intermediate 22-a) The procedure was performed as described in the first step of the preparation in Example 1, and the product was a white solid (400 mg, 12%).

[0100] GC-MS(EI): [M] + 363.95. 1 H NMR (600 MHz, Chloroform- d ) δ 7.60 (d, J = 8.6Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H). Step 2: Preparation of 4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 22-b) The operation steps were the same as the second step in the preparation of Example 1, and the product was a white solid (129 mg, 95%).

[0101] GC-MS(EI): [M] + 329.00. 1 H NMR (600 MHz, Chloroform- d ) δ 7.48 (dd, J =11.8, 8.3 Hz, 4H), 7.13 (t, J = 7.5 Hz, 1H), 6.99 (dd, J = 8.5, 4.0 Hz, 4H), 6.88(d, J = 7.7 Hz, 1H), 6.79 (s, 1H), 6.61 – 6.54 (m, 1H), 3.59 (s, 2H). Step 3: N Preparation of 3'-(4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 22) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (104 mg, 89%).

[0102] LC-MS(ESI): [MH] - 382.15. 1 H NMR (400 MHz, DMSO- d 6) δ 10.27 (s, 1H), 8.04 (t, J = 1.9 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.73 – 7.67 (m, 2H), 7.64(dt, J = 7.8, 1.6 Hz, 1H), 7.46 – 7.35 (m, 2H), 7.23 (ddd, J = 11.2, 7.7, 1.5 Hz,4H), 6.47 (dd, J = 17.0, 10.1 Hz, 1H), 6.29 (dd, J = 16.9, 2.0 Hz, 1H), 5.79 (dd, J= 10.1, 2.0 Hz, 1H). Example 23

[0103] Step 1: Preparation of 4-methoxy-4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 23-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (130 mg, 88%).

[0104] GC-MS(EI): [M] + 359.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.50 (d, J = 8.4Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.07 – 6.93 (m, 4H), 6.86 (d, J = 6.9 Hz, 2H), 6.78 (d, J = 8.3 Hz, 1H), 3.82 (s, 3H). Step Two: N Preparation of 3-(4-methoxy-4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 23) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (97 mg, 84%).

[0105] LC-MS(ESI): [M+H] + 414.15. 1 H NMR (400 MHz, DMSO- d 6) δ 9.52 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.70 – 7.64 (m, 2H), 7.42 (dd, J =8.5, 2.4 Hz, 1H), 7.24 – 7.19 (m, 3H), 7.19 – 7.14 (m, 2H), 6.75 (dd, J = 16.9,10.2 Hz, 1H), 6.26 (dd, J= 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.2, 2.1 Hz, 1H),3.90 (s, 3H). Example 24

[0106] Step 1: Preparation of 6-methyl-4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 24-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (130 mg, 92%).

[0107] GC-MS(EI): [M] + 343.15. 1 H NMR (600 MHz, Chloroform- d ) δ 7.51 (d, J = 8.4Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.98 (dd, J = 8.2, 6.3Hz, 3H), 6.57 – 6.48 (m, 2H), 3.43 (s, 3H), 2.09 (s, 3H). Step Two: N Preparation of 6-methyl-4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 24) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (105 mg, 91%).

[0108] GC-MS(EI): [M] + 397.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.16 (s, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 2.2 Hz, 1H), 7.55 (t, J = 8.9 Hz, 1H), 7.42 (d, J =8.8 Hz, 2H), 7.23 (td, J= 10.3, 7.9, 4.9 Hz, 5H), 6.43 (dd, J = 17.0, 9.9 Hz,1H), 6.29 – 6.21 (m, 1H), 5.79 – 5.72 (m, 1H), 2.22 (s, 3H). Example 25

[0109] Step 1: Preparation of 1-iodo-3-(4-(trifluoromethyl)phenoxy)benzene (intermediate 25-a) The operation steps are the same as the first step in the preparation of Example 1, and the product obtained is a colorless liquid (523 mg, 16%).

[0110] GC-MS(EI): [M] + 363.95. 1 H NMR (600 MHz, Chloroform- d ) δ 7.64 (d, J = 8.4Hz, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 2.0 Hz, 1H), 7.17 – 7.12 (m, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.06 (dd, J = 8.3, 2.4 Hz, 1H). Step 2: Preparation of 3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 25-b) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (135 mg, 95%).

[0111] GC-MS(EI): [M] + 329.05. 1 H NMR (600 MHz, Chloroform- d ) δ 7.50 (d, J = 8.5Hz, 2H), 7.33 (dt, J = 15.9, 8.0 Hz, 2H), 7.18 (t, J = 2.1 Hz, 1H), 7.14 (t, J =7.8 Hz, 1H), 7.00 (d, J= 8.4 Hz, 2H), 6.93 (dd, J = 7.8, 2.4 Hz, 1H), 6.88 (d, J =7.7 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.60 (dd, J = 8.0, 2.3 Hz, 1H), 3.65 (s,2H). Step 3: N Preparation of 3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 25) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (113 mg, 97%).

[0112] LC-MS(ESI): [MH] - 382.20. 1 H NMR (400 MHz, DMSO- d 6) δ 10.26 (s, 1H), 8.00 (t, J = 1.9 Hz, 1H), 7.78 – 7.74 (m, 2H), 7.69 (dt, J = 7.6, 1.9 Hz, 1H),7.61 – 7.50 (m, 2H), 7.45 – 7.36 (m, 3H), 7.23 – 7.18 (m, 2H), 7.16 (ddd, J =7.8, 2.5, 1.2 Hz, 1H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.28 (dd, J = 17.0, 2.0Hz, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H). Example 26

[0113] Step 1: Preparation of 4-methoxy-3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 26-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (145 mg, 98%).

[0114] GC-MS(EI): [M]+ 359.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.49 (d, J = 8.4Hz, 2H), 7.34 – 7.26 (m, 2H), 7.15 (t, J = 2.1 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.90 – 6.82 (m, 3H), 6.76 (d, J = 8.3 Hz, 1H), 3.80 (s, 3H). Step Two: N Preparation of 3-(4-methoxy-3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 26) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (97 mg, 84%).

[0115] LC-MS(ESI): [MH] - 412.15. 1 H NMR (400 MHz, DMSO- d 6) δ 9.52 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.56 – 7.42 (m, 3H), 7.34 (t, J =2.0 Hz, 1H), 7.23 – 7.12 (m, 3H), 7.08 (ddd, J = 7.7, 2.4, 1.3 Hz, 1H), 6.74(dd, J = 16.9, 10.2 Hz, 1H), 6.25 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.1,2.1 Hz, 1H), 3.90 (s, 3H). Example 27

[0116] Step 1: Preparation of 6-methyl-3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 27-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (133 mg, 94%).

[0117] GC-MS(EI): [M] + 343.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.50 (d, J = 8.4Hz, 2H), 7.32 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.00 (d, J = 8.3 Hz,2H), 6.98 – 6.84 (m, 3H), 6.54 (dd, J = 8.1, 2.5 Hz, 1H), 6.50 (s, 1H), 3.48 (s, 2H), 2.07 (s, 3H). Step Two: N Preparation of 6-methyl-3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 27) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (99 mg, 86%).

[0118] GC-MS(EI): [M] + 397.15. 1 H NMR (400 MHz, DMSO- d 6) δ 10.16 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 2.3 Hz, 1H), 7.59 – 7.52 (m, 2H), 7.27 – 7.18(m, 4H), 7.15 (ddd, J = 8.1, 2.5, 0.9 Hz, 1H), 7.09 (t, J = 2.0 Hz, 1H), 6.43(dd, J = 16.9, 10.1 Hz, 1H), 6.24 (dd, J = 17.0, 2.1 Hz, 1H), 5.75 (dd, J = 10.1,2.1 Hz, 1H), 2.20 (s, 3H). Example 28

[0119] Step 1: Preparation of 3-(7-chloroquinoline-4-yl)aniline (intermediate 28-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (102 mg, 97%).

[0120] GC-MS(EI): [M] + 254.10. 1 H NMR (600 MHz, DMSO- d 6) δ 8.92 (d, J = 4.4 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.58 (dd, J = 9.0, 2.3 Hz, 1H), 7.40 (d, J = 4.4 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.74 (dd, J = 8.0, 2.3 Hz, 1H), 6.72 (t, J = 2.0 Hz, 1H), 6.62 – 6.58 (m, 1H), 5.35 (s, 2H). Step Two: N Preparation of 3-(7-chloroquinoline-4-yl)phenyl)acrylamide (Example 28) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (99 mg, 82%).

[0121] GC-MS(EI): [M] + 308.05. 1 H NMR (400 MHz, DMSO- d 6) δ 10.38 (s, 1H), 9.00 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 9.0 Hz, 2H), 7.85 –7.78 (m, 1H), 7.66 (dd, J= 9.0, 2.3 Hz, 1H), 7.61 – 7.49 (m, 2H), 7.26 (dt, J =7.5, 1.4 Hz, 1H), 6.47 (dd, J = 17.0, 10.1 Hz, 1H), 6.28 (dd, J = 16.9, 2.0 Hz, 1H), 5.79 (dd, J = 10.1, 2.0 Hz, 1H). Example 29

[0122] Step 1: Preparation of 5-(7-chloroquinoline-4-yl)-2-methoxyaniline (Intermediate 29-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (162 mg, 92%).

[0123] GC-MS(EI): [M] + 284.10. 1 H NMR (600 MHz, Chloroform- d ) δ 8.85 (d, J = 4.4Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.39 (dd, J = 9.0, 2.2Hz, 1H), 7.26 (d, J = 4.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 6.9, 1.9Hz, 2H), 4.03 (s, 2H), 3.92 (s, 3H). Step Two: N Preparation of 5-(7-chloroquinoline-4-yl)-2-methoxyphenyl)acrylamide (Example 29) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (118 mg, 99%).

[0124] GC-MS(EI): [M] + 338.10. 1 H NMR (400 MHz, DMSO-d 6) δ 9.63 (s, 1H), 8.96 (d, J = 4.5 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.02 (d, J =9.1 Hz, 1H), 7.66 (dd, J = 9.1, 2.3 Hz, 1H), 7.49 (d, J = 4.5 Hz, 1H), 7.32 (dd, J = 8.3, 2.1 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 6.77 (dd, J = 17.0, 10.2 Hz, 1H),6.24 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 3.97 (s, 3H). Example 30

[0125] Step 1: Preparation of 3-(7-chloroquinoline-4-yl)-4-methylaniline (intermediate 30-b) The operation steps were the same as in step two of the preparation in Example 1, and the product was a white solid (130 mg, 78%).

[0126] GC-MS(EI): [M] + 268.10. 1 H NMR (600 MHz, Chloroform- d ) δ 8.94 (d, J = 4.4Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.40 (dd, J = 9.0, 2.1Hz, 1H), 7.25 (d, J = 4.4 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.75 (dd, J= 8.2, 2.6Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 3.70 (s, 2H), 1.89 (s, 3H). Step Two: N Preparation of 3-(7-chloroquinoline-4-yl)-4-methylphenyl)acrylamide (Example 30) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (118 mg, 99%).

[0127] GC-MS(EI): [M] + 322.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.24 (s, 1H), 9.02 (d, J = 4.4 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.70 (dd, J = 8.3, 2.3 Hz, 1H), 7.65– 7.58 (m, 2H), 7.51 – 7.43 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 6.43 (dd, J =17.0, 10.1 Hz, 1H), 6.23 (dd, J = 16.9, 2.1 Hz, 1H), 5.75 (dd, J = 10.0, 2.1 Hz,1H), 1.93 (s, 3H). Example 31

[0128] Step 1: Preparation of 3-(6-chloronaphth-2-yl)aniline (intermediate 31-b) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (142 mg, 90%).

[0129] GC-MS(EI): [M] + 253.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.87 (s, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.69 (t, J= 8.2 Hz, 2H), 7.63 (dd, J = 8.6, 1.8 Hz, 1H), 7.33 (dd, J = 8.8, 2.1 Hz, 1H), 7.21 – 7.14 (m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.90 (t, J = 2.1 Hz, 1H), 6.62 (dd, J = 7.9, 2.3 Hz, 1H), 3.67 (s, 2H). Step Two: N Preparation of 3-(6-chloronaphth-2-yl)phenyl)acrylamide (Example 31) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (80 mg, 81%).

[0130] GC-MS(EI): [M] + 307.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.31 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 8.11 – 8.00 (m, 3H), 7.87 (dd, J = 8.6, 1.9 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.59 – 7.46 (m, 3H), 6.49 (dd, J = 17.0, 10.1 Hz, 1H),6.31 (dd, J = 16.9, 2.1 Hz, 1H), 5.80 (dd, J = 10.0, 2.1 Hz, 1H). Example 32

[0131] Step 1: Preparation of 5-(6-chloronaphth-2-yl)-2-methoxyaniline (intermediate 32-b) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (155 mg, 88%).

[0132] GC-MS(EI): [M] + 283.10. 1H NMR (600 MHz, DMSO- d 6) δ 8.08 (s, 1H), 8.03 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.11 (s, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.91 (d, J =8.2 Hz, 1H), 4.86 (s, 2H), 3.82 (s, 3H). Step Two: N Preparation of 5-(6-chloronaphth-2-yl)-2-methoxyphenyl)acrylamide (Example 32) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (116 mg, 98%).

[0133] GC-MS(EI): [M] + 337.10. 1 H NMR (400 MHz, DMSO- d 6) δ 9.54 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.16 (d, J = 1.9 Hz, 1H), 8.09 – 7.96 (m, 3H), 7.85 (dd, J =8.6, 1.9 Hz, 1H), 7.56 (ddd, J = 11.2, 8.7, 2.3 Hz, 2H), 7.21 (d, J = 8.6 Hz, 1H), 6.76 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 2.1 Hz, 1H), 5.76 (dd, J = 10.1, 2.1 Hz, 1H), 3.92 (s, 3H). Example 33

[0134] Step 1: Preparation of 3-(6-chloronaphth-2-yl)-4-methylaniline (intermediate 33-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (142 mg, 85%).

[0135] GC-MS(EI): [M] + 267.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.91 (s, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.78 (s, 1H), 7.58 – 7.52 (m,1H), 7.49 (dd, J = 8.7, 2.1 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.75 – 6.68 (m,2H), 3.62 (s, 2H), 2.24 (s, 3H). Step Two: N Preparation of 3-(6-chloronaphth-2-yl)-4-methylphenyl)acrylamide (Example 33) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (98 mg, 82%).

[0136] GC-MS(EI): [M] + 321.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.18 (s, 1H), 8.11 (d, J = 2.2 Hz, 1H), 8.01 (dd, J = 16.8, 8.6 Hz, 2H), 7.93 (s, 1H), 7.69 (d, J =2.3 Hz, 1H), 7.64 – 7.53 (m, 3H), 7.29 (d, J = 8.4 Hz, 1H), 6.44 (dd, J = 17.0,10.1 Hz, 1H), 6.25 (dd, J = 16.9, 2.1 Hz, 1H), 5.75 (dd, J= 10.1, 2.1 Hz, 1H),2.23 (s, 3H). Example 34

[0137] Step 1: Preparation of cyclo-2-bromo-4-nitro-1-(4-(trifluoromethyl)phenoxy)benzene (intermediate 34-a) Weigh out 2-bromo-1-fluoro-4-nitrobenzene (1.00 g, 4.55 mmol), 4-trifluoromethylphenol (738 mg, 4.55 mmol), and potassium carbonate (944 mg, 6.83 mmol) and add them to the reaction flask. N , N Dissolve 3 mL of dimethylformamide and stir at room temperature for 16 h. Extract with ethyl acetate, dry with anhydrous sodium sulfate, filter, and separate by silica gel column chromatography to obtain a yellow solid (1.63 g, 82%).

[0138] EI-MS: [M] + 361.00. 1 H NMR (600 MHz, Chloroform- d ) δ 8.59 (d, J = 2.7 Hz, 1H), 8.18 (dd, J = 9.1, 2.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 9.1 Hz, 1H). Step 2: Preparation of 3-bromo-4-(4-(trifluoromethyl)phenoxy)aniline (intermediate 34-b) Intermediate 34-a (1.50 g, 4.14 mmol), ammonium chloride (332 mg, 6.21 mmol), and iron powder (1.16 g, 20.8 mmol) were weighed and added to a reaction flask. Ethanol (10 mL), tetrahydrofuran (10 mL), and H2O (3 mL) were added, and the mixture was refluxed at 95 °C for 1.5 h. The mixture was filtered, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered again, and separated by silica gel column chromatography to obtain a brown solid (1.08 g, 79%).

[0139] EI-MS: [M] + 331.00. 1 H NMR (600 MHz, Chloroform- d) δ 7.56 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 2.8 Hz, 1H), 6.98 – 6.92 (m, 3H), 6.66 (dd, J = 8.6, 2.7 Hz,1H), 3.76 (s, 2H). Step 3: Preparation of 2',4'-difluoro-6-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 34-c) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (214 mg, 97%).

[0140] GC-MS(EI): [M] + 365.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.35 (d, J = 8.5Hz, 2H), 7.19 – 7.15 (m, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.76 – 6.67 (m, 2H), 6.65 (dd, J = 8.5, 2.9 Hz, 1H), 6.63 (q, J = 2.9 Hz, 1H), 3.61 (s, 2H). Step 4: N Preparation of -(2',4'-difluoro-6-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 34) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (85 mg, 74%).

[0141] GC-MS(EI): [M] + 419.15. 1 H NMR (400 MHz, DMSO- d 6) δ 10.36 (s, 1H), 7.85 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 8.9, 2.6 Hz, 1H), 7.63 (d, J= 8.5 Hz, 2H), 7.43(td, J = 8.6, 6.6 Hz, 1H), 7.28 (td, J = 9.8, 2.6 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.11 (td, J = 8.5, 2.6 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.45 (dd, J = 16.9,10.1 Hz, 1H), 6.28 (dd, J = 16.9, 2.1 Hz, 1H), 5.79 (dd, J = 10.1, 2.1 Hz, 1H). Example 35

[0142] Step 1: Preparation of 6-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-amine (intermediate 35-c) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (195 mg, 98%).

[0143] GC-MS(EI): [M] + 329.05. 1 H NMR (400 MHz, DMSO- d 6) δ 7.56 (d, J = 8.8 Hz,2H), 7.40 – 7.35 (m, 2H), 7.33 – 7.28 (m, 2H), 7.26 – 7.21 (m, 1H), 6.91 –6.87 (m, 2H), 6.87 (d, J = 3.6 Hz, 1H), 6.69 (d, J = 2.7 Hz, 1H), 6.64 (dd, J =8.5, 2.8 Hz, 1H), 5.21 (s, 2H). Step Two: N Preparation of 6-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)acrylamide (Example 35) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (106 mg, 91%).

[0144] GC-MS(EI): [M] + 383.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 7.89 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.51 – 7.42 (m, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 9.5 Hz, 1H), 7.15 (t, J = 16.4 Hz, 2H), 6.99(d, J = 8.4 Hz, 1H), 6.53 – 6.39 (m, 1H), 6.28 (d, J = 17.1 Hz, 1H), 5.78 (d, J =10.4 Hz, 1H). Example 36

[0145] Step 1: Preparation of 3-(pyridin-3-yl)-4-(4-(trifluoromethyl)phenoxy)aniline (intermediate 36-c) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (196 mg, 99%).

[0146] GC-MS(EI): [M] + 330.15. 1 H NMR (600 MHz, Chloroform- d ) δ 8.71 (d, J = 2.3Hz, 1H), 8.50 (d, J = 3.3 Hz, 1H), 7.77 (dt, J = 7.8, 2.1 Hz, 1H), 7.45 (d, J = 8.4Hz, 2H), 7.25 (dd, J = 7.9, 4.8 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.87 (d, J= 8.4Hz, 2H), 6.79 (d, J = 2.9 Hz, 1H), 6.76 (dd, J = 8.5, 2.9 Hz, 1H), 3.60 (s, 2H). Step Two: N Preparation of 3-(pyridin-3-yl)-4-(4-(trifluoromethyl)phenoxy)phenyl)acrylamide (Example 36) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (106 mg, 91%).

[0147] LC-MS(ESI): [M+H] + 385.15. 1 H NMR (400 MHz, DMSO- d 6) δ 10.39 (s, 1H),8.66 (s, 1H), 8.51 (dd, J = 4.8, 1.7 Hz, 1H), 7.94 (d, J = 2.6 Hz, 1H), 7.88 (dt, J = 7.9, 2.0 Hz, 1H), 7.79 (dd, J = 8.8, 2.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H),7.46 – 7.38 (m, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.46(dd, J = 17.0, 10.1 Hz, 1H), 6.30 (dd, J = 17.0, 2.0 Hz, 1H), 5.80 (dd, J = 10.0, 2.1 Hz, 1H). Example 37

[0148] Step 1: 3-(1 H Preparation of pyrazol-5-yl)-4-(4-(trifluoromethyl)phenoxy)aniline (intermediate 37-c) The operation steps were the same as the second step in the preparation of Example 1, and the product was a white solid (130 mg, 68%).

[0149] GC-MS(EI): [M] + 319.10. 1 H NMR (600 MHz, Chloroform- d ) δ 7.41 (d, J = 2.1Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 2.9 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.6 Hz, 1H), 6.56 (dd, J = 8.7, 2.8 Hz, 1H), 6.47 (s, 1H). Step Two: N -(3-(1 H Preparation of pyrazol-5-yl)-4-(4-(trifluoromethyl)phenoxy)phenyl)acrylamide (Example 37) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (40 mg, 34%).

[0150] LC-MS(ESI): [M+H] + 374.10. 1 H NMR (400 MHz, DMSO- d 6) δ 13.02 (s, 1H), 10.34 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.5 Hz, 3H), 7.16 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 6.52 – 6.41 (m, 2H), 6.30(dd, J = 17.0, 2.1 Hz, 1H), 5.79 (dd, J = 9.9, 2.1 Hz, 1H). Example 38

[0151] The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (92 mg, 69%).

[0152] LC-MS(ESI): [M+H] + 428.20. 1 H NMR (400 MHz, DMSO- d 6) δ 10.43 (s, 1H), 8.46 (dd, J = 30.4, 2.8 Hz, 2H), 7.91 (dd, J = 9.1, 2.6 Hz, 1H), 7.70 (d, J = 8.5Hz, 2H), 7.41 (dd, J = 17.3, 10.5 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.10 (d, J =8.5 Hz, 2H), 6.89 (d, J = 2.9 Hz, 1H), 6.66 (d, J = 17.2 Hz, 1H), 6.48 (dd, J =16.9, 10.0 Hz, 1H), 6.37 – 6.28 (m, 1H), 6.23 (d, J = 10.6 Hz, 1H), 5.87 – 5.74(m, 1H). Example 39

[0153] Step 1: 3-(1-methyl-1-yl) H Preparation of pyrazol-5-yl)-4-(4-(trifluoromethyl)phenoxy)aniline (intermediate 39-c) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (221 mg, 73%).

[0154] GC-MS(EI): [M] + 333.15. 1 H NMR (600 MHz, Chloroform- d ) δ 7.30 (d, J = 8.8Hz, 2H), 7.24 (s, 1H), 6.82 (d, J = 9.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 2H), 6.62(dd, J= 8.7, 2.9 Hz, 1H), 6.52 (s, 1H), 5.98 (s, 1H), 3.81 (s, 2H), 3.66 (s, 3H). Step Two: N -(3-(1-methyl-1 H Preparation of pyrazol-5-yl)-4-(4-(trifluoromethyl)phenoxy)phenyl)acrylamide (Example 39) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (110 mg, 95%).

[0155] GC-MS(EI): [M] + 387.20. 1 H NMR (400 MHz, DMSO- d 6) δ 10.39 (s, 1H), 7.87 (d, J = 2.6 Hz, 1H), 7.79 (d, J = 2.7 Hz, 1H), 7.63 (dd, J = 8.8, 3.8 Hz, 2H), 7.37(t, J = 2.2 Hz, 1H), 7.25 (dd, J = 8.8, 4.3 Hz, 1H), 7.00 (dd, J = 8.7, 4.3 Hz, 2H), 6.45 (dd, J = 16.9, 10.1 Hz, 1H), 6.29 (dd, J = 17.0, 2.1 Hz, 1H), 6.21 (dd, J = 4.1, 1.9 Hz, 1H), 5.80 (dd, J = 10.0, 2.1 Hz, 1H), 3.74 (s, 3H). Example 40

[0156] Step 1: 3-(1-methyl-1-yl) H Preparation of pyrazol-3-yl)-4-(4-(trifluoromethyl)phenoxy)aniline (intermediate 40-c) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a white solid (193 mg, 64%).

[0157] GC-MS(EI): [M]+ 333.15. 1 H NMR (600 MHz, Chloroform- d ) δ 7.40 (d, J = 8.5Hz, 2H), 7.32 (d, J = 2.9 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 1H), 6.58 (dd, J = 8.6, 2.9 Hz, 1H), 6.43 (d, J = 2.3 Hz,1H), 3.81 (s, 3H), 3.65 (s, 2H). Step Two: N -(3-(1-methyl-1 H Preparation of pyrazol-3-yl)-4-(4-(trifluoromethyl)phenoxy)phenyl)acrylamide (Example 40) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (96 mg, 83%).

[0158] GC-MS(EI): [M] + 387.20. 1 H NMR (400 MHz, DMSO- d 6) δ 10.34 (s, 1H), 8.35 (d, J = 2.7 Hz, 1H), 7.83 (dd, J = 8.7, 2.7 Hz, 1H), 7.72 – 7.61 (m, 3H), 7.15(d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 6.51 – 6.40 (m, 2H), 6.30 (dd, J =17.0, 2.1 Hz, 1H), 5.78 (dd, J = 10.0, 2.1 Hz, 1H), 3.86 (s, 3H). Example 41

[0159] Step 1: Preparation of 3-(furan-2-yl)-4-(4-(trifluoromethyl)phenoxy)aniline (intermediate 41-c) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (190 mg, 99%).

[0160] GC-MS(EI): [M] + 319.05. 1 H NMR (600 MHz, Chloroform- d ) δ 7.40 (d, J = 8.7Hz, 2H), 7.29 (s, 1H), 7.15 (d, J = 2.9 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.75 (dd, J = 14.6, 8.7 Hz, 1H), 6.58 – 6.56 (m, 1H), 6.48 (dd, J = 8.6, 2.9 Hz, 1H), 6.26 (dd, J = 3.5, 1.8 Hz, 1H), 3.54 (s, 2H). Step Two: N Preparation of 3-(furan-2-yl)-4-(4-(trifluoromethyl)phenoxy)phenyl)acrylamide (Example 41) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (98 mg, 84%).

[0161] GC-MS(EI): [M] + 373.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.37 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 7.81 – 7.67 (m, 5H), 7.18 (d, J = 8.8 Hz, 1H), 7.11 (d, J =8.4 Hz, 3H), 6.75 – 6.70 (m, 1H), 6.55 (dd, J = 3.4, 1.8 Hz, 1H), 6.47 (dd, J =17.1, 10.0 Hz, 1H), 6.31 (dd,J = 17.0, 2.1 Hz, 1H), 5.80 (dd, J = 10.1, 2.1 Hz, 1H). Example 42

[0162] Step 1: Preparation of 3-(thiophen-3-yl)-4-(4-(trifluoromethyl)phenoxy)aniline (intermediate 42-c) The operation steps are the same as the second step in the preparation of Example 1, and the product is a white solid (190 mg, 99%).

[0163] GC-MS(EI): [M] + 335.00. 1 H NMR (600 MHz, Chloroform- d ) δ 7.36 (d, J = 8.4Hz, 2H), 7.32 (d, J = 3.0 Hz, 1H), 7.16 (s, 1H), 7.13 (dd, J = 5.0, 3.0 Hz, 1H), 6.82 – 6.76 (m, 4H), 6.52 (dd, J = 8.5, 2.9 Hz, 1H), 3.59 (s, 2H). Step Two: N Preparation of 3-(thiophen-3-yl)-4-(4-(trifluoromethyl)phenoxy)phenyl)acrylamide (Example 42) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (112 mg, 97%).

[0164] GC-MS(EI): [M] + 389.10. 1 H NMR (400 MHz, DMSO- d 6) δ 10.33 (s, 1H), 8.04 (d, J = 2.6 Hz, 1H), 7.74 – 7.69 (m, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.56 (dd, J =5.0, 3.0 Hz, 1H), 7.32 (dd, J = 5.0, 1.4 Hz, 1H), 7.17 (d,J = 8.8 Hz, 1H), 7.04(d, J = 8.5 Hz, 2H), 6.46 (dd, J = 16.9, 10.0 Hz, 1H), 6.30 (dd, J = 17.0, 2.0 Hz, 1H), 5.80 (dd, J = 10.0, 2.0 Hz, 1H). Example 43

[0165] Step 1: Preparation of 2,3',4-trifluoro-5'-nitro-1,1'-biphenyl (intermediate 43-b) The operation steps were the same as the second step in the preparation of Example 1, and the product was a yellow solid (385 mg, 98%).

[0166] EI-MS: [M] + 253.05. 1 H NMR (600 MHz, Chloroform- d ) δ 8.12 (s, 1H), 7.86 (dt, J = 8.2, 2.3 Hz, 1H), 7.55 – 7.47 (m, 1H), 7.39 (td, J = 8.6, 6.1 Hz, 1H), 6.96 (td, J = 8.3, 2.6 Hz, 1H), 6.91 (ddd, J = 11.0, 8.6, 2.6 Hz, 1H). Step 2: 4-(2',4'-difluoro-5-nitro-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 43-c) Weigh out intermediate 43-b (200 mg, 0.790 mmol). N 1-Phenylopirain-1-carboxamide (649 mg, 3.16 mmol) and cesium carbonate (515 mg, 1.58 mmol) were added to a reaction flask, dissolved in dimethyl sulfoxide (8 mL), and reacted at 100 °C for 72 h. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and separated by silica gel column chromatography to give a yellow solid (40 mg, 12%).

[0167] LC-MS(ESI): [M+H] +439.20. 1 H NMR (400 MHz, Chloroform- d ) δ 7.82 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.48 – 7.30 (m, 5H), 7.27 (d, J = 10.6 Hz, 1H), 7.07 (t, J = 7.3 Hz, 1H), 7.03 – 6.92 (m, 2H), 6.51 (s, 1H), 3.77 – 3.65 (m,4H), 3.39 (t, J = 5.2 Hz, 4H). Step 3: 4-(5-amino-2',4'-difluoro-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 43-d) Intermediate 43-C (40 mg, 0.091 mmol) and 10% palladium on carbon (5 mg, 0.005 mmol) were weighed and added to a reaction flask. Hydrogen gas was introduced, and methanol (3 mL) was added. The reaction was carried out at room temperature for 16 h. The mixture was filtered and the solvent was removed by vacuum distillation to obtain a brown solid (37 mg, 99%).

[0168] LC-MS(ESI): [MH] - 407.20. 1 H NMR (400 MHz, DMSO- d 6) δ 8.74 (s, 1H), 7.54 (dd, J = 25.4, 7.7 Hz, 4H), 7.36 (t, J = 9.9 Hz, 1H), 7.22 (dt, J = 17.0, 7.8Hz, 4H), 6.94 (t, J = 7.0 Hz, 1H), 6.86 (s, 1H), 6.79 (s, 1H), 6.73 (s, 1H), 3.72 – 3.54 (m, 4H), 3.31 – 3.14 (m, 4H). Step 4: 4-(5-Acrylamido-2',4'-difluoro-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (Example 43) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (41 mg, 98%).

[0169] LC-MS(ESI): [MH] - 461.20. 1 H NMR (400 MHz, DMSO- d 6) δ 10.16 (s, 1H),8.63 (s, 1H), 7.58 (td, J = 8.8, 6.6 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.41 – 7.30(m, 3H), 7.24 (dd, J = 8.6, 7.4 Hz, 2H), 7.19 (td, J = 8.5, 8.1, 2.2 Hz, 1H), 6.97 – 6.91 (m, 1H), 6.83 (s, 1H), 6.44 (dd, J = 16.9, 10.1 Hz, 1H), 6.26 (dd, J = 16.9, 2.1 Hz, 1H), 5.77 (dd, J = 10.0, 2.1 Hz, 1H), 3.71 – 3.52 (m, 4H), 3.22(t, J = 5.2 Hz, 4H). Example 44

[0170] Step 1: Preparation of 3'-fluoro-5'-nitro-2-(4-(trifluoromethyl)phenoxy)-1,1'-biphenyl (intermediate 44-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a yellow solid (289 mg, 93%).

[0171] EI-MS: [M] + 377.00. 1 H NMR (600 MHz, Chloroform- d ) δ 8.25 (s, 1H), 7.84 (dt, J = 8.1, 2.3 Hz, 1H), 7.62 (dt, J = 9.0, 2.0 Hz, 1H), 7.55 – 7.50 (m, 3H), 7.47 (td, J= 7.9, 1.8 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.5 Hz, 2H). Step 2: 4-(5-nitro-2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 44-c) The operation steps are the same as the second step in the preparation of Example 43, and the product is a yellow solid (71 mg, 24%).

[0172] LC-MS(ESI): [M+H] + 563.25. 1 H NMR (600 MHz, Chloroform- d ) δ 7.77 (s, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 8.1 Hz, 3H), 7.38 (t, J = 7.8 Hz, 1H), 7.29 (dd, J = 7.9, 3.9 Hz, 3H), 7.23 (t, J = 7.7 Hz, 2H), 7.18 (d, J = 5.9 Hz, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 3.56(t, J = 5.2 Hz, 4H), 3.16 (t, J = 5.2 Hz, 4H). Step 3: 4-(5-amino-2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 44-d) The operation steps are the same as the third step in the preparation of Example 43, and the product is a brown solid (46 mg, 97%).

[0173] LC-MS(ESI): [MH]- 531.20. 1 H NMR (600 MHz, Chloroform- d ) δ 7.42 (dd, J =13.6, 8.0 Hz, 3H), 7.29 (d, J = 7.8 Hz, 3H), 7.25 – 7.15 (m, 5H), 7.04 – 6.93(m, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 18.2 Hz, 3H), 6.10 (s, 1H), 3.48(t, J = 5.2 Hz, 4H), 3.00 (t, J = 5.2 Hz, 4H). Step 4: 4-(5-Acrylamido-2'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (Example 44) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (45 mg, 89%).

[0174] LC-MS(ESI): [MH] - 585.15. 1 H NMR (400 MHz, DMSO- d 6) δ 10.07 (s, 1H),8.59 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.1Hz, 3H), 7.39 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 12.0 Hz, 2H), 7.23 (q, J = 8.6, 8.1Hz, 3H), 7.00 (d, J = 8.3 Hz, 2H), 6.94 (t, J = 7.4 Hz, 1H), 6.73 (s, 1H), 6.42(dd, J = 16.9, 10.1 Hz, 1H), 6.24 (d,J = 17.0 Hz, 1H), 5.74 (d, J = 10.1 Hz, 1H), 3.54 (t, J = 4.7 Hz, 4H), 3.05 (t, J = 4.8 Hz, 4H). Example 45

[0175] Step 1: Preparation of 3'-fluoro-5'-nitro-4-(4-(trifluoromethyl)phenoxy)-1,1'-biphenyl (intermediate 45-b) The operation steps were the same as the second step in the preparation of Example 1, and the product was a yellow solid (303 mg, 97%).

[0176] EI-MS: [M] + 377.05. 1 H NMR (600 MHz, Chloroform- d ) δ 8.18 (s, 1H), 7.82 (dd, J = 8.0, 2.5 Hz, 1H), 7.56 – 7.53 (m, 5H), 7.10 (d, J = 8.3 Hz, 2H), 7.05(d, J = 8.4 Hz, 2H). Step 2: 4-(5-nitro-4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 45-c) The operation steps are the same as the second step in the preparation of Example 43, and the product is a yellow solid (70 mg, 23%).

[0177] LC-MS(ESI): [M+H] + 563.20. 1 H NMR (400 MHz, DMSO- d 6) δ 8.66 (s, 1H),7.91 – 7.85 (m, 2H), 7.82 (t, J = 1.7 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.71 (t, J= 2.1 Hz, 1H), 7.68 – 7.64 (m, 1H), 7.52 – 7.46 (m, 2H), 7.29 – 7.19 (m,6H), 6.95 (tt, J = 7.3, 1.2 Hz, 1H), 3.65 (t, J = 5.2 Hz, 4H), 3.48 – 3.41 (m,4H). Step 3: 4-(5-amino-4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 45-d) The operation steps are the same as the third step in the preparation of Example 43, and the product is a brown solid (47 mg, 99%).

[0178] LC-MS(ESI): [MH] - 531.20. 1 H NMR (400 MHz, DMSO- d 6) δ 8.64 (s, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.52 – 7.46 (m, 2H), 7.29 –7.22 (m, 2H), 7.19 (dd, J = 8.8, 2.6 Hz, 4H), 6.96 (t, J = 7.2 Hz, 1H), 6.69 (t, J = 1.8 Hz, 1H), 6.59 (t, J = 1.6 Hz, 1H), 6.46 (t, J = 2.1 Hz, 1H), 5.71 (s, 2H), 3.65 (t, J = 5.1 Hz, 4H), 3.27 – 3.24 (m, 4H). Step 4: 4-(5-Acrylamido-4'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (Example 45) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (40 mg, 77%).

[0179] LC-MS(ESI): [MH] - 585.25. 1 H NMR (600 MHz, DMSO- d 6) δ 10.19 (s, 1H),8.68 (s, 1H), 7.81 (dt, J = 6.2, 3.3 Hz, 2H), 7.62 – 7.59 (m, 2H), 7.54 – 7.52(m, 2H), 7.50 – 7.43 (m, 2H), 7.30 – 7.29 (m, 2H), 7.25 (d, J = 11.5 Hz, 2H),7.19 (s, 1H), 7.07 (s, 1H), 6.99 (d, J = 10.8 Hz, 1H), 6.56 – 6.45 (m, 1H), 6.32 (d, J = 14.9 Hz, 1H), 6.22 (s, 1H), 5.82 (d, J = 7.8 Hz, 1H), 3.69 – 3.67(m, 4H), 3.31 (t, J = 4.8 Hz, 4H). Example 46

[0180] Step 1: Preparation of 3'-fluoro-5'-nitro-3-(4-(trifluoromethyl)phenoxy)-1,1'-biphenyl (intermediate 46-b) The operation steps were the same as the second step in the preparation of Example 1, and the product was a yellow solid (306 mg, 98%).

[0181] EI-MS: [M] + 377.05. 1 H NMR (600 MHz, Chloroform- d ) δ 8.18 (s, 1H), 7.87– 7.80 (m, 1H), 7.53 (t, J = 7.0 Hz, 3H), 7.45 (t, J = 7.8 Hz, 1H), 7.36 (d, J =7.7 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.04 (dd, J= 16.1, 8.4 Hz, 3H). Step 2: 4-(5-nitro-3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 46-c) The operation steps are the same as the second step in the preparation of Example 43, and the product is a yellow solid (54 mg, 18%).

[0182] LC-MS(ESI): [M+H] + 563.20. 1 H NMR (400 MHz, DMSO- d 6) δ 8.65 (s, 1H), 7.84 (t, J = 1.7 Hz, 1H), 7.78 – 7.63 (m, 6H), 7.59 (t, J = 7.9 Hz, 1H), 7.51 –7.46 (m, 2H), 7.28 – 7.16 (m, 5H), 6.95 (tt, J = 7.3, 1.2 Hz, 1H), 3.68 – 3.60 (m, 4H), 3.48 – 3.40 (m, 4H). Step 3: 4-(5-amino-3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 46-d) The operation steps are the same as the third step in the preparation of Example 43, and the product is a brown solid (47 mg, 99%).

[0183] LC-MS(ESI): [M+H] + 533.15. 1 H NMR (400 MHz, DMSO- d 6) δ 8.62 (s, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.52 – 7.46 (m, 4H), 7.37 – 7.30 (m, 1H), 7.27 – 7.23(m, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.09 – 7.06 (m, 1H), 6.98 – 6.93 (m, 1H), 6.48 (dt, J= 5.8, 1.8 Hz, 1H), 6.36 (dt, J = 24.8, 1.7 Hz, 1H), 6.23 (dt, J =30.9, 2.1 Hz, 1H), 5.72 (s, 2H), 3.65 – 3.58 (m, 4H), 3.25 – 3.22 (m, 4H). Step 4: 4-(5-Acrylamido-3'-(4-(trifluoromethyl)phenoxy)-[1,1'-biphenyl]-3-yl)- N Preparation of 1-phenylpiperazine-1-carboxamide (Example 46) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (37 mg, 72%).

[0184] LC-MS(ESI): [MH] - 585.25. 1 H NMR (400 MHz, DMSO- d 6) δ 10.18 (s, 1H), 8.65 (s, 1H), 7.74 (dd, J = 17.4, 8.6 Hz, 4H), 7.55 – 7.46 (m, 3H), 7.35 (t, J =2.0 Hz, 1H), 7.27 – 7.19 (m, 6H), 7.02 – 6.92 (m, 2H), 6.47 (dd, J = 16.9, 10.1Hz, 1H), 6.28 (dd, J = 17.0, 2.1 Hz, 1H), 5.78 (dd, J = 10.0, 2.1 Hz, 1H), 3.64(t, J = 5.1 Hz, 4H), 3.26 (t, J = 5.2 Hz, 4H). Example 47

[0185] Step 1: Preparation of 7-chloro-4-(3-fluoro-5-nitrophenyl)quinoline (intermediate 47-b) The operation steps were the same as the second step in the preparation of Example 1, and the product was a yellow solid (402 mg, 86%).

[0186] EI-MS: [M] +302.05. 1 H NMR (600 MHz, Chloroform- d ) δ 9.02 (d, J = 4.4 Hz,1H), 8.27 – 8.16 (m, 2H), 8.10 (dt, J = 8.2, 2.2 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.59 (dt, J = 8.0, 2.0 Hz, 1H), 7.55 (dd, J = 9.0, 2.2 Hz, 1H), 7.38 (d, J =4.4 Hz, 1H). Step 2: 4-(3-(7-chloroquinoline-4-yl)-5-nitrophenyl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 47-c) The operation steps are the same as the second step in the preparation of Example 43, and the product is a yellow solid (135 mg, 42%).

[0187] LC-MS(ESI): [M+H] + 488.20. 1 H NMR (400 MHz, DMSO- d 6) δ 9.03 (d, J = 4.4Hz, 1H), 8.64 (s, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.93 – 7.85 (m, 2H), 7.71 –7.63 (m, 2H), 7.61 (d, J = 4.4 Hz, 1H), 7.57 (t, J = 1.9 Hz, 1H), 7.48 (d, J = 7.9Hz, 2H), 7.24 (t, J = 7.7 Hz, 2H), 6.94 (t, J = 7.3 Hz, 1H), 3.68 – 3.59 (m, 4H), 3.44 (t, J = 5.0 Hz, 4H). Step 3: 4-(3-amino-5-(7-chloroquinoline-4-yl)phenyl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 47-d) The operation steps are the same as the third step in the preparation of Example 43, and the product is a brown solid (88 mg, 94%).

[0188] LC-MS(ESI): [M+H] + 458.20. 1 H NMR (400 MHz, DMSO- d 6) δ 9.07 (d, J = 4.8Hz, 1H), 8.69 (s, 1H), 8.24 (dd, J = 8.5, 1.2 Hz, 1H), 8.04 (dd, J = 8.6, 1.4 Hz, 1H), 7.93 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.73 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H),7.65 (d, J = 4.7 Hz, 1H), 7.49 (dt, J = 8.6, 1.7 Hz, 2H), 7.23 (dd, J = 8.6, 7.3Hz, 3H), 6.94 (tt, J = 7.2, 1.2 Hz, 1H), 6.82 (s, 2H), 6.65 (t, J = 1.6 Hz, 1H), 3.64 (t, J = 5.1 Hz, 4H), 3.27 (t, J = 5.0 Hz, 4H). Step 4: 4-(3-Acrylamido-5-(7-chloroquinoline-4-yl)phenyl)- N Preparation of 1-phenylpiperazine-1-carboxamide (Example 47) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (54 mg, 96%).

[0189] LC-MS(ESI): [M+H] + 514.25. 1 H NMR (400 MHz, DMSO- d 6) δ 10.25 (s, 1H), 8.95 (d, J = 4.4 Hz, 1H), 8.63 (s, 1H), 8.12 (dd,J = 8.4, 1.3 Hz, 1H), 7.98 (dd, J = 8.5, 1.4 Hz, 1H), 7.81 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 7.62 (ddd, J = 8.3,6.8, 1.3 Hz, 1H), 7.50 – 7.47 (m, 3H), 7.35 (d, J = 1.6 Hz, 1H), 7.27 – 7.22(m, 2H), 6.97 – 6.91 (m, 1H), 6.89 (d, J = 1.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1Hz, 1H), 6.27 (dd, J = 17.0, 2.1 Hz, 1H), 5.77 (dd, J = 10.1, 2.1 Hz, 1H), 3.63(t, J = 5.1 Hz, 4H), 3.26 (t, J = 5.1 Hz, 4H). Example 48

[0190] Step 1: Preparation of 2-chloro-6-(3-fluoro-5-nitrophenyl)naphthalene (intermediate 48-b) The operation steps were the same as in the second step of the preparation in Example 1, and the product was a yellow solid (369 mg, 79%).

[0191] EI-MS: [M] + 301.05. 1 H NMR (600 MHz, Chloroform- d ) δ 8.29 (d, J = 2.3 Hz,1H), 7.96 (s, 1H), 7.89 – 7.82 (m, 1H), 7.81 – 7.74 (m, 3H), 7.65 (dd, J = 8.8, 2.2 Hz, 2H), 7.42 (dd, J = 8.7, 2.2 Hz, 1H). Step 2: 4-(3-(6-chloronaphthyl-2-yl)-5-nitrophenyl)- NPreparation of 1-phenylpiperazine-1-carboxamide (intermediate 48-c) The operation steps are the same as the second step in the preparation of Example 43, and the product is a yellow solid (53 mg, 16%).

[0192] LC-MS(ESI): [M+H] + 488.20. 1 H NMR (400 MHz, DMSO- d 6) δ 9.03 (d, J = 4.4Hz, 1H), 8.64 (s, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.93 – 7.85 (m, 2H), 7.71 –7.63 (m, 2H), 7.61 (d, J = 4.4 Hz, 1H), 7.57 (t, J = 1.9 Hz, 1H), 7.48 (d, J = 7.9Hz, 2H), 7.24 (t, J = 7.7 Hz, 2H), 6.94 (t, J = 7.3 Hz, 1H), 3.68 – 3.59 (m, 4H), 3.44 (t, J = 5.0 Hz, 4H). Step 3: 4-(3-amino-5-(6-chloronaphthyl-2-yl)phenyl)- N Preparation of 1-phenylpiperazine-1-carboxamide (intermediate 48-d) The operation steps are the same as the third step in the preparation of Example 43, and the product is a brown solid (80 mg, 85%).

[0193] LC-MS(ESI): [MH] - 455.15. 1 H NMR (400 MHz, DMSO- d 6) δ 8.68 (s, 1H), 8.16 (d, J = 1.8 Hz, 1H), 8.07 – 8.00 (m, 2H), 7.96 (d, J = 8.6 Hz, 1H), 7.83(dd, J = 8.5, 1.8 Hz, 1H), 7.52 (dd, J = 9.6, 7.7 Hz, 3H), 7.25 (t,J = 7.8 Hz, 2H), 6.95 (t, J = 7.4 Hz, 1H), 6.61 (t, J = 1.9 Hz, 1H), 6.53 (t, J = 1.7 Hz, 1H), 6.30 (d, J = 2.1 Hz, 1H), 5.11 (s, 2H), 3.64 (t, J = 5.1 Hz, 4H), 3.24 – 3.19 (m,4H). Step 4: 4-(3-Acrylamido-5-(6-chloronaphth-2-yl)phenyl)- N Preparation of 1-phenylpiperazine-1-carboxamide (Example 48) The procedure was performed as described in step 2 of the preparation in Example 15, and the product was a white solid (45 mg, 80%).

[0194] LC-MS(ESI): [M+H] + 511.20. 1 H NMR (400 MHz, DMSO- d 6) δ 10.25 (s, 1H), 8.95 (d, J = 4.4 Hz, 1H), 8.63 (s, 1H), 8.12 (dd, J = 8.4, 1.3 Hz, 1H), 7.98 (dd, J = 8.5, 1.4 Hz, 1H), 7.81 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 7.62 (ddd, J = 8.3,6.8, 1.3 Hz, 1H), 7.50 – 7.47 (m, 3H), 7.35 (d, J = 1.6 Hz, 1H), 7.27 – 7.22(m, 2H), 6.97 – 6.91 (m, 1H), 6.89 (d, J = 1.9 Hz, 1H), 6.45 (dd, J = 16.9, 10.1Hz, 1H), 6.27 (dd, J = 17.0, 2.1 Hz, 1H), 5.77 (dd, J = 10.1, 2.1 Hz, 1H), 3.63(t,J = 5.1 Hz, 4H), 3.26 (t, J = 5.1 Hz, 4H). Table 2. Names of products obtained in Examples 1-48 of this invention

[0195] To detect the inhibitory effect of the biaryl compounds in Examples 1-48 of this invention on TEAD transcriptional activity, relevant tests were conducted, and the specific test procedures are as follows: Experimental objective: To test the inhibitory effect of the compounds in Examples 1-48 on TEAD transcriptional activity.

[0196] Experimental instruments: centrifuge purchased from Eppendorf, CO2 incubator purchased from Thermo, biosafety cabinet purchased from Shanghai Boxun Company, pipettes purchased from Eppendorf, and ELISA reader purchased from BioTek.

[0197] Experimental Methods: A dual-luciferase reporter assay was used to test the inhibitory effect of the compounds in this study on TEAD transcriptional activity in HEK293T cells. HEK293T cells were transfected with 8×GTIIC-luciferase plasmid and pRL-CMV, which express firefly luciferase and kidney luciferase, respectively. The relative fluorescence intensity was determined by measuring the fluorescence intensity of firefly and kidney luciferase and calculating their ratio to characterize TEAD transcriptional activity. The inhibition rate of different compounds on TEAD transcriptional activity was also calculated.

[0198] The specific experimental procedure is as follows: HEK293T cells were cultured in DMEM medium containing 10% FBS and 1% penicillin-streptomycin at 37 °C and 5% CO2. HEK293T cells were seeded at a density of 3000 cells / well in 96-well plates and cultured overnight at 37 °C and 5% CO2. After cell attachment, the medium was discarded, and 50 ng of 8×GTIIC-luciferase plasmid and 0.5 ng of pRL-CMV plasmid were transfected into HEK293T cells using Lipofectamine 2000. After 4 h of transfection at 37 °C and 5% CO2, the transfection reagents were discarded, and 5 μmol / L solutions of each compound were added. A positive control (0.1‰ DMSO) and a negative control (no plasmid transfection) were also included, and the cells were cultured for another 24 h at 37 °C and 5% CO2. After discarding the culture medium, the fluorescence intensity of fireflies and sea urchins was measured on a microplate reader using the Dual-Luciferase Reporter Assay kit. The ratio between the two was calculated, and the inhibition rate of different compounds on TEAD transcriptional activity was further calculated.

[0199] Experimental data processing methods: The percentage inhibition rate of the test compound on TEAD transcriptional activity was calculated using the following formula: Relative fluorescence intensity = (fluorescence intensity of fireflies in the test group - fluorescence intensity of fireflies in the negative control group) / (fluorescence intensity of sea snails in the test group - fluorescence intensity of sea snails in the negative control group). Inhibition rate = (1 - relative fluorescence intensity of test compound / relative fluorescence intensity of positive control) × 100%.

[0200] Experimental conclusion: The above methods demonstrate that the compounds in the embodiments of this invention have a significant inhibitory effect on TEAD transcriptional activity. The percentage inhibition rate of TEAD transcriptional activity at a concentration of 5 μmol / L is shown in Table 3 below.

[0201] Table 3. Inhibition of TEAD transcriptional activity by compounds in Examples 1-48 of this invention and existing TEAD inhibitors (5 μmol / L, %) ±SD, n=3)

[0202] Furthermore, in order to verify the effects of the biaryl compounds in Examples 1-48 of this invention on... NF2 The inhibitory effect of deletion-type lung cancer cells NCI-H226 on cell proliferation was investigated, and the specific testing procedure is as follows: Experimental objective: To test the effects of compounds in Examples 1-48 on... NF2The proliferative inhibitory activity of deletion-type lung cancer cells NCI-H226.

[0203] Experimental instruments: centrifuge purchased from Eppendorf, CO2 incubator purchased from Thermo, biosafety cabinet purchased from Shanghai Boxun Company, pipettes purchased from Eppendorf, and ELISA reader purchased from BioTek.

[0204] Experimental method: CCK was used 8. Method for detecting compounds in the examples NF2 Inhibitory effect on the proliferation of deletion-type lung cancer cells NCI-H226. NCI-H226 cells were cultured in a solution containing 10% FBS and 1% penicillin. Streptomycin was cultured in RPMI-1640 medium at 37°C and 5% CO2. NCI-H226 cells were seeded at a density of 3000 / well in 96-well plates and cultured overnight at 37°C and 5% CO2. After cell attachment, different concentrations of the compound solution were added, along with negative and blank controls. The cells were then cultured for another 4 days at 37°C and 5% CO2. Afterward, 20 μL of CCK was added to each well. Add 8 reagents, vortex to mix, and continue incubation for 1.5 h. Wait for CCK... 8. After color development, the 96-well plate was placed on a microplate reader, and its absorbance was measured at a wavelength of 450 nm to calculate the cell proliferation inhibition rate.

[0205] Experimental data processing methods: The percentage inhibition rate of the compounds in the examples on the proliferation of NCI-H226 cells was calculated using the following formula: % Inhibition rate = [1 – (Test compound value – Blank control value) / (Negative control value – Blank control value)] × 100% The IC was calculated using a four-parameter nonlinear logic formula fitted with data of different concentrations and corresponding percentage inhibition rates using GraphPad Prism 8.0. 50 value.

[0206] Experimental conclusion: The above scheme demonstrates that compounds 1-48 of the embodiments shown in this invention are effective. NF2 The proliferation of deletion-type lung cancer cells NCI-H226 was significantly inhibited, with an IC50 value of [missing information]. 50 The values ​​are shown in Table 4 below.

[0207] Table 4. Inhibitory activity (IC50) of compounds in Examples 1-48 against NCI-H226 proliferation. 50 μmol / L, ±SD, n=3)

[0208] Furthermore, in order to verify and identify the covalent binding and binding site between TEAD and Example 44 of the present invention, tests 1 and 2 were conducted, and the specific test procedures are as follows: Experiment 1: Experimental objective: To verify the covalent binding of Example 44 with TEAD.

[0209] Experimental instruments: Ultimate 3000 high performance liquid chromatography system purchased from Thermo Fisher Scientific, TripleTOF 5600 mass spectrometer purchased from AB SCIEX, ACQUITY UPLC Protein BEH C4 column purchased from Waters, centrifuge and pipette purchased from Eppendorf.

[0210] Experimental methods: Purified TEAD2 222-447 Protein (20 μmol / L) was incubated overnight at 4 °C with either DMSO or a compound (20 μmol / L). After desalting, dilution, and centrifugation, the supernatant was loaded and analyzed using high-performance liquid chromatography-mass spectrometry (HPLC-MS). HPLC conditions were: buffer A (0.1% formic acid / water), buffer B (0.1% formic acid / acetonitrile), gradient elution, 15 min, flow rate 0.300 mL / min. Mass spectrometry deconvolution analysis was performed using Byonic 10.0 software, and graphs were generated using GraphpadPrism 8.0 software.

[0211] Experimental conclusion: The above methods were used to discover TEAD2. 222-447 After treatment with Example 44, the molecular weight of the protein increased by 586.50 Da, which corresponds exactly to the molecular weight of the protein covalently bound in Example 44, proving that Example 44 can covalently bind to TEAD. Its mass spectrum is shown below. Figure 1 As shown.

[0212] Experiment 2: Experimental objective: To identify the covalent binding site of Example 44 with TEAD.

[0213] Experimental instruments: The liquid chromatograph, electrospray ion trap Orbitrap mass spectrometer and vacuum centrifuge were all purchased from Thermo Fisher Scientific; the Reprosil-Pur 120 C18-AQ column was purchased from Dr. Maisch; and the centrifuge and pipettes were purchased from Eppendorf.

[0214] Experimental methods: Purified TEAD2 222-447 Protein (20 μmol / L) was incubated with the compound (20 μmol / L) overnight at 4 °C. An appropriate amount of sample was added to 6× Loading Dye, and the protein was denatured by heating in a 100 °C metal bath for 5 min, followed by SDS-PAGE. The target band was cut into 1 mm pieces. 3 The colloidal particles, after decolorization, dehydration, and reductive alkylation, were digested with trypsin or chymotrypsin at 37 °C for 16 h. Peptide extraction buffer (5% trifluoroacetic acid - 50% acetonitrile - 45% water) was added, and the mixture was incubated at 37 °C for 1 h, sonicated for 5 min, and centrifuged for 5 min. The extraction was repeated once, and the extracts were combined and dried by vacuum centrifugation. The digested peptides were desalted using a self-packed desalting column and the solvent was evaporated in a vacuum centrifuge at 45 °C. Analysis was performed using liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS). LC conditions were: buffer A (0.1% formic acid / water), buffer B (0.1% formic acid, 80% acetonitrile), gradient elution, 66 min, flow rate 600 nL / min. Raw mass spectrometry data were processed using PEAKS Studio 10.6 software, and the target protein was searched in a database.

[0215] Experimental conclusion: The above methods were used to discover TEAD2. 222-447 After treatment with Example 44, the protein showed an additional modification of cysteine ​​residue 380 with a molecular weight of 586.25 Da, which corresponds exactly to the molecular weight covalently bound in Example 44, demonstrating that Example 44 can bind to TEAD2. 222-447 The protein is covalently bound to cysteine ​​residue 380, and its secondary mass spectrum is shown below. Figure 2 As shown.

[0216] Furthermore, in order to detect the inhibitory effect of the compounds in the embodiments of the present invention on TEAD palmitoylation, relevant tests were conducted, and the specific test procedures are as follows: Experimental objective: To test the inhibitory effect of Example 44 on TEAD palmitoylation.

[0217] Experimental instruments: pipettes were purchased from Eppendorf, and electrophoresis apparatus, semi-dry transfer apparatus and chemiluminescence imaging system were purchased from Bio-Rad.

[0218] Experimental methods: Use purified 6×His-TEAD2 217-447 The following is an in vitro palmitoylation inhibition experiment of the protein: Experimental group: compound (6-4500 nmol / L) + 6×His-TEAD2 217-447 (400 nmol / L) Control group ×2: DMSO + 6×His-TEAD2 217-447 (400 nmol / L) The experimental and control groups were incubated at room temperature for 2 h. One control group and all experimental groups were given 1.5 μmol / L of alkyne-coupled palmitoyl-CoA, while another control group received an equal volume of buffer as a blank control. All were incubated on ice for 30 min. Click Reaction reagents were added: Biotin-azide (100 μmol / L), TBTA (100 μmol / L), CuSO4 (1 mmol / L), and TCEP (1 mmol / L). Incubation was continued at room temperature for 1 h. The reaction was terminated by adding 6×Loading Dye containing 30 mmol / L EDTA, and the protein was denatured by heating in a 100 °C metal bath for 5 min, followed by SDS-PAGE. Western blotting was used to detect the total protein content and palmitoylation status (primary antibody: Anti-His tag, Anti-Biotin). ImageJ software was used to statistically analyze the band gray values, and Graphpad Prism 8.0 software was used to fit the data for different concentrations and corresponding percentage inhibition rates to a four-parameter nonlinear logic formula to calculate the IC50. 50 value.

[0219] Experimental conclusion: The above methods demonstrate that Example 44 of this invention has a significant inhibitory effect on TEAD palmitoylation, with an IC50 value of [missing information]. 50 The value is 155 nmol / L, and its imprinted bands and fitting curves are as follows: Figure 3 As shown.

[0220] Furthermore, in order to test the inhibitory ability of the compounds in the embodiments of the present invention on the YAP-TEAD interaction, relevant tests were conducted, and the specific test procedures are as follows: Experimental objective: To test the inhibitory ability of Example 44 on YAP-TEAD interaction.

[0221] Experimental instruments: Centrifuges and pipettes were purchased from Eppendorf, CO2 incubators were purchased from Thermo, biosafety cabinets were purchased from Shanghai Boxun, and electrophoresis apparatus, semi-dry transfer apparatus and chemiluminescence imaging system were purchased from Bio-Rad.

[0222] Experimental methods: Purified 6×His-TEAD2 217-447 The protein was subjected to a YAP-TEAD pull-down assay based on Ni-NTA affinity chromatography as follows: Experimental group: compound (0.16-10 μmol / L) + 6×His-TEAD2 217-447 (1 μmol / L) Control group: DMSO + 6×His-TEAD2 217-447 (1 μmol / L) The experimental and control groups were incubated at room temperature for 2 h, followed by incubation with Ni-NTA agarose gel at 4 °C with shaking for 30 min. Simultaneously, MDA-MB-231 cells were cultured in DMEM medium containing 10% FBS and 1% penicillin-streptomycin at 37 °C and 5% CO2 until confluent. MDA-MB-231 cells were harvested with RBC lysis buffer containing 10 mmol / L imidazole, lysed with shaking at room temperature for 10 min, centrifuged at 13000 rpm for 20 min, and the supernatant was collected. Equal volumes of the cell lysis supernatant were added to the experimental and control groups, and incubated with shaking at 4 °C for 2 h. The experimental and control groups were then added to chromatography columns, washed three times with equal volumes of RBC lysis buffer containing 10 mmol / L imidazole, and eluted with equal volumes of RBC lysis buffer containing 250 mmol / L imidazole. 6× Loading Dye was added, and the cells were heated in a 100 °C metal bath for 5 min to denature the proteins before SDS-PAGE. Western blot analysis was used to detect 6×His-TEAD2. 217-447 The total amount of protein and the amount of protein binding to YAP (primary antibody: Anti-His tag, Anti-YAP). Image J software was used to statistically analyze the grayscale values ​​of the bands. Graphpad Prism 8.0 software was used to fit data for different concentrations and corresponding percentage inhibition rates to a four-parameter nonlinear logic formula to calculate the IC50. 50 value.

[0223] Experimental conclusion: The above methods demonstrate that Embodiment 44 of the present invention has a significant inhibitory effect on YAP-TEAD interaction, and its IC 50 The value was 1.22 μmol / L, and its imprinted bands and fitting curves are as follows: Figure 4 As shown.

[0224] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A biaryl compound, characterized in that, The compound has the structure shown in general formula (I), general formula (II) or general formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 、 、 ； in: R 1 It is selected from one of hydrogen, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxyl, substituted or unsubstituted amide, and substituted or unsubstituted sulfonamide. R 2 It is selected from one of hydrogen, hydroxyl, carboxyl, acrylamide, and C1-C6 alkoxy groups; R 3 Selected from hydrogen and substituted or unsubstituted phenoxy groups; R 4 It is selected from hydrogen, halogen, and substituted or unsubstituted phenoxy groups; R 5 Selected from hydrogen or halogen; R 6 -R 8 Independently selected from hydrogen, alkoxy, and alkyl or substituted amide groups; Ring A is independently selected from one of substituted phenyl, substituted naphthyl, and substituted quinolinyl groups; Ring B is independently selected from one of substituted or unsubstituted phenyl, pyridyl, substituted pyrazolyl, furanyl, and thiophenyl groups; The molecular structure of the general formula (I), general formula (II) or general formula (III) contains a biaryl skeleton and has at least one end connected to a pharmacophore that can bind to the TEAD protein, wherein the pharmacophore is selected from a carboxyl group, a sulfonamide group or an acrylamide group.

2. A biaryl compound according to claim 1, characterized in that, For R 1 The substituted alkoxy group is a C1-C6 alkyl-substituted alkoxy group; the substituted carboxyl group is a C1-C6 alkyl-substituted carboxyl group; the substituted amide group is... Ra is selected from substituted or unsubstituted C4-C8 heterocyclic groups, Rb is selected from substituted or unsubstituted aryl groups, and the substituted sulfonamide group is a C1-C6 alkyl-substituted sulfonamide group; For R 2 The C1-C6 alkoxy group is preferably methoxy; For R 3 The substituted phenoxy group, wherein the substituent is preferably a C1-C6 haloalkyl group; For R 4 For substituted phenoxy groups, the substituents are preferably C1-C6 haloalkyl groups.

3. A biaryl compound according to claim 1, characterized in that, For R 6 -R 8 The alkoxy group is methoxy, the alkyl group is methyl, and the substituted amide group is... Ra is selected from substituted or unsubstituted C4-C8 heterocyclic groups, and Rb is selected from substituted or unsubstituted aryl groups.

4. A biaryl compound according to claim 1, characterized in that, For ring A, the substituted phenyl group is substituted by one or two substituents selected from fluorine or substituted phenoxy groups.

5. A biaryl compound according to claim 1, characterized in that, For ring B, the nitrogen atom of the substituted pyrazolyl group is optionally replaced by a C1-C4 alkyl or acryloyl group.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a biaryl compound as described in any one of claims 1 to 5, and one or more pharmaceutically acceptable carriers, diluents, or excipients; the pharmaceutical composition is prepared into tablets, capsules, soft capsules, or injections by adding excipients to a biaryl compound as described in any one of claims 1 to 5; the excipients include one or more of additives, stabilizers, solubilizers, lubricants, and disintegrants.

7. The use of a biaryl compound according to any one of claims 1 to 5 and the pharmaceutical composition according to claim 6 in the preparation of TEAD inhibitor drugs and / or drugs that inhibit TEAD-YAP protein-protein interactions.

8. The use of a biaryl compound according to any one of claims 1 to 5 and / or the pharmaceutical composition according to claim 6 in the preparation of cancer drugs.

9. The use of a biaryl compound and / or pharmaceutical composition according to claim 8 in the preparation of cancer drugs, characterized in that, The cancers mentioned include any one of the following: breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, stomach cancer, kidney cancer, ovarian cancer, uterine cancer, prostate cancer, mesothelioma, glioma, myelodysplastic syndrome, acute myeloid leukemia, and colorectal cancer.

10. A method for preparing a biaryl compound according to any one of claims 1 to 5, characterized in that, Includes the following steps: S1: A biaryl skeleton intermediate is prepared by coupling a halophenol derivative with an arylboronic acid or its ester under a metal catalysis. S2: The biaryl skeleton intermediate is functionalized by any one of hydrolysis, esterification, reduction or amination to obtain a biaryl derivative containing carboxylic acid, amino or hydroxyl groups. S3: The obtained biaryl derivative containing carboxylic acid is subjected to an amidation condensation reaction with a nitrogen-containing heterocyclic compound or an aromatic amine compound in the presence of a condensing agent to obtain a biaryl compound represented by general formula (I) or general formula (II); S4: The obtained biaryl derivative containing an amino group is subjected to an amidation reaction with acryloyl chloride, or directly subjected to a Michael addition reaction with an acrylic acid derivative, to obtain a biaryl compound represented by general formula (II) or general formula (III).

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