CN115260165B

CN115260165B - Benzo nitrogen-containing five-membered heterocyclic compound and synthesis and application thereof

Info

Publication number: CN115260165B
Application number: CN202210426932.7A
Authority: CN
Inventors: 赵玉军; 李志强; 严子琴; 李亚芳; 吕细林; 周飞龙
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2021-04-29
Filing date: 2022-04-21
Publication date: 2024-08-06
Anticipated expiration: 2042-04-21
Also published as: CN115260165A

Abstract

The structure of the compound is shown in a general formula I, and the definition of each substituent is as described in the specification and the claims. The compound can competitively inhibit interaction of nuclear transcription factor TEAD and co-activator YAP protein thereof, and can be used for preventing and/or treating related diseases mediated by nuclear transcription factor TEAD, especially cancers and drug resistance of antitumor drugs.

Description

Benzo nitrogen-containing five-membered heterocyclic compound and synthesis and application thereof

Technical Field

The invention belongs to the field of medicine synthesis, and in particular relates to a compound with a benzo nitrogen-containing five-membered heterocyclic structure, a stereoisomer, an enantiomer or pharmaceutically acceptable salt thereof, a preparation method and application thereof.

Background

Functions of the Hippo signaling pathway include regulation of tissue organ size, regulation of cell proliferation, survival and differentiation, influencing the development and regeneration processes of the tissue, and its role is of paramount importance. The Hippo signaling pathway is regulated by a complex cascade of kinases whose core node includes the nuclear transcription factor TEAD and its cofactors YAP/TAZ. In the resting state of the cell, the kinase LATS1/2 phosphorylates YAP/TAZ to promote degradation of YAP/TAZ by the proteasome or to promote its binding to 14-3-3 in the cytoplasm and not into the nucleus. After kinase dysfunction of LATS1/2, the unphosphorylated YAP/TAZ is significantly elevated and enters the nucleus, binds to the nuclear transcription factor TEAD protein to initiate expression of downstream genes (CTGF, cyr61, axl, etc.), and promotes proliferation and growth of cells.

Studies have shown that YAP levels in cancer cells are abnormally elevated compared to normal cells, TEAD-mediated overactivation of gene transcription, characteristics closely related to overgrowth of tumor cells. In addition, YAP-over-expression-dependent cancer cells exhibit resistance to traditional oncology drugs.

YAP has no domain that directly binds DNA and regulates gene transcription through direct interaction with TEAD. The prior studies have clearly demonstrated that protein interactions that block TEAD/YAP in tumor cells have anti-tumor activity. First, in cells and animal models, the TEAD2-DN (dominant negative) protein which does not have a DNA binding domain but has a YAP binding domain is overexpressed, so that the interaction between wild-type TEAD and YAP proteins in cells can be competitively blocked, and liver cancer formation induced by the overexpression of YAP can be inhibited in mice. Second, the endogenous protein TEAD4-s is the TEAD4 protein N-terminal cutter. TEAD4-s has the ability to bind YAP proteins despite the lack of a domain that binds DNA. The intracellular high expression TEAD4-s can block the combination of YAP and full-length TEAD, inhibit the growth and metastasis of tumors, and show anti-tumor curative effect in a mouse transplanted tumor model. Third, endogenous proteins VgLL4 and YAP competitively bind TEAD, and the interface between the two binding TEAD partially overlaps. Clinical high-expression VgLL4 gastric cancer patients have higher 5-year survival rate, one of the important reasons is that intracellular VgLL4 is combined with TEAD, the quantity of TEAD/YAP dimer is competitively reduced, and the TEAD/YAP mediated gene expression level is inhibited. The biological research shows that the competitive blocking of TEAD/YAP protein interaction in tumor cells, the reduction of the quantity of wild TEAD/YAP dimers in cells, the inhibition of TEAD-mediated gene transcription, and the expression of anti-tumor effect are one of the research directions of drug development hot spots.

The reported compounds CPD3.1(Smith et al.,2019,J Med Chem 62,1291-1305),TEAD-347(Bum-Erdene et al.,2019,Cell Chem Biol 26,378-389),Verteporfin(Liu-Chittenden et al.,2012,Gene Dev 26,1300-1305) in the literature are capable of blocking TEAD/YAP protein interactions in cells and exhibit certain antitumor activity. In the patent, the compounds with different structures, such as WO2019232216, WO2020097389 (A1) and WO2020243415A2, are reported to have the function of blocking TEAD/YAP protein interaction and have potential in treating related diseases.

Disclosure of Invention

The invention aims to provide a compound for inhibiting interaction of TEAD and YAP/TAZ.

In a first aspect of the present invention, there is provided a compound of formula (I), a stereoisomer, an enantiomer thereof, or a pharmaceutically acceptable salt thereof:

Wherein R _a is selected from the group consisting of: a hydrogen atom, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy;

each of a ₁、A₂、A₃、A₄ and a ₅ is independently represented as CR _b or N, wherein R _b is independently selected from the group consisting of: a hydrogen atom, halogen, cyano, nitro, hydroxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, -NR ₁R₂、-CO₂R₃, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 cycloalkenyl, substituted or unsubstituted C5-C8 heterocycloalkyl, substituted or unsubstituted C5-C8 heterocycloalkenyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-8 membered heteroaryl; or two adjacent R _b groups form a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group with the attached carbon atom; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, nitro, hydroxy, carboxy, cyano, C1-C4 alkyl, C1-C4 alkoxy, -NR ₄R₅;

Under the condition of valence bond permission, each Independently a double bond or a single bond;

X, Y, Z, under valence bond permitting conditions, are each independently CR _c or NR _d, and form a five-membered heteroaromatic ring with two carbon atoms of the benzene ring;

R _c is independently selected from the following group at each occurrence under valence bond approval: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a carboxyl group, -CONH- (C1-C6 alkylene) Re, Substituted or unsubstitutedWherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, oxo groupHydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, 5-8 membered heteroaryl 、-(CH₂)_m1-CO₂R₆、-(CH₂)_m2-SO₃R₇、-SO₂NR₈R₉、-NR₈R₉、-NHCOC1-C6 alkyl;

Ar ₁ is selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-8 membered cycloalkyl, substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl 、-(CH₂)_m3-CO₂R₁₀、-CONR₁₁R₁₂、-SO₂NR₁₃R₁₄、-(CH₂)_m4-SO₃R₁₅、C1-C4 alkyl, C1-C4 alkoxy;

R _e is selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO ₂OR₁₅, oxo group Hydroxy, methanesulfonyl, trifluoromethyl, - (CH ₂)_m5-CO₂R₁₆;

ar ₂ is selected from the group consisting of: a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl 、-(CH₂)_m6-CO₂R₁₇、-CONR₁₈R₁₉、-SO₂NR₂₀R₂₁、-(CH₂)_m7-SO₃R₂₂、C1-C4 alkyl, C1-C4 alkoxy;

R _f is selected from: substituted or unsubstituted C1-C6 alkyl, carboxyl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, nitro;

Ar ₃ is selected from the group consisting of: a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;

E ₁ is NR ₃₃ or O; e ₂ is NR ₃₁R₃₂ OR OR ₃₄;

Ar ₄ is selected from the group consisting of: a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl 、-(CH₂)_m8-CO₂R₂₃、-CONR₂₄R₂₅、-SO₂NR₂₆R₂₇、-(CH₂)_m9-SO₃R₂₈、C1-C4 alkyl, C1-C4 alkoxy;

R _d is independently selected from the following group at each occurrence under valence license: absent, hydrogen atom, substituted or unsubstituted C1-C6 alkyl group, Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, - (CH ₂)_m8-CO₂R₂₃, cyano, nitro, hydroxy, oxo group)-NH ₂, methanesulfonyl, sulfonic acid, sulfamoyl, (C1-C4) alkoxy, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;

Ar ₅ is selected from the group consisting of: a substituted or unsubstituted C6-C10 aryl, a substituted or unsubstituted 5-8 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl 、-(CH₂)_m10-CO₂R₂₉、-CONR₃₀R₃₁、-SO₂NR₃₂R₃₃、-(CH₂)_m11-SO₃R₃₄、C1-C4 alkyl, C1-C4 alkoxy;

at each occurrence, R ₁-R₃₄ is independently selected from a hydrogen atom or a C1-C4 alkyl group;

n1 is 0, 1,2, 3 or 4;

n2 is 0, 1 or 2;

n3 is 0, 1 or 2;

n4 is 1,2 or 3;

m1 to m11 are each independently 0,1 or 2.

In the present invention, R ₁-R₆ means R ₁、R₂、R₃、R₄、R₅、R₆, and so on. m1-m5 are m1, m2, m3, m4, m5, and so on.

In the present invention, the halogen is F, cl, br or I.

In the present invention, the pharmaceutically acceptable salt of the present invention may be a salt of an anion with a positively charged group on a compound of formula I. Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methylsulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts may be formed from cations with negatively charged groups on the compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, such as tetramethylammonium.

In another preferred embodiment, "pharmaceutically acceptable salt" refers to the salt of a compound of formula I with an acid selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalacetic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid, and the like; or a sodium, potassium, calcium, aluminum or ammonium salt of a compound of formula I with an inorganic base; or the methylamine salt, ethylamine salt or ethanolamine salt of the compound of the formula I with an organic base

In another preferred embodiment, the C5-C8 heterocycloalkenyl structure isM is an oxygen atom (O) or-NH-; j. k are each independently integers from 1 to 4, and j+k=2, 3, 4 or 5.

In another preferred embodiment, ra is H.

In another preferred embodiment, the compound has a structure represented by formula (I-1):

Wherein R _z1 is selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, carboxy, cyano, nitro, amino, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;

ar ₆ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: nitro, halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl 、-(CH₂)_m12-CO₂R₃₅、-CONR₃₆R₃₇、-SO₂NR₃₈R₃₉、-(CH₂)_m13-SO₃R₄₀、C1-C3 alkyl, C1-C3 alkoxy;

r _x1 is selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, -CONH- (C1-C6 alkylene) Re,Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano;

Ar ₇ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 4-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl 、-(CH₂)_m14-CO₂R₄₁、-CONR₄₂R₄₃、-SO₂NR₄₄R₄₅、-(CH₂)_m15-SO₃R₄₆、C1-C4 alkyl, C1-C4 alkoxy;

R _h is selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO ₂OR₁₅, oxo group Hydroxy, - (CH ₂)_m16-CO₂R₄₇);

Ar ₈ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl 、-(CH₂)_m17-CO₂R₄₈、-CONR₄₉R₅₀、-SO₂NR₅₁R₅₂、-(CH₂)_m18-SO₃R₅₃、C1-C4 alkyl, C1-C4 alkoxy;

R _i is selected from substituted or unsubstituted C1-C6 alkyl, carboxyl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, nitro;

ar ₉ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;

Ar ₁₀ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl 、-(CH₂)_m19-CO₂R₅₄、-CONR₅₅R₅₆、-SO₂NR₅₇R₅₈、-(CH₂)_m20-SO₃R₅₉、C1-C4 alkyl, C1-C4 alkoxy;

R ₃₅-R₅₉ is independently selected from a hydrogen atom or a C1-C4 alkyl group;

n5 is 1, 2 or 3; n6 is 1, 2 or 3; n7 is0, 1, 2,3 or 4;

n8 is 0, 1 or 2; n9 is 0, 1 or 2;

m12 to m20 are each independently 0, 1 or 2;

R_a、Re、Ar₅、n4、A₁、A₂、A₃、A₄、A₅、E₁、E₂ The definition is the same as before.

In another preferred embodiment, the compound has the structure of formula (I-2):

Wherein R _y1 is

Ar ₁₁ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl 、-(CH₂)_m21-CO₂R₆₀、-CONR₆₁R₆₂、-SO₂NR₆₃R₆₄、-(CH₂)_m22-SO₃R₆₅、C1-C3 alkyl, C1-C3 alkoxy;

r ₆₀-R₆₅ is independently selected from a hydrogen atom or a C1-C4 alkyl group;

n10 is 0,1, 2 or 3;

m21, m22 are each independently 0, 1 or 2;

r _a、A₁、A₂、A₃、A₄、A₅ is as defined above.

In another preferred embodiment, the compound has a structure represented by formula (I-3):

wherein R _a、A₁、A₂、A₃、A₄、A₅ is as defined above;

represents a single bond or a double bond, wherein the carbon atom to which R _y2 is attached cannot participate simultaneously in forming two double bonds;

One of R _x2 and R _z2 is absent and the other is H, A substituted or unsubstituted C1-C6 alkyl group; ar ₁₂ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl 、-(CH₂)_m23-CO₂R₆₆、-CONR₆₇R₆₈、-SO₂NR₆₉R₇₀、-(CH₂)_m24-SO₃R₇₁、C1-C4 alkyl, C1-C4 alkoxy, 5-to 6-membered heteroaryl, 3-to 8-membered heterocyclyl, -NH ₂, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;

R _y2 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Ar ₁₃ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: oxo groupHalogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl 、-(CH₂)_m25-CO₂R₇₂、-CONR₇₃R₇₄、-SO₂NR₇₅R₇₆、-(CH₂)_m26-SO₃R₇₇、C1-C4 alkyl, C1-C4 alkoxy, 5-6 membered heteroaryl, 3-8 membered heterocyclyl, -NH ₂, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino, -NHCOC1-C4 alkyl;

R ₆₆-R₇₇ is independently selected from a hydrogen atom or a C1-C4 alkyl group;

n11 is 0,1, 2 or 3; n12 is 0,1, 2 or 3; m23 to m26 are each independently 0,1 or 2.

In another preferred embodiment, a ₁、A₂、A₃、A₄ and a ₅ are each independently represented as CR _b or N, wherein R _b is each independently selected from the group consisting of: a hydrogen atom, halogen, cyano, nitro, hydroxy, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy, -NR ₁R₂、-CO₂R₃, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C5-C6 cycloalkenyl, substituted or unsubstituted C5-C8 heterocycloalkyl, substituted or unsubstituted C5-C6 heterocycloalkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; or adjacent two R _b and attached carbon atoms form a substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, nitro, hydroxy, carboxy, cyano, C1-C4 alkyl, C1-C4 alkoxy, -NH ₂, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;

At each occurrence, R ₁、R₂、R₃ is independently selected from a hydrogen atom or a C1-C4 alkyl group.

In another preferred embodiment X, Y, Z is each independently CR _c or NR _d and forms a five membered heteroaromatic ring with two carbon atoms of the benzene ring;

R _c is independently selected from the following group at each occurrence under valence bond approval: a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group, a carboxyl group, -CONH- (C1-C6 alkylene) Re, Substituted or unsubstitutedWherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, oxo groupHydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl, 5-6 membered heteroaryl 、-(CH₂)_m1-CO₂R₆、-(CH₂)_m2-SO₃R₇、-SO₂NR₈R₉、-NR₈R₉、-NHCOC1-C4 alkyl;

Ar ₁ is selected from the group consisting of: substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl 、-(CH₂)_m3-CO₂R₁₀、-CONR₁₁R₁₂、-SO₂NR₁₃R₁₄、-(CH₂)_m4-SO₃R₁₅、C1-C4 alkyl, C1-C4 alkoxy;

R _e is selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C4 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted 5-6 membered heteroaryl group; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, -SO ₂OR₁₅, oxo group Hydroxy, methanesulfonyl, trifluoromethyl, - (CH ₂)_m5-CO₂R₁₆;

ar ₂ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl 、-(CH₂)_m6-CO₂R₁₇、-CONR₁₈R₁₉、-SO₂NR₂₀R₂₁、-(CH₂)_m7-SO₃R₂₂、C1-C4 alkyl, C1-C4 alkoxy;

R _f is a substituted or unsubstituted C1-C4 alkyl or carboxyl group; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, nitro;

Ar ₃ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;

Ar ₄ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, methanesulfonyl, trifluoromethyl 、-(CH₂)_m8-CO₂R₂₃、-CONR₂₄R₂₅、-SO₂NR₂₆R₂₇、-(CH₂)_m9-SO₃R₂₈、C1-C4 alkyl, C1-C4 alkoxy;

R _d is independently selected from the following group at each occurrence under valence license: absent, hydrogen atom, substituted or unsubstituted C1-C4 alkyl group, Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, - (CH ₂)_m8-CO₂R₂₃, cyano, nitro, hydroxy, oxo group)-NH ₂, methanesulfonyl, sulfonic acid, sulfamoyl, (C1-C4) alkoxy, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;

Ar ₅ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methanesulfonyl, trifluoromethyl 、-(CH₂)_m10-CO₂R₂₉、-CONR₃₀R₃₁、-SO₂NR₃₂R₃₃、-(CH₂)_m11-SO₃R₃₄、C1-C4 alkyl, C1-C4 alkoxy;

r ₁-R₃₄、n1-n4、m1-m11、E₁、E₂ is as defined above.

In another preferred embodiment, the compound is selected from any of the compounds listed in the tables of the examples.

In a second aspect of the invention there is provided a pharmaceutical composition comprising a compound according to the first aspect, a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In a third aspect of the invention there is provided the use of a compound according to the first aspect, a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as in the second aspect, for the preparation of a TEAD and YAP interaction inhibitor; or for the preparation of a medicament for the prevention and/or treatment of nuclear transcription factor TEAD mediated related diseases; or for non-therapeutic reversal of tumor cell resistance to anti-tumor drugs; or for the preparation of a medicament for reversing the resistance of tumor cells to an anti-tumor drug.

In another preferred embodiment, the TEAD and YAP interaction inhibitor is for use in the prevention and/or treatment of cancer.

In another preferred embodiment, the nuclear transcription factor tea mediated related disease is cancer.

In another preferred embodiment, the cancer is selected from: multiple myeloma, squamous cell carcinoma, breast cancer, colon cancer, gastric cancer, non-small cell lung cancer, and ovarian cancer.

In another preferred embodiment, the compound, stereoisomer, enantiomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition is used to block TEAD/YAP1 protein interactions.

In another preferred embodiment, the compound, stereoisomer, enantiomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition is used for preparing a medicament for treating cancer.

In another preferred embodiment, the compound, its stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition is used for preparing a medicament for treating gastric cancer.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.

Drawings

FIG. 1 shows the inhibition of CYR61, CTGF, CDX2 gene expression by compounds, wherein VP represents positive compound Verteporfin, QJ68 is the compound of example 4, and DMSO is a blank group without compound.

FIG. 2 shows the inhibition of CYR61, CTGF, CDX2 gene expression by compounds, wherein VP represents positive compound Verteporfin, QJ156 is the compound of example 30, QK3 is the compound of example 31, and DMSO is a blank group without compound.

FIG. 3 shows the inhibition of CTGF gene expression by compounds wherein VP represents positive compound Verteporfin, LYA95 is the compound of example 86, LYA102 is the compound of example 87, and DMSO is a blank group without compound.

FIG. 4 shows the inhibition of CYR61, CDX2 gene expression by compounds, wherein VP represents positive compound Verteporfin, FC3-2 is the compound of example 97, and DMSO is a blank group without compound.

Detailed Description

The inventors of the present invention have conducted intensive studies for a long time and have unexpectedly found that the compounds of the present invention are capable of inhibiting TEAD/YAP1 interaction, regulating TEAD-mediated gene expression in tumor cells, and thus can be used for inhibiting diseases associated with TEAD/YAP1 interaction, such as the prevention and treatment of cancer. Based on the above findings, the inventors have completed the present invention.

Synthesis method

1. Synthesis method of compound intermediates S1 and S1a

The method comprises the following steps: a method for synthesizing the compound S1.

1) In a proper solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water and the like), under the action of a proper palladium catalyst (such as Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C and the like) and alkali (such as Na ₂CO₃、K₂CO₃、NaOH、Et₃ N and the like), using the compound S2 and the compound S3 as raw materials, and carrying out a Suzuki coupling reaction to obtain a compound S4;

2) Reacting the compound S4 with hydrazine hydrate under a proper solvent (such as n-butanol) and a proper reaction temperature (such as oil bath heating reflux and microwave heating reflux) to generate a compound S1;

Wherein a3=cr _b;R_b is a monosubstituted group such as an F atom, a chlorine atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, etc.;

r represents OH, or two R together with the linking B atom represent pinacol borate, -BF ₃ K or the like can be used for generating a boric acid derivative of Suzkuki coupling reaction of S3.

Ra, rb, A1, A2, A3, A4, A5 are as defined above.

In the general formula S1, the intermediate S1a is described as represented by a3=cr _b. In a specific implementation process, the synthesis method of S1 and S1a is also applicable to any one unit of A1/A2/A4/A5 to represent CR _b.

The second method is as follows: a method for synthesizing the compound S1 a.

1) In a proper solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water and the like), under the action of a proper palladium catalyst (such as Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C and the like) and alkali (such as Na ₂CO₃、K₂CO₃、NaOH、Et₃ N and the like), taking a compound S5 containing an R _b group and a compound S6 as raw materials, and carrying out a Suzuki coupling reaction to obtain a compound S7;

2) Reacting compound S7 with pinacol ester of biboronate in a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water, etc.) under the action of a suitable palladium catalyst (e.g., Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C, etc.) and a base (e.g., na ₂CO₃、K₂CO₃、NaOH、Et₃ N, etc.), to give compound S8;

3) In a proper solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water and the like), under the action of a proper palladium catalyst (such as Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C and the like) and alkali (such as Na ₂CO₃、K₂CO₃、NaOH、Et₃ N and the like), taking a compound S8 and a compound S2 as raw materials, and carrying out a Suzuki coupling reaction to obtain a compound S9;

4) Reacting compound S9 with hydrazine hydrate in a suitable solvent (such as n-butanol) to form compound S1a;

wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above;

The definition of R is identical to that of method one.

And a third method: a method for synthesizing the compound S9.

1) Reacting compound S2 with pinacol biborate in a suitable solvent (e.g., 1, 4-dioxane) under the action of a palladium catalyst (e.g., pd (dppf) Cl ₂-CH₂Cl₂) to give compound S10;

2) Compound S9 can also be prepared by Suzuki coupling reaction starting from compound S7 and compound S10 in a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water, etc.) under the action of a suitable palladium catalyst (e.g., Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C, etc.) and a base (e.g., na ₂CO₃、K₂CO₃、NaOH、Et₃ N, etc.);

wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above.

The method four: a method for synthesizing the compound S9.

1) Compound S10 and compound S11 are used as raw materials in a proper solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water and the like) under the action of a proper palladium catalyst (such as Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C and the like) and alkali (such as Na ₂CO₃、K₂CO₃、NaOH、Et₃ N and the like), and compound S12 is obtained through a Suzuki coupling reaction;

2) Compound S9 can also be prepared by Suzuki coupling reaction starting from compound S12 and R _b -containing compound S5 in a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water, etc.) under the action of a suitable palladium catalyst (e.g., Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C, etc.) and a base (e.g., na ₂CO₃、K₂CO₃、NaOH、Et₃ N, etc.);

wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above;

The definition of R is identical to that of method one.

And a fifth method: a method for synthesizing the compound S9.

1) Compound S12 is obtained by Suzuki coupling reaction of compound S2 and compound S13 as raw materials in a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water, etc.) under the action of a suitable palladium catalyst (e.g., Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C, etc.) and a base (e.g., na ₂CO₃、K₂CO₃、NaOH、Et₃ N, etc.);

2) Compound S9 can also be prepared by Suzuki coupling reaction of compound S12 with R _b -containing compound S5 in a suitable solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water, etc.) under the action of a suitable palladium catalyst (e.g., Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C, etc.) and a base (e.g., na ₂CO₃、K₂CO₃、NaOH、Et₃ N, etc.);

wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above;

The definition of R is identical to that of method one.

The method six: a method for synthesizing the compound S1 a.

1) Reacting the compound S2 with hydrazine hydrate under a proper solvent (such as n-butanol) and a proper reaction temperature (such as oil bath heating reflux and microwave heating reflux) to generate a compound S14;

2) In a proper solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water and the like), under the action of a proper palladium catalyst (such as Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C and the like) and a base (such as Na ₂CO₃、K₂CO₃、NaOH、Et₃ N and the like), carrying out Suzuki coupling reaction on the compound S14 and the compound S8 to obtain a compound S1a;

wherein Ra, rb, A1, A2, A3, A4 and A5 are as defined above.

2. Synthetic methods for the end product I-1 include, but are not limited to, methods seven, eight, nine, ten, eleven.

And a seventh method:

1) Compound I-1a is obtained by reductive amination of compound S1a and compound S21 as starting materials in a suitable solvent (1, 2-dichloroethane) under the action of a suitable reducing agent (e.g., naBH (OAc) ₃、NaBH₃CN、NaBH₄、BH₃);

2) In a proper solvent (tetrahydrofuran/methanol/water), the reductive amination product I-1a is hydrolyzed by proper alkali (LiOH or NaOH, etc.), so as to obtain a final product I-1;

Wherein step2 is performed only when the unhydrolyzed carboxylate is contained in I-1 a;

r _s1 is selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, Wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano;

Ar _s1 is selected from the group consisting of substituted and unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano 、-(CH₂)_q1-CO₂R_t1、-CONR_t2R_t3、-SO₂NR_t4R_t5、-(CH₂)_q2-SO₃R_t6、 trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;

Ar _s2 is selected from the group consisting of substituted and unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy;

R _s2 is selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, nitro;

W _s、V_s is N or O respectively; when W _s or V _s is not completely substituted, filling with hydrogen atoms;

R _t1-R_t6 is independently a hydrogen atom or a C1-C4 alkyl group;

p1 is 0,1, 2 or 3;

q1, q2 are each independently 0, 1 or 2;

Ra, rb, A1, A2, A3, A4, A5, rx1, rz1 are as defined above.

Method eight:

1) In a proper solvent (methanol/water), the compound S1a and the compound S22 undergo a metal-catalyzed C-N coupling reaction to generate a compound I-1C;

2) In a proper solvent (tetrahydrofuran/methanol/water), the compound I-1c is hydrolyzed by proper alkali (LiOH or NaOH, etc.), so as to obtain a final product I-1;

Wherein step2 is performed only when the unhydrolyzed carboxylate is contained in I-1 c;

Ar _s3 is selected from the group consisting of substituted and unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, amino, cyano, carboxy, nitro, trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy;

Ra, rb, A1, A2, A3, A4, A5, R _x1、R_z1 are as defined above.

Method nine:

1) Reacting compound S1a with Boc ₂ O in a suitable solvent (tetrahydrofuran) under the action of a base (e.g., DMAP, et ₃ N) to form compound S23;

2) Reacting compound S23 with acylating agent S24 in an appropriate solvent (dichloromethane) under the action of a base (e.g., DMAP, et ₃ N) to form compound S25;

3) Reacting compound S25 with trifluoroacetic acid in a suitable solvent (dichloromethane) to form compound S26;

4) In a proper solvent (tetrahydrofuran/methanol/water), the compound S26 is hydrolyzed by proper alkali (LiOH or NaOH, etc.), and the final product I-1 is obtained;

wherein LG ₁ is a leaving atom or group such as chlorine atom, bromine atom, iodine atom, OTf, OSu, etc.;

R _s3 is a substituted or unsubstituted C1-C6 alkyl group; wherein said substitution means substitution with one or more groups selected from the group consisting of: oxo group Hydroxy, amino, carboxyl, cyano, nitro;

Ra, rb, A1, A2, A3, A4, A5, R _x1、R_z1 are as defined above.

Method ten:

1) Reacting compound S1a with S27 in a suitable solvent (N, N-dimethylformamide) under the action of a suitable base (e.g., liHMDS, naH, K ₂CO₃、Cs₂CO₃、Et₃ N) to form compound S28;

2) The compound S27 and the compound S21 are subjected to reductive amination reaction in a proper solvent (1, 2-dichloroethane) under the action of a proper reducing agent (such as NaBH (OAc) ₃、NaBH₃CN、NaBH₄、BH₃) to obtain a final product I-1;

Wherein R _s1、R_s2 has the definition as described in method seven;

LG ₂ is a leaving atom or group such as chlorine, bromine, iodine, OTf, OSu, etc.;

ra, rb, A1, A2, A3, A4, A5, R _x1、R_z1 are as defined above;

The definition of R is identical to that of method one.

Method eleven:

1) The compound S1a and the compound S21 undergo reductive amination reaction in a suitable solvent (1, 2-dichloroethane) under the action of a suitable reducing agent (for example NaBH (OAc) ₃、NaBH₃CN、NaBH₄、BH₃) to form a compound S29;

2) Compound S29 reacts with compound S30 in a suitable solvent (tetrahydrofuran) under the action of a suitable base (e.g., DMAP, et ₃ N) to form compound S31;

3) Removing the protecting group of the compound S31 in a proper solvent to obtain a final product I-1;

Wherein R _PG is a protecting group substituted R _s1; when the protected R _s1 contains a nitrogen group, the protecting group is an N protecting group such as Boc, fmoc or Cbz; when the protected R _s1 contains a carboxylic acid ester structure, the protecting group is a carboxylic acid protecting group such as methyl, ethyl, tert-butyl, etc. of the protected carboxylic acid;

R _s1 and R _s2 are defined in accordance with the definition set forth in method seven;

Ra, rb, A1, A2, A3, A4, A5, rx1, rz1 are as defined above.

3. Synthesis method of final product I-2

Method twelve:

1) Reacting compound S41 with compound S42 in a suitable solvent (isopropanol) under the action of a suitable reagent (e.g. Bu ₃P、Bu₃ P/orthoformate, (EtO) ₃ PO/orthoformate) to form compound S43;

2) Compound S43 and compound S8 are used as raw materials in a proper solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water and the like) under the action of a proper palladium catalyst (such as Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C and the like) and alkali (such as Na ₂CO₃、K₂CO₃、NaOH、Et₃ N and the like), and compound S44 is obtained through a Suzuki coupling reaction;

3) In a proper solvent (tetrahydrofuran/methanol/water), the compound S44 is hydrolyzed by proper alkali (LiOH or NaOH, etc.), and the final product I-2 is obtained;

wherein X is a leaving atom or group such as chlorine atom, bromine atom, iodine atom, OTf and the like;

r _s4 is A substituted or unsubstituted C1-C6 alkyl group;

Ar _s3 is a substituted or unsubstituted group of: phenyl, 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano 、-(CH₂)_q3-CO₂R_t7、-CONR_t8R_t9、-SO₂NR_t10R_t11、-(CH₂)_q4-SO₃R_t12、 trifluoromethyl, C1-C3 alkyl, C1-C3 alkoxy;

R _t7-R_t12 is independently a hydrogen atom or a C1-C4 alkyl group;

p2 is 0,1, 2 or 3;

q3, q4 are each independently 0, 1 or 2;

r, ra, rb, A1, A2, A3, A4, A5, ry1 are as defined above;

The definition of R is identical to that of method one.

4. Synthesis method of compound intermediates S54-1, S54-2 and S54-3

The method is thirteenth:

1) Reacting the compound S51 with the aldehyde group-containing compound S52 in a suitable solvent (e.g., ethanol) under the action of a suitable acid or oxidant (p-toluenesulfonic acid, sodium pyrosulfate) to produce compounds S53 and S54;

R _s5 is A substituted or unsubstituted C1-C6 alkyl group;

Ar _s4 is selected from the group consisting of substituted and unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl 、-(CH₂)_m23-CO₂R₆₆、-CONR₆₇R₆₈、-SO₂NR₆₉R₇₀、-(CH₂)_m24-SO₃R₇₁、C1-C4 alkyl, C1-C4 alkoxy, 5-to 6-membered heteroaryl, 3-to 8-membered heterocyclyl, -NH ₂, di (C1-C4 alkyl) amino, (C1-C4 alkyl) amino;

R ₆₆-R₇₁ is independently a hydrogen atom or a C1-C4 alkyl group;

p3 is 0, 1 or 2;

Ra is as defined above.

The method is fourteen:

1) Reacting compound S53 with compound S55 in a suitable solvent (e.g., N-dimethylformamide, DMSO) under the action of a suitable base (e.g., liHMDS, naH, K ₂CO₃、Cs₂CO₃、Et₃ N) to form compound S56;

wherein LG ₃ is a bromine atom, an iodine atom, OMs, OTs or other atom or group that is easy to leave;

x is a leaving atom or group such as chlorine atom, bromine atom, iodine atom, OTf, etc.;

R _s6 is A substituted or unsubstituted C1-C6 alkyl group; ;

Ar _s5 is selected from the group consisting of substituted and unsubstituted: phenyl, 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, hydroxy, cyano, nitro, methylsulfonyl, trifluoromethyl 、-(CH₂)_m25-CO₂R₇₂、-CONR₇₃R₇₄、-SO₂NR₇₅R₇₆、-(CH₂)_m26-SO₃R₇₇、C1-C4 alkyl, C1-C4 alkoxy, 5-to 6-membered heteroaryl, 3-to 8-membered heterocyclyl, -NH ₂, (C1-C4 alkyl) NH-, di (C1-C4 alkyl) amino;

R66-R77 are each independently selected from a hydrogen atom or a C1-C4 alkyl group;

m23-m26 are each independently 0, 1 or 2;

p4 is 1,2 or 3;

r _s5 is defined in accordance with the definition of the thirteenth method described above. Ra is as defined above.

5. Synthesis method of final product I-3

Fifteen methods:

1) In a proper solvent (ethylene glycol dimethyl ether/water, toluene/water, 1, 4-dioxane/water, DMF/water and the like), under the action of a proper palladium catalyst (such as Pd(PPh₃)₄、Pd(dppf)Cl₂-CH₂Cl₂、Pd₂(dba)₃、Pd(OAc)₂、Pd/C and the like) and a base (such as Na ₂CO₃、K₂CO₃、NaOH、Et₃ N and the like), performing Suzuki coupling reaction on the compound S53, the compound S54 or the compound S56 and the compound S8 to generate a compound S57;

2) In a suitable solvent (tetrahydrofuran/methanol/water), compound S57 is hydrolyzed by a suitable base (LiOH or NaOH, etc.), to give the final product I-3;

Wherein R _s8 is H, -CH ₂-R_S5 or R _s6;

Ra, A1, A2, A3, A4, A5, R _x2、R_y2、R_z2 are as defined above;

The definition of R is identical to that of method one.

The general synthesis method for synthesizing the intermediate comprises the following steps:

General synthetic method 1, see synthetic intermediate 1;

general synthetic method 2, see synthetic intermediate 8;

general synthetic method 3, see synthetic intermediate 19;

general synthetic method 4, see synthetic intermediate 21;

general synthetic method 5, see synthetic intermediate 22;

General synthetic method 10, see synthetic intermediate 38;

general synthetic method 11, see synthetic intermediate 42.

Example synthesis general procedure:

general synthetic method 6, see example 1;

General synthetic method 7, see example 26;

general synthetic method 8, see example 35;

General synthetic method 9, see example 89;

General synthetic method 12, see example 138;

General synthetic method 13, see example 92;

General synthetic method 14, see example 133;

General synthetic method 15, see example 140. The following compounds can be synthesized by referring to the above method using commercially available raw materials as a substrate and a reagent:

synthetic intermediate 1:4- (4-chlorophenyl) -1H-indazol-3-amine (QJ 50)

General method one:

Step one: synthesis of 4 '-chloro-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (QJ 49)

2-Bromo-6-fluorobenzonitrile (200 mg) and (4-chlorophenyl) boric acid (357 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (80 mg) was added, and after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 219mg.¹H NMR(400MHz,Chloroform-d)δ7.64(td,J＝8.17,5.75Hz,1H),7.52–7.43(m,4H),7.30–7.15(m,3H),6.79–6.73(m,1H).

Step two: synthesis of 4- (4-chlorophenyl) -1H-indazol-3-amine (QJ 50)

QJ49 (219 mg) was added to the eggplant-shaped flask, n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added, and the mixture was warmed to 110℃and stirred overnight. After the reaction is finished, cooling to room temperature, concentrating by a rotary evaporator, purifying by a silica gel column to obtain a target compound 207mg.¹H NMR(400MHz,Methanol-d₄)δ7.52–7.46(m,4H),7.37–7.30(m,2H),6.88(dd,J＝6.14,1.71Hz,1H).

Synthesis of intermediate 2:4- (3-chlorophenyl) -1H-indazol-3-amine (QJ 55)

Starting from 2-bromo-6-fluorobenzonitrile (200 mg) and (4-chlorophenyl) boronic acid (357 mg), 243mg of the title compound was obtained according to the general procedure one. ¹H NMR(400MHz,Methanol-d₄ ) Delta 7.47-7.27 (m, 6H), 6.81 (dd, j=5.76, 2.09hz, 1H).

Synthetic intermediate 3: 4-phenyl-1H-indazol-3-amine (QJ 59)

Starting from 2-bromo-6-fluorobenzonitrile (2000 mg) and phenylboronic acid (1342 mg), the title compound was obtained according to the general procedure one 1943mg.¹H NMR(500MHz,Chloroform-d)δ7.55–7.46(m,4H),7.46–7.40(m,1H),7.37(dd,J＝8.34,7.01Hz,1H),7.30(d,J＝8.40Hz,1H),6.95(d,J＝6.97Hz,1H).

Synthetic intermediate 4:4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 65)

Starting from 2-bromo-6-fluorobenzonitrile (500 mg) and (4- (tert-butyl) phenyl) boronic acid (490 mg), the title compound was obtained according to general procedure one 644mg.¹H NMR(400MHz,Chloroform-d)δ7.51(d,J＝8.43Hz,1H),7.46(d,J＝8.41Hz,1H),7.36(dd,J＝8.41,6.97Hz,1H),7.31–7.26(m,1H),6.95(d,J＝6.95Hz,1H),1.39(s,9H).

Synthetic intermediate 5:4- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 66)

Starting from 2-bromo-6-fluorobenzonitrile (500 mg) and (3- (tert-butyl) phenyl) boronic acid (490 mg), the title compound was obtained according to general procedure one 384mg.¹H NMR(400MHz,Chloroform-d)δ7.59(t,J＝1.84Hz,1H),7.51–7.41(m,2H),7.36(dd,J＝8.43,6.77Hz,2H),7.30(dd,J＝8.46,1.00Hz,1H),6.98(dd,J＝6.94,1.00Hz,1H),1.40(s,9H).

Synthetic intermediate 6:4- (naphthalen-2-yl) -1H-indazol-3-amine (QJ 71)

Starting from 2-bromo-6-fluorobenzonitrile (500 mg) and naphthalen-2-ylboronic acid (473 mg), the title compound was obtained according to the general procedure one 234mg.¹H NMR(500MHz,Chloroform-d)δ8.02–7.95(m,2H),7.92(dq,J＝7.36,2.52,2.11Hz,2H),7.67(dd,J＝8.40,1.76Hz,1H),7.59–7.51(m,2H),7.41(dd,J＝8.40,6.96Hz,1H),7.34(d,J＝8.39Hz,1H),7.05(d,J＝6.92Hz,1H).

Synthetic intermediate 7:4- (1H-indol-5-yl) -1H-indazol-3-amine (QJ 72)

Starting from 2-bromo-6-fluorobenzonitrile (500 mg) and (1H-indol-5-yl) boronic acid (668 mg), the title compound was obtained in accordance with the general procedure one 736mg.¹H NMR(400MHz,Methanol-d₄)δ7.70–7.53(m,3H),7.44–7.33(m,2H),7.22(dd,J＝8.29,1.74Hz,1H),7.11(d,J＝7.10Hz,1H),6.55(d,J＝3.15Hz,1H).

Synthetic intermediate 8:4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 99)

The general method II is as follows:

step one: synthesis of 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (QJ 92)

2-Fluoro-6-iodobenzonitrile (1 g) and (4-bromophenyl) boric acid (810 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (326 mg) was added, and after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 956mg.¹H NMR(500MHz,Chloroform-d)δ7.67–7.61(m,3H),7.46–7.41(m,2H),7.29(dd,J＝7.93,1.00Hz,1H),7.23(td,J＝8.47,1.01Hz,1H).

Step two: synthesis of 3-fluoro-2 ",3",4",5" -tetrahydro- [1,1':4',1 "-terphenyl ] -2-carbonitrile (QJ 95)

QJ92 (485 mg) and cyclohex-1-en-1-ylboronic acid (244 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (163 mg) was added, after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 432mg.¹H NMR(500MHz,Chloroform-d)δ7.60(td,J＝8.16,5.87Hz,1H),7.51(d,J＝0.97Hz,4H),7.31(dd,J＝7.81,1.02Hz,1H),7.17(td,J＝8.52,1.01Hz,1H),6.24(tq,J＝4.00,1.97Hz,1H),2.45(tq,J＝6.21,2.29Hz,2H),2.25(ddt,J＝8.53,6.33,2.70Hz,2H),1.82(dtt,J＝8.85,6.14,3.39Hz,2H),1.69(dhept,J＝9.27,3.41Hz,2H).

Step three: synthesis of 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 99)

QJ95 (432 mg) was added to the eggplant-shaped flask, n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added, and the mixture was warmed to 110℃and stirred overnight. After the reaction is finished, cooling to room temperature, concentrating by a rotary evaporator, purifying by a silica gel column to obtain a target compound 356mg.¹H NMR(500MHz,Chloroform-d)δ7.53–7.48(m,2H),7.48–7.44(m,2H),7.36(dd,J＝8.40,6.99Hz,1H),7.28(dd,J＝8.41,0.91Hz,1H),6.95(dd,J＝7.02,0.88Hz,1H),6.24(tt,J＝3.92,1.73Hz,1H),2.47(tq,J＝6.42,2.32Hz,2H),2.25(ddt,J＝8.70,6.56,2.99Hz,2H),1.86–1.78(m,2H),1.73–1.65(m,2H).

Synthetic intermediate 9:4- ([ 1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 125)

Starting from 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (230 mg) and phenylboronic acid (122 mg), the title compound was obtained according to general procedure two 183mg.¹H NMR(500MHz,Chloroform-d)δ7.75–7.71(m,2H),7.69–7.65(m,2H),7.63–7.59(m,2H),7.48(dd,J＝8.31,7.07Hz,2H),7.42–7.36(m,2H),7.32(dd,J＝8.39,0.87Hz,1H),7.00(dd,J＝6.98,0.92Hz,1H).

Synthetic intermediate 10:5- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 89)

Starting from 5-bromo-2-fluorobenzonitrile (500 mg) and (4- (tert-butyl) phenyl) boronic acid (490 mg), the title compound was obtained according to general procedure one 642mg.¹H NMR(500MHz,Chloroform-d)δ7.74(dd,J＝1.65,0.79Hz,1H),7.62(dd,J＝8.69,1.67Hz,1H),7.58–7.52(m,2H),7.49–7.44(m,2H),7.36(dd,J＝8.60,0.82Hz,1H),1.38(s,9H).

Synthetic intermediate 11:5- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 90)

Starting from 5-bromo-2-fluorobenzonitrile (500 mg) and (3- (tert-butyl) phenyl) boronic acid (490 mg), the title compound was obtained according to general procedure one 641mg.¹H NMR(500MHz,Chloroform-d)δ7.74(dd,J＝1.64,0.84Hz,1H),7.64–7.60(m,2H),7.45–7.35(m,4H),1.40(s,9H).

Synthetic intermediate 12:4- (4-isopropylphenyl) -1H-indazol-3-amine (QJ 98)

Starting from 2-bromo-6-fluorobenzonitrile (200 mg) and (4-isopropylphenyl) boronic acid (180 mg), the title compound was obtained according to the general procedure one 216mg.¹H NMR(500MHz,Chloroform-d)δ7.47–7.42(m,2H),7.38–7.33(m,3H),7.28(dd,J＝8.42,0.89Hz,1H),6.94(dd,J＝7.01,0.89Hz,1H),3.00(h,J＝6.94Hz,1H),1.32(d,J＝6.95Hz,6H).

Synthesis of intermediate 13:4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (QJ 100)

Starting from 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (471 mg) and phenylboronic acid (230 mg), the title compound was obtained according to general procedure two 423mg.¹H NMR(500MHz,Chloroform-d)δ7.58–7.54(m,2H),7.50–7.46(m,2H),7.44(d,J＝8.09Hz,1H),7.31–7.28(m,1H),6.95(ddd,J＝6.69,5.76,0.97Hz,1H),6.29(p,J＝2.14Hz,1H),2.77(ddt,J＝9.95,6.70,2.25Hz,2H),2.58(ddd,J＝7.73,6.03,2.50Hz,2H),2.10–2.02(m,2H).

Synthetic intermediate 14:4- (4-cyclohexylphenyl) -1H-indazol-3-amine (QJ 102)

4- (4- (Cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (174 mg) was added to an eggplant-shaped flask, methanol was added, oxygen was removed from the reaction solution, palladium on carbon (40 mg) was added, and after oxygen was removed again from the reaction solution, the mixture was stirred under a hydrogen atmosphere overnight. After the reaction is finished, filtering, washing a filter cake with methanol, and concentrating filtrate to obtain the target compound 163mg.¹H NMR(500MHz,Chloroform-d)δ7.46–7.42(m,2H),7.38–7.31(m,3H),7.28(dd,J＝8.40,0.89Hz,1H),6.94(dd,J＝7.01,0.90Hz,1H),2.58(ddt,J＝11.62,6.95,3.41Hz,1H),2.00–1.85(m,4H),1.78(dtt,J＝12.63,3.15,1.46Hz,1H),1.53–1.38(m,4H),1.34–1.28(m,1H).

Synthesis of intermediate 15:4- (4-cyclopentylphenyl) -1H-indazol-3-amine (QJ 106)

4- (4- (Cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (100 mg) was added to an eggplant-shaped flask, methanol was added, oxygen was removed from the reaction solution, palladium on carbon (20 mg) was added, and after oxygen was removed again from the reaction solution, the mixture was stirred under a hydrogen atmosphere overnight. After the reaction is finished, filtering, washing a filter cake with methanol, and concentrating filtrate to obtain the target compound 100mg.¹H NMR(500MHz,Methanol-d₄)δ7.36–7.26(m,6H),6.81(dd,J＝5.87,1.98Hz,1H),3.02(tt,J＝9.62,7.43Hz,1H),2.06(dddd,J＝13.79,10.97,5.60,2.08Hz,2H),1.81(ddt,J＝11.33,9.58,5.80Hz,2H),1.74–1.65(m,2H),1.60(tdd,J＝12.00,9.45,5.02Hz,2H).

Synthetic intermediate 16:4- (4- (3-amino-1H-indazol-4-yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (QJ 128)

Starting from 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (710 mg) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (877 mg), the title compound was obtained as per general procedure II 297mg.¹H NMR(500MHz,Chloroform-d)δ7.50(s,4H),7.37(dd,J＝8.42,7.00Hz,1H),7.30(dd,J＝8.51,0.91Hz,1H),6.95(dd,J＝7.01,0.91Hz,1H),6.15(s,1H),4.15–4.09(m,2H),3.68(t,J＝5.54Hz,2H),2.59(s,2H),1.51(s,9H).

Synthetic intermediate 17:5- (4- (3-amino-1H-indazol-4-yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (QJ 136)

Starting from 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (550 mg) and 5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (680 mg), the title compound 216mg.¹H NMR(500MHz,Chloroform-d)δ7.50(s,4H),7.37(t,J＝7.65Hz,1H),7.30(d,J＝8.43Hz,1H),6.95(d,J＝6.81Hz,1H),6.32(s,1H),4.34(s,2H),3.59(s,2H),2.36(s,2H),1.52(s,9H). was obtained as synthetic intermediate 18, referring to general procedure two: 4- (4- (pyridin-4-yl) phenyl) -1H-indazol-3-amine (QJ 135)

Starting from 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (275 mg) and pyridin-4-ylboronic acid (146 mg), the title compound was obtained according to general procedure two 224mg.¹H NMR(500MHz,Chloroform-d)δ8.72–8.69(m,2H),7.78(d,J＝8.30Hz,2H),7.65(d,J＝8.15Hz,2H),7.60–7.56(m,2H),7.41(dd,J＝8.43,6.94Hz,1H),7.36–7.33(m,1H),6.99(dd,J＝7.02,0.91Hz,1H).

Synthesis of intermediate 19:4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 160)

The general method is as follows:

step one: synthesis of 4' -bromo-3 ' -methoxy-2, 3,4, 5-tetrahydro-1, 1' -biphenyl (QJ 148)

Cyclohex-1-en-1-ylboronic acid (126 mg) and 1-bromo-4-iodo-2-methoxybenzene (343 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (80 mg) was added thereto, and after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 263mg.¹H NMR(500MHz,Chloroform-d)δ7.44(d,J＝8.20Hz,1H),6.92(d,J＝2.12Hz,1H),6.84(dd,J＝8.23,2.11Hz,1H),6.13(tt,J＝3.90,1.75Hz,1H),3.90(s,3H),2.39(tq,J＝6.48,2.28Hz,2H),2.21(tq,J＝5.24,2.63Hz,2H),1.84–1.75(m,2H),1.72–1.64(m,2H).

Step two: synthesis of 2- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (QJ 149)

QJ148 (263 mg), pinacol diboronate (318 mg) and potassium acetate (294 mg) were added to an eggplant-shaped flask, 1, 4-dioxane (10 mL) was added, the reaction solution was deoxygenated, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (41 mg) was added, the reaction solution was deoxygenated again, and then, the temperature was raised to 90℃and stirring was continued overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 294mg.¹H NMR(500MHz,Chloroform-d)δ7.59(d,J＝7.63Hz,1H),6.92(dd,J＝7.64,1.49Hz,1H),6.83(d,J＝1.48Hz,1H),6.13(tt,J＝3.88,1.71Hz,1H),3.82(s,3H),2.42–2.32(m,2H),2.17(th,J＝7.28,2.93,2.49Hz,2H),1.75(pd,J＝6.16,5.40,1.78Hz,2H),1.63(dtt,J＝8.49,5.71,2.38Hz,2H),1.31(s,12H).

Step three: synthesis of 3-fluoro-2 '-methoxy-2 ",3",4",5" -tetrahydro- [1,1':4',1 "-terphenyl ] -2-carbonitrile (QJ 146)

QJ149 (294 mg) and 2-bromo-6-fluorobenzonitrile (238 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (90 mg) was added, and after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 137mg.¹H NMR(500MHz,Chloroform-d)δ7.63–7.60(m,1H),7.52(tdd,J＝6.62,5.05,1.31Hz,1H),7.28(dd,J＝7.80,1.02Hz,1H),7.23(dd,J＝7.58,2.06Hz,1H),7.18(td,J＝8.56,0.99Hz,1H),7.14–7.06(m,2H),6.26(tt,J＝3.94,1.70Hz,1H),3.91(s,3H),2.49(tq,J＝6.15,2.05Hz,2H),2.33–2.27(m,2H),1.89–1.80(m,2H),1.77–1.69(m,2H).

Step four: synthesis of 4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 160)

QJ146 (137 mg) was added to the eggplant-shaped flask, n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added, and the mixture was warmed to 110℃and stirred overnight. After the reaction is finished, cooling to room temperature, concentrating by a rotary evaporator, purifying by a silica gel column to obtain a target compound 89mg.¹H NMR(500MHz,Chloroform-d)δ7.33(dd,J＝8.42,6.96Hz,1H),7.26–7.20(m,2H),7.13–7.09(m,1H),7.06(d,J＝1.61Hz,1H),6.92(t,J＝5.56Hz,1H),6.25(tt,J＝3.86,1.67Hz,1H),3.77(s,3H),2.49(tt,J＝6.23,1.75Hz,2H),2.27(tt,J＝6.12,3.01Hz,2H),1.87–1.80(m,2H),1.75–1.68(m,2H).

Synthetic intermediate 20:4- (2-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 13)

The target compound was obtained by using cyclohex-1-en-1-ylboronic acid (500 mg) and 4-bromo-1-iodo-2-methoxybenzene (1360 mg) as raw materials, referring to general method III 314mg.¹H NMR(500MHz,Chloroform-d)δ7.37(dd,J＝8.40,7.00Hz,1H),7.29(dd,J＝8.04,0.78Hz,1H),7.24(d,J＝7.63Hz,1H),7.05(dd,J＝7.60,1.66Hz,1H),7.02(d,J＝1.63Hz,1H),6.98(dd,J＝7.01,0.91Hz,1H),5.87(tt,J＝3.74,1.73Hz,1H),3.86(s,3H),2.42(tt,J＝6.34,2.27Hz,2H),2.23(dtd,J＝8.65,6.00,3.21Hz,2H),1.81–1.67(m,4H).

Synthetic intermediate 21:4- (3-ethoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 79)

The general method is four:

step one: synthesis of 2-bromo-5-iodophenol (QK 51)

1-Bromo-4-iodo-2-methoxybenzene (1 g) was added to an eggplant-shaped flask, dichloromethane (20 mL) was added, cooled to-78deg.C, and a solution of boron tribromide in dichloromethane (1M, 10 mL) was added dropwise. After stirring at-78 ℃ for 2h, naturally warming to room temperature and stirring overnight. After the reaction, slowly pouring the reaction solution into ice water, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 948mg.¹H NMR(500MHz,Chloroform-d)δ7.37(d,J＝1.96Hz,1H),7.16(d,J＝8.37Hz,1H),7.13(dd,J＝8.36,1.95Hz,1H),5.50(s,1H).

Step two: synthesis of 4-bromo-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-ol (QK 55)

QK51 (500 mg) and cyclohex-1-en-1-ylboronic acid (192 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (80 mg) was added, after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 451mg.¹H NMR(500MHz,Chloroform-d)δ7.36(d,J＝8.37Hz,1H),7.04(d,J＝2.17Hz,1H),6.85(dd,J＝8.39,2.21Hz,1H),6.13(tq,J＝3.46,1.71Hz,1H),2.35(tq,J＝6.23,2.33Hz,2H),2.19(ddt,J＝8.47,6.30,2.72Hz,2H),1.77(dtt,J＝8.84,6.14,2.75Hz,2H),1.68–1.62(m,2H).

Step three: synthesis of 4' -bromo-3 ' -ethoxy-2, 3,4, 5-tetrahydro-1, 1' -biphenyl (QK 72)

QK55 (100 mg) was added to the eggplant-shaped flask, N-dimethylformamide (5 mL) was added, sodium hydride (32 mg) was added, and ethyl iodide (93 mg) was added dropwise, and the temperature was raised to 100℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 106mg.¹H NMR(500MHz,Chloroform-d)δ7.43(d,J＝8.25Hz,1H),6.90(d,J＝2.11Hz,1H),6.83(dd,J＝8.23,2.10Hz,1H),6.11(tq,J＝3.89,2.08Hz,1H),4.12(q,2H),2.37(tq,J＝6.12,2.22Hz,2H),2.20(ddq,J＝6.28,4.28,2.65Hz,2H),1.78(dtt,J＝8.76,6.10,2.91Hz,2H),1.66(dtt,J＝9.29,6.19,3.01Hz,2H),1.47(t,J＝7.00Hz,3H).

Step four: synthesis of 2 '-ethoxy-3-fluoro-2 ",3",4",5" -tetrahydro- [1,1':4',1 "-terphenyl ] -2-carbonitrile (QK 75)

QK72 (106 mg) and 2-fluoro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzonitrile (148 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, oxygen was removed from the reaction solution, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (33 mg) was added, and after oxygen was removed again from the reaction solution, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 71mg.¹H NMR(500MHz,Chloroform-d)δ7.60–7.55(m,1H),7.25(dd,J＝8.13,1.22Hz,1H),7.19(d,J＝7.89Hz,1H),7.15(td,J＝8.61,1.01Hz,1H),7.05(dd,J＝7.93,1.67Hz,1H),7.02(d,J＝1.64Hz,1H),6.20(tt,J＝3.97,1.72Hz,1H),4.13(q,J＝6.96Hz,2H),2.44(tp,J＝6.20,2.43Hz,2H),2.24(tq,J＝6.33,2.75Hz,2H),1.80(ddt,J＝11.81,10.40,6.03Hz,2H),1.68(dqd,J＝11.66,5.92,2.96Hz,2H),1.37(t,J＝7.02Hz,3H).

Step five: synthesis of 4- (3-ethoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 79)

QK75 (71 mg) was added to the eggplant-shaped flask, n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added, and the mixture was warmed to 110℃and stirred overnight. After the reaction is finished, cooling to room temperature, concentrating by a rotary evaporator, purifying by a silica gel column to obtain a target compound 55mg.¹H NMR(500MHz,Chloroform-d)δ7.36(dd,J＝8.40,7.03Hz,1H),7.30–7.24(m,2H),7.12(dd,J＝7.79,1.75Hz,1H),7.08(d,J＝1.69Hz,1H),6.95(dt,J＝7.15,1.50Hz,1H),6.26(tq,J＝3.94,2.04Hz,1H),4.05(q,J＝6.98Hz,2H),2.49(tq,J＝6.56,2.37Hz,2H),2.28(ddt,J＝8.60,6.34,3.17Hz,2H),1.88–1.82(m,2H),1.73(dhept,J＝9.24,3.00Hz,2H),1.22(t,J＝6.97Hz,3H).

Synthetic intermediate 22:4- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -1H-indazol-3-amine (QK 83)

General method five:

Step one: synthesis of 2- (5-bromopyridin-2-yl) -6-fluorobenzonitrile (QK 73)

5-Bromo-2-iodopyridine (310 mg) and 2-fluoro-6- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzonitrile (247 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (80 mg) was added, and after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 50mg.¹H NMR(500MHz,Chloroform-d)δ8.83(dd,J＝2.32,0.77Hz,1H),7.98(dd,J＝8.40,2.36Hz,1H),7.72–7.65(m,2H),7.62(dd,J＝7.93,1.18Hz,1H),7.29(td,J＝8.34,1.14Hz,1H).

Step two: synthesis of 2- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -6-fluorobenzonitrile (QK 77)

QK73 (50 mg) and cyclohex-1-en-1-ylboronic acid (27 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (20 mg) was added, after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 52mg.¹H NMR(500MHz,Chloroform-d)δ8.81–8.76(m,1H),7.78(dd,J＝8.27,2.33Hz,1H),7.72(dd,J＝8.23,0.89Hz,1H),7.65(td,J＝3.89,2.59Hz,2H),7.23(ddd,J＝9.09,5.99,3.51Hz,1H),6.95–6.89(m,1H),6.29(tt,J＝3.91,1.71Hz,1H),2.43(tq,J＝6.28,2.28Hz,2H),2.26(tq,J＝6.23,2.74Hz,2H),1.85–1.78(m,2H),1.72–1.66(m,2H).

Step three: 4- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -1H-indazol-3-amine (QK 83)

QK77 (52 mg) was added to an eggplant-shaped flask, n-butanol (10 mL) and hydrazine hydrate (85%, 5 mL) were added, and the mixture was warmed to 110℃and stirred overnight. After the reaction is finished, cooling to room temperature, concentrating by a rotary evaporator, purifying by a silica gel column to obtain a target compound 43mg.¹H NMR(500MHz,Chloroform-d)δ8.76–8.72(m,1H),7.78(dd,J＝8.32,2.39Hz,1H),7.73–7.69(m,2H),7.39–7.28(m,2H),7.21(dd,J＝6.90,1.07Hz,1H),6.26(tt,J＝3.90,1.74Hz,1H),2.44(tq,J＝6.40,2.29Hz,2H),2.26(tq,J＝6.40,2.80Hz,2H),1.86–1.78(m,2H),1.74–1.65(m,2H).

Synthetic intermediate 23:4- (3-isopropoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 84)

Starting from 4-bromo-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-ol (200 mg), the title compound was obtained according to general procedure four 62mg.¹H NMR(500MHz,Chloroform-d)δ7.33(dd,J＝8.43,7.02Hz,1H),7.26–7.22(m,2H),7.12(dd,J＝7.86,1.75Hz,1H),7.08(d,J＝1.74Hz,1H),6.92(dd,J＝7.03,0.87Hz,1H),6.22(tt,J＝3.97,1.73Hz,1H),4.33(dt,J＝12.10,6.03Hz,1H),2.46(tq,J＝6.43,2.39Hz,2H),2.25(ddt,J＝8.38,6.32,2.77Hz,2H),1.85–1.78(m,2H),1.70(pd,J＝6.40,3.62Hz,2H),1.14(d,J＝6.10Hz,3H),1.07(d,J＝5.99Hz,3H).

Synthetic intermediate 24:4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-amine (QK 104)

The target compound was obtained by using 2-bromo-5-iodopyridine (500 mg) as a starting material and referring to general procedure five 72mg.¹H NMR(500MHz,Chloroform-d)δ8.71(d,J＝2.35Hz,1H),7.78(dd,J＝8.17,2.46Hz,1H),7.46(d,J＝8.21Hz,1H),7.34–7.24(m,2H),6.88(dd,J＝6.51,1.40Hz,1H),6.79(tt,J＝3.94,1.71Hz,1H),2.55(tq,J＝6.49,2.21Hz,2H),2.27(dh,J＝6.54,2.82Hz,2H),1.79(dtt,J＝11.13,7.59,4.03Hz,2H),1.71–1.65(m,2H).

Synthetic intermediate 25:4- (3- (dimethylamino) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 111)

Starting with cyclohex-1-en-1-ylboronic acid (158 mg) and 2-bromo-5-iodo-N, N-dimethylaniline (446 mg), the title compound was obtained according to general method IV 55mg.¹H NMR(500MHz,Chloroform-d)δ7.31–7.16(m,3H),6.87(d,J＝6.97Hz,1H),6.79–6.67(m,2H),5.76–5.66(m,1H),3.05(s,6H),2.01(ddq,J＝12.33,6.18,3.12Hz,2H),1.93–1.78(m,2H),1.49–1.36(m,4H).

Synthetic intermediate 26:4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 128)

Starting from 4-bromo-1-iodo-2-methylbenzene (1292 mg) and cyclohex-1-en-1-ylboronic acid (500 mg), the title compound was obtained by general method IV 412mg.¹H NMR(500MHz,Chloroform-d)δ7.38–7.30(m,3H),7.30–7.26(m,1H),7.23(d,J＝7.70Hz,1H),6.99–6.94(m,1H),5.69(tt,J＝3.62,1.72Hz,1H),2.40(s,3H),2.30(dp,J＝5.75,2.18Hz,2H),2.25(dq,J＝6.13,3.50Hz,2H),1.84(dhept,J＝9.07,3.04Hz,2H),1.76(dtt,J＝8.92,6.10,2.55Hz,2H).

Synthesis of intermediate 27:4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 129)

Starting from 1-bromo-4-iodo-2-methylbenzene (1292 mg) and cyclohex-1-en-1-ylboronic acid (500 mg), the title compound was obtained by general method IV 389mg.¹H NMR(500MHz,Chloroform-d)δ7.37–7.33(m,2H),7.31(dd,J＝7.83,1.93Hz,1H),7.28–7.26(m,1H),7.22(d,J＝7.93Hz,1H),6.86–6.80(m,1H),6.23(tt,J＝4.04,1.76Hz,1H),2.47(tq,J＝5.96,2.09Hz,2H),2.25(tt,J＝6.04,3.05Hz,2H),2.15(s,3H),1.81(qq,J＝5.34,2.91Hz,2H),1.73–1.66(m,2H).

Synthetic intermediate 28:4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-carboxylic acid methyl ester (QK 145)

The target compound was obtained by using cyclohex-1-en-1-ylboronic acid (250 mg) and methyl 2-bromo-5-iodobenzoate (746 mg) as starting materials according to the general procedure III 365mg.¹H NMR(500MHz,Chloroform-d)δ7.90(d,J＝1.93Hz,1H),7.58(dd,J＝7.83,1.99Hz,1H),7.54(d,J＝8.07Hz,1H),7.30–7.28(m,1H),7.03(ddd,J＝7.86,6.54,1.19Hz,1H),6.94–6.89(m,1H),5.65(tt,J＝3.75,1.69Hz,1H),3.86(s,3H),2.29(ddd,J＝8.14,5.02,3.05Hz,2H),2.18(dtt,J＝6.17,4.25,2.67Hz,2H),1.79(dtt,J＝11.19,7.53,4.17Hz,2H),1.70(pd,J＝6.70,6.03,4.07Hz,2H).

Synthetic intermediate 29:4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-carboxylic acid methyl ester (QK 140)

Starting from cyclohex-1-en-1-ylboronic acid (500 mg) and methyl 5-bromo-2-iodobenzoate (1479 mg), the title compound was obtained according to the general procedure III 175mg.¹H NMR(500MHz,Chloroform-d)δ7.90(d,J＝1.98Hz,1H),7.60(dd,J＝7.90,1.94Hz,1H),7.39–7.28(m,3H),6.98–6.92(m,1H),5.65(tt,J＝3.67,1.68Hz,1H),3.86(s,3H),2.30(tq,J＝6.14,2.24Hz,2H),2.19(dtd,J＝8.78,6.08,2.75Hz,2H),1.84–1.76(m,2H),1.74–1.66(m,2H).

Synthetic intermediate 30:4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-ol (QK 154)

Starting from cyclohex-1-en-1-ylboronic acid (189 mg) and 5-bromo-2-iodophenol (730 mg), the following general procedure three was followed to give the desired compound 117mg.¹H NMR(500MHz,Chloroform-d)δ7.46(d,J＝7.90Hz,1H),7.24–7.08(m,2H),7.01–6.91(m,2H),6.86(d,J＝6.70Hz,1H),5.98(tt,J＝3.83,1.73Hz,1H),2.44(td,J＝5.68,2.47Hz,2H),2.20(h,J＝3.30Hz,2H),1.81–1.74(m,2H),1.72–1.64(m,2H). as synthetic intermediate 31:4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-ol (QL 1)

Starting from cyclohex-1-en-1-ylboronic acid (366 mg) and 5-bromo-2-iodophenol (953 mg), the title compound was obtained according to general procedure III 151mg.¹H NMR(500MHz,Chloroform-d)δ7.73–7.67(m,1H),7.52–7.47(m,2H),7.26–7.21(m,1H),7.02–6.94(m,2H),6.29–6.23(m,1H),2.49–2.42(m,2H),2.29–2.22(m,2H),1.85–1.79(m,2H),1.74–1.66(m,2H).

Synthetic intermediate 32: 3-amino-4- (4- (tert-butyl) phenyl) -1H-indazole-1-carboxylic acid tert-butyl ester (QL 16)

4- (4- (Tert-butyl) phenyl) -1H-indazol-3-amine (500 mg) and 4-dimethylaminopyridine (49 mg) were added to an eggplant-shaped flask, acetonitrile (5 mL) and triethylamine (384 mg) were added, a solution of di-tert-butyl dicarbonate (452 mg) in dichloromethane (5 mL) was added dropwise, and stirring was carried out at room temperature for 30min. After the reaction, quench the reaction with water, extract the aqueous phase with ethyl acetate 3 times, combine the organic phases, wash with saturated saline, dry with anhydrous sodium sulfate, purify on silica gel column to obtain the target compound 536mg.¹H NMR(500MHz,DMSO-d₆)δ8.04(d,J＝8.40Hz,1H),7.60–7.51(m,3H),7.40(dd,J＝7.71,4.72Hz,2H),7.13(d,J＝7.26Hz,1H),5.04(s,2H),1.60(d,J＝3.52Hz,9H),1.34(s,9H).

Synthetic intermediate 33: 3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-1-carboxylic acid tert-butyl ester (QL 27)

The target compound was obtained by referring to the QL16 synthesis method using 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (500 mg) as a starting material 503mg.¹H NMR(500MHz,Chloroform-d)δ7.55–7.44(m,4H),7.43–7.37(m,2H),7.11(dd,J＝7.28,0.95Hz,1H),6.24(dtt,J＝5.73,3.95,1.65Hz,1H),2.46(dddt,J＝8.42,6.14,4.31,2.42Hz,2H),2.25(dtp,J＝6.33,4.50,2.39Hz,2H),1.82(qq,J＝6.10,2.75,2.35Hz,2H),1.72–1.67(m,11H).

Synthesis of intermediate 34:2- (3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) ethan-1-ol (QL 103)

Step one: synthesis of 2- (3-amino-4-iodo-1H-indazol-1-yl) ethan-1-ol (QL 92)

2-Fluoro-6-iodobenzonitrile (500 mg) was added to an eggplant-shaped flask, n-butanol (10 mL) and 2-hydroxyphenylalanine-1-ol (5 mL) were added, the temperature was raised to 110℃and stirred overnight. After the reaction, quench the reaction with water, extract the aqueous phase with ethyl acetate 3 times, combine the organic phases, wash with saturated saline, dry with anhydrous sodium sulfate, purify on silica gel column to obtain the target compound 242mg.¹H NMR(500MHz,Chloroform-d)δ7.41(dd,J＝7.28,0.71Hz,1H),7.21(dd,J＝8.45,0.69Hz,1H),6.97(dd,J＝8.50,7.27Hz,1H),4.21(dd,J＝5.52,4.16Hz,2H),4.03–3.99(m,2H).

Step two: synthesis of 2- (3-amino-4- (4-bromophenyl) -1H-indazol-1-yl) ethan-1-ol (QL 99)

QL92 (242 mg) and (4-bromophenyl) boric acid (160 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (65 mg) was added, and after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 247mg.¹H NMR(500MHz,Chloroform-d)δ7.62–7.57(m,2H),7.38–7.32(m,3H),7.25(dd,J＝8.61,0.78Hz,1H),6.86(dd,J＝7.03,0.80Hz,1H),4.28–4.24(m,2H),4.04–4.00(m,2H).

Step three: synthesis of 2- (3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) ethan-1-ol (QL 103)

QL99 (247 mg) and cyclohex-1-en-1-ylboronic acid (113 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and an aqueous sodium carbonate solution (2M, 5 mL) were added, oxygen was removed from the reaction solution, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (65 mg) was added, and after oxygen removal from the reaction solution again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 193mg.¹H NMR(500MHz,Chloroform-d)δ7.51–7.48(m,2H),7.44–7.40(m,2H),7.35(dd,J＝8.50,6.97Hz,1H),7.21(d,J＝8.50Hz,1H),6.90(d,J＝6.98Hz,1H),6.24(tt,J＝3.97,1.69Hz,1H),4.25(t,J＝5.08Hz,2H),4.02(t,J＝5.13Hz,2H),2.46(tq,J＝6.20,2.19Hz,2H),2.28–2.22(m,2H),1.86–1.79(m,2H),1.73–1.66(m,2H).

Synthetic intermediate 35:4- (4- (3, 6-dihydro-2H-pyran-4-yl) phenyl) -1H-indazol-3-amine (LYA 6)

Starting from 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (100 mg) and 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborane (76 mg), the title compound was obtained as per general procedure II 43.5mg.¹H NMR(500MHz,Chloroform-d)δ7.56–7.48(m,4H),7.41–7.34(m,1H),7.31(dd,J＝8.4,0.9Hz,1H),6.96(dd,J＝6.9,0.9Hz,1H),6.24(tt,J＝3.0,1.6Hz,1H),4.37(q,J＝2.8Hz,2H),3.98(t,J＝5.4Hz,2H),2.59(dddd,J＝5.7,4.5,2.9,1.5Hz,2H).

Synthetic intermediate 36:4- (4- (pyridin-3-yl) phenyl) -1H-indazol-3-amine (LYA 10)

Starting from 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (100 mg) and pyridin-3-ylboronic acid (44.7 mg), the following compound 48.7mg.¹H NMR(500MHz,Methanol-d₄)δ8.89(d,J＝2.3Hz,1H),8.54(dd,J＝4.9,1.6Hz,1H),8.17(ddd,J＝8.0,2.4,1.6Hz,1H),7.83–7.78(m,2H),7.67–7.61(m,2H),7.54(ddd,J＝7.9,4.9,0.9Hz,1H),7.41–7.30(m,2H),6.92(dd,J＝6.5,1.4Hz,1H). was obtained as a synthetic intermediate 37, according to general procedure two: 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylic acid (FB 55)

Step one: synthesis of 4-bromo-1H-indazole-3-carboxylic acid (FB 47)

4-Bromoindole-2, 3-dione (6 g) and sodium hydroxide (1176 mg) were added to an eggplant-shaped flask, water (48 mL) was added thereto, the temperature was raised to 50℃and stirred for 30min. After the reaction was completed, the mixture was cooled to 0 ℃. Sodium nitrite solution (2028 mg) and dilute sulfuric acid (concentrated sulfuric acid: water=4.2 ml:60 ml) were added dropwise, and stirred at 0 ℃ for 30min. Stannous chloride monohydrate (15 g) and concentrated hydrochloric acid (60 mL) were then added and slowly warmed to room temperature under N ₂ protection and stirred for 2h. After the reaction, the reaction was quenched with water, suction filtered under reduced pressure, and the filter cake was washed with water, dissolved in methanol, and concentrated by rotary evaporator to give the objective compound (7 g), which was used directly in the next step without further purification. ¹H NMR(500MHz,Methanol-d₄ ) Delta 7.60 (d, j=8.3 hz, 1H), 7.45 (d, j=7.3 hz, 1H), 7.32-7.27 (m, 1H).

Step two: synthesis of 4-bromo-1H-indazole-3-carboxylic acid methyl ester (FB 49)

FB47 (7 g) was added to the eggplant-shaped flask, methanol (80 mL) was added, concentrated sulfuric acid (0.5 mL) was added dropwise, and the mixture was heated to 65℃and stirred overnight. After the reaction was completed, cooling to room temperature, adding a saturated sodium bicarbonate solution, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with a saturated common salt solution, drying with anhydrous sodium sulfate, concentrating with a rotary evaporator, and purifying with a silica gel column to obtain the target compound 545mg.¹H NMR(500MHz,Chloroform-d)δ7.59(dd,J＝8.4,0.8Hz,1H),7.54(dd,J＝7.4,0.7Hz,1H),7.28(dd,J＝8.4,7.5Hz,1H),4.06(s,3H).

Step three: synthesis of methyl 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylate (FB 53)

FB49 (574 mg) and 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1,3, 2-dioxaborane (673 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (15 mL) and an aqueous sodium carbonate solution (2M, 10 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (179 mg) was added, after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 500mg.¹H NMR(500MHz,Chloroform-d)δ7.68–7.59(m,1H),7.49–7.38(m,3H),7.36–7.30(m,2H),7.18(t,J＝6.6Hz,1H),6.16(tq,J＝3.9,1.9Hz,1H),3.33(d,J＝1.5Hz,3H),2.43(ddt,J＝6.6,4.8,2.3Hz,2H),2.25–2.19(m,2H),1.83–1.74(m,2H),1.72–1.61(m,2H).

Step four: synthesis of 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylic acid (FB 55)

FB53 (500 mg) was added to the eggplant-shaped flask, 40mL of a mixed solvent (MeOH: H ₂ o=1:1) was added, followed by sodium hydroxide (361 mg), and the mixture was heated to 80 ℃ and stirred overnight. After the reaction is finished, cooling to room temperature, adding dilute hydrochloric acid, extracting an aqueous phase with ethyl acetate for 3 times, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, pulping and purifying to obtain the target compound 216mg.¹H NMR(500MHz,DMSO-d₆)δ7.60(d,J＝8.4Hz,1H),7.47(dd,J＝8.5,7.1Hz,1H),7.44(d,J＝8.1Hz,2H),7.33(d,J＝8.2Hz,2H),7.15(d,J＝7.1Hz,1H),6.31–6.20(m,1H),2.41(s,2H),2.27–2.17(m,2H),1.82–1.70(m,2H),1.69–1.59(m,2H).

Synthetic intermediate 38:3- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (FB 94)

General method ten:

Step one: synthesis of methyl 3- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (FB 94)

2-Bromo-6-nitrobenzaldehyde (130 mg) and methyl 3- (aminomethyl) benzoate (125 mg) were added to an eggplant-shaped flask, isopropyl alcohol (10 mL) was added thereto, and the mixture was stirred at 80℃for 4 hours. After the completion of the reaction, the mixture was cooled to room temperature, tributylphosphine (453 mg) was added dropwise thereto, and the mixture was stirred at 80℃for 16 hours. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the aqueous phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 95.2mg.¹H NMR(500MHz,Chloroform-d)δ8.01(dt,J＝9.1,1.9Hz,2H),7.94(d,J＝1.0Hz,1H),7.65(dd,J＝8.6,0.9Hz,1H),7.50–7.38(m,2H),7.25–7.20(m,1H),7.13(dd,J＝8.7,7.2Hz,1H),5.62(s,2H),3.90(s,3H).

Synthetic intermediate 39:4- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (FB 114)

Starting with 2-bromo-6-nitrobenzaldehyde (115 mg) and methyl 4- (aminomethyl) benzoate (90.7 mg), the title compound was obtained by the following general method 29.4mg.¹H NMR(500MHz,Chloroform-d)δ8.06–8.00(m,2H),7.95(s,1H),7.65(d,J＝8.6Hz,1H),7.32(d,J＝8.0Hz,2H),7.24(d,J＝7.2Hz,1H),7.14(dd,J＝8.7,7.2Hz,1H),5.64(s,2H),3.90(s,3H).

Synthetic intermediate 40:4- (2- (4-bromo-2H-indazol-2-yl) ethyl) benzoic acid methyl ester (FB 129)

Starting with 2-bromo-6-nitrobenzaldehyde (230 mg) and methyl 4- (2-aminoethyl) benzoate (211 mg), the title compound was obtained according to the general procedure described above 101mg.¹H NMR(500MHz,Chloroform-d)δ8.00–7.96(m,2H),7.78(s,1H),7.69(d,J＝8.6Hz,1H),7.26(d,J＝7.1Hz,1H),7.23–7.15(m,3H),4.68(t,J＝7.3Hz,2H),3.93(s,3H),3.43(t,J＝7.3Hz,2H).

Synthesis of intermediate 41:3- (2- (4-bromo-2H-indazol-2-yl) ethyl) benzoic acid methyl ester (FB 148)

Starting from 2-bromo-6-nitrobenzaldehyde (230 mg) and methyl 3- (2-aminoethyl) benzoate (192.3 mg), the following general procedure was followed, affording intermediate 42 for the synthesis of the title compound 57.6mg.¹H NMR(500MHz,Chloroform-d)δ7.91(d,J＝7.7Hz,1H),7.83(s,1H),7.74(s,1H),7.66(d,J＝8.6Hz,1H),7.32(t,J＝7.7Hz,1H),7.22(d,J＝7.0Hz,2H),7.17–7.10(m,1H),4.63(t,J＝7.4Hz,2H),3.88(s,3H),3.38(t,J＝7.4Hz,2H).: methyl 4- (4-bromo-1H-benzo [ d ] imidazol-2-yl) benzoate (FB 157-1) and methyl 4- (4-bromo-1- (4- (methoxycarbonyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) benzoate (FB 157-2)

General procedure eleven:

Step one: synthesis of methyl 4- (4-bromo-1H-benzo [ d ] imidazol-2-yl) benzoate (FB 157-1) and methyl 4- (4-bromo-1- (4- (methoxycarbonyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) benzoate (FB 157-2)

3-Bromobenzene 1, 2-diamine (187 mg) and methyl 4-formylbenzoate (181 mg) were added to an eggplant-shaped flask, ethanol (8 mL) was added, p-toluenesulfonic acid monohydrate was added, and the temperature was raised to 80℃and stirred for 24 hours. After the reaction, cooling to room temperature, adding water to quench the reaction, extracting the water phase with ethyl acetate for 3 times, mixing the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, purifying by a silica gel column to obtain a mixture of FB157-1 and FB157-2 286mg.¹H NMR(500MHz,Methanol-d_4,FB157-1)δ8.23(s,4H),7.71(dd,J＝8.2,0.8Hz,1H),7.64(dd,J＝7.8,0.8Hz,1H),7.38(t,J＝8.0Hz,1H),3.97(s,3H).¹H NMR(500MHz,Methanol-d₄,FB157-2)δ8.32–8.16(m,2H),8.04–7.94(m,2H),7.95–7.83(m,2H),7.75(dd,J＝7.9,0.8Hz,1H),7.63(d,J＝8.2Hz,1H),7.42(t,J＝8.1Hz,1H),7.22(d,J＝8.2Hz,2H),5.75(s,2H),3.96(s,3H),3.88(s,3H).

Synthetic intermediate 43: methyl 3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) benzoate (FB 160-1) and methyl 3- (4-bromo-1- (3- (methoxycarbonyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) benzoate (FB 160-2)

Starting from 3-bromobenzene 1, 2-diamine (561 mg) and methyl 3-formylbenzoate (541.2 mg), a mixture of FB160-1 and FB160-2 was obtained according to general procedure eleven 752mg.¹H NMR(500MHz,Chloroform-d,FB160-1)δ8.65(s,1H),8.38(d,J＝7.8Hz,1H),8.14(d,J＝7.8Hz,1H),7.65(s,1H),7.59(t,J＝7.8Hz,1H),7.45(d,J＝7.8Hz,1H),7.18(t,J＝7.9Hz,1H),3.95(s,3H).¹H NMR(500MHz,Methanol-d₄,FB160-2)δ8.26(t,J＝1.7Hz,1H),8.22(dt,J＝7.9,1.4Hz,1H),7.94(d,J＝7.8Hz,1H),7.93–7.90(m,1H),7.71–7.65(m,2H),7.62(dd,J＝7.8,0.9Hz,1H),7.58(dd,J＝8.3,0.8Hz,1H),7.42(t,J＝7.8Hz,1H),7.34–7.28(m,1H),5.64(s,2H),3.87(s,3H),3.83(s,3H).

Synthetic intermediate 44: methyl 2- (4- (4-bromo-1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (FC 56-1) and methyl 2- (4- (4-bromo-1- (4- (2-methoxy-2-oxoethyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (FC 56-2)

Starting from 3-bromobenzene 1, 2-diamine (156.7 mg) and methyl 3-formylbenzoate (163.7 mg), a mixture of FC56-1 and FC56-2 was obtained according to general procedure eleven 169mg.¹H NMR(500MHz,Methanol-d₄,FC56-1)δ8.12–8.06(m,2H),7.70(d,J＝8.1Hz,1H),7.64(d,J＝7.8Hz,1H),7.57(d,J＝8.1Hz,2H),7.38(t,J＝8.0Hz,1H),3.80(s,2H),3.72(s,3H).¹H NMR(500MHz,Chloroform-d,FC56-2)δ7.69–7.63(m,2H),7.57(dd,J＝7.2,1.5Hz,1H),7.45–7.38(m,2H),7.30–7.24(m,2H),7.23–7.15(m,2H),7.02(d,J＝8.1Hz,2H),5.46(s,2H),3.72–3.68(m,8H),3.62(s,2H).

Synthetic intermediate 45: methyl 2- (3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (FC 55-1) and methyl 2- (3- (4-bromo-1- (3- (2-methoxy-2-oxoethyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (FC 55-2)

Starting from 3-bromobenzene 1, 2-diamine (335 mg) and methyl 2- (3-formylphenyl) acetate (350 mg), a mixture of FC55-1 and FC55-2 was obtained according to general procedure eleven 419mg.¹H NMR(500MHz,Methanol-d₄,FC55-1)δ8.10–8.02(m,2H),7.72(dd,J＝8.1,0.8Hz,1H),7.67(dd,J＝7.9,0.8Hz,1H),7.64–7.62(m,2H),7.44–7.39(m,1H),3.83(s,2H),3.72(s,3H).¹H NMR(500MHz,Methanol-d₄,FC55-2)δ7.69(q,J＝1.6,1.1Hz,1H),7.65–7.52(m,5H),7.39–7.34(m,1H),7.24(dd,J＝7.6,2.7Hz,1H),7.19(dt,J＝7.8,1.4Hz,1H),7.04–6.97(m,2H),5.60(s,2H),3.74(s,2H),3.64(s,3H),3.60(s,3H),3.56(s,2H).

Synthetic intermediate 46:4- (4- (trifluoromethyl) phenyl) -1H-indazol-3-amine (QM 73)

Starting from 2-bromo-6-fluorobenzonitrile (521 mg) and (4- (trifluoromethyl) phenyl) boronic acid (521 mg), the title compound was obtained according to the general procedure one 577mg.¹H NMR(500MHz,Chloroform-d)δ7.76(d,J＝8.01Hz,2H),7.66(d,J＝7.93Hz,2H),7.42–7.32(m,2H),6.96(dd,J＝6.78,1.07Hz,1H).

Synthetic intermediate 47:4- (2-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 82)

The target compound was obtained by using cyclohex-1-en-1-ylboronic acid (630 mg) and 4-bromo-2-fluoro-1-iodobenzene (1500 mg) as starting materials according to the general procedure III 623mg.¹H NMR(500MHz,Chloroform-d)δ7.38–7.33(m,2H),7.32–7.28(m,1H),7.25(dd,J＝7.78,1.46Hz,1H),7.20(dd,J＝11.64,1.73Hz,1H),6.94(dd,J＝6.92,0.99Hz,1H),6.05(tt,J＝3.79,1.68Hz,1H),2.47–2.39(m,2H),2.28–2.21(m,2H),1.83–1.76(m,2H),1.74–1.67(m,2H).

Synthetic intermediate 48:4- (3-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 85)

Starting from cyclohex-1-en-1-ylboronic acid (630 mg) and 1-bromo-2-fluoro-4-iodobenzene (1500 mg), 551mg of the title compound was obtained according to general procedure three.

Synthesis of intermediate 49:4- (4-cyclopropylphenyl) -1H-indazol-3-amine (QM 107)

Starting from 4 '-bromo-3-fluoro- [1,1' -biphenyl ] -2-carbonitrile (500 mg) and cyclopropylboronic acid (156 mg), the title compound was obtained according to general procedure two 266mg.¹H NMR(500MHz,Chloroform-d)δ7.44(d,J＝7.68Hz,2H),7.40–7.27(m,2H),7.21(d,J＝7.83Hz,2H),6.95(d,J＝7.00Hz,1H),2.00(tt,J＝8.51,5.12Hz,1H),1.09–1.03(m,2H),0.84–0.77(m,2H).

Synthesis of intermediate 50:3- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FC 25)

Starting from 3-bromobenzene 1, 2-diamine (225 mg) and methyl 3- (2-oxoethyl) benzoate (425 mg), 125mg of the title compound was obtained according to the general method eleven. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d₄)δ8.09(s,1H),8.01(dt,J＝7.8,1.4Hz,1H),7.69(ddd,J＝15.8,8.2,0.8Hz,3H),7.55(d,J＝7.7Hz,1H),7.43(t,J＝8.1Hz,1H),4.61(s,2H),3.90(s,4H).¹³C NMR(126MHz,Methanol-d4)δ167.91,155.12,135.32,134.86,134.41,133.57,132.47,131.17,130.73,130.27,129.83,128.09,114.32,107.25,52.81,33.61.

Synthetic intermediate 51:4- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FE 72)

Starting from 3-bromobenzene 1, 2-diamine (2.3 g) and methyl 4- (2-oxoethyl) benzoate (2.2 g), the title compound 840.3mg was obtained according to the general procedure eleven. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d₄)δ8.08–7.98(m,2H),7.70(t,J＝8.6Hz,2H),7.51(d,J＝8.1Hz,2H),7.43(t,J＝8.0Hz,1H),4.62(s,2H),3.90(s,3H).¹³C NMR(126MHz,Methanol-d4)δ167.92,154.74,139.94,134.31,133.47,131.43,131.20,130.37,129.88,128.15,114.34,107.22,52.75,33.66.

Synthetic intermediate 52: 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FC 98)

Starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (1250 mg) and 4-bromo-2-methyl-1H-benzo [ d ] imidazole (775.3 mg), 764.3mg of the title compound was obtained according to the general procedure fourteen. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d₄)δ7.63(dd,J＝8.1,1.1Hz,1H),7.61–7.55(m,4H),7.53(t,J＝7.8Hz,1H),7.47(dd,J＝7.6,1.1Hz,1H),6.25(tt,J＝3.9,1.8Hz,1H),2.77(s,3H),2.48(tq,J＝6.3,2.2Hz,2H),2.26(tq,J＝6.0,2.8Hz,2H),1.88–1.80(m,2H),1.75–1.67(m,2H).¹³C NMR(126MHz,Methanol-d4)δ153.29,144.15,137.44,135.99,135.02,131.90,129.83,129.39,126.70,126.52,126.36,125.79,113.64,28.41,26.93,24.19,23.27,12.72.

Synthetic intermediate 53: 2-ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FE 2)

Step one: starting from 3-bromobenzene 1, 2-diamine (500 mg) and propionaldehyde (157 mg), 201mg of the target compound was obtained according to general method eleven. Trifluoroacetate type compound data ¹H NMR(500MHz,Chloroform-d)δ7.46(d,J＝8.0Hz,1H),7.38(d,J＝7.7Hz,1H),7.07(t,J＝7.9Hz,1H),3.01(q,J＝7.7Hz,2H),1.40(t,J＝7.6Hz,3H).

Step two: starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (312 mg) and 4-bromo-2-ethyl-1H-benzo [ d ] imidazole (201 mg), 211.5mg of the title compound was obtained according to the general procedure fourteen. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d4)δ7.71(dd,J＝8.2,1.1Hz,1H),7.65–7.54(m,6H),6.26(tt,J＝3.9,1.7Hz,1H),3.20(q,J＝7.7Hz,2H),2.48(tq,J＝6.3,2.3Hz,2H),2.27(ddt,J＝8.4,6.1,2.7Hz,2H),1.89–1.80(m,2H),1.75–1.67(m,2H),1.50(t,J＝7.7Hz,3H).¹³C NMR(126MHz,Methanol-d4)δ157.67,144.41,137.41,135.52,133.65,130.80,130.08,129.44,127.23,126.79,126.60,126.52,113.46,28.40,26.93,24.18,23.25,21.25,11.80.

Synthetic intermediate 54:2- (2- ((tert-Butyldiphenylsilyl) oxy) ethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FC 76)

Step one: starting from 3-bromobenzene 1, 2-diamine (617 mg) and 3- ((tert-butyldiphenylsilyl) oxy) propanal (1.0 g), the title compound 394.6mg was obtained according to general procedure eleven. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d4)δ7.76–7.70(m,2H),7.48(t,J＝8.1Hz,1H),7.42–7.35(m,6H),7.27–7.23(m,4H),4.18(t,J＝5.7Hz,2H),3.41(t,J＝5.7Hz,2H),0.93(s,9H).¹³C NMR(126MHz,Methanol-d4)δ155.26,136.39,135.93,133.67,133.63,131.15,129.90,128.83,128.24,114.21,106.94(d,J＝21.6Hz),62.51,31.48,27.14,19.79.

Step two: starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (458 mg) and 4-bromo-2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) -1H-benzo [ d ] imidazole (394.6 mg), 419.7mg of the title compound was obtained according to general procedure fourteen. Trifluoroacetate type compound data ¹H NMR(500MHz,Chloroform-d)δ7.61(d,J＝7.3Hz,5H),7.41(q,J＝7.1,6.5Hz,5H),7.33(dd,J＝9.7,5.6Hz,7H),6.14(d,J＝4.1Hz,1H),4.06(t,J＝5.6Hz,2H),3.15(t,J＝5.6Hz,2H),2.41(q,J＝5.2Hz,2H),2.24(tq,J＝6.1,2.8Hz,2H),1.81(ddt,J＝12.0,8.7,4.5Hz,2H),1.73–1.64(m,2H),1.03(s,9H).

Synthetic intermediate 55: methyl 4- ((2- (2-hydroxyethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (FD 77)

Step one: starting from 2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (200 mg) and methyl 4- (bromomethyl) benzoate (156 mg), 167.5mg of the title compound was obtained according to general procedure twelve. Trifluoroacetate type compound data ¹H NMR(500MHz,Chloroform-d)δ7.98(d,J＝8.1Hz,2H),7.94(d,J＝8.1Hz,2H),7.53–7.48(m,6H),7.43(d,J＝7.5Hz,1H),7.38–7.33(m,2H),7.25(td,J＝7.5,7.1,3.9Hz,5H),7.08(d,J＝8.0Hz,1H),7.03(d,J＝8.1Hz,2H),6.19(td,J＝4.0,1.9Hz,1H),5.42(s,2H),4.13(t,J＝6.3Hz,2H),3.90(s,3H),3.14(t,J＝6.3Hz,2H),2.47(td,J＝5.9,5.3,2.5Hz,2H),2.24(tq,J＝6.0,2.9Hz,2H),1.81(dtt,J＝8.7,6.1,3.1Hz,2H),1.69(ddd,J＝9.2,7.4,4.6Hz,2H),1.02(s,9H).

Step two: methyl 4- ((2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl)) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (167.5 mg) and tetrabutylammonium fluoride trihydrate (95 mg) were added to an eggplant-shaped flask, THF (10 mL) was added, and stirring was continued overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 99.1mg.¹H NMR(500MHz,Chloroform-d)δ7.98(dd,J＝11.7,8.1Hz,4H),7.53(d,J＝8.2Hz,2H),7.45(d,J＝7.5Hz,1H),7.28(t,J＝7.6Hz,1H),7.14(d,J＝8.0Hz,1H),7.09(d,J＝8.1Hz,2H),6.23(td,J＝3.9,1.9Hz,1H),5.33(s,2H),4.07(t,J＝5.4Hz,2H),3.89(s,3H),2.93(t,J＝5.4Hz,2H),2.47(tt,J＝4.6,2.3Hz,2H),2.25(dh,J＝5.9,2.7Hz,2H),1.89–1.77(m,2H),1.74–1.61(m,2H).

Synthesis of intermediate 56: methyl 3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) propanoate (FC 120)

Starting from 3-bromobenzene 1, 2-diamine (400 mg) and methyl 4-oxobutyrate (270 mg), 83.5mg of the title compound was obtained according to general method eleven. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d4)δ7.69(ddd,J＝9.3,8.1,0.8Hz,2H),7.42(t,J＝8.1Hz,1H),3.68(s,3H),3.43(t,J＝7.1Hz,2H),3.05(t,J＝7.1Hz,2H).¹³C NMR(126MHz,Methanol-d4)δ173.32,156.08,134.23,133.35,129.56,127.84,114.21,106.99,52.61,31.45,23.41.

Synthesis of intermediate 57: methyl 3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) propanoate (FD 33)

Starting from 3-bromobenzene 1, 2-diamine (412 mg) and methyl 5-oxopentanoate (573 mg), the title compound was obtained by the general procedure eleven 192.4mg.¹H NMR(500MHz,Chloroform-d)δ7.52(d,J＝8.1Hz,1H),7.38(d,J＝7.8Hz,1H),7.11(t,J＝7.9Hz,1H),3.68(s,3H),3.02(t,J＝7.4Hz,2H),2.46(t,J＝7.0Hz,2H),2.18(p,J＝7.3Hz,2H).

Synthetic intermediate 58: 4-bromo-2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -1H-benzo [ d ] imidazole (FD 126)

Starting from 3-bromobenzene 1, 2-diamine (2548 mg) and 4- ((tert-butyldiphenylsilyl) oxy) butanal (4.45 g), the title compound was obtained by reference to general procedure eleven 667.9mg.¹H NMR(500MHz,Chloroform-d)δ7.68–7.60(m,4H),7.49–7.28(m,8H),7.06(d,J＝7.9Hz,1H),3.77(t,J＝5.8Hz,2H),3.13(t,J＝7.4Hz,2H),2.10(ddd,J＝12.8,7.2,5.6Hz,2H),1.05(s,9H).

Synthetic intermediate 59: methyl 4- ((1- (3- (dimethylamino) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FC 158)

Step one: starting from methyl 4- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (97.6 mg) and 3-bromo-N, N-dimethylpropan-1-amine (280 mg), crude compound (56 mg) was obtained according to general procedure twelve.

Step two: starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (127 mg) and methyl 4- ((4-bromo-1- (3- (dimethylamino) propyl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (56 mg), crude compound (7.6 mg) was obtained, ms= 507.3, according to the general procedure fourteen.

Synthetic intermediate 60: methyl 4- ((1- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl)) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FD 125)

Step one: the title compound was obtained by using methyl 4- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (388.6 mg) and tert-butyl (3-iodopropoxy) diphenylsilane (932.8 mg) as starting materials according to the general procedure twelve 274.8mg.¹H NMR(500MHz,Chloroform-d)δ7.95–7.91(m,2H),7.64–7.60(m,4H),7.47–7.42(m,3H),7.38(dd,J＝7.9,6.6Hz,4H),7.27(dd,J＝11.3,8.0Hz,3H),7.09(t,J＝7.9Hz,1H),4.45(s,2H),4.13(td,J＝7.2,2.6Hz,2H),3.88(s,3H),3.58(t,J＝5.5Hz,2H),1.78–1.56(m,2H),1.10(s,9H).

Step two: starting from methyl 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (185 mg) and 4- ((4-bromo-1- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (274.8 mg), the title compound was obtained by reference to general procedure fourteen (198.1mg).¹H NMR(500MHz,Chloroform-d)δ8.07–8.02(m,2H),7.99–7.94(m,2H),7.69–7.65(m,4H),7.58–7.54(m,2H),7.50–7.39(m,7H),7.34–7.30(m,4H),6.23(tt,J＝3.9,1.7Hz,1H),4.47(s,2H),4.20(dd,J＝8.3,6.4Hz,2H),3.92(s,3H),3.65(t,J＝5.4Hz,2H),2.50(tq,J＝6.4,2.2Hz,2H),2.27(tt,J＝6.2,3.1Hz,2H),1.88–1.75(m,4H),1.75–1.67(m,2H),1.14(s,9H).

Synthetic intermediate 61: methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (FE 88)

Step one: methyl 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (572.7 mg) and Cs2CO3 (456 mg) were added to an eggplant-shaped flask, DMF (5 mL) was added, and the mixture was warmed to 90℃and stirred for 20H. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give a crude product (544.7 mg). LC-Ms 437.5.

Step two: methyl 4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole-2-carbonyl) benzoate (200 mg) and HO-NH ₂ HCl (324 mg) were added to an eggplant-shaped flask, mixed solvents (8 mL, ethanol: pyridine=1:1) and KOAc (461 mg) were added, and the mixture was warmed to 80 ℃ and stirred overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and purified by a silica gel column to give a crude compound. Zn (366 mg) was then added to the eggplant-shaped flask, acOH (5 mL) was added, and the mixture was allowed to stand overnight at room temperature. After the completion of the reaction, the pH was adjusted to be weakly alkaline with saturated sodium hydrogencarbonate, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to give 171.2mg of the objective compound. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d₄)δ8.10(d,J＝8.1Hz,2H),7.83(d,J＝8.0Hz,2H),7.65(d,J＝8.1Hz,2H),7.51(dd,J＝16.1,8.0Hz,3H),7.39(d,J＝7.4Hz,1H),7.33(t,J＝7.7Hz,1H),6.19(q,J＝2.8,2.1Hz,1H),5.96(s,1H),3.90(s,3H),2.45(tt,J＝4.5,2.4Hz,2H),2.23(dh,J＝6.1,2.8Hz,2H),1.86–1.77(m,2H),1.73–1.63(m,2H).¹³C NMR(126MHz,Methanol-d4)δ167.61,150.40,143.17,140.38,139.59,138.51,137.69,137.62,132.88,131.50,131.43,129.80,129.69,126.12,125.68,124.79,123.19,118.38,116.08,114.35,53.71,52.88,28.42,26.90,24.21,23.30.

Synthetic intermediate 62: 2-propyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FE 10)

Starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (233 mg) and 4-bromo-2-propyl-1H-benzo [ d ] imidazole (162 mg), 195mg of the title compound was obtained according to the general procedure fourteen. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d4)δ7.71(d,J＝8.1Hz,1H),7.65–7.52(m,6H),6.26(dq,J＝4.1,1.9Hz,1H),3.14(t,J＝7.6Hz,2H),2.48(ddt,J＝6.2,3.9,2.2Hz,2H),2.26(tq,J＝6.1,2.8Hz,2H),1.94(h,J＝7.4Hz,2H),1.84(dtt,J＝10.9,7.5,3.9Hz,2H),1.76–1.67(m,2H),1.06(t,J＝7.4Hz,3H).13C NMR(126MHz,Methanol-d4)δ156.42,144.48,137.38,135.33,133.22,130.42,130.12,129.45,127.51,126.82,126.57,113.40,29.20,28.39,26.93,24.17,23.24,22.19,13.78. synthesis of intermediate 63: 2-butyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FE 20)

Step one: the target compound was obtained by using 3-bromobenzene 1, 2-diamine (500 mg) and valeraldehyde (232 mg) as raw materials and referring to general procedure eleven 208mg.¹H NMR(500MHz,Chloroform-d)δ7.46(d,J＝8.0Hz,1H),7.38(d,J＝7.8Hz,1H),7.07(t,J＝7.9Hz,1H),3.00–2.88(m,2H),1.79(p,J＝7.7Hz,2H),1.38–1.29(m,2H),0.83(t,J＝7.4Hz,3H).

Step two: starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (284 mg) and 4-bromo-2-butyl-1H-benzo [ d ] imidazole (208 mg), 214mg of the title compound was obtained according to the general procedure fourteen. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d₄)δ7.71(d,J＝8.1Hz,1H),7.65–7.53(m,6H),6.26(tt,J＝3.7,1.6Hz,1H),3.17(t,J＝7.8Hz,2H),2.48(tt,J＝4.5,2.3Hz,2H),2.26(tq,J＝6.0,2.8Hz,2H),1.94–1.78(m,4H),1.77–1.63(m,2H),1.47(h,J＝7.4Hz,2H),1.01(t,J＝7.4Hz,3H).¹³C NMR(126MHz,Methanol-d₄)δ156.61,144.54,137.39,135.26,133.01,130.26,130.14,129.46,127.62,126.93,126.85,126.60,113.35,30.63,28.40,27.13,26.93,24.17,23.25,13.79.

Synthetic intermediate 64: 2-isopropyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FE 78)

Step one: the target compound was obtained by using 3-bromobenzene 1, 2-diamine (1000 mg) and isobutyraldehyde (385 mg) as raw materials and referring to general method eleven 409.3mg.¹H NMR(500MHz,Chloroform-d)δ7.45(d,J＝8.1Hz,1H),7.37(d,J＝7.7Hz,1H),7.06(t,J＝7.9Hz,1H),3.34(p,J＝7.0Hz,1H),1.45(s,3H),1.44(s,3H).

Step two: starting with 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (568 mg) and 4-bromo-2-isopropyl-1H-benzo [ d ] imidazole (409.3 mg), 470.2mg of the title compound was obtained according to the general procedure fourteen. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d₄)δ7.72(dd,J＝8.2,1.0Hz,1H),7.60(t,J＝7.9Hz,1H),7.58–7.54(m,4H),7.51(dd,J＝7.6,1.0Hz,1H),6.24(tt,J＝3.9,1.7Hz,1H),3.57(p,J＝7.0Hz,1H),2.46(tq,J＝6.3,2.3Hz,2H),2.24(dtt,J＝6.3,4.2,2.2Hz,2H),1.86–1.78(m,2H),1.73–1.65(m,2H),1.54(s,3H),1.52(s,3H).¹³C NMR(126MHz,Methanol-d₄)δ144.44,137.35,135.23,132.94,130.21,130.17,129.50,127.56,127.04,126.78,126.52,28.77,28.37,26.92,24.15,23.23,20.75.

Synthetic intermediate 65: methyl 4- ((2- (3-aminopropyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (FD 126)

Step one: starting with 2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (300 mg) and methyl 4- (bromomethyl) benzoate (229 mg), the title compound was obtained by general procedure twelve 338.9mg.¹H NMR(500MHz,Chloroform-d)δ8.04–8.01(m,2H),7.99–7.95(m,2H),7.63–7.60(m,4H),7.53–7.50(m,2H),7.47–7.43(m,2H),7.41–7.39(m,1H),7.33(dd,J＝7.9,6.7Hz,4H),7.28–7.24(m,1H),7.11(dd,J＝8.1,1.0Hz,1H),7.08(d,J＝8.2Hz,2H),6.21(tt,J＝4.0,1.6Hz,1H),5.40(s,2H),3.91(s,3H),3.81(t,J＝5.8Hz,2H),3.00(t,J＝7.7Hz,2H),2.48(ddq,J＝6.5,4.2,2.1Hz,2H),2.25(dt,J＝9.4,4.5Hz,2H),2.10(dq,J＝12.4,6.1Hz,2H),1.87–1.79(m,2H),1.73–1.66(m,2H),1.04(s,9H).

Step two: methyl 4- ((2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl)) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (338.9 mg) and tetrabutylammonium fluoride trihydrate (296 mg) were added to an eggplant-shaped flask, THF (20 mL) was added, and stirring was continued overnight at room temperature. After the reaction is finished, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 195.4mg.¹H NMR(500MHz,Chloroform-d)δ7.96(d,J＝8.1Hz,2H),7.91(d,J＝8.2Hz,2H),7.53(d,J＝8.3Hz,2H),7.41(d,J＝7.5Hz,1H),7.26(t,J＝7.7Hz,1H),7.11(d,J＝8.0Hz,1H),7.08(d,J＝8.1Hz,2H),6.21(tt,J＝3.7,1.6Hz,1H),5.34(s,2H),3.89(s,3H),3.71(t,J＝5.2Hz,2H),2.94(t,J＝6.5Hz,2H),2.45(ddt,J＝6.2,4.3,2.1Hz,2H),2.22(dq,J＝9.1,5.5,4.1Hz,2H),2.01(q,J＝5.9Hz,2H),1.82–1.76(m,2H),1.70–1.62(m,2H).

Step three: methyl 4- ((2- (3-hydroxypropyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (195.4 mg) and isoindoline-1, 3-dione (91 mg) were added to an eggplant-shaped flask, THF (10 mL) and triphenylphosphine (314 mg) were added, stirring was performed at 0deg.C for 0.5H, diisopropyl 1, 2-dicarboxylate (242 mg) was then added dropwise, the temperature was raised to room temperature, and stirring was performed overnight. After the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give a crude product. The crude product was then added to an eggplant-shaped flask and dissolved in methanol (10 mL) and N ₂H₄-H₂ O (50 mg) was added. Stirred overnight at room temperature and purified by silica gel column to give 76.1mg of the title compound. Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d₄)δ7.96–7.90(m,2H),7.84–7.78(m,2H),7.47(d,J＝8.3Hz,2H),7.31(dd,J＝5.6,2.9Hz,1H),7.26–7.20(m,2H),7.14(d,J＝8.2Hz,2H),6.18(tt,J＝3.9,1.7Hz,1H),5.53(s,2H),3.84(s,3H),2.93(t,J＝7.5Hz,2H),2.70(t,J＝6.9Hz,2H),2.43(tq,J＝6.5,2.2Hz,2H),2.21(tq,J＝6.2,2.7Hz,2H),1.86(p,J＝7.2Hz,2H),1.83–1.74(m,2H),1.71–1.58(m,2H).

Synthetic intermediate 66: methyl 2- (4- ((4-bromo-2-phenyl-1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetate (FE 128)

Step one: starting with 4-bromo-2-phenyl-1H-benzo [ d ] imidazole (489.6 mg) and (4- (bromomethyl) phenethyl) (tert-butyl) diphenylsilane (1.6 g), the title compound was obtained according to the general procedure twelve 284.5mg.¹H NMR(500MHz,Chloroform-d)δ7.74–7.70(m,2H),7.60–7.57(m,4H),7.51–7.46(m,3H),7.44–7.39(m,4H),7.34(d,J＝7.4Hz,3H),7.15–7.12(m,2H),7.07(d,J＝7.8Hz,1H),6.98(d,J＝7.8Hz,2H),5.41(s,2H),3.84(t,J＝6.7Hz,2H),2.84(t,J＝6.7Hz,2H),1.02(s,9H).

Step two: 4-bromo-1- (4- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) benzyl) -2-phenyl-1H-benzo [ d ] imidazole (284.5 mg) and tetrabutylammonium fluoride trihydrate (277 mg) were added to an eggplant-shaped flask, THF (10 mL) was added, and stirred at room temperature overnight. After the completion of the reaction, the mixture was concentrated by a rotary evaporator to give a crude compound (159 mg). IBX (280 mg) was then added to an eggplant-shaped flask, THF (5 mL) was added, and stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to give the crude compound (141.6 mg). The crude compound was then dissolved in H ₂ O: t-BuOH (0.1M, 5 mL), 2, 3-dimethyl-2-butene (0.1 mL), naH ₂PO₄ (35.6 mg), sodium chlorite (28 mg) were added, reacted at room temperature for 3 hours, after the completion of the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give the crude compound (147 mg). Then dissolved in methanol, concentrated sulfuric acid (0.1 mL) was added and stirred at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator to obtain a crude compound (140mg).¹H NMR(500MHz,Chloroform-d)δ7.66–7.63(m,2H),7.49–7.46(m,1H),7.45–7.42(m,1H),7.40(d,J＝7.5Hz,2H),7.22(d,J＝8.0Hz,2H),7.13(dd,J＝8.4,1.0Hz,1H),7.07(t,J＝7.9Hz,1H),7.00(d,J＝7.9Hz,2H),5.38(s,2H),3.68(s,3H),3.60(s,2H).

Synthesis of intermediate 67: methyl 2- (2- ((4-bromo-2-phenyl-1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetate (FD 157)

Step one: starting from 4-bromo-2-phenyl-1H-benzo [ d ] imidazole (400 mg) and (2- (bromomethyl) phenethyl) (tert-butyl) diphenylsilane (1.67 g), the title compound was obtained in an amount of 1.53g according to general procedure twelve.

Step two: 4-bromo-1- (2- (2- ((tert-butyldiphenylsilyl) oxy) ethyl) benzyl) -2-phenyl-1H-benzo [ d ] imidazole (300 mg) and tetrabutylammonium fluoride trihydrate (290 mg) were added to an eggplant-shaped flask, THF (15 mL) was added, and stirring was continued at room temperature overnight. After the completion of the reaction, the mixture was concentrated by a rotary evaporator to give a crude compound (130 mg). IBX (256 mg) was then added to an eggplant-shaped flask, THF (5 mL) was added, and stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to give the crude compound (135 mg). The crude compound was then dissolved in H ₂ O: t-BuOH (0.1M, 5 mL), 2, 3-dimethyl-2-butene (0.1 mL), naH ₂PO₄ (34 mg), sodium chlorite (25 mg) were added, reacted at room temperature for 3 hours, after the completion of the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give the crude compound (125 mg). Then dissolved in methanol, concentrated sulfuric acid (0.1 mL) was added and stirred at room temperature overnight. After the completion of the reaction, the mixture was concentrated by a rotary evaporator to give a crude compound (86.6 mg). Trifluoroacetate type compound data ¹H NMR(500MHz,Methanol-d₄)δ7.75–7.70(m,2H),7.66(td,J＝7.6,1.1Hz,2H),7.62–7.53(m,2H),7.48(dd,J＝8.3,0.9Hz,1H),7.35–7.25(m,3H),7.18(ddd,J＝8.9,7.0,2.0Hz,1H),6.74–6.69(m,1H),5.68(s,2H),3.75(s,2H),3.56(s,3H).¹³C NMR(126MHz,Methanol-d₄)δ173.00,155.56,138.10,136.51,135.15,133.47,133.01,132.71,130.77,130.32,129.44,129.19,128.96,127.32,127.07,126.97,112.81,111.02,52.63,38.81.

EXAMPLE 1 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (4-chlorophenyl) -1H-indazol-3-amine (QJ 54)

General method six:

4- (4-chlorophenyl) -1H-indazol-3-amine (99 mg) and 1H-imidazole-4-carbaldehyde (47 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane was added, followed by sodium triacetoxyborohydride (174 mg), acetic acid (0.1 mL) was added dropwise, and the mixture was stirred at room temperature under nitrogen atmosphere overnight. After the reaction, adding a saturated sodium bicarbonate solution, extracting with ethyl acetate for 3 times, combining organic phases, washing with saturated saline water, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, purifying by HPLC to obtain the trifluoroacetate of the target compound, and freeze-drying to obtain a solid 37.4mg.¹H NMR(400MHz,Methanol-d₄)δ8.74(d,J＝1.48Hz,1H),7.56–7.45(m,4H),7.40–7.30(m,3H),6.89(dd,J＝6.07,1.85Hz,1H),4.49(s,2H).ESI-MS theoretical calculated value C ₁₇H₁₅ ³⁵ClN₅ ⁺[M+H]⁺ = 324.1; the experiment shows that: 324.0.

EXAMPLE 2 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-chlorophenyl) -1H-indazol-3-amine (QJ 60)

Starting from 4- (3-chlorophenyl) -1H-indazol-3-amine (73 mg) and 1H-imidazole-4-carbaldehyde (35 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 64.2mg.¹H NMR(400MHz,Methanol-d₄)δ8.77(d,J＝1.44Hz,1H),7.52(t,J＝1.83Hz,1H),7.48–7.35(m,6H),6.90(dd,J＝6.27,1.62Hz,1H),4.53(s,2H).ESI-MS of the target compound C ₁₇H₁₅ ³⁵ClN₅ ⁺[M+H]⁺ = 324.1; the experiment shows that: 324.1.

EXAMPLE 3 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4-phenyl-1H-indazol-3-amine (QJ 64)

Starting from 4-phenyl-1H-indazol-3-amine (50 mg) and 1H-imidazole-4-carbaldehyde (28 mg), reference was made to general procedure six to give the theoretical calculation of trifluoroacetate 52.8mg.¹H NMR(400MHz,Methanol-d₄)δ8.74(d,J＝1.48Hz,1H),7.58–7.40(m,5H),7.40–7.24(m,3H),6.88(dd,J＝6.49,1.41Hz,1H),4.48(s,2H)..ESI-MS of the target compound C ₁₇H₁₆N₅ ⁺[M+H]⁺ =290.1; the experiment shows that: 290.1.

EXAMPLE 4 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 68)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (65 mg) and 1H-imidazole-4-carbaldehyde (28 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 70.4mg.¹H NMR(400MHz,Methanol-d₄)δ8.77(d,J＝1.47Hz,1H),7.56–7.48(m,2H),7.47–7.40(m,2H),7.40–7.29(m,3H),6.88(dd,J＝6.82,1.12Hz,1H),4.49(s,2H),1.36(s,9H).ESI-MS of the title compound C ₂₁H₂₄N₅ ⁺[M+H]⁺ = 346.2; the experiment shows that: 346.3.

EXAMPLE 5 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 73)

Starting from 4- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (96 mg) and 1H-imidazole-4-carbaldehyde (42 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 70.4mg.¹H NMR(400MHz,Methanol-d₄)δ8.77(d,J＝1.45Hz,1H),7.55–7.46(m,2H),7.46–7.39(m,2H),7.38–7.28(m,3H),6.92(dd,J＝6.95,0.99Hz,1H),4.52(s,2H),1.32(s,9H).ESI-MS of the target compound C ₂₁H₂₄N₅ ⁺[M+H]⁺ = 346.2; the experiment shows that: 346.2.

EXAMPLE 6 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (naphthalen-2-yl) -1H-indazol-3-amine (QJ 74)

Starting from 4- (naphthalen-2-yl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (36 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 81.4mg.¹H NMR(400MHz,Methanol-d₄)δ8.69(d,J＝1.57Hz,1H),8.04–7.97(m,2H),7.96–7.88(m,2H),7.66(dd,J＝8.48,1.76Hz,1H),7.58–7.50(m,2H),7.45–7.33(m,2H),7.25(d,J＝1.38Hz,1H),7.01(dd,J＝6.68,1.18Hz,1H),4.44(s,2H).ESI-MS of the target compound C ₂₁H₁₈N₅ ⁺[M+H]⁺ =340.1; the experiment shows that: 340.1.

EXAMPLE 7 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (1H-indol-5-yl) -1H-indazol-3-amine (QJ 75)

Starting from 4- (1H-indol-5-yl) -1H-indazol-3-amine (263 mg) and 1H-imidazole-4-carbaldehyde (122 mg), reference was made to general procedure six to give the theoretical calculated of trifluoroacetate 74.3mg.¹H NMR(400MHz,Methanol-d₄)δ8.72(d,J＝1.47Hz,1H),7.63(d,J＝1.75Hz,1H),7.51(d,J＝8.32Hz,1H),7.46(dd,J＝8.51,7.03Hz,1H),7.35–7.28(m,3H),7.25(d,J＝1.34Hz,1H),7.21(dd,J＝8.32,1.75Hz,1H),6.97(d,J＝7.01Hz,1H),4.48(s,2H).ESI-MS of the title compound C ₁₉H₁₇N₆ ⁺[M+H]⁺ =329.1; the experiment shows that: 329.0.

EXAMPLE 8 Synthesis of 4-phenyl-N- (thiazol-2-ylmethyl) -1H-indazol-3-amine (QJ 77)

Starting from 4-phenyl-1H-indazol-3-amine (60 mg) and thiazole-2-carbaldehyde (40 mg), reference was made to general procedure six to give the theoretical calculation of trifluoroacetate 11.2mg.¹H NMR(400MHz,Methanol-d₄)δ7.83(d,J＝3.55Hz,1H),7.63(d,J＝3.46Hz,1H),7.56–7.45(m,6H),7.38(dd,J＝8.48,0.88Hz,1H),6.98(dd,J＝6.97,0.89Hz,1H),4.83(s,2H).ESI-MS of the target compound C ₁₇H₁₅N₄S⁺[M+H]⁺ = 307.1; the experiment shows that: 306.6.

EXAMPLE 9 Synthesis of 4-phenyl-N- (pyridin-4-ylmethyl) -1H-indazol-3-amine (QJ 78)

Starting from 4-phenyl-1H-indazol-3-amine (60 mg) and isonicotinal (40 mg), reference is made to general procedure six to give the theoretical calculated value C ₁₉H₁₇N₄ ⁺[M+H]⁺ =301.1 of trifluoroacetate 8.6mg.¹H NMR(500MHz,Methanol-d₄)δ8.72–8.66(m,2H),8.01–7.94(m,2H),7.61–7.57(m,2H),7.55–7.51(m,2H),7.48–7.44(m,1H),7.39(dd,J＝8.44,6.94Hz,1H),7.32(dd,J＝8.47,0.86Hz,1H),6.92(dd,J＝7.02,0.89Hz,1H),4.73(s,2H).ESI-MS of the target compound; the experiment shows that: 300.6.

EXAMPLE 10 Synthesis of 4-phenyl-N- (pyridin-3-ylmethyl) -1H-indazol-3-amine (QJ 80)

Starting from 4-phenyl-1H-indazol-3-amine (50 mg) and nicotinaldehyde (28 mg), reference was made to general procedure six to give the theoretical calculated value C ₁₉H₁₇N₄ ⁺[M+H]⁺ =301.1 of trifluoroacetate 29.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.76–8.72(m,1H),8.70(d,J＝5.72Hz,1H),8.54(dt,J＝8.17,1.72Hz,1H),8.00(dd,J＝8.13,5.75Hz,1H),7.58–7.50(m,4H),7.48–7.43(m,1H),7.40(dd,J＝8.47,6.94Hz,1H),7.33(dd,J＝8.43,0.89Hz,1H),6.92(dd,J＝6.99,0.92Hz,1H),4.64(s,2H).ESI-MS of the target compound; the experiment shows that: 300.6.

EXAMPLE 11 Synthesis of N, 1-bis (((1H-imidazol-4-yl) methyl) -4- ([ [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 91)

Starting from 4- ([ 1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (35 mg) and 1H-imidazole-4-carbaldehyde (18 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 25.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.83(d,J＝1.46Hz,1H),8.72(d,J＝1.45Hz,1H),7.79–7.73(m,2H),7.70–7.65(m,2H),7.59–7.55(m,2H),7.52–7.43(m,5H),7.39–7.30(m,2H),6.99(dd,J＝6.95,1.02Hz,1H),5.57(s,2H),4.53(s,2H).ESI-MS of the target compound C ₂₇H₂₄N₇ ⁺[M+H]⁺ =446.2; the experiment shows that: 446.1.

EXAMPLE 12 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -5- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 93)

Starting from 5- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (92 mg) and 1H-imidazole-4-carbaldehyde (36 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 60.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.83(d,J＝1.51Hz,1H),8.00(dd,J＝1.73,0.84Hz,1H),7.73(dd,J＝8.75,1.70Hz,1H),7.58–7.53(m,2H),7.51(q,J＝1.02Hz,1H),7.48–7.44(m,2H),7.41(dd,J＝8.68,0.84Hz,1H),4.71(s,2H),1.35(s,9H).ESI-MS of the title compound C ₂₁H₂₄N₅ ⁺[M+H]⁺ = 346.2; the experiment shows that: 345.9.

EXAMPLE 13 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -5- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (QJ 94)

Starting from 5- (3- (tert-butyl) phenyl) -1H-indazol-3-amine (95 mg) and 1H-imidazole-4-carbaldehyde (37 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 107.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.86(d,J＝1.47Hz,1H),8.15–8.08(m,1H),7.82(dd,J＝8.82,1.69Hz,1H),7.64(t,J＝1.87Hz,1H),7.56(d,J＝1.33Hz,1H),7.46(d,J＝8.80Hz,1H),7.42–7.31(m,3H),4.76(s,2H),1.35(s,9H).ESI-MS of the title compound C ₂₁H₂₄N₅ ⁺[M+H]⁺ = 346.2; the experiment shows that: 345.6.

EXAMPLE 14 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4-isopropylphenyl) -1H-indazol-3-amine (QJ 101)

Starting from 4- (4-isopropylphenyl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (33 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₀H₂₂N₅ ⁺[M+H]⁺ =332.1 of trifluoroacetate 78.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.47Hz,1H),7.43(dd,J＝8.25,2.14Hz,2H),7.39–7.29(m,5H),6.87(dt,J＝6.78,1.54Hz,1H),4.48(s,2H),2.98(pd,J＝7.13,1.87Hz,1H),1.30(dd,J＝7.01,1.51Hz,6H).ESI-MS of the target compound; the experiment shows that: 332.0.

EXAMPLE 15 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 103)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (32 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₃H₂₄N₅ ⁺[M+H]⁺ =370.2 of trifluoroacetate 14.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.48Hz,1H),7.54–7.50(m,2H),7.46–7.43(m,2H),7.38(dd,J＝8.46,6.88Hz,1H),7.35–7.30(m,2H),6.90(dd,J＝6.97,0.96Hz,1H),6.23(tt,J＝3.85,1.70Hz,1H),4.50(s,2H),2.46(tq,J＝6.41,2.27Hz,2H),2.26(ddt,J＝8.54,6.26,3.11Hz,2H),1.87–1.80(m,2H),1.74–1.67(m,2H).ESI-MS of the target compound; the experiment shows that: 370.3.

EXAMPLE 16 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (QJ 104)

Starting from 4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (34 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 47.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.48Hz,1H),7.61–7.57(m,2H),7.49–7.45(m,2H),7.44–7.40(m,2H),7.34–7.30(m,1H),6.92(dd,J＝8.06,6.90Hz,1H),6.31(p,J＝2.26Hz,1H),4.51(s,2H),2.76(tq,J＝6.92,2.24Hz,2H),2.57(tq,J＝7.45,2.52Hz,2H),2.07(p,J＝7.57Hz,2H).ESI-MS of the target compound C ₂₂H₂₂N₅ ⁺[M+H]⁺ =356.1; the experiment shows that: 356.4.

EXAMPLE 17 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4-cyclohexylphenyl) -1H-indazol-3-amine (QJ 107)

Starting from 4- (4-cyclohexylphenyl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (32 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₃H₂₆N₅ ⁺[M+H]⁺ =372.1 of trifluoroacetate 31mg.¹H NMR(500MHz,Methanol-d₄)δ8.76(d,J＝1.42Hz,1H),7.44–7.41(m,2H),7.40–7.30(m,5H),6.89(dd,J＝6.94,0.94Hz,1H),4.49(d,J＝0.99Hz,2H),2.64–2.54(m,1H),1.95–1.75(m,5H),1.56–1.41(m,4H),1.39–1.29(m,1H).ESI-MS of the target compound; the experiment shows that: 372.3.

EXAMPLE 18 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4-cyclopentylphenyl) -1H-indazol-3-amine (QJ 109)

Starting from 4- (4-cyclopentylphenyl) -1H-indazol-3-amine (100 mg) and 1H-imidazole-4-carbaldehyde (32 mg), reference was made to general procedure six to give the theoretical calculated value of trifluoroacetate 33.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.77(s,1H),7.45–7.29(m,7H),6.90(d,J＝6.82Hz,1H),4.50(s,2H),3.08(ddd,J＝17.14,9.77,7.47Hz,1H),2.15–2.05(m,2H),1.86(tq,J＝10.28,5.85,4.28Hz,2H),1.75(qt,J＝6.12,3.67Hz,2H),1.70–1.56(m,2H).ESI-MS of the target compound C ₂₂H₂₄N₅ ⁺[M+H]⁺ = 358.2; the experiment shows that: 358.8.

EXAMPLE 19 Synthesis of 4- (4- (tert-butyl) phenyl) -N- (pyridin-4-ylmethyl) -1H-indazol-3-amine (QJ 111)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (80 mg) and isonicotinal (32 mg), reference is made to general procedure six to give the theoretical calculation of trifluoroacetate 10.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.71–8.67(m,2H),8.00–7.95(m,2H),7.60–7.56(m,2H),7.55–7.50(m,2H),7.38(dd,J＝8.47,6.94Hz,1H),7.30(dd,J＝8.39,0.87Hz,1H),6.91(dd,J＝7.00,0.89Hz,1H),4.74(s,2H),1.38(s,9H).ESI-MS of the target compound C ₂₃H₂₅N₄ ⁺[M+H]⁺ =357.2; the experiment shows that: 356.5.

EXAMPLE 20 Synthesis of 4- (4- (tert-butyl) phenyl) -N- (pyridin-3-ylmethyl) -1H-indazol-3-amine (QJ 112)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (80 mg) and nicotinaldehyde (32 mg), reference was made to general procedure six to give the theoretical calculation of trifluoroacetate 28.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.78–8.73(m,1H),8.69(d,J＝5.69Hz,1H),8.52(dt,J＝8.26,1.61Hz,1H),7.98(dd,J＝8.15,5.71Hz,1H),7.58–7.53(m,2H),7.52–7.47(m,2H),7.37(dd,J＝8.43,6.94Hz,1H),7.30(dd,J＝8.56,0.89Hz,1H),6.89(dd,J＝6.92,0.95Hz,1H),4.64(s,2H),1.37(s,9H).ESI-MS of the target compound C ₂₃H₂₅N₄ ⁺[M+H]⁺ =357.2; the experiment shows that: 357.3.

EXAMPLE 21 Synthesis of 4- (4- (tert-butyl) phenyl) -N- (pyridin-2-ylmethyl) -1H-indazol-3-amine (QJ 114)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (80 mg) and pyridylaldehyde (32 mg), reference was made to general procedure six to give the theoretical calculation of trifluoroacetate 27.7mg.¹H NMR(500MHz,Methanol-d₄)δ8.66(dt,J＝5.76,1.23Hz,1H),8.46(td,J＝7.92,1.58Hz,1H),7.98(d,J＝8.10Hz,1H),7.87(ddd,J＝7.48,5.82,1.24Hz,1H),7.60–7.52(m,4H),7.38(dd,J＝8.46,6.94Hz,1H),7.31(dd,J＝8.41,0.89Hz,1H),6.92(dd,J＝7.00,0.92Hz,1H),4.80(s,2H),1.38(s,9H).ESI-MS of the title compound C ₂₃H₂₅N₄ ⁺[M+H]⁺ =357.2; the experiment shows that: 357.2.

EXAMPLE 22 Synthesis of 4- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QJ 116)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (80 mg) and 4-formylbenzoic acid (45 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₅H₂₆N₃O₂ ⁺[M+H]⁺ =400.2 of trifluoroacetate 17.1mg.¹H NMR(500MHz,Methanol-d₄)δ8.03–7.96(m,2H),7.67(dd,J＝8.59,7.10Hz,1H),7.54–7.49(m,2H),7.47–7.41(m,3H),7.36(d,J＝8.05Hz,2H),7.10(d,J＝7.10Hz,1H),4.51(s,2H),1.29(s,9H).ESI-MS of the target compound; the experiment shows that: 399.7.

EXAMPLE 23 Synthesis of 3- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QJ 121)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (58 mg) and 3-formylbenzoic acid (31 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₅H₂₆N₃O₂ ⁺[M+H]⁺ =400.2 of trifluoroacetate 15.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.00(d,J＝1.85Hz,1H),7.96(dt,J＝7.63,1.58Hz,1H),7.62(dd,J＝8.57,7.11Hz,1H),7.53–7.47(m,3H),7.47–7.38(m,4H),7.06(d,J＝6.96Hz,1H),4.48(s,2H),1.26(s,9H).ESI-MS of the target compound; the experiment shows that: 399.6.

EXAMPLE 24 Synthesis of 2- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QJ 122)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (60 mg) and 2-formylbenzoic acid (32 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₅H₂₆N₃O₂ ⁺[M+H]⁺ =400.2 of trifluoroacetate 15.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.03(dd,J＝7.78,1.47Hz,1H),7.63(dd,J＝8.56,7.06Hz,1H),7.52(td,J＝7.55,1.50Hz,1H),7.46–7.38(m,5H),7.33–7.29(m,2H),7.05(dd,J＝7.14,0.80Hz,1H),4.71(s,2H),1.27(s,9H).ESI-MS of the target compound; the experiment shows that: 400.0.

EXAMPLE 25 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- ([ [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QJ 126)

Starting from 4- ([ 1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (80 mg) and 1H-imidazole-4-carbaldehyde (26 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₃H₂₀N₅ ⁺[M+H]⁺ =366.1 of trifluoroacetate 28.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.74(s,1H),7.77(d,J＝7.70Hz,2H),7.69(d,J＝7.63Hz,2H),7.61(d,J＝7.76Hz,2H),7.52–7.30(m,6H),6.98(d,J＝6.95Hz,1H),4.53(s,2H).ESI-MS of the target compound; the experiment shows that: 366.7.

EXAMPLE 26 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -1H-indazol-3-amine (QJ 131)

The general method seven:

Step one: synthesis of tert-butyl 4- (4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate (QJ 131-1)

4- (4- (3-Amino-1H-indazol-4-yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (80 mg) and 1H-imidazole-4-carbaldehyde (19 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane was added, followed by sodium triacetoxyborohydride (85 mg), acetic acid (0.1 mL) was added dropwise, and stirring was continued at room temperature under nitrogen. After the completion of the reaction, a saturated sodium hydrogencarbonate solution was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to be used directly in the next step.

Step two: synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (1, 2,3, 6-tetrahydropyridin-4-yl) phenyl) -1H-indazol-3-amine (QJ 131)

All of the QJ131 obtained in the previous step was put into an eggplant-shaped flask, methylene chloride (8 mL) was added thereto, trifluoroacetic acid (2 mL) was added dropwise thereto, and the mixture was stirred at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₂H₂₃N₆ ⁺[M+H]⁺ =371.1 of trifluoroacetate 58.2mg.¹H NMR(500MHz,Chloroform-d)δ8.74(d,J＝1.40Hz,1H),7.62–7.58(m,2H),7.54–7.51(m,2H),7.41(dd,J＝8.49,6.87Hz,1H),7.37–7.33(m,2H),6.92(dd,J＝6.86,0.99Hz,1H),6.24(tt,J＝3.55,1.68Hz,1H),4.52(s,2H),3.90(q,J＝2.66Hz,2H),3.50(t,J＝6.12Hz,2H),2.86(tt,J＝6.82,1.74Hz,2H).ESI-MS of the target compound; the experiment shows that: 370.7.

EXAMPLE 27 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4-bromophenyl) -1H-indazol-3-amine (QJ 132)

Starting from 4- (4-bromophenyl) -1H-indazol-3-amine (91 mg) and 1H-imidazole-4-carbaldehyde (29 mg), reference was made to general procedure six to give the theoretical calculated value C ₁₇H₁₅ ⁷⁹BrN₅ ⁺[M+H]⁺ =368.0 of trifluoroacetate 51.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.76(s,1H),7.65(d,J＝8.17Hz,2H),7.48–7.34(m,5H),6.93(d,J＝6.92Hz,1H),4.53(s,2H).ESI-MS of the target compound; the experiment shows that: 367.0.

EXAMPLE 28 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (1, 2,5, 6-tetrahydropyridin-3-yl) phenyl) -1H-indazol-3-amine (QJ 138)

Starting from 5- (4- (3-amino-1H-indazol-4-yl) phenyl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (80 mg) and 1H-imidazole-4-carbaldehyde (19 mg), referring to general procedure seven, the theoretical calculated value of trifluoroacetate 12.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.74(d,J＝1.46Hz,1H),7.56(s,4H),7.42–7.31(m,3H),6.91(d,J＝6.68Hz,1H),6.46(td,J＝4.13,2.06Hz,1H),4.51(s,2H),4.15(q,J＝2.25Hz,2H),3.41(t,J＝6.21Hz,2H),2.64(dh,J＝8.83,2.69Hz,2H).ESI-MS of the target compound C ₂₂H₂₃N₆ ⁺[M+H]⁺ =371.1; the experiment shows that: 370.1.

EXAMPLE 29 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (4- (pyridin-4-yl) phenyl) -1H-indazol-3-amine (QJ 143)

Starting from 4- (4- (pyridin-4-yl) phenyl) -1H-indazol-3-amine (224 mg) and 1H-imidazole-4-carbaldehyde (68 mg), reference was made to general procedure six to give the theoretical calculated trifluoroacetate 191.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.92–8.86(m,2H),8.73(d,J＝1.47Hz,1H),8.49–8.43(m,2H),8.14–8.09(m,2H),7.82–7.76(m,2H),7.46–7.38(m,2H),7.36(d,J＝1.37Hz,1H),6.99(dd,J＝6.16,1.70Hz,1H),4.53(s,2H).ESI-MS of the title compound C ₂₂H₁₉N₆ ⁺[M+H]⁺ = 367.1; the experiment shows that: 367.3.

EXAMPLE 30 Synthesis of 3- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QJ 156)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 3-formylbenzoic acid (28 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₆N₃O₂ ⁺[M+H]⁺ =424.2 of trifluoroacetate 2mg.¹H NMR(500MHz,Methanol-d₄)δ8.01–7.93(m,2H),7.59(dd,J＝8.54,7.04Hz,1H),7.52–7.36(m,7H),7.05(d,J＝7.05Hz,1H),6.12(tt,J＝3.85,1.68Hz,1H),4.48(s,2H),2.35(tq,J＝6.34,2.33Hz,2H),2.23(dh,J＝8.92,2.78Hz,2H),1.84–1.76(m,2H),1.72–1.64(m,2H).ESI-MS of the target compound; the experiment shows that: 422.8.

EXAMPLE 31 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 3)

Starting from 4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (89 mg) and 1H-imidazole-4-carbaldehyde (26 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₄H₂₆N₅O⁺[M+H]⁺ =400.2 of trifluoroacetate 48.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.43Hz,1H),7.40(dd,J＝8.48,6.97Hz,1H),7.34–7.28(m,2H),7.22–7.18(m,1H),7.13–7.07(m,2H),6.85(dd,J＝6.97,0.87Hz,1H),6.24(tt,J＝3.95,1.70Hz,1H),4.49(dd,J＝2.20,0.95Hz,2H),3.72(s,3H),2.46(tq,J＝6.38,2.32Hz,2H),2.26(ddt,J＝8.48,6.35,2.77Hz,2H),1.87–1.79(m,2H),1.74–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 399.8.

EXAMPLE 32 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (2-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 15)

Starting from 4- (2-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (105 mg) and 1H-imidazole-4-carbaldehyde (31 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₄H₂₆N₅O⁺[M+H]⁺ = 400.2 of trifluoroacetate 50.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.76(d,J＝1.44Hz,1H),7.39(dd,J＝8.46,6.88Hz,1H),7.36–7.31(m,2H),7.19(d,J＝7.60Hz,1H),7.06–6.99(m,2H),6.93(dd,J＝6.86,1.02Hz,1H),4.53(s,2H),3.80(s,3H),2.37(tq,J＝6.37,2.17Hz,2H),2.20(qd,J＝5.65,4.75,2.63Hz,2H),1.79–1.65(m,4H).ESI-MS of the target compound; the experiment shows that: 400.1.

EXAMPLE 33 Synthesis of 4- (4- (tert-butyl) phenyl) -N-phenethyl-1H-indazol-3-amine (QK 16)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (50 mg) and phenylacetaldehyde (23 mg), reference is made to general procedure six to give the theoretical calculation of trifluoroacetate 1.3mg.¹H NMR(500MHz,Methanol-d₄)δ7.50(dd,J＝8.50,7.05Hz,1H),7.43–7.39(m,2H),7.35(d,J＝8.40Hz,1H),7.28–7.18(m,5H),7.06–7.01(m,2H),6.92(d,J＝6.97Hz,1H),3.52(t,J＝6.38Hz,2H),2.82(t,J＝6.36Hz,2H),1.36(s,9H).ESI-MS of the target compound C ₂₅H₂₈N₃ ⁺[M+H]⁺ =370.2; the experiment shows that: 368.8.

EXAMPLE 34 Synthesis of N- (3- (1H-imidazol-4-yl) propyl) -4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QK 18)

Step one: synthesis of 4- (4- (tert-butyl) phenyl) -N- (3- (1-trityl-1H-imidazol-4-yl) propyl) -1H-indazol-3-amine

4- (4- (Tert-butyl) phenyl) -1H-indazol-3-amine (48 mg) and 3- (1-trityl-1H-imidazol-4-yl) propanal (56 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane was added, followed by sodium triacetoxyborohydride (64 mg), acetic acid (0.1 mL) was added dropwise, and stirring was continued at room temperature under nitrogen. After the completion of the reaction, a saturated sodium hydrogencarbonate solution was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to be used directly in the next step.

Step two: synthesis of N- (3- (1H-imidazol-4-yl) propyl) -4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (QK 18)

All the products are added into an eggplant-shaped flask, tetrahydrofuran (10 mL) and hydrochloric acid (1M, 3 mL) are added, heating is carried out until reflux, stirring is carried out for 2h, after the reaction is finished, a rotary evaporator is used for concentrating, and HPLC purification is carried out, thus obtaining the theoretical calculated value C ₂₃H₂₈N₅ ⁺[M+H]⁺ =374.2 of trifluoroacetate 32.1mg.¹H NMR(500MHz,Methanol-d₄)δ8.79(d,J＝1.46Hz,1H),7.65–7.57(m,3H),7.45(dq,J＝8.01,1.78,1.35Hz,3H),7.41(dd,J＝8.59,0.78Hz,1H),7.27(t,J＝1.20Hz,1H),7.05(dd,J＝7.15,0.81Hz,1H),3.35–3.31(m,2H),2.76–2.69(m,2H),1.95–1.86(m,2H).ESI-MS of the target compound; the experiment shows that: 373.4.

EXAMPLE 35 Synthesis of 4- (2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 23)

General method eight:

Step one: synthesis of methyl 4- (2- ((4- (4- (4-tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoate (QL 23-1)

4- (4- (Tert-butyl) phenyl) -1H-indazol-3-amine (118 mg) and methyl 4- (2-oxoethyl) benzoate (66 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane was added, followed by sodium triacetoxyborohydride (157 mg), acetic acid (0.1 mL) was added dropwise, and stirring was carried out at room temperature under nitrogen. After the completion of the reaction, a saturated sodium hydrogencarbonate solution was added, extraction was performed 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give 72mg of crude product, which was used directly in the next step.

Step two: synthesis of 4- (2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 23)

All of the crude product was added to an eggplant-shaped flask, 10mL of a mixed solvent (MeOH: THF: H ₂ O=1:1:1) was added, lithium hydroxide monohydrate (100 mg) was added, and stirred at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₆H₂₈N₃O₂ ⁺[M+H]⁺ =414.2 of trifluoroacetate 9.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.97–7.91(m,2H),7.57(dd,J＝8.52,7.08Hz,1H),7.41–7.34(m,3H),7.23–7.20(m,2H),7.19–7.15(m,2H),6.97(dd,J＝7.05,0.79Hz,1H),3.58(dd,J＝7.05,5.57Hz,2H),2.93(t,J＝6.27Hz,2H),1.33(s,10H).ESI-MS of the target compound; the experiment shows that: 414.3.

EXAMPLE 36 Synthesis of 3- ((((4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QK 44)

Starting from 4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (20 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₈H₂₈N₃O₃ ⁺[M+H]⁺ =454.2 of trifluoroacetate 5.9mg.¹H NMR(500MHz,Methanol-d₄)δ7.98–7.93(m,1H),7.90(d,J＝1.82Hz,1H),7.57(dd,J＝8.54,7.10Hz,1H),7.46–7.40(m,2H),7.37(d,J＝8.50Hz,1H),7.17(d,J＝7.75Hz,1H),7.06–6.99(m,2H),6.96(d,J＝7.05Hz,1H),6.09(tt,J＝3.86,1.69Hz,1H),4.43(q,J＝14.13Hz,2H),3.73(s,3H),2.33(tq,J＝6.30,2.31Hz,2H),2.23(ddt,J＝8.72,6.44,2.70Hz,2H),1.83–1.75(m,2H),1.72–1.65(m,2H).ESI-MS of the target compound; the experiment shows that: 453.9.

EXAMPLE 37 Synthesis of 3- (2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 60)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and methyl 3- (2-oxoethyl) benzoate (80 mg), reference is made to general procedure eight to give the theoretical calculated value C ₂₆H₂₈N₃O₂ ⁺[M+H]⁺ =414.2 of trifluoroacetate 11.6mg.¹H NMR(500MHz,Methanol-d₄)δ7.93(dt,J＝7.82,1.46Hz,1H),7.82(t,J＝1.84Hz,1H),7.54(dd,J＝8.50,7.10Hz,1H),7.41–7.33(m,4H),7.30(dt,J＝7.60,1.49Hz,1H),7.23–7.17(m,2H),6.95(dd,J＝7.13,0.84Hz,1H),3.57(dd,J＝6.95,5.72Hz,2H),2.90(t,J＝6.32Hz,2H),1.32(s,9H).ESI-MS of the target compound; the experiment shows that: 415.5.

EXAMPLE 38 Synthesis of 2- (2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 68)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and methyl 2- (2-oxoethyl) benzoate (80 mg), reference is made to general procedure eight to give the theoretical calculated value C ₂₆H₂₈N₃O₂ ⁺[M+H]⁺ =414.2 of trifluoroacetate 1.5mg.¹H NMR(500MHz,Methanol-d₄)δ7.99(dd,J＝7.79,1.50Hz,1H),7.60(dd,J＝8.50,7.07Hz,1H),7.47–7.35(m,5H),7.29–7.24(m,2H),7.09(dd,J＝7.63,1.30Hz,1H),7.01(dd,J＝7.04,0.78Hz,1H),3.57(t,J＝6.48Hz,2H),3.25(t,J＝6.49Hz,2H),1.36(s,9H).ESI-MS of the target compound; the experiment shows that: 414.3.

EXAMPLE 39 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-ethoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 85)

Starting from 4- (3-ethoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (55 mg) and 1H-imidazole-4-carbaldehyde (22 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₅H₂₈N₅O⁺[M+H]⁺ =414.2 of trifluoroacetate 14.6mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.48Hz,1H),7.38(dd,J＝8.45,6.95Hz,1H),7.33–7.30(m,2H),7.20(d,J＝7.65Hz,1H),7.12–7.08(m,2H),6.85(dd,J＝6.88,0.90Hz,1H),6.22(tt,J＝3.89,1.72Hz,1H),4.48(s,2H),3.98(q,J＝6.96Hz,2H),2.45(tq,J＝6.47,2.21Hz,2H),2.26(ddt,J＝8.60,6.36,3.32Hz,2H),1.86–1.80(m,2H),1.70(dtt,J＝9.87,6.81,3.15Hz,2H),1.09(t,J＝6.96Hz,3H).ESI-MS of the target compound; the experiment shows that: 415.4.

EXAMPLE 40 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -1H-indazol-3-amine (QK 91)

Starting from 4- (5- (cyclohex-1-en-1-yl) pyridin-2-yl) -1H-indazol-3-amine (43 mg) and 1H-imidazole-4-carbaldehyde (13 mg), 3.5mg of the trifluoroacetate salt of the title compound was obtained according to general method six.

¹H NMR(500MHz,Methanol-d₄)δ8.77(d,J＝2.28Hz,1H),8.76(d,J＝1.47Hz,1H),8.38(dd,J＝8.54,2.29Hz,1H),8.08(d,J＝8.44Hz,1H),7.56(d,J＝8.30Hz,1H),7.50(dd,J＝8.47,7.06Hz,1H),7.44(d,J＝1.38Hz,1H),7.35(d,J＝6.95Hz,1H),6.53(tt,J＝3.92,1.67Hz,1H),4.60(s,2H),2.48(tq,J＝6.44,2.22Hz,2H),2.30(td,J＝6.15,3.31Hz,2H),1.85(dtt,J＝11.29,7.84,4.14Hz,2H),1.76–1.67(m,2H).ESI-MS Theoretical calculation C ₂₂H₂₃N₆ ⁺[M+H]⁺ = 371.2; the experiment shows that: 371.2.

EXAMPLE 41 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (tert-butyl) phenyl) -1-methyl-1H-indazol-3-amine (QK 92)

Step one: synthesis of 4- (4- (tert-butyl) phenyl) -1-methyl-1H-indazol-3-amine (QK 92-1)

4- (4- (Tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) was added to an eggplant-shaped flask, acetonitrile (10 mL) was added, followed by methyl iodide (64 mg) and potassium carbonate (157 mg) in this order. The temperature was raised to 70℃and stirred overnight. After the reaction, quench the reaction with water, extract the aqueous phase with ethyl acetate 3 times, combine the organic phases, wash with saturated saline, dry with anhydrous sodium sulfate, purify on silica gel column to obtain the target compound 23mg.¹H NMR(500MHz,Chloroform-d)δ7.53–7.50(m,2H),7.44–7.41(m,2H),7.37–7.33(m,1H),7.28–7.25(m,1H),6.90(d,J＝7.09,0.57Hz,1H),2.93(s,2H),1.40(s,9H).

Step two: synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (tert-butyl) phenyl) -1-methyl-1H-indazol-3-amine (QK 92)

Starting from QK92-1 (23 mg) and 1H-imidazole-4-carbaldehyde (9 mg), referring to general procedure I, the theoretical calculated value C ₂₂H₂₆N₅ ⁺[M+H]⁺ = 360.2 of trifluoroacetate 3.9mg.¹H NMR(500MHz,Methanol-d₄)δ8.77(d,J＝1.47Hz,1H),7.55–7.52(m,2H),7.46–7.42(m,2H),7.41–7.37(m,1H),7.35(d,J＝1.31Hz,1H),7.31(d,J＝8.42Hz,1H),6.88(d,J＝6.92Hz,1H),4.48(s,2H),3.88(s,3H),1.37(s,9H).ESI-MS of the target compound was obtained; the experiment shows that: 361.0.

EXAMPLE 42 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-isopropoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 93)

Starting from 4- (3-isopropoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (62 mg) and 1H-imidazole-4-carbaldehyde (15 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₆H₃₀N₅O⁺[M+H]⁺ =428.2 of trifluoroacetate 23.6mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.45Hz,1H),7.40(dd,J＝8.46,6.97Hz,1H),7.34–7.30(m,2H),7.22(d,J＝7.81Hz,1H),7.14(dd,J＝7.86,1.73Hz,1H),7.11(d,J＝1.71Hz,1H),6.86(d,J＝6.83Hz,1H),6.21(tq,J＝4.49,2.76,2.23Hz,1H),4.49(s,2H),4.35(hept,J＝6.00Hz,1H),2.44(tq,J＝6.41,2.27Hz,2H),2.26(ddt,J＝8.47,6.32,3.18Hz,2H),1.86–1.79(m,2H),1.74–1.67(m,2H),1.06(d,J＝6.08Hz,3H),0.97(d,J＝6.02Hz,3H).ESI-MS of the target compound; the experiment shows that: 428.2.

EXAMPLE 43 Synthesis of N- (3- (1H-imidazol-4-yl) propyl) -4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 101)

Starting from 4- (3-methoxy-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 3- (1-trityl-1H-imidazol-4-yl) propanal (62 mg), reference is made to the method for synthesizing end product 34 (QK 018), to give the theoretical calculated value C ₂₆H₃₀N₅O⁺[M+H]⁺ =428.2 of trifluoroacetate 26mg.¹H NMR(500MHz,Methanol-d₄)δ8.76(d,J＝1.40Hz,1H),7.52(dd,J＝8.51,7.07Hz,1H),7.35(d,J＝8.50Hz,1H),7.23–7.19(m,2H),7.17–7.12(m,2H),6.92(d,J＝7.03Hz,1H),6.24(td,J＝3.96,1.94Hz,1H),3.76(s,3H),2.65(t,J＝7.69Hz,2H),2.45(tq,J＝6.35,2.34Hz,2H),2.24(tq,J＝6.18,2.81Hz,2H),2.07–2.01(m,2H),1.92–1.77(m,4H),1.72–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 428.7.

EXAMPLE 44 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-amine (QK 106)

Starting from 4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-amine (72 mg) and 1H-imidazole-4-carbaldehyde (21 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₂H₂₃N₆ ⁺[M+H]⁺ =371.2 of trifluoroacetate 20.9mg.¹H NMR(500MHz,Methanol-d₄)δ8.84(d,J＝2.09Hz,1H),8.76(d,J＝1.48Hz,1H),8.66(dd,J＝8.55,2.17Hz,1H),8.17(d,J＝8.54Hz,1H),7.54–7.45(m,2H),7.42(d,J＝1.39Hz,1H),7.11(dd,J＝6.85,1.04Hz,1H),7.01(td,J＝3.99,1.96Hz,1H),4.54(s,2H),2.61(tq,J＝6.19,2.27Hz,2H),2.44(tq,J＝5.82,2.81Hz,2H),1.96–1.89(m,2H),1.82–1.75(m,2H).ESI-MS of the target compound; the experiment shows that: 371.4.

EXAMPLE 45 Synthesis of 3- (1- ((4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-yl) amino) ethyl) benzoic acid (QK 116)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 3-acetylbenzoic acid (31 mg) were added to an eggplant-shaped flask, toluene (20 mL) was added, and water was removed under reflux overnight. After the reaction, concentrating by a rotary evaporator, adding methanol (1 mL) and sodium borohydride (100 mg), stirring at room temperature for 2h, concentrating by the rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₈H₂₈N₃O₂ ⁺[M+H]⁺ = 438.2 of trifluoroacetate 0.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.93(d,J＝1.83Hz,1H),7.88(dt,J＝7.44,1.57Hz,1H),7.58–7.52(m,2H),7.47–7.40(m,4H),7.37(t,J＝7.60Hz,1H),7.31(d,J＝8.41Hz,1H),6.94(d,J＝6.97Hz,1H),6.22(tt,J＝4.08,1.80Hz,1H),4.78(q,J＝6.78Hz,1H),2.45(tdq,J＝6.49,4.33,2.33Hz,2H),2.30–2.22(m,2H),1.88–1.80(m,2H),1.75–1.67(m,2H),1.35(d,J＝6.71Hz,3H).ESI-MS of the target compound; the experiment shows that: 437.9.

EXAMPLE 46 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3- (dimethylamino) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 120)

Starting from 4- (3- (dimethylamino) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (55 mg) and 1H-imidazole-4-carbaldehyde (19 mg), the theoretical calculation of trifluoroacetate 35.7mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.53Hz,1H),7.53(dd,J＝8.23,2.59Hz,1H),7.50–7.45(m,2H),7.35(d,J＝1.45Hz,1H),7.34(s,1H),7.30(d,J＝1.30Hz,1H),6.79(dd,J＝4.64,3.26Hz,1H),5.67(tt,J＝3.75,1.73Hz,1H),4.48(s,2H),3.33(s,6H),2.03–1.85(m,2H),1.84–1.70(m,2H),1.46–1.25(m,4H).ESI-MS of the target compound was obtained as C ₂₅H₂₉N₆ ⁺[M+H]⁺ = 413.2, according to general procedure six; the experiment shows that: 411.9.

EXAMPLE 47 Synthesis of N, 1-bis ((1H-imidazol-4-yl) methyl) -4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 133)

Starting from 4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 1H-imidazole-4-carbaldehyde (28 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₈H₃₀N₇ ⁺[M+H]⁺ =464.2 of trifluoroacetate 27.8mg.¹H NMR(500MHz,Methanol-d₄)δ8.84(d,J＝1.40Hz,1H),8.73(d,J＝1.45Hz,1H),7.49–7.42(m,3H),7.35(d,J＝1.94Hz,1H),7.30(dd,J＝7.88,1.96Hz,1H),7.25(d,J＝1.37Hz,1H),7.13(d,J＝7.89Hz,1H),6.82(dd,J＝6.51,1.31Hz,1H),6.19(tt,J＝3.82,1.69Hz,1H),5.55(s,2H),4.43(s,2H),2.43(tq,J＝6.37,2.29Hz,2H),2.24(tdq,J＝6.90,5.01,2.48Hz,2H),2.05(s,3H),1.86–1.78(m,2H),1.73–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 465.0.

EXAMPLE 48 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 136)

Starting from 4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 1H-imidazole-4-carbaldehyde (28 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₄H₂₆N₅ ⁺[M+H]⁺ = 384.2 of trifluoroacetate 32.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.77(d,J＝1.50Hz,1H),7.39(dd,J＝8.47,6.92Hz,1H),7.36–7.28(m,3H),7.25(dd,J＝7.67,1.92Hz,1H),7.15(d,J＝7.67Hz,1H),6.89(dd,J＝6.87,0.97Hz,1H),5.58(dp,J＝3.46,1.66Hz,1H),4.52(s,2H),2.32(s,3H),2.26–2.16(m,4H),1.81(pd,J＝5.95,3.58Hz,2H),1.73(tq,J＝5.89,2.32Hz,2H).ESI-MS of the target compound; the experiment shows that: 384.8.

EXAMPLE 49 Synthesis of (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) glycine (QK 141)

Step one: synthesis of ethyl (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) glycinate (QK 138)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (100 mg) and ethyl 2-bromoacetate (51 mg) were added to an eggplant-shaped flask, acetonitrile (10 mL) was added, potassium carbonate (70 mg) and potassium iodide (6 mg) were added, and the mixture was warmed to reflux and stirred overnight. After the reaction was completed, cooling to room temperature, quenching the reaction with water, extracting the aqueous phase with ethyl acetate 3 times, combining the organic phases, washing with saturated saline solution, drying over anhydrous sodium sulfate, and purifying with a silica gel column to obtain the target compound 59mg.¹H NMR(500MHz,Chloroform-d)δ7.52–7.49(m,2H),7.47–7.41(m,3H),7.26–7.22(m,1H),6.78(dd,J＝6.84,0.79Hz,1H),6.24(tt,J＝3.99,1.72Hz,1H),5.05(s,2H),2.50–2.44(m,2H),2.25(dq,J＝7.26,2.99,2.42Hz,2H),1.85–1.79(m,2H),1.73–1.66(m,2H).

Step two: synthesis of (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) glycine (QK 141)

QK138 (59 mg) was added to the eggplant-shaped flask, 10mL of a mixed solvent (MeOH: THF: H ₂ o=1:1:1) was added, lithium hydroxide monohydrate (100 mg) was added, and stirred at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₁H₂₂N₃O₂ ⁺[M+H]⁺ = 348.1 of trifluoroacetate 13.4mg.¹H NMR(500MHz,Methanol-d₄)δ7.65(dd,J＝8.56,7.07Hz,1H),7.60–7.56(m,2H),7.47–7.41(m,3H),7.11(d,J＝7.12Hz,1H),6.27(tq,J＝4.42,2.20Hz,1H),2.47(ddp,J＝7.53,5.32,2.49Hz,2H),2.25(tq,J＝8.35,5.45,4.46Hz,2H),1.83(qq,J＝7.69,4.91,3.96Hz,2H),1.70(ddd,J＝9.34,7.42,4.75Hz,2H).ESI-MS of the target compound; the experiment shows that: 349.1.

EXAMPLE 50 Synthesis of methyl 4- (3- ((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-carboxylate (QK 149)

Starting from 4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-carboxylic acid methyl ester (88 mg) and 1H-imidazole-4-carbaldehyde (25 mg), according to general procedure six, to give the theoretical calculated value C ₂₅H₂₆N₅O₂ ⁺[M+H]⁺ =428.2 of trifluoroacetate 54.6mg.¹H NMR(500MHz,Methanol-d₄)δ8.78(d,J＝1.43Hz,1H),7.80(d,J＝1.96Hz,1H),7.61(dd,J＝7.91,1.98Hz,1H),7.41–7.31(m,4H),6.90(dd,J＝6.27,1.60Hz,1H),5.55(tt,J＝3.70,1.67Hz,1H),4.52(s,2H),3.83(s,3H),2.26(tq,J＝6.48,2.31Hz,2H),2.20–2.11(m,2H),1.78(dtt,J＝10.15,6.47,3.60Hz,2H),1.73–1.65(m,2H).ESI-MS of the target compound; the experiment shows that: 427.3.

EXAMPLE 51 Synthesis of N- (((1H-imidazol-4-yl) methyl) -4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QK 152)

Starting from 4- (3-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 1H-imidazole-4-carbaldehyde (23 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₄H₂₆N₅ ⁺[M+H]⁺ = 384.2 of trifluoroacetate 17.8mg.¹H NMR(500MHz,Methanol-d₄)δ8.74(d,J＝1.50Hz,1H),7.40(dd,J＝8.51,6.87Hz,1H),7.37–7.29(m,3H),7.26(d,J＝1.33Hz,1H),7.17(d,J＝7.87Hz,1H),6.78(dd,J＝6.87,0.91Hz,1H),6.19(tt,J＝3.88,1.76Hz,1H),4.42(s,2H),2.44(tq,J＝6.44,2.34Hz,2H),2.25(ddt,J＝8.35,6.27,2.66Hz,3H),2.08(s,3H),1.82(dtt,J＝9.00,5.54,3.00Hz,2H),1.73–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 384.5.

EXAMPLE 52 Synthesis of 4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-carboxylic acid (QK 153)

4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-carboxylic acid methyl ester (72 mg) was added to an eggplant-shaped flask, 10mL of a mixed solvent (MeOH: THF: H ₂ O=1:1:1) was added, lithium hydroxide monohydrate (100 mg) was added, and stirring overnight at room temperature after completion of the reaction, concentrated by rotary evaporator, HPLC purified to give the theoretical calculated value C ₂₄H₂₄N₅O₂ ⁺[M+H]⁺ =414.2 of trifluoroacetate 21.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.47Hz,1H),7.85(d,J＝1.98Hz,1H),7.62(dd,J＝7.87,1.98Hz,1H),7.44–7.31(m,4H),6.94(dd,J＝6.75,1.08Hz,1H),5.61(tt,J＝3.69,1.69Hz,1H),4.52(s,2H),2.32(dp,J＝6.38,2.29Hz,2H),2.18(tq,J＝5.85,2.70Hz,2H),1.79(qq,J＝5.86,3.35Hz,2H),1.74–1.65(m,2H).ESI-MS of the target compound, experimentally measured: 413.0.

EXAMPLE 53 Synthesis of methyl 4- (3- ((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-carboxylate (QK 156)

Starting from 4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-carboxylic acid methyl ester (91 mg) and 1H-imidazole-4-carbaldehyde (30 mg), the theoretical calculation of trifluoroacetate 25.9mg.¹H NMR(500MHz,Methanol-d₄)δ8.78(d,J＝1.45Hz,1H),7.81(d,J＝1.92Hz,1H),7.63(dd,J＝7.83,1.98Hz,1H),7.43–7.31(m,4H),6.92(dd,J＝6.56,1.31Hz,1H),5.56(tt,J＝3.67,1.68Hz,1H),4.52(s,2H),3.84(s,3H),2.27(tq,J＝6.19,2.24Hz,2H),2.17(dtd,J＝8.66,5.99,2.66Hz,2H),1.80(dtt,J＝10.24,6.55,3.64Hz,2H),1.71(pd,J＝6.34,3.73Hz,2H).ESI-MS of the target compound was obtained as C ₂₅H₂₆N₅O₂ ⁺[M+H]⁺ = 428.2, according to general procedure six; the experiment shows that: 427.4.

EXAMPLE 54 Synthesis of 4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-ol (QL 2)

Starting from 4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -2-ol (117 mg) and 1H-imidazole-4-carbaldehyde (40 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₃H₂₄N₅O⁺[M+H]⁺ = 386.2 of trifluoroacetate 51mg.¹H NMR(500MHz,Chloroform-d)δ8.75(d,J＝1.51Hz,1H),7.39–7.29(m,3H),7.15(d,J＝7.55Hz,1H),6.92–6.86(m,3H),5.82(tt,J＝3.76,1.77Hz,1H),4.52(s,2H),2.40(tq,J＝6.32,2.19Hz,2H),2.20(tq,J＝5.97,2.73Hz,2H),1.77(qq,J＝4.77,2.83,2.37Hz,2H),1.70(ddp,J＝9.17,6.04,2.84Hz,2H).ESI-MS of the target compound; the experiment shows that: 385.5.

EXAMPLE 55 Synthesis of 4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-ol (QL 5)

Starting from 4- (3-amino-1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-ol (151 mg) and 1H-imidazole-4-carbaldehyde (46 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₃H₂₄N₅O⁺[M+H]⁺ = 386.2 of trifluoroacetate 46.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.74(d,J＝1.46Hz,1H),7.40(dd,J＝8.47,7.01Hz,1H),7.34–7.27(m,2H),7.14(d,J＝7.81Hz,1H),7.02(dd,J＝7.84,1.79Hz,1H),6.99(d,J＝1.73Hz,1H),6.88(d,J＝6.79Hz,1H),6.19(tt,J＝3.84,1.69Hz,1H),4.51(d,J＝4.61Hz,2H),2.41(tq,J＝6.37,2.26Hz,2H),2.24(ddt,J＝8.24,6.11,3.06Hz,2H),1.86–1.77(m,2H),1.73–1.64(m,2H).ESI-MS of the target compound; the experiment shows that: 386.0.

EXAMPLE 56 Synthesis of 3- ((((1- (carboxymethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 8)

Step one: synthesis of methyl 3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) formate (QK 158)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (500 mg) and methyl 3-formylbenzoate (340 mg), the title compound was obtained by purifying with a silica gel column according to general procedure six 524mg.¹H NMR(500MHz,Chloroform-d)δ8.00(t,J＝1.70Hz,1H),7.90(dt,J＝7.73,1.48Hz,1H),7.50–7.43(m,5H),7.38–7.32(m,2H),7.27(d,J＝0.88Hz,1H),6.93(dd,J＝7.03,0.84Hz,1H),6.17(tt,J＝3.94,1.71Hz,1H),4.54(d,J＝4.59Hz,2H),3.91(s,3H),2.40(tq,J＝5.88,1.73Hz,2H),2.24(dtt,J＝8.80,6.12,2.46Hz,2H),1.83–1.77(m,2H),1.69(ddp,J＝9.25,6.18,3.29Hz,2H).

Step two: synthesis of methyl 3- (((1- (2-ethoxy-2-oxoethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoate (QL 7)

QK158 (150 mg) and ethyl 3-bromo-2-oxopropionate (51 mg) were added to an eggplant-shaped flask, acetonitrile (10 mL) was added, potassium carbonate (64 mg) and potassium iodide (6 mg) were added, and the mixture was warmed to reflux and stirred overnight. After the reaction was completed, cooling to room temperature, quenching the reaction with water, extracting the aqueous phase with ethyl acetate 3 times, combining the organic phases, washing with saturated saline solution, drying over anhydrous sodium sulfate, and purifying with a silica gel column to obtain the target compound 123mg.¹H NMR(500MHz,Chloroform-d)δ7.99(s,1H),7.91(dt,J＝7.77,1.51Hz,1H),7.48–7.42(m,5H),7.38–7.31(m,2H),7.12(d,J＝8.36Hz,1H),6.93–6.90(m,1H),6.14(tt,J＝3.94,1.68Hz,1H),4.96(s,2H),4.52(d,J＝5.24Hz,2H),4.21(q,J＝7.11Hz,2H),3.92(s,3H),2.38(tq,J＝5.82,2.08Hz,2H),2.27–2.18(m,2H),1.83–1.76(m,2H),1.72–1.64(m,2H),1.26(t,J＝7.15Hz,3H).

Step three: synthesis of 3- ((((1- (carboxymethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 8)

QL7 (123 mg) was added to the eggplant-shaped flask, a mixed solvent (THF: meOH: H ₂ O=1:1:1, 10 mL) was added, sodium hydroxide (50 mg) was added, and stirred at room temperature overnight. After the reaction, the mixture was concentrated by a rotary evaporator and purified by HPLC to obtain 5.7mg of the trifluoroacetate salt of the objective compound. ESI-MS theoretical calculation C ₂₉H₂₈N₃O₄ ⁺[M+H]⁺ =482.2; the experiment shows that: 482.5.

EXAMPLE 57 Synthesis of 4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-carboxylic acid (QL 11)

4- (3- (((((1H-imidazol-4-yl) methyl) amino) -1H-indazol-4-yl) -2',3',4',5' -tetrahydro- [1,1' -biphenyl ] -3-carboxylic acid methyl ester (90 mg) was added to an eggplant-shaped flask, 10mL of a mixed solvent (MeOH: THF: H ₂ O=1:1:1) was added, lithium hydroxide monohydrate (100 mg) was added, and stirring overnight at room temperature after completion of the reaction, concentrated by rotary evaporator, HPLC purified to give the theoretical calculated value C ₂₄H₂₄N₅O₂ ⁺[M+H]⁺ =414.2 of trifluoroacetate 3.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.75(d,J＝1.52Hz,1H),7.86(d,J＝1.93Hz,1H),7.64(dd,J＝7.81,1.98Hz,1H),7.43–7.33(m,4H),6.94(dd,J＝6.70,1.16Hz,1H),5.62(tt,J＝3.70,1.70Hz,1H),4.51(d,J＝0.94Hz,2H),2.33(tq,J＝6.27,2.36Hz,2H),2.19(tq,J＝5.65,2.75Hz,2H),1.84–1.76(m,2H),1.75–1.66(m,2H).ESI-MS of the target compound, experimentally measured: 412.9.

EXAMPLE 58 Synthesis of 2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) -2-oxoacetic acid (QL 25)

Step one: synthesis of tert-butyl 4- (4- (tert-butyl) phenyl) -3- (2-methoxy-2-oxoacetamido) -1H-indazole-1-carboxylate (QL 19)

3-Amino-4- (4- (tert-butyl) phenyl) -1H-indazole-1-carboxylic acid tert-butyl ester (200 mg) was added to an eggplant-shaped flask, dichloromethane (10 mL) was added, methyl 2-chloro-2-oxoacetate (80 mg) and triethylamine (81 mg) were added dropwise, and the mixture was stirred at room temperature overnight. After the reaction, quench the reaction with water, extract the aqueous phase with ethyl acetate 3 times, combine the organic phases, wash with saturated saline, dry with anhydrous sodium sulfate, purify on silica gel column to obtain the target compound 121mg.¹H NMR(500MHz,Chloroform-d)δ8.81(s,1H),8.21(d,J＝8.50Hz,1H),7.58(dd,J＝8.57,7.20Hz,1H),7.51(d,J＝8.01Hz,2H),7.34(d,J＝8.09Hz,2H),7.24(d,J＝7.21Hz,1H),3.79(s,3H),1.71(s,9H),1.38(s,9H).

Step two: synthesis of methyl 2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) -2-oxoacetate (QL 22)

QL19 (121 mg) was added to the eggplant-shaped flask, methylene chloride (8 mL) was added, trifluoroacetic acid (2 mL) was added dropwise, and the mixture was stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched by adding a saturated sodium bicarbonate solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with a saturated common salt solution, dried over anhydrous sodium sulfate, and purified on a silica gel column to give the objective compound 94mg.¹H NMR(500MHz,Chloroform-d)δ8.97(s,1H),7.61–7.51(m,3H),7.44–7.34(m,3H),7.04(d,J＝6.96Hz,1H),3.83(s,3H),1.42(s,9H).

Step three: synthesis of 2- ((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) -2-oxoacetic acid (QL 25)

QL22 was added to the eggplant-shaped flask, N-dimethylformamide (6 mL) was added, lithium chloride (224 mg) was added, the temperature was raised to 160℃and the mixture was stirred overnight. After the reaction is finished, cooling to room temperature, and purifying by HPLC to obtain a theoretical calculated value C ₁₉H₂₀N₃O₃ ⁺[M+H]⁺ =338.1 of trifluoroacetate .¹H NMR(500MHz,Methanol-d₄)δ7.63–7.54(m,1H),7.52–7.39(m,3H),7.38–7.32(m,2H),7.13–7.02(m,1H),1.36(s,9H).ESI-MS of the target compound; the experiment shows that: 338.0.

EXAMPLE 59 Synthesis of 3- (((4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 43)

Starting from 4- (4- (cyclopent-1-en-1-yl) phenyl) -1H-indazol-3-amine (60 mg) and 3-formylbenzoic acid (39 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₆H₂₄N₃O₂ ⁺[M+H]⁺ = 410.2 of trifluoroacetate 2.7mg.¹H NMR(500MHz,Methanol-d₄)δ7.99(q,J＝2.15Hz,1H),7.93(dt,J＝7.72,1.58Hz,1H),7.59–7.50(m,3H),7.50–7.46(m,1H),7.46–7.36(m,4H),7.01(d,J＝7.07Hz,1H),6.25(p,J＝2.29Hz,1H),4.47(s,2H),2.68(ddt,J＝9.91,6.93,2.23Hz,2H),2.55(tq,J＝7.64,2.58Hz,2H),2.04(p,J＝7.56Hz,2H).ESI-MS of the target compound; the experiment shows that: 409.5.

EXAMPLE 60 Synthesis of 2-oxo-2- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) acetic acid (QL 53)

Using 3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-1-carboxylic acid tert-butyl ester (200 mg) as a raw material, referring to the method for synthesizing QL25, to obtain the theoretical calculated value C ₂₁H₂₀N₃O₃ ⁺[M+H]⁺ =362.1 of trifluoroacetate 10.2mg.¹H NMR(500MHz,Methanol-d₄)δ7.52–7.44(m,2H),7.40(d,J＝8.36Hz,2H),7.36(d,J＝8.39Hz,2H),7.10(dd,J＝6.77,1.06Hz,1H),6.15(tt,J＝3.88,1.77Hz,1H),2.45(tq,J＝6.44,2.33Hz,2H),2.24(ddt,J＝8.38,6.14,3.07Hz,2H),1.86–1.78(m,2H),1.73–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 361.4.

EXAMPLE 61 Synthesis of 3-oxo-3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) propionic acid (QL 56)

Using 3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-1-carboxylic acid tert-butyl ester (200 mg) as a raw material, and referring to the method for synthesizing QL25, obtaining a theoretical calculated value C ₂₂H₂₂N₃O₃ ⁺[M+H]⁺ = 376.2 of trifluoroacetate 4.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.60–7.31(m,6H),7.07(d,J＝6.63Hz,1H),6.24–6.14(m,1H),2.52–2.41(m,2H),2.29–2.17(m,2H),1.88–1.76(m,2H),1.76–1.62(m,4H).ESI-MS of the target compound; the experiment shows that: 376.8.

EXAMPLE 62 Synthesis of N- (3- (1H-imidazol-4-yl) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QL 61)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (41 mg) and 3- (1-trityl-1H-imidazol-4-yl) propanal (48 mg), the theoretical calculated C ₂₅H₂₈N₅ ⁺[M+H]⁺ =398.2 for trifluoroacetate 1.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.77(d,J＝1.46Hz,1H),7.56(d,J＝8.09Hz,2H),7.49–7.39(m,3H),7.34(d,J＝8.47Hz,1H),7.24(s,1H),6.92(d,J＝7.01Hz,1H),6.24(td,J＝4.04,2.02Hz,1H),2.71(t,J＝7.66Hz,2H),2.46(dp,J＝6.40,2.46Hz,2H),2.30–2.18(m,2H),1.93–1.77(m,4H),1.71(ddd,J＝9.22,7.35,4.60Hz,2H),1.32–1.23(m,2H).ESI-MS of the target compound was obtained by reference to the final product 34 (QK 18) synthesis; the experiment shows that: 396.8.

EXAMPLE 63 Synthesis of 2- (2- (((4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (QL 86)

Starting from 4- (6- (cyclohex-1-en-1-yl) pyridin-3-yl) -1H-indazol-3-amine (40 mg) and methyl 2- (2-formylphenyl) acetate (36 mg), the theoretical calculation of trifluoroacetate 3.6mg.¹H NMR(500MHz,Methanol-d₄)δ8.72(d,J＝2.04Hz,1H),8.58(dd,J＝8.52,2.11Hz,1H),8.01(d,J＝8.52Hz,1H),7.55–7.48(m,2H),7.41–7.36(m,1H),7.27–7.21(m,3H),7.11(dd,J＝6.49,1.37Hz,1H),6.81(td,J＝4.00,1.95Hz,1H),4.41(s,2H),3.74(s,2H),2.48(ddq,J＝6.29,4.29,2.22Hz,2H),2.41(dtt,J＝9.09,6.35,2.67Hz,2H),1.92–1.84(m,2H),1.80–1.72(m,2H).ESI-MS of the target compound, C ₂₇H₂₇N₄O₂ ⁺[M+H]⁺ = 439.2, was obtained according to general procedure eight; the experiment shows that: 439.9.

EXAMPLE 64 Synthesis of 4- (3- ((((1H-imidazol-4-yl) methyl) amino) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (QL 93)

Step one: synthesis of tert-butyl 4- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) -1H-imidazole-1-carboxylate (QL 83)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (100 mg) and 4-formyl-1H-imidazole-1-carboxylic acid tert-butyl ester (81 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (222 mg) was added, acetic acid (0.1 mL) was added dropwise, and stirring was continued at room temperature overnight. After the completion of the reaction, the reaction was quenched by adding a saturated sodium bicarbonate solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with a saturated common salt solution, dried over anhydrous sodium sulfate, and purified on a silica gel column to give the objective compound 87mg.¹H NMR(500MHz,Chloroform-d)δ7.96(d,J＝1.36Hz,1H),7.50(d,J＝8.37Hz,2H),7.47–7.43(m,2H),7.33(dd,J＝8.35,6.97Hz,1H),7.26(d,J＝8.29,1H),7.20(d,J＝1.29Hz,1H),6.90(dd,J＝7.01,0.92Hz,1H),6.23(tt,J＝3.92,1.68Hz,1H),4.43(s,2H),2.46(tq,J＝5.82,1.97Hz,2H),2.28–2.21(m,2H),1.85–1.78(m,2H),1.73–1.66(m,2H),1.58(s,9H).

Step two: synthesis of 4- (3- ((((1- (tert-butoxycarbonyl) -1H-imidazol-4-yl) methyl) amino) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (QL 88)

QL83 (87 mg) was added to the eggplant-shaped flask, 1, 4-dioxane (10 mL) was added, dihydrofuran-2, 5-dione (19 mg) was added, and the mixture was heated to 80℃and stirred overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 23mg.¹H NMR(500MHz,Chloroform-d)δ8.39(dd,J＝8.50,4.39Hz,1H),8.03(s,1H),7.56–7.44(m,3H),7.42–7.34(m,2H),7.24(d,J＝21.34Hz,1H),7.12(d,J＝7.28Hz,1H),6.27–6.20(m,1H),4.43(d,J＝5.69Hz,2H),3.42(t,J＝6.90Hz,2H),2.83(t,J＝6.79Hz,2H),2.51–2.39(m,2H),2.24(tt,J＝7.48,3.59Hz,2H),1.86–1.74(m,2H),1.72–1.64(m,2H),1.59(s,9H).

Step three: synthesis of 4- (3- ((((1H-imidazol-4-yl) methyl) amino) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (QL 93)

QL88 (23 mg) was added to the eggplant-shaped flask, and methylene chloride (8 mL) and trifluoroacetic acid (2 mL) were added thereto, followed by stirring at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₇H₂₈N₅O₃ ⁺[M+H]⁺ =470.2 of trifluoroacetate 11mg.¹H NMR(500MHz,Methanol-d₄)δ8.73(d,J＝1.46Hz,1H),8.33(d,J＝8.33Hz,1H),7.60–7.53(m,3H),7.47–7.38(m,3H),7.19(d,J＝7.27Hz,1H),6.26(tt,J＝3.93,1.73Hz,1H),4.58(s,2H),3.33(t,J＝6.45Hz,2H),2.76(t,J＝6.71Hz,2H),2.47(tq,J＝6.48,2.30Hz,2H),2.26(tq,J＝6.26,2.68Hz,2H),1.83(qq,J＝8.31,5.63,4.34Hz,2H),1.71(qq,J＝8.66,5.51,4.04Hz,2H).ESI-MS of the target compound; the experiment shows that: 469.7.

EXAMPLE 65 Synthesis of 3- ((((1- (3-carboxypropionyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 95)

Step one: synthesis of methyl 3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoate (QL 71)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (289 mg) and methyl 3-formylbenzoate (196 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (636 mg) was added, acetic acid (0.1 mL) was added dropwise, and stirring was continued overnight at room temperature. After the completion of the reaction, the reaction was quenched by adding a saturated sodium hydrogencarbonate solution, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with a saturated common salt solution, dried over anhydrous sodium sulfate, and purified by a silica gel column to give 192mg of the objective compound. ESI-MS theoretical calculation C ₂₈H₂₈N₃O₂ ⁺[M+H]⁺ = 438.2; the experiment shows that: 438.8.

Step two: synthesis of 4- (3- ((3- (methoxycarbonyl) benzyl) amino) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (QL 81)

QL71 (192 mg) was added to an eggplant-shaped flask, 1, 4-dioxane (10 mL) was added, dihydrofuran-2, 5-dione (52 mg) was added, and the mixture was heated to 80℃and stirred overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by a silica gel column to obtain the target compound 275mg.¹H NMR(500MHz,Chloroform-d)δ8.36(ddd,J＝8.39,2.93,0.89Hz,1H),7.99(dt,J＝7.79,1.83Hz,2H),7.90(ddt,J＝7.80,2.89,1.53Hz,2H),7.54–7.32(m,5H),7.12(dd,J＝7.32,0.86Hz,1H),6.16(tt,J＝3.88,1.64Hz,1H),4.70(s,2H),3.87(s,3H),3.38(t,J＝6.92Hz,2H),2.81(t,J＝6.80Hz,2H),2.37(ddt,J＝6.27,4.34,2.09Hz,2H),2.27–2.17(m,2H),1.79(dqd,J＝12.05,5.96,2.88Hz,2H),1.67(hd,J＝6.06,2.78Hz,2H).

Step three: synthesis of 3- ((((1- (3-carboxypropionyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 95)

QL81 (91 mg) was added to an eggplant-shaped flask, ethyl acetate (10 mL) was added, lithium iodide (450 mg) was added, and the mixture was warmed to reflux and stirred overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₃₁H₃₀N₃O₅ ⁺[M+H]⁺ =524.2 of trifluoroacetate 1.7mg.¹H NMR(500MHz,Methanol-d₄)δ8.33(d,J＝8.27Hz,1H),8.01(d,J＝1.77Hz,1H),7.91(dd,J＝7.76,1.53Hz,1H),7.58–7.54(m,1H),7.52–7.47(m,3H),7.42–7.37(m,3H),7.18(d,J＝7.21Hz,1H),6.14(tt,J＝3.93,1.78Hz,1H),4.48(s,2H),3.36(t,J＝6.65Hz,2H),2.75(t,J＝6.66Hz,2H),2.37(ddp,J＝6.78,4.53,2.18Hz,3H),2.24(tq,J＝6.27,2.71Hz,2H),1.86–1.75(m,2H),1.73–1.64(m,2H).ESI-MS of the target compound; the experiment shows that: 523.9.

EXAMPLE 66 Synthesis of 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) benzoic acid (QL 105)

Step one: synthesis of methyl 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) aminomethylbenzoate (QL 105-1)

Copper acetate (80 mg) was added to the eggplant-shaped flask, and methylene chloride (15 mL) and methanol (1 mL) were added thereto, followed by stirring at room temperature for 5min. 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (100 mg), (4- (methoxycarbonyl) phenyl) boronic acid (124 mg) and N, N-diisopropylethylamine (57 mg) were then added in this order, followed by stirring at room temperature for 20H. After the completion of the reaction, the reaction was quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified on a silica gel column to give 105mg of the objective compound.

Step two: synthesis of 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) benzoic acid (QL 105)

QL105-1 (30 mg) was added to the eggplant-shaped flask, a mixed solvent (MeOH: THF: H2: ₂ O=1:1:1, 10 mL) was added, lithium hydroxide (100 mg) was added, and stirred at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₆H₂₄N₃O₂ ⁺[M+H]⁺ =410.2 of trifluoroacetate 3.7mg.¹H NMR(500MHz,DMSO-d₆)δ8.07(d,J＝8.59Hz,2H),7.91(d,J＝8.58Hz,1H),7.85(d,J＝8.58Hz,2H),7.59(d,J＝8.07Hz,2H),7.52(dd,J＝8.59,7.13Hz,1H),7.46(d,J＝8.09Hz,2H),7.05(d,J＝7.13Hz,1H),6.35–6.29(m,1H),2.47–2.41(m,2H),2.26–2.19(m,2H),1.82–1.73(m,2H),1.67–1.60(m,2H).ESI-MS of the target compound; the experiment shows that: 410.3.

EXAMPLE 67 Synthesis of N-benzyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QL 106)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and benzaldehyde (21 mg), reference to general procedure six, gave the theoretical calculated value C ₂₆H₂₆N₃ ⁺[M+H]⁺ = 380.2 for trifluoroacetate 20.1mg.¹H NMR(500MHz,Methanol-d₄)δ7.63(dd,J＝8.60,7.10Hz,1H),7.47–7.35(m,5H),7.33–7.25(m,3H),7.23–7.17(m,2H),7.06(d,J＝7.14Hz,1H),6.14(dq,J＝3.99,1.94Hz,1H),4.41(s,2H),2.35(ddq,J＝6.49,4.65,2.30Hz,2H),2.23(tq,J＝6.14,2.83Hz,2H),1.84–1.75(m,2H),1.72–1.62(m,2H).ESI-MS of the target compound; the experiment shows that: 380.5.

EXAMPLE 68 Synthesis of 3- (((1- (2-hydroxyethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 108)

Starting from 2- (3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) ethan-1-ol (60 mg) and 3-formylbenzoic acid (32 mg), reference is made to general procedure six to give the theoretical calculated for trifluoroacetate 24.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.01–7.85(m,2H),7.51–7.25(m,9H),6.08(d,J＝4.19Hz,1H),4.76–4.08(m,4H),3.89(t,J＝5.48Hz,2H),2.32(td,J＝6.31,3.16Hz,2H),2.20(tq,J＝6.20,2.90Hz,2H),1.82–1.73(m,2H),1.70–1.59(m,2H).ESI-MS of the target compound C ₂₉H₃₀N₃O₃ ⁺[M+H]⁺ = 468.2; the experiment shows that: 467.8.

EXAMPLE 69 Synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) benzoic acid (QL 120)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (100 mg) and (3- (methoxycarbonyl) phenyl) boronic acid (124 mg), the theoretical calculated value C ₂₆H₂₄N₃O₂ ⁺[M+H]⁺ =410.2 of trifluoroacetate 1.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.32(s,1H),7.93(d,J＝8.32Hz,2H),7.70(d,J＝8.47Hz,1H),7.64(t,J＝7.93Hz,1H),7.57(d,J＝8.00Hz,2H),7.52–7.46(m,3H),7.04(d,J＝7.06Hz,1H),6.27(s,1H),2.53–2.47(m,2H),2.30–2.24(m,2H),1.89–1.82(m,2H),1.76–1.69(m,2H).ESI-MS of the target compound is obtained by referring to the QL105 synthesis method; the experiment shows that: 410.5.

EXAMPLE 70 Synthesis of 3- ((((4- (4-cyclohexylphenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QL 122)

Starting from 4- (4-cyclohexylphenyl) -1H-indazol-3-amine (60 mg) and 3-formylbenzoic acid (37 mg), reference was made to general procedure six to give the theoretical calculated for trifluoroacetate 17.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.01–7.95(m,2H),7.59(dd,J＝8.56,7.03Hz,1H),7.49(dt,J＝7.63,1.64Hz,1H),7.46–7.38(m,4H),7.33–7.29(m,2H),7.03(dd,J＝6.99,0.82Hz,1H),4.46(s,2H),2.49(tt,J＝11.52,3.42Hz,1H),1.89–1.65(m,4H),1.48–1.18(m,6H).ESI-MS of the target compound C ₂₇H₂₈N₃O₂ ⁺[M+H]⁺ =426.2; the experiment shows that: 425.8.

EXAMPLE 71 Synthesis of 4- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenol (LYA 13)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and 4-hydroxybenzaldehyde (41.39 mg), reference is made to general procedure six to give the theoretical calculation of trifluoroacetate 45mg.¹H NMR(500MHz,Methanol-d₄)δ7.67(dd,J＝8.6,7.1Hz,1H),7.48–7.41(m,3H),7.39–7.34(m,2H),7.09(d,J＝7.0Hz,1H),7.07–7.01(m,2H),6.78–6.71(m,2H),4.27(s,2H),1.28(s,9H).ESI-MS of the target compound C ₂₄H₂₆N₃O⁺[M+H]⁺ =372.2; the experiment shows that: 372.3.

EXAMPLE 72 Synthesis of 3- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenol (LYA 14)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and 3-hydroxybenzaldehyde (41.39 mg), reference is made to general procedure six to give the theoretical calculation of trifluoroacetate 28.4mg.¹H NMR(500MHz,Chloroform-d)δ7.60(dd,J＝8.5,7.1Hz,1H),7.49–7.43(m,2H),7.40(d,J＝8.5Hz,1H),7.35–7.29(m,2H),7.09(t,J＝7.8Hz,1H),7.05(s,1H),6.75(d,J＝8.1Hz,1H),6.62(s,1H),6.56(d,J＝7.5Hz,1H),1.28(s,9H).ESI-MS of the target compound C ₂₄H₂₆N₃O⁺[M+H]⁺ =372.2; the experiment shows that: 371.2.

EXAMPLE 73 Synthesis of 2- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenol (LYA 15)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (100 mg) and 2-hydroxybenzaldehyde (41.39 mg), reference is made to general procedure six to give the theoretical calculation of trifluoroacetate 41.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.56(dd,J＝8.5,7.1Hz,1H),7.50–7.45(m,2H),7.40–7.34(m,3H),7.12(td,J＝7.7,1.7Hz,1H),7.08(dd,J＝7.5,1.7Hz,1H),7.00(dd,J＝7.1,0.8Hz,1H),6.80(dd,J＝8.1,1.1Hz,1H),6.75(td,J＝7.5,1.2Hz,1H),4.35(s,2H),1.31(s,9H).ESI-MS of the target compound C ₂₄H₂₆N₃O⁺[M+H]⁺ =372.2; the experiment shows that: 372.2.

EXAMPLE 74 Synthesis of 2- (4- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 42)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (43.4 mg) and methyl 2- (4-formylphenyl) acetate (25 mg), reference was made to general method eight to give the theoretical calculated for trifluoroacetate 4.5mg.¹H NMR(500MHz,Methanol-d₄)δ7.53(dd,J＝8.5,7.1Hz,1H),7.50–7.47(m,2H),7.42–7.36(m,3H),7.25(d,J＝8.0Hz,2H),7.18(d,J＝8.1Hz,2H),6.99(dd,J＝7.0,0.9Hz,1H),4.38(s,2H),3.58(s,2H),1.31(s,9H).ESI-MS of the title compound C ₂₆H₂₈N₃O₂ ⁺[M+H]⁺ =414.2; the experiment shows that: 414.3.

EXAMPLE 75 Synthesis of 2- (2- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 58)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (54 mg) and methyl 2- (2-formylphenyl) acetate (25 mg), using methanol and sodium cyanoborohydride (12.6 mg), the theoretical calculation of trifluoroacetate 6mg.¹H NMR(500MHz,Methanol-d₄)δ7.55(dd,J＝8.5,7.0Hz,1H),7.41(d,J＝2.1Hz,2H),7.40–7.35(m,3H),7.28–7.25(m,2H),7.24–7.18(m,2H),7.00(dd,J＝7.1,0.9Hz,1H),4.43(s,2H),3.68(s,2H),1.26(s,9H).ESI-MS of the title compound, C ₂₆H₂₈N₃O₂ ⁺[M+H]⁺ =414.2, was obtained by reference to general procedure eight; the experiment shows that: 414.3.

EXAMPLE 76 Synthesis of- (3- (((4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 62)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (66.3 mg) and methyl 2- (3-formylphenyl) acetate (67.9 mg), using methanol and sodium cyanoborohydride (18.9 mg), the theoretical calculation of trifluoroacetate 51.1mg.¹H NMR(500MHz,Methanol-d₄)δ7.56(dd,J＝8.5,7.1Hz,1H),7.49–7.43(m,2H),7.41–7.34(m,3H),7.29–7.23(m,1H),7.20(dt,J＝4.4,2.1Hz,2H),7.09(dt,J＝7.7,1.5Hz,1H),7.00(dd,J＝7.1,0.8Hz,1H),4.38(s,2H),3.58(s,2H),1.27(s,9H).ESI-MS of the title compound, C ₂₆H₂₈N₃O₂ ⁺[M+H]⁺ =414.2, was obtained by reference to general procedure eight; the experiment shows that: 414.3.

EXAMPLE 77 Synthesis of 2- (3-amino-4- (4- (tert-butyl) phenyl) -1H-indazol-1-yl) acetic acid (LYA 47)

Step one: synthesis of ethyl 2- (3-amino-4- (4- (tert-butyl) phenyl) -1H-indazol-1-yl) acetate (LYA 39)

4- (4- (Tert-butyl) phenyl) -1H-indazol-3-amine (40 mg), ethyl 2-bromoacetate (28 mg) and potassium carbonate (62.2 mg) were added to an eggplant-shaped flask, acetonitrile was added, and the mixture was heated to 80℃and stirred for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified on a silica gel column to give 22.7mg of the objective compound, which was used directly in the next step.

Step two: synthesis of 2- (3-amino-4- (4- (tert-butyl) phenyl) -1H-indazol-1-yl) acetic acid (LYA 47)

LYA39 (22.7 mg) was added to the eggplant-shaped flask, 5mL of the mixed solvent (MeOH: THF: H ₂ O=1:1:1) was added, lithium hydroxide monohydrate (7.9 mg) was added, and the mixture was warmed to 60℃and stirred overnight. After the reaction is finished, cooling to room temperature, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₁₉H₂₂N₃O₂ ⁺[M+H]⁺ = 324.2 of trifluoroacetate 1.5mg.¹H NMR(500MHz,Methanol-d₄)δ7.73(dd,J＝8.6,7.2Hz,1H),7.67–7.60(m,2H),7.49–7.41(m,3H),7.14(dd,J＝7.2,0.8Hz,1H),5.07(s,2H),1.40(s,9H).ESI-MS of the target compound; the experiment shows that: 324.6.

EXAMPLE 78 Synthesis of (4- (4- (tert-butyl) phenyl) -1H-indazol-3-yl) glycine (LYA 45)

Starting from 4- (4- (tert-butyl) phenyl) -1H-indazol-3-amine (40 mg) and ethyl 2-oxoacetate (82.8 mg), using methanol and sodium cyanoborohydride (11.3 mg), the theoretical calculation of trifluoroacetate 2mg.¹H NMR(500MHz,Methanol-d₄)δ7.65–7.55(m,3H),7.51–7.43(m,3H),7.34(d,J＝8.4Hz,1H),4.00(s,2H),1.40(s,9H).ESI-MS of the target compound, C ₁₉H₂₂N₃O₂ ⁺[M+H]⁺ = 324.2, was obtained by reference to general procedure eight; the experiment shows that: 324.2.

EXAMPLE 79 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (3, 6-dihydro-2H-pyran-4-yl) phenyl) -1H-indazol-3-amine (LYA 53)

Starting from 4- (4- (3, 6-dihydro-2H-pyran-4-yl) phenyl) -1H-indazol-3-amine (32.4 mg) and 1H-imidazole-4-carbaldehyde (9.6 mg), reference was made to general procedure six to give the theoretical calculated value C ₂₂H₂₂N₅O⁺[M+H]⁺ = 372.2 of trifluoroacetate 3.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.74(d,J＝1.5Hz,1H),7.62–7.56(m,2H),7.54–7.48(m,2H),7.41–7.30(m,3H),6.90(dd,J＝6.8,1.1Hz,1H),6.34–6.25(m,1H),4.50(d,J＝0.9Hz,2H),4.34(q,J＝2.8Hz,2H),3.96(t,J＝5.5Hz,2H),2.58(dt,J＝4.6,2.8Hz,2H).ESI-MS of the target compound; the experiment shows that: 372.3.

EXAMPLE 80 Synthesis of N- (((1H-imidazol-4-yl) methyl ] -4- (4- (pyridin-3-yl) phenyl) -1H-indazol-3-amine (LYA 12)

Starting from 4- (4- (pyridin-3-yl) phenyl) -1H-indazol-3-amine (48.7 mg) and 1H-imidazole-4-carbaldehyde (14.7 mg), reference was made to general procedure six to give the theoretical calculation of trifluoroacetate 2mg.¹H NMR(500MHz,Methanol-d₄)δ9.15(d,J＝2.2Hz,1H),8.78(dd,J＝5.4,1.4Hz,1H),8.76–8.70(m,2H),8.00(dd,J＝8.1,5.4Hz,1H),7.97–7.91(m,2H),7.79–7.74(m,2H),7.46–7.37(m,2H),7.36(d,J＝1.4Hz,1H),6.98(dd,J＝6.5,1.3Hz,1H),4.53(d,J＝1.0Hz,2H).ESI-MS of the title compound C ₂₂H₁₉N₆ ⁺[M+H]⁺ =367.2; the experiment shows that: 367.3.

EXAMPLE 81 Synthesis of 4- (3-amino-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-1-yl) -4-oxobutanoic acid (LYA 132)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (70 mg) and dihydrofuran-2, 5-dione (24 mg) were added to an eggplant-shaped flask, tetrahydrofuran (10 mL) was added, and the mixture was warmed to 60℃and stirred overnight. After the reaction, cooling to room temperature, adding water for quenching, extracting the water phase with dichloromethane for 3 times, combining the organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₃H₂₄N₃O₃ ⁺[M+H]⁺ =390.2 of the trifluoroacetate 64mg.¹H NMR(500MHz,DMSO-d₆)δ8.29(dd,J＝8.3,0.8Hz,1H),7.64–7.56(m,3H),7.46–7.41(m,2H),7.19(dd,J＝7.3,0.9Hz,1H),6.31(tt,J＝4.0,1.7Hz,1H),3.22(dd,J＝7.4,5.9Hz,2H),2.64(t,J＝6.6Hz,2H),2.43(tq,J＝6.5,2.3Hz,2H),2.26–2.17(m,2H),1.79–1.71(m,2H),1.67–1.59(m,2H).ESI-MS of the target compound; the experiment shows that: 390.3.

EXAMPLE 82 Synthesis of 4- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) picolinic acid (LYA 83)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (70 mg) and methyl 4-formylpyridinium formate (60 mg), using methanol and sodium cyanoborohydride (18 mg), reference was made to general procedure eight to give the theoretical calculation of trifluoroacetate 9.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.52(d,J＝5.5Hz,1H),8.17(s,1H),7.55(d,J＝8.4Hz,3H),7.50(d,J＝8.3Hz,2H),7.39–7.34(m,1H),7.31(d,J＝8.4Hz,1H),6.90(d,J＝6.7Hz,1H),6.21(s,1H),4.16–4.06(m,2H),2.45(s,2H),2.25(s,2H),1.87–1.78(m,2H),1.71(d,J＝6.0Hz,2H).ESI-MS of the title compound C ₂₆H₂₅N₄O₂ ⁺[M+H]⁺ =425.2; the experiment shows that: 424.5.

EXAMPLE 83 Synthesis of 2- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) isonicotinic acid (LYA 101)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (70 mg) and methyl 2-formylisonicotinate (60 mg), the theoretical calculation of the title compound 14mg.¹H NMR(500MHz,Methanol-d₄)δ8.57(d,J＝5.3Hz,1H),8.01(s,1H),7.87(dd,J＝5.2,1.6Hz,1H),7.57–7.50(m,2H),7.50–7.45(m,2H),7.43(dd,J＝8.4,7.0Hz,1H),7.33(d,J＝8.4Hz,1H),6.94(d,J＝7.0Hz,1H),6.22(tt,J＝4.0,1.7Hz,1H),4.63(s,2H),2.45(tq,J＝6.5,2.4Hz,2H),2.25(ddt,J＝8.6,6.5,3.3Hz,2H),1.92–1.78(m,2H),1.77–1.65(m,2H).ESI-MS, C ₂₆H₂₅N₄O₂ ⁺[M+H]⁺ =425.2, was obtained using methanol and sodium cyanoborohydride (18 mg), with reference to general procedure eight; the experiment shows that: 425.6.

EXAMPLE 84 Synthesis of 6- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) picolinic acid (LYA 72)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (70 mg) and methyl 2-formylisonicotinate (60 mg), using methanol and sodium cyanoborohydride (18 mg), the theoretical calculation of trifluoroacetate 10mg.¹H NMR(500MHz,Methanol-d₄)δ8.11(d,J＝7.6Hz,1H),8.06(t,J＝7.7Hz,1H),7.67(d,J＝7.8Hz,1H),7.61–7.50(m,3H),7.48(d,J＝8.3Hz,2H),7.39(d,J＝8.4Hz,1H),7.04(d,J＝7.1Hz,1H),6.19(s,1H),4.65(s,2H),2.42(s,2H),2.24(q,J＝2.7Hz,2H),1.90–1.77(m,2H),1.77–1.65(m,2H).ESI-MS of the target compound C ₂₆H₂₅N₄O₂ ⁺[M+H]⁺ =425.2 was obtained with reference to general procedure eight; the experiment shows that: 425.6.

EXAMPLE 85 Synthesis of 5- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) nicotinic acid (LYA 129)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (56 mg) and methyl 2-formylisonicotinate (60 mg), using methanol and sodium cyanoborohydride (15 mg), the theoretical calculation of trifluoroacetate 6mg.¹H NMR(500MHz,DMSO-d₆)δ8.90(d,J＝2.0Hz,1H),8.71(d,J＝2.2Hz,1H),8.22(d,J＝2.2Hz,1H),7.53(d,J＝8.0Hz,2H),7.46(d,J＝7.9Hz,2H),7.36–7.24(m,2H),6.83(d,J＝6.2Hz,1H),6.24(d,J＝4.1Hz,1H),4.45(d,J＝5.8Hz,2H),2.39(q,J＝5.4Hz,2H),2.20(tt,J＝5.6,3.1Hz,2H),1.80–1.69(m,2H),1.62(ddt,J＝11.7,9.1,4.0Hz,2H).ESI-MS of the target compound C ₂₆H₂₅N₄O₂ ⁺[M+H]⁺ =425.2 was obtained with reference to general procedure eight; the experiment shows that: 424.3.

EXAMPLE 86 Synthesis of 2- (3- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl (LYA 95)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and methyl 2- (3-formylphenyl) acetate (55 mg), using methanol and sodium cyanoborohydride (16 mg), the theoretical calculated value of trifluoroacetate 14mg.¹H NMR(500MHz,Methanol-d₄)δ7.65(dd,J＝8.6,7.1Hz,1H),7.53–7.48(m,2H),7.46–7.40(m,3H),7.28(t,J＝7.6Hz,1H),7.22(dt,J＝7.7,1.4Hz,1H),7.18(d,J＝1.8Hz,1H),7.12(dt,J＝7.6,1.5Hz,1H),7.09(d,J＝7.1Hz,1H),6.18(tt,J＝4.0,1.7Hz,1H),4.43(s,2H),3.59(s,2H),2.39(tq,J＝6.3,2.3Hz,2H),2.25(ddt,J＝8.5,6.3,3.2Hz,2H),1.86–1.79(m,2H),1.74–1.67(m,2H).ESI-MS of the title compound C ₂₈H₂₈N₃O₂ ⁺[M+H]⁺ = 438.2 was obtained by reference to general procedure eight; the experiment shows that: 438.1.

EXAMPLE 87 Synthesis of 2- (2- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 102)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and methyl 2- (2-formylphenyl) acetate (55 mg), using methanol and sodium cyanoborohydride (16 mg), the theoretical calculated value of trifluoroacetate 15mg.¹H NMR(500MHz,Methanol-d₄)δ7.67(dd,J＝8.5,7.2Hz,1H),7.46–7.37(m,5H),7.28(dd,J＝3.9,1.8Hz,2H),7.24(ddd,J＝8.7,5.7,3.0Hz,1H),7.21–7.17(m,1H),7.11(d,J＝7.1Hz,1H),6.11(tt,J＝4.0,1.7Hz,1H),4.47(s,2H),3.68(s,2H),2.34(tq,J＝6.4,2.4Hz,2H),2.23(ddt,J＝8.6,6.3,3.3Hz,2H),1.84–1.77(m,2H),1.73–1.64(m,2H).ESI-MS of the target compound C ₂₈H₂₈N₃O₂ ⁺[M+H]⁺ = 438.2 was obtained by reference to general procedure eight; the experiment shows that: 438.4.

EXAMPLE 88 Synthesis of 2- (4- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) phenyl) acetic acid (LYA 84)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and methyl 2- (4-formylphenyl) acetate (55 mg), using methanol and sodium cyanoborohydride (16 mg), the theoretical calculated value of trifluoroacetate 22.1mg.¹H NMR(500MHz,Methanol-d₄)δ7.59(ddd,J＝8.4,7.1,1.4Hz,1H),7.51–7.46(m,2H),7.44–7.38(m,3H),7.25(d,J＝8.2Hz,2H),7.20–7.14(m,2H),7.04(d,J＝7.1Hz,1H),6.18(tt,J＝3.9,1.7Hz,1H),4.41(s,2H),3.59(s,2H),2.40(tq,J＝6.4,2.3Hz,2H),2.26(ddt,J＝8.6,6.4,3.3Hz,2H),1.88–1.79(m,2H),1.75–1.66(m,2H).ESI-MS of the title compound C ₂₈H₂₈N₃O₂ ⁺[M+H]⁺ = 438.2 was obtained by reference to general procedure eight; the experiment shows that: 438.4.

EXAMPLE 89 Synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxamide) methyl) benzoic acid (FB 11)

General method nine:

Step one: synthesis of methyl 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxamide) methylbenzoate (FB 5)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylic acid (FB 55,60 mg), (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (140 mg) and 1-hydroxybenzotriazole monohydrate (38 mg) were added to an eggplant-shaped flask, N-dimethylformamide and N, N-diisopropylethylamine (94 mg) were added, and after stirring at room temperature for 10min, methyl 3- (aminomethyl) benzoate hydrochloride (74 mg) was added, and stirring at room temperature overnight. After the completion of the reaction, the reaction was quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated on a rotary evaporator, and purified on a silica gel column to give 47mg of the objective compound.

Step two: synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxamide) methyl) benzoic acid (FB 11)

FB5 (47 mg) was added to the whole in an eggplant-shaped flask, 5mL of a mixed solvent (MeOH: H ₂ o=1:1.5) was added, sodium hydroxide (24 mg) was added, and the temperature was raised to 80 ℃, and stirred overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₈H₂₆N₃O₃ ⁺[M+H]⁺ =452.2 of trifluoroacetate 4mg.¹H NMR(500MHz,Methanol-d₄)δ8.00–7.92(m,2H),7.58(dd,J＝8.4,0.9Hz,1H),7.54–7.41(m,3H),7.39(d,J＝8.3Hz,2H),7.35–7.30(m,2H),7.20(dd,J＝7.0,0.9Hz,1H),4.32(s,2H),2.42(tq,J＝6.3,2.3Hz,2H),2.27(ddt,J＝8.3,6.3,2.7Hz,2H),1.88–1.79(m,2H),1.74–1.70(m,2H).ESI-MS of the target compound; the experiment shows that: 451.2.

Example 90 Synthesis: 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxamide) methyl) benzoic acid (FB 28)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylic acid (60 mg) and methyl 4- (aminomethyl) benzoate hydrochloride (140 mg), the theoretical calculation of trifluoroacetate 5mg.¹H NMR(500MHz,Methanol-d₄)δ8.00–7.92(m,2H),7.55(dd,J＝8.4,0.9Hz,1H),7.48(dd,J＝8.4,7.0Hz,1H),7.39–7.34(m,2H),7.32–7.26(m,4H),7.17(dd,J＝7.0,0.9Hz,1H),6.13(tt,J＝4.0,1.7Hz,1H),4.32(s,2H),2.39(tq,J＝6.4,2.3Hz,2H),2.24(dp,J＝8.8,3.2,2.7Hz,2H),1.86–1.77(m,2H),1.74–1.64(m,2H).ESI-MS of the target compound, C ₂₈H₂₆N₃O₃ ⁺[M+H]⁺ = 452.2, was obtained by reference to general procedure nine; the experiment shows that: 451.2.

Example 91 synthesis: (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) methanol (FB 85)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazole-3-carboxylic acid methyl ester (50 mg) was added to an eggplant-shaped flask, tetrahydrofuran (10 mL) was added, a solution of lithium borohydride in tetrahydrofuran (2M, 0.1 mL) was added, and stirring was performed at room temperature for 3H. After the reaction, adding water to quench the reaction, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated saline water, drying with anhydrous sodium sulfate, concentrating by a rotary evaporator, and purifying by HPLC to obtain the theoretical calculated value of the trifluoroacetate 3.1mg.¹H NMR(500MHz,Methanol-d₄)δ7.52–7.48(m,3H),7.47–7.43(m,2H),7.41(dd,J＝8.4,7.0Hz,1H),7.01(dd,J＝6.9,0.9Hz,1H),6.24(tt,J＝3.9,1.8Hz,1H),4.54(s,2H),2.49(tq,J＝6.2,2.2Hz,2H),2.26(ddp,J＝8.8,6.3,3.1,2.7Hz,2H),1.89–1.80(m,2H),1.76–1.67(m,2H).ESI-MS of the target compound, namely C ₂₀H₂₁N₂O⁺[M+H]⁺ =305.2; the experiment shows that: 305.2.

EXAMPLE 92 Synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) methyl) benzoic acid (FB 107)

The general method is thirteenth:

step one: 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) methyl) benzoate (FB 104)

(4, 5-Tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1,3, 2-dioxaborane (88 mg) and methyl 3- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (95 mg) were added to an eggplant flask, ethylene glycol dimethyl ether (6 mL) and an aqueous sodium carbonate solution (2M, 3 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (23 mg) was added, after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight, after the reaction was completed, cooled to room temperature, quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and purified by a silica gel column to give the target compound 59.4mg.¹H NMR(500MHz,Chloroform-d)δ8.02(d,J＝1.9Hz,1H),7.99(dt,J＝7.3,1.6Hz,1H),7.71(d,J＝8.7Hz,1H),7.59(d,J＝8.0Hz,2H),7.49(d,J＝8.2Hz,2H),7.45(dt,J＝7.6,1.6Hz,1H),7.41(d,J＝7.6Hz,1H),7.40–7.34(m,1H),7.18(d,J＝6.9Hz,1H),6.21(tt,J＝3.8,1.7Hz,1H),5.64(s,2H),3.90(d,J＝2.6Hz,3H),2.46(tq,J＝6.7,2.2Hz,2H),2.24(tq,J＝6.0,2.8Hz,2H),1.81(qd,J＝7.7,6.2,4.2Hz,2H),1.74–1.62(m,2H).

Step two: 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) methyl) benzoic acid (FB 107)

FB107 (59.4 mg) was added to the eggplant-shaped flask, 6mL of the mixed solvent (THF: H ₂ O: meoh=1:1:1) was added, lithium hydroxide monohydrate (58 mg) was added, and stirred at room temperature overnight. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₇H₂₅N₂O₂ ⁺[M+H]⁺ =409.2 of trifluoroacetate 21.2mg.¹H NMR(500MHz,DMSO-d₆)δ8.77(s,1H),7.92(d,J＝1.8Hz,1H),7.87(dt,J＝7.6,1.4Hz,1H),7.71–7.64(m,2H),7.60(dd,J＝11.5,8.2Hz,2H),7.57–7.52(m,2H),7.48(t,J＝7.7Hz,1H),7.33(dd,J＝8.7,6.9Hz,1H),7.18(d,J＝6.9Hz,1H),6.26(dt,J＝4.4,2.5Hz,1H),5.74(s,2H),2.43(dt,J＝6.3,3.4Hz,2H),2.22(dq,J＝6.6,3.6Hz,2H),1.76(qd,J＝7.6,6.1,3.9Hz,2H),1.64(tq,J＝6.3,2.7Hz,2H).ESI-MS of the target compound; the experiment shows that: 408.7.

EXAMPLE 93 Synthesis of 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) methyl) benzoic acid (FB 122)

Starting from (4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (145 mg) and methyl 4- ((4-bromo-2H-indazol-2-yl) methyl) benzoate (193 mg), the theoretical calculation of trifluoroacetate 4.8mg.¹H NMR(500MHz,DMSO-d₆)δ8.75(d,J＝1.0Hz,1H),7.95–7.87(m,2H),7.73–7.66(m,2H),7.59(d,J＝8.7Hz,1H),7.57–7.52(m,2H),7.41(d,J＝8.3Hz,2H),7.33(dd,J＝8.7,6.9Hz,1H),7.23–7.12(m,1H),6.31–6.23(m,1H),5.75(s,2H),2.43(s,2H),2.22(s,2H),1.80–1.70(m,2H),1.68–1.60(m,2H).ESI-MS of the target compound, C ₂₇H₂₅N₂O₂ ⁺[M+H]⁺ =409.2, was obtained with reference to the general procedure thirteen, experimental measurements 409.7.

EXAMPLE 94 Synthesis of 4- (2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) ethyl) benzoic acid (FB 141)

Starting from (4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (57 mg) and methyl 4- (2- (4-bromo-2H-indazol-2-yl) ethyl) benzoate (70 mg), the theoretical calculated C ₂₈H₂₇N₂O₂ ⁺[M+H]⁺ = 423.2 of trifluoroacetate 3.7mg.¹H NMR(500MHz,DMSO-d₆)δ8.37(s,1H),7.83(d,J＝7.9Hz,2H),7.58(dd,J＝12.4,8.3Hz,3H),7.50(d,J＝8.1Hz,2H),7.37–7.26(m,3H),7.14(d,J＝6.9Hz,1H),6.30–6.20(m,1H),4.73(t,J＝7.3Hz,2H),2.46–2.37(m,2H),2.22(td,J＝6.2,3.4Hz,2H),1.75(qd,J＝7.6,6.2,4.3Hz,2H),1.69–1.54(m,2H).ESI-MS of the target compound was obtained by reference to the general procedure thirteen, which was experimentally determined to be 423.8.

EXAMPLE 95 Synthesis of 3- (2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -2H-indazol-2-yl) ethyl) benzoic acid (FB 152)

Starting from (4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (64 mg) and methyl 3- (2- (4-bromo-2H-indazol-2-yl) ethyl) benzoate (57.6 mg), the theoretical calculation of trifluoroacetate 7.5mg.¹H NMR(500MHz,Chloroform-d)δ7.99(d,J＝7.7Hz,1H),7.91(d,J＝7.4Hz,2H),7.76(d,J＝8.7Hz,1H),7.57(t,J＝7.8Hz,1H),7.48(d,J＝7.9Hz,2H),7.38(dd,J＝24.9,7.8Hz,3H),7.33–7.27(m,2H),6.22(d,J＝4.2Hz,1H),4.85(t,J＝6.9Hz,2H),3.40(t,J＝7.0Hz,2H),2.44(dt,J＝7.7,3.9Hz,2H),2.24(tt,J＝6.5,2.9Hz,2H),1.80(td,J＝8.2,7.1,4.4Hz,2H),1.73–1.59(m,2H).ESI-MS of the target compound, C ₂₈H₂₇N₂O₂ ⁺[M+H]⁺ = 423.2, was obtained with reference to the general procedure thirteen, experimental measurements: 423.5.

Examples 96 and 97 Synthesis of 4- (7- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) benzoic acid (FC 3-1) and 4- (1- (4-carboxybenzyl) -4- (2', 3',4',5 '-tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) benzoic acid (FC 3-2)

Starting from a mixture of (4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (369 mg) and methyl 4- (4-bromo-1H-benzo [ d ] imidazol-2-yl) benzoate and methyl 4- (4-bromo-1- (4- (methoxycarbonyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) benzoate (286 mg), the theoretical calculation of trifluoroacetate for the target compound 96 (FC 3-1) C38 41.9mg.¹H NMR(500MHz,Methanol-d₄)δ8.30–8.25(m,2H),8.21(d,J＝8.6Hz,2H),7.79(dd,J＝8.2,1.0Hz,1H),7.72–7.64(m,3H),7.63–7.55(m,3H),6.27(tt,J＝4.0,1.7Hz,1H),2.49(tq,J＝6.4,2.3Hz,2H),2.27(tq,J＝6.1,2.8Hz,2H),1.91–1.80(m,2H),1.77–1.67(m,2H).ESI-MS =395.2 was obtained by reference to the general procedure thirteen, the theoretical calculation of trifluoroacetate for the target compound 3297 (FC 3-2) C ₃₄H₂₉N₂O₄ ⁺[M+H]⁺ =529.2 was obtained by experimental measurement of 395.5, and the theoretical calculation of trifluoroacetate for the target compound 97 (FC 3-2) was obtained by experimental measurement of 528.9.

Examples 98 and 99 Synthesis of 3- (7- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) benzoic acid (FC 11-1) and 3- (1- (3-carboxybenzyl) -4- (2', 3',4',5 '-tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) benzoic acid (FC 11-2)

The theoretical calculation of trifluoroacetate 39.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.81(t,J＝1.8Hz,1H),8.35(tt,J＝8.3,1.3Hz,2H),7.83–7.76(m,2H),7.66(dd,J＝15.8,7.9Hz,3H),7.58(dd,J＝8.5,7.4Hz,3H),6.26(tt,J＝4.0,1.7Hz,1H),2.48(tq,J＝6.5,2.3Hz,2H),2.26(dp,J＝8.9,3.1,2.6Hz,2H),1.89–1.80(m,2H),1.77–1.66(m,2H).ESI-MS of the target compound 98 (FC 11-1) C ₂₆H₂₃N₂O₂ ⁺[M+H]⁺ =395.2, the theoretical calculation of trifluoroacetate 6.0mg.¹H NMR(500MHz,Methanol-d₄)δ8.41(t,J＝1.8Hz,1H),8.35(dt,J＝7.9,1.4Hz,1H),7.99(dt,J＝7.8,1.6Hz,2H),7.82(q,J＝1.8Hz,1H),7.79–7.73(m,2H),7.72–7.64(m,4H),7.61–7.56(m,2H),7.47(t,J＝7.7Hz,1H),7.42(dt,J＝7.8,1.6Hz,1H),6.25(tt,J＝3.9,1.7Hz,1H),5.82(s,2H),2.55–2.42(m,2H),2.26(ddt,J＝8.6,6.3,3.4Hz,2H),1.90–1.76(m,2H),1.71(ddp,J＝9.3,6.2,3.0Hz,2H).ESI-MS of the target compound 99 (FC 11-2) C ₃₄H₂₉N₂O₄ ⁺[M+H]⁺ =529.2, experimental measurement 395.3, and experimental measurement 529.5 were obtained as a mixture of (4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (467 mg) and methyl 3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) benzoate (752 mg) with reference to the general procedure thirteen.

EXAMPLE 100 Synthesis of 3- ((((4- ([ 1,1' -biphenyl ] -4-yl ] -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 10)

Starting from 4- ([ 1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (32 mg), reference is made to general procedure six to give the theoretical calculated value of trifluoroacetate 9.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.04(d,J＝1.92Hz,1H),7.94(dt,J＝7.73,1.53Hz,1H),7.79–7.74(m,2H),7.67(dd,J＝8.56,7.08Hz,1H),7.63–7.57(m,4H),7.53–7.50(m,1H),7.48–7.40(m,4H),7.38–7.34(m,1H),7.15(d,J＝7.04Hz,1H),4.53(s,2H).ESI-MS of the target compound C ₂₇H₂₂N₃O₂ ⁺[M+H]⁺ =420.2; the experiment shows that: 419.7.

EXAMPLE 101 Synthesis of 3- ((((4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 11)

Starting from 4- (2-methyl-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (30 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₈H₂₈N₃O₂ ⁺[M+H]⁺ = 438.2 of trifluoroacetate 12.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.02–7.94(m,2H),7.64(t,J＝7.89Hz,1H),7.55–7.39(m,3H),7.29–7.19(m,2H),7.12(d,J＝7.69Hz,1H),7.07(d,J＝7.11Hz,1H),5.41(s,1H),4.48(s,2H),2.62–2.02(m,7H),1.81–1.64(m,4H).ESI-MS of the target compound; the experiment shows that: 437.7.

EXAMPLE 102 Synthesis of 3- ((((4-phenyl-1H-indazol-3-yl) amino) methyl) benzoic acid (QM 16)

Starting from 4-phenyl-1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (43 mg), reference was made to general procedure six to give the theoretical calculation of trifluoroacetate 22.7mg.¹H NMR(500MHz,Methanol-d₄)δ7.96–7.90(m,2H),7.58(dd,J＝8.56,7.06Hz,1H),7.52–7.44(m,5H),7.43–7.37(m,3H),7.02(d,J＝7.01Hz,1H),4.49(s,2H).ESI-MS of the target compound C ₂₁H₁₈N₃O₂ ⁺[M+H]⁺ = 344.1; the experiment shows that: 343.8.

EXAMPLE 103 Synthesis of N-methyl-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzamide (QM 25)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3-formyl-N-methylbenzamide (33 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₈H₂₉N₄O⁺[M+H]⁺ = 437.2 of trifluoroacetate 4.3mg.¹H NMR(500MHz,Methanol-d₄)δ7.80(dd,J＝2.05,1.00Hz,1H),7.73(ddd,J＝5.65,3.47,1.84Hz,1H),7.59(dd,J＝8.54,7.13Hz,1H),7.50–7.46(m,2H),7.45–7.38(m,5H),6.13(tt,J＝3.89,1.70Hz,1H),4.49(s,2H),2.93(s,3H),2.36(tq,J＝6.32,2.27Hz,2H),2.23(ddt,J＝8.54,6.37,2.96Hz,2H),1.83–1.77(m,2H),1.72–1.65(m,2H).ESI-MS of the target compound; the experiment shows that: 436.7.

EXAMPLE 104 Synthesis of N-isopropyl-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzamide (QM 27)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3-formyl-N-isopropylbenzamide (50 mg), 5.1mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six. ESI-MS theoretical calculation C ₃₀H₃₃N₄O⁺[M+H]⁺ =465.3; the experiment shows that: 464.7.

EXAMPLE 105 Synthesis of N, N-dimethyl-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzamide (QM 29)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3-formyl-N, N-dimethylbenzamide (92 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₉H₃₁N₄O⁺[M+H]⁺ =451.2 of trifluoroacetate 24mg.¹H NMR(500MHz,Methanol-d₄)δ7.60(dd,J＝8.55,7.10Hz,1H),7.51–7.47(m,2H),7.45–7.38(m,4H),7.37–7.30(m,3H),7.04(d,J＝7.11Hz,1H),6.18(tt,J＝3.86,1.70Hz,1H),4.49(s,2H),3.09(s,3H),2.92(s,3H),2.39(tq,J＝6.35,2.26Hz,2H),2.24(tp,J＝6.09,2.75Hz,2H),1.80(dtt,J＝10.28,6.71,3.68Hz,2H),1.69(dhept,J＝9.23,3.32Hz,2H).ESI-MS of the target compound; the experiment shows that: 450.7.

EXAMPLE 106 Synthesis of N-ethyl-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzamide (QM 31)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and N-ethyl-3-formylbenzamide (153 mg), reference general procedure six gave the theoretical calculation of trifluoroacetate 16.3mg.¹H NMR(500MHz,Methanol-d₄)δ7.80(s,1H),7.74(td,J＝4.71,1.90Hz,1H),7.56(dd,J＝8.54,7.07Hz,1H),7.50–7.46(m,2H),7.46–7.42(m,2H),7.42–7.37(m,3H),7.02(dd,J＝7.10,0.84Hz,1H),6.14(td,J＝3.96,2.02Hz,1H),4.48(s,2H),3.42(q,J＝7.36Hz,2H),2.40–2.33(m,2H),2.26–2.20(m,2H),1.84–1.77(m,2H),1.73–1.66(m,2H),1.24(t,J＝7.24Hz,3H).ESI-MS of the target compound C ₂₉H₃₁N₄O⁺[M+H]⁺ =451.2; the experiment shows that: 451.3.

EXAMPLE 107 Synthesis of N- (3- (1H-pyrazol-4-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 39)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (138 mg) and 3- (1H-pyrazol-4-yl) benzaldehyde (83 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₉H₂₈N₅ ⁺[M+H]⁺ =446.2 of trifluoroacetate 27.6mg.¹H NMR(500MHz,Methanol-d₄)δ8.01(s,2H),7.66(dd,J＝8.58,7.13Hz,1H),7.55(dt,J＝7.84,1.41Hz,1H),7.48(d,J＝1.80Hz,1H),7.44(d,J＝8.56Hz,1H),7.42–7.36(m,4H),7.33(t,J＝7.68Hz,1H),7.09(dd,J＝7.31,2.08Hz,2H),5.98(tt,J＝3.86,1.67Hz,1H),4.43(s,2H),2.19(tq,J＝6.17,2.16Hz,2H),2.14(dtt,J＝8.86,6.12,2.56Hz,2H),1.70(qq,J＝5.79,3.29Hz,2H),1.64–1.58(m,2H).ESI-MS of the target compound; the experiment shows that: 446.6.

EXAMPLE 108 Synthesis of N- (3- (pyridin-3-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 41)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (96 mg) and 3- (pyridin-3-yl) benzaldehyde (73 mg), reference is made to general procedure six to give the theoretical calculated value C ₃₁H₂₉N₄ ⁺[M+H]⁺ =457.2 of trifluoroacetate 22.7mg.¹H NMR(500MHz,Methanol-d₄)δ9.09(d,J＝2.11Hz,1H),8.82(d,J＝5.56Hz,1H),8.78(dt,J＝8.20,1.77Hz,1H),8.10(dd,J＝8.21,5.58Hz,1H),7.72(dt,J＝7.73,1.48Hz,1H),7.68(d,J＝1.85Hz,1H),7.54(t,J＝7.71Hz,1H),7.49(dd,J＝8.54,7.03Hz,1H),7.46–7.41(m,5H),7.37(d,J＝8.41Hz,1H),6.97(d,J＝6.89Hz,1H),6.07(tt,J＝3.86,1.69Hz,1H),4.53(s,2H),2.30(tq,J＝6.34,2.26Hz,2H),2.18(ddt,J＝8.28,6.14,2.58Hz,2H),1.78–1.71(m,2H),1.68–1.61(m,2H).ESI-MS of the target compound; the experiment shows that: 456.7.

EXAMPLE 109 Synthesis of N- (3- (1H-pyrazol-5-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 46)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3- (1H-pyrazol-5-yl) benzaldehyde (50 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₉H₂₈N₅ ⁺[M+H]⁺ =446.2 of trifluoroacetate 21.2mg.¹H NMR(500MHz,Methanol-d₄)δ7.77–7.70(m,3H),7.65(dd,J＝8.57,7.10Hz,1H),7.45–7.35(m,6H),7.20(dt,J＝7.68,1.47Hz,1H),7.08(d,J＝7.05Hz,1H),6.72(d,J＝2.36Hz,1H),5.97(tt,J＝3.82,1.67Hz,1H),4.47(s,2H),2.19(tq,J＝6.03,2.18Hz,2H),2.14(dtt,J＝8.80,6.06,2.56Hz,2H),1.70(qq,J＝5.82,3.30Hz,2H),1.64–1.58(m,2H).ESI-MS of the target compound; the experiment shows that: 446.8.

EXAMPLE 110 Synthesis of N- (3- (pyridin-4-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 50)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 3- (pyridin-4-yl) benzaldehyde (60 mg), reference is made to general method six to give the theoretical calculated value C ₃₁H₂₉N₄ ⁺[M+H]⁺ =457.2 of trifluoroacetate 2.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.91–8.83(m,2H),8.37–8.30(m,2H),7.89(dt,J＝7.75,1.57Hz,1H),7.86(d,J＝1.81Hz,1H),7.59(t,J＝7.65Hz,1H),7.56–7.49(m,2H),7.47–7.41(m,4H),7.38(d,J＝8.43Hz,1H),6.99(d,J＝6.93Hz,1H),6.06(tt,J＝3.97,1.70Hz,1H),4.55(s,2H),2.29(tq,J＝6.24,2.26Hz,2H),2.17(dtt,J＝8.81,6.01,2.64Hz,2H),1.79–1.71(m,2H),1.68–1.60(m,2H).ESI-MS of the target compound; the experiment shows that: 457.7.

EXAMPLE 111 Synthesis of N- (3- (1H-tetrazol-5-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 52)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (66 mg) and 3- (1H-tetrazol-5-yl) benzaldehyde (80 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₆N₇ ⁺[M+H]⁺ = 448.2 of trifluoroacetate 3.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.01(d,J＝1.74Hz,1H),7.94(dt,J＝7.74,1.48Hz,1H),7.60–7.52(m,2H),7.50–7.39(m,6H),7.03(dd,J＝7.07,0.83Hz,1H),5.98(tt,J＝3.93,1.70Hz,1H),4.52(s,2H),2.21(tq,J＝6.23,2.35Hz,2H),2.14(tdd,J＝6.24,4.07,2.60Hz,2H),1.75–1.68(m,2H),1.65–1.59(m,2H).ESI-MS of the target compound; the experiment shows that: 447.8.

EXAMPLE 112 Synthesis of 2- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 66)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 2-formylbenzoic acid (39 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₆N₃O₂ ⁺[M+H]⁺ =424.2 of trifluoroacetate 5.8mg.¹H NMR(500MHz,Methanol-d₄)δ8.03(dd,J＝7.77,1.47Hz,1H),7.62(dd,J＝8.55,7.11Hz,1H),7.51(td,J＝7.52,1.51Hz,1H),7.46–7.37(m,5H),7.34–7.29(m,2H),7.04(d,J＝7.11Hz,1H),6.15(tt,J＝3.88,1.70Hz,1H),4.72(s,2H),2.38(tq,J＝6.31,2.25Hz,2H),2.24(ddt,J＝8.37,6.15,3.13Hz,2H),1.86–1.77(m,2H),1.73–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 424.9.

EXAMPLE 113 Synthesis of 4- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 69)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 4-formylbenzoic acid (39 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₆N₃O₂ ⁺[M+H]⁺ =424.2 of trifluoroacetate 6mg.¹H NMR(500MHz,Methanol-d₄)δ7.97(d,J＝7.90Hz,2H),7.57(t,J＝7.80Hz,1H),7.46(d,J＝7.94Hz,2H),7.43–7.37(m,3H),7.32(d,J＝7.95Hz,2H),7.04(d,J＝7.03Hz,1H),6.17–6.10(m,1H),4.47(s,2H),2.41–2.31(m,2H),2.27–2.19(m,2H),1.85–1.77(m,2H),1.73–1.63(m,2H).ESI-MS of the target compound; the experiment shows that: 423.7.

EXAMPLE 114 Synthesis of 4- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) cyclohexane-1-carboxylic acid (QM 71)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 4-formylcyclohexane-1-carboxylic acid (39 mg), reference is made to general procedure six to give the theoretical calculation of trifluoroacetate 26.2mg.¹H NMR(500MHz,Methanol-d₄)δ7.67(dd,J＝8.59,7.12Hz,1H),7.63–7.58(m,2H),7.47–7.38(m,3H),7.10(d,J＝7.02Hz,1H),6.30(tt,J＝3.93,1.68Hz,1H),3.10(d,J＝6.14Hz,2H),2.48(tq,J＝6.65,2.35Hz,2H),2.26(tq,J＝5.72,2.73Hz,2H),2.19(tt,J＝12.29,3.62Hz,1H),1.94(dt,J＝12.33,3.59Hz,2H),1.87–1.79(m,2H),1.74–1.66(m,2H),1.62(dd,J＝13.60,3.50Hz,2H),1.51–1.40(m,1H),1.34(qd,J＝13.10,3.48Hz,2H),0.88(qd,J＝13.07,3.51Hz,2H).ESI-MS of the target compound C ₂₇H₃₂N₃O₂ ⁺[M+H]⁺ =430.2; the experiment shows that: 430.7.

EXAMPLE 115 Synthesis of 3- (((4- (4- (trifluoromethyl) phenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 74)

Starting from 4- (4- (trifluoromethyl) phenyl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (41 mg), reference is made to general procedure six to give the theoretical calculation of trifluoroacetate 8.8mg.¹H NMR(500MHz,Methanol-d₄)δ8.00(d,J＝1.90Hz,1H),7.92(dt,J＝7.61,1.57Hz,1H),7.80(d,J＝8.06Hz,2H),7.72(d,J＝8.04Hz,2H),7.57(dd,J＝8.55,6.97Hz,1H),7.51–7.47(m,1H),7.47–7.38(m,2H),7.05(d,J＝7.01Hz,1H),4.49(s,2H).ESI-MS of the target compound C ₂₂H₁₇F₃N₃O₂ ⁺[M+H]⁺ =412.1; the experiment shows that: 411.6. EXAMPLE 116 Synthesis of 3- ((((4- (2-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 83)

Starting from 4- (2-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 3-formylbenzoic acid (58 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₅FN₃O₂ ⁺[M+H]⁺ =442.2 of trifluoroacetate 5.5mg.¹H NMR(500MHz,Methanol-d₄)δ7.99(d,J＝1.79Hz,1H),7.95(dt,J＝7.71,1.49Hz,1H),7.57–7.50(m,2H),7.46–7.39(m,2H),7.35(t,J＝7.87Hz,1H),7.25(dd,J＝7.84,1.78Hz,1H),7.19(dd,J＝11.50,1.74Hz,1H),7.02(d,J＝6.97Hz,1H),5.88(tt,J＝3.73,1.73Hz,1H),4.49(s,2H),2.30(dtt,J＝5.61,3.80,1.83Hz,2H),2.22(dtt,J＝8.85,6.06,2.66Hz,2H),1.77(tdd,J＝8.49,5.28,2.72Hz,2H),1.70(dtt,J＝9.24,6.03,2.84Hz,2H).ESI-MS of the target compound; the experiment shows that: 442.7.

EXAMPLE 117 Synthesis of 3- ((((4- (3-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 87)

Starting from 4- (3-fluoro-2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzoic acid (49 mg), reference general procedure six gave the theoretical calculation of trifluoroacetate 14.5mg.¹H NMR(500MHz,Methanol-d₄)δ7.98(d,J＝1.82Hz,1H),7.96(dd,J＝7.63,1.53Hz,1H),7.64(t,J＝7.87Hz,1H),7.49(dt,J＝7.65,1.66Hz,1H),7.47–7.41(m,2H),7.37(t,J＝7.88Hz,1H),7.31(dd,J＝7.94,1.74Hz,1H),7.25(dd,J＝11.73,1.73Hz,1H),7.08(d,J＝7.09Hz,1H),6.19(tt,J＝3.93,1.73Hz,1H),4.48(s,2H),2.33(tq,J＝6.41,2.30Hz,2H),2.23(dp,J＝8.86,3.08Hz,2H),1.83–1.76(m,2H),1.71–1.64(m,2H).ESI-MS of the target compound C ₂₇H₂₅FN₃O₂ ⁺[M+H]⁺ =442.2; the experiment shows that: 442.7.

EXAMPLE 118 Synthesis of 3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzonitrile (QM 93)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3-formylbenzonitrile (45 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₅N₄ ⁺[M+H]⁺ =405.2 of trifluoroacetate 1.2mg.¹H NMR(500MHz,Methanol-d₄)δ7.63–7.59(m,2H),7.56(dt,J＝8.24,1.49Hz,1H),7.53–7.41(m,6H),7.35(d,J＝8.43Hz,1H),6.96(d,J＝6.97Hz,1H),6.19(tt,J＝3.95,1.74Hz,1H),4.45(s,2H),2.43(ddd,J＝8.19,5.03,3.08Hz,2H),2.25(dh,J＝8.92,2.73Hz,2H),1.86–1.79(m,2H),1.74–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 405.4.

EXAMPLE 119 Synthesis of N- (3- (3-aminooxetan-3-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 108)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (100 mg) and N- (3- (3-formylphenyl) oxetan-3-yl) -2-methylpropan-2-sulfinamide (194 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (212 mg) and acetic acid (0.1 mL) were added, and stirred at room temperature overnight. After the completion of the reaction, a saturated sodium hydrogencarbonate solution was added, the aqueous phase was extracted 3 times with methylene chloride, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to give QM106 (263 mg). ESI-MS theoretical calculation C ₃₃H₃₉N₄O₂S⁺[M+H]⁺ = 555.3; the experiment shows that: 556.6.

QM106 (131 mg) was put into an eggplant-shaped flask, methanol (5 mL) was added thereto, and a hydrochloric acid methanol solution (4M, 1 mL) was added dropwise at 0℃and stirred for 10 minutes. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₉H₃₁N₄O⁺[M+H]⁺ =451.2 of trifluoroacetate 14.6mg.¹H NMR(500MHz,Methanol-d₄)δ7.55–7.42(m,6H),7.41–7.33(m,4H),6.99(d,J＝7.01Hz,1H),6.19(tt,J＝3.98,1.73Hz,1H),5.03(d,J＝7.82Hz,2H),4.50(s,2H),2.41(tq,J＝6.44,2.34Hz,2H),2.25(pt,J＝6.24,3.24Hz,2H),1.86–1.77(m,2H),1.73–1.65(m,2H).ESI-MS of the target compound; the experiment shows that: 451.4.

EXAMPLE 120 Synthesis of 3- (3- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) phenyl) oxetan-3-ol (QM 110)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (50 mg) and 3- (3-hydroxyoxetan-3-yl) benzaldehyde (62 mg), the theoretical calculated value of trifluoroacetate 12.9mg.¹H NMR(500MHz,Methanol-d₄)δ7.62(dd,J＝8.54,7.11Hz,1H),7.61–7.56(m,2H),7.50–7.46(m,2H),7.44–7.40(m,3H),7.40–7.36(m,1H),7.20(dt,J＝7.64,1.51Hz,1H),7.06(d,J＝7.02Hz,1H),6.15(tt,J＝3.89,1.71Hz,1H),4.88(d,J＝6.77Hz,2H),4.76(d,J＝7.01Hz,2H),4.47(s,2H),2.37(dddt,J＝8.56,6.48,4.36,2.29Hz,2H),2.23(tq,J＝5.68,2.77Hz,2H),1.84–1.76(m,2H),1.71–1.65(m,2H).ESI-MS of the target compound C ₂₉H₃₀N₃O₂ ⁺[M+H]⁺ =452.2 is obtained according to general procedure six; the experiment shows that: 452.4.

EXAMPLE 121 Synthesis of 2-hydroxy-5- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 111)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 5-formyl-2-hydroxybenzoic acid (69 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₆N₃O₃ ⁺[M+H]⁺ =440.2 of trifluoroacetate 9.5mg.¹H NMR(500MHz,Methanol-d₄)δ7.79(d,J＝2.38Hz,1H),7.61(dd,J＝8.54,7.06Hz,1H),7.49–7.31(m,7H),7.06(d,J＝7.06Hz,1H),6.89(d,J＝8.52Hz,1H),6.08(tt,J＝3.87,1.73Hz,1H),4.31(s,2H),2.32(tq,J＝6.41,2.34Hz,2H),2.22(td,J＝6.12,3.36Hz,2H),1.82–1.75(m,2H),1.72–1.64(m,2H).ESI-MS of the target compound; the experiment shows that: 440.2.

EXAMPLE 122 Synthesis of 3- ((((4- (4-cyclopropylphenyl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 113)

Starting from 4- (4-cyclopropylphenyl) -1H-indazol-3-amine (133 mg) and 3-formylbenzoic acid (160 mg), 94.6mg of the trifluoroacetate salt of the title compound was obtained according to general method six. ESI-MS theoretical calculation C ₂₄H₂₂N₃O₂ ⁺[M+H]⁺ = 384.2; the experiment shows that: 384.3.

EXAMPLE 123 Synthesis of 3- (3- (((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) phenyl) azetidin-3-ol (QM 115)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (125 mg) and 3- (3-formylphenyl) -3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (240 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (273 mg) and acetic acid (0.1 mL) were added, and stirred at room temperature overnight. After the completion of the reaction, a saturated sodium bicarbonate solution was added, the aqueous phase was extracted 3 times with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to give QM112.ESI-MS theoretical calculation C ₃₄H₃₉N₄O₃ ⁺[M+H]⁺ =551.3; the experiment shows that: 552.0.

QM112 was all put into an eggplant-shaped flask, methylene chloride (4 mL) was added thereto, trifluoroacetic acid (1 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₉H₃₁N₄O⁺[M+H]⁺ =451.2 of trifluoroacetate 33.9mg.¹H NMR(500MHz,Methanol-d₄)δ7.60(dd,J＝8.55,7.12Hz,1H),7.54–7.46(m,4H),7.46–7.37(m,4H),7.26(dt,J＝7.64,1.49Hz,1H),7.04(d,J＝7.03Hz,1H),6.18(tt,J＝3.96,1.69Hz,1H),4.50(s,2H),4.48–4.42(m,2H),4.19–4.12(m,2H),2.39(tq,J＝6.43,2.29Hz,2H),2.24(tq,J＝5.71,2.67Hz,2H),1.85–1.76(m,2H),1.73–1.64(m,2H).ESI-MS of the target compound; the experiment shows that: 450.4.

EXAMPLE 124 Synthesis of 3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzenesulfonamide (QM 126)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (57 mg) and 3-formylbenzenesulfonamide (73 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₆H₂₇N₄O₂S⁺[M+H]⁺ = 459.2 of trifluoroacetate 7.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.90(d,J＝1.92Hz,1H),7.81(dt,J＝7.11,1.94Hz,1H),7.57–7.42(m,7H),7.38(dd,J＝8.56,0.78Hz,1H),7.01(dd,J＝7.06,0.81Hz,1H),6.20(tt,J＝3.92,1.67Hz,1H),4.52(s,2H),2.41(tq,J＝6.41,2.31Hz,2H),2.23(ddt,J＝8.45,6.24,2.67Hz,2H),1.85–1.75(m,2H),1.73–1.63(m,2H).ESI-MS of the target compound; the experiment shows that: 459.3.

EXAMPLE 125 Synthesis of 2-hydroxy-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QN 2)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 3-formyl-2-hydroxybenzoic acid (73 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₆N₃O₃ ⁺[M+H]⁺ =440.2 of trifluoroacetate 30.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.57(dd,J＝8.52,7.05Hz,1H),7.50–7.42(m,4H),7.41–7.35(m,3H),7.17(d,J＝7.76Hz,1H),7.03(d,J＝7.02Hz,1H),6.16(dq,J＝4.05,2.09Hz,1H),4.41(s,2H),2.43–2.35(m,2H),2.25(td,J＝6.15,3.32Hz,2H),1.86–1.78(m,2H),1.74–1.65(m,2H).ESI-MS of the target compound; the experiment shows that: 440.3.

EXAMPLE 126 Synthesis of N- (3- (3-Aminoazetidin-3-yl) benzyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (QM 134)

4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (144 mg) and 3- ((tert-butylsulfinyl) amino) -3- (3-formylphenyl) azetidine-1-carboxylic acid tert-butyl ester (386 mg) were added to an eggplant-shaped flask, 1, 2-dichloroethane (10 mL) was added, sodium triacetoxyborohydride (318 mg) and acetic acid (0.1 mL) were added, and stirred at room temperature overnight. After the completion of the reaction, a saturated sodium hydrogencarbonate solution was added, the aqueous phase was extracted 3 times with methylene chloride, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to give QM132 (231 mg). ESI-MS theoretical calculation C ₃₈H₄₈N₅O₃S⁺[M+H]⁺ = 654.3; the experiment shows that: 651.8.

QM132 (77 mg) was added to the eggplant-shaped flask, methylene chloride (4 mL) was added, trifluoroacetic acid (1 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated by a rotary evaporator, methanol (5 mL) was added thereto, and a hydrochloric acid methanol solution (4M, 1 mL) was added dropwise at 0℃and stirred for 10 minutes. After the reaction is finished, concentrating by a rotary evaporator, and purifying by HPLC to obtain a theoretical calculated value C ₂₉H₃₂N₅ ⁺[M+H]⁺ =450.2 of trifluoroacetate 21mg.¹H NMR(500MHz,Methanol-d₄)δ7.57–7.44(m,8H),7.42(dd,J＝7.67,1.46Hz,1H),7.37(d,J＝8.42Hz,1H),6.98(d,J＝7.01Hz,1H),6.24(tt,J＝3.98,1.75Hz,1H),4.74(d,J＝12.52Hz,2H),4.69(d,J＝12.79Hz,2H),4.54(s,2H),2.45(tq,J＝6.44,2.28Hz,2H),2.25(dp,J＝8.85,3.19,2.74Hz,2H),1.87–1.78(m,2H),1.74–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 449.7.

EXAMPLE 127 Synthesis of 4-hydroxy-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 136)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 3-formyl-4-hydroxybenzoic acid (69 mg), 65.5mg of the trifluoroacetate salt of the target compound was obtained according to general procedure six. ESI-MS theoretical calculation C ₂₇H₂₆N₃O₃ ⁺[M+H]⁺ =440.2; the experiment shows that: 440.2.

EXAMPLE 128 Synthesis of 2-fluoro-5- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 143)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and methyl 2-fluoro-5-formylbenzoate (76 mg), the theoretical calculation of trifluoroacetate 35.3mg.¹H NMR(500MHz,DMSO-d₆)δ7.84(dd,J＝7.23,2.42Hz,1H),7.56–7.50(m,3H),7.48–7.42(m,2H),7.33–7.25(m,2H),7.21(dd,J＝10.81,8.48Hz,1H),6.82(dd,J＝5.97,1.95Hz,1H),6.24(dq,J＝3.96,1.92Hz,1H),4.36(s,2H),2.38(ddt,J＝8.81,4.65,2.32Hz,2H),2.20(td,J＝6.08,3.19Hz,2H),1.79–1.69(m,2H),1.66–1.56(m,2H).ESI-MS of the target compound is C ₂₇H₂₅FN₃O₂ ⁺[M+H]⁺ =442.2, referred to general method eight; the experiment shows that: 442.3.

EXAMPLE 129 Synthesis of 3-hydroxy-5- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QN 18)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (86 mg) and 3-formyl-4-hydroxybenzoic acid (100 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₆N₃O₃ ⁺[M+H]⁺ =440.2 of trifluoroacetate 65.5mg.¹H NMR(500MHz,Methanol-d₄)δ7.62(dd,J＝8.56,7.08Hz,1H),7.50–7.46(m,2H),7.44–7.34(m,5H),7.05(d,J＝7.10Hz,1H),6.92(t,J＝2.02Hz,1H),6.12(tt,J＝3.79,1.65Hz,1H),4.39(s,2H),2.34(tq,J＝6.39,2.20Hz,2H),2.20(dp,J＝6.24,3.04,2.54Hz,2H),1.78(pd,J＝5.74,2.39Hz,2H),1.67(dtt,J＝9.31,6.16,2.89Hz,2H).ESI-MS of the target compound; the experiment shows that: 439.8.

EXAMPLE 130 Synthesis of 2-fluoro-3- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 154)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 2-fluoro-3-formylbenzoic acid (70 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₅FN₃O₂ ⁺[M+H]⁺ =442.2 of trifluoroacetate 34.7mg.¹H NMR(500MHz,DMSO-d₆)δ7.70(td,J＝7.40,1.87Hz,1H),7.57–7.49(m,3H),7.48–7.41(m,2H),7.35–7.26(m,2H),7.18(t,J＝7.66Hz,1H),6.83(dd,J＝6.11,1.84Hz,1H),6.25(t,J＝3.91Hz,1H),4.43(s,2H),2.40(dt,J＝7.73,3.81Hz,2H),2.20(dh,J＝5.92,2.75Hz,2H),1.79–1.70(m,2H),1.66–1.57(m,2H).ESI-MS of the target compound; the experiment shows that: 441.8.

EXAMPLE 131 Synthesis of 3-fluoro-5- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QM 155)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (60 mg) and 3-fluoro-5-formylbenzoic acid (70 mg), reference is made to general procedure six to give the theoretical calculated value C ₂₇H₂₅FN₃O₂ ⁺[M+H]⁺ =442.2 of trifluoroacetate 49.4mg.¹H NMR(500MHz,DMSO-d₆)δ7.79(d,J＝5.04Hz,1H),7.61–7.42(m,5H),7.40–7.23(m,3H),6.84(d,J＝6.15Hz,1H),6.25(s,1H),4.43(s,2H),2.44–2.34(m,2H),2.25–2.14(m,2H),1.80–1.68(m,2H),1.66–1.55(m,2H).ESI-MS of the target compound; the experiment shows that: 441.7.

EXAMPLE 132 Synthesis of 2-hydroxy-4- ((((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-yl) amino) methyl) benzoic acid (QN 1)

Starting from 4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-indazol-3-amine (82 mg) and methyl 2-fluoro-5-formylbenzoate (103 mg), reference is made to general procedure eight to give the theoretical calculated value C ₂₇H₂₆N₃O₃ ⁺[M+H]⁺ = 440.2 of trifluoroacetate 35.3mg.¹H NMR(500MHz,Methanol-d₄)δ7.82(dd,J＝7.96,1.76Hz,1H),7.58(dd,J＝8.52,7.00Hz,1H),7.43(d,J＝7.88Hz,2H),7.41–7.36(m,2H),7.33(d,J＝7.85Hz,2H),7.01(d,J＝6.97Hz,1H),6.83(t,J＝7.64Hz,1H),6.14(tt,J＝3.80,1.71Hz,1H),4.41(s,2H),2.38(tq,J＝6.18,2.26Hz,2H),2.24(tq,J＝5.83,2.76Hz,2H),1.85–1.78(m,2H),1.73–1.66(m,2H).ESI-MS of the target compound; the experiment shows that: 440.2.

EXAMPLE 133 Synthesis of 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FC 50)

The general method is fourteen:

(4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1,3, 2-dioxaborane (100 mg) and 4-bromo-2-phenyl-1H-benzo [ d ] imidazole (80 mg) were added to an eggplant-shaped flask, ethylene glycol dimethyl ether (10 mL) and aqueous sodium carbonate (2M, 5 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (25 mg) was added, after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight, after the reaction was completed, cooled to room temperature, water quenched, the aqueous phase was extracted 3 times with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by a rotary evaporator, and HPLC purified to give the trifluoroacetate of the target compound of calculated value C ₂₅H₂₃N₂ ⁺[M+H]⁺ = 351.2, as experimentally measured 350.9.

Examples 134 and 135 Synthesis of 2- (4- (7- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetic acid (FC 63-1) and 2- (4- (1- (4- (carboxymethyl) benzyl) -4- (2', 3',4',5 '-tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetic acid (FC 63-2)

The theoretical calculation of trifluoroacetate salt 21.7mg.¹H NMR(500MHz,Methanol-d₄)δ8.09(d,J＝8.2Hz,2H),7.77(d,J＝8.2Hz,1H),7.70–7.53(m,8H),6.26(tt,J＝3.9,1.7Hz,1H),3.79(s,2H),2.48(tq,J＝6.5,2.3Hz,2H),2.26(tq,J＝5.9,2.8Hz,2H),1.94–1.79(m,2H),1.77–1.61(m,2H).ESI-MS of the target compound 134 (FC 63-1) C ₂₇H₂₅N₂O₂ ⁺[M+H]⁺ =409.2 was obtained as a mixture of (4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (175 mg) and methyl 2- (4- (4-bromo-1H-benzo [ d ] imidazol-2-yl) phenyl) acetate and methyl 2- (4- (4-bromo-1- (4- (2-methoxy-2-oxoethyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (177 mg) by reference to general method fourteen, experimentally measured 409.2.

The theoretical calculation of trifluoroacetate 6.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.80–7.75(m,2H),7.73(dd,J＝6.9,2.5Hz,1H),7.70–7.64(m,4H),7.61(d,J＝8.0Hz,4H),7.34–7.24(m,2H),7.23–7.10(m,2H),6.27(tq,J＝4.0,2.2,1.7Hz,1H),5.75(s,2H),3.80(s,2H),3.61(s,2H),2.48(tq,J＝6.5,2.4Hz,2H),2.27(ddt,J＝8.4,6.1,3.3Hz,2H),1.91–1.79(m,2H),1.78–1.63(m,2H).ESI-MS to give the target compound 135 (FC 63-2) C ₃₆H₃₃N₂O₄ ⁺[M+H]⁺ =557.2; the experiment shows that: 557.3. examples 136 and 137 Synthesis of 2- (3- (7- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetic acid (FC 59-1) and 2- (3- (1- (3- (carboxymethyl) benzyl) -4- (2', 3',4',5 '-tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetic acid (FC 59-2)

Starting from a mixture of (4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (415 mg) and methyl 2- (3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) phenyl) acetate and methyl 2- (3- (4-bromo-1- (3- (2-methoxy-2-oxoethyl) benzyl) -1H-benzo [ d ] imidazol-2-yl) phenyl) acetate (419 mg), reference was made to the general procedure fourteen to give the theoretical calculation of trifluoroacetate 58.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.05(d,J＝1.8Hz,1H),8.01(dt,J＝7.6,1.5Hz,1H),7.76(dd,J＝8.2,0.9Hz,1H),7.69–7.48(m,8H),6.25(tt,J＝3.9,1.8Hz,1H),3.78(s,2H),2.46(tq,J＝6.4,2.2Hz,2H),2.26(tq,J＝6.0,2.7Hz,2H),1.90–1.78(m,2H),1.76–1.62(m,2H).ESI-MS for the target compound 136 (FC 59-1) C ₂₇H₂₅N₂O₂ ⁺[M+H]⁺ =409.2, experimental measurement was made 408.4, the theoretical calculation of trifluoroacetate 16.4mg.¹H NMR(500MHz,Methanol-d₄)δ7.80(dd,J＝7.9,1.4Hz,1H),7.75(d,J＝1.8Hz,1H),7.68(tt,J＝7.5,4.8Hz,6H),7.64–7.57(m,3H),7.30(t,J＝7.6Hz,1H),7.26(dt,J＝7.8,1.4Hz,1H),7.14(d,J＝1.8Hz,1H),7.10(dt,J＝7.6,1.5Hz,1H),6.26(tt,J＝4.0,1.7Hz,1H),5.76(s,2H),3.76(s,2H),3.57(s,2H),2.48(tq,J＝6.3,2.3Hz,2H),2.26(ddt,J＝8.1,5.8,3.0Hz,2H),1.84(pd,J＝5.9,2.6Hz,2H),1.76–1.64(m,2H).ESI-MS for the target compound 137 (FC 59-2) C ₃₆H₃₃N₂O₄ ⁺[M+H]⁺ =557.2, experimental measurement was made 556.9.

EXAMPLE 138 Synthesis of 4- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 65-14)

Twelve general methods:

2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (50 mg) and methyl 2- (4-bromophenyl) acetate (47 mg) were added to an eggplant-shaped flask, DMF (5 mL) was added, K ₂CO₃ (70 mg) was added, and the mixture was warmed to 80℃and stirred overnight. After the completion of the reaction, the reaction mixture was cooled to room temperature, quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to give 38mg of the crude compound.

The crude compound and LiOH-H ₂ O (15 mg) were added to an eggplant-shaped flask, and a mixed solvent (4 ml, thf: H ₂ o=1:1) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 138 (FC 65-14), and lyophilizing to obtain solid 22.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.00(d,J＝8.2Hz,2H),7.85–7.73(m,3H),7.73–7.63(m,7H),7.59(d,J＝8.2Hz,2H),7.30(d,J＝8.2Hz,2H),6.26(dq,J＝3.9,1.9Hz,1H),5.84(s,2H),2.47(td,J＝6.0,2.7Hz,2H),2.25(tq,J＝5.9,2.7Hz,2H),1.90–1.77(m,2H),1.77–1.62(m,2H).ESI-MS theoretical calculated value C ₃₃H₂₉N₂O₂ ⁺[M+H]⁺ = 485.2; the experiment shows that: 485.2.

EXAMPLE 139 Synthesis of 3- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 74-15)

Starting from 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (30 mg) and methyl 3- (bromomethyl) benzoate (23 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (10 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 139 (FC 74-15), and lyophilization to give solid 24mg.¹H NMR(500MHz,Methanol-d₄)δ7.99(dt,J＝7.6,1.4Hz,1H),7.85–7.73(m,5H),7.68(qd,J＝7.9,2.0Hz,6H),7.63–7.58(m,2H),7.47(t,J＝7.7Hz,1H),7.42(dt,J＝7.8,1.5Hz,1H),6.26(tt,J＝4.0,1.7Hz,1H),5.83(s,2H),2.48(tq,J＝6.6,2.3Hz,2H),2.26(tq,J＝6.3,2.7Hz,2H),1.89–1.79(m,2H),1.76–1.65(m,2H).ESI-MS, theoretical calculated C ₃₃H₂₉N₂O₂ ⁺[M+H]⁺ = 485.2; the experiment shows that: 485.3.

Example 140: synthesis of 3- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FC 83-9)

Fifteen general methods:

4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1 '-biphenyl ] -4-yl) -1,3, 2-dioxaborane (48 mg) and methyl 3- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (50 mg) were added to the eggplant flask, ethylene glycol dimethyl ether (5 mL) and aqueous sodium carbonate (2M, 2 mL) were added, the reaction solution was deoxygenated, and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (10 mg) was added, and after the reaction solution was deoxygenated again, the temperature was raised to 90℃and stirred overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, quenched with water, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give a crude product. Subsequently, liOH-H ₂ O (10 mg) was added to the eggplant-shaped flask, and the mixed solvent (4 ml, thf: H ₂ o=1:1) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 139 (FC 83-9), and lyophilizing to obtain solid 2.5mg.¹H NMR(500MHz,DMSO-d₆)δ7.99(d,J＝1.8Hz,1H),7.86(d,J＝7.7Hz,1H),7.78(d,J＝7.9Hz,2H),7.67–7.55(m,4H),7.53–7.39(m,3H),6.27(td,J＝3.9,1.8Hz,1H),4.45(s,2H),2.43(tt,J＝4.5,2.3Hz,2H),2.22(td,J＝6.1,3.2Hz,2H),1.81–1.72(m,2H),1.68–1.57(m,2H).ESI-MS theoretical calculated value C ₂₇H₂₅N₂O₂ ⁺[M+H]⁺ =409.2; the experiment shows that: 408.7.

Example 141: synthesis of 4- ((4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FC 92)

Starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (197 mg) and methyl 4- ((4-bromo-1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (199 mg), reference is made to the general procedure fifteen to give the trifluoroacetate of the target compound 141 (FC 92), which is lyophilized to give the theoretical calculated as solid 28mg.¹H NMR(500MHz,DMSO-d₆)δ8.00–7.89(m,2H),7.73(d,J＝8.0Hz,2H),7.70–7.63(m,1H),7.62–7.55(m,2H),7.56–7.46(m,4H),6.27(tt,J＝3.9,1.7Hz,1H),4.52(s,2H),2.42(tq,J＝6.6,2.2Hz,2H),2.21(tq,J＝5.8,2.7Hz,2H),1.81–1.71(m,2H),1.67–1.54(m,2H).ESI-MS, C ₂₇H₂₅N₂O₂ ⁺[M+H]⁺ =409.2; the experiment shows that: 409.8.

Example 142: synthesis of 4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 88-2)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (53 mg) and methyl 4- (bromomethyl) benzoate (51 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (17 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 142 (FC 88-2), and lyophilization to give solid 43mg.¹H NMR(500MHz,Methanol-d₄)δ8.06(d,J＝8.1Hz,2H),7.71(dd,J＝7.6,1.8Hz,1H),7.66–7.57(m,6H),7.43(d,J＝8.1Hz,2H),6.28(tt,J＝4.1,1.8Hz,1H),5.86(s,2H),2.91(s,3H),2.49(tq,J＝6.5,2.3Hz,2H),2.27(dh,J＝9.0,2.8Hz,2H),1.84(dp,J＝8.7,2.8Hz,2H),1.78–1.66(m,2H).ESI-MS, theoretical calculated C ₂₈H₂₇N₂O₂ ⁺[M+H]⁺ = 423.2; the experiment shows that: 422.7.

Example 143: synthesis of 3- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 95-2)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (30 mg) and methyl 3- (bromomethyl) benzoate (27 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (10 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 143 (FC 95-2), and lyophilization to give solid 22.9mg.¹H NMR(500MHz,Methanol-d₄)δ8.06–8.00(m,1H),7.98(s,1H),7.73(d,J＝8.0Hz,1H),7.66–7.49(m,8H),6.27(dt,J＝4.9,2.5Hz,1H),5.84(s,2H),2.92(s,3H),2.47(ddt,J＝6.9,4.6,2.4Hz,2H),2.25(dp,J＝9.3,3.1Hz,2H),1.89–1.78(m,2H),1.75–1.63(m,2H).ESI-MS, theoretical calculated C ₂₈H₂₇N₂O₂ ⁺[M+H]⁺ = 423.2; the experiment shows that: 422.3.

Example 144: synthesis of 4- ((2-ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 7)

Starting from 2-ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (30 mg) and methyl 4- (bromomethyl) benzoate (35 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (10 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 144 (FE 7), and lyophilization to give solid 12.3mg.¹H NMR(500MHz,Methanol-d4)δ8.06(d,J＝8.2Hz,2H),7.71–7.58(m,7H),7.39(d,J＝8.1Hz,2H),6.28(td,J＝4.0,1.9Hz,1H),5.91(s,2H),2.50(tq,J＝6.4,2.3Hz,2H),2.30–2.22(m,2H),1.91–1.80(m,2H),1.77–1.65(m,2H),1.35(t,J＝7.6Hz,3H)..ESI-MS, theoretical calculated C ₂₉H₂₉N₂O₂ ⁺[M+H]⁺ = 437.2; the experiment shows that: 437.2.

Example 146:4- ((2- (2-hydroxyethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FD 80)

Methyl 4- ((2- (2-hydroxyethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (99.1 mg) was added to an eggplant-shaped flask, 10mL of mixed solvent (THF: H ₂ o=1:1) was added, lithium hydroxide monohydrate (46 mg) was added, and stirred overnight at room temperature. After the reaction is finished, performing HPLC purification to obtain trifluoroacetate of the target compound, and performing freeze-drying to obtain a theoretical calculated value C ₂₉H₂₉N₂O₃ ⁺[M+H]⁺ =453.2 of solid 68.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.03(d,J＝8.1Hz,2H),7.60(d,J＝10.7Hz,7H),7.41(d,J＝8.1Hz,2H),6.27(td,J＝3.9,1.8Hz,1H),5.95(s,2H),3.98(t,J＝3.0Hz,2H),3.50(t,J＝5.8Hz,2H),2.47(dp,J＝6.3,2.4Hz,2H),2.26(tq,J＝6.0,2.7Hz,2H),1.89–1.78(m,2H),1.71(dp,J＝8.9,2.8Hz,2H).ESI-MS; the experiment shows that: 453.0.

Example 149:3- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) propionic acid (FC 121)

Starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (101 mg) and methyl 3- (4-bromo-1H-benzo [ d ] imidazol-2-yl) propionate (83.5 mg), reference is made to general procedure fifteen to give the trifluoroacetate of the target compound 149 (FC 121), which is lyophilized to give the theoretical calculated as solid 22.4mg.¹H NMR(500MHz,Methanol-d₄)δ7.71(dd,J＝8.2,1.0Hz,1H),7.65–7.54(m,6H),6.26(tt,J＝3.9,1.7Hz,1H),3.42(t,J＝7.0Hz,2H),3.02(t,J＝7.0Hz,2H),2.48(tq,J＝6.4,2.3Hz,2H),2.26(dp,J＝8.9,3.2Hz,2H),1.90–1.80(m,2H),1.77–1.66(m,2H).ESI-MS C ₂₂H₂₃N₂O₂ ⁺[M+H]⁺ =347.2; the experiment shows that: 347.0.

Example 151:2- (2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) acetic acid (FC 108)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (9 mg) and ethyl 2-chloroacetate (8 mg), crude compound was obtained according to general method twelve. Subsequently, liOH-H ₂ O (7 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 151 (FC 108), and lyophilization to give solid 2mg.¹H NMR(500MHz,Methanol-d₄)δ7.79(dd,J＝8.2,1.0Hz,1H),7.68(t,J＝7.9Hz,1H),7.65–7.58(m,5H),6.28(tt,J＝4.0,1.7Hz,1H),5.41(s,2H),2.86(s,3H),2.49(ddt,J＝8.5,4.3,2.2Hz,2H),2.28(ddt,J＝8.5,6.4,2.8Hz,2H),1.92–1.81(m,2H),1.80–1.63(m,2H).ESI-MS, theoretical calculated C ₂₂H₂₃N₂O₂ ⁺[M+H]⁺ =347.2; the experiment shows that: 346.7.

Example 152:4- (2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) butanoic acid (FE 139)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (60 mg) and methyl 4-bromobutyrate (57 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (20 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 152 (FE 139), and lyophilization to give solid 45.3mg.¹H NMR(500MHz,Methanol-d₄)δ7.90(d,J＝8.3Hz,1H),7.67(t,J＝8.0Hz,1H),7.60(dd,J＝7.9,4.3Hz,5H),6.27(tt,J＝3.8,1.6Hz,1H),4.62–4.49(m,2H),2.91(s,3H),2.55(t,J＝6.6Hz,2H),2.48(dp,J＝6.5,2.4Hz,2H),2.29–2.18(m,4H),1.84(dtt,J＝9.8,6.3,3.3Hz,2H),1.71(ddd,J＝9.2,7.4,4.6Hz,2H).ESI-MS, theoretical calculated C ₂₄H₂₇N₂O₂ ⁺[M+H]⁺ = 375.2; the experiment shows that: 374.7.

Example 241:4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methylbenzonitrile (FE 133)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (50 mg) and 4- (bromomethyl) benzonitrile (51 mg), purification by HPLC with reference to the general procedure twelve afforded the trifluoroacetate of the target compound 241 (FE 133) as a solid 29.4mg.¹H NMR(500MHz,Methanol-d4)δ7.77(d,J＝8.2Hz,2H),7.68(dd,J＝7.4,2.0Hz,1H),7.61(s,6H),7.50(d,J＝8.1Hz,2H),6.28(dq,J＝4.1,1.9Hz,1H),5.88(s,2H),2.91(s,3H),2.49(ddq,J＝6.0,4.2,2.1Hz,2H),2.27(s,2H),1.91–1.80(m,2H),1.78–1.63(m,2H).ESI-MS theoretical calculated as C ₂₈H₂₆N₃ ⁺[M+H]⁺ =404.2; the experiment shows that: 404.0.

Example 242:4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methylphenol (FG 17)

Starting with 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (50 mg) and (4- (bromomethyl) phenoxy) (tert-butyl) diphenylsilane (111 mg), crude compound was obtained according to general procedure twelve. Tetrabutylammonium fluoride trihydrate (79 mg), THF (10 mL) was then added, stirred overnight at room temperature, the silicon protection removed, HPLC purification afforded the trifluoroacetate salt of the target compound 242 (FG 17), and lyophilization afforded the theoretical calculation of solid 5.6mg.¹H NMR(500MHz,Methanol-d4)δ7.77(dd,J＝8.2,1.1Hz,1H),7.67–7.55(m,6H),7.24–7.16(m,2H),6.85–6.77(m,2H),6.27(tt,J＝3.9,1.7Hz,1H),5.62(s,2H),2.90(s,3H),2.48(tt,J＝6.2,3.1Hz,2H),2.27(td,J＝6.2,3.4Hz,2H),1.90–1.79(m,2H),1.71(dtt,J＝10.1,7.1,3.2Hz,2H).ESI-MS C ₂₇H₂₇N₂O⁺[M+H]⁺ =395.2; the experiment shows that: 395.3.

Example 248:2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) ethanol (FD 28)

2- (2- ((Tert-Butyldiphenylsilyl) oxy) ethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (80 mg) and tetrabutylammonium fluoride trihydrate (79 mg) were added to an eggplant-shaped flask, THF (10 mL) was added, and stirring overnight at room temperature. After the reaction is finished, concentrating by a rotary evaporator to obtain a crude product. Purification by HPLC gave the trifluoroacetate salt of the target compound, which was lyophilized to give the theoretical calculated as C ₂₁H₂₃N₂O⁺[M+H]⁺ = 319.2 for solid 15.6mg.¹H NMR(500MHz,Methanol-d₄)δ7.72(d,J＝8.1Hz,1H),7.67–7.51(m,6H),6.27(td,J＝4.1,1.9Hz,1H),4.02(t,J＝5.8Hz,2H),3.34(t,J＝5.8Hz,2H),2.49(td,J＝6.1,2.6Hz,2H),2.27(tt,J＝6.1,3.2Hz,2H),1.89–1.80(m,2H),1.77–1.68(m,2H).¹³C NMR(126MHz,DMSO-d6)δ153.93,141.80,135.46,134.26,132.57,128.52,127.76,125.42,125.29,125.14,124.40,112.66,58.39,30.50,26.66,25.46,22.60,21.69.ESI-MS; the experiment shows that: 318.8.

Example 249:2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) ethylamine (FD 57)

2- (4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) ethanol (50 mg) and isoindoline-1, 3-dione (35 mg) were added to an eggplant-shaped flask, THF (5 mL) and triphenylphosphine (126 mg) were added, stirred at 0℃for 0.5H, then diisopropyl 1, 2-dicarboxylate (113 mg) was added dropwise, and the temperature was raised to room temperature at 0℃and stirred overnight. After the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporator to give a crude product. The crude product was then added to an eggplant-shaped flask and dissolved in methanol (5 mL) and N ₂H₄-H₂ O (21 mg) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 249 (FD 57), and lyophilizing to obtain solid 20.1mg.¹H NMR(500MHz,Methanol-d₄)δ7.74(d,J＝8.1Hz,1H),7.58(tt,J＝12.2,6.1Hz,6H),6.25(td,J＝3.9,1.9Hz,1H),3.64–3.52(m,4H),2.48(tq,J＝4.4,2.1Hz,2H),2.26(tq,J＝6.1,2.8Hz,2H),1.91–1.78(m,2H),1.77–1.59(m,2H).ESI-MS theoretical calculation C ₂₁H₂₄N₃ ⁺[M+H]⁺ =318.2; the experiment shows that: 318.2.

Example 250: n, N-dimethyl-2- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) ethylamine (FD 76)

2- (4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) ethanamine (926.3 mg), HCHO hydrate (111 mg) and NaBH3CN (548.1 mg) as starting materials, methanol as solvent, purification by HPLC with reference to general procedure six, afforded the trifluoroacetate of the target compound 250 (FD 76), which was lyophilized to afford the theoretical calculated as solid 184.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.75(d,J＝8.1Hz,1H),7.69–7.55(m,6H),6.26(dq,J＝3.8,2.0Hz,1H),3.72(q,J＝4.5Hz,4H),3.01(s,6H),2.49(td,J＝6.2,3.3Hz,2H),2.27(td,J＝6.2,3.3Hz,2H),1.91–1.82(m,2H),1.79–1.62(m,2H).ESI-MS C ₂₃H₂₈N₃ ⁺[M+H]⁺ = 346.2; the experiment shows that: 345.4.

Example 251:4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) butanoic acid (FD 34)

Starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (369 mg) and methyl 4- (4-bromo-1H-benzo [ d ] imidazol-2-yl) butyrate (192.4 mg), reference is made to general procedure fifteen to give the trifluoroacetate of the target compound 251 (FD 34), which is lyophilized to give the theoretical calculated as solid 3.3mg.¹H NMR(500MHz,Methanol-d₄)δ7.71(d,J＝8.1Hz,1H),7.68–7.56(m,6H),6.27(dq,J＝3.8,2.1,1.6Hz,1H),3.24(t,J＝7.7Hz,2H),2.50(t,J＝6.9Hz,4H),2.27(dh,J＝6.2,2.8Hz,2H),2.20(p,J＝7.3Hz,2H),1.91–1.80(m,2H),1.77–1.67(m,2H).ESI-MS C ₂₃H₂₅N₂O₂ ⁺[M+H]⁺ =361.2; the experiment shows that: 361.3.

Example 252:3- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) propanol (FD 130)

Starting with 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (596.4 mg) and 4-bromo-2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -1H-benzo [ d ] imidazole (667.9 mg), crude compound 530.5mg was obtained according to general procedure fourteen. Subsequently, the crude product (57 mg) and tetrabutylammonium fluoride trihydrate (63 mg) were taken and added to an eggplant-shaped flask, and THF (15 mL) was added thereto and stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated by a rotary evaporator. Purification by HPLC gave the trifluoroacetate salt of the target compound 252 (FD 130), and lyophilization gave the theoretical calculated as C ₂₂H₂₅N₂O⁺[M+H]⁺ =333.2 as a solid 10.5mg.¹H NMR(500MHz,Methanol-d₄)δ7.71(dd,J＝8.1,1.0Hz,1H),7.66–7.53(m,6H),6.27(tt,J＝3.9,1.7Hz,1H),3.70(t,J＝5.8Hz,2H),3.28(t,J＝7.4Hz,2H),2.49(tq,J＝6.3,2.3Hz,2H),2.27(tq,J＝6.2,2.7Hz,2H),2.12(tt,J＝7.4,5.8Hz,2H),1.89–1.81(m,2H),1.77–1.65(m,2H).ESI-MS; the experiment shows that: 332.5.

Example 253:4- ((1- (3- (dimethylamino) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FD 1)

Methyl 4- ((1- (3- (dimethylamino) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (7.6 mg) and LiOH-H ₂ O (4.2 mg) were added to an eggplant-shaped flask, and a mixed solvent (4 ml, thf: H ₂ o=1:1) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 253 (FD 1), and lyophilizing to obtain solid 2.3mg.¹H NMR(500MHz,Methanol-d4)δ8.15–8.00(m,2H),7.85(dd,J＝8.1,1.1Hz,1H),7.75–7.59(m,6H),7.51–7.40(m,2H),6.27(tt,J＝3.9,1.8Hz,1H),4.75(s,2H),4.51(t,J＝7.7Hz,2H),3.16–3.07(m,2H),2.76(s,6H),2.49(tq,J＝6.4,2.2Hz,2H),2.27(tdt,J＝6.3,4.2,2.5Hz,2H),2.04(ddt,J＝12.2,8.0,4.5Hz,2H),1.92–1.80(m,2H),1.78–1.67(m,2H).ESI-MS theoretical calculation C ₃₂H₃₆N₃O₂ ⁺[M+H]⁺ = 494.3; the experiment shows that: 493.9.

Example 254:4- ((1- (3-hydroxypropyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FD 127-1)

Methyl 4- ((1- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl)) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (198 mg) and tetrabutylammonium fluoride trihydrate (176 mg) were added to an eggplant-shaped flask, THF (20 mL) was added, and stirring was continued overnight at room temperature. After the reaction, the crude compound is obtained by concentrating the mixture by a rotary evaporator. Subsequently, liOH-H ₂ O (21 mg) was added to the eggplant-shaped flask, and the mixed solvent (10 ml, thf: H ₂ o=1:1) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 254 (FD 127-1), and lyophilizing to obtain solid 5.6mg.¹H NMR(500MHz,Methanol-d4)δ8.05–8.01(m,2H),7.80(dd,J＝8.1,1.1Hz,1H),7.69–7.66(m,2H),7.65–7.56(m,4H),7.41(d,J＝8.3Hz,2H),6.26(tt,J＝4.0,1.7Hz,1H),4.72(s,2H),4.48(t,J＝7.3Hz,2H),3.57(t,J＝5.7Hz,2H),2.49(tq,J＝6.2,2.2Hz,2H),2.27(ddt,J＝8.2,6.0,3.1Hz,2H),1.95–1.87(m,2H),1.87–1.81(m,2H),1.75–1.69(m,2H).ESI-MS theoretical calculation C ₃₀H₃₁N₂O₃ ⁺[M+H]⁺ = 467.2; the experiment shows that: 466.6.

Example 255:4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole-2-carbonyl) benzoic acid (FD 156)

Methyl 4- (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole-2-carbonyl) benzoate (20 mg) and LiOH-H2O (7 mg) were added to an eggplant-shaped flask, and a mixed solvent (4 ml, thf: h2o=1:1) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 255 (FD 156), and lyophilizing to obtain solid 5.1mg.1H NMR(500MHz,DMSO-d6)δ8.68(d,J＝8.1Hz,2H),8.15(dd,J＝15.0,8.1Hz,4H),7.62–7.55(m,4H),7.51(t,J＝7.7Hz,1H),6.28(d,J＝4.2Hz,1H),2.44(d,J＝6.6Hz,2H),2.22(tt,J＝6.3,2.9Hz,2H),1.76(td,J＝8.8,7.4,4.8Hz,2H),1.69–1.54(m,2H).

Example 256:4- (hydroxy (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 6)

4- (4- (2 ',3',4',5' -Tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole-2-carbonyl) benzoic acid (18 mg) and NaBH ₄ (3.8 mg) were added to an eggplant-shaped flask, and a mixed solvent (4 ml, thf: H ₂ o=1:1) was added. Stirring for 5h at room temperature, purifying by HPLC to obtain trifluoroacetate of the target compound 256 (FE 6), and freeze-drying to obtain a theoretical calculated value C ₂₇H₂₅N₂O₃ ⁺[M+H]⁺ =425.2 of solid 7.4mg.¹H NMR(500MHz,Methanol-d4)δ8.08(d,J＝8.1Hz,2H),7.74(d,J＝8.2Hz,1H),7.65(d,J＝7.9Hz,3H),7.56(q,J＝4.3,3.9Hz,3H),7.53(d,J＝8.2Hz,2H),6.32(s,1H),6.28–6.20(m,1H),2.46(tt,J＝4.7,2.4Hz,2H),2.25(tq,J＝6.2,2.9Hz,2H),1.88–1.78(m,2H),1.74–1.65(m,2H).ESI-MS; the experiment shows that: 425.6.

Example 257:4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 43)

Methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (13 mg) and LiOH-H2O (10 mg) were added to an eggplant-shaped flask, and a mixed solvent (4 ml, thf: h2o=1:1) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 257 (FE 43), and lyophilizing to obtain solid 5.9mg.¹H NMR(500MHz,Methanol-d₄)δ8.12(d,J＝8.2Hz,2H),7.86(d,J＝8.2Hz,2H),7.63(d,J＝8.2Hz,2H),7.52(dd,J＝8.0,5.6Hz,3H),7.41(d,J＝7.4Hz,1H),7.35(t,J＝7.7Hz,1H),6.28–6.18(m,1H),5.94(s,1H),2.47(td,J＝6.0,2.6Hz,2H),2.25(tq,J＝6.1,2.8Hz,2H),1.88–1.78(m,2H),1.75–1.66(m,2H).ESI-MS theoretical calculation C ₂₇H₂₆N₃O₂ ⁺[M+H]⁺ =424.2; the experiment shows that: 424.6.

Example 258:4- ((dimethylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 45)

Methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (23 mg), aqueous formaldehyde (20 mg) and NaBH ₃ CN (7 mg) were used as starting materials, methanol was used as solvent, purification by HPLC was performed with reference to general procedure eight to give the trifluoroacetate of the target compound 258 (FE 45), and lyophilization gave the theoretical calculated as solid 5.8mg.¹H NMR(500MHz,Methanol-d₄)δ8.13(d,J＝8.2Hz,2H),7.77(dd,J＝12.6,8.1Hz,4H),7.57(dd,J＝7.8,1.3Hz,1H),7.52(d,J＝8.2Hz,2H),7.44–7.34(m,2H),6.21(td,J＝3.9,1.9Hz,1H),5.82(s,1H),2.93(s,6H),2.47(ddq,J＝6.3,4.4,2.2Hz,2H),2.25(dp,J＝6.2,3.0Hz,2H),1.89–1.79(m,2H),1.78–1.62(m,2H).ESI-MS C ₂₉H₃₀N₃O₂ ⁺[M+H]⁺ =452.2; the experiment shows that: 452.2.

Example 259:4- ((ethylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 92)

Methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (60 mg) and acetaldehyde (13 mg) were added to an eggplant-shaped flask, ti (OEt) ₄ (64 mg) and THF (5 mL) were added, and stirred at room temperature overnight. NaBH ₄ (11 mg) was then added and stirred at room temperature for 5h. After the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to give the crude compound. Subsequently LiOH-H ₂ O (8.4 mg) was added to the eggplant-shaped flask, and the mixed solvent (4 ml, thf: H ₂ o=1:1) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 259 (FE 92), and lyophilizing to obtain solid 8.5mg.¹H NMR(500MHz,Methanol-d₄)δ8.13(d,J＝8.1Hz,2H),7.84(d,J＝8.0Hz,2H),7.69(d,J＝8.2Hz,2H),7.52(t,J＝7.9Hz,3H),7.40(d,J＝7.3Hz,1H),7.35(d,J＝7.8Hz,1H),6.21(tt,J＝3.8,1.7Hz,1H),5.88(s,1H),3.25(dq,J＝12.2,7.3Hz,1H),3.16–3.05(m,1H),2.47(tq,J＝4.7,2.1Hz,2H),2.25(tq,J＝6.3,2.9Hz,2H),1.88–1.80(m,2H),1.77–1.66(m,2H),1.39(t,J＝7.2Hz,3H).ESI-MS theoretical calculated value C ₂₉H₃₀N₃O₂ ⁺[M+H]⁺ =452.2; the experiment shows that: 452.2.

Example 260:4- ((ethyl (methyl) amino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 96)

Methyl 4- ((ethylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (29.7 mg), aqueous formaldehyde (18 mg) and NaBH ₃ CN (8 mg) were used as starting materials, methanol as solvent, purified by HPLC with reference to general procedure eight to give the trifluoroacetate of the target compound 260 (FE 96), which was lyophilized to give solid 8.3mg.¹H NMR(500MHz,Methanol-d₄)δ8.13(d,J＝8.2Hz,2H),7.77(dd,J＝21.5,8.0Hz,4H),7.54(dd,J＝13.8,7.9Hz,3H),7.39(dt,J＝15.2,7.4Hz,2H),6.23(td,J＝3.9,1.9Hz,1H),5.78(s,1H),3.31–3.19(m,2H),2.48(td,J＝6.0,2.6Hz,2H),2.26(tq,J＝6.1,2.8Hz,2H),1.89–1.80(m,2H),1.77–1.67(m,2H),1.40(t,J＝7.2Hz,3H).ESI-MS as theoretical calculated C ₃₀H₃₂N₃O₂ ⁺[M+H]⁺ =466.2; the experiment shows that: 466.3.

Example 261:4- ((methyl (propyl) amino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FG 7)

Step one: methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (50 mg) and propionaldehyde (13 mg) were added to an eggplant-shaped flask, ti (OEt) ₄ (58 mg) and THF (5 mL) were added, and the mixture was stirred at room temperature overnight. NaBH ₄ (9 mg) was then added and stirred at room temperature for 5h. After the reaction, water was added to quench the reaction, the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by rotary evaporator, and purified by silica gel column to give the crude compound. LC-ms=480.3.

Step two: methyl 4- ((propylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (46.8 mg), aqueous formaldehyde (30 mg) and NaBH ₃ CN (9 mg) were used as starting materials, methanol as solvent, purification by HPLC was performed with reference to general procedure eight to give the trifluoroacetate of the target compound 261 (FG 7), and lyophilization gave the theoretical calculated as solid 4mg.¹H NMR(500MHz,Methanol-d4)δ8.17–8.12(m,2H),7.80(d,J＝7.9Hz,2H),7.76–7.72(m,2H),7.59–7.50(m,3H),7.47–7.36(m,2H),6.22(tt,J＝4.0,1.7Hz,1H),5.89(s,1H),3.29–3.23(m,1H),3.19–3.11(m,1H),2.84(s,3H),2.48(tq,J＝6.5,2.4Hz,2H),2.26(dtd,J＝8.9,7.4,6.4,4.2Hz,2H),1.96–1.81(m,4H),1.75–1.69(m,2H),0.98(t,J＝7.4Hz,3H).ESI-MS C ₃₁H₃₄N₃O₂ ⁺[M+H]⁺ = 480.2; the experiment shows that: 480.3.

Example 262:4- ((diethylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 84)

Methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (50 mg), acetaldehyde (48 mg) and NaBH ₃ CN (10 mg) are used as raw materials, methanol is used as a solvent, and the general method eight is referred to, HPLC purification to obtain the trifluoroacetate of the target compound 262 (FE 84), and lyophilization to obtain a solid 21.7mg.¹H NMR(500MHz,Methanol-d₄)δ8.13(d,J＝8.1Hz,2H),7.82(d,J＝8.3Hz,2H),7.78(d,J＝8.1Hz,2H),7.57(dd,J＝7.7,1.3Hz,1H),7.52(d,J＝8.2Hz,2H),7.42–7.34(m,2H),6.21(tt,J＝3.8,1.7Hz,1H),5.96(s,1H),3.42(dq,J＝14.4,7.2Hz,2H),3.21(dq,J＝14.7,7.5Hz,2H),2.46(ddq,J＝6.4,4.3,2.2Hz,2H),2.25(tq,J＝6.1,2.8Hz,2H),1.89–1.79(m,2H),1.77–1.65(m,2H),1.35(t,J＝7.2Hz,6H).

Example 263:4- ((dipropylamino) (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FE 91)

Methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (45.1 mg), propanal (58 mg) and NaBH ₃ CN (9 mg) are used as starting materials, methanol is used as solvent, purification is performed by HPLC with reference to general procedure eight to give the trifluoroacetate of the target compound 263 (FE 91), and lyophilization gives the theoretical calculated value C ₃₃H₃₈N₃O₂ ⁺[M+H]⁺ =508.3 of solid 3.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.14(d,J＝8.0Hz,2H),7.78(dd,J＝8.4,3.6Hz,4H),7.55(dd,J＝19.6,7.8Hz,3H),7.47–7.38(m,2H),6.26–6.20(m,1H),5.97(s,1H),3.30–3.23(m,2H),3.04(d,J＝14.1Hz,2H),2.48(td,J＝6.2,2.6Hz,2H),2.26(dh,J＝6.1,2.8Hz,2H),1.83(ddd,J＝19.6,11.2,5.9Hz,6H),1.76–1.66(m,2H),0.91(t,J＝7.3Hz,6H).ESI-MS; the experiment shows that: 508.3.

Example 264:4- (acetamido (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoic acid (FG 2)

Methyl 4- (amino (4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-2-yl) methyl) benzoate (45.1 mg) and acetic anhydride (7 mg) were added to an eggplant-shaped flask, followed by triethylamine (21 mg) and CH ₂Cl₂ mL, stirred at room temperature overnight, and concentrated by a rotary evaporator to give the crude compound. Subsequently LiOH-H ₂ O (8.4 mg) was added to the eggplant-shaped flask, and the mixed solvent (4 ml, thf: H ₂ o=1:1) was added. Stirring overnight at room temperature, purifying by HPLC to obtain trifluoroacetate of target compound 264 (FG 2), and lyophilizing to obtain solid 10.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.16–8.08(m,2H),7.75(dd,J＝8.3,1.0Hz,1H),7.65(t,J＝7.9Hz,1H),7.61–7.50(m,7H),6.49(s,1H),6.24(tt,J＝3.9,1.7Hz,1H),2.46(ddt,J＝8.5,4.4,2.2Hz,2H),2.25(ddt,J＝8.5,6.3,2.7Hz,2H),2.12(s,3H),1.87–1.79(m,2H),1.75–1.63(m,2H).ESI-MS theoretical calculated value C ₂₉H₂₈N₃O₃ ⁺[M+H]⁺ =466.2; the experiment shows that: 466.7.

Example 265:4- ((2-propyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 17)

Starting from 2-propyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (40 mg) and methyl 4- (bromomethyl) benzoate (44 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (15 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 265 (FE 17), and lyophilization to give solid 16.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.05(d,J＝8.2Hz,2H),7.68–7.56(m,7H),7.38(d,J＝8.1Hz,2H),6.28(tt,J＝3.8,1.7Hz,1H),5.92(s,2H),3.29–3.21(m,2H),2.49(tq,J＝6.4,2.2Hz,2H),2.27(dq,J＝6.2,3.4Hz,2H),1.89–1.81(m,2H),1.79–1.65(m,4H),1.02(t,J＝7.3Hz,3H).ESI-MS, theoretical calculated C ₃₀H₃₁N₂O₂ ⁺[M+H]⁺ =451.2; the experiment shows that: 451.4.

Example 266:4- ((2-butyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 22)

Starting from 2-butyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (40 mg) and methyl 4- (bromomethyl) benzoate (42 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (18 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 266 (FE 22), and lyophilization to give the theoretical calculated value C ₃₁H₃₃N₂O₂ ⁺[M+H]⁺ =465.3 of solid 4.8mg.¹H NMR(500MHz,Methanol-d₄)δ8.09–8.03(m,2H),7.69–7.60(m,7H),7.38(d,J＝8.3Hz,2H),6.28(tt,J＝3.9,1.7Hz,1H),5.91(s,2H),3.29–3.21(m,2H),2.50(tq,J＝6.4,2.3Hz,2H),2.28(dh,J＝8.8,2.7Hz,2H),1.91–1.80(m,2H),1.76–1.69(m,2H),1.66(ddt,J＝9.6,7.9,3.5Hz,2H),1.42(h,J＝7.4Hz,2H),0.90(t,J＝7.3Hz,3H).ESI-MS; the experiment shows that: 465.4.

Example 267:4- ((2-isopropyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 83)

Starting from 2-isopropyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (40 mg) and methyl 4- (bromomethyl) benzoate (44 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (18 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 267 (FE 83), and lyophilization to give solid 27.8mg.¹H NMR(500MHz,Methanol-d₄)δ8.12–8.02(m,2H),7.76(d,J＝8.2Hz,1H),7.65(t,J＝7.9Hz,1H),7.61(s,5H),7.37(d,J＝8.1Hz,2H),6.28(tt,J＝3.8,1.7Hz,1H),5.95(s,2H),3.72(hept,J＝7.1Hz,1H),2.50(tq,J＝6.2,2.2Hz,2H),2.28(tq,J＝6.0,2.7Hz,2H),1.92–1.80(m,2H),1.78–1.63(m,2H),1.45(s,3H),1.44(s,3H).ESI-MS, theoretical calculated C ₃₀H₃₁N₂O₂ ⁺[M+H]⁺ =451.2; the experiment shows that: 451.1.

Example 268:4- ((2- (3- (dimethylamino) propyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FD 134)

Methyl 4- ((2- (3-aminopropyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoate (76.1 mg), formaldehyde hydrate (64 mg) and NaBH ₃ CN (15 mg) were used as starting materials, methanol as solvent, and HPLC purification was performed according to general procedure eight to give the trifluoroacetate of target compound 268 (FD 134), which was lyophilized to give solid 74.4mg.¹H NMR(500MHz,Methanol-d₄)δ8.05(d,J＝8.2Hz,2H),7.67–7.63(m,3H),7.62–7.57(m,4H),7.38(d,J＝8.2Hz,2H),6.27(tt,J＝3.8,1.7Hz,1H),5.90(s,2H),3.35(dd,J＝9.4,6.1Hz,2H),3.26–3.18(m,2H),2.79(s,6H),2.49(td,J＝4.1,2.0Hz,2H),2.32–2.23(m,2H),2.23–2.13(m,2H),1.89–1.78(m,2H),1.77–1.66(m,2H).ESI-MS as theoretical calculated C ₃₂H₃₆N₃O₂ ⁺[M+H]⁺ = 494.3; the experiment shows that: 494.8.

Example 269:3- ((2-ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FE 73)

Starting from 2-ethyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (60 mg) and methyl 3- (bromomethyl) benzoate (70 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (24 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 269 (FE 73), and lyophilization to give solid 47.8mg.¹H NMR(500MHz,Methanol-d4)δ8.03(dt,J＝6.4,1.9Hz,1H),7.95(d,J＝1.9Hz,1H),7.70(dd,J＝7.9,1.3Hz,1H),7.65–7.58(m,6H),7.53(d,J＝6.5Hz,2H),6.27(dq,J＝3.7,1.9Hz,1H),5.90(s,2H),2.48(td,J＝6.1,3.3Hz,2H),2.26(tq,J＝6.1,2.8Hz,2H),1.89–1.80(m,2H),1.77–1.64(m,2H),1.35(t,J＝7.6Hz,3H).ESI-MS, theoretical calculated C ₂₉H₂₉N₂O₂ ⁺[M+H]⁺ = 437.2; the experiment shows that: 437.3.

Example 270:2- (2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) acetic acid (FC 144)

Starting from 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (50 mg) and methyl 3- (bromomethyl) benzoate (35 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (16 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 270 (FC 144), and lyophilization to give solid 9.6mg.¹H NMR(500MHz,Methanol-d₄)δ7.86(d,J＝8.3Hz,1H),7.84–7.78(m,3H),7.78–7.65(m,6H),7.60(d,J＝8.3Hz,2H),6.26(tt,J＝3.8,1.7Hz,1H),5.32(s,2H),2.48(tq,J＝6.3,2.2Hz,2H),2.26(tq,J＝6.0,2.8Hz,2H),1.92–1.78(m,2H),1.78–1.62(m,2H).ESI-MS, theoretical calculated C ₂₇H₂₅N₂O₂ ⁺[M+H]⁺ =409.2; the experiment shows that: 409.5.

Example 271:2- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 118)

Starting from 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (80 mg) and methyl 2- (bromomethyl) benzoate (79 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (27 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 271 (FC 118), and lyophilization to give solid 21.4mg.¹H NMR(500MHz,Methanol-d4)δ8.19(dd,J＝7.5,1.8Hz,1H),7.87–7.37(m,14H),7.06(dd,J＝7.5,1.4Hz,1H),6.28(tt,J＝3.9,1.8Hz,1H),6.16(s,2H),2.50(tq,J＝6.5,2.3Hz,2H),2.27(tq,J＝6.0,2.7Hz,2H),1.92–1.80(m,2H),1.81–1.60(m,2H).ESI-MS, theoretical calculated C ₃₃H₂₉N₂O₂ ⁺[M+H]⁺ = 485.2; the experiment shows that: 484.6.

Example 272:2- (3- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FC 143)

Starting from 2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (80 mg) and methyl 2- (3- (bromomethyl) phenyl) acetate (111 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (25 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 272 (FC 143), and lyophilization to give the theoretical calculated value C ₃₄H₃₁N₂O₂ ⁺[M+H]⁺ =499.2 of solid 8.3mg.¹H NMR(500MHz,Methanol-d₄)δ7.88–7.74(m,4H),7.68(d,J＝7.9Hz,6H),7.60(d,J＝8.1Hz,2H),7.32(t,J＝7.6Hz,1H),7.27(d,J＝7.6Hz,1H),7.14(s,1H),7.10(d,J＝7.6Hz,1H),6.27(tt,J＝3.8,1.6Hz,1H),5.75(s,2H),3.58(s,2H),2.48(tq,J＝6.3,2.2Hz,2H),2.26(tq,J＝5.9,2.7Hz,2H),1.91–1.78(m,2H),1.77–1.63(m,2H).ESI-MS; the experiment shows that: 499.1.

Example 273:2- (4- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FE 130)

Starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (73 mg) and methyl 2- (4- ((4-bromo-2-phenyl-1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetate (92.9 mg), purification by HPLC was carried out with reference to general procedure fifteen to give trifluoroacetate of the title compound 273 (FE 130) and lyophilization afforded a theoretical calculated as solid 30.1mg.¹H NMR(500MHz,Methanol-d₄)δ7.81(d,J＝7.7Hz,2H),7.78(t,J＝7.6Hz,1H),7.73(dd,J＝7.3,2.1Hz,1H),7.67(td,J＝8.0,2.3Hz,6H),7.59(d,J＝8.1Hz,2H),7.29(d,J＝7.9Hz,2H),7.15(d,J＝7.9Hz,2H),6.30–6.22(m,1H),5.74(s,2H),3.60(s,2H),2.47(tt,J＝4.6,2.4Hz,2H),2.25(tq,J＝6.1,2.8Hz,2H),1.89–1.79(m,2H),1.75–1.66(m,2H).ESI-MS, C ₃₄H₃₁N₂O₂ ⁺[M+H]⁺ =499.2; the experiment shows that: 499.1.

Example 274:2- (2- ((2-phenyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FG 12)

Starting from 4, 5-tetramethyl-2- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1,3, 2-dioxaborane (86.4 mg) and methyl 2- (2- ((4-bromo-2-phenyl-1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetate (86.6 mg), purification by HPLC was carried out according to general procedure fifteen to give trifluoroacetate of the target compound 274 (FG 12), which was lyophilized to give a solid 17.2mg.¹H NMR(500MHz,Methanol-d₄)δ7.76(dd,J＝20.3,7.6Hz,3H),7.70(d,J＝8.1Hz,2H),7.64(dt,J＝20.1,5.4Hz,7H),7.35(dt,J＝14.7,7.4Hz,2H),7.22(t,J＝7.4Hz,1H),6.88(d,J＝7.7Hz,1H),6.30–6.25(m,1H),5.86(s,2H),3.77(s,2H),2.49(td,J＝6.2,2.6Hz,2H),2.27(tq,J＝6.1,2.8Hz,2H),1.93–1.74(m,2H),1.79–1.56(m,2H).ESI-MS as calculated theoretical C ₃₄H₃₁N₂O₂ ⁺[M+H]⁺ = 499.2; the experiment shows that: 499.2.

Example 275: n, N-dimethyl-3- (2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) propan-1-amine (FE 132)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (60 mg) and 3-bromo-N, N-dimethylpropan-1-amine hydrochloride (100 mg), purification by HPLC was performed according to the general procedure twelve, to give the trifluoroacetate of the target compound 275 (FE 132), which was lyophilized to give the theoretical calculated as solid 35.5mg.¹H NMR(500MHz,Methanol-d4)δ7.90(d,J＝8.3Hz,1H),7.70(t,J＝7.9Hz,1H),7.66–7.54(m,5H),6.27(dq,J＝3.8,1.9Hz,1H),4.60(t,J＝7.6Hz,2H),3.41–3.33(m,2H),2.92(d,J＝1.3Hz,9H),2.49(ddt,J＝6.3,4.2,2.2Hz,2H),2.45–2.34(m,2H),2.32–2.21(m,2H),1.89–1.78(m,2H),1.79–1.63(m,2H).ESI-MS C ₂₅H₃₂N₃ ⁺[M+H]⁺ =374.3; the experiment shows that: 373.9.

Example 276:3- (2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) propan-1-ol (FG 26)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (30 mg) and tert-butyl (3-iodopropyl) diphenylsilane (85 mg), crude compound was obtained according to general procedure twelve. Tetrabutylammonium fluoride trihydrate (32 mg) was then added to the eggplant-shaped flask, THF (10 mL) was added, and the mixture was stirred at room temperature overnight. HPLC purification afforded the trifluoroacetate salt of target compound 276 (FG 26) and lyophilization afforded solid 6.5mg.¹H NMR(500MHz,Methanol-d4)δ7.88(dd,J＝8.3,0.9Hz,1H),7.71–7.66(m,1H),7.63–7.56(m,5H),6.27(tt,J＝3.7,1.8Hz,1H),4.61(t,J＝7.0Hz,2H),3.65(t,J＝5.6Hz,2H),2.92(s,3H),2.49(tq,J＝6.1,2.2Hz,2H),2.27(tq,J＝6.1,2.7Hz,2H),2.15(h,J＝6.0,5.5Hz,2H),1.90–1.80(m,2H),1.75–1.68(m,2H).ESI-MS as a theoretical calculation C ₂₃H₂₇N₂O⁺[M+H]⁺ =347.2; the experiment shows that: 346.6.

Example 277:5- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) picolinic acid (FE 140)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (52 mg) and methyl 5- (bromomethyl) picolinate (62 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (18 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 277 (FE 140), and lyophilization to give solid 42.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.98(d,J＝2.1Hz,1H),8.41(dd,J＝8.1,2.1Hz,1H),7.76(d,J＝8.2Hz,1H),7.70(dd,J＝8.1,1.2Hz,1H),7.63–7.50(m,6H),6.25(tt,J＝3.8,1.6Hz,1H),5.96(s,2H),2.97(s,3H),2.47(tq,J＝6.4,2.1Hz,2H),2.25(tt,J＝6.0,3.1Hz,2H),1.88–1.78(m,2H),1.75–1.64(m,2H).ESI-MS, theoretical calculated C ₂₇H₂₆N₃O₂ ⁺[M+H]⁺ =424.2; the experiment shows that: 423.6.

Example 278:1- (4-methoxybenzyl) -2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FG 4)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (50 mg) and 1- (bromomethyl) -4-methoxybenzene (68 mg), purification by HPLC was performed according to the general procedure twelve to give the trifluoroacetate salt of the target compound 278 (FG 4), which was freeze-dried to give the theoretical calculated as C ₂₈H₂₉N₂O⁺[M+H]⁺ =409.2 as solid 11.7mg.¹H NMR(500MHz,Methanol-d4)δ7.77(dd,J＝8.1,1.2Hz,1H),7.66–7.57(m,6H),7.35–7.26(m,2H),7.00–6.92(m,2H),6.30–6.24(m,1H),5.67(s,2H),3.78(s,3H),2.91(s,3H),2.49(tq,J＝6.5,2.2Hz,2H),2.27(tq,J＝5.8,2.7Hz,2H),1.92–1.77(m,2H),1.77–1.63(m,2H).ESI-MS; the experiment shows that: 409.0.

Example 279:4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenol (FG 17)

Starting with 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (50 mg) and (4- (bromomethyl) phenoxy) (tert-butyl) diphenylsilane (111 mg), crude compound was obtained according to general procedure twelve. Tetrabutylammonium fluoride trihydrate (79 mg) was then added to the eggplant-shaped flask, THF (10 mL) was added, and the mixture was stirred at room temperature overnight. Purification by HPLC gave the trifluoroacetate salt of the target compound 279 (FG 17), which was lyophilized to give the theoretical calculated as C ₂₇H₂₇N₂O⁺[M+H]⁺ =395.2 of solid 5.6mg.¹H NMR(500MHz,Methanol-d4)δ7.77(dd,J＝8.2,1.1Hz,1H),7.67–7.55(m,6H),7.24–7.16(m,2H),6.85–6.77(m,2H),6.27(tt,J＝3.9,1.7Hz,1H),5.62(s,2H),2.90(s,3H),2.48(tt,J＝6.2,3.1Hz,2H),2.27(td,J＝6.2,3.4Hz,2H),1.90–1.79(m,2H),1.71(dtt,J＝10.1,7.1,3.2Hz,2H).ESI-MS; the experiment shows that: 395.3.

Example 280: 2-methyl-1- (pyridin-4-ylmethyl) -4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (FG 20)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (30 mg) and 4- (bromomethyl) pyridine (30 mg), purification by HPLC was performed according to the general procedure twelve to give the trifluoroacetate salt of the target compound 280 (FG 20), which was freeze-dried to give the theoretical calculated as solid 4.5mg.¹H NMR(500MHz,Methanol-d4)δ8.83–8.73(m,2H),7.82–7.73(m,2H),7.64(d,J＝8.7Hz,7H),6.29(td,J＝3.9,1.9Hz,1H),6.09(s,2H),2.91(s,3H),2.50(tq,J＝6.2,2.2Hz,2H),2.28(tq,J＝6.2,2.8Hz,2H),1.91–1.82(m,2H),1.78–1.59(m,2H).ESI-MS C ₂₆H₂₆N₃ ⁺[M+H]⁺ = 380.2; the experiment shows that: 380.3.

Example 281:2- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) benzoic acid (FC 104)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (100 mg) and methyl 2- (bromomethyl) benzoate (120 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (26 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 281 (FC 104), and lyophilization to give the theoretical calculated value C ₂₈H₂₇N₂O₂ ⁺[M+H]⁺ = 423.2 of solid 99.2mg.¹H NMR(500MHz,Methanol-d₄)δ8.22–8.15(m,1H),7.61(s,4H),7.58–7.43(m,5H),6.96–6.87(m,1H),6.27(tt,J＝3.9,1.7Hz,1H),6.17(s,2H),2.85(s,3H),2.48(tq,J＝6.2,2.2Hz,2H),2.26(tq,J＝5.8,2.7Hz,2H),1.90–1.79(m,2H),1.77–1.64(m,2H).ESI-MS; the experiment shows that: 423.4.

Example 282:2- (4- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FC 131)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (80 mg) and methyl 2- (4- (bromomethyl) phenyl) acetate (101 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (28 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 282 (FC 131), and lyophilization to give solid 18.2mg.¹H NMR(500MHz,M;ethanol-d₄)δ7.76(dd,J＝7.9,1.4Hz,1H),7.68–7.57(m,6H),7.34(d,J＝8.2Hz,2H),7.30(d,J＝8.2Hz,2H),6.28(tt,J＝4.0,1.7Hz,1H),5.75(s,2H),3.62(s,2H),2.90(s,3H),2.49(ddt,J＝8.4,4.2,2.2Hz,2H),2.27(dh,J＝8.9,2.7Hz,2H),1.92–1.81(m,2H),1.79–1.66(m,2H).ESI-MS, theoretical calculated C ₂₉H₂₉N₂O₂ ⁺[M+H]⁺ = 437.2; the experiment shows that: 436.9.

Example 283:2- (3- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FC 136)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (80 mg) and methyl 2- (3- (bromomethyl) phenyl) acetate (136 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (21 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 283 (FC 136), and lyophilization to give solid 13.6mg.¹H NMR(500MHz,Methanol-d₄)δ7.76(dd,J＝8.0,1.4Hz,1H),7.62(d,J＝10.2Hz,6H),7.37(t,J＝8.0Hz,1H),7.34–7.28(m,2H),7.22(d,J＝7.8Hz,1H),6.27(tt,J＝3.8,1.7Hz,1H),5.75(s,2H),3.63(s,2H),2.91(s,3H),2.49(ddt,J＝6.2,4.1,2.1Hz,2H),2.27(ddt,J＝8.3,6.2,3.1Hz,2H),1.90–1.80(m,2H),1.76–1.65(m,2H).ESI-MS, theoretical calculated C ₂₉H₂₉N₂O₂ ⁺[M+H]⁺ = 437.2; the experiment shows that: 437.5.

Example 284:2- (2- ((2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazol-1-yl) methyl) phenyl) acetic acid (FD 158)

Starting from 2-methyl-4- (2 ',3',4',5' -tetrahydro- [1,1' -biphenyl ] -4-yl) -1H-benzo [ d ] imidazole (60 mg) and methyl 2- (2- (bromomethyl) phenyl) acetate (102 mg), crude compound was obtained according to general procedure twelve. Subsequently, liOH-H ₂ O (20 mg) was added to hydrolyze methyl ester, HPLC purification to give the trifluoroacetate salt of the target compound 284 (FD 158), and lyophilization to give solid 10.8mg.¹H NMR(500MHz,Methanol-d₄)δ7.69–7.56(m,7H),7.39(dd,J＝7.7,1.4Hz,1H),7.35(d,J＝7.3Hz,1H),7.23(td,J＝7.5,1.4Hz,1H),6.74(d,J＝7.7Hz,1H),6.28(tt,J＝3.8,1.6Hz,1H),5.87(s,2H),3.90(s,2H),2.82(s,3H),2.50(tq,J＝6.2,2.2Hz,2H),2.28(tq,J＝6.1,2.7Hz,2H),1.92–1.80(m,2H),1.78–1.62(m,2H).ESI-MS, theoretical calculated C ₂₉H₂₉N₂O₂ ⁺[M+H]⁺ = 437.2; the experiment shows that: 437.2.

The following compounds can be prepared by the method of the above examples by selecting the corresponding commercial reagents, catalysts, solvents and other raw materials:

biological Activity test method 1: data on the activity of compounds to inhibit TEAD2/YAP1 interactions:

YAP1 binding domain TEAD2 (217-447) of HIS-tag labeled TEAD2 was expressed in E.coli, and TEAD2 protein was purified by Ni affinity column and ion exchange chromatography column. Meanwhile, FAM-labeled YAP1 derived polypeptide (FAM-YAP 1) is synthesized, and the sequence of the polypeptide is as follows:

(5-FAM)-H₂N-(β-Ala)-(β-Ala)-DSETD-LEALF-NAVMN-PKTAN-VPQTV-P-Trp(6-Cl)-R-Ac3c-R-K-Cba-Hyp-D-S-F-(1-Nal)-K-E-P-CO₂H( Reference Bioorganic & MEDICINAL CHEMISTRY LETTERS (2019) 2316-2319. Based on the expressed and purified TEAD2 protein and fluorescent molecular probe FAM-YAP1, the dissociation constant K _d of FAM-YAP1 and TEAD2 was measured to be 1.9nM by using a fluorescence bias analysis method.

96-Well plates were purchased from Corning company (Black, # 3694). The multifunctional enzyme-labeled instrument is manufactured by TECAN company, and the model is as follows: SPARK 10M. Dilute compound buffer: 1 XPBS (pH 7.4), 20% DMSO (Sigma) and 0.01% Trition X-100 (Sigma), the water used for the experiments was Millipore-Q purified water. Detection buffer: 1 XPBS (pH 7.4), 0.01% Trition X-100 (Sigma).

Compounds to be tested were first dissolved in DMSO to 20mM standard stock solution. The standard mother liquor of the test compound is then diluted with a diluted compound buffer in the EP tube to a working sample solution, the working sample solution concentration prepared = 10 times the highest sample concentration required on the test plate (10 x test compound solution), and the compound is diluted in a 2-fold gradient in the EP tube for later use.

5. Mu.L of a 10 Xtest compound solution of the test compound A was added in a gradient to wells B1-D1 to B12-D12 of the 96-well plate, and 5. Mu.L of a 10 Xtest compound solution of the test compound B was added in a gradient to wells E1-G1 to E12-G12, respectively. To each well was added 40. Mu.L of 62.5nM TEAD2 protein solution. Finally 50nM tracker was added to each well.

A1-A3 wells served as blank: add 50. Mu.L of detection buffer. a4-A6 wells served as negative signal reference group: mu.L of buffer containing only 5nM FAM-YAP1 fluorescently labeled molecular probe was added. a7-A9 wells served as positive reference group: mu.L of a mixed solution containing 5nM FAM-YAP1 fluorescent-labeled molecular probe and 50nM TEAD2 protein was added.

After the reaction plate was covered with aluminum foil paper and the 96-well plate was placed on a 96-well plate shaking table and incubated at room temperature for 1h and 1.5h, fluorescence polarization mP values at Ex485nm/Em530nm were read with an ELISA reader. The measured mP values are plotted against compound concentration gradients, and the sample compound concentrations corresponding to the median of mP maxima and minima are the IC ₅₀ values ([ I ] ₅₀) for the binding of the compound to the protein.

Based on this IC ₅₀ value ([ I ] ₅₀), the binding rate of the compound to the protein was calculated as a well-known K _i:K_i＝[I]₅₀/([L]₅₀/K_d+[P]₀/K_d +1 using the formula.

Wherein [ L ] ₅₀ represents 50% of the concentration of the fluorescent-labeled molecular probe in the above-mentioned test system; [ P ] ₀ represents the TEAD2 protein concentration in the above test system, kd is the dissociation constant of the protein and the fluorescent-labeled molecular probe.

* IC ₅₀<10uM;***:IC₅₀ values in the range 10-50uM; * IC ₅₀ values in the range 50-250uM; * : IC ₅₀ value range 250-1000uM

The above data indicate that at the protein level, the compounds are able to block the protein interactions of TEAD2/YAP 1.

Biological Activity test method 2: data on the activity of compounds inhibiting TEAD4/YAP1 interaction:

YAP1 binding domain TEAD4 (217-434) of HIS-tag labeled TEAD4 was expressed in E.coli, and TEAD4 protein was purified by Ni affinity column and ion exchange chromatography column. Simultaneously, FAM-labeled YAP 1-derived polypeptides were synthesized (FAM-YAP 1, biological activity test method 1). Based on the expressed and purified TEAD4 protein and fluorescent molecular probe FAM-YAP1, the dissociation constant Kd of FAM-YAP1 and TEAD2 was measured to be 2.4nM by using a fluorescence bias analysis method.

5. Mu.L of a 10 Xtest compound solution of the test compound A was added in a gradient to wells B1-D1 to B12-D12 of the 96-well plate, and 5. Mu.L of a 10 Xtest compound solution of the test compound B was added in a gradient to wells E1-G1 to E12-G12, respectively. 40uL 37.5nM TEAD4 protein solutions were added to each well. Finally 50nM tracker was added to each well.

A1-A3 wells served as blank: add 50. Mu.L of detection buffer. a4-A6 wells served as negative signal reference group: mu.L of buffer containing only 5nM FAM-YAP1 fluorescently labeled molecular probe was added. a7-A9 wells served as positive reference group: mu.L of a mixed solution containing 5nM FAM-YAP1 fluorescent-labeled molecular probe and 30nM TEAD4 protein was added.

Wherein [ L ] ₅₀ represents 50% of the concentration of the fluorescent-labeled molecular probe in the above-mentioned test system; [ P ] ₀ represents the TEAD4 protein concentration in the above test system, and K _d is the dissociation constant of the protein and the fluorescent-labeled molecular probe.

The above data indicate that at the protein level, the compounds are able to block the protein interactions of TEAD4/YAP 1.

Biological Activity test method 3: in human gastric cancer cell line HGC-27, the compound of the example inhibits the expression level of TEAD target genes CYR61, CTGF, CDX2

Literature studies have shown that three genes CYR61, CTGF, CDX2 are target genes for TEAD, and blocking protein interactions of TEAD/YAP1 would inhibit expression of these three genes. The human gastric cancer cell line HGC-27 overexpresses YAP1, and the growth of the cell depends on TEAD/YAP1 signaling pathway and is sensitive to TEAD/YAP1 interaction inhibitors. HGC-27 cells were treated with the compounds, and changes in the gene expression levels of CYR61, CTGF, CDX2 were detected by quantitative PCR (qPCR).

After 24 hours of compound treatment of HGC-27 cells, the cells were collected and washed twice with PBS solution. Then, RNA extraction and reverse transcription were performed using RNA extraction kit (cat# 9767) and RNA reverse transcription kit (cat# RR 047) of Takara doctor materials, inc., in order, to obtain cDNA templates, and experimental procedures were as described in the kit specification. The quantitative detection was performed using the chimeric fluorescence detection reagent (cat# RR 820) from this company, and the procedure was as follows:

first, a PCR reaction solution was prepared on ice according to the following table composition.

Reagent(s)	Usage amount (mu L)	Final concentration
			TB Green Premix Ex Taq II(Tli RNase Plus)(2×)	2.5	1×
Gene upstream primer (10 mu M)	1	0.4μM
			Gene downstream primer (10 mu M)	1	0.4μM
CDNA template (< 100 ng)	2
			DEPC water	8.5
Total volume of	25

Next, after thoroughly mixing, the reaction solution was added to 384-well qPCR plates at 7. Mu.l/well. Then, the mixture was centrifuged at 4000rpm at 4℃for 10min. Using a CFX384 Real-Time PCR detection system and a two-step amplification procedure (30 seconds pre-heating at 95 ℃, denaturation at 95 ℃ for 5 seconds, annealing at 60 ℃ for 30 seconds, 40 cycles total), detection was performed and calculated using the 2-. DELTA.t method, and the gene primer sequences used in the experiments were as follows:

and (3) comparing the signals read by the PCR detection system with an internal reference, adopting 2-delta t to calculate and normalize, and plotting the obtained values with corresponding drug concentrations (the following figures 1-4), thus obtaining the change of the expression levels of CYR61, CTGF and CDX2 relative to the non-added compound (DMSO) treatment group.

The data in FIG. 1 shows that the compound of example 4 (QJ 68) dose-dependently inhibited the expression of the CYR61, CTGF, CDX2 genes compared to the non-compound-added placebo group (DMSO).

The data in FIG. 2 shows that the compounds of examples 30 (QJ 156) and 31 (QK 3) inhibited the expression of CYR61 and CTGF genes in a dose-dependent manner, and that the compound of example 30 inhibited the expression of CDX2 genes, as compared to the blank group (DMSO) without the compound.

The data in FIG. 3 shows that compounds 86 (LYA 95) and 87 (LYA 102) inhibit expression of CTGF gene compared to the blank (DMSO) without the compound.

The data in FIG. 4 shows that the compound of example 97 (FC 3-2) inhibits the expression of the CYR61, CDX2 genes compared to the blank (DMSO) without the compound.

The data show that the compounds of the listed examples can inhibit the expression level of TEAD target genes CYR61, CTGF and CDX2 in human gastric cancer cell line HGC-27, and demonstrate that the compounds can block TEAD/YAP1 protein interaction in cells.

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. A compound of the general formula (I-1), stereoisomers, enantiomers, or pharmaceutically acceptable salts thereof:

Wherein R _a is selected from the group consisting of: a hydrogen atom, cyano, C1-C4 alkyl, C1-C4 alkoxy;

Each of a ₁、A₂ is independently represented as CR _b or N, each of a ₃、A₄ and a ₅ is independently represented as CR _b, wherein each occurrence of R _b is independently selected from the group consisting of: a hydrogen atom, halogen, cyano, nitro, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, -NR ₁R₂、-CO₂R₃, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C8 heterocycloalkenyl, substituted or unsubstituted phenyl, 5-8 membered heteroaryl; or two adjacent R _b groups form phenyl, 5-8 membered heteroaryl with the attached carbon atom; wherein said substitution means substitution with one or more groups selected from the group consisting of: halogen, nitro, hydroxy, carboxy, cyano, C1-C4 alkyl, C1-C4 alkoxy, -NR ₄R₅;

Each of which is provided with Independently a double bond or a single bond;

at each occurrence, R ₁-R₅ is independently selected from a hydrogen atom or a C1-C4 alkyl group;

R _z1 is selected from the group consisting of: a hydrogen atom, a substituted or unsubstituted C1-C6 alkyl group, Wherein said substitution means substitution with one or more groups selected from the group consisting of: hydroxy, carboxy, cyano, nitro, NR ₃₁R₃₂;

n5 is 1 or 2; at each occurrence, R ₃₁、R₃₂ is independently selected from a hydrogen atom or a C1-C4 alkyl group;

Ar ₆ is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl; wherein said substitution means substitution with one or more groups selected from the group consisting of: hydroxy, -CO ₂ H;

r _x1 is selected from the group consisting of:

ar ₇ is selected from unsubstituted five membered heteroaryl;

n7 is1, 2, 3 or 4.

2. The compound of claim 1, wherein the C5-C8 heterocycloalkenyl structure isM is an oxygen atom (O) or-NH-; j. k are each independently integers from 1 to 4, and j+k=2, 3, 4 or 5.

3. The compound of claim 1, wherein Ra is H.

4. The compound of claim 1, wherein the compound is selected from the group consisting of:

5. a pharmaceutical composition comprising a compound of any one of claims 1-4, a stereoisomer, enantiomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

6. Use of a compound according to any one of claims 1 to 4, a stereoisomer, enantiomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 5 for the preparation of a TEAD and YAP interaction inhibitor for use in the prevention and/or treatment of cancer; wherein the cancer is gastric cancer.